Exploring the endocrine disrupting potential of lead through benchmark modelling – Study in humans

Exposure to low levels of a toxic metal lead (Pb) affects human health, and its effect as an endocrine disruptor has been reported. However, the precise role of Pb in endocrine health is still unclear because no dose-response relationship has been established for such an effect. The present study aimed to examine blood Pb levels (BLLs) in relation to serum levels of free triiodothyronine (fT3), free thyroxine (fT4), thyroid stimulating hormone (TSH), and insulin in 435 nonoccupationally exposed Serbian subjects (218 women, 217 men, 18–94 years of age, mean age 48). In addition, benchmark dose (BMD) values were calculated for these endocrine endpoints using the PROAST 70.1 software. An explicit dose-response dependency between BLL and TSH, fT3, fT4, testosterone, and insulin serum levels was evident from BMD modelling. The results support the positive association between BLLs and serum insulin levels, with observed dose-response and calculated BMD values of 1.49 and 0.74 μg Pb/dL in males and females, respectively. Collectively, our findings reported potential endocrine-disrupting effects of Pb at the environmental exposure levels experienced by current Serbian population. They also strengthen the notion that the blood Pb threshold level for an endocrine effect is low

Nivoi kadmijuma u humanom tkivu dojke i nivoi estradiola u serumu: Postoji li veza?

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

Benchmark dose approach in investigating the relationship between blood metal levels and reproductive hormones: Data set from human study

The main objective of this research was to conduct a dose–response modeling between the internal dose of measured blood Cd, As, Hg, Ni, and Cr and hormonal response of serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The study included 207 male participants from subjects of 5 different cohorts (patients with prostate, testicular, and pancreatic cancer, patients suffering from various thyroid and metabolic disorders, as well as healthy volunteers), enrolled from January 2019 to May 2021 at the Clinical Centre of Serbia in Belgrade, Serbia. Benchmark dose–response modeling analysis was performed with the PROAST software version 70.1, showing the hormone levels as quantal data. The averaging technique was applied to compute the Benchmark dose (BMD) interval (BMDI), with benchmark response set at 10%. Dose-response relationships between metal/metalloid blood concentration and serum hormone levels were confirmed for all the investigated metals/metalloid and hormones. The narrowest BMDI was found for Cd-testosterone and Hg-LH pairs, indicative of high confidence in these estimates. Although further research is needed, the observed findings demonstrate that the BMD approach may prove to be significant in the dose–response modeling of human data

VARIABILITY OF AMYLOSE AND AMYLOPECTIN IN WINTER WHEAT AND SELECTION FOR SPECIAL PURPOSES

Cilj ovoga istraživanja bio je ispitati varijabilnost amiloze i amilopektina kod 24 hrvatske i šest stranih sorata ozime pšenice te otkriti potencijal istih za posebne namjene. Analiza sastava škroba temeljila se na izdvajanju amiloze i amilopektina te određivanju njihove količine i omjera. Analiza količine amiloze i amilopektina utvrdila je statistički visoko opravdane razlike među ispitivanim sortama. Ispitivane sorte većinom su krušne pšenice različite kvalitete te imaju uobičajen sadržaj amiloze i amilopektina. Među njima izdvojile su se pojedine sorte s visokim sadržajem amilopektina i niskim sadržajem amiloze te jedna sorta s visokim sadržajem amiloze, koje imaju potencijal u budućim oplemenjivačkim programima i selekciji za posebne namjene.The aim of this study was to investigate the variability of amylose and amylopectin in 24 Croatian and six foreign winter wheat varieties and to detect the potential of these varieties for special purposes. Starch composition analysis was based on the separation of amylose and amylopectin and the determination of their amounts and ratios. Analysis of the amount of amylose and amylopectin determined statistically highly significant differences between the varieties. The tested varieties are mostly bread wheat of different quality which have the usual content of amylose and amylopectin. Some varieties were identified among them with high amylopectin and low amylose content and one variety with high amylose content. They have the potential in future breeding programs and selection for special purposes

In silico analiza utjecaja toksičnih metala na komplikacije bolesti COVID-19: molekularni uvidi

COVID-19 can cause a range of complications, including cardiovascular, renal, and/or respiratory insufficiencies, yet little is known of its potential effects in persons exposed to toxic metals. The aim of this study was to answer this question with in silico toxicogenomic methods that can provide molecular insights into COVID-19 complications owed to exposure to arsenic, cadmium, lead, mercury, nickel, and chromium. For this purpose we relied on the Comparative Toxicogenomic Database (CTD), GeneMANIA, and ToppGene Suite portal and identified a set of five common genes (IL1B, CXCL8, IL6, IL10, TNF) for the six metals and COVID-19, all of which code for pro-inflammatory and anti-inflammatory cytokines. The list was expanded with additional 20 related genes. Physical interactions are the most common between the genes affected by the six metals (77.64 %), while the dominant interaction between the genes affected by each metal separately is co-expression (As 56.35 %, Cd 64.07 %, Pb 71.5 %, Hg 81.91 %, Ni 64.28 %, Cr 88.51 %). Biological processes, molecular functions, and pathways in which these 25 genes participate are closely related to cytokines and cytokine storm implicated in the development of COVID-19 complications. In other words, our findings confirm that exposure to toxic metals, alone or in combinations, might escalate COVID-19 severity.COVID-19 može izazvati niz komplikacija, uključujući kardiovaskularnu, bubrežnu i/ili respiratornu insuficijenciju, ali se malo zna o njegovim potencijalnim učincima u osoba koje su izložene toksičnim metalima. Cilj ovog istraživanja bio je odgovoriti na to pitanje pomoću in silico toksikogenomske metode, koja može pružiti molekularni uvid u komplikacije bolesti COVID-19 uslijed izloženosti arsenu, kadmiju, olovu, živi, niklu i kromu. U tu su svrhu korišteni Komparativna toksikogenomska baza podataka (CTD), GeneMANIA i ToppGene Suite portal te je identificirana skupina od pet zajedničkih gena (IL1B, CXCL8, IL6, IL10, TNF) za šest metala i COVID-19, koji svi kodiraju proinflamatorne i antiinflamatorne citokine. Lista je proširena s dodatnih 20 srodnih gena. Fizičke interakcije dominirale su između gena na koje utječe kombinacija ispitivanih metala (77,64 %), a koekspresija je dominantna interakcija između gena na koje djeluju pojedinačni metali (As 56,35 %, Cd 64,07 %, Pb 71,5 %, Hg 81,91 %, Ni 64,28 %, Cr 88,51 %). Biološki procesi, molekulske funkcije i putovi u kojima sudjeluje tih 25 gena blisko su povezani s citokinima i citokinskom olujom, koja je uključena u razvoj komplikacija bolesti COVID-19. Drugim riječima, ovi rezultati potvrđuju da izloženost toksičnim metalima, bilo pojedinačno ili u kombinaciji, može dovesti do razvoja težih oblika bolesti COVID-19

Uloga farmaceuta u smanjenju uticaja zagađenja vazduha na zdravlje ljudi

Polluted air is significant factor with a negative impact on human health. Solving the problem of polluted air requires involvement of the health system and health workers, among whom pharmacists in public pharmacies can stand out as the most accessible health workers with the highest knowledge in the field of toxicology. Considering the indisputable role of pharmacists in improving health and disease prevention, raising public awareness of air pollution health impact and advising patients on activities in case of air pollution, pharmacists would contribute to maintaining health, reducing the burden on the health system and its efficiency and sustainability. The pharmaceutical profession can make a significant contribution to combating the impact of air pollution on human health by increasing the availability of guidelines in the case of polluted air, increasing the availability of air quality monitoring tools, strengthening educational capacity models, participating in regulatory frameworks and improving funding for pharmaceutical services. In order for these responsibilities to be fully incorporated into pharmaceutical practice, it is necessary to: implement education in the field of toxicology, both at basic and higher levels of study in order to develop the necessary competencies; increase public awareness of the health consequences of air pollution, as well as the new roles of pharmacists; develop appropriate guidelines, regulatory and financial support as well as screening tools. With this in mind, the role of pharmacists in reducing the impact of air pollution on human health should be recognized and developed in order to protect human health.Zagađen vazduh predstavlja značajan faktor koji ima negativan uticaj na zdravlje ljudi. Rešavanje problema zagađenog vazduha zahteva uključivanje zdravstvenog sistema i zdravstvenih radnika, među kojima se mogu istaći farmaceuti u javnim apotekama kao najdostupniji zdravstveni radnici, sa najvišim znanjima iz oblasti toksikologije. Imajući u vidu neospornu ulogu farmaceuta u unapređenju zdravlja i prevenciji bolesti, podizanjem svesti javnosti o uticaju zagađenja vazduha na zdravlje ljudi i davanjem saveta pacijentima o aktivnostima u slučaju zagađenja vazduha, farmaceuti bi doprineli očuvanju zdravlja, smanjenju opterećenja zdravstvenog sistema i njegovoj efikasnosti i održivosti. Farmaceutska profesija može značajno doprineti suzbijanju uticaja zagađenja vazduha na zdravlje ljudi i to: povećanjem dostupnosti smernica u slučaju zagađenog vazduha, povećanjem dostupnosti alata za monitoring kvaliteta vazduha, jačanjem obrazovnih kapaciteta, učestvovanjem u donošenju regulatornih okvira i poboljšanjem modela finansiranja farmaceutskih usluga kako bi se obezbedila održivost. Da bi navedene odgovornosti bile u potpunosti inkorporirane u farmaceutsku praksu, potrebno je: implementirati edukaciju iz oblasti toksikologije, kako na osnovnim tako i na višim nivoima studija kako bi se razvile neophodne kompetencije; povećati svest javnosti o zdravstvenim posledicama zagađenja vazduha, kao i o novim ulogama farmaceuta; razviti odgovarajuće smernice, regulatornu i finansijsku podršku kao i alate za skrining. Imajući navedeno u vidu, uloga farmaceuta u smanjenju uticaja zagađenja vazduha na zdravlje ljudi treba biti prepoznata i razvijena sa ciljem očuvanja zdravlja.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Toksičnist ivermektina

Uvod i cilj. Ivermektin je antiparazitik efikasan protiv širokog spektra parazita koji se kori- sti u veterinarskoj i humanoj medicini. Pružaoci zdravstvenih usluga i istraživači trenutno pre- ispituju već odobrene lekove u pokušaju da leče pacijente obolele od bolesti Covid-19, a iver- mektin je pokazao izvesna antivirusna svojstva. Cilj ovog rada bio je da se razmotri upotreba ivermektina u terapiji Covid 19 bolesti sa posebnim osvrtom na toksične efekte ivermektina. Metode. Vršen je detaljan pregled dostupne literature koja se tiče upotrebe ivermektina u svrhu lečenja Covid 19 bolesti. Rezultati. SZO je savetovala da ivermektin treba da se koristi samo u okviru kliničkih is- pitivanja, a ne kao deo rutinske kliničke prakse. Nakon medijskih izveštaja i publikacija o upotrebi ivermektina, EMA je pregledala najnovije objavljene dokaze iz laboratorijskih studija, opservacionih studija, kliničkih ispitivanja i meta-analiza. Laboratorijske studije su otkrile da ivermektin može da blokira replikaciju SARS-CoV-2 virusa ali u mnogo većim koncentracijama od onih koje se postižu sa trenutno odobrenim dozama. Zbog primene visokih doza leka radi postizanja adekvatnog efekta ne može se isključiti pojava toksičnih efekata ivermektina. Neki od zabeleženih simptoma trovanja bili su gastrointestinalni poremećaji, konfuzija, ataksija, slabost, hipotenzija, poremećaji vida. Usled velike potražnje i nedostatka leka za humanu upotrebu, pacijenti često posežu za veterinarskim lekovima što je takođe rezultovalo toksič- nim efektima usled predoziranja i reakcijama na neaktivne sastojke leka koji nisu odobreni za humanu upotrebu. Zaključak. U cilju prevencije neadekvatne primene ivermektina i razvoja toksičnih efekata kod pacijenata u doba pandemije korona virusa veoma je važno informisanje i adekvatno savetovanje opšte populacije vezano za pravilnu upotrebu ovog leka

Put štetnog ishoda kao novi pristup u proceni toksičnosti u razvoju lekova

Adverse outcome pathways (AOPs) represent a tool in toxicology, introduced in 2010 by scientists from the US Environmental Protection Agency as a framework to support ecotoxicological research and risk assessment. In 2012, Organization for Economic Cooperation and Development initiated an international AOPs development program. Since then, AOPs have been promoted as useful tool in health risk assessment, development of Integrated Approaches to Testing and Assessment and for developing novel animal-free test methods (1,2). AOPs provide structured frameworks for collecting, organizing and evaluating existing toxicological knowledge on mechanistic pathways. AOPs describe biologically plausible chains of events, linking a molecular initiating event to key events at different levels of biological organization and, finally, to an adverse outcome. Not being stressor-specific, the ultimate utility of AOPs should be to predict adverse effects of any type of stressor, including chemicals, nanomaterials, pharmaceuticals, etc. with unknown toxic effects for which the toxicological mechanisms are known or can be tested. AOPs have been suggested as structured basis for predicting drug-induced liver injury (steatosis, fibrosis, cholestasis) and for developing in silico and in vitro methods for screening, as well as targeted methods for pre-clinical testing to assess liver toxicity, common reason for withdrawing pharmaceuticals from the market. AOPs have also been proposed as useful framework for method development and integration of in vitro data in personalized cancer therapy. In conclusion, AOPs concept plays an important role in the 21 st century toxicology paradigm supporting predictive toxicology with alternative assays and reduction of the need for animal use.Put štetnog ishoda (engl. adverse outcome pathway, AOP) predstavlja alatku u toksikologiji prvi put uvedenu 2010. godine od strane naučnika Američke agencije za zaštitu životne sredine sa ciljem podrške istraživanjima u ekotoksikologiji. Već 2012. godine Organizacija za ekonomsku saradnju i razvoj pokrenula je međunarodni program razvoja AOP. Od tada, AOP je promovisan kao koristan pristup u proceni rizika po zdravlje ljudi, razvoju novih metoda i integrisanih pristupa testiranju i evaluaciji štetnih efekata (1,2). AOP daje struktuirani okvir za prikupljanje, organizaciju i procenu postojećeg znanja o mehanističkim putevima u toksikologiji. AOP opisuje biološki verovatan lanac događaja povezujući inicijalni molekularni događaj, preko tzv. ključnih događaja na različitim nivoima biološke organizacije, sa štetnim efektom. AOP nije specifičan i kao takav, treba da posluži za predviđanje štetnih efekata različitih stresora, kao npr. hemikalija, nanomaterijala, lekova i drugih, sa nepoznatim štetnim efektom, ali za koje su poznati ili se mogu ispitati mehanizmi toksičnosti. Opisani su AOP u cilju predviđanja lekovima indukovanih oštećenja jetre (steatoza, fibroza, holestaza), kao i u cilju razvoja in silico i in vitro metoda za skrining i pretkliničko ispitivanje ovih efekata, koji su jedan od čestih razloga povlačenja lekova sa tržišta. AOP je predložen i kao koristan okvir za razvoj metoda i integraciju in vitro podataka u personalizovanu terapiju karcinoma. Konačno, AOP koncept igra važnu ulogu u toksikologiji 21. veka, koja podržava prediktivnu toksikologiju sa altentativnim metodama i smanjenjem potrebe za eksperimentalnim životinjama.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Izloženost živi i funkcija štitaste žlezde: postoji li veza?

Mercury (Hg) is one of the most important environmental pollutants with endocrine- disrupting properties. There is little data from epidemiological studies describing the dose- response relationship between toxic metal levels and hormone levels. The aim of this study was to use the nearest neighbor matching analysis to determine the difference in Hg concentration in healthy/sick subjects with thyroid disease and to use Benchmark modeling to determine the dose- response relationship between Hg levels in the blood and thyroid-stimulating hormone (TSH) and thyroid hormones in serum. Blood samples were collected and used for Hg measurement using the ICP-MS method, and separated serum was used for hormone analysis. The study showed the existence of a statistically significant difference in Hg levels measured in healthy and sick subjects and the existence of a dose-response relationship between Hg and all measured hormones, with a narrow interval obtained for the Hg-TSH pair. The results of this research support the use of the Benchmark dose approach for the purpose of analyzing data from human studies, and our further research will be focused on examining the impact of low doses on animal models in order to determine more precise effects of low doses on the organism.Živa (Hg) je jedan od najznačajnijih zagađivača životne sredine sa osobinama endokrinog ometača. Malo je podataka iz epidemioloških studija koji opisuju odnos doza-odgovor između nivoa toksičnih metala i nivoa hormona. Cilj ovog rada bio je da primenom nearest neighbor matching analize utvrdi razliku u koncentraciji Hg kod zdravih/obolelih ispitanika od bolesti štitaste žlezde i da primenom Benchmark modelovanja utvrdi odnos doza-odgovor između nivoa Hg u krvi i tireostimulišućeg hormona (TSH) i tiroidnih hormona u serumu. Uzorci krvi su sakupljeni i korišćeni za merenje Hg uz pomoć ICP-MS metode, a izdvojeni serum korišćen je za analizu hormona. Studija je pokazala postojanje statistički značajne razlike u nivoima Hg koji su izmereni kod zdravih i bolesnih ispitanika i postojanje odnosa doza-odgovor između Hg i svih merenih hormona, pri čemu je uzak interval dobijen za Hg-TSH par. Rezultati ovog istraživanja podržavaju upotrebu Benchmark dose pristupa u svrhu analize podataka iz humanih studija, a naša dalja istraživanja će biti usmerena na ispitivanje uticaja niskih doza na životinjskim modelima, u cilju utvrđivanja preciznijih efekata niskih doza na organizam

Uzročnici akutnih trovanja sa smrtnim ishodom u Republici Srbiji u periodu od 2010. do 2018. godine

The aim of this investigation was to present data analysis on acute poisonings with fatal outcome in the Republic of Serbia in from 2010 to 2018, based on the published Annual reports of the National Poison Control Center of the Military Medical Academy (1). In the observed 9-year period, the most common cause of acute poisoning was alcohol (50%), followed by drugs (30.1%), while in the third and fourth place were psychoactive substances (7.1%) and gases 4%. Corrosive and pesticide poisoning was present in only 2% of the total number of examined patients per year. The most common reason for the hospitalization was due to drug poisoning (71%), corrosives (9%), pesticides (5%), psychoactive substances (4%), gases (4%) and other pathogens (7%). From 2010 to 2018, number of deaths due to acute poisoning ranged from 26 to 43 annually with an average value of 33. Of 290 deceased patients, 101 (34.9%) were of drug poisoning, 108 (38.5%) corrosives, 28 (9.8%) pesticides, 4 (1.4%) gases, 14 (4.6%) psychoactive substances and 37 (12.4%) other substances, predominantly alcohols and mushrooms. Combination of two or more drugs most often led to death (n=51), while among corrosives, hydrochloric acid was the most common (n=40). Of the pesticides, the most common were organophosphorus insecticides (n=14), while heroin was the most common psychoactive substance (n=7). The analyzed data indicated the importance of preventive measures that need to be carried out in our country to reduce the number of acute poisonings, especially the most severe forms that lead to death.Cilj ovog rada bio je da se prikaže analiza podataka o akutnim trovanjima sa smrtnim ishodom u Republici Srbiji u periodu od 2010. do 2018. godine na osnovu publikovanih Godišnjaka Nacionalanog centra za kontrolu trovanja Vojnomedicinske akademije (1). U posmatranom devetogodišnjem periodu najčešći uzročnik akutnih trovanja je alkohol (50%), zatim lekovi (30,1%), dok su na trećem i četvrtom mestu psihoaktivne supstance (7,1%) i gasovi 4%. Samo oko 2% od ukupnog broja pregledanih pacijenata godišnje su slučajevi trovanja korozivima i pesticidima. Najčešći razlog hospitalizacije je usled trovanja lekovima (71%), zatim korozivima (9%), pesticidima (5%), psihoaktivnim supstancama (4%), gasovima (4%) i drugim uzročnicima (7%). Od 2010. do 2018. godine broj letalnih ishoda usled akutnog trovanja se kretao od 26 do 43 slučaja godišnje sa prosečnom vrednošću od 33 slučaja po godini. Od 290 preminula pacijenta, 101 (34,9%) slučaj je bilo trovanje lekovima, 108 (38,5%) korozivima, 28 (9,8%) pesticidima, 4 (1,3%) gasovima, 14 (4,6%) psihoaktivnim supstancama i 37 (12,4%) ostalim supstancama, dominantno alkoholima i gljivama. Kombinacija dva i više lekova je najčešće dovela do smrtnog ishoda (n=51), dok je među korozivima, najzastupljenija bila hlorovodonična kiselina (n=40). Od pesticida kao uzročnika akutnih trovanja sa smrtnim ishodom najzastupljeniji su organofosforni insekticidi (n=14), a prema broju smrtnih ishoda od psihoaktivnih supstanci najviše je zastupljen heroin (n=7). Analizirani podaci ukazuju na značaj preventivnih aktivnosti koje je u našoj zemlji potrebno sprovesti kako bi se smanjio broj akutnih trovanja, a time i onih najtežih oblika koji dovode do smrtnog ishoda.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra