Perfluoroalkyl chemicals have been used since the 1950s in a wide variety of industrial and consumer products. Among them, perfluofooctanoic acid (PFOA) was used primarily in an ammonium salt form as an emulsifier in the production of fluoropolymers, such as poly(tetrafluoroethylene) and poly(vinylidine fluoride).1) These polymers have been used in various consumers and industrial products, such as water-repellants for leather paper and textiles. The toxicity of PFOA has been characterized in numerous studies with various species.2) Early studies have shown that organic fluorine accumulated in the serum of occupationally exposed people.3) Resent studies have revealed that PFOA and pefluorooctanesulfonic acid have been found in water, [4][5][6] sediment, 7) wildlife 8-10) and human. [11][12][13][14][15] These findings suggest that general population is exposed to such perfluorochemicals which have globally spread at very low levels.PFOA is thought to remain in humans for long time by the study that has estimated PFOA half-life for 9 retirees from chemical plant to be 4.37 years on the average. 16) On the other hand, several studies that have been carried out on the fate of PFOA in experimental animals including rats have shown that biological half-life of PFOA in male rats was calculated to be 105 h after an intraperitoneal administration at the dose of 50 mg/kg, 17) 9 d after an intraperitoneal administration at a dose of 4 mg/kg, 18) and 6.8 d after an intravenous administration at a dose of 20 mg/kg, 19) respectively. In the studies using experimental animals, PFOA has been shown to be mainly distributed to the liver and serum/plasma, and easily excreted into urine. [18][19][20] The reason for such species difference in half-life of PFOA between humans and experimental animals may be due to the differences in the proteins responsible for distribution, binding and transport of PFOA. Alternative explanation is that the concentrations of PFOA used for the calculation of half-life of PFOA were quite different between humans and the experimental animals. In fact, serum concentrations of PFOA were shown be 11.7 mg/ml 24 h after an intraperitoneal administration at a dose of 4 mg/kg 18) and 61.5 mg/ml 24 h after an intravenous injection at a dose of 20 mg, 19) respectively, while serum samples of human that have been used for the calculation of half-life contained PFOA at the concentrations of 0.06-1.84 mg/ml.16) To date, however, toxicokinetic study has not been performed at the serum concentrations of PFOA corresponding to the levels in serum of humans.In the view of toxicological aspects, it is important to know the toxicokinetic data of PFOA at very low serum concentrations. In the present study, we demonstrated that tissue distribution of PFOA at very low dose is markedly different from those at high doses in experimental animals. MATERIALS AND METHODSMaterials PFOA was purchased from Sigma Aldrich Japan (Tokyo, Japan Faculty of Pharmaceutical Sciences, Josai University; 1-1 Keyakidai, Sakado, Saitama 350-0295,...

Aberrant promoter methylation of genes is a common molecular event in breast cancer. Thus, DNA methylation analysis is expected to be a new tool for cancer diagnosis. In this article, we have established a new, high-performance DNA methylation assay, the one-step methylation-specific polymerase chain reaction (OS-MSP) assay, which is optimized for analyzing gene methylation in serum DNA. The OS-MSP assay is designed to detect aberrant promoter methylation of GSTP1, RASSF1A, and RARβ2 genes in serum DNA. Moreover, two quality control markers were designed for monitoring the bisulfite conversion efficiency and measuring the DNA content in the serum. Serum samples were collected from patients with primary (n = 101, stages I-III) and metastatic breast cancers (n = 58) as well as from healthy controls (n = 87). If methylation of at least one of the three genes was observed, the OS-MSP assay was considered positive. The sensitivity of this assay was significantly higher than that of the assay involving conventional tumor markers (CEA and/or CA15-3) for stages I (24 vs. 8%) and II (26 vs. 8%) breast cancer and similar to that of the assay involving the conventional tumor markers for stage III (18 vs. 19%) and metastatic breast cancers (55 vs. 59%). The results of the OS-MSP assay and those of the assay involving CEA and/or CA15-3 seemed to compensate for each other because sensitivity of these assays increased to 78% when used in combination for metastatic breast cancer. In conclusion, we have developed a new OS-MSP assay with improved sensitivity and convenience; thus, this assay is more suitable for detecting aberrant promoter methylation in serum DNA. Moreover, the combination of the OS-MSP assay and the assay involving CEA and/or CA15-3 is promising for enhancing the sensitivity of diagnosis of metastatic breast cancer.

Background and study aims: Endoscopic submucosal dissection (ESD) has become widely accepted as a minimally invasive treatment for early gastric cancer (EGC), and opportunities to use ESD to treat EGC in elderly patients are increasing. The objective of this study was to elucidate the safety and efficacy of ESD in elderly patients. Patients and methods: Between April 2006 and March 2013, a total of 892 patients with EGC were prospectively recruited to undergo ESD according to definite inclusion criteria. The short-term outcomes and incidence of complications in 345 of these patients who were 75 years of age or older (elderly group) were compared with the short-term outcomes and incidence of complications in the remaining 547 patients (non-elderly group). Factors associated with the occurrence of pneumonia and delirium were also investigated. Results: The R0 resection rate did not differ between the two groups (96.2 % in the elderly group vs. 96.7 % in the non-elderly group; P = 0.65). The incidence of pneumonia (7.5 % vs. 1.8 %; P < 0.01) and incidence of delirium (10.1 % vs. 1.1 %; P < 0.01) were significantly higher in the elderly group. The incidence of post-ESD bleeding and incidence of perforation were similar in the two groups. No emergency surgery was required, but one patient in the non-elderly group died of aspiration pneumonia. On multivariate analysis, age 75 years or older, cerebrovascular disease, chronic obstructive pulmonary disease, delirium, and remnant stomach or gastric tube were independent risk factors for pneumonia, and age 75 years or older, diabetes, dementia, and pneumonia were independent risk factors for delirium. Conclusion: ESD for EGC was feasible for elderly patients in good condition. However, pneumonia and delirium may develop more frequently after ESD in elderly patients with co-morbidities.

Cell transformation assays (CTAs) have long been proposed as in vitro methods for the identification of potential chemical carcinogens. Despite showing good correlation with rodent bioassay data, concerns over the subjective nature of using morphological criteria for identifying transformed cells and a lack of understanding of the mechanistic basis of the assays has limited their acceptance for regulatory purposes. However, recent drivers to find alternative carcinogenicity assessment methodologies, such as the Seventh Amendment to the EU Cosmetics Directive, have fuelled renewed interest in CTAs. Research is currently ongoing to improve the objectivity of the assays, reveal the underlying molecular changes leading to transformation and explore the use of novel cell types. The UK NC3Rs held an international workshop in November 2010 to review the current state of the art in this field and provide directions for future research. This paper outlines the key points highlighted at this meeting.

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The brain level of perfluorododecanoic acid (PFDoA) was compared with those of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) in rats 9 days after a single oral dose (50 mg/kg). The PFDoA level in the brain was 44.0 ± 2.0 µg/g, which was higher than that in the serum (24.4 ± 1.0 µg/ml). In contrast, the concentrations of PFOA and PFDA in the brain were low (<0.8 and 4.7 ± 0.4 µg/g, respectively), and less than one-tenth of those in the serum. Next, to investigate the effects on brain function, the cognitive function alterations of PFOA, PFDA, and PFDoA were estimated by the novel object recognition test 5-6 days after dosing. A significant decrease in the discrimination index was observed in PFDoA-treated rats while no significant alteration was observed in PFDA- and PFOA-treated rats. The effects of PFDoA were further assessed by other behavioral tests. PFDoA-associated alteration was observed in the elevated-plus maze test, but not in the Y-maze test, open-field test, and forced swim test. A decrease in the discrimination index of the novel object recognition test was dependent on the PFDoA dose and the PFDoA concentration in the brain. PFDoA concentration in the brain was 28.6 ± 2.6 µg/g 30 days after dosing, and a decrease in discrimination index was observed. Taken together, these results suggest that PFDoA distributes in the brain easier than PFOA and PFDA and causes cognitive deficit.

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