bluuebunny/crossref_metadata_2025 huggingface dataset:
Involvement of μ‐Opioid Receptor in the Salsolinol‐Associated Place Preference in Rats Exposed to Conditioned Fear Stress
Authors: Matsuzawa Shigeki , Suzuki Tsutomu , Misawa Miwa
Published: May 2006

Background: Salsolinol, a condensation product of dopamine with acetaldehyde (the initial oxidation product of ethanol), has long been discussed as an endogenous opioid system‐activating factor contributing to the etiology of alcoholism. Moreover, psychological stress has been considered to play an important role in the development of alcoholism.

Methods: Male Sprague Dawley rats were subjected to conditioned fear stress (at 24 hr after electric footshock exposure), and then salsolinol or saline was injected intraperitoneally. For conditioning, rats were immediately confined to the nonpreferred compartment after salsolinol injection and to the preferred compartment after saline injection on alternate days. This conditioning session was repeated twice daily (for 8 days). Test session was carried out 1 day after the last conditioning session.

Results: Salsolinol [10 mg/kg, but not 1, 3 or 30 mg/kg, intraperitoneally (ip)] without conditioned fear stress induced a slight, but significant, place preference. In contrast, salsolinol (1, 3, and 10 mg/kg, ip) with conditioned fear stress induced a marked and significant place preference. The nonselective opioid receptor antagonist naloxone hydrochloride (which can pass into the brain), but not the nonselective peripheral opioid receptor antagonist naloxone methiodide (which cannot pass into the brain), significantly attenuated the salsolinol (3 mg/kg, ip)‐induced place preference under conditioned fear stress. Moreover, the selective μ‐opioid receptor antagonist β‐funaltrexamine significantly attenuated the salsolinol‐induced place preference. Furthermore, 0.3 mg/kg salsolinol (which produced no significant place preference) combined with the μ‐opioid receptor agonist morphine [0.1 mg/kg, subcutaneously (sc)], at the dose which alone produced no significant place preference, produced a marked and significant place preference. Both naloxone hydrochloride and β‐funaltrexamine significantly attenuated the salsolinol plus morphine‐induced place preference.

Conclusions: Salsolinol may have some rewarding effect, and its rewarding effect may be potentiated by psychological stress. In addition, the rewarding effect of salsolinol especially under psychological stress may involve the endogenous central opioid system, i.e., μ‐opioid receptor.
A Behavioral Economic Analysis of Concurrent Ethanol‐ and Water‐Reinforced Responding in Different Preference Conditions
Authors: Williams Keith L. , Woods James H.
Published: May 2006

Background: The reinforcing properties of orally self‐administered drugs have been evaluated by using choice procedures. The preference for the drug over a nondrug alternative has indicated that the drug has greater value than the nondrug alternative as a reinforcer at some drug concentrations. However, at large drug concentrations, the fluid deliveries of the drug may be equal to or less than those of the nondrug alternative, whereas the actual drug intake (milligrams per kilogram of body weight) may continue to increase. In this study, we used behavioral economics to evaluate the reinforcing strength of ethanol in conditions where baseline ethanol fluid deliveries were greater than, equal to, or less than those of the concurrently available water.

Methods: Four male rhesus monkeys were allowed access to ethanol (2%, 8%, or 32%) and water for 2 hr/day under a fixed ratio (FR) 4 reinforcement schedule. At each ethanol concentration, the FR for both fluids was gradually increased to FR 64.

Results: During the FR 4 schedule, the fluid deliveries of ethanol at 2%, 8%, and 32% were greater than, equal to, and less than those of water, respectively. When the FR was increased at 2% ethanol, fluid deliveries and responding decreased for both the ethanol and water. When the FR was increased at 8% ethanol, water fluid deliveries and responding decreased more rapidly than did those of ethanol. When the FR was increased at 32% ethanol, the ethanol fluid deliveries remained the same across all FRs, whereas water fluid deliveries decreased rapidly. At 8% and 32% ethanol, the responding for ethanol, relative to water, increased dramatically.

Conclusions: In behavioral economic terms, demand for ethanol was more inelastic regardless of whether the ethanol or water maintained more absolute fluid deliveries at baseline FRs. Therefore, researchers should examine the reinforcing effects of ethanol in a variety of concentration and schedule conditions rather than drawing inferences regarding reinforcing effects simply based on a preference measure.
Tolerance to Acute Ethanol Inhibition of Peptide Hormone Release in the Isolated Neurohypophysis
Authors: Knott Thomas K. , Dayanithi Govindan , Coccia Vincent , Custer Edward E. , Lemos José R. , Treistman Steven N.
Published: May 2006

Background:Acute ethanol (EtOH) exposure reduces the evoked release of vasopressin (AVP) and oxytocin (OT) from excised neurohypophyses and from dissociated neurohypophysial terminals of the rat.

Methods and Results:Rats placed on a diet that maintained blood levels of 30 mM EtOH for 20 to 40 days developed tolerance to acute EtOH inhibition of release. In the presence of 10 mM EtOH, high (50 mM) K+‐induced release of AVP from isolated neurohypophysial terminals of EtOH‐naive rats was reduced by 77.7 ± 1.4%, whereas in the chronic EtOH group, release was reduced by only 9.4 ± 8.7%. Similar tolerance was evident during acute challenge with 75 mM EtOH, as well as for release of OT from isolated terminals. Animals treated with an intraperitoneal injection of EtOH and sacrificed 90 min postinjection did not exhibit the reduced EtOH inhibition of release from dissociated terminals during a 75 mM EtOH acute challenge.

Conclusions:The altered component responsible for the tolerance to inhibition of release resides in the isolated terminal, because tolerance measured in vitro from intact neurohypophyses was similar to that seen in isolated terminals. The failure of EtOH‐injected animals to exhibit reduced inhibition of release in response to an acute EtOH challenge indicates that short‐term elevated blood alcohol level does not induce this tolerance. The finding of tolerance to EtOH‐induced inhibition of release from the intact neurohypophysis and isolated terminals provides a physiological preparation in which to examine the molecular targets of acute drug action modified after chronic exposure to the drug.
Effects of Fetal Ethanol Exposure on Pituitary‐Adrenal Sensitivity to Secretagogues
Authors: Osborn J. A. , Yu C , Stelzl G. E. , Weinberg J.
Published: May 2006

Background: Rodents prenatally exposed to ethanol demonstrate hormonal hyper‐responsiveness to stressors in adulthood. The present study examined the hypothesis that an increased sensitivity of the adrenal to ACTH and/or the pituitary to corticotropin releasing hormone (CRH) after dexamethasone suppression, may play a role in the hormonal hyper‐responsiveness seen in fetal ethanol‐exposed rats.

Methods: Sprague‐Dawley males and females from prenatal ethanol‐exposed (E), pair‐fed (PF), and ad libitum‐fed control (C) groups were tested in adulthood (90‐120 days). Testing was done in a series of two experiments carried out during the trough of the corticosterone rhythm, the time of greatest sensitivity to feedback inhibition. Twenty‐four to 48 hr before testing, jugular cannulae were implanted for hormone infusion and blood sample collection. In both experiments, animals were injected intraperitoneally with dexamethasone‐21‐phosphate (DEX) (15 μg/100 g body weight for males or 30 μg/100 g body weight for females) 3 hr before testing to suppress endogenous hypothalamic‐pituitary‐adrenal (HPA) activity. Animals were given a bolus infusion of ACTH (0‐0.10 mg/rat) and blood samples (0.2 cc) were drawn at 60‐min intervals over 240 min for determination of plasma corticosterone (CORT) levels (Experiment 1), or were given a bolus infusion of CRH (0‐20 μg/kg body wt) and samples drawn at 0, 5, 15, and 30 min for determination of plasma ACTH and CORT levels (Experiment 2).

Results: As expected, sex differences in adrenal response to ACTH and pituitary response to CRH were observed; females had higher CORT and ACTH levels than males at all concentrations of ACTH and CRH. In addition, dose‐response relationships between exogenously administered ACTH or CRH and plasma CORT were demonstrated; increasing concentrations of secretagogues resulted in higher and/or more prolonged CORT responses in both males and females. There were no significant differences among E, PF, and C males or females in adrenal sensitivity to ACTH. However, prenatal ethanol exposure altered pituitary sensitivity to CRH in both males and females. E and PF mmales demonstrated increased plasma ACTH but not CORT compared with C males, wwhereas E females demonstrated increased plasma ACTH and CORT levels compared with PF and C females after CRH infusion.

Conclusions: Together these data suggest that (1) E animals do not show increased adrenal sensitivity to ACTH compared with controls; (2) the insult of prenatal ethanol exposure may result in altered pituitary sensitivity to CRH after DEX suppression; and (3) there may be a sex‐specific difference in sensitivity of the mechanism(s) underlying HPA hyper‐responsiveness.
Place Conditioning: Age‐Related Changes in the Rewarding and Aversive Effects of Alcohol
Authors: Philpot R. M. , Badanich K. A. , Kirstein C. L.
Published: May 2006

Background: Alcohol abuse levels are very high in adolescents, creating a significant societal issue. It has been shown that people who begin alcohol use as adolescents are more likely to become addicts than people who initiate alcohol use as adults. It is important to note that the development of addiction in humans is more rapid with initiation in adolescence than in adulthood.

Methods: To determine changes in the reinforcing efficacy of alcohol as a function of adolescent development, we used a place‐conditioning paradigm. In this study, we assessed the ability of ethanol to support a conditioned place preference (CPP) or aversion. Animals [postnatal days (PND) 25, 35, 45, and 60] were tested for alcohol‐induced conditioning in response to a range of ethanol doses (0.2, 0.5, 1.0, and 2.0 g/kg intraperitoneally) or saline.

Results: In general, there was a trend for alcohol to produce an aversion to the ethanol‐paired compartment at higher doses. These patterns differed significantly as a function of age. Younger animals (PND 25) exhibited a CPP to a low dose and an aversion at high doses. Late‐adolescent (PND 45) animals exhibited a CPP at two moderate doses but a conditioned place aversion at the highest dose. PND 35 and 60 animals did not exhibit a CPP at any examined dose, and PND 60 animals exhibited a progressive aversion with increasing dose.

Conclusions: The data show that the developmental processes of adolescence influence general responsiveness to alcohol. Specifically, late‐adolescent animals (PND 45) seem to prefer doses of alcohol that are either not reinforcing (0.5 g/kg) or are aversive (1.0 g/kg) at other ages. These processes need to be examined thoroughly to understand the development of addiction in adolescence. This is especially important given that alcohol abuse in adolescence may interfere with the usual pattern of brain development as it relates to alcohol reinforcement.
The Role of Neurotrophic Factors, Apoptosis‐Related Proteins, and Endogenous Antioxidants in the Differential Temporal Vulnerability of Neonatal Cerebellum to Ethanol
Authors: Heaton Marieta Barrow , Moore D. Blaine , Paiva Michael , Madorsky Irina , Mayer Joanne , Shaw Gerry
Published: May 2006

Background: Ethanol produces abnormalities in the developing nervous system, with certain regions being vulnerable during well‐defined periods. Neonatal rodent cerebellum is particularly susceptible to ethanol during the early postnatal period [on postnatal days 4‐5 (P4‐5)], while this region is resistant to ethanol at a slightly later time (P7‐9). We assessed basal levels of several substances which may be involved in differential temporal ethanol vulnerability in neonatal cerebellum, and analyzed alterations in these substances after early ethanol exposure.

Methods: Assessments were made of neurotrophic factors nerve growth factor, brain‐derived neurotrophic factor, neurotrophin‐3, and neurotrophin‐4; apoptosis‐related proteins Bcl‐2, Bcl‐xl, Bax, Bcl‐xs, Bad, phosphorylated‐Bad, phosphorylated‐Akt, and phosphorylated‐c‐Jun N‐terminal kinase; and the antioxidants superoxide dismutase, glutathione reductase, and catalase. These analyses quantified basal levels (in controls), and sequential changes following acute ethanol exposure at the vulnerable and resistant cerebellar periods (P4, P7).

Results: Comparisons of basal levels of the molecules assessed between P4 and P7 revealed higher levels of total proapoptotic Bad at p4, higher levels of the protective pAkt kinase at P7, and lower levels of proapoptotic pJNK at P7. Other basal levels did not differ. While ethanol‐mediated alterations were found at both ages favoring both apoptosis and survival, the apoptosis‐promoting changes produced on P4 exceeded those on P7, and most occurred within the first 2 hr after exposure, a critical survival/death period. The number of alterations favoring survival were similar at the two ages, but at P7 most occurred within the first 2 hr after exposure, possibly acting in a protective manner.

Conclusions: Differential temporal vulnerability to ethanol in the neonatal cerebellum appears to be paralleled by cellular alterations in neurotrophic factors, apoptosis‐regulatory proteins, and/or antioxidant activities which generally favor apoptosis at the most sensitive age and survival at the resistant age.
Chronic Prenatal Ethanol Exposure Alters Ionotropic Glutamate Receptor Subunit Protein Levels in the Adult Guinea Pig Cerebral Cortex
Authors: Dettmer Todd S. , Barnes Alicia , Iqbal Umar , Bailey Craig D. C. , Reynolds James N. , Brien James F. , Valenzuela C. Fernando
Published: May 2006

Background: The superfamily of glutamate‐gated ion channels mediates fast excitatory synaptic transmission in the central nervous system and is composed of the NMDA, AMPA, and kainate receptors. Binding studies have shown that chronic prenatal and/or neonatal ethanol exposure produces persistent effects on the numbers of some of these channels. However, whether or not this chronic ethanol exposure produces long‐lasting effects on the expression of specific ionotropic receptor subunits remains an open question.

Methods: Timed pregnant Dunkin‐Hartley strain guinea pigs received oral administration of one of the following regimens between gestational days 2 and 67: (1) 4 g of ethanol per kilogram of maternal body weight per day with ad libitum access to pellet food and water (ethanol group), (2) isocaloric sucrose‐ and pair‐feeding with ad libitum access to water (sucrose group), or (3) isovolumetric water with ad libitum access to food and water (water group). The maternal blood ethanol concentration produced by the ethanol regimen was 71 ± 12 mM. Adult offspring were killed on postnatal day 61, and cerebral cortical tissue was analyzed for ionotropic glutamate receptor subunit expression by Western immunoblotting.

Results: There was a statistically significant decrease in NR2B subunit protein expression and an increase in GluR2/3 subunit protein expression in the ethanol group. Expression of NR1, NR2A, NR2C, GluR1, GluR6/7, and KA2 subunit proteins was not affected.

Conclusions: These results demonstrate that chronic prenatal ethanol exposure produces long‐lasting effects on the subunit composition of NMDA and AMPA receptors in the cerebral cortex of the adult guinea pig.
Brain fMRI Activation Associated with Self‐Paced Finger Tapping in Chronic Alcohol‐Dependent Patients
Authors: Parks Mitchell H. , Morgan Victoria L. , Pickens David R. , Price Ronald R. , Dietrich Mary S. , Nickel Mark K. , Martin Peter R.
Published: May 2006

Background: Fine and gross motor dysfunction in chronic alcoholic patients is prevalent, but not extensively studied. Brain autopsy studies of brain regions involved in motor movements indicate cerebellum and frontal lobes are particularly sensitive to alcohol‐induced damage, in contrast to motor cortex.

Methods: Using functional magnetic resonance imaging (fMRI), we compared the pattern of activation of the cerebral cortex and cerebellum during repetitive, self‐paced dominant (DH) and nondominant (NDH) index finger tapping in eight uncomplicated alcohol‐dependent patients after approximately 2 weeks of abstinence and in nine normal controls.

Results: Whereas alcoholic patients tapped significantly more slowly than normal controls, a greater percentage of pixels were activated in the ipsilateral cortex during DH tapping. Furthermore, alcoholics tapped significantly less efficiently (tapping rate divided by percent pixels activated [weighted by pixel intensity] in a given region of interest [ROI]) than normal controls in every ROI examined while using DH, but only in ipsilateral hemi‐cerebellum using NDH. Finally, the alcohol‐dependent patients did not demonstrate the greater mean pixel activation, percentage activated pixels, and lesser activation efficiency in the ipsilateral cortex during NDH compared to DH tapping that was observed in the normal control group.

Conclusions: These findings are compatible with motor inefficiency and compensatory alterations of cortical‐cerebellar circuits. Further studies are needed to determine whether these deficits recover with prolonged abstinence and how they relate to cognitive inefficiency throughout the clinical course of alcoholism.
Does Price Matter? The Effect of Decreased Price on Spirits Consumption in Switzerland
Authors: Kuo Meichun , Heeb Jean‐Luc , Gmel Gerhard , Rehm Jürgen
Published: May 2006

Background: On July 1st, 1999, the spirits market in Switzerland was reformed based on the World Trade Organization (WTO) agreement. The tax reform, in addition to increased competition, has resulted in a 30–50% decrease in price for foreign spirits (liquor). The purpose of the present study is to examine whether decreased prices due to the tax reform and the liberalized spirits market in Switzerland have had an effect on spirits consumption, and whether the effect differs by demographic and other correlates.

Methods: The present study uses data from a longitudinal study on changes in alcohol consumption in Switzerland's resident population. The baseline survey was conducted 3 months before the tax reform and the follow‐up was conducted 28 months after the tax reform. A randomly selected sample of 4007 residents aged 15 years or older participated in the baseline survey and 73% in the follow‐up survey. The data were obtained by computer‐assisted telephone interview, including detailed questions on alcohol consumption, drinking habits, problem drinking, purchase of spirits and socio‐demographic characteristics.

Results: Consumption of spirits increased after the price of spirits decreased. The increase in spirits consumption was consistent across subgroups, with the exception of the group aged 60 or older. Moreover, the increase in spirits consumption persisted even after adjustment for significant correlates of spirits consumption. Apart from age, there was no evidence that the increase in spirits consumption differed between subgroups as defined by sex, region, working status, education, smoking, drinking frequency, or average number of drinks.

Conclusions: The findings demonstrate that younger people are more affected by price than older persons. This study demonstrated that price should be considered an effective policy to reduce alcohol misuse and alcohol‐related problems, especially among the younger population.
Hepatitis C and Alcohol: Fundamental and Translational Research Directions
Authors: Morgan Timothy R. , Brenner David , Everhart James , French Samuel W. , Fried Michael W. , Gretch David R. , Koziel Margaret James , McClain Craig J. , Peters Marion G. , Weinman Steven A. , Lucas Diane L.
Published: May 2006

Abstract: Infection with hepatitis C and the alcohol abuse that frequently accompanies it, impose major worldwide healthcare burdens. The scientific knowledge base that would inform and direct the development of more effective treatment and intervention strategies for these linked pandemics is inadequate. Therefore, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) organized a workshop in which a multidisciplinary group of experts was asked to review the state‐of‐the‐science specific to alcohol in the context of hepatitis C infection. The panel was charged with identifying newly emerging areas likely to lead to advances in fundamental research and to identify those with the greatest potential for accelerating the development of more effective treatment options. The workshop panel made recommendations for research in four major categories: clinical studies of alcohol and HCV; virology and immunology; liver fibrosis and mechanisms of liver injury; and the development of model systems. This article summarizes the panel's deliberations and their recommendations for future research on alcohol and hepatitis C.
Alcohol Intoxication Induces Greater Reductions in Brain Metabolism in Male Than in Female Subjects
Authors: Wang Gene‐Jack , Volkow Nora D. , Fowler Joanna S. , Franceschi Dinko , Wong Christopher T. , Pappas Naomi R. , Netusil Noelwah , Zhu Wei , Felder Christoph , Ma Yeming
Published: May 2006

Background: The mechanisms underlying the gender differences in alcohol drinking behavior and alcohol's effects are poorly understood and may reflect gender differences in brain neurochemistry. Alcohol decreases glucose metabolism in the human brain in a pattern that is consistent with its facilitation of GABAergic neurotransmission. We compared the regional changes in brain glucose metabolism during alcohol intoxication between female and male subjects.

Methods: Ten female and 10 male healthy controls were scanned with positron emission tomography and 2‐deoxy‐2[18F]fluoro‐d‐glucose twice: 40 min after placebo (diet soda) or alcohol (0.75 g/kg mixed with diet soda).

Results: Alcohol significantly and consistently decreased whole‐brain metabolism. The magnitude of these changes was significantly larger in male (−25 ± 6%) than in female (−14 ± 11%;p < 0.005) subjects. Half of the female subjects had reductions in metabolism during intoxication that were significantly lower than those in male subjects. This blunted response in the female subjects was not due to differences in alcohol concentration in plasma, because these did not differ between the genders. In contrast, the self‐reports for the perception of intoxication were significantly greater in female than in male subjects. The cognitive deterioration during alcohol intoxication, although not significant, tended to be worse in female subjects.

Conclusions: This study shows a markedly blunted sensitivity to the effects of acute alcohol on brain glucose metabolism in female subjects that may reflect gender differences in alcohol's modulation of GABAergic neurotransmission. The greater behavioral effects of alcohol in female subjects despite the blunted metabolic responses could reflect other effects of alcohol, for which the regional metabolic signal may be hidden within the large decrements in metabolism that occur during alcohol intoxication.
Ethanol and Estradiol Modulate Alternative Splicing of Dopamine D2 Receptor Messenger RNA and Abolish the Inhibitory Action of Bromocriptine on Prolactin Release From the Pituitary Gland
Authors: Oomizu Souichi , Boyadjieva Nadka , Sarkar Dipak K.
Published: May 2006

Background: Several reports show evidence for the existence of high levels of prolactin (PRL) in alcoholic men and women. Previously we have shown that ethanol increases PRL release both in vivo and in vitro. How ethanol increases PRL release is not well understood.

Methods: In this study, we determined the effects of ethanol in the presence and absence of estradiol‐17β on PRL messenger RNA (mRNA) levels, dopamine D2 receptor mRNA splicing, and the PRL‐inhibitory response of a dopaminergic agent, bromocriptine, in the pituitary of Fischer‐344 rats and in primary cultures of anterior pituitary cells. Real‐time reverse transcriptase‐polymerase chain reaction was used for mRNA detection, and radioimmunoassay was used for hormone detection.

Results: Estradiol and ethanol alone increased PRL mRNA expression in the pituitary gland. Ethanol also potentiated estradiol action on PRL mRNA expression in the pituitary. Determination of the D2 receptor splicing, by determining the changes in the percentage of D2 receptor mRNA expressed as its long form (D2L) and as its short form (D2S), revealed that both ethanol and estradiol altered D2 receptor splicing. Ethanol and estradiol, alone and together, increased the percentage of the D2L receptor but decreased the D2S receptor percentage. Similarly, ethanol and estradiol alone and in combination increased D2L, but decreased the D2S receptor percentage in primary cultures of pituitary cells. Evaluation of bromocriptine's inhibition of PRL release in primary cultures of pituitary cells indicated that ethanol reduced the ability of this D2 receptor agonist to inhibit PRL release.

Conclusions: These results confirm estradiol's inhibition of D2 function and provide novel evidence that ethanol, like estradiol, reduces dopamine's ability to inhibit PRL release by modifying alternative splicing of the dopamine D2 receptor in the pituitary.
Interaction Between Alcohol and Nitric Oxide on ACTH Release in the Rat
Authors: Seo Dong Ook , Rivier Catherine
Published: May 2006

Background: This work was designed to determine whether alcohol increased nitric oxide (NO) levels within the hypothalamic‐pituitary (HP) axis, whether endogenous NO participated in the known ability of alcohol to release ACTH and, conversely, whether prior alcohol treatment altered the ACTH response to NO.

Methods: In a first group of experiments, intact adult male rats were injected with the vehicle or alcohol intragastrically (4.5 g/kg). The effect of alcohol on NO was studied by measuring nitrite + nitrate levels, as well as NOS activity, as indexes of formation of this gas. The role of endogenous NO then was studied by blocking the activity of NO synthase, the enzyme responsible for formation of this gas, and determining whether this treatment altered the ACTH response to alcohol. Finally, we investigated the influence of alcohol on the ACTH response to NO. These studies were done in rats exposed to alcohol vapors (4 hr/day for 1–5 days) to avoid the confounding influence of HP axis stimulation by acutely injected alcohol.

Results: The acute intragastric injection of alcohol significantly (p < 0.01) increased NO levels in the paraventricular nucleus of the hypothalamus, the anterior pituitary, and peripheral blood. The ACTH response to acute intragastric alcohol injection was significantly (p < 0.01) decreased by the arginine derivative Nω‐nitro‐L‐arginine‐methylester, which nonspecifically blocks NOS activity, as well as by the specific neuronal NOS antagonist 7‐nitroindazole. A 5 but not 1 or 3 day exposure to intermittent alcohol vapors interfered with the ACTH response to the intracerebroventricular injection of the NO donor 3‐morpholino‐sydnonimine.

Conclusion: Acute alcohol injection increases NO levels in blood and the HP axis, and these responses seem to facilitate the ACTH response to alcohol. Reciprocally, prolonged (5 days) exposure to ethanol vapors blunts the HP axis response to centrally administered NO.
Chronic Ethanol Ingestion Increases Expression of the Angiotensin II Type 2 (AT2) Receptor and Enhances Tumor Necrosis Factor‐α‐ and Angiotensin II‐Induced Cytotoxicity Via AT2 Signaling in Rat Alveolar Epithelial Cells
Authors: Bechara Rabih I. , Brown Lou Ann S. , Eaton Douglas C. , Roman Jesse , Guidot David M.
Published: May 2006

Background: Alcohol abuse increases the risk of acute lung injury in critically ill patients. We have shown that alveolar epithelial cell (AEC) apoptosis in response to inflammatory mediators, including tumor necrosis factor‐α (TNF‐α), parallels endotoxin‐mediated acute lung injury in ethanol‐fed rats. Although angiotensin II mediates TNF‐α‐induced apoptosis of AECs in vitro, its role in ethanol‐mediated susceptibility to AEC apoptosis is unknown.

Methods: Adult male rats were fed the Lieber‐DeCarli diet for 6 weeks. AECs were isolated, and TNF‐α‐ and angiotensin II‐induced cytotoxicity (by terminal transferase‐mediated dUTP nick end labeling staining) was determined with or without the addition of the angiotensin‐converting enzyme inhibitor (lisinopril) or a selective blocker of the angiotensin II type 1 receptor (AT1) or type 2 receptor (AT2). Finally, the relative expression of the AT1 and AT2 receptors in AECs was determined by Western blot analysis.

Results: TNF‐α‐induced cytotoxicity, but not angiotensin II‐induced cytotoxicity, was prevented by lisinopril, indicating that de novo angiotensin II synthesis is required for TNF‐α‐induced apoptosis in these cells. Both TNF‐α‐ and angiotensin II‐induced cytotoxicity in AECs from control‐fed and ethanol‐fed rats were inhibited by the selective AT2 blocker, PD123319, but not by the selective AT1 blocker, losartan. In parallel, ethanol ingestion doubled AT2 expression in AECs (by Western blot) but had no significant effect on AT1 receptor expression.

Conclusions: Chronic ethanol ingestion increases AT2 expression in the alveolar epithelium and enhances TNF‐α‐ and angiotensin II‐induced cytotoxicity, both of which act via AT2. Together, these findings suggest that selective AT2 receptor inhibition could limit the development of acute lung injury in alcoholic patients.
Additive Inhibition of Dendritic Cell Allostimulatory Capacity by Alcohol and Hepatitis C Is Not Restored by DC Maturation and Involves Abnormal IL‐10 and IL‐2 Induction
Authors: Dolganiuc Angela , Kodys Karen , Kopasz Andrea , Marshall Christopher , Mandrekar Pranoti , Szabo Gyongyi
Published: May 2006

Background: Excessive alcohol use results in impaired immunity, and it is associated with increased incidence and progression of chronic hepatitis C virus (HCV) infection. Here we investigated the effects of HCV infection and alcohol on myeloid dendritic cells (DC) that are critical in antiviral immunity.

Methods: Immature and mature DCs were generated from monocytes of chronic HCV infected patients (HCV‐DC) and controls (N‐DC) with IL‐4 plus granulocyte‐macrophage colony stimulating factor (GM‐CSF) in the presence or absence of alcohol (25 mM). DC allostimulatory capacity was tested in mixed lymphocyte reaction (MLR) and cytokine production by ELISA.

Results: Allostimulatory capacity of HCV‐DCs was reduced compared to N‐DCs and it was further inhibited by alcohol treatment (p < 0.01). MLR was also decreased with alcohol‐treated N‐DCs. DC phenotypic markers and apoptosis were comparable between HCV‐DCs and N‐DCs irrespective of alcohol treatment. However, HCV‐DCs and alcohol‐treated N‐DCs exhibited elevated IL‐10 and reduced IL‐12 production. Reduced MLR with HCV‐DCs and its further inhibition by alcohol coexisted with decreasing IL‐2 levels (p < 0.017). DC maturation partially improved but failed to fully restore the reduced allostimulatory function of either alcohol‐treated or alcohol‐naïve HCV‐DCs (p < 0.018).

Conclusions: Alcohol and HCV independently and together inhibit DC allostimulatory capacity, increase IL‐10, reduce IL‐12 and IL‐2 production that cannot be normalized by DC maturation. HCV and alcohol interact to modulate innate and adaptive immune responses via dendritic cells.
On The Quantitative Definition of Risk
Authors: Kaplan Stanley , Garrick B. John
Published: May 2006

A quantitative definition of risk is suggested in terms of the idea of a “set of triplets”. The definition is extended to include uncertainty and completeness, and the use of Bayes' theorem is described in this connection. The definition is used to discuss the notions of “relative risk”, “relativity of risk”, and “acceptability of risk”.
Regulation of Carcinogens
Authors: Crouch Edmund , Wilson Richard
Published: May 2006

We propose a procedure, suitable for regulatory use, for estimating individual and societal risks of carcinogenic materials by using information on interspecies comparisons of carcinogenic potency. The consistent treatment of uncertainties allows evaluation of confidence limits and hence regulatory measures of risk which incorporate safety factors and incentives for better information. Numerical examples are given, together with discussion of the treatment of undetected carcinogens. Applications of the procedure to setting priorities for carcinogenicity testing and to product substitution are mentioned.
A Quantitative Estimate of Leukemia Mortality Associated with Occupational Exposure to Benzene3
Authors: White Mary C. , Infante Peter F. , Chu Kenneth C.
Published: May 2006

In 1980, the U.S. Supreme Court vacated a revised occupational standard for benzene, stating that the Occupational Safety and Health Administration (OSHA) had failed to demonstrate that significant health risks existed under the current standard. This decision has been interpreted by OSHA as requiring the consideration of quantitative risk assessments, whenever possible, in the development of regulations for occupational carcinogens. In light of this decision, the available epidemiologic evidence was used to generate a quantitative risk assessment for benzene. Uncertainties regarding the levels and lengths of benzene exposure for the studied cohorts were incorporated into the analysis. Based on the one‐hit model, the assessment indicates that a working lifetime exposure to benzene at the current permissible exposure level (10 ppm) poses a substantial excess risk of death from leukemia. This report discusses the calculation of the risk estimates, the basis for relying on certain assumptions, and the inherent limitations of using epidemiologic studies to quantify cancer risks.
$s for Lives: Ethical Considerations in the Use of Cost/Benefit Analysis by For‐Profit Firms
Authors: May William W.
Published: May 2006

Cost/benefit analysis is often an imprecise tool because of assumptions that must be made about matters that are difficult to quantify. The problems become especially acute when lives or serious bodily injuries are at stake because of the serious nature of that which is being risked. Furthermore, the literature on cost/benefit analysis focuses on public decision‐making situations and decisions by individuals. This paper examines the distinctiveness of the use of cost/benefit analysis involving putting dollar values on human life by for‐profit firms. The argument developed in the paper is that the lack of participation by the affected party (or government representative) in balancing costs and benefits raises special ethical concerns. A formula that was developed by the Ford Motor Company concerning accidents involving fuel leakage and fire with resultant loss of life and serious burn injuries is used as an example of both the imprecision of the method and the distinctive factors of the decision process that raise special ethical considerations. The paper examines why the for‐profit‐decision is distinct, what the special ethical considerations are, and concludes with a discussion of several alternative procedures to monitor the use of cost/benefit analysis so that it would be an effective business tool while at the same time the individual is provided maximum protection.
Fault Trees vs. Event Trees in Reliability Analysis
Authors: Paté‐Cornell M. Elisabeth
Published: May 2006

Reliability analysis is the study of both the probability and the process of failure of a system. For that purpose, several tools are available, for example, fault trees, event trees, or the GO technique. These tools are often complementary and address different aspects of the questions. Experience shows that there is sometimes confusion between two of these methods: fault trees and event trees. Sometimes identified as equivalent, they, in fact, serve different purposes. Fault trees lay out relationships among events. Event trees lay out sequences of events linked by conditional probabilities. At least in theory, event trees can handle better notions of continuity (logical, temporal, and physical), whereas fault trees are most powerful in identifying and simplifying failure scenarios. Different characteristics of the system in question (e.g., a dam or a nuclear reactor) may guide the choice between fault trees, event trees, or a combination of the two. Some elements of this choice are examined, and observations are made about the relative capabilities of the two methods.
Use of Acute Toxicity to Estimate Carcinogenic Risk
Authors: Zeise Lauren , Wilson Richard , Crouch Edmund
Published: May 2006

Data on the effects of human exposure to carcinogens are limited, so that estimation of the risks of carcinogens must be obtained indirectly. Current risk estimates are generally based on lifetime animal bioassays which are expensive and which take more than two years to complete. We here show how data on acute toxicity can be used to make a preliminary estimate of carcinogenic risk and give an idea of the uncertainty in that risk estimate. The estimates obtained are biased upwards, and so are useful for setting interim standards and determining whether further study is worthwhile. A general scheme which incorporates the use of such estimates is outlined, and it is shown by example how adoption of the procedures suggested could have prevented regulatory hiatus in the past.
Probability of Causation and the Attributable Proportion Risk
Authors: Cox Louis Anthony
Published: May 2006

A uranium miner who smokes develops lung cancer: what is the probability that radiation, rather than tobacco, caused it? This paper briefly explains the principles and limits of probability models for which this question makes sense, and then shows how principles of risk accounting can be applied to obtain a solution to the general problem of attributing risk in the presence of joint, possibly interacting, causes. A procedure for calculating each factor's “share” in a jointly caused risk is proposed, and shown to be a generalization of the “probability of causation” concept. Problems of implementation and interpretation for the proposed attribution procedure are discussed, and illustrative error bounds are derived for a simple decision rule, in which probability of causation or attributable risk share calculations are made using aggregate data as a proxy for unknown individual data.
Binary Event String Analysis: A Compact Numerical Representation of the Event Tree
Authors: Unwin Stephen D.
Published: May 2006

While the event tree is a useful diagrammatic aid to an appreciation of various event sequence possibilities, it is of a nature that suggests no obvious manner in which the associated probability data may be compiled as computer input. Here, we propose a complementary numerical representation of scenario possibilities which incorporates probability data in a succinct fashion. While its mnemonic properties facilitate the logical development of a system's characteristics, its compactness and unambiguity permit its utilization directly as computer input.
Experimental Design of Bioassays for Screening and Low Dose Extrapolation
Authors: Gaylor David W. , Chen James J. , Kodell Ralph L.
Published: May 2006

Relatively high doses of chemicals generally are employed in animal bioassays to detect potential carcinogens with relatively small numbers of animals. The problem investigated here is the development of experimental designs which are effective for high to low dose extrapolation for tumor incidence as well as for screening (detecting) carcinogens. Several experimental designs are compared over a wide range of different dose response curves. Linear extrapolation is used below the experimental data range to establish an upper bound on carcinogenic risk at low doses. The goal is to find experimental designs which minimize the upper bound on low dose risk estimates (i.e., maximize the allowable dose for a given level of risk). The maximum tolerated dose (MTD) is employed for screening purposes. Among the designs investigated, experiments with doses at the MTD, 1/2 MTD, 1/4 MTD, and controls generally provide relatively good data for low dose extrapolation with relatively good power for detecting carcinogens. For this design, equal numbers of animals per dose level perform as well as unequal allocations.
Fire Risk Analysis for Nuclear Power Plants: Methodological Developments and Applications
Authors: Kazarians Mardyros , Siu Nathan O. , Apostolakis George
Published: May 2006

A methodology to quantify the risk from fires in nuclear power plants is described. This methodology combines engineering judgment, statistical evidence, fire phenomenology, and plant system analysis. It can be divided into two major parts: (1) fire scenario identification and quantification, and (2) analysis of the impact on plant safety. This article primarily concentrates on the first part. Statistical analysis of fire occurrence data is used to establish the likelihood of ignition. The temporal behaviors of the two competing phenomena, fire propagation and fire detection and suppression, are studied and their characteristic times are compared. Severity measures are used to further specialize the frequency of the fire scenario. The methodology is applied to a switchgear room of a nuclear power plant.
Synthetic‐Fuel Plants: Potential Tumor Risks to Public Health
Authors: Moskowitz Paul D. , Morris Samuel C. , Fischer Harris , Thode, Jr. Henry C. , Hamilton Leonard D.
Published: May 2006

This article quantifies potential public health risks from tumor‐producing pollutants emitted from two synthetic‐fuel plants (direct liquefaction—Exxon Donor Solvent; and indirect liquefaction—Lurgi Fischer‐Tropsch) located at a representative site in the eastern United States. In these analyses gaseous and aqueous waste streams were characterized; exposures via inhalation, terrestrial and aquatic food chains, and drinking water supplies were modeled. Analysis suggested that emissions of “polycyclic aromatic hydrocarbons,”“aromatic amines,”“neutral N, O, S heterocyclics,”“nitriles,” and “other trace elements” pose the largest quantifiable risks to public health. Data and analysis for these pollutant categories should be refined to more accurately match compound‐specific estimated exposure levels with tumorigenic potency estimates. Before these results are used for regulatory purposes, more detailed analysis for selected pollutant classes are needed, and more sophisticated aquatic exposure models must be developed. Also, differences in geographic scales among the environmental transport models used need to be rectified.
Assessment of Health Risk from Exposure to Contaminated Soil
Authors: Hawley John K.
Published: May 2006

The risk to human health posed by contaminated soil in a residential area depends on the potential extent of exposure to soil and on the toxic properties of the contaminants. A detailed soil exposure analysis is presented for young children, older children, and adults living in a house surrounded by contaminated soil. From this analysis, a lifetime exposure model is derived and used to assess chronic health risks.
Computerized Estimates of Potential Occupational Health Risk Due to Chemical Exposure
Authors: Pedersen David H. , Hornung Richard W.
Published: May 2006

Estimating the potential health risk encountered by workers due to their exposure to various chemicals is enormously complex, since many chemicals be involved and each may have multiple toxic effects. As an aid to this estimation process, a computer program, or model, which computes index numbers expressing the relative health risk of occupational groups due to their potential chemical exposures was developed at the National Institute for Occupational Safety and Health (NIOSH). This model considers an inventory of the chemicals to which specific occupational groups are potentially exposed, the published information regarding the toxic effects of each chemical, and the conditions of occupational exposure. The system then develops indices of potential occupational group health risk by considering weighted combinations of eight distinct health effects. No direct comparison with external occupational risk indices is currently possible, but internal testing of the model reveals no obvious inconsistencies.
Use of Fractals to Estimate Environmental Dilution Factors in River Basins
Authors: Seiler Fritz A.
Published: May 2006

Every source of liquid pollutants lies somewhere on a watershed. Leachwaters derived from water percolating through solid waste deposits and liquid effluents from industry are diluted on their way down the river until they interact with man or particular environmental systems. This environmental dilution of potentially toxic effluents has to be estimated in assessing health and environmental risks. The problem for the risk assessor is to find an appropriate mathematical model. In this paper, the recent mathematical theory of fractal objects is used to demonstrate that, within certain limits, rivers of all lengths and their river basins are self‐similar. Simple general relations exist, therefore, between the length and drainage area of rivers both large and small. These relations and a few additional assumptions are then used to derive an improved set of models for estimating environmental dilution of some pollutants.
Modeling the Detection Rates of Fires in Nuclear Plants: Development and Application of a Methodology for Treating Imprecise Evidence1
Authors: Siu Nathan , Apostolakis George
Published: May 2006

A model is developed for the detection time of fires in nuclear power plants, which differentiates between competing modes of detection and between different initial fire severities. Our state‐of‐knowledge uncertainties in the values of the model parameters are assessed from industry experience using Bayesian methods. Because the available data are sparse, we propose means to interpret imprecise forms of evidence to the develop quantitative information, which can be used in a statistical analysis; the intent is to maximize our use of all available information. Sensitivity analyses are performed to indicate the importance of structural and distributional assumptions made in the study. The methods used to treat imprecise evidence can be applied to a wide variety of problems. The specific equations developed in this analysis are useful in general situations, where the random quantity of interest is the minimum of a set of random variables (e.g., in “competing risks” models). The computational results indicate that the competing modes formulation can lead to distributions different from those obtained via analytically simpler models, which treat each mode independently of the others.
EDB: A Case Study in Communicating Risk
Authors: Sharlin Harold Issadore
Published: May 2006

This is a report on the Environmental Protection Agency's (EPA's) efforts to communicate with the public about the risks of ethylene dibromide (EDB), what the agency said it was doing about these risks and what information the public actually received through television and newspapers. Although special in many ways, the EDB case illustrates the problems that regulatory agencies have when they must take regulatory action and assure the public that the risks in question are being dealt with adequately. It also illustrates issues that the press faces. Above all, it illustrates the barriers to communication presented by the different perspectives of regulatory agencies and individuals and the types of information they each are most interested in.