1,720,994 research outputs found
[Dosimetry of DNA and protein adducts in occupational health]
No full textGenotoxic carcinogenic compounds react chemically with DNA and proteins to form covalent adducts which, in the case of DNA adducts, are strongly believed to be the first step in cancer process (biologically effective dose). The paper reviews the main studies on the dosimetry of adducts in the biological monitoring of occupational exposure to mutagens and carcinogens. Dosimetry of DNA adducts has been used to assess exposure to polycyclic aromatic hydrocarbons in environments such as foundries, coke ovens and the aluminium industry. In many cases, adduct levels higher than those of control populations were found in exposed workers. Only one study reported increased levels of DNA adducts in workers exposed to styrene. Dosimetry of hemoglobin adducts has been used to identify occupational exposure to ethylene oxide, styrene, BaP and arylamines. The results obtained in the last few years confirm the usefulness of dosimetry of DNA and protein adducts in assessing occupational exposure to genotoxic carcinogens occurring in working environments, even at very low exposure levels, but the methods in question require high standardization and validation if systematic errors in measurement are to be avoided. In the coming years, dosimetry of adducts, together with evaluation of individual genetic sensitivity to mutagens and carcinogens, will be one of the new frontiers in research on the prevention of occupational cancer. Current research already makes use of sophisticated analytical techniques such as mass spectrometry, and both specificity and sensitivity in the determination of adducts have been considerably improved. In the future, therefore, dosimetry of adducts may also be applied to industrial health practices
[Individual susceptibility to occupational carcinogens: the evidence from biomonitoring and molecular epidemiology studies]
No full textThis paper reviews the literature on the influence of metabolic and DNA repair polymorphisms of biological indicators of genotoxic risk commonly used in biomonitoring occupational exposure to carcinogens. Genetic polymorphisms which influence biomarkers (urinary metabolites, protein and DNA adducts), include P450 cytochromes (CYPs) and glutathione S-transferases (GSTs) in exposure to polycyclic aromatic hydrocarbons (PAHs), and acetyltransferases (NATs) in exposure to aromatic amines (AAs). As regards exposure to benzene, also relevant is the influence of epoxydohydrolase (EPHX) and NAD(P)H quinone oxidoreductase (NQO1) on the urinary excretion of t,t-muconic and phenylmercapturic acids. With respect to occupational exposure to styrene, EPHX significantly influences the levels of Chromosome Aberrations (CAs), strongly predictive genotoxic biomarkers of cancer risk. Some recent studies examine the role of polymorphisms linked to DNA repair genes in the modulation of genotoxic risk associated with PAH exposure, both for life-style (dietary and smoking behaviour) and for occupational reasons. In addition, molecular epidemiology studies (case/control studies) of lung cancer in smokers published since 2000 may also be viewed as representing models of effects due to exposure to carcinogenic mixtures, some of which are present in the working environment (e.g., BaP, benzene, AAs). Almost all studies show the clearcut influence (i.e., increased lung cancer risk with OR > or = 2) of genetic polymorphisms linked to PAH metabolism (in particular, CYPIA1, GSTM1 and P1). Among the risk factors are the different mutagen sensitivity towards, for instance, bleomycin and BaP (tested in vitro), the reduced repair capacity to DNA damage induced by BaP, and increases in some biomarkers of early biological effect (DNA adducts and stable CAs). Other risk factors, such as heredity (siblings of cancer patients have a risk factor > or = 3 with respect to the general population), ethnicity (Chileans > Caucasians; Japanese > Americans) and gender (women > men), have still not been clearly characterized and these are also reported in this paper. It is clear from the above that genetic differences underlie individual susceptibility to lung cancer, whether caused by exposure to tobacco smoke or to occupational carcinogens like PAHs. Some of these indicators of exposure/individual susceptibility can be evaluated in groups at high risk of occupational lung cancer, such as coke-oven and aluminium workers and those exposed to coal tar fumes and soot, etc., with the aim of identifying subjects who are susceptible due to the high concentrations of carcinogens found in their working environment
[Biomarkers of gentotoxic risk and metabolic polymorphism]
No full textThis paper reviews studies published in the international scientific literature evaluating the influence of genetically based metabolic polymorphisms on biological indicators of genotoxic risk in environmental or occupational exposure. Exposures due to life style (i.e. diet or smoking) were not considered. Indicators are subdivided into internal dose indicators (concentration of the substance or its metabolites in biological fluids, urinary mutagenicity, adducts of hemoglobin, plasma proteins and DNA), and early biological effects (chromosome aberrations, sister chromatid exchanges, micronuclei, COMET assay, HPRT mutants). The metabolic genotypes (or phenotypes) examined by various authors are: ALDH2 (aldehyde dehydrogenase), CYP (P450 cytochrome) 1AI, CYP1A2, CYP2E1, CYP2D6, EPHX (epoxidohydrolase), NAT2 (N-acetyl transferase), NQO1 (NAD(P)H: kinone oxidoreductase), PON1 (paraoxonase), GST (glutathione S-transferase) M1, GSTT1 and GSTP1. In more than half the studies (52 out of 96), no influence of genotype was found in the biological indicator. This may be due either to the poor sensitivity of the indicator used, or to low exposure. In studies examining the effect of genotype on the indicator, the biological plausibility of the result was evaluated, i.e., whether the effect is consistent with the type of enzymatic activity expressed. Four studies reported not very reliable results and suggest either the unfavourable influence of genotype GSTM1 with high detoxifying activity, or enzymatic activity poorly involved in the metabolism of the xenobiotics in question (NAT2 in the case of PAH). As regards urinary metabolites of genotoxic agents, eight studies reported the modulating effect of genotype. The urinary excretion of mercapturic acids was greater in subjects with high GST activity. In exposure to PAH, urinary 1-pyrenol and PAH metabolites turn out to be significantly influenced by genotypes CYP1A1 or GSTM1 null; in exposure to aromatic amines, the influence of NAT2 on exposure indicators (levels of acetylated and non-acetylated metabolites) was confirmed. Exposure to benzene led to an increase in t-t-MA in some genotypes, although experimental verification is still necessary. As regards urinary mutagenicity, the effect of genotype GSTM1 null is reported, and of the same genotype combined with NAT2 slow, in non-smoking individuals subjected to high exposure to PAH and in cigarette-smoking/coke-oven workers. Lastly, the determination of urinary metabolites in monitoring exposure to genotoxic substances, provides sufficient evidence that genetically based metabolic polymorphisms must be taken into account in the future. There is still little evidence regarding the importance of genotype on the level of protein adducts in environmental and occupational exposure. A relatively large number of publications (22) dealt with DNA adduct levels in PAH exposure. In 18 studies, the biological indicator clearly increases with respect to values in control subjects. Of these studies, seven reported the influence of GSTM1 null on DNA adducts and, of the five studies which also examined genotype CYP1A1, four reported the influence on DNA adduct level of genotype CYP1A1, alone or in combination with GSTM1 null. It therefore seems as if the unfavourable association for the activating/detoxifying metabolism of PAH is a risk factor for the formation of PAH-DNA adducts. Most publications (25 out of 41; 61%) dealing with metabolic polymorphisms in effect indicators (cytogenetic markers, COMET assay, HPRT mutants) did not report any increase in the indicator due to exposure to the genotoxic agents studied. These indicators of genotoxic damage, including mainly the frequency of HPRT mutants (100%), Mn (90%) and the COMET assay (67%), are not sufficiently sensitive in revealing exposure, confirming that they are not particularly suitable for measuring exposure to genotoxic substances in occupational or environmental exposures. It is therefore difficult to assess the influence of metabolic genotypes by means of this type of biological indicator. The few positive results reported for SCE in occupational studies mentioned the influence of genotype ALDH2, either alone or in combination with genotype CYP2E1 in exposure to CVM, or in combination with GSTM1 null in exposure to epichlorohydrin. For CA the results showed unfavourable combinations of genotypes CYP2E1, GSTM1 and PON1 in exposure to pesticides, and GSTM1 null in combination with NAT2 slow in exposure to urban air. All the remaining studies on the effect of genotype on biological indicators of cytogenetic damage reported negative results
Five cases of "fluoride asthma" [Osservazione di cinque casi di asma da fluoro]
No full textAbstract
Five cases of bronchial asthma in aluminium potroom workers with no previous occupational exposure to respiratory irritants, no history of asthma or other respiratory - heart disease are described. The first attack of asthma occurred on average 1.5 years (7 to 36 months) after the subjects had started work in the potrooms and the symptoms appeared both at the time of exposure as well as after a work shift. In 4 cases, symptoms disappeared completely within a week of being transferred from the potroom; only one worker still suffered from occasional wheezing after a year. Two subjects had positive skin tests for common allergens. Six to 24 months after cessation of exposure, all workers had normal lung volumes but they showed high sensitivity to a bronchial provocation test with inhaled carbachol. On the basis of the patients' histories and clinical and respiratory function findings, it is concluded that a causal relationship exists betweet potroom work and the onset of asthma
Biological indicators of genotoxic risk and metabolic polymorphisms
No full textInternational scientific publications on the influence of metabolic genotypes on biological indicators of genotoxic risk in environmental or occupational exposure are reviewed. Biomarkers of exposure (substance or its metabolites in biological fluids, urinary mutagenicity, protein and DNA adducts) and of effects (chromosome aberrations (CAs), sister chromatid exchanges (SCEs), micronuclei (Mn), COMET assay, HPRT mutants) have been evaluated according to different genotypes (or phenotypes) of several activating/detoxifying metabolic activities. In less than half the studies (43 out of 95), the influence of genotype on the examined biological indicator was found, of which four report poorly reliable results (i.e., with scarce biological plausibility, because of the inconsistency of modulated effect with the type of enzymatic activity expressed). As regards urinary metabolites, the excretion of mercapturic acids (MA) is greater in subjects with high GST activity, that of 1-pyrenol and other PAH metabolites turns out to be significantly influenced by genotypes CYP1A1 or GSTM1 null, and that of exposure indicators to aromatic amines (AA) (acetylated and non-acetylated metabolites) is modulated by NAT2. In benzene exposure, preliminary results suggest an increase in urinary t, t-muconic acid (t,t-MA) in subjects with some genotypes. On urinary mutagenicity of PAH-exposed subjects, the effects of genotype GSTM1 null, alone or combined with NAT2 slow are reported. When DNA adduct levels are clearly increased in PAH-exposed group (18 out of 22), 7 out of 18 studies report the influence of GSTM1 null on this biomarker, and of the five studies which also examined genotype CYP1A1, four report the influence of genotype CYP1A1, alone or in combination with GSTM1 null. A total of 25 out of 41 publications (61%) evaluating the influence of metabolic polymorphisms on biomarkers of effect (cytogenetic markers, COMET assay, HPRT mutants) do not record any increase in the indicator due to exposure to the genotoxic agents studied, confirming the scarce sensitivity of these indicators (mainly HPRT mutants, Mn, COMET assay) for assessing environmental or occupational exposure to genotoxic substances. Concluding, in determining urinary metabolites for monitoring exposure to genotoxic substances, there is sufficient evidence that genetically-based metabolic polymorphisms must be taken into account in the future. The unfavourable association for the activating/detoxifying metabolism of PAH is also confirmed as a risk factor due to the formation of PAH-DNA adducts. The clearly protective role played by GSTT1 on DEB (and/or related compound)-induced sister chromatid exchanges (SCEs) should be noted. The modulating effects of genotypes on protein adduct levels in environmental and occupational exposure have not yet been documented, and most studies on the influence of genotype on biological indicators of early genotoxic effects report negative results
[Molecular epidemiology in occupational medicine: methodological features and impact of individual genetic susceptibility]
No full textA review of main methodological questions regarding biomarkers is reported focusing on validation, laboratory variability, study design and statistical analysis. The indicated perspective is the setup of protocols finalized at the study of multiple panels of genotoxicity biomarkers taking into account the influence of gene-environment interaction at low doses, of the modulation of the biomarkers associated to the genetic polymorphism. An overview on the influence of metabolic and DNA repair polymorphisms on biological indicators of genotoxic risk in occupational, environmental or life-style exposure is also presented. Genetic polymorphisms that influence human genotoxic risk are those of glutathione s-transferase and cytochrome P450 in exposure to polycyclic aromatic hydrocarbons (PAHs), those of N-acetyltransferase in both occupational and environmental exposures to aromatic amines (AAs) and similar compounds. Lastly recent and important studies, on the effect of the newly discovered polymorphisms affecting DNA repair enzymes on the modulation of genotoxic risk linked to life style (i.e., aflatoxin and PAHs from diet) and smoking behaviour and to environmental genotoxic exposure, are reported. To date biomarkers represent a new tool for epidemiological research in occupational medicine and they could represent a valid instrument for group evaluation but they are not useful for the risk assessment on individual basis. To achieve this objective it is necessary to demonstrate a stronger association with the endpoint that perhaps the future development of genetic and molecular epidemiology will make possible
Mutagenic activity of carbon black dyes used in the leather industry
No full textSeven carbon black pastes used as commercial leather dyes were tested for their mutagenicity in the Salmonella/microsome test (TA98 and TA100 strains). All the samples assayed either directly or after extraction with a 30-min sonication in benzene were devoid of mutagenicity both in the presence and absence of a metabolic activation preparation. After a 48-h extraction with boiling toluene in a Soxhlet apparatus, four samples were mutagenic in TA98 strain in the presence of S9 mix. The activity ranged from 1.3 to 9.6 induced revertants/mg equivalent of extract. A weak direct mutagenic activity in strain TA98 was shown by one extract. Polycyclic aromatic hydrocarbons (PAH) were determined in the toluene extracts by high resolution gas chromatography/mass spectrometry. The presence of PAH could explain the mutagenicity of only one sample (8.79 micrograms of total PAH/100 mg equivalents of extract), while low or undetectable levels of PAH were found in the other mutagenic extracts. The mutagenic activity was evident only after a vigorous extraction process, thus a low bioavailability of the mutagens present in these compounds is suggested
Release of mutagens from finished leather.
No full textExtracts of a leather widely used in the furniture and dress-making industries were tested for their mutagenic activity in the Salmonella/microsome assay. Extracts obtained after vigorous treatment of leather samples in a Soxhlet apparatus with toluene or ethanol were mutagenic in strain TA98 of S. typhimurium in the absence of S9 mix. The analysis of extracts of leather at various intermediate stages of processing showed that the mutagenic activity appeared after the coloration process. The responsible compound was identified to be an azo dye (Color Index: Acid Brown 83) whose mutagenic potency was about 4 revertants/micrograms
Mutagenesis test on urine of workers exposed to polycyclic aromatic hydrocarbons in a anode plant.
No full text«Attività mutagena nell'urina di lavoratori esposti a idrocarburi policiclici aromatici in un'azienda produttrice di anodi». Abbiamo esaminato lavoratori di uno stabilimento per la produzione di anodi nell'industria primaria dell'alluminio esposti a bassi livelli di sostanze mutagene (campionamento personale: 30-60 μg PAH/m3, 1.1-1.7 μg BaP/m3). I campioni di urina sono stati concentrati su resina Amberlite XAD-2, estratti con acetone, e dopo evaporazione a bassa pressione sono stati saggiati per la mutagenicità su S. typhimurium TA98, con e senza attivazione metabolica mediante la frazione microsomiale epatica di ratto S-9 e β-glucuronidasi. Nei lavoratori esposti a PAH, ma non fumatori, la mutagenicità degli estratti urinari non è aumentata in modo significativo (revertenti indotti/spontanei ≤2), mentre è stata evidenziata un'alta attività mutagena negli estratti urinari dei fumatori, indipendentemente dall'esposizione o meno a PAH; i controlli (non esposti e non fumatori) hanno dato gli stessi reperti negativi. I risultati fanno supporre che nelle nostre condizioni i metaboliti urinari dei PAH siano troppo diluiti per potere essere rilevati con il test di Ames nella metodica standard
Test di mutagenicità urinaria nel monitoraggio dell'esposizione ad idrocarburi policiclici aromatici di lavoratori dell'industria di alluminio.
No full textThe sensitivity of 3 urinary mutagenicity tests was assayed: the plate test, the fluctuation test and the micropreincubation test, in order to assess their possible use in monitoring human exposure to polycyclic aromatic hydrocarbons (PAH). Urine samples from workers of an anode production plant exposed to coal tar and from psoriatic patients undergoing treatment with coal-tar ointments were tested for mutagenic activity on strain TA98 Salmonella typhimurium, in the presence of the microsome fraction and deconjugating enzymes. Parallelly, the urinary concentration of PAH metabolites or one of their trace metabolites, 1-hydroxypyrene, was determined. Increased levels of PAH metabolites were observed in the urine of anode production workers after a work shift compared with controls. Results of the plate test and the fluctuation test performed on urine of exposed subjects, both smokers and nonsmokers, showed mutagenicity values similar to the controls. Much higher 1-hydroxypyrene concentrations were found in the urine of psoriatic patients treated with coal tar than in post-shift urine of anode production workers. The urine of the former was also mutagenic in the 3 mutagenicity tests used. The minimum mean dose of PAH metabolites was calculated, expressed as quantity of 1-hydroxypyrene, that would give a mutagenic response in the 3 tests: the micropreincubation test was found to be about 100 times more sensitive than the plate test and about 30 times more sensitive than the fluctuation test. The theoretical minimum urinary concentration of 1-hydroxypyrene detectable by each test was determined: the micropreincubation test was 15 times more sensitive than the plate test and 7 times more sensitive than the fluctuation test. The theoretical minimum urinary concentration of 1-hydroxypyrene detectable by each test was determined: the micropreincubation test was 15 times more sensitive than the plate test and 7 time more sensitive than the fluctuation test. Comparison of the sensitivity of the 3 tests with the urinary concentrations of 1-hydroxypyrene measured in subjects occupationally exposed to coal-tar showed that the plate test and the fluctuation test detect only high PAH exposures whereas themicropreincubation test also detects low level exposures. These results suggest that only the micropreincubation test is sufficiently sensitive for use in biological monitoring of the majority of occupational exposures to coal-tar, including of aluminium industry workers of the present study
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