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  Continuous exposure of Mongolian gerbils to perchloroethylene (PCE) (120 ppm) for 12 months in an inhalation chamber caused no changes in body or brain weights. The protein content, the concentration of lipid phosphorus or cholesterol were unaltered in the cerebral cortex and hippocampus. Howeve, a small change in the fatty acid pattern of phospholipid was observed. In the phosphatidylethanolamine of cerebral cortex and hippocampus a decrease was found among the long-chain, linolenic acid-derived, fatty acids. The ratio 22:4 (N-6)/22:5 (N-3) was increased, indicating a shift towards the corresponding linoleic acid-derived 22-carbon fatty acids. The observed changes among poly-unsaturated fatty acids are similar to those appearing after peroxidation and either protein or essential fatty acid malnutrition. However, an attractive explanation for the changes is that they represent a response to the fluidizing properties of PCE.

Abstract  Although formation of DNA adducts has been postulated for several halomethanes, no chemical identification of such adducts has been performed so far. There is, however, evidence that methyl chloride does not act biologically as a DNA methylating agent. 1,2-Dichloroethane and 1,2-dibromoethane are activated through conjugation with glutathione. There is some evidence for formation on an N-7 adduct of guanine which carries an ethyl-S-cysteinyl moiety. Extensive work has been published on adducts of vinyl chloride, both in vitro and in vivo. The major DNA adduct is 7-(2-oxoethyl)guanine; a minor adduct appears to be N2,3-ethenoguanine. Other etheno adducts, i.e., 1,N6-ethenoadenine and 3,N4-ethenocytosine, are readily formed with DNA, vinyl chloride, and a metabolizing system in vitro and with RNA in vivo, but are usually not detected as DNA adducts in vivo. The data on DNA alkylation by vinyl chloride (and vinyl bromide) metabolites are compared with those of structurally related compounds (acrylonitrile, vinyl acetate, vinyl carbamate).

Abstract   Rats received inhalation exposure to trichloroethylene (TriCE) or tetrachloro-ethylene (TetraCE) at concentrations of 200, 400 and 800 ppm for a month. Effects of the exposure on free amino acid content of midbrain were investigated by high-performance liquid chromatography. (1) A component on the chromatogram which contains glutamine, threonine and serine was greatly increased by the exposure to TetraCE in a concentration-dependent manner. By TriCE, it was significantly in-creased at 800 ppm. (2) Glutamate showed a tendency to decrease after the exposure to TetraCE. TriCE at 800 ppm significantly decreased glutamate content. (3) TriCE at 400 ppm significantly increased glycine content. (4) TetraCE decreased GABA, but on the contrary TriCE increased it. Both changes were not large and statis-tically not significant. (5) Both TetrCE and TriCE caused no significant change in taurine, aspartate and alanine contents. Exposure of rats to TetraCE and TriCE produced increase in some inhibitory putative neurotransmitter substances and decrease in some excitatory ones.

Abstract  Comparative toxicity studies in animals indicate that tetrachloroethane (79345) exhibits the highest inhalation poisoning, followed by dichloroethane (1300216), pentachloroethane (76017), tetrachloroethylene (127184) and trichloroethylene (79016). Chronic toxicity tests revealed that all agents tested, except pentachloroethane, caused dose dependent suppression of agglutinin production and increased phagocytosis. Data are also given in regard to the effect of the industrial solvents on cholinergic mediation, urinary 17-ketosteroid excretion, serum proteins, blood sugar, and blood picture. Histopathological examination revealed kidney and liver disorders. (Ukrainian; English translation available)

Abstract  The percutaneous absorption of 8 chlorinated solvents were studied. The ex-perimental method consisted of the application of the solvent to the abdominal mouse skin and quantitating its absorption through the skin by its presence in whole body and its appearance in expiration. Determination of the solvent in tissues and expiration was carried out by gas chromatographic methods. There was a great diversity of ability among solvents to penetrate the mouse skin. Dichloromethane was absorbed to an amount which was 53 times as large as the amount of tetrachloroethyene. Among tested solvents, those which had the highest solubility in water showed the greatest absorption rate, while those having the lowest solubility in water gave the smallest absorption rate from skin. The linear relationship between the absorption rate from skin and the solubility in water was found: in case of X ?? 16, Y=30.8+2.13X, r=0.87; in case of X ?? 16, Y= -52.8+6.59X, r=1.00; where Y is the percutaneous absorption rate (nM/min/cm2 of skin) and X is the solubility in water of solvent (mM at 25°C).

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  Inhalation pharmacokinetics of the halogenated ethylenes vinyl fluoride (VF), vinylidene fluoride (VF2), vinyl chloride (VC1), vinylidene chloride (VC12), cis- and trans-dichloroethylene (cis-DCE and trans-DCE), trichloroethylene (Tri), perchloroethylene (Per), and vinyl bromide (VBr) have been comparatively studied in the rat. Rats were exposed in a closed inhalation system to various initial atmospheric levels of halogenated ethylenes, and the decline of atmospheric concentration was followed using gas Chromatographic analysis. From pharmacokinetic analysis of the experimental curves the following general patterns of the halogenated ethylenes were derived. Distribution of the compounds in the organism and in the gas phase is determined by physical factors. For practical purposes, a relation of the equilibrium constants with the volatilities of the compounds, expressed by the boiling points, may be used: compounds with a low boiling point are enriched in tissues much less than those of a higher boiling point, and vice versa. Compounds with high accumulation in tissues (Tri, Per) need much more time for completion of the equilibration process than more volatile compounds. Metabolic elimination of halogenated ethylenes is a saturable, dose-dependent process. If animals are exposed to atmospheric concentrations of a halogenated ethylene which exceed the point of saturation (Sp), elimination is determined by a zero-order law, i.e., its rate is independent of the concentration of the compound. In contrast, below saturation normal first-order kinetics apply. If the rate of metabolic elimination is related to the concentrations of the compounds in the tissue compartment, very similar rates for first-order elimination of the different halogenated ethylenes are found. This suggests a common rate limiting factor applicable for the lower concentration range. The maximal velocities (V max) of metabolic elimination of halogenated ethylenes which are reached above the saturation points depend on the chemical structures of the individual compounds. In general, with the exception of Tri, further halogen substitution inhibits metabolic conversion. Of the halogenated ethylenes, VF2 and Per are extremely slowly metabolized. The present report also provides the data necessary for calculation of the rates of metabolism of halogenated ethylenes in rats at a given concentration of atmospheric exposure.

Abstract  A case-referent study of occupational risk indicators of renal cell adenocarcinoma was conducted. Each incident case in Finland in 1977-1978 was matched with two population referents. Lifelong job histories were collected and translated into indicators of industry, occupation, and occupational exposures. The analyses of 338 sets of cases and referents revealed elevated risks for a history of employment in white-collar occupations; the printing industry; the chemical industry; the manufacturing of metal products; mail, telephone, and telegraph services; and iron and metalware work. A decreased risk was observed for male farmers. An elevated risk and an exposure-response relationship were found for gasoline exposure. The excess risk was highest at a latency period of approximately 30 years. The findings support the hypothesis that exposure to some constituent(s) of gasoline increases the incidence of renal adenocarcinoma in humans. Suggestions of elevated risks appeared for exposures to inorganic lead, cadmium, and nonchlorinated solvents.

Abstract  BACKGROUND: Paternal exposure to mutagenic agents has been suggested to affect pregnancy outcome adversely. METHODS: A nationwide data base of medically diagnosed spontaneous abortions and other pregnancies and national census data was used to evaluate the effects of men's occupational exposures on risk of spontaneous abortion in 99,186 pregnancies in Finland. Census data from the years 1975 and 1980 provided information about the occupation, industry, and socioeconomic status. A job-exposure classification was developed to classify women and their husbands according to possible occupational exposures on the basis of their occupational title and industry. RESULTS: In 10% of the pregnancies, the husband was exposed to one or more of the mutagens, and the rate of spontaneous abortion was unaffected (OR = 1.0). Of the 25 specific mutagenic exposures evaluated, paternal exposure to four (ethylene oxide, rubber chemicals, solvents used in refineries, and solvents used in the manufacturing of rubber products) was associated with an increased relative risk of spontaneous abortion. In addition, the risk of spontaneous abortion was higher among wives of rubber products workers than among unexposed men. CONCLUSIONS: Although there is some biological rationale for the findings of this study, these findings need to be confirmed by studies in which individual exposures can be measured directly.

Abstract  Mortality studies have indicated that workers in agriculture and forestry may be at increased risk of developing malignant lymphoma and multiple myeloma. The authors report the findings from a case-control study of 734 male malignant lymphoma and multiple myeloma patients (International Classification of Diseases (ICD) 200-203) registered with the New Zealand Cancer Registry in the period 1977-1981 and aged 20 years or more at time of registration. Controls also were males chosen from the cancer registry with four controls per case, matched on age and year of registration. The case group contained a significant excess of the occupational category involving agriculture and forestry (odds ratio = 1.25, 95% confidence limits = 1.00, 1.56). This excess was almost entirely among those aged less than 65 years at time of registration (odds ratio = 1.45, 95% confidence limits = 1.08, 1.95), particularly among patients with multiple myeloma (ICD 203) (odds ratio = 2.22, 95% confidence limits = 1.31, 3.75) and the category including nodular lymphoma, mycosis fungoides, and unspecified non-Hodgkin's lymphoma (ICD 202) (odds ratio = 1.76, 95% confidence limits = 1.03, 3.02). Mortality from malignant lymphoma and multiple myeloma increased significantly during the period 1955-1979.

Abstract  To evaluate the risk of cancer and other diseases among workers engaged in aircraft manufacturing and potentially exposed to compounds containing chromate, trichloroethylene (TCE), perchloroethylene (PCE), and mixed solvents.

A retrospective cohort mortality study was conducted of workers employed for at least 1 year at a large aircraft manufacturing facility in California on or after 1 January 1960. The mortality experience of these workers was determined by examination of national, state, and company records to the end of 1996. Standardised mortality ratios (SMRs) were evaluated comparing the observed numbers of deaths among workers with those expected in the general population adjusting for age, sex, race, and calendar year. The SMRs for 40 cause of death categories were computed for the total cohort and for subgroups defined by sex, race, position in the factory, work duration, year of first employment, latency, and broad occupational groups. Factory job titles were classified as to likely use of chemicals, and internal Poisson regression analyses were used to compute mortality risk ratios for categories of years of exposure to chromate, TCE, PCE, and mixed solvents, with unexposed factory workers serving as referents.

The study cohort comprised 77,965 workers who accrued nearly 1.9 million person-years of follow up (mean 24.2 years). Mortality follow up, estimated as 99% complete, showed that 20,236 workers had died by 31 December 1996, with cause of death obtained for 98%. Workers experienced low overall mortality (all causes of death SMR 0.83) and low cancer mortality (SMR 0.90). No significant increases in risk were found for any of the 40 specific cause of death categories, whereas for several causes the numbers of deaths were significantly below expectation. Analyses by occupational group and specific job titles showed no remarkable mortality patterns. Factory workers estimated to have been routinely exposed to chromate were not at increased risk of total cancer (SMR 0.93) or of lung cancer (SMR 1.02). Workers routinely exposed to TCE, PCE, or a mixture of solvents also were not at increased risk of total cancer (SMRs 0.86, 1.07, and 0.89, respectively), and the numbers of deaths for specific cancer sites were close to expected values. Slight to moderately increased rates of non-Hodgkin's lymphoma were found among workers exposed to TCE or PCE, but none was significant. A significant increase in testicular cancer was found among those with exposure to mixed solvents, but the excess was based on only six deaths and could not be linked to any particular solvent or job activity. Internal cohort analyses showed no significant trends of increased risk for any cancer with increasing years of exposure to chromate or solvents.

The results from this large scale cohort study of workers followed up for over 3 decades provide no clear evidence that occupational exposures at the aircraft manufacturing factory resulted in increases in the risk of death from cancer or other diseases. Our findings support previous studies of aircraft workers in which cancer risks were generally at or below expected levels.

Abstract  This report represents continued progress by the Agency for Toxic Substances and Disease Registry (ATSDR) in identifying methods to characterize the adverse effects of toxic substances released from hazardous waste sites (and other point sources of pollution) on the health of people living or working nearby. In preparing this report, ATSDR has drawn considerable expertise and technical guidance from the participants and planners of an international workshop convened in Atlanta, Georgia, by the Centers for Disease Control and Prevention in September 1995. Internationally recognized experts from the United States and Europe were convened to discuss a variety of tests available to assess kidney function in people exposed to nephrotoxic substances. These discussions were useful to ATSDR in enhancing its existing battery of tests used to identify kidney dysfunction in environmental health field studies. This battery is used in conjunction with test batteries adopted by ATSDR for other priority health conditions (immune function disorders, lung and respiratory diseases, neurobehavioral disorders in adults and children, and liver dysfunction to assess the health effects of environmental exposures). In addition, national workshops have been convened to discuss the role of biomarkers in assessing environmentally associated cancers, birth defects, and reproductive disorders.

Abstract  In this review we have evaluated the relationship between peroxisome proliferation and hepatocarcinogenesis. To do so, we identified all chemicals known to produce peroxisome proliferation and selected those for which there are data (on peroxisome proliferation and hepatocarcinogenesis) which meet certain criteria chosen to facilitate comparison of these phenomena. The summarised data and definition of the methodology used has been collected in appendices. These comparisons enabled us to evaluate the relationship between these phenomena using reliable data. As there is a good correlation between them, we further explored the mechanisms of action that have been proposed (direct genotoxic activity, production of hydrogen peroxide, cell proliferation and receptor activation). The relationship between these events in other species, including humans, was also reviewed and finally an overview of the assessment of human hazard is presented in section IX. Some of the first chemicals which were shown to produce peroxisome proliferation were also hepatocarcinogens whose carcinogenicity could not be readily explained by genotoxic activity. This raised the suggestion that the unusual phenomenon of peroxisome proliferation was intricately linked to the carcinogenic activity of these agents. Three questions have exercised the attention of regulatory, industrial and academic toxicology since then; are chemicals which elicit peroxisome proliferation in the liver actually a coherent class of chemical carcinogens?; does the early biological phenomenon of peroxisome proliferation have real predictive value for and mechanistic association with rodent carcinogenesis?; and what hazard/risk do these agents pose to humans that may be exposed to them? Whether peroxisome proliferators are indeed a discrete class of rodent carcinogens would appear to be the single, most important question. If so, then the assumptions and procedures relevant to human hazard and risk assessment should be applied to the class and should be essentially generic; if not, each chemical should be considered independently. Our critical analysis of the published data for over 70 agents which have been shown to possess intrinsic ability to induce peroxisome proliferation in the livers of rodents has led to the conclusion that there exists a strong correlation between peroxisome proliferation as n early effect in the liver and hepatocarcinogenicity in chronic exposure studies. An almost perfect correlation was observed between the induction of peroxisomes in the rodent liver and the eventual appearance of tumours following chronic exposure The few exceptions to this were largely explainable (section II).(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract  In 1995, the agency for Toxic Substances and Disease Registry began data collection for a study of environmental exposure to volatile organic compounds (VOCs) in drinking water and adverse pregnancy outcomes at the U.S. Marine Corps Base at Camp LeJeune, NC. This report describes a study of past exposure to VOC contaminated drinking water and "mean birth weight" (MBW), "small for gestational age" (SGA), and preterm births in residents of base family housing during January 1, 1968, through December 31, 1985. Birth certificates were studied from 6,117 women exposed to tetrachloroethylene (PCE), 141 women with short-term exposure to trichloroethylene (TCE), and 5,681 women who were unexposed. Preterm delivery was not associated with VOC exposure in any category. For most live births, there was no association between PCE-contaminated drinking water and MEW or SGA. In mothers with two or more fetal deaths, the differences in MBW and SGA between PCE-exposed and unexposed mothers were much larger, but the number of births to women in this group was fairly small.

Abstract  The relation of hepatocellular carcinoma (HCC) to occupation and chemical exposures was evaluated in a case-control study. The study included 80 cases and 146 matched hospital controls on whom a work history was obtained. No persuasively positive association between HCC and any particular occupation, industry, or chemical exposure was found. However, the relative rate (RR) of HCC for persons employed in highway construction compared with those never so employed is 5.0 with 95% confidence limits (CL), 1.0 to 26. The RR for farming occupations, 1.4 (95% CL, 0.7 to 2.9), is also slightly elevated. The RR for persons exposed to pesticides compared with those not exposed is 2.4 (95% CL, 0.9 to 6.5). Asphalt exposures are associated with a RR of 3.2 (95% CL, 0.9, 11). These findings are compared to the results of other epidemiologic studies.

Abstract  Agonists and antagonists at the NMDA, GABA, and nicotinic acetylcholine receptors were administered to adult male rats to evaluate the contribution of these pathways to the visual-evoked potential (VEP). Rats were presented with an onset/offset pattern at a temporal frequency (4.55 Hz) resulting in a steady-state VEP. Averaged VEPs were Fourier transformed and VEP amplitudes were calculated at 1x stimulus frequency (F1) and 2x stimulus frequency (F2). About 30 min after administration, NMDA (10 mg/kg, i.p.; n = 9) increased F1 amplitude by 350% and decreased F2 amplitude by 48%. Memantine (4.5 mg/kg, i.p.; n = 10) increased F1 amplitude by 50%, 10 min post-injection. Similarly, nicotine (0.1 mg/kg, s.c.; n = 9) increased F1 amplitude by 55%, 20 min after drug administration. Muscimol (1 mg/kg, i.p.; n = 10) increased F1 amplitude significantly from 20 to 45 min post-injection. Mecamylamine (6 mg/kg, i.p.; n = 10) decreased F2 amplitude by 70% during the 60-min testing session. Bicuculline (0-0.5 mg/kg, i.p.; n = 8-10 rats/dose) did not significantly alter either F1 or F2 amplitudes. Results indicate important roles for glutamate and nicotinic acetylcholine receptors in both F1 and F2, while GABA receptors contribute to F1.

Abstract  Lifetime occupational histories as well as information on known and suspected breast cancer risk factors were collected by means of a self-administered questionnaire from 1018 women with incident breast cancer ascertained from the British Columbia Cancer Registry, and from 1020 population controls. A matched case-control study design was used. Conditional logistic regression for matched sets data and the likelihood ratio were used in a two-step procedure and were performed separately for pre-menopausal women, post-menopausal women, and for all cases combined. Excess risk was noted for several white-collar occupations. Significantly increased risk was observed: (1) among pre-menopausal women: in electronic data-processing operators; barbers and hairdressers; in sales and material processing occupations; and in the food, clothing, chemical and transportation industries; (2) among post-menopausal women: in schoolteaching; in medicine, health, and nursing occupations; in laundry and dry-cleaning occupations; and in the aircraft and automotive, including gasoline service station, industries. Several significant associations were also seen in the combined group of pre- and post-menopausal women, particularly in crop farmers and in the fruit and vegetable, publishing and printing, and motor vehicle repair industries. The results of this study suggest excess breast cancer risk in a number of occupations and industries, notably those that entail exposure to solvents and pesticides.

Abstract  Neoplastic cells simultaneously harbor widespread genomic hypomethylation, more regional areas of hypermethylation, and increased DNA-methyltransferase (DNA-MTase) activity. Each component of this "methylation imbalance" may fundamentally contribute to tumor progression. The precise role of the hypomethylation is unclear, but this change may well be involved in the widespread chromosomal alterations in tumor cells. A main target of the regional hypermethylation are normally unmethylated CpG islands located in gene promoter regions. This hypermethylation correlates with transcriptional repression that can serve as an alternative to coding region mutations for inactivation of tumor suppressor genes, including p16, p15, VHL, and E-cad. Each gene can be partially reactivated by demethylation, and the selective advantage for loss of gene function is identical to that seen for loss by classic mutations. How abnormal methylation, in general, and hypermethylation, in particular, evolve during tumorigenesis are just beginning to be defined. Normally, unmethylated CpG islands appear protected from dense methylation affecting immediate flanking regions. In neoplastic cells, this protection is lost, possibly by chronic exposure to increased DNA-MTase activity and/or disruption of local protective mechanisms. Hypermethylation of some genes appears to occur only after onset of neoplastic evolution, whereas others, including the estrogen receptor, become hypermethylated in normal cells during aging. This latter change may predispose to neoplasia because tumors frequently are hypermethylated for these same genes. A model is proposed wherein tumor progression results from episodic clonal expansion of heterogeneous cell populations driven by continuous interaction between these methylation abnormalities and classic genetic changes.

Abstract  Inhalable solvents possess significant abuse liability and produce many of the neurobehavioral effects typically associated with central nervous system-depressant agents, including motor incoordination, anxiolysis, and the elicitation of signs of physical dependence on withdrawal. We tested the hypothesis that the commonly abused solvents toluene, 1,1,1-trichloroethane (TCE), and trichloroethylene (TCY) affect ligand-gated ion channel activity, as do other classes of central nervous system-depressive agents. TCE and toluene, like ethanol, reversibly enhanced gamma-aminobutyric acid (GABA)(A) receptor-mediated synaptic currents in rat hippocampal slices. All three inhalants significantly and reversibly enhanced neurotransmitter-activated currents at alpha1beta1 GABA(A) and alpha1 glycine receptors expressed in Xenopus oocytes. We previously identified specific amino acids of glycine and GABA(A) receptor subunits mediating alcohol and volatile anesthetic enhancement of receptor function. Toluene, TCE, and TCY were tested on several glycine receptor mutants, some of which were insensitive to ethanol and/or enflurane. Toluene and TCY enhancement of glycine receptor function was seen in all these mutants. However, the potentiating effects of TCE were abolished in three mutants and enhanced in two, a pattern more akin to that seen with enflurane than ethanol. These data suggest that inhaled drugs of abuse affect ligand-gated ion channels, and that the molecular sites of action of these compounds may overlap with those of ethanol and the volatile anesthetics.

Abstract  The potential for trichloroethylene (TCE) and perchloroethylene (PERC) to induce developmental toxicity was investigated in Crl:CD (SD) rats whole-body exposed to target concentrations of 0, 50, 150 or 600 ppm TCE or 0, 75, 250 or 600 ppm PERC for six hours/day, seven days/week on gestation day (GD) 6-20 and 6-19, respectively. Actual chamber concentrations were essentially identical to target with the exception of the low PERC exposure level, which was 65 ppm. The highest exposure levels exceeded the limit concentration (2 mg/L) specified in the applicable test guidelines. Maternal necropsies were performed the day following the last exposure. Dams exposed to 600 ppm TCE exhibited maternal toxicity, as evidenced by decreased body weight gain (22% less than control) during GD 6-9. There were no maternal effects at 50 or 150 ppm TCE and no indications of developmental toxicity (including heart defects or other terata) at any exposure level tested. Therefore, the TCE NOEC for maternal toxicity was 150 ppm, whereas the embryo/fetal NOEC was 600 ppm. Maternal responses to PERC were limited to slight, but statistically significant reductions in body weight gain and feed consumption during the first 3 days of exposure to 600 ppm, resulting in a maternal NOEC of 250 ppm. Developmental effects at 600 ppm consisted of reduced gravid uterus, placental and fetal body weights, and decreased ossification of thoracic vertebral centra. Developmental effects at 250 ppm were of minimal toxicological significance, being limited to minor decreases in fetal and placental weight. There were no developmental effects at 65 ppm

Abstract  The influence of exposure duration and pattern on body's kinetics during and after environmental tetrachloroethylene exposure were examined using exhaled breath analysis. A subject was exposed to tetrachloroethylene in dry-cleaning stores for three durations, during which personal exposure (breathing-zone air) and alveolar breath samples were collected concurrently, and in a controlled environment facility for different exposure duration and pattern combinations, all of which had the same total exposures. Three dynamic processes that affect elimination were examined: absorption, distribution and elimination. Absorption kinetics were examined using the relationships between the exposure air and exhaled breath concentrations measured simultaneously. It was found that shorter exposure duration resulted in higher percent absorption and therefore higher internal dose The distributions of Perc within the body were studied using both compartment and pharmacokinetic models. Shorter exposure duration or higher exposure intensity resulted in higher Perc body burden, higher peak brain concentration and higher short-term metabolic burden than a longer exposure with lower exposure concentration. A shorter exposure (30-minute) also resulted in greater percent amounts expired, larger area under the postexposure curve and longer first elimination half-lives than longer (90-minute) exposures. The exposure pattern did not have a large influence on the elimination kinetics for 30-minute exposures, but showed significant effects for the longer, 90 minutes, exposures. These findings support the current hypothesis that exposure conditions affect body elimination kinetics. These measurements were also used to evaluate a pharmacokinetic model for tetrachloroethylene. The use of an integrated air concentration as the model input resulted in similar prediction as the actual exposure profiles. The pharmacokinetic model with optimized parameters effectively predicted the postexposure breath concentrations of short-term exposures with small fluctuation in exposure concentration, but is insufficient to predict under extreme exposure scenarios, especially for longer exposure duration. The results also indicated that the assumption of instantaneous exchange between alveolar air and blood may not be valid. The percent Perc metabolized in the liver was predicted to be 36% for the current exposure levels.

Abstract  The role of exposure to solvents was investigated in female patients with connective tissue disease and Raynaud's phenomenon using a questionnaire. Sixteen out of the 63 patients with systemic sclerosis had been exposed to solvents. A borderline significance was demonstrated compared to matched female controls (P < 0.05). Fourteen out of the 66 patients with undifferentiated connective tissue disease, 18/86 of patients with Raynaud's phenomenon, 6/45 with systemic lupus erythematosus, 1/16 with dermatopolymyositis, 1/15 with rheumatoid arthritis and 0/13 with primary Sjogren's syndrome had been exposed to solvents. None of these groups of patients showed a statistical significance compared to matched controls. Our present findings indicate that, at least in certain areas of the world, exposure to solvents may be a provoking factor in female scleroderma, but it must be emphasised that only a borderline significance was found between the scleroderma patients and controls. A large multicenter study seems to be required to clarify the importance of solvents as provoking factors of scleroderma. Furthermore, exposure to solvents does not seem to be a provoking factor among females for the other connective tissue diseases