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1.
Toxicol Lett ; 283: 100-105, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29180287

RESUMO

Arylamine N-acetyltransferase 1 (NAT1) and 2 (NAT2) catalyze the acetylation of arylamine carcinogens. Single nucleotide polymorphisms in the NAT2 coding exon present in NAT2 haplotypes encode allozymes with reduced N-acetyltransferase activity towards the N-acetylation of arylamine carcinogens and the O-acetylation of their N-hydroxylated metabolites. NAT2 acetylator phenotype modifies urinary bladder cancer risk following exposures to arylamine carcinogens such as 4-aminobiphenyl. 4, 4'-methylene bis (2-chloroaniline) (MOCA) is a Group 1 carcinogen for which a role of the NAT2 acetylation polymorphism on cancer risk is unknown. We investigated the role of NAT2 and the genetic acetylation polymorphism on both MOCA N-acetylation and N-hydroxy-MOCA O-acetylation. MOCA N-acetylation exhibited a robust gene dose response in rabbit liver cytosol and in cryopreserved human hepatocytes derived from individuals of rapid, intermediate and slow acetylator NAT2 genotype. MOCA exhibited about 4-fold higher affinity for recombinant human NAT2 than NAT1. Recombinant human NAT2*4 (reference) and 15 variant recombinant human NAT2 allozymes catalyzed both the N-acetylation of MOCA and the O-acetylation of N-hydroxy-MOCA. Human NAT2 5, NAT2 6, NAT2 7 and NAT2 14 allozymes catalyzed MOCA N-acetylation and N-hydroxy-O-acetylation at rates much lower than the reference NAT2 4 allozyme. In conclusion, our results show that NAT2 acetylator genotype has an important role in MOCA metabolism and suggest that risk assessments related to MOCA exposures consider accounting for NAT2 acetylator phenotype in the analysis.


Assuntos
Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/metabolismo , Carcinógenos/metabolismo , Metilenobis (cloroanilina)/metabolismo , Acetilação , Animais , Biotransformação , Citosol/metabolismo , Hepatócitos/enzimologia , Hepatócitos/metabolismo , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Polimorfismo Genético , Coelhos , Proteínas Recombinantes , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologia
2.
Occup Environ Med ; 74(1): 30-38, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27679675

RESUMO

OBJECTIVES: We investigated the relationship between 4,4'-methylene-bis(2-chloroaniline) (MBOCA) exposure and micronucleus (MN) frequency, and how this association was affected by genetic polymorphism of the cytochrome P450 enzyme (CYP3A4). METHODS: We divided the study population into an exposed group (n=44 with total urine MBOCA ≥20 µg/g creatinine) and a control group (n=47 with total urine MBOCA <20 µg/g creatinine). Lymphocyte MN frequency (MNF) and micronucleated cell (MNC) frequency were measured by the cytokinesis-block MN assay method. MNF reported as the number of micronuclei in binucleated cells per 1000 cells, and MNC reported as the number of binucleated cells with the presence of MN per 1000 cells. CYP3A4 alleles were measured by PCR-based restriction fragment length polymorphism (PCR-RFLP). RESULTS: The mean MNF (6.11 vs 4.46 MN/1000 cells, p<0.001) and MNC (5.75 vs 4.15 MN/1000 cells, p<0.001) in the exposed workers was significantly higher than that in the controls. The CYP3A4 polymorphism A/A+A/G influenced the difference in the mean MNF (5.97 vs 4.38 MN/1000 cells, p<0.001) and MNC (5.60 vs 4.15 MN/1000 cells, p<0.001) between the MBOCA-exposed and control groups. After adjusting risk factors, the MNF level in the MBOCA-exposed workers was 0.520 MN cells/1000 cells (p<0.001) higher than the control group among the CYP3A4 A/A+A/G genotype. Similarly, the MNC level in the MBOCA-exposed workers was 0.593 MN/1000 cells (p<0.001) higher than the control group among the CYP3A4 A/A+A/G genotype. However, the difference in adjusted MNF and MNC between the exposed and control groups was not significant for the CYP3A4 polymorphism with the G/G genotype. CONCLUSIONS: We recommend that lymphocytes MNF and MNC are good indicators to evaluate MBOCA genotoxicity. Individuals with the CYP3A4 polymorphism A/A and A/G genotypes appear to be more susceptible to MBOCA genotoxicity.


Assuntos
Compostos de Anilina/efeitos adversos , Citocromo P-450 CYP3A/genética , Metilenobis (cloroanilina)/efeitos adversos , Exposição Ocupacional/efeitos adversos , Polimorfismo Genético , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Análise de Variância , Compostos de Anilina/urina , Índice de Massa Corporal , Citocromo P-450 CYP3A/sangue , Citocromo P-450 CYP3A/urina , Sistema Enzimático do Citocromo P-450 , Feminino , Genótipo , Humanos , Linfócitos/química , Masculino , Metilenobis (cloroanilina)/análise , Pessoa de Meia-Idade , Testes de Mutagenicidade , Reação em Cadeia da Polimerase , Fatores de Risco , Fumar/epidemiologia , Taiwan/epidemiologia
3.
J Occup Health ; 56(5): 347-50, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25069897

RESUMO

OBJECTIVES: The purpose of this study was to develop a simple and cost-effective method for the determination of urinary 4,4'-methylenebis (2-chloroaniline) (MBOCA) by gas chromatography-electron capture detection (GC-ECD) for biological monitoring of occupational exposure to MBOCA. METHODS: MBOCA was prepared by liquid-liquid extraction after alkaline hydrolysis, derivatized with N-methyl-bis (trifluoroacetamide) and then analyzed using GC-ECD. The proposed method was validated in accordance with the US Food and Drug Administration guidance. RESULTS: The calibration curve showed linearity in the range 1-100 µg/l, with a correlation coefficient of >0.999. The limits of detection and quantification were 0.3 µg/l and 1 µg/l, respectively. The recovery was 94-99%. Intraday accuracy, expressed as the deviation from the nominal value, was 90.5-100.3%, and intraday precision, expressed as the relative standard deviation, was 0.3-2.4%. Interday accuracy and precision were 87.8-100.2% and 0.3-4.1%, respectively. CONCLUSIONS: The proposed method is a simple and cost-effective method suitable for routine analyses and could be useful for biological monitoring of occupational exposure to MBOCA.


Assuntos
Compostos Benzidrílicos/urina , Monitoramento Ambiental/métodos , Metilenobis (cloroanilina)/análise , Metilenobis (cloroanilina)/metabolismo , Exposição Ocupacional/análise , Urina/química , Cromatografia Gasosa , Humanos , Estados Unidos
5.
Int J Hyg Environ Health ; 216(4): 515-20, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23491024

RESUMO

OBJECTIVES: In this study, we explored the association between a marker of oxidative stress, 8-hydroxydeoxyguanosine (8-OHdG), and genetic polymorphism of the carcinogen-metabolizing enzyme N-acetyltransferase 2 (NAT2) among 4,4'-methylenebis(2-chloroaniline) (MBOCA)-exposed workers. METHODS: The study population was recruited from four MBOCA-producing factories, and included 57 MBOCA-exposed workers and 101 unexposed control workers. Personal characteristics were collected by questionnaire. Plasma 8-OHdG levels were measured by LC/MS/MS. NAT2 alleles were measured by polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). RESULTS: NAT2 polymorphism influenced the plasma 8-OHdG levels of MBOCA-exposed workers, but not of non-exposed workers. No difference between exposed and control groups was found for the crude 8-OHdG levels among rapid, intermediate, and slow acetylators. After adjusting for gender, age, smoking, and alcohol consumption habit, the 8-OHdG concentration in the MBOCA-exposed workers was 0.18pg/ml (95% CI -1.80 to -0.12) lower than the control group among rapid and intermediate acetylators. However, the difference between exposed and control groups was not significant for slow acetylators. CONCLUSION: Gene-environment interactions could play a role in the carcinogenesis of occupational MBOCA exposure. We suggest that the impact of the NAT2 acetylator status is low, if at all, on the generation of the oxidative stress marker 8-OHdG in the investigated exposed group.


Assuntos
Arilamina N-Acetiltransferase/genética , Desoxiguanosina/análogos & derivados , Metilenobis (cloroanilina)/metabolismo , Exposição Ocupacional/análise , 8-Hidroxi-2'-Desoxiguanosina , Acetilação , Adulto , Arilamina N-Acetiltransferase/metabolismo , Desoxiguanosina/sangue , Feminino , Interação Gene-Ambiente , Genótipo , Humanos , Masculino , Estresse Oxidativo , Polimorfismo Genético
6.
Talanta ; 93: 117-21, 2012 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-22483886

RESUMO

Extraction techniques for 4,4'-methylenebis(2-chloroaniline) (MOCA) in air samples and water solutions were developed and compared. Classic techniques for air sampling of MOCA were enhanced by incorporating a derivatization step (3,5-dinitrobenzoyl chloride solution in toluene), thus increasing the limit of detection and limit of quantification. Sampling of MOCA from water solution was performed using novel nanoporous polymeric (polypyrrole and polythiophene) fiber coatings and solid phase microextraction. Samples were analyzed by high-performance liquid chromatography coupled with a UV detector. Using the modified method for air sampling of MOCA, we found that the limit of detection was 7.90 ng m(-3) and the limit of quantification was 23.8 ng m(-3). In contrast, the limit of detection for MOCA in water samples was 11.26 ng mL(-1) (polypyrrole) and 84.62 ng mL(-1) (polythiophene) and the limit of quantification for MOCA was from 33.78 (polypyrrole) and 253.86 ng mL(-1) (polythiophene). Correlation coefficients were 0.9997 for air and 0.8790-0.9852 for water samples, respectively. The techniques presented provide alternative methods for the determination of MOCA in air samples and in water solutions that are more sensitive, quicker and less expensive than previously established procedures.


Assuntos
Ar/análise , Metilenobis (cloroanilina)/análise , Metilenobis (cloroanilina)/isolamento & purificação , Microextração em Fase Sólida/métodos , Água/química , Polímeros/química , Pirróis/química , Soluções , Solventes/química , Tiofenos/química
7.
Toxicol Lett ; 213(1): 3-8, 2012 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-21501672

RESUMO

This is a follow up survey of exposure to 4,4'-methylene-bis(2-chloroaniline) (MbOCA) and isocyanates in the UK polyurethane industry. Urine samples (n=446) were collected from 90 different workers. MbOCA levels were below the limit of detection in 170 samples and 26 were above the UK Biological Monitoring Guidance Value (BMGV) of 15 µmol MbOCA/mol creatinine. Detailed advice and guidance was given to each workplace at the end of the survey in 2008 and the 90% value reduced from 10 to 3 µmol MbOCA/mol creatinine in samples collected since. There was a positive correlation between glove contamination and urinary MbOCA and levels were dependent upon individual working practices especially how gloves were used. Of the 446 samples analysed for urinary metabolites of toluene diisocyanate 280 were below the detection limit and 126 were above the BMGV (1 µmol/mol creatinine). Of the 326 urine samples that were analysed for metabolites of methylenediphenyl diisocyanate, 270 were below the detection limit and 13 were above the BMGV for isocyanates. There was no correlation between urinary levels of isocyanates and MbOCA suggesting different routes of absorption, most likely inhalation and dermal respectively.


Assuntos
Indústria Química , Isocianatos/urina , Metilenobis (cloroanilina)/análise , Exposição Ocupacional , Poliuretanos/síntese química , Creatinina/urina , Seguimentos , Luvas Protetoras , Humanos , Exposição por Inalação , Concentração Máxima Permitida , Reino Unido
9.
Toxicol Mech Methods ; 21(7): 554-60, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21473712

RESUMO

A new procedure has been developed for the assay of 2,2'-dichloro-4,4'-methylenedianiline (MOCA) using high-performance liquid chromatography with diode array detector. MOCA was sampled from workplace air and derivative before determination using 3,5-dinitrobenzoyl chloride. The determination was carried out in the reverse-phase system (mobile phase: acetonitrile: water) using an Ultra C(18) column. The measurement range was 2-40 µg/m(3) for a 100 dm(3) air sample. Limit of detection: 7.9 ng/m(3) and limit of quantification: 23.8 ng/m(3).


Assuntos
Poluentes Ocupacionais do Ar/análise , Ar/normas , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento Ambiental/métodos , Metilenobis (cloroanilina)/análise , Local de Trabalho/normas , Ar/análise , Calibragem , Cromatografia Líquida de Alta Pressão/instrumentação , Monitoramento Ambiental/instrumentação , Limite de Detecção , Reprodutibilidade dos Testes
10.
Occup Med (Lond) ; 59(6): 402-5, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19564173

RESUMO

AIMS: To monitor the occurrence of cancer in a recently defined cohort of UK workers engaged in the manufacture of polyurethane elastomers using 4,4'-methylene-bis-ortho-chloroaniline. METHODS: A cohort of 308 male production workers from seven factories have been enumerated. All employees had a minimum of 12 months employment and were first employed at one of the participating factories in the period 1973-2000. Mortality and cancer incidence data for the period 1979-2007 were compared with expected values based on national rates. RESULTS: Mortality from all cancers combined was below the expected value [observed (Obs) 5, standardized mortality ratio (SMR) 68]. There was a single death from bladder cancer (SMR 560). The incidence of all cancers combined was also below expectation [Obs 9, standardized registration ratio (SRR) 77]. Site-specific incidence was unexceptional except there was a non-significant excess of bladder cancer based on two cases (SRR 328). CONCLUSIONS: The findings for bladder cancer should be treated with caution as they relate to a relatively early period of follow-up and are based on very small numbers.


Assuntos
Poluentes Ocupacionais do Ar/toxicidade , Indústria Química , Metilenobis (cloroanilina)/toxicidade , Neoplasias/epidemiologia , Exposição Ocupacional/efeitos adversos , Poluentes Ocupacionais do Ar/urina , Estudos de Coortes , Humanos , Incidência , Masculino , Neoplasias/induzido quimicamente , Exposição Ocupacional/estatística & dados numéricos , Poliuretanos/síntese química , Fumar/epidemiologia , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/epidemiologia
11.
Ann Occup Hyg ; 53(5): 499-507, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19447850

RESUMO

OBJECTIVES: The main objective of the study was to gather information about the current controls and levels of exposure to 4,4'-methylene-bis (2-chloroaniline) (MbOCA) in a representative cross section of workplaces that use it to manufacture polyurethane elastomers. The study also aimed to investigate whether controls and guidance could be improved and to investigate exposure to isocyanates in these workplaces using biological monitoring. METHODS: An occupational hygienist and a field scientist visited the two UK suppliers and 20 out of the 25 workplaces known to be using MbOCA in the UK during 2005 and 2006. They collected air samples, surface wipes, gloves, and urine samples and made observations to assess exposure and the adequacy of controls. All samples were analysed for MbOCA and urine samples were additionally analysed for isocyanate metabolites. A statistical analysis was made of the results. RESULTS: Only 2.5% of the 80 personal inhalation exposures to MbOCA exceeded the workplace exposure limit of 5 microg m(-3) 8-h time-weighted average and 84% were below the limit of detection (LOD). Surface samples (n = 334) were collected from MbOCA users and suppliers and 60% had detectable levels of MbOCA ranging from 0.019 to 400 microg cm(-2). The highest levels were around a hopper, ovens, and the weighing and pouring areas. MbOCA was also detected in 8 of the 75 samples collected from areas not likely to be in contact with MbOCA. At the two suppliers, samples (n = 28) were collected from the outside surfaces of recently imported kegs, pallets, and the floor around kegs. Six samples had detectable levels and four of these (0.2, 0.8, 1, and 6 microg cm(-2)) were from the floor and pallets in both suppliers. The other two positive results were found on the outside rim (18 microg cm(-2)) and side (23 microg cm(-2)) of a keg at one supplier indicating contamination by the manufacturer. Urine samples (n = 79) were collected and 49% were below the LOD for MbOCA and only three samples had levels of MbOCA that exceeded the biological monitoring guidance value (BMGV) of 15 micromol mol(-1) creatinine. The highest urinary MbOCA concentrations were in samples from workers casting and moulding. The 90th percentile of the urine MbOCA results was 8.6 micromol MbOCA per mol creatinine. Urine samples were also analysed for the diamine metabolites of toluene diisocyanate and hexamethylene diisocyanate and 33% had detectable levels with 22 and 13% of results, respectively, above the BMGV for isocyanates (1 micromol isocyanate-derived diamine per mol creatinine). The maximum urinary concentration of toluene diamine and hexane diamine were 15.6 and 10.1 micromol mol(-1) creatinine, respectively. CONCLUSIONS: The survey found that the measures used to control exposure to MbOCA could be improved. Although air levels of MbOCA were generally low, there was evidence of spread of surface contamination and poor maintenance of controls such as local exhaust ventilation. A BMGV based on the 90th percentile of data from workplaces with good control would be less than the 90% value of 8.6 micromol mol(-1) creatinine found in this study and suggests that the current BMGV of 15 micromol mol(-1) creatinine is no longer acting as a stimulus to reduce exposure. The metabolites of isocyanates found in urine samples in this study could arise from inhalation exposure to isocyanates or from dermal exposure to either isocyanates or their diamine breakdown product and need further investigation.


Assuntos
Poluentes Ocupacionais do Ar/análise , Carcinógenos/análise , Indústrias , Metilenobis (cloroanilina)/análise , Poliuretanos , Poluentes Ocupacionais do Ar/urina , Coleta de Dados , Monitoramento Ambiental/métodos , Humanos , Exposição por Inalação/análise , Exposição Ocupacional/análise , Saúde do Trabalhador , Reino Unido , Local de Trabalho
12.
Rapid Commun Mass Spectrom ; 21(24): 4073-8, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-18008389

RESUMO

Analysis of 4,4'-methylenebis(2-cholroaniline) (MOCA) or its metabolites in urine has been considered as the appropriate method to assess MOCA exposures through inhalation and skin absorption. MOCA and its metabolite, N-acetyl 4,4'-methylenebis(2-chloroaniline) (acetyl-MOCA), are analyzed using methods either limited by sensitivity or sample preparation. Therefore, a solid-phase extraction (SPE) and liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed to simultaneously analyze MOCA and acetyl-MOCA in urine to serve as biomarkers for MOCA exposure. Protein was precipitated by using acetonitrile, and SPE were applied to clean up samples to eliminate the matrix effect and to improve the recovery. The limit of quantitation of this method was at 1.0 ng/mL for MOCA and 0.03 ng/mL for acetyl-MOCA (signal-to-noise (S/N) ratio = 10). Urinary MOCA and acetyl-MOCA levels in MOCA-exposed workers were analyzed and quantitated to be 191.9 +/- 373.2 (mean +/- standard deviation (SD)) and 11.79 +/- 23.8 ng/mL (N = 54) with the median values 38.6 and 1.8 ng/mL, respectively. MOCA concentrations are significantly correlated with their corresponding acetyl-MOCA levels in urine (Spearman correlation coefficient r = 0.916, p < 0.001). These results show that this method has been successfully developed and provides high-throughput potential to analyze MOCA and acetyl-MOCA to serve as exposure biomarkers for future study of the potential health effects associated with MOCA exposures.


Assuntos
Poluentes Ocupacionais do Ar/urina , Metilenobis (cloroanilina)/análogos & derivados , Metilenobis (cloroanilina)/análise , Extração em Fase Sólida/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Poluentes Ocupacionais do Ar/química , Biomarcadores/química , Biomarcadores/urina , Cromatografia Líquida de Alta Pressão , Humanos , Metilenobis (cloroanilina)/química , Metilenobis (cloroanilina)/metabolismo , Exposição Ocupacional/análise
13.
J Occup Health ; 49(5): 389-98, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17951971

RESUMO

Oxidative DNA damage may play an important role in the human carcinogenic process. Recently, we reported a case of bladder cancer among 4, 4'-methylenebis (2-chloroaniline) (MBOCA)-exposed workers. By measuring the plasma level of 8-hydroxydeoxyguanosine (8-OHdG), we investigated the association between oxidative DNA damage and MBOCA exposure. In addition, we examined the effects of different confounders on the plasma level of 8-OHdG. We undertook a cross-sectional survey at four MBOCA-producing factories in Taiwan (158 subjects). Plasma 8-OHdG levels and urinary MBOCA concentrations were measured by liquid chromatography coupled with tandem mass spectrometry (LC/MS/MS). Personal characteristics were collected by questionnaire. The workers were classified according to their job titles as exposed (n=57) or unexposed (n=101) groups as well as classified according to urinary MBOCA levels as high urinary MBOCA (>20 microg/g creatinine) (n=45) or low urinary MBOCA (n=108) groups. Neither the MBOCA-exposed workers nor the high urinary MBOCA workers had a significant increase in the mean plasma 8-OHdG level, even after adjustment for potential confounders. Age and gender were significantly positively correlated with plasma 8-OHdG levels. Smokers among high urinary MBOCA workers also had significantly higher 8-OHdG levels than non-smokers among high urinary MBOCA workers. Our study provides evidence that smoking rather than MBOCA exposure induces elevation of plasma 8-OHdG levels among workers exposed to MBOCA, indicating that oxidative DNA damage does not play an important role in the carcinogenic processes of MBOCA.


Assuntos
Dano ao DNA/fisiologia , Desoxiguanosina/análogos & derivados , Metilenobis (cloroanilina)/toxicidade , Exposição Ocupacional/efeitos adversos , Estresse Oxidativo/fisiologia , Fumar/efeitos adversos , 8-Hidroxi-2'-Desoxiguanosina , Adulto , Distribuição por Idade , Poluentes Ocupacionais do Ar/análise , Poluentes Ocupacionais do Ar/toxicidade , Consumo de Bebidas Alcoólicas/epidemiologia , Biomarcadores/sangue , Biomarcadores/urina , Índice de Massa Corporal , Cromatografia Líquida , Fatores de Confusão Epidemiológicos , Estudos Transversais , Dano ao DNA/efeitos dos fármacos , Desoxiguanosina/sangue , Relação Dose-Resposta a Droga , Humanos , Modelos Lineares , Masculino , Metilenobis (cloroanilina)/análise , Pessoa de Meia-Idade , Exposição Ocupacional/análise , Estresse Oxidativo/efeitos dos fármacos , Distribuição por Sexo , Fumar/epidemiologia , Inquéritos e Questionários , Taiwan/epidemiologia
14.
Int J Hyg Environ Health ; 210(3-4): 383-6, 2007 May.
Artigo em Inglês | MEDLINE | ID: mdl-17321210

RESUMO

The UK Health and Safety Laboratory (HSL) provides research and analytical support to the Health and Safety Executive, other Government Departments and employers. In the area of biomonitoring HSL conducts research studies and provides an analytical service for regular surveillance of worker exposure to hazardous substances. This paper gives brief examples of how data from such studies can be used to develop biological monitoring guidance values for isocyanates, polycyclic aromatic hydrocarbons and hexavalent chromium. In addition, a study of occupational exposure to copper chrome arsenic wood preservatives is briefly described to show how biological monitoring can be used for post-approval surveillance of a biocide.


Assuntos
Monitoramento Ambiental/métodos , Laboratórios , Metilenobis (cloroanilina)/análise , Exposição Ocupacional/análise , Hidrocarbonetos Policíclicos Aromáticos/urina , Arsenicais/urina , Cromo/urina , Saúde Ambiental , Monitoramento Ambiental/normas , Guias como Assunto , Humanos , Laboratórios/normas , Laboratórios/estatística & dados numéricos , Exposição Ocupacional/prevenção & controle , Saúde do Trabalhador , Hidrocarbonetos Policíclicos Aromáticos/metabolismo , Valores de Referência , Segurança , Reino Unido
15.
Mutat Res ; 605(1-2): 94-102, 2006 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-16690349

RESUMO

Six chemicals, known to induce lung tumors in rats, were examined for their ability to induce DNA fragmentation in primary cultures of rat and human lung cells, and in the lung of intact rats. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measured by the single-cell gel electrophoresis (Comet) assay, were obtained in primary lung cells from male rats with the following, minimally toxic, concentrations of the six test compounds: N-nitrosodimethylamine (NDMA; 2.5-10 mM), hydrazine (HZ; 0.5-4 mM), cadmium sulfate (CD; 31.2 and 62.5 µM), 4,4'-methylene bis (2-chloroaniline) (MOCA; 31.2-125 µM), isobutyl nitrite (IBN; 7.8-31.2 µM) and tetranitromethane (TNM; 1.9-15.6 µM). Similar degrees of DNA fragmentation were obtained in primary human lung cells; however, due to inter-donor differences, the minimum effective concentrations were in some donors lower and in others higher than in rats, and IBN induced DNA damage only in one of three donors. The DNA-damaging potency of HZ was higher in rats than in humans, and the opposite was true for MOCA. In agreement with these findings, statistically significant increases in the average frequency of DNA breaks were obtained in the lung of rats given a single oral dose (1/2 LD50) of the six test compounds. These findings give evidence that genotoxic lung carcinogens may be identified by use of the DNA fragmentation/Comet assay on rat lung cells as targets cells, and show that the six compounds tested produce in primary cultures of lung cells from human donors DNA-damaging effects substantially similar to those observed in rats.


Assuntos
Adenocarcinoma/patologia , Carcinógenos/toxicidade , Quebras de DNA de Cadeia Simples/efeitos dos fármacos , Fragmentação do DNA/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Neoplasias Pulmonares/patologia , Idoso , Animais , Compostos de Cádmio/toxicidade , Ensaio Cometa , Dimetilnitrosamina/toxicidade , Células Epiteliais/química , Células Epiteliais/citologia , Feminino , Humanos , Hidrazinas/toxicidade , Pulmão/química , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Metilenobis (cloroanilina)/toxicidade , Pessoa de Meia-Idade , Nitritos/toxicidade , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Mucosa Respiratória/química , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Sulfatos/toxicidade , Tetranitrometano/toxicidade , Microambiente Tumoral
17.
Rev Environ Health ; 20(3): 163-76, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16335575

RESUMO

Cytogenetic end-points used to estimate risk of genotoxic events in workers include the measurement of micronuclei (MN) in exfoliated cells, lymphocytes, and other tissues. Micronuclei are chromatin-containing bodies outside the cell nucleus resulting from contaminant-induced DNA damage. A review of 71 reports of human genotoxic responses to chemical or physical agents published between 1999 and 2001 revealed that 14% of such studies measured genotoxicity endpoints in specific target tissues relevant to the site of disease for the agent examined; 18% used endpoints in surrogate or non-target tissues but considered the relations between endpoints in surrogate and disease target tissues, and 68% measured genotoxicity endpoints in accessible tissues without reference to specific targets for disease. Methylenebis-(2-chloroaniline) (MOCA), used in polyurethane manufacture, is a suspected bladder carcinogen. Bitumen, used in road surfacing, contains skin and lung carcinogens. In this study, we aimed to compare genotoxicity in urothelial cells and in lymphocytes of workers exposed to these materials. Twelve men employed in polyurethane manufacture, twelve bitumen road layers, and eighteen hospital stores personnel (controls) were recruited and all provided blood and urine samples on the same day. Blood cultures were prepared using a cytochalasin B-block method. Exfoliated urothelial cells were collected from urine and stained for light microscopy. The number of MN in urothelial cells was higher in MOCA-exposed (14.27 +/- 0.56 MN/1000, 9.69 +/- 0.32 MN cells/1000) than in bitumen exposed workers (11.99 +/- 0.65 MN/1000, 8.66 +/- 0.46 MN cells/1000) or in control subjects (6.88 +/- 0.18 MN/1000, 5.17 +/- 0.11 MN cells/1000). Conversely, in lymphocytes, MN were higher in bitumen-exposed (16.24 +/- 0.63 MN/1000, 10.65 +/- 0.24 MN cells/1000) than in MOCA-exposed workers (13.25 +/- 0.48 MN/1000, 8.54 +/- 0.14 MN cells/1000) or in control subjects (9.24 +/- 0.29 MN/ 1000, 5.93 +/- 0.13 MN cells/1000). The results of this study suggest that genotoxins can cause different rates of micronuclei formation in different tissues. Thus, the sensitivity and relevance to cancer risk may be greater if the tissues selected for genotoxicity studies reflect the target tissue for the chemicals concerned.


Assuntos
Dano ao DNA , Hidrocarbonetos/envenenamento , Exposição por Inalação , Metilenobis (cloroanilina)/envenenamento , Exposição Ocupacional , Adulto , Estudos de Casos e Controles , Humanos , Linfócitos , Masculino , Testes para Micronúcleos , Pessoa de Meia-Idade , Testes de Mutagenicidade , Sensibilidade e Especificidade , Urotélio/citologia
18.
Urology ; 66(2): 305-10, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16098360

RESUMO

OBJECTIVES: Transitional cell carcinoma of the urinary bladder is associated with occupational exposure to 4,4'-methylenebis(2-chloroaniline) (MBOCA). A program to monitor MBOCA levels in the work environment and to screen for bladder cancer was performed at four MBOCA manufacturing factories. METHODS: The U.S. Occupational Safety and Health Administration analytic method No. 24 was adopted in this study to measure air MBOCA concentrations. A total of 70 MBOCA-exposed workers and another 92 nonexposed workers were recruited for screening. Urine occult blood tests, urine cytology, tests for the urine tumor marker nuclear matrix protein, and abdominal ultrasonography were performed in all patients. Intravenous urography and cystoscopy were used to confirm the presence of bladder cancer. RESULTS: The air concentration of MBOCA was greatest in the purification area (0.23 to 0.41 mg/m3), followed by the washing area (less than 0.02 to 0.08 mg/m3) and neutralization area (less than 0.05 to 0.06 mg/m3). This study identified a current worker with proved bladder cancer. In addition, we also identified 1 worker with suspected malignant cells on urine cytology and 1 worker with atypical cytology combined with gross hematuria. Although the prevalence of atypical urinary cells and the nuclear matrix protein 22 tumor marker was not significantly different between the MBOCA-exposed workers and nonexposed workers as a whole or when grouped by sex, the prevalence of positive occult blood was marginally significantly (P = 0.055) greater in male exposed workers (18%) than in male nonexposed workers (7%). CONCLUSIONS: The findings of this study support the conclusions from other studies that MBOCA is potentially carcinogenic to humans. Control measures are needed to prevent overexposure from inhalation and skin absorption.


Assuntos
Carcinoma de Células de Transição/induzido quimicamente , Carcinoma de Células de Transição/diagnóstico , Metilenobis (cloroanilina)/efeitos adversos , Doenças Profissionais/induzido quimicamente , Doenças Profissionais/diagnóstico , Exposição Ocupacional , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/diagnóstico , Adulto , Feminino , Humanos , Masculino , Programas de Rastreamento , Taiwan
19.
Environ Health Perspect ; 113(6): 771-4, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15929884

RESUMO

A 52-year-old male chemical worker was admitted to the hospital with a history of paroxysmal microscopic hematuria for about 2 years and nocturia with gross hematuria about five times per night for 2 months. He was a nonsmoker and denied a history of any other bladder carcinogen exposure except for occasional pesticide application during agricultural work. Intravenous urogram imaging showed a mass occupying half of the bladder capacity. Cystoscopy revealed a mass over the left dome of the bladder. Cystoscopic biopsy revealed a grade 3 invasive transitional cell carcinoma with marked necrosis. From 1987 until hospital admission in 2001, the patient had worked in a company that produced the 4,4 -methylenebis(2-chloroaniline) (MBOCA) curing agent. He did not wear any personal protective equipment during work. Ambient air MBOCA levels in the purification process area (0.23-0.41 mg/m3) exceeded the U.S. Occupational Safety and Health Administration's permissible exposure level. Urinary MBOCA levels (267.9-15701.1 microg/g creatinine) far exceeded the California Occupational Safety and Health Administration's reference value of 100 microg/L. This patient worked in the purification process with occupational exposure to MBOCA for 14 years. According to the environmental and biologic monitoring data and latency period, and excluding other potential bladder carcinogen exposure, this worker was diagnosed as having occupational bladder cancer due to high exposure to MBOCA through inhalation or dermal absorption in the purification area. This case finding supports that MBOCA is a potential human carcinogen. Safe use of skin-protective equipment and respirators is required to prevent workers from MBOCA exposure.


Assuntos
Carcinoma de Células de Transição/induzido quimicamente , Metilenobis (cloroanilina)/toxicidade , Doenças Profissionais/induzido quimicamente , Exposição Ocupacional , Neoplasias da Bexiga Urinária/induzido quimicamente , Indústria Química , Monitoramento Ambiental , Hematúria , Humanos , Masculino , Metilenobis (cloroanilina)/análise , Pessoa de Meia-Idade , Taiwan , Transtornos Urinários
20.
Arch Toxicol ; 78(10): 589-98, 2004 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15167984

RESUMO

Avian embryos are a potential alternative model for chemical toxicity and carcinogenicity research. Because the toxic and carcinogenic effects of some chemicals depend on bioactivation, activities of biotransformation enzymes and formation of DNA adducts in embryonic turkey liver were examined. Biochemical analyses of 22-day in ovo turkey liver post-mitochondrial fractions revealed activities of the biotransformation enzymes 7-ethoxycoumarin de-ethylase (ECOD), 7-ethoxyresorufin de-ethylase (EROD), aldrin epoxidase (ALD), epoxide hydrolase (EH), glutathione S-transferase (GST), and UDP-glucuronyltransferase (GLUT). Following the administration of phenobarbital (24 mg/egg) on day 21, enzyme activities of ECOD, EROD, ALD, EH and GLUT, but not of GST, were increased by two-fold or higher levels by day 22. In contrast, acute administration of 3-methylcholanthrene (5 mg/egg) induced only ECOD and EROD activities. Bioactivation of structurally diverse pro-carcinogens was also examined using (32)P-postlabeling for DNA adducts. In ovo exposure of turkey embryos on day 20 of gestation to 2-acetylaminofluorene (AAF), 4,4'-methylenebis(2-chloroaniline) (MOCA), benzo[a]pyrene (BaP), and 2-amino-3,8-dimethylimidazo[4,5- f]quinoxaline (MeIQx) resulted in the formation of DNA adducts in livers collected by day 21. Some of the DNA adducts had (32)P-postlabeling chromatographic migration patterns similar to DNA adducts found in livers from Fischer F344 rats exposed to the same pro-carcinogens. We conclude that 21-day embryonic turkey liver is capable of chemical biotransformation and activation of genotoxic carcinogens to form DNA adducts. Thus, turkey embryos could be utilized to investigate potential chemical toxicity and carcinogenicity.


Assuntos
Alternativas aos Testes com Animais , Carcinógenos/metabolismo , Adutos de DNA/metabolismo , Embrião não Mamífero/enzimologia , Enzimas/metabolismo , Fígado/enzimologia , 2-Acetilaminofluoreno/metabolismo , 2-Acetilaminofluoreno/toxicidade , Animais , Benzo(a)pireno/metabolismo , Benzo(a)pireno/toxicidade , Biotransformação , Carcinógenos/toxicidade , Adutos de DNA/análise , Dano ao DNA , Relação Dose-Resposta a Droga , Embrião não Mamífero/efeitos dos fármacos , Feminino , Fígado/efeitos dos fármacos , Fígado/embriologia , Metilcolantreno/metabolismo , Metilcolantreno/toxicidade , Metilenobis (cloroanilina)/metabolismo , Metilenobis (cloroanilina)/toxicidade , Fenobarbital , Radioisótopos de Fósforo , Quinoxalinas/metabolismo , Quinoxalinas/toxicidade , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Turquia
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