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Estarreja is a highly industrialized municipality in NW Portugal, well known for its historical mercury contamination. Some reports have linked hypertension and mercury exposure. In this work, we collected house dust samples and hair from the residents of this area, together with systolic (SBP) and diastolic (DBP) blood pressure. Hair mercury levels varied between 624 and 4535 ng/g, and mercury in dust varied from 93 to 9100 ng/g. No statistically significant association between dust and hair could be established (Spearman Rank Order Correlation, p=0.199). SBP varied between 175 and 116 whereas DBP ranged from 70 to 121 mm Hg, meaning that 28% of the participants were hypertensive. However, no statistically significant differences in mercury concentration between the hypertensive and normal group were found (One-tailed P-value = 0.444). Furthermore, no significant associations between SBP (p=0.826) or DBP (p=0.695) and hair mercury levels were obtained. However, 44% of individuals exhibited hair mercury levels higher than the acceptable dose set by the WHO (2000 ng/g), 72% exhibited levels higher than the acceptable dose set by the USEPA (1000 ng/g), and all participants exhibited mercury concentrations above the safe limit for Europe (580 ng/g).

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　Recently, an outbreak of occupational bile duct cancer in young employees was reported in printing factories where 1,2-dichloropropane (1,2-DCP)-enriched cleaning solvents had been used for a long time in daily operation. Nevertheless, little is known about the relating carcinogenesis mechanisms. For the better understanding of cancer-causing risk of this industrial chemical, its carcinogenic property should be further addressed. However, contrary to tumor-initiating activity, there is little information about in vitro trials exploring whether 1,2-dichloropropane has tumor-promoting activity or not.

　In the present study, to examine the tumor-promoting activity of 1,2-DCP, we conducted in vitro cell transformation assay, one of the major alternatives to animal bioassays for the detection of carcinogenic potential. According to an authorized protocol by OECD with minor modifications, we employed Bhas 42 cells, a mouse cell line that has been considered to be a model of initiated cells, for promotion test. Our results show that 1,2-DCP could act as tumor-promoting agent, at least, in the culture system that mimics some key stages of in vivo multistep carcinogenesis. Together with our previous studies that focused on the potential mechanisms relating to the 1,2-DCP-associated occupational bile duct cancer in terms of metabolism and disposition (1, 2), our findings might provide a new route to better understanding of chemical hazard of 1,2-DCP.

(1) Toyoda et al., Sci Rep. 6:24586, 2016.

(2) Toyoda et al., Oxid. Med. Cell. Longev. 2017:9736836, 2017.

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Nintedanib (NDN), a tyrosine kinases inhibitor, has been revealed anti-tumor, anti-inflammatory, and anti-fibrotic effects in several reports. In the present study, we investigated the protective effects of NDN against polyhexamethylene guanidine phosphate (PHMG)-induced lung fibrosis in mice. The following three experimental groups were evaluated: (1) vehicle control, (2) PHMG (1.1 mg/kg), and (3) PHMG&NDN (60 mg/kg). Mice in the PHMG group exhibited increased numbers of total cells and inflammatory cells in the bronchoalveolar lavage fluid (BALF) accompanied by inflammation and fibrosis in lung tissue. In contrast. mice in the PHMG&NDN group were attenuated these lesions in lung tissue. Moreover, the inflammatory cytokines and fibrotic factors, and the activation of NLRP3 inflammasome were significantly decreased in lung tissue of PHMG&NDN group compared with that the PHMG group. These results suggest that NDN may alleviate the inflammatory response and development of pulmonary fibrosis in the lungs of PHMG-treated mice.

Polycyclic aromatic hydrocarbons (PAHs) are widespread contaminants resulting from the incomplete combustion of organic materials in the environment. The primary concern for the hazardous effect of PAHs is their ability to activate the pathway linked to the aryl hydrocarbon receptor (AhR) and lead to carcinogenesis. While previous research has demonstrated that oxidative stress plays a critical role in the AhR-dependent toxic response, the effect of PAHs on the biosynthesis of glutathione (GSH), which is a powerful endogenous antioxidant, has been paid only limited attention. In the present study, we utilized a global metabolomic approach, via high resolution magic angle spinning nuclear magnetic resonance spectroscopy, and found significant metabolome differences between non-tumorigenic liver cells (BNL CL.2; CL2) and transformed liver cells (BNL 1ME A. 7R.1; 1MEA) chronically exposed to 3-methylcholanthrene (3MC), a well-known carcinogenic PAH. One significant change identified was a lower GSH level for 1MEA cells as compared to CL2 cells. This was contrasted by increased levels of precursor metabolites to GSH synthesis, such as S-adenosylmethionine and cysteine. These changes were accompanied by a significantly reduced expression of γ-glutamylcysteine ligase (GCL), known to be the rate-limiting step of GSH synthesis. Furthermore, the protein level of cysteine dioxygenase was down-regulated; however, the concentration of taurine was unaltered. Taken together, this study demonstrated that transformed cells by chronic exposure of 3MC showed the inhibition of GSH biosynthesis by suppressing GCL protein expression and reducing cysteine availability, which could subsequently make cells vulnerable to oxidative stress.

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Beryllium toxicity is a long-known issue in the workplace. Beryllium exposure is associated notably with pulmonary disease preceded by sensitization to the element, and lung cancer. To protect workers exposed to beryllium, workplace exposure threshold limit values have been lowered to 50 ng.m^-3 by the American Conference of Governmental Industrial Hygienists.

The relevance of urinary beryllium as a biological indicator of exposure was investigated. Skin-wipe samples were also collected from some workers before and after the working day.

Three French enterprises were visited: a copper-beryllium alloy foundry, an aluminium-beryllium alloy foundry and an aluminium smelter. Seventy-eight volunteers, working as foundrymen, millers and blacksmiths, were monitored. Their beryllium urinary excretion levels were all close to those observed in populations with no occupational exposure, except for the foundrymen. The urinary beryllium profile for the aluminium smelter mirrored the fluoride one.

A relationship between atmospheric exposure and urinary excretion could not be established from statistical analysis. The urinary beryllium dose cannot therefore be used as a marker of beryllium exposure. Variations in urinary concentrations might be explained by different parameters, such as skin exposure or beryllium solubility, and by individual factors such as hygiene and smoking status. In contrast, skin-wipe samples showed a systematic increase in beryllium content before and after the working day. Skin-wipe samples may be the most appropriate indicator to evaluate beryllium exposure.

Cigarette smoke (CS) causes chronic diseases, particularly lung diseases such as chronic obstructive pulmonary disease (COPD), lung cancer, and desquamative interstitial pneumonia. The present study aimed to assess the effects of repeated exposure to CS in polyhexamethylene guanidine (PHMG)-induced pulmonary fibrosis. Mice were exposed nose-only inhalation to CS (300 mg/m³) for 4 hours/day, 14 days/week. The following four experimental groups were evaluated: vehicle control (VC), PHMG, CS, and PHMG + CS. Animals in the PHMG group exhibited increased the numbers of total cells and inflammatory cells in the bronchoalveolar lavage fluid (BALF), lung hydroxyproline (HP) content, and histopathological changes, including macrophage infiltration and granulomatous inflammation/fibrosis in the lung. These parameters were exacerbated in mice in the PHMG + CS group. In contrast, mice in the CS group alone displayed only minimal macrophage infiltration in pulmonary tissue. The expression of fibrogenic mediators was significantly elevated in lungs of mice in the PHMG group compared with that VC. Further, the expression of fibrogenic mediators was enhanced in pulmonary tissue in mice administered PHMG + CS. These results demonstrate that repeated exposure to CS may enhance the development of PHMG-induced pulmonary fibrosis.

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　Dasatinib is a divond-generation multi-target tyrosine kinase inhibitor (TKI) that has activity against many imatinib-resistant BCR-ABL mutant forms, c-Kit tyrosine kinases, and Src. While skin hypopigmentation is a well-recognized adverse effect of first generation TKIs; it has rarely been reported with dasatinib yet. We report a rare case of vitiligo induced by dasatinib. A 41-year-old male with a history of chronic myeloid leukemia was initiated on dasatinib as part of a treatment. After 2 months of treatment, he developed skin hypopigmentation on left shoulder and arm area. With skin biopsy, the histopathologic diagnosis with HMB45 and Melan-A staining was confirmed by vitiligo. The patient with dasatinib-induced vitiligo continued to receive treatment with the drug during which time areas of skin hypopigmentation persisted and progressed. We reported rare case of vitiligo induced by treatment of dasatinib.

As the voluntarily reporting Adverse Drug Reaction (ADR) by Electronic Medical Record (EMR) it is possible to manage the history of ADR from individual patients, and be able to contribute to patient safety. Therefore, the ADR monitoring team at Daegu Catholic University Medical Center has been studying ADR collected through EMR.

From JAN 2014 to DEC 2017 voluntarily reported ADRs are 796 Cases. The prevalence of ADR was as follow: non-narcotic analgesics (33.2%), antibiotics (27%), contrast medium (20.1%), narcotics (9.5%), circulatory drugs (2.6%), anti-cancer drugs (1.4%), digestive drugs (1.4%). The most common symptom was skin reaction (39.4%), followed by nausea/vomiting (38.4%), nervous symptom (8.9%), circulatory symptom (3.5%), respiratory symptom (3.1%). 13 cases were reported as serious adverse reaction such as anaphylaxis (1.6%). According to The World Health Organization-Uppsala Monitoring Center (WHO-UMC) causality criteria, 258 cases (32.4%) were 'Certain', 507 cases (63.7%) were 'Probable'. 19 cases (2.4%) were 'Possible' and 8 cases (1%) were 'Unrelated'.

Based on this study, non-narcotic analgesics and antibiotics were the most common causative drugs, and the most common clinical features were skin reaction and gastrointestinal symptoms. However, since there is a limit to the single center study, it is necessary to look at trends in multi-center studies or long-term studies in the future.

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　Polyhexamethylene guanidine (PHMG) is a guanidine derivative that is used as a biocidal disinfectant, often in the form of its salt polyhexamethylene guanidine hydrochloride (PHMG-HCl). PHMG-HCl is one of the cause agents of the humidifier fungicide accidents in Korea. Therefore, this study was conducted to investigate the inhalation toxicity of PHMG-HCl. The inhalation toxicity of PHMG-HCl was assessed by observing F344 rats exposed for 4 hr using the whole body chambers. The rats were exposed to the concentrations of test chemical 0, 20, 80, 160 and 280 mg/m³. Three males and three females died in the rats exposed to the concentration of 280 mg/m³. As the results of clinical signs, nasal hemorrhage, rale, decrease respiration rate, and decrease in locomotor activity were observed in the rats inhaled to the concentrations of 160 and 280 mg/m³. Animal’s appearance were overall emaciation or weakening after exposure. Nasal hemorrhage in the rats exposed to the concentration of 280 mg/m³ was observed in 2 males on the day of exposure. In the changes of body weight, the rats exposed to the concentration of 160 and 280 mg/m³ showed continuous weight loss after exposure. At necropsy, the findings of ballooning and pale discoloration of lung, and small of thymus were observed in the rats exposed to the concentration of 160 and 280 mg/m³. Based on these results, LC₅₀ value was calculated to be 276.9 mg/m³ in both gender under the study conditions.

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