Weight-of-evidence analysis of human exposures to dioxins and dioxin-like compounds and associations with thyroid hormone levels during early development

Thyroid hormones play a critical role in the proper development of brain function and cell growth. Several epidemiological studies have been conducted to assess potential associations between pre- and post-natal exposure to dioxins or dioxin-like compounds (DLCs) and the levels of circulating thyroid hormones during early development. Dioxins and DLCs include chlorinated dibenzo-p-dioxins, chlorinated dibenzofurans, and mono- and non-ortho polychlorinated biphenyls (PCBs). We identified a total of 23 relevant epidemiological studies (21 cohort studies and 1 case–control study) that measured exposures to various types of dioxins and DLCs as well as markers of thyroid function, such as thyroid stimulating hormone (TSH), total thyroxine (T4), free T4, total triiodothyroxine (T3), free T3, and thyroid-binding globulin concentrations in cord blood or circulation. While some of the studies reported associations between concentrations of dioxins and/or DLCs and some biomarkers of thyroid function, the majority of the observed associations were not statistically significant. Moreover, there were no clear and consistent effects across studies for any of the hormone levels examined, and while a number of studies showed a statistically significant association with exposure for a given marker of thyroid function, other studies showed either no change or changes in the opposite direction for the same thyroid function marker. Similarly, when the results were analyzed considering developmental stage, there generally were no clear and consistent effects at any age from birth through 12 years of age. The absence of a clear correlation between background exposures to dioxins and DLCs and thyroid function biomarkers during development is not consistent with the hypothesis that background exposures to these chemicals cause effects on thyroid function during development.     

The effect on plasma prolactin,growth hormone and luteinising hormone concentrations of single oral doses of propranolol and tolamolol in normal man

Summary In a placebo controlled double-blind study in six healthy male volunteers the effects of single oral doses of 100 mg and 200 mg of tolamolol on plasma concentrations of prolactin, growth hormone and luteinising hormone were investigated. In a second placebo controlled single-blind study in a further six healthy male volunteers the effects of single oral doses of 200 mg tolamolol and 160 mg propranolol on the same plasma hormone concentrations were compared. A dose dependent increase in plasma prolactin concentration was demonstrated after tolamolol. The increase in plasma prolactin concentration was not evident after propranolol. Plasma growth hormone and luteinising hormone concentrations were not significantly changed by either propranolol or tolamolol.Report prepared by Pfizer Central Research, Europe     

Endosulfan effects on pituitary hormone and both nitrosative and oxidative stress in pubertal male rats

The present study was undertaken to investigate in pubertal male rats possible effects of endosulfan administered throughout lactation and gestation on: (a) pituitary gene expression of prolactin, luteinizing hormone (LH), growth hormone (GH) and thyroid stimulating hormone (TSH); (b) circulating levels of these hormones; and (c) expression of nitric oxide synthase 1 and 2 (NOS1 and NOS2), and heme oxygenase-1 (HO-1) at pituitary level. Endosulfan was administered orally at the doses of 0.61 mg/kg/day or 6.12 mg/kg/day, and possible toxic effects were studied in pubertal male pups (at postnatal day 30). Gene expression was evaluated by RT-PCR and plasma hormone levels by RIA. Exposure to both administered doses down-regulated LH, GH and TSH. Treatment with 0.61 mg endosulfan/kg/day decreased prolactin expression, although its plasmatic concentration was decreased by both administered doses. LH secretion was stimulated by both doses, whereas the highest dose increased GH levels and decreased plasma TSH concentration. Endosulfan up-regulated NOS1 and NOS2. We can conclude that in pubertal male rat, prenatal and lactational exposure to endosulfan modifies expression and release of prolactin, LH, GH and TSH, and pituitary NOS1 and NOS2 mRNA levels, suggesting that nitrosative stress can be implicated in the endocrine toxicity of endosulfan at pituitary level.     

Glutathione and glutathione S-transferases in rat liver after inhalation of halothane and enflurane

Male Sprague-Dawley rats were exposed in inhalation chambers to halothane and enflurane in concentrations from 50 ppm-1000 ppm (0.0025-0.05 minimum alveolar concentration; MAC) 6 h a day for 3-9 days. Repeated subanaesthetic concentrations were used to avoid effects of general anaesthesia and to increase the metabolized fraction of the inhaled anaesthetics. Exposure to 0.05 MAC of halothane (500 ppm) and enflurane (1000 ppm) for 9 days reduced the activity of glutathione S-transferases. A decrease in liver concentration of reduced glutathione (GSH) was observed after inhalation of enflurane, probably caused by metabolic release of inorganic fluoride. The results indicate a decreased detoxifying capacity of rat liver under the given conditions. Inhalation of occupational related concentrations of the anaesthetics (50 ppm) did neither affect the activity of the transferases nor the concentration of GSH in rat liver.     

Comparative metabolic effects of halothane and enflurane in rat heart cell culture

The effects of halothane and enflurane on the oxygen consumption rates and substrate utilization by beating and nonbeating rat heart myocytes in cell culture were compared. Halothane, on an equal dose and equal MAC (minimum alveolar concentration producing immobilization of 50% of subjects) basis, was significantly more effective than enflurane in reducing total myocyte oxygen consumption and contractile rate. The greater effect of halothane on oxygen consumption was not due entirely to its effect on myocyte contractile rate, since quiescent (nonbeating) cells and cells rendered nonbeating by large doses of halothane also showed greater reductions in oxygen consumption than with large doses of enflurane. Both halothane and enflurane reduced glucose and palmitic acid metabolism by myocytes when compared with controls. However, there were no significant differences between halothane or enflurane with regard to glucose metabolism. Halothane was significantly more effective than enflurane in reducing cellular palmitic acid metabolism. Although palmitic acid uptake by myocytes was reduced to the same extent by both anesthetics when compared with control uptake values, halothane reduced myocyte uptake of glucose to a greater degree than enflurane. The results of this study indicate that halothane is a more potent myocardial metabolic depressant than enflurane.     

肽类激素兴奋剂对人体的危害

兴奋剂是国际体育组织规定的禁用药物和方法的总称，可分为蛋白同化制剂、肽类激素、β2受体激动剂、利尿剂、麻醉剂等不同种类。肽类激素是一类较新的兴奋剂，包括促红细胞生成素、生长激素及胰岛索样生长因子-1、促性腺激素、胰岛素、促皮质激素5大类。肽类激素属于人体内源性物质，很难被检测到，但滥用误用会对人体健康造成损害，如促红细胞生成素可引起过敏反应，生长激素可造成肢端肥大症，胰岛索样生长因子-1可引起急性低磷血症，促性腺激素可造成男性性早熟，胰岛素可造成视物模糊，促皮质激素可造成女性闭经等。     

Effects of exposure concentrations on distribution of halothane metabolites in the body

The effect of exposure concentration on halothane metabolism was studied in rats exposed to subanesthetic concentrations of halothane in air. Concentrations of halothane, total nonvolatile fluorine, and volatile metabolites (CF3CH2Cl and CF2 = CHCl) were determined in liver, kidneys, muscles, and brains excised at the end of a 3-hr exposure. It was observed that concentrations of all halothane metabolites in tissues rose less than exposure concentrations, that nonvolatile fluorine was present in all tissues in approximately the same concentrations, and that concentrations of volatile metabolites in liver were much higher than in any other tissues. A simulation model was used to support the following conclusions. Metabolism of halothane by all metabolic pathways is flow limited at small exposure concentrations and is capacity limited at high exposure concentrations. Volatile metabolites formed in livers are efficiently removed from circulation by pulmonary clearance, but trifluoroacetic acid is accumulated in the body. Halothane is most susceptible to biodegradation to trifluoroacetic acid, but this pathway is saturated at very small exposure concentrations. Susceptibility to biodegradation of volatile metabolites is small, but the pathways are not saturated even at anesthetic concentrations. The contribution of each of the three metabolites to total metabolic clearance depends on exposure concentrations. Trifluoroacetic acid was the major metabolite during exposure to small halothane concentrations; formation of more toxic, volatile metabolites increased during exposure to high concentrations. Postmortem formation of metabolites was studied in order to prevent its interference with tissue analysis. The method for determination of volatile metabolites is described.     

Use of heart cell cultures as a tool for the evaluation of halothane arrhythmia

The effects of various combinations of epinephrine-halothane and epinephrine-enflurane were tested on beating myocardial muscle cells cultured from 2- to 3-day-old rats. A series of culture plates containing myocytes were exposed to 0.5, 1.0, 1.5, and 2% halothane. At each halothane concentration, 9 ng of epinephrine was added, and the rate of contraction and rhythm of myocytes were observed. With increasing halothane concentrations, a significant and progressive increase in the percentage of plates demonstrating arrhythmia was observed. In a separate series of experiments, doses of epinephrine were added following exposure to 1.5% halothane. As the dose of epinephrine was increased progressively more plates displayed arrhythmia. In addition, culture plates were exposed to enflurane (3 and 6%), and epinephrine was added to each plate. No arrhythmia was observed in any of the 3% enflurane exposed plates. However at 6%, 100% of the plates displayed arrhythmia. In another series of experiments the efficaciousness of quinidine, procaine amide, lidocaine, propranolol, and verapamil in converting cell culture arrhythmia to normal rhythm following epinephrine and halothane was tested. Quinidine converted 96% of all arrhythmic plates to normal rhythm, procaine amide 80%, lidocaine 50%, and propranolol 10%. Verapamil failed to convert any arrhythmic plates to normal rhythm. It was concluded from this study that halothane directly “sensitizes” heart cells in tissue culture, and that the “sensitization” process is a linear, dose-dependent phenomenon.     

Acute effects of halothane and enflurane on drug metabolism and protein synthesis in isolated rat hepatocytes

The metabolism of sulphanilamide, antipyrine and paracetamol was studied in the absence and presence of the anaesthetics halothane and enflurane at three different concentrations (0.5, 1.0 and 2.0 mM) in isolated hepatocytes from the rat. Cell viability and protein synthesis were monitored to evaluate toxic effects. A strong concentration related inhibition of antipyrine oxidation (40-70%) and paracetamol conjugation (20-40%) was caused by both halothane and enflurane. Acetylation of sulphanilamide was not inhibited, however, as a slight augmentation was noticed. A significant dose related decrease of cell viability (3-13%) was caused by both anaesthetics. Dose dependent inhibition of the synthesis of stationary cell proteins (15-60%) and the synthesis/secretion of medium proteins (35-85%) was caused by halothane. Similar but slightly less pronounced effects were caused by enflurane. The present findings show that volatile anaesthetics may have general effects as well as different degrees of specific effects on both membrane bound enzyme and soluble enzyme activities.     

色谱-质谱联用技术测定人体内类固醇激素的研究进展

类固醇激素是高效能的生物化学物质,在多种生理活动中发挥显著的调节作用,但在体内的含量极低,因此对其进行准确定量具有重要意义。在各种检测方法中,色谱-质谱联用技术因具有高效、快速、灵敏的优点而得以广泛应用。笔者综述近年来色谱-质谱联用技术在内源性类固醇激素测定中的应用,为进一步的临床研究提供参考依据。     

Toxicity and biotransformation of volatile halogenated anesthetics in rat hepatocyte suspensions

This study examines the toxicity (as measured by reduced intracellular K+) and metabolism (defluorination) of halothane and enflurane in rat hepatocytes in suspension (RHS) with regards to O2 tension, time, and concentration. In 95% O2 halothane is more toxic than enflurane when RHS are exposed to 5-20 microliters of these anesthetics. At these levels halothane is not metabolized while enflurane is metabolized. At 21% O2 a similar pattern was seen with regards to toxicity. However, metabolism of halothane rapidly reached an elevated level while that of enflurane is reduced when compared to 95% O2. Thus toxicity of halothane and enflurane at these dose levels appears to be unrelated to metabolism and due solely to a solvent effect.     

Thyroid hormone, glucocorticoids, and prolactin at the nexus of physiology, reproduction, and toxicology

A symposium at the 2003 Annual Meeting of the Society of Toxicology brought together an expert group of endocrinologists to review how non-reproductive hormones can affect the endocrine system. This publication captures the essence of those presentations. Paul Cooke and Denise Holsberger recapitulate the evidence of how thyroid hormones affect male and female reproduction, and reproductive development. Ray Witorsch summarizes the many effects of glucocorticoids on the reproductive system. Finally, Paul Sylvester reviews the mechanism of action of prolactin, and reminds us that this ancient hormone has many functions beyond lactation.     

The effects of propranolol and acebutolol on the overnight plasma levels of anterior pituitary and related hormones

1 The effects of single evening doses of the beta-adrenoceptor blocking agents propranolol (80 mg orally) and acebutolol (200 mg orally) on plasma levels throughout the night of prolactin, growth hormone, luteinising hormone, follicle stimulating hormone, cortisol and testosterone have been studied in seven healthy male volunteers. 2 Three way analysis of variance showed that acebutolol significantly reduced circulating levels of prolactin and follicle stimulating hormone, but did not alter the levels of the other hormones studied. 3 Propranolol significantly reduced follicle stimulating hormone and testosterone, and significantly increased circulating levels of cortisol, but caused no change in the other hormones studied. 4 Prolactin, luteinising hormone, testosterone and cortisol showed a significant variation with time indicating the existence of a diurnal rhythm in the pattern of their secretion. 5 There was a significant inter-subject variability in all the hormones studied. 6 There was a significant between-subject variation in response to both propranolol and acebutolol. 7 Different subjects showed significant variations with respect to time in prolactin, growth hormone and cortisol levels. 8 Neither propranolol nor acebutolol significantly altered the time course of secretion of any of the hormones studied. 9 Possible relationships of these beta-adrenoceptor blocker-induced changes in anterior pituitary and related hormones to the antihypertensive mechanism of acebutolol and propranolol are discussed.     

Membrane expansion and inhalation anesthetics. Mean excess volume hypothesis

High-precision solution densimetry was used to determine volume parameters for the interaction of inhalation anesthetics with water, nonpolar solvent, and phospholipid vesicles. The precision of the densimeter is mainly limited by the constancy of the temperature during measurement. Therefore, temperature stability was maintained within +/- 0.0005 degrees and monitored by a microprocessor-controlled Thermistor thermometer with 0.0001 degrees resolution. All values were obtained at 25 degrees. Because volatile anesthetics in liquid form usually contain water, they were purified by passage through activated aluminum oxide columns. The molal volumes of dried preparations at the pure liquid states were: halothane, 106.3(3); isoflurane, 123.6(6); and enflurane, 121.9(9) cm3 X mole-1 at 298.150 degrees K. The mean molal excess volumes of anesthetic-water mixtures were negative at dilute anesthetic concentrations in water and positive at dilute water concentrations in liquid anesthetics. These values were dependent on the mole fractions of each component and showed a minimum in the water-rich region and a maximum in the anesthetic-rich region. In water, the partial molal volumes were halothane 93.7, isoflurane 103.4, and enflurane 98.6 cm3 X mole-1 at infinite dilution, and increased as the anesthetic concentration was increased. The partial molal volumes of water in liquid anesthetics were in halothane 21.7, isoflurane 21.0, and enflurane 20.5 cm3 X mole-1 at infinite dilution, and decreased as the anesthetic concentration was decreased. The mean excess volumes of the anesthetic-decane mixture were positive in the entire mixing range. The partial molal volumes of anesthetics in n-decane at infinite dilution were halothane 114.9, isoflurane 135.3, and enflurane 135.2 cm3 X mole-1. The mean specific excess volumes of the mixture of anesthetics and dimyristoylphosphatidylcholine vesicle suspension showed positive values. The partial molal volume was not evaluated because of the theoretical difficulty in estimating it in a dispersed two-phase system. Because the mean excess volume of anesthetics dissolved in water is always negative and that incorporated into phospholipid suspension is positive, anesthetics expand the total volume of the model membrane system when translocated from water to the membrane. Anesthesia occurs when the mean excess volume of the total system exceeds a limiting value, and the bulk membrane size is irrelevant. Although the present result in no way disclaims alternative hypotheses, it demonstrates that the pressure reversal of anesthesia can be explained without assuming any specific receptors for these anesthetics.     

青少年青春期性激素水平

为了解性激素在青春期的变化，制定出青少年青春期性激素水平，采用放射免疫分析法测定了８～１９岁正常青少年２９５名（男１２８名，女１６７名）的血清性激素ＦＳＨ，ＬＨ，ＰＲＬ，Ｅ２，Ｔ，并测定检查其性发育状况，结果发现，各项性激素水平基本随年龄和性发育程度的提高而升高，结果揭示；对青春期性激素的研究，应从年龄和性发育两个来探讨。     

Lack of Alterations in Thyroid Hormones Following Exposure to Polybrominated Diphenyl Ether 47 during a Period of Rapid Brain Development in Mice

Thyroid alterations have been shown to occur following exposure to polybrominated diphenyl ether (PBDE) mixtures, possibly indicating that disruptions in thyroid hormone levels may underlie behavior deficits observed in animals following postnatal PBDE exposure. This study determined whether acute postnatal exposure to PBDE-47 would alter thyroid hormones. Mice were dosed with PBDE-47 on postnatal day 10, and serum collected either 1, 5, or 10 days after the dose. No effect was observed on thyroxine and triiodothyronine levels at any age examined. This suggests that the neurological abnormalities reported in mice exposed to PBDE-47 are not due to acute changes in circulating thyroid hormones at these observed periods.     

Respiratory and cardiovascular effects of halothane, isoflurane and enflurane delivered via a Jackson-Rees breathing system in temperature controlled and uncontrolled rats

We studied the respiratory and cardiovascular effects of 1.25 MAC halothane, isoflurane and enflurane in oxygen delivered via the Jackson-Rees breathing system in 10 rats. Mean arterial pressure, heart rate and respiratory rate were depressed significantly (P less than 0.05) in rats (n = 5) whose body temperature was not controlled after 2 hr of anesthesia regardless of the inhalational agent. Respiratory and metabolic acidosis developed. The respiratory and cardiovascular depression was most marked under enflurane anesthesia. In normothermic rats (n = 5) the initial cardiovascular depression stabilized after 30 min of halothane and isoflurane anesthesia. Moderate respiratory depression developed (PCO2 48.42 +/- 2.48 torr with halothane vs. 41.02 +/- 1.68 torr with isoflurane). Because the cardiovascular and respiratory changes caused by halothane and isoflurane were far less than changes produced by enflurane, halothane or isoflurane is preferable to enflurane for maintaining anesthesia in rats. Maintenance of constant temperature minimizes the cardiovascular and respiratory disturbances.     

Toxicity and Biotransformation of Volatile Halogenated Anesthetics in Rat Hepatocyte Suspensions

ABSTRACT

This study, examines the toxicity (as measured by reduced intracellular K⁺ and metabolism (defluorination) of halothane and enflurane in rat hepatocytes in suspension (RHS) with regards to O₂ tension, time, and concentration. In 95% O₂ halothane is more toxic than enflurane when RHS are exposed to 5-20 μ1 of these anesthetics. At these levels halothane is not metabolized while enflurane is metabolized. At 21% O₂ a similar pattern was seen with regards to toxicity. However, metabolism of halothane rapidly reached an elevated level while that of enflurane is reduced when compared to 95% O₂. Thus toxicity of halothane and enflurane at these dose levels appears to be unrelated to metabolism and due solely to a solvent effect.     

男性肺心病急性发作期患者血清促性腺激素——性激素变化的临床研究

用放射免疫方法测定35例男性肺心病急性发作期患者和22名性别、年龄匹配的正常健康男性血清睾酮(T)、雌二醇(E_2)、黄体生成素(LH)、卵泡刺激素(FSH)水平,结果提示男性肺心病患者急性发作期存在明显的性激素紊乱。