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Toxicology of sensory systems: a perspective.

This brief review is the result of a recent meeting of the British Toxicology Society (Toxicology of Sensory Systems, University of York, April 2-3, 1992). The meeting provided the opportunity to discuss the anatomy, physiology and function of the eye, ear, nasal epithelium and peripheral sensation and the methods that are available to detect injury or dysfunction both in the preclinical and clinical situation. In addition, the mechanism whereby certain chemicals can perturb some of these organs was discussed. The aim of this short article is to highlight some of the recent advances in understanding in these areas with regard to their relevance or impact on toxicology. For convenience the areas will be discussed under separate headings.

Animals↗

Recommendations for establishing a drug and toxicology information center in a developing country.

The purpose of this work was to formulate guidelines to help health professionals in establishing or strengthening the capabilities of drug and toxicology information centers and related facilities in developing countries. These guidelines are based on the experience of an established drug and toxicology information service in Zimbabwe which has been operating for more than ten years and on information obtained from other centers in developed countries. The guidelines provide advice rather than a unique model and should therefore be adapted rather than adopted. We conclude that national drug policies should include provision for establishing drug information centers. The World Health Organization and similar organizations should assist in establishing these centers. We believe that a drug and toxicology information center is more beneficial to the community when it is part of the teaching curriculum and continuing education for health professionals. Therefore, the center should be located in a medical teaching institution.

Developing Countries↗

Antimicrobial and toxicological evaluation of the leaves of Baissea axillaries Hua used in the management of HIV/AIDS patients.

BACKGROUND: Persistent diarrhea is a common endemic disease with high incidence among the Africans including Nigerians. It also represents a frequent opportunistic disease in people living with HIV. Diarrhea represents one of the most distressful and persistent symptoms of HIV/AIDS, which may or may not be accompanied by an infection. The leaves decoction of Baissea axillaries Hua (Apocynaceae) is used by traditional herbalists in Edo state, Nigeria for the management of people living with HIV/AIDS. Determination of its antimicrobial activity and toxicological profile will provide supportive scientific evidence in favour of its continuous usage. METHOD: Chemical and chromatographic tests were employed in phytochemical investigations. Inhibitory activities of aqueous and ethanolic extracts against clinical strains of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus faecalis were compared with Togamycin (Spectinomycin). Our report includes minimum inhibitory concentration (MIC) against the test organisms. Toxicological evaluation was determined by administering 250 mg/kg and 500 mg/kg of extracts on male Wister rats for 14 days with normal saline as control. The kidneys, liver, heart and testis tissues were examined. RESULTS: Phytochemical studies revealed the presence of alkaloids, tannins, and cyanogenetic glycosides. The extracts inhibited the growth of Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus to varying extents, but only the ethanolic extract inhibited growth in Streptococcus faecalis. The LD50 of the extract in mice was above 5000 mg/kg body weight when administered intraperitoneally. Toxicological evaluation showed mere ballooning degeneration of the liver at 250 mg/kg while at 500 mg/kg there was tissue necrosis. The low and high doses showed ill-defined leydig cells in the testis and no remarkable changes in the heart and kidneys. CONCLUSION: Extracts of Baissea axillaries have demonstrated antimicrobial activity against clinical strains of selected microorganisms. While there is toxicity at the dose of 500 mg/kg, the therapy shows potential for application in the treatment of diarrhoea associated with AIDS/HIV. Further studies of Baissea axillaries on diarrhoea and toxicity are necessary to evaluate its mechanism of action and to fully establish its safety profile.

Animals↗

Toxicological features of deliberate self-poisonings.

BACKGROUND: Deliberate self-poisoning (DSP) is a major health problem with increasing incidence mainly among young people. OBJECTIVE: To examine the clinical and toxicological characteristics of DSP, it is compared to unintentional (non-DSP) exposures and those characteristics which might be associated with increased toxicological risk are identified. METHODS: Two-year retrospective poison centre chart review. STATISTICS: chi2 analysis. RESULTS: 3802 DSP cases were reported. Most calls (95%) were made by physicians compared to 51% in non-DSP exposures, P <0.0001. There were almost twice as many females as males, contrary to unintentional exposures (P <0.001). Peak frequency involvement was at the age of 15-20 years for females and older for males. Only 19.8% of DSP calls were made within the first hour of exposure compared to 46% of the non-DSP calls (P < 0.001). Younger patients tended to present earlier. The vast majority of exposures occurred by ingestion and at home. Pharmaceuticals and chemicals were involved in 86% and 12% of DSP cases, respectively (compared to 29% and 44% in non-DSP exposures, respectively, P < 0.001). Psychiatric drugs were more commonly used in older age groups and analgesics among the younger. Insecticides, sodium hypochlorite and rodenticides were the most frequently used chemicals. Neurological involvement was observed in 48.2% of DSP patients compared to 16.9% in non-DSP exposures. DSP was associated with greater severity than non-DSP exposures (21% and 10% had moderate to severe toxicity, respectively, P <0.001). Severity was greater among males, aged older than 45 years, with time from exposure to consultation 8 hours or longer and with exposure to chemicals, psychiatric drugs or combinations. CONCLUSIONS: Most DSP patients were females, aged 15-20 years, used pharmaceuticals and had neurological involvement. Males, aged over 45 years, with longer time to toxicology consult and the use of chemicals were associated with increased severity. These parameters should alert the treating physician to the possibility of a poor course and hence to a more aggressive therapeutic approach.

Adolescent↗

Electrophysiology and pathology evaluation of the Yucatan pig as a non-rodent animal model for regulatory and mechanistic toxicology studies.

Six male and six female Yucatan pigs were utilized to investigate the feasibility of this species as a non-rodent model for routine regulatory and mechanistic toxicology studies. This study evaluated disease surveillance and computerized electrophysiology, along with possible gross and micropathology changes. Two pigs were used as sentinel animals to evaluate the microbiological status of the vendor upon arrival; the other pigs were maintained as biomonitors and to provide baseline clinical chemistry, urinalysis, pathology and electrophysiology data. The electrophysiology tests conducted included electrocardiography (ECG), electroretinography (ERG) and quantitative electroencephalography (qEEG), which achieved consistent baseline values with acceptable intrasubject variation. Tissue cholinesterase and histochemical staining were done to determine their suitability for testing cholinesterase compounds. Evaluation of the serum chemistry profile demonstrated increased CPK and LDH, which was likely associated with slight haemolysis or minor subclinical muscle stress during handling. There were no additional clinical chemistry changes or findings in haematology, urinalysis parameters or gross pathology. Micropathology found an absence of background lesions which would interfere with routine toxicology studies, except for a mild rhinitis. The aetiological agent was identified by electron microscopy as being consistent with inclusion body rhinitis of swine, previously unreported in miniature swine. This would most notably interfere with inhalation studies. The anatomical and physiological similarities of the Yucatan pig, along with its ability to accept the performance of electrophysiology tests allow this species to be considered as a suitable model for organ system testing in toxicology studies.

Animals↗

[An investigation of drug abuse and the utility of toxicology screening for use in emergency centers].

The results of toxicology screening of samples from 725 patients admitted to the Critical Care Medical Center (CCMC) of Nippon Medical School during a 10-month period from 1992-1993 (Group A) and a 4-month period from 1995-1996 (Group B) were discussed. We investigated the drug use of emergency patients using immunoassay. EMIT and Triage. The results were confirmed by Gas Chromatography/Mass Spectrometry (GC/MS). Blood samples were analyzed for ethanol (EtOH) by head space gas chromatography. Overall, 18% of the 725 cases tested positive for drugs, 13% for EtOH. Recently the positive rates of drugs and EtOH have been increasing. The positive rates for drugs in Group A and Group B were 15% and 23%, and EtOH were 11% and 17%, respectively. False positive cases caused by the cross-reactivity to analog were found in both EMIT and Triage. But the reliability of both methods was sufficient for clinical use. Rapid in easy toxicology screening can provide useful clinical information for patients admitted to a CCMC, especially for patients who have been injured, have sustained unknown-etiology consciousness disturbances, have CPAOA (Cardio Pulmonary Arrest on Arrival) or have committed drug abuse. We conclude that toxicology screening using immunoassay methods is suitable for use in an emergency center.

Adolescent↗

Human exposure assessment and the National Toxicology Program.

The National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP) is developing a new interagency initiative in exposure assessment. This initiative involves the NIEHS, the Centers for Disease Control and Prevention through its National Center for Environmental Health, the National Institute for Occupational Safety and Health, the EPA, and other participating institutes and agencies of the NTP. This initiative will benefit public health and priority setting in a number of ways. First, as discussed above, it will strengthen the scientific foundation for risk assessments by the development of more credible exposure/response relationships in people by improving cross-species extrapolation, the development of biologically based dose-response models, and the identification of sensitive subpopulations and for "margin of exposure" based estimates of risk. Second, it will provide the kind of information necessary for deciding which chemicals should be studied with the limited resources available for toxicological testing. For example, there are 85,000 chemicals in commerce today, and the NTP can only provide toxicological evaluations on 10-20 per year. Third, we would use the information obtained from the exposure initiative to focus our research on mixtures that are actually present in people's bodies. Fourth, we would obtain information on the kinds and amount of chemicals in children and other potentially sensitive subpopulations. Determinations of whether additional safety factors need to be applied to children must rest, in part, upon comparative exposure analyses between children and adults. Fifth, this initiative, taken together with the environmental genome initiative, will provide the science base essential for meaningful studies on gene/environment interactions, particularly for strengthening the evaluation of epidemiology studies. Sixth, efficacy of public health policies aimed at reducing human exposure to chemical agents could be evaluated in a more meaningful way if body burden data were available over time, including remediation around Superfund sites and efforts to achieve environmental justice. The exposure assessment initiative is needed to address public health needs. It is feasible because of recent advances in analytical technology and molecular biology, and it is an example of how different agencies can work together to better fulfill their respective missions.

Environmental Exposure↗

Biological markers of male reproductive toxicology.

Reproduction is a complex, stepwise series of processes that begins with gametogenesis, continues through gamete interaction, implantation, embryonic development, growth, parturition, and postnatal adaptation, and is completed with the development and sexual maturation of the newly formed organism. These reproductive processes do not take place in a chemically pristine environment, but rather in an environment increasingly contaminated with the products and by-products of the chemical age in which we live. Some environmental pollutants are known to be carcinogenic, mutagenic, or toxic to the reproductive system, but most have not been adequately tested for reproductive toxicity. Just as reproduction is complex, biological mechanisms underlying toxicology are similarly complex and involve absorption, distribution, metabolism (toxification and/or detoxification), excretion, and repair. The synthesis of these sciences into the relatively nascent science of reproductive toxicology includes teratology, pharmacology, epidemiology, and occupational and environmental health. Female reproductive function (especially pregnancy outcome) has historically been the focus of attention, but there is increasing interest in the effects of chemical exposure on male reproductive function. Several reports have documented the physiology, biochemistry, and toxicology of male mammalian reproduction, and evaluated susceptibility of the male to the effects of exogenous chemicals.

Animals↗

Pharmacokinetics and expert systems as aids for risk assessment in reproductive toxicology.

A minimal approach to risk assessment in reproductive toxicology involves four components: hazard identification, hazard characterization, exposure characterization, and risk characterization. In practice, risk assessment in reproductive toxicology has been reduced to arbitrary safety factors or mathematical models of the dose-response relationship. These approaches obscure biological differences across species rather than using this important and frequently accessible information. Two approaches that are formally capable of using biologically relevant information (pharmacokinetics and expert system shells) are explored as aids to risk assessment in reproductive toxicology.

Animals↗

Review, discussion, and summary: toxicology.

The research presented in the toxicology session of the Symposium on the Health Effects of Acid Aerosols significantly advances our understanding of the health effects of acid aerosols and clearly illustrates the importance of animal inhalation toxicology to risk assessment. The description of the effects of acid on airway mucus buffering capacity and viscosity helps explain some of the mechanisms responsible for the effects of sulfuric acid on mucociliary clearance and pulmonary function observed in man and animals. Several of the papers illustrate that other pollutants interact with sulfuric acid (H2SO4), causing concern about exposure risks and helping in elucidating the effects observed in epidemiology studies that have not yet been duplicated in a laboratory. For example, H2SO4 absorbed in zinc oxide (ZnO) particles appears to be about a log more potent than H2SO4 alone in causing pulmonary function decrements. Low levels of H2SO4 and O3 were found to be synergistic in increasing collagen synthesis, implying a risk in development of lung fibrosis. More complex mixtures containing H2SO4 cause a variety of interactions, depending upon the end points examined and the chemistry of the mixture. Other reports indicate that dose rate and length of exposure issues are critical to toxicological outcomes. Animal data on mucociliary clearance, which parallels that of human data, was extended to show that concentration of exposure was more important than time of exposure in eliciting a response, although time played a significant role. A recent chronic study showed that H2SO4 caused effects that also can occur in the development of chronic bronchitis.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid Rain↗

Inhalation toxicology of isoprene in F344 rats and B6C3F1 mice following two-week exposures.

Isoprene (2-methyl-1,3-butadiene) was selected for toxicologic evaluations because of its structural similarity to 1,3-butadiene, a potent rodent carcinogen. Two-week inhalation toxicology studies of isoprene were conducted in F344 rats and B6C3F1 mice at exposure concentrations of 0, 438, 875, 1750, 3500, or 7000 ppm. For rats, there were no chemically related changes in survival, body weight gain, clinical signs, hematologic or clinical chemistry parameters, or gross or microscopic lesions. Exposure of mice to isoprene did not produce mortalities and only caused a decrease in body weight gain for male mice in the 7000 ppm exposure group; however, hematologic changes and microscopic lesions including testicular atrophy, olfactory epithelial degeneration, and forestomach epithelial hyperplasia were observed in isoprene-exposed mice. Similar toxicologic effects have been previously observed in B6C3F1 mice exposed to 1,3-butadiene. A species difference in susceptibility between rats and mice exposed to isoprene was evident in these short-term exposure studies.

Administration, Inhalation↗

Application of DNA arrays to toxicology.

DNA array technology makes it possible to rapidly genotype individuals or quantify the expression of thousands of genes on a single filter or glass slide, and holds enormous potential in toxicologic applications. This potential led to a U.S. Environmental Protection Agency-sponsored workshop titled "Application of Microarrays to Toxicology" on 7-8 January 1999 in Research Triangle Park, North Carolina. In addition to providing state-of-the-art information on the application of DNA or gene microarrays, the workshop catalyzed the formation of several collaborations, committees, and user's groups throughout the Research Triangle Park area and beyond. Potential application of microarrays to toxicologic research and risk assessment include genome-wide expression analyses to identify gene-expression networks and toxicant-specific signatures that can be used to define mode of action, for exposure assessment, and for environmental monitoring. Arrays may also prove useful for monitoring genetic variability and its relationship to toxicant susceptibility in human populations.

Environmental Exposure↗

Occupational cancer in France: epidemiology, toxicology, prevention, and compensation.

This article is a description of the current situation in France with regard to occupational cancer: research, prevention, and occupation. Toxicologic experiments are carried out using (italic)in vitro(/italic) and (italic)in vivo(/italic) tests, particularly using transgenic mice. Several epidemiologic studies have been conducted over the last decades: population-based case-control studies; mortality studies and cancer incidence studies carried out in historical cohorts of workers employed in the industry; and case-control studies nested in occupational cohorts. French ethical aspects of toxicologic and epidemiologic studies are described. The results thus obtained are used to establish regulations for the prevention and the compensation of cancers attributable to occupational exposure. This French regulation for prevention of occupational cancer involves several partners: (italic)a(/italic)) the states authorities, including labor inspectors, responsible for preparing and implementing the labor legislation and for supervising its application, particularly in the fields of occupational health and safety and working conditions; (italic)b(/italic)) the Social Security Organisation for the analysis of present or potential occupational risks based on tests, visits in plants, complaints or requests from various sources, and statistics. These activities are performed within the framework of the general French policy for the prevention of occupational cancer. This organization includes the National Institute for Research and Safety, particularly involved in research in the various fields of occupational risks--animal toxicology, biologic monitoring, exposure measurements epidemiology, psychology, ergonomy, electronic systems and machineries, exposure to chemicals, noise, heat, vibration, and lighting; and (italic)c(/italic)) companies where the regulation defines the role of the plant manager, the occupational physician, and the Health, Safety and Working Conditions Committee (comprising the manager, employees' representatives, the occupational physician, and the safety department) in dealing with any problem regarding safety, occupational hygiene, and working conditions. These organizations along with medical practitioners are involved with the compensation of occupational cancers. The regulation for compensation includes the tables of occupational cancer, the possibility of recognition of a cancer case when the requirements of the tables are not met, and the postprofessional follow-up of workers exposed to a carcinogenic agent.

Animals↗

cDNA microarray gene expression analysis and toxicological phenotype for anticancer drug.

Toxicogenomics, the subdiscipline that merges genomics with toxicology, hold the promise to contributing toward the goal of elucidating mechanism by studying genomic profiling related with various drugs. The application of gene expression profiling technology to examine multiple genes and signaling pathways promises a significant advance in understanding the toxic mechanisms of various drugs and prediction of new drug candidate. Toxicogenomics is emerging field combining genomics and bioinformatics to identify and characterize mechanisms of toxicity of drug and various compounds. The principal hypothesis underlying on this field is that chemical-specific pattern of altered gene expression is related with each chemicals properties, especially toxicological property, and it will be revealed using high-density microarray analysis of sample from exposed organisms. So, in this study we compare the gene expression pattern of two anticancer drugs paclitaxel and orally absorbable paclitaxel, using the cDNA microarray. And from the result of this study, it is possible to provide the new possibility for genome-wide insight into mechanism of their anticancer activity and toxicological phenotype.

Administration, Oral↗

Pharmacokinetics, toxicology and safety of lamotrigine in epilepsy.

Optimisation of pharmacotherapy for epilepsy requires consideration of the impact of drug metabolism and toxicology on the therapeutic profiles and clinical use of antiepileptic drugs (AEDs). This review discusses the pharmacokinetics and toxicology of the AED lamotrigine, and considers the implications of these data for optimising its use in the management of epilepsy. Lamotrigine has good absorption, minimal plasma protein binding and linear pharmacokinetics. Partly because of these properties, frequent dosing adjustments are generally unnecessary, and therapeutic monitoring is not required under most circumstances. Lamotrigine is not associated with clinically significant neurological, cognitive, metabolic, hepatic or reproductive endocrine toxicity. Like other AEDs, including carbamazepine and phenytoin, lamotrigine has been associated with serious rash. With some exceptions, lamotrigine has relatively few clinically relevant drug interactions, a characteristic important in reducing safety risks, especially among patients who require polytherapy. The clinical impact of pharmacokinetic interactions between lamotrigine and enzyme-inducing AEDs or valproate can be minimised by adhering to recommended dose-escalation schedules with demonstrated reliability in clinical trials and clinical practice. Likewise, adhering to recommended dosing guidelines can minimise the risk of lamotrigine-associated rash. The pharmacokinetic, toxicology and safety profiles of lamotrigine make the drug suitable for use across a spectrum of patients with epilepsy.

Anticonvulsants↗

Application of DNA microarray to toxicological research.

DNA microarray technology is becoming increasingly popular in the field of toxicological research. Information on the global gene expression profile may provide clues to understanding biological actions of toxic substances at the molecular, cellular, tissue, and individual animal levels. This review focuses on the practical aspects of DNA microarray experiments and their applications to relatively small sizes of research projects in toxicology. First, different types of DNA microarrays and their characters are reviewed. Then, two fundamental concepts of DNA microarray data analysis--supervised and unsupervised methods--and their applications to toxicological research projects are discussed. Typical pitfalls of DNA microarray experiments are examined. Finally, strategies of experimental design and data analysis of minimum scale DNA microarray project are provided.

Animals↗

Traditional remedies and food supplements. A 5-year toxicological study (1991-1995).

Since 1991, the Medical Toxicology Unit (MTU) at Guys' Hospital, London, has been assessing the toxicological problems associated with the use of traditional and herbal remedies and dietary supplements. This assessment was carried out by evaluating reports to the National Poisons Information Service (London) [NPIS(L)] which provides emergency information to medical professionals. Relevant telephone enquiries to NPIS(L) were identified. Further case details were obtained by follow-up questionnaire, clinical consultation, toxicological analysis of samples from patients and/or products and botanical identification of plant material. Of 1297 symptomatic enquiries evaluated there was a possible/confirmed association in 785 cases. Case series have been identified which substantiate previous reports, including liver problems following the use of Chinese herbal medicine for skin disorders, allergic reactions to royal jelly and propolis and heavy metal poisoning caused by remedies from the Indian subcontinent. Although the overall risk to public health appears to be low, certain groups of traditional remedies have been associated with a number of potentially serious adverse effects. Considering the extent of use of herbal remedies and food supplements a comprehensive surveillance system for monitoring the adverse health effects of these products is essential. Surveillance of a large population is needed for the complex task of identifying the uncommon and unpredictable adverse effects which are potentially serious. In the UK, the Medicines Control Agency responded to the MTU report by recognising the need for vigilance and by incorporating adverse reactions reporting on unlicensed herbal remedies into their drug reaction monitoring function. As a further step to safeguard the patients/consumers an effective single regulatory system is required which would ensure the safety and quality of all herbal remedies and food supplements available in the UK.

Amino Acids↗

The toxicology of mycotoxins.

Mycotoxin problems are one of great concern to health scientists. Toxic fungal metabolites such as aflatoxins, trichothecenes, zearalenone and others are contaminated in our environments and induce various diseases. In this manuscript, the author will summarize the recent advances on toxicology of mycotoxins in special references to toxicological characters, cytotoxicity, genotoxicity (mutagenicity and carcinogenicity), metabolism, and biochemical mode of action. Interaction of mycotoxins with cellular components will be reviewed in order to clarify the toxicological characteristics of mycotoxins such as aflatoxins, trichothecenes, zearalenone, toxic peptides, and anthraquinoid mycotoxins.

Adenosine Triphosphatases↗