7 research outputs found
Modeling of toxicity of multicomponent pharmaceutical and pesticide solutions
Kao posljedica nezaustavljivog ekonomskog razvoja te ubrzanog rasta ljudske populacije, oÄekuje se da Äe dostupnost Äiste i svježe vode postati jedan od najveÄih problema buduÄnosti. U proteklih nekoliko desetljeÄa, u vodama su pronaÄene brojne tvari koje tamo izvorno ne pripadaju, a njihovo je podrijetlo najÄeÅ”Äe vezano uz ljudsku aktivnost. Å irok spektar oneÄiÅ”Äivala, ukljuÄujuÄi industrijske kemikalije, farmaceutike, pesticide i metale, pronaÄen je ne samo u otpadnim, veÄ i u povrÅ”inskim, pa Äak i pitkim vodama. U posljednje vrijeme posebnu pozornost znanstvene zajednice, ali i regulatornih tijela, privlaÄe farmaceutici i pesticidi buduÄi da su prepoznati kao spojevi Äija prisutnost u okoliÅ”u može imati Å”tetno djelovanje na Äovjeka, floru i faunu. Procjena rizika od prisutnosti Å”tetnih tvari u okoliÅ”u uglavnom se temelji na poznatim vrijednostima toksiÄnosti za pojedine tvari. MeÄutim takav pristup sadrži u sebi pozamaÅ”an nedostatak. Naime, rijetke su situacije u kojima je u okoliÅ”u prisutna samo jedna Å”tetna tvar: živi organizmi obiÄno su u doticaju sa smjesama Å”tetnih tvari. U takvim situacijama može doÄi do združenog djelovanja tvari koje, nažalost, nerijetko ima intenzivniji Å”tetni utjecaj po organizme nego Å”to bi bilo u sluÄaju da svaka tvar djeluje zasebno. Stoga je procjena rizika na temelju informacija o toksiÄnosti smjesa bolji pristup. No razliÄitih smjesa je bezbroj i nemoguÄe je za svaku kombinaciju oneÄiÅ”ÄujuÄih tvari eksperimentalno odrediti toksiÄnost. TakoÄer, u okoliÅ”u je sve viÅ”e novih kemikalija za koje joÅ” ne postoje podaci o toksiÄnosti. Tom se problemu pokuÅ”ava doskoÄiti primjenom kemometrije, konkretnije: primjenom matematiÄkih modela za procjenu toksiÄnosti otopina. U proteklim desetljeÄima razvijeni su i testirani razliÄiti pristupi i modeli. Najprimjenjivaniji model procjene toksiÄnosti smjesa je tzv. aditivni model (CA model), a odmah nakon njega dolazi model neovisnog djelovanja (IA model). Intenzivan razvoj raÄunala omoguÄio je znaÄajniju primjenu razliÄitih naprednih raÄunalnih metoda i alata gdje je potrebno istaknuti modele kvantitativnog odnosa strukture i aktivnosti tvari (QSAR) koji povezuju strukturne karakteristike tvari s nekom njihovom aktivnoÅ”Äu, primjerice toksiÄnoÅ”Äu. Cilj disertacije bio je klasificirati naÄine združenoga toksiÄnog djelovanja odabranog skupa farmaceutika i pesticida te razviti adekvatne QSAR-modele koji bi omoguÄili predviÄanje toksiÄnosti smjesa na temelju sastava i molekulske strukture konstituenata. U disertaciji su ispitivane binarne smjese tvari pripravljene u molarnim omjerima: 25:75, 50:50 i 75:25. ToksiÄnosti su odreÄene mjerenjem inhibicije luminiscencije bakterije Vibrio fischeri prema normi ISO 11348 te iskazane na tri razine: kao EC50, EC30 i EC10- vrijednosti. Za istraživanje združenoga toksiÄnog djelovanja odabrano je 10 oneÄiÅ”Äivala, od toga Å”est farmaceutika: azitromicin, eritromicin, karbamazepin, oksitetraciklin, deksametazon i diklofenak te Äetiri pesticida: alaklor, izoproturon, diuron i klorfenvinfos. Ispitana su djelovanja u binarnim smjesama, a zasebno su promatrane smjese farmaceutika i smjese pesticida. Prilikom analize združenog djelovanja primijenjeni su CA i IA-modeli toksiÄnosti te su rezultati usporeÄeni s eksperimentalno dobivenim vrijednostima. Ulazne varijable modela bile su toksiÄnosti Äistih otopina odabranih farmaceutika i pesticida, a združena djelovanja klasificirana su kao aditivno djelovanje te sinergistiÄko ili antagonistiÄko odstupanje od aditivnog djelovanja. Odstupanja od aditivnog modela dodatnu potvrdu su dobila kroz veÄu podudarnost u sluÄaju IA-modela. Rezultati su pokazali pojavu sinergistiÄkog djelovanja u smjesi diklofenaka i oksitetraciklina. Ostale binarne kombinacije diklofenaka ili oksitetraciklina pokazale su sliÄno djelovanje: sinergizam u smjesama s karbamazepinom te antagonizam u smjesama s makrolidnim antibioticima eritromicinom i azitromicinom. U preostalim binarnim smjesama farmaceutika je uoÄeno aditivno djelovanje. U svim binarnim smjesama pesticida uoÄeno je aditivno djelovanje, s izuzetkom binarne smjese izoproturona i klorfenvinfosa u kojoj je dokazano sinergistiÄko djelovanje. U zadnjoj fazi istraživanja, razvijeni su i testirani QSAR-modeli. S ciljem poveÄanja broja otopina na kojima Äe se razvijati i testirati QSAR-modeli, u istraživanje su dodana Äetiri nova farmaceutika: omeprazol, desloratadin, imatinib i tobramicin te njihove binarne smjese. Primjenom raÄunalnih alata optimirane su konformacije molekula te matematiÄki opisane strukture svih odabranih oneÄiÅ”Äivala (izraÄunati su molekulski deskriptori). Za potrebe kvalitetnog predstavljanja binarnih smjesa, ispitana su razliÄita pravila mijeÅ”anja ne bi li se otopine takoÄer opisale deskriptorima. Pri tome su na razliÄite naÄine kombinirane vrijednosti molekulskih deskriptora i sastav smjese. Modeliranje je provedeno viÅ”estrukom linearnom regresijom, a odabir najboljih deskriptora primjenom genetiÄkog algoritma. QSAR-modeli razvijeni su za svaku od tri ispitivane razine toksiÄnosti: EC50, EC30 i EC10. Razvijeni modeli testirani su na vanjskom skupu podataka, tj. na smjesama Äije toksiÄnosti nisu bile koriÅ”tene pri razvoju modela. Sva tri modela pokazala su zavidnu razinu toÄnosti. QSAR-modeli poslužili su za otkrivanje strukturnih karakteristika koje imaju znaÄajan utjecaj na toksiÄnost prema Vibrio fischeri. Rezultati su pokazali da najveÄi utjecaj na EC50 i EC30-vrijednosti ima geometrijska udaljenost izmeÄu duÅ”ikovih i sumporovih atoma. Nadalje, istovremena prisutnost kisikovih i klorovih atoma može djelovati na poveÄanje toksiÄnosti smjese. Pri EC10, najznaÄajniji utjecaj na toksiÄnost smjese ima dipolni moment.Unavailability of clean and fresh water will surely become one of the greatest mankind problems if steady development of global economy and the population growth are going to continue. Various odd substances have been found in waters in the past few decades: they were found in wastewater, surface water or even drinking water; the devastating fact is that the origin of these substances is mostly related to human activities. These water pollutants include various industrial chemicals, pharmaceuticals, pesticides, metals, etc. Among them, pharmaceuticals and pesticides have been identified recently as compounds with severe hazardous potential for humans, flora and fauna, since these substances are aimed to interact with living beings. Accordingly, the related risk assessment is required by regulatory bodies. The risk assessment is mostly based on information about toxicities of single pollutants. Unfortunately, such approach has a considerable defect. Namely, situation when only one pollutant is present in the environment is generally very rare; the living beings are mostly exposed to mixtures of pollutants. In such mixtures, a joined activity of substances is possible, such which might have more hazardous influence then the both substances acting alone. Therefore, risk assessment based on information about mixture toxicity is much more acceptable approach. The number of possible mixtures is infinite and, accordingly, it is impossible to experimentally determine toxicity for each mixture. Evermore, the number of newly-created substances in the environment is also increasing and for such substances there is mostly no toxicity information. The scientists are trying to solve this problem by chemometrics or more precisely by the application of various toxicity models. Two most common models are: Concentration Addition model (CA) and Independent Action model (IA). The rapid development of computer technology allowed for the application of various advanced computational methods and tools. The one with great potential is the so-called QSAR approach (Quantitative Structure-Activity Relationship) which correlates the structural characteristics of the substances with their certain activity, for example toxicity. The aim of this dissertation was: I. to classify the modes of joint toxic activity of selected pharmaceuticals and pesticides, and II. to develop QSAR models which would provide prediction of mixture toxicity based on information about mixture composition and of molecular structures of its constituents. Binary mixtures of substances contained in molar ratios of 25:75, 50:50 and 75:25 were tested in this work. Toxicities were determined according to ISO 11348 by measuring the luminescence of Vibrio fischeri bacteria; they were expressed on three levels: as EC50, EC30 and EC10 values. Ten pollutants were selected for the analysis of joint toxic activity; this referred to six pharmaceuticals: azithromycin, erythromycin, carbamazepine, oxytetracycline, dexamethasone and diclofenac, and four pesticides: alachlor, isoproturon, diuron and chlorfenvinphos. Toxic activities were studied on binary mixtures: mixtures of pharmaceuticals and mixtures of pesticides were analyzed separately. CA and IA toxicity models were applied for the analysis of joint toxic activity and the model-predicted values were compared to experimentally determined ones. Toxicities of single-pollutant solutions were used as inputs to the models and joint toxic activities were classified as: I. the additive behavior, and II. synergistic or antagonistic deviation from the additive behavior. Deviations from the additive action were confirmed additionally through better fitting of the experimental values in the case of IA model. The results indicated synergistic behavior in the mixture of diclofenac and oxytetracycline. Other binary combinations of diclofenac and oxytetracycline were acting similarly: thus the synergism was observed for their mixtures with carbamazepine, while the antagonistic behavior was shown for the mixtures with azithromycin and erythromycin. All the remaining binary mixtures of pharmaceuticals indicated additive behavior. The analysis revealed additive behavior for all binary mixtures of pesticides; the exception was the mixture of isoproturon and chlorfenvinphos whose combination resulted with synergistic deviation from the additive behavior. In the last stage of the research, QSAR models were developed and validated. Four new pharmaceuticals were added to the study: omeprazole, desloratadine, imatinib, and tobramycin, as well as their binary mixtures. The intention was to increase the number of data for development and validation of QSAR models. Molecular conformations of all selected pollutants were optimized and the descriptors were calculated. Different mixing rules were tested in order to find the best way to present mathematically the binary mixtures. These rules included various ways of combining molecular descriptor values with mixture composition. Modeling was performed by Multiple Linear Regression and Genetic Algorithm was applied in the selection of most-informative descriptors. QSAR models were developed for each of the three tested toxicity levels: EC50, EC30 and EC10. The models were validated using the external data set, i.e. by the mixtures whose toxicities were not included in development of the models. Each of the models showed a high level of accuracy. QSAR models were used in revealing the structural characteristics that had a significant impact on toxicity towards Vibrio fischeri. The results indicated that EC50 and EC30 values were mostly influenced by geometrical distances between nitrogen and sulfur atoms. Additionally, the simultaneous presence of oxygen and chlorine atoms could induce the increase in mixture toxicity. At the lowest tested level (EC10), dipole moment had the highest impact on the mixture toxicity
Modeling of toxicity of multicomponent pharmaceutical and pesticide solutions
Kao posljedica nezaustavljivog ekonomskog razvoja te ubrzanog rasta ljudske populacije, oÄekuje se da Äe dostupnost Äiste i svježe vode postati jedan od najveÄih problema buduÄnosti. U proteklih nekoliko desetljeÄa, u vodama su pronaÄene brojne tvari koje tamo izvorno ne pripadaju, a njihovo je podrijetlo najÄeÅ”Äe vezano uz ljudsku aktivnost. Å irok spektar oneÄiÅ”Äivala, ukljuÄujuÄi industrijske kemikalije, farmaceutike, pesticide i metale, pronaÄen je ne samo u otpadnim, veÄ i u povrÅ”inskim, pa Äak i pitkim vodama. U posljednje vrijeme posebnu pozornost znanstvene zajednice, ali i regulatornih tijela, privlaÄe farmaceutici i pesticidi buduÄi da su prepoznati kao spojevi Äija prisutnost u okoliÅ”u može imati Å”tetno djelovanje na Äovjeka, floru i faunu. Procjena rizika od prisutnosti Å”tetnih tvari u okoliÅ”u uglavnom se temelji na poznatim vrijednostima toksiÄnosti za pojedine tvari. MeÄutim takav pristup sadrži u sebi pozamaÅ”an nedostatak. Naime, rijetke su situacije u kojima je u okoliÅ”u prisutna samo jedna Å”tetna tvar: živi organizmi obiÄno su u doticaju sa smjesama Å”tetnih tvari. U takvim situacijama može doÄi do združenog djelovanja tvari koje, nažalost, nerijetko ima intenzivniji Å”tetni utjecaj po organizme nego Å”to bi bilo u sluÄaju da svaka tvar djeluje zasebno. Stoga je procjena rizika na temelju informacija o toksiÄnosti smjesa bolji pristup. No razliÄitih smjesa je bezbroj i nemoguÄe je za svaku kombinaciju oneÄiÅ”ÄujuÄih tvari eksperimentalno odrediti toksiÄnost. TakoÄer, u okoliÅ”u je sve viÅ”e novih kemikalija za koje joÅ” ne postoje podaci o toksiÄnosti. Tom se problemu pokuÅ”ava doskoÄiti primjenom kemometrije, konkretnije: primjenom matematiÄkih modela za procjenu toksiÄnosti otopina. U proteklim desetljeÄima razvijeni su i testirani razliÄiti pristupi i modeli. Najprimjenjivaniji model procjene toksiÄnosti smjesa je tzv. aditivni model (CA model), a odmah nakon njega dolazi model neovisnog djelovanja (IA model). Intenzivan razvoj raÄunala omoguÄio je znaÄajniju primjenu razliÄitih naprednih raÄunalnih metoda i alata gdje je potrebno istaknuti modele kvantitativnog odnosa strukture i aktivnosti tvari (QSAR) koji povezuju strukturne karakteristike tvari s nekom njihovom aktivnoÅ”Äu, primjerice toksiÄnoÅ”Äu. Cilj disertacije bio je klasificirati naÄine združenoga toksiÄnog djelovanja odabranog skupa farmaceutika i pesticida te razviti adekvatne QSAR-modele koji bi omoguÄili predviÄanje toksiÄnosti smjesa na temelju sastava i molekulske strukture konstituenata. U disertaciji su ispitivane binarne smjese tvari pripravljene u molarnim omjerima: 25:75, 50:50 i 75:25. ToksiÄnosti su odreÄene mjerenjem inhibicije luminiscencije bakterije Vibrio fischeri prema normi ISO 11348 te iskazane na tri razine: kao EC50, EC30 i EC10- vrijednosti. Za istraživanje združenoga toksiÄnog djelovanja odabrano je 10 oneÄiÅ”Äivala, od toga Å”est farmaceutika: azitromicin, eritromicin, karbamazepin, oksitetraciklin, deksametazon i diklofenak te Äetiri pesticida: alaklor, izoproturon, diuron i klorfenvinfos. Ispitana su djelovanja u binarnim smjesama, a zasebno su promatrane smjese farmaceutika i smjese pesticida. Prilikom analize združenog djelovanja primijenjeni su CA i IA-modeli toksiÄnosti te su rezultati usporeÄeni s eksperimentalno dobivenim vrijednostima. Ulazne varijable modela bile su toksiÄnosti Äistih otopina odabranih farmaceutika i pesticida, a združena djelovanja klasificirana su kao aditivno djelovanje te sinergistiÄko ili antagonistiÄko odstupanje od aditivnog djelovanja. Odstupanja od aditivnog modela dodatnu potvrdu su dobila kroz veÄu podudarnost u sluÄaju IA-modela. Rezultati su pokazali pojavu sinergistiÄkog djelovanja u smjesi diklofenaka i oksitetraciklina. Ostale binarne kombinacije diklofenaka ili oksitetraciklina pokazale su sliÄno djelovanje: sinergizam u smjesama s karbamazepinom te antagonizam u smjesama s makrolidnim antibioticima eritromicinom i azitromicinom. U preostalim binarnim smjesama farmaceutika je uoÄeno aditivno djelovanje. U svim binarnim smjesama pesticida uoÄeno je aditivno djelovanje, s izuzetkom binarne smjese izoproturona i klorfenvinfosa u kojoj je dokazano sinergistiÄko djelovanje. U zadnjoj fazi istraživanja, razvijeni su i testirani QSAR-modeli. S ciljem poveÄanja broja otopina na kojima Äe se razvijati i testirati QSAR-modeli, u istraživanje su dodana Äetiri nova farmaceutika: omeprazol, desloratadin, imatinib i tobramicin te njihove binarne smjese. Primjenom raÄunalnih alata optimirane su konformacije molekula te matematiÄki opisane strukture svih odabranih oneÄiÅ”Äivala (izraÄunati su molekulski deskriptori). Za potrebe kvalitetnog predstavljanja binarnih smjesa, ispitana su razliÄita pravila mijeÅ”anja ne bi li se otopine takoÄer opisale deskriptorima. Pri tome su na razliÄite naÄine kombinirane vrijednosti molekulskih deskriptora i sastav smjese. Modeliranje je provedeno viÅ”estrukom linearnom regresijom, a odabir najboljih deskriptora primjenom genetiÄkog algoritma. QSAR-modeli razvijeni su za svaku od tri ispitivane razine toksiÄnosti: EC50, EC30 i EC10. Razvijeni modeli testirani su na vanjskom skupu podataka, tj. na smjesama Äije toksiÄnosti nisu bile koriÅ”tene pri razvoju modela. Sva tri modela pokazala su zavidnu razinu toÄnosti. QSAR-modeli poslužili su za otkrivanje strukturnih karakteristika koje imaju znaÄajan utjecaj na toksiÄnost prema Vibrio fischeri. Rezultati su pokazali da najveÄi utjecaj na EC50 i EC30-vrijednosti ima geometrijska udaljenost izmeÄu duÅ”ikovih i sumporovih atoma. Nadalje, istovremena prisutnost kisikovih i klorovih atoma može djelovati na poveÄanje toksiÄnosti smjese. Pri EC10, najznaÄajniji utjecaj na toksiÄnost smjese ima dipolni moment.Unavailability of clean and fresh water will surely become one of the greatest mankind problems if steady development of global economy and the population growth are going to continue. Various odd substances have been found in waters in the past few decades: they were found in wastewater, surface water or even drinking water; the devastating fact is that the origin of these substances is mostly related to human activities. These water pollutants include various industrial chemicals, pharmaceuticals, pesticides, metals, etc. Among them, pharmaceuticals and pesticides have been identified recently as compounds with severe hazardous potential for humans, flora and fauna, since these substances are aimed to interact with living beings. Accordingly, the related risk assessment is required by regulatory bodies. The risk assessment is mostly based on information about toxicities of single pollutants. Unfortunately, such approach has a considerable defect. Namely, situation when only one pollutant is present in the environment is generally very rare; the living beings are mostly exposed to mixtures of pollutants. In such mixtures, a joined activity of substances is possible, such which might have more hazardous influence then the both substances acting alone. Therefore, risk assessment based on information about mixture toxicity is much more acceptable approach. The number of possible mixtures is infinite and, accordingly, it is impossible to experimentally determine toxicity for each mixture. Evermore, the number of newly-created substances in the environment is also increasing and for such substances there is mostly no toxicity information. The scientists are trying to solve this problem by chemometrics or more precisely by the application of various toxicity models. Two most common models are: Concentration Addition model (CA) and Independent Action model (IA). The rapid development of computer technology allowed for the application of various advanced computational methods and tools. The one with great potential is the so-called QSAR approach (Quantitative Structure-Activity Relationship) which correlates the structural characteristics of the substances with their certain activity, for example toxicity. The aim of this dissertation was: I. to classify the modes of joint toxic activity of selected pharmaceuticals and pesticides, and II. to develop QSAR models which would provide prediction of mixture toxicity based on information about mixture composition and of molecular structures of its constituents. Binary mixtures of substances contained in molar ratios of 25:75, 50:50 and 75:25 were tested in this work. Toxicities were determined according to ISO 11348 by measuring the luminescence of Vibrio fischeri bacteria; they were expressed on three levels: as EC50, EC30 and EC10 values. Ten pollutants were selected for the analysis of joint toxic activity; this referred to six pharmaceuticals: azithromycin, erythromycin, carbamazepine, oxytetracycline, dexamethasone and diclofenac, and four pesticides: alachlor, isoproturon, diuron and chlorfenvinphos. Toxic activities were studied on binary mixtures: mixtures of pharmaceuticals and mixtures of pesticides were analyzed separately. CA and IA toxicity models were applied for the analysis of joint toxic activity and the model-predicted values were compared to experimentally determined ones. Toxicities of single-pollutant solutions were used as inputs to the models and joint toxic activities were classified as: I. the additive behavior, and II. synergistic or antagonistic deviation from the additive behavior. Deviations from the additive action were confirmed additionally through better fitting of the experimental values in the case of IA model. The results indicated synergistic behavior in the mixture of diclofenac and oxytetracycline. Other binary combinations of diclofenac and oxytetracycline were acting similarly: thus the synergism was observed for their mixtures with carbamazepine, while the antagonistic behavior was shown for the mixtures with azithromycin and erythromycin. All the remaining binary mixtures of pharmaceuticals indicated additive behavior. The analysis revealed additive behavior for all binary mixtures of pesticides; the exception was the mixture of isoproturon and chlorfenvinphos whose combination resulted with synergistic deviation from the additive behavior. In the last stage of the research, QSAR models were developed and validated. Four new pharmaceuticals were added to the study: omeprazole, desloratadine, imatinib, and tobramycin, as well as their binary mixtures. The intention was to increase the number of data for development and validation of QSAR models. Molecular conformations of all selected pollutants were optimized and the descriptors were calculated. Different mixing rules were tested in order to find the best way to present mathematically the binary mixtures. These rules included various ways of combining molecular descriptor values with mixture composition. Modeling was performed by Multiple Linear Regression and Genetic Algorithm was applied in the selection of most-informative descriptors. QSAR models were developed for each of the three tested toxicity levels: EC50, EC30 and EC10. The models were validated using the external data set, i.e. by the mixtures whose toxicities were not included in development of the models. Each of the models showed a high level of accuracy. QSAR models were used in revealing the structural characteristics that had a significant impact on toxicity towards Vibrio fischeri. The results indicated that EC50 and EC30 values were mostly influenced by geometrical distances between nitrogen and sulfur atoms. Additionally, the simultaneous presence of oxygen and chlorine atoms could induce the increase in mixture toxicity. At the lowest tested level (EC10), dipole moment had the highest impact on the mixture toxicity
Modeling of toxicity of multicomponent pharmaceutical and pesticide solutions
Kao posljedica nezaustavljivog ekonomskog razvoja te ubrzanog rasta ljudske populacije, oÄekuje se da Äe dostupnost Äiste i svježe vode postati jedan od najveÄih problema buduÄnosti. U proteklih nekoliko desetljeÄa, u vodama su pronaÄene brojne tvari koje tamo izvorno ne pripadaju, a njihovo je podrijetlo najÄeÅ”Äe vezano uz ljudsku aktivnost. Å irok spektar oneÄiÅ”Äivala, ukljuÄujuÄi industrijske kemikalije, farmaceutike, pesticide i metale, pronaÄen je ne samo u otpadnim, veÄ i u povrÅ”inskim, pa Äak i pitkim vodama. U posljednje vrijeme posebnu pozornost znanstvene zajednice, ali i regulatornih tijela, privlaÄe farmaceutici i pesticidi buduÄi da su prepoznati kao spojevi Äija prisutnost u okoliÅ”u može imati Å”tetno djelovanje na Äovjeka, floru i faunu. Procjena rizika od prisutnosti Å”tetnih tvari u okoliÅ”u uglavnom se temelji na poznatim vrijednostima toksiÄnosti za pojedine tvari. MeÄutim takav pristup sadrži u sebi pozamaÅ”an nedostatak. Naime, rijetke su situacije u kojima je u okoliÅ”u prisutna samo jedna Å”tetna tvar: živi organizmi obiÄno su u doticaju sa smjesama Å”tetnih tvari. U takvim situacijama može doÄi do združenog djelovanja tvari koje, nažalost, nerijetko ima intenzivniji Å”tetni utjecaj po organizme nego Å”to bi bilo u sluÄaju da svaka tvar djeluje zasebno. Stoga je procjena rizika na temelju informacija o toksiÄnosti smjesa bolji pristup. No razliÄitih smjesa je bezbroj i nemoguÄe je za svaku kombinaciju oneÄiÅ”ÄujuÄih tvari eksperimentalno odrediti toksiÄnost. TakoÄer, u okoliÅ”u je sve viÅ”e novih kemikalija za koje joÅ” ne postoje podaci o toksiÄnosti. Tom se problemu pokuÅ”ava doskoÄiti primjenom kemometrije, konkretnije: primjenom matematiÄkih modela za procjenu toksiÄnosti otopina. U proteklim desetljeÄima razvijeni su i testirani razliÄiti pristupi i modeli. Najprimjenjivaniji model procjene toksiÄnosti smjesa je tzv. aditivni model (CA model), a odmah nakon njega dolazi model neovisnog djelovanja (IA model). Intenzivan razvoj raÄunala omoguÄio je znaÄajniju primjenu razliÄitih naprednih raÄunalnih metoda i alata gdje je potrebno istaknuti modele kvantitativnog odnosa strukture i aktivnosti tvari (QSAR) koji povezuju strukturne karakteristike tvari s nekom njihovom aktivnoÅ”Äu, primjerice toksiÄnoÅ”Äu. Cilj disertacije bio je klasificirati naÄine združenoga toksiÄnog djelovanja odabranog skupa farmaceutika i pesticida te razviti adekvatne QSAR-modele koji bi omoguÄili predviÄanje toksiÄnosti smjesa na temelju sastava i molekulske strukture konstituenata. U disertaciji su ispitivane binarne smjese tvari pripravljene u molarnim omjerima: 25:75, 50:50 i 75:25. ToksiÄnosti su odreÄene mjerenjem inhibicije luminiscencije bakterije Vibrio fischeri prema normi ISO 11348 te iskazane na tri razine: kao EC50, EC30 i EC10- vrijednosti. Za istraživanje združenoga toksiÄnog djelovanja odabrano je 10 oneÄiÅ”Äivala, od toga Å”est farmaceutika: azitromicin, eritromicin, karbamazepin, oksitetraciklin, deksametazon i diklofenak te Äetiri pesticida: alaklor, izoproturon, diuron i klorfenvinfos. Ispitana su djelovanja u binarnim smjesama, a zasebno su promatrane smjese farmaceutika i smjese pesticida. Prilikom analize združenog djelovanja primijenjeni su CA i IA-modeli toksiÄnosti te su rezultati usporeÄeni s eksperimentalno dobivenim vrijednostima. Ulazne varijable modela bile su toksiÄnosti Äistih otopina odabranih farmaceutika i pesticida, a združena djelovanja klasificirana su kao aditivno djelovanje te sinergistiÄko ili antagonistiÄko odstupanje od aditivnog djelovanja. Odstupanja od aditivnog modela dodatnu potvrdu su dobila kroz veÄu podudarnost u sluÄaju IA-modela. Rezultati su pokazali pojavu sinergistiÄkog djelovanja u smjesi diklofenaka i oksitetraciklina. Ostale binarne kombinacije diklofenaka ili oksitetraciklina pokazale su sliÄno djelovanje: sinergizam u smjesama s karbamazepinom te antagonizam u smjesama s makrolidnim antibioticima eritromicinom i azitromicinom. U preostalim binarnim smjesama farmaceutika je uoÄeno aditivno djelovanje. U svim binarnim smjesama pesticida uoÄeno je aditivno djelovanje, s izuzetkom binarne smjese izoproturona i klorfenvinfosa u kojoj je dokazano sinergistiÄko djelovanje. U zadnjoj fazi istraživanja, razvijeni su i testirani QSAR-modeli. S ciljem poveÄanja broja otopina na kojima Äe se razvijati i testirati QSAR-modeli, u istraživanje su dodana Äetiri nova farmaceutika: omeprazol, desloratadin, imatinib i tobramicin te njihove binarne smjese. Primjenom raÄunalnih alata optimirane su konformacije molekula te matematiÄki opisane strukture svih odabranih oneÄiÅ”Äivala (izraÄunati su molekulski deskriptori). Za potrebe kvalitetnog predstavljanja binarnih smjesa, ispitana su razliÄita pravila mijeÅ”anja ne bi li se otopine takoÄer opisale deskriptorima. Pri tome su na razliÄite naÄine kombinirane vrijednosti molekulskih deskriptora i sastav smjese. Modeliranje je provedeno viÅ”estrukom linearnom regresijom, a odabir najboljih deskriptora primjenom genetiÄkog algoritma. QSAR-modeli razvijeni su za svaku od tri ispitivane razine toksiÄnosti: EC50, EC30 i EC10. Razvijeni modeli testirani su na vanjskom skupu podataka, tj. na smjesama Äije toksiÄnosti nisu bile koriÅ”tene pri razvoju modela. Sva tri modela pokazala su zavidnu razinu toÄnosti. QSAR-modeli poslužili su za otkrivanje strukturnih karakteristika koje imaju znaÄajan utjecaj na toksiÄnost prema Vibrio fischeri. Rezultati su pokazali da najveÄi utjecaj na EC50 i EC30-vrijednosti ima geometrijska udaljenost izmeÄu duÅ”ikovih i sumporovih atoma. Nadalje, istovremena prisutnost kisikovih i klorovih atoma može djelovati na poveÄanje toksiÄnosti smjese. Pri EC10, najznaÄajniji utjecaj na toksiÄnost smjese ima dipolni moment.Unavailability of clean and fresh water will surely become one of the greatest mankind problems if steady development of global economy and the population growth are going to continue. Various odd substances have been found in waters in the past few decades: they were found in wastewater, surface water or even drinking water; the devastating fact is that the origin of these substances is mostly related to human activities. These water pollutants include various industrial chemicals, pharmaceuticals, pesticides, metals, etc. Among them, pharmaceuticals and pesticides have been identified recently as compounds with severe hazardous potential for humans, flora and fauna, since these substances are aimed to interact with living beings. Accordingly, the related risk assessment is required by regulatory bodies. The risk assessment is mostly based on information about toxicities of single pollutants. Unfortunately, such approach has a considerable defect. Namely, situation when only one pollutant is present in the environment is generally very rare; the living beings are mostly exposed to mixtures of pollutants. In such mixtures, a joined activity of substances is possible, such which might have more hazardous influence then the both substances acting alone. Therefore, risk assessment based on information about mixture toxicity is much more acceptable approach. The number of possible mixtures is infinite and, accordingly, it is impossible to experimentally determine toxicity for each mixture. Evermore, the number of newly-created substances in the environment is also increasing and for such substances there is mostly no toxicity information. The scientists are trying to solve this problem by chemometrics or more precisely by the application of various toxicity models. Two most common models are: Concentration Addition model (CA) and Independent Action model (IA). The rapid development of computer technology allowed for the application of various advanced computational methods and tools. The one with great potential is the so-called QSAR approach (Quantitative Structure-Activity Relationship) which correlates the structural characteristics of the substances with their certain activity, for example toxicity. The aim of this dissertation was: I. to classify the modes of joint toxic activity of selected pharmaceuticals and pesticides, and II. to develop QSAR models which would provide prediction of mixture toxicity based on information about mixture composition and of molecular structures of its constituents. Binary mixtures of substances contained in molar ratios of 25:75, 50:50 and 75:25 were tested in this work. Toxicities were determined according to ISO 11348 by measuring the luminescence of Vibrio fischeri bacteria; they were expressed on three levels: as EC50, EC30 and EC10 values. Ten pollutants were selected for the analysis of joint toxic activity; this referred to six pharmaceuticals: azithromycin, erythromycin, carbamazepine, oxytetracycline, dexamethasone and diclofenac, and four pesticides: alachlor, isoproturon, diuron and chlorfenvinphos. Toxic activities were studied on binary mixtures: mixtures of pharmaceuticals and mixtures of pesticides were analyzed separately. CA and IA toxicity models were applied for the analysis of joint toxic activity and the model-predicted values were compared to experimentally determined ones. Toxicities of single-pollutant solutions were used as inputs to the models and joint toxic activities were classified as: I. the additive behavior, and II. synergistic or antagonistic deviation from the additive behavior. Deviations from the additive action were confirmed additionally through better fitting of the experimental values in the case of IA model. The results indicated synergistic behavior in the mixture of diclofenac and oxytetracycline. Other binary combinations of diclofenac and oxytetracycline were acting similarly: thus the synergism was observed for their mixtures with carbamazepine, while the antagonistic behavior was shown for the mixtures with azithromycin and erythromycin. All the remaining binary mixtures of pharmaceuticals indicated additive behavior. The analysis revealed additive behavior for all binary mixtures of pesticides; the exception was the mixture of isoproturon and chlorfenvinphos whose combination resulted with synergistic deviation from the additive behavior. In the last stage of the research, QSAR models were developed and validated. Four new pharmaceuticals were added to the study: omeprazole, desloratadine, imatinib, and tobramycin, as well as their binary mixtures. The intention was to increase the number of data for development and validation of QSAR models. Molecular conformations of all selected pollutants were optimized and the descriptors were calculated. Different mixing rules were tested in order to find the best way to present mathematically the binary mixtures. These rules included various ways of combining molecular descriptor values with mixture composition. Modeling was performed by Multiple Linear Regression and Genetic Algorithm was applied in the selection of most-informative descriptors. QSAR models were developed for each of the three tested toxicity levels: EC50, EC30 and EC10. The models were validated using the external data set, i.e. by the mixtures whose toxicities were not included in development of the models. Each of the models showed a high level of accuracy. QSAR models were used in revealing the structural characteristics that had a significant impact on toxicity towards Vibrio fischeri. The results indicated that EC50 and EC30 values were mostly influenced by geometrical distances between nitrogen and sulfur atoms. Additionally, the simultaneous presence of oxygen and chlorine atoms could induce the increase in mixture toxicity. At the lowest tested level (EC10), dipole moment had the highest impact on the mixture toxicity
Mandarins from Neretva valley-Chemical characterization and Innovative postharvest TREAtments
skup podatak
Chitosan-based layer-by-layer edible coatings application for the preservation of mandarin fruit bioactive compounds and organic acids
The layer-by-layer application of biopolymeric coatings to mandarin fruits as a postharvest treatment to improve fruit coating efficacy has been reported. A single 1Ā % (w/v) chitosan application was evaluated, and polyelectrolyte complexes such as 1.5Ā % (w/v) alginate/chitosan, 1Ā % (w/v) hydroxypropyl methylcellulose/chitosan, and 0.2Ā % (w/v) locust bean gum/chitosan were applied to mandarin fruits. The quality of coated mandarin fruits was observed at temperatures: 20Ā Ā±Ā 2Ā Ā°C (up to 10Ā days) and 5Ā Ā°C (up to 28Ā days). Changes in the fruit metabolism were observed by evaluating bioactive compounds (polyphenolic compounds and flavonoids), antioxidant activity, and organic acids during the preservation of mandarin fruits. All of the tested combinations of layer-by-layer coatings significantly impacted the quality of mandarin fruits throughout storage, both at room temperature and cold storage, respectively. The overall best performance was observed for a layer-by-layer hydroxypropyl methylcellulose/chitosan coating in terms of visual aspects, bioactive compounds, antioxidant activity, and organic acids content
RužiÄka days : International conference 19th RužiÄka Days āToday Science ā Tomorrow Industryā : Proceedings
Dear colleagues, we are extremely honoured to present to you the Proceedings of the international conference 19th RužiÄka Days, which was successfully held on September 21ā23, 2022, in Vukovar, Croatia, in the hometown town of our famous Croatian scientist and first Nobel laureate, professor Leopold (Lavoslav) RužiÄka. The main goals of the Conference were to promote excellence, originality and innovation of interdisciplinary scientific research as well as the practical application of the obtained results through collaboration with industry, emphasizing thus the recognizable slogan of the RužiÄka Days conference: "Today Science ā Tomorrow Industry". In addition, the Conference gave the opportunity for meetings, exchanging the ideas, opinions, experiences and cooperation among participants from different working surroundings. It is also important to point out that since 2008, within the international conference RužiÄka Days, Meeting of Young Chemists has also been held, where high school students, with the help of their mentors, present papers in the field of chemistry, with the aim to direct students and young people to the technical and natural sciences, especially chemistry. In its seventh issue (2011, 2013, 2015, 2017, 2019, 2021) the Proceedings publishes scientific and professional full papers of high quality in the following sections: Chemical analysis and synthesis (10), Chemical and biochemical engineering (3), Food technology and biotechnology (4), Chemistry in agriculture and forestry (1), Environmental protection (9) and 8th Meeting of Young Chemists (3). Full-length papers were subjected to an international review procedure done by eminent experts from the corresponding fields, to whom we express our gratitude, but they were not subjected to linguistic proofreading. On behalf of the Scientific and Organizing Committee of the 19th RužiÄka Days we cordially thank all the authors, reviewers, participants, lecturers, organizers, especially the international organizers EuCheMS and EHEDG, auspices and sponsors, and all the others who, in any way, supported the Conference and contributed to the preparation of the Proceedings, especially to our highly skilled and committed associates, who have put a lot of effort in the preparation of these Proceedings. At the very end, special thanks to our young, future scientists and their mentors who are faithful participants of the Meeting of Young Chemists of the RužiÄka Days conference. Enjoy the extremely interesting scientific and professional papers contained in these Proceedings, until the next 20th jubilee of RužiÄka Days in 2024! We are looking forward to meeting you again in Vukovar! Yours sincerely, Chief Editors Jurislav BabiÄ Vesna OceliÄ BulatoviÄ Dajana KuÄiÄ Grgi
RužiÄka days : International conference 18th RužiÄka Days āToday Science ā Tomorrow Industryā : Proceedings
Proceedings contains articles presented at Conference divided into sections: chemical analysis and synthesis, chemical and biochemical engineering, food technology and biotechnology, medical chemistry and pharmacy, environmental protection and meeting of young chemists