Carcinogenic activity of pentabrominated diphenyl ether mixture (DE-71) in rats and mice

Pentabrominated diphenyl ether (PBDE) flame retardants have been phased out in Europe and in the United States, but these lipid soluble chemicals persist in the environment and are found human and animal tissues. PBDEs have limited genotoxic activity. However, in a 2-year cancer study of a PBDE mixture (DE-71) (0, 3, 15, or 50 mg/kg (rats); 0, 3, 30, or 100 mg/kg (mice)) there were treatment-related liver tumors in male and female Wistar Han rats [Crl:WI(Han) after in utero/postnatal/adult exposure, and in male and female B6C3F1 mice, after adult exposure. In addition, there was evidence for a treatment-related carcinogenic effect in the thyroid and pituitary gland tumor in male rats, and in the uterus (stromal polyps/stromal sarcomas) in female rats. The treatment-related liver tumors in female rats were unrelated to the AhR genotype status, and occurred in animals with wild, mutant, or heterozygous Ah receptor. The liver tumors in rats and mice had treatment-related Hras and Ctnnb mutations, respectively. The PBDE carcinogenic activity could be related to oxidative damage, disruption of hormone homeostasis, and molecular and epigenetic changes in target tissue. Further work is needed to compare the PBDE toxic effects in rodents and humans. Keywords: Pentabrominated diphenyl ethers, Liver toxicity, Carcinogenic activit

Study of the sensitisation of a highly alloyed austenitic stainless steel, Alloy 926 (UNS N08926), by means of scanning electrochemical microscopy

The feedback mode of a scanning electrochemical microscope (SECM) was applied to study differences in the reactivity of a highly alloyed austenitic stainless steel, Alloy 926 (UNS N08926), in its unsensitised and sensitised state. Alloy 926 was heated at 825 °C for 1 h in an inert atmosphere in order to produce a sensitised metallurgical condition. Sensitisation was due to chromium carbide formation at the grain boundaries. The oxygen reduction reaction was used as an indicator to monitor the effect of the sensitisation process on the corrosion activity of the Alloy 926 surface in a 35 g l−1 NaCl solution. Higher oxygen consumption was observed above the sensitised sample than above the unsensitised sample due to differences in the oxide films of the two alloy conditions

Resident Kupffer cells and neutrophils drive liver toxicity in cancer immunotherapy.

Immunotherapy is revolutionizing cancer treatment but is often restricted by toxicities. What distinguishes adverse events from concomitant antitumor reactions is poorly understood. Here, using anti-CD40 treatment in mice as a model of T <sub>H</sub> 1-promoting immunotherapy, we showed that liver macrophages promoted local immune-related adverse events. Mechanistically, tissue-resident Kupffer cells mediated liver toxicity by sensing lymphocyte-derived IFN-γ and subsequently producing IL-12. Conversely, dendritic cells were dispensable for toxicity but drove tumor control. IL-12 and IFN-γ were not toxic themselves but prompted a neutrophil response that determined the severity of tissue damage. We observed activation of similar inflammatory pathways after anti-PD-1 and anti-CTLA-4 immunotherapies in mice and humans. These findings implicated macrophages and neutrophils as mediators and effectors of aberrant inflammation in T <sub>H</sub> 1-promoting immunotherapy, suggesting distinct mechanisms of toxicity and antitumor immunity