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PubMedDate not supplied

Hazard identification by methods of animal-based toxicology.

This paper is one of several prepared under the project "Food Safety In Europe: Risk Assessment of Chemicals in Food and Diet" (FOSIE), a European Commission Concerted Action Programme, organised by the International Life Sciences Institute, Europe (ILSI). The aim of the FOSIE project is to review the current state of the science of risk assessment of chemicals in food and diet, by consideration of the four stages of risk assessment, that is, hazard identification, hazard characterisation, exposure assessment and risk characterisation. The contribution of animal-based methods in toxicology to hazard identification of chemicals in food and diet is discussed. The importance of first applying existing technical and chemical knowledge to the design of safety testing programs for food chemicals is emphasised. There is consideration of the presently available and commonly used toxicity testing approaches and methodologies, including acute and repeated dose toxicity, reproductive and developmental toxicity, neurotoxicity, genotoxicity, carcinogenicity, immunotoxicity and food allergy. They are considered from the perspective of whether they are appropriate for assessing food chemicals and whether they are adequate to detect currently known or anticipated hazards from food. Gaps in knowledge and future research needs are identified; research on these could lead to improvements in the methods of hazard identification for food chemicals. The potential impact of some emerging techniques and toxicological issues on hazard identification for food chemicals, such as new measurement techniques, the use of transgenic animals, assessment of hormone balance and the possibilities for conducting studies in which common human diseases have been modelled, is also considered.

Animals↗

PubMedDate not supplied

Methods of in vitro toxicology.

In vitro methods are common and widely used for screening and ranking chemicals, and have also been taken into account sporadically for risk assessment purposes in the case of food additives. However, the range of food-associated compounds amenable to in vitro toxicology is considered much broader, comprising not only natural ingredients, including those from food preparation, but also compounds formed endogenously after exposure, permissible/authorised chemicals including additives, residues, supplements, chemicals from processing and packaging and contaminants. A major promise of in vitro systems is to obtain mechanism-derived information that is considered pivotal for adequate risk assessment. This paper critically reviews the entire process of risk assessment by in vitro toxicology, encompassing ongoing and future developments, with major emphasis on cytotoxicity, cellular responses, toxicokinetics, modelling, metabolism, cancer-related endpoints, developmental toxicity, prediction of allergenicity, and finally, development and application of biomarkers. It describes in depth the use of in vitro methods in strategies for characterising and predicting hazards to the human. Major weaknesses and strengths of these assay systems are addressed, together with some key issues concerning major research priorities to improve hazard identification and characterisation of food-associated chemicals.

Animal Testing Alternatives↗

PubMedDate not supplied

Confusion of concepts in mixture toxicology.

Regulatory limit values are generally set for single compounds. However, humans are exposed both simultaneously and sequentially to a wide variety of compounds. Some concepts on mixture toxicology are discussed in this introduction to the European Conference on Combination Toxicology. Studies on mixtures are often accompanied by statements about the type of combined action, which can be, for example, additive, synergistic or antagonistic. Unfortunately, comparison of results is hardly possible for various reasons. First, the terminology for indicating combined action is far from consistent. Bearing this in mind, researchers should be explicit in the definitions of terms. Secondly, depending on the model, different conclusions may be drawn from the same results. It is therefore important to provide clear definitions of the null hypothesis. Thirdly, adequate statistical methods should be used for testing the null hypothesis. In the past, many mixtures studies either used no statistics or used statistics incorrectly. Last, but not least, the study should be designed in such a way that it should be possible to obtain clear answers. In this introduction, it is stressed that environmental toxicologists should focus on the low-dose region of the dose-effect curves. It appears that interactions are less plausible at low doses. Dose additivity, however, cannot be excluded.

Animals↗

PubMedDate not supplied

Statistical designs in combination toxicology: a matter of choice.

Combination toxicological studies with statistically designed experiments do not often elaborate on the qualities of the design. Therefore, it may seem that the design used is the only one to meet the objectives of the study. This article demonstrates, on the contrary, that there are often several possibilities. Three recent toxicological experiments, featuring economy of experimentation, robustness against inhomogeneity of experimental material and increasing precision of results, respectively are used for illustration. The alternatives differ statistically in the number of distinct effects for which information can be obtained or in the safeguards to counter both inhomogeneity of material and incorrect models. Practically they differ in complexity of experimental conduct. It is concluded that the choice between the alternatives is a result of balancing practical complexity of the design against informational gain. Continuous co-operation between toxicologists and statisticians is needed to strike the balance again and again.

Aldehydes↗

PubMed2001

Toxicology information resources at the Environmental Protection Agency.

Article presents toxicology information resources available to the public from the United States Environmental Protection Agency (EPA). This includes digital information directly usable or downloadable from their web site, or referrals as to where the resource can be obtained. Contents include advice on effective search strategies, a 'guided tour' of the web site and its main categories, and concludes with an extensive annotated bibliography of toxicological databases.

Information Services↗

PubMed2001

Subnational sources of toxicology information: state, territorial, tribal, county, municipal, and community resources online.

The rapid assimilation data and information on the Internet and the World Wide Web (WWW) is reflected in the development of these electronic services by state, county, local, and other subnational agencies, departments, offices, bureaus, and intergovernmental bodies. The content of state and territorial, tribal, county, and local government Web pages varies considerably. However, information about health and the environment are among the most frequently posted resources by subnational government bodies. This article describes the environmental health and toxicology-related data and information resources provided by government agencies and representative associations for subnational government bodies. Standard reference sources for identifying subnational government bodies are described with particular reference to those in electronic and digital formats. Means for identifying and locating electronic resources are described for appropriate subnational environmental quality, environmental (public) health agencies, occupational health and safety, toxicology-related agencies and departments, emergency response, fish consumption advisories, and cancer registries are provided. Professional organizations of state, county, municipal (local) governments and intergovernmental bodies are also described.

Environmental Health↗

PubMed2002

Toxicological implications of hepatobiliary transporters.

Recent progress in molecular biological research has revealed that many types of transporters are expressed in the liver. Such xenobiotic transporters have a wide range of substrate specificity, which allows them to act as a barrier to protect the body from potentially harmful xenobiotics. Most of them mediate active transport of the substrates, leading to concentrative uptake and excretion into the hepatocytes and bile. Transport properties such as these may play a role in the toxicity of certain types of substrates. For example, anticancer agents such as methotrexate and irinotecan are efficiently excreted into the bile and such excretion has been suggested to account for their toxic gastrointestinal side-effects. A similar hypothesis has also been proposed for NSAIDs. Considering their tissue-specific expression, these transporters also appear to be a promising target for the delivery of small molecules, while simultaneously minimizing their side-effects. For example, transporters involved in the oral absorption, hepatic uptake, and biliary excretion of pravastatin, an HMG-CoA reductase inhibitor, ensure its enterohepatic circulation giving it an important pharmacokinetic advantage since its pharmacological target is the liver. Of the major ACE inhibitors currently available, temocaprilat is a substrate of hepatic transporters. Since the major elimination route for other ACE inhibitors is via urinary excretion, their plasma concentrations exhibit a high degree of inter-patient variability over a wide range of renal function whereas the concentrations of temocaprilat exhibit a much lower degree of inter-patient variability due to its elimination into the bile. Thus, the hepatobiliary transporters are involved in some aspects of toxicology and, therefore, a rational strategy for regulating the recognition by such transporters may be required for optimum drug design. This presentation will discuss the possible role of hepatic transporters from a toxicological point of view.

Animals↗

PubMed2003

Germany: toxicology information on the World Wide Web.

Following a brief introduction to the history of toxicology in Germany, this article deals with institutions concerned with toxicological information and research in Germany. The web addresses, responsibilities and main topics of federal authorities, federal state authorities, institutions for statutory accident insurance and prevention, non-university and university research institutes, funding institutions, scientific societies, industry representatives and poison information centers are described and links are given to databases provided on the web sites of these institutions.

Academies and Institutes↗

PubMed2001

The importance of drug-transporting P-glycoproteins in toxicology.

The importance of specific transport in toxicology is becoming increasingly clear and the work on P-glycoprotein has certainly been a major contribution to these growing insights. P-Glycoproteins were discovered by their ability to confer multidrug resistance in mammalian tumour cells. They are localised in the cell membrane where they actively extrude a wide range of compounds including many anti-cancer drugs from the cell. Besides in tumour cells, drug-transporting P-glycoproteins are also expressed in a polarised fashion in normal tissues that perform an excretory or barrier function, such as the liver, kidneys, intestines, brain endothelial cells. Based on this expression profile, it has been proposed that P-glycoproteins are important in protecting the host by reducing exposure to xenobiotics. Further studies with P-glycoprotein knockout mice have clearly established this protective function. In general, the clearance of substrate drugs is lower in knockout mice due to a diminished hepatobiliary excretion, direct intestinal excretion and/or increased enterohepatic cycling. Moreover, their uptake in sanctuary sites, such as the brain or the foetus, was profoundly higher in P-glycoprotein knockout mice, as was the uptake of drugs from the gastro-intestinal tract into the systemic circulation following oral ingestion. These results clearly highlight the impact that transport proteins can play in toxicology.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Currently available in vitro methods used in the regulatory toxicology.

About two decades ago in vitro mutagenicity tests were adopted as the first in vitro methods in regulatory toxicology. For reasons of animal welfare and better science, many validation studies of various in vitro methods were performed between 1985 and 1995 for their potential to replace the Draize eye irritation test. Albeit the fact that four in vitro methods (HET-CAM, BCOP, IRE, and ECE) have gained regulatory tolerance in Europe for the classification of severe eye irritants, the lessons learned mainly from these validation studies led to the definition of internationally harmonised OECD validation principles and acceptance criteria (Final Report of the OECD Workshop on Harmonization of Validation and Acceptance Criteria for Alternative Toxicological Tests Methods, 1996. OECD Publication Office, Paris, France). Application of these principles to prevalidation and validation studies, and additional special studies performed in Europe with the support of ECVAM, ended in the scientific validation of new in vitro methods for the prediction of skin corrosivity and phototoxicity. They were accepted for regulatory use in Europe and adopted on 8 June 2000 as test methods B. 40 and B. 41 of Annex V of Directive 67/548/EEC. In quite a different approach, European industry has submitted in-house validation data to support a Draft OECD Test Guideline for in vitro dermal absorption testing, which-after peer review and a long lasting international discussion-will now be adopted by the OECD. The increasing importance of regulatory measures derived from quantitative cytotoxicity tests, and some examples of regulatory accepted in vitro methods, where the specific purpose is restricted to a specific regulation (e.g. testing of medicinal products, or medical devices), are also addressed.

Animal Testing Alternatives↗

PubMed2002

An EU perspective on the use of in vitro methods in regulatory pharmaceutical toxicology.

Some in vitro methods such as those used in the assessment of genotoxicity, receptor-binding and QT-prolongation are well established in regulatory pharmaceutical toxicology. In vitro systems to study metabolic profiles, P450 isoforms, drug interactions, etc. or to provide metabolic activation in genotoxicity assays are extremely useful, but are subject to a number of important limitations. In vitro models are also employed on an ad-hoc basis for other purposes, for example, to help investigate mechanisms underlying in vivo findings. At the current stage of technical development of alternative methods, rapid replacement of the pivotal animal studies used in drug safety assessment seems unlikely. The existing in vivo models have good predictive ability regarding toxic effects in humans, are underpinned by an extensive literature and form the basis of most regulatory toxicology guidelines. Integrated in vitro testing strategies, meant to replace conventional repeated-dose studies, are still relatively undeveloped. Emerging technologies such as transgenics, toxicogenomics and toxicoproteomics, although they rely on the continued use of animals, have considerable potential in terms of reduction and refinement of in vivo methods.

Animals↗

PubMed1998

Integrating computer prediction systems with in vitro methods towards a better understanding of toxicology.

Structure Activity Relationships (SARs) or Quantitative Structure Activity Relationships (QSARs) form the basis of most computer prediction systems in toxicology. The underlying premise of SARs and QSARs is that the properties of a chemical are implicit in its molecular structure. For an SAR or QSAR to be valid and reliable, the dependent property for all of the chemicals covered by the relationship has to be elicited by a mechanism which is both common to the set of chemicals as well as relevant to that dependent property. Similar principles must also be applied to the development of in vitro alternatives to animal tests if those methods are to be reliable. A number of ways in which computer prediction systems and in vitro toxicology can complement each other in the development of alternatives to live animal experiments are described.

Animal Testing Alternatives↗

PubMed1998

Computer modeling and computational toxicology in new chemical and pharmaceutical product development.

A theoretical basis for use of computer modeling and bioinformatics resources including the internet in decisions about whether to attempt synthesis and toxicology testing of new chemical or pharmaceutical products is described. Steps in the process include: (1) identification of a potentially efficacious chemical or pharmaceutical product; (2) structure-activity relationship (SAR) modeling; (3) synthesis methods and cost screening; (4) market screening for potential revenues; (5) regulatory impacts screening; (6) toxicology modeling and screening; (7) decision making about whether to attempt synthesis and testing. Some such computer modeling and screening processes are already in use. Others may reasonably be expected to be adopted in the near future. More development of structure-activity and structure-toxicity databases and therapeutic and toxicity molecular endpoints computerized libraries remains to be done. The internet is a rapidly developing source of information, but there are major problems with time-effectiveness, quality control, 'junk information' (misinformation), and deliberate 'disinformation'.

Computer Simulation↗

PubMed2000

The toxicology expert: what is required?

In contrast to many traditional professions, toxicologists form a group with very different backgrounds, i.e. they may have been educated to become medical doctors, veterinarians, pharmacists, chemists, biochemists or biologists. Professional competence can be gained in different ways by candidate toxicologists, and according to the European system, their training can be divided into two parts. (i) Theoretical training on several topics such as analytical methods, organ toxicity, mutagenicity, carcinogenicity can be obtained by attending courses organised by the national societies of toxicology. (ii) Spending several years on active experimental work in the fields of modern toxicology (e.g. analytical methods, toxic and genotoxic mechanisms, reproductive toxicity) is necessary to develop the capability to design and carry out experimental studies and to evaluate one's own and other people's research results. Candidate toxicologists should learn to evaluate data with a strictly scientific 'plausibility above numbers' approach.

Employment↗

PubMed1998

Liquid chromatography-mass spectrometry in forensic and clinical toxicology.

This paper reviews liquid chromatographic-mass spectrometric (LC-MS) procedures for the identification and/or quantification of drugs of abuse, therapeutic drugs, poisons and/or their metabolites in biosamples (whole blood, plasma, serum, urine, cerebrospinal fluid, vitreous humor, liver or hair) of humans or animals (cattle, dog, horse, mouse, pig or rat). Papers published from 1995 to early 1997, which are relevant to clinical toxicology, forensic toxicology, doping control or drug metabolism and pharmacokinetics, were taken into consideration. They cover the following analytes: amphetamines, cocaine, lysergide (LSD), opiates, anabolics, antihypertensives, benzodiazepines, cardiac glycosides, corticosteroids, immunosuppressants, neuroleptics, non-steroidal anti-inflammatory drugs (NSAID), opioids, quaternary amines, xanthins, biogenic poisons such as aconitines, aflatoxins, amanitins and nicotine, and pesticides. LC-MS interface types, mass spectral detection modes, sample preparation procedures and chromatographic systems applied in the reviewed papers are discussed. Basic information about the biosample assayed, work-up, LC column, mobile phase, interface type, mass spectral detection mode, and validation data of each procedure is summarized in tables. Examples of typical LC-MS applications are presented.

Animals↗

PubMed1998

Fully-automated systematic toxicological analysis of drugs, poisons, and metabolites in whole blood, urine, and plasma by gas chromatography-full scan mass spectrometry.

The availability of automated, rapid and reliable methods for the systematic toxicological analysis (STA) of drugs and poisons in biosamples is of great importance in clinical and forensic toxicology laboratories. Gas chromatography-continuous scan mass spectrometry (GC-MS) possesses a high potential in STA because of its selectivity and identification power. However, in order to develop a fully automated STA method based on GC-MS two main obstacles have to be overcome: (a) sample preparation is rather sophisticated owing to the need to isolate analytes from the aqueous matrix and to allow a correct GC repartition of polar analytes; (b) the large amount of information collected within a single analysis makes it difficult to isolate relevant analytical information (mass spectra of analytes) from the chemical noise. Using a bench-top GC-MS system equipped with a laboratory robot for sample preparation (the Hewlett-Packard 7686 PrepStation) and an original method for mass spectral purification, a fully automated STA procedure was developed involving isolation of drugs from the sample (whole blood with minimal pretreatment, plasma, urine) by means of solid-phase extraction, derivatization (trimethylsilylation) of the acidic-neutral and of the basic extracts, GC-MS analysis, processing of data, and reporting of results. Each step of the procedure, and the method for data analysis in particular, can be easily integrated with other existing STA methods based on GC-MS.

Autoanalysis↗

PubMed2000

Studies on the metabolism and toxicological detection of the amphetamine-like anorectic fenproporex in human urine by gas chromatography-mass spectrometry and fluorescence polarization immunoassay.

Studies on the metabolism and the toxicological analysis of fenproporex (R,S-3-[(1-phenyl-2-propyl)-amino]-propionitrile, FP) using GC-MS and fluorescence polarization immunoassay are described. The metabolites were identified in urine samples of volunteers by GC-MS after cleavage of conjugates, extraction and acetylation. Besides unchanged FP, fourteen metabolites, including amphetamine, could be identified. Two partially overlapping metabolic pathways could be postulated: ring degradation by one- and two-fold aromatic hydroxylation followed by methylation and side chain degradation by N-dealkylation to amphetamine (AM). A minor pathway leads via beta-hydroxylation of AM to norephedrine. For GC-MS detection, the systematic toxicological analysis procedure including acid hydrolysis, extraction at pH 8-9 and acetylation was suitable (detection limits 50 ng/ml for FP and 100 ng/ml for AM). Excretion studies showed, that only AM but neither FP nor its specific metabolites were detectable 30-60 h after ingestion of 20 mg of FP. Therefore, misinterpretation can occur. The Abbott TDx FPIA amphetamine/methamphetamine II gave positive results up to 58 h. All the positive immunoassay results could be confirmed by the described GC-MS procedure.

Acetylation↗

PubMed2002

External quality assessment schemes for toxicology.

A variety of external quality assurance (EQA) schemes monitor quantitative performance for routine biochemical analysis of agents such as paracetamol, salicylate, ethanol and carboxyhaemoglobin. Their usefulness for toxicologists can be lessened where the concentrations monitored do not extend fully into the toxic range or where the matrix is synthetic, of animal origin or serum as opposed to whole human blood. A scheme for quantitative determinations of a wider range of toxicological analytes such as opioids, benzodiazepines and tricyclics in human blood has been piloted by the United Kingdom National External Quality Assessment Scheme (UKNEQAS). Specialist schemes are available for drugs of abuse testing in urine and for hair analysis. Whilst these programmes provide much useful information on the performance of analytical techniques, they fail to monitor the integrated processes that are needed in investigation of toxicological cases. In practice, both qualitative and quantitative tests are used in combination with case information to guide the evaluation of the samples and to develop an interpretation of the analytical findings that is used to provide clinical or forensic advice. EQA programs that combine the analytical and interpretative aspects of case studies are available from EQA providers such as UKNEQAS and the Dutch KKGT program (Stichting Kwaliteitsbewaking Klinische Geneesmiddelanalyse en Toxicologie).

Forensic Medicine↗