RESUMO
Alpha-diketones, notably diacetyl, have been used as flavoring agents. When airborne in occupational settings, exposures to diacetyl have been associated with serious respiratory disease. Other α-diketones, such as 2,3-pentanedione, and analogues such as acetoin (a reduced form of diacetyl), require evaluation, particularly, in light of recently available toxicological studies. The current work reviewed mechanistic, metabolic, and toxicology data available for α-diketones. Data were most available for diacetyl and 2,3-pentanedione, and a comparative assessment of their pulmonary effects was performed, and an occupational exposure limit (OEL) was proposed for 2,3-pentanedione. Previous OELs were reviewed and an updated literature search was performed. Respiratory system histopathology data from 3-month toxicology studies were evaluated with benchmark dose (BMD) modelling of sensitive endpoints. This demonstrated comparable responses at concentrations up to 100 ppm, with no consistent overall pattern of greater sensitivity to either diacetyl or 2,3-pentanedione. In contrast, based on draft raw data, no adverse respiratory effects were observed in comparable 3-month toxicology studies that evaluated exposure to acetoin at up to 800 ppm (highest tested concentration), indicating that acetoin does not present the same inhalation hazard as diacetyl or 2,3-pentanedione. To derive an OEL for 2,3-pentanedione, BMD modelling was conducted for the most sensitive endpoint from 90-day inhalation toxicity studies, namely, hyperplasia of nasal respiratory epithelium. On the basis of this modelling, an 8-hour time-weighted average OEL of 0.07 ppm is proposed to be protective against respiratory effects that may be associated with chronic workplace exposure to 2,3-pentanedione.
Assuntos
Diacetil , Exposição Ocupacional , Diacetil/toxicidade , Acetoína , Cetonas , Pentanonas/toxicidadeRESUMO
A banding scheme theory has been proposed to assess the potency/toxicity of biologics and assist with decisions regarding the introduction of new biologic products into existing manufacturing facilities. The current work was conducted to provide a practical example of how this scheme could be applied. Information was identified for representatives from the following four proposed bands: Band A (lethal toxins); Band B (toxins and apoptosis signals); Band C (cytokines and growth factors); and Band D (antibodies, antibody fragments, scaffold molecules, and insulins). The potency/toxicity of the representative substances was confirmed as follows: Band A, low nanogram quantities exert lethal effects; Band B, repeated administration of microgram quantities is tolerated in humans; Band C, endogenous substances and recombinant versions administered to patients in low (interferons), intermediate (growth factors), and high (interleukins) microgram doses, often on a chronic basis; and Band D, endogenous substances present or produced in the body in milligram quantities per day (insulin, collagen) or protein therapeutics administered in milligram quantities per dose (mAbs). This work confirms that substances in Bands A, B, C, and D represent very high, high, medium, and low concern with regard to risk of cross-contamination in manufacturing facilities, thus supporting the proposed banding scheme.
Assuntos
Produtos Biológicos/normas , Contaminação de Medicamentos/prevenção & controle , Indústria Farmacêutica/normas , Indústria Farmacêutica/métodos , Humanos , Indústria Manufatureira/métodos , Indústria Manufatureira/normas , Medição de Risco/métodos , Medição de Risco/normasRESUMO
To better understand the relationships between chemical exposures and human cancer causation, incidence data for human cancer types were identified and pancreatic and colorectal cancers were studied in-depth to assess whether data supporting the causation of pancreatic or colorectal tumors by chemicals in rodents is predictive of causation by the same chemicals of the same tumors in humans. A search of the Carcinogenic Potency Database, the National Toxicology Program (NTP) technical report database, and the published literature identified 38 and 39 chemicals reported to cause pancreatic and colorectal tumors, respectively, in mice or rats. For each of these chemicals, searches were conducted of the International Agency for Research on Cancer monographs, the NTP Report on Carcinogens, and the published literature for evidence of induction of the same tumors in humans. Based on this evaluation, no conclusive evidence was identified to suggest that chemicals reported to cause pancreatic or colorectal tumors in rodents also cause these tumors in humans. These findings suggest that pancreatic tumor data from mouse and rat bioassays are of limited utility with regard to predicting similar tumor induction in humans. For colorectal cancer, a lack of correlation was noted for the vast majority of chemicals.
Assuntos
Carcinógenos/toxicidade , Neoplasias Colorretais/induzido quimicamente , Neoplasias Pancreáticas/induzido quimicamente , Animais , Testes de Carcinogenicidade/métodos , Neoplasias Colorretais/epidemiologia , Bases de Dados Factuais , Humanos , Camundongos , Neoplasias Pancreáticas/epidemiologia , Ratos , Especificidade da EspécieRESUMO
Transient receptor potential channels (TRPCs) are widely expressed and regulate Ca²âº entry in the cells that participate in the pathophysiology of airway hyperreactivity, inflammation, and remodeling. In vitro studies point to a role for TRPC1-mediated Ca²âº signaling in several of these cell types; however, physiological evidence is lacking. Here we identify TRPC1 signaling as proinflammatory and a regulator of lung hyperresponsiveness during allergen-induced pulmonary response. TRPC1-deficient (Trpc1(-/-)) mice are hyposensitive to methacholine challenge and have significantly reduced allergen-induced pulmonary leukocyte infiltration coupled with an attenuated T helper type 2 (Th2) cell response. Upon in vitro allergen exposure, Trpc1(-/-) splenocytes show impaired proliferation and T cell receptor-induced IL-2 production. A high number of germinal centers in spleens of Trpc1(-/-) mice and elevated levels of immunoglobulins in their serum are indicative of dysregulated B cell function and homeostasis. Thus we propose that TRPC1 signaling is necessary in lymphocyte biology and in regulation of allergen-induced lung hyperresponsiveness, making TRPC1 a potential target for treatment of immune diseases and asthma.
Assuntos
Hiper-Reatividade Brônquica/imunologia , Pulmão/imunologia , Canais de Cátion TRPC/fisiologia , Células Th2/imunologia , Alérgenos/imunologia , Animais , Feminino , Interleucina-2 , Masculino , Camundongos , Transdução de Sinais/imunologia , Baço/citologia , Canais de Cátion TRPC/deficiência , Canais de Cátion TRPC/genéticaRESUMO
Nanotechnology is providing new and innovative means to detect, diagnose, and treat disease. In this regard, numerous nanoparticle-based approaches have been taken in an effort to develop an effective oral insulin therapy for the treatment of diabetes. This review summarizes efficacy data from studies that have evaluated oral insulin therapies in experimental models. Also provided here is an overview of the limited safety data that have been reported in these studies. To date, the most promising approaches for nanoparticle-based oral insulin therapy appear to involve the incorporation of insulin into complex multilayered nanoparticles that are mucoadhesive, biodegradable, biocompatible, and acid protected and into nanoparticles that are designed to take advantage of the vitamin B(12) uptake pathway. It is anticipated that the continued investigation and optimization of nanoparticle-based formulations for oral delivery of insulin will lead to a much sought-after noninvasive treatment for diabetes. Such investigations also may provide insight into the use of nanoparticle-based formulations for peptide- and protein-based oral treatment of other diseases and for various food-related purposes.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Nanopartículas/administração & dosagem , Administração Oral , Animais , Humanos , Nanopartículas/efeitos adversosRESUMO
Prostaglandin E(2) (PGE(2)) is a lipid mediator that is produced via the metabolism of arachidonic acid by cyclooxygenase enzymes. In the lung, PGE(2) acts as an anti-inflammatory factor and plays an important role in tissue repair processes. Although several studies have examined the role of PGE(2) in the pathogenesis of pulmonary fibrosis in rodents, results have generally been conflicting, and few studies have examined the therapeutic effects of PGE(2) on the accompanying lung dysfunction. In this study, an established model of pulmonary fibrosis was used in which 10-12-wk-old male C57BL/6 mice were administered a single dose (1.0 mg/kg) of bleomycin via oropharyngeal aspiration. To test the role of prostaglandins in this model, mice were dosed, via surgically implanted minipumps, with either vehicle, PGE(2) (1.32 µg/h), or the prostacyclin analog iloprost (0.33 µg/h) beginning 7 days before or 14 days after bleomycin administration. Endpoints assessed at 7 days after bleomycin administration included proinflammatory cytokine levels and measurement of cellular infiltration into the lung. Endpoints assessed at 21 days after bleomycin administration included lung function assessment via invasive (FlexiVent) analysis, cellular infiltration, lung collagen content, and semiquantitative histological analysis of the degree of lung fibrosis (Ashcroft method). Seven days after bleomycin administration, lymphocyte numbers and chemokine C-C motif ligand 2 expression were significantly lower in PGE(2)- and iloprost-treated animals compared with vehicle-treated controls (P < 0.05). When administered 7 days before bleomycin challenge, PGE(2) also protected against the decline in lung static compliance, lung fibrosis, and collagen production that is associated with 3 wk of bleomycin exposure. However, PGE(2) had no therapeutic effect on these parameters when administered 14 days after bleomycin challenge. In summary, PGE(2) prevented the decline in lung static compliance and protected against lung fibrosis when it was administered before bleomycin challenge but had no therapeutic effect when administered after bleomycin challenge.
Assuntos
Bleomicina/efeitos adversos , Colágeno/biossíntese , Dinoprostona/farmacologia , Iloprosta/farmacologia , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/tratamento farmacológico , Animais , Bleomicina/administração & dosagem , Líquido da Lavagem Broncoalveolar/citologia , Colágeno/análise , Citocinas/biossíntese , Dinoprostona/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Histocitoquímica , Humanos , Iloprosta/metabolismo , Bombas de Infusão Implantáveis , Contagem de Leucócitos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Fibrose Pulmonar/fisiopatologia , Fibrose Pulmonar/prevenção & controle , Reação em Cadeia da Polimerase em Tempo Real , Índice de Gravidade de DoençaRESUMO
Nanotechnology is poised to impact the food and food-related industries through improvements in areas as diverse as production, packaging, shelf life, and bioavailability of food and beverage components. An evaluation was undertaken to characterize the published literature pertaining to the safety of oral exposure to food-related nanomaterials and to identify research needs in this area. Thirty publications were identified in which a toxicological endpoint was assessed following in vivo (oral) or in vitro exposure to food-related nanomaterials. These publications were evaluated for overall quality using a two-step method that determined the reliability of the study design and the extent of nanomaterial characterization within each study. Of the 21 in vivo studies evaluated, 20 used mice or rats, 15 were lacking in some critical component of study design (e.g., oral gavage dose volume was not reported), none was longer than 90 days in duration, and only seven reported more than five physicochemical parameters for the nanomaterial(s) being evaluated. Of the nine in vitro studies evaluated, seven focused on cytotoxicity, two evaluated genotoxicity, only five reported more than five physicochemical parameters for the nanomaterial(s) being evaluated, and none discussed the potential interference by the nanomaterial(s) of the experimental assays that were employed. The results of this evaluation indicate that there is currently insufficient reliable data to allow clear assessment of the safety of oral exposure to food-related nanomaterials. Significant investment must be made to generate studies of sufficient quality and duration and that report comprehensive nanomaterial characterization such that results can be judged reliable and interpretable. Failure to do so will result in the perpetuation of the publication of studies that are inadequate for use in risk characterization.
Assuntos
Inocuidade dos Alimentos , Nanopartículas/toxicidade , Nanoestruturas/toxicidade , Testes de Toxicidade , Administração Oral , Animais , Fenômenos Químicos , Alimentos , Camundongos , Nanotecnologia , RatosRESUMO
Nanotechnology and nanomaterials have tremendous potential to enhance the food supply through novel applications, including nutrient and bioactive absorption and delivery systems; ingredient functionality; improved colors and flavors; microbial, allergen, and contaminant detection and control; and food packaging properties and performance. To determine the current state of knowledge regarding the safety of these potential uses of nanomaterials, an appraisal of the published literature on the safety of food-related nanomaterials was undertaken. A method of assessment of reliability of toxicology studies was developed to conduct this appraisal. The review of the toxicology literature on oral exposure to food-related nanomaterials found that the number of studies is limited. Exposure to nanomaterials in the human food chain may occur not only through intentional uses in food manufacturing, but also via uses in agricultural production and carry over from use in other industries. Although a number of analytical methods are useful in physicochemical characterization of manufactured nanomaterials, new methods may be needed to more fully detect and characterize nanomaterials incorporated into foods and in other media. There is a need for additional toxicology studies of sufficient quality and duration on different types of nanomaterials to further our understanding of the characteristics of nanomaterials that affect safety of oral exposure resulting from use in various food applications.
Assuntos
Aditivos Alimentares/efeitos adversos , Aditivos Alimentares/química , Tecnologia de Alimentos , Nanoestruturas/efeitos adversos , Nanoestruturas/química , Animais , Aditivos Alimentares/análise , Contaminação de Alimentos , Inspeção de Alimentos/métodos , Embalagem de Alimentos , Conservantes de Alimentos/efeitos adversos , Conservantes de Alimentos/análise , Conservantes de Alimentos/química , Tecnologia de Alimentos/tendências , Alimentos Fortificados/efeitos adversos , Alimentos Fortificados/análise , Indústria de Processamento de Alimentos/tendências , Humanos , Nanoestruturas/análise , Nanotecnologia/tendênciasRESUMO
As reports on the safety of various nanomaterials have yielded conflicting results, assessment of the reliability of each study is required to objectively interpret overall safety of the nanomaterial. A 2-step method to assess the quality of nanotoxicity studies is described. The first step uses a publicly available tool to rank the reliability of the study based on adequacy of design and documentation of methods, materials, and results, providing a "study score." The second step determines the completeness of physicochemical characterization of the nanomaterial/nanomaterials assessed within the study, providing a "nanomaterial score." This approach is encouraged to promote the notion that for studies conducted with nanomaterials, the combination of a reliable study and sufficient nanomaterial characterization is of significantly greater value than either of these alone. It is anticipated that the use and evolution of this approach will assist with the design and interpretation of studies assessing nanomaterial toxicity.
Assuntos
Nanoestruturas , Testes de Toxicidade , Animais , Masculino , Camundongos , Reprodutibilidade dos TestesRESUMO
Accumulating evidence suggests that bacteria associated with periodontal disease may exert systemic immunomodulatory effects. Although the improvement in oral hygiene practices in recent decades correlates with the increased incidence of asthma in developed nations, it is not known whether diseases of the respiratory system might be influenced by the presence of oral pathogens. The present study sought to determine whether subcutaneous infection with the anaerobic oral pathogen Porphyromonas gingivalis exerts a regulatory effect on allergic airway inflammation. BALB/c mice sensitized and subsequently challenged with ovalbumin exhibited airway hyperresponsiveness to methacholine aerosol and increased airway inflammatory cell influx and Th2 cytokine (interleukin-4 [IL-4], IL-5, and IL-13) content relative to those in nonallergic controls. Airway inflammatory cell and cytokine contents were significantly reduced by establishment of a subcutaneous infection with P. gingivalis prior to allergen sensitization, whereas serum levels of ovalbumin-specific IgE and airway responsiveness were not altered. Conversely, subcutaneous infection initiated after allergen sensitization did not alter inflammatory end points but did reduce airway responsiveness in spite of increased serum IgE levels. These data provide the first direct evidence of a regulatory effect of an oral pathogen on allergic airway inflammation and responsiveness. Furthermore, a temporal importance of the establishment of infection relative to allergen sensitization is demonstrated for allergic outcomes.
Assuntos
Asma/imunologia , Asma/patologia , Tolerância Imunológica , Porphyromonas gingivalis/imunologia , Hipersensibilidade Respiratória/imunologia , Hipersensibilidade Respiratória/patologia , Animais , Citocinas/antagonistas & inibidores , Feminino , Imunoglobulina E/sangue , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Drawing accurate conclusions from toxicology studies is of critical importance, including the relatively new field of nanotoxicology, as results of these toxicity studies will likely have significant impact on regulatory decisions with regard to their use in consumer products, as well as consumer understanding of these materials. Therefore, we feel it necessary to point out our concerns with the recent report by Wu and colleagues (Wu et al., 2009).
Assuntos
Nanopartículas Metálicas/toxicidade , Titânio/toxicidade , Administração Cutânea , Animais , Abrigo para Animais , Hidroxiprolina/metabolismo , Nanopartículas Metálicas/administração & dosagem , Camundongos , Modelos Animais , Suínos , Testes de Toxicidade/métodosRESUMO
Numerous studies in humans and experimental animals have identified considerable sex differences in respiratory physiology and in the response of the lung to environmental agents. These differences appear to be mediated, at least in part, by sex hormones and their nuclear receptors. Moreover, animal models are increasingly used to study pathogenic mechanisms and test potential therapies for a variety of human lung diseases, many of which appear to be influenced by sex and sex hormones. In this article, data are summarized from studies of lung function and disease in which sex differences have been observed. Specific attention is paid to animal models of acute lung injury, nonallergic and allergic lung inflammation, and lung fibrosis. It is anticipated that continued investigation of the role of sex and sex hormones in animal models will provide valuable insight into the pathogenesis and potential treatments for a variety of acute and chronic human lung diseases.
Assuntos
Hormônios Esteroides Gonadais/fisiologia , Pulmão/fisiologia , Doenças Respiratórias/fisiopatologia , Animais , Modelos Animais de Doenças , Humanos , Fatores SexuaisRESUMO
Recently published literature has been reviewed to determine whether lycopene, beta-carotene, alpha-carotene, and beta-cryptoxanthin are associated with reductions in cancer risk and whether study findings differ by study design. A total of 57 publications meeting pre-defined inclusion and exclusion criteria were identified, with the majority (55) being observational studies. None of the intervention studies supported a significant reduction in cancer risk with carotenoid (beta-carotene) supplementation. The majority of observational studies did not support significant reductions in cancer risk with increased carotenoid dietary intakes/circulating levels. A larger percentage of case-control studies supported significant associations between increased dietary intakes/circulating levels of carotenoids relative to prospective (cohort and nested case-control) studies. Compared to prospective studies, case-control studies cannot be used to establish temporality and may be more susceptible to selection and recall biases. Thus, diet-disease relationships suggested by case-control studies should ideally be confirmed by additional evidence from prospective studies.
Assuntos
Anticarcinógenos , Carotenoides/administração & dosagem , Dieta , Neoplasias/prevenção & controle , Projetos de Pesquisa , Comportamento de Redução do Risco , Carotenoides/sangue , Carotenoides/farmacologia , Humanos , Fatores de RiscoAssuntos
Sistemas de Liberação de Medicamentos , Hipertensão Pulmonar/tratamento farmacológico , Nanopartículas/administração & dosagem , Oligodesoxirribonucleotídeos/administração & dosagem , Animais , NF-kappa B/antagonistas & inibidores , NF-kappa B/fisiologia , Nanopartículas/toxicidade , Nanotubos de Carbono , RatosRESUMO
Because of their unique physicochemical properties, engineered nanoparticles have the potential to significantly impact respiratory research and medicine by means of improving imaging capability and drug delivery, among other applications. These same properties, however, present potential safety concerns, and there is accumulating evidence to suggest that nanoparticles may exert adverse effects on pulmonary structure and function. The respiratory system is susceptible to injury resulting from inhalation of gases, aerosols, and particles, and also from systemic delivery of drugs, chemicals, and other compounds to the lungs via direct cardiac output to the pulmonary arteries. As such, it is a prime target for the possible toxic effects of engineered nanoparticles. The purpose of this article is to provide an overview of the potential usefulness of nanoparticles and nanotechnology in respiratory research and medicine and to highlight important issues and recent data pertaining to nanoparticle-related pulmonary toxicity.
Assuntos
Pulmão/efeitos dos fármacos , Nanopartículas/toxicidade , Nanopartículas/uso terapêutico , Animais , Sistemas de Liberação de Medicamentos , Humanos , Pulmão/metabolismo , Modelos Biológicos , Nanotecnologia , Distribuição TecidualRESUMO
The roles of sex hormones as modulators of lung function and disease have received significant attention as differential sex responses to various lung insults have been recently reported. The present study used a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice to examine potential sex differences in physiological and pathological outcomes. Endpoints measured included invasive lung function assessment, immunological response, lung collagen deposition, and a quantitative histological analysis of pulmonary fibrosis. Male mice had significantly higher basal static lung compliance than female mice (P < 0.05) and a more pronounced decline in static compliance after bleomycin administration when expressed as overall change or percentage of baseline change (P < 0.05). In contrast, there were no significant differences between the sexes in immune cell infiltration into the lung or in total lung collagen content after bleomycin. Total lung histopathology scores measured using the Ashcroft method did not differ between the sexes, while a quantitative histopathology scoring system designed to determine where within the lung the fibrosis occurred indicated a tendency toward more fibrosis immediately adjacent to airways in bleomycin-treated male versus female mice. Furthermore, castrated male mice exhibited a female-like response to bleomycin while female mice given exogenous androgen exhibited a male-like response. These data indicate that androgens play an exacerbating role in decreased lung function after bleomycin administration, and traditional measures of fibrosis may miss critical differences in lung function between the sexes. Sex differences should be carefully considered when designing and interpreting experimental models of pulmonary fibrosis in mice.
Assuntos
Bleomicina/toxicidade , Di-Hidrotestosterona/farmacologia , Estradiol/deficiência , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/fisiopatologia , Animais , Colágeno/metabolismo , Feminino , Inflamação/induzido quimicamente , Inflamação/fisiopatologia , Complacência Pulmonar/efeitos dos fármacos , Complacência Pulmonar/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Orquiectomia , Ovariectomia , Reação em Cadeia da Polimerase , RNA/genética , Testes de Função Respiratória , Caracteres SexuaisAssuntos
Resistência das Vias Respiratórias , Pneumopatias/fisiopatologia , Pulmão/fisiopatologia , Mecânica Respiratória , Animais , Modelos Animais de Doenças , Elasticidade , Impedância Elétrica , Pulmão/patologia , Complacência Pulmonar , Pneumopatias/patologia , Medidas de Volume Pulmonar , Modelos Biológicos , Pressão , Reprodutibilidade dos Testes , Testes de Função RespiratóriaRESUMO
Accumulating evidence suggests that gender affects the incidence, susceptibility and severity of several lung diseases. Gender also influences lung development and physiology. Data from both human and animal studies indicate that sex hormones might contribute to disease pathogenesis or serve as protective factors, depending on the disease involved. In this review, the influence of gender and sex hormones on lung development and pathology will be discussed, with specific emphasis on pulmonary fibrosis, asthma and cancer.