There is a need of guidance on how local irritancy data should be incorporated into risk assessment procedures, particularly with respect to the derivation of occupational exposure limits (OELs). ...Therefore, a board of experts from German committees in charge of the derivation of OELs discussed the major challenges of this particular end point for regulatory toxicology. As a result, this overview deals with the question of integrating results of local toxicity at the eyes and the upper respiratory tract (URT). Part 1 describes the morphology and physiology of the relevant target sites, i.e., the outer eye, nasal cavity, and larynx/pharynx in humans. Special emphasis is placed on sensory innervation, species differences between humans and rodents, and possible effects of obnoxious odor in humans. Based on this physiological basis, Part 2 describes a conceptual model for the causation of adverse health effects at these targets that is composed of two pathways. The first, “sensory irritation” pathway is initiated by the interaction of local irritants with receptors of the nervous system (e.g., trigeminal nerve endings) and a downstream cascade of reflexes and defense mechanisms (e.g., eyeblinks, coughing). While the first stages of this pathway are thought to be completely reversible, high or prolonged exposure can lead to neurogenic inflammation and subsequently tissue damage. The second, “tissue irritation” pathway starts with the interaction of the local irritant with the epithelial cell layers of the eyes and the URT. Adaptive changes are the first response on that pathway followed by inflammation and irreversible damages. Regardless of these initial steps, at high concentrations and prolonged exposures, the two pathways converge to the adverse effect of morphologically and biochemically ascertainable changes. Experimental exposure studies with human volunteers provide the empirical basis for effects along the sensory irritation pathway and thus, “sensory NOAEC
human
” can be derived. In contrast, inhalation studies with rodents investigate the second pathway that yields an “irritative NOAEC
animal
.” Usually the data for both pathways is not available and extrapolation across species is necessary. Part 3 comprises an empirical approach for the derivation of a default factor for interspecies differences. Therefore, from those substances under discussion in German scientific and regulatory bodies, 19 substances were identified known to be human irritants with available human and animal data. The evaluation started with three substances: ethyl acrylate, formaldehyde, and methyl methacrylate. For these substances, appropriate chronic animal and a controlled human exposure studies were available. The comparison of the sensory NOAEC
human
with the irritative NOAEC
animal
(chronic) resulted in an interspecies extrapolation factor (iEF) of 3 for extrapolating animal data concerning local sensory irritating effects. The adequacy of this iEF was confirmed by its application to additional substances with lower data density (acetaldehyde, ammonia,
n
-butyl acetate, hydrogen sulfide, and 2-ethylhexanol). Thus, extrapolating from animal studies, an iEF of 3 should be applied for local sensory irritants without reliable human data, unless individual data argue for a substance-specific approach.
Two previously healthy women developed nausea, vomiting, headache and dizziness for several days, a massive hair loss about 2 weeks later and a discoloration of the fingernails. Detailed diagnostic ...procedures did not reveal any pathological results. Therapeutic measures did not show any effect. Thallium and arsenic were within normal range in plasma. Delayed quantitative determination of selenium in blood, however revealed toxic values (in case I: 479 μg/L of serum, 8 weeks after ingestion, and in case II 300 μg/L of serum, 9 weeks after ingestion). In retrospect, a relation to the ingestion of paradise nuts could be established.
Reports on adverse effects of chemical substances and mixtures (poisonings in the broader sense) are of great importance both for the improvement of medical care as well as for substance and product ...safety and for medical education and training. Case reports are the basis of toxicovigilance, i.e. the detection and assessment of poisoning risks in a community arising from clinical cases. Reports on poisonings are created mainly by medical doctors, but also by toxicologically trained nurses and non-medical scientists of poison centres and toxicology labs.In this article, basic terms of clinical toxicology are explained and the important roles of reporting on poisoning are described.Standards for poisoning reporting are partly developed. Reports differ in structure, information content and the degree of assignment of evaluation categories (administrative, clinical, product safety, e.g. agent group, degree of poisoning severity, causality). Methodologically, a distinction is made between detailed individual case reports and aggregated case series with little clinical information.As a result, case reports have recently been used to describe novel intoxications (e.g. new psychoactive substances NPSs). Case series facilitated the detection of poisoning outbreaks (sealant spray, ciguatera fish poisoning) and novel products with increased risk of poisoning (e.g. liquid laundry detergent capsules). Systematic toxicovigilance at the national level in Germany will be considerably improved by a national register of poisoning planned at German Federal Institute for Risk Assessment (BfR). For a European toxicovigilance scheme, the recently developed EuPCS product category system forms an important basis.
Zusammenfassung
Fallberichte über gesundheitsschädliche Einwirkungen von chemischen Stoffen und Gemischen (Vergiftungen im weiteren Sinne) haben große Bedeutung für die Verbesserung der ...Patientenversorgung, die Stoff- und Produktsicherheit sowie für die medizinische Aus- und Weiterbildung. Sie sind die Basis der Toxikovigilanz, d. h. der vom klinischen Fall ausgehenden Erkennung und Bewertung von Vergiftungsrisiken in der Gesellschaft. Die Vergiftungsdokumentation erfolgt v. a. durch Ärztinnen und Ärzte sowie Fachkräfte in der Pflege, toxikologischen Laboratorien und Giftinformationszentren (GIZ) der Bundesländer.
In diesem Beitrag werden Begrifflichkeiten der klinischen Toxikologie erläutert und die Bedeutung der Vergiftungsdokumentation beschrieben. Standards für Vergiftungsberichterstattung sind teilweise entwickelt. Die Berichte unterscheiden sich je nach Verwendungszweck (administrativ, klinisch, Produktsicherheit) in Struktur, Informationsgehalt und Zuweisung von Auswertungskategorien (z. B. Noxengruppe, Vergiftungsschweregrad, Kausalität). Methodisch wird zwischen Einzelfallberichten und aggregierten Fallserien mit wenig klinischer Information unterschieden.
Einzelfallberichte können der Beschreibung neuer Vergiftungen dienen, z. B. in jüngster Zeit jener durch neue psychoaktive Substanzen (NPS). Auf Grundlage von Fallserien können Vergiftungsausbrüche (z. B. Versiegelungsspray, Ciguatera-Fischvergiftung) erkannt und neuartige Produkte mit erhöhtem Vergiftungsrisiko (z. B. Gelkapselwaschmittel) identifiziert werden. Zukünftig wird die systematische nationale Toxikovigilanz durch ein nationales Vergiftungsregister im Bundesinstitut für Risikobewertung (BfR) erheblich verbessert. Für die europäische Toxikovigilanz ist das neue Produktkategoriesystem EuPCS eine wichtige Voraussetzung.
Recent proof-of-principle data showed that the haematopoietic growth factor granulocyte colony-stimulating factor (filgrastim) mediates neuroprotection in rodent models of Parkinson's disease. In ...preparation for future clinical trials, we performed a preclinical characterization of a pegylated derivative of granulocyte colony-stimulating factor (pegfilgrastim) in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. We determined serum and cerebrospinal fluid drug levels after subcutaneous injection. A single injection of pegfilgrastim was shown to achieve stable levels of granulocyte colony-stimulating factor in both serum and cerebrospinal fluid with substantially higher levels compared to repetitive filgrastim injections. Leucocyte blood counts were only transiently increased after repeated injections. We demonstrated substantial dose-dependent long-term neuroprotection by pegfilgrastim in both young and aged mice, using bodyweight-adjusted doses that are applicable in clinical settings. Importantly, we found evidence for the functionally relevant preservation of nigrostriatal projections by pegfilgrastim in our model of Parkinson's disease, which resulted in improved motor performance. The more stable levels of pegylated neuroprotective proteins in serum and cerebrospinal fluid may represent a general advantage in the treatment of chronic neurodegenerative diseases and the resulting longer injection intervals are likely to improve patient compliance. In summary, we found that pegylation of a neuroprotective growth factor improved its pharmacokinetic profile over its non-modified counterpart in an in vivo model of Parkinson's disease. As the clinical safety profile of pegfilgrastim is already established, these data suggest that evaluation of pegfilgrastim in further Parkinson's disease models and ultimately clinical feasibility studies are warranted.
Poisoning by chemical substances and products Begemann, Kathrin; Glaser, Nina; Desel, Herbert
Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz
62, Številka:
11
Journal Article
Recenzirano
Exposure to chemical substances results in a multitude of poisonings or suspected poisonings every year. Poison centres (PCs) advise the public and medical staff on these issues and register cases in ...their databases. Additionally, the Federal Institute for Risk Assessment (BfR) maintains a case database with notifications reported by attending physicians within the framework of the Chemicals Act.This article describes important poisons from the field of chemicals and products and gives an example of poisoning risk management for a new product group. For this purpose, exemplary case information published in the annual reports of different PCs and the cases notified to the BfR were examined.An overview is provided on the product groups leading most frequently to poisonings and requests to the PCs. The spectrum of poisonings registered by the BfR and PCs differs clearly between reporting persons, route of exposure and severity. Substance groups with a relatively high risk compared to other chemical substances and products are highly concentrated detergents, acids and alkalis as well as carbon monoxide.PCs and the BfR databases contain valuable information to estimate the frequency and severity of various poisonings. By merging these data in a national poisoning register, new risks would be discovered more quickly in the future and a national overview of poisoning events would be gained.
Toxin-producing microalgae are thriving worldwide due to coral reef destruction and global warming with major consequences on ecosystems, international trade and human health. Microalgae belonging to ...the family of flagellate protists, in particular dinoflagellates, secrete a variety of high-molecular-weight polyether toxins that accumulate through the marine food chain to cause disease in humans by acting as sodium channel activator toxins; ciguatera is the most frequent seafood-borne illness worldwide with 50,000 to 500,000 global incidences per annum and is usually limited to endemic areas located between 35° northern and 35° southern latitude. The rising global incidence frequency renders it a major human health problem, because no curative treatment is available yet and reliable detection assays are lacking. During the last decade ciguatera has increasingly become endemic in previously unaffected areas for two reasons: first global warming has contributed to the emergence of dinoflagellate species in subtropical and even temperate regions that previously had been constrained to tropical areas and second: in Europe globalization of fishing industry and tourism has led to a progressive increase in the number of ciguatera cases and a lack of awareness among medical personnel contributes to under-reporting. We review, through a recent ciguatera outbreak in Germany, the risk for ciguatera poisoning in Europe and highlight characteristic symptoms, current knowledge about disease pathomechanisms and treatment options.
•Ciguatoxins, polyether sodium channel activators, are biotoxins accumulating in fish flesh via the marine food chain.•Cold allodynia and pruritus are pathognomonic symptoms of Ciguatera and correspond to the clinical picture of a distal sensory axonopathy.•Global warming and coral reef destruction cause a rise of ciguatera incidence through thriving of poisonous microalgae.•In addition global trade and tourism pose previously non-endemic areas in temperate climates at risk.
Vergiftungen durch chemische Stoffe und Produkte Begemann, Kathrin; Glaser, Nina; Desel, Herbert
Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz,
2019/11, Letnik:
62, Številka:
11
Journal Article
Recenzirano
Zusammenfassung
Chemische Stoffe und Produkte führen jedes Jahr zu einer Vielzahl von Vergiftungen oder Verdachtsfällen von Vergiftungen. Die Giftinformationszentren (GIZ) beraten dazu Laien und ...medizinisches Personal und dokumentieren die Anfragen in ihren Datenbanken. Zusätzlich führt das Bundesinstitut für Risikobewertung (BfR) eine Falldatenbank mit ärztlichen Mitteilungen zu Vergiftungen, die gemäß Chemikaliengesetz gemeldet werden.
In diesem Beitrag werden wichtige Noxen aus dem Bereich chemischer Stoffe und Produkte beschrieben und an einem Beispiel wird auf das Management von Vergiftungsrisiken einer neuen Produktgruppe eingegangen. Hierzu werden exemplarisch Fallinformationen untersucht, die in Jahresberichten verschiedener GIZ publiziert wurden, sowie Vergiftungsfälle, die an das BfR gemeldet wurden.
Es wird eine Übersicht über die Produktgruppen gegeben, die am häufigsten zu Vergiftungen bzw. zu Anfragen in den GIZ führen. Das Spektrum der Vergiftungen unterscheidet sich zwischen den Fällen von GIZ und BfR hinsichtlich Melder, Eintrittspforte und Schweregrad deutlich. Stoffgruppen mit einem relativ hohen Risiko im Vergleich zu anderen chemischen Stoffen und Produkten sind hoch konzentrierte Tenside, Säuren und Laugen sowie Kohlenmonoxid.
Die Datenbanken der GIZ und des BfR enthalten wertvolle Informationen zur Einschätzung von Häufigkeit und Schwere verschiedener Vergiftungen. Durch die Zusammenführung dieser Daten in Form eines nationalen Vergiftungsregisters könnten neue Risiken zukünftig schneller erkannt und ein nationaler Überblick über das Vergiftungsgeschehen gewonnen werden.
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