Ambient BTEX exposure and mid-pregnancy inflammatory biomarkers in pregnant African American women.

Air pollution is associated with preterm birth (PTB), potentially via inflammation. We recently showed the mixture benzene, toluene, ethylbenzene, and xylene (BTEX) is associated with PTB. We examined if ambient BTEX exposure is associated with mid-pregnancy inflammation in a sample of 140 African-American women residing in Detroit, Michigan. The Geospatial Determinants of Health Outcomes Consortium study collected outdoor air pollution measurements in Detroit; these data were coupled with Michigan Air Sampling Network measurements to develop monthly BTEX concentration estimates at a spatial density of 300 m2. First trimester and mid-pregnancy BTEX exposure estimates were assigned to maternal address. Mid-pregnancy (mean 21.3 ± 3.7 weeks gestation) inflammatory biomarkers (high-sensitivity C-reactive protein, interleukin [IL]-6, IL-10, IL-1ß, and tumor necrosis factor-α) were measured with enzyme immunoassays. After covariate adjustment, for every 1-unit increase in first trimester BTEX, there was an expected mean increase in log-transformed IL-1ß of 0.05 ± 0.02 units (P = 0.014) and an expected mean increase in log-transformed tumor necrosis factor-α of 0.07 ± 0.02 units (P = 0.006). Similarly, for every 1-unit increase in mid-pregnancy BTEX, there was a mean increase in log IL-1ß of 0.06 ± 0.03 units (P = 0.027). There was no association of either first trimester or mid-pregnancy BTEX with high-sensitivity C-reactive protein, IL-10, or IL-6 (all P > 0.05). Ambient BTEX exposure is associated with inflammation in mid-pregnancy in African-American women. Future studies examining if inflammation mediates associations between BTEX exposure and PTB are needed.

The concentration of benzene, toluene, ethylbenzene, and xylene in ambient air of the gas stations in Iran: A systematic review and probabilistic health risk assessment.

Exposure to benzene, toluene, ethylbenzene, and xylene (BTEX) has been reported in gas stations. Exposure to BTEX can result in adverse health outcomes in workers such as cancer and neurological effects. The health risk assessments of exposure to BTEX could be useful in choosing suitable control measures. In this review, data from previous studies of gas station environments in Iran were collected from years 2000 to 2020. The health risk assessments were conducted through the estimation of cancer and noncancer risks using a Monte Carlo simulation based on the US Environmental Protection Agency method. The results showed that exposure to BTEX in some cities of Iran was greater than the occupational exposure limits. The results of cancer risk assessments demonstrated that cancer risk was not increased. However, results of noncancer risk assessments demonstrated that neurological toxicity from exposure to BTEX was significant in different cities of Iran. The health risk assessments indicated that workers at gas station are at health risk.

Hypermethylation in Gene Promoters Are Induced by Chronic Exposure to Benzene, Toluene, Ethylbenzene and Xylenes.

BACKGROUND AND OBJECTIVE: Gas station attendants are occupationally exposed to benzene, toluene, ethylbenzene and xylene (BTEX) compounds and thus more susceptible to the biological effects of this mixture present in gasoline, especially due to the carcinogenicity of benzene. Furthermore, the harmful effects of BTEX exposure may be potentiated by genetic and epigenetic inactivation of critical genes. The objective was to evaluate such gene-BTEX interactions accessing the promoter methylation status of p14ARF, p16INK4A and GSTP1 in peripheral blood leukocyte samples. MATERIALS AND METHODS: The 59 exposed and 68 unexposed participants from Rio de Janeiro, Brazil, were included. The promoter methylation status was accessed by methylation-specific PCR (MSP) and GSTP1 Ile105Val polymorphism was investigated by PCR-restriction fragment length polymorphism (PCR-RFLP) technique. RESULTS: Both p14ARF and p16INK4A were significantly hypermethylated in exposed subjects compared to unexposed (p = 0.004 and p<0.001, respectively). Additionally, p16INK4A hypermethylation in the exposed group was correlated with chromosomal abnormalities (CAs) (p = 0.018), thus highlighting the influence of the gene-environment interactions on genome instability. Noteworthy, p16INK4A methylation was significantly associated with miscarriage among female attendants (p = 0.047), in which those who reported miscarriage exhibited hypermethylation in at least 2 of the 3 genes analyzed. The GSTP1 heterozygote genotype, which could affect the metabolism of benzene detoxification, was found in both groups but was more frequent in those occupationally exposed. No significant association was observed between GSTP1 genotypes and methylation status. CONCLUSION: Together, these findings indicate that gas station attendants with the aforementioned epigenetic and genetic profiles may be at greater risk of occupational BTEX exposure-induced genome instability, which could require concerted efforts to establish more preventive actions and constant biomonitoring in gas station attendants.

Association of organic solvents and occupational noise on hearing loss and tinnitus among adults in the U.S., 1999-2004.

PURPOSE: Exposure to organic solvents and noise may be causal agents in the development of hearing loss and tinnitus. The objectives of the present study were to examine the association of organic solvents with hearing loss and tinnitus and to assess the interaction of organic solvent and occupational noise exposure on hearing loss and tinnitus. METHODS: A secondary data analysis of data from the National Health and Nutrition Examination Survey and Occupational Information Network (O*NET) among a study population ranging from 1085 to 2471 study participants from 1999 to 2004. Multiple multivariate logistic regression models were used to assess the associations of individual organic solvent exposures as measured by blood biomarkers (1,4-dichlorobenzene, benzene, ethylbenzene, styrene, toluene, o-xylene, and m-/p-xylene) with self-reported hearing loss, audiometrically assessed hearing loss, and self-reported tinnitus. Models were adjusted for age, gender, race/ethnicity, diabetes, non-occupational noise exposure, smoking, and income. Organic solvents found to be statistically significantly associated with the outcome after adjusting for covariates were tested for interaction with occupational noise exposure. RESULTS: Solvent exposure was not statistically significantly associated with self-reported tinnitus. Benzene (OR 1.43, 95% CI 1.15-1.78), ethylbenzene (OR 1.24, 95% CI 1.02-1.50), and toluene (OR 1.27, 95% CI 1.06-1.52) concentrations were statistically significantly associated with increased adjusted odds of high-frequency hearing loss. No statistically significant interaction was observed between these solvents and occupational noise on high-frequency hearing loss. CONCLUSIONS: We found no evidence of an association between organic solvents and tinnitus; however, there was evidence of an association between organic solvent exposure and prevalence of high-frequency hearing loss.

Adductomic signatures of benzene exposure provide insights into cancer induction.

Although benzene has long been recognized as a cause of human leukemia, the mechanism by which this simple molecule causes cancer has been problematic. A complicating factor is benzene metabolism, which produces many reactive intermediates, some specific to benzene and others derived from redox processes. Using archived serum from 20 nonsmoking Chinese workers, 10 with and 10 without occupational exposure to benzene (exposed: 3.2-88.9 ppm, controls: 0.002-0.020 ppm), we employed an adductomic pipeline to characterize protein modifications at Cys34 of human serum albumin, a nucleophilic hotspot in extracellular fluids. Of the 47 measured human serum albumin modifications, 39 were present at higher concentrations in benzene-exposed workers than in controls and many of the exposed-control differences were statistically significant. Correlation analysis identified three prominent clusters of adducts, namely putative modifications by benzene oxide and a benzene diolepoxide that grouped with other measures of benzene exposure, adducts of reactive oxygen and carbonyl species, and Cys34 disulfides of small thiols that are formed following oxidation of Cys34. Benzene diolepoxides are potent mutagens and carcinogens that have received little attention as potential causes of human leukemia. Reactive oxygen and carbonyl species-generated by redox processes involving polyphenolic benzene metabolites and by Cyp2E1 regulation following benzene exposure-can modify DNA and proteins in ways that contribute to cancer. The fact that these diverse human serum albumin modifications differed between benzene-exposed and control workers suggests that benzene can increase leukemia risks via multiple pathways involving a constellation of reactive molecules.

A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma.

BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m-2, was performed to determine the safety of combination treatment and the recommended phase 2 dose (RP2D). Secondary and tertiary objectives included tumour response, plasma and tumour MK-0752 concentration, and inhibition of the Notch pathway in hair follicles and tumour. RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.

Diphenyl Diselenide Reduces Oxidative Stress and Toxicity Caused by HSV-2 Infection in Mice.

Herpes simplex viruses can cause uncommon systemic complications as acute liver failure (ALT) or urinary tract dysfunctions. Diphenyl diselenide, (PhSe)2 , a classical studied organic selenium compound, has a novel antiviral action against HSV-2 infection and well-known antioxidant and anti-inflammatory properties. This study aimed to investigate if (PhSe)2 reduces oxidative stress and systemic toxicity caused by HSV-2 infection in mice. Adult BALB/c mice were pre-treated with (PhSe)2 (5 mg kg-1 /day, intragastric, i.g.) during 5 days; at day 6 mice were infected with HSV-2 (10 µl-105 PFU/mL-1 ) and post-treated with (PhSe)2 for more 5 days. At day 11, they were killed and samples of liver and kidney were obtained to determine: reactive species (RS); malondialdehyde (MDA), and non-protein thiols (NPSH) levels; the activities of antioxidant enzymes, superoxide dismutase (SOD), and catalase (CAT). The activities of adenosine deaminase (ADA), Na+ /K+ -ATPase (liver and kidney); alanine aminotransferase (ALT), aspartate aminotransferase (AST), and the levels of urea (plasma) were determined as markers of hepatic and renal toxicity. The results revealed that (PhSe)2 treatment was effective against the increase of renal and hepatic oxidative stress in infected mice and also normalized hepatic and renal ADA activity. It recovered the activity of Na+ /K+ - and was not effective against the increase in urea levels in infected mice. Different from (PhSe)2 , acyclovir (positive control), caused an increase in ADA activity and a decrease in hepatic CAT activity. Considering the interest of alternative therapies to treat HSV-2 infections and secondary complications, (PhSe)2 become a notable candidate. J. Cell. Biochem. 118: 1028-1037, 2017. © 2016 Wiley Periodicals, Inc.

Investigation of outdoor BTEX: Concentration, variations, sources, spatial distribution, and risk assessment.

The aim of this study was to measure BTEX (benzene, toluene, ethylbenzene, and xylenes) concentrations in the ambient air of Tehran, the capital of Iran, and investigate their seasonal variations, probable sources, spatial mapping, and risk assessment. The concentrations of BTEX were measured using a continuous monitoring device installed in seven stations around the city. Spatial mapping procedure was conducted using the inverse distance weighting (IDW) method. Monte Carlo simulation was used to assess the carcinogenic and noncarcinogenic risks imposed by BTEX. The highest and lowest annual mean concentrations of toluene and ethylbenzene were recorded as 16.25 and 3.63 µg m(-3), respectively. The maximum (6.434) and minimum (3.209) toluene/benzene (T/B) ratio was observed in summer and winter, respectively. The spatial distribution of BTEX pollution indicated that the highest concentrations were found along the major roads because of heavy traffic. Spearman's rank correlation coefficients and concentration ratios showed that BTEX were produced by the multiemission sources. The mean of inhalation lifetime cancer risk (LTCR) for benzene was 3.93 × 10(-7), which is lower than the limits recommended by the United States Environmental Protection Agency (US EPA) and the World Health Organization (WHO). The hazard quotient (HQ), noncarcinogenic risk index, for all BTEX compounds was <1. The obtained results showed no threat of BTEX concentrations to human health. However, as the concentrations of BTEX will increase due to the rapid growth of vehicles and industrial activities, much effort is required to control and manage the levels of these compounds in the future.

Blood miRNAs as sensitive and specific biological indicators of environmental and occupational exposure to volatile organic compound (VOC).

To date, there is still shortage of highly sensitive and specific minimally invasive biomarkers for assessment of environmental toxicants exposure. Because of the significance of microRNA (miRNA) in various diseases, circulating miRNAs in blood may be unique biomarkers for minimally invasive prediction of toxicants exposure. We identified and validated characteristic miRNA expression profiles of human whole blood in workers exposed to volatile organic compounds (VOCs) and compared the usefulness of miRNA indicator of VOCs with the effectiveness of the already used urinary biomarkers of occupational exposure. Using a microarray based approach we screened and detected deregulated miRNAs in their expression in workers exposed to VOCs (toluene [TOL], xylene [XYL] and ethylbenzene [EBZ]). Total 169 workers from four dockyards were enrolled in current study, and 50 subjects of them were used for miRNA microarray analysis. We identified 467 miRNAs for TOL, 211 miRNAs for XYL, and 695 miRNAs for XYL as characteristic discernible exposure indicator, which could discerned each VOC from the control group with higher accuracy, sensitivity, and specificity than urinary biomarkers. Current observations from this study point out that the altered levels of circulating miRNAs can be a reliable novel, minimally invasive biological indicator of occupational exposure to VOCs.

Health risk assessment of ambient air concentrations of benzene, toluene and xylene (BTX) in service station environments.

A comprehensive evaluation of the adverse health effects of human exposures to BTX from service station emissions was carried out using BTX exposure data from the scientific literature. The data was grouped into different scenarios based on activity, location and occupation and plotted as Cumulative Probability Distributions (CPD) plots. Health risk was evaluated for each scenario using the Hazard Quotient (HQ) at 50% (CEXP50) and 95% (CEXP95) exposure levels. HQ50 and HQ95 > 1 were obtained with benzene in the scenario for service station attendants and mechanics repairing petrol dispensing pumps indicating a possible health risk. The risk was minimized for service stations using vapour recovery systems which greatly reduced the benzene exposure levels. HQ50 and HQ95 < 1 were obtained for all other scenarios with benzene suggesting minimal risk for most of the exposed population. However, HQ50 and HQ95 < 1 was also found with toluene and xylene for all scenarios, suggesting minimal health risk. The lifetime excess Cancer Risk (CR) and Overall Risk Probability for cancer on exposure to benzene was calculated for all Scenarios and this was higher amongst service station attendants than any other scenario.

[Exposure to VOCs in furniture factories in two populations in northern Colombia]. / Exposición a COVs en fábricas de muebles de dos poblaciones del norte de Colombia.

OBJECTIVES: Assess the exposure to volatile organic compounds (VOCs)in furniture handicraft factories workers in two populations of Sucre (Sincelejo and Sampués), North of Colombia.Identify possible signs and/or symptoms related to exposure to these contaminants. METHODS: This was an analytical cross sectional study (2011), using a questionnaire. Study population consisted of 66 individuals, 41 exposed and 25 controls. Personal samples were collected for concentration quantifying of benzene, toluene, ethylbenzene and xylenes (both groups) and contrasting them with health effects possible attributed to these contaminants. RESULTS: The concentrations of benzene, toluene and m/p-xylene were higher in the exposed group (9.5 mg/m(3), 8.1 mg/m(3) and 12.1 mg/m(3))compared with the control group (0.2 mg/m(3), 0.3 mg/m(3) and 0.03 mg/m(3)). Muscular pain 82.9 % (PR=3.8; CI95%:1.2-11.8) and somnolence 65.9 % (PR=4.9; CI95%:1.7-14.7)were associated with a higher exposure.Factor such as mixtures of solvents (thinner) in the work and vehicles' traffic can contribute to these results. CONCLUSIONS: Several sources contribute to increases personal exposure of VOCs in furniture handicraft factories workers North of Colombia. Additionally, excessive use of these compounds may be generating adverse effects on the health of workers.

Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors.

PURPOSE: Accumulating evidence supports the existence of breast cancer stem cells (BCSC), which are characterized by their capacity to self-renew and divide indefinitely and resistance to conventional therapies. The Notch pathway is important for stem cell renewal and is a potential target for BCSC-directed therapy. EXPERIMENTAL DESIGN: Using human breast tumorgraft studies, we evaluated the impact of gamma secretase inhibitors (GSI) on the BCSC population and the efficacy of combining GSI with docetaxel treatment. The mouse experimental therapy paralleled a concurrent clinical trial in patients with advanced breast cancer, designed to determine the maximum-tolerated dose of the GSI, MK-0752, administered sequentially with docetaxel, and to evaluate BCSC markers in serial tumor biopsies. RESULTS: Treatment with GSI reduced BCSCs in MC1 and BCM-2147 tumorgrafts by inhibition of the Notch pathway. GSI enhanced the efficacy of docetaxel in preclinical studies. In the clinical trial, 30 patients with advanced breast cancer were treated with escalating doses of MK-0752 plus docetaxel. Clinically, meaningful doses of both drugs were possible with manageable toxicity and preliminary evidence of efficacy. A decrease in CD44(+)/CD24(-), ALDH(+), and mammosphere-forming efficiency were observed in tumors of patients undergoing serial biopsies. CONCLUSIONS: These preclinical data show that pharmacologic inhibition of the Notch pathway can reduce BCSCs in breast tumorgraft models. The clinical trial shows feasibility of combination GSI and chemotherapy, and together these results encourage further study of Notch pathway inhibitors in combination with chemotherapy in breast cancer.

Combined effects of exposure to occupational noise and mixed organic solvents on blood pressure in car manufacturing company workers.

BACKGROUND: Recent studies suggest that occupational exposures such as noise and organic solvents may affect blood pressure. The aim of this study was to investigate interaction of noise and mixed organic solvents on blood pressure. METHODS: Four hundred seventy-one workers of a car manufacturing plant were divided into four groups: group one or G1 workers exposed to noise and mixed organic solvents in the permitted limit or control group, G3 exposed to noise only, G2 exposed to solvents only, and G4 workers exposed to noise and mixed organic solvents at higher than the permitted limit or co-exposure group. Biological interaction of two variables on hypertension was calculated using the synergistic index. RESULTS: The workers of co-exposure group (G4), noise only group (G3), and solvents only group (G2) had significantly higher mean values of SBP and DBP than workers of control group (G1) or office workers (P < 0.05). Also logistic regression analysis showed a significant association between hypertension and exposure to noise and mixture of organic solvents. Odds ratio for hypertension in the co-exposure group and the noise only and solvents only exposed groups was 14.22, 9.43, and 4.38, respectively, compared to control group. In this study, the estimated synergism index was 1.11. CONCLUSIONS: Our results indicate that exposure to noise or a mixture of organic solvents may be associated with the prevalence of hypertension in car manufacturing company workers and co-exposure to noise and a mixture of solvents has an additive effect in this regard. Therefore appropriate preventive programs in these workers recommended.

Personal exposure to volatile organic compounds in the Czech Republic.

Personal exposures to volatile organic compounds (VOCs) were measured in the three industrial cities in the Czech Republic, Ostrava, Karvina and Havirov, while the city of Prague served as a control in a large-scale molecular epidemiological study identifying the impacts of air pollution on human health. Office workers from Ostrava and city policemen from Karvina, Havirov and Prague were monitored in the winter and summer of 2009. Only adult non-smokers participated in the study (N=160). Radiello-diffusive passive samplers were used to measure the exposure to benzene, toluene, ethylbenzene, meta- plus para-xylene and ortho-xylene (BTEX). All participants completed a personal questionnaire and a time-location-activity diary (TLAD). The average personal BTEX exposure levels in both seasons were 7.2/34.3/4.4/16.1 µg/m(3), respectively. The benzene levels were highest in winter in Karvina, Ostrava and Prague: 8.5, 7.2 and 5.3 µg/m(3), respectively. The personal exposures to BTEX were higher than the corresponding stationary monitoring levels detected in the individual localities (P<0.001; except m,p-xylene in summer). The indoor environment, ETS (environmental tobacco smoke), cooking, a home-heating fireplace or gas stove, automobile use and being in a restaurant were important predictors for benzene personal exposure. Ostrava's outdoor benzene pollution was a significant factor increasing the exposure of the Ostrava study participants in winter (P<0.05).

Chemical production in electrocautery smoke by a novel predictive model.

OBJECTIVES: The hazards of electrocautery smoke have been known for decades. However, few clinical studies have been conducted to analyze the responsible variables of the smoke production. This study collected clinical smoke samples and systematically analyzed all possible factors. METHODS: Thirty diathermy smoke samples were collected during mastectomy and abdominal cavity operations. Samples were analyzed using a gas chromatographer with a flame ionization detector. Data were applied to construct prediction models for chemical production from electrosurgeries to identify all possible factors that impact chemical production during electrosurgery. RESULTS: Toluene was detected in 27 smoke samples (90%) with concentrations of 0.003-0.463 mg/m(3) and production of 176.0-2,780.0 ng. Ethyl benzene and styrene were identified in very few cases. General linear regression analysis demonstrates that surgery type, patient age, electrocautery duration and imparted coagulation energy explained 67.63% of the variation in toluene production. CONCLUSION: Surgery type and patient age are known prior to surgery. In terms of risk precaution, the operating team should pay close attention to exposure when certain positive factors of increasing the chemical production are known in advance.

Changes in oxidative stress biomarker and gene expression levels in workers exposed to volatile organic compounds.

Exposure to volatile organic compounds (VOCs) was known to result in immunologic, respiratory, carcinogenic, reproductive, neurologic, and cardiovascular effects. However, the mechanisms by which VOCs induce these adverse health effects are not well understood. To evaluate the change of oxidative stress biomarker and gene expression levels in workers exposed to VOCs, we obtained urine and blood samples from 21 subjects before and after occupational exposure to VOCs. We measured levels of muconic acid (MuA), hippuric acid (HA), mandelic acid (MaA), and methyl hippuric acid (MHA) as urinary exposure biomarkers for benzene, toluene, ethylbenzene, and xylene (collectively BTEX), and malondialdehyde (MDA) and 8-hydroxydeoxyguanine (8-OHdG) as oxidative stress biomarkers in all subjects. We also evaluated BTEX-mediated RNA expression using cDNA microarray in 14 subjects. HA and MHA levels were higher following occupational exposure to VOCs (p < 0.01). In the linear regression analysis, HA ratios of after- and before-exposure were found to be significantly associated with increase of MDA ratios of after- and before-exposure after controlling for age, body mass index, and smoking (ß = 0.06, p = 0.031). Evaluation of the gene expressions by HA showed that 23 gene expressions were found to be significantly associated with HA levels after adjusting for age, body mass index, and smoking (p < 0.001). In particular, expressions of ENO3 and CDNA FLJ39461 fis among the 23 genes were significantly associated with the change in MDA level (p < 0.05). Our study results suggest that exposure to VOCs, specifically toluene, induces oxidative stress and various gene expression change of which some may be responsible for oxidative stress.

[BTEX exposure and its health effects in pregnant women following the Hebei Spirit oil spill].

OBJECTIVES: We evaluated the health effects of exposure to BTEX (Benzene, Toluene, Ethylbenzene, m,p-Xylene, o-Xylene) in the Taean area after the Hebei Spirit oil spill. METHODS: We used a questionnaire survey to look for health effects among 80 pregnant women 2 to 3 months following the Hebei Spirit oil spill. Their BTEX exposures were estimated using the CALPUFF method. We then used a multiple logistic regression analysis to evaluate the effects of BTEX exposure on the women's health effets. RESULTS: Pregnant women who lived near the accident site reported more symptoms of eye irritation and headache than those who lived farther from the site. There was a trend of decreasing symptoms with an increase in distance from the spill site. Pregnant women exposed to higher ambient cumulative levels of Xylene were significantly more likely to report symptoms of the skin (OR 8.01 95% CI=1.74-36.76) in the first day after the accident and significantly more likely to report abdominal pain (OR 3.86 95% CI=1.02-14.59 for Ethylbenzene, OR 6.70 95% CI=1.82-24.62 for Xylene) during the 1st through 4th days following the accident. CONCLUSIONS: This study suggests that exposure to BTEX from an oil spill is correlated with an increased risk of health effects among pregnant women. This implies the need to take proper measures, including the development of a national policy for environmental health emergencies and a plan for studying the short- and long-term chronic health effects associated with such spills.

A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals.

A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID methods was applied as a tool to study and predict the mechanism of action of 100 carcinogenic benzene derivatives. Two 3D-QSAR models were obtained: (i) model of mouse carcinogenicity on the basis of 100 chemicals (model 1) and (ii) model of the differences in mouse and rat carcinogenicity on the basis of 73 compounds (model 2). 3D-QSAR regression maps indicated the important differences in species carcinogenicity, and the molecular positions associated with them. In order to evaluate the role of P450 metabolic process in carcinogenicity, the following approaches were used. The 3D models of CYP2E1 for mouse and rat were built up. A docking study was applied and the important ligand-protein residues interactions and oxidation positions of the molecules were identified. A new approach for quantitative assessment of metabolism pathways was developed, which enabled us to describe the species differences in CYP2E1 metabolism, and how it can be related to differences in the carcinogenic potential for a subset of compounds. The binding energies of the important substituents (local-binding energy-LBE) were calculated, in order to quantitatively demonstrate the contribution of the substituents in metabolic processes. Furthermore, a computational procedure was used for determining energetically favourable binding sites (GRID examination) of the enzymes. The GRID procedure allowed the identification of some important differences, related to species metabolism in CYP2E1. Comparing GRID, 3D-QSAR maps and LBE results, a similarity was identified, indicating a relationship between P450 metabolic processes and the differences in the carcinogenicity.

Epidemiology of the plasma-cell disorders.

This review of the plasma-cell disorders begins with the definition of monoclonal gammopathy of undetermined significance (MGUS). The prevalence of MGUS in white and black populations is described. MGUS is a common finding in the medical practice of all physicians, and thus it is important to both the patient and the physician to determine whether the monoclonal protein remains stable or progresses to multiple myeloma (MM), Waldenström's macroglobulinemia (WM), primary systemic amyloidosis (AL), or a related disorder. The long-term (almost 40 years) follow-up data of 241 patients in the Mayo Clinic population is provided. In a large study of 1384 patients with MGUS from southeastern Minnesota, the risk of progression to MM, WM, AL, or other disorders was approximately 1% per year. Risk factors for progression are provided. The incidence of MM in Olmsted County, Minnesota, remained stable for the 56-year span 1945-2001. The apparent increase in incidence and mortality rates among patients with MM in many studies is due to improved case ascertainment, especially among the elderly. The incidence and mortality rates of MM in the United States and other countries are presented. The major emphasis is on the cause of MM, which is unclear. Exposure to radiation from atomic bombs, therapeutic and diagnostic radiation, and in workers in the nuclear industry field are addressed. Many studies involving agricultural occupations, exposure to benzene, petroleum products, and engine exhaust and other industrial exposures are discussed. Tobacco use, obesity, diet, and alcohol ingestion are all possible causes of MM. Clusters of MM have been noted. Multiple cases of MM have been found in first-degree relatives.