Background
Engineered nanoparticles (NPs) are being developed and incorporated in a number of commercial products raising the potential of human exposure during manufacture, use and disposal. Although data about the potential toxicity of some NPs have been reported, validated simple assays are lacking for predicting their in vivo toxicity.
Objective
To evaluate new response-metrics based on chemical and biological activity of NPs for screening assays that can be used to predict NP toxicity in vivo.
Methods
Two cell-free and two cell-based assays were evaluated for their power in predicting in vivo toxicity of eight distinct particle types with widely differing physico-chemical characteristics. The cell-free systems comprised fluorescence- and electron spin resonance-based assays of oxidant activity. The cell-based systems also used electron spin resonance as well as luciferase reporter activity to rank the different particle types in comparison to benchmark particles of low and high activity. In vivo experiments evaluated acute pulmonary inflammatory responses in rats. Endpoints in all assays were related to oxidative stress and responses were expressed per unit NP surface area to compare the results of the different assays.
Results
Results indicate that NPs are capable of producing reactive species, which in biological systems can lead to oxidative stress. Copper NPs had the greatest activity in all assays, while TiO2 and gold NPs generally were the least reactive. Differences in the ranking of NP activity among the assays were found when comparisons were based on measured responses. However, expressing the chemical (cell-free) and biological (cells; in vivo) activity per unit particle surface area showed that all in vitro assays correlated significantly with in vivo results (R>0.81), with the cellular assays correlating best (R>0.87).
Conclusions
Data from this study indicate that it is possible to predict acute in vivo inflammatory potential of NPs with cell-free and cellular assays by using NP surface area-based dose and response metrics, but that a cellular component is required to achieve a higher degree of predictive power.
We present in this paper a review of the toxicological and environmental hazards, exposures and risks of tetrahydrofuran (THF; CASRN 109-99-9). THF is a polar solvent and monomer that is easily absorbed by all routes of exposure. The acute toxicity of THF is low to moderate by all routes. Irreversible corrosive damage to the eye can result from direct contact. However, THF is neither a skin irritant, nor sensitizer. Studies in vitro and in vivo have shown that THF is not mutagenic. Chronic studies have found benign tumors in the kidneys of male rats and in the livers of female mice. These findings have been examined, and although a mode of action is not known, the weight of evidence suggests that these tumors are likely not relevant to human health, but instead secondary to rodent-specific modes of action. THF produces transient sedative effects in rats at high concentrations but no significant neurobehavioral changes or neuropathology in sub-chronic studies. There were no specific effects reported on reproduction or developmental toxicity in rats or mice, with non-specific developmental toxicity observed only in the presence of significant maternal toxicity. The log K(ow) value for THF is less than 3, indicating a low potential for bioaccumulation. THF is inherently biodegradable, thus is not expected to be environmentally persistent. THF does not present an ecotoxicity hazard based on test results in fish, aquatic invertebrates and plants. Exposures to THF in the workplace, to consumers and via environmental releases were modeled and all found to fall below the derived toxicity thresholds.
2-methyl 1,3-propandiol (MPD) is a low molecular weight, colorless glycol used in polymer and coating applications. The log Kow of -0.6 suggests partitioning to aqueous phases with a low concern for possible bioaccumulation. MPD was found to be inherently biodegradable. Ecotoxicological results in several aquatic and terrestrial species found no significant hazard potential. MPD is rapidly absorbed via the oral and dermal routes, metabolized to 3-hydroxybutyrate, and excreted in urine with a half-life of 3.6 h. Acute toxicity testing found low toxicity via all routes. Barely perceptible skin irritation was observed in human volunteers, whereas there was no evidence of irritation in rabbits. Skin sensitization in Guinea pigs was negative. Human skin patch results indicated minimal response in about 1% of individuals. There was no evidence of mutagenicity using bacterial and mammalian test systems. A 90-day oral study in rats found no adverse effects at any dose. Three developmental toxicity studies in rats and rabbits, found no treatment-related maternal toxicity, fetal toxicity or malformations. A two-generation reproduction study in rats found no consistent treatment-related adverse effects on reproduction in either generation. No carcinogenicity studies with MPD were identified. MPD presents a low degree of toxicological and ecotoxicological or environmental hazard.
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