Differential Gene Expression in Bladder Tumors from Workers Occupationally Exposed to Arylamines.

Occupational exposure to the arylamines benzidine and ß-naphthylamine increase bladder cancer risk up to 100-fold, making them some of the most powerful human carcinogens. We hypothesize that tumors arising in people with occupational exposures have different patterns of gene expression than histologically similar tumors from people without such exposures. In a case-case study, we compare gene expression in 22 formalin-fixed paraffin-embedded (FFPE) bladder tumors from men with high-level occupational exposure to arylamines to that in 26 FFPE bladder tumors from men without such exposure. Gene expression analysis was performed on the NanoString nCounter system using a PanCancer Progression Panel comprised of 740 cancer progression-related genes and a custom panel of 69 arylamine- and bladder cancer-related genes which were chosen from in vitro studies. Although fold differences were small, there was evidence of differential expression by exposure status for 17 genes from the Progression Panel and 4 genes from the custom panel. In total, 10 genes showed dose-response association at a p < 0.01, of which 4 genes (CD46, NR4A1, BAX, and YWHAZ) passed a false discovery rate (FDR) q value cutoff of 0.05 but were not significant after Bonferroni correction. Overall, we find limited evidence for differentially expressed genes in pathways related to DNA damage signaling and epithelial-to-mesenchymal transition (EMT).

Precipitating factors causing hyperbilirubinemia during chronic hepatitis C treatment with paritaprevir/ritonavir/ombitasvir and dasabuvir.

BACKGROUND: Hepatic decompensation is a fatal on-treatment side effect during chronic hepatitis C treatment with paritaprevir/ritonavir/ombitasvir and dasabuvir (PrOD). Prompt bilirubin testing can reveal hepatic failure in susceptible patients, and clinical parameters precipitating early elevation of bilirubin can warn clinicians to avoid PrOD prescription. METHODS: This retrospective study included 169 Hepatitis C virus (HCV)-genotype 1b patients who underwent a 12-week course of PrOD with or without ribavirin. Laboratory data underwent χ analysis with Fisher's exact test to determine the precipitating factors causing hyperbilirubinemia in patients who had received 1 week of treatment. RESULTS: Sustained viral response was achieved in 164 patients (97.0%). Total bilirubin was ≥2 mg/dL (21.3%) in 36 patients after 1 week of treatment. Pretreatment white blood cell (WBC) <4500/µL and platelet <100,000/µL correlated with total bilirubin ≥2 mg/dL (relative risk [RR]: 21.64, 95% CI: 5.23-89.64, p < 0.001) after 1 week of treatment. Pretreatment platelet ≥100 000/µL and WBC <4500/µL correlated with direct bilirubin ≥0.45 mg/dL (RR: 6.56, 95% CI: 1.42-30.38, p = 0.016) and indirect bilirubin ≥0.6 mg/dL (RR: 4.77, 95% CI: 1.03-22.15, p = 0.046). Pretreatment platelet <100,000/µL with F3/F4 fibrosis correlated with first week total bilirubin ≥2 mg/dL (RR: 3.57, 95% CI: 1.35-9.09, p = 0.010). CONCLUSION: PrOD is an effective antiviral regimen for HCV genotype 1b patients. Total bilirubin ≥2 mg/dL after 1 week of treatment serves as an early warning of irreversible progression toward hepatic decompensation, and the current study provides a guide by which to monitor chronic hepatitis C patients undergoing PrOD treatment.

Patch testing in Lao medical students.

BACKGROUND: Dermatological services in Laos, South East Asia are limited to the capital and patch testing is currently not available, so no data exists regarding the common cutaneous allergens in this population. OBJECTIVES: The aim of this study was to document positive patch tests in medical students without evidence of contact dermatitis in Laos. PATIENTS/MATERIALS/METHODS: One hundred and fifty medical students were patch tested using TRUE Test® panels 1 to 3 (35 allergens). Readings were taken at Days 2 and 4. RESULTS: Thirty-eight students (25.3%) had a positive reaction to at least one allergen, accounting for 52 reactions in total. The proportion of the students with positive patch test reading was significantly higher in the female [33/96 (34%)] than in the male [5/54 (9%)], p<0.001. The most common allergens were: nickel (10%), gold (6.6%), thiomersal (6.6%), cobalt dichloride (2%) and p-tert-Butylphenol formaldehyde resin (2%). Balsam of Peru (0.66%), black rubber mix (0.66%), Cl+Me-Isothiazolinone (0.66%), fragrance mix 1 (0.66%), quinolone mix (0.66%), methyldibromo glutaronitrile (0.66%), mercapto mix (0.66%), epoxy resin (0.66%), paraben mix (0.66%), thiuram (0.66%) and wool alcohols (0.66%) accounted for all of the other positive reactions. CONCLUSION: This study represents the first documented patch test results in Lao medical students and in the adult Lao population. The results of this study will inform any future research into contact allergy in Laos and give an insight into the background level of contact sensitivity in this population.

Black rubber sensitization by bicycle handgrips in a child with palmar hyperhidrosis.

Black rubber is mainly an occupational source of contact sensitization; however, several unusual causes of non-occupational black rubber allergy are reported in the literature. A 10-year-old nonatopic Turkish boy with palmar hyperhidrosis developed acute vesicular bilateral palmar dermatitis following 2 to 3 weeks of intensive use of a new bicycle. The handgrips of the bicycle were made of black rubber. Patch testing showed a strong positive reaction to N-isopropyl-N-phenyl-4-phenylenediamine (the main sensitizer in black rubber) and questionable papular reactions to pieces of the black rubber handgrip. Additional cross-sensitization was found to p-phenylenediamine. There was no previous contact with black rubber or with any material that would contain p-phenylenediamine (eg, black henna dye). In conclusion, this was an unusual pediatric case of non-occupational allergic contact dermatitis from N-isopropyl-N-phenyl-4-phenylenediamine in black rubber bicycle handgrips. The young age of the patient and the development of contact sensitization within a relatively short period were striking. The release of the sensitizer from black rubber and the skin penetration were possibly enhanced by continuous friction and the accompanying hyperhidrosis, suggesting that the black rubber bicycle handgrip was the primary source of sensitization.

Soccer shin guard reactions: allergic and irritant reactions.

In spite of the worldwide popularity of soccer among youth and the common requirement of the use of protective shin guards, reports of allergy to shin guards is sparse. This is surprising in light of the fact that this equipment is often made of materials that are reported to cause allergies, and that friction and moisture from the use of these shin guards during the sport would seem to predispose soccer players to the development of an allergic response. We present eight patients that presented for evaluation of dermatitis under their shin guards--some of which had allergy to their shin guards and some of which were diagnosed as having an irritant reaction.

Biological activity resulting from exposure to aquatic environmental genotoxic pollutants in northern Egypt.

We estimated pollution in Lake Edku and the Mediterranean Sea, El-Maadiya Region, with 3 aromatic amines (1-naphthylamine, 2-naphthylamine and benzidine) in the muscle tissue of fish. There were marked seasonal variations in the aromatic amine levels. We also determined oxidative stress (blood glutathione, and catalase activity) and genotoxic effects (chromosomal aberrations and urinary metabolites) in fishermen from each area. The fishermen suffered from oxidative stress and had high levels of the urinary metabolite sulfanilamide [mean (microg/mg creatinine): Lake Edku 20.7, Mediterranean 14.5, controls 5.3]. Frequencies for total chromosomal aberrations were significantly raised in the peripheral blood lymphocytes of fishermen in both areas [frequency (per 100 metaphases): Mediterranean 67, Lake Edku 45, controls 14].

Is contact allergy to disperse dyes and related substances associated with textile dermatitis?

BACKGROUND: Disperse dyes (DDs) are the most common sensitizers among textile dyes, but there is little knowledge of the clinical relevance of positive patch test reactions. OBJECTIVE: To investigate if patient-reported textile-related skin problems can be explained by contact allergy to eight different DDs and/or to chemically related substances, by occupation or by atopic constitution, and if the skin problems are influenced by age or sex. METHODS: A questionnaire on textile-related skin problems was answered by 858 of 982 consecutively patch tested patients in Malmö, Sweden and in Leuven, Belgium. The baseline series used for patch testing was supplemented with a textile dye mix (TDM) consisting of the eight DDs and with the separate dyes. The association between textile-related skin problems and contact allergy to the DDs and other risk factors was investigated using multiple logistic regression analysis. RESULTS: Eighteen per cent of the patients suspected textiles as a cause of their skin problems. Atopic constitution and female sex were risk factors for skin reactions. Synthetic materials were the most common textiles to give skin problems. A significant association was found between self-reported textile-related skin problems and contact allergy to para-phenylenediamine (PPD) [adjusted odds ratio (OR) 2.1; 95% confidence interval (CI) 1.0-4.3]. A similar, but more imprecise, adjusted OR was found for TDM (OR 1.9; 95% CI 0.57-5.6). Contact allergy to black rubber mix was too rare to be evaluated. CONCLUSIONS: Contact allergy to PPD was a more prevalent indicator for skin reactions to textiles than the TDM used in this study.

Bladder tumours in rubber workers: a factory study 1946-1995.

BACKGROUND: Prior to December 1949, some British rubber industry workers were inadvertently exposed to the human bladder carcinogen beta-naphthylamine, which was present as a contaminant (at 0.25%) in antioxidants used in manufacturing. This study follows a composite cohort of 6450 men employed at a large tyre factory either during the 'at-risk' period or just after it. METHODS: A group of 2090 at-risk men (employed 1945-1949) and 3038 men, first employed only after January 1950, when the carcinogen had been removed, were followed for their bladder cancer morbidity and mortality experiences. RESULTS: Fifty-eight tumours were registered for those at risk, whereas only 33.9 were expected at national standardized registration rates [SRRN = 171 and 95% confidence interval (CI) = 130-221]. Thirty-nine bladder tumours were reported for the post-1950 intake, whereas 38.3 were expected (SRRN = 102 and 95% CI = 72-139). The use of mortality data did not reveal any underlying hazard because 12 of the 58 at-risk workers with tumours were still alive at the study end date. In only 16 instances was bladder cancer actually certified as the underlying cause of death. Plotting cases by their location of work on a factory plan assisted the interpretation. CONCLUSIONS: A statistically significant elevated risk of bladder cancer for the exposed workforce was evident, but this reversed when the carcinogen was removed from processing in October 1949. The use of morbidity (incidence) data in long-term studies of occupational bladder cancer should be the required methodology if the hazard and risk are not to be underestimated.

Occupational allergic contact dermatitis from antioxidant amines in a dental technician.

We describe an 18-year-old dental technician who presented with dry hyperkeratotic lesions on his left palm that were limited to an area that was in contact with a container in which he had prepared the molds for a dental prosthesis. On patch testing, he had a positive reaction to black rubber mix and its components N-cyclohexyl-N'-phenyl-4-phenylenediamine, N,N'-diphenyl-4-phenylenediamine, and N-isopropyl-N'-phenyl-4-phenylenediamine, as well as to a piece of the rubber container. Thin-layer chromatography (TLC) of a piece of the rubber container confirmed the presence of the para-phenylenediamine mix. Results of patch-testing with TLC were positive after 48 and 96 hours. The lesions resolved when the patient stopped using the container. The patient was diagnosed with occupational allergic contact dermatitis. We also review the dermatoses caused by antioxidant amines.

The Drake Health Registry Study: findings from fifteen years of continuous bladder cancer screening.

BACKGROUND: The Drake Health Registry Study (DHRS) is an ongoing bladder cancer screening program initiated in 1986 due to workers' probable past exposure to the bladder carcinogen, beta-naphthylamine (BNA). METHODS: At periodic screening visits, a health survey is administered and three screening tests are applied to a urine sample, urinalysis (UA), papanicolaou (PAP), and quantitative fluorescence image analysis (QFIA). Positive screens are eligible for a free bladder cystoscopy with random biopsies. RESULTS: Forty of 51 persons eligible for diagnostic evaluation underwent cystoscopy. One person was diagnosed with carcinoma in situ, two with transitional cell papilloma, 14 with dysplasia, two of which developed transitional cell carcinoma; 26 had bladder abnormalities such as chronic inflammation, chronic cystitis, atypical changes, atypia, hyperplasia, or papillary clusters. CONCLUSIONS: The DHRS continues to identify early stage bladder cancer and other abnormalities among workers exposed to BNA before 1981 and generates useful clinical, psycho-social, and epidemiologic data.

Re-evaluation of the latent period of bladder cancer in dyestuff-plant workers in Japan.

BACKGROUND: The carcinogenesis of benzidine (BZ) and beta-naphthylamine (BNA) for bladder is well known. Although it was thought to be rare to develop occupational bladder cancer more than 20 years after the exposure to these chemicals, there are still new clinical cases even 30 years after exposure. The purpose of this study was to re-evaluate the latent carcinogenic period of BZ and BNA, in order to set the safety period after exposure for the health surveillance system. METHODS: The subjects were 236 dyestuff-plant workers in Tokyo, who had been exposed to these dyestuffs. The incidence of bladder cancer and its histopathology in this group was surveyed in the period from 1962 to 1996. RESULTS: Nineteen workers (8.1%) were found to have bladder cancers. The exposure period for these 19 patients was 82.0 +/- 50.2 months. The mean +/- SD latent period from the subjects' initial and final exposure until tumor development was 29.5 +/- 8.2 years and 20.1 +/- 10.6 years, respectively. Significantly, a negative correlation (Pearson) was observed between the exposure period and the latent period from the end of exposure to cancer onset (R = -0.544, P < 0.05). All tumors except one were transitional cell carcinoma. Flow cytometric analysis was performed in 11 patients and all of these patients had DNA aneuploidy. CONCLUSIONS: The latent periods of bladder cancer caused by BZ and BNA were longer than previously expected. It is necessary to survey the onset of bladder cancer in exposed workers more than 30 years after the initial exposure.

A further cohort study of workers employed at a factory manufacturing chemicals for the rubber industry, with special reference to the chemicals 2-mercaptobenzothiazole (MBT), aniline, phenyl-beta-naphthylamine and o-toluidine.

OBJECTIVES: To investigate mortality and cancer morbidity in workers from a factory manufacturing chemicals for the rubber industry. METHODS: The mortality (1955-96) and cancer morbidity experience (1971-92) of a cohort of 2160 male production workers from a chemical factory in north Wales were investigated. All subjects had at least 6 months employment at the factory and some employment in the period 1955-84. Detailed job histories were abstracted from company computerised records and estimates of individual cumulative exposure to 2-mercaptobenzothiazole (MBT) and its derivatives were obtained, with a job exposure matrix derived by a former factory hygienist. Durations of employment in the aniline, phenyl-beta-naphthylamine (PBN) and o-toluidine departments were also calculated. Two analytical approaches were used, indirect standardisation and Poisson regression. RESULTS: Based on serial rates for the general population of England and Wales, observed mortality for the total cohort was close to expectation for all causes (observed (obs) deaths 1131, expected (exp) deaths 1114.5, standardised mortality ratio (SMR) 101), and for all cancers (obs 305, exp 300.2, SMR 102). There was a significant (p < 0.05) excess mortality from cancer of the bladder in the 605 study subjects potentially exposed to one or more of the four chemicals being investigated (obs 9, exp 3.25, SMR 277, 95% confidence interval (95% CI) 127 to 526). This excess was dependent primarily on deaths occurring > 20 years after first exposure in those who started employment before 1955 (obs 7, exp 1.25, SMR 560, 95% CI 225 to 1154, p < 0.001). There were 30 subjects in the total study cohort who, on the basis of death certificates or cancer registration particulars, had had malignant bladder cancer. In separate analyses of the four exposure history variables (after adjustment for age), Poisson regression showed significant positive trends for risk of notification of bladder cancer increasing with cumulative duration of employment in the PBN (p < 0.001) and o-toluidine departments (p < 0.01); similar findings were not obtained for cumulative exposure to MBT or for duration of employment in the aniline department. In a simultaneous analysis of all four chemical exposure variables, a significant positive trend remained for duration of employment with exposure to PBN (p < 0.05). Further analyses of all cases of bladder cancer (malignant and benign diagnoses) used employment histories lagged by 15 years; similar findings were obtained. CONCLUSIONS: It seems likely that some members of this cohort have had occupational bladder cancer. Confident interpretation is difficult because of small numbers in the exposed subcohorts, relatively crude measures of exposure assessment for the four chemicals under study, and presence of unconsidered potential chemical confounders. The simplest interpretation of the findings about bladder cancer may be that PBN (or a chemical reagent or chemical intermediate associated with its production at this factory in the 1930s and 1940s) is a bladder carcinogen. Priority should be given, however, to obtaining information on the cancer experience of other working populations exposed to PBN or to o-toluidine.

Detection of carcinogenic aromatic amines in the urine of non-smokers.

Smoking is thought to be one of the most important anthropogenic risk factors involved in the development of urinary bladder cancer in humans. Tobacco smoke contains a complex mixture of chemicals including potent carcinogens such as aromatic amines. In the present study the amounts of several freebase aromatic amines including the potent carcinogens 2-aminonaphthalene and 4-aminobiphenyl have been analyzed in the urine of 48 German urban living smokers and non-smokers. The results indicate that (i) both groups excrete the identical set of four aromatic amines; (ii) smokers excrete approximately twice the total amount of these amines, but similar amounts of 2-aminonaphthalene and 4-aminobiphenyl are found in non-smokers; and (iii) the excreted aromatic amines are decomposed in the urine within a few hours thus, explaining why aromatic amines are difficult to detect in this matrix. Their decomposition could be prevented by adding small amounts of p-toluidine to the freshly collected urine. Unlike smokers the origin of aromatic amines detected in the urine of non-smokers is at present unknown. Based on the cotinine levels found in the urine of non-smokers environmental tobacco smoke can be excluded as a major source of aromatic amines. In addition, neither diesel exhaust-related nitroarenes nor the corresponding amino-derivatives, to which they may be metabolically converted, were found. The detected urinary levels of aromatic amines arising from sources other than tobacco smoke or diesel exhaust may play a role in the bladder cancer etiology of non-smokers.

[Occupational experience, epidemiologic observations, and scientific evidence in an illustrative case: adverse effects of the production and use of aromatic amines in Italy]. / Esperienza operaia, osservazione epidemiologica ed evidenze scientifiche in un caso emblematico: gli effetti nocivi della produzione e dell'impiego di amine aromatiche in Italia.

Economical, social and technical interrelations between synthetic dyes' production and bladder cancer in workmen engaged in the manufacture are reviewed. International situation is the background of Italian situation, mainly of the Lombardy region and Turin area. For decades social actors, individuals and institutions, acted as separate bodies, contributed to delay and omit the protection of workers' health. The situation changed when scientific knowledge, technical developments and workers' commitment prioritized workers' health as a main goal. The epidemic of bladder cancers among dyestuff workers was a cornerstone in the development of a different scenario in the production responsibility, workers' participation and eventually scientific community. The authors hypothesise that in our country these events stimulated the growth of epidemiology and epidemiologists; furthermore since then institutions promulgated a new and up-to-date wave of protective legislation in the workers' H&S field.