Herbert Desel

Sensory irritation as a basis for setting occupational exposure limits

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 NOAEChuman” can be derived. In contrast, inhalation studies with rodents investigate the second pathway that yields an “irritative NOAECanimal.” 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 NOAEChuman with the irritative NOAECanimal (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.

Bites and stings by exotic pets in Europe: An 11 year analysis of 404 cases from Northeastern Germany and Southeastern France

Introduction. The presence of exotic, and sometimes venomous, pets in European homes is becoming more common. This phenomenon is the basis of a French-German cooperative evaluation of the species causing the injuries and the circumstances, severity, and treatment of the envenomations Methods. A retrospective, descriptive, cross-sectional, case series of data from 1996 to 2006. The study sample consists of all cases of bites and stings by exotic pets that were registered at four poisons European poisons centers. The inclusion criteria were bites and stings of human beings. Results. From 1996 to 2006 four poisons centers in Europe were consulted on 404 bites and stings by exotic pets. The average age of the patients was 36 (2 to 75) years and 73% of the patients were male. The severity of the envenomations, according to the Poisoning Severity Score, was as follows: 29 severe (7.1%), 55 moderate (14.2%) and 320 minor (78.7%). There were no fatalities in this case series. Exotic snakebites from rattlesnakes, cobras, mambas, and other venomous snakes caused 39% of envenomations, aquatic animals (mostly lionfish of the Pterois genus and stingrays) caused 30% of envenomations and arthropods (tarantulas and scorpions) caused 27% of envenomations. All severe envenomations were caused by venomous snakes. Conclusions. European healthcare professionals may encounter patients bitten or stung by exotic pets. Poisons center consultation can help manage these unusual presentations and help obtain rarely used antivenoms.

Surgical treatment in cocaine body packers and body pushers

ObjectiveBody packers smuggle cocaine by swallowing containers filled with the drugs, whilst body pushers conceal the containers in the rectum or vagina. In a collaborative effort between the Department of General Surgery, two major airports and Poisons Centre, we performed a retrospective study to develop an algorithm for the treatment of ruptured cocaine-filled containers.Materials and methodsThe data of all cocaine body packers and body pushers who were identified at the airports of Frankfurt and Paris from 1985 to 2002 were evaluated concerning incidence, demographics and surgical aspects.ResultsFrom 1985 to 2002, 312 body pushers and 4,660 body packers were identified. The sex ratio was 1:1. Sixty-four “mules” (1.4%) developed life-threatening symptoms of cocaine overdose after the rupture of a container. In 20 patients, an emergency laparotomy was performed and the containers were removed; all of these patients survived. Forty-four body packers died before surgical treatment could be performed. Only one body pusher required medical attention.ConclusionCocaine overdose can be life-threatening. If the cause is the rupture of a container in a body packer, the only possible treatment is immediate laparotomy for the removal of the container.

Pegylated granulocyte colony-stimulating factor conveys long-term neuroprotection and improves functional outcome in a model of Parkinson’s disease

Recent proof-of-principle data showed that the haematopoietic growth factor granulocyte colony-stimulating factor (filgrastim) mediates neuroprotection in rodent models of Parkinsons 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 Parkinsons 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 Parkinsons 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 Parkinsons disease. As the clinical safety profile of pegfilgrastim is already established, these data suggest that evaluation of pegfilgrastim in further Parkinsons disease models and ultimately clinical feasibility studies are warranted.

Slow elimination of mannitol from human cerebrospinal fluid

AbstractObjective: The rise of intracranial pressure above the pre-treatment level (rebound phenomenon) is considered, in part, a consequence of osmotherapeutics penetrating into the intracranial compartments. Methods: The kinetics of mannitol in the ventricular CSF were studied in 10 patients with cerebrovascular stroke after a single i.v. infusion of 37.5 g over 15 min. Results: Maximum mannitol CSF concentrations (mean = 51.1 mg · l−1) were reached 2–12 h after termination of the infusion. Mean t1/2CSF (18.3 h) by far exceeded t1/2S (3.71 h). AUCCSF/AUCS, as a measure of mannitol CSF penetration, ranged from 0.037 to 0.390. Conclusion: The slow elimination of mannitol from CSF implies a high risk of accumulation in the central nervous compartments after repeated dosing.

Determination of 2-hydroxyphenylacetic acid (2HPAA) in urine after oral and parenteral administration of coumarin by gas-liquid chromatography with flame-ionization detection

The urinary excretion of 2-hydroxyphenylacetic acid (2HPAA) was studied in human volunteers after oral and parenteral doses of coumarin. The presence of 2HPAA in the urine was confirmed by gas chromatography mass spectroscopy (GC MS). Mass spectra of reference material and samples are presented. The determination of 2HPAA was carried out by GC with flame-ionization detection. Prior to analysis samples were extracted into ethyl ether and the analytes were derivatized with trimethlyphenylammonium hydroxide. A calibration range from 0.3 to 150 micrograms ml-1 was established using 3-hydroxyphenyl acetic acid (3HPAA) as an internal standard. On average less than 10% of the coumarin administered were excreted into the urine in the form of 2HPAA.

Acute selenium poisoning by paradise nuts (Lecythis ollaria).

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.

Common Causes of Poisoning: Etiology, Diagnosis and Treatment

BACKGROUND In 2011, German hospitals treated approximately 205 000 patients suffering from acute poisoning. Change is seen over time both in the types of poisoning that occur and in the indications for specific treatment. METHODS This article is based on a selective review of the literature, with special attention to the health reports of the German federal government, the annual reports of the GIZ-Nord Poisons Center (the poison information center for the four northwestern states of Germany, i.e. Bremen, Hamburg, Lower Saxony and Schleswig-Holstein), and the recommendations of international medical associations. RESULTS From 1996 to 2011, the GIZ-Nord Poisons Center answered more than 450 000 inquiries, most of which involved exposures to medical drugs, chemicals, plants, foods, or cosmetics. Poisoning was clinically manifest in only a fraction of these cases. Ethanol intoxication is the commonest type of acute poisoning and suicide by medical drug overdose is the commonest type of suicide by poisoning. Death from acute poisoning is most commonly the result of either smoke inhalation or illegal drug use. Severe poisoning is only rarely due to the ingestion of chemicals (particularly detergents and cleaning products), cosmetics, or plant matter. Medical procedures that are intended to reduce the absorption of a poison or enhance its elimination are now only rarely indicated. Antidotes (e.g., atropine, 4-dimethylaminophenol, naloxone, toluidine blue) are available for only a few kinds of poisoning. Randomized clinical trials of treatment have been carried out for only a few substances. CONCLUSION Most exposures to poisons can be treated with general emergency care and, if necessary, with symptomatic intensive-care measures. Poison information centers help ensure that cases of poisoning are dealt with efficiently. The data they collect are a useful aid to toxicological assessment and can serve as a point of departure for research projects.

Vergiftung durch Tropenfisch: Ciguatera-Epidemie in Deutschland

Ciguatera is a seafood-borne illness caused by consumption of tropical fish contaminated with ciguatoxins, lipophilic polyethers that are produced in benthic dinoflagellates and accumulate through the marine food chain. Ciguatera cases in Europe usually occur in travellers returning from tropical and subtropical regions of the Pacific and Carribean, where ciguatera is endemic. In 2012, several cases of ciguatera occurred in Germany due to sale of contaminated fish products originating from the Indian Ocean. Although the symptomatology in these cases were typical of ciguatera, with patients reporting gastrointestinal discomfort including nausea, vomiting and diarrhea as well as neurological effects including widespread intense pruritus, paresthesias, hypothermia or altered temperature sensation and diffuse pain, correct diagnosis was delayed in all cases due to lack of awareness of the treating medical practitioners. In light of increasing global mobility, trade, and occurrence of ciguatoxic fish in previously non-endemic areas, ciguatera should be considered as a possible diagnosis if gastrointestinal and neurological symptoms occur shortly after consumption of fish.

Systematic forensic toxicological analysis by GC-MS in serum using automated mass spectral deconvolution and identification system

Non-targeted screening of body fluids for psychoactive agents is an essential task for forensic toxicology. The challenge is the identification of xenobiotics of interest from background noise and endogenous matrix components. The aim of the present work was to evaluate the use of an Automated Mass Spectral Deconvolution and Identification System (AMDIS) for gas chromatography-mass spectrometry (GC-MS) based toxicological serum screening. One hundred fifty serum samples submitted to the authors´ laboratory for systematic forensic toxicological analysis underwent GC-MS screening after neutral and basic liquid-liquid extraction. Recorded datasets were routinely evaluated both by experienced personnel and automatically using the AMDIS software combined with the Maurer/Pfleger/Weber GC-MS library MPW_2011. The results from manual and automated data evaluation were then systematically compared. AMDIS parameters for data deconvolution and substance identification had been successfully adapted to the GC-MS screening procedure in serum. The number of false positive hits could substantially be reduced without increasing the risk of overlooking relevant compounds. With AMDIS-based data evaluation, additional drugs were identified in 25 samples (17%) that had not been detected by manual data evaluation. Importantly, among these drugs, there were frequently prescribed and toxicologically relevant antidepressants and antipsychotic drugs such as citalopram, mirtazapine, quetiapine, or venlafaxine. For most of the identified drugs, their serum concentrations were in the therapeutic or subtherapeutic range. Thus, our study indicated that automated data evaluation by AMDIS provided reliable screening results. Copyright