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UDC 613.26:616-037:615.9:612.014.46 https://doi.Org/10.26641/2307-0404.2020.4.221663
HYGIENIC SUBSTANTIATION OF CALCULATING MODELS FOR PROGNOSIS OF TOXICITY OF DIFFERENT CLASSES INSECTICIDES (SECOND PART)
Bogomolets National Medical University Department Hygiene and Ecology No. 1 1
Institute of Hygiene and Ecology of Bogomolets National Medical University 2 Peremohy av., 34, Kyiv, 03057, Ukraine «Syngenta» LCC 3,
Kozatska str., 120/4, Kyiv, 02000, Ukraine
Нацюналъний медичний ymeepcumem iM. O.O. Богомолъця Кафедра ziziem ma екологИ № 1 1
(зав. - член-кор. HAMH Украши, д. мед. н., проф. В.Г. Бардов)
Incmumym гшени та екологИ Нацюналъного медичного ynieepcumemy iM. О. О. Богомолъця 2 пр. Перемоги, 34, Kuie, 03057, Укра'та ООО «Сингента»
вул. Козацъка, 120/4, Kuie, 02000, Украгна 3 e-mail: antonenko1985@ukr.net
Цитування: Медичт перспективы. 2020. Т. 25, № 4. С. 166-173 Cited: Medicni perspektivi 2020;25(4):166-173
Key words: insecticide, toxicology, calculation models, regression equations Ключов1 слова: тсектицид, токсиколог1я, розрахунков1 модел1, р1вняння регресИ' Ключевые слова: инсектицид, токсикология, расчетные модели, уравнения регрессии
O.P. Vavrinevych 1, B.I. Shpak 3, A.M. Antonenko 1, S.T. Omelchuk 2, T.I. Zinchenko 1
Abstract. Hygienic substantiation of calculating models for prognosis of toxicity of different classes insecticides (second part). Vavrinevych O.P., Shpak B.I., Antonenko A.M., Omelchuk S.T., Zinchenko T.I. This work is the second part of our study to develop alternative experimental mathematic models for predecting toxicity of insecticides, where we carried out a statistical analysis and comparative estimation of the toxicometric parameters obtained experimentally and calculated according to the proposed equations. In the first stage calculations were carried out and the most reliable models were proposed. The purpose of the research is the scientific substantiation and statistical analysis of the calculation models for predicting the toxicity of insecticides of different classes. For research we took the insecticides of the following chemical classes: neonicotinoids, pyrethroids, organophosphorus compounds. Statistical analysis of the linear and nonlinear regression equations obtained for insecticides was conducted. The equations described the dependence of subthreshold doses in the chronic experiment of all insecticides, the median lethal doses at oral admission of pyrithoids and neonicotinoids from molecular weight; and toxicometry parameters of all insecticides and their individual groups (pyrithoids, neonicotinoids, organophosphorus compounds) on melting temperature and the octanol-water partition coefficient. On the basis of a comparison of the toxicometry parameters obtained experimentally (actual parameters) and calculated according to the proposed equations checking of possibility of using of the calculating models for predicting the danger of the investigated groups of insecticides was performed. For substantiated pairs of resultant and factorial variables for pyrethroids, neonicotinoids, and organophosphorus pesticides a reliable correlation was established (ractucal> rtable at p = 0.05) or trend (ractucal> rtable at p = 0.1). A good and very good consistency of the features selected for the calculations according to the Cronbach 's alpha (index ranged from 0.8 and above) was indicated. The developed algorithm makes it possible to significantly simplify the conduction of toxicological studies of the studied classes of insecticides.
Реферат. Ппешчне обгрунтування розрахункових моделей прогнозування токсичност! шсектицид!в |)Ьим\ клаив (друга частина). Вавршевич О.П., Шпак Б.1., Антоненко А.М., Омельчук С.Т., Зшченко Т.1.
Ця робота е другою частиною нашого досл1дження щодо розробки альтернативних експериментальних математичних моделей прогнозування токсичност1 тсектицид1в, де ми провели статистичний анал1з та пор1вняльну оцтку токсикометричних параметр1в, отриманих експерименталъно та обчислених зг1дно 1з запропонованими р1вняннями. На першому етат були проведет розрахунки та запропоноват достов1рт модел1. Метою досл1дження було наукове обгрунтування та статистичний анал1з розрахункових моделей
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МЕДИЧН1 ПЕРСПЕКТИВЕ / MEDICNIPERSPEKTIVI
прогнозуеання токсичностг /нсектицидгв ргзних класгв. Для дослгдження ми взяли обран/ тсектициди таких хгмгчних клаав: неон1котино1ди, п1ретро'1'ди, фосфороргатчн/ сполуки. Ми провели статистичний аналгз лгнтних та нелШйних ргвнянъ регресИ, отриманих для тсектицидгв. У ргвняннях описано залежнгсть пгдпорогових доз у хронгчному експериментг всгх ¡нсектицидгв, середнгх летальних доз при пероральному надходженн! пгритоШв та неон1котино'1'д1в вгд молекулярной маси; параметргв токсикометрИ вах Iнсектицидгв та IX окремих груп (п1рито'1'ди, неон1котино1ди, фосфороргатчт сполуки) / температури плавления та коефщгенту розподшу октанол-вода. На основ/ поргвняння параметргв токсикометрИ, отриманих експериментально (фактичнг параметри), та розрахованих за запропонованими ргвняннями здтснено перевгрку можливостг використання розрахункових моделей для прогнозуеання небезпеки дослгджуваних груп ¡нсектицидгв. Для обтрунтованих пар результуючих та факторгальних змгнних для п1ретро'1'д1в, неонгкотиноШв та фосфороргангчних пестицидгв було встановлено достовгрну кореляцгю. Виявлено добрий / дуже добрий зв 'язок характеристик, вибраних для розрахункгв, за альфою Кронбаха (тдекс коливався вгд 0,8 / вище). Розроблений алгоритм дозволяе значно спростити проведения токсикологгчних дослгджень тсектицидгв дослгджуваних клаав.
This work is the continuation of our project on development of calculation models for toxicological assessment of pesticides in silico. Nowadays specialists of Hygiene and Ecology Institute of Bogo-molets National Medical proposed calculating models for predicting fungicides and herbicides toxicity [4, 8, 10]. In the previous article we have proposed alternative experimental mathematic models for insecticides [5]. In the first stage, calculations will be carried out and the most reliable models will be proposed. And it is second part of our study on development of alternative experimental mathematic models for predicting insecticides toxicity.
Methods of mathematical modeling are in accordance with modern principles of bioethics. They are, in comparison with laboratory experiments, fast, labor-saving, cost-effective [3, 7, 9]. However, when developing such methods, care must be taken to evaluate their adequacy and the reliability of the possible results.
That is why we have subjected the calculated equations to a careful statistical analysis.
The purpose of the research was scientific substantiation and statistical analysis of the calculation models for predicting toxicity of insecticides of different classes.
MATERIALS AND METHODS OF RESEARCH
We conducted a statistical analysis of the linear and nonlinear regression equations obtained for insecticides [5].
The equation described the dependence of NO(A)EL in the chronic experiment of all insecticides, the median lethal doses at oral admission (LD50 per os) of pyrithoids and neonicotinoids from molecular weight; toxicometry parameters of all insecticides and their individual groups (pyrithoids, neonicotinoids, organophosphorus compounds) on melting temperature and the octanol-water partition coefficient, log P0/w-
Only those equations were used for further analysis which were adequate for Fisher's criterion, and
the coefficients of its regression were reliable according to Student's criterion (p<0.05).
Statistical processing of the results was performed using the package of licensed statistical software IBM SPSS StatisticsBase v.22 and MS Excel (v. 14.0.4760.1000; license 02260-018-00001064863).
The standardized Cronbach's alpha coefficient (a) was calculated by the formula:
N-r
ast = -
1 + (N - 1) • r
where N - the number of observation components; r - average correlation coefficient between components.
When the Cronbach's alpha coefficient is a^O.9 -consistency of characteristics is very good; >0.8 -consistency of characteristics is good; >0.7 -consistency of characteristics is acceptable; >0.6-consistency of characteristics is questionable; >0.5 -consistency of characteristics is poor; <0.5 -consistency of characteristics is not sufficient.
Cronbach's alpha may take values from -®to 1, but only positive values have been interpreted. If the coefficient takes the value 1, then the test results are completely identical.
RESULTS AND DISCUSSION
Previously [5] the following significant correlations (at p <0.05) have been established:
- with increasing molecular weight of pyrithoids and neonicotinoids values of NO(A)ELs in the chronic experiment of all insecticides and the median lethal doses at oral admission also increased:
- with increasing melting temperature and the octanol-water partition coefficient, log Po/w toxicometry parameters values of all insecticides and their individual groups (pyrithoids, neonicotinoids, organophosphorus compounds) decreased.
The checking of using possibility of the calculating models for predicting the danger of the
investigated groups of insecticides was performed on the basis of a comparison of the parameters of toxicometry obtained experimentally (actual parameters) and the calculated according to the proposed equations (Fig. 1-4).
In most cases, the calculated values correlated with those established experimentally (Table). For the substantiated pairs of resultant and factorial variables for pyrethroids, neonicotinoids, and organophosphorus pesticides, a reliable correlation was established (ractucai>rtabie at p=0.05) or trend
(ractucal>rtable at p= 0.1).
In addition, the internal consistency of the object-describing characteristics was evaluated using the Cronbach's alpha. For all the proposed equations, the value of this index ranged from 0.8 and above, which indicates a good and very good consistency of the features selected forthe calculations.
In most cases, the calculated percutaneous LD50 indices were higher than previously established, but this is due to the fact that almost all experimentally established indices of these values are presented as "more than...". That is, they really could have been much higher.
Relationship between experimentally established and estimated values of toxicological parameters
Statistical parameters
Chemical class Resulting variable Factorial variable correlation coefficient
Tactual rtabi at p n "St
1 nl 0,05 0,1 1 nl
Insecticides LD50 per cut, mg/kg octanol-water partition coefficient, log P0/w 0.005 0.209 0.334 0.283 35 0.3 7.2
NO(A)EL, mg/kg 0.241 0.204 0.374 0.317 28 13.3 8.2
Pyre-throids LD5o per os, mg/kg molecular weight 0.501** 0.589* 0.602 0.521 11 10.5 12.1
Oganophos- phorus compounds NO(A)EL, mg/kg LC50 inhal, mg/m3 melting temperature, °C 0.744 0.757 0.938* 0.721 0.878 0.878 0.805 0.805 5 5 6.7 6.8 10.0 7.8
Neonicotinoids LD5o per os, mg/kg molecular weight 0.846** 0.958* 0.878 0.805 5 7.6 11.1
Notes: * - the results are reliable at p<0.05; ** - trend, 0.05<p<0.1; 1 - linear; nl - non linear.
It should be noted that the correlations we obtained (Table) between the toxicity criteria of the investigated fungicides and their physicochemical properties, as confirmed by the inverse calculations (Fig. 1-4), are similar to those previously substantiated for neonicotinoid insececticides [1].
We also performed similar calculations for 3 compounds of derivatives of tetram and tetronic acids class (spiromesifen, spirodiclofen and spiro-tetramat); 3 benzoyl-ureas (diflubenzuron, nava-lurone, teflubenzuron); 4 compounds of the carbamates class (carbosulfan, methomyl, carbaryl, phenoxycarb); 2 avermectins (abamectin and ema-mectin benzoate) [6], but no reliable correlation of
their toxicological parameters with physicochemical properties was found.
In the case of carbamates, this can be explained by the fact that the thresholds for their toxic effects were justified more than 30 years ago, often according to outdated approaches, on different species of animals (rodents, mammals). And probably when revaluating according to current approaches, we could get somewhat other values. For the rest of the classes mentioned, there is likely to be a problem in the small number of samples to study. Later, when more representatives of classes appear, the correlation analysis needs to be repeated.
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■ aftual bdexer ■ indexes, cibuhted udn§ lineir regredoa eqiutinii^ □ indexes, calculated udng nonlinear ™grrikmequatkns
A
1 n il ■ In 1 L1 1 1 n
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B
Fig. 1. A comparative analysis of the experimentally established LDS0 per cut (A) and NO(A)EL (B) values calculated for insecticides
600
500
400
300
200
100
actual indexes ■ indexes, calculated using linear regietion equations □ indexes, calculated usingnonlinear regretion equations
Fig. 2. A comparative analysis of the experimentally established LDS0 per os values calculated for pyrethroids class compounds
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chloipyiifos-methyl dimethoate malathion fosa km pyiimifos -methyl phenyth roth ion
■ actual indexes ■ indexes, calculated using linear legietiun equations □ indexes, calculated using nonlinear legietiun equations
B
Fig. 3. A comparative analysis of the experimentally established LCS0 inhal (A) and NO(A)EL (B) values
calculated for organophosphorus class compounds
1600
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thia clop l id
im id a clop rid thiainethoxam
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actual indexes ■ indexes, calculated using Ins ear regietion equations □ indexes, calculated using nonlinear regretion equations
Fig. 4. A comparative analysis of the experimentally established LD50 per os values calculated for neonicotinoid s class compounds
The same situation (which proves the above explanations) was with methoxyacrylates fungicides (dimoxystrobin, trifloxystrobin, fluoxystrobin, pico-xystrobin, kresoxim-methyl, azoxystrobin, pyraclos-trobin). There was no significant relationship between their toxicological parameters and physicochemical properties. Given that for most of the active substances in this chemical class the toxicity thresholds were justified in the 1990s, often according to outdated approaches, for different species of animals (rats, mice, dogs), such an exception only confirms the established links for molecules of modern groups of fungicides.
CONCLUSIONS 1. For substantiated pairs of resultant and factorial variables for pyrethroids, neonicotinoids, and
organophosphorus pesticides a reliable correlation was established (ractucal> rtable at p = 0.05) or trend (ractucal> rtable atp = 0.1).
2. It was indicated a good and very good consistency of the features selected for the calculations according to the Cronbach's alpha (index ranged from 0.8 and above).
3. The developed algorithm makes it possible to significantly simplify the conduction of toxicological studies of the studied classes of insecticides.
Conflict of interests. The authors declare no conflict of interest.
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[cc)
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МЕДИЧН1 ПЕРСПЕКТИВЕ / MEDICNIPERSPEKTIVI
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Статгя надшшла до редакци 12.03.2020
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