Toxicology | Year: 2011
Under the new European chemicals regulation, REACH (Registration, Evaluation, Authorization and Restriction of Chemicals) a Derived No-Effect Level (DNEL), i.e., the level of exposure above which humans should not be exposed, is defined. The focus of this paper is to develop a weight-of-evidence-based DNEL-approach for inhaled poorly soluble particles. Despite the common mode of action of inhaled insoluble, spherical particulate matter (PM), a unifying, most appropriate metric conferring pulmonary biopersistence and toxicity has yet not been demonstrated. Nonetheless, there is compelling evidence from repeated rat inhalation exposure studies suggesting that the particle displacement volume is the most prominent unifying denominator linking the pulmonary retained dose with toxicity. Procedures were developed to analyze and model the pulmonary toxicokinetics from short-term to long-term exposure. Six different types of poorly soluble nano- to submicron PMs were compared: ultrafine and pigmentary TiO2, synthetic iron oxide (Fe3O4, magnetite), two aluminum oxyhydroxides (AlOOH, Boehmite) with primary isometric particles approximately of either 10 or 40nm, and MWCNT. The specific agglomerate densities of these materials ranged from 0.1g/cm3 (MWCNT) to 5g/cm3 (Fe3O4). Along with all PM, due to their long retention half-times and associated biopersistence in the lung, even short-term inhalation studies may require postexposure periods of at least 3 months to reveal PM-specific dispositional and toxicological characteristics. This analysis provides strong evidence that pulmonary toxicity (sustained inflammation) is dependent on the volume-based cumulative lung exposure dose. Lung toxicity, evidenced by PMN in BAL occurred at lung doses exceeding 10-times the overload threshold. Furthermore, the conclusion is supported that repeated inhalation studies on rats should utilize an experimental window of cumulative volume loads of respirable PM in the range of 1μl/lung (no-adverse-effect range); however, not exceeding ≈10μl/lung that would lead to retention half-times increasing 1 year. This can be targeted best by computational toxicology, i.e., the modeling of particle deposition and lung retention biokinetics during the exposure and recovery periods. Inhalation studies exceeding that threshold volume may lead to meaningless findings difficult to extrapolate to any real-life scenario. In summary, this analysis supports a volume-based generic mass concentration of 0.5μlPMrespirable/m3×agglomerate density, independent on nano- or submicron-sized properties, as a generic no-adverse effect level in both rats and humans. © 2010 Elsevier Ireland Ltd.
Regulatory Toxicology and Pharmacology | Year: 2010
Carbon nanotubes come in a variety of types, but one of the most common forms is multi-walled carbon nanotubes (MWCNT). This paper focuses on the dose-response and time course of pulmonary toxicity of Baytubes®, a more flexible MWCNT type with the tendency to form assemblages of nanotubes. This MWCNT has been examined in previous single and repeated exposure 13-week rat inhalation studies. Kinetic endpoints and the potential to translocate to extrapulmonary organs have been examined during postexposure periods of 3 and 6months, respectively. The focus of both studies was to compare dosimetric endpoints and the time course of pulmonary inflammation characterized by repeated bronchoalveolar lavage and histopathology during the respective follow-up periods. To better understand the etiopathology of pulmonary inflammation and time-related lung remodeling, two metrics of retained lung dose were compared. The first used the mass metric based on the exposure concentration obtained by filter analyses and aerodynamic particle size of airborne MWCNT. The second was based on calculated volumetric lung burdens of retained MWCNT. Kinetic analyses of lung burdens support the conclusion that Baytubes®, in principal, act like poorly soluble agglomerated carbonaceous particulates. However, the difference in pulmonary toxic potency (mass-based) appears to be associated with the low-density (≈0.1-0.3g/m3) of the MWCNT assemblages. Of note is that assemblages of MWCNT were found predominantly both in the exposure atmosphere and in digested alveolar macrophages. Isolated fibers were not observed in exposure atmospheres or biological specimens. All findings support the conclusion that the low specific density of microstructures was conducive to attaining the volumetric lung overload-related inflammatory response conditions earlier than conventional particles. Evidence of extrapulmonary translocation or toxicity was not found in any study. Thus, pulmonary overload is believed to trigger the cascade of events leading to a stasis of clearance and consequently increased MWCNT doses high enough to trigger sustained pulmonary inflammation. This mechanism served as conceptual basis for the calculation of the human equivalent concentration. Accordingly, multiple interspecies adjustments were necessary which included species-specific differences in alveolar deposition, differences in ventilation, and the time-dependent particle accumulation accounting for the known species-specific differences in particle clearance half-times in rats and humans. Based on this rationale and the NOAEL (no-observed adverse effect level) from the 13-week subchronic inhalation study on rats, an occupational exposure limit (OEL) of 0.05mg Baytubes/m3 (time weighted average) is considered to be reasonably protective to prevent lung injury to occur in the workplace environment. © 2010 Elsevier Inc.
Schering | Date: 2012-03-23
Schering | Date: 2012-03-07
Engineered antibodies to human IL-23p19 are provided, as well as uses thereof, e.g., in treatment of inflammatory, autoimmune, and proliferative disorders.
Schering | Date: 2012-01-13
Nucleic acids encoding mammalian, e.g., primate, receptors, purified receptor proteins and fragments thereof. Antibodies, both polyclonal and monoclonal, are also provided. Methods of using the compositions for both diagnostic and therapeutic utilities are described.
Schering | Date: 2014-04-21
The present invention relates to fluorinated glutamic acid (glutamate) and glutamine derivatives wherein the fluorine atom is 19F. The glutamic acid (glutamate) and glutamine derivatives are compound(s) of general Formula I, which encompasses all possible diastereoisomers and/or enantiomere derivatives or mixtures thereof.
Schering | Date: 2013-01-02
The invention describes novel and stable precursors for the direct radiosynthesis of protected derivatives of O-([^(18)F]Fluoromethyl) tyrosines, and methods for obtaining thoses compounds.
Schering | Date: 2013-02-01
This invention describes the use of a therapeutic gestagen (e.g., drospirenone, cyproterone acetate, dienogest) for the production of a pharmaceutical agent for the treatment of premenstrual dysphoric disorder (PMDD), optionally in combination with a natural or synthetic estrogen (e.g., estradiol or ethinylestradiol).
Schering | Date: 2013-10-08
The invention relates to binding compounds that specifically bind to human TSLP, as well as uses thereof, e.g., in the treatment of inflammatory disorders.
Schering | Date: 2014-01-13
The compounds and the synthesis of [F-18]-labeled L-glutamic acid, [F-18]-labeled L-glutamate, their derivatives as set forth in formula (I) and their uses are described.