1,721,123 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
Valori di riferimento nel monitoraggio biologico dell'esposizione professionale ad agenti mutageni e cancerogeni
No full text[CYP1A2, NAT2, and GSTM1 phenotype/genotype modulate human exposure and various environmental mutagens: our experience]
No full textSince some years in our research group has been studied the influence of metabolic genotypes on two biomarkers of genotoxic risk (BPDE-DNA adducts and urinary mutagenicity) in humans exposed to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines. The aim was to identify possible genetic susceptible factors capable of modulating individual response to these carcinogens. Humans exposed to PAHs: dermatological patients therapeutically treated with coal tar based ointments (CT), coke oven workers and chimney sweeps. People exposed to aromatic amines will be volunteers after a meal of pan-fried hamburgers and smokers. An overview of the results we found until now will be presented
[Reference values in biological monitoring of occupational exposure to mutagens and carcinogens]
No full textThis work reports values of biological markers indicating mutagenic/carcinogenic risk in professionally non-exposed populations. The main confounding factors for most of these biomarkers are tobacco smoke, diet and air pollution. With the sole exception of compounds specifically present in work environments, in which determination in biological fluids of unchanged substances or their metabolites has high sensitivity and specificity (e.g., some aromatic amines), other biomarkers (urinary mutagenicity, DNA adducts and cytogenetic analyses), in order to be used properly as reference values, require ad hoc study of suitable control groups paired for the main confounding factors. Analytical determination of some protein adducts appears to be promising, due to its sensitivity and specificity
[New perspectives in monitoring of exposures to carcinogens]
No full textBiomonitoring occupational and environmental exposures to carcinogens is a common practice and several biomarkers have been developed for risk assessment. However, in particular, because of the lack of prospective studies, the place of these biomarkers within the complex scenario of the gene-environment interactions leading to cancer cannot be defined. New opportunities and suggestions for biomonitoring exposures to carcinogens could derive from exploring the exposome, from the results of genomewide association and omic studies. Based on these premises it is possible to envisage personalized biomonitoring procedures, as those already actuated in nutrition and clinical oncology, allowing a better predictivity of biomarkers in the preventive settings
[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
Internal exposure to carcinogenic polycyclic aromatic hydrocarbons and DNA damage
No full textIn the August issue of the Archives, Käfferlein et al. report no association between occupational exposures to polycyclic aromatic hydrocarbons (PAHs) and DNA damage on the individual level (Käfferlein et al. 2012). Internal PAH exposure, assessed in a variety of occupations by means of urinary 3-hydroxy benzo[a]pyrene (3-OH-B[a]P) and 1- and 2-naphtol (∑OHNaph), was unrelated with DNA strand break frequencies and the levels of 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxo-dGuo), perhaps with the exception of a small group of converter workers where an uncertain correlation between ∑OHNaph and 8-oxo-dGuo was observed. Authors discuss reasons for this lack of association suggesting to focus on the individual exposure circumstances. These include possible different routes of exposure and co-exposures and a better understanding and assessment of the kinetics and dynamics of the endpoints.
We report here the lack of correlations on the individual level in a group of coke oven non-smoker workers between other endpoints of exposure such as urinary 1-hydroxypyrene (1-OHP) and lymphocyte anti-benzo[a]pyrene diolepoxide DNA adduct (anti-B[a]PDE-DNA) and of genotoxic effect such as lymphocyte micronuclei (MN) frequency
Determination of anti-BPDE-DNA adducts in pah-exposed humans using the HPLC/fluorescence technique
No full textIn the present study, HPLC/fluorescence was applied to determine anti (±)-r-7,t-8-dihydroxy-t-9,10-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE)-DNA adducts formed in lymphocytes plus monocytes (LMF) from humans exposed to polycyclic aromatic hydrocarbons (PAH). Subjects were: 10 psoriatic patients (3 days after clinical coal tar (CT) treatment), 15 coke oven workers, 19 chimney sweeps, 35 aluminum anode plant workers, and 10 control subjects. Chronic and high PAH exposure in coke oven workers significantly increased the levels of BPDE-DNA adducts and the highest levels were seen in samples from smokers. Skin-acute (or short-term) and high PAH exposure of psoriatic patients do not increase DNA adduct levels. Determination of anti-BPDE-DNA adducts by means of this method is very promising for its sensitivity, specificity and simplicity and it may be applied in DNA adduct measurements to assesss high chronic PAH exposure and that it is thus suitable for industrial health purposes
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