Biomarkers of susceptibility and effect in car painters exposed to organic solvents / Biomarcadores de susceptibilidad y efecto en pintores de carros expuestos a solventes orgánicos

Abstract Introduction: Car painters are routinely exposed to organic solvents classified as carcinogenic and mutagenic substances. Objective: To characterize the population susceptibility and evaluate the genotoxic effects of exposure to organic solvents. Methods: A cross-sectional study comparing a group of car painters exposed to organic solvents with a non-exposed group. CYP2E1 polymorphisms and the presence of micronuclei in lymphocytes were determined. Results: One hundred twenty-two workers participated in the study: 62 who worked in car paint shops and were exposed to solvents, and 60 who were not exposed. There were statistically significant differences between the two groups regarding micronucleated cells and nucleoplasmic bridges frequencies (p=0.042 and p=0.046, respectively; exact likelihood ratio). Significant differences were found at the interaction between the CYP2E1 genotype c1c1 and occupational exposure to solvents, with higher frequencies of micronuclei (p= 0.013) and micronucleated cells (p= 0.015). However, when the frequencies of micronuclei, micronucleated cells and nucleoplasmic bridges in the exposure group were compared between the c1c1 and c2c2/c1c2 allele groups of the CYP2E1 polymorphism, statistically significant differences were found. Conclusions: This study confirms that when workers with CYP2E1 polymorphisms, specifically the c1c1 genotype, are exposed to organic solvents, they are more likely to have somatic cell mutations, a condition associated with increased susceptibility to diseases such as cancer

Resumen Introducción: Los pintores de vehículos automotores están rutinariamente expuestos a agentes como los solventes orgánicos, capaces de producir efectos mutágenos y carcinógenos. Objetivo: Caracterizar la susceptibilidad poblacional y evaluar los efectos genotóxicos debidos a la exposición a solventes orgánicos. Métodos: Estudio de corte transversal que comparó a un grupo de pintores de carros expuestos a solven tes orgánicos con un grupo de personas no expuestas. Fueron determinados tanto los polimorfismos de CYP2E1 como la presencia de micronúcleos en linfocitos. Resultados: Participaron 122 personas, 62 trabajadores de talleres de pintura de autos expuestos a solventes y 60 personas no expuestas. Con relación al cuestionario Q 16, 32% de los expuestos refirieron síntomas sugestivos de neurotoxicidad. Las frecuencias de células micronucleadas y de puentes nucleoplásmicos fueron significativamente mayores en los expuestos que en los no expuestos: p= 0.042 y p= 0.046, respectivamente, Razón de verosimilitud exacta). Fueron halladas diferencias significativas en la interacción de CYP2E1 (c1c1) y la exposición ocupacional a solventes, con mayores frecuencias de micronúcleos (p= 0.013) y de células micronucleadas (p= 0.015). Conclusiones: Este estudio reafirma que los trabajadores expuestos a solventes orgánicos con polimorfismos de CYP2E1, específicamente con genotipo c1c1, tienen mayor probabilidad de presentar mutaciones en las células somáticas, condición asociada con una mayor susceptibilidad a enfermedades como el cáncer

Lung cancer related to occupational exposure: an integrative review / Cáncer de pulmón relacionado con la exposición ocupacional: revisión integrativa / Câncer de pulmão relacionado à exposição ocupacional: revisão integrativa

ABSTRACT Objective: To identify in the literature the carcinogenic agents found in the work environment, the occupations and the risk for lung cancer. Method: A descriptive and analytical study of the Integrative Literature Review type was carried out in national and international databases from the last ten years in the period from 2009 to 2018, concerning 32 studies referring to association between carcinogenic substances to which the worker is exposed and lung cancer. Results: Nine (28.1%) publications originated in China and only one in Brazil. The most exposed workers were from the secondary sector, 50% being from industry and 6.2% from construction, mostly male. Asbestos and silica stood out among the carcinogenic substances most associated with lung cancer risk, accounting for 37.5% and 28.1%, respectively. Conclusions: The association between occupational exposure and the risk for lung cancer was characterized in this research by the substantial scientific evidence from the described studies that confirm this association.

RESUMEN Objetivo: Identificar en la literatura los agentes cancerígenos presentes en el entorno laboral, las ocupaciones y el riesgo de cáncer de pulmón. Método: Estudio descriptivo y analítico de una revisión integradora realizada en una base de datos nacional e internacional de los últimos diez años, entre 2009 y 2018, que comprende 32 estudios referidos a la vinculación entre el cáncer de pulmón y las sustancias cancerígenas de exposición ocupacional. Resultados: Nueve (28,1%) publicaciones tuvieron su origen en China y solo una en Brasil. Los trabajadores más expuestos pertenecían al sector secundario, el 50% a la industria y un 6,2% a la construcción, siendo en su mayoría hombres. El asbesto y la sílice se destacaron entre las sustancias cancerígenas más asociadas con el riesgo de cáncer de pulmón, con índices de 37,5% y el 28,1%, respectivamente. Conclusiones: La vinculación entre la exposición ocupacional y el riesgo de cáncer de pulmón se caracterizó en esta investigación por la evidencia científica sustancial de los estudios descriptos que confirman esta asociación.

RESUMO Objetivo: Identificar na literatura os agentes carcinogênicos presentes no ambiente ocupacional, as ocupações e o risco do câncer de pulmão. Método: Estudo descritivo e analítico de revisão integrativa realizada em base de dados nacionais e internacionais dos últimos dez anos, entre 2009 e 2018, compreendendo 32 estudos referentes à associação entre câncer de pulmão e substâncias carcinogênicas de exposição ocupacional. Resultados: Nove (28,1%) publicações originadas na China e apenas uma brasileira. Os trabalhadores mais expostos foram do setor secundário, sendo 50% da indústria e 6,2% da construção civil, em sua maioria do sexo masculino. O amianto e a sílica sobressaíram-se entre as substâncias carcinogênicas mais associadas ao risco de câncer de pulmão correspondendo a 37,5% e 28,1%, respectivamente. Conclusões: A associação entre a exposição ocupacional e o risco de câncer de pulmão ficou caracterizada nesta pesquisa pelas substanciais evidências científicas dos estudos descritos que confirmam essa associação.

Pollution in the Americas: a leading cause of disease burden and an opportunity for cancer prevention / Contaminación en las Américas: causa principal de carga de la enfermedad y una oportunidad para prevención del cáncer

Abstract: Objective: Environmental and occupational agents are causes of cancer and disease worldwide while their control and the reduction of the associated disease burden remains complex. Materials and methods: This paper summarizes the current status of the burden of environmental and occupational causes of disease in the Americas based on presentations from a panel on environment, occupation and other environmental risk factors for cancer in the Americas, delivered in Panama, at the international conference Promoting Health Equity and Transnational Collaborations for the Prevention and Control of Cancer in the Americas. Results: Three case studies are presented to illustrate the impact of specific environmental and occupational agents and the challenge of control. Conclusions: There are still fully avoidable exposures to carcinogens, as well documented in the case of asbestos in Brazil. Thus, there are abundant targets for intervention to reduce cancer in the Americas.

Resumen: Objetivo: Los agentes ambientales y ocupacionales son causas de cáncer y enfermedades en todo el mundo, mientras que su control y reducción de la carga de enfermedad asociada siguen siendo puntos complejos. Material y métodos: Este documento resume el estado actual de la carga de las causas ambientales y ocupacionales de las enfermedades en las Américas a partir de las presentaciones de un panel sobre medio ambiente, ocupación y otros factores de riesgo ambientales para el cáncer en las Américas, realizado en Panamá, en la conferencia internacional Promoviendo la Equidad en Salud y las Colaboraciones Transnacionales para la Prevención y el Control del Cáncer en las Américas. Resultados: Se presentan tres estudios de caso para ilustrar el impacto de agentes ambientales y ocupacionales específicos y el desafío del control. Conclusiones: Todavía hay exposiciones totalmente evitables a los carcinógenos, como está bien documentado en el caso del asbesto en Brasil. Hay abundantes puntos estratégicos de intervención para reducir el cáncer en las Américas.

Cigarrillo electrónico: ¿otra herramienta para ayudar a dejar de fumar o una nueva estrategia para promover la adicción a la nicotina? / Electronic cigarette: another tool to help quit smoking or a new strategy to promote nicotine addiction?

Los autores de este artículo describen las principales características del cigarrillo electrónico y sus componentes, anali-zan la controversia sobre su potencial uso como terapia de sustitución del tabaco y describen las experiencias regulato-rias de Argentina y de otros países. (AU)

The authors of this article describe the main features of electronic cigarettes and its components, analyze the controversy about its potential use as tobacco substitution therapy, and summarize the regulatory experiences in Argentina and other countries. (AU)

Uma proposta de criação de um sistema para monitoramento dos casos de mesotelioma maligno em Curitiba, Paraná, Brasil / A proposal for the creation of a system to monitor cases of malignant mesothelioma in Curitiba, Paraná, Brazil / Una propuesta de creación de un sistema para la supervisión de los casos de mesotelioma maligno en Curitiba, Paraná, Brasil

Este estudo objetivou propor a criação de um sistema de monitoramento dos casos de mesotelioma maligno no Município de Curitiba, Paraná, Brasil, desenvolvido com base no modelo italiano. Trata-se de uma pesquisa-ação tipo diagnóstica, que utiliza as fases exploratória e de planejamento, desenvolvida no período de julho de 2015 a maio de 2017. Utilizaram-se como ferramentas de busca os seguintes instrumentos: Integrador de Registro Hospitalar de Câncer, com as morfologias específicas para mesotelioma; Registro Hospitalar de Câncer, com os códigos C38.4 e C45, da Classificação Internacional de Doenças, 10ª revisão, e/ou registros codificados pelo CID-O, com as topografias C38 e C48; Registro de Câncer de base populacional da Secretaria Municipal de Saúde de Curitiba, com os mesmos códigos. Também foram conhecidos, analisados e adaptados para a realidade brasileira o modelo, os questionários e o software de registro de mesotelioma da Lombardia, na Itália. Observou-se que, no Integrador de Registro Hospitalar de Câncer, foram registrados 15 casos de mesotelioma. No Registro Hospitalar de Câncer do hospital universitário, foram dois. No hospital oncológico, 16. Os dados do Registro de Câncer de Base Populacional, por sua vez, indicaram 317 registros relativos ao período. Apesar de algumas informações estarem mais completas, existe a falta de dados relacionados à história laboral, impossibilitando estabelecer o nexo causal. Com o aumento do número de casos de mesotelioma previstos para as próximas décadas e o atendimento às demandas legais, a implantação de registros torna-se essencial para auxiliar no conhecimento, no acompanhamento, na determinação de nexo causal e nas fontes de contaminação específicas no país.

The study proposes the creation of a system to monitor cases of malignant mesothelioma in the municipality of Curitiba, Paraná State, Brazil, based on the Italian model. This diagnosis-type action-research project featured exploratory and planning phases conducted from July 2015 to May 2017. The following search tools were used: Hospital-Based Cancer Registries Integrator with specific morphologies for mesothelioma; Hospital-Based Cancer Registry with codes C38.4 and C45 of the International Classification of Diseases, 10th revision, and/or records coded by the ICD-O with topographies C38 and C48; Population-Based Cancer Registry of the Curitiba Municipal Health Department, with the same codes. The study also identified, analyzed, and adapted to the Brazilian reality the model, questionnaires, and registry software for mesothelioma from Lombardy, Italy. Fifteen cases of mesothelioma were recorded in the Hospital-Based Cancer Registries Integrator. Two cases were recorded in the University Hospital-Based Cancer Registry and 16 in the Cancer Hospital. There were 317 cases recorded in the Population-Based Cancer Registry during the same period. Although some information was complete, data were lacking on patients' occupational history, thereby preventing the determination of a causal nexus. Given a predicted increase in cases of mesothelioma in the coming decades and the response to court cases, the implementation of registries has become essential to facilitate knowledge and follow-up on the determination of the causal link and specific sources of asbestos exposure in the country.

El objetivo de este estudio fue proponer la creación de un sistema de monitoreo de casos de mesotelioma maligno en el municipio de Curitiba, Paraná, Brasil, desarrollado en base al modelo italiano. Se trata de una investigación-acción de tipo diagnóstica, que usa fases de carácter exploratorio y de planificación, desarrolladas durante el período de julio de 2015 a mayo de 2017. Se utilizaron como herramientas de búsqueda los siguientes instrumentos: Integrador del Registro Hospitalario de Cáncer con morfologías específicas para mesotelioma; Registro Hospitalario de Cáncer con los códigos C38.4 y C45, procedentes de la Clasificación Internacional de Enfermedades décima revisión, y/o registros codificados por el CID-O con topografías C38 y C48; Registro de Cáncer de base poblacional de la Secretaría Municipal de Salud de Curitiba con los mismos códigos. También se presentaron, analizaron y adaptaron a la realidad brasileña el modelo, los cuestionarios y el software de registro de mesotelioma de Lombardía, en Italia. Se observó que, en el Integrador de Registro Hospitalario de Cáncer, se registraron 15 casos de mesotelioma. En el Registro Hospitalario de Cáncer del hospital universitario, fueron dos. En el hospital oncológico, 16. Los datos del Registro de Cáncer de Base Poblacional, a su vez, indicaron 317 registros relacionados con este período. A pesar de que algunos datos estaban más completos, existe una falta de datos relacionados con la historia laboral, imposibilitando establecer el nexo causal. Con el aumento del número de casos de mesotelioma previstos para las próximas décadas, y la atención a las demandas legales, la implantación de los registros se convierte en esencial para apoyar el conocimiento, el seguimiento, así como la determinación del nexo causal y las fuentes de contaminación específicas en el país.

Secondary bile acids effects in colon pathology. Experimental mice study

ABSTRACTPURPOSE:To assess whether deoxycholic acid (DOC) and lithocholic acid (LCA) administered in a period of six months in a concentration of 0.25% may have a carcinogenic role in mice colon.METHODS:The study used C57BL6 female mice divided into four groups. The control group received a balanced diet and the others received diets supplemented with 0.25% DOC, 0.25% LCA and 0.125% DOC+0.125% LCA, respectively. After euthanasia, the lesions found in the resected gastrointestinal tracts were stained with hematoxylin-eosin and examined microscopically.RESULTS:No gastrointestinal tract changes were observed in the control group, while hyperplastic Peyer's patches in the small intestine, flat adenomas with mild dysplasia and chronic colitis at the level of the colon were found in all three test groups. The colonic lesions prevailed in the proximal colon. The highest number of flat adenoma lesions (8), hyperplasia of Peyer's patches (25) and chronic colitis (2) were found in mice fed with diet and LCA.CONCLUSION: Precancerous or cancerous pathological lesions could not be identified. Instead, adenomatous colonic injuries occurred in a shorter period of time (six months), compared to the reported data.

Thyroid Cancer: We Need a Carcinogen-specific Genome Study

No abstract available.

Compensation for Occupational Cancer

The legal scope and criteria for occupational cancer in Korea was out of date. The aim of this study was to review the current criteria for occupational cancer and amend the existent criteria on the basis of recent scientific evidence. The scientific evidence and the legal list of occupational cancer were analyzed to identify the causes of occupational cancer on a global scale. The relationship between compensated occupational cancer cases and carcinogen exposure in Korea was examined. The factors associated with specific causes and target cancers were determined to produce additional criteria. Five-hundred and nineteen cases of 2,468 were awarded compensation for occupational cancer including lung, malignant mesothelioma, lymphohematopoietic, and liver cancers from January 2000 to October 2012. Between 1996 and 2005, benzene accounted for 84.4% of cases, and between 1999 and 2005, asbestos was associated with 62.3% of cases. Fourteen novel causative agents and 12 additional target cancers were identified and the final guidelines were amended to include 23 causative agents and 21 target cancers. This amendment of the criteria for occupational cancer represents the widest change in Korean history and is expected to improve the understanding of occupational cancer by providing an up-to-date and accurate reference guide.

Estimate of dietary intake of chloropropanols (3-MCPD and 1, 3-DCP) and health risk assessment / Estimativa da ingestão de cloropropanóis (3-MCPD e 1,3-DCP) e avaliação do risco à saúde

Chloropropanols, including 3-monochloropropane-1,2-diol (3-MCPD) and 1,3-dichloropropan-2-ol (1,3-DCP), comprise a group of chemicalcontaminants with carcinogenic and genotoxic properties. They have been found in a variety of processed foods and food ingredients, suchas hydrolyzed vegetable protein, soy sauce, cereal-based products, malt-derived ingredients, and smoked foods. This study aimed to assessthe dietary exposure to 3-MCPD and 1,3-DCP in Brazil and verify whether the presence of these substances in foods could represent healthrisks. The intake was calculated by combining data on food consumption, provided by the Consumer Expenditure Survey 2008-2009, withthe levels of contaminant occurrence determined by gas chromatography-mass spectrometry. The exposure to 3-MCPD ranged from 0.06 to0.51 µg.kg bw–1.day–1 considering average and high consumers, while the intake of 1,3-DCP was estimated to be 0.0036 µg.kg bw–1.day–1 inthe worst case scenario evaluated. Based on these results, it was verified that the Brazilians’ exposure to chloropropanols does not present asignificant health risk. However, the consumption of specific foods containing high levels of 3-MCPD could exceed the provisional maximumtolerable daily intake of 2 μg.kg bw–1 established for this compound and, therefore, represent a potential concern.

Os cloropropanóis, entre eles o 3-monocloropropano-1,2-diol (3-MCPD) e o 1,3-dicloropropan-2-ol (1,3-DCP), compreendem um grupo de contaminantes químicos com propriedades carcinogênicas e genotóxicas, encontrados em diversos alimentos processados e ingredientes alimentícios, como proteína vegetal hidrolisada, molho de soja, produtos à base de cereais, ingredientes derivados de malte e alimentos defumados. Este trabalho teve como objetivo avaliar a exposição ao 3-MCPD e 1,3-DCP pela dieta no Brasil e verificar se a presença destes compostos em alimentos pode representar um risco à saúde da população. A ingestão foi calculada combinando-se dados sobre o consumo alimentar, fornecidos pela Pesquisa de Orçamento Familiares 2008-2009, com os níveis de ocorrência dos contaminantes, determinados por cromatografia gasosa – espectrometria de massas. A exposição ao 3-MCPD variou de 0,06 a 0,51 µg.kg pc–1.dia–1 considerando médios e grandes consumidores, enquanto que a ingestão de 1,3-DCP foi estimada em 0,0036 µg.kg pc–1.dia–1 no pior cenário avaliado. Com base nesses resultados, verificou-se que a exposição aos cloropropanóis não representa um risco significativo à saúde da população brasileira.Entretanto, o consumo de determinados alimentos contendo altos níveis de 3-MCPD poderia ultrapassar a ingestão diária máxima tolerável provisória de 2 μg.kg pc–1 estabelecida para este composto e, assim, representar uma preocupação potencial.

Experimental model of smoking and simulation of reflux with acid and pepsin in rats / Modelo experimental de tabagismo e simulação de refluxo com ácido e pepsina em ratos

PURPOSE: To develop experimental models to evaluate the effects of hydrochloric acid associated with the pepsin instilled in the mucosa of the upper esophagus and the esophagogastric junction of young male rats Wistar, simulating injury caused by gastroesophageal reflux on the mucosa of aero-digestive tract in humans as well as the action of the risk exposure of mucosa to cigarette smoke. METHODS: Fifty young male Wistar rats divided in 5 groups with 10 animals each one, respectively simulating pharyngo-laryngeal reflux and gastroesophageal reflux, pharyngo-laryngeal reflux and smoking, smoking only, gastroesophageal reflux and control group. RESULTS: The histopathologic studies no recorded neoplasias, only mild changes and no significant alterations. The hemo-oximetry (carboxyhemoglobin and methemoglobim) and CO2 concentration confirm that the animals were submitted to high intensity of exposure to carcinogens in tobacco and its derivatives. CONCLUSION: The experimental models were highly efficient, practical, easy to use and economical and can be employed in other similar studies to determine the harmful effects by smoking and reflux.

OBJETIVO: Desenvolver modelos experimentais para avaliar os efeitos do ácido clorídrico associado a pepsina, instilados na mucosa da parte superior do esôfago e da junção esofagogástrica de jovens ratos Wistar, simulando lesão causada por refluxo gastroesofágico na mucosa do trato aero-digestivo em humanos, bem como a ação da exposição ao risco de mucosa, como a fumaça de cigarro. MÉTODOS: Cinqüenta jovens ratos Wistar divididos em cinco grupos com 10 animais cada um, respectivamente, simulando o refluxo faringo-laríngeo e refluxo gastroesofágico, refluxo faringo-laríngeo e tabagismo, tabagismo só, refluxo gastroesofágico e grupo controle. RESULTADOS: os estudos histopatológicos não registraram neoplasias, apenas leves alterações e não significativas. O hemo-oximetria (carboxiemoglobina e metemoglobina) e concentração de CO2 corroboram que os animais foram submetidos a alta intensidade de exposição a substâncias cancerígenas do tabaco e seus derivados. CONCLUSÃO: os modelos experimentais desenvolvidos foram altamente eficientes, práticos, fáceis de usar e econômicos podendo ser empregados em outros estudos semelhantes para determinar os efeitos prejudiciais causados pelo tabagismo e refluxo.

Effect of a hyperlipidic diet rich in omegas 3, 6 and 9 on aberrant crypt formation in rat colonic mucosa / Efeito de uma dieta hiperlipídica rica em ômegas 3, 6 e 9 na formação de criptas aberrantes em mucosa cólica de ratos

PURPOSE: To determine whether a hypercaloric and hyperlipidic diet enriched with polyunsaturated fatty acids influences the formation of aberrant crypt foci (ACF) in colonic mucosa of Wistar rats treated with azoxymethane (AOM). METHODS: At eight weeks of life, the rats were assigned to four groups: Group I―standard diet (STD) not treated with AOM; Group II―hypercaloric and hyperlipidic diet (FED), not treated with AOM; Group III―STD, treated with AOM; Group IV―FED, treated with AOM. At 16 weeks, the animals were injected intraperitoneal with 0.9 percent saline solution (Group I and II) or AOM at 15mg/Kg (Groups III and IV) once a week for two weeks. Fifteen weeks later, the animals were euthanized. RESULTS: FED promoted weight gain in Groups II and IV compared to Groups I and III, respectively. The groups did not differ with regard to the total number of ACF. The Chi-square test revealed no predominance of the presence of foci with <4 crypts. However, foci with ≥5 crypts were proportionally more prevalent in Group III than in Group IV (p=0.043). CONCLUSION: The administration of polyunsaturated fatty acids did not interfere with the formation of aberrant crypt foci, but reduced ACF multiplicity, exercising an attenuating effect on carcinogenesis.

OBJETIVO: Determinar se uma dieta hipercalórica, hiperlipídica, rica em ácidos graxos poliinsaturados (FED) tem influência na formação de focos de cripta aberrante (FCA) em mucosa cólica de ratos Wistar expostos ao azoximetano (AOM). MÉTODOS: Com oito semanas de vida, os ratos foram distribuídos em quatro grupos: Grupo I: Dieta padrão (SD) sem AOM; Grupo II: FED, sem AOM; Grupo III: SD, com AOM; Grupo IV: FED com AOM. Com 16 semanas, os animais dos grupos I e II receberam injeções intraperitoneais de solução salina 0,9 por cento, enquanto os dos grupos III e IV receberam AOM na dose de 15mg/Kg de peso, 1 vez por semana por duas semanas. Quinze semanas após, os animais foram mortos. RESULTADOS: FED promoveu aumento de peso nos grupos II e IV em relação aos grupos I e III. Não houve aumento significante no número total de FCA entre os grupos. Em relação à multiplicidade das criptas por FCA, o teste do qui-quadrado mostrou que não houve predominância da presença <4 criptas por foco. Contudo, focos ≥5 criptas foram proporcionalmente mais prevalentes no grupo III que no grupo IV (p=0,043). CONCLUSÃO: Os ácidos graxos poliinsaturados não interferem na formação de focos de cripta aberrante, contudo reduz sua multiplicidade, exercendo efeito atenuador na carcinogênese.

Development and validation of a robust QSAR model for prediction of carcinogenicity of drugs.

Carcinogenicity is one of the toxicological endpoints causing the highest concern. Also, the standard bioassays in rodents used to assess the carcinogenic potential of chemicals and drugs are extremely long, costly and require the sacrifice of large numbers of animals. For these reasons, we have attempted development of a global quantitative structure–activity relationship (QSAR) model using a data set of 1464 compounds (the Galvez data set available from http://www.uv.es/~galvez/tablevi.pdf), including many marketed drugs for their carcinogenesis potential. Though experimental toxicity testing using animal models is unavoidable for new drug candidates at an advanced stage of drug development, yet the developed global QSAR model can in silico predict the carcinogenicity of new drug compounds to provide a tool for initial screening of new drug candidate molecules with reduced number of animal testing, money and time. Considering large number of data points with diverse structural features used for model development (ntraining = 732) and model validation (ntest = 732), the model developed in this study has an encouraging statistical quality (leave-one-out Q2 = 0.731, R2pred = 0.716). Our developed model suggests that higher lipophilicity values and conjugated ring systems, thioketo and nitro groups contribute positively towards drug carcinogenicity. On the contrary, tertiary and secondary nitrogens, phenolic, enolic and carboxylic OH fragments and presence of three-membered rings reduce the carcinogenicity. Branching, size and shape are found to be crucial factors for drug-induced carcinogenicity. One may consider all these points to reduce carcinogenic potential of the molecules.

Acute Liver Failure Associated with Occupational Exposure to Tetrachloroethylene

Tetrachloroethylene is a chlorinated solvent that is primarily used in dry cleaning and degreasing operations. Although the hepatotoxicity caused by tetrachloroethylene has been well documented in literature, it is rarely considered as a cause of acute liver failure. We report a case of a 39-yr-old man who was admitted to our hospital for acute liver failure due to tetrachloroethylene exposure. Histological examination of the liver revealed massive hepatic necrosis, prominently, in zone 3 of the hepatic lobules. The patient underwent supportive treatment along with 3 sessions of plasmapheresis, and consequently, he presented a favorable outcome. Repeat liver biopsy performed 6 months after the patient's discharge showed architectural distortion with postnecrotic cirrhosis. Physicians should be aware of the possibility of acute liver failure induced by tetrachloroethylene. Early plasmapheresis can be effective for individuals with sufficient capacity for hepatocyte regeneration.

Quantificação de danos em DNA induzidos por acetaldeído: potencial biomarcador de poluição ambiental / Quantification of DNA damage induced by acetaldehyde: potential biomarker for environmental pollution

O acetaldeído é um comprovado agente mutagênico e carcinogênico, pode ser produzido endogenamente pela oxidação do álcool ingerido em bebidas alcoólicas e alimentos ou exogenamente, inalado como poluente, advindo da oxidação de combustíveis fósseis e etanol. O efeito do acetaldeído foi avaliado em modelos celulares e animais com o propósito de avaliarmos o aumento do estresse oxidativo, por lipoperoxidação, fragmentação do DNA, e a formação de adutos DNA, tais como 8-oxo-7,8-dihidro-2-desoxiguanosina, além de, 1,N2-eteno-2-desoxiguanosina e 1,N2-propano-2-desoxiguanosina que foram analisados por HPLC acoplado a espectrometria de massa com a utilização de metodologia ultra-sensível e reprodutiva. O tratamento de fibroblastos pulmonares humanos normais (IMR-90) com diversas concentrações de acetaldeído (58 µM a 711 µM) resultou em aumentos de morte celular, lipoperoxidação, fragmentação do DNA, cálcio intracelular e adutos de DNA. O efeito protetor do licopeno (20 µM) foi comprovado minimizando todos os efeitos deletérios promovidos pelo acetaldeído. O tratamento dos ratos Wistar por 8 e 30 dias com 150 mg/kg e 60 mg/kg via intra-peritoneal ou gavage, evidenciaram os efeitos tóxicos provocados pelo acetaldeído, como aumento significativo de lipoperoxidação, adutos e fragmentação de DNA no fígado e cérebro destes animais. A detecção dos adutos de DNA se mostrou uma ferramenta importante para a detecção dos efeitos provocados por exposição ao aldeído. No tratamento de animais por inalação com variadas concentrações de acetaldeído, que expôs os animais a quantidades do aldeído similares às encontradas em atmosferas poluídas, foi observado aumento de lipoperoxidação, sendo este dose dependente no fígado e pulmão. Já no cérebro, os níveis de MDA foram significativamente maiores em 10 ppb e 30 ppb em relação a 0 ppb e controle, e diminuíram significativamente em 90 ppb. Em relação aos níveis de fragmentação do DNA, observamos no pulmão aumento foi dose dependente...

Acetaldehyde is a known mutagen and carcinogen that can be produced endogenously by ethanol oxidation or directly inhaled as an air pollutant produced by fuel oxidation. The toxicity of acetaldehyde was evaluated in vitro and in vivo models, by means of oxidative stress parameters such as lipid peroxidation (measured as malonaldialdehyde -MDA), DNA fragmentation and DNA adducts such as 8-oxo-7,8-dihydro-2-desoxiguanosine, 1,N2-eteno-2-desoxiguanosine and 1,N2-propano-2-desoxiguanosine, this adducts were analyzed by an ultra-sensible and reproducible HPLC coupled to mass spectrometry assay. Treatment of human normal fibroblast (IMR-90) with a wide range of concentrations (58 µM to 711 µM) resulted in an increase in citotoxicity, lipid peroxidation, DNA fragmentation, intracellular calcium release and DNA adducts. Furthermore, lycopene (20 µM) presented a protective effect against the cellular deleterious properties of acetaldehyde. Treatment of Wistar rats for 8 and 30 days with 150 mg/kg and 60 mg/kg intra-peritonially or by gavage resulted in increased toxicity, measured by lipid peroxidation and DNA damage in liver and brain. The detection of DNA adducts was shown an important tool for the identification of deleterious effects induced by exposure to the aldehyde. Animals treated by inhalation, of amounts commonly found in polluted air samples, presented increased levels of lipid peroxidation in a dose dependent manner in liver and lungs. Nevertheless, in the brain of those animals the higher concentration was devoid of toxic effect measured as MDA levels. Lung tissue presented increased levels of DNA fragmentation. Furthermore, increased levels of 1,N2-εdGuo and 1,N2-propanodGuo was also observed in lungs of all animals. In DNA from livers, 1,N2-propanodGuo presented increased levels. Formation of 8-oxo-7,8-dihydro-2-desoxiguanosine, 1,N2-eteno-2-desoxiguanosine and 1,N2-propano-2-desoxiguanosine in urine samples of people living in the city of São Paulo…

Cancer Morbidity of Foundry Workers in Korea

Foundry workers are potentially exposed to a number of carcinogens. This study was conducted to describe the cancer incidence associated with employment in small-sized Korean iron foundries and to compare those findings to the Korean population. Cancer morbidity in 208 Korean foundries was analyzed using the Standardized Incidence Ratio (SIR) and Standardized Rate Ratio (SRR). Overall cancer morbidity in foundry workers (SIR=1.11, 95% confidence interval [CI]=1.01-1.21) was significantly higher than that of Korean general population. Lung cancer (SIR=1.45, 95%CI=1.11-1.87) and lymphohematopoietcic cancer (SIR=1.58, 95%CI=1.00-2.37) in production workers were significantly high compared to Korean general population. Stomach cancer in fettling (SRR=2.10, 95%CI=1.10-4.01) and lung cancer in molding (SRR=3.06, 95%CI=1.22-7.64) and in fettling (SRR=2.63, 95%CI=1.01-6.84) were there significant elevations compared to office workers. In this study, statistically significant excess lung cancer was observed in production workers comparing to Korean general population and office workers. Also, cancer morbidity of overall cancer, lung cancer and stomach cancer was significantly increased with duration of employment at ten and more years comparing to Korean general population. These findings suggest in causal association between exposure to carcinogens during foundry work and cancer morbidity.

Occupational Respiratory Cancer in Korea

Malignant mesothelioma and lung cancer are representative examples of occupational cancer. Lung cancer is the leading cause of cancer death, and the incidence of malignant mesothelioma is expected to increase sharply in the near future. Although information about lung carcinogen exposure is limited, it is estimated that the number of workers exposed to carcinogens has declined. The first official case of occupational cancer was malignant mesothelioma caused by asbestos exposure in the asbestos textile industry in 1992. Since then, compensation for occupational respiratory cancer has increased. The majority of compensated lung cancer was due to underlying pneumoconiosis. Other main causative agents of occupational lung cancer included asbestos, hexavalent chromium, and crystalline silica. Related jobs included welders, foundry workers, platers, plumbers, and vehicle maintenance workers. Compensated malignant mesotheliomas were associated with asbestos exposure. Epidemiologic studies conducted in Korea have indicated an elevated risk of lung cancer in pneumoconiosis patients, foundry workers, and asbestos textile workers. Occupational respiratory cancer has increased during the last 10 to 20 yr though carcinogen-exposed population has declined in the same period. More efforts to advance the systems for the investigation, prevention and management of occupational respiratory cancer are needed.

Animal model for age- and sex-related genotoxicity of diethylstilbestrol

Environmental xenoestrogens pose a significant health risk for all living organisms. There is growing evidence concerning the different susceptibility to xenoestrogens of developing and adult organisms, but little is known about their genotoxicity in pre-pubertal mammals. In the present study, we developed an animal model to test the sex- and age-specific genotoxicity of the synthetic estrogen diethylstilbestrol (DES) on the reticulocytes of 3-week-old pre-pubertal and 12-week-old adult BALB/CJ mice using the in vivo micronucleus (MN) assay. DES was administered intraperitoneally at doses of 0.05, 0.5, and 5 µg/kg for 3 days and animals were sampled 48, 72 and 96 h, and 2 weeks after exposure. Five animals were analyzed for each dose, sex, and age group. After the DES dose of 0.05 µg/kg, pre-pubertal mice showed a significant increase in MN frequency (P < 0.001), while adults continued to show reference values (5.3 vs 1.0 MN/1000 reticulocytes). At doses of 0.5 and 5 µg/kg, MN frequency significantly increased in both age groups. In pre-pubertal male animals, MN frequency remained above reference values for 2 weeks after exposure. Our animal model for pre-pubertal genotoxicity assessment using the in vivo MN assay proved to be sensitive enough to distinguish age and sex differences in genome damage caused by DES. This synthetic estrogen was found to be more genotoxic in pre-pubertal mice, males in particular. Our results are relevant for future investigations and the preparation of legislation for drugs and environmentally emitted agents, which should incorporate specific age and gender susceptibility.

Carcinogenicity of hexavalent chromium.

Hexavalent chromium (Cr(VI)), a commonly used industrial metal, is a well known human lung carcinogen. Epidemiology and animal studies suggest that the particulate Cr(VI) compounds, specifically the water insoluble compounds, are the more potent carcinogens; however, the carcinogenic mechanism remains unknown. Here we summarize recent Cr(VI)-induced human tumour, in vivo, cell culture and in vitro studies and put the data into context with three major paradigms of carcinogenesis: multistage carcinogenesis, genomic instability, and epigenetic modifications. Based on these studies, we propose a mechanism for chromate carcinogenesis that is primarily driven by the genomic instability paradigm.