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PubMed1990

Setting human-health-based groundwater protection standards when toxicological data are inadequate.

Toxicological data are not adequate to assess fully the health effects of many of the pesticides that currently contaminate or have the potential to contaminate groundwater. The National Academy of Sciences estimated in 1984 that data to conduct a complete health hazard assessment exist for only 10% of the pesticides currently on the market. Many pesticides have not been tested for their ability to cause cancer, genetic mutation, or birth defects. There are significant gaps in the toxicological data base for the majority of pesticides for which the Environmental Protection Agency proposed health advisories in 1987. To help assure that groundwater standards are adequately protective of human health when toxicological data are not adequate, additional uncertainty factors can be incorporated into such standards. Alternatively, standards can be set at the level of detection. This should be the approach when no data exist to assess major potential health effects. For example, the detection limit could be the standard if no adequate oncogenicity studies have been conducted. In addition, generic standards may be employed when data are inadequate to set chemical-specific standards. New York State has recently taken this innovative generic standard approach.

Databases, Factual↗

PubMed1990

[Progress report. What can one expect from a "functional prenatal toxicology?"].

In the strategy of investigation applied and demanded in prenatal toxicology partial aspects have been overstressed until now, although here as well as in postnatal toxicology the problems should be viewed in its complexity (in this case, F1-generation in its several pre- and postnatal stages of development). Therefore, there was the urgent need to summarize the existing methods of functional investigation in the field of prenatal toxicology and to compare them with conventional morphological methods as to their meaningfulness and sensitivity. As a result, the routine introduction of clinical-functional investigations is demanded.

Abnormalities, Drug-Induced↗

PubMed1994

Toxicology and seafood toxins: domoic acid.

Marine and terrestrial food sources are susceptible to contamination by various industrial chemicals and microbial pathogens. Both types of hazard are amenable to regulatory assessment using a single toxicology data base, along with some knowledge of contaminant levels and consumption figures for food. On the other hand, regulatory problems persist with acutely toxic naturally occurring phycotoxins, which may accumulate unpredictably to toxic levels in seafood. However, a scarce supply of pure toxin often precludes the availability of acceptable toxicology studies describing their biological effects. An exception to this situation is domoic acid, a neurotoxin phycotoxin that produced numerous cases of severe human intoxication which demanded extensive toxicological study. This paper describes a series of ongoing studies initiated in the wake of the outbreak of domoic acid toxicity that occurred in 1987 in Eastern Canada.

Animals↗

PubMed1998

The evaluation and hazard classification of toxicological information for workplace hazardous materials information system material safety data sheets

Hazardous materials used occupationally in Canada are subject to the legislated requirements of the Workplace Hazardous Materials Information System (WHMIS). This paper describes the administrative framework of WHMIS and how toxicological data are evaluated to determine if a substance triggers WHMIS classification for the toxicological endpoints of acute toxicity, skin irritation, eye irritation, corrosion, dermal sensitization, respiratory sensitization, chronic toxicity, mutagenicity, teratogenicity/embryotoxicity, and carcinogenicity. Problems encountered with the information on material safety data sheets are also discussed for each of the toxicological endpoints. Copyright 1998 Academic Press.

Journal Article↗

PubMed1980

Fatal case of propoxyphene overdose. Morphological and toxicological findings.

The pathomorphological and toxicological findings of a case of fatal overdose of propoxyphene are reported. The chemico-toxicological findings revealed the presence of only one active substance that has been administered (in an amount of not less than 1.5 g dextropropoxyphene) in form of an analgesic tablet preparation (marketed under the trade name Dolo-Neurotrat), in which it represents the main active constituent. The most striking histological findings are the changes in the myocardium which are consistent with cardiotoxicity. It is suggested that an estimation of shock duration by means of pathomorphological findings in combination with toxicological and other data be utilised for survival time determination.

Adult↗

PubMed1998

Comparative toxicology of borates.

Inorganic borates, including boric acid, Na, ammonium, K, and Zn borates generally display low acute toxicity orally, dermally, and by inhalation. They are either not irritant or mild skin and eye irritants. Exceptions owing to physiochemical properties do occur. Longer-term toxicological studies have been reported mainly on boric acid or borax where the properties are generally similar on an equivalent boron (B) basis. The critical effects in several species are male reproductive toxicity and developmental toxicity. The doses that cause these effects are far higher than any levels to which the human population could be exposed. Humans would need to consume daily some 3.3 g of boric acid (or 5.0 g borax) to ingest the same dose level as the lowest animal NOAEL. No effects on fertility were seen in a population of workers exposed to borates or to a population exposed to high environmental borate levels. There is remarkable similarity in the toxicological effects of boric acid and borax across different species. Other inorganic borates that simply dissociate to boric acid are expected to display similar toxicity, whereas those that do not dissociate simply to boric acid may display a different toxicological profile.

Animals↗

PubMed1991

A long-term toxicological investigation on the effect of tris(maltolate)aluminum(III) in rabbits.

The toxicity of i.v. injected hydrophilic aluminum complex tris(maltolate)aluminum(III) was studied in New Zealand white rabbits for a period of time ranging from 5 to 63 wk. Animals were injected 3-5 times a week with 1 mL of 7.5 mM Al(malt)3 and one rabbit with a dose 10 times higher after 14 wk of treatment. Autopical examination was performed on all animals. Chemoclinical analysis (glucose, urea, creatinine, cholesterol, bilirubin, alanin aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl-transferase, LDH, CK, total protein, triglycerides, and Ca2+) gave no variation in treated animals with respect to the control. The toxicological data show a moderate systemic general toxicity at doses far higher than those used in similar previous experiments using Al(acac)3 (acac = 2,4 pentanedionate), a hydrolytically stable and more lipophilic aluminum(III) complex (1). The diversity of behavior is discussed in terms of metal speciation as well as respect to the thermodynamic and kinetic properties of the two complexes in aqueous solution. The toxicological model presented here emphasizes that neutral, water compatible aluminum(III) complexes are to be considered as promising tools for toxicological experiments providing biological models of human pathologies.

Aluminum↗

PubMed1998

Application of the queueing theory with Monte Carlo simulation to inhalation toxicology.

Various models have been developed in modelling of inhalation toxicology. The deterministic approach, which has been used to date in most of the models, needs to consider numerous factors, e.g. anatomical structure, breathing frequency, humidity, metabolism rate, partition coefficients, pulmonary ventilation, perfusion rates, unidirectional/cyclic air flow, non-steady-state, steady-state, etc. In the present study, a stochastic approach was used in the modelling of inhalation toxicology, because there is a phenomenological analogy between the queueing system and respiratory system dealing with inhaled toxicants. Using the queueing theory, the amounts of toxicants in the respiratory system, the time needed to remove the accumulated amounts of toxicants from the respiratory system, etc. can be estimated. The Monte Carlo simulation of queueing process was performed to analyse cigarette smoking, and shows the potential use of the queueing theory in inhalation toxicology.

Administration, Inhalation↗

PubMed2001

Providing toxicokinetic support for reproductive toxicology studies in pharmaceutical development.

A package of toxicokinetic and disposition studies is generally conducted in support of reproductive toxicology studies in the development of new drugs. The content of the package often varies between companies and sometimes either insufficient data or inappropriate/over-interpreted data are presented. This paper was written to aid investigators in the design of toxicokinetic and disposition studies in support of reproductive toxicology. It offers: (1) an overview on the regulatory guidelines for toxicokinetics, (2) methods for the derivation of toxicokinetic parameters, (3) suggestions on general toxicokinetic study design, (4) suggestions on the specific design of toxicokinetic support for reproductive toxicology studies, and (5) an overview of species differences in placental transfer and the applicability (or otherwise) of transfer studies in drug development. Toxicokinetic and drug disposition studies should be carefully designed in order to gather relevant information, and consideration should be given to the usefulness of any data before embarking on a series of supporting or routine experiments.

Animals↗

PubMed2001

Comparative toxicological study on the hepatic safety of entacapone and tolcapone in the rat.

Entacapone and tolcapone are novel COMT (catechol-O-methyltransferase) inhibitors indicated for the adjunctive treatment of Parkinson's disease (PD) in combination with levodopa. The marketing authorisation of tolcapone was suspended in the European Union (EU) in 1998 mainly due to severe abnormal hepatic reactions. This fact raised concern about the safety of COMT inhibitors in the treatment of parkinsonian patients. In order to investigate whether these COMT inhibitors exhibit different effects on the liver comparative toxicological studies were performed in the rat. Short term toxicological studies in rats at high oral doses of entacapone and tolcapone (200, 400 or 600mg/kg daily) were carried out. Tolcapone (400 mg/kg/day or 600 mg/kg/day) increased mortality after only one week treatment and induced signs of toxicity such as a rise in body temperature, stimulation of respiration and rapid onset of rigor mortis after death. Entacapone did not show any adverse effects at the tested dose levels. In the histopathological examination liver cell necrosis was observed in the tolcapone (400 and 600mg/kg/day) treated rats, but it revealed no treatment related signs of toxicity in entacapone-treated rats. We conclude that the toxicological profile of the two COMT inhibitors, entacapone and tolcapone, differ from each other, tolcapone--unlike entacapone--showed hepatotoxicity.

Animals↗

PubMed1987

Preclinical toxicology of pirmenol hydrochloride.

Pirmenol hydrochloride, a novel pyridinemethanol derivative, is a long-acting class Ia antiarrhythmic agent. Preclinical toxicology data were obtained in rat, mouse, dog and rabbit. In acute toxicity studies by oral and intravenous routes, no pathologic changes were observed in surviving mice, rats and dogs. In repeated dose toxicity studies, no drug-related pathologic changes were evident; dryness of the oral mucosa in dogs and body weight gain reductions in rodents were the only significant clinical signs. In a chronic (52 week) toxicity study in rats, pirmenol given in the diet was tolerated clinically at doses up to 100 mg/kg/day. No drug-related aberrations in clinical laboratory parameters or ophthalmic or pathologic findings were evident. In a similar study in beagle dogs, pirmenol was tolerated clinically at a dosage up to 30 mg/kg/day. No significant changes in biochemical, hematologic, urinary or bone marrow determinations were found in either species. In reproductive toxicology studies in rats, pirmenol had no significant effect on litter size or embryonic viability. In rabbits pirmenol had no effect on average litter size, embryonic viability or fetal wastage. Given to male rats, pirmenol had no overt effects on fertility. Pirmenol failed to elicit deoxyribonucleic acid damage or induce cytogenetic alterations. Pirmenol appears to be without significant limiting toxicologic properties.

Administration, Oral↗

PubMed1986

Immuno-, neuro-, and general toxicologic animal studies on a synthetic pyrethroid: cypermethrin.

The toxicologic properties of the synthetic pyrethroid insecticide cypermethrin have been studied in animal experiments. In the course of acute and subchronic experiments performed by the administration of 1/2 and 1/40, 1/20, and 1/10 proportions of the oral LD50 value, no considerable changes were found in the general toxicologic tests. The compound known to affect the central nervous system, however, induced only a mild enhancement of the central excitation level shown by the EEG investigations in the doses applied. In the immunotoxicologic studies an early and dose-dependent suppression was induced as a result of humoral immune response of rabbits immunised by S. typhi following the administration of cypermethrin. The cell-mediated immune response was also decreased. In rats the immune response determined by anti-sheep erythrocyte and antiovalbumin titer as well as by autologous rosette formation of spleen lymphocytes was hindered. The earliest detectable group of symptoms indicating the effect of a mild cypermethrin exposure is the appearance of the positivity of the immunotoxicologic tests. On the basis of the experimental findings the sensitive immunotoxicologic tests have been regarded as of great importance in the series of toxicologic methods.

Animals↗

PubMed1992

Recombinant DNA approaches for the development of metabolic systems used in in vitro toxicology.

In the past few years there has been considerable progress in the development of mammalian cell systems for use in genetic toxicology by the stable transfer of genes/cDNAs coding for drug metabolizing enzymes directly into the target cell. Alternative approaches have also been developed in which mammalian cells are transiently transfected with cDNAs coding for drug-metabolizing enzymes and S9 preparations expressing a single metabolizing enzyme isolated and used for metabolic activation. Progress in these areas is reviewed here and the relative merits of the different approaches are discussed. Work to date has focused primarily on the cytochrome P450 family of enzymes, although other enzyme systems involved in xenobiotic metabolism have been used. The central theme of this review is the transfer of genetic information to improve the metabolic capability of cell systems used in genetic toxicology. However, a basic philosophy of the review is that genetic manipulation of cultured mammalian cells has the potential for developing systems to be used to better understand chemically induced toxicological effects.

Animals↗

PubMed1979

Rhesus monkey (Macaca mulatta) model in genetic toxicology mitomycin C clastogenicity in germ cells.

The value of rhesus monkeys (Macaca mulatta) as a genetic toxicology model is limited by their scarcity, expense, and impracticality of progeny testing. However, in some special circumstances, e.g., accidental exposure of humans to potential mutagens, rhesus monkeys or other primates may provide a superior animal model to help to cope with a difficult public health situation. Using the testis as a target organ we found that when primary spermatocytes were treated in pre-leptotene stage with 1 mg mitomycin C/kg body weight, the frequency of exchanges, fragments, sex-chromosome and autosomal univalents increased significantly at diakinesis-metaphase I. This response was absent in cells treated during diplotene, late pachytene or during spermatogonial stages. We suggested that animals should be evaluated not only for genetic toxicology parameters, but also toxicologically, histologically, behaviorally, for carcinogenesis and seminal cytology. Whenever possible, the animals should be recycled.

Animals↗

PubMed1990

Pharmacological and toxicological properties of arotinoids SMR-2 and SMR-6 in mice.

Studies were conducted to define primary pharmacological and toxicological properties of two arotinoids, SMR-2 and SMR-6, in male B6D2F1 mice. Mice were gavaged daily for up to 22 days with retinoids in corn oil (0.1, 0.2, or 0.4 mg/kg day SMR-2 or SMR-6 or 2.5, 10, or 30 mg/kg all-trans-retinoic acid as a reference control). Toxicological and biochemical endpoints were assayed after 8, 15, and 22 days. At toxic doses, i.e., those inducing weight loss, morphological changes were observed in skin, lymph nodes, spleen, bone marrow, liver, thymus, forestomach, adrenal, bone, and testes. Biochemical alterations included elevated serum alkaline phosphatase, corticosterone, and interleukins-1, -2, and -3. Additional immune alterations included increased responsiveness of spleen cells to both thymus-dependent and thymus-independent mitogens and increases in the total number of B cells in the spleen. At doses not inducing weight loss, target organ effects included the appearance of plasma cells and infiltration of polymorphonuclear cells in lymph nodes; myeloid cell hypercellularity in bone marrow; hematopoiesis in spleen; subacute inflammation in forestomach; and periportal cytoplasmic vacuolization in liver. At the low doses, SMR-2 resulted in decreased responsiveness of spleen cells to mitogens and SMR-6 caused increased responsiveness. SMR-6 also increased interleukin-1 and-2 production at low doses. Biochemical effects included reduced activities of liver aryl hydrocarbon hydroxylase (AHH) and soluble brain protein kinase C. Overall, the results suggest that leukopoiesis and reduced liver AHH and reduced soluble protein kinase C activities are the primary and initial pharmacological and toxicological effects of retinoids.

Animals↗

PubMed1992

Health effects of atmospheric acid aerosols: a model problem in inhalation toxicology and air pollution risk assessment.

A symposium entitled, Health Effects of Atmospheric Acid Aerosols: A Model Problem in Inhalation Toxicology and Air Pollution Risk Assessment, was held at the 30th Annual Meeting of the Society of Toxicology (SOT) in Dallas, Texas. The symposium was sponsored by the Inhalation Toxicology Specialty Section of SOT, and was organized to integrate evidence from various disciplines concerning health effects from acid aerosols in ambient air.

Acids↗

PubMed1983

Toxicological evaluations of carcinogens and noncarcinogens: pros and cons of different approaches.

Toxicological evaluations are performed to provide estimates of the safety/risk entailed in specified exposures to chemicals. This paper presents the two common approaches to toxicological evaluations. One of these assumes the presence of threshold doses. It involves determination of no-effect levels and extrapolation to acceptable daily intakes in man. This procedure has been widely and successfully used for noncarcinogens. For carcinogens, a number of mathematical models have been proposed for estimating the level of risk associated with a specified exposure level or the dose that is considered virtually safe, e.g., with a risk level of 10(-6). Variations of these major approaches are also outlined. Examples are included to indicate that a deficiency of significant biological data, such as an unexpected toxic effect and the marked influence of modifying factors, can invalidate a toxicological evaluation. It is also pointed out that such deficiencies cannot be overcome by any mathematical manipulation of the available dose-response data.

Animals↗

PubMed1987

Preclinical toxicology of platinum analogues in dogs.

A toxicology study of cis-diamminedichloroplatinum (II) (CDDP), aqua(1,1-bis-(aminomethyl)cyclohexane)sulfatoplatinum(II) (TNO-6), diammine(1,1-cyclobutanedicarboxylato)platinum(II) (CBDCA), cis-dichloro-trans-dihydroxo-cis-bis(isopropylamine)platinum-(IV) (CHIP) and ethylenediaminemalonatoplatinum(II) (JM-40) was carried out in dogs. The main purpose of the study was to compare the results with those obtained earlier in mice and rats and with the toxicology data in humans. Each platinum compound was tested in three dogs. Each dog received three intravenous bolus injections at intervals of 3 weeks. The compounds were administered in dosages of 1.2, 1.0, 12, 10 (or 6) and 10 mg/kg, respectively. Toxic death occurred for two dogs (both on day 54) from haematotoxicity (10 mg/kg CHIP) and renal toxicity (TNO-6), respectively. Serum urea nitrogen and creatinine concentrations were variable after TNO-6 and remained within normal values after treatment with the other compounds. Severe proteinuria was observed in all three dogs treated with TNO-6. Values returned to normal within 16 days. JM-40 did not cause significant proteinuria. CDDP, CBDCA and CHIP caused short-lasting and slight proteinuria. CHIP caused a severe reduction in the number of leukocytes and platelets, while the other drugs caused acceptable reductions. Except after the high dose CHIP regimen, haematotoxicity was of a transient nature. Vomiting in order of severity occurred after TNO-6, CHIP, CDDP and JM-40, while CBDCA did not cause any vomiting. The dogs were sacrificed 6 weeks after the last drug dose. Organs were fixed for histopathology to complete and support clinical-toxicological parameters. On the basis of the results from the single-dose study in dogs and those obtained earlier in mice and rats it can be concluded that the gain from the use of the dog as a prognosticator for organ toxicity in man was disappointing and limited to the prediction of vomiting.

Animals↗