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PubMed2003

Impact factors of forensic science and toxicology journals: what do the numbers really mean?

This article presents review and opinion about the use and abuse of journal impact factors for judging the importance and prestige of scientific journals in the field of forensic science and toxicology. The application of impact factors for evaluating the published work of individual scientists is also discussed. The impact factor of a particular journal is calculated by dividing the number of current year citations to a journal's articles that were published in the previous 2 years by the total number of citable items (articles and reviews) published in the same 2-year period. Journal impact factors differ from discipline to discipline and range from 0 for a journal whose articles are not cited in the previous 2 years to 46 for a journal where the average recent article is cited 46 times per year. The impact factor reflects the citation rate of the average article in a journal and not a specific article. Many parameters influence the citation rate of a particular journal's articles and, therefore, its impact factor. These include the visibility and size of the circulation of the journal including availability of electronic formats and options for on-line search and retrieval. Other things to consider are editorial standards especially rapid and effective peer-reviewing and a short time lag between acceptance and appearance in print. The number of self-citations and citation density (the ratio of references to articles) and also the inclusion of many review articles containing hundreds of references to recently published articles will boost the impact factor. Judging the importance of a scientist's work based on the average or median impact factor of the journals used to publish articles is not recommended. Instead an article-by-article citation count should be done, but this involves much more time and effort. Moreover, some weighting factor is necessary to allow for the number of co-authors on each article and the relative positioning of the individual names should also be considered. Authors should submit their research results and manuscripts to journals that are easily available and are read by their peers (the most interested audience) and pay less attention to journal impact factors. To assess the true usefulness of a person's contributions to forensic science and toxicology one needs to look beyond impact factor and citation counts. For example, one might consider whether the articles contained new ideas or innovations that proved useful in routine forensic casework or are widely relied upon in courts of law as proof source.

Bibliometrics↗

PubMed1997

Exhumations: synopsis of morphological and toxicological findings in relation to the postmortem interval. Survey on a 20-year period and review of the literature.

Before an exhumation the question of its possible success usually arises. This paper aims to act as an aid by providing comprehensive lists ("expectation catalogues") of morphological and toxicological findings with their corresponding postmortem intervals. All organ systems are included. The results are based on the retrospective evaluation of 46 exhumations performed at the Cologne Institute of Forensic Medicine in a 20-year period (1974-1994) and a review of the literature. In our own material (34 males, 12 females, age range: 2 days-91 years) the postmortem interval varied from 6 days to 20.5 years. Exhumations were performed by order of criminal courts (n = 28), social insurances (n = 13) and private persons (n = 5). Main indications were problems of causality in social and civil law (n = 14), suspected intoxications (n = 10), possible medical malpractice (n = 7), criminal aspects of traffic accidents (n = 7) and identifications (n = 5). The expectation catalogues include the following remarkable items (with postmortem interval) from our own material: coronary thrombosis (3.5 months), granulation tissue in myocardial infarction (3.5 months), myocardial fibrosis (2.5 years), coronary sclerosis (7.5 years), femoral vein thrombosis and pulmonary embolism (3.75 months), pneumonia (3 months), pulmonary emphysema and chronic bronchitis (2.5 years); detection of strangulation marks (2 months); preservation of bone marrow histology (3 months), gastrointestinal tract in continuity (7.5 years), macroscopic and histological cerebral structures (17 years); toxicological detection of phenobarbital (6 weeks), CO-Hb (9.5 weeks), chlorprothixene (5.5 years), diazepam (7.5 years), furosemide (7.5 years) and parathion (E 605) (17 years). The cause of death could be clarified with sufficient certainty in 36/46 cases (78%). Exhumation problems could be answered completely in 39 cases and partly in seven further cases. On the whole this review again underlines the importance and value of this special kind of body examination even after long postmortem periods.

Academies and Institutes↗

PubMed1999

Toxicology training of paramedic students in the United States.

A 16-item survey was mailed to the directors of 618 paramedic training programs in the United States to determine (1) the number of lecture hours devoted to toxicology topics and (2) how often paramedic training includes a rotation in a poison control center. The response rate was 82%. Toxicology accounts for approximately 2% of paramedic students' total training. Cardiovascular drug toxicity and hazardous materials are discussed for over 60 minutes by more than 50% of paramedic training programs. Four paramedic programs have no lecture time on cyclic antidepressant overdoses and one program has no lecture time on carbon monoxide poisoning. Eighty-one percent (377 of 467) have access to a regional poison control center; 11% (42 of 377) use the poison control center as a paramedic training site. Some US paramedic training programs spend insufficient time covering topics that have significant out-of-hospital morbidity. Although poison control centers are often available, they are underutilized for paramedic training.

Allied Health Personnel↗

PubMedDate not supplied

Harmonisation of rat fetal skeletal terminology and classification. Report of the Third Workshop on the Terminology in Developmental Toxicology. Berlin, 14-16 September 2000.

The initial efforts of the Federal Institute for Health Protection of Consumers and Veterinary Medicine (BgVV) and the Free University of Berlin to standardise terminology in the field of developmental toxicology began in 1995. Procedures were undertaken to harmonise the terminology used by the International Federation of Teratology Societies (IFTS) and the International Programme on Chemical Safety (IPCS). This article reflects these activities and is a report on the Third Workshop on the Terminology in Developmental Toxicology held in September 2000. This Workshop served as a forum to discuss the results of a survey on the classification of skeletal anomalies that had been previously sent to scientists active in the field. Although high agreement was reached among the evaluators for several terms, the use of a number of terms was rather variable. Therefore, the discussions at the workshop among the experts from research institutions, regulatory agencies, and industry were mainly focussed on those terms for which there was disagreement and/or uncertainties and the possible reasons. Pictures provided by the participants for the illustration of "grey zone" anomalies constituted the basis for detailed discussions. In many of the cases with lower agreement, decisions were facilitated by the provision of the corresponding picture. The main reasons for lower agreement were imprecise terms, insufficient knowledge on postnatal consequences, theoretical terms that are unlikely to occur in isolation, and the possibility of observing a range of severity that might be decisive for the classification of either a malformation or variation. The attendees concluded that "grey-zone" anomalies will never disappear completely and that for the assessment, the grade of severity and/or the frequency of the observation can be decisive for the terminology chosen. A Joint IPCS/IFTS Project was proposed to further consensus of terminology and classification and to link these anomalies to pictures at different skeletal sites. In order to support the harmonisation of regulatory decisions, it was proposed to establish a "Clearinghouse" System under the umbrella of the IPCS. The Clearinghouse could be contacted either by the regulatory authorities or by any company to clarify their queries, particularly with regard to registration or authorisation processes. Finally, it was recommended to also carry out a similar survey on "soft tissue anomalies" and "external findings." The results of this survey will be discussed at a Joint IPCS/IFTS Workshop in Berlin in 2002.

Abnormalities, Drug-Induced↗

PubMed2002

Application of gas chromatography-surface ionization organic mass spectrometry to forensic toxicology.

Surface ionization (SI), which consists in the formation of positive and negative ions along the course of thermal desorption of particles from a solid surface, was first applied as a detector for gas chromatography (GC), GC-surface ionization detection (SID); we developed many new sensitive methods for the determination of abused and other drugs by GC-SID. Recently, Fujii has devised a combination of SI and a quadrupole mass spectrometer and named this system a surface ionization organic mass spectrometer (SIOMS), which is highly selective and sensitive for organic compounds containing tertiary amino groups. We have tried to apply this mass spectrometer to forensic toxicological study; so far we have succeeded in determining important drugs-of-abuse and toxic compounds, such as phencyclidine (PCP), pethidine, pentazocine, MPTP and its derivatives from human body fluids with high sensitivity and selectivity. In this review, we describe our recent studies on the application of GC-SIOMS to forensic toxicology.

Forensic Medicine↗

PubMedDate not supplied

Effect of molecular descriptor feature selection in support vector machine classification of pharmacokinetic and toxicological properties of chemical agents.

Statistical-learning methods have been developed for facilitating the prediction of pharmacokinetic and toxicological properties of chemical agents. These methods employ a variety of molecular descriptors to characterize structural and physicochemical properties of molecules. Some of these descriptors are specifically designed for the study of a particular type of properties or agents, and their use for other properties or agents might generate noise and affect the prediction accuracy of a statistical learning system. This work examines to what extent the reduction of this noise can improve the prediction accuracy of a statistical learning system. A feature selection method, recursive feature elimination (RFE), is used to automatically select molecular descriptors for support vector machines (SVM) prediction of P-glycoprotein substrates (P-gp), human intestinal absorption of molecules (HIA), and agents that cause torsades de pointes (TdP), a rare but serious side effect. RFE significantly reduces the number of descriptors for each of these properties thereby increasing the computational speed for their classification. The SVM prediction accuracies of P-gp and HIA are substantially increased and that of TdP remains unchanged by RFE. These prediction accuracies are comparable to those of earlier studies derived from a selective set of descriptors. Our study suggests that molecular feature selection is useful for improving the speed and, in some cases, the accuracy of statistical learning methods for the prediction of pharmacokinetic and toxicological properties of chemical agents.

Algorithms↗

PubMed1976

The toxicology data bank.

The paper describes the Toxicology Data Bank, a new system under development that will provide on-line access to chemical, physical, toxicologic, pharmacologic, use, and manufacturing data on 4000-5000 selected chemicals including drugs.

Abstracting and Indexing↗

PubMed2001

Metabonomic characterization of genetic variations in toxicological and metabolic responses using probabilistic neural networks.

Current emphasis on efficient screening of novel therapeutic agents in toxicological studies has resulted in the evaluation of novel analytical technologies, including genomic (transcriptomic) and proteomic approaches. We have shown that high-resolution 1H NMR spectroscopy of biofluids and tissues coupled with appropriate chemometric analysis can also provide complementary data for use in in vivo toxicological screening of drugs. Metabonomics concerns the quantitative analysis of the dynamic multiparametric metabolic response of living systems to pathophysiological stimuli or genetic modification [Nicholson, J. K., Lindon, J. C., and Holmes, E. (1999) Xenobiotica 11, 1181-1189]. In this study, we have used 1H NMR spectroscopy to characterize the time-related changes in the urinary metabolite profiles of laboratory rats treated with 13 model toxins and drugs which predominantly target liver or kidney. These 1H NMR spectra were data-reduced and subsequently analyzed using a probabilistic neural network (PNN) approach. The methods encompassed a database of 1310 samples, of which 583 comprised a training set for the neural network, with the remaining 727 (independent cases) employed as a test set for validation. Using these techniques, the 13 classes of toxicity, together with the variations associated with strain, were distinguishable to >90%. Analysis of the 1H NMR spectral data by multilayer perceptron networks and principal components analysis gave a similar but less accurate classification than PNN analysis. This study has highlighted the value of probabilistic neural networks in developing accurate NMR-based metabonomic models for the prediction of xenobiotic-induced toxicity in experimental animals and indicates possible future uses in accelerated drug discovery programs. Furthermore, the sensitivity of this tool to strain differences may prove to be useful in investigating the genetic variation of metabolic responses and for assessing the validity of specific animal models.

Animals↗

PubMed2003

In silico approaches to predicting drug metabolism, toxicology and beyond.

The discovery and optimization of new drug candidates is becoming increasingly reliant upon the combination of experimental and computational approaches related to drug metabolism, toxicology and general biopharmaceutical properties. With the considerable output of high-throughput assays for cytochrome-P450-mediated drug-drug interactions, metabolic stability and assays for toxicology, we have orders of magnitude more data that will facilitate model building. A recursive partitioning model for human liver microsomal metabolic stability based on over 800 structurally diverse molecules was used to predict molecules with known log in vitro clearance data (Spearman's rho -0.64, P <0.0001). In addition, with solely published data, a quantitative structure-activity relationship for 66 inhibitors of the potassium channel human ether-a-gogo (hERG) that has been implicated in the failure of a number of recent drugs has been generated. This model has been validated with further published data for 25 molecules (Spearman's rho 0.83, P <0.0001). If continued value is to be realized from these types of computational models, there needs to be some applied research on their validation and optimization with new data. Some relatively simple approaches may have value when it comes to combining data from multiple models in order to improve and focus drug discovery on the molecules most likely to succeed.

Drug Design↗

PubMed1997

Pharmacokinetics and pharmacodynamics in toxicology.

1. Pharmacokinetics aids interpretation of the dose-response relationship in individual toxicology studies. 2. When used to compare across studies, even in a single species other factors, including variation in pharmacodynamic response, must be taken into account. Variation in pharmacodynamic response becomes more profound when one compares across species. 3. Examples do occur where plasma concentration-response relationships are constant across species, particularly when corrected for unbound drug. These examples should not be taken as support, however, of a general universal principle. 4. Owing to multiple factors such as species differences in receptors, enzymes and ion channels, dose or plasma concentration-response relationships can vary enormously across species. In the light of this, the results of toxicology studies should be viewed as qualitative rather than quantitative. Once sufficient clinical experience is gained the human database is the overriding measure of drug safety.

Animals↗

PubMedDate not supplied

Application of cDNA microarray technology to in vitro toxicology and the selection of genes for a real-time RT-PCR-based screen for oxidative stress in Hep-G2 cells.

Large-scale analysis of gene expression using cDNA microarrays promises the rapid detection of the mode of toxicity for drugs and other chemicals. cDNA microarrays were used to examine chemically induced alterations of gene expression in HepG2 cells exposed to a diverse group of toxicants at an equitoxic exposure concentration. The treatments were ouabain (43 microM), lauryl sulfate (260 microM), dimethylsulfoxide (1.28 M), cycloheximide (62.5 microM), tolbutamide (12.8 mM), sodium fluoride (3 mM), diethyl maleate (1.25 mM), buthionine sulfoximine (30 mM), potassium bromate (2.5 mM), sodium selenite (30 microM), alloxan (130 mM), adriamycin (40 microM), hydrogen peroxide (4 mM), and heat stress (45 degrees C x 30 minutes). Patterns of gene expression were correlated with morphologic and biochemical indicators of toxicity. Gene expression responses were characteristically different for each treatment. Patterns of expression were consistent with cell cycle arrest, DNA damage, diminished protein synthesis, and oxidative stress. Based upon these results, we concluded that gene expression changes provide a useful indicator of oxidative stress, as assessed by the GSH:GSSG ratio. Under the conditions of this cell culture test system, oxidative stress upregulated 5 genes, HMOX1, p21(waf1/cip1), GCLM, GR, TXNR1 while downregulating CYP1A1 and TOPO2A. Primers and probes for these genes were incorporated into the design of a 7-gene plate for RT-PCR. The plate design permitted statistical analysis and allowed clear discrimination between chemicals inducing oxidative vs nonoxidative stress. A simple oxidative stress score (0-1), based on the responses by the 7 genes (including p-value) on the RT-PCR plate, was correlated with the GSH:GSSG ratio using linear regression and ranking (Pearson product) procedures. These analyses yielded correlation coefficients of 0.74 and 0.87, respectively, for the treatments tested (when 1 outlier was excluded), indicating a good correlation between the biochemical and transcriptional measures of oxidative stress. We conclude that it is essential to measure the mechanism of interest directly in the test system being used when assessing gene expression as a tool for toxicology. Tables 1-15, referenced in this paper, are not printed in this issue of Toxicologic Pathology. They are available as downloadable text files at http://taylorandfrancis.metapress.com/openurl.asp?genre=journal&issn=0192-6233. To access them, click on the issue link for 30(4), then select this article. A download option appears at the bottom of this abstract. In order to access the full article online, you must either have an individual subscription or a member subscription accessed through www.toxpath.org.

Dose-Response Relationship, Drug↗

PubMedDate not supplied

Issues related to the use of fish models in toxicologic pathology: session introduction.

Ready or not, fish models are "here to stay." No longer are fish confined to a few specialized laboratories, nor are they exclusively the purview of zoologists or environmental toxicologists. In fact, the institution that does not house at least 1 fish facility is probably not at the forefront of cutting edge research. In toxicologic pathology, fish models are increasingly being used to provide high animal numbers at relatively low cost in carcinogenicity testing and developmental research, and to provide mechanistic information on fundamental cellular processes. In this session, we attempt to provide some perspective for the pathologist that is faced with planning or performing experiments or testing protocols using fish models, or with reading or interpreting fish studies. First, we cover how to approach fish studies from the contract laboratory standpoint, including sectioning, quality control, and GLP considerations. Then, we discuss specifics on the use of the rainbow trout, zebrafish, and Japanese medaka models. The rainbow trout has a rich history in carcinogenicity and mechanistic cancer research. Similarly, the 2 workhorses in the small fish category, zebrafish and medaka, have found their way into many laboratories doing developmental biology and genomics research as well as carcinogenicity testing. Some fascinating genetically altered fish models have been developed with both of these species. This manuscript provides a session overview of the use of small fish models in toxicologic pathology, along with some historical perspective on how these models have played a role in the current state of the science.

Animals↗

PubMedDate not supplied

Toxicology and new social ethics for animals.

The issue of animal treatment has emerged as a major social concern over the past three decades. This ramified in a new ethic for animal treatment that goes beyond concern about cruelty and attempts to eliminate animal pain and suffering, whatever its source. This is evidenced by laws governing animal research in many countries. Insofar as toxicology can entail significant and prolonged animal suffering, it is at loggerheads with this new ethic. Ways are suggested for the toxicological community to put itself in harmony with the ethic and thereby preserve its autonomy.

Animal Experimentation↗

PubMedDate not supplied

Environmental enrichment of nonhuman primates, dogs and rabbits used in toxicology studies.

The increasing emphasis on the provision of environmental enrichment to laboratory animals, vis-à-vis the USDA Animal Welfare Regulations, the Guide for the Care and Use of Laboratory Animals (NRC 1996), and a potential forthcoming policy from the USDA on the subject, can be difficult to accommodate in a toxicology research environment. A summary will be provided of current requirements and recommendations. Then, strategies for meeting regulatory requirements will be described for non-rodent animals used in toxicology research. These strategies will address methods of both social enrichment, such as pair or group housing, as well as non-social enrichment, such as cage furniture, food enrichments, and toys. In addition, the value of positive interactions with staff (e.g., through training paradigms or socialization programs) will also be discussed. Apparent in the discussion of these strategies will be an overarching recognition of the necessity to avoid introducing confounding variables into the research project and to avoid compromising animal health. The roles of the Institutional Animal Care and Use Committee (IACUC) and the attending veterinarian in helping scientists balance animal well-being, the scientific enterprise and the regulatory environment will be described.

Animal Husbandry↗

PubMed2005

The comparative power of the discriminant methods used in toxicological pathology.

It is highly desirable to use experimental methodologies in toxicological pathology that combine statistical power, practicality, and objective reviewability to detect small differences. The different ways of gathering data at the microscope can result in clear differences in power to discriminate small, but real, differences between treated and control rodent groups with nonneoplastic lesions. Six alternative methods of gathering and analysing results are compared. They are referred to as the Measuring, Ordering, Scoring (or Grading), Pair-contrast, Outside-control, and Affected methods. Measuring and Ordering methods are uniformly more powerful than other more common and highly esteemed methods, such as Scoring/Grading. From the practical perspective, Measuring and Ordering can be applied objectively, reviewed objectively, and interpreted to standards that are widely accepted as valid throughout experimental science e.g., using confidence limits and intervals. They also are intuitively natural extensions of routine toxicological histopathological examinations. Establishing a small difference between control and treated groups is commonly a problem when reporting no-observed-effect levels. Ordering is the recommended method for assessing if a small difference between treated and control groups is within chance variation or is the result of a true treatment effect, when measurement is impractical.

Animals↗

PubMed2006

Modern imaging technologies in toxicologic pathology: An overview.

Modern imaging technology, now utilized in most biomedical research areas (bioimaging), enables the detection and visualization of biological processes at various levels of the molecule, organelle, cell, tissue, organ and/or whole body. In toxicologic pathology, the impact of modern imaging technology is becoming apparent from digital histopathology to novel molecular imaging for in vivo studies. This overview summarizes recent progresses in digital microscopy imaging and newly developed digital slide techniques. Applications of virtual microscopy imaging are discussed and compared to traditional optical microscopy reading. New generation digital pathology approaches, including automatic slide inspection, digital slide databases and image management are briefly introduced. Commonly used in vivo preclinical imaging technologies are also summarized. While most of these new imaging techniques are still undergoing rapid development, it is important that toxicologic pathologists embrace and utilize these technologies as advances occur.

Animals↗

PubMed1999

Development, characterization and application of predictive-toxicology models.

The adoption of SAR techniques for risk assessment purposes requires that the predictive performance of models be characterized and optimized. The development of such methods with respect to CASE/MULTICASE are described. Moreover, the effects of size, informational content, ratio of actives/inactives in the model on predictivity must be determined. Characterized models can provide mechanistic insights: nature of toxicophore, reactivity, receptor binding. Comparison of toxicophores among SAR models allows a determination of mechanistic overlaps (e.g., mutagenicity, toxicity, inhibition of gap junctional intercellular communication vs. carcinogenicity). Methods have been developed to combine SAR submodels and thereby improve predictive performance. Now that predictive toxicology methods are gaining acceptance, the development of Good Laboratory Practices is a further priority, as is the development of graduate programs in Computational Toxicology to adequately train the needed professional.

Algorithms↗

PubMedDate not supplied

Hot topics in toxicology.

Toxicology is facing new challenges in addressing issues that will have an impact on developing and meeting new regulatory guidance, public health protection and research directions. Efforts are made to define the exposures to potential toxicants, assess the associated risks, and reduce the uncertainties. This discussion presents an overview of the associated regulatory mandates, how various programs are approaching the current issues and the progress made, particularly here in California and also globally. It includes children sensitivity, differences between adults and children, exposure to pesticides, health effects and exposure endpoint measurement, and assessment to chemicals found in drinking water. Furthermore, it addresses issues associated with defining occupational exposure, community exposure and health risk, public perception of hazard, and the role of diet or nutrition in the overall toxicology and health considerations.

Adult↗