Abstract  This article addresses the evidence that trichloroethylene (TCE) or its metabolites might mediate tumor formation via a mutagenic mode of action. We review and draw conclusions from the published mutagenicity and genotoxicity information for TCE and its metabolites, chloral hydrate (CH), dichloroacetic acid (DCA), trichloroacetic acid (TCA), trichloroethanol, S-(1, 2-dichlorovinyl)-l-cysteine (DCVC), and S-(1, 2-dichlorovinyl) glutathione (DCVG). The new U.S. Environmental Protection Agency proposed Cancer Risk Assessment Guidelines provide for an assessment of the key events involved in the development of specific tumors. Consistent with this thinking, we provide a new and general strategy for interpreting genotoxicity data that goes beyond a simple determination that the chemical is or is not genotoxic. For TCE, we conclude that the weight of the evidence argues that chemically induced mutation is unlikely to be a key event in the induction of human tumors that might be caused by TCE itself (as the parent compound) and its metabolites, CH, DCA, and TCA. This conclusion derives primarily from the fact that these chemicals require very high doses to be genotoxic. There is not enough information to draw any conclusions for trichloroethanol and the two trichloroethylene conjugates, DCVC and DCVG. There is some evidence that DCVC is a more potent mutagen than CH, DCA, or TCA. Unfortunately, definitive conclusions as to whether TCE will induce tumors in humans via a mutagenic mode of action cannot be drawn from the available information. More research, including the development and use of new techniques, is required before it is possible to make a definitive assessment as to whether chemically induced mutation is a key event in any human tumors resulting from exposure to TCE

Abstract  Dichloroacetate (DCA) is a xenobiotic of interest to both environmental toxicologists and clinicians. The chemical is a product of water chlorination and of the metabolism of various drugs and industrial chemicals. Its accumulation in groundwater and at certain Superfund sites is considered a potential health hazard. However, concern about DCA toxicity is predicated mainly on data obtained in inbred rodent strains administered DCA at doses thousands of times higher than those to which humans are usually exposed. In these animals, chronic administration of DCA induces hepatotoxicity and neoplasia. Ironically, the DCA doses used in animal toxicology experiments are very similar to those used clinically for the chronic or acute treatment of several acquired or hereditary metabolic or cardiovascular diseases. As a medicinal, DCA is generally well tolerated and stimulates the activity of the mitochondrial pyruvate dehydrogenase enzyme complex, resulting in increased oxidation of glucose and lactate and an amelioration of lactic acidosis. By this mechanism, the drug may also enhance cellular energy metabolism. DCA is dehalogenated in vivo to monochloroacetate and glyoxylate, from which it can be further catabolized to glycolate, glycine, oxalate, and carbon dioxide. It remains to be determined whether important differences in its metabolism and toxicology exist in humans between environmentally and clinically relevant doses.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. The transformability of trihalomethanes, carbon tetrachloride, 1,1,1-trichloroethane, 1,2-dibromomethane, tetrachloroethylene, dibromochloropropane, and chlorinated benzenes was evaluated by a biofilm utilizing a mixture of primary electron acceptors (oxygen, nitrate, and sulfate). These compounds at concentrations commonly found in groundwater were continuously administered for 4 years to a biofilm column reactor that resembled polluted groundwater environments. Acetate was the primary substrate to support microbial growth. Sequential biofilm zones of aerobic respiration, denitrification, and sulfate reduction developed within the column. Transformation of the halogenated aliphatic compounds coincided with the onset of sulfate reduction in the column. The temporary absence of nitrate and sulfate in the column feed decreased the steady-state removals for several of the halogenated aliphatic compounds. These results suggest that sulfate was an important primary electron

Abstract  Development of practical techniques to predict the mobility of halogenated hydrocarbons in aquifers is an important step toward protecting the quality of groundwater resources. This study involved the use of laboratory-column and field-column experiments to estimate retardation coefficients of five halogenated hydrocarbons (bromoform, carbon tetrachloride, tetrachloroethylene, 1,2-dichlorobenzene and hexachloroethane) in the Borden aquifer. These compounds were selected because they were used in the highly-monitored, natural-gradient field-tracer experiment conducted in the unconfined sand aquifer at Canadian Forces Base Borden in southern Ontario, Canada. The field-column experiments were conducted in the vicinity of the natural-gradient tracer experiment, and the laboratory experiments were conducted using aquifer material collected from the field site. The retardation coefficients were found to increase as the average pore-water velocity in the columns decreased, suggesting the presence of non-equilibrium conditions in the reactive transport process. Analysis of the data with a two-site reactive-solute transport model, that allows for time-dependent interaction between solutes and a fraction of reaction sites, provided significant improvement over analysis with a reactive-solute transport model that assumes local equilibrium. For experiments conducted at similar velocities, the mobilities were in close agreement for both the laboratory-and field-column experiments. Retardation factors calculated from batch experiments also agreed closely with the column results and were consistent with those obtained from previous studies at the Borden site. While the retardation factors calculated from the present small-scale methods were in close agreement with those observed during the first month of the large-scale natural-gradient experiment, large deviations were observed for longer travel times.

Abstract  BIOSIS COPYRIGHT: BIOL ABS. The series of study about the effect of environmental pollutants on cell functions, the influence of several volatile halocarbons (trichloroethylene, tetrachloroethylene, trichloroethanol, bromodichlomethane, chlorodibromomethane and bromoform) and styrene on calcium ionophore (A-23187) or thrombin induced activation of washed rabbit platelets has been examined. Platelet activation was measured by thromboxane B2 synthesis. As a result, tetrachloroethylene and trichloethanol inhibited both A-23187 and thrombin induced platelet activation significantly. Bromoform had an inhibitory action at its highest concentration (10uM) against A-23187 induced platelet activation. Styrene and bromoform revealed a strong inhibitory action against thrombin induced platelet activation. There seemed to be no concentration dependent inhibition of these compounds against platelet activation induced by both agonists. When platelet was pretreated with these compounds, all compounds except tri

Abstract  People are exposed to a variety of chemicals throughout their daily lives. To protect public health, regulators use risk assessments to examine the effects of chemical exposures. This book provides guidance for assessing the risk of phthalates, chemicals found in many consumer products that have been shown to affect the development of the male reproductive system of laboratory animals. Because people are exposed to multiple phthalates and other chemicals that affect male reproductive development, a cumulative risk assessment should be conducted that evaluates the combined effects of exposure to all these chemicals. The book suggests an approach for cumulative risk assessment that can serve as a model for evaluating the health risks of other types of chemicals.

Abstract  Peroxisome proliferator-activated receptor alpha (PPARalpha) is responsible for peroxisome proliferator-induced pleiotropic responses, including the development of hepatocellular carcinoma in rodents. However, it remains to be determined whether activation of PPARalpha only in hepatocytes is sufficient to induce hepatocellular carcinomas. To address this issue, transgenic mice were generated that target constitutively activated PPARalpha specifically to hepatocytes. The transgenic mice exhibited various responses that mimic wild-type mice treated with peroxisome proliferators, including significantly decreased serum fatty acids and marked induction of PPARalpha target genes encoding fatty acid oxidation enzymes, suggesting that the transgene functions in the same manner as peroxisome proliferators to regulate fatty acid metabolism. However, the transgenic mice did not develop hepatocellular carcinomas, even though they exhibited peroxisome proliferation and hepatocyte proliferation, indicating that these events are not sufficient to induce liver cancer. In contrast to the transgenic mice, peroxisome proliferators activate proliferation of hepatic non-parenchymal cells (NPCs). Thus, activation of hepatic NPCs and/or associated molecular events is an important step in peroxisome proliferators-induced hepatocarcinogenesis.

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  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  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  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  The atmosphere as a source of volatile organic compounds (VOCs) in shallow groundwater was evaluated over an area in southern New Jersey. Chloroform, methyl tertbutyl ether (MTBE), 1,1,1-trichloroethane, tetrachloroethylene (PCE), and carbon disulfide (not a VOC) were detected frequently at low-level concentrations in a network of 78 shallow wells in the surficial Kirkwood-Cohansey aquifer system. The atmosphere was sampled for these compounds and only MTBE concentrations were high enough to potentially explain frequent detection in shallow groundwater. A mathematical model of reactive transport through the unsaturated zone is presented to explain how variations in unsaturated properties across the study area could explain differences in MTBE concentrations in shallow groundwater given the atmosphere as the source. Even when concentrations of VOCs in groundwater are low compared to regulatory concentration limits, it is critical to know the source. If the VOCs originate from a point source(s), concentrations in groundwater could potentially increase over time to levels of concern as groundwater plumes evolve, whereas if the atmosphere is the source, then groundwater concentrations would be expected to remain at low-level concentrations not exceeding those in equilibrium with atmospheric concentrations, This is the first analysis of VOC occurrence in shallow groundwater involving colocated atmosphere data.

Abstract  The public depends on competent risk assessment from the federal government and the scientific community to grapple with the threat of pollution. When risk reports turn out to be overblown--or when risks are overlooked--public skepticism abounds. This comprehensive and readable book explores how the U.S. Environmental Protection Agency (EPA) can improve its risk assessment practices, with a focus on implementation of the 1990 Clean Air Act Amendments. With a wealth of detailed information, pertinent examples, and revealing analysis, the volume explores the "default option" and other basic concepts. It offers two views of EPA operations: The first examines how EPA currently assesses exposure to hazardous air pollutants, evaluates the toxicity of a substance, and characterizes the risk to the public. The second, more holistic, view explores how EPA can improve in several critical areas of risk assessment by focusing on cross-cutting themes and incorporating more scientific judgment. This comprehensive volume will be important to the EPA and other agencies, risk managers, environmental advocates, scientists, faculty, students, and concerned individuals.

Abstract  RAGS Part A is one of a three-part series: Part B addresses the development of risk-based preliminary remediation goals; and Part C addresses human health risk evaluations of remedial alternatives. RAGS Part A: Human Health Evaluation Manual provides guidance on the human health evaluation activities that are conducted during the baseline risk assessment - the first step of the Remedial Investigation/Feasibilty Study (RI/FS). The baseline risk assessment is an analysis of the potential adverse health effects (current or future) caused by hazardous substance releases from a site in the absence of any actions to control or mitigate these releases (i.e., under an assumption of no action). The baseline risk assessment contributes to the site characterization and subsequent development, evaluation, and selection of appropriate response alternatives. The results of the baseline risk assessment are used to help determine whether additional response action is necessary at the site, modify preliminary remediation goals, help support selection of the "no- action" remedial alternative, where appropriate, and document the magnitude of risk at a site, and the primary causes of that risk. Baseline risk assessments are site-specific and therefore may vary in both detail and the extent to which qualitative and quantitative analyses are used, depending on the complexity and particular circumstances of the site, as well as the availability of applicable or relevant and appropriate requirements (ARARs) and other criteria, advisories, and guidance. After an initial planning stage, there are four steps in the baseline risk assessment process: data collection and analysis; exposure assessment; toxicity assessment; and risk characterization. The potential users of Part A are the individuals actually conducting health risk assessments for sites, who frequently are contractors to the EPA, other federal agencies, states, or potentientially responsible parties. It is also targeted to EPA staff, including those responsible for review and oversight of risk assessments (e.g. technical staff in the regions) and those responsible for ensuring adequate evaluations of human health risks (i.e., RPMs).

Abstract  A physiologically based pharmacokinetic model which describes the behavior of inhaled styrene in rats accurately predicts the behavior of in baled styrene in humans. The model consists of a series of mass-balance differential equations which quantify the time course of styrene concentration within four tissue groups representing (1) highly perfused organs, (2) moderately perfused tissues such as muscle. (3) slowly perfused fat tissue, and (4) organs with high capacity to metabolize styrene (principally liver). The pulmonary compartment of the model incorporates uptake of styrene controlled by ventilation and perfusion rates and the blood:air partition coefficient The metabolizing tissue group incorporates saturable Michaelis-Menten metabolism controlled by the biochemical constants Vmax and Km. With a single set of physiological and biochemical constants, the model adequately simulates styrene concentrations in blood and fat of rats exposed to 80, 200, 600, or 1200 ppm styrene (data from previously published studies). The simulated behavior of styrene is particularly sensitive to changes in the constants describing the fat tissue group, and to the maximum metabolic rate described by Vmax, The constants used to simulate the fate of stvrene in rats were scaled up to represent humans. Simulated styrene concentrations in blood and exhaled air of humans are in good agreement with previously published data. Model simulations show that styrene metabolism is saturated at inhaled concentrations above approximately 200 ppm in mice, rats, and humans. At inhaled concentrations below 200 ppm, the ratio of styrene concentration in blood to inhaled air is controlled by perfusion limited metabolism. At inhaled concentrations above 200 ppm. This ratio is controlled by the blood:air partition coefficient and is not linearly related to the ratio attained at lower (nonsaturating) exposure concentrations. These results show that physiologically based pharmacokinetic models provide a rational basis with which (1) to explain the relationship between blood concentration and air concentration of an inhaled chemical, and (2) to extrapolate this relationship from experimental animals to humans.

Abstract  Partition coefficients are required for developing physiologically based pharmacokinetic models used to assess the uptake, distribution, tabolism, and elimination of volatile chemicals in mammals. A gas-phase vial equilibration technique is presented for determining the liquid:air and tissue:air partition coefficients for low-molecular-weight volatile chemicals. This technique was developed from two previously described medium:air methods, relied solely on measurement of chemical concentration in the gas phase, and, compared to earlier work, extends the range of chemicals and tissues examined. Partition coefficients were determined with 0.9% saline, olive oil, and blood, liver, muscle, and fat tissues from rats for 55 compounds. Human blood:air coefficients were determined for 36 compounds and several blood:air values were also determined in the mouse and for one compound in the hamster. An approach is described for predicting the tissue solubilities of untested compounds based on oil:air and saline:air coefficients using regression analyses. A similar approach is used to model fat:air coefficients in terms of oil:air values and to model human blood: air coefficients in terms of rat blood:air coefficients.

Abstract  Childhood cancer, malformations, and spontaneous abortions in Finland were analyzed according to the parents' occupations. Children of women working in the food industry and farming and of men working in motor vehicle driving and farming appeared to have an elevated risk of cancer. Women in industrial and construction occupations had an increased risk of having malformed children and spontaneous abortions.

Abstract  1. Various polychlorinated hydrocarbons were administered intragastrically to rats to examine their effects on the biotransformation capacity of the liver. Due to high toxicity, 1,1,2,2-tetrachloroethane and pentachloroethane were given at a dose level equivalent to one quarter of that of CCl4 and the other chlorohydrocarbons (i.e. 2-6 mmol/kg). 2. Carbon tetrachloride at 10-3 mmol/kg was the most active in decreasing cytochrome P-450 content and the overall drug hydroxylation activities in rat liver. 1,1,2,2-Tetrachloroethane was the next most active in decreasing the hepatic drug oxidizing enzymic activities. 3. Expoxide hydratase activity in rat liver declined significantly after CCl4, 1,1,2,2-tetrachloroethane and pentachloroethane administrations. 4. UDP-Glucuronosyltransferase was affected to a lesser extent than the microsomal mono-oxygenase or epoxide hydratase by chlorohydrocarbon treatment.

Abstract  Trichloroacetic acid (TCA) as a phytotoxic substance affects health status of coniferous trees. It is known as a secondary air pollutant (formed by photooxidation of tetrachloroethene and 1,1,1-trichloroethane) and as a product of chlorination of humic substances in soil. Its break-down in soil, however, influences considerably the TCA level, i.e. the extent of TCA uptake by spruce roots. In connection with our investigations of TCA effects on Norway spruce, microbial processes in soil were studied using 14C-labeling. It was shown that TCA degradation in soil is a fast process depending on TCA concentration, soil properties, humidity and temperature. As a result, the TCA level in soil is determined by a steady state between uptake from the atmosphere, formation in soil, leaching and degradation. The process of TCA degradation in soil thus participates significantly in the chlorine cycle in forest ecosystems.