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Trichloroethylene (TRI) is readily absorbed into the body through the lungs and gastrointestinal mucosa. Exposure to TRI can occur from contamination of air, water, and food; and this contamination may be sufficient to produce adverse effects in the exposed populations. Elimination of TRI involves two major processes: pulmonary excretion of unchanged TRI and relatively rapid hepatic biotransformation to urinary metabolites. The principal site of metabolism of TRI is the liver, but the lung and possibly other tissues also metabolize TRI, and dichlorovinyl-cysteine (DCVC) is formed in the kidney. Humans appear to metabolize TRI extensively. Both rats and mice also have a considerable capacity to metabolize TRI, and the maximal capacities of the rat versus the mouse appear to be more closely related to relative body surface areas than to body weights. Metabolism is almost linearly related to dose at lower doses, becoming dose dependent at higher doses, and is probably best described overall by Michaelis-Menten kinetics. Major end metabolites are trichloroethanol (TCE), trichloroethanol-glucuronide, and trichloroacetic acid (TCA). Metabolism also produces several possibly reactive intermediate metabolites, including chloral, TRI-epoxide, dichlorovinyl-cysteine (DCVC), dichloroacetyl chloride, dichloroacetic acid (DCA), and chloroform, which is further metabolized to phosgene that may covalently bind extensively to cellular lipids and proteins, and, to a much lesser degree, to DNA. The toxicities associated with TRI exposure are considered to reside in its reactive metabolites. The mutagenic and carcinogenic potential of TRI is also generally thought to be due to reactive intermediate biotransformation products rather than the parent molecule itself, although the biological mechanisms by which specific TRI metabolites exert their toxic activity observed in experimental animals and, in some cases, humans are not known. The binding intensity of TRI metabolites is greater in the liver than in the kidney. Comparative studies of biotransformation of TRI in rats and mice failed to detect any major species or strain differences in metabolism. Quantitative differences in metabolism across species probably result from differences in metabolic rate and enterohepatic recirculation of metabolites. Aging rats have less capacity for microsomal metabolism, as reflected by covalent binding of TRI, than either adult or young rats. This is likely to be the same in other species, including humans. The experimental evidence is consistent with the metabolic pathways for TRI being qualitatively similar in mice, rats, and humans. The formation of the major metabolites--TCE, TCE-glucuronide, and TCA--may be explained by the production of chloral as an intermediate after the initial oxidation of TRI to TRI-epoxide.(ABSTRACT TRUNCATED AT 400 WORDS)

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The rationale for extrapolation or "scaling" across species is founded in the commonality of anatomic characteristics and the universality of physiologic functions and biochemical reactions. The development of the allometric equation, Y = aWn, relating species body size (W) with various morphological, physiological, biochemical, pharmacological, and toxicological characteristics, as the fundamental basis for extrapolation of biological data from laboratory animals to man is outlined. The familiar methods of extrapolation on the basis of "milligrams per kilogram body weight" and "body surface area" are simply examples, W1.0 and W0.67, respectively, of this equation. The experimental observations used to support these two, and other extrapolation bases, are reviewed. Criteria for the selection of an appropriate base for transfer of specific biologic data from laboratory animals to man, and the expected reliability of the extrapolation, are discussed with the enunciation of four guiding principles. The application of these principles to the extrapolation to man of dose-tumor incidence data from carcinogenicity bioassays of laboratory animals is discussed. The components are identified, and illustrative examples are given.

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The isometric contractile response of rabbit aortic strips in response to histamine was studied. Biphasic dose-dependent contractions reflecting release of internal Ca2+ (phasic component) and simultaneous mobilization of external Ca2+ stores (tonic component) were produced.

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Phasic and tonic components of contraction are functional properties of vascular smooth muscle reflecting, respectively, release of intracellular calcium and utilization of extracellular calcium. Recently, it has been appreciated that different agonists may manifest discrete actions on these functional properties of vascular smooth muscle. We have analyzed the contractile response of rabbit aortic strips in response to maximal effective concentrations of the agonists norepinephrine, angiotensin II and acetylcholine in the absence and presence of their specific antagonists: phentolamine, saralasin and atropine in order to determine the actions of the antagonists on these functional properties of vascular smooth muscle. When contractions produced by norepinephrine or acetylcholine were plotted as ln velocity vs. time, characteristic curves described by a two-term function Qt = phi 1e-phi 2t + theta 1e-theta 2t were found (Qt = velocity at any time t: phi 1 and theta 1 are velocity of contraction at zero time for phasic and tonic components; phi 2 and theta 2 are contraction velocity constants for their respective components of contraction). The first term represents the phasic component and the second term the tonic component of contraction. The contraction velocity parameters were different for norepinephrine and acetylcholine. Angiotension II-induced contractions gave velocity curves described by a single term, i.e. phasic component of contraction. Phentolamine blocked completely the tonic component and the decreased tension achieved with norepinephrine was completely accounted for by inhibition of the tonic contribution to total tension development. Atropine completely blocked acetylcoholine's tonic component and also attenuated slightly the phasic component. Saralasin reduced angiotensin II-induced tension development and contraction velocity analysis suggested a non-competitive action. We conclude that competitive antagonists may exert distinct actions on the phasic and tonic components of vascular smooth muscle contraction.

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The contractile response of vascular smooth muscle is known to consist of fast and slow components of contraction. We investigated the effect of norepinephrine and angiotensin-II on these functional properties of vascular smooth muscle in a quantitative fashion by analyzing the velocity of isometric tension development in rabbit aortic strips as a function of time. Basic premises for contraction velocity analysis are: (1) tension development is proportional to agonist concentration and relates to the amount of calcium fixed by the contractile proteins; (2) the rate of tension development (Qt) reflects the rate calcium is mobilized; (3) the rate at which calcium is made available relates to agonist concentration; (4) calcium is available from internal and external sites; (5) the calcium source)s) activated are characteristic of the mechanism of action of a particular agonist, and (6) the source of calcium activated is identifiable. Aortic strips were contracted maximally with norepinephrine and the velocity of contraction found to decrease with time according to the empirical expression Qt = phi 1e-phi 2t + theta 1e-the 2t. Experiments in calcium-free medium served to identify the tonic component of norepinephrine-induced contraction as the second term while angiotensin demonstrated only one term (phasic) which was independent of extracellular calcium. Strips contracted with different concentrations of norepinephrine or angiotensin showed dose-dependent actions on these functional properties of vascular smooth muscle as revealed by their effects on the contraction velocity parameters. An expression describing the contribution of each component to total tension developed was derived by integrating the above expression to give Qtot = phi 1 (1--e-phi 2tmax)/phi 2 + theta 1 (1--e-theta 2tmax)/theta 2. The contribution of each component to total tension development was donse-dependent and their sum gave the total tension observed experimentally with norepinephrine. For angiotensin, the first term of the preceeding expression gave the observed tension response. It is concluded that contraction velocity analysis affords a new approach for studying the effects of vasoactive agents on the functional properties of vascular smooth muscle.

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The incidence of antibodies to maize using an immunofluorescent technique has been found to be 14% in controls, 33% in Crohn's disease, 50% in ulcerative colitis and 44% in coeliac disease. This result indicates that humoral immunity to maize is probably unimportant in the pathogenesis of Crohn's disease. The similar incidence of antibodies in the inflammatory bowel disease and coeliac groups suggests absorption of dietary antigen secondary to an increased mucosal permeability.

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Crohn's-disease tissue was tested by indirect immunofluorescence for antigens of rotavirus, Pseudomonas maltophilia, and Mycobacterium kansasii. No reactions were obtained with anti-serum to P. maltophilia and M. kansasii, and a granular fluorescence seen with rotavirus antibody was probably non-specific.

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The metabolism of l-bunolol, a new beta-blocking drug, was studied in man after single oral 3-mg doses of 3H-labeled compound. Absorption from the gut was rapid and virtually complete. Peak levels of bunolol and of dihydrobunolol, an active metabolite, were observed at 1 hr. Excretion of the administered radioactivity was mainly into the urine (78% in 4 days), with only 3% appearing in the feces. Bunolol, bunolol glucuronide, bunolol sulfate, dihydrobunolol, and dihydrobunolol glucuronide were identified and quantified in the plasma. These compounds represented 82% of the radioactivity in plasma at 30 min and 55% at 24 hr. Plasma half-lives (+/-S.D.) were estimated to be 6.1 +/- 0.3 hr for bunolol, 9.1 +/- 1.9 hr for bunolol glucuronide, 17.4 +/- 2.5 hr for bunolol sulfate, 7.1 +/- 0.5 hr for dihydrobunolol, and 7.7 +/- 0.8 hr for dihydrobunolol glucuronide.

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The absorption, excretion, and biotransformation of 14C-labeled pentaerythritol (PE) trinitrate was studied in man. The administration of a single sublingual dose was followed by rapid absorption and extensive biotransformation. Six drug metabolites were identified. Final excretion of the drug and its metabolites was almost totally through the kidney. Low levels of unchanged drug were present in plasma and urine. PE mononitrate was the major drug metabolite in plasma and urine. Glucuronides of PE trinitrate, dinitrate, and mononitrate were identified for the first time in man. PE trinitrate glucuronide appeared in plasma rapidly and about 8% of the dose was excreted in urine. Reversible and irreversible pathways are proposed for the formation of the metabolites. The reconversion of PE trinitrate glucuronide to PE trinitrate is postulated to explain the duration of drug activity and excretion.

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Experience with 1 patient undergoing second trimester therapeutic abortion induced by prostaglandin F2alpha administration is described. Serious hypokalemia in association with cardiac arrhythmia followed intraamniotic administration of the drug. Further observations on a group of normal subjects receiving prostaglandin injections for induction of abortion showed a small but significant serum hypokalemia after treatment.

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The alginate depolymerase associated with bacteriophage infection of Azotobacter vinelandii has been used in the analysis of sodium alginate. The enzyme degraded the polysaccharide to a series of oligouronides each containing a terminal 4-deoxy-alpha-L-erythro-hex-4-enopyranuronosyl residue. Analysis of these oligouronides, together with kinetic information, indicated that the enzyme was specific for mannuronic acid-containing regions of the polyuronide. The specificity of the enzyme made it possible to determine the primary structure of the macro-molecule. The phage-induced enzyme was shown to be distinct from the alginate lyase elaborated by the host organisms by its pH optimum, molecular weight, Michaelis constant and stability.

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An unidentified pseudomonad isolated by enrichment procedures from decomposing seaweed was grown in defined medium containing sodium alginate as the sole carbon source. The alginate lyase recovered from disrupted bacterial cells was purified by a procedure of (NH4)2SO4 precipitation, gel filtration and ion-exchange chromatography. From sodium dodecyl sulphate/polyacrylamide-gel-electrophoresis experiments a mol.wt. of about 50 000 was determined. The enzyme was active against both algal and bacterial alginate preparations. Kinetic studies together with analysis of the unsaturated oligouronide products of alginate lyase action indicated the enzyme was specific for guluronic acid-containing regions of the macromolecular substrate. The specificity of the enzyme can be used to give information about the primary composition of alginate samples.

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Previous studies in man have shown pentaerythritol (PE) trinitrate, given either sublingually or orally, produces a prolonged hypotensive effect. The coronary vasodilator and systemic vasodepressor activities of PE trinitrate and its metabolites, PE dinitrate, PE mononitrate and PE, were evaluated in dogs to determine whether the metabolites were active and contributory. Coronary vasodilator activity was estimated with a flow transducer placed on the left anterior descending artery, and reduction of arterial pressure was determined directly via the femoral artery. Quantitative comparisons were made from dose-response curves established for nitroglycerin (ng), PE nitrates, and other common organic nitrates after intrajugular administration. Increase of coronary blood flow and reduction of arterial pressure were proportionally related, and the proportionality was the same for all drugs. Relative to NG, the potency of PE trinitrate was about 20 percent, erythrityl tetranitrate 12 percent, and isosorbide dinitrate 3.5 percent. The ratios of vasodilator activity of PE trinitrate and its metabolities were: PE trinitrate 100; PE dinitrate 1.5; PE mononitrate 0.5; and PE O. Tachyphylaxis was observed after close-order injections of NG or PE trinitrate. In addition, there was cross tolerance between NG and PE trinitrate and also between PE trinitrate and its less active metabolites.

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