Non-targeted analysis based on quantitative prediction and toxicity assessment for emerging contaminants in tire particle leachates.

Non-targeted analysis (NTA) has great potential to screen emerging contaminants in the environment, and some studies have conducted in-depth investigation on environmental samples. Here, we used a NTA workflow to identify emerging contaminants in used tire particle (TP) leachates, followed by quantitative prediction and toxicity assessment based on hazard scores. Tire particles were obtained from four different types of automobiles, representing the most common tires during daily transportation. With the instrumental analysis of TP leachates, a total of 244 positive and 104 negative molecular features were extracted from the mass data. After filtering by a specialized emerging contaminants list and matching by spectral databases, a total of 51 molecular features were tentatively identified as contaminants, including benzothiazole, hexaethylene glycol, 2-hydroxybenzaldehyde, etc. Given that these contaminants have different mass spectral responses in the mass spectrometry, models for predicting the response of contaminants were constructed based on machine learning algorithms, in this case random forest and artificial neural networks. After five-fold cross-validation, the random forest algorithm model had better prediction performance (MAECV = 0.12, Q2 = 0.90), and thus it was chosen to predict the contaminant concentrations. The prediction results showed that the contaminant at the highest concentration was benzothiazole, with 4,875 µg/L in the winter tire sample. In addition, the joint toxicity assessment of four types of tires was conducted in this study. According to different hazard levels, hazard scores increasing by a factor 10 were developed, and hazard scores of all the contaminants identified in each TP leachate were summed to obtain the total hazard score. All four tires were calculated to have relatively high risks, with winter tires having the highest total hazard score of 40,751. This study extended the application of NTA research and led to the direction of subsequent targeting studies on highly concentrated and toxic contaminants.

In vitro assessment of mechanistic events induced by structurally related chemical rubber sensitizers.

Allergic contact dermatitis (ACD) is one of the most common forms of immunotoxicity, and increased understanding of how chemicals trigger these adverse reactions is needed in order to treat or design testing strategies to identify and subsequently avoid exposure to such substances. In this study, we investigated the cellular response induced by rubber chemicals in a dendritic cell (DC) model, focusing on the structurally similar chemicals diethylthiocarbamylbenzothiazole sulfide and dimethylthiocarbamylbenzothiazole sulfide, with regard to regulation of microRNA, and messenger RNA expression. Only a few miRNAs were found to be commonly regulated by both rubber chemicals, among them miR1973, while the overall miRNA expression profiles were diverse. Similarly, out of approximately 500 differentially regulated transcripts for each chemical, about 60% overlapped, while remaining were unique. The pathways predicted to be enriched in the cell model by stimulation with the rubber chemicals were linked to immunological events, relevant in the context of ACD. These results suggest that small structural differences can trigger specific activation of the immune system in response to chemicals. The here presented mechanistic data can be valuable in explaining the immunotoxicological events in DC activation after exposure to skin sensitizing chemicals, and can contribute to understanding, preventing and treating ACD.

Human health risk assessment of synthetic turf fields based upon investigation of five fields in Connecticut.

Questions have been raised regarding possible exposures when playing sports on synthetic turf fields cushioned with crumb rubber. Rubber is a complex mixture with some components possessing toxic and carcinogenic properties. Exposure is possible via inhalation, given that chemicals emitted from rubber might end up in the breathing zone of players and these players have high ventilation rates. Previous studies provide useful data but are limited with respect to the variety of fields and scenarios evaluated. The State of Connecticut investigated emissions associated with four outdoor and one indoor synthetic turf field under summer conditions. On-field and background locations were sampled using a variety of stationary and personal samplers. More than 20 chemicals of potential concern (COPC) were found to be above background and possibly field-related on both indoor and outdoor fields. These COPC were entered into separate risk assessments (1) for outdoor and indoor fields and (2) for children and adults. Exposure concentrations were prorated for time spent away from the fields and inhalation rates were adjusted for play activity and for children's greater ventilation than adults. Cancer and noncancer risk levels were at or below de minimis levels of concern. The scenario with the highest exposure was children playing on the indoor field. The acute hazard index (HI) for this scenario approached unity, suggesting a potential concern, although there was great uncertainty with this estimate. The main contributor was benzothiazole, a rubber-related semivolatile organic chemical (SVOC) that was 14-fold higher indoors than outdoors. Based upon these findings, outdoor and indoor synthetic turf fields are not associated with elevated adverse health risks. However, it would be prudent for building operators to provide adequate ventilation to prevent a buildup of rubber-related volatile organic chemicals (VOC) and SVOC at indoor fields. The current results are generally consistent with the findings from studies conducted by New York City, New York State, the U.S. Environmental Protection Agency (EPA), and Norway, which tested different kinds of fields and under a variety of weather conditions.

Benzothiazole toxicity assessment in support of synthetic turf field human health risk assessment.

Synthetic turf fields cushioned with crumb rubber may be a source of chemical exposure to those playing on the fields. Benzothiazole (BZT) may volatilize from crumb rubber and result in inhalation exposure. Benzothiazole has been the primary rubber-related chemical found in synthetic turf studies. However, risks associated with BZT have not been thoroughly assessed, primarily because of gaps in the database. This assessment provides toxicity information for a human health risk assessment involving BZT detected at five fields in Connecticut. BZT exerts acute toxicity and is a respiratory irritant and dermal sensitizer. In a genetic toxicity assay BZT was positive in Salmonella in the presence of metabolic activation. BZT metabolism involves ring-opening and formation of aromatic hydroxylamines, metabolites with mutagenic and carcinogenic potential. A structural analogue 2-mercaptobenzothiazole (2-MBZT) was more widely tested and so is used as a surrogate for some endpoints. 2-MBZT is a rodent carcinogen with rubber industry data supporting an association with human bladder cancer. The following BZT toxicity values were derived: (1) acute air target of 110 µg/m(3) based upon a BZT RD(50) study in mice relative to results for formaldehyde; (2) a chronic noncancer target of 18 µg/m(3) based upon the no-observed-adverse-effect level (NOAEL) in a subchronic dietary study in rats, dose route extrapolation, and uncertainty factors that combine to 1000; (3) a cancer unit risk of 1.8E-07/µg-m(3) based upon a published oral slope factor for 2-MBZT and dose-route extrapolation. While there are numerous uncertainties in the BZT toxicology database, this assessment enables BZT to be quantitatively assessed in risk assessments involving synthetic turf fields. However, this is only a screening-level assessment, and research that better defines BZT potency is needed.

Toxicity assessment of pramipexole in juvenile rhesus monkeys.

Pramipexole (PPX) is a dopamine agonist approved for the treatment of the signs and symptoms of idiopathic Parkinson's disease as well as restless leg syndrome. The objective of this study was to investigate the toxicity of PPX when administered orally to juvenile rhesus monkeys once daily for 30 weeks, and to assess the reversibility of toxicity during a 12-week recovery. Rhesus monkeys (N=4 males and 4 females/group; 22-24 months of age) were orally treated daily for 30 weeks with 0.0, 0.1, 0.5 or 2.0 mg/kg PPX, and subjects were assessed daily using the NCTR Operant Test Battery (OTB). Clinical chemistry, hematology, ophthalmology and other standard postmortem toxicological evaluations, including histopathology and neuropathology as well as toxicokinetics were performed. The systemic exposure to PPX was higher than that at therapeutic doses in man and AUC(0-24 h)-data increased proportionally to dose. Blood pressure significantly decreased over time in all groups including control. Near the end of treatment, there were statistically significant decreases in heart rate for the 0.5 and 2.0 mg/kg/day groups compared to control. After 4 weeks of dosing, serum prolactin was significantly decreased in all treatment groups compared to control. This decrease remained at the end of treatment in the 0.5 and 2.0 mg/kg/day groups. In summary, administration of PPX at doses of up to 2.0 mg/kg/day for 30 weeks to juvenile rhesus monkeys produced adverse findings which were attributable to its pharmacological properties, including hypoprolactinemia.

Polymeric micelles for parenteral delivery of sagopilone: physicochemical characterization, novel formulation approaches and their toxicity assessment in vitro as well as in vivo.

PURPOSE: The block copolymers PEG(2000)-b-PLA(2200), PEG(2000)-b-PCL(2600) and PEG(5000)-b-PCL(5000) have been currently identified as optimal solubilizing agents for Sagopilone, a poorly water-soluble anticancer drug. In the present study, the stability, formulation feasibility and in vitro as well as in vivo toxicity were evaluated. METHODS: Dispersion media, storage conditions, and dilutions were varied for stability assessment. The critical micelle concentration (CMC) was determined using a fluorescent probe technique. Lyophilizates and polymeric films were investigated as formulation options. Furthermore, the toxicity was studied in vitro and in vivo using HeLa/MaTu cells and a nude mouse model, respectively. RESULTS: A drug-polymer ratio as low as 1:20 (w/w) was sufficient to solubilize Sagopilone effectively and to obtain stable dispersions (24h: drug content >or= 95%). Although the micelles exhibited a similar thermodynamic stability (CMC: 10(-7)-10(-6)M), PEG-b-PCL micelles were kinetically more stable than PEG(2000)-b-PLA(2200) (24h at 37 degrees C: drug content >or= 90% compared to 30%, respectively). Lyophilization of PEG-b-PCL micelles and storage stability of solid drug-loaded PEG(2000)-b-PLA(2200) films (3m, 6 degrees C: drug content of (95.6+/-1.4)%) were demonstrated for the first time. The high antiproliferative activity has been maintained in vitro (IC(50)<1 nM). Carrier-associated side effects have not been observed in vivo and the maximum tolerated dose of micellar Sagopilone was determined to be 6 mg/kg. CONCLUSION: The results of this study indicate that polymeric micelles, especially PEG-b-PCL micelles, offer excellent potential for further preclinical and clinical cancer studies using Sagopilone.