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Scandinavian Journal of Work,... 1985While many organic solvents are, in large doses, capable of inducing an acute, reversible narcotic state, few unequivocally induce chronic, long-lasting, or irreversible... (Review)
Review
While many organic solvents are, in large doses, capable of inducing an acute, reversible narcotic state, few unequivocally induce chronic, long-lasting, or irreversible changes in nervous system structure and/or function. For organic solvents with proved neurotoxic properties, the type of neurological damage is closely related to the structure of the chemical agent, while the degree of impairment and the extent of reversibility are related to the potency, dose, and duration of exposure. Examples include solvents containing n-hexane or methyl n-butyl ketone, which have caused many cases of occupational neuropathy. Chronic inhalation abuse of pure toluene produces irreversible cerebellar, brainstem, and pyramidal-tract dysfunction, but comparable changes have not been found in solvent workers occupationally exposed to toluene. Ototoxicity is found in experimental animals exposed to toluene, xylene, or styrene. Impure trichloroethylene has a predilection for damaging the trigeminal nerve; dichloroacetylene, a breakdown product of trichloroethylene, is probably responsible for this neurotoxic property. Prolonged occupational exposure to mixed solvents, notably white spirit, has been reported to induce a mild, nonprogressive dementing illness with or without peripheral nerve dysfunction, but supporting data from neuropathological and experimental animal studies are lacking. Many other solvents have been reported to induce adverse effects in workers. The pivotal biological role of the nervous system and its vulnerability to selected organic solvents widely used in industry underline the urgent need for further clinical and experimental research on this problem.
Topics: Alkanes; Animals; Carbon Disulfide; Humans; Hydrocarbons; Ketones; Nervous System; Research Design; Solvents; Trichloroethylene; Xylenes
PubMed: 3906869
DOI: No ID Found -
Regulatory Toxicology and Pharmacology... Mar 2017Management of organic non-mutagenic impurities (NMIs) in medicinal products is regulated by the ICH Q3A, B and C guidelines that are applicable at late stages of... (Review)
Review
Management of organic non-mutagenic impurities (NMIs) in medicinal products is regulated by the ICH Q3A, B and C guidelines that are applicable at late stages of clinical development (Phase III onwards) and as a consequence there is no guidance for the assessment and control of NMIs in early clinical trials. An analysis of several key in vivo toxicology databases supports the ICH Q3A defined concept that a lifetime dose to 1 mg/day of a NMI would not represent a safety concern to patients. In conjunction with routine (Q)SAR approaches, this 1 mg/day value could be used as a universal qualification threshold for a NMI during any stage of clinical development. This analysis also proposes that modification of this 1 mg/day dose using an established methodology (i.e. Modified Haber's Law) could support 5 mg/day or 0.7% (whichever is lower) as an acceptable limit for a NMI in a drug substance or product in early clinical studies (<6 months). Given the controlled nature of clinical development and the knowledge that most toxicities are dose and duration dependent, these proposed NMI limits provide assurance of patient safety throughout clinical development, without the requirement to commission dedicated in vivo toxicology impurity qualification studies.
Topics: Animals; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Contamination; Drug Discovery; Drug and Narcotic Control; Government Regulation; Health Policy; Humans; No-Observed-Adverse-Effect Level; Organic Chemicals; Patient Safety; Pharmaceutical Preparations; Policy Making; Quality Control; Risk Assessment; Risk Factors; Threshold Limit Values; Time Factors; Toxicity Tests
PubMed: 28038978
DOI: 10.1016/j.yrtph.2016.12.011 -
Science Advances Sep 2023Saturated fatty acids are abundant organic compounds in oceans and sea sprays. Their photochemical reactions induced by solar radiation have recently been found as an...
Saturated fatty acids are abundant organic compounds in oceans and sea sprays. Their photochemical reactions induced by solar radiation have recently been found as an abiotic source of volatile organic compounds, which serve as precursors of secondary organic aerosols. However, photoabsorption of wavelengths longer than 250 nanometers in liquid saturated fatty acids remains unexplained, despite being first reported in 1931. Here, we demonstrate that the previously reported absorption of wavelengths longer than 250 nanometers by liquid nonanoic acid [CH(CH)COOH)] originates from traces of impurities (0.1% at most) intrinsically contained in nonanoic acid reagents. Absorption cross sections of nonanoic acid newly obtained here indicate that the upper limit of its photolysis rate is three to five orders of magnitude smaller than those for atmospherically relevant carbonyl compounds.
PubMed: 37729407
DOI: 10.1126/sciadv.adj6438 -
Molecules (Basel, Switzerland) Aug 2022Dinotefuran (DNT) is a neonicotinoid insecticide widely used in pest control. Identification of structurally related impurities is indispensable during material...
Dinotefuran (DNT) is a neonicotinoid insecticide widely used in pest control. Identification of structurally related impurities is indispensable during material purification and pesticide registration and certified reference material development, and therefore needs to be carefully characterized. In this study, a combined strategy with liquid chromatography high-resolution mass spectrometry and SIRIUS has been developed to elucidate impurities from DNT material. MS and MS/MS spectra were used to score the impurity candidates by isotope score and fragment tree in the computer assisted tool, SIRIUS. DNT, the main component, worked as an anchor for formula identification and impurity structure elucidation. With this strategy, two by-product impurities and one stereoisomer were identified. Their fragmentation pathways were concluded, and the mechanism for impurity formation was also proposed. This result showed a successful application for combined human intelligence and machine learning, in the identification of pesticide impurities.
Topics: Chromatography, High Pressure Liquid; Drug Contamination; Guanidines; Humans; Neonicotinoids; Nitro Compounds; Pesticides; Tandem Mass Spectrometry
PubMed: 36014490
DOI: 10.3390/molecules27165251 -
Journal of Chromatography. A May 2009In the biopharmaceutical industry, column chromatography residuals are routinely assessed by the direct measurement of mock eluates. In this study, we evaluated virus...
In the biopharmaceutical industry, column chromatography residuals are routinely assessed by the direct measurement of mock eluates. In this study, we evaluated virus and other impurity carryover between protein A cycles and the feasibility of using a total organic carbon (TOC) analyzer to monitor for column impurity leakage as a correlate for actual measured carryover in mock eluates. Commercial process intermediates were used in scaled down studies of two protein A media, ProSep A (Millipore, Bedford, MA, USA) and MabSelect SuRe (GE Healthcare, Uppsala, Sweden). The chromatography system was programmed to run up to 200 normal load/elution cycles with periodic blank cycles to measure protein and phage carryover, and water flush cycles to measure TOC release. Sustained phage carryover was evident in each study. Carryover and TOC release was lowest in the case where cleaning was most stringent (50 mM NaOH/0.5 M Na(2)SO(4) with MabSelect SuRe). The TOC analysis at this time does not appear to be a viable practical means of measuring impurity carryover; direct measurements in mock eluates appears to be more predictive of column performance.
Topics: Animals; Bacteriophages; CHO Cells; Carbon; Chromatography, Affinity; Cricetinae; Cricetulus; Pharmaceutical Preparations; Protein Binding; Staphylococcal Protein A; Viral Proteins
PubMed: 19285678
DOI: 10.1016/j.chroma.2009.02.050 -
Biotechnology Progress Jul 2022Cell culture medium (CCM) formulations are chemically defined to reduce lot-to-lot variability and complexity of the medium while still providing all essential nutrients...
Cell culture medium (CCM) formulations are chemically defined to reduce lot-to-lot variability and complexity of the medium while still providing all essential nutrients supporting cell growth and productivity of various cell lines. However, raw material impurities may still introduce variations and inconsistencies to final CCM formulations. In one of our previous studies (Weiss et al. Biotechnol Prog. 2021;37(4):e3148), we have demonstrated the impact of iron raw material impurity on Chinese hamster ovary (CHO) cell performance and critical quality attributes (CQAs) of recombinant proteins within the Cellvento® 4CHO CCM platform by identifying manganese impurity as the main root cause for improved cell performance and altered glycosylation profiles. This study sought to investigate the impact of iron raw material impurities within another medium platform, namely EX-CELL® Advanced CHO Fed-Batch-Medium. As opposed to previously published results, in this platform, copper instead of manganese impurity present within the used ferric ammonium citrate (FAC) iron source was responsible for an improved cell performance of a CHOZN® cell line and a slight difference in CQAs of the produced recombinant protein. The use of tightly controlled raw material specifications or the use of low impurity iron sources is therefore crucial to minimize the impact of impurities on cell performance in any CCM platform and thereby guarantee consistent and reproducible cell culture processes.
Topics: Animals; CHO Cells; Cell Culture Techniques; Copper; Cricetinae; Cricetulus; Culture Media; Iron; Manganese; Recombinant Proteins
PubMed: 35318833
DOI: 10.1002/btpr.3251 -
The Journal of Toxicological Sciences 2019Abuse of recreational drugs (i.e., synthetic chemicals with the structure or expected neurotropic effects, or both, similar to those of controlled substances) is a...
Abuse of recreational drugs (i.e., synthetic chemicals with the structure or expected neurotropic effects, or both, similar to those of controlled substances) is a serious and continuous social harm. Designer drugs are often manufactured or synthesized in small-scale clandestine laboratories with impure starting materials, poor handling skills and inferior storage conditions. Therefore, in addition to the objective compound, diverse impurities may be present, for example, from the starting material, intermediates, catalytic metals formed during chemical synthesis, and materials from the environment. Impurity profiling of drug seizures is a useful scientific tool to obtain information on the clandestine manufacturers and drug trafficking networks. 1-Phenyl-2-(1-pyrrolidinyl)-1-pentanone (α-PVP), a novel psychoactive substance of the cathinone type that is banned in many countries, is still supplied and distributed within the illicit drug market. By using GC-MS and ICP-MS, we identified and estimated the relative contents of organic and inorganic impurities in the bulk powder of 15 batches of α-PVP. We then conducted multivariate data analyses to reveal characteristic patterns of the profiles. Hierarchical cluster analysis of both the organic and inorganic impurities revealed two groups that showed similar impurity profiles, which suggested that the batches in these groups were synthesized in similar routes under similar synthetic environments. The initial groups revealed by the organic impurities were further divided when combined with the data from the inorganic impurities. The present study, therefore, demonstrated the effectiveness of integrated analyses of organic and inorganic impurities for the accurate clustering of designer drugs, to provide precise information to drug investigation authorities.
Topics: Cluster Analysis; Designer Drugs; Drug Contamination; Drug and Narcotic Control; Inorganic Chemicals; Organic Chemicals; Pentanones; Pyrrolidines
PubMed: 31813904
DOI: 10.2131/jts.44.849 -
The Journal of Physical Chemistry... Feb 2020We develop a spin diffusion theory based on the exchange mechanism among polarons to understand the organic pure spin current. It is demonstrated that the exchange...
We develop a spin diffusion theory based on the exchange mechanism among polarons to understand the organic pure spin current. It is demonstrated that the exchange coupling is strong enough to induce spin transport within the organic layer with impurity concentrations higher than 10 cm. By calculating the inverse spin Hall voltage in an organic spin device, we predict that the voltage depends nonmonotonically on the impurity concentration of the organic material. By tuning the doping concentration, one can achieve a maximum inverse spin Hall voltage. Our results not only explain some recent experimental data but also inspire further experimental investigation on pure spin current in organic devices with variable impurity doping.
PubMed: 31957440
DOI: 10.1021/acs.jpclett.9b03703 -
Physical Chemistry Chemical Physics :... May 2018A bulk-heterojunction structure is often employed to develop high-performance organic photocells, in which the donor and acceptor regions are complexly intertwined. In...
A bulk-heterojunction structure is often employed to develop high-performance organic photocells, in which the donor and acceptor regions are complexly intertwined. In such situations, mesoscopic-scale islands and peninsulas that compose the donor materials may be formed in the acceptor region. Alternatively, the donor region may extend deeply into the acceptor region. This yields mesoscopic-size impurities that can create obstacles in the charge separation (exciton dissociation) process of organic photocells and prevents the dissociation of excitons (electron-hole pairs). We previously reported on the effect of the cooperative behavior between the hot charge transfer (CT) state and the dimensional (entropy) effect on the charge separation process. In this paper, we discuss the mesoscopic-scale impurity effect on the charge separation process in PCBM acceptor models by considering the hot CT state and dimensional effects. In addition, we discuss atomic-scale effects such as molecular distortions and conformation changes using molecular dynamics (MD) simulations.
PubMed: 29781001
DOI: 10.1039/c7cp08125a -
Journal of Pharmaceutical and... Dec 2014Peptides are an increasingly important group of pharmaceuticals, positioned between classic small organic molecules and larger bio-molecules such as proteins. Currently,... (Review)
Review
Peptides are an increasingly important group of pharmaceuticals, positioned between classic small organic molecules and larger bio-molecules such as proteins. Currently, the peptide drug market is growing twice as fast as other drug markets, illustrating the increasing clinical as well as economical impact of this medicine group. Most peptides today are manufactured by solid-phase peptide synthesis (SPPS). This review will provide a structured overview of the most commonly observed peptide-related impurities in peptide medicines, encompassing the active pharmaceutical ingredients (API or drug substance) as well as the finished drug products. Not only is control of these peptide-related impurities and degradants critical for the already approved and clinically used peptide-drugs, these impurities also possess the capability of greatly influencing initial functionality studies during early drug discovery phases, possibly resulting in erroneous conclusions. The first group of peptide-related impurities is SPPS-related: deletion and insertion of amino acids are related to inefficient Fmoc-deprotection and excess use of amino acid reagents, respectively. Fmoc-deprotection can cause racemization of amino acid residues and thus diastereomeric impurities. Inefficient deprotection of amino acid side chains results into peptide-protection adducts. Furthermore, unprotected side chains can react with a variety of reagents used in the synthesis. Oxidation of amino acid side chains and dimeric-to-oligomeric impurities were also observed. Unwanted peptide counter ions such as trifluoroacetate, originating from the SPPS itself or from additional purification treatments, may also be present in the final peptide product. Contamination of the desired peptide product by other unrelated peptides was also seen, pointing out the lack of appropriate GMP. The second impurity group results from typical peptide degradation mechanisms such as β-elimination, diketopiperazine, pyroglutamate and succinimide formation. These SPPS- and degradation-related impurity types can also found in the finished peptide drug products, which can additionally contain a third group of related impurities, i.e. the API-excipient degradation products.
Topics: Drug Contamination; Drug Discovery; Humans; Peptides
PubMed: 25044089
DOI: 10.1016/j.jpba.2014.06.012