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Saccharin: a toxicological and historical perspective.

Saccharin, first synthesized in 1879, eventually became popular as an inexpensive substitute for sugar, particularly as a non-caloric sweetner. The dispute concerning the safety of saccharin for human consumption is almost as old as saccharin itself. In this article, the history concerning the uses of saccharin and the accompanying controversy are reviewed. In addition, the spectrum of toxicological and epidemiological studies to which saccharin has been subjected are also examined. While the toxicological data indicate that saccharin is probably the agent solely responsible for the bladder tumors observed in second generation male rats, the epidemiological studies provide, at best, an equivocal relationship between the consumption of saccharin and bladder cancer. A benefit-risk evaluation for saccharin showed few, if any documentable benefits from the use of saccharin and much genuine uncertainty concerning the potential risks for ingestion by man. This element of genuine uncertainty as to the extent of human risk posed to man is the crux of saccharin's past and its foreseeable future.

Animals↗

Inhalation exposure technology used for varying exposure modes and profiles in toxicology studies.

Current technology used in inhalation toxicology studies employs various exposure modes and concentration profiles. Inhalation exposure modes typically utilize wholebody techniques, whereas other exposure modes include nose- and head-only exposure systems and, in some cases, whole- or partial-lung exposure systems. The latter two conditions are utilized when safety considerations are warranted by the hazardous nature of the chemical or agent being tested, the test substance may be dermally adsorbed, and/or the costs of the chemical used are of concern. Inhalation exposure studies may span several minutes to 24 h of continuous exposure and from one day to the full life span of the animal being tested. Time-varying profile exposures, on the other hand, are typically used to mimic human exposures to chemical agents and, in some cases, to more accurately extrapolate animal toxicity data in assessing human risk. Automation of inhalation exposure systems has expedited the timely operation of both accurate and repeatable profiles, and it has allowed for reexamination of classical time-weighted average concentration information relating to human health concerns. The toxicological assessment of potential health effects resulting from exposure to airborne substances typically involves thorough characterizing of the test agent via acute, subchronic, and chronic toxicity testing.

Administration, Inhalation↗

National Association of Medical Examiner's Pediatric Toxicology (PedTox) Registry.

In 1985, the National Association of Medical Examiners (St. Louis, MO) established a Pediatric Toxicology (PedTox) Registry to collect case reports of drugs and substances detected in children. For many drugs and substances detected in children, to date, the medical and toxicology literature contain little useful information regarding toxic and lethal concentrations, and the PedTox Registry was established to provide additional information to those who must interpret observed concentrations of drugs and substances in children. This article includes a description of the development of the PedTox Registry, its management, and a brief summary of data that have been published, including information for acetaminophen, benzene, carboxyhemoglobin, codeine, desipramine, dextromethorphan, ethanol, phenobarbital, phenylpropanolamine, and pseudoephedrine.

Adolescent↗

Quantitative perspectives on behavioral toxicology.

Behavioral endpoints offer special challenges to toxicology. One arises from the sometimes conflicting ways in which adverse effects may be expressed. For example, both increases and decreases in response rates of schedule-controlled performance may be produced by a specific agent, depending on the specific schedule. Interpretations of such an outcome depend upon a close analysis of the experimental circumstances and the behavioral findings. Another arises from the many disparate variables that can influence a particular outcome. Accurate measures of sensory thresholds, for instance, depend upon precise means for delivering stimuli and upon appropriate psychophysical procedures. Such examples emphasize that quantification in behavioral toxicology is more than a matter of attaching numbers to some arbitrarily selected measure. Instead, meaningful quantification first requires that the investigator understand in principle the sources of the measures to which the numbers are being attached. This is especially critical when the measures are being used not for the relatively straightforward purpose of hazard identification, but for the more subtle aim of risk assessment and dose-response (effect) extrapolation. For these aims, behavioral microanalyses, based on the coordination of multiple measures in individual subjects, usually provide the most robust guides.

Animals↗

In vitro models for toxicological research and testing.

The objective of this report is to discuss some of the issues involved in utilizing in vitro methods in toxicological research and testing. The subject is not new, in vitro methods have been used for many years in this context. However, there has been a significant increase in interest in the topic within the scientific community recently as witnessed by the increase in scientific journals dedicated to the topic, symposia held by scientific societies, and commitment of resources to in vitro toxicological research activities. Toxicologists should be aware of these developments as the future directions of the science will be influenced significantly by in vitro methodology.

Animals↗

Isocratic reversed-phase liquid chromatography of all-trans-retinoic acid and its major metabolites in new potential supplementary test systems for developmental toxicology.

An isocratic reversed-phase high-performance liquid chromatographic procedure for the determination of all-trans-retinoic acid (all-trans-RA) and its metabolites, all-trans-4-oxo-RA, 5,6-epoxy-RA, 9-cis-RA and 13-cis-RA, in mouse plasma and embryo and in new in vitro potential test systems for developmental toxicology has been developed. These compounds, their biological precursor retinol (vitamin A) and the internal standard were resolved on a Spherisorb ODS-2 (5 microns) column (250 x 4.6 mm I.D.) with acetonitrile-water-methanol-n-butyl alcohol (56:37:4:3, v/v) containing 100 mM ammonium acetate and 70 mM acetic acid as the elution system, with a total run time of 23 min. The assay was linear over a wide range, with a lower limit of quantitation of 50 ng/ml or 10 ng/mg of protein for all-trans-RA, 13-cis-RA and 9-cis-RA and of 25 ng/ml or 5 ng/mg protein for the 4-oxo- and 5,6-epoxy-metabolites. At these concentrations, intra-assay coefficients of variation (C.V.) of the retinoids were 3-9%. Mean intra-assay C.V. averaged 5-7% in the tissues studied. Its use is discussed for RA measurements in some of the new test systems--Drosophila melanogaster, sea urchin embryos and cultured human keratinocytes--that have to be evaluated in toxicological testing, supplementary to standard assays in mammals.

Animals↗

Computer storage of toxicology methods and postmortem drug determinations.

Two data bases have been developed by toxicologists from the Department of Scientific and Industrial Research in New Zealand. The data bases are designed to store and retrieve postmortem drug and poison levels (TOXFILE) and methods used in drug and poison determinations (TOXMETH). TOXFILE contains a list of all the analytical results determined in toxicological cases received by the three laboratories. This method of storing the data has been found superior to the previously used card systems. The file also contains a reference to the analytical method which is very important for the interpretation of the results. TOXMETH contains a list of the analytical methods which have been developed and are in use in one or more of the three Chemistry Division toxicology laboratories. Methods can be added, modified and superseded as approaches change. A Chemistry Division Report (Pannell, L.K. et al., Chemistry Division Report No. CD: 2195, 1983) has been published containing all the programs and instructions. Copies of this are available from the authors on request. Computer magnetic tapes of the programs, the report and the data are also available. The names of the deceased on the TOXFILE data file are encrypted to provide increased security of the information. The TOXFILE data file which will be supplied on magnetic tape to overseas laboratories will have the name file on all records changed to 'CD' to provide complete confidentiality.

Autopsy↗

Toxicology case data reporting system.

A computerized system has been organized to serve the toxicology sections of seven R.C.M.P. laboratories across Canada. Scientists may view and retrieve information concerning drugs and drug combinations, blood and liver drug concentrations, etc. from cases of sudden death or impaired driving which were analyzed in the laboratories. This has proven to be a great help in interpreting toxicology case results for the investigator or the courts and also in choosing methodology to be used in analyzing specimens for unusual drugs or poisons.

Canada↗

Wide-bore capillary column gas chromatography in toxicological analysis of biological samples from multidrug overdoses fatalities.

Fatalities from multidrug overdoses account for 25% of the total number of all poisoning fatalities and as such deserve greater attention from researchers than single drug overdoses. High resolution, good sensitivity, and repeatability provided by gas chromatography (GC) with wide-bore capillary silica and glass columns make GC particularly useful for identification and quantitative analysis of drugs in toxicological screening of autopsy specimens. Results of toxicological findings in three deaths from multidrug overdoses (methaqualone, doxepine, methotrimeprazine, pernazine-aspirin, paracetamol, codeine-morphine, diazepam) occurring in routine medical practice are reported.

Adult↗

Toxicological findings in military aircraft fatalities from 1986-1990.

Toxicological findings in all military aircraft fatalities investigated by the Division of Forensic Toxicology at the Armed Forces Institute of Pathology from 1986-1990 are presented. Carbon monoxide saturation levels greater than 10% were found in 4% of the 535 cases where appropriate specimens were collected. Positive ethanol findings were more indicative of postmortem formation than antemortem consumption. In only 1 case were abused drugs (cannabinoids in a passenger) detected. Other drugs identified included nicotine, chloroquine and over-the-counter analgesic agents, antihistamines and sympathomimetic drugs.

Accidents, Aviation↗

Toxicological index of paraquat: a new strategy for assessment of severity of paraquat poisoning in 128 patients.

A new assessment of the severity of paraquat poisoning in 128 patients has been developed. It involves toxicological index of paraquat and discriminant function score. This system not only allows a more accurate assessment of severity of the poisoning, but also provides a more reliable prediction of the outcome in an early stage for the purpose of forensic and clinical toxicology.

Discriminant Analysis↗

Application of radioreceptor assays for systematic toxicological analysis--1. Procedures for radioreceptor assays for antihistaminics, anticholinergics and benzodiazepines.

Radioreceptor assays can be a useful tool for systematic toxicological analysis in that they can be applied for the detection of an entire pharmacological class of drugs. In the present paper procedures for radioreceptor assays for benzodiazepines, anticholinergics and antihistaminics have been described in detail. The development of the assay for antihistaminics in urine is given in order to illustrate the prerequisites for these types of assays with regard to the incubation conditions. In part 2 the applicability of the three assays for systematic toxicological analysis will be evaluated on the basis of testing a large number of urine samples after administration of a selected number of drugs to healthy volunteers and patients.

Animals↗

From comparative physiology to toxicological risk assessment.

1. Comparative physiology may help to improve the toxicologists' ability to assess and predict toxicological risks of chemicals. 2. Three main lines of approach have been distinguished, A: comparative research concerning the toxicokinetics of chemicals in different species; B: research concerning ecophysiological characteristics and C: studies aimed at the identification of biological markers that can be used to signal toxic effects in both experimental and free living populations of organisms. 3. Some remarks are made on limiting conditions to be fulfilled in order to make comparative physiology valuable from a toxicological point of view.

Animals↗

The National Toxicology Program chemical nomination selection and testing process.

The NTP is an interagency program of the Federal Government which coordinates toxicological programs at the NIH (NIEHS), FDA (NCTR), and CDC (NIOSH) with input from NCI, NIH, OSHA, CPSC, EPA, and ATSDR. The NTP has the capability to completely characterize the toxicologic profile of a chemical, including studies of chemical disposition, genetic toxicity, immunotoxicity, teratology, reproductive toxicity, carcinogenicity, neurotoxicity, and specific organ toxicity. The NTP encourages nominations of chemicals of human health concern from all sectors of the public, including industry, labor, and the general public. The specific process of nomination, evaluation, and selection of chemicals for testing by the NTP is described. It is a multicomponent system with several evaluations and a public peer review step to assure adequate consideration of all nominated chemicals. The results of NTP studies are all peer reviewed and available to the general public as well as to the scientific community.

Animals↗

In vitro approaches in developmental toxicology.

While the usefulness of in vitro screens in developmental toxicology seemed obvious a decade or more ago, integration of in vitro or short-term screens for developmental toxicity into the toxicology armamentarium of tests has been very slow. The large number and complexity of critical events in normal development in vivo limit the usefulness of in vitro systems that measure a very narrow range of developmental events, even though such systems are very useful for mechanistic research. Better understanding of the regulatory mechanisms involved in normal development that is evolving from molecular and developmental biology laboratories should help to identify critical events and processes in development that could serve as functional screens for abnormal development in the future.

Abnormalities, Drug-Induced↗

Repeated measures designs in behavioral toxicology: application to chronic marijuana smoke exposure.

This paper discusses the application of repeated measures methods in the statistical analysis of an experiment in behavioral toxicology. The chronic marijuana smoke exposure study conducted at the National Center for Toxicological Research is used for an example of the types of problems that one encounters in analyzing these types of studies. In particular, the standard univariate analysis most frequently used for repeated measures analyses has some very restrictive assumptions on the form of the covariance matrices. These assumptions are not met in the example discussed and are rarely met in many other problems. Other possible models for analyzing repeated measures when these assumptions are not met are presented and discussed. Other problems specific to the chronic marijuana smoke exposure study that may occur in similar type studies are presented. These include pooling the experimental units into groups with comparable baselines, choosing a function of the measures to be analyzed, dealing with a large data set with many observation times and missing data, unequal group sizes and different designs for different subsets of the experimental animals. The standard univariate repeated measures analysis was chosen to analyze the data even though the violations of the covariance assumptions may lead to finding differences that do not exist (Type I or false-positive errors), since the other methods presented also had covariance assumptions that were not met or had low power. Use of Bonferroni-type multiple comparisons on the single degree of freedom contrasts of interest hopefully reduced the chances of these false-positive results.

Analysis of Variance↗

The fathead minnow in aquatic toxicology: past, present and future.

This paper reviews the roles of the fathead minnow (Pimephales promelas) as a small fish model in the field of aquatic toxicology. The species has been (and is) extensively used both for regulatory testing and research, especially in North America. For example, tests with the fathead minnow, ranging from 48-h lethality through partial and full life-cycle assays, are routinely used for regulatory programs aimed at assessing potential risks of new chemicals such as high-production volume materials and pesticides, as well as impacts of complex mixtures like effluents. The species also has been used for a wide variety of research applications focused on topics like the development of quantitative structure-activity relationship models, mixture toxicity, extrapolation of the effects of chemicals across species, and understanding the results of laboratory assays relative to impacts in the field. Attributes of the fathead minnow also make it an excellent model for addressing new challenges in aquatic toxicology, including identification of sensitive life-stages/endpoints for chemicals with differing modes/mechanisms of action, predicting population-level effects based on data collected from lower levels of biological organization, and exploring/understanding the emerging role of genomics in research and regulation.

Animals↗

Harmonization of immunotoxicity guidelines in the ICH process--pathology considerations from the guideline Committee of the European Society of Toxicological Pathology (ESTP) .

As part of the ICH process of harmonization of testing guidelines for immunotoxicity, the European Society of Toxicologic Pathology (ESTP) has contributed to the scientific discussion on methods and evaluation of immunotoxicity studies with technical and scientific recommendations on toxicologic pathology. The weighing and sampling of immune organs is discussed taking into consideration specifically the value of lymph node weighing and the selection of appropriate lymph nodes for the detection of local and systemic effects. The different techniques of bone marrow preparation are considered for routine and extended investigations. Criteria are given for the gross and histopathological detection of effects in Peyer's patches. For the histopathological evaluation it is strongly recommended that each compartment within the different lymphoid organs is investigated separately and semiquantitatively since this approach has shown to increase the sensitivity and specificity of immunohistopathology.

Animals↗