It is well recognized that physical and chemical properties of materials can alter dramatically at nanoscopic scale, and the growing use of nanotechnologies requires careful assessment of unexpected ...toxicities and biological interactions. However, most
in vivo toxicity concerns focus primarily on pulmonary, oral, and dermal exposures to ultrafine particles. As nanomaterials expand as therapeutics and as diagnostic tools, parenteral administration of engineered nanomaterials should also be recognized as a critical aspect for toxicity consideration. Due to the complex nature of nanomaterials, conflicting studies have led to different views of their safety. Here, the physicochemical properties of four representative nanomaterials (dendrimers, carbon nanotubes, quantum dots, and gold nanoparticles) as it relates to their toxicity after systemic exposure is discussed.
Ginkgo biloba
extract (GbE) is a dietary supplement derived from an ethanolic extract of
Ginkgo biloba
leaves. Unfinished bulk GbE is used to make finished products that are sold as dietary ...supplements. The variable, complex composition of GbE makes it difficult to obtain consistent toxicological assessments of potential risk. The National Toxicology Program (NTP) observed hepatotoxicity in its rodent studies of a commercially available, unfinished GbE product, but the application of these results to the broader GbE supplement market is unclear. Here, we use a combination of non-targeted and targeted chromatographic and spectrophotometric methods to obtain profiles of 24 commercially available finished GbE products and unfinished standardized and unstandardized extracts with and without hydrolysis, then used principal component analysis to group unfinished products according to their similarity to each other and to National Institute of Standards and Technology (NIST) standard reference materials (SRM), and the finished products. Unfinished products were grouped into those that were characteristic and uncharacteristic of standardized GbE. Our work demonstrates that different analytical approaches produced similar classifications of characteristic and uncharacteristic products in unhydrolyzed samples, but the distinctions largely disappeared once the samples were hydrolyzed. Using our approach, the NTP GbE was most similar to two unfinished GbE products classified as characteristic, finished products, and the NIST GbE SRM. We propose that a simple analysis for the presence, absence, or amounts of compounds unique to GbE in unhydrolyzed samples could be sufficient to determine a sample’s authenticity.
Graphical abstract
Cisplatin (CDDP) intravenous treatments suffer several dose-limiting toxicity issues. Hyaluronan (HA), a naturally occurring biopolymer in the interstitium, is primarily cleared by the lymphatic ...system. An alteration in input rate and administration route through pulmonary delivery of hyaluronan–cisplatin (HA–Pt) conjugate may increase local lung CDDP concentrations and decrease systemic toxicity.
Sprague–Dawley rats were split into four groups: i.v. CDDP (3.5
mg/kg), i.v. HA–Pt conjugate (3.5
mg/kg equivalent CDDP), lung instillation CDDP and lung instillation HA–Pt conjugate. Total platinum level in the lungs of the HA–Pt lung instillation group was 5.7-fold and 1.2-fold higher than the CDDP intravenous group at 24 and 96
h, respectively. A 1.1-fold increase of Pt accumulation in lung draining nodes for the HA–Pt lung instillation group was achieved at 24
h relative to the CDDP i.v. group. In the brain and kidneys, the CDDP i.v. group had higher tissue/plasma ratios compared to the HA–Pt lung instillation group. Augmented tissue distribution from CDDP i.v. could translate into enhanced tissue toxicity compared to the altered input rate and distribution of the intrapulmonary nanoformulation.
In conclusion, a local pulmonary CDDP delivery system was developed with increased platinum concentration in the lungs and draining nodes compared to i.v. therapy.
Tris(chloropropyl) phosphate (TCPP) is an organophosphorus flame retardant and plasticizer used in manufacturing and multiple consumer products. Commercial TCPP is a ubiquitous environmental ...contaminant and TCPP or its metabolites have been detected in human plasma and urine. In response to the demonstrated widespread human exposure and lack of toxicity data, the Division of the National Toxicology Program is investigating the chronic toxicity of TCPP following perinatal exposure in HSD:Sprague Dawley®SD® (HSD) rats (up to 20,000 ppm) and adult exposure in B6C3F1/N mice (females, up to 10,000 ppm; males up to 5000 ppm) to TCPP via feed. Systemic exposure and bioaccumulation were assessed by measuring plasma concentrations of tris(1-chloro-2-propyl)phosphate (TCIPP), the most abundant TCPP isomer. TCIPP concentrations in TCPP-exposed rats and mice ranged from 3.43 to 1180 ng/mL and increased with exposure concentration at all time points. No sex differences were observed in rats, but male mice had higher TCIPP concentrations than females. TCIPP did not bioaccumulate in rats or mice over the course of the study. Low TCIPP concentrations were seen in some control rats and mice that were attributed to background TCPP present during sample collection, preparation and/or analysis. Bis(2-chloroisopropyl) 1-carboxyethyl phosphate (BCPCP), a TCPP metabolite, was quantified in plasma from control and selected exposed animals. Results showed increases in BCPCP concentration that were proportional to exposure concentration in rats and mice at concentrations much higher than TCIPP, indicating that BCPCP might be a more suitable biomarker of TCPP exposure.
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•Tris(chloropropyl)phosphate (TCPP) has widespread environmental exposure.•We measured plasma levels of TCPP following chronic feed exposure in rodents.•The most abundant isomer of TCPP (TCIPP) increased with exposure with no accumulation.•Bis(2-chloroisopropyl)1-carboxyethyl phosphate (BCPCP) levels were higher than TCIPP.•Metabolite BCPCP may be a more suitable biomarker for TCPP exposure.
Aerosolized contrast agents may improve the resolution of biomedical imaging modalities and enable more accurate diagnosis of lung diseases. Many iodinated compounds, such as diatrizoic acid, have ...been shown to be safe and useful for radiographic examination of the airways. Formulations of such compounds must be improved in order to allow imaging of the smallest airways. Here, diatrizoic acid nanoparticle agglomerates were created by assembling nanoparticles into inhalable microparticles that may augment deposition in the lung periphery. Nanoparticle agglomerates were fully characterized and safety was determined
in vivo. After dry powder insufflation to rats, no acute alveolar tissue damage was observed 2
h post-dose. Diatrizoic acid nanoparticle agglomerates possess the characteristics of an efficient and safe inhalable lung contrast agent.
Improvements to contrast media formulations may be an effective way to increase the accuracy and effectiveness of thoracic computed tomography (CT) imaging in disease evaluation. To achieve contrast ...enhancement in the lungs, a relatively large localized concentration of contrast media must be delivered. Inhalation offers a noninvasive alternative to intrapleural injections for local lung delivery, but effective aerosolization may deter successful imaging strategies. Here, NanoCluster technology was applied to N1177, a diatrizoic acid derivative, to formulate low density nanoparticle agglomerates with aerodynamic diameters ≤5 μm. Excipient-free N1177 NanoCluster powders were delivered to rats by insufflation or inhalation and scanned using CT up to 1 h post dose. CT images after inhalation showed a ∼120 (HU) Hounsfield units contrast increase in the lungs, which was more than sufficient contrast for thoracic CT imaging. Lung tissue histology demonstrated that N1177 NanoClusters did not damage the lungs. NanoCluster particle engineering technology offers a novel approach to safely and efficiently disseminate high concentrations of contrast agents to the lung periphery.
Due to structural similarity to bisphenol A and lack of safety data, the National Toxicology Program (NTP) is evaluating the potential toxicity of bisphenol AF (BPAF) in rodent models. The current ...investigation reports the internal exposure data for free (unconjugated BPAF) and total (free and conjugated forms) BPAF during critical stages of development following perinatal dietary exposure in Hsd:Sprague Dawley®SD® rats to 0 (vehicle control), 338, 1125, and 3750 ppm BPAF from gestation day (GD) 6 to postnatal day (PND) 28. Free and total BPAF concentrations in maternal plasma at GD 18, PND 4, and PND 28 increased with the exposure concentration; free BPAF concentrations were ≤ 1.61% those of total BPAF demonstrating extensive first pass metabolism of BPAF following dietary exposure in adults. Free and total BPAF were quantified in GD 18 fetuses and PND 4 pups with free concentrations 11.7–53.4% that of corresponding total concentrations. In addition, free concentrations were higher (130–571%) and total concentrations were lower (1.71–7.23%) than corresponding concentrations in dams, demonstrating either preferential transfer of free BPAF and/or inability of fetuses and pups to conjugate BPAF. Free and total concentrations in PND 28 pups were similar to maternal concentrations demonstrating direct exposure of pups via feed and that conjugating enzymes are developed in PND 28 pups. In conclusion, these data demonstrate considerable gestational and lactational transfer of parent aglycone from the mother to offspring. Since the ontogeny of conjugating enzymes in humans is similar to that of rodents, the data from rodent BPAF studies may be useful in predicting human risk from exposure to BPAF.
•Systemic exposure in dams increased with the BPAF concentration in the feed.•Parent BPAF was transferred to developing fetuses.•Parent BPAF was transferred to lactating pups.•Transfer of conjugated forms of BPAF from dam to offspring was minimal.
We investigated the toxicokinetics and bioavailability of bisphenol AF (BPAF) in male and female Harlan Sprague Dawley rats and B6C3F1/N mice following a single gavage administration of 34, 110, or ...340 mg/kg. A validated analytical method was used to quantitate free (unconjugated parent) and total (unconjugated and conjugated) BPAF in plasma. BPAF was rapidly absorbed in rats with the maximum plasma concentration, Cmax, of free BPAF reached at ≤2.20 h. BPAF was cleared rapidly with a plasma elimination half-life of ≤3.35 h. Cmax and the area under the concentration versus time curve, AUC0-∞, increased proportionally to the dose. Total BPAF Cmax was reached ≤1.07 h in rats with both Cmax (≥27-fold) and AUC0-∞ (≥52-fold) much higher than corresponding free values demonstrating rapid and extensive conjugation of BPAF following oral administration. Absorption of BPAF following a 34 mg/kg gavage dose in mice was more rapid than in rats with free BPAF Cmax reached ≤0.455 h. Free BPAF was cleared rapidly in mice with an elimination half-life of ≤4.22 h. Similar to rats, total BPAF was much higher than corresponding free BPAF. There was no apparent sex-related effect in plasma toxicokinetic parameters of free or total BPAF in mice and rats. Bioavailability in rats was ~ 1% with no apparent dose-related effect. Bioavailability in mice was slightly higher than in rats (male ~ 6%, female 3%). These data demonstrate that BPAF was rapidly absorbed following gavage administration in rodents, rapidly and extensively conjugated with low bioavailability.
•Bisphenol AF (BPAF), a bisphenol analogue, is used in a variety of applications.•This work investigates the kinetics of BPAF in rodents following oral exposure.•BPAF was rapidly absorbed and cleared in rodents with a plasma half-life of ≤4 h.•Bioavailability of BPAF in rats (~1%) and mice (3–6%) was low.•There were no apparent sex-related effects in toxicokinetic parameters.
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