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PubMed1993

The science of toxicology and its relevance to MCS.

The definitions and current practice of multiple chemical sensitivity (MCS) are considered in relation to the fundamental principles of toxicology. The salient problem with MCS is that there is no consistent and specific effect from exposure to any specific chemical. This does not allow for any objective test for any disease entity which might be caused by the chemicals as indicated by the theory of MCS. The effects of exposure to chemicals as defined today as MCS are subjective and no report is available to convincingly demonstrate that these effects would not have occurred merely by chance. It is concluded that (1) MCS, as defined, does not allow specificity or consistency for biological reactions to the effects of chemicals; (2) MCS does not provide a testable hypothesis; (3) MCS is contradictory to the fundamental principles of toxicology; (4) current testing procedures for MCS are so subjective that they are useless; (5) there is no evidence that the responses attributed to MCS are any other than those that would occur merely by chance; and (6) the MCS literature attaches an emotional bias to chemicals.

Environmental Pollutants↗
PubMed1998

Current and future contributions of transgenic mice to the analysis of germline toxicology.

Evermore sophisticated tests are need to study germline toxicology. The gene conversion-based systems developed in Leicester and in the USA are steps in the right direction, but a lot of validation both in vivo and in vitro is required. Transgenic technology can also be used to research the biology of testis, so that we know more how to make it more human-like. If you talk to toxicologists, they always complain: 'but it 's only a rat, it's only a mouse, it's not a man'. In future, once we understand more biology--it might be possible to make the toxicological response of a transgenic mouse more human-like. As we all know, the testis is a complex biological system and it is only when we get a better understanding of what is going on to the fundamental level are such developments possible. Indeed, it might be possible to do even more exciting things, such as taking mitotic human tissue culture cells and to inducing them to enter meiosis in vitro. Such a system would be a natural complement to the in vitro tests widely used in industry.

Animals↗
PubMed1982

Measurement of urinary metabolites of xenobiotics as a non-invasive technique in toxicology.

Most xenobiotics undergo biotransformation in living organisms and are excreted as metabolites in urine. There are three major reasons why the measurement of urinary metabolites may be important in toxicology: 1. To obtain pertinent information on the biotransformation of a compound in the body. By identifying metabolites it is often possible to assess which metabolic pathways at the enzymic level are followed and whether, for example, reactive intermediates are formed. Also quantitative and kinetic information on the disposition of a xenobiotic can be obtained. 2. To use in exposure tests (biological monitoring). The metabolites may be specific or nonspecific for the compound to which exposure takes place. 3. To use as a measure for the activity of metabolic pathways in order to assess interindividual differences in biotransformation, or to assess changes in such pathways by exposure to or ingestion of xenobiotics. In particular in the identification of genetically determined polymorphism of metabolism in man, urinary metabolites have proved to be a very useful tool. Large interindividual differences in the rate of biotransformation of xenobiotics exist and this has important biological (toxicological) implications. The possible value of measuring the urinary metabolite profile of the model compound antipyrine, as a tool in the assessment of the activity of different xenobiotic oxidizing enzymes, is discussed.

Animals↗
PubMed1982

Statistical analysis and normality of selected hematologic and clinical chemistry measurements used in toxicologic studies.

The statistical comparison of hematological and clinical chemistry measurements of treated and control groups in toxicological studies has frequently, in the past, been done by methods that assumed, in the population of such values, normality of the data. This assumption was tested on pairs of concurrent control groups of rats from three long-term toxicological studies; two feeding and one inhalation routes of exposure were used. The normality of the data from three treated groups in one of these studies was also tested. The measurements examined were erythrocyte count, hemoglobin, white blood cell count, neutrophils, monocytes, urea nitrogen, and creatinine. In many cases significant skewness, kurtosis and deviation from normality as measured by the Kolmogorov-Smirnov test were present. The lack of consistency of normality versus nonnormality or, in some cases, direction of skewness, suggests that nonparametric statistical procedures be considered for use in the future for comparison of these types of data. Furthermore, the agreement of the data of the concurrent control groups as compared to the divergence of the values among the three studies affirms the importance of concurrent, in preference to historical, control data.

Animals↗
PubMed1992

Biologically based modeling in toxicology research.

Biologically based modeling can be described as the process by which the specific mechanistic steps governing tissue disposition and toxic action of chemicals are expressed in quantitative terms by a set of equations leading to prediction of the outcome of specific toxicological experiments by computer simulation. These models are useful in risk assessment because their mechanistic biological basis permits the high-to-low dose, route to route and interspecies extrapolation of the tissue disposition and toxic action of chemicals. By far their greatest utility is not as "finished" risk assessment models, but as research tools that convey a quantitative expression of our hypotheses of tissue disposition and toxic action of a chemical. A structured modeling approach to toxicology problems helps identify the data gaps in the areas of chemical disposition and toxic action, thus prioritizing on-going research to obtain critical information required to conduct quantitative risk assessment. This paper examines progress in developing comprehensive biologically based models for cancer induction by non-genotoxic carcinogens that are cytotoxic in target tissues. The strategies for linking the models on dosimetry, cytotoxicity, and carcinogenicity are described in detail. The basic concepts and approaches discussed here can be applied to many other toxic chemicals and to toxicity endpoints other than cancer.

Animals↗
PubMed1994

The role of investigative toxicology in pharmaceutical industry.

In summary, the benefits of a mechanistic toxicology approach include increased understanding of the processes underlying primary pathology, the development of predictive capability, enhanced decision making and improved responsiveness to regulatory agencies. The overall objective of toxicology in the pharmaceutical industry is risk benefit assessment in order to support product registration. This requires both that studies be conducted in accordance with regulatory guidelines and that the biological processes underlying pathology be understood. These should be regarded as inseparable components of the risk assessment process.

Animals↗
PubMed1984

Potentials of capillary gas chromatography in toxicology today.

The usefulness, the applicability and the limitations of capillary gas chromatography in various types of toxicological analysis were discussed. Technical parameters of capillary gas chromatography, such as type of injector, type of column with regard to material, size, and stationary phase were assessed in view of the requirements of toxicological analysis. The main advantage of capillary gas chromatography, i.e. high separation power, is unfortunately counterbalanced by low loadability and/or speed of analysis. In the present situation capillary gas chromatography is a method of choice in drug screening despite some disadvantages, but in drug-oriented analysis the conventional chromatography on packed; columns is probably more useful.

Chromatography, Gas↗
PubMed1975

[The use of combined spectroscopy in analytical toxicology (author's transl)].

The combined application of the four spectrometric techniques UV, IR, NMR and MS is an important analytical tool for the identification of the increasing number of potential poisons with which the analysts in the fields of forensic sciences and toxicology are confronted. Some of the contributions of these techniques to toxicological analyses are reviewed and illustrated by a few examples. Furthermore, the incorporation of the four methods into the analytical scheme, the requirements with respect to quantity and purity of the unkown substances, as well as the different possibilities for the combination of separation and identification techniques are outlined.

Magnetic Resonance Spectroscopy↗
PubMed1985

A test procedure based on ranks for the statistical evaluation of toxicological studies.

For testing the significance of dose-related effects, a test procedure was developed for the typical situation in toxicological studies where several dosage groups are compared to one control group. Using a closed testing procedure in the sense of Marcus et al. (1976), the algorithm is sensitive to the detection of toxicological effects without increase in type-one errors. Furthermore, all significance tests applied in the algorithm are based on ranks and the calculation of the error probability is performed by a random-permutation technique (Wall 1974, 1985); the algorithm is therefore also applicable to non-normally distributed data. In the case of discrete quantities, this technique takes into account tie-structures of all kinds (Lüdin 1985). An application of the proposed test-procedure is given in the work of Kistler and Hummler (1985).

Dose-Response Relationship, Drug↗
PubMed2002

Children as a sensitive subgroup and their role in regulatory toxicology: DGPT workshop report.

There is increasing discussion that children might be considered as a specific subgroup in public health regulations which could be more sensitive than the average "adult" human being. Differences between children and adults, with regard to susceptibility towards toxicants, may result from a combination of toxicokinetic, toxicodynamic and exposure factors. Kinetic factors are of importance mainly in the early postnatal period, largely as the result of immature elimination systems, i.e. metabolising enzymes and/or renal function. Specific vulnerability may prevail during several time periods, related to the development and maturation of organs (for example, brain, bone, endocrine system). For some substances, it has been shown that children at a specific age are less sensitive than adults. Specific exposures of toddlers to environmental chemicals may be high due to their moving behaviour and hand-to-mouth activities. Existing scenarios and models for exposure of children should be improved, in particular with respect to different ages. The outcome of model calculations must be verified by human biomonitoring analysis. At present, there is ongoing discussion of toxicological test models suitable to delineate human postnatal development. Experience with infant-orientated test systems is scarce (for example in developmental neurotoxicity). In general, tools for predicting toxicological sensitivity of children must be further improved. Regulators should also be aware that reduction of lifestyle-related toxic exposures such as smoking and drug abuse in children and adolescents is now an increasing public health problem in many countries.

Adolescent↗
PubMed2004

Advances in analytical toxicology: the current role of liquid chromatography-mass spectrometry in drug quantification in blood and oral fluid.

This paper reviews procedures for quantification of drugs in the biosamples blood, plasma, serum, or oral fluid (saliva, etc.) using liquid chromatography coupled with single-stage or tandem mass spectrometry (LC-MS, LC-MS-MS). Such procedures are important prerequisites for competent toxicological judgment and consultation in clinical and forensic toxicology. They cover blood (plasma, serum) analysis of amphetamines and related designer drugs, anesthetics, anticonvulsants, benzodiazepines, opioids, serotonergic drugs, tricyclic antidepressants, neuroleptics, antihistamines, beta-blockers, muscle relaxants, and sulfonylurea-type antidiabetics, and oral fluid analysis of amphetamines and related designer drugs, cocaine, benzoylecgonine, codeine, morphine, enantiomers of methadone and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), the nicotine metabolites cotinine and hydroxycotinine, and finally risperidone and its metabolite 9-hydroxyrisperidone. Basic information on the procedures is given in two tables and an example of quantification is illustrated in two figures. The pros and cons of such LC-MS procedures including sample work-up and ion suppression effects are critically discussed.

Chemistry Techniques, Analytical↗
PubMed1996

Automation of toxicological screenings on a Hewlett Packard Chemstation GC-MS system.

OBJECTIVES: To optimize the interpretation of GC-MS toxicological screenings (i.e., to facilitate ion specific queries, create custom reports specifically adapted to each confirmation procedure, and eliminate redundant and/or inaccurate data on library search reports). DESIGN AND METHODS: The MS Chemstation software of the Hewlett Packard 5972 is constructed in a modular way. We made extensive modifications to two modules, the data analysis and the report modules, using the built-in MS Chemstation macro language. RESULTS: Ion specific queries were automated for over 60 commonly encountered analytes. Custom reports were created for the confirmation of positive drugs-of-abuse immunoassay results. With the incorporation of decision support rules into the data processing and the reporting phases, we obtained sensitive, accurate, and concise reports. CONCLUSIONS: The MS Chemstation software can be tailored to the needs of each individual application. The incorporation of a rule-based decision support system enhances the quality of the GC-MS toxicological screenings and results in faster, easier, and more reliable processing.

Gas Chromatography-Mass Spectrometry↗
PubMed1991

A toxicological perspective on ecosystem characteristics to track sustainable development. VII. Ecosystem health.

"Ecosystem health," an emerging science paralleling human and veterinary medicine, has as its goals the systematic diagnosis and treatment of stressed ecosystems. Ecosystems are stressed by physical factors such as boat traffic, biological factors such as introduction of an exotic species, and chemical factors such as pH change. Even if these classes of stressors affect the same trophic levels, the resulting ecosystem disease states have different etiologies because the stress is introduced and propagated by different mechanisms. This paper presents a toxicological perspective on ecosystem sustainability. I discuss how classical toxicological concepts have to be modified when the experimental unit is an ecosystem. When exposures are high, effects are acute and are often measurable (e.g., fish kill). However, when exposures are low and chronic, effects are often hard to separate from the background. Evidence of high risk for lack of sustainable development is the exceeding of ecosystem "threshold criteria."

Biomarkers↗
PubMed1985

The value of chronic animal toxicology studies of pharmaceutical compounds: A retrospective analysis.

Extensive animal studies are carried out during the development of new medicines to assess toxicity and predict their safety for use in man. There are, however, differences of opinion concerning the nature of safety evaluation studies required prior to marketing. Any prospect of rationalizing the number and design of animal studies must stem from a reappraisal of conventional animal testing procedures and better use of available data on the toxicity of compounds previously investigated. The Centre for Medicines Research has therefore established a toxicology databank containing comprehensive data from repeated-dose animal safety evaluation studies provided by pharmaceutical companies. Thirteen companies within the United Kingdom have provided toxicological data for 32 pharmaceutical compounds studied in the rat, dog, or primate, resulting in 45 case studies for which both short-term (less than or equal to 6 months) and long-term (greater than 6 months) tests had been completed. A comprehensive analysis of these studies has been carried out to determine what new findings, if any, become apparent in studies after 6 months. The results do not support the need for animal toxicity studies of longer than 6 months duration, apart from those designed to investigate carcinogenicity.

Animals↗
PubMed1986

The necessary minimal duration of final long-term toxicologic tests of drugs.

The optimal, and thus mandatory duration of final, long-term toxicologic tests of drugs in animals prior to marketing for use in human beings remains controversial. Some regulatory authorities contend that exposure for 6 or 12 months is adequate. However, the Bureau of Human Prescription Drugs of the Health Protection Branch of Health and Welfare Canada has evaluated a number of confidential reports from manufacturers in which significant, non-neoplastic, pathologic changes occurred only after exposure of animals for more than 1 year. Fifteen examples from these files and the literature are described. These studies support the current Canadian guidelines' requirement for the duration of final long-term toxicologic tests of drugs to be at least 18 months.

Animals↗
PubMed1984

Toxicological assessment of the hemostatic system, regulatory requirements, and industry practice.

Disturbances of the hemostatic system which may be caused by chemicals include hemorrhagic diathesis, caused by inhibition of blood clotting, impairment of platelet function, and hyperactivity of fibrinolysis. Activation of the plasmatic clotting system, platelet aggregation, and inhibition of fibrinolysis may lead to thromboembolic complications. Although much is known about the functions of the hemostatic system a rational and cost-effective approach for its assessment in industrial toxicology is lacking. In this review the physiology of hemostasis and the available laboratory tests are discussed, current regulatory requirements are described, and industry practice is analyzed based on experience accumulated over the last 23 years. Proposals for a more flexible and scientific approach to testing of hemostatic mechanisms in toxicology are made.

Animals↗
PubMed1986

The weight of evidence: regulatory toxicology in Canada.

The legislative application of regulatory toxicology in Canada is reviewed, together with the sources of experimental evidence used for action. Examples are given of the critical toxicological information that led to a regulatory decision. Risk numbers have only been used to a limited extent in Canada. Some possibilities for future research are offered.

Amaranth Dye↗
PubMed1985

Ethical considerations in toxicology.

Since most of the research necessary for the safety evaluation of chemicals requires the killing of laboratory animals, toxicologists are faced with an ethical conflict between their professional duties and the interests of the animals. In the past, the protection of consumers against chemical injury was considered to be of the greatest importance, and society approved of all efforts to detect even the slightest hazards from man-made and environmental chemicals. In recent years, toxicologists have become aware of their ethical responsibilities not only for the safety of the human population but also for the welfare of the animals. They have begun to review the classical toxicological procedures critically and now require that the maximum amount of relevant information is obtained from the smallest number of laboratory animals. Toxicologists have also become aware of the alternative methods that permit the investigation of toxicological responses in unicellular organisms and cell cultures. The problem of testing chemicals for irritant properties on skin and mucous membranes is an excellent example of how concern for animals has generated a range of original and imaginative research leading not only to a reduction in the use of animals but also to a more efficient and scientific approach to an important health problem.

Animals↗