Questionnaire or objective assessment for studying exposure to tobacco smoke among asthmatic and healthy children: The French VESTA Study.

BACKGROUND: The underreporting of environmental tobacco smoke (ETS) exposure by parents of study children may depend on the instrument used and population studied, underlining the need for questionnaire validation in specific study settings. This study explores the validity of parent-reported ETS exposure in a French multicenter study on asthma. METHODS: The study population was composed of 313 children ages 4 to 14 years. Exposure to ETS was evaluated both by questionnaires on recent ETS exposure and by assessment of urinary cotinine by an enzyme immunoassay. RESULTS: According to parents' reports, about one-third of children were exposed to ETS within the past 2 days before cotinine measurement, and on average 14.9 +/- 15.4 cigarette-equivalent were smoked in their homes. The mean urinary cotinine was 435 +/- 530 nmol/mol creatinine and increased with the reported number of cigarette-equivalents smoked at home but it did not differ between children registered as being exposed to 1-10 cigarettes and children registered as unexposed. Agreement between questionnaire and urinary cotinine was moderate to poor according to our correlation coefficient (0.22) and kappa coefficient (0.09). CONCLUSION: These results show that our questionnaire is not discriminating enough to distinguish between nonexposure and mild exposure, but reveals gradients of higher exposure.

Exposure to traffic pollution: comparison between measurements and a model.

French researchers from the Building Scientific and Technical Center have produced a traffic-exposure index. To achieve this, they used an air pollution dispersion model that enabled them to calculate automobile pollutant concentrations in front of subjects' residences and places of work. Researchers used this model, which was tested at 27 Paris canyon street sites, and compared nitrogen oxides measurements obtained with passive samplers during a 6-wk period and calculations derived from the model. There was a highly significant correlation (r = .83) between the 2 series of values; their mean concentrations were not significantly different. The results suggested that the aforementioned model could be a useful epidemiological tool for the classification of city dwellers by present-or even cumulative exposure to automobile air pollution.

Usefulness of markers in managing tobacco withdrawal.

To evaluate the usefulness of tobacco markers in dependent smokers being treated with transdermal nicotine patches, a study was conducted at the Tobacco Withdrawal Consultation Centre at the Hôpital Laennec, Paris, France. 125 patients were included in the study and, in a first time, carbon monoxide in exhaled air, carboxyhaemoglobin, urinary nicotine and cotinine, Fagerström index, were measured and correlated to the amount of nicotine inhaled per day. The most significant value was observed for cotinine. In a second time, 25 patients were followed clinically and biologically with urinary continine monitoring (group FC) and 73 were followed up only clinically (group FC). The success rate of therapy 12 weeks after the end of treatment was 72% in group FB and 28% in group FC. The nicotine patch dose was positively correlated (p < 0.01) with successful outcome. The lower the urinary cotinine level at 4 weeks, the more likely was successful outcome (p < 0.05). If psychological factors remain important, urinary cotinine monitoring in the course of nicotine patch treatment thus favours successful withdrawal.

Use of Salmonella typhimurium TA 98, YG 1024 and YG 1021 and deconjugating enzymes for evaluating the mutagenicity from smokers' urine.

Four smokers were chosen for their different smoking habits, and their declared cigarette consumption confirmed by urinary measurement of nicotine and its metabolites. The promutagenicity of their urine was evaluated by the Ames test, modified according to Kado et al. (Mutation Res., 31 (1983)25-32) after extraction on XAD2 Amberlite resin. The different Salmonella typhimurium strains TA 98, YG 1021 and YG 1024 were compared to determine the presence of amino aromatic compounds in the urine of smokers of blond and black tobacco. The strain YG 1024 shows higher mutagenicity than TA 98 for extracts from the smoker's urine and more particularly from black tobacco smokers. In addition, the pretreatment of urine by external enzymatic systems (beta-glucuronidase or arylsulfatase) reveals the presence in the urine of glucurono- and sulfoconjugated forms of promutagens, including amino aromatic compounds.

Relationship between acid neutralization capacity of saliva and gastro-oesophageal reflux.

Saliva is an important factor in neutralization of oesophageal acid exposure, clinically manifested as gastrooesophageal reflux (GOR). The aim of this study is to compare the composition and the "capacity in acid neutralization" (CAN) of saliva in controls and patients suffering of GOR. We compared the composition of saliva from 56 patients who had symptoms of GOR with that of saliva from 20 healthy control subjects. After a standardized 24-hour period of pH-monitoring, 39 patients had normal pH reflux scores (normal acid score: NAc-GOR) and 17 had abnormal pH reflux scores (pathological acid score: PAc-GOR). Then, following a 10-h fast, total saliva was collected during ten minutes in all patients and in the healthy control subjects. The composition of the saliva samples was analysed and the titration curve was determined on 200 microliters aliquots by successive addition of 5 microliters volumes of 0.1 N Hcl. The GOR patients had significantly lower salivary concentrations of Na+ and of both free and bound sialic acids and had higher salivary concentrations of inorganic phosphates than the controls. These disorders were more marked in PAc-GOR patients. Initial pH was 7.43 +/- 0.43 in controls, 7.35 +/- 0.45 in NAc-GOR patients, and 6.91 +/- 0.53 in PAc-GOR patients. In the beginning of the titration curve, PAc-GOR patients were significantly different from NAc-GOR patients and from controls. Saliva of both groups of patients presented significant differences in the acidic portion of the titrations curves, at high volumes of added HCl. These data show that the composition of saliva was modified in patients with GOR disease compared to that of normal subjects. A difference in titration curves was also observed with a higher acidic buffering capacity in these GOR patients. The modifications in saliva composition suggest a role for inorganic phosophates in the acid neutralization capacity observed in GOR, perhaps linked with a adaptation to chronic acid exposure.

Urinary promutagens of smokers: comparison of concentration methods and relation to cigarette consumption.

Different extraction techniques can be used to concentrate the promutagens of cigarette smokers' urine before evaluation of their mutagenic potency by Ames test. In this study, three solid adsorbents, C18, XAD2 and CN were compared for their ability to concentrate the promutagens of smokers' urine prior to acetone elution. C18 extracts were observed to have a higher promutagenicity than XAD2 and CN extracts. The mutagenicity of smokers' urine depended on the smoking habits, and a strong correlation was observed between urinary promutagenicity, daily cigarette consumption, and the tobacco type (black or blond). Smokers of black tobacco had a higher urinary genotoxicity than smokers of blond tobacco, after taking into account the level of tobacco consumption. Urinary promutagenicity did not appear to depend on the tar level of cigarettes.

A new anthracycline with potent antileukemic activity exhibits reduced mutagenicity.

The mutagenicity of a new anthracycline (moflomycin) with potent antileukemic activity was studied by the Ames test in four strains of Salmonella typhimurium (TA97a, TA98, TA100 and TA102), and compared to the mutagenicity of doxorubicin, widely used as antineoplastic agent. Unlike doxorubicin, moflomycin displayed no mutagenic activity in strains TA98 and TA100. Low mutagenicity was only observed in TA102 strain and was not enhanced after metabolic activation. This result indicates that moflomycin induce mutagenicity by reverting base-pair substitution. The structural changes in the sugar moiety may be involved in the reduced mutagenicity of moflomycin. The low mutagenicity of moflomycin shown in this study enhances the potential advantage of this new derivative which displays a high antileukemic activity.

Smokers' behaviour and exposure according to cigarette yield and smoking experience.

The influence of cigarette yield and length of smoking experience on smoking behaviour and biomarker levels was sought in 108 smokers who have never changed cigarette class. Smoking parameters carboxyhaemoglobin percentage (COHb), urinary nicotine, and its metabolites, mutagens, and thioethers were measured. Cigarette yield does not affect daily consumption or smoke volume puffed per cigarette. But the inhalation depth increases with decreasing cigarette yield and with length of smoking habit. The COHb level after the first cigarette in the morning increases significantly with CO cigarette yield and length of smoking experience. In the evening, only the cigarette yield has an effect on COHb level. Biomarker levels excreted in urine are generally lower for females than for males. They tend to increase with smoking history. Only COHb level and total urinary nicotine metabolites (Barlow index) are weakly correlated with cigarette yield. The absence of significant differences due to cigarette class in urinary biomarkers can be explained by changes in inhalation depth, individual differences of metabolism, and limited specificity of some markers (mutagens, thioethers).

Structure-mutagenicity relationships in series of 11H-indolo[3,2-c]quinoline-1,4-diones, tetrahydro-11H-indolo[3,2-c]quinoline-1,4-diones and 11H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline-1,4-diones with leukemia cytotoxic properties. Relations with topoisomerase I inhibiting properties.

Six heterocyclic quinones with topoisomerase I inhibiting properties and cytotoxic activities on L1210 leukemia cells were studied for their mutagenicity in four strains of Salmonella typhimurium. The tested compounds are 3-methoxyindolo[3,2-c]quinoline-1,4-diones and their derivatives in which the common pyrroloquinoline nucleus is annelated either with a benzene or a cyclohexane on a pyridine ring. Almost all quinones were found to be direct-acting mutagens at different levels in all strains, mainly TA97a and TA98. Relations were established between their structure and their mutagenic activities. The mutagenicity was found to be influenced (i) by the nature of the fourth nucleus: the pyridinic compounds were the most active, the non-aromatic ones were practically inactive; (ii) by the presence of a methyl group in the 6-position that decreased the mutagenicity. Then, the mutagenic properties were compared with the topoisomerase I inhibiting property that is one of the possible mechanisms of action for these cytotoxic quinones. The results indicated a correlation between mutagenicity and enzyme inhibiting properties.

Structure-mutagenicity relationships in a series of indolo[3,2-c]quinoline-1,4-diones that have shown cytotoxic properties on leukemia cells.

A series of seven 6-methylindolo[3,2-c]quinoline-1,4-diones substituted either in the 2 position or in 3 position by various groups were examined for their ability to induce mutation in the Ames test at several concentrations in four strains of Salmonella typhimurium (TA97, TA98, TA100, and TA102). First, relationships were established between their mutagenic activities and either the nature or the position of the substituent on the quinonic nucleus. Compounds substituted in the 2 position were less mutagenic than the 3 isomers. In the second study, the mutagenic properties were compared to the in vitro antitumor activity. Interestingly, some very cytotoxic quinones were only weak mutagens. So where the cytotoxicity is similar, the less mutagenic compounds may be suitable for clinical use as antitumor drugs, in order to avoid important side effects; the Ames test can then be used guide the selection of molecules for further in vivo antitumor screening. It can also be very helpful in selecting the best candidate molecules to be synthesized.

Structure-activity relationships of a series of antitumoral 5,8-quinazolinediones in mutagenicity studies.

Four antitumoral 5,8-quinazolinediones were examined for their ability to induce mutation in Salmonella typhimurium. Each compound was tested at several concentrations in 4 strains. Relationships were established between the structure of the quinones and their mutagenic activities. The mutagenicity was influenced by (i) the nature of the substituent(s) of the quinonic moiety: the methoxyquinone had no mutagenic properties and the aziridinylquinones were mutagenic in the 4 strains with or without activation by S9 mix; (ii) the presence or the absence of a diaminopolymethylenic chain in the 4 position; (iii) the monomeric or the dimeric structure of the tested compound. Interestingly, the data indicated that the aziridinylquinazolinedione bearing the dimethylaminopropylamino chain in the 4 position was less mutagenic and had greater antitumor activity than the dimeric quinone.

[Mutagenic activity of the condensates from thermal decomposition of different polyamides]. / Activité génotoxique de condensats provenant de la décomposition thermique de différents polyamides.

The mutagenic activity of the condensates from oxydative pyrolysis of various polyamides at 500, 800 and 1,000 degrees C has been searched for by AMES preincubation test in strains TA 98 and TA 100 with or without metabolic activation by an Aroclor 1254 induced rat liver microsomal S9mix fraction. All condensates are mutagenic in the presence of this fraction and most of them are far less or not mutagenic in the absence of S9mix. Strain TA 98 is more sensitive than strain TA 100 for detecting the mutagenic activity of these condensates. So, they mainly contain indirect mutagenic substances responsible for frameshift mutation. In all cases, mutagenic activity is maximum at 800 degrees C. This observation should draw the attention upon the genotoxic (carcinogenic) long term risk induced by thermal decomposition of plastics and then upon the necessary protection of firemen and others in charge of domestic or hospital solid waste incineration.

[Mutagenic activity of organic esters are likely to form from bromo-2 ethanol generated during fumigation using ethylene oxide]. / Activité mutagène d'esters organiques susceptibles de se former à partir du bromo-2 éthanol résultant de la fumigation par l'oxyde d'éthylène.

The mutagenic potencies of 13 bromoethyl esters of natural organic acids, have been studied, by Ames's test (strains TA 98 and TA 100, with and without system of metabolisation, S9 mix). None of the 8 bromoethyl esters of linoleic, oleic, palmitic, stearic, lauric, myristic, cinnamic and fumaric acids is genotoxic. On the other hand the 5 others derived from gallic, oxalic, tartric acids (strain TA 100 with and without S9 mix), malic and citric acids (strain TA 100 with S9 mix) are mutagenic, the ester of gallic acid giving still a doubtful mutagenic response; their mutagenic potencies are 2 to 3 times smaller than that of bromo-2 ethanol. This observation, complemently with the mutagenicity of some organic esters of the chloro-2 ethanol, proves the potential danger of ethylene oxide used for the fumigation of foods or vegetables and medicinal plants containing much chloride and/or bromide.

Genotoxicity of organic extracts from atmospheric particles.

Experiments to evaluate the genotoxic potentialities of urban air particles sampled in Paris (France) after organic solvent extraction have been carried out using four in vitro genotoxicity tests. The two bacterial tests (the Ames test and the SOS Chromotest) demonstrate the genotoxicity of the organic extracts of atmospheric particles; two additional tests (induction of 6-thioguanine mutants and sister chromatid exchanges), carried out on V79 Chinese hamster cells, also confirm these potentialities. These results show clearly that particulate organic extracts induce point mutations in both bacteria and mammalian cells, or the cellular response (SOS repair) to these mutations in bacteria; likewise, they are responsible for clastogenic effects in mammalian cells. Genotoxicity is due either to direct genotoxic chemicals or to active metabolic products of the action of microsomal enzymes. The optimalization of testing procedures is discussed in order to appreciate the contribution of genotoxicity tests to the study of atmospheric pollution.

Mutagenicity in urine from nurses handling cytostatic agents.

A cohort study of 29 nurses who extensively handle cytostatic drugs, 29 controls matched on sex and age, and seven patients under chemotherapy was carried out between 1983 and 1985. In a first study, urinary mutagenicity assays performed with the Ames test towards Salmonella typhimurium TA 98 with and without S9 mix gave an increased mutagenic activity, although not significant, for nurses as compared to controls, after adjustment on smoking habits. The results of mutagenicity assays for patients were significantly higher (P less than 0.01) than for non-smoker nurses and non-smoker controls with TA 98 without S9 mix. Of the 29 pairs, complementary assays were performed for non-smokers, that is 11 nurses and 11 matched controls, with TA 98, TA 100 and TA 1535 +/- S9 mix. A significant increase in mutagenic activity (P less than 0.05) was detected for nurses as compared to matched controls towards TA 98 with and without S9 mix. Moreover, the mutagenicity was significantly increased (P less than 0.05) in nurses who handled at least one electrophilic agents as compared to nurses who handled non-electrophilic drugs towards TA 98 with and without S9 mix.

Trehalase activity in genetically diabetic mice (serum, kidney, and liver).

Trehalase activity was determined in serum, liver, and kidney in alloxan treated Swiss mice and in homozygous (Ob/Ob, Db/Db) and heterozygous (Ob/+, Db/m+) diabetic mice. Both alloxan and genetic diabetic mice exhibited a large increase in serum and liver trehalase activity with no change in kidney trehalase activity. The heterozygotes (Ob/+, Db/m+) showed only a slight increase of enzyme activity. Further quantitative differences were noticed between the genetic and alloxan diabetic animals. The liver enzyme activity increased from 10- to more than 20-fold in the liver of the homozygous Ob/Ob and Db/Db strains and only 3-fold (not significant compared to controls) in the alloxan treated animals. The above results suggest a regulatory relationship between the genes coding for trehalase and the enzymes of glucose metabolism activity involved in the development of the metabolic anomalies of diabetes. The structural gene for trehalase may well have survived elimination of selective pressure during phylogenesis and remained part of a co-regulated group of glucose metabolising enzymes. This could explain its sensitivity to mutations affecting glucose metabolism and its sensitivity to insulin directed regulatory mechanisms.