Detection of high PBDD/Fs levels and dioxin-like activity in toys using a combination of GC-HRMS, rat-based and human-based DR CALUX® reporter gene assays.

Brominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs) are increasingly reported at significant levels in various matrices, including consumer goods that are manufactured from plastics containing certain brominated flame retardants. PBDD/Fs are known ligands for the aryl hydrocarbon receptor (AhR) but are not yet considered in the hazard assessment of dioxin mixtures. The aim of the present study was to determine if PBDD/Fs levels present in plastic constituents of toys could pose a threat to children's health. PBDD/Fs, unlike their chlorinated counterparts (PCDD/Fs), have not been officially assigned toxic equivalence factors (TEFs) by the WHO therefore, we determined their relative potency towards AhR activation in both human and rodent cell-based DR CALUX® bioassays. This allowed us to compare GC-HRMS PBDD/F congener levels, converted to total Toxic Equivalents (TEQ) by using the PCDD/F TEFs, to CALUX Bioanalytical Equivalents (BEQ) levels present in contaminated plastic constituents from children's toys. Finally, an estimate was made of the daily ingestion of TEQs from PBDD/Fs-contaminated plastic toys by child mouthing habits. It is observed that the daily ingestion of PBDD/Fs from contaminated plastic toys may significantly contribute to the total dioxin daily intake of young children.

Introducing the Alba® Primary Packaging Platform. Part 2: Inorganic Extractables Evaluation.

Sensitivity of drugs to one or more elements of the primary packaging is a serious concern for the pharmaceutical industry. Biologics in particular are highly sensitive, leading to a higher risk of incompatibility and stability test failure as worst-case scenario.This potential incompatibility-and the consequent formulation instability due to the interactions between the drug and the primary container surface-may have multiple causes: the intrinsic nature of the container surface, leachables coming from the materials used, substances coming from the production process, or silicone oil droplets or other particles.The Alba primary packaging platform was designed to have the same interface between the drug and the glass container surface on the different primary packaging containers in order to minimize the emergence of instabilities at later stages of formulation development. Alba containers are internally treated with an innovative cross-linked coating based on silicone oil lubricant, and the additional rubber components have been selected to minimize the possible differences between the container typologies.This paper shows in great detail the reduction of the inorganic extractables released and the comparability of the performances of the different containers obtained using Alba technology.The improvement has been demonstrated by stressing the containers with different extract solutions; Alba-coated containers show a strong reduction of inorganic extractables and of corrosion degree compared to spray-on siliconized and bulk products. The containers included in the Alba platform present comparable results, and this represents a strong advantage during the drug formulation development by facilitating the transition from one container to another.LAY ABSTRACT: The sensitivity of drugs to one or more elements of the primary packaging is a serious concern for the pharmaceutical industry. Biologics in particular are highly sensitive, leading to a higher risk of incompatibility and stability test failure worst-case scenario.This potential incompatibility-and the consequent formulation instability due to the interactions between the drug and the primary container surface-may have multiple causes: the intrinsic nature of the container surface, leachables coming from the materials used, substances coming from the production process, or silicone oil droplets or other particles.The Alba primary packaging platform was designed to minimize these problems associated with the interaction between the drug and its primary packaging. This paper shows in great detail and with robust data the inorganic extractables release reduction and the delamination risk mitigation obtained using the Alba technology.

A Comparison of Protein Stability in Prefillable Syringes Made of Glass and Plastic.

The development of protein therapeutics requires stabilization of these labile molecules during shipment and storage. Biologics, particularly monoclonal antibodies, are frequently packaged at high concentration in prefillable syringes traditionally made of glass. However, some biologics are unstable in glass due to sensitivity to silicone oil, tungsten, glue, or metal ions. Syringes made from the plastic cyclic olefin polymer, Daikyo Crystal Zenith® (CZ), with a Flurotec-laminated piston, have none of these issues. This study compared the stability of several proteins including biotherapeutics when stored up to 14 months at 5 °C and 25 °C in prefillable siliconized syringes made of glass or silicone oil-free CZ syringes, and when subjected to mild agitation by end-over-end rotation at room temperature. At each time point, proteins were analyzed by several techniques including turbidity, size exclusion high-performance liquid chromatography, reversed phase high-performance liquid chromatography, ion-exchange chromatography, electrophoresis, and light scattering to monitor changes in aggregation and degradation. The results show that proteins have comparable stability when stored in glass syringes or in syringes made of CZ sterilized by E-beam or autoclave. In addition, proteins stressed by agitation were generally more stable and aggregated less in syringes made of CZ than in ones made of glass.LAY ABSTRACT: Biotherapeutic protein drugs such as monoclonal antibodies are frequently packaged at high concentration in prefillable syringes, which allows the drug to be directly administered by the patient or caregiver. Protein drugs, or biologics, can be unstable, and may aggregate, particularly when shaken. These aggregates can be immunogenic, stimulating the body's immune system to produce antibodies that can reduce the drug's efficacy. Although prefillable syringes are traditionally made of glass, some biologics are unstable in glass syringes due to the presence of substances used in their manufacture, including silicone oil, which is necessary for lubricity. Syringes made from the plastic cyclic olefin polymer, Daikyo Crystal Zenith® (CZ), have none of these issues. This study compared the stability of several biotherapeutic proteins when stored up to 14 months at 5 °C and 25 °C in prefillable siliconized syringes made of glass or silicone oil-free CZ syringes, and when mildly agitated at room temperature. Proteins were analyzed by several techniques to detect changes in aggregation and degradation. The results show that biotherapeutic proteins have similar stability whether stored in syringes made of glass or CZ. In addition, proteins subjected to agitation were generally more stable and aggregated less in CZ syringes than in glass syringes.

Evidence of bad recycling practices: BFRs in children's toys and food-contact articles.

Brominated flame retardants (BFRs) have been used intentionally in a wide range of plastics, but are now found in an even wider range of such materials (including children's toys and food contact articles) as a result of recycling practices that mix BFR-containing waste plastics with "virgin" materials. In this study Br was quantified in toy and food contact samples on the assumption that its concentration can be used as a metric for BFR contamination. Subsequently, compound specific determination of BFRs was performed to evaluate the validity of the aforementioned assumption, crucial to render rapid, inexpensive, in situ Br determination in non-laboratory environments (such as waste handling facilities) a viable option for sorting wastes according to their BFR content. We report semi-quantitative compound specific BFR concentrations to give an overview of the distribution of individual BFRs in the analyzed samples. Finally, we evaluated the correlations between waste electrical and electronic equipment (WEEE) related substances (Ca, Sb and rare earth elements (REEs)) and Br as a proxy for identifying poor sorting practices in different waste streams. 26 samples of toys, food-contact articles and WEEE were analyzed with a suite of different techniques in order to obtain comprehensive information about their elemental and molecular composition. The information obtained from principal component analysis about WEEE-related compounds provides new insights into the influence of sorting practices on the extent of products' contamination and bringing out polymer-related trends in the pollutants' signature. 61% of all samples were Br positive: of these samples, 45% had decaBDE concentrations exceeding the concentration limits for PBDEs and their main constituent polymer was - according to the REE signature of such samples - Acrylonitrile Butadiene Styrene (ABS), uses of which include copying equipment, laptops and computers. The ability to better track chemicals of concern and their trends in products is the main requirement for high-level management and control of material cycles to become non-toxic in the future as proposed in the EU's 7th Environmental Action Plan.

The practical application of scintillation dosimetry in small-field photon-beam radiotherapy.

Plastic scintillation detectors are a new instrument of stereotactic photon-beam dosimetry. The clinical application of the plastic scintillation detector Exradin W1 at the Siemens Artiste and Elekta Synergy accelerators is a matter of current interest. In order to reduce the measurement uncertainty, precautions have to be taken with regard to the geometrical arrangement of the scintillator, the light-guide fiber and the photodiode in the radiation field. To determine the "Cerenkov light ratio" CLR with a type A uncertainty below 1%, the Cerenkov calibration procedure for small-field measurements based on the two-channel spectral method was used. Output factors were correctly measured with the W1 for field sizes down to 0.5×0.5cm2 with a type A uncertainty of 1.8%. Measurements of small field dose profiles and percentage depth dose curves were carried out with the W1 using automated water phantom profile scans, and a type A uncertainty for dose maxima of 1.4% was achieved. The agreement with a synthetic diamond detector (microDiamond, PTW Freiburg) and a plane parallel ionization chamber (Roos chamber, PTW Freiburg) in relative dose measurements was excellent. In oversight of all results, the suitability of the plastic scintillation detector Exradin W1 for clinical dosimetry under stereotactic conditions, in particular the tried and tested procedures for CLR determination, output factor measurement and automated dose profile scans in water phantoms, have been confirmed.

Acute water quality criteria for polycyclic aromatic hydrocarbons, pesticides, plastic additives, and 4-Nonylphenol in seawater.

Probabilistic environmental quality criteria for Naphthalene (Nap), Phenanthrene (Phe), Fluoranthene (Flu), Pyrene (Pyr), Triclosan (TCS), Tributyltin (TBT), Chlorpyrifos (CPY), Diuron (DUR), γ-Hexaclorocyclohexane (γ-HCH), Bisphenol A (BPA) and 4-Nonylphenol (4-NP) were derived from acute toxicity data using saltwater species representative of marine ecosystems, including algae, mollusks, crustaceans, echinoderms and chordates. Preferably, data concerns sublethal endpoints and early life stages from bioassays conducted in our laboratory, but the data set was completed with a broad literature survey. The Water Quality Criteria (WQC) obtained for TBT (7.1·10-3 µg L-1) and CPY (6.6· 10-3 µg L-1) were orders of magnitude lower than those obtained for PAHs (ranging from 3.75 to 45.2 µg L-1), BPA (27.7 µg L-1), TCS (8.66 µg L-1) and 4-NP (1.52 µg L-1). Critical values for DUR and HCH were 0.1 and 0.057 µg L-1 respectively. Within this context, non-selective toxicants could be quantitatively defined as those showing a maximum variability in toxicity thresholds (TT) of 3 orders of magnitude across the whole range of marine diversity, and a cumulative distribution of the TT fitting to a single log-logistic curve, while for selective toxicants variability was consistently found to span 5 orders of magnitude and the TT distribution showed a bimodal pattern. For the latter, protective WQC must be derived taking into account the SSD of the sensitive taxa only.

Simulated Leaching (Migration) Study for a Model Container-Closure System Applicable to Parenteral and Ophthalmic Drug Products.

A simulating leaching (migration) study was performed on a model container-closure system relevant to parenteral and ophthalmic drug products. This container-closure system consisted of a linear low-density polyethylene bottle (primary container), a polypropylene cap and an elastomeric cap liner (closure), an adhesive label (labeling), and a foil overpouch (secondary container). The bottles were filled with simulating solvents (aqueous salt/acid mixture at pH 2.5, aqueous buffer at pH 9.5, and 1/1 v/v isopropanol/water), a label was affixed to the filled and capped bottles, the filled bottles were placed into the foil overpouch, and the filled and pouched units were stored either upright or inverted for up to 6 months at 40 °C. After storage, the leaching solutions were tested for leached substances using multiple complementary analytical techniques to address volatile, semi-volatile, and non-volatile organic and inorganic extractables as potential leachables.The leaching data generated supported several conclusions, including that (1) the extractables (leachables) profile revealed by a simulating leaching study can qualitatively be correlated with compositional information for materials of construction, (2) the chemical nature of both the extracting medium and the individual extractables (leachables) can markedly affect the resulting profile, and (3) while direct contact between a drug product and a system's material of construction may exacerbate the leaching of substances from that material by the drug product, direct contact is not a prerequisite for migration and leaching to occur.LAY ABSTRACT: The migration of container-related extractables from a model pharmaceutical container-closure system and into simulated drug product solutions was studied, focusing on circumstances relevant to parenteral and ophthalmic drug products. The model system was constructed specifically to address the migration of extractables from labels applied to the outside of the primary container. The study demonstrated that (1) the extractables that do migrate can be correlated to the composition of the materials used to construct the container-closure systems, (2) the extent of migration is affected by the chemical nature of the simulating solutions and the extractables themselves, and (3) even though labels may not be in direct contact with a contained solution, label-related extractables can accumulate as leachables in those solutions.

The discharge of certain amounts of industrial microplastic from a production plant into the River Danube is permitted by the Austrian legislation.

Numerous studies have quantified the amount of plastic litter in aquatic ecosystems and tried to assess its impacts and threats. This reflects a rising awareness of plastic as an environmental problem. As a next logical step, identifying and regulating the sources must be in the focus of scientific efforts. We report on a spillage of industrial microplastic (IMP) from a production plant situated at an Austrian Danube tributary. This is the first identified point source of IMP litter in freshwater systems. However, due to generous thresholds established by the Austrian government substantial amounts of IMP are legally introduced into running waters.

Characterization of hindered amine light stabilizers employing capillary electrophoresis coupled to quadrupole time-of-flight mass spectrometry.

In the current work, a fast and reliable CE method for characterizing of six hindered amine light stabilizers (HALS), technical products commonly employed as UV-stabilizing agents for various polymeric materials, is presented. These compounds can be monomeric or oligomeric species whereby there is no or only limited information available concerning purity or actual structural composition of the respective stabilizer. Using a BGE based on formic acid with 10% acetonitrile, different constituents of several HALS could be separated by CE and identified employing QTOF/MS detection. In the case of Cyasorb 3529, ten different oligomers were discovered and possible structures were suggested based on exact mass measurements. The majority of the elucidated structures is not fully congruent with the information provided by the manufacturers. Furthermore, in the case of Chimassorb 119 and Tinuvin 770 impurities or unreacted compounds remaining from the manufacturing process could be identified. Besides performing such basic characterizations of technical grade HALS, the presented method is also shown to be suitable for a reliable identification of these stabilizers in real polymer samples.

Baseline for beached marine debris on Sand Island, Midway Atoll.

Baseline measurements were made of the amount and weight of beached marine debris on Sand Island, Midway Atoll, June 2008-July 2010. On 23 surveys, 32,696 total debris objects (identifiable items and pieces) were collected; total weight was 740.4 kg. Seventy-two percent of the total was pieces; 91% of the pieces were made of plastic materials. Pieces were composed primarily of polyethylene and polypropylene. Identifiable items were 28% of the total; 88% of the identifiable items were in the fishing/aquaculture/shipping-related and beverage/household products-related categories. Identifiable items were lowest during April-August, while pieces were at their lowest during June-August. Sites facing the North Pacific Gyre received the most debris and proportionately more pieces. More debris tended to be found on Sand Island when the Subtropical Convergence Zone was closer to the Atoll. This information can be used for potential mitigation and to understand the impacts of large-scale events such as the 2011 Japanese tsunami.

Comparison of quantitative analysis techniques for the determination of heat seal lacquer layers on aluminum blister foils.

For decades a gravimetric method has been common standard for the determination of heat seal lacquers on aluminum blister foils. With the availability of appropriate techniques such as interferometric, infrared reflection absorption spectroscopic (IRRAS), beta backscatter, impedance spectroscopic and eddy current techniques respectively, more efficient determinations can be foreseen which are subject of the present communication. The different methods were compared to each other regarding parameters required for validation of analytical procedures according to the ICH guidelines Q2 (R1) such as linearity, precision, accuracy, robustness and quantitation limits. The interferometric, IRRAS and beta backscatter techniques were well suitable for the measurements. Using these techniques novel procedures applicable for routine quality control of pharmaceutical packaging materials are suggested.

Phthalates and food-contact materials: enforcing the 2008 European Union plastics legislation.

The migration of phthalates into foodstuffs from food-contact materials (FCM) is a well-known source of food contamination. In 2005, the European Food Safety Authority finalized its risk assessment for several of the classical phthalate plasticizers. In their risk management procedure the European Commission transformed the tolerable daily intakes established by the Authority into legislative limits for phthalates in both plastic and food simulants, while taking exposure from other sources into consideration. These limits have been into force since 1 July 2008. A detailed interpretation of the regulation of these substances was agreed upon in the European network of FCM reference laboratories. This paper reports results from a Danish control campaign of samples collected by official food inspectors and analysed by a newly validated analytical method run under accreditation. Samples were from FCM producers, FCM importers and importers of packed foodstuffs from third-party countries. Products containing phthalates above the current limits were found in several categories of FCM: conveyor belts (six of six), lids from packed foodstuffs in glasses (eight of 28), tubes for liquid foodstuffs (four of five) and gloves (five of 14). More than 20% of the samples analysed contained dibutylphthalate (DBP) or di-(2-ethylhexyl)phthalate (DEHP) above the compositional limits of 0.05% and 0.1%, respectively. Analysis of residual phthalates in metal lid gaskets instead of analysis of phthalates in the food when controlling foodstuffs packed outside the European Union proved to be an efficient and simple control method. All findings of phthalates were associated with the use of plasticized polyvinylchloride (PVC).

Load sharing and stabilization effects of anterior cervical devices.

STUDY DESIGN: Biomechanical human cadaveric cervical flexibility testing with direct load-sharing measurement. OBJECTIVE: To determine if the flexibility and load-sharing characteristics of a functional spinal unit were affected by anterior treatments for cervical pathologies. SUMMARY OF BACKGROUND DATA: With advancements in polymers, anterior cervical plates have used thermoplastics including recent designs from biodegradable polylactide acids. However, the difference in material properties between metal and polymer can be significant. METHODS: Thirteen cervical spine specimens were subjected to 5 treatments at C4-C5. Each treatment for each specimen was subjected to multidirectional flexibility testing. The third cycle was used for treatment comparisons. RESULTS: With the integrated load cell spacer, the mean range of motion for the functional spinal unit measured on average 104% + or - 40% normalized to the intact control. The mean biodegradable and titanium plate were 55% + or - 31% and 40% + or - 36%, respectively. Both plates exhibited statistically lower mean range of motions (P = 0.001 and P < 0.001) compared with spacers. The load transmitted through the interbody space was 54% + or - 20%, 43% + or - 20%, and 33% + or - 15% on average for the spacer, biodegradable, and titanium plate constructs, respectively. No statistically significant difference was detected between the biodegradable plate and spacer (P = 0.214). CONCLUSIONS: From this research, a biodegradable plate offers immediate postoperative stability significantly different than spacer alone treatments but with graft load sharing that is statistically no different. Thus, the intrinsic lower native material modulus of elasticity of biodegradable polymers has biomechanical implications. However, clinical evidence, particularly for long-term outcomes, will be required in understanding the efficacy of biodegradable polymers.

Disposables in downstream processing.

Disposable equipment has been used for many years in the downstream processing industry, but mainly for filtration and buffer/media storage. Over the last decade, there has been increasing interest in the use of disposable concepts for chromatography, replacing steel and glass fixed systems with disposable plastic modules that can be discarded once exhausted, fouled or contaminated. These modules save on cleaning and validation costs, and their reduce footprints reduce buffer consumption, water for injection, labor and facility space, contributing to an overall reduction in expenditure that lowers the cost of goods. This chapter examines the practical and economic benefits of disposable modules in downstream processing.

[Influence of sterilization treatments on continuous carbon-fiber reinforced polyolefin composite].

OBJECTIVE: To evaluate the influence of sterilization treatment on continuous carbon-fiber reinforced polyolefin composite (CFRP) so as to provide experimental reference for selection of sterilization method for CFRP. METHODS: Seventy bars of CFRP were divided into 7 equal groups to undergo sterilization by autoclave, 2% glutaraldehyde soaking, 75% alcohol soaking, ethylene oxide sterilization, and Co-60 gamma ray irradiation of the dosages 11 kGy, 25 kGy, and 18 kGy respectively, and another 10 bars were used as blank controls. Then the bars underwent three-point bending test and longitudinal compression test so as to measure the biomechanical changes after sterilization treatment, including the maximum load, ultimate strength, and elastic modulus. RESULTS: Three-point bending test showed that the levels of maximum load of the all experimental groups were lower than that of the control group, however, only those of the 3 Co-60 irradiation groups were significantly lower than that of the control group and that Co-60 radiation lowered the level of maximum load dose-dependently; and that the levels of ultimate strength of all the all experimental groups were lower than that of the control group, however, only those of the 3 Co-60 groups were significantly lower than that of the control group and that the higher the dosage of Co-60 radiation the lower the level of ultimate strength, however, not dose-dependently. The elastic modulus of the Co-60 25 KGy group was significantly higher than that of the control group, and there was no significant difference in the level of ultimate strength among the other groups. Longitudinal compression test showed that the levels of maximum load and ultimate strength of the 3 Co-60 irradiation groups, autoclave group, and circular ethylene groups were significantly lower than that of the control group, and there was no significant difference in elastic modulus among different groups. CONCLUSION: During sterilized package of CFRP products produced in quantity autoclave sterilization and Co-60 gamma ray irradiation sterilization should be avoided. Ethylene oxide is proposed as the best sterilization method. If gamma ray irradiation is to be used further technology improvement is necessary.

Early failure of bioabsorbable anterior cervical fusion plates: case report and failure analysis.

STUDY DESIGN: Case report with forensic failure analysis. OBJECTIVE: To determine the failure modes of 3 explanted 70:30 PLDLA Mystique (Medtronic Sofamor Danek, Memphis, TN) graft containment plates retrieved from revision surgery for early device failure. SUMMARY OF BACKGROUND DATA: To reduce the problems of stress-shielding and radiopacity associated with metallic systems, bioabsorbable polymers have been used in anterior cervical discectomy and fusion procedures. Degradation of mechanical properties in vivo is a major concern when using bioabsorbable systems. Three of 6 patients who underwent anterior cervical discectomy with instrumented fusion, using Mystique graft containment systems experienced early failure requiring revision to alternate hardware. METHODS: Devices were retrieved after failure and analyzed by light microscopy and environmental scanning electron microscopy. Simulations were performed with an unused plating system to induce damage for comparison with the retrieved devices. A detailed case review was performed to identify possible sources of extraordinary loading or damage. RESULTS: One plating system failed at 6 weeks postimplantation due to fatigue fracture of the screws. Crack initiation sites were identified at the interface of the thread root and mold line of the screw. Another plating system failed at 16 weeks postimplantation due to the coalescence of radial microcracking between holes in the plate, leading to catastrophic failure of the plate. The final plating system failed during the implantation surgery, when the screw fractured in torsion. CONCLUSIONS: Stress concentrations at the screw head-shaft interface and thread-shaft interface reduce the fatigue performance of bioabsorbable screws. Hydrolysis of the polymer may also play a role in the reduction of resistance to crack initiation and propagation.