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PubMed1997

Potential of high-performance liquid chromatography with photodiode array detection in forensic toxicology.

The potentials and limitations of high-performance liquid chromatography-photodiode array detection are highlighted in respect to its use in the analysis of different biological matrices followed by the identification of unknowns. The logical analytical approach used in clinical and forensic toxicology, vital for the identification of one or more toxic substances as a cause of intoxication, is largely based on both simple and fast "general unknown screening" methods which cover most relevant drugs and potentially hazardous chemicals. In this field of systematic toxicological analysis, a literature overview shows that HPLC can play a substantial role. Both column packing material and eluent composition have their impact on intra- and interlaboratory reproducibility. In view of the sometimes different retention characteristics of various HPLC columns, several possibilities are addressed to enhance the discriminating power of primary retention parameters. The advantages of photodiode array detection as compared to UV detection have been of paramount importance to the success of HPLC in toxicological analysis. Dedicated libraries with spectral information and searching software are powerful tools in the process of identification of an unknown substance. In the present paper, these aspects are also verified in a number of real cases, i.e., trazodone and dothiepin, azide, chloroquine and cocaine, in which we illustrate from our own experience the potentials of HPLC-photodiode array detection in systematic toxicological analysis.

Adult↗
PubMed1999

Hyphenated liquid chromatographic techniques in forensic toxicology.

The prerequisite of applicability of hyphenated methods in forensic analysis is the achievement of a stage of "final maturity". In the field of liquid chromatography, HPLC coupled with diode array detection (DAD) seems to fulfill this criterion, whilst the combination with atmospheric pressure ionization mass spectrometry (HPLC-API-MS) is still in a development stage. HPLC-DAD is broadly used as identification tool in forensic and in emergency toxicology. Two main approaches were observed; development of retention index scales for intra-laboratory exchange of data and establishing of databases only for intra-laboratory use. Using these approaches, several databases were established for toxicological relevant substances (illicit and therapeutic drugs and their metabolites, environmental poisons etc.) in biological fluids. Also, complete HPLC-DAD identification systems are commercially available. Further possibility of progress depends on the on-line combination ("triple hyphenation") with other detection methods, preferably API-MS. HPLC-API-MS, both in electrospray (ESI) and atmospheric pressure chemical ionization (APCI) options, underwent dramatic development in the last decade and is reaching its final shape. The method was broadly applied for various groups of toxicologically relevant substances, a lot of them unaccessible for other techniques, including GC-MS. Particularly important was application of HPLC-API-MS for detection and quantitation of active, polar metabolites of various drugs and for analysis of macromolecules. APCI seems to be more useful for analysis of less polar compounds, whereas ESI is particularly valuable for determination of polar, large molecules (e.g., toxic peptides, polar metabolites etc.) Up to now, HPLC-API-MS has been mainly applied for dedicated analyses, but the introduction of APCI or ESI in systematic toxicological screening may be expected in the near future.

Chromatography, High Pressure Liquid↗
PubMed2004

Toxicogenomics and systems toxicology: aims and prospects.

Toxicogenomics combines transcript, protein and metabolite profiling with conventional toxicology to investigate the interaction between genes and environmental stress in disease causation. The patterns of altered molecular expression that are caused by specific exposures or disease outcomes have revealed how several toxicants act and cause disease. Despite these success stories, the field faces noteworthy challenges in discriminating the molecular basis of toxicity. We argue that toxicology is gradually evolving into a systems toxicology that will eventually allow us to describe all the toxicological interactions that occur within a living system under stress and use our knowledge of toxicogenomic responses in one species to predict the modes-of-action of similar agents in other species.

Animals↗
PubMed2003

Accuracy of self-report and toxicological assays to detect substance misuse disorders in parasuicide patients.

OBJECTIVE: To assess the accuracy of self-reported substance use and toxicological assays in subjects admitted for Intentional Drug Overdose (IDO), using as a reference diagnosis of substance use disorder. METHOD: Self-reported substance use was collected and toxicological assays were carried out in urine samples in 507 patients with IDO. A standardized psychiatric evaluation was performed in 100 randomly selected subjects. RESULTS: In routine practice, the emergency department staff did not investigate substance use in nearly one of two patients. Patients' statements and toxicological assays were more specific than sensitive, with lower scores for toxicological assays. Patients' statements made it possible to detect nearly 80% of subjects with substance use disorder. CONCLUSION: Identification of substance use disorder in subjects with IDO has strong clinical consequences regarding treatment and prevention of suicidal behaviour. Thus, emergency department staff should be made aware of the value of more systematically exploring self-reported substance use.

Adolescent↗
PubMed2002

Applications of computational toxicology methods at the Agency for Toxic Substances and Disease Registry.

In its efforts to provide consultations to state and local health departments, other federal agencies, health professionals, and the public on the health effects of environmental pollutants, the Agency for Toxic Substances and Disease Registry relies on the latest advances in computational toxicology. The computational toxicology laboratory at the agency is continually engaged in developing and applying models for decision-support tools such as physiologically based pharmacokinetic (PBPK) models, benchmark dose (BMD) models, and quantitative structure-activity relationship (QSAR) models. PBPK models are suitable for connecting exposure scenarios to biological indicators such as tissue dose or end point response. The models are used by the agency to identify the significance of exposure routes in producing tissue levels of possible contaminants for people living near hazardous waste sites. Additionally, PBPK models provide a credible scientific methodology for route-to-route extrapolations of health guidance values, which are usually determined from a very specific set of experiments. Also, scientists at the computational toxicology laboratory are using PBPK models for advancing toxicology research in such areas as joint toxicity assessment and child-based toxicity assessments. With BMD modeling, all the information embedded in an experimentally determined dose-response relationship is used to estimate, with minimum extrapolations, human health guidance values for environmental substances. Scientists in the laboratory also rely on QSAR models in the many cases where consultations from the agency are reported for chemicals that lack adequate experimental documentation.

Benchmarking↗
PubMed2003

Toxicity characterization of environmental chemicals by the US National Toxicology Program: an overview.

The US National Toxicology Program (NTP) is an interagency program whose mission is to evaluate agents of public health concern by developing and applying the tools of modern toxicology and molecular biology. Chemicals substances or physical agents selected for toxicology and carcinogenesis evaluations by the NTP are usually studied in a series of subacute (14-day exposure), subchronic (90-day exposure) and chronic (2-year exposure) studies in rodents. The NTP has published more than 500 reports of the findings and conclusions from its toxicology and carcinogenesis studies. In more specialized studies, the NTP also evaluates adverse effects on the structure and function of the immune, reproductive, nervous, and respiratory systems. The program attempts to evaluate and appropriately incorporate new technologies to improve the way we study the toxicity of chemicals. For example, the program has extensively evaluated several transgenic mouse models for their potential use as short-term cancer screens and has been a full participant in an international effort to examine their usefulness in pharmaceutical registration. Toxicogenomics, an emerging scientific field that examines the expression of thousands of genes simultaneously in response to chemical exposure, holds promise for future application to better understand the underlying mechanisms of chemical toxicity. A number of public health issues being addressed by the NTP are not only of national importance but also have global impact, such as the potential for endocrine disruptors to influence development and carcinogenesis and the safety of herbal medicines and dietary supplements. The program participates in the preparation of national and international toxicity testing guidelines and the findings from NTP studies are widely used for risk assessments by international organizations and federal agencies. The NTP maintains databases that contain toxicity, and health and safety information on a large number of chemicals. These databases are available from the NTP web site (http://ntp-server.niehs.nih.gov) and are accessed over 100000 times a month from around the world.

Animals↗
PubMedDate not supplied

Simian retrovirus infections: potential confounding variables in primate toxicology studies.

Various species of nonhuman primates are natural hosts for 6 exogenous retroviruses, including gibbon-ape leukemia virus (GaLV), simian sarcoma virus, simian T-lymphotropic virus (STLV), simian immunodeficiency virus (SIV), simian type D retrovirus (SRV), and simian foamy virus (SFV). These viruses establish persistent infections with a broad spectrum of pathogenic potential, ranging from highly pathogenic to nonpathogenic, depending on various host, virus, and environmental factors. Latent or subclinical infections are common, and various procedures associated with experimental protocols may lead to virus reactivation and disease. Adverse effects on toxicologic research by undetected retroviral infections can occur in several ways, including loss of experimental subjects (and statistical power) due to increased morbidity and mortality. In addition, results may be confounded by virus-induced clinical abnormalities, histologic lesions, alteration of physiologic parameters and responses, and interference with in vitro assays and/or destruction of primary cell cultures. Key clinical and epidemiological features of several important retroviruses are reviewed, with emphasis on viruses infecting species of macaques most commonly used as research subjects in primate toxicology studies. Examples of actual and potential confounding of toxicologic studies by retroviruses are discussed, including altered cytokine profiles in healthy STLV carriers, and clinical and pathological abnormalities induced by SRV infection. Adequate prestudy viral screening is critical to exclude retrovirus-infected primates from toxicologic research protocols and prevent potential confounding of research results.

Animals↗
PubMedDate not supplied

Application of toxicogenomics to toxicology: basic concepts in the analysis of microarray data.

Toxicology and the practice of pathology are rapidly evolving in the postgenomic era. Observable treatment related changes have been the hallmark of toxicology studies. Toxicogenomics is a powerful new tool that may show gene and protein changes earlier and at treatment levels below the limits of detection of traditional measures of toxicity. It may also aid in the understanding of toxic mechanisms. It is important to remember that it is only a tool and will provide meaningful results only when properly applied. As is often the case with new experimental tools, the initial utilization is driven more by the technology than application to problem solving. Toxicogenomics is interdisciplinary in nature including at a minimum, pathology, toxicology, and genomics. Most studies will require the input from the disciplines of toxicology, pathology, molecular biology, bioinformatics, biochemistry, and others depending on the types of questions being asked.

Acetaminophen↗
PubMed2001

Genetic aspects of nutrition and toxicology: report of a workshop.

The health and resilience of humans and animals is, in large part, determined by the quality and quantity of the diet. This, in turn, may influence an individual's capability to deal with stress including toxic insult. In addition, there may be specific components of the diet that modulate the toxicity of specific toxicants whether the latter are ingested as food or absorbed via other routes. Many examples attest to the importance of interactions between dietary components and toxicants after absorption in the body. Such interactions occur at every level of biological organization from the molecular to the whole organism. Some may be synergistic, others antagonistic. Some may involve direct chemical reaction between the nutrient molecule and the toxicant, others may occur by indirect action at the cellular or organ levels. All examples point to the importance of considering diet when measuring the response to toxic agents whether in animals or humans. In order to foster interaction between the sciences of nutrition and toxicology, The Heinz Institute of Nutritional Sciences as sponsoring a series of workshops. The first of these was held in June, 1999 at the University of Ulster to address evolutionary aspects of nutrition--toxicology (for report see Eur. J. Nutr, 39, 49-52, 2000). In June, 2000, a second workshop was held at the University of Toronto to address genetic aspects, and this is a brief summary of the proceedings. We are beginning to understand the molecular basis of the regulation of gene expression by dietary factors and how genetic changes can affect response to toxicants. Recent advances in technology and a detailed understanding of disease etiology has led to the ability to study molecular determinants of disease risk. The workshop provided a forum for nutritionists, toxicologists, molecular biologists, epidemiologists and others to discuss common interests and to merge their efforts towards an integrated approach to nutrition--toxicology via genetics and genomics. The first session dealt with the mechanism by which nutrients such as fatty acids (Clarke), amino acids (Jefferson) and metal ions (Cousins) can regulate gene expression. In the second session, there were presentations on the effects of nutritional factors on genes of toxicological significance such as phase I and phase II enzymes of drug metabolism (Guengerich, Goodfellow and Grant) as well as on oxidative DNA damage and its repair (Collins, Weindruch). Session three dealt with gene-nutrient interactions in the development of chronic diseases such as diabetes (Hegele, Berdanier) and cancer (Kim, Ambrosone et al.). New developments such as DNA microarrays (McGlynn) and the use of transgenic and knockout models (Sehayek) were presented in the final session.

Aging↗
PubMed2002

Particle toxicology: from coal mining to nanotechnology.

Particle research has been historically closely connected to industrial activities or materials, such as coal, asbestos, man-made mineral fibers, and more recently ambient particulate matter (PM). It is the purpose of this review to combine insights and developments in particle toxicology with the historical context of exposure and organizations sponsoring such research in Europe. In supporting research on particle-induced respiratory effects and mechanisms, research programs of the European Community on Steel and Coal (ECSC) have played a tremendous role. Current particle research in Europe is dominated by PM, and funded by the World Health Organization (WHO), European Union Framework programs, and the Health Effects Institute (HEI). Differences between historical and current research in particle toxicology include the exposure concentrations, particle size, target populations, endpoints, and length of exposure. Inhaled particle effects are no longer confined to the lung, since particles are suggested to translocate to the blood while lung inflammation invokes systemic responses. Finally, the particle size and concentrations have both been reduced about 100-fold from 2-5 mg/m3 to 20-50 mg/m3 and from 1-2 microm to 20-100 nm (ultrafine) as domestic fuel burning has decreased and vehicle sources have increased and attention has moved from coal mining industry to general environment. There is, however, a further occupational link to nanotechnology, which continuously produces new materials in the ultrafine range. Although inhalation exposure is considered to be minimal in this technology, some particles are produced to be used for carrier purpose in medical applications. Based on our current knowledge of particle toxicology, it is highly desirable that toxicology and technology are linked in this extremely rapid developing area, to learn more about potential risks and also to develop knowledge on the role of surface and size in particle toxicity.

Coal↗
PubMed1996

Trace element food toxicology: an old and ever-growing discipline.

Food toxicology (FT) is an old science whose origins may go back to primitive humans. However, due to major environmental damage, daily market launches of new food products, and the analytical ability to detect ever small quantities of toxicants in foods, FT is also an ever-growing science with an enormous task ahead. With respect to trace elements, current research trends can be encompassed under the headings of detection, control, and toxicological evaluation. Under the heading detection, quality, sensitivity, speed, automation, and specificity for each food type are the characteristics currently sought when developing new methodologies. Under control, there is a great need for constant monitoring, on an international level, of the levels of trace elements present in foods; and for development and application of new methodologies to guarantee product and process safety. Under toxicological evaluation, information about the bioavailability of trace elements and consequently studies of the chemical species present in foods have top priority. The work still outstanding in the study of trace element FT is immense, because it is necessary to achieve a profound understanding of the toxicological characteristics of food products in relation to trace elements; to give information to food manufacturers that they can use to adapt their production so that it meets the requirements of international legislation and demands for quality and innocuousness on the part of the market and consumers; and to develop standards regulating the maximum content of trace elements, according to the content of the various species.

Food Analysis↗
PubMedDate not supplied

The role of proteomics in toxicology: identification of biomarkers of toxicity by protein expression analysis.

Proteomics, i.e. the high throughput separation, display and identification of proteins, has the potential to be a powerful tool in drug development. It could increase the predictability of early drug development and identify non-invasive biomarkers of toxicity or efficacy. This review provides an introduction to modern proteomics, with particular reference to applications in toxicology. A literature search was carried out to identify studies in two broad classes: screening/predictive toxicology, and mechanistic toxicology. The strengths and limitations of current methods and the likely impact of techniques in drug development are also considered. Proteomics can increase the speed and sensitivity of toxicological screening by identifying protein markers of toxicity. Proteomics studies have already provided insights into the mechanisms of action of a wide range of substances, from metals to peroxisome proliferators. Current limitations involving speed of throughput are being overcome by increasing automation and the development of new techniques. The isotope-coded affinity tag (ICAT) method appears particularly promising. The application of proteomics to drug development has given rise to the new field of pharmacoproteomics. New associations between proteins and toxicopathological effects are constantly being identified, and major progress is on the horizon as we move into the post-genomic era.

Animals↗
PubMed2002

Advances in the use of mass spectral libraries for forensic toxicology.

Gas chromatography in combination with mass spectrometry (GC-MS) plays an important role in the field of analytical toxicology. The identification of unknown compounds is very frequently undertaken with GC-MS and utilizing mass spectral libraries. Currently available libraries for analytical toxicology were compared for overlapping and uniqueness of their entries. Furthermore, the widely known Pfleger-Maurer-Weber-Drugs-and-Pesticides-Library for toxicology (PMW_tox2) was used to compare the search algorithms PBM (Probability Based Matching, Agilent Technologies), INCOS (Finnigan/Thermoquest), and MassLib (Max Planck Institute). To our knowledge, direct comparisons of mass spectral libraries and search programs for analytical toxicology have not been published previously. The capabilities and necessities of modern MS technology in the field of general unknown analysis are revealed, and some of the potential pitfalls are described.

Databases, Factual↗
PubMed2002

Progress of liquid chromatography-mass spectrometry in clinical and forensic toxicology.

The use of liquid chromatography-mass spectrometry (LC-MS) has recently exploded in various analytic fields, including toxicology and therapeutic drug monitoring (although still far behind pharmacokinetics). There is no doubt that LC-MS is currently competing with gas chromatography (GC)-MS for the status of the reference analytic technique in toxicology. This review presents, for the nonspecialist reader, the principles, advantages, and drawbacks of LC-MS systems using atmospheric pressure interfaces. It also gives an overview of the analytic methods for xenobiotics that could be set up with these instruments for clinical or forensic toxicology. In particular, as far as quantitative techniques are concerned, this review tries to underline the large number and variety of drugs or classes of drugs (drugs of abuse, therapeutic drugs) or toxic compounds (e.g., pesticides) that can be readily determined using such instruments, the respective merits of the different ionization sources, and the improvements brought about by tandem MS. It also discusses new applications of LC-MS in the field of toxicology, such as "general unknown" screening procedures and mass spectral libraries using LC-atmospheric pressure ionization (API)-MS or MS-MS, presenting the different solutions proposed to overcome the naturally low fragmentation power of API sources. Finally, the opportunities afforded by the most recent or proposed instrument designs are addressed.

Chromatography, Liquid↗
PubMed2005

Recent trends in analytical procedures in forensic toxicology.

Forensic toxicology is a very demanding discipline,heavily dependent on good analytical techniques. That is why new trends appear continuously. In the past years. LC-MS has revolutionized target compound analysis and has become the trend, also in toxicology. In LC-MS screening analysis, things are less straightforward and several approaches exist. One promising approach based on accurate LC-MSTOF mass measurements and elemental formula based library searches is discussed. This way of screening has already proven its applicability but at the same time it became obvious that a single accurate mass measurement lacks some specificity when using large compound libraries. CE too is a reemerging approach. The increasingly polar and ionic molecules encountered make it a worthwhile addition to e.g. LC, as illustrated for the analysis of GHB. A third recent trend is the use of MALDI mass spectrometry for small molecules. It is promising for its ease-of-use and high throughput. Unfortunately, re-ports of disappointment but also accomplishment, e.g. the quantitative analysis of LSD as discussed here, alternate, and it remains to be seen whether MALDI really will establish itself. Indeed, not all new trends will prove themselves but the mere fact that many appear in the world of analytical toxicology nowadays is, in itself, encouraging for the future of (forensic) toxicology.

Chemistry Techniques, Analytical↗
PubMed2000

Toxicological bases for the setting of health-related air pollution standards.

The development of air pollution standards ideally involves the integration of data from the disciplines of epidemiology, controlled clinical studies, and animal toxicology. Epidemiological studies show statistical associations between health outcomes and exposure; they cannot establish a definite cause-effect relationship. The utility of toxicological studies is to establish this relationship. Recently, there was simultaneous promulgation of a new National Ambient Air Quality Standard (NAAQS) for particulate matter < 2.5 microns in aerodynamic diameter (PM2.5) and a revised NAAQS for ozone (O3). The O3 NAAQS was based, in part, on a sound foundation of toxicological data from controlled exposure studies in humans and animals. It also relied on epidemiological studies of hospital admissions for respiratory diseases. Such studies also served as important bases for the new PM2.5 NAAQS. However, the most influential bases for the PM NAAQS were the numerous and generally consistent epidemiological studies that associated exposure with premature mortality in susceptible subpopulations and the inability of numerous hypothesized confounding factors to negate the associations. Using ozone and PM as examples, this paper discusses the scientific basis for NAAQS promulgations in situations in which the underlying database differed greatly in the extent of toxicological support.

Air Pollutants↗
PubMed1987

The role of conventional pathology and toxicology in evaluating the immunotoxic potential of xenobiotics.

Investigating the immunotoxic potential of candidate drugs as part of a preclinical safety evaluation poses several problems. These include the need for practical, validated tests, the difficulty in establishing the toxicologic significance of positive findings, and a poor understanding of the predictive value such findings hold for drug effects in man. A key component of this investigation is the toxicologic profile generated through preclinical toxicity and safety studies. As this "routine" assessment becomes increasingly comprehensive and sophisticated, most toxicologically significant drug-associated effects are revealed. Such findings may serve as "triggers" for investigating possible immune mechanisms. Decisions to test specifically for immunotoxicity may also be influenced by the molecular structure and pharmacologic profile of the compound, as well as the intended use of the drug. Examples of such indications and follow-up studies are discussed in this review. We are presently poorly equipped to effectively screen drugs indiscriminately for an immunotoxic potential. We are better prepared, however, to investigate whether a drug-associated change is due to an adverse effect on the immune system. This problem-oriented approach to immunotoxicology challenges us as diagnosticians and immunopathologists, and requires a close working relationship among the toxicologic pathologist, the basic immunologist, the immunopharmacologist, and the clinician.

Animals↗
PubMed1991

Approaches to the identification and recording of nasal lesions in toxicology studies.

The identification, recording, and interpretation of nasal lesions can be a difficult task in toxicology studies. The objective of this article is to provide some guidelines for approaches to nasal toxicologic pathology, based on the author's experience and information available in the published literature. Identification of treatment-induced nasal lesions requires adequate in-life and post-mortem observation, and thorough histopathology. Histopathologic assessment is dependent upon high quality and consistent histologic preparations, adequate knowledge of nasal anatomy and histology, and experience with the range of aging, background, and treatment-induced lesions that may be encountered. In recent years there has been a marked increase in the number of articles reporting nasal pathology in studies for which materials were delivered by inhalation and by non-inhalation routes. Because of the increasing size of this database, it is recommended that standardized and systematic nomenclature be developed for these changes. The following points are considered to be particularly important: 1) alert animal care staff to clinical changes that may indicate nasal lesions; 2) screen animals for nasal disease, such as nasal nematodes in non-human primates; 3) record gross lesions during trimming of decalcified nasal tissues; 4) save spare tissue in fixative; 5) remember that the normal bilateral symmetry of the nose can be a valuable diagnostic aid; 6) avoid excessive lumping or splitting of diagnoses; 7) develop a logical order for recording of lesions (the approach preferred by the author is degenerative, inflammatory, regenerative, proliferative, for each of the epithelial types in a logical anatomical order, such as squamous, transitional, respiratory, and olfactory); 8) accurately determine the site of toxic responses; 9) keep a notebook of interesting or important observations and ideas if you are using a computerized data acquisition system; 10) consider the role of factors that may account for lesion distribution (regional dose and tissue susceptibility) during interpretation of tissue responses; and 11) during preparation of the descriptive narrative, clearly define what occurred, where and when it occurred, and consider the use of simple anatomical diagrams as an adjunct to the text. Adequate lesion detection and characterization by the toxicologic pathologist is often a critical feature of toxicology studies, and can play an important role in determination of human risks associated with exposure to xenobiotics. A systematic but flexible approach is recommended.

Aging↗