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PubMed1991

Review of lead toxicology relevant to the safety assessment of lead acetate as a hair colouring.

The literature on lead toxicology has been critically reviewed to provide a safety assessment of lead acetate as a hair colouring. The main objectives were: (i) to determine the additional lead contribution from hair-colouring use to the total daily environmental lead intake; and (ii) to assess the toxicological significance of this additional contribution. The review also focuses attention on newer issues of concern over the effects of environmental lead on human health. Data available in animals and humans (including occupational exposure), mainly on lead acetate and other inorganic lead salts, have been presented and evaluated in respect of the following: absorption, distribution and excretion following ingestion; percutaneous absorption; carcinogenicity; genotoxicity; reproductive toxicity; neurological/behavioural status with particular reference to neuropsychological effects in children; and effects on other systems (e.g. cardiovascular). It is concluded that the absorption of lead from hair-colouring use represents about 0.5% of the lead absorption from the current average daily environmental lead intake. No convincing evidence could be found of any deleterious effect of current environmental lead levels on human health and thus the tiny contribution of lead acetate exposure from hair-colouring use can be regarded unequivocally as being toxicologically insignificant.

Animals↗
PubMed1993

Caveats regarding the use of the laboratory rat as a model for acute toxicological studies: modulation of the toxic response via physiological and behavioral mechanisms.

The rodent, specifically the laboratory rat, is the primary experimental animal used in toxicology testing. Despite its popularity, recent studies from our laboratory and others raise a number of questions concerning the rat's appropriateness as an animal model for toxicological studies. While there may be additional areas in which the rat and other small rodents fail to adequately mimic the human response to xenobiotic agents, this article will focus on the area of temperature regulation. Thus, this article will review the thermoregulatory response of the laboratory rat following acute exposure to toxic agents and examine the impact of this response on the extrapolation of toxicological data from experimental animals to humans. In general, the rat responds to acute intoxication by lowering its core temperature via both physiological and behavioral mechanisms, thereby attenuating the induced toxicity. Similar responses have not been reported in humans.

3,4-Methylenedioxyamphetamine↗
PubMed1995

Toxicological consequences of multiple chemical interactions: a primer.

The capacity to understand and successfully predict the toxicological consequences of multiple chemical interactions is a critical challenge facing the scientific community. This article is designed to provide a broad framework introducing the concept of interaction, use of consistent and meaningful terminology and a descriptive assessment of toxicological foundations within which chemical interactions may be evaluated. The article offers guidance on the need to place a high priority on assessing the mechanistic basis of 'superinteractions', that is, unique interactions far exceeding even those of a multiplicative nature. The final section of the article provides a detailed perspective on how the extensive and successful experience of the pharmaceutical industry in assessing and interpreting any interaction for patients can be useful to the issues and concerns of chemical interactions for the field of environmental toxicology and risk assessment.

Animals↗
PubMed1988

Urine toxicology as a predictor of continuation in outpatient alcoholism treatment.

Urine for toxicology was obtained from 93% of 62 alcoholics (60 males, 2 females) applying for alcoholism treatment. Fourteen urines were positive, with cocaine (35%) and minor tranquilizers (35%) being most common. History of drug use did not correlate with toxicology results nor was there an association with simultaneously obtained alcohol levels. Treatment outcome was analyzed retrospectively at 4 months. Subjects were more likely to remain in outpatient therapy if the screening urine toxicology was negative.

Adult↗
PubMed1995

Quantitative structure-activity relationships and ecological risk assessment: an overview of predictive aquatic toxicology research.

In the field of aquatic toxicology, quantitative structure-activity relationships (QSARs) have developed as scientifically credible tools for predicting the toxicity of chemicals when little or no empirical data are available. A fundamental understanding of toxicological principles has been considered an important component to the acceptance and application of QSAR approaches as biologically relevant in ecological risk assessments. As a consequence, there has been an evolution of QSAR development and application from that of a chemical-class perspective to one that is more consistent with assumptions regarding modes of toxic action. In this review, techniques to assess modes of toxic action from chemical structure are discussed, with consideration that toxicodynamic knowledge bases must be clearly defined with regard to exposure regimes, biological models/endpoints and compounds that adequately span the diversity of chemicals anticipated for future applications. With such knowledge bases, classification systems, including rule-based expert systems, have been established for use in predictive aquatic toxicology applications. The establishment of QSAR techniques that are based on an understanding of toxic mechanisms is needed to provide a link to physiologically based toxicokinetic and toxicodynamic models, which can provide the means to extrapolate adverse effects across species and exposure regimes.

Animals↗
PubMedDate not supplied

Toxicological findings in deaths due to ingestion of pentazocine: a report of two cases.

Two cases of fatal suicidal ingestion of pentazocine are presented. Toxicological findings in these deaths are compared to those of twelve similar pentazocine fatalities gleaned from various compilation of toxicology data. Pentazocine blood and liver concentrations in the presented cases were 3.3 and 9.2 mg/l, and 34 and 43 mg/kg, respectively. Blood and liver concentrations in references cases ranged from 0.8 - 38 mg/l and 3 - 197 mg/kg, respectively. The interpretation of toxicology findings following the ingestion of pentazocine is discussed.

Adult↗
PubMed1983

Chromatography in analytical toxicology--state of the art and future perspectives.

The aims of systematic toxicological analysis are considered with respect to the principal techniques available for quantitative and qualitative purposes. The use of thin-layer (TLC), gas-liquid (GLC), capillary GLC and high-performance liquid chromatography (HPLC) is discussed, with special reference to the need for standardized systems for toxicological analysis. The selectivity of correlations presented as mean list length values, derived from archives of Kováts retention indices in GLC and of Rf-values in up to eight TLC systems, is illustrated by some typical examples. The dependence of Kováts retention indices on column packing materials and on load capacity in CGLC is discussed and the particular difficulties of comparable standard systems in HPLC are considered. Conclusions are drawn concerning the established 'workhorse' techniques, such as TLC and GLC. The need to adapt and standardize other powerful analytical methods, such as HPLC, MS and GLC-MS, is examined with regard to the requirements of toxicological analysis.

Journal Article↗
PubMed1985

Comprehensive toxicology screening in the emergency department: an aid to clinical diagnosis.

An audit of 2,641 toxicology requests from the Georgetown University Hospital Emergency Department from 1981 through 1984 was conducted to assess the contribution of toxicology laboratory results to the clinical evaluation of the intoxicated patient. Positive findings were obtained in 80% of the patients tested. Ethanol was the most common intoxicant, accounting for 48% of all positive results and an average serum concentration of 250 mg/dl. Multiple drug use was documented in 28% of the patients with positive results; some ingested as many as six substances. Women were more likely than men to be polydrug users. A comparison of laboratory findings with diagnosis based on history and examination for 76 patients revealed that the laboratory provided additional information on the nature of the intoxication two-thirds of the time. Our conclusion is that the toxicology laboratory offering a broadly based screening service when properly utilized by the emergency department staff can aid in establishing an accurate diagnosis and provide a guide to therapy in the intoxicated patient.

Adult↗
PubMedDate not supplied

The use of traditional toxicologic data in assessing neurobehavioral dysfunction.

In the United States, the regulation and testing of chemicals that may impact on human health is mandated by a number of different laws and regulated by several government agencies. Toxicologic screening in laboratory animals has created a major database for predicting adverse health effects of drugs, food and cosmetic ingredients, and manufactured chemicals. Test protocols and reporting requirements frequently differ between government agencies within the United States and between nations. Until recently, the emphasis for this required testing has been to identify those chemicals that may result in cancer or birth defects with little or no emphasis placed on neurobehavioral testing. The so-called "traditional toxicologic screen" presently includes acute, subchronic, chronic, teratology, and reproductive multispecies testing. The report for each segment of the test screen contains a myriad of data elements that have been observed by numerous technicians in the testing laboratory. These laboratory tests vary from general animal observations of animal body weight and food consumption to tests for hematology, blood chemistry, urinalysis, and histopathology. In addition, specialized tests may include other physiological measurements, neurologic tests, eye exams as well as functional testing to evaluate performance (e.g., open field, swimming maze, and T-maze). Reliability, quality control, and the difficulty in converting technician observation into quantifiable data elements that are free from bias is a primary concern for all testing laboratories. This paper focuses on the neurotoxicologic and behavioral information that can be gleaned from traditional toxicologic screens, the collection of study data, the effect of model selection, and the environmental considerations that may affect study outcome. The paper includes examples of compounds previously reported in the literature.

Animals↗
PubMed2004

Multi-species toxicology approaches for oncology drugs: the US perspective.

The Toxicology and Pharmacology Branch (T&PB) of the National Cancer Institute (NCI) performs pharmacological and toxicological evaluations of new oncology agents according to an agent-directed paradigm in which all studies are tailored to each agent. The United States Food and Drug Administration (US FDA) requires that preclinical toxicology studies be conducted in two species, a rodent and a non-rodent for all small molecules, and T&PB has successfully used this formula. While pharmacokinetic (PK) studies are considered optional, T&PB routinely develops new methods for plasma/tissue drug analysis and employs this methodology throughout development to determine kinetics in various species and toxicokinetics in the toxicity studies. In the current era of molecular target-based development, the T&PB also develops or employs methodology to evaluate effects of the new chemical entity on appropriate biomarkers in tumour and normal tissues. In this comprehensive programme, T&PB is able to correlate safety and toxicity with both plasma drug levels and biomarker modulation in two species for a seamless entry into Phase I.

Animals↗
PubMed2004

The Cancer Research UK experience of pre-clinical toxicology studies to support early clinical trials with novel cancer therapies.

Pre-clinical toxicology studies in rodents and Phase I clinical trial data are summarised for 14 novel anticancer therapies. With only one exception, an antifolate antimetabolite, rodent toxicology predicted a safe Phase I trial starting dose and the majority of the dose limiting toxicities, in particular haematological toxicity. For targeted agents with well-defined pharmacodynamic markers, illustrated in the current study by 3 anti-endocrine drugs and one resistance modifier, the definition of a maximum tolerated dose can be avoided. Together with earlier data, the current study confirms that pre-clinical toxicology studies in a non-rodent species are not routinely needed for the safe conduct of early clinical trials with new cancer chemotherapies.

Animals↗
PubMed2004

Automatic screening in postmortem toxicology.

The systematic analysis of postmortem samples is one of the most challenging tasks in forensic toxicology. For determining cause of death, analysis of different tissues can be indispensable. Automation of these analyses would increase reproducibility and therefore lead to more reliable and comparable results. Recent developments in analytical toxicology and the availability of automation devices for various analytical stages, such as sampling, preliminary testing, sample extraction, chromatographic separation, identification, and data processing are examined and discussed. At present only parts of the analytical procedure have been automated-however, the goal should be the integration of these parts into a single, continuous process. Currently, only one "fully-automated" procedure for the comprehensive screening of blood and urine (excluding sample pretreatment, which remains separate) has been published. But it can be expected that automation of analytical procedures in forensic toxicology will indeed progress, even with regard to the very complex screening of postmortem samples.

Chromatography, Liquid↗
PubMed2004

Acute and chronic toxicological studies of Ajuga iva in experimental animals.

Ajuga iva (L.) Schreber (AI), is widely used in the Moroccan pharmacopoeia as a panacea (cure-all), and specifically for gastrointestinal disorders and diabetes, and as an anthelmintic. No toxicological investigations have been carried out on this plant. We have previously observed that single oral doses (2-14 g/kg) of a lyophilised aqueous extract of AI (AI-extract) in mice or daily oral administration of 10 mg/kg of AI-extract in rats for 2 weeks did not result in any adverse effects. We have now evaluated AI-extract for its behavioural and pharmaco-toxicological effects after acute and chronic administration by the oral and intraperitoneal routes in rats and mice. No toxicity was observed in mice after single oral doses of as high as 14 g/kg of the AI-extract. However, single intraperitoneal injections of the AI-extract (1500-5500 mg/kg BW) produced a dose-dependent increase in adverse effects in the general behaviour and the mortality rate; the LD50 of acute intraperitoneal dose was 3.6 g/kg. In chronic toxicological studies in rats, the AI-extract (administered orally at daily doses of 100, 300 and 600 mg/kg for 3 months), did not cause any changes in haematological and biochemical parameters, with the exception of a transient rise in platelet counts and a short-term decrease in serum glucose levels. Histopathological examination of the brain, liver and the kidneys at the end of the study (3 months) showed normal architecture suggesting no morphological disturbances.

Administration, Oral↗
PubMed2006

Toxicological assessment of ambient and traffic-related particulate matter: a review of recent studies.

Particulate air pollution (PM) is an important environmental health risk factor for many different diseases. This is indicated by numerous epidemiological studies on associations between PM exposure and occurrence of acute respiratory infections, lung cancer and chronic respiratory and cardiovascular diseases. The biological mechanisms behind these associations are not fully understood, but the results of in vitro toxicological research have shown that PM induces several types of adverse cellular effects, including cytotoxicity, mutagenicity, DNA damage and stimulation of proinflammatory cytokine production. Because traffic is an important source of PM emission, it seems obvious that traffic intensity has an important impact on both quantitative and qualitative aspects of ambient PM, including its chemical, physical and toxicological characteristics. In this review, the results are summarized of the most recent studies investigating physical and chemical characteristics of ambient and traffic-related PM in relation to its toxicological activity. This evaluation shows that, in general, the smaller PM size fractions (<PM(10)) have the highest toxicity, contain higher concentrations of extractable organic matter (comprising a wide spectrum of chemical substances), and possess a relatively high radical-generating capacity. Also, associations between chemical characteristics and PM toxicity tend to be stronger for the smaller PM size fractions. Most importantly, traffic intensity does not always explain local differences in PM toxicity, and these differences are not necessarily related to PM mass concentrations. This implies that PM regulatory strategies should take PM-size fractions smaller than PM(10) into account. Therefore, future research should aim at establishing the relationship between toxicity of these smaller fractions in relation to their specific sources.

Air Pollutants↗
PubMed2007

Experimental and mathematical modeling methods for the investigation of toxicological interactions.

While procedures have been developed and used for many years to assess risk and determine acceptable exposure levels to individual chemicals, most cases of environmental contamination can result in concurrent or sequential exposure to more than one chemical. Toxicological predictions of such combinations must be based on an understanding of the mechanisms of action and interaction of the components of the mixtures. Statistical and experimental methods test the existence of toxicological interactions in a mixture. However, these methods are limited to experimental data ranges for which they are derived, in addition to limitations caused by response differences from experimental animals to humans. Empirical methods such as isobolograms, median-effect principle and response surface methodology (RSM) are based on statistical experimental design and regression of data. For that reason, the predicted response surfaces can be used for extrapolation across dose regions where interaction mechanisms are not anticipated to change. In general, using these methods for predictions can be problematic without including biologically based mechanistic descriptions that can account for dose and species differences. Mechanistically based models, such as physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models, include explicit descriptions of interaction mechanisms which are related to target tissues levels. These models include dose-dependent mechanistic hypotheses of toxicological interactions which can be tested by model-directed experimental design and used to identify dose regions where interactions are not significant.

Animals↗
PubMed2004

Metabolic viability and pharmaco-toxicological reactivity of cryopreserved human precision-cut renal cortical slices.

We have tested the suitability of cryopreserved human precision-cut renal cortical slices for metabolic and pharmaco-toxicological studies. The viability of these slices and their pharmaco-toxicological reactivity were assessed using intracellular ATP and protein contents, lactate dehydrogenase (LDH) leakage, lactate and glutamine metabolism and the ammoniagenic effect of valproate. Despite a decrease in ATP and protein contents when compared with those of fresh slices, cryopreserved slices did not show any LDH leakage and retained the capacity to metabolize glutamine and lactate. Glutamine removal and ammonia, lactate and alanine production were similar in fresh and cryopreserved slices; by contrast, cryopreserved slices accumulated more glutamate as a result of decreased flux through glutamate dehydrogenase which catalyses an oxygen-dependent reaction. Valproate markedly and similarly stimulated glutamine metabolism in fresh and cryopreserved slices. Cryopreservation did not alter lactate removal but inhibited lactate gluconeogenesis. In conclusion, these results demonstrate that, although their mitochondrial oxidative metabolism seems to be diminished, cryopreserved human precision-cut renal cortical slices remain metabolically viable and retain the capacity to respond to the ammoniagenic effect of valproate. Thus, this experimental model may be helpful to optimize the use of human renal tissue for metabolic and pharmaco-toxicological studies.

Adenosine Triphosphate↗
PubMed1989

Animal safety and toxicology of simvastatin and related hydroxy-methylglutaryl-coenzyme A reductase inhibitors.

Simvastatin, a hydroxy-methylglutaryl-coenzyme A reductase inhibitor intended for use as a hypocholesterolemic agent, has undergone a thorough preclinical toxicology evaluation. This review describes preclinical toxicology findings associated with simvastatin administration in animals and provides the rationale for our conclusion that these changes are not indicative of potential human toxicity. Although it was not surprising to find that a potent inhibitor of this key biochemical pathway produces toxicity at high dosages in animals, none of the observed changes poses a significant risk to humans at clinical dosages. Many of the toxicities produced by high dosage levels of simvastatin in animals are directly related to the drug's biochemical mechanism of action and are the result of a profound, sustained inhibition of the target enzyme that is not anticipated at clinical dosages. Furthermore, several of the simvastatin-induced changes are species-specific responses to this agent and are not relevant to human risk assessment. Of the treatment-related changes reported for simvastatin, the development of cataracts in dogs has received considerable attention. The available data demonstrate a wide margin of safety in terms of dosage levels required to elicit this response as well as the plasma concentrations associated with the development of these ocular lesions. The data suggest that the development of lenticular opacities at clinical doses of simvastatin is highly improbable. Overall, simvastatin is highly improbable. Overall, simvastatin was well-tolerated by animals in preclinical toxicology studies, and no findings contraindicating its use in humans were identified.

Animals↗
PubMed1997

Arsenic and antimony: comparative approach on mechanistic toxicology.

A chemico-toxicological similarity between arsenic and antimony exists and their toxicology is often seen. Indeed, both elements possess several common properties, e.g. they are clastogenic but not mutagenic in the trivalent state and they have a carcinogenic potential: trivalent arsenicals are known to be human carcinogens and antimony(III) oxide (by inhalation) has been shown to cause lung cancer in female rats. For years, arsenic has been known to be environmentally toxic. Elevated human exposure to this element, mostly caused by the intake of contaminated tap water, is associated with increased incidences of cancer at various sites. It is still not clear how arsenic compounds exert their genotoxic effect. It may be connected with an inhibition of DNA repair or the induction of oxidative stress. Little work has been done on the toxicology of antimony as it is less widely present in the environment. There is evidence that in mammals antimony, unlike arsenic, is not detoxified via methylation but it still remains unclear what mechanism is responsible for antimony's genotoxicity. In general, there is little information known about this element to accurately determine its impact on human health. Thus, the aim of this paper is to review current knowledge for future risk assessment and further scientific work.

Animals↗