Novel aminoarylcysteine adducts in globin of rats dosed with naphthylamine and nitronaphthalene isomers.

Novel aminonaphthylcysteine (ANC) adducts, formed via naphthylnitrenium ions and/or their metabolic precursors in the biotransformation of naphthylamines (NA) and nitronaphthalenes (NN), were identified and quantified in globin of rats dosed intraperitoneally with 0.16 mmol/kg b.w. of 1-NA, 1-NN, 2-NA and 2-NN. Using HPLC-ESI-MS2 analysis of the globin hydrolysates, S-(1-amino-2-naphthyl)cysteine (1A2NC) together with S-(4-amino-1-naphthyl)cysteine (4A1NC) were found in rats given 1-NA or 1-NN, and S-(2-amino-1-naphthyl)cysteine (2A1NC) in those given 2-NA or 2-NN. The highest level of ANC was produced by the most mutagenic and carcinogenic isomer 2-NA (35.8 ± 5.4 nmol/g globin). The ratio of ANC adduct levels for 1-NA, 1-NN, 2-NA and 2-NN was 1:2:100:3, respectively. Notably, the ratio of 1A2NC:4A1NC in globin of rats dosed with 1-NA and 1-NN differed significantly (2:98 versus 16:84 respectively), indicating differences in mechanism of the adduct formation. Moreover, aminonaphthylmercapturic acids, formed via conjugation of naphthylnitrenium ions and/or their metabolic precursors with glutathione, were identified in the rat urine. Their amounts excreted after dosing rats with 1-NA, 1-NN, 2-NA and 2-NN were in the ratio 1:100:40:2, respectively. For all four compounds tested, haemoglobin binding index for ANC was several-fold higher than that for the sulphinamide adducts, generated via nitrosoarene metabolites. Due to involvement of electrophilic intermediates in their formation, ANC adducts in globin may become toxicologically more relevant biomarkers of cumulative exposure to carcinogenic or non-carcinogenic arylamines and nitroarenes than the currently used sulphinamide adducts.

2-naphthylamine toxicity.

In the past, 2-naphthylamine (2-NA) was used for the production of azo dyes, as an antioxidant in the cable industry and in the rubber industry. Despite the fact that 2-NA is not produced on an industrial scale, it is still used in small quantities as a model bladder carcinogen in laboratories, and also for sewage control, water analysis and oxytocinase assays. In addition, it is detected in the air in coke ovens, where it is formed as one of the pyrolysis products. The main aim of this work is to provide an actual literature review for health risk assessments related to 2-NA which is still used in laboratories. Occupational exposure to 2-NA is important for the respiratory tract, mucous membranes and the skin, and, to a lesser extent, for absorption from the gastrointestinal tract. It is absorbed into the body through the skin and by inhalation, and then undergoes metabolic changes. Most of the absorbed 2-NA dose is excreted in the urine, in the form of metabolites, metabolites conjugated to acids, and even in an unchanged form. Based on literature data, the effects of 2-NA toxicity in sub-chronic and chronic exposure include contact dermatitis, chronic cystitis and bladder cancer. The authors have concluded that it is recommended to determine the occupational exposure limit which will allow preparing the exposure assessment of people at work. Med Pr. 2020;71(2):205-20.

A novel near-infrared fluorescent probe for detection of early-stage Aß protofibrils in Alzheimer's disease.

Detection of Aß protofibrils at the early stage of Alzheimer's disease was realized by a novel near-infrared probe (DCM-AN) based on dicyanomethylene-4H-pyran. This probe exhibits high affinity towards Aß protofibrils in vitro and in brain sections of transgenic mouse models for Alzheimer's disease.

Bioactivation of the tobacco carcinogens 4-aminobiphenyl (4-ABP) and 2-amino-9H-pyrido[2,3-b]indole (AαC) in human bladder RT4 cells.

Occupational and tobacco exposure to aromatic amines (AAs) including 4-aminobiphenyl (4-ABP) and 2-naphthylamine (2-NA) are associated with bladder cancer (BC) risk. Several epidemiological studies have also reported a possible role for structurally related heterocyclic aromatic amines (HAAs) formed in tobacco smoke or cooked meats with BC risk. We had screened for DNA adducts of 4-ABP, 2-NA, and several prominent HAAs formed in tobacco smoke or grilled meats including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), 2-amino-3,8-dimethylmidazo[4,5-f]quinoxaline (MeIQx), and 2-amino-9H-pyrido[2,3-b]indole (AαC) in the bladder DNA of BC patients, using liquid chromatography/mass spectrometry. We detected DNA adducts of 4-ABP, but not adducts of the other carcinogens. In this study, we have examined the capacity of RT4 cells, an epithelial human bladder cell line, to bioactivate AAs and HAAs to DNA damaging agents, which may contribute to BC. 4-ABP and AαC formed DNA adducts, but DNA adducts of 2-NA, PhIP, and MeIQx were not detected. 4-ABP DNA adducts were formed at tenfold higher levels than AαC adducts. Pretreatment of RT4 cells with α-naphthoflavone (1-10 µM), a specific cytochrome P450 1 (CYP1) inhibitor, decreased AαC adduct formation by 50% but did not affect the level of 4-ABP adducts. However, cell pretreatment with 8-methoxypsoralen (0.1-1 µM), a potent inhibitor of CYP2A, resulted in a 90% decrease of 4-ABP DNA adducts levels. These data signify that CYP2A and CYP1A isoforms expressed in the target urothelium bioactivate 4-ABP and AαC, respectively, and may be a critical feature of aromatic amine-induced urinary bladder carcinogenesis. The bioactivation of other tobacco and environmental AAs by bladder CYPs and their ensuing bladder DNA damage warrants further study.

Quantification of N-phenyl-2-naphthylamine by gas chromatography and isotope-dilution mass spectrometry and its percutaneous absorption ex vivo under workplace conditions.

N-Phenyl-2-naphthylamine (P2NA) is an antioxidant used to protect rubbers from flex-cracking. P2NA can be converted in vivo to 2NA, one of the most potent bladder carcinogens. Here, we report the specific and ultra-sensitive quantification of P2NA in the receptor fluid of Franz diffusion cells by gas chromatography and isotope-dilution tandem-mass spectroscopy (GC-MS/MS). The experimental conditions were optimized to minimize losses of P2NA due to surface absorption on glass, plastic, and rubber material, and subsequently validated. Static and dynamic diffusion cell conditions were used to study the percutaneous penetration of P2NA into freshly prepared porcine skin. The experimental settings closely resembled those of the printing industry in the 1960s/1970s in Germany where P2NA-containing solutions in dichloromethane have been used. P2NA penetrated the skin at very low levels (0.02 ± 0.01 µg/cm2/h) with a cumulative penetrated amount of 0.80 ± 0.26 µg/cm2, a lag time of 6.33 ± 2.21 h and under dynamic conditions. Compared to the receptor fluid, 10-40-fold higher concentrations were found in the skin, predominantly in the dermis and the stratum corneum. Dichloromethane acted as a penetration enhancer by increasing the cumulative penetrated amounts and the recovery of P2NA in both the receptor fluid and the skin, while shortening its lag time. However, the flux remained unaffected. Due to its accumulation in subcutaneous layers, we finally proved that P2NA is continuously released into the receptor fluid despite exposure cessation up to 160 h. Overall, the results show that close attention has to be paid to dermal absorption of P2NA in exposed workers.

Comparative biotoxicity of N-Phenyl-1-naphthylamine and N-Phenyl-2-naphthylamine on cyanobacteria Microcystis aeruginosa.

N-Phenyl-1-naphthylamine (P1NA) and N-Phenyl-2-naphthylamine (P2NA) are both widely used as antioxidant and plant secondary metabolites. In this study, growth, esterase, photosynthetic activity and cell membrane integrity were used as biomarkers to compare biotoxicity of P1NA and P2NA on Microcystis aeruginosa. According to the results, a dose-response relationship was observed only between P1NA concentrations and growth inhibition. The EC50 (48 h) of P1NA calculated from growth inhibition was 16.62 µM, while that of P2NA was not detected. When the esterase and photosynthetic activity were applied to evaluate the biotoxicity, it was found that a concentration of 20 µM P1NA, P2NA caused reduction of esterase activity and Fv/Fm of M. aeruginosa to 22.2 and 3.3%, 97.5 and 92.1%, respectively, after 48 h exposure. The percentage of membrane-damaged cells was increased as P1NA exposure concentration increased, but that was not detected when exposure to P2NA. The difference substituted position in the molecular structure of P1NA and P2NA leads to different toxicological properties and only P1NA was found highly toxic to M. aeruginosa. The toxicity is due to that only P1NA can be biotransformed to 1,4-naphthoquinone, which could induce overproduction of intracellular ROS as well as result in oxidative damage and growth inhibition of test organism.

Risk of Lung Cancer in Workers Exposed to Benzidine and/or Beta-Naphthylamine: A Systematic Review and Meta-Analysis.

Benzidine (BZ) and beta-naphthylamine (BNA) have been classified as definite human carcinogens for bladder cancer by the International Agency for Research on Cancer. However, the epidemiological evidence for an association between exposure to BZ and/or BNA and lung cancer has been inconclusive. We conducted a systematic review and meta-analysis to determine the risk for lung cancer among workers exposed to BZ/BNA. A systematic literature search was conducted to identify studies that had reported occupational BZ/BNA exposure and the outcome of interest (lung cancer death and/or incidence). Meta-analyses were performed using random effects models to combine standardized mortality ratios (SMRs) or standardized incidence ratios (SIRs). We identified 23 retrospective cohort studies including 1745 cases of lung cancer; only one study reported smoking-adjusted lung cancer risk. A significantly increased lung cancer risk (pooled SMR/SIR 1.28; 95% CI, 1.14-1.43) was observed by combining all studies, with significant heterogeneity among studies (I(2) = 64.1%, P < 0.001). Effect estimates were higher for studies with direct BZ/BNA exposure (ie, dyestuff and manufacturing industries) (pooled SMR/SIR 1.58; 95% CI, 1.31-1.89), and studies that identified BZ/BNA-associated bladder cancer with SMR/SIR ≥4.7 (pooled SMR/SIR 1.68; 95% CI, 1.35-2.09). Effect estimates were similar for studies with and without concomitant occupational exposure to chromium, asbestos, arsenic, or bis(chloromethyl) ether. The cumulative meta-analysis showed that the evidence of association between occupational BZ/BNA exposure and lung cancer has been stable since 1995. Although the results of this meta-analysis have the potential for confounding by smoking and heterogeneity, our findings suggest that a finding of lung cancer following occupational BZ/BNA exposure should be considered to be a potential occupational disease.

Pollution-Induced Community Tolerance To Diagnose Hazardous Chemicals in Multiple Contaminated Aquatic Systems.

Aquatic ecosystems are often contaminated with large numbers of chemicals, which cannot be sufficiently addressed by chemical target analyses. Effect-directed analysis (EDA) enables the identification of toxicants in complex contaminated environmental samples. This study suggests pollution-induced community tolerance (PICT) as a confirmation tool for EDA to identify contaminants which actually impact on local communities. The effects of three phytotoxic compounds local periphyton communities, cultivated at a reference (R-site) and a polluted site (P-site), were assessed to confirm the findings of a former EDA study on sediments. The sensitivities of R- and P-communities to prometryn, tributyltin (TBT) and N-phenyl-2-naphthylamine (PNA) were quantified in short-term toxicity tests and exposure concentrations were determined. Prometryn and PNA concentrations were significantly higher at the P-site, whereas TBT concentrations were in the same range at both sites. Periphyton communities differed in biomass, but algal class composition and diatom diversity were similar. Community tolerance of P-communities was significantly enhanced for prometryn, but not for PNA and TBT, confirming site-specific effects on local periphyton for prometryn only. Thus, PICT enables in situ effect confirmation of phytotoxic compounds at the community level and seems to be suitable to support confirmation and enhance ecological realism of EDA.

Increased risk of lung cancer associated with occupational exposure to benzidine and/or beta-naphthylamine.

PURPOSE: To evaluate non-urological cancer risks associated with benzidine (BZ) and beta-naphthylamine (BNA), a historical cohort study was undertaken. METHODS: A total of 224 male workers exposed to BZ/BNA from a single factory were followed from 1953 to 2011. To estimate BZ/BNA exposure dose, duration of exposure (DOE) was defined as duration of employment between 1953 and 1972, the period when BZ and BNA were produced and used at this factory. Subjects were dichotomized (into long- and short-term groups) based on the median of DOE. Cancer-specific standardized incidence ratios (SIRs) were calculated using national and regional incidence rates as reference. Smoking history was obtained through questionnaires and other sources. Association between lung cancer (LC) or bladder cancer (BC) incidence and DOE was assessed using Cox's proportional hazards model. RESULTS: Vital status follow-up was successful for 216 (96.4%). Follow-up duration averaged 44.0 (SD 10.7) years. Increased SIRs based on national rates were found for all cancers (81 cases, SIR = 1.58, 95% CI 1.26-1.98), LC (18 cases, SIR = 2.58, 95% CI 1.53-4.07), and BC (7 cases, SIR = 4.70, 95% CI 1.89-9.67). Among workers with >20 years after first exposure, the SIR for LC was statistically elevated in the long DOE group (15 cases, SIR = 3.34, 95% CI 1.87-5.51). After adjustment for smoking, exposure to bis(chloromethyl) ether, and age at first exposure, a marginally significant hazard ratio (HR) was observed for the long DOE group (adjusted HR = 3.02, 95% CI 0.84-10.93, p = 0.091), compared to the short DOE group. DOE did not affect BC incidence. CONCLUSIONS: This study confirms the high risk of LC besides BC, suggesting that BZ/BNA have the potential to cause LC.

Activation of the aryl hydrocarbon receptor by carcinogenic aromatic amines and modulatory effects of their N-acetylated metabolites.

Aromatic amines (AAs) are an important class of chemicals which account for 12 % of known carcinogens. The biological effects of AAs depend mainly on their biotransformation into reactive metabolites or into N-acetylated metabolites which are generally considered as less toxic. Although the activation of the aryl hydrocarbon receptor (AhR) pathway by certain carcinogenic AAs has been reported, the effects of their N-acetylated metabolites on the AhR have not been addressed. Here, we investigated whether carcinogenic AAs and their N-acetylated metabolites may activate/modulate the AhR pathway in the absence and/or the presence of a bona fide AhR ligand (benzo[a]pyrene/B(a)P]. In agreement with previous studies, we found that certain AAs activated the AhR in human liver and lung cells as assessed by an increase in cytochrome P450 1A1 (CYP1A1) expression and activity. Altogether, we report for the first time that these properties can be modulated by the N-acetylation status of the AA. Whereas 2-naphthylamine significantly activated the AhR and induced CYP1A1 expression, its N-acetylated metabolite was less efficient. In contrast, the N-acetylated metabolite of 2-aminofluorene was able to significantly activate AhR, whereas the parent AA, 2-aminofluorene, did not. In the presence of B(a)P, activation of AhR or antagonist effects were observed depending on the AA or its N-acetylated metabolite. Activation and/or modulation of the AhR pathway by AAs and their N-acetylated metabolites may represent a novel mechanism contributing to the toxicological effects of AAs. More broadly, our data suggest biological interactions between AAs and other classes of xenobiotics through the AhR pathway.

Risk for lung cancer in workers exposed to benzidine and/or beta-naphthylamine: a protocol for systematic review and meta-analysis.

BACKGROUND: Risk for lung cancer in workers exposed to benzidine (BZ) and/or beta-naphthylamine (BNA), which are well-known bladder carcinogens, has been examined in many epidemiological studies, but individual epidemiological studies generally lack the power to examine the association between BZ/BNA exposure and lung cancer. We conduct a systematic review and meta-analysis to determine the risk for lung cancer among workers exposed to BZ/BNA occupationally. METHODS/DESIGN: Studies will be identified by a MEDLINE, EMBASE, CDSR, and CINAHL search and by the reference lists of articles/relevant reviews. Eligible studies will be cohort and case-control studies that report occupational BZ/BNA exposure and the outcome of interest (lung cancer death/incidence). The method of meta-analysis will be used to combine standardized mortality ratios (SMRs) and/or standardized incidence ratios (SIRs) from retrospective and prospective cohort studies and odds ratios (ORs) from case-control studies. Two reviewers will independently screen articles, extract data, and assess scientific quality using standardized forms and published quality assessment tools tailored for each study design. Overall pooled risk estimates and their corresponding 95% confidence intervals (CIs) will be obtained using random effects model. This systematic review and meta-analysis will be conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines, and results will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. DISCUSSION: This review will identify and synthesize studies of the association between occupational BZ/BNA exposure and lung cancer. The findings will help to identify whether BZ/BNA could cause lung cancer and might indicate whether workers with exposure to BZ/BNA have a need for preventive measures against non-urological cancer besides bladder cancer. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014010250.

Miniaturization of cytotoxicity tests for concentration range-finding studies prior to conducting the pH 6.7 Syrian hamster embryo cell-transformation assay.

The Syrian hamster embryo (SHE) cell-transformation assay (SHE assay) is a promising alternative method to animal testing for the identification of potential carcinogens in vitro. Prior to conducting the SHE assay the appropriate concentration range for each test chemical must be established, with a maximum concentration causing approximately 50% cytotoxicity. Concentration range-finding is done in separate experiments, which are similar to the final SHE assay but with less replicates and more concentrations. Here we present an alternative for the cytotoxicity testing by miniaturization of the test procedure by use of 24-well plates and surpluses from feeder-cell preparations as target cells. In addition, we integrated the photometry-based neutral red (NR) assay. For validation of the assay, incubations with dimethyl sulf-oxide, p-phenylenediamine-2HCl, aniline, o-toluidine-HCl, 2,4-diaminotoluene, and 2-naphthylamine were carried out in the miniaturized approach and compared with the standard procedure in terms of calculating the relative plating efficiencies (RPEs). To directly compare both methods, concentrations that produced 50% cytotoxicity (IC50) were calculated. Excellent associations were observed between the number of colonies and NR uptake. For all test substances a concentration-dependent, concomitant decrease of NR uptake in the miniaturized approach and RPEs in the standard test was observed after a 7-day incubation. The results from both test setups showed a comparable order of magnitude and the IC50 values differed by a factor <2 (1.4-1.9), depending on the substance in question. Overall, the miniaturized approach should be considered an improved alternative for cytotoxicity testing in the SHE assay, as it saves valuable SHE cells and speeds-up the time, to obtain test results more rapidly.

Studies on the toxic interaction mechanism between 2-naphthylamine and herring sperm DNA.

The toxic interaction between 2-naphthylamine (2-NA) and herring sperm deoxyribonucleic acid (hs-DNA) has been thoroughly investigated by UV absorption, fluorescence, and circular dichroism (CD) spectroscopic methods. UV absorption result indicates that 2-NA may intercalate into the stack base pairs of DNA during the toxic interaction of 2-NA with DNA. A fluorescence quenching study shows that DNA quenches the intrinsic fluorescence of 2-NA via a static pathway. The studies on effects of ionic strength and anionic quenching rule out electrostatic and groove bindings as the dominant binding modes. Further studies on denatured DNA fluorescence quenching and thermal melting studies confirm that the dominant binding mode of 2-NA-DNA is intercalative binding. A CD spectral study shows that the binding interaction of 2-NA with DNA leads to the disorganization of the neat double-helical structure of hs-DNA.

Metabolic dephenylation of the rubber antioxidant N-phenyl-2-naphthylamine to carcinogenic 2-naphthylamine in rats.

N-Phenyl-2-naphthylamine (P2NA) was widely used as oxidation inhibitor, particularly in rubber manufacturing. Technical-grade P2NA was contaminated with carcinogenic 2-naphthylamine (2NA), and bladder cancer risk in exposed workers was attributed to this impurity. Investigations in humans and mammalian species revealed that small amounts of 2NA are excreted into urine after exposure to P2NA. However, since 2NA per se is not carcinogenic and main downstream metabolites of 2NA have not been found in urine so far, it remained uncertain if 2NA derived from P2NA dephenylation is further activated to carcinogenic downstream metabolites. An experimental animal study was therefore designed to indicate if, and if yes to which extent, 2NA from P2NA dephenylation is accessible to the metabolic pathway that is held responsible for the carcinogenicity of 2NA. Groups of 5 male and female CD rats were dosed with P2NA (2-550 mg/kg b.w.) and 2NA (0.075-75 mg/kg b.w.); 2NA-haemoglobin adducts and urinary 2NA excretion were determined applying GC-MS/MS. 2NA haemoglobin adducts originated dose-dependently after 2NA and P2NA dosing. To induce identical adduct concentrations, an approximately 100-200-fold higher dose of P2NA was necessary compared to 2NA. Since haemoglobin adducts are formed by the same pathway (N-hydroxylation) as the ultimate carcinogens from 2NA, the comparison of adduct concentrations after 2NA and P2NA dosage permits a quantitative estimate of the carcinogenicity of P2NA. The results show that 2NA derived from dephenylation of P2NA enters the carcinogenic downstream pathway of 2NA in rats. Hence, the bladder cancer risk after human exposures to P2NA must be re-evaluated.

Spectroscopic investigation of the interaction of the toxicant, 2-naphthylamine, with bovine serum albumin.

The mechanism of interaction between bovine serum albumin (BSA) and 2-naphthylamine (2-NA) in aqueous solution was investigated by fluorescence spectroscopy, circular dichroism (CD) spectra, and UV-vis spectroscopy. It was proved from fluorescence spectra that the fluorescence quenching of BSA by 2-NA was a result of the formation of complex between 2-NA and BSA, and the binding constants (K(a) ) as well as the numbers of binding sites for 2-NA in BSA were determined according to the modified Stern-Volmer equation. The results of synchronous fluorescence and CD spectra demonstrated 2-NA could decrease the amount of α-helix of BSA, leading to the loosening of protein skeleton. UV-vis spectroscopy and resonance light scattering spectra (RLS) results also suggested the conformation of BSA were changed and the BSA aggregation occured, which could induce toxic effects on the organism.

Initial and continued adherence with bladder cancer screening in an occupationally exposed cohort.

OBJECTIVE: To identify significant predictors of initial and repeated adherence with bladder cancer screening in a high-risk occupationally exposed cohort. METHODS: We analyzed longitudinal (13 years) health survey data and a cross-sectional behavioral health survey from the Drake Health Registry Study. Construct validity of the behavioral health survey scales was evaluated using factor analysis. Initial compliance and repeated adherence were examined in separate logistic regression models. RESULTS: "Barriers to screening" and "social influence" were associated with initial participation. Lower or no alcohol consumption, comorbidities, worry that screening would find bladder cancer, and ease of arranging schedules were associated with continued adherence. CONCLUSIONS: Factors affecting adherence with bladder cancer screening change for initial participation and for continued adherence. To enhance overall adherence, specific strategies should be implemented when initiating a screening program and revised accordingly over time.

Effects of copper sulfate, hydrogen peroxide and N-phenyl-2-naphthylamine on oxidative stress and the expression of genes involved photosynthesis and microcystin disposition in Microcystis aeruginosa.

Algal blooms have been increasing in prevalence all over the world, destroying ecosystems and placing other organisms at risk. Chemical remediation is one of most important methods of controlling algal bloom formation. The effects of copper sulfate, hydrogen peroxide (H(2)O(2)) and N-phenyl-2-naphthylamine on photosynthesis-related and microcystin-related gene transcription and physiological changes of Microcystis aeruginosa were analyzed. The results suggest that transcription of psaB, psbD1 and rbcL was inhibited by the three algaecides, which blocked the electron transport chain, significantly enhanced reactive oxygen species (ROS) accumulation and overwhelmed the antioxidant system. The increase in ROS destroyed pigment synthesis and membrane integrity, which inhibited or killed the algal cells. Furthermore, H(2)O(2) treatment down-regulated mcyD transcription, which indicated a decrease in the microcystin level in the cells. Our results demonstrate that H(2)O(2) has the greatest potential as an algaecide because it not only inhibits algae growth but may reduce microcystin synthesis.

Anchoring metabolic changes to phenotypic effects in the chlorophyte Scenedesmus vacuolatus under chemical exposure.

In order to derive a causal understanding of toxic effects in organisms, ecotoxicology may benefit from linking molecular changes, evaluated by 'omics'-techniques, to phenotypic observations. However, an approach to link these observation levels is still lacking. The aim of this study was to relate metabolic changes in the chlorophyte Scenedesmus vacuolatus to established parameters of toxicity. Therefore, synchronized cultures of the alga were exposed for 14 h to the phytotoxicant N-phenyl-2-naphthylamine (PNA) in the range of 0.00089 µmol L⁻¹ (environmental concentrations) up to 1.82 µmol L⁻¹. Cell growth and photosynthesis inhibition were evaluated but revealed no effect of PNA at experimental concentrations below 0.456 µmol L⁻¹. Changes in the biochemical composition of algae were measured by GC-MS in both polar and non-polar phases. PCA uncovered no separation in the multivariate pattern of mass spectral features at exposure concentrations below 0.00356 µmol L⁻¹ of PNA. However, a clear separation was detected at concentrations higher than 0.00713 µmol L⁻¹. A combined visualization of PCA results for metabolic changes and concentration-response relationships for growth and photosynthesis inhibition revealed (I) a two orders of magnitude higher sensitivity of metabolomics to detects changes after PNA exposure compared to the phenotypic parameters measured and (II) two types of metabolic responses: one group of features was reflecting pharmacological effects at low exposure concentrations and the second group corresponded to adverse effects along with conventional observations of toxicity.

Occupational reproductive function abnormalities and bladder cancer in Korea.

The purpose of this study was to review occupational reproductive abnormalities and occupational bladder cancer in Korea and to discuss their toxicological implications. Reproductive dysfunction as a result of 2-bromopropane poisoning was first reported in Korean workers. In 1995, 23 of the 33 workers (25 female and 8 male workers) who were exposed to 2-bromopropane during the assembly of tactile switch parts developed reproductive and/or hematopoietic disorders. A total of 17 (68%) workers were diagnosed with ovarian failure. Two of the eight male workers experienced azoospermia and four workers experienced some degree of oligospermia or reduced sperm motility. In summary, 2-bromopropane poisoning caused severe reproductive effects in Korean workers. The prognosis was poor for reproductive dysfunction. A few cases of occupational bladder cancer have been reported in Korea, whereas other cancers of the urinary tract have not been reported after occupational exposure. A few cases of benzidine-induced cancer have been reported in Korea and 592 workers in Japan have received compensation for benzidine and ß-naphthylamine-induced cancer. In conclusion, a few cases of benzidine-induced occupational bladder cancer have been reported in Korea. However, benzidine-induced bladder cancer will likely be an important occupational health issue in Korea in the coming years.