Genotoxic mixtures and dissimilar action: Concepts for prediction and assessment

This article has been made available through the Brunel Open Access Publishing Fund. This article is distributed under the terms of the creative commons Attribution license which permits any use, distribution, and reproduction in any medium, provided the original author(s)and the source are credited.Combinations of genotoxic agents have frequently been assessed without clear assumptions regarding their expected (additive) mixture effects, often leading to claims of synergisms that might in fact be compatible with additivity. We have shown earlier that the combined effects of chemicals, which induce micronuclei (MN) in the cytokinesis-block micronucleus assay in Chinese hamster ovary-K1 cells by a similar mechanism, were additive according to the concept of concentration addition (CA). Here, we extended these studies and investigated for the first time whether valid additivity expectations can be formulated for MN-inducing chemicals that operate through a variety of mechanisms, including aneugens and clastogens (DNA cross-linkers, topoisomerase II inhibitors, minor groove binders). We expected that their effects should follow the additivity principles of independent action (IA). With two mixtures, one composed of various aneugens (colchicine, flubendazole, vinblastine sulphate, griseofulvin, paclitaxel), and another composed of aneugens and clastogens (flubendazole, doxorubicin, etoposide, melphalan and mitomycin C), we observed mixture effects that fell between the additivity predictions derived from CA and IA. We achieved better agreement between observation and prediction by grouping the chemicals into common assessment groups and using hybrid CA/IA prediction models. The combined effects of four dissimilarly acting compounds (flubendazole, paclitaxel, doxorubicin and melphalan) also fell within CA and IA. Two binary mixtures (flubendazole/paclitaxel and flubendazole/doxorubicin) showed effects in reasonable agreement with IA additivity. Our studies provide a systematic basis for the investigation of mixtures that affect endpoints of relevance to genotoxicity and show that their effects are largely additive.UK Food Standards Agenc

Toksikološka svojstva citrinina

Citrinin (CTN) is a nephrotoxic mycotoxin produced by several fungal strains belonging to the genera Penicillium, Aspergillus, and Monascus. It contaminates various commodities of plant origin, cereals in particular, and is usually found together with another nephrotoxic mycotoxin, ochratoxin A (OTA). These two mycotoxins are believed to be involved in the aetiology of endemic nephropathy. In addition to nephrotoxicity, CTN is also embryocidal and fetotoxic. The genotoxic properties of CTN have been demonstrated with the micronuleus test (MN), but not with single-cell gel electrophoresis. The mechanism of CTN toxicity is not fully understood, especially not whether CTN toxicity and genotoxicity are the consequence of oxidative stress or of increased permeability of mitochondrial membranes. CTN requires complex cellular biotransformation to exert mutagenicity. Compared with other mycotoxins, CTN contamination of food and feed is rather scarce. However, it is reasonable to believe that humans are much more frequently exposed to CTN than generally accepted, because it is produced by the same moulds as OTA, which is a common contaminant of human food all over the world. At present, there are no specifi c regulations either in Croatia or in the European Union concerning CTN in any kind of commodity.Citrinin (CTN) nefrotoksičan je mikotoksin koji proizvode različiti sojevi plijesni iz rodova Penicillium, Aspergillus i Monascus. CTN se može naći u različitim namirnicama biljnog podrijetla, osobito u žitaricama i obično se nalazi zajedno s drugim nefrotoksičnim mikotoksinom, okratoksinom A (OTA). Pretpostavlja se da je izloženost ovim mikotoksinima povezana s nastankom endemske nefropatije. Osim što je nefrotoksičan, CTN je još i embricidan i fetotoksičan. Na genotoksičnost citrinina upućuje pozitivan mikronukleusni test na različitim vrstama staničnih kultura, iako je kometski test negativan. Mutagenost CTN-a očituje se na različitim vrstama stanica samo ako se pridodaju stanični aktivatori kao npr. S9-mix. Mehanizam toksičnosti CTN-a nije potpuno razjašnjen pa još uvijek traje znanstvena rasprava je li njegova toksičnost i genotoksičnost posljedica oksidacijskog stresa ili povećane permeabilnosti mitohondrijskih membrana. U dostupnoj literaturi podaci o kontaminiranosti hrane i krmiva ovim mikotoksinom mnogo su rjeđi od onih za druge mikotoksine. Može se pretpostaviti da su ljudi često izloženi ovom mikotoksinu zato što ga proizvode iste plijesni koje proizvode i OTA, a one kontaminiraju hranu po cijelom svijetu. U Hrvatskoj i u zemljama Europske Unije ne postoje zakonske odredbe o dopuštenim granicama CTN-a u bilo kojoj vrsti hrane

MHD Mixed Convection Nanofluid Flow over Convectively Heated Nonlinear due to an Extending Surface with Soret Effect

The aim of this paper is to investigate the flow of MHD mixed convection nanofluid flow under nonlinear heated due to an extending surface. The transfer of heat in nanofluid subject to a magnetic field and boundary conditions of convective is studied to obtain the physical meaning of the convection phenomenon. The governing partial differential equations (PDEs) of the boundary layer are reduced to ordinary differential equations (ODEs) considering a technique of the transformation of similarity. The transformed equations are solved numerically considering the technique of an efficient numerical shooting applying the Runge–Kutta technique scheme from the fourth-fifth order. The results corresponding to the dimensionless speed, temperature, concentration profiles, and the Nusselt number reduced, and the Sherwood numbers are presented by figures to display the physical meaning of the phenomena. A comparison has been made between the obtained results with the previous results obtained by others and agrees with them if the new parameters vanish. The results obtained indicate the impacts of the nondimensional governing parameters, namely, magnetic field parameter M, Soret number Sr, heat source λ, thermal buoyancy parameterλT , and solutal buoyancy parameterλC on the flow, temperature, and concentration profiles being discussed and presented graphically

Predication and Photon Statistics of a Three-Level System in the Photon Added Negative Binomial Distribution

Statistical and artificial neural network models are applied to forecast the quantum scheme of a three-level atomic system (3LAS) and field, initially following a photon added negative binomial distribution (PANBD). The Mandel parameter is used to detect the photon statistics of a radiation field. Explicit forms of the PANBD are given. The prediction of the Mandel parameter, atomic probability of the 3LAS in the upper state, and von Neumann entropy are obtained using time series and artificial neural network methods. The influence of probability success photons and the number of added photons to the NBD are examined. The total density matrix is used to compute and analyze the time evolution of the initial photonic negative binomial probability distribution that governs the 3LAS–field photon entanglement behavior. It is shown that the statistical quantities are strongly affected by probability success photons and the number of added photons to the NBD. Also, the prediction of quantum entropy is achieved by the time series and neural network

Generalized Type-I Hybrid Censoring Scheme in Estimation Competing Risks Chen Lifetime Populations

Different types of censoring scheme are investigated; however, statistical inference on censoring scheme which can save the ideal test time and the minimum number of failures is needed. The generalized type-I hybrid censoring scheme (GHCS) solves this problem. Competing the risk models under the GHCS when time to failure has Chen lifetime distribution (CD) is adopted in this research with consideration of only two cases of failure. Partially step-stress accelerated life tests (ALTs) are applied to obtain enough failure times in a small period to achieve a highly reliable product. The problem of parameter estimation under maximum likelihood (ML) and Bayes methods is discussed. The asymptotic confidence interval as well as the Bayes credible interval is constructed. The validity of theoretical results is assessed and compared through simulation study. Finally, brief comments are reported to describe the behaviour of the estimation results