Improving uncertainty in Widmark equation calculations: Alcohol volume, strength and density.

The Widmark equation is probably the most commonly used calculation for medicolegal purposes. Recently the National Research Council (USA) and the Forensic Science Regulator (UK) have called for the uncertainty of all results to be given with all forensic measurements and calculations. To improve the uncertainty of measurement of results from Widmark calculations we have concentrated on the uncertainties of measurement involved in the calculation of amount of alcohol, that of the volume of alcohol, the concentration of alcohol and the density of alcohol as previous studies have investigated some of the other factors involved. Using experimental studies, the scientific literature and legal statutes, we have determined revised and improved uncertainties of the concentration of ethanol for Widmark calculations for both the USA and UK. Based on the calculations that we have performed we recommend the use of Monte Carlo Simulation for the determination of uncertainty of measurement for Widmark Calculations.

Alcohol, diabetes, and public health in the Americas.

This article describes epidemiological evidence on the association between alcohol use and diabetes, and the implications for clinical management and public health policies in the Americas. Heavy alcohol use is a risk factor for both diabetes and poor treatment adherence, despite evidence that moderate drinking can protect against type 2 diabetes under some circumstances. The burden of disease from diabetes associated with excessive alcohol consumption warrants both clinical and public health measures. On the clinical level, research on early interventions to prevent hazardous drinking shows that new screening, brief intervention, and referral techniques are effective ways to manage hazardous drinking in primary care settings. On the population level, restrictions on alcohol marketing and other alcohol control policies reduce the frequency and intensity of alcohol consumption in at-risk populations. These policy actions are recommended within the context of the World Health Organization's global strategy to reduce the harmful use of alcohol.

Alcohol and older people from a public health perspective.

OBJECTIVES AND METHODS: As part of the European project VINTAGE, a systematic review of scientific literature was undertaken to document the evidence base on the impact of alcohol on the health and well-being of older people, and on effective policies and preventive approaches to face the problem in this steadily increasing segment of the population. RESULTS: 369 references were identified, from which 78 papers were selected. CONCLUSIONS: The review confirms the paucity of data on this topic and the need for more specific research. Although there is scarce evidence, the elderly seems to respond equally well to alcohol policy, screening instruments and brief interventions as do younger adults. According to a lifecycle approach, a future focus on the middle aged is also recommended.

Alcohol, diabetes, and public health in the Americas / Alcohol, diabetes y salud pública en las Américas

This article describes epidemiological evidence on the association between alcohol use and diabetes, and the implications for clinical management and public health policies in the Americas. Heavy alcohol use is a risk factor for both diabetes and poor treatment adherence, despite evidence that moderate drinking can protect against type 2 diabetes under some circumstances. The burden of disease from diabetes associated with excessive alcohol consumption warrants both clinical and public health measures. On the clinical level, research on early interventions to prevent hazardous drinking shows that new screening, brief intervention, and referral techniques are effective ways to manage hazardous drinking in primary care settings. On the population level, restrictions on alcohol marketing and other alcohol control policies reduce the frequency and intensity of alcohol consumption in at-risk populations. These policy actions are recommended within the context of the World Health Organization's global strategy to reduce the harmful use of alcohol

Este artículo describe las pruebas epidemiológicas de la asociación entre el consumo de alcohol y la diabetes, así como sus implicaciones para el manejo clínico y las políticas de salud pública en las Américas. Aunque existe evidencia de que, en determinadas circunstancias, el consumo moderado de alcohol puede proteger contra la diabetes de tipo políticas de control reducen la frecuencia y la intensidad del consumo de alcohol en las poblaciones en riesgo. Estas acciones de política se recomiendan en el contexto de la estrategia mundial de la Organización Mundial de la Salud para reducir el consumo de alcohol nocivo

Alcohol and bariatric surgery: review and suggested recommendations for assessment and management.

BACKGROUND: Established clinical guidelines identify current alcohol abuse and dependence as contraindications for weight loss surgery. However, guidance on how to best assess alcohol use in bariatric patients has not been elucidated. Furthermore, concerns with postoperative alcohol use/abuse and increased sensitivity warrant the development of recommendations on appropriate interventions for patients pursuing weight loss surgery. Our objective was to review the current data on bariatric surgery and substance abuse/addiction, with an emphasis on alcohol use, offer guidance on how to assess the risk of such problems, and provide preliminary recommendations on treating high-risk patients. METHODS: The relevant published data on alcohol use, abuse, and dependence in pre- and postoperative bariatric patients was reviewed. Also, the putative mechanisms of increased alcohol sensitivity after weight loss surgery were examined. RESULTS: Although current alcohol abuse/dependence is less than that in population-base rates, bariatric surgery candidates have a greater history of alcohol use disorders. Physiologic changes after surgery can also change vulnerability to problematic alcohol use, and many patients continue to consume alcohol after surgery. Assessment techniques and strategies to provide informed consent and education on alcohol were included from the Bariatric and Metabolic Institute at the Cleveland Clinic. CONCLUSION: Weight loss surgery candidates might have a greater lifetime risk of alcohol use disorders and greater sensitivity to the intoxicating effects of alcohol after surgery. Adequate screening, assessment, and preoperative preparation could help mitigate this risk. Future research should examine the efficacy of such risk management strategies.

An assessment of potential cancer risk following occupational exposure to ethanol.

Recognition of the carcinogenic properties of ethanol has resulted from comprehensive evidence regarding the effect of consumption of alcohol; indeed, ethanol in alcoholic beverages is now considered a Group 1 carcinogen by the International Agency for Research on Cancer. However, there is little information on the effects of ethanol following exposure via the occupationally relevant routes of inhalation and dermal exposure. This review therefore focuses on these exposure routes, to assess potential carcinogenic risk associated with occupational exposure to ethanol. Inhalatory exposure at the current occupational exposure limit (OEL) for the United Kingdom (1000 ppm ethanol over an 8-h shift) was estimated to be equivalent to ingestion of 10 g ethanol (approximately 1 glass of alcohol) per day. However, in the occupational setting the dose-rate delivery of this amount of ethanol is low, allowing for its rapid and effective elimination, for the majority of individuals. Similarly, while dermal absorption in an occupational setting could potentially add to overall body ethanol burden, additional carcinogenic risk of such exposure is considered negligible. Thus, on balance, there appears little cause to suppose occupational exposure at or below the current OEL associates with any appreciable increase in risk of cancer. However, available occupational exposure data to confirm this view are currently limited. It is also suggested that adoption of a more flexible classification regime, considering risk in the context of hazard and exposure (such as that adopted by the German MAK commission), would represent an improvement over traditional occupational risk assessment practices.

Comparative study of transcatheter renal arterial embolization with and without closed renal circuit: pharmacokinetic and histologic assessment in pigs.

PURPOSE: To assess the degree of renal necrosis and the leakage of absolute ethanol by using two methods: transcatheter renal artery embolization (TAE) and TAE performed with a closed renal circuit (CRC) (TAE/CRC), both performed by using ethanol and iodized oil, in a pig model. MATERIALS AND METHODS: All animal experiments were conducted in accordance with our university guidelines for animal care and experimentation. Fourteen pigs were classified in two groups: standard TAE and TAE/CRC groups. In the TAE/CRC group, the renal artery and vein were occluded with balloon catheters; in the TAE group, only the renal artery was occluded. An emulsion of absolute ethanol (0.5 mL per kilogram of body weight) and iodized oil (emulsion ratio, 4:1) was injected in the renal artery in both groups. In the TAE/CRC group, we aspirated the blood containing the emulsion via the renal vein during arterial infusion. We measured the ethanol concentrations of the systemic circulation. Four days after embolization, the kidneys in both groups were removed and histopathologic examination was performed and results were compared. RESULTS: The mean systemic ethanol concentration was less than 0.1 mg/mL in the TAE/CRC group and 0.28 mg/mL +/- 0.15 (standard deviation) in the TAE group (P < .002). In both groups, about 90% of the kidney was shown histopathologically to have undergone coagulation necrosis (no significant difference). The frequency of venous thrombus formation was significantly lower (P = .009) in the TAE/CRC group. CONCLUSION: TAE/CRC dramatically reduces ethanol leakage to the systemic circulation without a decrease in embolization effect in the normal swine kidney, and it also reduces the likelihood of venous thrombus formation.

Hepatic and renal concentrations of vitamins E and C in lead- and ethanol-exposed rats. An assessment of their involvement in the mechanisms of peroxidative damage.

The study was aimed at investigating vitamin E and vitamin C concentrations in a liver and kidney as well as their involvement in the mechanism of peroxidative action of lead (Pb) and ethanol (EtOH) in these organs in rats receiving 500 mg Pb/l (in drinking water) or/and 5 g EtOH/kg body wt./24h (p.o.) for 12 weeks. The exposure to Pb and EtOH alone and in combination led to a decrease in vitamin E concentration in the liver compared to the control group (by 30%, 26% and 50%, respectively). The decrease in the liver vitamin E concentration in the rats co-exposed to Pb and EtOH was more marked than in those separately treated with these xenobiotics. The treatment with Pb alone and in combination with EtOH led to a decrease in vitamin E concentration in the kidney (by 13% and 21%, respectively). The liver vitamin C concentration decreased as a result of exposure to EtOH, both separately (by 17%) and in combination with Pb (by 11%). The kidney vitamin C concentration increased in the rats exposed to EtOH alone (by 10%), whereas in those treated with Pb, both separately and in combination with EtOH it decreased (by 26% and 6%, respectively). ANOVA/MANOVA analysis revealed that the changes in vitamin E concentration in the liver and kidney at co-exposure to Pb and EtOH resulted from their independent action, whereas those in vitamin C were due to an independent action of these xenobiotics (EtOH in the liver, Pb and EtOH in the kidney) and an interaction between them. There was no correlation between vitamins E and C concentrations in the liver and kidney. The liver concentration of vitamin E and the liver and kidney concentration of vitamin C negatively correlated with malondialdehyde concentration (MDA, lipid peroxidation index) in these organs. Based on the results of the present study and our previous findings in this experimental rat model it can be hypothesized that vitamins E and C are involved in the mechanism of peroxidative action of Pb and EtOH in the liver and kidney, both at separate and combined exposure. The probable protective involvement of vitamins E and C in the damaging action of EtOH and Pb may be related to scavenging of free radicals directly and indirectly generated by these xenobiotics.

Short-term metabolic ethanol tolerance in dogs.

Metabolic ethanol tolerance was studied in a cohort of five dogs with ethanol challenge repeated weekly over a 7-week period. During the 7-week period, the area under the blood alcohol versus time curve (AUC) increased slightly while the rate of ethanol elimination also increased slightly. During the repeated ethanol dosing, ethanol absorption shifted from approximately equal absorption in the stomach and intestine to three-fold more absorption in the intestine than in the stomach. The likely cause of the shift in absorption site was probably a concomitant change in gastric emptying that occurred with repeated dosing. This shift is significant since ethanol absorption in the small intestine has been shown to be over six-fold more rapid than ethanol absorption in the stomach.

Alcohol levels in Chinese lactating mothers after consumption of alcoholic diet during postpartum "doing-the-month" ritual.

This study examined the effects of exposure to ethanol through cultural practices by lactating mothers. Specifically, the pharmacokinetics of alcohol in Chinese lactating mothers was investigated after they consumed chicken soup flavored with sesame oil and rice wine (CSSR), a typically prescribed diet during the postpartum "doing-the-month" period. Experimental findings were employed to estimate the potential ethanol dose to neonates and determine associated health risks. Twenty-three lactating mothers were examined. Informed consent was obtained from each subject. The target alcohol dosage was 0.3g/kg. Milk and blood samples were collected at fixed time intervals from each subject following exposure to CSSR, and alcohol levels were determined. Acute health risks to infants were estimated by comparing the potential infant dosage to an established criterion dose. Blood alcohol level peaked at 20 min after exposure to CSSR and decreased almost linearly thereafter. Alcohol in milk reached a plateau roughly at 20-40 min after exposure to CSSR and then decreased. Alcohol pharmacokinetics among subjects varied widely. The coefficients of variation in subject alcohol concentrations were 16.5-46.2% (mean, 30.0%) for blood and 32.8-57.6% (mean, 44.4%) for milk. Mean maximal alcohol concentration in blood (30.2+/-5.0 mg/dl) was achieved at 23.5+/-7.6 min and in milk (31.6+/-10.3 mg/dl) at 31.7+/-12.7 min. Potential infant doses were 3.0-58.8 mg (mean, 13.4 mg), and the predicted time required for milk alcohol level to return to zero level was 175 min. The acute health risks for infants exposed to alcohol through their mothers' milk under the current exposure scenario are low (hazard index<0.2). Nursing infants at least 3h after ingesting a diet containing alcohol would further reduce potential health risks.

Observer-rated ataxia: rating scales for assessment of genetic differences in ethanol-induced intoxication in mice.

Identification of genetic and physiological mechanisms underlying a drug's or mutation's effects on motor performance could be aided by the existence of a simple observation-based rating scale of ataxia for mice. Rating scales were developed to assess ataxia after ethanol (2.75, 3.0, and 3.25 g/kg) in nine inbred mouse strains. Each scale independently rates a single behavior. Raters, blinded to dose, scored four behaviors (splay of hind legs, wobbling, nose down, and belly drag) at each of four time points after injection. The severities of hind leg splaying and wobbling were quantifiable, whereas nose down and belly dragging were expressed in all-or-none fashion. Interrater reliabilities were substantial (0.75 0 at some time), but all doses were equally effective. Incidence of nose down and belly dragging behaviors increased strain dependently after ethanol, but strains did not differentially respond to dose. Ethanol-induced splaying was modestly, and negatively, genetically correlated with wobbling. Nose down and belly dragging tended to be associated with splaying and wobbling at later times. Four distinct ataxia-related behaviors were sensitive to ethanol. Strains differed in ethanol sensitivity for all measures. Modest strain mean correlations among behaviors indicate that these behaviors are probably under control of largely different genes and that ataxia rating scales should rate separate behaviors on discrete scales.

Incorporation of the genetic control of alcohol dehydrogenase into a physiologically based pharmacokinetic model for ethanol in humans.

The assessment of the variability of human responses to foreign chemicals is an important step in characterizing the public health risks posed by nontherapeutic hazardous chemicals and the risk of encountering adverse reactions with drugs. Of the many sources of interindividual variability in chemical response identified to date, hereditary factors are some of the least understood. Physiologically based pharmacokinetic modeling linked with Monte Carlo sampling has been shown to be a useful tool for the quantification of interindividual variability in chemical disposition and/or response when applied to biological processes that displayed single genetic polymorphisms. The present study has extended this approach by modeling the complex hereditary control of alcohol dehydrogenase, which includes polygenic control and polymorphisms at two allelic sites, and by assessing the functional significance of this hereditary control on ethanol disposition. The physiologically based pharmacokinetic model for ethanol indicated that peak blood ethanol levels and time-to-peak blood ethanol levels were marginally affected by alcohol dehydrogenase genotypes, with simulated subjects possessing the B2 subunit having slightly lower peak blood ethanol levels and shorter times-to-peak blood levels compared to subjects without the B2 subunit. In contrast, the area under the curve (AUC) of the ethanol blood decay curve was very sensitive to alcohol dehydrogenase genotype, with AUCs from any genotype including the ADH1B2 allele considerably smaller than AUCs from any genotype without the ADH1B2 allele. Furthermore, the AUCs in the ADH1C1/C1 genotype were moderately lower than the AUCs from the corresponding ADH1C2/C2 genotype. Moreover, these simulations demonstrated that interindividual variability of ethanol disposition is affected by alcohol dehydrogenase and that the degree of this variability was a function of the ethanol dose.

Monte Carlo simulation of an ethanol pharmacokinetic model.

BACKGROUND: One challenge of using even relatively simple pharmacokinetic models is valuation of model parameters. Unknown model parameter values can be determined by fitting the model to measured data. Goals of the present study were to (1) obtain ethanol pharmacokinetic data from a cohort of dogs, (2) propose a physiologic ethanol pharmacokinetic model, (3) and perform Monte Carlo simulation to determine model parameter values. The rationale for the particular model proposed here was to account for the interrelationship between blood ethanol concentration and gastrointestinal physiology. METHODS: To each of five fasted dogs, 1 g of ethanol/kg body weight was administered as a gavage of 20% w/v ethanol solution. Developed was an ethanol pharmacokinetic model that comprised a gastric emptying mechanism, a body water compartment, ethanol diffusion through the stomach mucosa, gastric alcohol dehydrogenase (GADH) oxidation of ethanol, diffusion through the small intestine epithelia to the villi, a countercurrent exchanger model of the villi, and liver alcohol dehydrogenase oxidation of ethanol. Monte Carlo simulation was used to estimate model parameter values and standard deviations by minimization of the chi function. RESULTS: Fitting the experimental data to the model using Monte Carlo simulation yielded reasonable values for model parameters. The model predicted that the capacity for ethanol absorption in the intestine was 6.79-fold greater than the ethanol absorption capacity in the stomach. The model indicated that 23.8 +/- 8.3% of the ethanol dose was actually absorbed in the stomach, and an insignificant amount of ethanol was metabolized by GADH. CONCLUSIONS: Ethanol metabolism by GADH is insignificant in the present case. The blood ethanol profile was strongly determined by gastric emptying. Differences between experimental data and simulation results largely result from the gastric emptying model selected. Therefore, accuracy of the complete pharmacokinetic model can be improved significantly by improving the gastric emptying model.

Analysis of solvent central nervous system toxicity and ethanol interactions using a human population physiologically based kinetic and dynamic model.

The effect of acute ethanol-mediated inhibition of m-xylene metabolism on central nervous system (CNS) depression in the human worker population was investigated using physiologically based pharmacokinetic (PBPK) models and probabilistic random (Monte Carlo) sampling. PBPK models of inhaled m-xylene and orally ingested ethanol were developed and combined by a competitive enzyme (CYP2E1) inhibition model. Human interindividual variability was modeled by combining estimated statistical distributions of model parameters with the deterministic PBPK models and multiple random or Monte Carlo simulations. A simple threshold pharmacodynamic model was obtained by simulating m-xylene kinetics in human studies where CNS effects were observed and assigning the peak venous blood m-xylene concentration (C(V,max)) as the dose surrogate of toxicity. Probabilistic estimates of an individual experiencing CNS disturbances given exposure to the current UK occupational exposure standard (100 ppm time-weighted average over 8 h), with and without ethanol ingestion, were obtained. The probability of experiencing CNS effects given this scenario increases markedly and nonlinearly with ethanol dose. As CYP2E1-mediated metabolism of other occupationally relevant organic compounds may be inhibited by ethanol, simulation studies of this type should have an increasingly significant role in the chemical toxicity risk assessment.

Reducing high-risk drinking by young Americans south of the border: the impact of a partial ban on sales of alcohol.

OBJECTIVE: Determine the effect of a partial sales ban on cross border drinking in Mexico. METHOD: On weekend evenings, thousands of youths (younger than 21 years) and young adults (21 to 25 years) residing in communities along the U.S. border cross over into Mexico to patronize all-night bars where the drinking age is 18 rather than 21 years and where the price of alcohol is considerably less than in the United States. On January 1, 1999, Juárez, Mexico, across the border from El Paso, Texas, implemented a 2 AM bar closing policy replacing the previous 5 AM closing time. Breath alcohol tests of pedestrians at the Juárez/El Paso border before and after the policy change were compared with a similar sample of pedestrians at the Tijuana, Mexico/San Diego, California border. RESULTS: At the Juárez/El Paso border, the total number of youths with positive BACs returning from Juárez after 3 AM when the bars were closed was reduced 89%, whereas the number returning between midnight and 3 AM remained unchanged. There was no change in either period at the Tijuana/San Diego comparison site. CONCLUSIONS: Early closing of the bars in Juárez reduced the number of youths returning after 3 AM to the United States with positive BACs.

Effects of food on ethanol metabolism.

The goals of the present study were (1) to obtain ethanol pharmacokinetic data from fed dogs, and (2) perform Monte Carlo simulation to determine the effect of food on pharmacokinetic model parameter values. To a cohort of five fed dogs, 1 g ethanol per km body weight was administered as a gavage of 20% w/v ethanol solution. Blood samples taken at 0, 10, 20, 30, 40, 60, 80, 100, 120, 180, 240, and 360 minutes after the dose were mixed with anticoagulant and stored on ice. Blood ethanol concentration was determined via headspace chromatograph. Monte Carlo simulation with an ethanol pharmacokinetic model was used to estimate model parameter values and parameter standard deviations by minimization of the chi-squared function. Results indicate that 50.6 +/- 21.0% of the ethanol dose was absorbed in the stomach, and an insignificant amount of ethanol was metabolized by gastric alcohol dehydrogenase postulated for the model. At 6 hours after the ethanol dose 59.4 +/- 21.0% of the ethanol dose was retained in the dogs' stomachs.

Sensitivity to ethanol-induced motor incoordination in 5-HT(1B) receptor null mutant mice is task-dependent: implications for behavioral assessment of genetically altered mice.

Neuromuscular impairment by ethanol likely involves complex effects on balance, gait, muscle strength, and other features of motor coordination. The present experiments showed that relative sensitivity to ethanol-induced motor impairment in serotonin 1B (5-HT(1B)) null mutant and control mice was task dependent. We found that ethanol-treated null mutant mice made fewer missteps on a balance beam than did ethanol-treated wild-type mice, and confirmed a previous finding of their lesser ethanol sensitivity in the grid test. The genotypes did not differ in ethanol sensitivity as measured by the screen test, static dowel, fixed-speed rotarod, accelerating rotarod, grip strength, or loss of righting reflex tests. These experiments suggest that within a behavioral domain, alternative tests of function are not equivalent, so multiple assessment tools should be used to avoid misinterpretation of gene function.

An assessment of the genetic relationship between alcohol metabolism and alcoholism risk in Australian twins of European ancestry.

The present analyses examined genetic influences on alcohol metabolism and their possible relationship to risk of alcohol dependence. Subjects were 206 Australian twin pairs who participated in an alcohol challenge protocol in 1979-1981, in which they were given a 0.75 g/kg dose of alcohol; blood alcohol concentrations (BACs) measured at five times over a 3-hr period after alcohol ingestion were examined. Structural equation modeling, fitting a combined autoregressive and common factor model, indicated significant heritabilities for both men and women (h2 range = 0.19-0.71), with significant parameter heterogeneity as a function of gender. In 1992-1993, both twins from 159 of the alcohol challenge pairs completed a telephone-administered psychiatric diagnostic interview. Repeated-measures MANOVAs were used to examine whether respondent's or cotwin's DSM-III-R alcohol dependence status, or parental history of alcohol problems, was associated with variation in alcohol metabolism. There was some evidence that individuals at increased genetic risk of alcohol dependence [with either a paternal history of alcohol problems (women) or an MZ male cotwin who reported a history of alcohol dependence by 1992-1993] showed lower initial BACs than other groups. However, this effect was not seen in those who themselves had a history of alcohol dependence by interview follow-up, perhaps because this relationship was already masked by a history of excessive drinking at baseline.

Electrophysiological assessment (The Multiple Sleep Latency Test) of the biphasic effects of ethanol in humans.

The Multiple Sleep Latency Test (MSLT) was used to assess the effects of ethanol at the peak and descending phases of the breath ethanol curve. Ethanol (0.75 g/kg) was administered (at 0900 hr) to 8 healthy, normal-sleeping men, aged 21 to 45 years old after 8 hr of sleep the previous night. MSLTs were conducted and breath ethanol concentrations (BrECs) were measured at 15, 45, 75, 105, 225, and 345 min after drinking was completed. Subjective measures were administered immediately before each sleep latency test. BrECs over the first 75 min (tests 1 to 3) peaked and differed from all subsequent tests (tests 4 to 6) over which BrECs declined. Sleep latency and subjective measures were averaged over tests 1 to 3 and 4 to 6. There was a significant increase in mean sleep latency relative to placebo for tests 1 to 3 and a significant reduction for tests 4 to 6. The subjective measure of stimulation sedation, the Biphasic Alcohol Effects Scale, showed lessened sedation after ethanol versus placebo on tests 1 to 3, compared with tests 4 to 6. This study confirmed the presence of a biphasic ethanol effect using an electrophysiological method (MSLT), showing increased physiological alertness on the peak phase of the BrEC curve and increased sedation on the descending phase. Relative to the effects observed on the MSLT with other low-dose stimulant drugs, the stimulatory effect of ethanol was mild.