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PubMed2006

Future of toxicology--predictive toxicology: An expanded view of "chemical toxicity".

A chemistry approach to predictive toxicology relies on structure-activity relationship (SAR) modeling to predict biological activity from chemical structure. Such approaches have proven capabilities when applied to well-defined toxicity end points or regions of chemical space. These approaches are less well-suited, however, to the challenges of global toxicity prediction, i.e., to predicting the potential toxicity of structurally diverse chemicals across a wide range of end points of regulatory and pharmaceutical concern. New approaches that have the potential to significantly improve capabilities in predictive toxicology are elaborating the "activity" portion of the SAR paradigm. Recent advances in two areas of endeavor are particularly promising. Toxicity data informatics relies on standardized data schema, developed for particular areas of toxicological study, to facilitate data integration and enable relational exploration and mining of data across both historical and new areas of toxicological investigation. Bioassay profiling refers to large-scale high-throughput screening approaches that use chemicals as probes to broadly characterize biological response space, extending the concept of chemical "properties" to the biological activity domain. The effective capture and representation of legacy and new toxicity data into mineable form and the large-scale generation of new bioassay data in relation to chemical toxicity, both employing chemical structure information to inform and integrate diverse biological data, are opening exciting new horizons in predictive toxicology.

Animals↗

PubMedDate not supplied

New achievements in human cell toxicology: the 20th annual workshop on in vitro toxicology.

The 20th Annual Workshop on In Vitro Toxicology (Oxford, UK, September 22-24, 2002) was convened as part of a European meeting entitled Human Cell Culture 2002. The meeting was arranged by the Scandinavian Society for Cell Toxicology (SSCT), the European Tissue Culture Society and the British Prostate Group. Two sessions, which are summarised in this report, were devoted to in vitro toxicology: Human Cell Toxicology and The SSCT Free Paper Session. Outstanding experts in the field of toxicology outlined contemporary approaches in toxicity testing in their lectures. Short oral presentations demonstrated a variety of in vitro model systems and methodologies, which can be useful for investigating human toxicity, as well as for studies on mechanisms of toxicity.

Cell Line↗

PubMed1995

Development of toxicological information in the Department of Toxicology Collegium Medicum, Jagiellonian University.

The Poisons Information Centre at the Department of Toxicology gives toxicological information every day for full 24 hours. The information is based on the file of chemical compounds and substances. Each telephone enquiry is recorded and then analysed by the staff of Poisons Information Centre. The toxicological information covers children, adults and mass-poisonings cases, Most of the enquires concern consultation, then information and last consultation and information. During the regular telephone service most enquires are made about drug poisonings, ethanol, pesticides and mushrooms. Most of the enquiries are made by physicians. Private persons come next. Further activity of Poisons Information Centre depends on the access to the world literature and popularisation of toxicological knowledge among the people. This will contribute to higher rate toxicological enquires from private persons.

Adult↗

PubMed1987

Toxicological studies of chemical mixtures of environmental concern at the National Toxicology Program: health effects of groundwater contaminants.

In cooperation with the Agency for Toxic Substances and Disease Registry, the National Toxicology Program is participating in a Public Health Service activity related to the Comprehensive Environmental Response, Compensation and Liability Act (Superfund Act) by conducting toxicology studies on chemicals found in high-priority hazardous waste sites and for which adequate toxicological data are not available. As part of this effort, a project on the toxicology of chemical mixtures of groundwater contaminants was initiated. The first study, centered on the health effects of groundwater contaminants, is at the contractual stage. Nineteen organic and six inorganic chemicals, selected from more than 1000 known groundwater contaminants, will be given in drinking water to Fischer 344 rats and B6C3F1 mice for 3 or 6 months. Controls and five dose levels, based on average concentrations (i.e., baseline level) of individual component chemicals, or 0.1-, 10-, or 1000-fold of the baseline level, will be used. Toxicological end points include mortality, clinical signs, water and food consumption, body and organ weights, clinical pathology analytes (e.g., hematology, clinical chemistry, and urinalysis), gross and histopathology, neurobehavioral tests, sperm morphology and vaginal cytology evaluations (SMVCE), and cytogenetics. This paper summarizes the rationale behind our experimental design and the factors one must consider when designing studies of complex chemical mixtures.

Animals↗

PubMed1994

The use of pharmacokinetics as an interpretive and predictive tool in chemical toxicology testing and risk assessment: a position paper on the appropriate use of pharmacokinetics in chemical toxicology.

It has been recognized for several decades in the pharmaceutical industry that the safety evaluation of pharmacological agents must include pharmacokinetic (PK) studies, which are designed to determine the rate of absorption, distribution, metabolism, and excretion (ADME). In recent years the importance of such ADME studies in toxicology has also become increasingly apparent to the chemical industry. This increased focus has led to testing strategies that can produce ADME/PK data with greater applicability to toxicity testing and risk assessment. An example of such a strategy is the concept of a tiered approach to the conduct of ADME/PK studies (Wilson, A. G. E., Frantz, S. W., and Keifer, L. C. (1994). Environ. Health Perspect., in press). However, in practice, PK data are often viewed as being of limited usefulness and of only ancillary importance to the determination of chemical toxicity. As a consequence, the close integration of PK studies with toxicity-testing protocols is not always practiced within the chemical industry and is thus frequently scheduled independently from toxicity testing. This lack of integration has resulted in the design of subchronic (13-week) and chronic (2-year) toxicity studies without the benefit of PK information to establish the appropriate dose levels to be used, often because of inappropriate timing. The result is that much of the PK data which have been generated is without a clear consideration of its application to toxicity testing and risk assessment. This position paper is intended to provide recommendations for the appropriate design and interpretation of a PK study, as well as when and how to use PK data in the interpretation of toxicology data. Additional issues discussed in the paper include the design of PK studies to evaluate tissue time-course relationships and chemical persistence, the overall usefulness of PK data to toxicology testing, and the utility of PK as a useful interpretive and predictive tool in toxicology and risk assessment.

Animals↗

PubMed1996

New research avenues in toxicology: 7-gas N-Gas Model, toxicant suppressants, and genetic toxicology.

Three research areas -- a 7-gas N-Gas Model, toxicant suppressants, and genetic toxicology -- are presented as new research approaches in toxicology. The current 6-gas N-Gas Model predicts the toxic potency of the combustion products of materials based on the toxicological interactions of the fire gases carbon monoxide (CO), carbon dioxide (CO2), low oxygen (O2) concentrations, hydrogen cyanide (HCN), hydrogen chloride, and hydrogen bromide. The present research includes nitrogen dioxide (NO2) in a new 7-gas model which incorporates the synergistic effects of NO2 and CO2, the antagonistic effects of NO2 and HCN, and the additive effects of NO2 with CO and low O2. The area of toxicant suppressants concerns chemicals, which when added to a material, will inhibit or reduce the concentration of a specific toxic gas normally generated during thermal decomposition of that material. The effectiveness of this approach was demonstrated at the US National Institute of Standards and Technology when HCN generation was reduced by 90% and the resultant toxicity of the combustion products was lowered by 50% when a flexible polyurethane (FPU) foam was treated with 0.1% (by weight) cuprous oxide (Cu2O). Although melamine-treated FPU foams are being promoted as more fire safe than standard foams, a melamine-treated foam generated 10 times more HCN than a foam without melamine. The addition of Cu2O to this melamine foam also reduced the HCN generation by 90%. The genetic toxicology research entails the examination of DNA damage that results from the exposure of human cells to various environmental toxicants and gases.

Animals↗

PubMed1995

Toxicological and neuropsychological findings in patients presenting to an environmental toxicology service.

Patients presenting to an environmental toxicology service are frequently convinced that their multiple symptoms are caused by exposure to environmental toxicants. In order to evaluate the patients' hypotheses, 120 consecutive patients referred by health care providers to the environmental toxicology service for various symptoms were included in an open prospective study. The basic diagnostic procedure included an environmental toxicology questionnaire, psychological tests, a 45 minute interview, a physical examination and standard biomonitoring for cadmium, mercury, lead, lindane, hexachlorobenzene, DDT, DDE, DDD, and pentachlorophenol and a salivary test for mercury released from amalgam. Allergic disease was found in 42 patients. Nineteen of the 42 patients also had psychosomatic disorders. An unusually high release of mercury from amalgam fillings in the saliva test was found in six patients. An environmental toxic exposure was demonstrated in 19 patients (4 lead, 8 DDE, 6 mercury--most likely from broken thermometers, 1 neurotoxic alkyl naphtol derivatives). Ten of the 19 patients had psychosomatic disorders and six had medical/neurological disorders. Only two patients had symptoms attributable to environmental exposure alone. Rather classical psychosomatic disorders were diagnosed in 83 patients. Of the 37 patients without identifiable neuropsychological dysfunction, 18 had allergic disorders and 12 had other medical diagnoses. The diagnosis of a toxic environmental exposure should be performed in an integrated diagnostic approach covering environmental toxicology and medicine as well as psychosomatic medicine.

Adolescent↗

PubMed2004

Toxicology databases and the concept of thresholds of toxicological concern as used by the JECFA for the safety evaluation of flavouring agents.

Since 1996 the FAO/WHO Joint Expert Committee on Food Additives (JECFA) has evaluated the safety of 1259 flavouring substances, based on a decision tree that incorporates a series of thresholds of toxicological concern. Safety conclusions are based on the predicted consequences of metabolism and whether the estimated intake is above or below a threshold of toxicological concern that is relevant to that compound. Compounds are allocated to one of three structural classes, and the intake compared with a threshold of toxicological concern derived using data from chronic and sub-chronic toxicity studies on compounds in the same structural class. If the substance is predicted to be metabolised to innocuous products there is no safety concern if the intake is below the threshold, but suitable toxicity data on the compound or structural analogues are required if the intake exceeds the threshold. If the substance is not predicted to be metabolised to innocuous products, and the intake is below the appropriate threshold, safety evaluation is based on data on the compound or structural analogues. An additional threshold of 1.5 microg per day, derived from doses of investigated chemicals giving a calculated cancer risk of one in a million, is applied when appropriate toxicity data are not available.

Animals↗

PubMed1997

Gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) in toxicological analysis. Studies on the detection of clobenzorex and its metabolites within a systematic toxicological analysis procedure by GC-MS and by immunoassay and studies on the detection of alpha- and beta-amanitin in urine by atmospheric pressure ionization electrospray LC-MS.

GC-MS is the method of choice for toxicological analysis of toxicants volatile in GC while non-volatile and/or thermally labile toxicants need LC-MS for their determination. Studies are presented on the toxicological detection of the amphetamine-like anorectic clobenzorex in urine by GC-MS after acid hydrolysis, extraction and acetylation and by fluorescence polarization immunoassay (FPIA, TDx (meth)amphetamine II). After ingestion of 60 mg of clobenzorex, the parent compound and/or its metabolites could be detected by GC-MS for up to 84 h or by FPIA for up to 60 h. Since clobenzorex shows no cross-reactivity with the used immunoassay, the N-dealkylated metabolite amphetamine is responsible for the positive TDx results. The intake of clobenzorex instead of amphetamine can be differentiated by GC-MS detection of hydroxyclobenzorex which is detectable for at least as long as amphetamine. In addition, the described GC-MS procedure allows the simultaneous detection of most of the toxicologically relevant drugs. Furthermore, studies are described on the atmospheric pressure ionization electrospray LC-MS detection of alpha- and beta-amanitin, toxic peptides of amanita mushrooms, in urine after solid-phase extraction on RP-18 columns. Using the single ion monitoring mode with the ions m/z 919 and 920 the amanitins could be detected down to 10 ng/ml of urine which allows us to diagnose intoxications with amanita mushrooms.

Amanitins↗

PubMed1999

Systematic toxicological analysis procedures for acidic drugs and/or metabolites relevant to clinical and forensic toxicology and/or doping control.

This paper reviews systematic toxicological analysis (STA) procedures for acidic drugs and/or metabolites relevant to clinical and forensic toxicology or doping control using gas chromatography, gas chromatography-mass spectrometry, liquid chromatography, thin-layer chromatography and capillary electrophoresis. Papers from 1992 to 1998 have been taken into consideration. Screening procedures in biosamples (whole blood, plasma, serum, urine, vitreous humor, brain, liver or hair) of humans or animals (horse, or rat) are included for the following drug classes: angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (AT-II) blockers, anticoagulants of the 4-hydroxy coumarin type, barbiturates, dihydropyridine calcium channel blockers (calcium antagonists), diuretics, hypoglycemic sulfonylureas and non-steroidal anti-inflammatory drugs (NSAIDs). Methods for confirmation of preliminary results obtained by screening procedures using immunoassay or chromatographic techniques are also included. Furthermore, procedures for the simultaneous detection of several drug classes are reviewed. The toxicological question to be answered and the consequences for the choice of an adequate method, the sample preparation and the chromatography itself are discussed. The basic information about the biosample assayed, work-up, separation column, mobile phase or separation buffer, detection mode and validation data of each procedure is summarized in 16 tables. They are arranged according to the drug class and the analytical method. Examples of typical applications are presented. Finally, STA procedures are reviewed and described allowing simultaneous screening for different (acidic) drug classes.

Chromatography↗

PubMed1991

[Industrial toxicology and ecological toxicology].

The development of the chemical industry and subsequent intensive use of chemical products in other industrial branches, incl. e.g. agriculture, leads to the demand of hygienic and ecological wholesomeness. A sufficiently accurate background for this evaluation can be provided by experimental disciplines such as toxicology and ecotoxicology. The contemporary development of their methodology has reached a state which provides adequate guarantees for their application in particular in legislative activities. Not only final products are evaluated but also intermediary products in chemical production and finally also waste products. Evaluations of biological wholesomeness are implemented within the framework of international cooperation at levels which make it possible to use the results of toxicological and ecotoxicological evaluation also in other countries. With regard to the extensive character of the subject, attention is paid in the submitted paper in particular to basic toxicological and ecotoxicological tests.

Environmental Health↗

PubMed1988

Research activities in toxicology and toxicological requirements of the FDA for food and color additives.

The Center for Food Safety and Applied Nutrition of the Food and Drug Administration has published guidelines for the safety assessment of direct food and color additives. These guidelines are to be updated beginning in 1988. The safety of a food and color additive must be established prior to marketing by an evaluation of probable exposure of consumers and appropriate toxicological information. "Safe" and "safety" are defined as a reasonable certainty that a substance is not harmful under the intended conditions of use. A number of tests are used in determining the safety of food additives. Some of these are: subchronic toxicity studies, chronic toxicity studies, carcinogenicity, reproduction, teratogenicity, and occasionally short-term tests for carcinogenicity. The Center also has a research program in toxicology which in part focuses on diet/toxicity interaction and risk assessment. Examples of such activities are investigation of the teratogenicity of textured vegetable protein and of the potential of zinc to prevent or ameliorate such effects, the development of whole rat embryo cultures as a model to investigate the mechanisms by which teratogens may act, and a program in pharmacokinetics and molecular toxicology to aid in studying assumptions underlying risk assessment.

Food Additives↗

PubMed2004

INVITOX 2004: 13th Workshop of the European Society of Toxicology In Vitro, organised in cooperation with the Scandinavian Society for Cell Toxicology.

INVITOX 2004, the 13th Workshop of the European Society of Toxicology In Vitro, was held on 8-11 September 2004, in Zegrze, Poland, in cooperation with the Scandinavian Society for Cell Toxicology. The workshop was attended by 112 participants from 19 countries. The programme included 11 main sessions and two round table discussions. The lectures of the invited speakers, together with short oral presentations and posters, covered the most important aspects of current research in the field of in vitro toxicology. ECVAM's strategies for the replacement of animal testing for toxic chemicals by alternative test systems were discussed.

Animal Testing Alternatives↗

PubMed2005

Systems toxicology: applications of toxicogenomics, transcriptomics, proteomics and metabolomics in toxicology.

Toxicogenomics can facilitate the identification and characterization of toxicity, as illustrated in this review. Toxicogenomics, the application of the functional genomics technologies (transcriptomics, proteomics and metabolomics) in toxicology enables the study of adverse effects of xenobiotic substances in relation to structure and activity of the genome. The advantages and limitations of the different technologies are evaluated, and the prospects for integration of the technologies into a systems biology or systems toxicology approach are discussed. Applications of toxicogenomics in various laboratories around the world show that the crucial steps and sequence of events at the molecular level can be studied to provide detailed insights into mechanisms of toxic action. Toxicogenomics allowed for more sensitive and earlier detection of adverse effects in (animal) toxicity studies. Furthermore, the effects of exposure to mixtures could be studied in more detail. This review argues that in the (near) future, human health risk assessment will truly benefit from toxicogenomics (systems toxicology).

Animals↗

PubMedDate not supplied

[From industrial hygiene and toxicology to environmental hygiene and toxicology: problems and prospects].

BACKGROUND: Low-dose exposures to mixtures of substances have received increasing interest and they involve many different occupational and environmental situations. The presence in the population (working and general) of groups of susceptible individuals is an important public health issue that poses new challenges to science and society. OBJECTIVES: To discuss the evolution from traditional occupational hygiene and toxicology to the new environmental (general and occupational) hygiene and toxicology. RESULTS: Environmental hygiene and toxicology have remarkably improved analytical tools available to solve most of the analytical issues posed by the present exposure scenario. Biomarkers of low-dose exposure, early effects and individual susceptibility are being intensively investigated. CONCLUSIONS: The challenge in this field for the coming years appears to be not the analytical but the medical and ethical implications.

Disease Susceptibility↗

PubMed2003

Evaluation of testicular toxicology: a synopsis and discussion of the recommendations proposed by the Society of Toxicologic Pathology.

BACKGROUND: Detection of chemically induced effects on male fertility and on testicular spermatogenesis in particular, has become of increasing concern. More stringent regulatory guidelines, introduced by ICH, EPA and OECD (Table 1) have raised the awareness of toxicologists and pathologists for the need to conduct sensitive and careful evaluation of the male reproductive tract for potential toxic effects of administered compounds. With it has come confusion and in many cases, inappropriate procedures, often based on misunderstanding of what is required and on inadequate understanding of spermatogenesis. This article summarizes and discusses the main recommendations recently proposed by the Society of Toxicologic Pathology on recommended approaches for the evaluation of testicular and epididymal toxicity [Lanning LL, Creasy DM, Chapin RE, Mann PC, Barlow NJ, Regan KS, Goodman DG. Toxicologic Pathology 30:518-531, 2002]. The major recommendations are: Use sexually mature animals to evaluate effects on spermatogenesis. Sample left and right testes and epididymides and record organ weights. Use modified Davidson's fixative to fix testes from all species from studies of 13 wks duration and less. Examine transverse sections of the testes (including part of the rete), and longitudinal sections of the epididymides. Embed tissues in paraffin wax. For rodent studies up to 28 days, examine periodic acid-Schiff's-hematoxylin stained sections. For all other studies examine hematoxylin and eosin stained sections. Microscopic evaluation of the testis should be a qualitative evaluation carried out with an awareness of the spermatogenic cycle. Quantitative procedures are inappropriate for screening studies. Nomenclature and grading of findings for spermatogenic disturbances will vary on a case by case basis.

Animals↗

PubMed2003

Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project.

The role that metabonomics has in the evaluation of xenobiotic toxicity studies is presented here together with a brief summary of published studies. To provide a comprehensive assessment of this approach, the Consortium for Metabonomic Toxicology (COMET) has been formed between six pharmaceutical companies and Imperial College of Science, Technology and Medicine (IC), London, UK. The objective of this group is to define methodologies and to apply metabonomic data generated using (1)H NMR spectroscopy of urine and blood serum for preclinical toxicological screening of candidate drugs. This is being achieved by generating databases of results for a wide range of model toxins which serve as the raw material for computer-based expert systems for toxicity prediction. The project progress on the generation of comprehensive metabonomic databases and multivariate statistical models for prediction of toxicity, initially for liver and kidney toxicity in the rat and mouse, is reported. Additionally, both the analytical and biological variation which might arise through the use of metabonomics has been evaluated. An evaluation of intersite NMR analytical reproducibility has revealed a high degree of robustness. Second, a detailed comparison has been made of the ability of the six companies to provide consistent urine and serum samples using a study of the toxicity of hydrazine at two doses in the male rat, this study showing a high degree of consistency between samples from the various companies in terms of spectral patterns and biochemical composition. Differences between samples from the various companies were small compared to the biochemical effects of the toxin. A metabonomic model has been constructed for urine from control rats, enabling identification of outlier samples and the metabolic reasons for the deviation. Building on this success, and with the completion of studies on approximately 80 model toxins, first expert systems for prediction of liver and kidney toxicity have been generated.

Animals↗

PubMedDate not supplied

The state of the art of the zebrafish model for toxicology and toxicologic pathology research--advantages and current limitations.

The zebrafish (Danio rerio) is now the pre-eminent vertebrate model system for clarification of the roles of specific genes and signaling pathways in development. The zebrafish genome will be completely sequenced within the next 1-2 years. Together with the substantial historical database regarding basic developmental biology, toxicology, and gene transfer, the rich foundation of molecular genetic and genomic data makes zebrafish a powerful model system for clarifying mechanisms in toxicity. In contrast to the highly advanced knowledge base on molecular developmental genetics in zebrafish, our database regarding infectious and noninfectious diseases and pathologic lesions in zebrafish lags far behind the information available on most other domestic mammalian and avian species, particularly rodents. Currently, minimal data are available regarding spontaneous neoplasm rates or spontaneous aging lesions in any of the commonly used wild-type or mutant lines of zebrafish. Therefore, to fully utilize the potential of zebrafish as an animal model for understanding human development, disease, and toxicology we must greatly advance our knowledge on zebrafish diseases and pathology.

Animals↗