Endocrine disruption by PFAS: A major concern associated with legacy and replacement substances

Perand poly-fluorinated alkyl substances (PFAS) have been used for decades in a great variety of processes and products by virtue of their exceptional properties, versatility and chemical stability. Nevertheless, it is increasingly recognized that these substances can represent a serious hazard to human health and living organisms due to their persistence, long-range transport potential and tendency to accumulate in biota. For this reason, some efforts have been made across the EU to identify alternative molecules, with a shorter carbon chain and theoretically safer profile, that might replace the previous generation of legacy PFAS. Unfortunately, this strategy has not been entirely successful and serious concerns are still posed by PFAS in different human populations. Among others, an emerging aspect is represented by the adverse effects that both legacy and alternative PFAS can exert on the human endocrine system, with respect to vulnerable target subpopulations. In this review we will briefly summarize PFAS properties, uses and environmental fate, focusing on their effects on human reproductive capacity and fertility, body weight control and obesity as well as thyroid function

Ekspozom i endokrino zdravlje ljudi

The term exposome describes every exposure from the environment to which an individual is subjected from conception to death. Rapidly increasing evidence has documented that exposure to endocrine-disrupting chemicals (EDCs), an important part of the exposome, substantially contributes to disease and dysfunction across the life span. To date, however, there have been few studies investigating simultaneous exposure to multiple EDCs in mixtures, although this scenario entails real-life exposures. This paper will present the “Decoding the role of exposome in endocrine health” – DecodExpo project funded by the Science Fund of the Republic of Serbia. The project aims to provide scientific evidence for the role of toxic metal(oid)s mixtures (As, Pb, Hg, Cd, Cr, and Ni) in the development of various endocrine disorders. The project consists of human biomonitoring (HBM), exposome-wide association, and animal studies. Namely, data on blood levels of toxic metal(oid)s in different cohort groups within the Serbian general population were collected (435 participants) and, by performing mathematical modelling, dose-response relationships were determined between certain toxic metals and hormone blood levels. The study protocol for the animal study was chosen based on the results of the HBM study, to address the main challenges in studies on EDCs (non-monotonic dose-response, long-term exposure to low doses, exposure to mixtures of EDCs, sex differences). Furthermore, various endpoints are tested to ensure better insight into molecular, biochemical, and structural changes in the endocrine system. The project revealed an important role of exposure to the investigated toxic metal(oid)s mixture in human endocrine health.Izraz ekspozom opisuje sve uticaje iz životne sredine kojima je pojedinac izložen od začeć a do smrti. Brojni naučni dokazi ukazuju da izloženost hemikalijama koje ometaju rad endokrinog sistema, endokrinim ometačima, važnim komponentama ekspozoma, značajno doprinosi nastanku bolesti i različitim poremećajima tokom životnog veka. Međutim, malo je studija koje istražuju istovremenu izloženost endokrinim ometačima koji su u prirodi prisutni u smešama, iako baš ovaj scenario odslikava izloženost u stvarnom životu. Ovo predavanje daje kratak prikaz projekta „Dekodiranje uloge ekspozoma u endokrinom zdravlju” – DecodExpo koji finansira Fond za nauku Republike Srbije u okviru PROMIS programa. Projekat ima za cilj da pruži naučne dokaze o ulozi smeše toksičnih metal(oid)a (As, Pb, Hg, Cd, Cr, i Ni) u razvoju različitih endokrinih poremeć aja i bolesti. Ovo istraživanje obuhvatilo je studije humanog biomonitoringa (HBM), ispitivanje veze ekspozoma i zdravlje, te studije na životinjama. Naime, prikupljeni su podaci o nivoima toksičnih metala u krvi kod ispitanika iz opšte populacije Srbije (435 učesnika) i matematičkim modeliranjem utvrđeni su odnosi doza-odgovor između nivoa pojedinih metal(oida)a i nivoa hormona u krvi. Protokol studije na životinjama izabran je na osnovu rezultata HBM studije, kako bi se odgovorilo na glavne izazove sa kojima se naučnici suočavaju pri sprovođenju studija o endokrinim ometačima (nemonotoni odnos doza-odgovor, dugotrajno izlaganje niskim dozama, izloženost smešama, razlike među polovima). Pored toga, ispitani su različiti parametri kako bi se obezbedio bolji uvid u molekularne, biohemijske i strukturne promene u endokrinom sistemu. Projekat otkriva važnu ulogu koju izloženost ovoj toksičnoj smeši metal(oid)a ima u ljudskom endokrinom zdravlju.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Toxic effects of prolonged exposure to cadmium and /or polychlorinated biphenyls in rats

tokom prethodnih decenija, kadmijum (Cd), metal bez biološke funkcije, je zbog svoje toksičnosti i sposobnosti bioakumulacije postao predmet brojnih toksikoloških istraživanja...In previous decades, cadmium (Cd), a metal of no bioogical function, has gained attention due to its toxicity and ability to bioaccumulate..

Lekovi endokrini ometači u životnoj sredini ‐ pretnja po zdravlje ljudi i vodene vrste?

The potential negative effects of pharmaceuticals, especially those with endocrine disrupting (ED) properties, present in the environment has been attracting considerable attention in recent years. These pharmaceuticals enter the environment via anthropogenic activities; however, limited data are available on their fate, behaviour, and pathways. Literature data point to adverse ecological effects of these compounds for example, the feminization of aquatic species due to estrogenic compounds present in different aquatic compartments (1). However, there is no consensus on what risk, if any, these compounds pose to human health. Namely, a lot has been discussed about potential estrogenicity of drinking water and the possible contribution of this phenomenon in the observed rise in human reproductive problems. Although estimations pointed to a negligible risk from synthetic estrogens in drinking water (2), these chemicals have been detected in drinking water at nanogram per litre to microgram per litre concentrations which are the concentrations that potentially can produce adverse effects in humans leading to various endocrine disorders (3). Moreover, it must be considered that humans and other organisms are often exposed to various chemicals mixtures of unknown composition and effects, hence, making the assessment based on a single substance sometimes inadequate. It can be concluded that the presence of pharmaceuticals with ED properties is a rather complex phenomena difficult to predict both due to various pathways they can have in the environment and multiplicity of the effects they can have on human health. However, the evidence collected worldwide are confirming their presence in the environment; hence, future studies need to be pointed towards a better understanding of their fate in the environment, effects of low doses of EDCs exposure and endocrine disorders they can trigger in both animals and humans. Special attention should be also given to the identification of the strengths and limitations of current analytical methods used for their detection and further development of treatment technologies for their removal from water. It is evident that in the future, pharmaceutical research should be pointed not only towards the pharmaceuticals’ development, but also towards the development of risk-based models that can predict the potential sources, fate, behaviour and effects of pharmaceuticals once they enter the environment.Potencijalni štetni efekti lekova, posebno onih sa svojstvima endokrinih ometača, prisutnih u životnoj sredini, poslednjih godina privlače sve više pažnje. Ovi lekovi ulaze u životnu sredinu kao posledica antropogenih aktivnosti, ali njihova sudbina i ponašanje, nakon što se nađu u životnoj sredini, i dalje predstavlja nepoznanicu. Literaturni podaci ukazuju na štetne ekološke efekte ovih jedinjenja, na primer, utvrđeno je da estrogena jedinjenja prisutna u različitim vodenim delovima ekosistema izaziva feminizaciju vodenih vrsta (1). Međutim, ne postoji konsenzus o tome kakav rizik ove supstance predstavljaju za ljudsko zdravlje. Naime, mnogo se govori o potencijalnoj estrogenosti vode za piće i mogućoj ulozi ove pojave u uočenom porastu reproduktivnih problema kod ljudi. Iako su procene ukazivale na zanemarljiv rizik od prisustva sintetičkih estrogena u vodi za piće (2), ove hemikalije su ipak izmerene u vodi za pić e u koncentracijama od nekoliko nanograma po litru do nekoliko mikrograma po litru, što su koncentracije koje potencijalno mogu izazvati štetne efekte na ljude i dovesti do različitih endokrinih poremećaja (3). Takođe, mora se uzeti u obzir da su ljudi i drugi organizmi često izloženi različitim smešama hemikalija nepoznatog sastava i efekata, pa je procena zasnovana na jednoj supstanci ponekad neadekvatna. Može se zaključiti da je prisustvo lekova sa svojstvima endokrinih ometača u životnoj sredini prilično kompleksna pojava čije je efekte i posledice teško predvideti kako zbog različitih puteva koje mogu imati u životnoj sredini, tako i zbog višestrukih efekata koje mogu imati na zdravlje ljudi. Međutim, dokazi prikupljeni širom sveta potvrđuju njihovo prisustvo u okruženju, pa je buduće studije potrebno usmeriti ka boljem razumevanju njihove sudbine u životnoj sredini, te efekata izloženosti niskim dozama i potencijalnih endokrinih poremeć aja koje mogu izazvati kako kod životinja, tako i kod ljudi. Posebnu pažnju treba posvetiti i identifikaciji ograničenja postojeć ih analitičkih metoda koje se koriste za utvrđivanje prisustva ovih supstanci u vodi, kao i daljem razvoju tretmana za njihovo uklanjanje iz vode. Očigledno je da bi u budućnosti farmaceutska istraživanja trebalo da budu usmerena ne samo na razvoj farmaceutskih proizvoda, već i na razvoj modela koji mogu predvideti potencijalne izvore, sudbinu, ponašanje i efekte lekova kada se nađu u životnoj sredini.Drugi naučni simpozijum Saveza farmaceutskih udruženja Srbije sa međunarodnim učešćem, 28. 10. 2021. Beogra

Dekodiranje uloge koktela toksičnih metala u endokrinom zdravlju: studija na opštoj populaciji Republike Srbije

The human population is exposed to a vast number of chemicals that are known or suspected endocrine disruptors. Although thresholds are mainly determined concerning a single compound, in real life we are indeed exposed to multiple chemicals in mixtures, i.e. toxic cocktails. The focus of this research was to determine the effects that toxic cocktails of metal(oid)s have on human endocrine health The study involved 435 participants from the general population of Serbia (218 women and 217 men) from five different cohorts (prostate and testes cancer patients, breast cancer and benign breast dysplasia, pancreatic cancer, thyroid, and metabolic disorders patients, and healthy volunteers). Blood cadmium (Cd), lead (Pb), arsenic (As), mercury (Hg), nickel (Ni), and chromium (Cr) levels and serum levels of various hormones were measured in all collected samples. The statistical analyses were performed using the R language while dose-response analysis was performed in PROAST software. Levels estimated to produce the 10% extra risk of testosterone serum levels disturbances were lower than median Hg levels measured in the general population. The obtained results also provided support for the positive association between Pb exposure and higher insulin levels. Similarly, the calculated levels that can produce 10% of extra risk for the disturbances in free thyroxine levels were lower than the medium determined As levels. These findings provide strong support for the endocrine-disrupting effects of the investigated toxic cocktail of metal(oid)s present in our environment and suggest that threshold values for such effects might be lower than those currently implemented.Opšta populacija je svakodnevno izložena velikom broju hemikalija za koje se zna ili se sumnja da su endokrini ometači. Iako se referentne doze uglavnom određuju za pojedinačne hemikalije, u stvarnom životu smo zapravo izloženi hemikalijama u smešama, odnosno toksičnim koktelima. Fokus istraživanja bio je na utvrđivanju uticaja koje toksični koktel metala(oida) imaju na endokrino zdravlje ljudi. Istraživanje je obuhvatilo 435 učesnika iz opšte populacije Republike Srbije (218 žena i 217 muškaraca) iz pet različitih kohorti (pacijenti sa: karcinomima prostate ili testisa, karcinomom dojke ili benignom displazijom dojke, karcinomom pankreasa, poremećajima štitaste žlezde i metaboličkim poremeć ajima, te zdravi dobrovoljci). U prikupljenim uzorcima mereni su nivoi kadmijuma (Cd), olova (Pb), arsena (As), žive (Hg), nikla (Ni) i hroma (Cr) u krvi, kao i nivoi različitih hormona u serumu. Statističke analize su obavljene korišćenjem R statističkog paketa, dok je doza-odgovor analiza vršena u PROAST softveru (RIVM, Holandija). Nivoi za koje se procenjuje da dovode do dodatnog rizika od 10% za nastanak poremeć aja nivoa testosterona u serumu bili su niži od medijane izmerenih nivoa Hg kod ispitanika. Dobijeni rezultati su takođe pružili podršku postojanju veze između nivoa izloženosti Pb i viših nivoa insulina. Slično, izračunati nivoi As u krvi koji mogu da izazovu 10% dodatnog rizika za poremeć aje nivoa slobodnog tiroksina bili su niži od izračunate medijane za nivoe ovog metaloida u krvi. Ovi nalazi pružaju dokaze o endokrinim efektima ispitivanog koktela toksičnih metal(oid)a i sugerišu da bi granične vrednosti za takve efekte mogle biti niže od onih koje se trenutno primenjuju.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Akutna trovanja lekovima

Data collected from poison control centers indicate on millions of poisoning due to drug overdoses and acute drug poisonings represent one of the major causes of deaths. Groups of drugs that most commonly cause acute poisoning include sedatives/hypnotics/antipsychotics (benzodiazepines above all), paracetamol and different combinations with paracetamol, drugs used in the treatment of cardiovascular diseases, opioids, antiepileptics, antihistamines, etc. The trend of drug poisoning is increasing in the world and in our country as well where the most common poisoning are those caused by psychoactive drugs, especially by benzodiazepines. This paper gives a brief overview of the toxicity of antidepressants and antianxiety drugsbenzodiazepines, antipsychotics, antiepileptic-carbamazepine, drugs used in treatment of cardiovascular diseases, antihistaminics, methotrexate, and paracetamol which is a rather significant cause of poisoning despite the fact it is OTC drug.Podaci centara za kontrolu trovanja ukazuju na milionske slučajeve trovanja usled predoziranja lekovima, a akutna trovanja lekovima predstavljaju i jedan od značajnih uzročnika smrtnih ishoda. Grupe lekova koje najčešće dovode do akutnih trovanja su: sedativi/hipnotici/antipsihotici pre svih benzodiazepini, zatim paracetamol i različite kombinacije sa paracetamolom, lekovi koji se koriste u terapiji kardiovaskularnih bolesti, opioidi, antiepileptici, antihistaminici itd. Trend trovanja lekovima raste kako u svetu, tako i u našoj zemlji, gde su najzastupljenija trovanja psihoaktivnim lekovima, posebno benzodiazepinima. U radu je dat kratak prikaz toksičnosti benzodiazepina, antidepresiva, antipsihotika, lekova koji se koriste u terapiji kardiovaskularnih oboljenja, karbamazepina kao predstavnika antiepileptika, kao i nekih drugih lekova koji mogu biti uzročnici trovanja

Osnovni principi izučavanja toksikologije smeša

The vast majority of toxicity studies and risk assessments deals with single chemicals. In reality, however, humans are exposed simultaneously to a large number of chemicals, indicating that exposure assessment and safety evaluation should focus on mixtures rather than on single chemicals. This review on the toxicology of chemical mixtures covers widely varying issues, ranging from the basic concepts and terminology of joint action and interaction of chemicals to different designs for studying the toxicity of mixtures. Literature data indicate that exposure to mixtures which contain low levels of chemicals, levels lower than their no observed adverse effect levels (NOAELs), can exert toxic effects whether their components have similar modes of action or not. Different approaches and examples of studies on priority real-life mixtures, strategy and guidelines for mixture risk assessment as well as challenges ahead are also presented.Većina toksikoloških studija i evaluacija rizika odnose se na pojedinačne hemikalije. Međutim, u realnom okruženju izloženi smo istovremeno velikom broju hemikalija, što ukazuje da bi pri proceni izloženosti i rizika trebalo posmatrati smeše, a ne samo pojedinačne hemikalije. Ovaj pregledni rad o toksikologiji hemijskih smeša pokriva više stavki, od osnovnih koncepata i terminologije zajedničkog dejstva i interakcija hemikalija do različitih modela za ispitivanje toksičnosti smeša. Literaturni podaci ukazuju na činjenicu da izloženost smešama koje sadrže niske nivoe hemikalija, nivoe koji su niži od njihovih doza bez štetnog efekta (No observed adverse effect level - NOAEL) vrednosti, može rezultirati toksičnim odgovorom bez obzira da li komponente smeše imaju ili ne sličan način dejstva. Dati su i različiti pristupi i primeri koncepata i modela procene toksičnosti prioritetnih smeša iz realnog života, strategija i smernice, kao i dalji izazovi

O psihoaktivnim kontrolisanim supstancama - situacija u svetu

Although the psychoactive substances are strictly controlled in most of the countries in the world, their abuse is still very present, as confirmed by the data from the year of 2009 when over 200 million drug addicts were registered. The most commonly used psychoactive controlled substance in the world is cannabis, followed by amphetamine-type stimulants (methamphetamine, amphetamine and ecstasy), opioids (opium, heroin and opioids used in medical purposes), and cocaine. A similar situation is in Europe: most frequently abused substance is cannabis, followed by cocaine and ecstasy and recent epidemiological study conducted in Serbia points to the widespread use of psychoactive substances among young population. Increasingly problem in many countries is the abuse of prescription drugs, particularly painkillers, sedatives and tranquilizers. Prevention of psychoactive substance abuse should be an essential part of the each country strategy in its efforts to protect human health, particularly health of children and young people.Iako se psihoaktivne supstance nalaze pod strogom kontrolom u većini zemalja sveta, njihova zloupotreba je i dalje izuzetno prisutna, što potvrđuju i podaci da je u 2009. godini registrovano preko 200 miliona zavisnika. Najčešće korišćena psihoaktivna kontrolisana supstanca u svetu je kanabis, a slede ga stimulansi tipa amfetamina (metamfetamin, amfetamin i ekstazi), zatim opijati (opijum, heroin i opijati koji se koriste i u medicinske svrhe) i kokain. Slična je situacija i u zemljama Evrope: najčešće zloupotrebljavana supstanca je kanabis, a potom slede kokain i ekstazi, a poslednje epidemiološko istraživanje sprovedeno u Srbiji ukazuje na rasprostranjenost upotrebe psihoaktivnih supstanci među mladima u našoj zemlji. Sve prisutniji problem u velikom broju zemalja sveta predstavlja i zloupotreba lekova, pre svega analgetika, sedativa i trankilizera. Prevencija zloupotrebe psihoaktivnih supstanci predstavlja neophodan deo strategije svake države u njenim nastojanjima da zaštiti zdravlje ljudi, posebno dece i mladih

Xenobiotics, trace metals and genetics in the pathogenesis of tauopathies

Tauopathies are a disease group characterized by either pathological accumulation or release of fragments of hyperphosphorylated tau proteins originating from the central nervous system. The tau hypotheses of Parkinson’s and Alzheimer’s diseases contain a clinically diverse spectrum of tauopathies. Studies of case records of various tauopathies may reveal clinical phenotype characteristics of the disease. In addition, improved understanding of different tauopathies would disclose environmental factors, such as xenobiotics and trace metals, that can precipitate or modify the progression of the disorder. Important for diagnostics and monitoring of these disorders is a further development of adequate biomarkers, including refined neuroimaging, or proteomics. Our goal is to provide an in-depth review of the current literature regarding the pathophysiological roles of tau proteins and the pathogenic factors leading to various tauopathies, with the perspective of future advances in potential therapeutic strategies

The Validity of Benchmark Dose Limit Analysis for Estimating Permissible Accumulation of Cadmium

Cadmium (Cd) is a toxic metal pollutant that accumulates, especially in the proximal tubular epithelial cells of kidneys, where it causes tubular cell injury, cell death and a reduction in glomerular filtration rate (GFR). Diet is the main Cd exposure source in non-occupationally exposed and non-smoking populations. The present study aimed to evaluate the reliability of a tolerable Cd intake of 0.83 μg/kg body weight/day, and its corresponding toxicity threshold level of 5.24 μg/g creatinine. The PROAST software was used to calculate the lower 95% confidence bound of the benchmark dose (BMDL) values of Cd excretion (ECd) associated with injury to kidney tubular cells, a defective tubular reabsorption of filtered proteins, and a reduction in the estimated GFR (eGFR). Data were from 289 males and 445 females, mean age of 48.1 years of which 42.8% were smokers, while 31.7% had hypertension, and 9% had chronic kidney disease (CKD). The BMDL value of ECd associated with kidney tubular cell injury was 0.67 ng/L of filtrate in both men and women. Therefore, an environmental Cd exposure producing ECd of 0.67 ng/L filtrate could be considered as Cd accumulation levels below which renal effects are likely to be negligible. A reduction in eGFR and CKD may follow when ECd rises from 0.67 to 1 ng/L of filtrate. These adverse health effects occur at the body burdens lower than those associated with ECd of 5.24 µg/g creatinine, thereby arguing that current health-guiding values do not provide a sufficient health protection