Newly synthesized derivatives with a thiosemicarbazide group reduce the viability of cancer cell lines. Acute toxicity assessment in Zebrafish (Danio rerio) early life stages.

Due to the variability and ability of tumor to mutate, as well as the heterogeneity of tumor tissue, such drugs are sought that would act selectively and multidirectionally on the cancer cell. Therefore, two newly synthesized semicarbazide structured substances were evaluated for anticancer properties in our study: 1a and 1b. In order to evaluate the cytotoxicity and selectivity of the tested compounds, MTT and Neutral Red uptake assay on cell lines (HEK293, LN229, 769-P, HepG2 and NCI-H1563) and cell cycle analysis were performed. Acute toxicity and cardiotoxicity were also evaluated in the zebrafish model. The tested compounds (1a, 1b) showed cytotoxic activity, with the greatest selectivity noted against the glioblastoma multiforme cell line (LN229). However, compound 1b showed stronger selective activity than 1a. Both of compounds were shown to significantly affect the M phase of the cell cycle. Whereas, the conducted toxicological examination of newly synthesized thiosemicarbazide derivates showed, that direct exposition of Danio rerio embryos to compound 1a, but not 1b, causes a concentration-dependent increase in developmental malformations, indicating possible teratogenic effects.

A new consensus on reconciling fire safety with environmental & health impacts of chemical flame retardants.

Flame retardants are chemical substances that are intended to mitigate fire safety risks posed by a range of goods including furniture, electronics, and building insulation. There are growing concerns about their effectiveness in ensuring fire safety and the potential harms they pose to human health and the environment. In response to these concerns, on 13 June 2022, a roundtable of experts was convened by the UKRI Six Clean Air Strategic Priorities Fund programme 7. The meeting produced a Consensus Statement that summarises the issues around the use of flame retardants, laying out a series of policy recommendations that should lead to more effective fire safety measures and reduce the human and environmental health risks posed by these potentially toxic chemicals.

Cancer incidence amongst UK firefighters.

Firefighters suffer an increased risk of cancer from exposures to chemicals released from fires. Our earlier research has found that fire toxicants not only remain on firefighters' PPE, but are also tracked back to fire stations. The UK Firefighter Contamination Survey assesses firefighters' risk of developing cancer due to occupational exposure to fire toxins. Over 4% of surveyed firefighters were found to have a cancer diagnosis, with the age-specific cancer rate up to 323% higher (35-39 year olds) than that of the general population. Firefighters who had served ≥ 15 years were 1.7 times more likely to develop cancer than those who had served less time. Firefighters were at least twice as likely to be diagnosed with cancer if they noticed soot in their nose/throat (odds ratio (OR) = 2.0, 1.1-3.5), or remained in their PPE for more than four hours after attending a fire incident (OR = 2.3, 1.1-5.2). Also associated with an increased likelihood of cancer was: eating while wearing PPE (OR = 1.8, 1.2-2.7); failing to store clean/dirty PPE separately (OR = 1.3, 1.0-1.7); working in a station that smells of fire (OR = 1.3, 1.0-1.8) or not having designated (separated) clean and dirty areas (OR = 1.4, 1.1-1.7); using an on-site washing machine to launder fire hoods (OR = 1.3, 1.0-1.7); feeling that cleaning is not taken seriously at work (OR = 1.5, 1.2-2.0).

Culture and awareness of occupational health risks amongst UK firefighters.

Firefighters are exposed to toxic chemicals not only from the fire incidents they attend, but also from their contaminated station and/or personal protective equipment (PPE). Little is currently known about firefighters' awareness, attitudes, and behaviours towards contaminants which was assessed in the UK firefighter contamination survey. Results revealed that lack of training on fire effluents and their health outcomes are strongly associated with increased fire smoke/contaminant exposure. Notably, untrained firefighters were at least twice as likely to: never clean personal protective equipment (PPE) (Crude Odds Ratio, OR 2.0, 1.5-2.7), infrequently send their PPE for professional cleaning (OR 2.0, 1.6-2.4), remain in the workwear (t-shirt etc.) worn while attending a fire incident (OR up to 3.6, 2.3-5.6), and indicate that cleaning at fire stations is not taken seriously (OR 2.4, 2.2-2.6). Firefighters personally viewing contamination as a "badge of honour" (BoH) were at least twice as likely to: remain in contaminated PPE after fire incidents (OR 2.3, 1.4-3.9), eat with sooty hands (OR 2.2, 1.9-2.5), notice soot in the nose/throat (OR 3.7, 2.7-5.2), and smell fire smoke on the body for more than a day after incidents (OR 2.0, 1.6-2.4). They were also more likely to indicate that cleaning at fire stations is not taken seriously (OR 2.5, 2.2-2.9) and that fire stations smell of smoke always/most of the time (OR 2.3, 2.0-2.6). Strong links were also found between belief in the BoH and never cleaning PPE (OR 1.9, 1.4-2.7), and eating while wearing contaminated PPE (OR 1.8, 1.5-2.2).

Contamination of UK firefighters personal protective equipment and workplaces.

Firefighters' personal protective equipment (PPE) is a potential source of chronic exposure to toxic contaminants commonly released from fires. These contaminants have also been found in fire stations. However, little research characterises the routes via which fire contaminants travel back to fire stations. The UK Firefighter Contamination Survey provides information on firefighters' PPE provision, decontamination, and storage practices. All serving UK firefighters were eligible to take part in the survey, which comprised 64 questions. A total of 10,649 responses were included for analysis, accounting for roughly 24% of the UK's firefighting workforce. Results revealed that most firefighters (84%) de-robe contaminated PPE/workwear after re-entering the appliance cab. There was a significant decreasing tendency to send PPE for cleaning after every incident with increasing seniority of role, length of service, and fire attendance frequency. Around one third of firefighters cleaned PPE after every incident. A number of issues were linked to external professional cleaning services, e.g. shrinkage, fit, turn-around time, and stock of reserve/pooled PPE. PPE storage was found to be a potential source of cross contamination, with almost half of firefighters (45%) indicating clean and dirty PPE is not stored separately. More than half of firefighters (57%) stored fire gloves (an item sent for professional decontamination by only 19% of firefighters, and never cleaned by 20%) within other items of PPE such as helmets, boots and tunic/trouser pockets. The survey's results can be used to target gaps in decontamination measures within UK Fire and Rescue Services.

Mental health of UK firefighters.

Exposure to trauma, high-stress situations, and disrupted sleep are well known risk factors affecting firefighters' mental health. Little is known about the association between firefighters' exposure to fire contaminants and mental health disorders. The UK Firefighter Contamination Survey assessed firefighters' health and capacity for occupational exposure to contaminants. Participants were invited to anonymously complete its 64 questions online. Logistic regression analyses assessed the associations between self-reported mental health disorders and proxies of contaminant exposure. Results found that firefighters who notice soot in their nose/throat for more than a day after attending fires (Odds Ratio (OR) = 1.8, 1.4-2.4), and those who remain in their personal protective equipment (PPE) for over 4 h after fires (OR = 1.9, 1.2-3.1), were nearly twice as likely to report mental health disorders. Significantly increased odds ratios for all three outcomes of interest (anxiety, depression and/or any mental health disorders) were also found among firefighters who take PPE home to clean. Sleeping problems were reported by 61% of firefighters. These firefighters were 4.2 times more likely to report any mental health disorder (OR = 4.2, 3.7-4.9), 2.9 times more likely to report anxiety (OR = 2.9, 2.4-3.5) and 2.3 times more likely to report depression (OR = 2.3, 1.9-2.8) when compared to firefighters who did not report sleep issues. Effective decontamination measures within UK Fire and Rescue Services, together with firefighters' wellness, may play a crucial role in protecting firefighters' mental health.

Evaluation of developmental toxicity in zebrafish embryos and antiproliferative potential against human tumor cell lines of new derivatives containing 4-nitrophenyl group.

The aim of the studies was to evaluate the antiproliferative potential against human tumor cell lines of newly synthetized derivatives containing 4-nitrophenyl group, as well as its impact on developmental toxicity in zebrafish model. We selected 1-(4-nitrobenzoyl)-4-ethylsemicarbazide (APS-1) and 1-[(4-nitrophenyl)acetyl]-4-hexyl-thiosemicarbazide (APS-18) for research. The antiproliferative properties of semicarbazide derivatives were assessed against human cancer cell lines derived from hepatocellular adenocarcinoma (HepG2), renal cell carcinoma (769-P), non-small cell lung cancer (NCI-H1563) and glioblastoma multiforme (LN229) in comparison to the physiological human embryonic kidney (HEK-293) cell line. The influence of the tested substances on the cell cycle and apoptosis was also evaluated. Fish embryo acute toxicity test (FET) was performed based on OECD Guidelines (Test No. 236), and was carried out for the first 5 days post fertilization. The following concentrations of APS-1 and APS-18 were tested: 125-2000 µM and 0.125-1000 µM, respectively. The presented studies on the antiproliferative properties of the new semicarbazide derivatives showed that the compounds APS-1 and APS-18 reduce the viability of human tumor lines. Particularly noteworthy is the strong and selective antiproliferative activity of APS-18 against all neoplastic cell lines, in particular against glioblastoma. Against this tumor line, the compound APS-1 showed an effective inhibitory effect. In the FET we noted that the direct exposure of zebrafish embryos to APS-1 and APS-18 in used range of concentration did not cause morphological abnormalities, including cardiotoxicity. On basis of obtained outcomes it could be concluded that APS-1 and APS-18 may constitute models for further research, design and synthesis of new, safer drugs with more favorable anticancer properties.

Antioxidant Activity of 1,2,4-Triazole and its Derivatives: A Mini-Review.

The information about the presence of free radicals in biological materials was given for the first time about 70 years ago. Since then, numerous scientific studies have been conducted and the science of free radicals was introduced. Today we know that free radicals are by-products of enzymatic reactions occurring in the organism. They are produced during endogenous processes such as cell respiration, phagocytosis, biosynthesis, catalysis, and biotransformation. They can also be produced by exogenous processes (radiation, sunlight, heavy metals, bacteria, fungi, protozoa, and viruses). The overproduction of free radicals affects the aging processes, Oxidative Stress (OS) and takes part in the pathogenesis of various diseases. Among them are cancer, rheumatoid arthritis, neurodegenerative diseases: Alzheimer and Parkinson, pulmonary diseases, atherosclerosis, and DNA damage. Compounds with antioxidant activity are very important nowadays because they allow organisms to keep a balance between the production of free radicals and the speed of their neutralization in the body. Next to the natural antioxidants (flavonoids, carotenoids, vitamins, etc.), synthetic ones are also of great importance. Among synthetic compounds with antioxidant activity are 1,2,4-triazoles and their derivatives. 1,2,4-Triazoles are heterocyclic compounds with three nitrogen atoms. Due to a broad spectrum of biological activities, these derivatives have been of interest to scientists for many years. Some of them are also used as drugs. The finding of new synthetic compounds with antioxidant features in the triazole group has become an important problem of medicinal chemistry.

Smoke toxicity of rainscreen façades.

The toxic smoke production of four rainscreen façade systems were compared during large-scale fire performance testing on a reduced height BS 8414 test wall. Systems comprising 'non-combustible' aluminium composite material (ACM) with polyisocyanurate (PIR), phenolic foam (PF) and stone wool (SW) insulation, and polyethylene-filled ACM with PIR insulation were tested. Smoke toxicity was measured by sampling gases at two points - the exhaust duct of the main test room and an additional 'kitchen vent', which connects the rainscreen cavity to an occupied area. Although the toxicity of the smoke was similar for the three insulation products with non-combustible ACM, the toxicity of the smoke flowing from the burning cavity through the kitchen vent was greater by factors of 40 and 17 for PIR and PF insulation respectively, when compared to SW. Occupants sheltering in a room connected to the vent are predicted to collapse, and then inhale a lethal concentration of asphyxiant gases. This is the first report quantifying fire conditions within the cavity and assessing smoke toxicity within a rainscreen façade cavity.

Burning behaviour of rainscreen façades.

Four reduced-height (5 m) BS 8414-1 façade flammability tests were conducted, three having mineral-filled aluminium composite material (ACM-A2) with polyisocyanurate (PIR) and phenolic (PF) foam and stone wool (SW) insulation, the fourth having polyethylene-filled ACM (ACM-PE) with PIR insulation. Each façade was constructed from a commercial façade engineer's design, and built by practising façade installers. The ACM-PE/PIR façade burnt so ferociously it was extinguished after 13.5 min, for safety. The three ACM-A2 cladding panels lost their structural integrity, and melted away from the test wall, whereupon around 40% of both the combustible PIR and PF insulation burnt and contributed to the fire spread. This demonstrates why all façade products must be non-combustible, not just the outer panels. For the three ACM-A2 tests, while the temperature in front of the cavity was independent of the insulation, the temperatures within it varied greatly, depending on the insulation. The system using PF/A2 allowed fire to break through to the cavity first, as seen by a sharp increase in temperature after 17 min. For PIR/A2, the temperature increased sharply at 22 minutes, as the panel started to fall away from the wall. For SW/A2, no rapid temperature rise was observed.

New Application of 1,2,4-Triazole Derivatives as Antitubercular Agents. Structure, In Vitro Screening and Docking Studies.

A series of 1,2,4-triazole derivatives were synthesized and assigned as potential anti-tuberculosis substances. The molecular and crystal structures for the model compounds C1, C12, and C13 were determined using X-ray analysis. The X-ray investigation confirmed the synthesis pathway and the assumed molecular structures for analyzed 1,2,4-triazol-5-thione derivatives. The conformational preferences resulting from rotational degrees of freedom of the 1,2,4-triazole ring substituents were characterized. The lipophilicity (logP) and electronic parameters as the energy of frontier orbitals, dipole moments, NBO net charge distribution on the atoms, and electrostatic potential distribution for all structures were calculated at AM1 and DFT/B3LYP/6-311++G(d,p) level. The in vitro test was done against M. tuberculosis H37Ra, M. phlei, M. smegmatis, and M. timereck. The obtained results clearly confirmed the antituberculosis potential of compound C4, which turned out to be the most active against Mycobacterium H37Ra (MIC = 0.976 µg/mL), Mycobaterium pheli (MIC = 7.81 µg/mL) and Mycobacerium timereck (62.6 µg/mL). Satisfactory results were obtained with compounds C8, C11, C14 versus Myc. H37Ra, Myc. pheli, Myc. timereck (MIC = 31.25-62.5 µg/mL). The molecular docking studies were carried out for all investigated compounds using the Mycobacterium tuberculosis cytochrome P450 CYP121 enzyme as molecular a target connected with antimycobacterial activity.

1,2,4-Triazolin-5-thione derivatives with anticancer activity as CK1γ kinase inhibitors.

The optimization and synthesis of new CK2 and CK1 inhibitors are the basis for the development of new therapeutic strategies for the treatment of cancer and neurodegenerative disorders associated with overexpression and abnormal functioning of these enzymes. Triazole derivatives appear to be especially interesting as potential kinase inhibitors. In this context we synthesized a series of 1,2,4-triazolin-5-thione derivatives as CK1γ kinase inhibitors. The antiproliferative activity of synthesized compounds was assessed against cancer cells: human lung adenocarcinoma (A549), human hepatoma (HepG2), and human breast adenocarcinoma (MCF-7). Compound 1 exhibited antiproliferative potency against A549 cancer cells and was characterized by a selective antiproliferative effect. Additionally, this compound has high apoptotic activity against A549, HepG2, MCF-7 cells and induced only slight amount of necrotic cells in these cell lines. In order to decipher the mechanism of anticancer activity of the studied compounds PASS software was used and these compounds were assayed for the inhibition of CK1γ and CK2α kinases. The reported series of 1,2,4-triazolin-5-thiones inhibits CK1γ and CK2α kinases in micromolar range. The most active compound shows activity against isoform γ3 which at concentration of 50 µM reduced the kinase activity by 69% while at 100 µM by 80%. CK2α was found to be less susceptible to the effects of the triazoles tested, as the reduction in kinase activity by 29% was observed for compound 15, and by 27% for compound 1 only at the concentration of 100 µM. The inhibition of CK1γ and CK2α kinases was rationalized using molecular docking.

Environmental contamination following the Grenfell Tower fire.

The Grenfell Tower fire in central London, started within a flat, engulfed the whole 24 storey building in flames, killed 72 people and spread toxic effluent via the plume and particulate deposits. Soil samples from 6 locations up to 1,2 km from the Tower, together with semi-burnt fire debris and char samples, were collected 1 and 6 months after the fire. Additionally, dust samples and condensates were collected from a flat 160 m away from the Tower after 17 months. Samples were analysed for common potentially toxic components of fire effluents and synthetic vitreous fibres. Samples collected within 140 m of the Tower showed, amongst other toxicants, polychlorinated dibenzo-p-dioxin concentrations 60 times greater than UK urban reference soil levels; benzene levels were 40 times greater; levels of 6 key polycyclic aromatic hydrocarbons (PAHs) were approximately 160 times greater. PAHs levels are approximately 20 times greater than those reported from nearby Hyde Park before the fire. To explain the presence of these pyrogenic contaminants char and partially burnt debris were also collected and analysed. Benzene, PAHs, isocyanates and phosphorus flame retardants were found. Hydrogen cyanide and synthetic vitreous fibres were present in both soil and debris. Particulate and pyrogenic contamination in the immediate vicinity is clearly evident, and may have leached out of fire debris, char and dust. Further analysis of the area around the Tower is necessary to understand potential health risks.

Synthesis and Antioxidant Activity of New Norcantharidin Analogs.

New norcantharidin analogs were designed and obtained as compounds with biological activity. As a starting material, exo-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid anhydride was used. Three groups of compounds: dicarboximides, triazoles and thiazolidines were obtained in multistep reactions. The 1 H- and 13 C-NMR spectra were used to confirm the structures of all obtained products and they were in agreement with the proposed structure of substances. All derivatives were screened for their antioxidant activity. The most promising group was dicarboximides (1-4, 6). Derivatives 2-4 displayed antioxidant activity with EC50 =7.75-10.89 µg/ml, which may be comparable to strong antioxidant Trolox (EC50 =6.13 µg/ml). Excellent activity with EC50 =10.75 µg/ml also presented norcantharidin analog with 1,2,4-triazole system (12).

Fire behaviour of modern façade materials - Understanding the Grenfell Tower fire.

The 2017 Grenfell Tower fire spread rapidly around the combustible façade system on the outside of the building, killing 72 people. We used a range of micro- and bench-scale methods to understand the fire behaviour of different types of façade product, including those used on the Tower, in order to explain the speed, ferocity and lethality of the fire. Compared to the least flammable panels, polyethylene-aluminium composites showed 55x greater peak heat release rates (pHRR) and 70x greater total heat release (THR), while widely-used high-pressure laminate panels showed 25x greater pHRR and 115x greater THR. Compared to the least combustible insulation products, polyisocyanurate foam showed 16x greater pHRR and 35x greater THR, while phenolic foam showed 9x greater pHRR and 48x greater THR. A few burning drips of polyethylene from the panelling are enough to ignite the foam insulation, providing a novel explanation for rapid flame-spread within the facade. Smoke from polyisocyanurates was 15x, and phenolics 5x more toxic than from mineral wool insulation. 1 kg of burning polyisocyanurate insulation is sufficient to fill a 50m3 room with an incapacitating and ultimately lethal effluent. Simple, additive models are proposed, which provide the same rank order as BS8414 large-scale regulatory tests.

Stability of Isocyanates Sampled in Fire Smokes.

Inhalation of airborne isocyanates is associated with acute asthma attacks and inflammation in the respiratory tract as well as cancer. These highly reactive compounds are used as monomers in various applications such as foams for insulation materials and upholstery furniture and are therefore commonly found in fire smoke from insulation materials, such as rigid polyisocyanurate (PIR) foams. Consequently, there is an increasing concern regarding the potential adverse health effects they may cause during this type of exposure.The aim of this study was to investigate the stability of generated isocyanates from aerobic pyrolysis of PIR after sampling in the derivatization solution as well as after sample preparation to establish the optimal storage conditions and rate of degradation. Both airborne and particle-bound isocyanates were collected, using dibutylamine as derivatization agent in a midget impinger and impregnated filter after the impinger. The rapid degradation of the generated isocyanates after sampling emphasizes the need for a prompt sample preparation and analysis, in particular for the collected mono-isocyanates, as the concentration decreased by 50% within 4-8 h.

Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Elevated Cancer Incidence in Firefighters.

Cancer incidence appears to be higher amongst firefighters compared to the general population. Given that many cancers have an environmental component, their occupational exposure to products of carbon combustion such as polycyclic aromatic hydrocarbons (PAHs) is of concern. This is the first UK study identifying firefighters exposure to PAH carcinogens. Wipe samples were collected from skin (jaw, neck, hands), personal protective equipment of firefighters, and work environment (offices, fire stations and engines) in two UK Fire and Rescue Service Stations. Levels of 16 US Environmental Protection Agency (EPA) PAHs were quantified together with more potent carcinogens: 7,12-dimethylbenzo[a]anthracene, and 3-methylcholanthrene (3-MCA) (12 months post-initial testing). Cancer slope factors, used to estimate cancer risk, indicate a markedly elevated risk. PAH carcinogens including benzo[a]pyrene (B[a]P), 3-MCA, and 7,12-dimethylbenz[a]anthracene PAHs were determined on body surfaces (e.g., hands, throat), on PPE including helmets and clothing, and on work surfaces. The main exposure route would appear to be via skin absorption. These results suggest an urgent need to monitor exposures to firefighters in their occupational setting and conduct long-term follow-up regarding their health status.