RESUMO
The development of a risk management system for nanoscale or ultrafine particle-types requires a base set of hazard data. Assessing risk is a function of hazard and exposure data. Previously, we have suggested "parallel tracks" as a strategy for conducting nanoparticle research. On the one hand, mechanistic studies on "representative" nanoparticles could be supported by governmental agencies. Alternatively, with regard to commercial nanoparticles, the environmental, health and safety (EHS) framework would include a minimum base set of toxicity studies which should be supported by the companies that are developing nano-based products. The minimum base set could include the following criteria: substantial particle characterization, pulmonary toxicity studies, acute dermal toxicity and sensitization studies, acute oral and ocular toxicity studies, along with screening type genotoxicity, and aquatic toxicity studies. We report here the toxicity results of a base set of hazard tests on a set of newly developed, well-characterized, ultrafine TiO(2) (uf-TiO(2)) particle-types. In vivo pulmonary toxicity studies in rats demonstrated low inflammatory potential and lung tissue toxicity. Acute dermal irritation studies in rabbits and local lymph node assay results in mice indicated that uf-TiO(2) was not a skin irritant or dermal sensitizer. Acute oral toxicity studies demonstrated very low toxicity and uf-TiO(2) produced short-term and reversible ocular conjunctival redness in rabbits. Genotoxicity tests demonstrated that uf-TiO(2) was negative in both the bacterial reverse mutation test and in an in vitro mammalian chromosome aberration test with Chinese hamster ovary cells. The results of aquatic toxicity screening studies demonstrated that uf-TiO(2) exhibited low concern for aquatic hazard in unaerated, 48h, static acute tests using the water flea, Daphnia magna; exhibited low concern for aquatic hazard in unaerated, 96h, static acute tests using the rainbow trout, Oncorhynchus mykiss; and exhibited medium concern in a 72h acute test using the green algae Pseudokirchneriella subcapitata. To summarize the findings, the results of most of the studies demonstrated low hazard potential in mammals or aquatic species following acute exposures to the ultrafine TiO(2) particle-types tested in this program.
Assuntos
Nanopartículas/toxicidade , Titânio/toxicidade , Animais , Células CHO , Clorófitas , Aberrações Cromossômicas/induzido quimicamente , Cricetinae , Cricetulus , Daphnia , Oftalmopatias/induzido quimicamente , Oftalmopatias/patologia , Irritantes , Ensaio Local de Linfonodo , Pneumopatias/induzido quimicamente , Pneumopatias/patologia , Camundongos , Microscopia Eletrônica de Varredura , Testes de Mutagenicidade , Oncorhynchus mykiss , Tamanho da Partícula , Quartzo/toxicidade , Coelhos , Ratos , Gestão de Riscos , Salmonella typhimurium/efeitos dos fármacos , Salmonella typhimurium/genética , Dermatopatias/induzido quimicamente , Dermatopatias/patologiaRESUMO
The purpose of this study was to compare the toxicity of linear/branched ammonium perfluorooctanoate (APFO) with that of linear and branched APFO. Linear/branched APFO (approximately 80% linear and 20% branched isomers) was formerly used in the production of commercial products. The extensive toxicologic database for APFO has been developed essentially using this mixture of isomers. The trend now is to use APFO containing only the linear isomer. The current study was performed to determine if the toxicological database developed for the linear/branched isomer is applicable to the linear isomer. To determine the contribution of branched APFO to the toxicity of linear/branched APFO, a form of APFO that was 100% branched was synthesized. Rats and mice were given doses by oral gavage ranging from 0.3 to 30 mg/kg of either the linear/branched, linear, or branched APFO for 14 days. Clinical signs, body weights, food consumption, selected hematology and serum lipid parameters, liver and kidney weights, hepatic peroxisomal beta-oxidation, and serum PFOA concentrations were evaluated. Mean body weights were about 20% lower in rats and mice dosed with 30 mg/kg of linear/branched or linear APFO compared to controls, and 3-5% lower in animals dosed with 30 mg/kg of branched APFO. In rats, all three forms reduced lipids. In mice, all three forms reduced total and HDL cholesterol similarly but triglycerides were increased at lower doses. Increased peroxisomal beta-oxidation activity and serum PFOA concentrations were seen in both species but these effects were least pronounced in rats dosed with the branched material. In rats, serum PFOA levels were 20-51 ppm at Lowest Observed Effect Levels (LOEL) of 0.3-1 mg/kg, based primarily upon lipid parameters. In mice, serum PFOA levels were 10-14 ppm at the LOEL of 0.3 mg/kg, based primarily upon relative liver weight. In both rats and mice, the overall responses to the linear/branched and the linear forms of PFOA were similar, but the branched form appears to be less potent. Based on these results, and for the endpoints evaluated in this study, the toxicological database developed primarily from testing linear/branched APFO is applicable to linear APFO.
Assuntos
Caprilatos/toxicidade , Fluorocarbonos/toxicidade , Animais , Caprilatos/química , Caprilatos/farmacocinética , Fluorocarbonos/química , Fluorocarbonos/farmacocinética , Rim/efeitos dos fármacos , Rim/crescimento & desenvolvimento , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/crescimento & desenvolvimento , Camundongos , Camundongos Endogâmicos , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , Peroxissomos/metabolismo , Ratos , Ratos Endogâmicos , Aumento de Peso/efeitos dos fármacosRESUMO
The glyphosate acetyltransferase (gat) gene from Bacillus licheniformis was subjected to multiple rounds of gene shuffling to optimize kinetics of corresponding GAT proteins to acetylate the herbicide active ingredient glyphosate. Genetically modified soybeans expressing the gat4601 gene (356043 soybeans) are tolerant to the application of glyphosate. The current manuscript reports the outcome of the allergenicity and toxicity assessment for the GAT4601 protein. Bioinformatic comparison of the amino acid sequence of GAT4601 did not identify similarities to known allergenic or toxic proteins. In vitro studies conducted with heterologously produced GAT4601 protein demonstrated that it was rapidly degraded in simulated gastric fluid containing pepsin (< 30 s) and in simulated intestinal fluid containing pancreatin (< 2 min) and completely inactivated at temperatures above 56 degrees C. The GAT4601 protein expressed in planta is not glycosylated and similar protein profiles were observed in flour extracts from 356043 soybeans and nontransgenic near isoline comparator soybeans (Jack) using serum from soy allergic persons. No evidence of adverse effects was observed in mice following acute oral exposure to 2000 mg/kg of GAT4601 protein or in a repeated dose dietary exposure study at doses of 800-1000 mg/kg/day. This comprehensive assessment demonstrates that the GAT4601 protein does not present a risk for adverse effects in humans when used in the context of agricultural biotechnology.
Assuntos
Acetiltransferases/toxicidade , Alérgenos/toxicidade , Bacillus/enzimologia , Proteínas de Bactérias/toxicidade , Hipersensibilidade Alimentar/imunologia , Acetiltransferases/química , Acetiltransferases/imunologia , Alérgenos/química , Alérgenos/imunologia , Sequência de Aminoácidos , Ração Animal , Fenômenos Fisiológicos da Nutrição Animal , Animais , Proteínas de Bactérias/química , Proteínas de Bactérias/imunologia , Técnicas In Vitro , Camundongos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Plantas Geneticamente Modificadas , Engenharia de Proteínas/métodos , Glycine max/efeitos dos fármacos , Glycine max/enzimologia , Glycine max/genética , Testes de ToxicidadeRESUMO
The object of this study was to evaluate the toxicity of norbornene fluoroalcohol (NBFOH), which is used as an intermediate in the production of fluorinated monomers and polymers. NBFOH was evaluated for acute oral, dermal, and inhalation toxicity, dermal sensitization using the Local Lymph Node Assay (LLNA), mutagenesis by the Ames assay, and subchronic toxicity in a 4-week inhalation rat study. NBFOH demonstrated slight acute toxicity in oral, dermal, and inhalation studies. Approximate lethal doses of 3400 and > 5000 mg/kg for the oral and dermal routes, respectively, and an approximate lethal concentration of 4300 mg/m(3) were determined. NBFOH demonstrated moderate skin irritation, was a severe eye irritant, produced dermal sensitization, but did not cause bacterial mutagenicity either in the presence or absence of S9 activation. Male and female rats were exposed nose only to airborne NBFOH at levels of 0, 410, 1400, and 1500 mg/m(3), 6 h/day, 5 days/week for 4 weeks with clinical and histopathology specimens collected 1 day after the final exposure. Due to the vapor pressure of NBFOH, the 1500 mg/m(3) atmosphere was 27% aerosol and 73% vapor; the 1400 mg/m(3) atmosphere was 5% aerosol and 95% vapor, and the 410 mg/m(3) level was only vapor. No test substance-related mortality or clinical signs of toxicity were observed over the course of the study, and male rats demonstrated significant weight loss and decreased food consumption at 1400 mg/m(3). Male rats from the 1500 mg/m(3) group demonstrated an 11% increase in prothrombin time that was significantly higher than the control value. Examination of fluoride in the urine did not demonstrate a concentration-response relationship, with minimal elevations observed in male rats at all exposure levels and sporadic increases in females. Both male and female rats exposed to 1400 mg/m(3) or greater had squamous metaplasia of the laryngeal mucosa and degeneration of the nasal olfactory and respiratory mucosa. Based on the above findings, NBFOH demonstrates the potential to produce allergic contact dermatitis, and subchronic inhalation studies indicate a no-observed-adverse-effect-level (NOAEL) of 410 mg/m(3).