In Vitro Human Dermal Absorption Studies on Pesticides in Complex Mixtures: Investigation of Guidance Criteria and Possible Impact Parameters.

Pesticides must not pose unacceptable risks to human health, so risk assessments are conducted before products are authorised. Dermal exposure is often the main route of intake, so estimating realistic and trustworthy dermal absorption values is crucial for risk assessment. Although there are agreed test guidelines for in vitro dermal absorption studies, not every product is tested due to cost reasons.

A comparative assessment of the CLP calculation method and in vivo testing for the classification of plant protection products.

In Europe, animal testing for the purpose of regulatory plant protection product (PPP) assessment should be undertaken only as a last resort. Nevertheless, there is a need to improve the acceptance of alternative methods, which has been slow due to a lack of data regarding the predictivity of in vivo effects. The CLP calculation method is an alternative method based on the concentration addition of all adverse substances in a mixture.

Illustrative case using the RISK21 roadmap and matrix: prioritization for evaluation of chemicals found in drinking water.

The HESI-led RISK21 effort has developed a framework supporting the use of twenty-first century technology in obtaining and using information for chemical risk assessment. This framework represents a problem formulation-based, exposure-driven, tiered data acquisition approach that leads to an informed decision on human health safety to be made when sufficient evidence is available. It provides a transparent and consistent approach to evaluate information in order to maximize the ability of assessments to inform decisions and to optimize the use of resources.

WNT10B/β-catenin signalling induces HMGA2 and proliferation in metastatic triple-negative breast cancer.

Wnt/β-catenin signalling has been suggested to be active in basal-like breast cancer. However, in highly aggressive metastatic triple-negative breast cancers (TNBC) the role of β-catenin and the underlying mechanism(s) for the aggressiveness of TNBC remain unknown. We illustrate that WNT10B induces transcriptionally active β-catenin in human TNBC and predicts survival-outcome of patients with both TNBC and basal-like tumours.

ERα regulates lipid metabolism in bone through ATGL and perilipin.

A decrease in bone mineral density during menopause is accompanied by an increase in adipocytes in the bone marrow space. Ovariectomy also leads to accumulation of fat in the bone marrow. Herein we show increased lipid accumulation in bone marrow from estrogen receptor alpha (ERα) knockout (ERαKO) mice compared to wild-type (WT) mice or estrogen receptor beta (ERβ) knockout (ERβKO) mice.

ERα signaling regulates MMP3 expression to induce FasL cleavage and osteoclast apoptosis.

The benefits of estrogens on bone health are well established; how estrogens signal to regulate bone formation and resorption is less well understood. We show here that 17β-estradiol (E2)-induced apoptosis of bone-resorbing osteoclasts is mediated by cleavage and solubilization of osteoblast-expressed Fas ligand (FasL). U2OS-ERα osteoblast-like cells expressing an EGFP-tagged FasL at the C-terminus showed decreased fluorescence after E2 treatment, indicative of a cleavage event.

Tissue-Specific Effects of Loss of Estrogen during Menopause and Aging.

The roles of estrogens have been best studied in the breast, breast cancers, and in the female reproductive tract. However, estrogens have important functions in almost every tissue in the body. Recent clinical trials such as the Women's Health Initiative have highlighted both the importance of estrogens and how little we know about the molecular mechanism of estrogens in these other tissues.

Altered tissue distribution of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA adducts in mice transgenic for human sulfotransferases 1A1 and 1A2.

Soluble sulfotransferases (SULTs) generate electrophilically reactive metabolites from numerous food-borne compounds, environmental contaminants and drugs, often resulting in mutagenicity and carcinogenicity. Substrate specificity, regulation and tissue distribution of SULTs show large interspecies differences. In humans, therefore, SULTs may be involved in the induction of cancer in different tissues than in standard animal models.