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Biomedical subjects

H J Klimisch

Publications and source records attributed to H J Klimisch.

At least 37 records · Page 2Linked to original sources
PubMed1991

Studies on the prenatal toxicity of N,N-dimethylformamide in mice, rats and rabbits.

Prenatal toxicity studies with N,N-dimethylformamide (DMF) in rabbits, rats and mice were carried out using the oral (gavage), dermal, inhalation and ip injection routes of administration. Administration of DMF by gavage led to an increase in malformations in rats and mice in the absence of overt maternal toxicity. The lowest-observable-effect level was 182 mg/kg body weight/day in mice and 166 mg/kg body weight/day in rats. After dermal administration a dose-dependent incidence of teratogenicity was observed in rats at 94-944 mg/kg/body weight/day in the absence of overt maternal toxicity. In rabbits dermal administration led to a steeper increase in the dose-response relationship and at 400 mg/kg body weight/day to a clear teratogenic effect in the presence of slight maternal toxicity. The 200 mg/kg body weight/day dose appeared to be the no-adverse-effect level. Inhalation in rats caused foetotoxicity and embryolethality at 287 ppm. A clear teratogenic effect was shown in rabbits at 450 ppm and a marginal effect at 150 ppm. The no-effect level for does and foetuses was 50 ppm. Ip injection in mice caused clear teratogenicity at 944 mg/kg body weight/day and slight embryotoxicity at 378 mg/kg body weight/day. The rabbit appears to be more sensitive than the rat to DMF-related prenatal toxicity and should, therefore, be used as the basis for the evaluation of teratogenic risk in humans.

Abnormalities, Drug-Induced↗
PubMed1991

Chronic toxicity and oncogenicity of inhaled methyl acrylate and n-butyl acrylate in Sprague-Dawley rats.

No exposure-related clinical signs or lesions of systemic toxicity and no oncogenic responses were observed in male and female Sprague-Dawley rats exposed by inhalation to methyl acrylate (MA) or n-butyl acrylate (BA) vapours, at concentrations of 0, 15, 45 and 135 ppm. The rats were whole-body-exposed 6 hr/day, 5 days/wk, for 24 consecutive months. There was a 6-month post-exposure observation period for subgroups of BA-exposed rats. Atrophy of the neurogenic epithelial cells and hyperplasia of reserve cells were observed in the nasal mucosa of all MA- and BA-exposed groups. These changes were dose related and mainly affected the anterior part of the olfactory epithelium. Opacity and neovascularization of the cornea were seen in all MA-exposed groups and in the group exposed to 135 ppm BA. These toxic effects of the olfactory epithelium and cornea were attributed to the known irritancy of MA and BA. In the BA subgroups kept for a 6-month post-exposure observation, reconstructive effects, such as replacement of altered olfactory epithelium with respiratory epithelium, and partial regression of corneal neovascularization were observed.

Acrylates↗
PubMed1989

Dermal oncogenicity study of 2-ethylhexyl acrylate by epicutaneous application in male C3H/HeJ mice.

A carcinogenicity bioassay of 2-ethylhexyl acrylate (2-EHA) was conducted by applying 25 microliters 86.5%, 21%, or 2.5% 2-EHA in acetone three times a week to the clipped dorsal skin of male C3H/HeJ mice (80 per group) over their lifetime. Another group was treated with a 43% 2-EHA solution for 24 weeks and thereafter observed for lifetime (stop-test). An untreated group and a group that received only the diluent acetone served as controls. Treatment-related changes in the skin indicative of irritation (scaling, scabbing, hyperkeratosis, hyperplasia) were found in all 2-EHA-treated groups. These lesions were reversible in the 43% group immediately after treatment was stopped, and in the 2.5% group after the 11th week of treatment. Only in the 86.5% and 21% test groups showing chronic irritative skin damage was there a high incidence of nepolastic skin lesions (papillomas, carcinomas, and melanomas) with no dose dependency. In contrast, no skin tumors were found in the control groups, in the group treated with 2.5% 2-EHA for lifetime or in the group treated with 43% 2-EHA for about 6 months and observed for lifetime.

Acrylates↗
PubMed1988

The Inhalation Hazard Test; principle and method.

The Inhalation Hazard Test (IHT) measures the hazard rather than the toxicity of volatile substances. Generation methods for saturated vapor atmospheres and exposure systems are described. The determination of the nominal concentration gives in most cases sufficient information on the concentration in the inhalation atmosphere. The temperature at which the saturation occurs and the exposure time are parameters which influence the test results. The determination of the LT0 (the exposure time at which no animals die) is used to compare substances with different inhalation hazards. A classification system is proposed to differentiate the toxic hazard of volatile substances. The IHT is an appropriate method to characterize the acute inhalation hazard of volatile substances. It requires fewer animals and is less elaborate than the LC50.

Administration, Inhalation↗
PubMed1988

Inhalation hazard test. Interlaboratory trial with OECD method 403.

Six industrial laboratories validated the Inhalation Hazard Test (OECD Method 403) using eight volatile chemicals. The test gave similar results in all laboratories, despite variation in inhalation exposure systems and strain of rat used. Detailed atmosphere analyses are not necessary, since nominal atmosphere concentrations were close to the analysed values. The method gives reproducible results directly applicable to hazard evaluation, and is quicker and cheaper and uses fewer animals than the conventional LC50 test.

Administration, Inhalation↗
PubMed1988

Developmental toxicity in rats after inhalation exposure of di-2-ethylhexylphthalate (DEHP).

Di-2-ethylhexylphthalate (DEHP) was investigated in Wistar rats for developmental toxicity after head-nose exposure to aerosol concentrations of 0, 0.01, 0.05 and 0.3 mg/l for 6 h per day from gestation day 6 through 15. A range finding study revealed peroxisome proliferation in the liver of the dams throughout exposure levels of 0.2, 0.5 and 1.0 mg/l with an increasing trend. 0.3 mg/l was therefore regarded as an exposure level leading to peroxisome proliferation as a marker for maternal effects. All concentrations were tolerated without clinical signs of maternal toxicity. The fetuses of 20 animals per exposure group were investigated for structural defects. Five additional animals per group were allowed to litter and the offsprings were raised and observed for postnatal signs of toxicity. No significant developmental toxicity or changes in the postnatal physical development were observed. DEHP is assumed not to exhibit developmental toxicity under the experimental conditions employed.

Abnormalities, Drug-Induced↗
PubMed1987

Prenatal toxicity of 2-methoxypropylacetate-1 in rats and rabbits.

2-Methoxypropylacetate-1 was investigated in Wistar rats and Himalayan rabbits for embryotoxic potential. Rats after inhalation exposure to 0, 0.6, 3.0, or 14.9 mg/liter (approximately 0, 110, 550, or 2700 ppm, respectively) for 6 hr per day from gestation Days 6 through 15 exhibited some degree of maternal toxicity at 2700 and 550 ppm. At 2700 ppm an increase of skeletal anomalies of the thoracic vertebrae among the fetuses was observed and interpreted as an exposure-related slight teratogenic effect. In Himalayan rabbits exposed via inhalation to 0, 0.2, 0.8, or 3.0 mg/liter (approximately 0, 36, 145, or 550 ppm, respectively) for 6 hr per day from gestation Days 6 through 18 teratogenicity was much more pronounced: at 550 ppm, in the absence of clear maternal toxicity, the fetuses of all litters showed severe malformations. No maternal or fetal effects were observed at 145 and 36 ppm. Dermal application of 1000 and 2000 mg/kg to Himalayan rabbits from gestation Days 6 through 18 failed to produce maternal or fetal toxicity.

Abnormalities, Drug-Induced↗
PubMed1987

Classification of dangerous substances and pesticides in the European economic community directives: a proposed revision of criteria for inhalation toxicity.

Criteria for the classification of dangerous substances with respect to their inhalation toxicity were originally proposed by the European Economic Community (EEC) on the basis of a 1-hr LC50, as were the similar United Nations (UN) "transport" criteria. Both sets of criteria have since been amended for a 4-hr LC50, but whereas the UN criteria limits have been decreased to compensate for the increased exposure time, the EEC limits have not. This has introduced an anomaly into the EEC classification scheme whereby substances are classified more severely than they were previously. The EEC scheme is now out of line with the UN criteria and other international guidelines and gives a much more stringent toxicity classification for individual substances by inhalation than by the oral route, as well as causing an unjustifiable duplication of animal tests. This anomaly has led to a proposal by the Federal Republic of Germany for revised criteria. This paper examines the scientific basis for the relationship between inhalation exposure duration and toxicity, and for a comparison of the LD50 and LC50 classifications for individual substances. It is concluded that the proposed German revised classification scheme is more in line with the UN transport criteria and international guidelines and provides a rational basis for a classification scheme for inhalation toxicity. The classification criteria therefore should be harmonized by a revision of the EEC classification limits for inhalation toxicity.

Aerosols↗
PubMed1983

Vinylidene chloride: changes in drug-metabolizing enzymes, mutagenicity and relation to its targets for carcinogenesis.

Results of various studies have shown that male Swiss Webster mice are more susceptible to toxic effects of vinylidene chloride (VDC) than are females of the same mouse strain, females and males of the C57BL mouse strain, Chinese hamsters and rats. The main targets of toxicity are kidney and liver. The kidney of male Swiss Webster mice is the only organ where VDC unambiguously induces tumours. In the present study we have investigated the ability of NADPH-foritifed postmitochondrial supernatant fractions (S-9 mix) of kidney and liver from susceptible and nonsusceptible animals to activate VDC to a bacterial mutagen. The following sequence of activating potencies was observed: mouse liver (both strains and sexes) and Chinese hamster liver greater than rat liver greater than human liver greater than Chinese hamster kidney greater than kidney from male mice of both strains greater than kidney from rats and female mice. The last two preparations only occasionally showed weak activation of VDC. Addition of purified microsomal epoxide hydrolase to S-9 mix did not affect the mutagenicity of VDC; addition of glutathione reduced the mutagenicity up to 50%. Pretreatment of animals (male rats, male and female Swiss Webster mice) with VDC did not potentiate the ability of the subcellular preparations to activate this compound. In fact, in some cases, a weaker activation was observed. Following this treatment, microsomal 7-ethoxy-coumarin O-dealkylase was decreased in mouse kidney and in rat liver. The enzyme was not affected in mouse liver and was not measurable in rat kidney. Microsomal epoxide hydrolase activity (with styrene 7,8-oxide as substrate) was not affected in mouse liver and rat kidney. In the kidney of male mice treated with a high concentration of VDC, epoxide hydrolase activity was decreased initially, but after longer treatment, in some cases a weak increase above control was noticed. A stronger increase in activity of epoxide hydrolase was observed in the rat liver and the kidney of female mice. Cytosolic glutathione transferase activity (with 2,4-dinitrochlorobenzene as substrate) was not affected by the VDC treatment in the liver of male mice, but was decreased in the kidney of male mice, and was elevated in the kidney and liver of rats and of female mice. The different effects of VDC on this enzyme may be one of the reasons for the differences in susceptibility towards the toxic and carcinogenic actions of this compound in different species, strains and sexes.

Animals↗
PubMed1977

[Experimental investigations on the tumorigenic activity of cigarette smoke condensate on mouse skin. VII. Comparative studies of condensates from different modified cigarettes (author's transl)].

Condensate from different modified cigarettes were compared with condensate from a standard cigarette with regard to its tumorigenic activity on mouse skin. Significant lower effects were observed in test series with cigarettes from expanded tobacco. Different results were obtained in experiments with cigarettes from the new smoking materials. In one case the effect was higher, in two another cases the effect was lower in comparison to the effect of condensate from reference cigarettes. A certain influence may be referred to the diameter of the cigarette, i.e. a thinner cigarette shows a lower biological effect. The lowest tumoringenic effect was observed in tests with cigarettes with a high content of Burley-stems.

Animals↗
PubMed1977

[Quantitative determination of nitrogen oxide in cigarette smoke by means of chemiluminescence (author's transl)].

A measuring method with a chemiluminescence-analyzer is developed for determining the content of nitrogen oxide in cigarette smoke. This method is suitable for puff/puff analysis. It could be demonstrated that a determination of fresh smoke is necessary as nitrogen oxides react very quickly with other constituents of the vapor phase. Measured values have to be corrected for a quench factor in analogy to the CO2 concentration, as carbon dioxide shows an influence on the measuring sensitivity of the chemiluminescence-analyzer.

Luminescent Measurements↗
PubMed1977

Investigations of cigarette smoke dosages in inhalation experiments with Syrian hamsters. I. Concentration of cigarette smoke in the inhalation chamber and of carbon monoxide in the blood.

We tested 20 different smoke inhalation machines and determined that 60% of the gas phase and 40% of the total paritulate matter reached the inhalation chamber; the remainder was lost in the exhaust gases. After determining these concentration percentages, we were able to calculate precisely the dosage of each puff of smoke administered to Syrian hamsters in our smoking machine. We also determined that the CO-Hb content in the blood of the hamsters rose to 60%; this CO-Hb value was a limiting factor for time of exposure to smoke, since too-high concentrations of CO-Hb would have killed the animals. On the basis of these results, we concluded that the animals should be exposed as long as possible to attain a high dose of smoke, but because of toxic effects the exposure time should not exceed 20 minutes, and the CO-Hb content should not exceed 60%.

Air↗
PubMed1977

Investigations of cigarette smoke dosages in inhalation experiments with Syrian hamsters. II. Uptake of cigarette smoke by the animals; comparisons of the influence of the gas phase and the whole smoke of different cigarettes.

An increased CO2 content (CO2 enrichment) in the smoke-air mixture was measured in an inhalation chamber containing Syrian hamsters. Since these additional CO2 concentrations originated from the animals' expiratory air, the level of CO2 (CO2 enrichment) was considered a function of the respiratory capacity. Results obtained with this method of characterizing the respiratory behavior of hamsters in inhalation experiments led us to conclude that the vapor phase of cigarettes reduced respiration up to 45% and the whole smoke, up to 60%. Qualitative and quantitative differences in the composition of the vapor phase and particulate phase as offered in animal inhalation experiments for comparing different cigarettes did not induce measurable differences in the respiratory behavior. Therefore, such inhalation experiments were found to be suitable for comparing the relative effects of different cigarette types. Estimations on the inhaled amounts of TPM led to results that were similar to those obtained in experiments with radioactively labeled smoke.

Animals↗
PubMed1976

[Experimental studies on tumorigenic activity of cigarette smoke condensate on mouse skin. V. Comparative studies of condensates from different modified cigarettes (author's transl)].

The tumorigenic effect of smoke condensates from reference cigarettes and different modified cigarettes has been investigated on the mouse skin. The following results have been obtained: 1. Reconstituted tobacco sheets made from the blend of the reference cigarette T as well as different other tobacco mixtures showed a reduced tumorigenic effect. 50% or 20% of reconstituted tobacco sheets as additive to the tobacco T showed reduced tumorigenic effect too. 2. A dark tobacco mixture (cigar type) as well as the Virginia tobacco of the mixture T showed no significant differences in biological activity compared to the reference tobacco. Condensate of the Burley tobacco of the blend T showed a reduced tumorigenic effect. 3. A small amount of nitrate as additive (1.8% total nitrate) only showed a limited reduction of the tumorigenic effect. 4. Condensate of a cigarette with commercially used filters, 20% reconstituted tobacco sheets and a total nitrate content of 1.8% showed a distinctly reduced tumorigenic effect. 5. Statistical evaluations of this experiment indicated that each of the applied dose should not be too high. Application of high doses did not lead to a further increase of tumor incidence. Cytotoxicity and viscosity of higher concentrated solutions may be responsible for this fact.

Animals↗