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Ferroptosis, an iron-dependent form of programmed cell death, is characterized by iron overload, increased reactive oxygen species (ROS) generation, and depletion of glutathione (GSH) and lipid peroxidation. Lipophilic antioxidants and iron chelators can prevent ferroptosis. GSH-dependent glutathione peroxidase 4 (GPX4) prevents lipid ROS accumulation. Ferroptosis is thought to be initiated through GPX4 inactivation. Moreover, mitochondrial iron overload derived from the degradation of ferritin is involved in increasing ROS generation. Ferroptosis has been suggested to explain the mechanism of action of organ toxicity induced by several drugs and chemicals. Inhibition of ferroptosis may provide novel therapeutic opportunities for treatment and even prevention of such organ toxicities.

Environmental chemicals and drugs can induce cardiotoxicity, mainly by generating free radicals. Reactive oxygen species play a critical role in the pathogenesis of cardiac tissue injury. This highlights a need for prevention of cardiotoxicity by scavenging free radicals. Melatonin has been shown to act as a protector against various conditions in which free radicals cause molecular and tissue injury. Some of the mechanisms by which melatonin operates as a free radical scavenger and antioxidant have been identified. The importance of endogenous melatonin in cardiovascular health and the benefits of melatonin supplementation in different cardiac pathophysiological disorders have been shown in a variety of model systems. Melatonin continues to attract attention for its potential therapeutic value for cardiovascular toxicity. The therapeutic potential of melatonin in treatment of cardiotoxicities caused by various chemicals along with suggested molecular mechanisms of action for melatonin is reviewed.

Doxorubicin (DOX) is an antineoplastic agent obtained from Streptomyces peucetius. It is utilized in treating different kinds of cancers, such as leukemia, lymphoma, and lung, and breast cancers. The main side effect of DOX is cardiotoxicity. Metformin (MET) is an antihyperglycemic drug used for type 2 diabetes treatment. It is proposed that MET has a protective effect against DOX cardiotoxicity. Our review demonstrated that MET has several possible mechanisms of action, which can prevent or at least reduce DOX cardiotoxicity including a decrease of free radical generation and oxidative stress, 5' adenosine monophosphate-activated protein kinase activation, and ferritin heavy chain expression in cardiomyocytes cells. The combination of MET and DOX has been shown to enhance the anticancer activity of DOX by a number of authors. The literature reviewed in the present report supports the hypothesis that MET can reduce the cardiotoxicity that often occurs with DOX treatment.

In real life, consumers are exposed to complex mixtures of chemicals via food, water and commercial products consumption. Since risk assessment usually focuses on individual compounds, the current regulatory approach doesn't assess the overall risk of chemicals present in a mixture. This study will evaluate the cumulative toxicity of mixtures of different classes of pesticides and mixtures of different classes of pesticides together with food additives (FAs) and common consumer product chemicals using realistic doses after long-term exposure. Groups of Sprague Dawley (CD-SD) rats (20 males and 20 females) will be treated with mixtures of pesticides or mixtures of pesticides together with FAs and common consumer product chemicals in 0.0, 0.25 × acceptable daily intake (ADI)/tolerable daily intake (TDI), ADI/TDI and 5 × ADI/TDI doses for 104 weeks. All animals will be examined every day for signs of morbidity and mortality. Clinical chemistry hematological parameters, serum hormone levels, biomarkers of oxidative stress, cardiotoxicity, genotoxicity, urinalysis and echocardiographic tests will be assessed periodically at 6 month intervals. At 3-month intervals, ophthalmological examination, test for sensory reactivity to different types of stimuli, together with assessment of learning abilities and memory performance of the adult and ageing animals will be conducted. After 24 months, animals will be necropsied, and internal organs will be histopathologically examined. If the hypothesis of an increased risk or a new hazard not currently identified from cumulative exposure to multiple chemicals was observed, this will provide further information to public authorities and research communities supporting the need of replacing current single-compound risk assessment by a more robust cumulative risk assessment paradigm.

Tetrabromobisphenol A (TBBPA) is used to protect a wide range of electrical and electronic equipment, consumer electronics and office and communication equipment from catching fire. TBBPA reacts covalently with other monomers becoming an integral part of the cross-linked molecular structure. This study was conducted to evaluate the subchronic toxicity of TBBPA administered by gavage daily for 13 weeks at 0, 100, 300, and 1000 mg/kg/day in male and female CD® rats. A 6-week post-treatment control and 1000 mg/kg/day recovery groups were included. TBBPA exerted no marked effect on the rate of mortality, clinical signs, body or organ weights, feed consumption, histopathology, urinalysis, ophthalmology, and neurological outcomes in a functional observation battery, motor activity, serum thyroid stimulating hormone, serum triiodothyronine, or other serum chemistries. Although differences were observed for bilirubin and alkaline phosphatase, the observed alterations were within the normal range and thus were neither biologically or toxicologically meaningful. The single thyroid-related parameter affected by TBBPA was a reduction in serum thyroxine levels, but the decrease was not of sufficient magnitude to induce other more sensitive indicators of thyroid perturbation. The No Observed Adverse Effect Level was at least 1000 mg/kg/day, the highest dose tested. Based on an upper bound aggregate exposure for adults estimated by the European Union, the margin of exposure is approximately 5000, suggesting that, for the endpoints examined in this study, exposure to TBBPA presents a reasonable certainty of no harm.

Lethal cardiac complications leading to death and various arrhythmias have been reported after organophosphate and/or carbamate poisonings. The present study focuses on the long-term effects of repeated low-level exposure to diazinon, propoxur, and chlorpyrifos (CPF) on cardiac function in rabbits. The yearly based experimental scheme of exposure consisted of two oral administration periods, lasting 3 months and 1 month each, interrupted by an 8-month washout period (total duration 12 months). At the end of the experimental scheme, the rabbits underwent an echocardiographic evaluation under sedation, after which they were killed and the tissue and serum samples were collected. A mild localized cardiotoxic effect was established by echocardiography for the three pesticides tested. Severe histological alterations were identified, especially in the diazinon-treated animals in agreement with increased persistence of this pesticide established in the cardiac tissue. In addition, all pesticides tested increased the oxidative stress and oxidative modifications in the genomic DNA content of the cardiac tissues, each one following a distinct mechanism., (© The Author(s) 2014.)

A grape pomace extract enhanced antioxidant mechanisms in muscle and endothelial cells both in the absence and in the presence of oxidative stress-induced agent tert-butyl hydroperoxide (tBHP). In particular, muscle (C2C12) and endothelial (EA.hy926) cells were treated with the extract at noncytotoxic concentrations for 24 h, and the oxidative stress markers, total reactive oxygen species (ROS), glutathione (GSH), thiobarbituric reactive substances (TBARS), and protein carbonyl levels were assessed. The results showed that the grape extract treatment reduced significantly ROS, TBARS, and protein carbonyl levels and increased GSH in C2C12 cells, while it increased GSH and decreased protein carbonyl levels in EA.hy926 cells. In the presence of tBHP, the grape extract treatment in C2C12 cells reduced significantly ROS, TBARS, and protein carbonyls and increased GSH compared with tBHP alone treatment, while, in EA.hy926 cells, the extract decreased significantly TBARS and protein carbonyls but increased GSH. The antioxidant potency of the extract was different between muscle and endothelial cells suggesting that the antioxidant activity depends on cell type. Moreover, the antioxidant activity of the grape extract, in both cell lines, exerted, at least in part, through increase in GSH levels. The present work is the first to report the effects of grape extract shown for skeletal muscle cells., (© The Author(s) 2014.)

Industrial chemicals are needed for chemical synthesis or technical purposes. These beneficial effects are counterbalanced by the potential health risks for all who come into contact with them. The new chemical legislation of the EU, Registration, Evaluation and Authorization of Chemicals (REACH) will force the responsibility of manufacturers and importers of chemical substances to gather the right information needed to decide on the right circumstances of use and control of chemical substances and products. In order to understand the roots of REACH, experiences gained with regard to existing chemicals legislation, particularly in Germany, will be reviewed. Since Council Directive 67/548/EEC all chemicals placed on the market need a set of standard information and provisions for safe transportation. This directive and its amendments (Council Directive(s) 79/831/EEC and 92/32/EEC) have established for new substances a sound information data basis for classification of dangerous properties. Under Council Regulation 793/93/EEC, regulations and administrative provisions have established the requirement to assess the risk to man and the environment of existing substances. So far, only 119 substances have been evaluated under the forces of this regulation. This separation has led to a substantial imbalance between existing substances and new substances with respect to available data needed to recognize hazards for health. The register of produced and imported chemical substances under REACH should eliminate some of this separation and will also be the key for selection of substances of very high concern by the authorization process to restrict the use and distribution accordingly.

Industrial chemicals have been in use for many decades and new products are regularly invented and introduced to the market. Also for decades, many different chemical laws have been introduced to regulate safe handling of chemicals in different use patterns. The patchwork of current regulation in the European Union is to be replaced by the new regulation on industrial chemical control, REACH. REACH stands for registration, evaluation, and authorization of chemicals. REACH entered force on June 1, 2007. REACH aims to overcome limitations in testing requirements of former regulation on industrial chemicals to enhance competitiveness and innovation with regard to manufacture safer substances and to promote the development of alternative testing methods. A main task of REACH is to address data gaps regarding the properties and uses of industrial chemicals. Producers, importers, and downstream users will have to compile and communicate standard information for all chemicals. Information sets to be prepared include safety data sheets (SDS), chemical safety reports (CSR), and chemical safety assessments (CSA). These are designed to guarantee adequate handling in the production chain, in transport and in use and to prevent the substances from being released to and distributed within the environment. Another important aim is to identify the most harmful chemicals and to set incentives to substitute them with safer alternatives. On one hand, REACH will have substantial impact on the basic understanding of the evaluation of chemicals. However, the toxicological sciences can also substantially influence the workability of REACH that supports the transformation of data to the information required to understand and manage acceptable and non acceptable risks in the use of industrial chemicals. The REACH regulation has been laid down in the main document and 17 Annexes of more than 849 pages. Even bigger technical guidance documents will follow and will inform about the rules for application and work out of dossiers. The following article gives a comprehensive overview on the concept of REACH to give deeper insight into this document. Members of the scientific community will have to define their own position as researchers, teachers, and experts to support the efforts to protect human health and the environment. The concept of REACH as well as new approaches to adapt standard testing regimes to foster a risk oriented approach in required work load to decrease animal based tests and to strengthen weight of evidence are explained in detail in this article.

Methylene diphenylisocyanate (MDI) and toluene diisocyanate (TDI) are widely used in industry to produce polyurethane foam products. Small amounts of methylenedianiline (MDA) and toluene diamine (TDA) are released during MDI and TDI polymerization and may be present in newly finished polyurethane foam parts. MDA and TDA concentrations in foam decline exponentially within several hours of demolding. MDA and the 2,4-isomer of TDA are known animal carcinogens and, in addition, have significant non-carcinogenic health effects. Our goal was to determine whether worker exposure to MDA or TDA in freshly produced polyurethane foams was associated with unacceptable health risks. Sampling and analysis of the fresh foam indicated that MDA and TDA concentrations varied considerably among products, but concentrations in all materials evaluated declined rapidly over time. We found that, under a worst-case exposure scenario, cancer risks from TDA exposure were approximately 5 x 10(-6), whereas cancer risks from MDA exposure resulted in a tumorigenic margin of exposure (MOE) of 85 000. Non-cancer chronic hazard indices were well below 1.0. Therefore, the potential cancer and non-cancer health risks from MDA or TDA exposure to newly manufactured foam parts appear to fall well within acceptable health risk criteria.