Abstract  A wide variety of chemicals, both naturally occurring and synthetic, have exhibited carcinogenic activity in rodent liver. Some are clearly DNA reactive whereas others produce only epigenetic effects. Hepatocarcinogens are categorized according to these properties and the characteristics of examples of both types are reviewed. DNA-reactive rodent hepatocarcinogens represent human cancer risks even at non-toxic exposures, whereas epigenetic agents pose either no risk because their effects are specific to rodents, or a risk only at high exposures at which they produce the same cellular effects in humans that are the basis for their carcinogenic activity in rodents.

Abstract  The Report on Carcinogens (RoC) is a scientific and public health document mandated by Congress in 1978. The RoC identifies and discusses substances, chemicals, mixtures, or exposure circumstances (collectively called substances) that may pose a cancer hazard to human health and to which persons in the United States are exposed. Nominations to the RoC go through a rigorous review process with multiple opportunities for public comment. The RoC is a compilation of substance profiles and each new edition replaces the previous one. Each substance profile in the RoC identifies a substance as known or reasonably anticipated to be a human carcinogen and provides information on (1) the scientific evidence that supports the listing (human epidemiological studies, cancer studies in experimental animals, and toxicokinetic, genotoxic, and mechanistic data), (2) the potential for human exposure, such as data on use, production, environmental occurrence, occupational exposure, and exposure to the general population, and (3) current Federal regulations to limit exposure.

Abstract  Exposure-response analysis of acute noncancer risks should consider both concentration (C) and duration (T) of exposure, as well as severity of response. Stratified categorical regression is a form of meta-analysis that addresses these needs by combining studies and analyzing response data expressed as ordinal severity categories. A generalized linear model for ordinal data was used to estimate the probability of response associated with exposure and severity category. Stratification of the regression model addresses systematic differences among studies by allowing one or more model parameters to vary across strata defined, for example, by species and sex. The ability to treat partial information addresses the difficulties in assigning consistent severity scores. Studies containing information on acute effects of tetrachloroethylene in rats, mice, and humans were analyzed. The mouse data were highly uncertain due to lack of data on effects of low concentrations and were excluded from the analysis. A model with species-specific concentration intercept terms for rat and human central nervous system data improved fit to the data compared with the base model (combined species). More complex models with strata defined by sex and species did not improve the fit. The stratified regression model allows human effect levels to be identified more confidently by basing the intercept on human data and the slope parameters on the combined data (on a C x T plot). This analysis provides an exposure-response function for acute exposures to tetrachloroethylene using categorical regression analysis.

Abstract  THIO, used in the production of pesticides, polymers, and pharmaceuticals, and as a food additive, was tested for developmental toxicity in Sprague-Dawley rats (25/group) and New Zealand White rabbits (15-26/group). THIO was given po in corn oil to rats (0, 20, 35, or 50 mg/kg/day; gestational days (gd) 6-15) or rabbits (0, 10, 30 or 40 mg/kg/day; gd 6-19). Maternal body wt., food and water consumption (rats) were recorded. On gd 20 (rats) or 30 (rabbits), maternal organs and fetuses were weighed, and fetuses were examined for malformations (external, visceral, and skeletal). In rats, maternal body wt. change and food consumption were depressed in all THIO-treated groups on gd. 6-9. Gravid uterine wt. was decreased, and relative maternal liver wt. was increased at 50 mg/kg/day; kidney wt. was unaffected. Increased postimplantation loss and incidence of external malformations, and decreased live litter size were observed at 50 mg/kg/day. Female fetal body wt. was decreased at 35 mg/kg/day. In rabbits, maternal food intake tended to be lower, and body wt. change was decreased at 30 and 40 mg/kg/day on gd 12-15. Gravid uterine wt., liver and kidney wt. were unaffected. Postimplantation loss, litter size, average fetal body wt. and morphological development were unaffected. In summary, for rats, 20 mg/kg/day THIO was the low observed adverse effect level (LOAEL) for maternal toxicity, based on transient decreases in maternal wt. gain and food intake. A maternal no observed adverse effect level (NOAEL) was not determined. The developmental NOAEL in rats was 20 mg/kg/day; clear evidence of developmental toxicity was seen at greater than or equal to 35 mg/kg/day. In rabbits, the maternal NOAEL was 10 mg/kg/day. Maternal toxic effects at greater than or equal to 30 mg/kg/day were minor. The developmental NOAEL was greater than or equal to 40 mg/kg/day.

Abstract  Biological exposure indices (BEIs) of toluene, perchloroethylene (PCE) and methyl ethyl ketone (MEK) for Korean workers were studied respectively. Exposure in workplace to organic solvents were measured by personal sampling. Blood toluene, blood PCE, urinary trichloroacetic acid and urinary MEK were determined by headspace GC. Urinary hippuric acid was determined by HPLC and corrected for creatinine. BEIs for Korean workers were calculated with the levels of the determinants corresponding to permissible exposure limits in Korea which were the same with TLV of ACGIH. Blood toluene level of 2.2 mg/l and urinary hippuric acid level of 1.7 g/g creatinine corresponded to exposure of 100 ppm toluene. Blood PCE concentration of 1.6 mg/l and urinary trichloroacetic acid concentration of 2.9 mg/l corresponded to exposure to 50 ppm PCE. Urinary MEK concentration of 1.4 mg/l corresponded to exposure to 200 ppm of MEK. In conclusion, BEIs for Korean workers determined in this study were different to ACGIH's BEI as urinary determinants were lower and blood determinants were higher than ACGIH's BEI.

Abstract  Nanoscale Pd/Fe bimetallic particles were synthesized and used to hydrodechlorinate 2,4-dichlorophenol. 2,4-dichlorophenol was transformed to phenol with a small amount of 2-chlorophenol and 4-chlorophenol produced. The reaction pathway and reaction rate constants for each step have been determined. The effects of various Pd bulk loadings in the bi-metals, temperatures and pH conditions on the hydrodechlorination of 2,4-dichlorophenol were examined. The results showed that higher Pd bulk loadings, higher temperatures and weak acid conditions are beneficial to the catalytic dechlorination of 2,4-dichlorophenol.

Abstract  A survey on the mutation induction capacity was made in the microbial system on 166 pesticides including 57 fungicides, 63 herbicides and 46 insecticides. The screening methods consisted of the rec-assay procedure, a sensitivity test utilizing H17 Rec+ and M45 Rec− strains of Bacillus subtilis, as well as the reversion assays on plates utilizing auxotrophic strains of Escherichia coli (WP2) and Salmonella typhimurium (Ames series). Chemicals inducing reversions were detected only among those showing positive effects in the rec-assay but not among negative samples. In addition to Captafol, Captan, Dexon and NBT of which mutagenicities have been previously reported, Dichlorvos, Folpet, 2-hydrazinoethanol (HEH), 5-nitro-1-naphthonitrile (NNN) and Vamidothion were found to be mutagens in our systems.

Abstract  The tumorigenicity of chloral hydrate (CH), trichloroacetic acid (TCA), trichloroethanol (TCE), malondialdehyde (MDA), crotonaldehyde, acrolein, and 4-hydroxy-2-nonenal (HNE) was tested in the B6C3F(1) neonatal mouse. Mice were administered i.p. injections of CH (1000, 2000, 2500, and 5000 nmol per animal), TCA (1000 and 2000 nmol), TCE (1000 and 2000 nmol), MDA (1500 and 3000 nmol), crotonaldehyde (1500 and 3000 nmol), acrolein (75 and 150 nmol), and HNE (750 and 1500 nmol) at 8 and 15 days of age. At 12 months, only male mice treated with the positive control chemicals, 4-aminobiphenyl (500 and 1000 nmol) and benzo[a]pyrene (150 and 300 nmol), had incidences of tumors in the liver significantly higher than the solvent control. Additional male mice were dosed as described above and their livers were excised at 24, 48 h, and 7 days after the final dose. Liver DNA was isolated and analyzed by 32P-postlabeling/high-performance liquid chromatography (HPLC) and HPLC/electrochemical detection for MDA-derived adduct (M(1)G) and 8-oxo-2'-deoxyguanosine (8-OHdG) formation, respectively. At 24 and 48 h after the final dose, CH- and TCA-treated mice exhibited significantly higher M(1)G levels than the controls. 8-OHdG formation was also induced by CH, TCA, and MDA. These results suggest that under these experimental conditions the B6C3F(1) neonatal mouse is not sensitive to carcinogens that induce an increase in endogenous DNA adduct formation through lipid peroxidation or oxidative stress.

Abstract  The mechanism of action of 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucopyra noside) (VP-16), an important antitumor agent, is unclear. There is evidence that DNA may be the target of action because VP-16 causes single-strand and double-strand breaks in DNA and produces cytotoxicity over a similar dose range. We have hypothesized that an enzyme system, such as dehydrogenase, catalyzes an oxidation-reduction reaction involving the pendant phenolic group which forms an active metabolite that causes the DNA damage and cytotoxicity. To test our hypothesis, we investigated the effect of disulfiram, an aldehyde dehydrogenase inhibitor, and its metabolite, diethyldithiocarbamate, on VP-16-induced DNA damage in L1210 cells. Using the alkaline elution technique to assay DNA damage, we found that disulfiram and diethyldithiocerbamate inhibited VP-16-induced single-strand breaks. Both compounds were also capable of significantly reducing VP-16-induced cytotoxicity. Oxalic acid, pyrophosphate, and malonic acid, competitive inhibitors of succinate dehydrogenase, and the naturally occurring dehydrogenase substrates, succinic acid, beta-glycerophosphate, and isocitric acid, also blocked the effects of VP-16. Free-radical scavengers were also studied. While sodium benzoate was particularly effective in preventing drug-induced DNA damage and cytotoxicity, a number of other scavengers were not. Our data are consistent with the hypothesis that VP-16 is activated by an enzyme such as a dehydrogenase which transforms it into an active intermediate resulting in DNA damage and, consequently, cell death.

Abstract  Circulating tumor cells are responsible for seeding metastatic growth at distant sites. Kim et al. (2009) now discover that circulating tumor cells can reinfiltrate tumors at their primary organs and promote tumor progression.

Abstract  This paper describes a set of multipathway, multimedia models for estimating potential human exposure to environmental contaminants. The models link concentrations of an environmental contaminant in air, water, and soil to human exposure through inhalation, ingestion, and dermalcontact routes. The relationship between concentration of a contaminant in an environmental medium and human exposure is determined with pathway exposure factors (PEFs). A PEF is an algebraic expression that incorporates information on human physiology and lifestyle together with models of environmental partitioning and translates a concentration (i.e., mg/m3 in air, mg/liter in water, or mg/kg in soil) into a lifetime-equivalent chronic daily intake (CDI) in mg/kg-day. Human, animal, and environmental data used in calculating PEFs are presented and discussed. Generalized PEFs are derived for air → inhalation, air → ingestion, water → inhalation, water → ingestion, water → dermal uptake, soil → inhalation, soil → ingestion, and soil → dermal uptake pathways. To illustrate the application of the PEF expressions, we apply them to soil-based contamination of multiple environmental media by arsenic, tetrachloroethylene (PCE), and trinitrotoluene (TNT).

Abstract  Measures of bronchial responsiveness are widely used for the diagnosis and monitoring of asthma. A vast array of non-specific bronchoconstrictor stimuli is available. Methacholine and histamine cause airflow limitation predominantly through a direct effect on airway smooth muscle. Indirect challenges (adenosine, exercise and hypertonic saline) induce airflow limitation by an action on cells other than smooth muscle cells, with a variety of cells, mediators and receptors being involved in this process. Bronchial responsiveness to a direct stimulus is only weakly related to airway inflammation, whereas indirect airway challenges might better reflect active airway inflammation. Both direct and indirect airway challenges are useful outcome parameters in clinical studies of asthma. For example, an indirect challenge responds to treatment with inhaled steroids within hours to days, whereas improvement in direct responsiveness might take months to years. Bronchial challenges are also an essential step in the development of new anti-asthma treatments, such as adenosine or tachykinin receptor antagonists.

Abstract  AP-1/cJun, NF-κB and STAT3 transcription factors control expression of numerous genes, which regulate critical cell functions including proliferation, survival and apoptosis. Sodium arsenite is known to suppress both the IKK-NF-κB and JAK2-STAT3 signaling pathways and to activate the MAPK/JNK-cJun pathways, thereby committing some cancers to undergo apoptosis. Indeed, sodium arsenite is an effective drug for the treatment of acute promyelocytic leukemia with little nonspecific toxicity. Malignant melanoma is highly refractory to conventional radio- and chemotherapy. In the present study, we observed strong effects of sodium arsenite treatment on upregulation of TRAIL-mediated apoptosis in human and mouse melanomas. Arsenite treatment upregulated surface levels of death receptors, TRAIL-R1 and TRAIL-R2, through increased translocation of these proteins from cytoplasm to the cell surface. Furthermore, activation of cJun and suppression of NF-κB by sodium arsenite resulted in upregulation of the endogenous TRAIL and downregulation of the cFLIP gene expression (which encodes one of the main anti-apoptotic proteins in melanomas) followed by cFLIP protein degradation and, finally, by acceleration of TRAILinduced apoptosis. Direct suppression of cFLIP expression by cFLIP RNAi also accelerated TRAIL-induced apoptosis in these melanomas, while COX-2 suppression substantially increased levels of both TRAIL-induced and arsenite-induced apoptosis. In contrast, overexpression of permanently active AKTmyr inhibited TRAIL-mediated apoptosis via downregulation of TRAIL-R1 levels. Finally, AKT overactivation increased melanoma survival in cell culture and dramatically accelerated growth of melanoma transplant in vivo, highlighting a role of AKT suppression for effective anticancer treatment

Abstract  Whereas a lot of marine research work has been done on heavy metals and semivolatile organic compounds, far less attention has been paid to the fate of volatile organic compounds in this area. This work focuses on 13 volatile organic compounds in marine waters and the marine atmosphere. During six campaigns in September 1994−December 1995, simultaneous air and water sampling was carried out in both the southern North Sea area and the Scheldt Estuary. Mean water concentrations for individual compounds were in the 2.2−72.9 ppt range (n = 38), whereas atmospheric concentrations varied between 2.3 and 854 pptv. Samples from the Scheldt Estuary proved to have elevated concentrations of chlorinated compounds. A number of water and air samples showed enhanced concentrations of C2-substituted monocyclic aromatic hydrocarbons, which could not clearly be linked to anthropogenic activities. Back-trajectory calculations showed that a number of over sea atmospheric samples were affected by atmospheric transport from industrial sites, 250−300 km up wind. Fugacity modeling showed that the North Sea acts as a source to the atmosphere, not as a sink. Mean water to air mass transfer rates varied between 0.6−52.7 μg m-2 day-1 for all VOCs. It was statistically shown that water to air exchange rates of tetrachloroethylene, benzene, and toluene were slowed when air masses from continental origin were at the marine sampling sites instead of air masses from remote noncontinental origin.

Abstract  This study examines the applicability of the iron-based degradative solidification/stabilization (DS/S-Fe(II)) process to 1,1,1-trichloroethane (1,1,1-TCA), which is one of common chlorinated aliphatic hydrocarbons (CAHs) of concern at contaminated sites. DS/S-Fe(II) combines contaminant degradation by Fe(II) and immobilization by the hydration reactions of Portland cement. The transformation of 1,1,1-TCA by Fe(II) in 10% Portland cement slurries was studied using a batch slurry reactor system. The effects of Fe(II) dose, pH, and initial concentration of 1,1,1-TCA on the kinetics of 1,1,1-TCA degradation were evaluated. Degradation of 1,1,1-TCA in cement slurries including Fe(II) was very rapid and could be described by a pseudo-first-order rate law. The half-lives for 1,1,1-TCA were measured between 0.4 and 5h when Fe(II) dose ranged from 4.9 to 39.2mM. The pseudo-first-order rate constant increased with pH to a maximum near pH 12.5. A saturation rate equation was able to predict degradation kinetics over a wide range of target organic concentrations and at higher Fe(II) doses. The major transformation product of 1,1,1-TCA in mixtures of Fe(II) and cement was 1,1-dichloroethane (1,1-DCA), which indicates that degradation occurred by a hydrogenolysis pathway. A small amount of ethane was observed. The conversion of 1,1,1-TCA to ethane was better described by a parallel reaction model than by a consecutive reaction model.

Abstract  We have developed a rapid and simple immunodetection assay for the in situ identification of aneuploidy in mitotic fibroblasts. Kinetochore (centromere)-containing micronuclei can be detected easily and rapidly by immunofluorescence. The action of colchicine and its derivatives on the mitotic spindle apparatus of mammalian cells induces chromosome lag and aneuploidy. The treatment of normal human fibroblasts with Colcemid resulted in increased levels of micronuclei. Using an immunofluorescence stain (scleroderma CREST antiserum, biotinylated goat antihuman IgG and streptavidin-Texas Red) to detect the presence of kinetochores, it was observed that 90% of the Colcemid-induced micronuclei contained one or more fluorescent bodies (kinetochores). Cultured skin fibroblasts from a patient with ataxia telangiectasia (AT), which is a chromosome breakage syndrome, were used as a control. The AT fibroblasts exhibited elevated levels of spontaneous micronuclei when compared with normal fibroblasts, and 85% of these micronuclei were kinetochore-negative. This finding supports the hypothesis that the majority of spontaneous micronuclei in AT cells arise from chromosome breakage. The spontaneous micronucleus frequencies for 8 strains of human fibroblasts were in the order of 0.5-2%. Spontaneous levels of kinetochore-positive micronuclei were measured for these 8 strains; in 5 of the strains, about 25% of the micronuclei were kinetochore-positive, and in the other 3 strains approximately 50% of the micronuclei were kinetochore-positive. These data suggest that genetic factors may play a role in the control of the spontaneous levels of chromosome breakage and/or segregation errors which result in aneuploidy.

Abstract  The mode of action of trichloroethylene on electrical properties of squid giant axons has been studied by means of voltage clamp techniques. Trichloroethylene decreased the resting membrane potential in a manner dependent upon the concentration, the depolarization by 50% saturated trichloroethylene attaining 28.4 and 32.7% of the initial value at 20 and 10 degrees C, respectively. Leakage conductance was decreased to 34.6% of the control by 30% saturated trichloroethylene at 10-12 degrees C. It appears that the trichloroethylene-induced depolarization is at least in part due to a decrease in resting potassium permeability. Both peak transient and steady-state conductance increases were suppressec by trichloroethylene, and the curve relating the steady-state conductance to the membrane potential was shifted in the depolarizing direction while the peak transient conductance curve was not appreciably shifted. The reversal potential for the peak transient current was greatly shifted by trichloroethylene in the direction of hyperpolarization in a manner dependent on the concentration, the maximum shift amounting to 25 mV at 10 degrees C. This effect was less pronounced at 20 degrees C. The shift in the reversal potential is mostly due to a decrease in selectivity of the peak transient channel and partly due to an accumulation of sodium ions inside. Analyes of dose-response relation in suppressing peak transient and steady-state conductances show that trichloroethylene interacts with receptor on a one-to-one stoichiometric basis. Steady-state sodium inactivation curve was shifted by trichloroethylene in the direction of hyperpolarization. All of these effects were partially reversed after washing the axon with anesthetic-free media. The accumulation of sodium ions inside would be much more pronounced in small nerve fibers in the brain than in giant axon and, together with the observed decrease in the selectivity of peak transient channels, would play a significant role in general anesthesia.

Abstract  Concern over the potential adverse health effects of chemically contaminated groundwater has existed for many years. In general, these studies have focused on retrospective epidemiological studies for cancer risk. In the present studies, immune function was monitored in female B6C3F1 mice exposed to a chemical mixture in drinking water for either 14 or 90 days. The mixture consisted of 25 common groudwater contaminants frequently found near toxic waste dumps, as determined by EPA surveys. None of the animals developed overt signs of toxicity such as body or liver weight changes. Mice exposed to the highest dose of this mixture for 14 or 90 days showed immune function changes which could be related to rapidly proliferating cells, including suppression of hematopoietic stem cells and of antigen-induced antibody-forming cells. Some of these responses, e.g., granulocyte-macrophage colony formation, were also suppressed at lower concentrations of the chemical mixture. There were no effects on T cell function or T and B cell numbers in any of the treatment groups. Altered resistance to challenge with an infectious agent also occurred in mice given the highest concentration, which correlated with the immune function changes. Paired-water studies indicated that the immune effects were related to chemical exposure and not to decreased water intake. These results suggest that longterm exposure to contaminated groudwater may represent a risk to the immune system in humans.

Abstract  To examine the concordance of two microbial genotoxicity short-term assays, 330 experimental results for the SOS chromotest using tester strain Escherichia coli PQ37 were compared with the results of the Salmonella/mammalian microsome mutagenicity assay with Salmonella typhimurium TA97, TA98, TA100, TA102, TA104, TA1535, TA1537 and/or TA1538. With respect to qualitative features, the concordance between SOS chromotest and Salmonella mutagenicity test results was 86.4% (sensitivity, 78.6%; specificity, 100%; {chi}2 = 188.6). None of the non-mutagens (N = 120) were able to induce the SOS system. Additionally, 45 of the 210 S.typhimurium mutagens (21.5%) did not induce the SOS repair system. On closer examination, the majority of these 45 compounds (84%) were mutagens with activities between 0.001 and 10 rev/nmol. Even though the experimental protocols of both systems were not standardized, the correlation coefficient for the experimental results of the two test systems was 0.7 for the 330 chemicals. Except for aliphatic epoxides (r = 0.47), the mutagenicity/SOS induction correlations for congeneric data sets (polycyclic aromatic hydrocarbons, nitroarenes, nitroarenofurans, mycotoxins) were even better (r = 0.72–0.95). Additionally, computer automated structure evaluation (CASE) analyses of the nature of the structural determinants associated with each endpoint indicate extensive homologies. The data can be taken to indicate that the two phenomena reflect common mechanisms of action.

Abstract  Barr-Nea and Wolman in their studies on petroleum toxicity and carcinogenesis rubbed petroleum into the skin of mice and found that the animals developed malignant tumors of the lymphatic system and papilloma. The authors suggested that the effect observed was due to the presence in petroleum of aromatic hydrocarbons as well as hydrcarbons of different degree of oxidation. Although the benzene fraction of mineral oil contains only trace amounts of these types of hydrocarbons, it was found to cause hypertropy of hypophysis and adrenal cortex in animals subjected to chronic intoxication. In the present work the authors demonstrated that the R-33 benzene fraction of petroleum caused in the rat, hypertrophy of liver and kidney, changes in total protein content in these organs and changes in the protein synthetizing system, both when it was applied intraperitoneally and in the form of chronic inhalation of vapors.

Abstract  Acute Exposure Guideline Level (AEGL) recommendations are developed for 10-minute, 30-minute, 1-hour, 4-hours, and 8-hours exposure durations and are designated for three levels of severity: AEGL-1 represents concentrations above which acute exposures may cause noticeable discomfort including irritation; AEGL-2 represents concentrations above which acute exposure may cause irreversible health effects or impaired ability to escape; and AEGL-3 represents concentrations above which exposure may cause life-threatening health effects or death. The default procedure for setting AEGL values across durations when applicable data are unavailable involves estimation based on Haber's rule, which has an underlying assumption that cumulative exposure is the determinant of toxicity. For acute exposure to trichloroethylene (TCE), however, experimental data indicate that momentary tissue concentration, and not the cumulative amount of exposure, is important. We employed an alternative approach to duration adjustments in which a physiologically-based pharmacokinetic (PBPK) model was used to predict the arterial blood concentrations [TCE(a)] associated with adverse outcomes appropriate for AEGL-1, -2, or -3-level effects. The PBPK model was then used to estimate the atmospheric concentration that produces equivalent [TCE(a)] at each of the AEGL-specific exposure durations. This approach yielded [TCE(a)] values of 4.89 mg/l for AEGL-1, 18.7 mg/l for AEGL-2, and 310 mg/l for AEGL-3. Duration adjustments based on equivalent target tissue doses should provide similar degrees of toxicity protection at different exposure durations.