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Biomedical subjects

D Henschler

Publications and source records attributed to D Henschler.

At least 91 records · Page 5Linked to original sources
PubMed1984

Carcinogenicity study of trichloroethylene, with and without epoxide stabilizers, in mice.

Previous analytical studies of industrial samples of trichloroethylene (TRI) have revealed the presence of mutagenic and carcinogenic epoxides which, it was proposed, might be responsible for the carcinogenicity of such samples, as demonstrated with mice in other laboratories. To test this hypothesis, Swiss mice (ICR/HA) of both sexes, bred and kept in SPF conditions, were dosed daily with TRI in corn oil by gavage (males: 2.4 g/kg, females: 1.8 g/kg) with or without the addition of epichlorohydrin (EPC, 0.8%, w/w), 1,2-epoxybutane (BO, 0,8%), or EPC + BO (0.25% + 0,25%) for 18 months. The ensuing observation period terminated at 106 weeks (from start of experiment). Gross and microscopic examination of all organs revealed a statistically significant increase in the incidence of forestomach papillomas and carcinomas after EPC-, BO-, and (EPC + BO)-stabilized samples of TRI, but not after pure, amine base-stabilized TRI. This type of tumor is believed to be induced by the direct alkylating epoxides epichlorohydrin and epoxybutane, whose industrial use in stabilizing chlorinated aliphatic hydrocarbons should be discontinued. No other significant increase in tumor incidences was found. Again, this study does not support the suggestion that trichloroethylene itself is carcinogenic under realistic exposure conditions.

Animals↗
PubMed1984

Induction of morphological transformation and unscheduled DNA synthesis in Syrian hamster embryo fibroblasts by hexachlorobutadiene and its putative metabolite pentachlorobutenoic acid.

Hexachloro-1,3-butadiene (HCBD) is a well known environmental carcinogen. The genotoxic properties of HCBD and its monooxidation product pentachloro-3-butenoic acid (PCBA) were investigated by comparative induction of unscheduled DNA synthesis (UDS) and morphological transformation in the same cell system (Syrian hamster embryo fibroblasts). HCBD and PCBA induce unscheduled DNA synthesis both in the presence and absence of an exogenous metabolizing system. The lowest effective dose for UDS induction is smaller for PCBA (1 microgram/ml) than for HCBD (2 micrograms/ml). The intensity of UDS induction is increased about 3-fold for both compounds after metabolic activation. HCBD and PCBA induce morphological transformation. The lowest effective dose for transformation differs considerably between PCBA (0.8 micrograms/ml) and HCBD (10 micrograms/ml). The results are indicative of a genotoxic mechanism for the carcinogenic actions of HCBD and PCBA.

Animals↗
PubMed1984

Carcinogenicity of dichloroacetylene: an inhalation study.

Dichloroacetylene (DCA) is a by-product of the synthesis of certain chlorinated, aliphatic hydrocarbons (e.g., vinylidene chloride). In a long-term carcinogenicity inhalation study, groups of 30 male and 30 female rats and mice were exposed to DCA vapour under the following conditions: mice, group I: 9 p.p.m. 6 h/day, 1 day/week for 12 months; group II: 2 p.p.m. 6 h/day, 1 day/week for 18 months; group III: 2 p.p.m. 6 h/day, 2 days/week for 18 months; rats: 14 p.p.m. 6 h/day, 2 days/week for 18 months; controls: under identical conditions except for addition of DCA to breathing air. The most important result is a striking increase in the formation of kidney cystadenomas of the proximal tubuli in all DCA exposed animals. The median latency time of this tumor varied widely in both mice and rats. Renal cystic adenocarcinomas were found in statistically significant numbers in male mice. In addition to kidney tumors, the development of cystadenomas of the Harderian gland in mice and of liver cholangiomas in rats were highly significant findings. DCA failed to induce liver tumors in mice. Our results confirm that DCA possesses a high carcinogenic potential, pronounced organotropic properties and distinct species differences referring to the number and nature of the induced tumors. The risk associated with handling chlorinated aliphatic hydrocarbons is essentially increased by the decomposition product DCA.

Acetylene↗
PubMed1983

A new pathway of acrolein metabolism in rats.

The excretion of metabolites of acrolein in rat urine after single oral administration of 10 mg/kg was investigated. S-Carboxyethylmercapturic acid (S-carboxyethyl-N-acetyl-cysteine), or S-(propionic acid methyl ester)mercapturic acid, was found as the major metabolite. An unidentified metabolite was found in expired air. Acrylic acid and methyl acrylate are suggested as intermediates in the metabolism of acrolein.

Acrolein↗
PubMed1983

Mutagenicity of dichloroacetylene and its degradation products trichloroacetyl chloride, trichloroacryloyl chloride and hexachlorobutadiene.

Dichloroacetylene (DCA) is a highly reactive compound that decomposes rapidly in contact with air into a series of chlorinated aliphatic hydrocarbons (e.g., phosgene, trichloroacetyl chloride, trichloroacryloyl chloride and hexachlorobutadiene). Experiments were performed to compare the mutagenic properties of DCA and its degradation products on the histidine-dependent tester strains TA98 and TA100 of Salmonella typhimurium. In these experiments, DCA vapour was streamed under analytical control through the bacterial suspensions. DCA is soluble in aqueous solution and was stable under the experimental steady-state conditions of the bacterial exposure. There is a linear correlation between the supply of DCA vapour and solubilized DCA in the range of 1000 and 16 000 ppm. Mutagenic response was observed with strain TA100 if the bacteria were suspended in Oxoid medium. No mutagenicity could be detected with strain TA98. DCA mixtures with acetylene, as used as stabilizer for animal experiments, were not mutagenic in either bacterial strain, irrespective of the presence or absence of S9 mix in the cell suspension. One of the degradation products of DCA, trichloroacryloyl chloride, showed pronounced mutagenic properties with and without drug-metabolizing enzymes. Other degradation products of DCA, such as trichloroacetyl chloride and hexachlorobutadiene, were not mutagenic, either in the presence or absence of liver homogenate.

Acetylene↗
PubMed1983

Induction of unscheduled DNA synthesis in HeLa cells by allylic compounds.

Thirteen allylic compounds, mostly with close structural relationship, were tested for their ability to induce unscheduled DNA synthesis (UDS) in HeLa cells and mutations in the Ames test; 11 induced UDS in dose dependence. Allyl isothiocyanate was negative in UDS (borderline in the Ames test) and acrolein (positive in the Ames test) proved toxic to HeLa cells, therefore UDS measurement was excluded. In general, positive qualitative and quantitative correlation between UDS, Ames test and alkylating properties (as measured in the 4-nitrobenzyl-pyridine test, NBP) were found. Among structural analogs and typical allylic compounds with various leaving groups, the amount of induced DNA repair at equimolar concentrations decreased in the same order as the mutagenic and alkylating activities in the other 2 test systems: 1,3-dichloropropene (cis) greater than 1,3-dichloropropene (trans) greater than 2,3-dichloro-1-propene; 1-chloro-2-butene greater than 3-chloro-1-butene greater than 3-chloro-2-methyl-1-propene greater than allyl chloride; allyl-methane-sulfonate greater than -iodide greater than -bromide greater than -chloride.

Allyl Compounds↗
PubMed1982

Correlation of alkylating and mutagenic activities of allyl and allylic compounds: standard alkylation test vs. kinetic investigation.

Thirty-nine allylic and non-allylic compounds have been tested in the standard 4-(p-nitrobenzyl)pyridine (NBP) alkylating procedure and the Salmonella typhimurium mutagenicity assay. Fourteen of these were found directly mutagenic (without addition of S-9 mix activating enzyme system). With twelve of these compounds, a good correlation of alkylating and mutagenic potencies was established; the remaining two do not meet the chemical conditions of the NBP procedure on account of HCl elimination with these two compounds. The other 25 substances were inactive in both systems. The quantitative correlation proved to be almost linear in the lower activity ranges (E approximately 2; revertants/muml approximately 600). The reasons for some deviations from the linear relationship have been analyzed and discussed on the basis of structural features. In addition to the standard alkylation test, a modified NBP-test was performed in order to obtain kinetic data and activation energy values. The results with 6 representative allylic compounds show that the overall correlation is not substantially improved above that of the standard procedure: nonetheless, additional information on reaction characteristics is obtained with some substances.

Alkylating Agents↗
PubMed1982

Mutagenic properties of allylic and alpha, beta-unsaturated compounds: consideration of alkylating mechanisms.

1. Allyl and allylic compounds may exert alkylating activities by SN1, SN2 and SN2' mechanisms. This direct alkylating potential can be determined quantitatively by a modified 4-NBP (4-nitrobenzyl pyridine) test. 2. The alkylating activities in a systematically selected series of allyl and allylic compounds correlate well with the direct mutagenic potential as determined in the Ames test using Salmonella typhimurium TA 100 as tester strain. 3. The allylic structure is a prerequisite for these types of activities since structurally related molecules lacking the allylic moiety are inactive in this respect. 4. The potency of both the alkylating and mutagenic activity is determined by the strength of the leaving group: --OSO2CH3 greater than I greater than Br greater than Cl greater than--NCS. 5. Indirect mutagenicity, through metabolic activation of the olefinic bond (by addition of S9 mix to the tester medium), can be ruled out for practically all compounds, the only exception found being 2,3-dichloro-1-propene where an increase of mutagenicity is encountered after addition of S9 mix; mechanistic explanations for this exception are provided. 6. Analogous activation is demonstrated for benzyl halides, the alkylating potency of which is even higher than that of genuine allylic compounds. 7. A variety of methyl- and chlorine-substituted allyl compounds has been included in the study: both groups increase activity, either by +I (CH3) or by +M effects (Cl). 8. alpha, beta-Unsaturated carbonyl compounds, e.g. acrolein and crotonaldehyde, also display direct mutagenic activity which is due to a completely different mechanism: covalent binding to nucleophilic sites of DNA bases by Michael addition. Methyl and other alkyl substitutions decrease the mutagenic potential in this type of compound. The corresponding alcohols, also displaying mutagenic activity but to a lesser degree, are metabolically activated by ADH (alcohol dehydrogenase) of the tester strain microbes to the aldehydes or ketones.

Alkylating Agents↗
PubMed1981

[Halothane hazards for the team in the operation theatre (author's transl)].

Reports on undesirable side effects of halothane in patients undergoing anaesthesia and in persons with long-term exposure in the operation theatre require establishment of safe upper limits and of methods for monitoring. The main metabolite trifluoroacetic acid is most suitable for biological monitoring. During systematic exposure with graded halothane concentrations (8, 24 and 50 ppm, 6 hours daily, 5 days weekly, for one and two weeks) trifluoroacetic acid concentrations in blood and urine were determined regularly. It was shown that for biologic monitoring estimation in blood is clearly preferential to estimation in urine because of a narrower scatter. At the end of one week of exposure a steady state concentration is found in blood. There is a linear relation between its height and the inhalation concentration of halothane. A trifluoroacetic acid concentration of 2.5 micrograms/ml is considered as a risk-free value. This corresponds to a maximal theatre air concentration of 5 ppm halothane.

Halothane↗
PubMed1981

[Osteoporosis therapy and thyroid function. Influence of 6 months of sodium fluoride treatment on thyroid function and bone density].

26 women were treated for osteoporosis with 40 mg of sodium fluoride twice a day (equivalent 36 mg of fluorine) for a longer period. Mostly by reason of incompatibility, a reduction to half of the dose was necessary in six of these patients. The control of plasma fluoride concentration indicated that only 10 patients took their medicine regularly. Before treatment as well as three and six months after beginning of treatment the patients were examined. In these examinations bone density was measured across the middle phalanx of the middle finger with a I-125-profile scanner. Size and function of the thyroid gland were evaluated by clinical aspects and with in vivo- and in vitro-methods for thyroid diagnostic. The program includes also a check up with a 12 canal-serum-autoanalyzer. In 10 patients with warranted regular intake of the drug the increase of bone density was significant after three months already. In all 26 patients a considerable increase of the alkaline phosphatase after three months was evident. Under the influence of sodium fluoride no change was seen in function and size of thyroid gland. This result verifies the efficiency of sodium fluoride in osteoporosis-therapy without any measurable influence on thyroid function.

Alkaline Phosphatase↗