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Chlorohydroxyfuranones (CHFs) are mutagenic disinfection by-products found in chlorine-treated drinking water. In the current study, the genotoxicity of four CHFs, 3,4-dichloro-5-hydroxy-2(5H)-furanone (MCA), 3-chloro-4-methyl-5-hydroxy-2(5H)-furanone (MCF), 3-chloro-4-(chloromethyl)-5-hydroxy-2(5H)-furanone (CMCF) and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (MX), was determined. Two in vitro assays, the microscale micronucleus assay on L5178Y mouse lymphoma cells and the unscheduled DNA synthesis assay on a hepatocyte primary culture from Fisher F344 rats, were carried out. All four CHFs demonstrated genotoxic effects in both assays. In the two systems used, CMCF was the most genotoxic compound, followed by MCA, MX and MCF, respectively. This work was the first study of the DNA damaging properties of all four CHFs in two in vitro genotoxicity tests. These new data expand the range of genetic damages induced by this group of compounds.

New developments in mutagenic risk assessment have appeared in the past few years. New methods have been developed such as in vitro micronucleus assay for chromosomal alterations, comet assay for primary DNA damage, use of transgenic animals to detect in vivo gene mutations, and fluorescent in situ hybridization method to detect aneuploidy. Other new methods will be developed in the few next years, including the use of DNA chips and the use of molecular biological methods. Several micromethods have been developed to test a great number of chemical compounds. New concepts have appeared concerning interpretation of data, and particularly of thresholds especially in the case of aneugens; in some cases metabolic or mechanistic thresholds were demonstrated. Genotoxic studies are best integrated into toxicological testing: for example, some genotoxicity tests can be integrated into subacute toxicology; interpretation of data includes metabolism; and toxicokinetic data relate to other toxicological studies. Conversely, genotoxicity data can be used to interpret toxicology studies.

A micromethod for the in vitro micronucleus assay was developed using L5178Y cells to enable the rapid screening of a large number of molecules. The method is quick, simple to perform and needs very small amounts of compound, i.e.

Three short-term assays (SOS chromotest, Ames fluctuation test and newt micronucleus test) were performed to detect the genotoxic activity of organohalides, compounds likely to be found in chlorinated and/or ozonated drinking water: monochloro-, dichloro- and trichloroacetic acids and mono-bromo-, dibromo- and tribromoacetic acids. With the SOS chromotest, only three of the chemicals studied (dichloroacetic acid, dibromo- and tribromoacetic acids) were found to induce primary DNA damage in Escherichia coli PQ 37. In the Ames fluctuation test, all the compounds except monochloroacetic acid showed mutagenic activity in Salmonella typhimurium strain TA100. In these two in vitro tests, a good correlation between increasing number of substituents and decreasing mutagenicity was observed. Namely, the toxicity of brominated and chlorinated acetic acids decreased when the number of substituents increased. The newt micronucleus test detected a weak clastogenic effect on the peripheral blood erythrocytes of Pleurodeles waltl larvae for trichloroacetic acid only.

Three short-term assays (the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test) were carried out to evaluate the genotoxicity of four trihalomethanes (chloroform, bromodichloromethane, chlorodibromomethane and bromoform). With the SOS chromotest, all the chemicals studied except chloroform were found to induce primary DNA damage in Escherichia coli PQ37. In the Ames-fluctuation test, only bromoform showed mutagenic activity on Salmonella typhimurium strain TA100. The newt micronucleus assay detected a clastogenic effect on the peripheral blood erythrocytes of Pleurodeles waltl larvae for bromodichloromethane and bromoform. It appeared that the presence of bromine substituent(s) generally led to significant genotoxic activity. Moreover, the use of the metabolic system significantly increased the genotoxicity of the brominated trihalomethanes in the SOS chromotest. Unlike previous investigations in which the SOS chromotest was always the least interesting assay, this study exhibited the good efficiency of this in vitro test on E.coli for the detection of trihalomethanes with bromine substituents.

Three short-term assays (the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test) were carried out to evaluate the genotoxicity of six halogenated acetonitriles identified in chlorinated waters (monochloro-, dichloro-, trichloro-, monobromo-, dibromo- and bromochloroacetonitrile). With the SOS chromotest, three of the chemicals studied (dichloro-, dibromo- and bromochloroacetonitrile) were found to induce primary DNA damage in Escherichia coli PQ37. In the Ames-fluctuation test, all the compounds except dibromoacetonitrile showed muta- genic activity on Salmonella typhimurium strain TA100. The newt micronucleus assay detected a clastogenic effect on the peripheral blood erythrocytes of Pleurodeles waltl larvae for all the six haloacetonitriles studied. Moreover, two structure-activity relationships were noted: (l) the genotoxic activity of haloacetonitriles containing bromine substituents appeared higher than the corresponding chlorinated acetonitriles and (2) the clastogenic activity of the chlorinated acetonitriles increased with the number of chlorine substituents.

Three short-term assays (the SOS chromotest, the Ames-fluctuation test and the newt micronucleus test) were carried out to evaluate the genotoxicity of five chlorinated propanones identified in several chlorinated waters (monochloropropanone, 1,1-dichloropropanone, 1,3-dichloropropanone, 1,1,1-trichloropropanone and 1,1,3-trichloropropanone). In the SOS chromotest, all the compounds except monochloropropanone were found to induce primary DNA damage in Escherichia coli. With the fluctuation test, all five chloropropanones showed mutagenic activity on Salmonella typhimurium strain TA100. The newt micronucleus assay detected a clastogenic effect on the peripheral blood erythrocytes of Pleurodeles waltl larvae only for 1,3-dichloropropanone and 1,1,3-trichloropropanone. Moreover, two structure-activity relationships are noticeable: (1) chloropropanones with chlorine substituents on both carbon positions (1,3-DCP and 1,1,3-TCP) are by far more genotoxic than chloropropanones substituted only on one carbon position (1,1-DCP and 1,1,1-TCP); (2) the increase of the number of chlorine substituents decreases the mutagenic activity (fluctuation test) of the chlorinated propanones studied.

24 depressed inpatients received a standardized treatment by imipramine, 6 among them receiving also levomepromazine. Plasma concentrations of imipramine and DMI were controlled weekly during the study, and standardized assessment of clinical state were made by a psychiatrist who was unaware of biochemical findings. Interaction between the antidepressant and neuroleptic metabolism is shown by a significant increase of DMI levels, though the clinical effect of the drug association could not be asserted. The therapeutic effect seems mainly dependant of etiology of depression. Endogeneous depressions improve more than other types. Among endogeneous depressions a significant correlation was found between the degree of clinical improvement after three weeks and DMI level, sum of imipramine + DMI level, but not with concentration of imipramine alone.

The mutagenicity of eight anthracycline derivatives, doxorubicin (adriamycin, ADM), daunorubicin (DNR), rubidazone (zorubicin), detorubicin (DTR), 4'-epi-adriamycin (4' epi-ADM), AD 32, N-leucyl daunorubicin (N-leu DNR) and aclacinomycin A, has been tested on Salmonella typhimurium TA 100, Ta 98, TA 1535, TA 1537 and TA 1538. All but aclacinomycin A were mutagenic. Adriamycin and daunorubicin were mutagenic in all five strains, but only at very high doses (40-100 micrograms/plate) in TA 1535 and 1537. TA 98 was the most sensitive strain. In general S9 mix (liver homogenate) increased the mutagenicity of the low doses of both compounds. Zorubicin, 4'-epi-adriamycin and detorubicin were mutagenic for TA 98 and TA 100 and slightly mutagenic in TA 1538. They were also activated by S9 mix. N-leu DNR and AD 32 were slightly but significantly mutagenic for TA 98 and TA 1538 and were also activated by S9 mix. Aclacinomycin A lacked mutagenic activity in the five strains even at cytotoxic doses, both in the presence and absence of S9 mix. The results with AD 32 N-leu DNR and aclacinomycin A strengthen the hypothesis according to which amino moiety of the anthracycline glycosides is essential for mutagenesis.

Summary Radioimmunoassay, rate nephelometric inhibition immunoassay and substrate-labelled fluorescent immunoassay were employed for the quantitative determination of dibekacin in serum. The cross-reactivity of the antibody provided with each assay allowed the use of tobramycin assay procedures for measuring dibekacin concentrations. With radioimmunoassay and nephelometric immunoassay, a dibekacin calibration curve was required, whereas fluorescent immunoassay was directly suitable for dibekacin assay, with cross-reactivity of nearly 100%. This allows the purchase of one assay kit for testing two antibiotics and thus reduces the cost to medical laboratories.