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  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  The massive exploitation of natural resources, of which tobacco and asbestos are two conspicuous, though very different examples, and the synthesis of industrial chemicals have generated new hazards and new carcinogens which have been added to older ones. The majority of the over 50 agents that have been firmly identified so far as being human carcinogens belong to the relatively new hazards, that is environmental chemicals or chemical mixtures to which humans have been exposed only during the last century and a half. They are of more importance for cancer occurring in men than in women, and there is no evidence so far that they are related to cancers occurring at some of the most common target sites in either sex. It would be mistaken to believe that complete cancer prevention could be achieved solely by controlling these new, or relatively new, carcinogenic agents, but it would be similarly wrong to deny the importance of trying to control them and of continuing to do so. The experimental approach for the identification of carcinogens has an irreplaceable role to play in preventing the dispersal into our environment of new hazards and in identifying among the chemicals already in use, those that are carcinogenic. That a closer integration between the epidemiological and the experimental approaches may succeed in substantially reducing the size of the unknown region within the spectrum of cancer-causing factors, is today's hope that awaits confirmation. At the same time, advances in the understanding of the mechanisms underlying the different steps of the process leading to the clinical manifestation of cancer may help in the uncovering of agents and risk factors that the approaches used, at least in the way they have been used until now, may not have been apt to identify.

Abstract  Potential risk factors in renal cell carcinoma (RCC) were studied in a case-control study of 315 RCC cases and 313 hospital and 336 population controls. Risk factors included medical history, radiation exposure, predominant lifetime occupation, exposure to high-risk industries, and summary of important risk factors by a linear logistic regression model based on the comparison of RCC cases and controls selected from hospitals and the general population for 33 variables. A significant increase in urologic, cardiovascular, malignant, digestive, and metabolic disease was observed among cases over population controls. Exposure to radiation increased the risk, especially in females. A predominant lifetime occupation as a professional decreased the risk, whereas work as an operative increased the risk significantly. Work in petroleum-related and dry-cleaning industries were associated with elevated risk. Multivariate analysis comparing cases with each of the control groups for males and females identified obesity as the most important risk factor in RCC. Weight control at an early age might help to prevent the occurrence of a significant proportion of this rare but increasing malignant disease.

Abstract  A number of short-term methods have been developed in recent years to test chemical compounds and other agents for metagenic activity. These tests involve a number of species, both mammalian and nonmammalian, and are conducted both in vivo and in vitro. A correlation has been shown between the mutagenicity and the carcinogenicity of a compund. It has been estimated that approximately 80% (B.N. Ames, pers. comm.; M.S. Legator, pers. comm.) of all mutagenic compounds are also carcinogenic, although not all carcinogens are mutagens. Therefore, the value of tests to determine the mutagenicity of a compound is important in that these tests may, at least in some cases, give some indication of the carcinogenicity of that chemical as well. The mutagenicity tests alone, however, cannot difinitively identify a carcinogen. However, some of these test can be used for monitoring at-risk population groups and to aid in the evaluation of acceptable exposure standards. Mutational events may occur either at the gene level, where they result in mutant alleles, or at the chromosome level, where they cause chromosomal aberrations (usually the deletions or addition of some part of the chromosome arm). These may occur either during meiosis (in germ cells resulting in possible genetic transmission of that mutation) or during mitosis (occurring in somatic cells and not hereditary). Chromosomal aberrations may be either numerical or structural. Numerical abberations affect the whole chromosome set by the addition or deletion of one or more chromosomes from the cell. Structural anomalies, however, are generally deletions, breaks, gaps, or translocations in choromosomes and do not affect the chromosome number. Although many of these mutational events may result in cellular death, many may be repaired. In addition to the genetic end points of gene mutation or chromosomal aberration primary DNA damage may result from chemical mutagenesis. There are a number of tests that evaluate damage-induced genetic recombination. These include mitotic crossing over, gene coversion, sister chromatid exchange, and unscheduled DNA synthesis, as well as others.

Abstract  In recent years physiologically based pharmacokinetic models have come to play an increasingly important role in risk assessment for carcinogens. The hope is that they can help open the black box between external exposure and carcinogenic effects to experimental observations, and improve both high-dose to low-dose and interspecies projections of risk. However, to date, there have been only relatively preliminary efforts to assess the uncertainties in current modeling results. In this paper we compare the physiologically based pharmacokinetic models (and model predictions of risk-related overall metabolism) that have been produced by seven different sets of authors for perchloroethylene (tetrachloroethylene). The most striking conclusion from the data is that most of the differences in risk-related model predictions are attributable to the choice of the data sets used for calibrating the metabolic parameters. Second, it is clear that the bottom-line differences among the model predictions are appreciable. Overall, the ratios of low-dose human to bioassay rodent metabolism spanned a 30-fold range for the six available human/rat comparisons, and the seven predicted ratios of low-dose human to bioassay mouse metabolism spanned a 13-fold range. (The greater range for the rat/human comparison is attributable to a structural assumption by one author group of competing linear and saturable pathways, and their conclusion that the dangerous saturable pathway constitutes a minor fraction of metabolism in rats.) It is clear that there are a number of opportunities for modelers to make different choices of model structure, interpretive assumptions, and calibrating data in the process of constructing pharmacokinetic models for use in estimating “delivered” or “biologically effective” dose for carcinogenesis risk assessments. We believe that in presenting the results of such modeling studies, it is important for researchers to explore the results of alternative, reasonably likely approaches for interpreting the available data—and either show that any conclusions they make are relatively insensitive to particular interpretive choices, or to acknowledge the differences in conclusions that would result from plausible alternative views of the world.

Abstract  Toluene and 5 aliphatic chlorinated hydrocarbons of wide industrial use were injected into the air space of fertilized chicken eggs at 2,3 and 6 days of incubation. The embryotoxicity was evaluated as survival and death incidences after 14 days of incubation, and also the the weights and lengths of the embryo were recored. The approximate LD50 value for trichloroethylene and trichlorethanes varied between 50 and 100 μmol/egg while for toluene, tetrachlorethylene and methylene chloride it was over 100 μmol/egg. Macroscopic malformations of various kinds were produced with doses of 5–100 μmol/egg. The teratogenic potential of the tested compounds decreased in the following order: 1,1,1-trichloroethane > trichloroethylene > methylene chloride, tetrachloroethylene, 1,1,2-trichloroethane > toluene > olive oil control.

Abstract  The acute toxicity (96-hr median lethal concentrations (LC50s) of ten chlorinated isomers of benzene, phenol, ethane, and ethylene to the American flagfish (Jordanella floridae) were determined in both static and flow-through systems. Chronic toxicity to embryo-larval fish was also estimated from hatching success and post-hatch survival as well as fry growth rates and survival. Maximum acceptable toxicant concentrations (MATC) were estimated where possible. In general, for both acute and chronic toxicity tests, the order of increasing relative toxicity based on the water-borne exposure concentrations was: chloroethanes, chloroethylenes, chlorobenzenes, and chlorophenols. Within groups, more highly chlorinated isomers were usually more toxic. The presence of suspended or colloidal 1,2,4,5-tetrachlorobenzene was observed in acute toxicity testing and affected toxicity estimates.

Abstract  Several chronic bioassays have been conducted in multiple strains of mice in which various concentrations of arsenate or arsenite were administered in the drinking water without a tumorigenic effect. However, one study (Ng et al., 1999) reported a significant increase in tumor incidence in C57Bl/6J mice exposed to arsenic in their drinking water throughout their lifetime, with no tumors reported in controls. A physiologically based pharmacokinetic model for arsenic in the mouse has previously been developed (Gentry et al., 2004) to investigate potential differences in tissue dosimetry of arsenic species across various strains of mice. Initial results indicated no significant differences in blood, liver, or urine dosimetry in B6C3F1 and C57Bl/6 mice for acute or subchronic exposure. The current work was conducted to compare model-predicted estimates of tissue dosimetry to additional kinetic information from the (C57Bl/6 xCBA)F1 and TgAc mouse. The results from the current modeling indicate that the pharmacokinetic parameters derived based on information in the B6C3F1 mouse adequately describe the measured concentrations in the blood/plasma, liver, and urine of both the (C57Bl/6 x CBA)F1 and TgAc mouse, providing further support that the differences in response observed in the chronic bioassays are not related to strain-specific differences in pharmacokinetics. One significant finding was that no increases in skin or lung concentrations of arsenic species in the (C57Bl/6 x CBA)F1 strain were observed following administration of low concentrations (0.2 or 2 mg/U of arsenate in the drinking water, even though differences in response in the skin were reported. These data suggest that pharmacodynamic changes may be observed following exposure to arsenic compounds without an observable change in tissue dosimetry. These results provided further indirect support for the existence of inducible arsenic efflux in these tissues.

Abstract  GADD153 is a CCAAT/enhancer-binding-protein-related gene that may function to control cellular growth in response to stress signals. In this study, a variety of oxidant treatments were shown to stimulate endogenous GADD153 mRNA expression and to transcriptionally activate a GADD153 promoter-reporter gene construct in transfected HeLa cells. Both commonalities and distinctions in the induction of GADD153 by H2O2 and the thiol-reactive compound arsenite were demonstrated. GADD153 mRNA induction by both H2O2 and arsenite was potentiated by GSH depletion, and completely inhibited by N-acetyl-cysteine. o-Phenanthroline and mannitol blocked GADD153 induction by H2O2, indicating that iron-generated hydroxyl radical mediates this induction. Concordantly, GSH peroxidase overexpression in WI38 cells attenuated GADD153 mRNA induction by H2O2. However, GADD153 induction by arsenite was only modestly reduced in the same cells, suggesting a lesser contribution of peroxides to gene activation by arsenite. We also demonstrated that oxidative stress participates in the induction of GADD153 by UVC (254 nm) irradiation. Finally, both promoter-deletion analysis and point mutation of the AP-1 site in an otherwise intact promoter support a significant role for AP-1 in transcriptional activation of GADD153 by UVC or oxidant treatment. Indeed, exposure of cells to oxidants or UVC stimulated binding of Fos and Jun to the GADD153 AP-1 element. Together, these results demonstrate that both free-radical generation and thiol modification can transcriptionally activate GADD153, and that AP-1 is critical to oxidative regulation of this gene. This study further supports a role for the GADD153 gene product in the cellular response to oxidant injury.

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  The annual SEER Cancer Statistics Review (CSR) contains incidence, mortality, prevalence, and survival statistics from 1975 through the most recent year for which data are available. This report is published by the Surveillance Research Program of the National Cancer Institute, which manages the Surveillance, Epidemiology, and End Results (SEER) Program. The scope and purpose of the CSR follow a report to the Senate Appropriations Committee, which recommended that a broad profile of cancer be presented regularly to the American public. The SEER program is an authoritative source of information on cancer incidence and survival in the United States. SEER collects and publishes these statistics from population-based registries covering 26% of the US population. The 17 SEER registries routinely collect data on patient demographics, primary tumor site, tumor morphology, extent of disease, first course of treatment, and active follow-up for vital status.

Abstract  In May of 1979, the Massachusetts Department of Environmental Quality Engineering (DEQE) discovered that Wells G and H, two public drinking water wells in Woburn, Massachusetts, were contaminated with toxic chemicals. These wells were then shut off. Subsequent studies of the health of the people of Woburn have indicated that the city had a higher level of childhood illness than would normally be expected. Research is currently being undertaken to determine the rate of adverse reproductive outcomes within Woburn, and to test associations between these outcomes and exposure to environmental contaminants, including the water from Wells G and H during the periods of their operation. This report presents the calculation of this exposure as a function both of roughly fifty hydraulically distinct neighborhoods within Woburn and of the 114 months of Wells’ G and H operation. The method used to calculate this exposure to water from the wells begins with a computer model of the water distribution system that was developed by the author under a previous contract with DEQE. This Woburn water distribution model was applied to the various pumping and water use configurations that occurred during each month that Wells G and H were in operation. The results of these calculations were then individually analyzed with a hydraulic mixing model to calculate the mixture of water supplied to each neighborhood. Finally, the resulting mixtures were combined in proportion to the period of their occurrence during each month to provide a monthly average exposure index for each neighborhood and each month. These indices were also summed to determine the cumulative exposure. The validity and error levels of the distribution and mixing models were analyzed by comparing computer predictions of fluoride concentration distributions in both San Jose, California and Woburn with concentrations measured during field tests. The locations of the boundary between the zones with and without the fluoride tracer were predicted within one pipe junction of where they were observed. The root-mean-square differences between predicted and observed dilutions were roughly thirty percent. The levels of exposure to water from Wells G and H were found to vary widely as is shown by Figures 10 – 15. Typically the neighborhoods south and west of the center of the city, Main Street and Montvale Avenue, received no or very little water from Wells G and H. The neighborhoods of east Woburn along and near Washington Street received water mostly from Wells G and H whenever those wells were pumping. The mixture zone between the two water sources ran along, or just to the east of, Main Street.

Abstract  Dysregulation of fatty acid metabolism is important in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor (PPAR)alpha is a master regulator of fatty acid catabolism, and PPARalpha activators delay the onset of type 2 diabetes. We examined association between three PPARalpha gene polymorphisms (an A-->C variant in intron 1, the L162V variant, and the intron 7 G-->C variant) and age at diagnosis of type 2 diabetes in 912 Caucasian type 2 diabetic subjects. Individually, PPARalpha gene variants did not influence age at diagnosis, but in combination, the rare alleles of both the intron 1 A-->C (P < 0.001) and intron 7 G-->C (P = 0.025) variants synergistically lowered age at diagnosis (interaction P < 0.001). Overall, the PPARalpha haplotype signficantly influenced age at diagnosis (P = 0.027), with the C-L-C and C-V-C haplotypes (intron 1-L162V-intron 7) accelerating onset of diabetes by 5.9 (P = 0.02) and 10 (P = 0.03) years, respectively, as compared with the common A-L-G haplotype, and was associated with an odds ratio for early-onset diabetes (age at diagnosis

Abstract  We have studied liver biopsies obtained in 12 hyperlipoproteinemic (HLP) patients (type II, 6; type IV, 6) treated with diet and fenofibrate, and in 15 patients (type II, 11; type IV, 4) receiving diet only. Electron microscopy of liver biopsies and the morphometric analysis according to the method of Weibel and Rohr showed mitrochondrial changes in patients treated with fenofibrate, these changes depending on the type of hyperlipoproteinemia. In type II HLP, we found a decreased volume of normal mitochondria (fenofibrate, 125.72 +/- 17.04 X 10(-3) cm3/cm3; diet only, 185.84 +/- 8.96 10(-3), P less than .05). In type IV HLP we found a decreased number of giant mitochondria (fenofibrate, 0.08 +/- 0.03 X 10(10) cm-3; diet only, 0.32 +/- 0.08 X 10(10) cm-3, P less than .05) and a decreased volume of altered mitochondria (fenofibrate, 6.00 +/- 1.44 X 10(-3) cm3/cm3; diet only, 13.61 +/- 1.17 X 10(-3), P less than .05). In contrast with the rodent studies, the present study shows no change in the number of volume of peroxisomes.

Abstract  Peroxisome proliferators activate nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) and enhance the transcription of several genes in liver. We report here that synthetic PPARalpha ligands Wy-14,643, ciprofibrate, clofibrate, and others induce the nuclear translocation of constitutive androstane receptor (CAR) in mouse liver cells in vivo. Adenoviral-enhanced green fluorescent protein-CAR expression demonstrated that PPARalpha synthetic ligands drive CAR into the hepatocyte nucleus in a PPARalpha- and PPARbeta-independent manner. This translocation is dependent on the transcription coactivator PPAR-binding protein but independent of coactivators PRIP and SRC-1. PPARalpha ligand-induced nuclear translocation of CAR is not associated with induction of Cyp2b10 mRNA in mouse liver. PPARalpha ligands interfered with coactivator recruitment to the CAR ligand binding domain and reduced the constitutive transactivation of CAR. Both Wy-14,643 and ciprofibrate occupied the ligand binding pocket of CAR and adapted a binding mode similar to that of the CAR inverse agonist androstenol. These observations, therefore, provide information for the first time to indicate that PPARalpha ligands not only serve as PPARalpha agonists but possibly act as CAR antagonists.

Abstract  Chloral hydrate (CAS 302-17-0), a widely used hypnotic and sedative agent, is reassessed on its mutagenic and carcinogenic potential on the evidence of recently unpublished and already published data. The compound was administered to rats in a carcinogenicity study in the drinking water for 124 (males) or 128 (females) weeks at dosages of 15, 45 and 135 mg/kg b.w./day. The administration of chloral hydrate produced no effects on survival, appearance and behaviour. At necropsy, there was no evidence of treatment-related changes, histopathology revealed an increased incidence of hepatocellular hypertrophy at the high dose level. There was no indication for a carcinogenic potential of chloral hydrate examined as life-time carcinogenicity study in rats. Further, in several in vitro and in vivo test systems no indication for a mutagenic potential was detected. Still unresolved is the end-point 'aneuploidy'. However, no validated in vivo test systems are available at the moment to confirm the positive results observed in vitro under certain experimental conditions and to assess the relevance of the in vitro findings for man, above all, since chloral hydrate is quickly metabolised to trichloroethanol in man. Based on the extensive range of data available, it can be concluded, that chloral hydrate has to be considered as a safe and effective substance.

Abstract  Chloral hydrate (CH) has been assayed for its ability to induce chromosome number variation in human lymphocytes in culture. Aneuploidy induction has been detected by means of in situ hybridization on interphase nuclei with a chromosome Y-specific DNA probe. A dose-dependent increase in the number of hyperdiploid nuclei was found at CH concentrations ranging from 250 to 750 micrograms/ml. These results represent a further contribution to the validation of the method which gave a positive response with drugs characterized by different mechanisms of action and therefore may be of general use in detecting aneuploidy in mammalian cells.

Abstract  Considerable evidence for a role of Kupffer cells in alcoholic liver disease has accumulated and they have recently been shown to be a predominant source of free radicals. Several approaches including pharmacological agents, knockout mice, and viral gene transfer have been used to fill critical gaps in understanding key mechanisms by which Kupffer cell activation, oxidant formation, and cytokine production lead to liver damage and subsequent pathogenesis. This review highlights new data in support of the hypothesis that Kupffer cells play a pivotal role in hepatotoxicity due to ethanol by producing oxidants via NADPH oxidase.