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The review article of Leist and colleagues about adverse outcome pathways (AOPs) has stimulated a fruitful discussion and belongs to the most cited articles of our journal published in the past years (Leist et al. [19]). 5 Chaudhari U, Nemade H, Wagh V. Identification of genomic biomarkers for anthracycline-induced cardiotoxicity in human iPSC-derived cardiomyocytes: an in vitro repeated exposure toxicity approach for safety assessment. Human pluripotent stem cell based developmental toxicity assays for chemical safety screening and systems biology data generation. [Extracted from the article]

Apoptosis can be induced by extrinsic death receptor-mediated pathways (Yuan [16]; Reed [12]; Chaudhary et al. [2]) where caspase 8 acts as downstream executioner of cell death (Alnemri et al. [1]; Li et al. [10]; Desbarats and Newell [4]; Yuan [16]). This has been explained by inhibition of apoptosis in immune cells, leading to stronger infiltration of mononuclear cells into the liver tissue and to immune cell-mediated liver damage. [Extracted from the article]

Abstract: Boric acid and sodium borates have been considered as being “toxic to reproduction and development”, following results of animal studies with high doses. However unfavorable effects of boron exposure on reproduction and development have not been proved in epidemiological studies so far. The aim of the present study was to investigate the reproductive toxicity indicators in highly exposed workers employed in a boric acid production plant in Bandırma, Turkey. Two hundred and four workers participated in this study. The mean blood boron concentration of the high exposure group of workers was 223.89±69.49 (152.82–454.02)ng/g. Unfavorable effects of boron exposure on the reproductive toxicity indicators were not observed. [Copyright &y& Elsevier]

The article discusses various reports published within the issue, including one by Gerhard Triebig regarding the knowledge on chemosensory systems and another by Richard Doty on the adversity of sensory irritations.

A review of the article that discusses monitoring of food contaminations and contaminants using biomarkers is presented

The "totality" of the human exposure is conceived to encompass life-associated endogenous and exogenous aggregate exposures. Process-related contaminants (PRCs) are not only formed in foods by heat processing, but also occur endogenously in the organism as physiological components of energy metabolism, potentially also generated by the human microbiome. To arrive at a comprehensive risk assessment, it is necessary to understand the contribution of in vivo background occurrence as compared to the ingestion from exogenous sources. Hence, this review provides an overview of the knowledge on the contribution of endogenous exposure to the overall exposure to putative genotoxic food contaminants, namely ethanol, acetaldehyde, formaldehyde, acrylamide, acrolein, α,β-unsaturated alkenals, glycation compounds, N-nitroso compounds, ethylene oxide, furans, 2- and 3-MCPD, and glycidyl esters. The evidence discussed herein allows to conclude that endogenous formation of some contaminants appears to contribute substantially to the exposome. This is of critical importance for risk assessment in the cases where endogenous exposure is suspected to outweigh the exogenous one (e.g. formaldehyde and acrolein). [ABSTRACT FROM AUTHOR]

The development of hepatic enzyme-altered foci (ATPase, GGTase) was investigated after dosing vinyl acetate (200 and 400 mg/kg per day, orally) to newborn rats for 3 weeks, with or without subsequent promotion by phenobarbital. Whereas the structurally related compounds vinyl carbamate and vinyl chloride induce enzyme-altered foci under comparable experimental conditions, no foci were observed in vinyl acetatetreated animals at the age of 14 weeks. This is consistent with investigations on metabolism and pharmacokinetics of vinyl acetate which show that this compound, after entering the organism, is immediately split by blood esterases and thus may not be available for epoxidation to an ultimately carcinogenic metabolite. [ABSTRACT FROM PUBLISHER]

The article presents Satirical contributions in toxicology including provides of a platform for distinguished toxicologists to share opinions and wisdom.

A letter to the editor is presented in response to the article "N-acetyltransferase 2 phenotype, occupation, and bladder cancer risk: results from the EPIC cohort" by B. Pesch and colleagues which appeared in a 2013 issue of the journal "Cancer Epidemiology, Biomarkers & Prevention."

Information regarding the Round Table Discussion during the International Congress on Toxicology, which was held in Barcelona, Spain on July 19-23, 2010 is presented. Topics include the scientific quality of the manuscripts on toxicology, the difficulties faced during the process of peer review and plagiarism. The symposium featured several editors including Allan Boobis, Wolfgang Dekant and Jan G. Hengstler.

An introduction to the journal is presented in which the authors discuss issues related to new documentation on the carcinogenic effects of formaldehyde.

In this article the authors discuss the benefits of modern toxicology. According to the authors, modern toxicology has been successful in the identification of gene expression patterns that are associated with specific toxic mechanisms. They refer to the classification algorithm differentiating between genotoxic and non-genotoxic liver carcinogens. They also state that in recent years, protease inhibitors have contributed to the reduction of the morbidity and mortality caused by AIDS.

The author reflects on the applications and advancements in the field of oxidative stress and hepatic carcinogenesis. He discusses that high consumption of alcohol remains the cause for non-alcoholic fatty liver diseases in developed countries. Referring to an article by Kawai M. Saegusa and colleagues, he explains that even without oxidative DNA damage, effects like activation of cell growth are noticed. He also discusses the causes of liver tumor promotion.

The author reflects on the toxic effects of arsenic. The author states besides arsenic's carcinogenicity, arsenic impact some functions in the immune system, lessened glucose tolerance. The author says that some effects are oxidative mycordial, induction of changes in DNA methylation patterns, liver injury and inhibition of neurite growth.

The article presents the authors' comments on the article about the role of oxidative stress in alcohol-induced liver injury, by Arthur I. Cederbaum and others in this issue of the periodical. The authors say that the generation of oxidative stress is the most important mechanisms causing alcoholic liver disease, and it is a cutting edge topic of their journal.

The discusses the report by Dr. Li Phing Liew and Dr. Chris J. Norbury concerning tolomere maintenance published within the issue.

The author reflects on the strategy in toxicity estimation. He argues that estimating toxicity in low doses by connecting the high level risk and determining the high doses' risks may effect unreasonable conclusions. He states that a genotoxic carcinogen's single molecule is not sufficient in transforming a healthy cell to a cancer cell. He mentions that the historical and scientific foundations of how low doses become the carcinogenic risk assessment's basis is reviewed by Ed Calabrese.

The article presents information on the International symposium on genotoxic and carcinogenic thresholds by the Japanese National Institute of Health Science and the Japan Bioassay Research Center in Tokyo. The symposium discussed ingredients of food, heterocyclic amines, nitrosamines or mycotoxins. It revealed that the usage of novel toxicological concepts within the regulatory context requires an intensive and well-founded dialogue between stakeholders, scientists and authorities.

The author reflects on the induction and control of oxidative stress. He examines oxidative stress as a mechanism of non-genotoxic carcinogenesis. He also explores RNA expression signatures as a response to oxidative stress. He then looks into oxidative stress in alcohol toxicity, focusing on the role of diacetyl.

Introduces a series of articles which deals with toxicology in drugs presented at the 9th International Congress of Toxicology held on July 8-12, 2001 in Brisbane, Queensland hosted by the Australasian Society of Clinical and Experimental Pharmacologists & Toxicologists and the International Union of Toxicology.

The article presents the new Editorial Manager System which will be the web site for online manuscript submissions to the journal.

The article offers information on an International symposium titled "Benzene 2009: Health effects and mechanism of bone marrow toxicity," to be held in Munich/Germany from September 7-11, 2009.

Cigarette smoking is a risk factor for bladder cancer. Since urothelial cells express phase I and II enzymes these cells are able to metabolize precarcinogens into DNA reactive intermediates. Cigarette smoke is a complex mixture containing at least 80 known carcinogens. In this context especially aromatic amines and polycyclic aromatic hydrocarbons are discussed as being responsible for bladder-carcinogenicity. Cell cultures of primary porcine urinary bladder epithelial cells (PUBEC) have been useful models for studies on bladder-specific effects. These cells are metabolically competent and found to be a valuable tool for examining effects of cigarette smoke constituents. In the present study PUBEC were utilized to investigate the effects of the complex mixture cigarette smoke condensate total particulate matter (CSC TPM) with emphasis on induction of cytochrome P-450 1A1 (CYP1A1) and genotoxic effects. CYP1A1 induction was investigated by Western blot and flow cytometry. The most pronounced effects were found after 24 h of incubation with 1–10 μg/ml CSC TPM. Maximal induction was observed at 5 μg/ml by flow cytometry and at 10 μg/ml by Western blot analysis. Genotoxic effects were investigated by means of alkaline single-cell gel electrophoresis (“comet assay”) with and without the use of the DNA repair enzyme formamidopyrimidine-DNA glycosylase (Fpg) and the micronucleus (MN) test. A numerical concentration-dependent increase in Fpg-sensitive sites indicating oxidative DNA damage and a quantitative rise in MN formation were noted. The CSC utilized in this study contained low amounts of benzo[a]pyrene, 4-aminobiphenyl, and 2-naphthylamine. With regard to the observed CYP1A1 induction, these substances cannot explain the CYP1A1 inducing effect of CSC TPM. It is possible that other compounds within CSC TPM contribute to CYP1A1 induction in our cellular model. [ABSTRACT FROM PUBLISHER]

In 187 bladder cancer cases reported to the employers' liability insurance association in Germany as suspected cases of an occupational disease produced by aromatic amines, N- acetyltransferase-2 (NAT2) activity status, occupational exposure data, period of latency, and clinical parameters were determined. In 83 out of 187 cases surveyed within the period 1991-1999, the NAT2 acetylator status was investigated by determining the molar ratio of an acetylated and a nonacetylated caffeine metabolite in urine (phenotyping) and/or by NAT2 genotyping according to standard polymerase chain reaction (PCR) protocol. The proportion of slow NAT2 acetylators in the surveyed 83 bladder cancer cases was 67%. In the entire group of surveyed 187 cases, mean duration of exposure was 17.6 yr and mean period of latency was 34.7 yr. Occupational exposures to potential bladder carcinogens were observed in 73 occupations, including chemical industry (25%), and occupations as a painter and/or varnisher (23%) were most often encountered. In 12% of the surveyed bladder cancer cases, a second primary malignancy was observed. The NAT2 distribution observed in the 83 cases is comparable to the proportion in 40 occupationally exposed bladder cancer cases in a Department of Urology located close to a former German production site of benzidine-based azo dyes, but higher than in most studies involving NAT2 genetic status in bladder cancer cases. [ABSTRACT FROM AUTHOR]

A concept relating the lipophilicity of chemicals with their genotoxicity on a chromosomal level had been generated by Schultz and Önfelt (Chem Biol Interact 126:97–123, 2000). It was shown that aneuploidy in Chinese hamster V79 cells was elicited by lipophilic chemicals at concentrations related to their hydrophobicity (log P), whereas toxicants with a specific mode of action acted at concentrations consistently lower than predicted based on log P. We have now combined available data sets on aneuploidy/micronucleus formation with procedures used in QSAR modelling, in order to find new molecular descriptors for modelling non-specific chromosomal genotoxicity, and to optimise combinations thereof. Molecular structures of 26 chemicals, including steroids, were converted into single 3D models using Corina (version 3.20), and 11 descriptors of molecular properties were calculated. The data of 16 compounds assigned to a non-specific mode of action were imported into the QSAR module of the software package Cerius2 (version 4.10). Applying genetic function approximation (GFA), linear equations were set up relating molecular descriptors with experimental concentrations at which doubling of micronuclei occurred in V79 cells (exp −log C). The number of variables (molecular descriptors) was limited to a maximum of three, and linear and quadratic terms were allowed. Based on the descriptions provided by the GFA procedure, log P was the most suitable single property to describe non-specific genotoxicity [ r 2 = 0.88], confirming the original concept of Schultz and Önfelt. Using more descriptors (up to three in combination) resulted in an optimization of correlations up to r 2 = 0.97. Such optimal correlation coefficients were obtained by combinations (a) of the numbers of hydrogen bond acceptors, the polar surface and total surface areas of molecules on one hand, and by (b) the dipole moment, polar surface and total surface descriptors on the other hand. In essence, the relation of polar surface to the total molecular surface appears pivotal to determine the non-specific chromosomal genotoxicity of lipophilic compounds. [ABSTRACT FROM AUTHOR]

On the background of the neurotoxicity of mercury compounds, the interaction of mercury(II) with the cytoskeleton was investigated in vitro using IMR-32 neuroblastoma cells. Conditions for culture of these cells on microscopic slides and procedures for immunofluorescence staining of the microtubule network were optimised. Both morphology and viability of IMR-32 cells were affected by mercury(II) at concentrations higher than 15 μM. Pronounced disintegration of the microtubule cytoskeleton was detected at 30 μM mercury(II). Compared to previous studies with fibroblasts, the no-observed-effect concentration was markedly lower, pointing to a particular sensitivity of nerve cells to mercury. This could be due to disturbed information transfer processes depending on an intact microtubule system. [Copyright &y& Elsevier]

• No significant DNA damage was observed in the sperm cells of Boron exposed workers. • No significant DNA damage was observed in the lymphocytes of Boron exposed workers. • No significant DNA damage was observed in the buccal cells of Boron exposed workers. • Application of Comet assay in human biomonitoring. Industrial production and use of boron compounds have increased during the last decades, especially for the manufacture of borosilicate glass, fiberglass, metal alloys and flame retardants. This study was conducted in two districts of Balıkesir; Bandırma and Bigadic, which geographically belong to the Marmara Region of Turkey. Bandırma is the production and exportation zone for the produced boric acid and some borates and Bigadic has the largest B deposits in Turkey. 102 male workers who were occupationally exposed to boron from Bandırma and 110 workers who were occupationally and environmentally exposed to boron from Bigadic participated to our study. In this study the DNA damage in the sperm, blood and buccal cells of 212 males was evaluated by comet and micronucleus assays. No significant increase in the DNA damage in blood, sperm and buccal cells was observed in the residents exposed to boron both occupationally and environmentally (p = 0.861) for Comet test in the sperm samples, p = 0.116 for Comet test in the lymphocyte samples, p = 0.042 for micronucleus (MN) test, p = 0.955 for binucleated cells (BN), p = 1.486 for condensed chromatin (CC), p = 0.455 for karyorrhectic cells (KHC), p = 0.541 for karyolitic cells (KLY), p = 1.057 for pyknotic cells (PHC), p = 0.331 for nuclear bud (NBUD)). No correlations were seen between blood boron levels and tail intensity values of the sperm samples, lymphocyte samples, frequencies of MN, BN, KHC, KYL, PHC and NBUD. The results of this study came to the same conclusions of the previous studies that boron does not induce DNA damage even under extreme exposure conditions. [ABSTRACT FROM AUTHOR]

Boron-associated shifts in sex ratios at birth were suggested earlier and attributed to a decrease in Y- vs. X-bearing sperm cells. As the matter is pivotal in the discussion of reproductive toxicity of boron/borates, re-investigation in a highly borate-exposed population was required. In the present study, 304 male workers in Bandirma and Bigadic (Turkey) with different degrees of occupational and environmental exposure to boron were investigated. Boron was quantified in blood, urine and semen, and the persons were allocated to exposure groups along B blood levels. In the highest ("extreme") exposure group (n = 69), calculated mean daily boron exposures, semen boron and blood boron concentrations were 44.91 ± 18.32 mg B/day, 1643.23 ± 965.44 ng B/g semen and 553.83 ± 149.52 ng B/g blood, respectively. Overall, an association between boron exposure and Y:X sperm ratios in semen was not statistically significant (p > 0.05). Also, the mean Y:X sperm ratios in semen samples of workers allocated to the different exposure groups were statistically not different in pairwise comparisons (p > 0.05). Additionally, a boron-associated shift in sex ratio at birth towards female offspring was not visible. In essence, the present results do not support an association between boron exposure and decreased Y:X sperm ratio in males, even under extreme boron exposure conditions. [ABSTRACT FROM AUTHOR]

Boric acid and sodium borates are currently classified in the EU-CLP regulation as “toxic to reproduction” under “Category 1B”, with hazard statement of H360FD. However, so far field studies on male reproduction in China and in Turkey could not confirm such boron-associated toxic effects. As validation by another independent study is still required, the present study has investigated possible boron-associated effects on male reproduction in workers (n = 212) under different boron exposure conditions. The mean daily boron exposure (DBE) and blood boron concentration of workers in the extreme exposure group (n = 98) were 47.17 ± 17.47 (7.95-106.8) mg B/day and 570.6 ± 160.1 (402.6-1100) ng B/g blood, respectively. Nevertheless, boron-associated adverse effects on semen parameters, as well as on FSH, LH and total testosterone levels were not seen, even within the extreme exposure group. With this study, a total body of evidence has accumulated that allows to conclude that male reproductive effects are not relevant to humans, under any feasible and realistic conditions of exposure to inorganic boron compounds. [ABSTRACT FROM AUTHOR]

Boric acid and sodium borates are currently classified as being toxic to reproduction under “Category 1B” with the hazard statement of “H360 FD” in the European CLP regulation. This has prompted studies on boron-mediated reprotoxic effects in male workers in boron mining areas and boric acid production plants. By contrast, studies on boron-mediated developmental effects in females are scarce. The present study was designed to fill this gap. Hundred and ninety nine females residing in Bandirma and Bigadic participated in this study investigating pregnancy outcomes. The participants constituted a study group covering blood boron from low (< 100 ng B/g blood, n = 143) to high (> 150 ng B/g blood, n = 27) concentrations. The mean blood boron concentration and the mean estimated daily boron exposure of the high exposure group was 274.58 (151.81-975.66) ng B/g blood and 24.67 (10.47-57.86) mg B/day, respectively. In spite of the high level of daily boron exposure, boron-mediated adverse effects on induced abortion, spontaneous abortion (miscarriage), stillbirth, infant death, neonatal death, early neonatal death, preterm birth, congenital anomalies, sex ratio and birth weight of newborns were not observed. [ABSTRACT FROM AUTHOR]