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PubMed1979

Influence of genetic variables on means, variances, and covariances in behavioral responses to toxicological and pharmacological substances.

Inbred strains and F1 generations provide strong experimental control in toxicological studies by virtue of the relative stability of their means. Their variances do not always conform to simple expectations, with respect either to each other or to segregating populations. For the evaluation of covariances or correlations, populations of choice are genetically segregating ones. A genetic approach of demonstrated power but as yet limited application to toxicological problems is that of selective breeding, a procedure by which lines of animals can be developed to precise specifications.

Analysis of Variance↗

PubMed1996

Results of limited versus comprehensive toxicology screening in a university medical center.

Both comprehensive toxicology screening (COM) and limited toxicology screening (LIM) were performed on the same urine in 1,734 consecutive cases over a 6-month period at a university medical center. About half of the screens originated from inpatient services and half from outpatient services (mostly emergency department). In 71 % of the cases, there was agreement between the results of LIM and COM, with 47% of cases being negative. For 500 screens (accounting for 655 individual discrepant findings), at least one discrepancy was noted between LIM and COM. Of these, 399 cases demonstrated at least one finding with COM, but not with LIM ("false-negative" LIM). Topical anesthetics (including cocaine and cocaethylene), antiepileptics, and sympathomimetic amines accounted for 65% of findings. In contrast, 147 cases showed a finding with LIM, but not with COM ("false-positive" LIM), mostly amphetamines. In certain specified clinical circumstances, LIM may be a more cost effective and efficient approach than COM.

Academic Medical Centers↗

PubMed2002

Efficiency of 22 online databases in the search for physicochemical, toxicological and ecotoxicological information on chemicals.

The objective of this study was to evaluate the efficiency of 22 free online databases that could be used for an exhaustive search of physicochemical, toxicological and/or ecotoxicological information about various chemicals. Twenty-two databases with free access on the Internet were referenced. We then selected 27 major physicochemical, toxicological and ecotoxicological criteria and 14 compounds belonging to seven different chemical classes which were used to interrogate all the databases. Two indices were successively calculated to evaluate the efficiency with taking or not taking account of their specialization. More than 50% of the 22 databases 'knew' all of the 14 chemicals, but the quantity of information provided is very different from one to the other and most are poorly documented. Two categories clearly appear with specialized and non-specialized databases. The HSDB database is the most efficient general database to be searched first, because it is well documented for most of the 27 criteria. However, some specialized databases (i.e. EXTOXNET, SOLVEDB, etc.) must be searched secondarily to find additional information.

Databases, Bibliographic↗

PubMed2001

Trangenic fish as models in environmental toxicology.

Historically, fish have played significant roles in assessing potential risks associated with exposure to chemical contamination in aquatic environments. Considering the contributions of transgenic rodent models to biomedicine, it is reasoned that the development of transgenic fish could enhance the role of fish in environmental toxicology. Application of transgenic fish in environmental studies remains at an early stage, but recent introduction of new models and methods demonstrates progress. Rapid advances are most evident in the area of in vivo mutagenesis using fish carrying transgenes that serve as recoverable mutational targets. These models highlight many advantages afforded by fish as models and illustrate important issues that apply broadly to transgenic fish in environmental toxicology. Development of fish models carrying identical transgenes to those found in rodents is beneficial and has revealed that numerous aspects of in vivo mutagenesis are similar between the two classes of vertebrates. Researchers have revealed that fish exhibit frequencies of spontaneous mutations similar to rodents and respond to mutagen exposure consistent with known mutagenic mechanisms. Results have demonstrated the feasibility of in vivo mutation analyses using transgenic fish and have illustrated their potential value as a comparative animal model. Challenges to development and application of transgenic fish relate to the needs for improved efficiencies in transgenic technology and in aspects of fish husbandry and use. By taking advantage of the valuable and unique attributes of fish as test organisms, it is anticipated that transgenic fish will make significant contributions to studies of environmentally induced diseases.

Animal Husbandry↗

PubMedDate not supplied

Use of short, wide-bore capillary columns in GC toxicological screening.

The usefulness of wide-bore, thick film capillary columns for routine toxicological screening was assessed. Two such columns were examined: fused silica CPSil 5CB (i.d., 0.53 mm; length, 10 m; film thickness, 5.2 microns) and glass SPB-1 (i.d. 0.75 mm; length, 30 m; film thickness, 1.0 micron). A standard packed column filled with 3% OV-1 (i.d., 2 mm; length, 1.5 m) and a medium-bore fused silica column CPSil 5 (i.d., 0.32 mm; length, 25 m; film thickness, 0.4 micron) were examined for comparison. Mixtures of alkanes and drugs, as well as biological samples from routine casework, were analyzed. Both types of wide-bore columns proved to be very useful in routine toxicological practice, due to satisfactory efficiency, high capacity, and ease of installation. The retention index values of various drugs, examined on wide-bore columns, were in agreement with the reference database obtained from packed columns.

Autopsy↗

PubMedDate not supplied

Automated rule-based decision systems in forensic toxicology using expert knowledge: basic principles and practical applications.

This paper presents the basic principles and practical benefits of the application of expert systems (ES) and artificial intelligence (AI) to problem solving in forensic toxicology. We acknowledge the complexity and elegance of the theoretical substance and program algorithms of existing work in these disciplines, while simultaneously observing that many presentations of this material cloak the essential facts and concepts in unnecessary jargon and hyperbole. We attempt to remove the cloak without misrepresenting or oversimplifying the underlying structures. We first present a summary of the history, basic functions, technical fundamentals, and typical applications in three major categories of established ES/AI systems. We then assess the status of ES/AI in the forensic toxicology laboratory (FTL) with emphasis on potential applications. We conclude with an analysis of experiences with ESs in our laboratory where we have used an integrated expert system to reduce laboratory errors, detect internal inconsistencies in data, discover new substance abuse subpopulations, and reduce the frequency of sample reprocessing. We have minimized specimen processing time and instrument wear while maximizing technician efficiency and thus performing more tests for the same or reduced costs.

Artificial Intelligence↗

PubMedDate not supplied

Applications of liquid chromatography--mass spectrometry in analytical toxicology: a review.

Liquid chromatography-mass spectrometry (LC-MS), after long-term development that has introduced seven major interfacing techniques, is finally suitable for application in the field of analytical toxicology. Various compound classes can be analyzed, and sensitivities for more or less polar analytes that are as good as or better than those of gas chromatography-mass spectrometry can be obtained with modern interfaces. In addition, because ionization is often softer than classical electron impact, some LC-MS interfaces are able to handle fragile species that are otherwise not amenable to MS. This review is intended to present LC-MS to less familiarized readers and to give an extensive overview of the application of the different coupling techniques to doping agents, drugs of abuse, forensic analysis, toxic compounds of various nature, and several toxicologically relevant therapeutic drugs. Experimental parameters such as the interfaces used, ionization methods, detection limits, and experimental details for exemplary applications are given.

Animals↗

PubMed2000

GC-MS identification of sympathomimetic amine drugs in urine: rapid methodology applicable for emergency clinical toxicology.

A method was developed that permitted rapid identification in urine of the following sympathomimetic amines: amphetamine, benzphetamine, cathinone, desmethylsegiline, diethylpropion, ephedrine, fenfluramine, mazindol, methylenedioxyamphetamine, methylenedioxyethylamphetamine, methylenedioxymethamphetamine, mescaline, methamphetamine, methcathinone, methylaminorex, methylphenidate, pemoline, phendimetrazine, phenylepherine, phentermine, phenylpropanolamine, pseudoephedrine, and selegiline. In addition, two alpha-phenylethylamine-like monoamine oxidase inhibitors, phenelizine and tranylcypromine, were studied. Those sympathomimetic amines containing a primary or secondary amine, a hydrazine, and/or hydroxyl (except mazindol) functional groups were derivatized effectively using an on-column derivatization technique that used a reagent consisting of 10% fluoroanhydride in hexane, whereas the other sympathomimetic amines, including mazindol, were analyzed underivatized. Three different fluoroanhydrides, trifluoroacetic (TFAA), pentafluoropropionic (PFPA), and heptafluorobutyric (HFBA), and three different injection-port temperatures (160, 200, and 260 degrees C) were investigated. Both TFAA and PFPA gave sympathomimetic amine derivatives with essentially identical retention times, whereas HFBA gave longer retention times and better separation of individual compounds. The base fragmentation ion was noted to increase 50 amu (CF2) for each derivatized sympathomimetic amine as the length of the carbon-fluorine chain increased. Fragmentation ion abundance was maximized at an injection-port temperature of 260 degrees C, and this enhanced sensitivity coupled with the better chromatographic resolution of the individual sympathomimetic amines prompted the selection of HFBA as the derivatizing agent of choice. Assignments were made for the fragmentation ions produced by each derivatized drug. The developed method was adapted to analyze urine specimens that might be encountered in emergency toxicology testing. For identification of sympathomimetic amines requiring derivatization, 0.1 mL of the patient specimen had amphetamine-d5 and methamphetamine-d5 added as internal standard followed by adjustment of pH to 9.3 with borate buffer, extraction with 9:1 chloroform/isopropanol, centrifugation and separation of the organic phase, addition of 10% methanolic HCI and evaporation under nitrogen, reconstitution with HFBA reagent, and on-column derivatization during gas chromatographic-mass spectrometric (GC-MS) analysis. For those sympathomimetic amines not requiring derivatization, 1.0 mL of urine specimen had diazepam-d5 added as internal standard followed by the same extraction procedure and reconstitution accomplished with ethyl acetate. Because precolumn derivatization was eliminated and only 8 min was required for GC-MS analysis, complete analysis time was approximately 30 min, making the method suitable for clinical emergency toxicology purposes.

Emergency Service, Hospital↗

PubMedDate not supplied

JAT's impact factor--room for improvement? Journal of Analytical Toxicology.

The impact factor of a scientific journal is simply the ratio of the number of citations to the number of citable items (articles and reviews) over a given time period, usually two years after the year of publication. Trends in the impact factor of Journal of Analytical Toxicology (JAT) are reviewed and compared with other leading journals in the forensic sciences and toxicology. In particular, the journals that frequently cite JAT articles (citing journals) and the journals cited in articles published in JAT (cited journals) are compared and contrasted. The reasons for citing a particular article are considered, and some suggestions are made for improving the impact factor of JAT, if this is deemed necessary. This could be achieved in a number of ways, such as speeding the editorial-handling and peer-review processes, by including one or more invited review articles in each issue of the journal, or by increasing the number of references cited so the references/article ratio increases. Regardless of journal impact factor, an article should be judged by its usefulness to the field and not the prestige of the journal where it is published.

Bibliometrics↗

PubMedDate not supplied

Survey of drug-abuse patterns and toxicology analysis in an emergency-room population.

A retrospective survey of 150 patients who presented to a university hospital emergency room with suspected drug abuse was performed. In 74 instances, biological fluids were submitted to the laboratory for toxicology analysis. Drugs implicated in the clinical history were compared with those actually found by the laboratory in order to evaluate the diagnostic utility of toxicology testing. The laboratory found either some or all of the drugs suspected from the history in 68% of the laboratory-analyzed cases. In an additional 16% the laboratory found none of the implicated drugs but did find other drugs not suggested by the history, and in one of every four cases at least one drug not implicated by history was found. The most frequently involved drugs in this study are identified, and epidemiologic parameters including age, sex, frequency of multiple-drug ingestions, patient disposition, and patient and laboratory-sample arrival times are analyzed.

Adolescent↗

PubMedDate not supplied

Progress in forensic toxicology: beyond analytical chemistry.

The dominant role of analytical chemistry in applied forensic toxicology is described briefly from an historical perspective. It is argued, however, that obligations imposed on forensic toxicologists by the law, medicine, and society for understanding toxicity in an increasing variety of case problems is really the major challenge and obligation facing toxicologists today. Case examples and rationale are presented in support of this argument. Needs and possible solutions to redress the current professional imbalance are suggested; such as a program to monitor prospectively adverse drug actions and interactions, forensic toxicology reference centers, graduate training programs, and collaborative research involving analytical toxicologists and biomedical researchers, including pathologists. There is a need to develop an industrial, governmental, and professional partnership. These proposals are discussed and justified.

Chemistry Techniques, Analytical↗

PubMed1991

On the rodent bioassays currently being conducted on 44 chemicals: a RASH analysis to predict test results from the National Toxicology Program.

We use a method of relative potency comparisons to rank the potential strength of 44 compounds being tested in rodent carcinogenicity bioassays. All of our previous hazard evaluations have been for human conditions where great numbers of simultaneous and serial exposures may act in combination to produce a neoplasm comprised of 2(20) to 2(30) cells commonly expected to derive from a single precancerous cell. For human exposures, we have always assumed an initiated target tissue containing at least one transformed but subcarcinogenic cell per organ. Thus, for man we have focused on empirical correspondences that may help to index the monoclonal growth of a particular cell lineage during cancer expansion. In contrast to humans, initiation of target tissues in animals subjected to National Toxicity Program (NTP) bioassays may not be a given condition, because of extensive precautions taken to minimize exposures to contaminates in food, water and cage environments. For this evaluation, we used categorical assignments of 'unlikely', 'possible' and 'probable' carcinogens adapted from NTP tests. Our rank ordering, of compounds according to maximum doses tested in male mice and male rats, is coded accordingly to the three outcomes taken from the NTP tests, but the magnitude of potency depend completely upon our particular method of comparing toxicological data. We have attempted to demonstrate that a relative potency based analysis of a diversity of toxicological data may be useful for rank ordering potentially hazardous compounds to be tested by the NTP and for range-finding of their effective test doses to be administered during chronic test protocols.

Animals↗

PubMed2001

The frequency of U-shaped dose responses in the toxicological literature.

Hormesis has been defined as a dose-response relationship in which there is a stimulatory response at low doses, but an inhibitory response at high doses, resulting in a U- or inverted U-shaped dose response. To assess the proportion of studies satisfying criteria for evidence of hormesis, a database was created from published toxicological literature using rigorous a priori entry and evaluative criteria. One percent (195 out of 20,285) of the published articles contained 668 dose-response relationships that met the entry criteria. Subsequent application of evaluative criteria revealed that 245 (37% of 668) dose-response relationships from 86 articles (0.4% of 20,285) satisfied requirements for evidence of hormesis. Quantitative evaluation of false-positive and false-negative responses indicated that the data were not very susceptible to such influences. A complementary analysis of all dose responses assessed by hypothesis testing or distributional analyses, where the units of comparison were treatment doses below the NOAEL, revealed that of 1089 doses below the NOAEL, 213 (19.5%) satisfied statistical significance or distributional data evaluative criteria for hormesis, 869 (80%) did not differ from the control, and 7 (0.6%) displayed evidence of false-positive values. The 32.5-fold (19.5% vs 0.6%) greater occurrence of hormetic responses than a response of similar magnitude in the opposite (negative) direction strongly supports the nonrandom nature of hormetic responses. This study, which provides the first documentation of a data-derived frequency of hormetic responses in the toxicologically oriented literature, indicates that when the study design satisfies a priori criteria (i.e., a well-defined NOAEL, > or = 2 doses below the NOAEL, and the end point measured has the capacity to display either stimulatory or inhibitory responses), hormesis is frequently encountered and is broadly represented according to agent, model, and end point. These findings have broad-based implications for study design, risk assessment methods, and the establishment of optimal drug doses and suggest important evolutionarily adaptive strategies for dose-response relationships.

Dose-Response Relationship, Drug↗

PubMed2005

Metabonomics in toxicology: a review.

Metabonomics and its many pseudonyms (metabolomics, metabolic profiling, etc.) have exploded onto the scientific scene in the past 2 to 3 years. Nowhere has the impact been more profound than within the toxicology community. Within this community there exists a great deal of uncertainty about whether metabonomics is something to count on or just the most recent technological flash in the pan. Much of the uncertainty is due to unfamiliarity with analytical and chemometric facets of the technology and the attendant fear of any "black-box." With those fears in mind, metabonomics technology is reviewed with particular emphasis on toxicologic applications in preclinical drug development. The jargon, logistics, and applications of the technology are covered in some detail with emphasis on recent work in the field.

Animals↗

PubMed2005

Supplement to the Carcinogenic Potency Database (CPDB): results of animal bioassays published in the general literature through 1997 and by the National Toxicology Program in 1997-1998.

The Carcinogenic Potency Database (CPDB) is a systematic and unifying resource that standardizes the results of chronic, long-term animal cancer tests which have been conducted since the 1950s. The analyses include sufficient information on each experiment to permit research into many areas of carcinogenesis. Both qualitative and quantitative information is reported on positive and negative experiments that meet a set of inclusion criteria. A measure of carcinogenic potency, TD(50) (daily dose rate in mg/kg body weight/day to induce tumors in half of test animals that would have remained tumor-free at zero dose), is estimated for each tissue-tumor combination reported. This article is the ninth publication of a chronological plot of the CPDB; it presents results on 560 experiments of 188 chemicals in mice, rats, and hamsters from 185 publications in the general literature updated through 1997, and from 15 Reports of the National Toxicology Program in 1997-1998. The test agents cover a wide variety of uses and chemical classes. The CPDB Web Site (http://potency.berkeley.edu/) presents the combined database of all published plots in a variety of formats as well as summary tables by chemical and by target organ, supplemental materials on dosing and survival, a detailed guide to using the plot formats, and documentation of methods and publications. The overall CPDB, including the results in this article, presents easily accessible results of 6153 experiments on 1485 chemicals from 1426 papers and 429 NCI/NTP (National Cancer Institute/National Toxicology program) Technical Reports. A tab-separated format of the full CPDB for reading the data into spreadsheets or database applications is available on the Web Site.

Animals↗

PubMed1986

Toxicological findings in fatal aircraft accidents in the United Kingdom.

Toxicology studies can contribute much to investigations into the causes of accidents. This paper examines toxicological data from 485 fatal aircraft accidents over a 24-year period in terms of relevance to causing accidents and difficulties in procuring samples for analysis.

Accidents, Aviation↗

PubMed1990

Fly larvae and their relevance in forensic toxicology.

Toxicological analyses on a putrefied cadaver are sometimes difficult to perform because of the absence of blood and urine. In this study, fly larvae, being living material, are proposed as a new medium of investigation in forensic toxicology. Bromazepam and levomepromazine were identified and assayed in the remains of cerebral tissue, in the clavicle of a putrefied cadaver, and in the fly larvae found on and in the corpse.

Aged↗

PubMed2002

Toxicologic analysis in cases of possible sudden infant death syndrome: a worthwhile exercise?

The diagnosis of sudden infant death syndrome (SIDS) is one of exclusion. At the Department of Forensic Medicine, Westmead Hospital, toxicologic analysis is performed as part of the postmortem examination of all apparent SIDS deaths. The results for the 5-year period January 1, 1994, to December 31, 1999, were audited to determine whether such routine testing was worthwhile. During this time there were 117 cases with a history consistent with SIDS. Drugs were detected in 19 (16%) of these cases. In 1 case, death was attributed to the finding of methadone. The presence of methadone was regarded as a possible contributing factor to death in a further 2 cases. The presence of possible methadone toxicity had not been expected from the history given before the examination in these 3 cases. In 114 cases there was a suitable sample for alcohol testing; in no case was alcohol detected. In 13 cases the postmortem examination revealed an anatomic cause of death (including 3 cases consistent with whiplash/shaken baby/impact head injury), which excluded a diagnosis of SIDS. In conclusion, routine toxicologic testing in all possible cases of SIDS death supplements the postmortem examination in excluding cases of non-SIDS.

Autopsy↗