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Results for “Toxicological evaluation”

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PubMedDate not supplied

Toxicologic evaluation of bumetanide, potent diuretic agent.

The studies reported represent the preclinical toxicologic evaluation of bumetanide. Toxicity testing in rats, rabbits, dogs, and baboons indicate that bumetanide is well tolerated in various species. The toxicity that was observed is, for the most part, the direct consequence of its potent diuretic activity and is similar to that produced by other "loop" diuretics. Bumetanide was fetotoxic at maternal toxic doses in the rabbit, but no evidence of teratogenic effects was observed in rabbits, rats, mice, or hamsters. The compound was devoid of mutagenic activity by the Ames test and was found to be noncarcinogenic in long-term rat studies.

Abnormalities, Drug-Induced↗

PubMed1981

Toxicological evaluation of fluproquazone.

The toxicological characteristics of 4-(p-fluorophenyl-1-isopropyl-7-methyl-2-(1H)quinazolinone (fluproquazone), an analgesic with distinct antiinflammatory properties, were evaluated in acute and chronic toxicity studies as well as in reproduction toxicity, carcinogenicity and mutagenicity studies. The following overall results were obtained: The acute oral toxicity in mice, rats, and rabbits is of low order. In the chronic oral studies fluproquazone was generally well tolerated when given to rats and dogs for 13 weeks, to dogs and monkeys for 52 weeks, to mice for 78 weeks and to rats for 104 weeks. In particular, there was no indication of gastrointestinal irritations or lesions in any of these studies. The results of the studies in dogs and rats showed the major target organs for the toxicity of fluproquazone to be the liver and kidney, where mild, reversible changes were observed. These findings were considerably less severe than those found with several other antiphlogistic-analgesic compounds. In the reproduction toxicity studies, the only drug-related effects seen in experiments on female fertility or peri- and postnatal development in rats were a prolongation of pregnancy and an impairment of delivery leading to an increased perinatal mortality. These findings may be related to an inhibition of prostaglandin synthesis by fluproquazone. Similar effects are known to occur after administration of other inhibitors of prostaglandin synthesis. The oral teratological studies in rats and rabbits did not reveal any embryolethal or teratogenic effects. The drug had no mutagenic effects in either the micronucleus test and the dominant-lethal test using mice, or in the Ames-Test using Salmonella typhimurium. The carcinogenicity studies showed that fluproquazone has no carcinogenic potential in rats and mice.

Animals↗

PubMed1990

[Methods of toxicologic evaluation--possibilities and limits].

Toxicological knowledge is founded on observation in humans consisting of casuistic presentations and epidemiologic research and on animal experiments. The possibilities and limitations of these sources of knowledge are presented with special reference to the problems of the dose and of toxic interactions. The limitations of toxicological knowledge primarily result from the impossibility to prove "no action". Therefore, it is not possible to prove the absolute safety of a substance but only the acceptability by assessing its advantages and risks.

Animals↗

PubMedDate not supplied

Behavioral toxicology: evaluating cognitive functions.

Behavioral toxicology is concerned with the identification of adverse effects on neural and behavioral functions resulting from exposure to a neurotoxicant. Many substances are known to have effects on cognitive functions such as memory, attention and perception. This paper reviews some of the issues that must be addressed when trying to assess these neurotoxic effects on cognition, and identifies a variety of paradigms that have been explored for use in behavioral toxicology.

Arousal↗

PubMed1977

Toxicological evaluation of Norpace after intravenous administration to rat and dog.

Norpace (disopyramide phosphate) is a drug for treating cardiac arrhythmias. It has been evaluated for potential toxicological effects in albino rats and Beagle dogs, to provide safety support for clinical studies involving intravenous infusion. The compound was dissolved in Sodium Chloride for Injection, U.S.P. and administered daily by continuous intravenous infusion to groups of rats and dogs. Dose levels to 4.95 mg/kg/h for 14 and 28 consecutive days, respectively were employed. Rats received the formulation for 6--12 h daily; dogs were infused for 6 h daily. Conventional physical, cardiovascular, hematology, clinical chemistry and postmortem gross and microscopic examinations were performed. No compound-related changes were observed in the physical examinations (including ophthalmic), blood pressure (rat), ECG (dog), body weight, or clinical lab parameters evaluated; Food consumption was unontinuous restraining procedure employed during infusions reduced food consumption in all dogs, however, Postmortem examination did not reveal any lesions unique to treated animals. Some dogs exhibited intravenous fibrin thrombi at the site of injection. Organizing blood clots were occasionally present in the thoracic cavity of the rat. These findings were considered related to the infusion technique employed, rather than the drug administered. It was concluded that daily intravenous infusions of Norpace at doses up to 4.65 mg/kg/h to rats and dogs for 14 and 28 consecutive rays respectively, cause no biologically meaningful detrimental effects.

Animals↗

PubMed1989

Mechanistic studies: their role in the toxicological evaluation of pesticides.

To date, studies on the mechanism of toxicity of pesticides are not yet an integral part of the toxicological evaluation process. However, in recent years mechanistic studies have played an increasing role in the assessment of toxicological hazards to man, and in this paper we have described two examples where an understanding of mechanism has contributed positively to risk assessment or has provided a surer scientific basis for the judgement of whether a potential hazard will be expressed in man. In the first example, an evaluation of the scientific literature leads to the conclusion that hepatic peroxisome proliferation in rats and mice is directly, or indirectly, related to the development of hepatocellular tumours. A wide range of non-mutagenic chemicals elicit peroxisome proliferation in mouse and rat liver, but not the guinea pig or marmoset liver. Using one of the diphenyl ether herbicides, fomesafen, we have shown that isolated hepatocytes from mice and rats, but not those from guinea pigs, marmosets and significantly man, undergo peroxisome proliferation. Therefore, it seems reasonable to conclude that although fomesafen causes peroxisome-related tumours in the mouse, man is neither susceptible nor sensitive to this mechanism. Consequently, we can conclude that fomesafen will not cause liver tumours in humans exposed to this herbicide. The herbicide paraquat, although safe in normal agricultural use, has been responsible for numerous human fatalities, almost exclusively as a result of the intentional ingestion of the concentrated commercial product.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Toxicological evaluation of 1-chloroacetophenone and dibenz[b,f]-1,4-oxazepine after repeated inhalation exposure in mice.

Toxicological evaluation was made on the effects of two peripheral sensory irritants (tear gases): 1-chloroacetophenone (CN) and dibenz[b,f]-1,4-oxazepine (CR). Animals had a 15-min daily inhalation exposure to average vapour concentrations of 87.6 mg CN m-3 or 1008 mg CR m-3 (both equal to 0.05 LC50) for 5 or 10 days and were sacrificed 24 h after the last exposure, when biochemical and histopathological observations were made. Both chemicals caused a significant decrease in body weight gain. Histological changes in lung, liver and kidneys were more severe after 10 than after 5 days of exposure and were more severe in CN-exposed than in CR-exposed mice. Organ weight to body weight ratios remained normal except for the spleen to body weight ratio, which decreased in CN-exposed mice after both 5 and 10 days of exposure. Biochemical indicators showed a toxic response only in CN-exposed mice, but the only consistent change was an increase in blood glucose. Hepatic alkaline phosphatase was not influenced, malondialdehyde concentration and acid phosphatase activity were increased only after 5 days of exposure and liver GSH concentration decreased after 10 days of exposure. Results indicate that CN is not only more toxic than CR in absolute terms but is also more toxic at the 5% level of their LC50.

Administration, Inhalation↗

PubMed1989

Analysis, characterization, and purification: requirements for toxicological evaluation of 1,4-dithiane.

1,4-Dithiane is an organo-sulfur chemical associated with production and storage of munitions. Toxicological evaluation of this chemical was scheduled in rats because of the paucity of such information. Prerequisite for the evaluation was the development of gas chromatographic procedures using flame ionization detection to determine the purity of the test chemical and to certify the concentration and stability of the chemical in the dosage form, sesame oil. Mass and nuclear magnetic resonance spectrometry procedures are described for assessing the structural character and purity of the test chemical. A procedure for the purification of the test chemical and data concerning its solubility in various solvents are also presented.

Chromatography, Gas↗

PubMedDate not supplied

Toxicological evaluation of an electrically heated cigarette. Part 1: Overview of technical concepts and summary of findings.

This series of papers provides a description of the toxicological evaluation of an electrically heated cigarette (EHC). With this novel cigarette design the tobacco is heated by a series of electric heating elements, which allows for greater control of the available heat and results in lower temperatures and less combustion compared with conventional lit-end cigarettes. This design was subjected to testing, including an evaluation of smoke chemistry, in vitro bacterial genotoxicity, in vitro mammalian cell cytotoxicity and a 90-day smoke inhalation study in rats. A conventional lit-end cigarette, the University of Kentucky Reference Cigarette 1R4F, was used as a point of comparison in these experiments. When adjusted for the yield of total particulate matter, the EHC delivered 50% lower amounts of about two-thirds of the 69 smoke constituents measured. Mutagenic activity (Salmonella reverse mutation assay) of the particulate phase material in the presence of metabolic activation was ca. 90% lower, with a slight reduction of activity in the absence of metabolic activation. Cytotoxic activity (neutral red assay) of the particulate phase material was ca. 40% lower, with about equal activity of the gas/vapor-phase material. Equal activity was noted between cigarette types in a whole smoke rat inhalation assay. The results from this series of tests demonstrate that the EHC produces a much different smoke--with an at least partially reduced yield of smoke constituents and biological activity--from that of a standard reference cigarette.

Animals↗

PubMed2003

The use of a non-lethal tool for evaluating toxicological hazard of organochlorine contaminants in Mediterranean cetaceans: new data 10 years after the first paper published in MPB.

In the Mediterranean Sea, top predators, and particularly cetacean odontocetes, accumulate high concentrations of organochlorine contaminants and toxic metals, incurring high toxicological risk. In this paper we investigate the use of the skin biopsies as a non-lethal tool for evaluating toxicological hazard of organochlorines in Mediterranean cetaceans, presenting new data 10 years after the paper published by Fossi and co-workers [Mar. Poll. Bull. 24 (9) (1992) 459] in which this new methodology was first presented. Some organochlorine compounds, now with worldwide distribution, are known as endocrine disrupting chemicals (EDCs). Here the unexplored hypothesis that Mediterranean cetaceans are potentially at risk due to organochlorines with endocrine disrupting capacity is investigated. High concentrations of DDT metabolites and PCB congeners (known as EDCs) were found in the different Mediterranean species (Stenella coeruleoalba, Delphinus delphis, Tursiops truncatus and Balaenoptera physalus). In this paper we also propose benzo(a)pyrene monooxygenase (BPMO) activity in marine mammal skin biopsies (non-lethal biomarker) as a potential indicator of exposure to organochlorines, with special reference to the compounds with endocrine disrupting capacity. A statistically significant correlation was found between BPMO activity and organochlorine levels (DDTs, pp(')DDT, op(')DDT, PCBs and PCB99) in skin biopsies of males of B. physalus. Moreover a statistical correlation was also found between BPMO activity and DDT levels in skin biopsies of the endangered Mediterranean population of D. delphis. These results suggest that BPMO induction may be an early sign of exposure to organochlorine EDCs and can be used for periodic monitoring of Mediterranean marine mammal toxicological status.

Animals↗

PubMed1990

[Morphologic and toxicologic evaluation of response to subcutaneous para-osseous implants Medpol-1 and Medpol-2 in rats].

Cobalt alloys produced in Poland and meant for orthopedic implants were morphologically and toxicologically evaluated. They were implanted subcutaneously in the para-osseous region of rats' heads. The results of the experimental tests strongly suggest the advisability of a clinical research project (study) on the examined cobalt alloys: Medpol-1 and Medpol-2.

Animals↗

PubMed1983

[Evaluation of a systematic analysis scheme used in clinical toxicology. Evaluation of 4 years' experience in a national health laboratory].

The author describes briefly a systematic analytical approach in emergency toxicology during the past 4 years. In all cases, a systematic toxicological investigation was performed and the results are listed. In 30% of the cases, the nature of the poison suspected by the clinician could not be confirmed by toxicological analysis and in an other 30% of the cases, the toxicologist had no clinical information at all.

Body Fluids↗

PubMed2002

Integration of mechanistic data in the toxicological evaluation of endocrine modulators.

Controversy has arisen concerning the likelihood of adverse health effects due to exposure to hormonally active agents or endocrine modulators such as environmental estrogens. With the aim to improve the basis for their toxicological evaluation, several chemicals of anthropogenic (bisphenol A, octylphenol, o,p'-DDT) and of natural origin (daidzein, genistein) were investigated with regard to their mode of hormonal action and potency as well as toxicokinetics. Experimental toxicodynamic and toxicokinetic data illustrate important points in a comparative assessment of environmental estrogens. A novel concept, the Hygiene-Based Margine of Safety (HBMOS), has been suggested to characterize the relative impact of these potential endocrine modulators on human health: It integrates exposure scenarios (i.a. those generated within the European Existing Chemicals Programme) and in vivo rodent potency data for xenoestrogens and for dietary phytoestrogens. On the basis of these informations, HBMOS values calculated for the alkylphenol and bisphenol A appear sufficiently high to ensure the absence of a practical risk to human health under the present exposure conditions. For slowly accumulating compounds (e.g. DDT) with much longer half-lifes than isoflavones, such comparison should be based on comparative blood levels rather than on scenarios of daily exposures.

Animals↗

PubMed1986

Reduction of animal use for toxicological evaluation: the Netherlands Health Council report on the LD50.

In 1981 the Health Council of the Netherlands installed a committee to report on the scientific value of the LD50 and on ways of obtaining the information needed for the toxicological evaluation of chemical products at the expense of less experimental animals and of less suffering. This was done at the request of the Minister of Public Health and Environmental Hygiene. The first four reports have been published. The first one discusses the different methods for estimating the median lethal dose, and stresses that a high precision is seldom needed. A limit test would suffice in many cases. The test for abnormal toxicity of the European Pharmacopoeia (General method) has a power of discrimination of 0.96 when the dose injected in fact is equal to the LD50; the power of the version of this test intended for immunosera and vaccines is even higher. The second report deals with pharmaceutical preparations, immunosera and vaccines. The types of toxicity data and the precision required differ in the successive stages of screening, selection, development up to registration and quality control. Determination of an LD50 with a high precision is required only for preparations with a narrow therapeutic margin, and in very exceptional cases for quality control.

Animal Testing Alternatives↗

PubMed1984

Reproductive toxicological evaluation of Omadine MDS.

Reproductive toxicology studies with Omadine MDS were conducted using rats and rabbits, and plasma levels of the metabolite, 2-methylsulfonylpyridine (2-MSP), were assayed. In phase I (treated males, untreated females) of the fertility study, the no-effect level, for oral dosing, was 3.0 mg/kg; 7.5 mg/kg caused a decrease in male weight gain. In phase II (treated females, untreated males), the no-effect oral dose level was 1.0 mg/kg. At 3.0 mg/kg, decreases were seen in maternal body weight gain, the fertility index, and in total implantations and viable embryos at the 13-day uterine examination. Severe maternal toxicity including impaired motor function of limbs, decrease in weight gain, and mortality occurred at 7.5 mg/kg. In the perinatal/postnatal study, the no-effect level was 3.0 mg/kg. At 7.5 mg/kg, mortality was high, with a majority of animals dying during mid lactation. In the rat teratology study, the high dosage level, 30 mg/kg, dermally administered on Gestation Days 6 through 15 caused slight maternal toxicity, whereas 10 mg/kg produced none. These dosage levels corresponded to peak plasma levels on Gestation Day 10 of 470 and 1950 ng/ml 2-MSP at the 10- and 30-mg/kg dosage levels, respectively. In the rabbit, 5 mg/kg topically applied on Gestation Days 6 through 18 produced slight maternal toxicity while 1.5 mg/kg produced no maternal effects. The plasma levels of 2-MSP peaked on Days 12 and 15 of gestation. At 1.5 mg/kg these levels were 155 and 148 ng/ml; at 5.0 mg/kg, levels were 513 and 573 ng/ml. There was no teratogenic response seen in either species.

Abnormalities, Drug-Induced↗

PubMed1989

Toxicologic evaluation of ofloxacin.

Results of studies conducted to characterize local, systemic, reproductive, and mutagenic effects indicate that ofloxacin is well tolerated within reasonable multiples of the intended clinical dose. Quinolone-associated arthropathic effects characterized by blister, erosion, and increased synovial fluid occurred in rats and dogs and appeared to be both age- and dose-related. Maternal toxicity and embryotoxicity were noted, but there was no teratogenicity in rats or rabbits. There was no impairment of fertility, and no adverse effects on late fetal development, labor, delivery, lactation, neonatal viability, or growth of offspring occurred. Target-organ studies revealed no evidence of ocular toxicity in rats, nephrotoxicity in rabbits, or antigenicity or ototoxicity in guinea pigs. Overall, the toxicologic evaluation of ofloxacin has shown this compound to be a drug with a low toxicologic potential.

Abnormalities, Drug-Induced↗

PubMed1982

The Council of Europe approach to toxicity testing and toxicological evaluation.

The differences in national requirements for testing the safety-in-use of certain chemicals such as pesticides, flavourings, plastics food packaging and cosmetic products and their ingredients, has prompted the Council of Europe, an international inter-governmental organisation, to approach these problems through the elaboration of general guidelines for toxicity testing and toxicological evaluation. These are intended as a model for national authorities and manufacturers on the information to be supplied and the procedure to be followed for the inclusion in positive lists of the substances in question and are open to revision or modification at any time.

Animals↗

PubMed1991

New derivatives of kanamycin B obtained by combined modifications in positions 1 and 6". Synthesis, microbiological properties, and in vitro and computer-aided toxicological evaluation.

Substitution of the C-1 atom in the 2-deoxystreptamine moiety of gentamicin C2, a broad-spectrum aminoglycoside antibiotic, by an axial hydroxymethyl group has been reported to confer protection against most clinically important bacterial enzymes inactivating aminoglycosides, while simultaneously reducing the nephrotoxic potential of this drug. We report here on a similar modification of kanamycin B. Microbiological evaluation, however, revealed no useful protection, as established by the almost complete lack of activity of 1-C-(hydroxymethyl)kanamycin B against an array of organisms producing defined types of aminoglycoside-inactivating enzymes and against which 1-C-(hydroxymethyl)gentamicin C2 and amikacin (1-N-[(S)-2-hydroxy-4-aminobutyryl]kanamycin A) are active. Moreover, toxicological evaluation, based on the in vitro measurement of the drug inhibitory potential toward lysosomal phospholipases, a predictive test of the intrinsic nephrotoxic potential of aminoglycosides, showed not decreased but rather increased toxicity. Comparative conformational analysis of the interactions of the drug with a phosphatidylinositol monolayer explained the lack of protective effect, since no significant change of the mode of insertion of the derivative in this monolayer was detected compared to that of kanamycin B. Combination of a 1-C-(hydroxymethyl) substituent with a 6"-chloro, 6"-acetamido substituent resulted in a partial improvement of the toxicological behavior with no loss of activity for the 6"-chloro and the 6"-azido derivatives, but not to the extent of obtaining better derivatives than kanamycin B itself. We, therefore, suggest that the advantages of an axial hydroxymethyl substituent at C-1 are probably restricted to the gentamicin family and do not extend to kanamycins. It might be concluded that the structural differences between gentamicins and kanamycins play an important, still undescribed role both in their effective recognition by aminoglycoside-inactivating enzymes, which are responsible for most of the clinically important cases of resistance to aminoglycosides, and also in the interactions with phospholipids, which in turn cause nephrotoxicity.

Gram-Positive Bacteria↗