Abstract  Experimental data obtained in vivo with the closed-chamber gas uptake technique have been reported for a series of volatile chemicals. Pharmacokinetic analyses of these data have been performed either by using a two-compartment model or physiological models. In the former the transfer rate of chemical from ambient air to body is defined by the clearance of uptake. In the latter models the transfer rate depends on alveolar ventilation, cardiac output, and blood: air partition coefficient. In this communication we describe the quantitative relationship between clearance of uptake and alveolar ventilation, cardiac output, and blood: air partition coefficient. Theoretical values of clearance of uptake were calculated for a variety of volatile chemicals using literature data on alveolar ventilation, cardiac output, and blood: air partition coefficient. For most chemicals the experimentally determined values in rats and mice were about 60% of the theoretical values. This suggests that the inhalatory uptake rate of chemical may be overestimated if literature values of alveolar ventilation are used in physiological pharmacokinetic models for rodents.

Abstract  Data from the large-scale biological monitoring program in Japan were assembled and analyzed and the following results were obtained. All workers handling lead and eight kinds of major organic solvents received physical examinations and biological monitoring at the same time. Therefore, the number of workers handling industrial chemicals and that received physical examinations and the number of workers been examined by biological monitorings were similar to each other. The total number of cases examined from 1989 to 1994 was about 661,000 for lead in the blood and about 4,173,000 for the urinary metabolites of eight organic solvents. The results were classified into three categories and category 3 consists of workers having exposure concentrations above the 1988-1989 biological exposure indices of the ACGIH with the exception of lead concentration in the blood where the limit in Japan was set at 40 micrograms/100 ml. The percentage of exposed workers in category 3 was 1.4% for blood lead and 0.2-2.4% for the urinary metabolites of the eight organic solvents. The percentage of exposed workers in category 3 for blood lead, delta-aminolevulinic acid, urinary mandelic acid, N-methylformamide and 2,5-hexanedione in the urine has decreased with time. In ambient monitoring, the percentage of workplaces in classification 3 for lead and styrene also has decreased with time.

Abstract  Male Wistar rats (8 animals/group; 180-200 g) were exposed continuously to trichloroethylene (TRI) for 48 or 240 h or methylchloroform (1,1, 1-trichloroethane: MC for 48 h at 50, 400 and 800 ppm. The inhibition of delta-aminolevulinic acid dehydratase (ALA-D) was examined in liver, blood and bone marrow of naive and phenobarbital pretreated animals exposed to TRI. A clear cut dose-effect relationship between the exposure concentration or duration of exposure and the inhibition of ALA-D activity was seen for rats exposed to TRI. In addition to this finding, significant interaction between TRI exposure and phenobarbital treatment was observed in the inhibition of ALA-D in liver and blood. MC did not produce inhibition. Trichloroacetic acid and trichloroethanol failed to inhibit the ALA-D activity in vitro. It seems that a metabolite(s) of TRI other than the above 2 substances may play a role in the inhibition of ALA-D. The inhibition of ALA-D (38% or 48% of the control in liver or in blood, respectively) observed after the 240 h exposure at 400 ppm to TRI was accompanied by the significant elevation of delta-aminolevulinic acid synthase (186% of the control) in liver and the increase in excretion of delta-aminolevulinic acid in urine (142% of the control). This occurred without an apparent weight loss, liver injury or hematological changes.

Abstract  A method of estimating the bioconcentration factor of organic chemicals in fathead minnows (Pimephales promelas) is described. Water at 25 °C was intermittently dosed with the chemical at a nontoxic concentration in a flow-through aquarium. Thirty minnows are placed in the aquarium, and composite samples of five fish are removed for analysis after 2, 4, 8, 16, 24, and 32 d of exposure. The bioconcentration process is summarized by using the first-order uptake model, and the steady-state bioconcentration factor is calculated from the 32-d exposure. A structure-activity correlation between the bioconcentration factor (BCF) and the n-octanol/water partition coefficient (P) of individual chemicals is summarized by the equation log BCF = 0.85 log P − 0.70, which permits the estimation of the bioconcentration factor of chemicals to within 60% before laboratory testing. The facilities and resources for testing need be used only for those chemicals that are likely to result in substantial bioconcentration in organisms. The bioconcentration factors derived from tests of mixtures of chemicals are shown to be the same as those derived from tests with the chemicals individually. Key words: bioconcentration factor, bioaccumulation, structure-activity, bioassay

Abstract  The implementation of a risk-based corrective action approach often requires consideration of soil vapor migration into buildings and potential inhalation exposure and risk to human health. Due to the uncertainty associated with models for this pathway, there may be a desire to analyze indoor air samples to validate model predictions, and this approach is followed on a somewhat frequent basis at sites where risks are considered potentially significant. Indoor air testing can be problematic for a number of reasons. Soil vapor intrusion into buildings is complex, highly dependent on site-specific conditions, and may vary over time, complicating the interpretation of indoor air measurements when the goal is to deduce the subsurface-derived component. An extensive survey of indoor air quality data sets highlights the variability in indoor volatile organic compound (VOC) concentrations and numerous sources that can lead to elevated VOC levels. The contribution from soil vapor is likely to be small relative to VOCs from other sources for most sites. In light of these challenges, we discuss how studies that use indoor air testing to assess subsurface risks could be improved. To provide added perspective, we conclude by comparing indoor air concentrations and risks arising from subsurface VOCs, predicted using standard model equations for soil vapor fate and intrusion into buildings, to those associated with indoor sources.

Abstract  The peroxisome proliferator (PPs) class of non-genotoxic rodent hepatocarcinogens induce mouse hepatocyte DNA synthesis and suppress apoptosis. This phenotype can be reproduced in vitro using exogenous tumour necrosis factor alpha (TNFalpha), suggesting a role for TNFalpha in mediating the liver growth response to PPs. In hepatocytes isolated from the peroxisome proliferator activated receptor alpha (PPARalpha) null mouse, PPs are unable to stimulate DNA synthesis or to suppress either spontaneous or TGFbeta1-induced apoptosis. However, the ability of TNFalpha to modulate hepatocyte survival and growth is unaltered, suggesting that TNFalpha acts independently or downstream of PPARalpha to mediate the growth changes associated with PPARalpha activation. Since PPARalpha is a ligand activated transcription factor, we determined if TNFalpha gene expression was altered by PP treatment during an early time window preceding PP-induced growth changes. However there was no induction of TNFalpha expression by nafenopin over the constitutive levels noted in control cultured cells. In summary, TNFalpha acts downstream or independently of PPARalpha to mediate the suppression of apoptosis and induction of DNA synthesis by PPs. In this in vitro model, the PP nafenopin do not appear to mediate de novo TNFalpha gene expression suggesting that the response to nafenopin may be mediated by bioactivation or release of pre-existing TNFalpha protein from Kupffer cells.

Abstract  The 1 mg dexamethasone suppression test was used to assess pituitary-adrenal activity in 23 depressed patients and 8 healthy volunteers. At 1600h, after administration of the test dose of dexamethasone at 2300h, levels of cortisol, 11-deoxycortisol, and corticotropin were determined following a chromatographic extraction step applying highly specific radioimmunoassay techniques. Cortisol nonsuppressors had significantly increased adrenocorticotropic hormone (ACTH) values and cortisol/11-deoxycortisol ratios. The cortisol/11-deoxycortisol ratio was regarded as a measure of biologically active ACTH. The present results, which indicate a concordance of corticotropin and corticosteroid response, suggest that the parent abnormality of dexamethasone-resistant cortisol concentrations is elevation of biologically active corticotropin.

Abstract  In previous studies, smooth pursuit eye movements (SPEM) have been shown to be disordered in about 70% of schizophrenics and about 45% of their first-degree relatives. In this report, the role of attention in these eye movements is addressed in three experiments (using as subjects schizophrenics, their first-degree relatives, and normals administered chloral hydrate) that recruit focused attention to the task. These studies show that voluntary attention in the form of inattention, "heedless negligence," or failure to cooperate, is not the specific attentional quality that is disordered in SPEM of schizophrenics and their relatives. Rather, the data both indicate that nonvoluntary attending is specifically disordered in these persons, and implicate a neurophysiological substrate that can be described as a failure of inhibitory, synchronizing integrating systems which may be located in the brain stem.

Abstract  Ethanol-inducible CYP2E1 is an enzyme of major toxicological interest because it metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. CYP2E1 has also been implicated in alcohol liver disease because of its contribution to oxidative stress. Previously, polymorphic alleles with mutations in introns and in the 5'-flanking regulatory region have been described, and their presence has been related to the incidence of alcohol liver disease and lung cancer. In the present investigation, we investigated whether any functional mutations are linked to the above-mentioned rare alleles and also screened for mutations in the open reading frame using single-stranded conformation polymorphism and genomic DNA from almost 200 individuals belonging to either a Chinese, an Italian, or a Swedish population. Two new CYP2E1 gene variants were found with functional mutations: one (CYP2E1*2) in which a G1168A point mutation in exon 2 caused an R76H amino acid substitution, and the other (CYP2E1*3) in which a G10059A base substitution in exon 8 yielded a V3891 amino acid exchange. The corresponding CYP2E1 cDNAs were constructed, subcloned into the pCMV4 expression vector, and expressed in COS-1 cells. The cellular levels of CYP2E1 mRNA, CYP2E1 protein, and rate of chlorzoxazone hydroxylation were monitored. The CYP2E1*3 cDNA variant was indistinguishable from the wild-type cDNA on all variables investigated, whereas CYP2E1*2 cDNA, although yielding similar amounts of mRNA, only caused 37% of the protein expression and 36% of the catalytic activity compared with the wild-type cDNA. Complete screening by single-stranded conformation polymorphism of the three populations studied revealed that these variant alleles were rare. We conclude that the human CYP2E1 gene is functionally surprisingly well conserved compared with other cytochrome P450 enzymes active in drug metabolism, which suggests an important endogenous function in humans.

Abstract  The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-dependent nuclear receptor that has been implicated in the modulation of critical aspects of development and homeostasis, including adipocyte differentiation, glucose metabolism and macrophage development and function. PPAR-gamma is activated by a range of synthetic and naturally occurring substances, including antidiabetic thiazolidinediones, polyunsaturated fatty acids, 15-deoxy-delta prostaglandin J2 and components of oxidized low-density lipoprotein, such as 13-hydroxyoctadecadienoic acid (13-HODE) and 15-hydroxyeicosatetraenoic acid (15-HETE). However, the identities of endogenous ligands for PPAR-gamma and their means of production in vivo have not been established. In monocytes and macrophages, 13-HODE and 15-HETE can be generated from linoleic and arachidonic acids, respectively, by a 12/15-lipoxygenase that is upregulated by the TH2-derived cytokine interleukin-4. Here we show that interleukin-4 also induces the expression of PPAR-gamma and provide evidence that the coordinate induction of PPAR-gamma and 12/15-lipoxygenase mediates interleukin-4-dependent transcription of the CD36 gene in macrophages. These findings reveal a physiological role of 12/15-lipoxygenase in the generation of endogenous ligands for PPAR-gamma, and suggest a paradigm for the regulation of nuclear receptor function by cytokines.

Abstract  Single unit recordings were conducted to examine the effects of systemic D1 agonist SKF 38393 on the firing rate of substantia nigra pars compacta dopamine (DA) neurons in rats pretreated subchronically with reserpine or chronically with a D1 antagonist. The effect of N-methyl-D-aspartate receptor antagonists on these processes was also investigated. An i.v. injection of SKF 38393 (10 mg/kg) significantly inhibited DA cell activity by approximately 70% in rats pretreated with reserpine (1 mg/kg, s.c.) for 6 days and studied under conditions of local anesthesia. SKF 38393 exerted no effect in reserpinized rats anesthetized with chloral hydrate. The SKF 38393-induced inhibition was reversed by the D1 antagonist SCH 23390, but not by the preferential D2 antagonist haloperidol. This effect of SKF 38393 was observed in 60% of the rats as early as 3 to 8 hr after the first reserpine injection, and the inhibition remained significant 5 to 15 days (averaging 64 and 58%) after termination of the 6-day reserpine treatment. The N-methyl-D-aspartate antagonists ketamine, at anesthetic doses (100 mg/kg, i.p.), and MK 801, at a nonanesthetic dose (0.15 mg/kg, i.v.), completely blocked the inhibitory effect of SKF 38393. In contrast, DA cells recorded in rats pretreated with SCH 23390 for 7 to 21 days, followed by a 4-day washout period, failed to respond to SKF 38393. Because nigrostriatal DA neurons do not appear to express D1 receptors, these results suggest that D1 receptors can exert an indirect inhibitory effect on the activity of nigral DA neurons, presumably through striatonigral neuronal pathways.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract  We reported that the forebrain is responsible for a significant component (38%) of inferior cardiac postganglionic sympathetic nerve discharge (SND) in baroreceptor-denervated cats anesthetized with alpha-chloralose [Huang et al., Am. J. Physiol. 252 (Regulatory Integrative Comp. Physiol. 21): R645-R652, 1987]. The current study was initiated to assess the contribution of various diencephalic regions to the forebrain-dependent component of SND in this preparation. For this purpose, the reductions in inferior cardiac SND and blood pressure produced acutely by midbrain transection at stereotaxic plane A3 in nonlesioned control cats were compared with those in cats in which diencephalic lesions were made with radio-frequency current. Lesions of the anterior medial hypothalamus including the paraventricular nucleus failed to attenuate the decreases in SND and blood pressure produced by midbrain transection. In contrast, the effects of midbrain transection were significantly attenuated by lesions of the lateral hypothalamus (including medial forebrain bundle), posterior medial hypothalamus, or the medial thalamus. We conclude that both the hypothalamus and medial thalamus contribute to SND in anesthetized cats.

Abstract  Adequate sedation remains one of the most important parts of performing high quality cross-sectional imaging in children. This is a noncomparative retrospective analysis of existing sedation protocols used in 1,158 children between the ages of 1 day and 18 years, checking for safety and efficacy. The most commonly used drugs were chloral hydrate (60-120 mg/kg) by mouth for infants less than 18 months and intravenous Nembutal (2-6 mg/kg) for older children. Sedation was successful in 97% of patients.

Abstract  1. In rabbits intravenously injected with tetanus toxin (2 x 10(5) mouse LD50), a rhythmic electrical activity was recorded in the cerebellum and in the spinal cord. 2. The motor system appears to be strongly involved in this event, since the ventral roots displayed rhythmic activity correlated to the spinal cord rhythm. Extracellular recordings showed the same rhythmic discharge pattern in many alpha- and gamma-motoneurons and Renshaw cells of hindlimb flexor and extensor muscles. 3. Upon high spinalization at C1, the rhythm could be recorded in the cerebellum but no longer in the spinal cord. Cooling of the cerebellar surface suppressed the rhythm in both structures. 4. The data are discussed under the current view, that generalized tetanus is a special form of local tetanus. 5. We suggest that the rhythmic activity is of supraspinal origin and is transmitted to alpha- and gamma-motoneurons of both the flexor and extensor motor systems.

Abstract  A male Japanese subject, single, aged 38, who worked at a workshop washing metal parts with trichloroethylene, was admitted to our clinic due to addiction to the solvent. Analyses of urine revealed the presence of up to 160 μg/ml of trichloro-compounds (mostly trichloroacetic acid) which gradually disappeared in three weeks as the psychotic symptoms cleared up. The excretion half-lives of trichloroethylene metabolites for the initial rapid phase (succeeding slow phase in parentheses) were 5·8 (49·7) hours for trichloroethanol, 22·5 (72·6) hours for trichloroacetic acid, and 7·5 (72·6) hours for total trichloro-compounds.

Abstract  This study was conducted to examine the effect of dietary sodium alginate and fish oil on bodily accumulated trichloroethylene (TCE), which has been widely used as a halogenated solvent and is metabolized at a high rate. Each of three groups of rats was fed on either of diets containing cellulose-soybean oil (control), Na-alginate-soybean oil or cellulose-fish oil for 3 wk, and thereafter given a single oral dose of TCE (100 mg (0.76 mmol)/rat). TCE levels in the blood were monitored for 10 h after the administration of TCE. The peak concentrations of TCE in the blood tended to be higher in the alginate and fish oil groups as compared with those in the cellulose-soybean oil group, but not to a significant extent. TCE concentrations in the liver, kidney, brain and the three fat tissues (epididymal, perirenal and subcutaneous) were significantly lower in the alginate and fish oil groups than in the cellulose-soybean oil group. Fat tissue weights were also lower in the alginate group and fish oil group. The hepatic drug metabolizing enzymes could not account for the remarkable decreases of residual TCE contents in the alginate and fish oil groups. These findings indicate that the metabolism and excretion of TCE might be accelerated in animals with reduced fat tissue mass.