RESUMO
Because of global mobility and migration resulting in a growing diversity of the donor pool, the risk for donor-derived tuberculosis in solid organ transplant recipients becomes more and more relevant, even in countries with a low overall tuberculosis incidence. Here, we describe a case series of donor-derived tuberculosis in 2 of 3 solid organ transplant recipients and one medical staff member in Germany resulting in the death of one recipient. This case series highlights the relevance of this topic to clinicians. It advocates for a better communication between organ procurement organizations and transplant centers regarding donor information and transplant recipient outcome. Furthermore, it underpins the necessity for a standardized critical incident reporting system in the german transplant system to improve short- and long-term recipient's safety, health and survival.
Assuntos
Transplante de Órgãos/efeitos adversos , Doadores de Tecidos , Transplantados , Transplantes/microbiologia , Tuberculose , Idoso , Antituberculosos/administração & dosagem , Antituberculosos/uso terapêutico , Feminino , Pessoal de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia , Tuberculose/transmissãoRESUMO
We report a case of a 27-year-old anesthetist who acquired tuberculosis (TB) while performing general anesthesia in a renal transplant (RTX) patient who had donor-derived contagious TB. The anesthetist developed pleural TB 6 months after exposure. Contact investigations (CIs) did not include health care workers (HCWs) of the Department of Anesthesiology, thereby missing the opportunity for the early diagnosis and treatment of TB. Genomic fingerprinting revealed identical Mycobacterium tuberculosis (MT) isolates in the anesthetist and in the RTX patient. The recipient had acquired disseminated TB from the harvested renal graft. The donor (liver and kidneys), a 67-year-old immigrant, had died from brain death by cerebral herniation after a stroke. She had been treated for tuberculosis with a pneumectomy 40 years ago. Since that time, she had been suffering from latent tuberculous infection (TBI), but had been considered to have been cured.
Assuntos
Transmissão de Doença Infecciosa do Paciente para o Profissional , Transplante de Rim/efeitos adversos , Tuberculose Pulmonar/etiologia , Tuberculose Pulmonar/transmissão , Adulto , Idoso , Anestesistas , Antibióticos Antituberculose/uso terapêutico , Feminino , Humanos , Transplante de Fígado/efeitos adversos , Mycobacterium tuberculosis , Doadores de Tecidos , Tuberculose Pulmonar/terapiaRESUMO
Low-temperature scanning tunneling microscopy and spectroscopy combined with first-principles simulations reveal a nondissociative physisorption of ferrocene molecules on a Cu(111) surface, giving rise to ordered molecular layers. At the interface, a 2D-like electronic band is found, which shows an identical dispersion as the Cu(111) Shockley surface-state band. Subsequent deposition of Cu atoms forms charged organometallic compounds that localize interface-state electrons.
RESUMO
Liver tumors from a previous National Toxicology Program study were examined using global gene expression and mutation analysis to define the mechanisms of carcinogenesis in mice exposed to oxazepam. Five hepatocellular adenomas and 5 hepatocellular carcinomas from male B6C3F1 mice exposed to 5000 ppm oxazepam and 6 histologically normal liver samples from control animals were examined. One of the major findings in the study was upregulation of the Wnt/ß-catenin signaling pathway. Genes that activate ß-catenin, such as Sox4, were upregulated, whereas genes that inhibit Wnt signaling, such as APC and Crebbp, were downregulated. In addition, liver tumors from oxazepam-exposed mice displayed ß-catenin mutations and increased protein expression of glutamine synthetase, a downstream target in the Wnt signaling pathway. Another important finding in this study was the altered expression of oxidative stress-related genes, specifically increased expression of cytochrome p450 genes, including Cyp1a2 and Cyp2b10, and decreased expression of genes that protect against oxidative stress, such as Sod2 and Cat. Increased oxidative stress was confirmed by measuring isoprostane expression using mass spectrometry. Furthermore, global gene expression identified altered expression of genes that are associated with epigenetic mechanisms of cancer. There was decreased expression of genes that are hypermethylated in human liver cancer, including tumor suppressors APC and Pten. Oxazepam-induced tumors also exhibited decreased expression of genes involved in DNA methylation (Crebbp, Dnmt3b) and histone modification (Sirt1). These data suggest that formation of hepatocellular adenomas and carcinomas in oxazepam-exposed mice involves alteration of the Wnt signaling pathway, oxidative stress, and potential epigenetic alterations.
Assuntos
Carcinógenos/toxicidade , Epigênese Genética/fisiologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/induzido quimicamente , Oxazepam/toxicidade , Animais , Feminino , Genoma , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Mutação , Estresse Oxidativo , Reação em Cadeia da Polimerase/métodos , Análise Serial de Proteínas , Reprodutibilidade dos Testes , Transdução de Sinais , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMO
Cresols, monomethyl derivatives of phenol, are high production chemicals with potential for human exposure. The three isomeric forms of cresol are used individually or in mixtures as disinfectants, preservatives, and solvents or as intermediates in the production of antioxidants, fragrances, herbicides, insecticides, dyes, and explosives. Carcinogenesis studies were conducted in groups of 50 male F344/N rats and 50 female B6C3F1 mice exposed to a 60:40 mixture of m- and p-cresols (m-/p-cresol) in feed. Rats and mice were fed diets containing 0, 1500, 5000, or 15,000 ppm and 0, 1000, 3000, or 10,000 ppm, respectively. Survival of each exposed group was similar to that of their respective control group. Mean body weight gains were depressed in rats exposed to 15,000 ppm and in mice exposed to 3000 ppm and higher. A decrease of 25% over that of controls for the final mean body weight in mice exposed to 10,000 ppm appeared to be associated with lack of palatability of the feed. A marginally increased incidence of renal tubule adenoma was observed in the 15,000-ppm-exposed rats. The increased incidence was not statistically significant, but did exceed the range of historical controls. No increased incidence of hyperplasia of the renal tubules was observed; however, a significantly increased incidence of hyperplasia of the transitional epithelium associated with an increased incidence of nephropathy was observed at the high exposure concentration. The only significantly increased incidence of a neoplastic lesion related to cresol exposure observed in these studies was that of squamous cell papilloma in the forestomach of 10,000-ppm-exposed mice. A definitive association with irritation at the site-of-contact could not be made because of limited evidence of injury to the gastric mucosa at the time of necropsy. However, given the minimal chemical-related neoplastic response in these studies, it was concluded that there was no clear evidence of carcinogenicity in male rats or female mice exposed to the cresol mixture.
Assuntos
Testes de Carcinogenicidade , Carcinógenos/toxicidade , Cresóis/toxicidade , Neoplasias Renais/patologia , Neoplasias/induzido quimicamente , Adenoma/induzido quimicamente , Adenoma/patologia , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Neoplasias Renais/induzido quimicamente , Túbulos Renais/efeitos dos fármacos , Túbulos Renais/patologia , Masculino , Camundongos , Neoplasias/patologia , Papiloma/induzido quimicamente , Papiloma/patologia , Ratos , Ratos Endogâmicos F344 , Neoplasias Gástricas/induzido quimicamente , Neoplasias Gástricas/patologia , Fatores de TempoRESUMO
Benzophenone, an aryl ketone, is used primarily as a photoinitiator and fragrance enhancer. Groups of 50 male and 50 female F344 rats and B6C3 F1 mice were fed diets containing 0, 312, 625, and 1250 ppm benzophenone for 105 weeks. Survival of males exposed to 1250 ppm benzophenone was significantly less than that of controls. There was a positive trend in the incidence of renal tubule adenoma in male rats; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Increased incidences of mononuclear cell leukemia were observed in male rats exposed to 312 or 625 ppm benzophenone and in female rats exposed to 625 ppm benzophenone. Liver lesions observed included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of rats. In mice, survival of all exposed groups was generally similar to that of the control groups. In male mice, there were significantly increased incidences of hepatocellular adenoma in the 625 and 1250 ppm groups. In female mice, the incidences of hepatocellular adenoma in the 625 and 1250 ppm groups were higher than expected after adjusting for the lower body weights in these groups. The incidences of kidney nephropathy in exposed groups of female mice, as well as the severity of nephropathy in exposed groups of males, were significantly increased. The incidences of metaplasia of the olfactory epithelium were significantly increased in 1250 ppm mice. Rare histiocytic sarcomas were observed in female rats and mice in the 625 and 1250 ppm groups. Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of benzophenone in male F344/N rats based on increased incidences of renal tubule adenoma. There was equivocal evidence of carcinogenic activity of benzophenone in female F344/N rats based on the marginal increased incidences of mononuclear cell leukemia and histiocytic sarcoma. There was some evidence of carcinogenic activity of benzophenone in male B6C3F(1) mice based on increased incidences of hepatocellular neoplasms, primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in female B6C3F(1) mice based on increased incidences of histiocytic sarcoma; the incidences of hepatocellular adenoma in female B6C3F(1) mice may have been related to benzophenone exposure.
Assuntos
Benzofenonas/toxicidade , Testes de Carcinogenicidade/métodos , Neoplasias Experimentais/induzido quimicamente , Fármacos Fotossensibilizantes/toxicidade , Adenoma/induzido quimicamente , Adenoma/patologia , Animais , Relação Dose-Resposta a Droga , Feminino , Transtornos Histiocíticos Malignos/induzido quimicamente , Transtornos Histiocíticos Malignos/patologia , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/patologia , Leucemia/induzido quimicamente , Leucemia/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos , Neoplasias Experimentais/patologia , Ratos , Ratos Endogâmicos F344 , Sarcoma/induzido quimicamente , Sarcoma/patologia , Fatores SexuaisRESUMO
Fischer 344 rats and B6C3F1 mice were exposed for 2 years to vapors of tetranitromethane at concentrations below (0.5 ppm) and slightly above (2 or 5 ppm) the current U.S. recommended occupational exposure limit. Under the conditions of exposure of 6 h/day, 5 days/week, tetranitromethane was found to cause mild irritation and hyperplastic lesions in the nasal passages, but not nasal cavity neoplasms were observed. In contrast, nearly all animals exposed to the higher TNM concentrations, and the majority of animals exposed to the lower concentrations developed alveolar/bronchiolar adenoma or carcinoma; squamous cell neoplasms of the lung also occurred in exposed rats. The extent of the lung tumor response, and the low concentrations of tetranitromethane required for this response, are unprecedented in National Toxicology Program (NTP) studies.
Assuntos
Adenocarcinoma Bronquioloalveolar/induzido quimicamente , Carcinoma de Células Escamosas/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Rinite/induzido quimicamente , Tetranitrometano/toxicidade , Administração por Inalação , Animais , Brônquios/efeitos dos fármacos , Brônquios/patologia , Relação Dose-Resposta a Droga , Feminino , Hiperplasia/induzido quimicamente , Masculino , Ratos , Ratos Endogâmicos F344 , Tetranitrometano/administração & dosagemRESUMO
Hydrogen peroxide reacts with reduced transition metals to generate the highly reactive hydroxyl radical (X OH), most often proposed as the predominant species for initiating microsomal lipid peroxidation. To assess the potential involvement of X OH, generated from hydrogen peroxide, in microsomal lipid peroxidation, we have altered the concentration of microsomal hydrogen peroxide and measured the resulting rates of malondialdehyde production. Hydrogen peroxide concentration in microsomes was changed by adding exogenous catalase, by washing to reduce both endogenous catalase activity and hydrogen peroxide-dependent glutathione oxidase activity, and by inhibiting endogenous catalase activity with azide in either the presence or absence of exogenous hydrogen peroxide. In only one instance was the rate of lipid peroxidation affected; exogenous hydrogen peroxide added to microsomes, previously incubated with azide, inhibited lipid peroxidation, the opposite effect from that predicted if X OH, generated from hydrogen peroxide, is actually the major initiating species. Neither these results, nor the inability of known X OH traps to inhibit microsomal lipid peroxidation, support the role of free hydrogen peroxide in the initiation of microsomal lipid peroxidation.
Assuntos
Peróxido de Hidrogênio/farmacologia , Peróxidos Lipídicos/metabolismo , Microssomos Hepáticos/metabolismo , Animais , Azidas/farmacologia , Catalase/metabolismo , Catalase/farmacologia , Técnicas In Vitro , Cinética , Masculino , Malondialdeído/metabolismo , Microssomos Hepáticos/efeitos dos fármacos , NADP/metabolismo , Ratos , Ratos Endogâmicos , Azida SódicaRESUMO
The NTP is evaluating several lines of genetically altered mice for possible use in identifying and assessing carcinogens. The NIEHS/NTP programs and progress in this area were recently reviewed by the NTP Board of Scientific Counselors (BSC). A number of comments and concerns were raised. This commentary summarizes and responds to the BSC review and offers some thoughts on future directions for this line of research as well as possible ways genetically altered mice might be integrated into a comprehensive testing strategy.
Assuntos
Testes de Carcinogenicidade/métodos , Camundongos Transgênicos , Toxicologia/métodos , Animais , Camundongos , National Institutes of Health (U.S.) , Pesquisa , Estados UnidosRESUMO
Fish and shellfish caught in polluted waters contain potentially dangerous amounts of toxic and carcinogenic chemicals. Public concern was heightened when a large percentage of winter flounder taken from Boston Harbor was found to have visible cancer of the liver; winter flounder outside the estuary area had no liver lesions. Long-term chemical carcinogenesis studies could be easily and feasibly designed using laboratory rodents offered diets containing fish caught in polluted waters. Induced cancers in rodents would corroborate field observations in fish; positive results from these studies would provide further evidence about potential human health hazards from eating substantial amounts of chemically contaminated fish. Nonetheless, fish and aquatic organisms should be viewed as environmental biological monitors of pollution or of potential human health hazards, and authorities responsible for assuring clean and safe rivers, bodies of water, and biota should give more attention to these valid biological indicators or sentinels of environmental pollution. Consequently, fish and other sea creatures alone should serve as alarms regarding whether water areas constitute public health hazards.
Assuntos
Carcinógenos Ambientais/efeitos adversos , Peixes , Contaminação de Alimentos/análise , Poluentes Químicos da Água/efeitos adversos , Animais , Testes de Carcinogenicidade/métodos , Fatores de Confusão Epidemiológicos , Neoplasias Hepáticas/induzido quimicamente , Camundongos , Projetos de Pesquisa , RiscoRESUMO
The National Institute of Environmental Health Sciences (NIEHS) has several new initiatives involving chemical mixtures and has recognized the need to develop new experimental approaches to enhance our efforts in this area. Responding to recent increases in nominations of complex occupational exposures for toxicologic assessment by the U.S. National Toxicology Program, the NIEHS and the National Institute for Occupational Safety and Health have begun a program to characterize exposures through field studies, identify biomarkers of exposure in workers, and recreate relevant mixed exposures in a laboratory setting. A second initiative with the National Center for Environmental Health/Centers for Disease Control and Prevention will examine blood samples from the U.S. National Health and Nutrition Examination Survey population surveys for selected endocrine-disrupting agents and for common patterns of persistent xenobiotics, providing critical information for the design of animal studies to assess risks of relevant chemical mixtures to humans. New toxicology testing methods (lower cost, faster) will enhance our ability to study chemical mixtures (e.g., dioxin and dioxinlike chemicals, combination AIDS therapies). Ongoing method development efforts involve in vitro functional toxicology assays, screens for estrogenic activity, and carcinogenesis studies in transgenic mice. A major scientific initiative with mixtures involves studies of individual and mixtures of dioxin and dioxinlike chemicals to determine if toxic equivalence factors predict carcinogenic potency in traditional and transgenic bioassays. Complementing these studies is an increased emphasis on physiologically based pharmacokinetic modeling, an activity central to the proper interpretation of chemical mixture studies.
Assuntos
Saúde Ambiental , Xenobióticos/toxicidade , Animais , Interações Medicamentosas , Humanos , Camundongos , National Institutes of Health (U.S.) , Exposição Ocupacional/efeitos adversos , Estados Unidos , Xenobióticos/análiseRESUMO
The carcinogenicity data base used for this paper originated in the late 1960s by the National Cancer Institute and since 1978 has been continued and made more comprehensive by the National Toxicology Program. The extensive files contain among other sets of information detailed pathology data on more than 400 long-term (most often 24 month) chemical carcinogenesis studies, comprised of nearly 1600 individual experiments having at least 10 million tissue sections that have been evaluated for toxicity and carcinogenicity. Using the current data set of 379 studies made up of 1394 experiments, we have compiled listings of chemicals having like carcinogenic target sites for each of the 34 organs or systems for which histopathology diagnoses have been recorded routinely. The most common tumor site is the liver (15% of all experiments), followed in rank order by: lung, hematopoietic system and kidneys, mammary glands, forestomach, thyroid glands, Zymbal glands, urinary bladder, skin and uterus/cervix, and circulatory system and adrenal glands. These compilations are most useful for maintaining a historic perspective when evaluating the carcinogenicity of contemporary experiments. Equally important, the chemical-tumor-organ connection permits an evaluation of how well chemically induced cancers in a particular organ in one sex or species will predict or correlate with the other sex or species. Using liver cancers as an example, the overall interspecies concordance is 80%. Likewise target site predictions can be made for chemicals selected for study that may be similar to those already evaluated; thereby experimental protocols could be adjusted to allow, for example, more extensive pathology on preselected target organs (i.e., serial sections of the kidney). Further from these observations, one could decide to use two strains of mice to evaluate a short-chain chlorinated aliphatic compound or to study a human carcinogen in a sex-species known to develop chemically induced tumors in the same site observed in humans. Structural classes of chemicals having a propensity for certain organs can be easily identified from these data. Sex-species responders to particular induced cancers become clearly evident, such as in the ovary of female mice or in the kidney of male rats.
Assuntos
Testes de Carcinogenicidade , Carcinógenos , Neoplasias Experimentais/induzido quimicamente , Especificidade de Órgãos , Animais , Feminino , Humanos , Incidência , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Testes de Mutagenicidade , Neoplasias/epidemiologia , Neoplasias/mortalidade , Valor Preditivo dos Testes , Distribuição Aleatória , Ratos , Ratos Endogâmicos F344 , Salmonella typhimurium/efeitos dos fármacos , Fatores Sexuais , Especificidade da EspécieRESUMO
The effects of a 4-day inhalation exposure (6 hr/day) to 0, 1, and 3 ppm methyl isocyanate (MIC) on bone marrow parameters in female mice were examined at 5, 8, and 21 days following exposure. The MIC exposure was associated with myelotoxicity as evidenced by hypocellularity, suppression of pluripotent stem cells (CFU-S), granulocyte-macrophage progenitors (CFU-GM) and erythroid precursors (CFU-E) in both dose groups. Hematopoietic parameters returned to normal by 21 days in the 1 ppm dose group, but not in the 3 ppm dose group. This indicates that the alterations in the bone marrow parameters persist for a relatively long period at dose levels where there are little or no changes in body weight, clinical pathology, or immunological parameters, suggesting that the bone marrow may be a sensitive endpoint for MIC exposure in mice. MIC is a highly reactive chemical that appears to exert its effect directly on the lining epithelium of the nasal cavity and major airways; there was no histological evidence of a systemic effect. The pathogenesis of the bone marrow depression is unknown; however, there were chronic bronchitis and bronchial fibrosis in the 3 ppm dose group. One possible explanation is that the cell injury induced in the lung is associated with the release of inhibitory factors for hematopoiesis, as the rodent lung is a potent source of both stimulatory and inhibitory growth factors for bone marrow progenitor cells. A second possibility is that the thymic atrophy found in MIC-exposed mice might be related to myelotoxicity. The pathogenesis of myelotoxicity in MIC exposure and its relationship with pulmonary injury require further study.
Assuntos
Medula Óssea/efeitos dos fármacos , Cianatos/toxicidade , Isocianatos , Animais , Medula Óssea/patologia , Ensaio de Unidades Formadoras de Colônias , Cianatos/administração & dosagem , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Feminino , Granulócitos/efeitos dos fármacos , Granulócitos/patologia , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/patologia , Camundongos , Fatores de TempoRESUMO
The accidental release of methyl isocyanate gas in Bhopal, India, was reported to cause temporary blindness and other eye injuries in many of the exposed people. Methyl isocyanate (MIC) is known to be corrosive and to irritate intact skin and mucous membranes, but little is known about the extent of ocular damage incurred during exposure to its vapors. The eyes of male and female Fischer 344 rats were evaluated immediately after a 2-hr exposure to 0, 3, 10, or 30 ppm of MIC, and periodically thereafter during a 91-day recovery period. During exposure to 10 ppm and higher concentrations, rats kept their eyes partially closed. Copious lacrimation and occasional frothy nasal discharge were evident. Eyes were examined under ultraviolet light after topical application of sodium fluorescein, and histopathologic examination included lids, cornea, lens, retina, optic nerve, and Harderian gland. There was no significant gross or microscopic evidence of epithelial erosion or ulceration of the cornea, or of adjacent tissues immediately after, or at any time following exposures. No skin irritation was noted. It would appear that the natural protective mechanisms of the eye of rats were adequate to prevent ocular damage at these exposure levels.
Assuntos
Cianatos/toxicidade , Olho/efeitos dos fármacos , Isocianatos , Animais , Córnea/efeitos dos fármacos , Córnea/patologia , Cianatos/administração & dosagem , Olho/patologia , Feminino , Masculino , Ratos , Ratos Endogâmicos F344 , Lágrimas/efeitos dos fármacos , Lágrimas/metabolismoRESUMO
F344/N rats and B6C3F1 mice were exposed to 0, 1, 3, or 6 ppm methyl isocyanate by inhalation for 6 hr on 4 consecutive days. Deaths of rats were observed following 3 ppm exposures, and mice died after exposures to 6 ppm. Deaths appeared to be related to severe respiratory distress. Survivors in high dose groups lost weight initially, then gained weight at rates equal to controls throughout a 91-day recovery period. Lung weights increased significantly in male and female rats exposed to 3 ppm, but no persistent changes in brain, kidney, thymus, spleen, liver, or testis weights were seen in either mice or rats. Blood and serum from male and female rats were taken for clinical pathology and hematology assessments on day 7 of postexposure, the day prior to the first observed deaths of these animals. No changes or only slight changes were seen in measures of serum alanine aminotransferase, sorbitol dehydrogenase, alkaline phosphatase, or in blood and brain cholinesterase activities. However, serum creatine kinase increased with dose in both males and females. Blood urea nitrogen, creatinine, and methemoglobin were unchanged. No changes were seen in counts of red blood cells or platelets, or in red cell indices. Hemoglobin concentrations and hematocrits were slightly elevated. No changes were noted in absolute leukocyte counts, but counts of segmented neutrophils increased and lymphocytes decreased.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Cianatos/toxicidade , Isocianatos , Animais , Sangue/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cianatos/administração & dosagem , Feminino , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/patologia , Fatores de TempoRESUMO
B6C3F1 mice were exposed by inhalation to 0, 3, 10, and 30 ppm methyl isocyanate for 2 hr followed by a 90-day recovery period. Sixteen of eighty (20%) male mice in the 30 ppm group died following exposure. There were no other unscheduled deaths in the mice. Five mice/sex/group were examined at 2 hr or at 1, 3, 7, 14, 28, 49, or 91 days following exposure. Chemical-related changes were restricted to the respiratory system. At 30 ppm there were extensive necrosis and erosion of the respiratory and olfactory epithelium in the nasal cavity. Severe necrosis and epithelial erosion were also found in the trachea and main bronchi. Regeneration of the mucosal epithelium occurred rapidly in the nasal cavity and airways. In the turbinates, mild incomplete olfactory epithelial regeneration persisted to day 91 in the male mice. Intraluminal fibrotic projections covered by respiratory epithelium and bronchial fibrosis were found in the major airways of the 30 ppm male and female mice by day 7. The intraluminal fibrosis persisted to day 91. In males with severe bronchial fibrosis, chronic alveolitis and atelectasis were found. In mice exposed to 3 or 10 ppm, persistent pulmonary changes were not found. These studies indicate that methyl isocyanate inhalation at or near lethal concentrations can cause persistent fibrosis of the major bronchi in mice.
Assuntos
Cianatos/toxicidade , Isocianatos , Animais , Cianatos/administração & dosagem , Epitélio/efeitos dos fármacos , Epitélio/patologia , Feminino , Pneumopatias/induzido quimicamente , Masculino , Camundongos , Necrose , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/patologia , Fatores Sexuais , Timo/efeitos dos fármacos , Timo/patologia , Fatores de TempoRESUMO
Pulmonary function was assessed in male, F344 rats 1,2,4,7, and 13 weeks after a single 2-hr exposure to 0, 3, 10, or 30 ppm methyl isocyanate. No significant changes were observed in the rats exposed to 3 ppm through 13 weeks. Diffusing capacity (DLco), quasistatic lung compliance, and homogeneity of ventilation, as determined by multibreath nitrogen washout, were depressed in the rats exposed to 10 and 30 ppm by 1 week after exposure. None of the rats exposed to 30 ppm survived beyond 1 week. By 13 weeks, dramatic increases in lung volumes were observed in the rats exposed to 10 ppm, while DLco and lung compliance were only mildly affected. However, volume-specific DLco and compliance were depressed in the rats exposed to 10 ppm, suggesting that lung hyperinflation or other compensatory means of increasing lung size occurred in response to the methyl isocyanate-induced lung lesion. This group also exhibited increased expiratory times during tidal breathing and severely impaired distribution of ventilated air. Collectively, these results suggest the development and likely progression of a severe, obstructive airway lesion with associated gas trapping, and the existence of a pronounced concentration-response relationship between 3 and 10 ppm methyl isocyanate exposures.
Assuntos
Obstrução das Vias Respiratórias/induzido quimicamente , Cianatos/toxicidade , Isocianatos , Animais , Cianatos/administração & dosagem , Masculino , Troca Gasosa Pulmonar/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Fatores de Tempo , Capacidade Pulmonar TotalRESUMO
The immunotoxicity of methyl isocyanate (MIC) was evaluated in female B6C3F1 mice exposed via inhalation to 0, 1, or 3 ppm for 6 hr per day on 4 consecutive days. The antibody response to sheep erythrocytes and natural killer cell activity were found to be unaffected by MIC exposure. Although lymphoproliferative responses to mitogens were moderately suppressed by MIC, the differences were not statistically significant. The response of splenic lymphocytes to allogeneic leukocytes in a mixed leukocyte response (MLR) was suppressed in a dose-related fashion and was significantly different from the control response at the 3 ppm level. This effect was thought to be secondary and a result of general toxicity, rather than a direct effect of MIC on the immune system. Furthermore, resistance to the infectious agents Listeria monocytogenes, mouse malaria parasite, and influenza virus, or to transplantable tumor cells was not compromised by MIC exposure. Thus, the immune system does not appear to be a primary target for MIC toxicity.
Assuntos
Cianatos/toxicidade , Sistema Imunitário/efeitos dos fármacos , Isocianatos , Animais , Formação de Anticorpos/efeitos dos fármacos , Cianatos/administração & dosagem , Citotoxicidade Imunológica/efeitos dos fármacos , Feminino , Células Matadoras Naturais/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Teste de Cultura Mista de Linfócitos , CamundongosRESUMO
Male and female F344/N rats and B6C3F1 mice were exposed to lethal and sublethal concentrations of methyl isocyanate by inhalation. Mortality, clinical signs, body and organ weights, and changes in clinical pathology and hematology were monitored immediately after 2-hr exposures and during the ensuing 3 months. Additional studies investigated the possible involvement of cyanide in the toxicity of methyl isocyanate. During exposures, signs of restlessness, lacrimation, and a reddish discharge from the nose and mouth were evident in rats and mice. Following exposures, rats and mice were dyspneic and weak. Deaths of rats and mice exposed to lethal concentrations (20 to 30 ppm) began within 15-18 hr, with males more prone to early death than females. A second wave of deaths occurred after 8 to 10 days, affecting primarily female rats and mice exposed to 20 to 30 ppm of methyl isocyanate, and male and female rats exposed to 10 ppm. Most deaths occurred during the first month following the exposures and were preceded by periods of severe respiratory distress. Body weights decreased in proportion to dose early, but then weight gain resumed in survivors at control rates. The only organ with a consistent, dose-related weight change was the lung, which was heavier throughout the studies in animals exposed to high concentrations of methyl isocyanate. No significant clinical pathology, or hematologic changes were observed in exposed rats. Blood and brain cholinesterase were not inhibited. Studies attempting to measure cyanide in the blood of methyl isocyanate-exposed rats, and attempting to affect lethality with a cyanide antidote (sodium nitrite and sodium thiosulfate) gave negative results.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Cianatos/toxicidade , Isocianatos , Animais , Antídotos/farmacologia , Sangue/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cianatos/administração & dosagem , Cianetos/antagonistas & inibidores , Cianetos/sangue , Feminino , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Tamanho do Órgão/efeitos dos fármacos , Ratos , Ratos Endogâmicos F344 , Sistema Respiratório/efeitos dos fármacos , Fatores de TempoRESUMO
The accidental release of methyl isocyanate (MIC) in Bhopal, India, was reportedly responsible for the deaths of more than 2,000 people. To study the pathology of acute inhalation exposure to MIC, the tissues of male and female Fischer 344 rats were evaluated immediately after a single 2-hr exposure to 0, 3, 10, or 30 ppm MIC, and through day 91. Early gross pathologic changes in the 30 ppm-exposed rats included a reddish white encrustation around the mouth and nose, a small thymus, and distension of the gastrointestinal tract with gas. Lungs (middle and median lobes) showed consolidation and hemorrhage and failed to deflate when the chest cavity was opened. Microscopic changes in the upper respiratory tract 3 hr after exposure included marked erosion and separation of olfactory and respiratory epithelia from the basement membrane with accumulation of serofibrinous fluid. On day 1, acute inflammation and fibrinopurulent exudate partially blocked the nasal passages. Epithelial cells had sloughed from the nasopharynx, trachea, bronchi, and major bronchioles, leaving the basement membrane covered with fibrin and exudate. Granulomatous inflammation and intraluminal fibrosis of the airways were observed by day 3, with increased intraluminal fibrosis by day 7. Lower airways became blocked by exfoliated cells, mucous plugs, and/or intraluminal fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)