Archives of toxicology. Supplement. = Archiv fur Toxikologie. Supplement最新文献

Ultraviolet light can affect the immune system locally as well as systemically leading to an impaired resistance to neoplastic cells and/or infections. Prior to the biological effect, UVB must be absorbed by a chromophore in the skin where it will give a signal that can lead to an altered immune response in the skin or elsewhere. These altered immune responses may be constituted by alteration in among others: cytokine profile, growth factors and costimulatory signals. Several hypotheses about the identity of the photoreceptor have been put forward. One photoreceptor in the skin is urocanic acid (UCA), that can isomerize from the trans- to the cis-isomer. The cis-isomer has immunosuppressive properties. Another photoreceptor is DNA that also efficiently absorbs UV wavelengths. After absorption the structure of the DNA molecule is altered. This alteration might lead to gene activation responsible for the immunotoxic outcome (altered gene expression). It has been demonstrated that the formation of DNA photoproducts by UV light is associated with the activation of many genes. Several studies indicate that UV-induced DNA damage, in the form of cyclobutyl pyrimidine dimers plays a role in UV-induced suppression of the immune system locally as well as systemically. In mice that were injected with liposomes containing the excision repair enzyme T4 endonuclease UVB-induced dimers were removed more efficiently as compared to control mice. In these mice UV-induced immunosuppression was prevented. Pilot studies by Kripke et al. indicated that the release of IL-IO and TNF alpha that are both induced by DNA damage might be involved. In preliminary studies with mice that were deficient with respect to DNA repair lower doses of UV were needed for the induction of immunosuppression as compared to their normal littermates. These studies indicate that altered gene expression plays a pivotal role in UVB-induced immunosuppression. In addition to a role for UCA and DNA in UV-induced immunosuppression it is postulated recently that signal transduction (EGF-receptor mediated upregulation of phospholipase A2) and transcription factors (NF kappa B, p91) are involved in UV-induced immunomodulation.

Specific and sensitive detection or precise quantification of xenobiotics in biosamples (e.g. blood, urine, saliva, sweat, hair) are great challenges in analytical toxicology. GC-MS is the most sensitive, specific and universal analytical method for low mass xenobiotics. Precise quantification can be performed using the selected ion mode (SIM) and stable isotopes as internal standards. Negative chemical ionization (NCI) can improve severalfold the sensitivity for the determination of compounds with electronegative sites (e.g. halogens). For screening and identification of most of the basic and neutral drugs (e.g. drugs of abuse, psychotropics, hypnotics, analgesics, cardiacs) in urine, a systematic toxicological analysis procedure (STA) was developed using GC-MS after acid hydrolysis, extraction and acetylation. for detection of acidic xenobiotics (e.g. anticoagulants, ACE inhibitors, diuretics, antirheumatics) in urine, a further GC-MS procedure was developed using extractive alkylation. For the detection of non-volatile xenobiotics (e.g. toxic peptides like alpha- and beta-amanitin or phase II metabolites) electrospray LC-MS procedures were developed. The procedures and examples show that in analytical toxicology GC-MS is the method of choice for low mass xenobiotics while LC-MS is that for non-volatiles.

Antidotes may play an important role in the treatment of poisoning. For many physicians and toxicologists an antidote is an antidote. According to the IPCS definition, an antidote is a therapeutic substance used to counteract the toxic action(s) of a specified xenobiotic. Given this wide definition, the efficacy of an antidote may vary considerably depending on which toxic action(s) is/are being counteracted and on the level of counteracting power: An almost 100% efficacy is seen using specific antagonists, such as naloxone in opiate poisoning or flumazenil in benzodiazepine poisoning, e.g. resulting in complete reversal of opiate toxicity unless complications, such as anoxic brain damage, have developed. At the other end of the efficacy scale, we may place chelating agents for heavy metal poisoning and diazepam for organophosphorus insecticide poisoning. Therefore, in the IPCS/EC evaluation series of antidotes, some chelating agents are considered only to be an adjunct to supportive care which is the cornerstone of treatment. When teaching clinical toxicology or recommending the use of antidotes in poisoned patients, the expected efficacy level of the antidote in question should be stressed. This may be particularly important in severe poisonings when the antidote may only be considered as an adjunct to supportive care, e.g. deferoxamine in acute iron poisoning. Unless this is stressed, the unexperienced physician may rely too much on the antidote and may not pay sufficient attention to the supportive care. In this presentation, the varying efficacy levels of antidotes are discussed as based on the presently ongoing IPCS/EC evaluation programme on antidotes.

European Union chemical legislation requires the calculation of local and regional Predicted Environmental Concentrations (PEC) for the assessment of the exposure of new and existing chemicals to aquatic and terrestrial ecosystems. Current methods use local models for air, water and soil to estimate chemical concentrations close to the source and a generic multimedia 'unit world' approach to estimate regional PECs. These models assume generic environmental scenarios representing typical situations in European countries and do not account for the spatial heterogeneity and temporal variability in ecosystem characteristics, soil properties, river flow rates, chemical emissions, etc. The environmental and ecological complexity can best be represented in a Geographic Information System (GIS). By coupling a GIS with a fate simulation model the concentrations of substances in a specific environment are predicted more realistically. The GREAT-ER project (Geography-referenced Regional Exposure Assessment Tool for European Rivers) was launched to refine regional and local exposure assessments for down-the-drain chemicals by applying real, spatial-referenced datasets instead of generic or average values. A modular approach was developed consisting of a hydrological model and a waste-flow, river quality and fate model which are linked to a regional GIS-database. For the calibration and validation in two European study areas representative detergent chemicals (LAS, boron) are used. In a parallel study, high-volume intermediates discharged into the river Rhine are simulated.