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DNA damage (alkaline filter elution) and sister chromatid exchange (SCE) frequencies were measured in lymphocytes of 39 welders and 39 controls. The welders showed a significantly higher rate of DNA single-strand breakages and significantly elevated SCE values. These results are not in accordance with those of a former study in which only DNA-protein cross-links were measured. The different results may be explained on the basis of different exposure levels for chromium(VI) and nickel. Both methods are not specific but sensitive enough to measure genotoxic damage after occupational exposure to chromium(VI) and nickel in the range of threshold values for the workplace on a collective basis. Additionally, the results indicate that DNA single-strand breakage and DNA-protein cross-links show different increases depending on the exposure levels for chromium and nickel.

OBJECTIVES: To investigate the specificity of biological monitoring variables (excretion of phenanthrene and pyrene metabolites in urine) and the usefulness of some biomarkers of effect (alkaline filter elution, 32P postlabelling assay, measurement of sister chromatid exchange) in workers exposed to polycyclic aromatic hydrocarbons (PAHs). METHODS: 29 coke oven workers and a standardised control group were investigated for frequencies of DNA single strand breakage, DNA protein cross links (alkaline filter elution assay), sister chromatid exchange, and DNA adducts (32P postlabelling assay) in lymphocytes. Phenanthrene and pyrene metabolites were measured in 24 hour urine samples. 19 different PAHs (including benzo(a)pyrene, pyrene, and phenanthrene) were measured at the workplace by personal air monitoring. The GSTT1 activity in erythrocytes and lymphocyte subpopulations in blood was also measured. RESULTS: Concentrations of phenanthrene, pyrene, and benzo(a)pyrene in air correlated well with the concentration of total PAHs in air; they could be used for comparisons of different workplaces if the emission compositions were known. The measurement of phenanthrene metabolites in urine proved to be a better biological monitoring variable than the measurement of 1-hydroxypyrene. Significantly more DNA strand breaks in lymphocytes of coke oven workers were found (alkaline filter elution assay); the DNA adduct rate was not significantly increased in workers, but correlated with exposure to PAHs in a semiquantitative manner. The number of sister chromatid exchanges was lower in coke oven workers but this was not significant; thus counting sister chromatid exchanges was not a good variable for biomonitoring of coke oven workers. Also, indications for immunotoxic influences (changes in lymphocyte subpopulations) were found. CONCLUSIONS: The measurement of phenanthrene metabolites in urine seems to be a better biological monitoring variable for exposure to PAHs than measurement of hydroxypyrene. The alkaline filter elution assay proved to be the most sensitive biomarker for genotoxic damage, whereas the postlabelling assay was the only one with some specificity for DNA alterations caused by known compounds.

Between 1982 and 1990 seven cases of bladder cancer were detected in a group of 49 workers who were synthesising chlordimeform from 4-chloro-o-toluidine. Latency periods ranged from 15 to 23 years. The incidence of bladder tumours in this group was significantly higher than that of the cancer registers of the former GDR, Saarland, and Denmark by factors of 89.7, 53.8, and 35.0 respectively. This provides further evidence that monocyclic aromatic amines such as 4-chloro-o-toluidine may be carcinogenic in humans.

Comparative investigations with synthetic N7-phenylguanine were carried out to clarify whether this compound is eliminated via the urine of rats as a benzene-derived nucleic acid adduct. As sensitive methods for detecting trace amounts of the compound, gas chromatography-mass spectroscopy, high performance liquid chromatography, and two immunoassays (enzyme-linked immunosorbent assay and fluoroimmunoassay) with appropriate monoclonal antibodies were used. The results indicate the excretion of several benzene-related guanine adducts slightly different from N7-phenylguanine that may possibly be hydroxylated. These adducts differ also from (O6-, N2- and C8-phenylguanine, respectively.

Nach Behandlung mit Endoxan last sich bei Ratten ein fluchtiges Alkylans in der Ausatmungsluft nachweisen. Dieses wird auch nach Gaben von NH-Lost von den Tieren abgeatmet und konnte als N-2-Chlorathyl-aziridin identifiziert werden. Die ausgeatmeten Mengen betragen nach Endoxan-Gabe innerhalb von 8 Std etwa 1 Mol-% und sind dosisabhangig. Die Abgabe uber die Zeit verlauft mehr protrahiert als nach Gaben von NH-Lost, und insgesamt wird ein Mehrfaches abgeatmet, wenn man von den NH-Lost-Anteilen ausgeht, die nicht in der Bindung an unverandertes Endoxan bzw. seine Metabolite mit Harn und Faeces ausgeschieden werden. Die Abatmung des Alkylans wird als ein Entgiftungsmechanismus angesprochen, aus dessen Kenntnis sich weitere Einblicke in die komplizierten Verhaltnisse des Wirkungsmechanismus und der Pharmakodynamik des Endoxans gewinnen lassen.

Cyclophosphamid wird im Organismus durch Oxidation an C4 neben dem Ringstickstoff umgewandelt. Dabei entsteht mit geringem Anteil 4-Ketocyclophosphamid im wesentlichen aber das ringoffene Anion N,N-Bis-(2-chlorathylester)diamidophosphorsaure(2-carboxylathylester). Beide Verbindungen sind biologisch nicht aktiv genug, um die Wirkungen des Cyclophosphamids zu erklaren. Daher mus die wirksame Verbindung ein Prakursor des ringoffenen Anions sein oder unabhangig von den oxidativen Veranderungen an C4 entstehen. Ein Stoffwechselnebenweg fuhrt angeblich zu N3-Hydroxycyclophosphamid. Es liegen Hinweise fur die Annahme vor, das durch die Konstellation des wirksamen Metaboliten die Bildung hochreaktiver Aziridinringe begunstigt ist.

On experimental rat tumors, preferentially on DS-Carcinosarcoma, special glass electrodes were used to measure and to register development of tissue-pH after injection of glucose into the rats. On tumor surface pH-values were lowered more quickly and increased much faster as in tumor depth. The lowest registered pH was about 5,9. High s. c. dosages of Insulin caused a marked decrease of pH-values for nearly one hour too. In metabole effective small tumors tumor acidity could be regulated satisfactory with administered glucose and insulin between pH 7,0 and 6,0. Determination of lactate concentration in tumor tissue, surrounding the electrode, indicated a linear correlation between pH-value und lactate concentration in the range between pH 6,0 and 7,0. Regression coefficient comes to — 40,9 ± 2,2 ×10-3 mMol/g wet weight and pH-unit. It is emphasized that according to the varying cell supply the compact tumor shows no homogeneity on pH-rates, acidification kinetics, and sensibility against acidotic cell lesion. Results are criticized with reference to other publications and their significance for the theory of tumor lesion by alkylating agents is discussed.

Correlation of lactate-concentration and H⊕-concentration in tissue of rat DS-carcinosarcoma was tested with an improved method by intravital pH-measuring. After i. v. dosages of glucose the testing was effected by measurement of 24 points equally distributed within the pH-range of about 6.1 — 7.1. Therefrom we compute the acidification factor In the tested pH-range the factor is practically constant.

Die Wanderungsgeschwindigkeit von Rattenerythrocyten im elektrischen Feld wird durch Behandlung der Versuchstiere mit NH-Lost und Endoxan gegensatzlich beeinflust. Sie nimmt bei Behandlung mit Endoxan dosisabhangig zu. Die Zunahme wird als ein Mas fur die Adsorption steigender Mengen phosphathaltiger Endoxan-Metabolite an die Erythrocytenoberflache betrachtet, durch welche die negative Membranladung erhoht wird.