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Archives of Toxicology (v.85, #5)

Is the replacement strategy, as it exists today in the EU for cosmetics, the way forward ? by Vera Rogiers (pp. 363-364).

Towards an integrated in vitro strategy for repeated dose toxicity testing by Tamara Vanhaecke; Marleen Pauwels; Mathieu Vinken; Liesbeth Ceelen; Vera Rogiers (pp. 365-366).

Alternative (non-animal) methods for cosmetics testing: current status and future prospects—2010 by Sarah Adler; David Basketter; Stuart Creton; Olavi Pelkonen; Jan van Benthem; Valérie Zuang; Klaus Ejner Andersen; Alexandre Angers-Loustau; Aynur Aptula; Anna Bal-Price; Emilio Benfenati; Ulrike Bernauer; Jos Bessems; Frederic Y. Bois; Alan Boobis; Esther Brandon; Susanne Bremer; Thomas Broschard; Silvia Casati; Sandra Coecke; Raffaella Corvi; Mark Cronin; George Daston; Wolfgang Dekant; Susan Felter; Elise Grignard; Ursula Gundert-Remy; Tuula Heinonen; Ian Kimber; Jos Kleinjans; Hannu Komulainen; Reinhard Kreiling; Joachim Kreysa; Sofia Batista Leite; George Loizou; Gavin Maxwell; Paolo Mazzatorta; Sharon Munn; Stefan Pfuhler; Pascal Phrakonkham; Aldert Piersma; Albrecht Poth; Pilar Prieto; Guillermo Repetto; Vera Rogiers; Greet Schoeters; Michael Schwarz; Rositsa Serafimova; Hanna Tähti; Emanuela Testai; Joost van Delft; Henk van Loveren; Mathieu Vinken; Andrew Worth; José-Manuel Zaldivar (pp. 367-485).

The 7th amendment to the EU Cosmetics Directive prohibits to put animal-tested cosmetics on the market in Europe after 2013. In that context, the European Commission invited stakeholder bodies (industry, non-governmental organisations, EU Member States, and the Commission’s Scientific Committee on Consumer Safety) to identify scientific experts in five toxicological areas, i.e. toxicokinetics, repeated dose toxicity, carcinogenicity, skin sensitisation, and reproductive toxicity for which the Directive foresees that the 2013 deadline could be further extended in case alternative and validated methods would not be available in time. The selected experts were asked to analyse the status and prospects of alternative methods and to provide a scientifically sound estimate of the time necessary to achieve full replacement of animal testing. In summary, the experts confirmed that it will take at least another 7–9 years for the replacement of the current in vivo animal tests used for the safety assessment of cosmetic ingredients for skin sensitisation. However, the experts were also of the opinion that alternative methods may be able to give hazard information, i.e. to differentiate between sensitisers and non-sensitisers, ahead of 2017. This would, however, not provide the complete picture of what is a safe exposure because the relative potency of a sensitiser would not be known. For toxicokinetics, the timeframe was 5–7 years to develop the models still lacking to predict lung absorption and renal/biliary excretion, and even longer to integrate the methods to fully replace the animal toxicokinetic models. For the systemic toxicological endpoints of repeated dose toxicity, carcinogenicity and reproductive toxicity, the time horizon for full replacement could not be estimated.

Keywords: Alternative methods; Toxicokinetics; Skin sensitisation; Repeated dose toxicity; Carcinogenicity; Reproductive toxicity

Persistence of deposited metals in the lungs after stainless steel and mild steel welding fume inhalation in rats by James M. Antonini; Jenny R. Roberts; Samuel Stone; Bean T. Chen; Diane Schwegler-Berry; Rebecca Chapman; Patti C. Zeidler-Erdely; Ronnee N. Andrews; David G. Frazer (pp. 487-498).

Welding generates complex metal fumes that vary in composition. The objectives of this study were to compare the persistence of deposited metals and the inflammatory potential of stainless and mild steel welding fumes, the two most common fumes used in US industry. Sprague–Dawley rats were exposed to 40 mg/m³ of stainless or mild steel welding fumes for 3 h/day for 3 days. Controls were exposed to filtered air. Generated fume was collected, and particle size and elemental composition were determined. Bronchoalveolar lavage was done on days 0, 8, 21, and 42 after the last exposure to assess lung injury/inflammation and to recover lung phagocytes. Non-lavaged lung samples were analyzed for total and specific metal content as a measure of metal persistence. Both welding fumes were similar in particle morphology and size. Following was the chemical composition of the fumes—stainless steel: 57% Fe, 20% Cr, 14% Mn, and 9% Ni; mild steel: 83% Fe and 15% Mn. There was no effect of the mild steel fume on lung injury/inflammation at any time point compared to air control. Lung injury and inflammation were significantly elevated at 8 and 21 days after exposure to the stainless steel fume compared to control. Stainless steel fume exposure was associated with greater recovery of welding fume-laden macrophages from the lungs at all time points compared with the mild steel fume. A higher concentration of total metal was observed in the lungs of the stainless steel welding fume at all time points compared with the mild steel fume. The specific metals present in the two fumes were cleared from the lungs at different rates. The potentially more toxic metals (e.g., Mn, Cr) present in the stainless steel fume were cleared from the lungs more quickly than Fe, likely increasing their translocation from the respiratory system to other organs.

Keywords: Welding fume; Inhalation; Lung burden; Lung clearance; Pulmonary toxicity

Acrolein, an I-κBα-independent downregulator of NF-κB activity, causes the decrease in nitric oxide production in human malignant keratinocytes by Ki-Young Moon (pp. 499-504).

Acrolein, a reactive electrophilic α, β-unsaturated aldehyde, is known to be an alkylating chemical carcinogen. The effect of acrolein on the activation of NF-κB in human malignant epidermal keratinocytes was examined to elucidate the molecular mechanism associated with this NF-κB-acrolein regulation and its consecutive sequence, nitric oxide (NO) production. Acrolein significantly downregulated the cellular NF-κB activity up to 60% compared with control as well as the lipopolysaccharide (LPS)-induced NO production in a dose response manner at concentrations of 10~30 μM. To investigate the regulatory mechanism associated with this NF-κB-acrolein downregulation, the relative level of phosphorylation of I-κBα (serines-32 and -36), a principle regulator of NF-κB activation, represented by acrolein, was quantified. Acrolein inhibited NF-κB activity without altering cellular levels of the phosphorylated and nonphosphorylated forms of I-κBα, implying that the downregulatory effect of acrolein on cellular NF-κB activity in human skin cells is an I-κBα-independent activation pathway. The results suggests that acrolein causes the decrease in nitric oxide production as an I-κBα-independent downregulator of NF-κB activity in human malignant keratinocytes, and acrolein-induced carcinogenesis may be associated with the modulation of cellular NF-κB activity.

Keywords: Acrolein; NF-κB activity; I-κB; Nitric oxide; Chemical carcinogenesis; Human malignant keratinocytes

Study on species differences in nephropathy induced by FYX-051, a xanthine oxidoreductase inhibitor by Takeo Shimo; Naoki Ashizawa; Mitsuyoshi Moto; Takashi Iwanaga; Osamu Nagata (pp. 505-512).

To clarify the toxicological aspects of FYX-051, a xanthine oxidoreductase inhibitor, which is currently being developed as a therapeutic agent against gout and hyperuricemia, we performed the study focused on species differences in FYX-051-induced nephropathy. In the repeated toxicology testing by oral administration, nephropathy was seen at 1 mg/kg and more in rats and at 100 mg/kg in dogs, in contrast to no toxicity even at the practical maximum dose (300 mg/kg) in monkeys. The HPLC and LC-MS/MS analyses of intrarenal deposits in dogs have proven that the entity was xanthine. The study on dose dependency of pharmacokinetics, pharmacodynamics, urinary xanthine excretion, and kidney xanthine content by oral administration at 0.3, 1, and 3 mg/kg to rats revealed the involvement of xanthine in the occurrence of nephropathy, thus suggesting that plasma concentrations of FYX-051 can contribute to species differences. Regarding the possible factors of species differences, the daily urinary excretion of total purine metabolites was 30.5- and 6.3-fold greater in rats and dogs, respectively, than in monkeys. Urinary xanthine solubility was 2.3- and 6.3-fold higher in dogs and monkeys, respectively, than in rats. Plasma concentrations of FYX-051 were fivefold higher in rats than in dogs and monkeys, without differences between the latter two species. Therefore, the present study indicated that species differences in nephropathy were produced by the combined effects of purine metabolism, urinary xanthine solubility, and plasma concentrations of FYX-051.

Keywords: FYX-051; Xanthine oxidoreductase inhibitor; Nephropathy; Species differences

Role of cytochrome P450c17α in dibromoacetic acid-induced testicular toxicity in rats by Tracy L. Carr; Rita Ciurlionis; Ivan Milicic; Katharine Whitney; Michael J. Liguori; Scott E. Warder; Marina I. Strakhova; Eric A. G. Blomme (pp. 513-523).

Dibromoacetic acid (DBAA), a by-product formed during disinfection of drinking water, alters spermatogenesis in rats through defective spermiation. The mechanism underlying this toxicity is not fully understood. In this study, gene expression data generated with microarrays from testes were used to generate a mechanistic understanding of DBAA-induced testicular toxicity. Testes were collected from male Sprague–Dawley rats dosed orally for 1 and 4 days with DBAA at 250 mg/kg/day. At both time points, DBAA administration induced delayed spermiation in Stage X tubules and regulated the expression of a small number of genes, including a mild but consistent downregulation of cytochrome P450c17α (CYP17) mRNA, an enzyme expressed by Leydig cells and essential for the production of testicular androgens. Downregulation of CYP17 was confirmed at the protein level and its biological significance was substantiated by demonstrating reduced testicular testosterone levels in DBAA-dosed rats. Furthermore, testosterone production by human chorionic gonadotrophin (hCG)-stimulated rat primary Leydig cells was reduced following treatment with 100 μM DBAA. Collectively, these results indicate that DBAA can directly target rat Leydig cells and downregulate testicular CYP17 expression with a resulting decreased testicular testosterone production. This disruption of testicular steroidogenesis is likely to contribute to the mechanism of failed spermiation observed in rats following exposure to DBAA.

Keywords: Rat; Testis; Halogenated acids; Dibromoacetic acid; Spermiation

In vivo and in vitro assessment of the role of glutathione antioxidant system in anthracycline-induced cardiotoxicity by Anna Vávrová; Olga Popelová; Martin Štěrba; Eduard Jirkovský; Pavlína Hašková; Helena Mertlíková-Kaiserová; Vladimír Geršl; Tomáš Šimůnek (pp. 525-535).

The clinical usefulness of anthracycline antineoplastic drugs is limited by their cardiotoxicity. Its mechanisms have not been fully understood, although the induction of oxidative stress is widely believed to play the principal role. Glutathione is the dominant cellular antioxidant, while glutathione peroxidase (GPx) together with glutathione reductase (GR) constitutes the major enzymatic system protecting the cardiac cells from oxidative damage. Therefore, this study aimed to assess their roles in anthracycline cardiotoxicity. Ten-week intravenous administration of daunorubicin (DAU, 3 mg/kg weekly) to rabbits induced heart failure, which was evident from decreased left ventricular ejection fraction and release of cardiac troponins to circulation. However, no significant changes in either total or oxidized glutathione contents or GR activity were detected in left ventricular tissue of DAU-treated rabbits when compared with control animals. GPx activity in the cardiac tissue significantly increased. In H9c2 rat cardiac cells, 24-h DAU exposure (0.1–10 μM) induced significant dose-dependent toxicity. Cellular content of reduced glutathione was insignificantly decreased, oxidized glutathione and GR activity were unaffected, and GPx activity was significantly increased. Neither buthionine sulfoximine (BSO, glutathione biosynthesis inhibitor) nor 2-oxo-4-thiazolidine-carboxylic acid (OTC, glutathione biosynthetic precursor) had significant effects on DAU cytotoxicity. This contrasted with model oxidative injury induced by hydrogen peroxide, which cytotoxicity was increased by BSO and decreased by OTC. In conclusion, our results suggest that the dysfunction of glutathione antioxidant system does not play a causative role in anthracycline cardiotoxicity.

Keywords: Anthracycline cardiotoxicity; Daunorubicin; Glutathione; Glutathione peroxidase; Glutathione reductase

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Archives of Toxicology (v.85, #5)