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Objectives: We aimed to develop a method to determine workers' personal exposure levels to N‐(phosphonomethyl)glycine (glyphosate) for their risk assessments. Methods: The proposed method was assessed as follows: recovery, stability of samples on storage, method limit of quantification, and reproducibility. Glyphosate in air was sampled using an air‐sampling cassette containing a glass fiber filter. Ultrapure water was used to extract glyphosate from sampler filters. After derivation with 9‐fluorenylmethyloxycarbonyl chloride, samples were analyzed by high‐performance liquid chromatography using a fluorescence detector. Results: Spiked samples indicated an overall recovery of 101%. After 7 days of storage at 4°C, recoveries were approximately 100%. The method limit of quantification was 0.060 μg/sample. Relative standard deviations representing overall reproducibility, defined as precision, were 1.4%–1.8%. Conclusions: The method developed in this study allows 4‐h personal exposure monitoring of glyphosate at 0.250–500 μg/m3. Thus, this method can be used to estimate worker exposure to glyphosate. [ABSTRACT FROM AUTHOR]

Objectives: The aim of this study was to develop and validate a simple and reliable gas chromatography‐mass spectrometry (GC‐MS) method to simultaneously determine urinary 1‐naphthol (1‐NAP) and 2‐naphthol (2‐NAP) for biological monitoring of occupational exposure to naphthalene. Methods: NAPs were derivatized in situ with acetic anhydride after enzymatic hydrolysis, extracted with n‐hexane, and analyzed using GC‐MS. Validation of the proposed method was conducted in accordance with US Food and Drug Administration guidance. A final validation was performed by analyzing a ClinChek®‐Control for phenolic compounds. Results: The linearity of calibration curves was indicated by a high correlation coefficient (>0.999) in the concentration range 1‐100 μg/L for each NAP. The limits of detection and quantification for each NAP were 0.30 and 1.00 μg/L, respectively. The recovery was 90.8%‐98.1%. The intraday and interday accuracies, expressed as the deviation from the nominal value, were 92.2%‐99.9% and 93.4%‐99.9%, respectively. The intraday and interday precision, expressed as the relative standard deviation, was 0.3%‐3.9% and 0.4%‐4.1%, respectively. The ClinChek® values obtained using our method were sufficiently accurate. Conclusions: The proposed method is simple, reliable, and appropriate for routine analyses, and is useful for biological monitoring of naphthalene exposure in occupational health practice. [ABSTRACT FROM AUTHOR]

Acetoaceto- o -toluidide (AAOT) is made from ortho -toluidine (OTD) and is used for the synthesis of pigments. A report of occupational urinary bladder carcinomas in Japanese workers chronically exposed to OTD and AAOT has recently been published. OTD is a well-known human urinary bladder carcinogen; however, little is known about the toxicity and the carcinogenicity of AAOT. The aim of the present study is to evaluate the toxic effects of AAOT on urinary bladder epithelium. In vitro, the cytotoxicities of AAOT and OTD were evaluated in rat (MYP3) and human (1T1) urothelial cells. The LC50 of AAOT was higher than that of OTD in both MYP cells and 1T1 cells. In vivo, 6-week-old male and female F344 rats were fed diets supplemented with 0%, 1.5%, or 3% AAOT for 4 weeks. Incidences of simple hyperplasia, cell proliferative activity, and γ-H2AX expression, which is a novel marker for the prediction of carcinogenicity, were significantly increased in a dose-dependent manner in the bladder urothelium of male and female rats administered AAOT. Furthermore, in male and female rats administered AAOT, the major urine metabolite of AAOT was OTD. These results demonstrate that AAOT has proliferation-enhancing activity and suggest that OTD metabolized from AAOT may play a pivotal role in the deleterious effects of AAOT in rats. The results of the present study also indicate that AAOT, like other carcinogenic aromatic amines, is likely to be a human bladder carcinogen. [ABSTRACT FROM AUTHOR]

1,2-dichloropropane (1,2-DCP) was reclassified recently by IARC as a Group 1 carcinogen based on epidemiological studies on an outbreak of cholangiocarcinoma in offset-printing workers exposed to 1,2-DCP in Japan. However, the underlying mechanism of 1,2-DCP-induced cholangiocarcinoma remains obscure. A previous whole-genome mutation analysis of cholangiocarcinoma of 4 cases exposed to 1,2-DCP suggested the involvement of activation-induced cytidine deaminase (AID), based on specific signatures of mutation patterns. The objective of the present study is to determine whether exposure to 1,2-DCP induces expression of AID in human cholangiocytes. Human MMNK-1 cholangiocytes, differentiated THP-1 macrophages, and co-cultures of MMNK-1/THP-1 cells were exposed to 1,2-DCP at different concentrations and time intervals. The mRNA expression levels of AID and related genes were quantified by real-time PCR. Protein expression was measured by immunostaining. Alkaline Comet assay was performed to examine DNA damage. The results showed that 1,2-DCP alone did not change AID expression in MMNK-1 cholangiocytes. 1,2-DCP significantly increased pro-inflammatory cytokine TNF-α expression in THP-1 macrophages. TNF-α treatment upregulated expression of AID, NF-κB, and IκB in MMNK-1 cholangiocytes. SN50, a NF-κB inhibitor, significantly downregulated TNF-α-induced AID expression, suggesting the involvement of NF-κB pathway in TNF-α-induced AID expression. Exposure to 1,2-DCP significantly increased AID expression in MMNK-1 cholangiocytes co-cultured with THP-1 macrophages. Comet assay showed that 1,2-DCP-induced DNA damage in MMNK-1 cholangiocytes, as indicated by increased tail DNA% and tail moment, was enhanced when co-cultured with macrophages. The results suggest that inflammatory response of macrophages and consequent aberrant AID expression or DNA damage in the cholangiocytes underlie the mechanism of 1,2-DCP-induced cholangiocarcinoma in humans. [ABSTRACT FROM AUTHOR]

Tonsillectomy is being frequently used in Japan, while Western nephrologists are more reluctant to adopt tonsillectomy as a treatment for IgAN…(In this issue of NDT) Isseki et al. report the outcome of 200 Japanese patients with biopsy-proven IgAN followed in mean for up to 7 years after renal biopsy.Background Indication of tonsillectomy in IgA nephropathy is controversial. The purpose of this study was to examine the efficacy of tonsillectomy on remission and progression of IgA nephropathy. Methods We conducted a single-center 7-year historical cohort study in 200 patients with biopsy-proven IgA nephropathy. Study outcomes were clinical remission defined as disappearance of urine abnormalities at two consecutive visits, glomerular filtration rate (GFR) decline defined as 30% GFR decrease from baseline and GFR slope during the follow-up. Results Seventy of the 200 patients received tonsillectomy. Tonsillectomy was associated with increased incidence of clinical remission (P + 0.01, log-rank test) and decreased incidence of GFR decline (P = 0.01, log-rank test). After adjustment for age and gender, hazard ratios in tonsillectomy were 3.90 (95% confidence interval 2.46–6.18) for clinical remission and 0.14 (0.02–1.03) for GFR decline. After further adjustment for laboratory (baseline mean arterial pressure, GFR, 24-h proteinuria and hematuria score), histological (mesangial score, segmental sclerosis or adhesion, endocapillary proliferation and interstitial fibrosis) or treatment variables (steroid and renin–angiotensin system inhibitors), similar results were obtained in each model. Even after exclusion of 69 steroid-treated patients, results did not change. GFR slopes in tonsillectomy and non-tonsillectomy groups were 0.60 ± 3.65 and − 1.64 ± 2.59 mL/min/1.73 m2/year, respectively. In the multiple regression model, tonsillectomy prevented GFR decline during the follow-up period (regression coefficient 2.00, P = 0.01). Conclusion Tonsillectomy was associated with a favorable renal outcome of IgA nephropathy in terms of clinical remission and delayed renal deterioration even in non-steroid-treated patients. [ABSTRACT FROM PUBLISHER]

There is abundant epidemiological evidence that arsenic is an environmental carcinogen related to human cancers of the skin, lung, liver and urinary bladder, in particular. Dimethylarsinic acid (DMA) has also been reported to act as a carcinogen/or a promoter in rat models. To elucidate molecular mechanisms, we conducted an 18 month carcinogenicity study of DMA in p53 heterozygous (+/–) knockout mice, which are susceptible to early spontaneous development of various types of tumors, and wild-type (+/+) C57BL/6J mice. Totals of 88–90 males, 7–8 weeks of age, were divided into three groups each administered 0, 50 or 200 p.p.m. DMA in their drinking water for 18 months. Mice that were found moribund or died before the end of the study were autopsied to evaluate the tumor induction levels, as well as those killed at the end. Both p53+/– knockout and wild-type mice demonstrated spontaneous tumor development, but lesions were more prevalent in the knockout case. Carcinogenic effect of DMA was evident by significant early induction of tumors in both treated p53+/– knockout and wild-type mice, significant increase of the tumor multiplicity in 200 p.p.m.-treated p53+/– knockout mice, and by significant increase in the incidence and multiplicity of tumors (malignant lymphomas) in the treated wild-type mice. By the end of 80 weeks, tumor induction, particularly malignant lymphomas and sarcomas, were similar in treated and control p53+/– knockout mice. No evidence for organ-tumor specificity of DMA was obtained. Molecular analysis using PCR–SSCP techniques revealed no p53 mutations in lymphomas from either p53+/– knockout or wild-type mice. In conclusion, DMA primarily exerted its carcinogenic effect on spontaneous development of tumors with both of the animal genotypes investigated here. [ABSTRACT FROM PUBLISHER]

Arsenic is a well-documented human carcinogen, and contamination with this heavy metal is of global concern, presenting a major issue in environmental health. However, the mechanism by which arsenic induces cancer is unknown, in large part due to the lack of an appropriate animal model. In the present set of experiments, we focused on dimethylarsinic acid (DMA), a major metabolite of arsenic in most mammals including humans. We provide, for the first time, the full data, including detailed pathology, of the carcinogenicity of DMA in male F344 rats in a 2-year bioassay, along with the first assessment of the genetic alteration patterns in the induced rat urinary bladder tumors. Additionally, to test the hypothesis that reactive oxygen species (ROS) may play a role in DMA carcinogenesis, 8-hydroxy-2′-deoxyguanosine (8-OHdG) formation in urinary bladder was examined. In experiment 1, a total of 144 male F344 rats at 10 weeks of age were randomly divided into four groups that received DMA at concentrations of 0, 12.5, 50 and 200 p.p.m. in the drinking water, respectively, for 104 weeks. From weeks 97–104, urinary bladder tumors were observed in 8 of 31 and 12 of 31 rats in groups treated with 50 and 200 p.p.m. DMA, respectively, and the preneoplastic lesion, papillary or nodular hyperplasias (PN hyperplasia), was noted in 12 and 14 rats, respectively. DMA treatment did not cause tumors in other organs and no urinary bladder tumors or preneoplastic lesions were evident in the 0 and 12.5 p.p.m.-treated groups. Urinary levels of arsenicals increased significantly in a dose-responsive manner except for arsenobetaine (AsBe). DMA and trimethylarsine oxide (TMAO) were the major compounds detected in the urine, with small amounts of monomethylarsonic acid (MMA) and tetramethylarsonium (TeMa) also detected. Significantly increased 5-bromo-2′-deoxyuridine (BrdU) labeling indices were observed in the morphologically normal epithelium of the groups treated with 50 and 200 p.p.m. DMA. Mutation analysis showed that DMA-induced rat urinary bladder tumors had a low rate of H-ras mutations (2 of 20, 10%). No alterations of the p53, K-ras or β-catenin genes were detected. Only one TCC (6%) demonstrated nuclear accumulation of p53 protein by immunohistochemistry. In 16 of 18 (89%) of the TTCs and 3 of 4 (75%) of the papillomas, decreased p27kip1 expression could be demonstrated. Cyclin D1 overexpression was observed in 26 of 47 (55%) PN hyperplasias, 3 of 4 (75%) papillomas, and 10 of 18 (56%) TCCs. As a molecular marker of oxidative stress, increased COX-2 expression was noted in 17 of 18 (94%) TCCs, 4 of 4 (100%) papillomas, and 39 of 47 (83%) PN hyperplasias. In experiment 2, 8-OHdG formation in urinary bladder was significantly increased after treatment with 200 p.p.m. DMA in the drinking water for 2 weeks compared with the controls. The studies demonstrated DMA to be a carcinogen for the rat urinary bladder and suggested that DMA exposure may be relevant to the carcinogenic risk of inorganic arsenic in humans. Diverse genetic alterations observed in DMA-induced urinary bladder tumors imply that multiple genes are involved in stages of DMA-induced tumor development. Furthermore, generation of ROS is likely to play an important role in the early stages of DMA carcinogenesis. [ABSTRACT FROM PUBLISHER]

Arsenicals are epidemiologically significant chemicals in relation to induction of urinary bladder cancer in man. In the present study, we investigated the dose-dependent promotion potential of dimethylarsinic acid (DMA), a major metabolite of inorganic arsenicals in mammals, for rat urinary bladder carcinogenesis. In experiment 1, 6-week-old male F344 rats were treated with 0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) for 4 weeks and then given one of several concentrations of DMA in their drinking water (groups 1–6: 0, 2, 10, 25, 50 and 100 p.p.m.) for 32 weeks. The development of preneoplastic lesions and tumors (papillomas and carcinomas) in the urinary bladder was enhanced by treatment with DMA in a dose-dependent manner. A significant increase in multiplicity of tumors (papillomas and carcinomas) was observed even at a low concentration of DMA (10 p.p.m.). On the other hand, no preneoplastic lesions and tumors were observed in the rats treated with DMA alone. In experiment 2, different concentrations of DMA (groups 1–4: 0, 10, 25 and 100 p.p.m.) in drinking water were administered to the rats for 8 weeks without prior initiation by BBN. A significant increase in the 5-bromo-2'-deoxyuridine labeling index and alteration of the surfaces of the urinary bladder epithelial cells, as revealed by scanning electron microscopy, provided evidence of a dose-dependent increase in cell proliferation due to the DMA treatment. These results suggest that DMA has the potential to promote rat urinary bladder carcinogenesis and one of the mechanisms involved is its stimulation of cell proliferation in the urinary bladder epithelium. [ABSTRACT FROM PUBLISHER]