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While experimental animal investigation has historically been the most conventional approach conducted to assess drug safety and is currently considered the main method for determining drug toxicity, these studies are constricted by cost, time, and ethical approvals. Over the last 20 years, there have been significant advances in computational sciences and computer data processing, while knowledge of alternative techniques and their application has developed into a valuable skill in toxicology. Thus, the application of in silico methods in drug safety assessment is constantly increasing. They are very complex and are grounded on accumulated knowledge from toxicology, bioinformatics, biochemistry, statistics, mathematics, as well as molecular biology. This review will summarize current state-of-the-art scientific data on the use of in silico methods in toxicity testing, taking into account their shortcomings, and highlighting the strategies that should deliver consistent results, while covering the applications of in silico methods in preclinical trials and drug impurities toxicity testing., Ispitivanja na eksperimentalnim životinjama ne samo da su u prošlosti bila smatrana najkonvencionalnijim pristupom za procenu bezbednosti lekova, već su i trenutno osnovna metoda za utvrđivanje njihove toksičnosti. Međutim, ova ispitivanja su skupa, vremenski zahtevna i za njihovo sprovođenje neophodne su etičke dozvole. Tokom poslednjih 20 godina došlo je do napretka u računarskoj nauci i kompjuterskoj obradi podataka, dok se znanje o alternativnim tehnikama i njihovoj primeni razvilo u dragocenu veštinu u toksikologiji. Stoga, primena in silico metoda u proceni bezbednosti lekova neprestano raste. Ove metode su veoma složene i zasnivaju se na saznanjima iz toksikologije, bioinformatike, biohemije, statistike, matematike i molekularne biologije. Ovaj pregledni rad će rezimirati trenutna naučna saznanja koja se tiču upotrebe in silico metoda u ispitivanju toksičnosti lekova, uzimajući u obzir njihova ograničenja i ističući strategije pomoću kojih se mogu dobiti konzistentni rezultati, sa posebnim osvrtom na primenu in silico metoda u pretkliničkim ispitivanjima i ispitivanjima toksičnosti nečistoća u lekovima.

Cadmium (Cd), one of the most abundant environmental pollutants, is considered to have endocrine disrupting properties. However, data on the dose-response relationship between Cd dose and levels of hormones have been insufficiently studied, especially in human data sets. Thus, the aim of this study was to determine the possibility of analyzing data obtained from a case- control study in female patients with benign/malignant breast tumors, using the Benchmark dose (BMD) concept. The collected data on Cd levels in breast tissue and estrogen serum levels were processed in PROAST software using different variables. The dose-response relationship between the internal dose of Cd and estradiol levels in the serum was investigated and BMD intervals were calculated. The dose-response relationship between the Cd concentration in breast tissue and the estradiol serum level was shown, indicating lower estradiol serum levels as a consequence of higher Cd concentrations in breast tissue. As one of the few studies analyzing human data using the BMD approach, these findings could have a pivotal role in dose response analysis of data collected from human studies., Kadmijum (Cd), jedan od najzastupljenijih zagađivača životne sredine, dokazan je endokrini ometač. Međutim, podaci o postojanju odnosa između doze Cd i odgovora-nivoa hormona nisu dovoljno istraženi, posebno podaci sakupljeni iz studija na ljudima. Stoga je cilj ove studije bio da se utvrdi mogućnost analize podataka dobijenih iz studije slučaja-kontrole kod pacijentkinja sa benignim/malignim tumorom dojke, primenom koncepta Benčmark doze (BMD). Prikupljeni podaci o nivoima Cd u tkivu dojke i serumskim nivoima estrogena obrađeni su u PROAST softveru uz korišćenje različitih varijabli. Ispitivan je odnos doza-odgovor između unutrašnje doze Cd (koncentracije u tkivu dojke) i estradiola u serumu i izračunati BMD intervali. Utvrđeno je postojanje odnosa između koncentracije Cd u tkivu dojke i nivoa estradiola u serumu koje ukazuje na niže nivoe estradiola u serumu kao posledica veće koncentracije Cd u tkivu dojke. Kao jedno od retkih istraživanja ovog tipa, dobijeni rezultati mogli bi predstavljati početak otkrivanja mogućnosti analize podataka prikupljenih u studijama na ljudima primenom BMD pristupa.

Bearing in mind that cosmetic products are applied throughout the lifetime and that they can contain potentially harmful and toxic substances, valid EU regulation in this area has set strict requirements regarding their safety. Manufacturers are required to provide a cosmetic product safety report containing a toxicological assessment made by experts. Toxicological assessment is based on existing in vivo toxicological data, and in particular in silico and in vitro, since EU regulations in the field of cosmetic products prohibit new animal studies. Although sporadic cases of serious poisoning after the application of cosmetic products have been recorded, adverse effects after normal and reasonably foreseeable use of cosmetic products are usually mild (allergic reactions and skin irritation) and completely reversible. EU regulations require mandatory reporting of serious adverse effects (functional incapacity, hospitalization, disability, etc.) in order to detect ingredients of cosmetic products that potentially endanger human health and prevent similar effects from recurred. The paper describes the procedure of toxicological risk assessment for cosmetic ingredients because the assessment of the safety of the cosmetic product is based on the assessment of the safety of its ingredients., Imajući u vidu da se kozmetički proizvodi primenjuju tokom celog života a da mogu sadržati potencijalno štetne i toksične supstance, važeća regulativa EU u ovoj oblasti (Uredba (EC) 1223/2009) postavila je stroge zahteve u pogledu njihove bezbednosti. Proizvođači su u obavezi da dostave izveštaj o bezbednosti koji sadrži toksikološku procenu koju rade osobe kvalifikovane za ovu vrstu poslova. Toksikološka procena se vrši na osnovu postojećih podataka in vivo toksikoloških ispitivanja, i posebno in silico i in vitro budući da EU regulativa u oblasti kozmetičkih proizvoda zabranjuje nova ispitivanja na životinjama. Iako se sporadično javljaju i ozbiljni slučajevi trovanja nakon primene kozmetičkih proizvoda, neželjeni efekti pri uobičajenoj i predvidivoj upotrebi kozmetičkog proizvoda su obično blagi (alergijske reakcije i iritacija kože) i potpuno reverzibilni. Regulativa EU zahteva obavezno prijavljivanje ozbiljnih neželjenih efekata (privremena sprečenost za rad, hospitalizacija, invaliditet itd.) u cilju otkrivanja sastojaka kozmetičkih proizvoda koji potencijalno ugrožavaju zdravlje ljudi i preduzimanja određenih mera kako bi se sprečilo da se slični efekti ponovo jave. U radu je opisana procedura toksikološke procene rizika za kozmetičke sastojke jer se procena bezbednosti kozmetičkog proizvoda zasniva na proceni bezbednosti njegovih sastojaka.

Interprofesionalno obrazovanje (IPO) predstavlja jednu od ključnih reformi u obrazovanju zdravstvenih profesionalaca preporučenih u cilju jačanja zdravstvenog sistema. Ovaj važan pedagoški pristup razvija zdravstvene profesionalce za pružanje zdravstvene zaštite u zajedničkom okruženju, budući da interprofesionalni timovi poboljšavaju kvalitet pružene zdravstvene usluge, smanjuju finansijske troškove lečenja i umanjuju mogućnost medicinske greške. U ovom radu predstavljamo prvo iskustvo IPO na fakultetima zdravstvenih nauka Univerziteta u Beogradu. Zajednički izborni predmet „Interprofesionalno obrazovanje” realizovan je na Medicinskom fakultetu, Farmaceutskom fakultetu i Stomatološkom fakultetu tokom školske 2017/2018 godine. Nastavu je pohađalo ukupno 69 studenata sa četiri studijska programa: Medicina (10), Farmacija (26), Dentalna Medicina (17) i Sestrinstvo (16). Interprofesionalne grupe studenata (n=6) sastojale su se od studenata završnih godina navedenih zdravstvenih profilakoji imaju specifična znanja, veštine i sposobnosti. Nastava je organizovana on‐line (e‐platforma) i on‐site u okviru radionica. Na tri radionice, interprofesionalni timovi studenata razmatrali su kliničke slučajeve pacijenta sa akutnim koronarnim sindromom, pacijenta sa dijabetesom i slučaj gerijatrijskog pacijenta. Radionice su vodili moderatori ‐ nastavnici i saradnici sva tri fakulteta. Praćenjem procesa nastave i evaluacije studenata zapaženo je da su studenti bili veoma zainteresovani za ovakav vid učenja, ali bi trebalo da se bolje pripreme za radionice(deo nastave na e–platformi) jer IPO zahteva efikasnu komunikaciju, jasno razumevanje uloga i dinamike tima, kao i sposobnost za efikasno rešavanje konflikta. Inteprofesionalne grupe studenata su sumirale svoja zapažanja i ekspertizu karakterističnu za svoju profesiju i komunicirale kao tim za pružanje optimalne nege pacijenta u svakom analiziranom kliničkom slučaju. Međutim, pojedini nastavnici u ulozi moderatora izveli su individua, Interprofessional education (IPE) is one of the key health education reforms recommended to strengthen health systems. It is an important pedagogical approach to develop health sciences students to provide patient care in a collaborative team environment. Interprofessional teams enhance the quality of patient care, lower costs, and reduce medical errors. In this paper, we present the first experience ofIPE at the faculties of health sciences of University of Belgrade. The joint elective subject „Interprofessional education” was conducted at the Faculty of Medicine, Faculty of Pharmacy and School of Dental Medicine during the school year 2017/2018. The subject was attended by a total of 69 students from the four study programs: Medicine (10), Pharmacy (26), Dental Medicine (17) and Nursing (16). Interprofessional student groups (n=6) were composed of students from the different study programs who have specialized knowledge, skills, and abilities. Teaching and learning was organized on‐line (e‐ platform) and on‐situ through joint workshops. In three workshops, students examined clinical cases of a patient with acute coronary syndrome, a patient with diabetes, and a geriatric patient case. The workshops were facilitated by academic staffs of all three faculties. Through monitoring of the process of teaching and evaluation of students, it was observed that students were very interested in this type of learning, but should be better prepared for the workshop because interprofessional practice requires effective communication, clear understanding of roles and team dynamics, as well as ability to effectively resolve conflict. Interporfessional student groups were synthesizing their observations and profession‐specific expertise to collaborate and communicate as a team for optimal patient carein each clinical case considered. However, some teachers in the role of facilitators carried out individual assessments of a patient that does not represent an interprofessional educat

This paper aims to present the importance of the benchmark dose (BMD) as a point of departure (the lowest dose or concentration in the experiment that deviates from the response that differs from the normal response) in toxicological risk assessment, as well as to present commonly used software for its calculation (BMDS and PROAST). Benchmark dose is defined as a statistical lower confidence limit of a dose that results in a small change in effect (5-10%) in comparison with the control value. The BMD approach is considered a substitution for the NOAEL approach, which uses the highest observed no-effect level (NOAEL) to obtain the reference dose. The BMD approach is a methodically more forward-thinking technique than the NOAEL approach because it has statistical power and provides a wide range of dose-response relationships and allows the determination of their uncertainty and variability. Moreover, the BMD approach contributes to the reduction of experimental animals in toxicity studies. Therefore, the European Food Safety Authority (EFSA) recommends the use of BMDL10values for quantal and BMDL05for continuous data., Cilj ovog rada je da predstavi značaj granične benchmark doze (engl. benchmark dose, BMD) kao polaznog doznog nivoa (najniže doze ili koncentracije u eksperimentu koja odstupa od normalnog odgovora) u toksikološkoj proceni rizika, kao i da prikaže najčešće korišćene softvere za njeno izračunavanje (BMDS i PROAST). Benchmark doza predstavlja statističku donju granicu pouzdanosti doze koja dovodi do malog povećanja efekta (5-10%) u odnosu na kontrolnu vrednost. Benchmark pristup predstavlja alternativu NOAEL (engl. no observed adverse effects level, NOAEL) pristupu, u kome se u svrhu dobijanja referentnih vrednosti koristi najviša doza koja ne izaziva štetan efekat. Benchmark pristup naučno je napredniji metod od tradicionalnog NOAEL pristupa, jer je statistički utemeljen, daje širok opseg podataka o odnosu doza-odgovor i omogućava kvantifikaciju njihove nesigurnosti i varijabilnosti. Takođe, BMD pristup doprinosi smanjenju broja eksperimentalnih životinja u toksikološkim studijama. Samim tim, Evropska agencija za bezbednost hrane (EFSA) preporučuje primenu doza BMDL10 za kvantalne i BMDL05 za kontinuirane podatke.

For over a century, one of the main toxicologists’ goals was finding the relationship between the chemical structure and toxicity. The development of computer technologies has lead to the production of software models that could be applied for this purpose. However, use of in silico methodology in toxicology is very complex. Having in mind that toxic effect occurs through multiple mechanisms on different tissues and organs, creating software that can make reliable toxicity predictions is very complicated. In silico methods found the application in toxicity assessment of substances for which data obtained from traditional toxicity tests is lacking (metabolites, drug impurities, etc.). Also, in silico methods can be used in the process of chemical synthesis, with the aim of designing safer chemicals. Currently, in silico methods for toxicity predictions are most commonly used along with standard toxicological tests, with a tendency to replace in vitro and in vivo toxicity tests in the future. This paper will present the strengths and limitations of commonly used software in in silico toxicology (OECD QSAR Toolbox, Derek Nexus, ToxTree i MultiCASE)., Već više od sto godina jedan od glavnih ciljeva toksikologa je povezivanje hemijske strukture supstanci sa njihovom toksičnošću. Progres u razvoju kompjuterskih tehnologija omogućio je kreiranje softverskih modela za ovu namenu. Međutim, primena in silicometodologije u toksikologiji je veoma složena. Kako se toksični efekat može ostvariti preko više mehanizama na različitim tkivima i organima, veoma je kompleksno kreirati softvere kojima se može dovoljno pouzdano predvideti toksičnost ispitivane supstance. Upotreba in silico metoda našla je primenu u proceni toksičnosti onih supstanci za koje ne postoji dovoljno podataka dobijenih tradicionalnim testovima toksičnosti (metaboliti, nečistoće u lekovima, itd.). Takođe, in silico metode se mogu koristiti u procesu sinteze hemikalija, sa ciljem dobijanja bezbednijih hemikalija, dajući uvid u strukturne karakteristike odgovorne za toksičnost. In silicometode za predviđanje toksičnosti trenutno se najčešće koriste uz standardna toksikološka ispitivanja, dok je tendencija da u budućnosti zamene deo in vitro i in vivo testova toksičnosti. U ovom radu biće prikazane mogućnosti i ograničenja najčešće korišćenih softvera u in silico toksikologiji (OECD QSAR Toolbox, Derek Nexus, ToxTree i MultiCASE).

The beneficial effects of fluoride, especially in reducing dental caries, are well known (recommended value 1mg/L of drinking water). However, prolonged intake of fluoride levels exceeding 1,5 mg/L can cause detrimental effects, mostly on teeth and skeleton. Since water is one of the principal sources of fluoride intake, the objective of this study was to determine fluoride content in bottled mineral waters of Serbia. 20 samples of different bottled mineral waters produced in Serbia were analyzed. Fluoride levels were determined electrochemically, using fluoride-selective electrode, after mixing with TISAB buffer in ratio 1:1. In 3 of 20 samples of bottled mineral waters fluoride levels exceeded 1 mg/L - carbonated mineral water 'Vrnjci' (1,34 mg/L), 'Heba' (1,19 mg/L) and 'Knjaz Miloš' (1,15 mg/L). Lower fluoride content was detected in 'Voda Voda' (0,64 mg/L), 'Minaqua' (0,43 mg/L) and 'Mivela' (0,43 mg/L). Other analyzed mineral waters contained very low fluoride concentration, lower than 0,25 mg/l; 'Aqua Gala' (0,23 mg/L), 'Aqua Bella' (0,2 mg/L), 'Life' (0,19 mg/L), 'Aqua viva' (0,14 mg/L), 'Prolom voda' (0,12 mg/L), 'Vujić voda' (0,1 mg/L), 'Vrnjačko vrelo' (0,09 mg/L), 'Aqua Balkanika' (0,07 mg/L), 'Rosa'-carbonated (0,06 mg/L), 'Rosa'-non-carbonated (0,06 mg/L), 'Vrnjci'-non-carbonated (0,06 mg/L), 'Zlatibor'-carbonated (0,04 mg/L) and 'Zlatibor'-non-cabonated (0,04 mg/L). These results show that carbonated mineral water 'Vrnjci', 'Heba' and 'Knjaz Miloš' contain fluoride in concentrations similar to recommended value, so they can induce beneficial effects in reducing dental caries. Most of other analysed bottled waters contain very low fluoride concetrations, indicating that the consumers of those waters need additional fluoride intake via food or fluoride preparations., Pozitivni efekti fluorida, naročito u suzbijanju karijesa, dobro su poznati (preporučeni sadržaj u pijaćoj vodi iznosi 1 mg/L). Međutim, produženi unos fluorida, u koncentracijama višim od 1,5 mg/L vode može dovesti do neželjenih efekata, koji se ispoljavaju uglavnom na zubima i skeletu. Obzirom da je voda jedan od najznačajnijih izvora unošenja fluorida, cilj ovog rada je bio određivanje sadržaja fluorida u flaširanim mineralnim vodama Srbije. Analizirano je 20 uzoraka flaširanih mineralnih voda proizvedenih u Srbiji. Sadržaj fluorida je određen elektrohemijski, korišćenjem fluoridne jon-selektivne elektrode. Koncentracija fluorida je viša od 1 mg/L u 3 od 20 analiziranih flaširanih mineralnih voda - u gaziranoj mineralnoj vodi 'Vrnjci' (1,34 mg/L), i vodama 'Heba' (1,19 mg/L) i 'Knjaz Miloš' (1,15 mg/L). Niži sadržaj detektovan je u mineralnim vodama 'Voda voda' (0,64 mg/L), 'Minaqua' (0,43 mg/L) i 'Mivela' (0,43 mg/L), a u izuzetno niskim koncentracijama, nižim od 0,25 mg/L, fluoridi se nalaze u mineralnim vodama 'Aqua Gala' (0,23 mg/L), 'Aqua Bella' (0,2 mg/L), 'Life' (0,19 mg/L), 'Aqua viva' (0,14 mg/L), 'Prolom voda' (0,12 mg/L), 'Vujić voda' (0,1 mg/L), 'Vrnjačko vrelo' (0,09 mg/L), 'Aqua Balkanika' (0,07 mg/L), 'Rosa'-gazirana (0,06 mg/L), 'Rosa'-negazirana (0,06 mg/L), 'Vrnjci'-negazirana (0,06 mg/L), 'Zlatibor'-gazirana (0,04 mg/L) i 'Zlatibor'-negazirana (0,04 mg/L). Dobijeni rezultati ukazuju da gazirana mineralna voda 'Vrnjci', 'Heba' i 'Knjaz Miloš' sadrže fluoride u koncentracijama bliskim optimalnim vrednostima, te mogu ispoljiti pozitivan efekat u prevenciji karijesa. Većina ostalih ispitivanih flaširanih voda ima veoma nizak sadržaj fluorida, pa bi osobe koje konzumiraju ovakve vode trebalo da obezbede potreban unos fluorida putem hrane ili preparata fluorida.