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.

Caryocar brasiliense camb protects against genomic and oxidative damage in urethane-induced lung carcinogenesis

The antioxidant effects of Caryocar brasiliense Camb, commonly known as the pequi fruit, have not been evaluated to determine their protective effects against oxidative damage in lung carcinogenesis. In the present study, we evaluated the role of pequi fruit against urethane-induced DNA damage and oxidative stress in forty 8-12 week old male BALB/C mice. An in vivo comet assay was performed to assess DNA damage in lung tissues and changes in lipid peroxidation and redox cycle antioxidants were monitored for oxidative stress. Prior supplementation with pequi oil or its extract (15 µL, 60 days) significantly reduced urethane-induced oxidative stress. A protective effect against DNA damage was associated with the modulation of lipid peroxidation and low protein and gene expression of nitric oxide synthase. These findings suggest that the intake of pequi fruit might protect against in vivo genotoxicity and oxidative stress.

Clinical and Prognostic Features of Erionite-Induced Malignant Mesothelioma

This review analytically examines the published data for erionite-related malignant pleural mesothelioma (E-MPM) and any data to support a genetically predisposed mechanism to erionite fiber carcinogenesis. Adult patients of age > or =18 years with erionite-related pleural diseases and genetically predisposed mechanisms to erionite carcinogenesis were included, while exclusion criteria included asbestos- or tremolite-related pleural diseases. The search was limited to human studies though not limited to a specific timeframe. A total of 33 studies (31042 patients) including 22 retrospective studies, 6 prospective studies, and 5 case reports were reviewed. E-MPM developed in some subjects with high exposures to erionite, though not all. Chest CT was more reliable in detecting various pleural changes in E-MPM than chest X-ray, and pleural effusion was the most common finding in E-MPM cases, by both tests. Bronchoalveolar lavage remains a reliable and relatively less invasive technique. Chemotherapy with cisplatin and mitomycin can be administered either alone or following surgery. Erionite has been the culprit of numerous malignant mesothelioma cases in Europe and even in North America. Erionite has a higher degree of carcinogenicity with possible genetic transmission of erionite susceptibility in an autosomal dominant fashion. Therapeutic management for E-MPM remains very limited, and cure of the disease is extremely rare.

Myeloid-derived suppressor cells and associated events in urethane-induced lung cancer

OBJECTIVES: Myeloid-derived suppressor cells contribute to the immunosuppressive microenvironment during tumor development and limit the efficacy of cancer immunotherapy. Identifying myeloid-derived suppressor cells and associated factors is the first step in creating strategies to reverse the suppressive effects of these cells on the immune system. METHODS: To induce lung cancer, we administered 2 doses of urethane to BALB/c mice and observed these animals for 120 days. After this period, we evaluated the percentage of myeloid-derived suppressor cells in the blood, lung and bone marrow. The expression of alpha-smooth muscle actin, transforming growth factor-β, Toll-like receptor 2, Toll-like receptor 4, and interleukin-6 was also determined in the lung tissue. RESULTS: Myeloid-derived suppressor cells were increased in all evaluated tissues after lung cancer development in association with increased Toll-like receptor 4 expression and decreased interleukin-6 expression in the lung. We observed alpha-smooth muscle actin and transforming growth factor-β expression in lung nodules. CONCLUSIONS: We believe that the early diagnosis of cancer through determining the blood levels of myeloid-derived suppressor cells followed by the depletion of these cells should be further investigated as a possible approach for cancer treatment. .

Urban, traffic- related particles and lung tumors in urethane treated mice

OBJECTIVE: The present study was designed to evaluate the effects of urban, traffic-related, fine particulate matter (PM2.5) on mice lung tumorigenesis under controlled exposure conditions. METHODS: Four groups of female Swiss mice were treated with intraperitonial injections of urethane and saline solution. Urethane was used to start the carcinogenesis process. The animals were housed in two chambers receiving filtered and polluted air. In the polluted air chamber, pollutant levels were low. After two months of exposure, the animals were euthanized and lung tumoral nodules were counted. RESULTS: Saline-treated animals showed no nodules. Urethane-treated animals showed 2.0+2.0 and 4.0+3.0 nodules respectively, in the filtered and non-filtered chambers (p = 0.02), thus showing experimental evidence of increased carcinogenic-induced lung cancer with increasing PM2.5 exposure. CONCLUSION: Our data support the concept that low levels of PM2.5 may increase the risk of developing lung tumors.

Análisis numérico de una prótesis endobronquial utilizada para el tratamiento de cáncer pulmonar / Numerical analysis of intrabronchial prosthesis used for the treatment of lung cancer

En México, la mortalidad debido a enfermedades bronco-respiratorias se ubica en el sexto lugar según datos estadísticos dados por el Instituto Nacional de Enfermedades Respiratorias (INER). Esto genera la necesidad de incrementar la eficiencia en la aplicación de los tratamientos usados para este tipo de patología. Algunos de los métodos utilizados con mayor frecuencia para el tratamiento de estas dolencias hacen uso de micro dispositivos, también conocidos como válvulas endobronquiales. Este es un sistema alternativo que evita cirugías invasivas y logra prolongar e incrementar la calidad de vida de los pacientes. En este trabajo se presenta el análisis del desempeño de la válvula IBV®. Para el desarrollo del estudio numérico se determinaron las dimensiones y propiedades mecánicas del modelo a partir de catálogos del fabricante. Se desarrolló un modelo para el cual se consideraron las propiedades del Nitinol® y Silastic®. Asimismo, se propusieron dos condiciones de operación para la válvula, una anclada en el bronquio y la otra en la condición en la que se encuentra plegada dentro del broncoscopio. Se utilizó el Método del elemento finito (MEF) para simular las condiciones de trabajo de la válvula. Los resultados encontrados muestran el funcionamiento estructural y el nivel de los esfuerzos generados en el implante durante el ciclo de respiración forzada del individuo. Además, se proporcionan las bases para generar un nuevo dispositivo que pueda emular el funcionamiento de este tipo de implantes y aumente la eficiencia del tratamiento de dicha patología.

In Mexico, the mortality rate due to bronchial respiratory sickness is placed in the sixth position, according to statistics from the National Institute of Breathing Sickness (INER), so it is convenient to increment the efficiency of treatments for those pathologies. The intrabronchial valve is a recommended alternative method; being it main objective to avoid invasive surgery and increase the time and quality of patient´s life. Within this work a biomechanical analysis of an IBV® valve is carried out. Regarding the numerical analysis, the dimensions and mechanical properties of the valve were proposed based on catalogues published by the manufacturer as more reliable information was not available in the open literature. As a result, a new model was developed in which both materials Nitinol® and Silastic® are considered as the main valve materials. The proposed working conditions assume that the valve is implanted in folded form at the bronchus and then anchored when it is unfolded. Finite Element Method (FEM) was used to simulate the proposed working conditions. Results obtained show the structural performance and the level of stress generated in the implant during the breathing cycle. In addition, it provides the knowledge to generate a new device that could emulate the performance of these implants and develop a more efficient treatment this disease.

Diagnóstico precoz de enfermedades pulmonares por tabaquismo / Early diagnose of smoking lung diseases

El tabaquismo es una epidemia y en Chile la prevalencia no ha disminuido. Entre las causas más importantes de muerte por tabaquismo están el cáncer pulmonar y la enfermedad pulmonar obstructiva crónica (EPOC). La erradicación del tabaquismo es la mejor estrategia de prevención de estas enfermedades. La segunda estrategia es la detección precoz de ellas. Sin embargo la EPOC está sub diagnosticada en todo el mundo. No está claro si la solución es hacer más espirometrías en población de riesgo. Es posible que otros métodos diagnósticos como la tomografía axial computada de tórax (TAC) y la difusión pulmonar, puedan mejorar la capacidad de diagnóstico precoz de esta enfermedad. El cáncer pulmonar es el más mortal de los cánceres. El diagnóstico en etapas tempranas mejora significativamente su pronóstico. Hay varios estudios en curso que evalúan el beneficio de hacer pesquisa de cáncer pulmonar con TAC

Cigarette smoking is worldwide epidemic and in Chile its prevalence is not decreasing. Lung cancer and COPD are important causes of smoking related mortality. Primary prevention of smoking is the best way to avoid these diseases. The second best strategy is an early detection of them. However COPD is under diagnosed all over the world and it is not clear if the solution is doing spirometry in risk population. CT scan of the chest and DLCO could increase the early diagnose. Lung cancer is a deadly disease. Its prognosis is much better in early stages. Currently there are some studies in progress evaluating the benefit of doing screening for lung cancer with CT of the chest

A study to evaluate asbestos fiber burden in lung and pleural malignancies.

Background: There is scarcity of data on asbestos fiber burden in lung and pleural malignancies. Aim: To evaluate asbestos fiber burden in biopsy samples of suspected lung and pleural malignancies. Study Design: This was a single-centre, observational study. Study Period: From August 2010 to July 2010. Setting: Department of Pulmonary Medicine, CSMMU, UP, Lucknow, a tertiary care hospital in India. Study Population: Suspected cases of lung and pleural malignancy. Materials and Methods: Biopsy tissues taken by computed tomography (CT)-guided biopsy, bronchoscopic biopsy, and pleural biopsy by Cope's needle were analyzed for histopathology and asbestos burden by Haq et al.'s method. Results: 20 patients were studied. Mean fiber burden was 9.25 × 10 4 fibers/g. Average burden in lung malignancies (11 patients) was 9.178 × 10 4 fibers/g and in pleural tissue (9 patients) was 9.332 × 10 4fibers/g. Among the different cell types, mean fiber burden in squamous cell carcinoma was 8.99 × 10 4 fibers/g, in adenocarcinoma was 9.71 × 10 4 fibers/g, and in small cell carcinoma was 7.54 × 10 4 fibers/g. Mean fiber burden in bronchoscopic endobronchial biopsy tissue was 10.69 × 10 4 fibers/g, while in CT-guided biopsy was 8.60× 10 4fibers/g. Conclusion: Maximum number of fibers was found in adenocarcinoma.

Association between decreases in type V collagen and apoptosis in mouse lung chemical carcinogenesis: a preliminary model to study cancer cell behavior

OBJECTIVE: The importance of type V collagen and its relationships with other types of collagen and with vascular and epithelial apoptosis were studied in a model of chemical carcinogenesis in the mouse lung. METHODS: Two groups of male Balb/c mice were studied: a) animals that received two intraperitoneal doses of 3 g/kg urethane carcinogen (urethane group = 24); and b) animals submitted to a sham procedure, comparable to the test group (control group = 7). Both groups were sacrificed after 120 days. In situ detection of apoptosis, immunohistochemistry, immunofluorescence and histomorphometry were used to evaluate the fraction occupied by the tumor, vascular and epithelial apoptosis, and type V, III and I collagen fibers in the lung parenchyma from both groups. RESULTS: The lung parenchyma from the urethane group showed low fractions of vascular and epithelial apoptosis as well as reduced type V collagen fibers when compared to the control group. A significant direct association was found between type V and III collagen fibers and epithelial apoptosis, type V collagen fibers and vascular apoptosis, and type V and type I collagen fibers. CONCLUSION: The results show that a direct link between low amounts of type V collagen and decreased cell apoptosis may favor cancer cell growth in the mouse lung after chemical carcinogenesis, suggesting that strategies aimed at preventing decreased type V collagen synthesis or local responses to reduced apoptosis may have a greater impact in lung cancer control.

[Evaluation of the levels of industrial cadmium in the worker's serum and defining its role in cancer disease]

Many studies show the toxic effects of cadmium and its active role in cancerous. So in this perspective, we try to investigate these toxic effects in workers of some specific industries with the cadmium is considered as one of its substance components, such as batteries pigments' and paintings. We analyze in our study the serum of some patients suffering by the cancer and working in direct contact with the cadmium, and compare the results with that concerning a sample of worker suffering by the cancer but working in industries clean by this material. To Perform our study, we use the atomic absorption spectrometer assay to calibrate the level of cadmium in the serum, and we follow the student test between groups in the statistical study of the laboratory results. This research shows the rising of the level of cadmium in the workers who are in direct contact with this material; where it reached the double of whom work in clean industries and it reveal its active role in the development of the cancer

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.

Overview of Asbestos Issues in Korea

Asbestos is a carcinogen that causes diseases such as mesothelioma and lung cancer in humans. There was a sharp increase in the use of asbestos in Korea in the 1970s as Korea's economy developed rapidly, and asbestos was only recently banned from use. Despite the ban of its use, previously applied asbestos still causes many problems. A series of asbestos-related events that recently occurred in Korea have caused the general public to become concerned about asbestos. Therefore, it is necessary to take proper action to deal with asbestos-related events, such as mass outbreaks of mesothelioma among residents who lived near asbestos textile factories or asbestos mines. Although there have been no rapid increases in asbestos-related illnesses in Korea to date, such illnesses are expected to increase greatly due to the amount of asbestos used and long latency period. Decreasing the asbestos exposure level to levels as low as possible is the most important step in preventing asbestos-related illnesses in the next few decades. However, there is a lack of specialized facilities for the analysis of asbestos and experts to diagnose and treat asbestos-related illnesses in Korea; therefore, national-level concern and support are required.

Experimental model of pulmonary carcinogenesis in Wistar rats

PURPOSE: To elaborate an experimental model of pulmonary carcinogenesis in Wistar rats. METHODS: Male Rattus norvegicus albinus, Wistar lineage was carried through an intra-pulmonary instillation of the Benzo[a]pyrene (B[a]P) dilution in alcohol 70 percent, a polycyclic aromatic hydrocarbon widely known by its power of tumoral induction. Three experimental groups had been formed with 08 animals each: Control Group (Alcohol 70 percent); B[a]P Group 10 mg/kg; e B[a]P Group 20mg/kg, submitted to euthanasia 08, 10, 12 and 14 weeks after the experimental procedure. The pulmonary sections had been colored by hematoxilin-eosin (HE) and submitted to the morphometrical analysis to describe the tissue alterations. RESULTS: The presence of diffuse inflammatory alterations was observed in all groups, however, at the analysis of the pulmonary tissue of the experimental groups, it had been observed hyperplasic alterations (BALT hyperplasia), and in one of the animals of the experimental group 20mg/kg (12 weeks), it was noticed the presence of cellular epithelial tracheal pleomorphism, suggesting the adenocarcinoma formation in situ. CONCLUSION: The main secondary alterations to the intra-pulmonary instillation of B[a]P in Wistar rats were: cellular proliferation, inflammatory alterations of several degrees and nodular lymphoid hyperplasias. The association of an activator agent of the pulmonary metabolic reply is necessary to establish the ideal reply-dose to the development of the lung cancer.

OBJETIVO: Elaborar um modelo experimental de carcinogênese pulmonar em ratos wistar. MÉTODOS: Rattus norvegicus albinus, linhagem Wistar foram submetidos a instilação intra-pulmonar da diluição em álcool 70 por cento de Benzo[a]pireno (B[a]P), um hidrocarboneto aromático policíclico amplamente conhecido por seu poder de indução tumoral. Foram formados três grupos experimentais com 08 animais cada: Grupo Controle (álcool 70 por cento); Grupo B[a]P 10 mg/kg; e Grupo B[a]P 20mg/kg, submetidos a eutanásia 08, 10, 12 e 14 semanas após o procedimento experimental. As secções pulmonares foram coradas por HE e submetidas a análise morfométrica para descrição das alterações teciduais. RESULTADOS: em todos os grupos observou-se a presença de alterações inflamatórias difusas, porém na análise do tecido pulmonar dos grupos experimentais, observou-se alterações hiperplásicas (hiperplasia de BALT), e em um dos animais do grupo experimental 20mg/kg (12 semanas) notou-se a presença de pleomorfismo celular epitelial traqueal, sugerindo a formação de adenocarcinoma in situ. CONCLUSÃO: as principais alterações secundárias à instilação intra-pulmonar de B[a]P em ratos Wistar foram: proliferação celular, alterações inflamatórias de diversos graus e hiperplasias nodulares linfóides. A associação de um agente ativador da resposta metabólica pulmonar pode ser necessária para estabelecimento da dose-resposta ideal ao desenvolvimento do câncer de pulmão.

Black tea polyphenols restrict benzopyrene-induced mouse lung cancer progression through inhibition of Cox-2 and induction of caspase-3 expression.

Lung cancer is one of the leading causes of cancer related death in most developed and many developing countries of the world. Due to lack of validated screening methods and poor prognosis, treatment of lung cancer has not improved significantly over the last two decades. Therefore the risk of the disease needs to be minimized by preventive measures. One approach for lung cancer prevention envisages reversal or restriction of precancerous lesions by chemopreventive intervention. It demands a deeper understanding of the pathogenesis of the disease and identification of the ideal point of intervention. In the present investigation, tea components, epigallocatechin gallate (EGCG) and theaflavins (TF) were assessed for their chemopreventive potential when administered in the post initiation phase of lung carcinogenesis in an experimental mouse model. Histopathological changes in lungs of mice administered benzo(a)pyrene (BP) were followed serially and correlated with the expression of Cox-2, caspase-3 and caspase-7, which play key roles in histopathogenesis of neoplasia. The observations strongly indicate that both EGCG and TF can influence the expression of these genes to modulate the process of carcinogenesis, resulting in delayed onset and lowered incidence of pre-invasive lung lesions.

Usefulness of argyrophilic nucleolar organizer regions in detection of lung cells alterations after benzo[a]pyrene instillation

PURPOSE: To verify the relationship between AgNOR expression and lung tissues changes of Wistar rats after pulmonary instillation of benzo[a]pyrene (B[a]P). METHODS: Male Rattus norvegicus albinus,Wistar lineage were given a single intrapulmonary instillation of B[a]P at doses of 10 and 20 mg/kg in a volume of approximately 0,3 ml. After 7 and 21 days the rats were killed and the lung slices submitted to a histological technique of AgNOR. AgNOR dots were quantified and the result analyzed by statistical tests; p <= 0,05 was considered significant. RESULTS: The mean values of AgNOR dots for the experimental groups 10/7 (1,51±0,86) and 10/21 (1,84±0,13) were statistically different (p = 0,009). Among the groups 20/7 (1,63±0,11) and 20/21 (2,48±0,28) was observed statistically significant difference (p = 0,003). CONCLUSION: The AgNOR technique can be useful in identification of cells changes induced by B[a]P.

OBJETIVO: Verificar a relação entre a expressão de AgNOR e alterações teciduais pulmonares em ratos Wistar após instilação pulmonar de benzo[a]pireno (B[a]P). MÉTODOS: Rattus norvegicus albinus, linhagem Wistar machos foram submetidos à instilação pulmonar única de B[a]P em doses de 10 e 20mg/kg, em um volume aproximado de 0,3 ml. Os animais foram sacrificados após 7 e 21 dias e o tecido pulmonar submetido a técnica histológica de AgNOR. Os pontos AgNOR foram quantificados e os resultados analisados estatisticamente; foram considerados significantes os valores de p <= 0,05. RESULTADOS: Os valores médios de pontos AgNOR no grupo experimental 10/7 (1,51±0,86) e 10/21 (1,84±0,13) foram estatisticamente significantes (p = 0,009). Entre os grupos 20/7 (1,63±0,11) e 20/21 (2,48±0,28) a diferença observada foi também considerada significante (p = 0,003). CONCLUSÃO: A técnica de AgNOR pode ser útil na identificação de alterações celulares induzidas pelo B[a]P.

Câncer de pulmão em trabalhadores expostos à sílica / Lung cancer in workers exposed to silica

A sílica é um dos principais agentes ocupacionais relacionados ao câncer de pulmão, sendo classificada pela Agência Internacional para Pesquisa em Câncer (IARC) como substância do grupo 1, ou seja, carcinogênica para humanos, desde 1996. O objetivo deste trabalho é relatar dois casos de trabalhadores previamente expostos à sílica que apresentaram câncer de pulmão, atendidos ambulatorialmente, enfocando pontos relevantes da literatura atual sobre o assunto

Tumores provocados por metilcolantreno y lapachol. Seguimiento del desarrollo mediante citología / Tumors caused by methylcholanthrene and lapachol. Follow-up of desenvolviment by cytology

El presente trabajo fue realizado con el objetivo de estudiar el efecto por el lapachol (LAP) al ser administrado a rats en forma simultánea con un carcinógeno químico, el 20-merilcolantreno (MCA). Los animales fueron divididos en 4 lotes: A-Lote tratado con 80 mg de MCA (n=11 animales), B-Lote tratado con 80 mg de MCA+LAP 100 mg/Kg peso/día (n=15 animales), C-Lote tratado con LAP 100 mg/Kg peso día (n=12 animales), D-Lote control sin tratamiento (n=13 anisales). Los estudios citológicos así como la aplicación de técnicas citoquímicas permitieron conocer el diagnóstico de benegnidad o malignidad apenas producida la aparición del tumor. Estudios histopatológicos posteriores confiraaron la aparición el el 53 por ciento de los animales del lote B de tumores compatibles con adenocarcinomas pobremente diferenciados de glándula salival y en el 18.2 por ciento (2/11) de los animales del lote A de fibroadenomas de la glándula mamaria. Asimismo fue observada la presencia de uno o varios nódulos suprahepáticos en vencidad al ligamento suspensorio e histológicamente definidos como de hiperplasia nodular en el 33 por ciento (4/12) de los animales del lote C y en 13.3 por ciento (2/15) del B no produciéndose desarrollo de dichos nódulos en los lotes A y D. En el riñón fue observada dilatación quística de los túbulos en el 60 por ciento (9/15) y 83.3 por ciento (10/12) de los animales del lote B y C respectivamente. A partir del tumor primitivo de glándula salival fue desarrollada uma linea de tumores transplantables cuyo seguimiento fue realizado citológicamente. Se reafirma la importancia del diagnostico citológico e histopatológico para el estudio del efecto farmacológico de drogas que como el Lapachol son empleadas como antitumorales sin conocerse sus efectos nocivos.