Abstract  Inhalation of volatile chemicals released during household water use is a recognized exposure pathway. Models previously developed to estimate inhalation exposure to radon gas, radon progeny, and volatile organic compounds (VOCs) were limited in their ability to predict exposure to compounds of low volatility due to a lack of appropriate experimental data. Recently, a comprehensive series of experimental studies has been completed in which mass-transfer coefficients for a shower, bath, faucet, washing machine, and dishwasher have been measured, making more detailed and accurate predictions possible. In this paper, the theoretical basis for mass transfer between water and air is reviewed and then extended to include the pH-dependent transfer of volatile compounds that participate in rapid acid/base reactions. This class of compound has not previously been considered in exposure assessment models. The evolution of inhalation exposure models is briefly reviewed and an improved version is developed. Sample calculations are made demonstrating the influence of both low volatility and pH on inhalation exposure. The paper concludes with illustrative examples assessing the toxicological implications of exposure to radon and hydrogen cyanide. The analysis confirms that inhalation is an important exposure pathway for waterborne chemicals.

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  This article is a critical review of the application of toxicokinetic models to the biological monitoring of occupational exposure to industrial chemicals. The experimentally based toxicokinetic models are used to determine the elimination half-lives, the metabolic clearance, the elimination rate constants and the volume of distribution. The physiologically based multicompartmental simulation models, which describe the uptake, distribution and elimination of inhaled or percutaneously adsorbed organic solvents, contributed to the understanding of the transport of the xenobiotics in the body. They are used for describing and predicting the dependence of concentrations of indicators of exposure in biological specimens on the extent of exposure and time (duration of exposure and sampling time), and for depicting the contribution of various biological and exposure factors to differences in biological response to the exposure. In biological monitoring, toxicokinetic models are used for matching biological concentrations and body burden of indicators of exposure with extent of inhalation or dermal exposure, and for predicting half-lives. They lay the grounds for the strategy used in collecting biological specimens and controlling external and internal factors which alter the biological concentrations and possibly increase the health risk from the exposure. Elimination half-lives are used as guidelines in selecting the appropriate indicators of exposure, in designing the procedure for the collection of biological specimens, and in interpreting the measured data. Predictive models are needed for heavy metals, particulates and compounds undergoing binding to constituents of tissues.

Abstract  This paper models general survival and the distribution of tumor onset times for various tumors in the data base of control animals developed by the National Toxicology Program. For general survival, a modified Weibull model is shown to give an adequate fit for both Fischer 344 rats and C57BL/6 x C3H F1 mice. In addition, data from control animals in a lifetime study of asbestos are used to support the extension of these survival curves beyond 2 years in Fischer rats. The distributions of tumor onset times are modeled using a two-parameter Weibull model. For many common tumor types, this model yielded a very good fit to the data. Finally, a summary measure of the contribution of a tumor to mortality is given.

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  The effects of trichloroethylene (79016) and 1,1,1-trichloroethane (71556) on plasma lipoproteins of rats were studied and related to the changes in liver and plasma transaminase activities. The effects were compared with effects of carbon-tetrachloride (56235). Male Fischer-344-rats were used in the study. The solvents were dissolved in 1 milliliter of olive-oil/kilogram of body weight and injected intraperitoneally at 19 hours before sacrifice. On the administration of carbon-tetrachloride at 30 to 1000mg/kg, very low density lipoproteins (VLDL) and high density lipoproteins (HDL) were dose dependently reduced, but the reduction in low density lipoproteins (LDL) was not dose dependent. Injection of trichloroethylene at 30 to 30mg/kg decreased the lipid contents of VLDL and LDL fractions. Trichloroethylene at 1000mg/kg increased VLDL and LDL. The HDL was decreased with increasing doses of trichloroethylene at 30 to 1000mg/kg. VLDL and LDL were increased by treatment with 100 or 300mg/kg 1,1,1-trichloroethane. HDL levels rose at 100 but fell at 1000mg/kg. Liver to body weight ratios were raised with increasing doses of the three compounds. Plasma GOT and GPT activities rose at much higher doses of solvents than dose levels which produce the changes in lipoproteins and the increases in liver weights.

Abstract  Trichloroethylene (TCI) is a member of a family of unsaturated chlorinated aliphatic compounds. Trichloroethylene, though a water and solid waste contaminant, is primarily of interest in situations involving ambient air exposure. It is released into ambient air as a result of evaporative losses during production, storage, and/or use. It has no known natural sources. It is photochemically reactive in the troposphere and is removed by scavenging mechanisms, principally via hydroxyl radicals. The scientific data base concerning the effects of TCI on humans is limited. Effects on humans have generally been ascertained from studies involving individuals occupationally or accidentally exposed. During such exposures, the concentrations associated with adverse effects on human health were either unknown or far in excess of concentrations found or expected in ambient air. Controlled TCI exposure studies have been directed toward elucidating the effects on the CNS, effects on clinical chemistries, and pharmacokinetic parameters of TCI exposure. The available epidemiologic studies have not been able to adequately assess the overall impact of TCI on human health. It has therefore been necessary to rely greatly on animal studies to derive indications of potential harmful effects. Although animal data cannot always be extrapolated to humans, indications of probable or likely effects in animal species increase confidence that similar effects may occur in humans. This document is intended to provide an evaluation of the scientific data base concerning TCI. The publications cited in this document represent a majority of the known scientific references to TCI. Reports which had little or no bearing on the issues discussed were not cited. Some topic areas, such as effects on terrestrial ecosystems, are only briefly discussed. Such topics reflect the nature of the scientific data base. On-going literature searches have been conducted through 1985, resulting in the inclusion of selected references in this document. However, the basic literature search for Chapter 8 is current through 1982; the basic literature search for Chapter 7 is current through 1983. The Agency is aware of additional carcinogenicity and mutagenicity information that has subsequently become available. This information will be considered for incorporation in any future updates of this document.

Abstract  We examined biogeochemistry and microbiology associated with natural attenuation of trichloroethene (TCE), trichloroethane (TCA), and benzene in a subarctic aquifer. Identification of a predominant terminal electron-accepting process (TEAP) and characterization of typical natural attenuation footprints was difficult. Hydrogen and ferrous iron concentrations suggested that iron reduction was the predominant TEAP; calculated in situ Gibbs free energies for iron reduction were energetically feasible at all wells although a source of ferric iron has not been conclusively determined. The presence of dissolved sulfide and favorable free energies for sulfate reduction provided support of concurrent iron and sulfate reduction. Methanogenesis from H2/CO2 was generally not energetically favorable. The presence of TCE and TCA degradation intermediates suggested that biological reductive dechlorination occurred, although proportions of intermediates relative to parent compounds remained stable. By September 2000, contaminant concentrations were within regulatory standards at most sampling points. However, low rates of microbial activity and incomplete degradation imply that intrinsic bioremediation did not likely represent an important contribution to contaminant removal atthis site, where dilution appeared to be the primary attenuation mechanism.

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  OBJECTIVES: This study aimed to develop a physiologically based pharmacokinetic model for chlorobenzene and to investigate the effect of variation in exposure to chlorobenzene on the chlorobenzene concentration in blood and the urinary concentration of 4-chlorocatechol.

METHODS: A physiologically based pharmacokinetic model was developed and the simulated results of urinary 4-chlorocatechol concentrations were compared with the values found in experiments and field surveys. The area under the chlorobenzene concentration-time curve in blood (CBBauc) was selected as the measure of internal exposure related to the chronic effect of chlorobenzene. The maximum one-hour time weighted average value of chlorobenzene concentration in blood (CBBmax) was chosen as the measure of internal exposure related to the acute effect of chlorobenzene. The total amount of urinary 4-chlorocatechol (TOTCC) and that excreted during the last four hours (CC(4-8)) or two hours (CC(6-8)) of exposure as well as that excreted during two hours on the next morning (CC(22-24)) were used to represent concentrations of urinary metabolites. The effects of variation of the one-hour time weighted averages of airborne chlorobenzene exposure (CBAs) on the internal exposures and the concentrations of urinary metabolites were investigated with the pharmacokinetic model.

RESULTS: The comparison of the simulated results with the observed data showed that the pharmacokinetic model can be used to estimate the urinary concentrations of 4-chlorocatechol. The CBBauc and TOTCC were not affected by changes in both the geometric SD (GSD) of CBAs or the variations in CBAs. The CBBmax varied with changes in both the GSD and CBAs. The CC(4-8) and CC(6-8) did not vary with the GSD, but these concentrations were affected by the change in the CBAs. Although there was little effect of the GSD and CBAs on the CC(22-24), this value highly reflected the exposure over the preceding days.

CONCLUSION: To protect workers from the chronic effect of chlorobenzene, it may be sufficient to control the daily average exposure. To protect from the acute effect, however, the short term exposure must be controlled as well. The values of CC(4-8) and CC(6-8) were acceptable for estimating daily average exposure, but the CC(22-24) was not.

Abstract  S-(1,2-Dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-DL-cysteine are potent nephrotoxins. Agents that inhibit gamma-glutamyl transpeptidase, cysteine conjugate beta-lyase, and renal organic anion transport systems, namely L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125), aminooxyacetic acid, and probenecid, respectively, protected against S-conjugate-induced nephrotoxicity. Furthermore, S-(1,2-dichlorovinyl)-DL-alpha-methylcysteine, which cannot be cleaved by cysteine conjugate beta-lyase, was not nephrotoxic. These results strongly support a role for renal gamma-glutamyl transpeptidase, cysteine conjugate beta-lyase, and organic anion transport systems in S-(1,2-dichlorovinyl)glutathione- and S-(1,2-dichlorovinyl)cysteine-induced nephrotoxicity.

Abstract  The major initial metabolites of the chlorinated ethylenes in hepatocyte suspensions isolated from phenobarbital treated rats were as follows (rates of metabolite production in nmol/10(6) cells/min are given in brackets): vinylidene chloride, dichloroacetic acid (0.015); cis-1,2-dichloroethylene, 2,2-dichloroethanol (0.24); trans-1,2-dichloroethylene, dichloroacetic acid (0.005); trichloroethylene, chloral hydrate (2.7); tetrachloroethylene, trichloroacetic acid (0.08). Comparison of the metabolism of the chlorinated ethylenes by isolated hepatocyte suspensions and hepatic microsomes indicates that the initial products of the three dichlorinated ethylenes from cytochrome P-450 in hepatic microsomes are rapidly and extensively metabolized in the hepatocyte, where the Phase II enzymes are present. In contrast, the initial metabolites of trichloroethylene and of tetrachloroethylene in the two systems are identical. The abilities of the chlorinated ethylenes to induce unscheduled DNA synthesis was assessed in isolated hepatocytes using a method which does not require the blocking of semi-conservative DNA synthesis. Vinylidene chloride, cis-1,2-dichloroethylene and trichloroethylene induced unscheduled DNA synthesis, while trans-1,2-dichloroethylene and tetrachloroethylene did not.

Abstract  The absorption, distribution, and excretion of trichloroethylene, as well as the kinetics of formation and elimination of trichloroethanol (TCE) and trichloroacetic acid (TCA) were simulated by a mathematical model. The results of this model have been satisfactorily compared with those obtained experimentally from pulmonary elimination of the solvent and from urinary excretion of the metabolites. The model permitted a study of the distribution of the solvent in the different tissues of the organism as well as an evaluation of the body burden of TCE and TCA. The influence of the duration and repetition of the exposure on the urinary eliminations of TCE and TCA was studied, and showed that the excretion of the first metabolite represents the most recent exposure while that of the second is related to the average exposure of the preceding days. The study of the pulmonary elimination of trichloroethylene during single or repeated exposures showed a linear relationship between the alveolar concentration of the solvent approximately 15 hours after the end of the exposure and the quantity of trichloroethylene accumulated in the fatty tissues.

Abstract  A linear correlation exists between the trichloroethylene concentration in the work environments and the level of total trichloro compounds in the urine of the workers, as expressed by the equation: Gamma = 7.25=chi + 5.5, where Gamma is trichloroethylene in air (ppm) is Chi is total trichloro compounds in urine (mg/l). Trichloroethanol level is also linearly related to trichloroethylene concentration, while trichloroacetic acid level deviates from the linear relation when trichloroethylene level exceeds 50 ppm. In the case of tetrachloroethylene exposure, both trichloroethanol and trichloroacetic acid levels, and consequently the total trichloro compound level, reach a plateau at tetrachloroethylene level well below 100 ppm. The mean urinary biological half-life is 41 hr for trichloroethylene and 144 hr for tetrachloroethylene. The two values are the largest of the values so far obtained with organic solvents. The respiratory half-life is shorter than the urinary half-life, both in richloroethylene and in tetrachloroethylene. Applications of the urinalyses in clinical cases are described. In one case of trichlorethylene dependency, a longer urinary half-life of 73 hr was observed. An automated system is presented for the determination of total trichloro compounds in human urine. The system can analyze the samples at the rate of 20 samples per hour with an accuracy comparable to that of the time-consuming manual analysis.

Abstract  To investigate the relation between trichloroethylene and tetrachloroethylene concentrations in working environments and metabolite concentrations in urine, a series of surveys was conducted at 17 workshops where the vapour concentration in the air of each workshop was relatively constant. Urine samples collected from 85 male workers were analysed for total trichloro-compounds (TTC), and trichloroacetic acid (TCA). Trichloroethanol (TCE) was estimated by difference. Statistical analyses of the data revealed that the urinary concentrations of both TTC and TCE were proportional to the atmospheric concentration of trichloroethylene. The concentration of TCA was also related to the vapour concentration up to 50 p.p.m. but not at higher concentrations. Further calculations suggested that only one-third of the trichloroethylene absorbed through the lungs was excreted in the urine during working time. In tetrachloroethylene exposure, urinary metabolite levels increased until the atmospheric concentration of the solvent reached 50 to 100 p.p.m., but little increase occurred at higher concentration. This observation was further confirmed by experimental exposure of rats. The toxicological significance of changes in the metabolism of the two solvents is discussed in relation to the possible necessity of reducing the threshold limit value from the current value of 100 p.p.m.

Abstract  Four male volunteers inhaled for 4 h 70 and 140 ppm trichloroethylene (TRI) at rest and also at rest combined with exercise. To estimate the amount retained in the body (dose), minute volume and concentration in exhaled air were determined. Concentrations of TRI, trichloroethanol (TCE) and trichloroacetic acid (TCA) were determined in blood. Exhaled air was analysed for TRI and TCE; urine for TCE and TCA. During more than 60 h after exposure the concentration of TRI and TCE in blood and exhaled air were proportional to the dose, but the interindividual variation was large; workload increased the dose, but no influence was found on the distribution and metabolism. The total recovery was 67%; 10% as TRI by the lungs and in urine 39% as TCE and 18% as TCA.

Abstract  Five male volunteers inhaled 70 ppm trichloroethylene (TRI) for 4 h on 5 consecutive days. TRI, trichloroethanol (TCE) and trichloroacetic acid (TCA) were measured, as far as present in exhaled air, blood, and urine. The uptake was 6.6 ± 0.4 mg/kg lean body mass in 4 h. The concentration of TRI in blood and exhaled air at 18 h after the 5th exposure was twice as high as at 18 h after the 1st exposure. The amount of TCE excreted per 24 h reached a level during the last exposure days, a diurnal rythm was evident. TCA in blood and urine increased during exposure days. Total recovery of the amount absorbed of TRI was 78%, 11% as TRI excreted unchanged by the lung, 43% as WE and 24% as TCA excreted in urine. Amounts of WE and TCE+TCA excreted in urine were related to lean body mass. Because of its small interindividual variation TCA in blood seems to be the most promising parameter for biological monitoring in repeated exposure.

Abstract  Male Sprague-Dawley rats and male B6C3F1 mice excreted 5-15% of a tracer dose of [14C]trichloroethylene as 14CO2 within 24 h after ip injection of a single dose in a corn-oil vehicle. The proportion of the dose excreted as CO2 was greater in mice than in rats, but increased in the rats after starvation or pretreatment with phenobarbital. As the dose was increased toward the LD50 level, the proportion excreted as 14CO2 decreased slightly, but this was largely due to increased loss of unchanged trichloroethylene. The excretion of 14CO2 was thus correlated with the expected level of microsomal metabolism of trichloroethylene to an electrophilic intermediate capable of binding to glutathione or macromolecules. Liver protein labeling was observed to be relatively high (10,000-23,000 cpm/mg in the mouse), while DNA labeling was consistently observed to be very low, not allowing identification of any adducts by high-performance liquid chromatography (HPLC). Also, no effect on DNA fragmentation was seen by alkaline sucrose gradient centrifugation after injection of an LD50 dose of trichloroethylene. The ability of trichloroethylene to interact with DNA in vivo was thus observed to be very slight.

Abstract  HEEP COPYRIGHT: BIOL ABS. Groups of adult male volunteers were exposed to alcohol, CO or trichloroethylene; performance in mental loading tests and effects on physiological parameters were studied. Using alcohol as reference substance, producing marked effects at blood alcohol levels greater than 0.3 g/1, the effects from CO and of trichloroethylene in dosages as encountered in social and occupational life proved to be much less severe, at most borderline. The experimental results only apply to the specific conditions of the study: healthy male adults of 20-30 yr, no vigilance tasks, no long-term exposure. The experiments suggest the possibility of hazardous impairment of performance in older subjects, particularly in case of combined exposure to various external loads.

Abstract  Metal workers exposed to trichloroethylene for the degreasing of metals were studied to evaluate the genotoxicity of this exposure. For 15 workers presently exposed to high doses of trichloroethylene there was no difference from unexposed persons with respect to sperm count and morphology, and a small increase of two fluorescent bodies (YFF%) in spermatozoa. In contrast, there was a highly significant increase in frequency of structural aberrations (breaks, gaps, translocation, deletions, inversions) and hyperdiploid cells in cultured lymphocytes from trichloroethylene degreasers. As control groups, physicians from chemically non-exposed surroundings and a concurrently sampled reference from cytogenetic investigations were used. This study indicates positive correlations between exposure to trichloroethylene and somatic chromosome aberrations, whereas no effect on male germ cells could be demonstrated.

Abstract  In an earlier report [Feldman and Lessell, 1967], neurologic findings following acute intoxication to trichloroethylene were presented. Facial anesthesia, asymmetric pupillary responses, and electrical evidence of sensorimotor neuropathy accompanied neuropsychological deficits, manifested by difficulty in solving sequential problems and poor memory affecting the acquisition of new information. Twelve years after the initial exposure, patches of hypalgesia over the malar eminences persisted and corneal reflexes remained absent, although sensation in the snout region was totally normal. Neuropsychological test results continued to demonstrate impaired attention and short-term memory as well as diminished visuospatial organization and sequencing, 16 years after exposure. In addition, MMPI profile and interview suggested continued depressive symptomatology. Eighteen years after exposure, findings included paresthesia and hypalgesia in the malar area of the face as well as myokymia of the facial muscles. Facial nerve latency studies were normal as were pattern shift visual evoked responses. The patient continued to have large pupils that reacted asymmetrically to light. In the right eye, contraction was synchronous in all segments of the sphincter. In the left eye, there was segmental contraction, suggestive of a tonic pupil. This report offers evidence of long-term residual oculomotor and ciliary reflex dysfunction as well as impaired neuropsychological performance as a result of acute TCE intoxication.

Abstract  A case study was reported of a worker suffering from pneumatosis cystoides intestinalis (PCI) following trichloroethylene (79016) (TRI) exposure. The 23 year old male lathe operator had been soaking metal parts in warm TRI in an ultrasonic degreasing tank; general air concentration of TRI as determined by gas chromatography was 18 to 56 parts per million in the unit work area where he had been working for over 5 years. He had been exposed to higher TRI concentration during the washing process for about 1 minute per day during the 5 year span. The patient had constipation from February to April, 1985 which disappeared spontaneously. In May of 1987 he again suffered from severe constipation, with defecation once per week; he sought hospital treatment in August of that year. Honeycomb gas shadows were detected on x-rays, and PCI diagnosis was confirmed by barium enema and colonfiberscopic examination. Intestinal cysts disappeared with hyperbaric oxygen inhalation therapy and constipation was relieved. Trichloroacetic-acid (76039) concentrations in bile and urine were determined by colorimetry. The authors conclude that this was a case of primary PCI possibly related to TRI exposure.

Abstract  Inhalation effects of trichloroethylene, at levels of 0, 200 and 600 ppm for a period of 4 and 12 weeks, on the contents of hepatic microsomal protein, cytochrome P sub(450), cytochrome b sub(5), and on the activities of NADPH cytochrome C reductase, aminopyrine N-demethylase and aniline hydroxylase were investigated. Body weight remained unaltered at 200 ppm level, whereas at 600 ppm level a significant decrease in body weight was observed. Liver weight showed increases at an exposure level of 200 ppm by the end of 4 and 12 weeks. Relative liver weight (% body weight) showed an increase at 200 and 600 ppm level by the end of week 4, whereas, after 12 weeks increase was observed only in animals exposed to the 600 ppm level. Hepatic microsomal protein was decreased by the end of 4 weeks at both the exposure levels. Cytochrome P sub(450) and cytochrome b sub(5) contents were increased at the 200 ppm level after 4 and 12 weeks. NADPH cytochrome C reductase activity showed a marked increase at both the 200 and 600 ppm levels after 4 and 12 weeks.

Abstract  Changes in phase II drug-metabolizing enzyme expression during development, as well as the balance between phase I and phase II enzymes, can significantly alter the pharmacokinetics for a given drug or toxicant. Although our knowledge is incomplete, many of the phase II enzymes are expressed early in development. There is evidence for glutathione S-transferase A1/A2 (GSTA1/A2), GSTM, and GSTP1 in fetal liver, lung and kidney, although tissue-specific patterns and changes with time are observed. N-Acetyltransferase 1 (NAT1) activity also has been reported throughout gestation in fetal liver, adrenal glands, lung, kidney, and intestine. Only postnatal changes in NAT1 expression were apparent. Nothing is known about human NAT2 developmental expression. Some UDP-glucuronosyltransferase and sulfotransferase isoforms also are detectable in fetal liver and other tissues by the first or second trimester, and substantial changes in isoform expression patterns, as well as overall expression levels, are observed with increasing maturity. Finally, expression of both epoxide hydrolases 1 and 2 (EPHX1 and EPHX2) is observed in fetal liver, and for the former, increased expression with time has been documented. Less is known about ontogenic molecular control mechanisms. Limited data suggest that the hepatocyte nuclear factor and CCAAT/enhancer binding protein families are critical for fetal liver drug-metabolizing enzyme expression whereas D element binding protein and related factors may regulate postnatal hepatic expression. There is a paucity of data regarding mechanisms for the onset of extrahepatic fetal expression or specific mechanisms determining temporal switches, such as those observed within the CYP3A and flavin-containing monooxygenase families.