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At least 793 records · Page 44Linked to original sources
PubMed2004

Substance identification: the weak link in analytical toxicology.

Although substance identification is a key factor in analytical toxicology, it is amazing that the subject is receiving very limited and often inappropriate attention. With regard to the latter, a "confirmation" approach is usually chosen, which does not yield unambiguous identification. Moreover, the criteria for establishing a "positive match" leave much to be desired. These observations are corroborated when comparing some recent guidelines for qualitative analysis (issued for various forensic areas by SOFT/AAFS, NCCLS, NLCP, WADA and EU). Apart from showing substantial differences between them on pivotal issues, the guidelines contain various elements that appear scientifically incorrect and/or legally untenable. Also, the guidelines focus primarily on mass spectrometry (MS) and pay little or no attention to other identification possibilities (such as chromatographic techniques, either in combination with MS or as stand-alone techniques. Moreover, they do not offer alternatives in situations where access to MS is not available. One must conclude, therefore, that substance identification is a neglected and misunderstood domain in analytical toxicology. Rapid and concerted actions are needed to: (1) improve the general knowledge; (2) to define uniform strategies in the analytical approach and in the interpretation of the results; and (3) to set up and maintain suitable banks of reference substances and computerized data bases to allow unambiguous identification.

Chemistry Techniques, Analytical↗
PubMed2005

Neurodevelopmental toxicology.

The fields of neurotoxicology and developmental toxicology are exploding in research and interest. Much of the data currently known are from epidemiologic human studies or studies of animal models. Each of these modes is difficult to translate to individual clinical encounters. It is often difficult to state with certainty which of the numerous chemical or physical agents in our environment are neurotoxic. Basic scientists will help with advances in molecular biology and toxicology. Improved clinical understanding of these issues may help patients to understand the medical issues; allay feelings of anxiety, guilt, or fear; and avoid unnecessary testing. For exposures that manifest as threshold phenomena, such as lead, the risk to society is even greater than to an individual. Individual risk may be less of a concern than the population's risk because small elevations in the average BLL can cause profound shifts in the normative curve of intelligence, increasing the burden on our institutions and bankrupting the brain trust. Good scholarship and interpersonal judgement are vital when counseling patients on the potential consequences of chemical exposures and are no less important when making policy. The challenge for the clinician reading the research is to remain aware of the limitations and biases of our science.

Adult↗
PubMedDate not supplied

Proteomics in developmental toxicology.

The objective of this presentation is to review the major proteomic technologies available to developmental toxicologists and, when possible, to provide examples of how various proteomic technologies have been used in developmental toxicology or toxicology in general. The field of proteomics is too broad for us to go into great depth about each technology, so we have attempted to provide brief overviews supplemented with many references that cover the subjects in more detail. Proteomics tools produce a global view of complex biological systems by examining complex protein mixtures using large-scale, high-throughput technologies. These technologies speed up the process of protein separation, quantification, and identification. As an important complement to genomics, proteomics allows for the examination of the entire complement of proteins in an organism, tissue, or cell-type. Current proteomics technologies not only identify protein expression, but also post-translational modifications and protein interactions. The field of proteomics is expanding rapidly to provide greater volume and quality of protein information to help understand the multifaceted nature of biological systems.

Animals↗
PubMed2005

The occurrence of hormetic dose responses in the toxicological literature, the hormesis database: an overview.

A relational retrieval database has been developed compiling toxicological studies assessing the occurrence of hormetic dose responses and their quantitative characteristics. This database permits an evaluation of these studies over numerous parameters, including study design and dose-response features and physical/chemical properties of the agents. The database contains approximately 5600 dose-response relationships satisfying evaluative criteria for hormesis across over approximately 900 agents from a broadly diversified spectrum of chemical classes and physical agents. The assessment reveals that hormetic dose-response relationships occur in males and females of numerous animal models in all principal age groups as well as across species displaying a broad range of differential susceptibilities to toxic agents. The biological models are extensive, including plants, viruses, bacteria, fungi, insects, fish, birds, rodents, and primates, including humans. The spectrum of endpoints displaying hormetic dose responses is also broad being inclusive of growth, longevity, numerous metabolic parameters, disease incidences (including cancer), various performance endpoints such as cognitive functions, immune responses among others. Quantitative features of the hormetic dose response reveal that the vast majority of cases display a maximum stimulatory response less than two-fold greater than the control while the width of the stimulatory response is typically less than 100-fold in dose range immediately contiguous with the toxicological NO(A)EL. The database also contains a quantitative evaluation component that differentiates among the various dose responses concerning the strength of the evidence supporting a hormetic conclusion based on study design features, magnitude of the stimulatory response, statistical significance, and reproducibility of findings.

Animals↗
PubMed2005

ESTIV questionnaire on the acquisition and use of primary human cells and tissue in toxicology.

The ability to use human cells and tissues in toxicology research and testing has the benefit that it obviates the need to undertake species extrapolation when assessing human hazard. However, obtaining and using human cells and tissues is logistically difficult, ethically complex and is a potential source of infections to those coming into contact with human cell material. The issue is also controversial, with the recent EU legislation draft on tissue engineering, and also due to some instances of human material being obtained and used without informed consent. There are also varying regulations and attitudes relating to the use of human cells and tissues throughout Member States of the EU, and there is a need for harmonisation. The European Society of Toxicology in Vitro (ESTIV) Executive Board and the European Network of Human Research Tissue Banks (ENRTB) have conducted a survey to ascertain the extent to which human cells and tissues are used by its members, how these are obtained, what local regulations are in force, how the material is used, and the advantages and disadvantages experienced by members in using such material, as opposed to cell lines. The results obtained have been compared with the results from a previous survey conducted in 2000. It is hoped that this information will help to facilitate the process of acquiring and using human cells and tissues in a safe and effective way to promote the use of non-animal approaches for investigating the mechanisms of toxicity, and for predicting the toxic hazard of substances.

Animal Testing Alternatives↗
PubMed2004

Fraud, errors and gamesmanship in experimental toxicology.

We expect moral behaviour from scientists. Morality implies being a good person and being good at one's profession. The general view appears to be that the vast majority of scientists aim to achieve these high standards. Science prides itself on the 'self-correcting' mechanism in the scientific method, namely the requirement to reproduce findings before they are taken seriously. However, when findings are related to the adverse effects of chemicals there are several features that make this less effective than in some other fields of science. First, is the perception that everyone is exposed to chemicals and observations about chemical danger are immediately applicable to many people. Second, it is often easy to summarize adverse findings in attention-getting headlines seen by the lay public before the slow process of replication and interpretation has time to work. Third, most regulatory toxicology studies on a particular compound are only done once to minimise cost and the use of animals. Finally, the question posed about chemicals--are they safe?--is easy to ask but more difficult to test with appropriate studies. Fabrication of data in regulatory studies was found to occur in several contract laboratories in the 1960s and this lead directly to the introduction of Good Laboratory Practice regulations. Now studies submitted for regulatory purposes must comply with GLP regulations and this has virtually eliminated flawed studies due to fraudulent or careless behaviour. It is possible to discern different ways in which the expected standards have not been met. The first is in the intention of the work. Thus reports that the Roodeplaats Research Laboratory in South Africa was seeking to identify toxins that would kill without trace is an example where the intention is unacceptable. The second is in the conduct of the studies. Here the examples of William McBride and Michael Briggs who falsified data are pertinent. The example of the retraction of reports on the toxicity of ecstasy because the wrong compound had been administered indicates a degree of carelessness in the conduct of the study. The third is in the design and interpretation of studies. The report that genetic modification per se could render potatoes toxic has been criticised because of the inappropriate design and interpretation of the studies. Finally, that the reports of studies are biased because of conflicts of interest. Journals often require a declaration that the author has no financial conflict of interest. However, there are many other conflicts of interest with just as large an impact on the author's impartiality which are omitted from consideration. Gamesmanship has also entered the practice of toxicology, for example where strong assertions about conflict of interest are used to justify particular points of view. The main casualty from fraud, errors and gamesmanship is the perceived status of science itself. It is only gamesmanship that is on the increase. The remedies for these activities are explored.

Conflict of Interest↗
PubMed2026

Multitarget interactions of bisphenol A in polycystic ovary syndrome: evidence from integrated network toxicology, mendelian randomization, and molecular docking.

OBJECTIVE: To study the potential pathogenic mechanisms of bisphenol A (BPA) in polycystic ovary syndrome (PCOS) using an integrative computational strategy. DESIGN: Integrative computational study combining network toxicology, Mendelian randomization (MR), and molecular docking. SUBJECTS: For MR analysis, genetic data were sourced from large European-ancestry cohorts, including plasma protein quantitative trait loci data and genome-wide association study summary statistics for PCOS (3,045 cases and 267,780 controls). EXPOSURE: In silico exposure to BPA for target prediction; genetically predicted plasma protein levels for causal inference. MAIN OUTCOME MEASURES: Identification of overlapping targets between BPA and PCOS; functional enrichment pathways; causal effects of prioritized proteins on PCOS risk (odds ratios with 95% confidence intervals); binding affinities between BPA and core targets (kcal/mol). RESULTS: Network toxicology identified 310 overlapping targets between BPA and PCOS. Enrichment analyses revealed significant involvement in endocrine signaling, inflammatory pathways (eg, IL-17), and cellular processes. MR demonstrated that genetically elevated levels of RET, CXCL8, HTR6, MMP1, MMP9, NTRK1, and TNNI2 were significantly associated with increased PCOS risk, whereas higher PSAP and SHBG levels were protective. Molecular docking confirmed stable binding between BPA and all nine key targets, with strongest affinity for SHBG (-8.4 kcal/mol), followed by NTRK1, TNNI2, and RET. CONCLUSION: This integrative investigation suggests that BPA may contribute to PCOS pathogenesis through multitarget interactions involving inflammatory mediators, endocrine regulators, and tissue remodeling proteins. The findings provide prioritized targets and mechanistic insights for future experimental validation and environmental risk assessment.

Female↗
PubMed2006

Report of an ISRTP workshop: progress and barriers to incorporating alternative toxicological methods in the U.S.

The workshop objectives were to explore progress in implementing new, revised and alternative toxicological test methods across regulatory evaluation frameworks and decision-making programs in the United States, to identify barriers and to develop recommendations to further promote adoption of approaches that reduce, refine, or replace the use of animal methods. The workshop included sessions on: (1) current research, development, and validation of alternative methods within the U.S. federal government; (2) emerging alternative methodologies with potential applications to a broad spectrum of toxicity evaluation strategies; (3) tiered evaluation ("intelligent testing") strategies; and (4) identification of, and recommendations to address, critical barriers that affect adoption and use of new, revised alternative toxicological test methods by U.S. regulatory agencies. Through facilitated discussion, a list of barriers and recommendations were developed and grouped into categories of economic/financial, scientific/technical, and regulatory/policy. Overall, participants from all sectors collectively supported catalyzing actions to promote more meaningful and rapid progress for research to develop alternative methods focused for use in regulatory programs, accelerated lab investigations to validate such alternative methods and adoption of regulatory frameworks which embrace and incorporate these validated alternatives.

Animal Testing Alternatives↗
PubMed1986

Optimization of a toxicology program.

This presentation covers a multiphasic approach to toxicological service. The service is to the hospital and the community as a whole. The optimization includes the analytical aspects of clinical, forensic, and industrial toxicology along with service associated with interpretations, chemical disasters and employee monitoring.

Air Pollutants↗
PubMed1996

Comparison of new solid-phase extraction methods for chromatographic identification of drugs in clinical toxicological analysis.

OBJECTIVES: Newly presented solid-phase extraction methods (Solid Phase Disc Extraction, SPEC-Plus, Multi-Modal, and Solid Phase Micro Extraction, SPME have been checked with respect to their applicability to clinical toxicological analysis. In comparison with conventional liquid/liquid-extraction and a common mixed-phase column technology, their use in general screening and selective extraction methodology is discussed. DESIGN AND METHODS: Recovery studies were performed with urine-based samples including model substances, as well as drugs and metabolites from native urine samples. Chromatographic performance of the resulting extracts is presented in some examples. RESULTS: Liquid/liquid extraction, common mixed-phase column technique and the new SPEC-Plus, Multi-Modal disc extraction method gave the best recoveries with respect to broad-spectrum general screening. The purity of the concentrates was somewhat different, however. Solid-phase C18 and Solid-Phase Micro Extraction methodologies are better suited for selective drug extraction. In SPEC Disc or SPME extraction, the use of solvents is greatly reduced or omitted. Recovery of some volatile substances is enhanced. SPEC discs can be inserted directly into TLC chromatographic plates, SPME fibers into GC injection ports. CONCLUSIONS: The new solid-phase extraction technologies offer advantages in different respects: The mixed-phase disc extraction SPEC 1 Plus AR/MP3 Multi-Modal delivers promising results with respect to broad-spectrum general screening. Solvent consumption is low, throughput times are short, the extracts are clean, and recovery rates are good, comparable, or even higher than with common mixed-phase column techniques. The new SPME extraction method shows benefits in dedicated, selective extraction procedures (e.g., analysis of volatile substances such as amphetamines). Sampling is solvent-free, the handling is easy, and the yields of extraction are good, but only for selected substances. Broad-spectrum general screening still remains problematic with this technique. Further examinations have to be carried out including a larger number of drugs of toxicological relevance. Headspace sampling by SPME offers a good alternative to conventional mechanized sampling in the analysis of volatile substances in biological samples, omitting the need for expensive instrumentation.

Blood Chemical Analysis↗
PubMed1980

Gas--liquid chromatographic retention indices of 296 non-drug substances on SE-30 or OV-1 likely to be encountered in toxicological analyses.

The advent of the widespread use of selective detectors (electron capture detector, phosphorus/nitrogen dectector) for gas--liquid chromatography used in toxicological analyses has revealed the presence of hitherto unseen interfering materials. These substances may be conveniently grouped into (1), anti-oxidants; (2), putrefactive and endogenous compounds; (3), pesticides; (4), food additives, flavours and fragrances; (5) plasticisers, plastic additives and vulcanising agents and (6), scintillation reagents. To facilitate the identification of these materials, retention indices on the dimethyl silicone phases SE-30 or OV-1 have been compiled by the two laboratories to include 296 such compounds. Most gave single peaks, but some gave complex patterns indicating that they were mixtures of compounds. Of the 296 compounds, 14 did not give observable peaks, 8 gave 2 or 3 peaks and 44 gave more than 3 peaks. To determine the interlaboratory difference between retention index measurements, 17 compounds were chromatographed by both laboratories: the mean difference was +/- 13 retention index units with only one greater than +/- 50 retention index units. Examples of how these materials may be encountered during toxicological analyses are given. Data are also presented on compounds which have been used as internal standards.

Chromatography, Gas↗
PubMed2001

Rodent models of susceptibility: what is their place in inhalation toxicology?

There is renewed interest in inhalation toxicology regarding 'susceptibility' as associated with host variables, including genetics, age, diet, and disease. This interest derives from epidemiology that shows air pollution-related human mortality/morbidity, especially among individuals with cardiopulmonary disease. Several animal models with experimental or genetically-based cardiopulmonary diseases are now being incorporated into inhalation toxicology studies to investigate mechanisms that underlie host susceptibility. However, current models have strengths and limitations as to how they mimic the essential features of human diseases. To date, animal models of pulmonary hypertension, bronchitis, asthma, and cardiovascular disease, but not emphysema, appear to exhibit greater susceptibility to air pollution particulate matter. As in humans, host susceptibility appears to involve multiple genetic and environmental factors, and is poorly understood, but the database of information is growing rapidly. As existing models gain wider use, our understanding of the models will improve and encourage refinements/development of models that integrate both genetic and environmental factors to better mimic the human condition.

Administration, Inhalation↗
PubMed2002

Method for determining toxicologically relevant cadmium residues in the earthworm Eisenia fetida.

We investigated a method to isolate toxicologically relevant Cd in earthworms (Eisenia fetida) exposed in a 14-d Cd bioaccumulation study. A procedure involving acid insoluble ash (AIA) content was combined with homogenization and centrifugation techniques to divide total earthworm Cd burdens into supernatant (metallothionein-bound), pellet (toxicologically active), and soil-associated Cd fractions. Whereas the supernatant fraction of the earthworm digests increased linearly throughout the exposure period (from approximately 0 to 3.59 mmol/kg), the pellet fraction reached a steady-state concentration (95% CI) of 1.2 (0.9-1.4) mmol/kg, suggesting the ability of the metallothionein detoxification system to sequester incoming Cd. The AIA method was useful for correcting earthworm Cd concentrations for ingested soil-associated Cd and observing soil ingestion, which was suppressed in Cd-spiked artificial soil (1.06 (0.57-1.55)%) compared to controls (17.25 (14.36-20.15)%). These methods may be useful in investigating soil ingestion and Cd uptake and detoxification in earthworms.

Animals↗
PubMed1981

Value of toxicological investigation in the diagnosis of acute drug poisoning in children.

In the 2 years 1978 and 1979 specimens from 287 children aged between 10 days and 14 years were received for general toxicological investigations. Of the 95 (33%) cases of confirmed poisoning, the diagnosis was established as a direct result of the analyses in 48 patients. No diagnosis was made in at least 85 (30%) of the remaining cases. Benzodiazepines were the drugs most commonly encountered (33%), followed by barbiturates, glutethimide, and meprobamate (15%), salicylate and paracetamol (15%), tricyclic antidepressants (12%), and ethanol (11%). 36 patients were severely poisoned (grade 3 or 4 coma, or convulsions), although only 1 patent died. There was evidence that drug(s) had been administered without authorisation in at least 7 instances, and in 51 (54%) of the poisoned patients there was sufficient concern about the safety of the child or the mode of administration of the drug(s) to institute legal proceedings (8 cases), involve the social services (25 cases), or arrange further medical appointments (18 cases). Drugs are readily available in most households and offer a means of inflicting injury that is less easily detectable than physical assault. For this reason, comprehensive toxicological investigations should be considered in children not only when they may assist in management but also in the presence of unusual or unexplained symptoms which could be drug-induced.

Adolescent↗
PubMed2002

Applications of hormesis in toxicology, risk assessment and chemotherapeutics.

There is much debate over the fundamental shape of the dose-response curve in the low-dose zone, particularly in the fields of toxicology and risk assessment. The defaults, principally accepted dose-response models in the major texts in these areas and in government regulatory activities, are a threshold model for non-carcinogens and a linear model for most carcinogens. We have argued that in properly designed studies the U-shaped hormetic response predominates and is more fundamental. In this article, a broad range of basic issues associated with the acceptance of U-shaped dose responses as central to toxicology, pharmacology and their applications to risk assessment and medicine will be discussed.

Animals↗
PubMed1991

Use of clinical toxicology resources by emergency physicians and its impact on poison control centers.

STUDY OBJECTIVE: The need for clinical toxicology resources by emergency physicians is unclear and may have implications for future training and resource availability. This study was designed to assess current emergency physician use of available resources. DESIGN: Prospective evaluation by mail using a 49-item questionnaire. TYPE OF PARTICIPANTS: All 170 emergency physicians in Utah. INTERVENTIONS: None. RESULTS: The response rate was 75.3% (128 of 170). Resources "outside their own fund of knowledge" were consulted "occasionally" to "frequently" by 98.3%. They used the following resources "occasionally" to "frequently": poison control center (PCC) (93.7%), toxicology textbook (77.6%), "expert colleague" (34.0%), and "in-house POISINDEX" (23.9%). They often contacted the PCC for toxicity information (93.7%) and management recommendations (87.3%) and for acute, symptomatic overdose cases (88.3%). They "almost never" contacted the PCC for adverse drug reactions (76.6%), pill identification (70.2%), consultation with physician toxicologist (68.1%), asymptomatic exposures (62.9%), chronic toxicity (50.4%), or solely to report the case to the American Association of Poison Control Centers data base (90.2%). Those who had access to in-house POISINDEX often did not consult the PCC (82.6%). Of those who did not have in-house POISINDEX, 42.8% contacted the PCC to access it. Providing access to physician toxicologist consultations was thought to be an important role for the PCC by 86.7%, but only 32% of physicians were using this option. CONCLUSION: The vast majority of emergency physicians in Utah consult the PCC only for acute, symptomatic overdoses. They view access to physician toxicologist consultation as an important role for the PCC but seldom use it. The availability of in-house POISINDEX decreases the likelihood of PCC consultations from emergency departments. The frequency of emergency physician consultation with the PCC may decrease as POISINDEX becomes available at more hospitals.

Adult↗
PubMed1993

The integration of investigative toxicology in the drug discovery process.

Integrating toxicology early in the drug discovery process adds value by providing the earliest possible identification of a compound's potential for toxicological and pathological effects relevant to intended clinical use. With this approach true 'lead' candidates, with a high probability of clinical success, are identified and advanced while reducing effort and resources expended on compounds without the requisite therapeutic index. Resources are focussed on the speed of getting a discovery 'lead' into early clinical development, defining the mechanisms of observed preclinical toxicity and their relevance to human use, and developing early safety data with in vitro test systems ahead of in vivo systems where possible, thus reducing animal use.

Animals↗
PubMed2003

Particulate matter in ambient air and mortality: toxicologic perspectives.

U.S. regulations that set standards for acceptable concentrations of respirable particulate matter (PM) in outdoor air, particularly total fine particulate matter (PM(2.5)), are based largely on the belief that current concentrations cause death and illness, and that reducing these concentrations will save lives. Because the mortality risk estimates from important observational epidemiologic studies are extremely weak, derived from studies unable to control for relevant confounding causes, and inconsistent by location, toxicologic and clinical information is necessary to judge the likelihood and degree to which such findings are causal. Toxicologic data on typical forms of pollution-derived PM strongly suggest that current ambient concentrations in the U.S. are too small to cause significant disease or death. We review here the results of inhalation studies using concentrated ambient particles, diesel engine exhaust particulate matter, and sulfate and nitrate salts, and find no evidence that moderate concentrations are lethal. The expectation that lives will be saved by reducing ambient PM(2.5) in the U.S. is not supported by the weight of scientific evidence, although other bases for regulating PM may be justifiable.

Air Pollutants↗