A 90-day toxicological study was carried out administering equimolar doses of either 3-MCPD (respectively 29.5, 7.37, and 1.84 mg/kg b.w. per day) or 3-MCPD dipalmitate (respectively 156.75, 39.19, and 9.78 mg/kg b.w. per day) to both male and female rats (10 animals per group). Urinary 3-MCPD and 3-MCPD mercapturate were used to monitor exposure to both 3-MCPD and its dipalmitate, and to assess the bioavailability of the latter (equimolar doses of dipalmitate gave rise to urinary metabolites lower by 30 % as compared to the administration of 3-MCPD). Histopathological examination confirmed that the kidney and, in male rats, the testes are critical organs for 3-MCPD. Changes observed after treatment with dipalmitate were similar, but milder and proportional to the urinary excretion of metabolites. The overall picture of nephrotoxicity was consistent with tubulotoxicity, which in female rats was severe enough to cause acute renal failure in 20 to 50 % of animals receiving high doses of 3-MCPD (29.5 mg/kg b.w. per day). BMD 10 and BMDL 10 for mortality in female rats were 7.4 and 2.3 mg/kg b.w. per day, respectively. At such high doses, male rats showed extensive testicular toxicity, with extensive cell depletion. Nephrotoxicity was milder and apparently chronic in nature. Benchmark doses (BMD 10 ) for severe damage to renal and testicular structures in male rats were 5.6 and 8.4 mg/kg b.w. per day, respectively. The corresponding BMDL 10 were 2.5 and 6.0 mg/kg b.w. per day. Different BMDs were obtained for 3-MCPD dipalmitate, depending on the contribution of the 3-MCPD moiety to the molecule and probably a slower and/or lower bioavailability and excretion rate. In male rats, BMD 10 for severe renal and testicular damage were 41.1 and 64.4 mg/kg b.w. per day, respectively. The corresponding BMDL 10 were 17.4 and 44.3 mg/kg b.w. per day. CFP/EFSA/CONTAM/2009/01. Accepted for publication on 22 August 2011.The present document has been produced and adopted by the bodies identified above as author (s). In accordance with Article 36 of Regulation (EC) No 178/2002, this task has been carried out exclusively by the author (s) in the context of a grant agreement between the European Food Safety Authority and the author (s). The present document is published complying with the transparency principle to which the European Food Safety Authority is subject. It may not be considered as an output adopted by EFSA. EFSA reserves its rights, view and position as regards the issues addressed and the conclusions reached in the present document, without prejudice to the rights of the authors. 90-day toxicological study of 3-MCPD and its dipalmitateThe present document has been produced and adopted by the bodies identified above as author (s). In accordance with Article 36 of Regulation (EC) No 178/2002, this task has been carried out exclusively by the author (s) in the context of a grant agreement between the European Food Safety Authority and the author (s). The present document is published complying with the transparency ...

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We studied the responses to hypertonicity of cultured endothelial cells from swine pulmonary arteries. In 0.5 osmol/kgH(2)O medium, initial cell shrinkage was followed by a regulatory volume increase (RVI), complete after 1 h, concomitant with an increase in cellular K(+) content. Then the activity of amino acid transport System A increased, accompanied by an accumulation of ninhydrin-positive solutes (NPS), reaching a peak at approximately 6 h. The subsequent decline in System A activity was paralleled by an induction of the betaine-GABA transporter (BGT-1), detected as increases of BGT-1 mRNA and of transport activity, which peaked at approximately 24 h. Inhibitors of transcription or translation prevented induction of both transport activities. The increased expression of BGT-1, which involved activation of "tonicity-responsive enhancer," was inhibited by 5 mM extracellular betaine. Cellular K(+) concentration gradually declined after the accumulation of NPS and during the induction of BGT-1. This very effective adaptation to hypertonicity suggests it has a physiological role.

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A panel of international breast cancer experts formulated a declaration of consensus regarding many key issues in the use of primary systemic therapy (PST) either in clinical routine or research practice. The attainment of pathological complete response (pCR), defined as no residual invasive tumor in the surgical specimens both in breast and in axillary nodes, is one of the main goals of PST, and pCR can be used as the primary objective in prospective clinical trials. However, pCR is not a reliable endpoint with all treatment approaches, and alternatives such as Ki67 index of the residual invasive disease or after 2 weeks of PST are also potential endpoints. PST has several advantages: breast conservation and the unique opportunity to obtain information on the interaction between treatment and tumor biology. Changes in tumor biology after PST are an early phenomenon; so, an additional core biopsy performed after 14 days from treatment start should be considered in clinical trials.