Ethanol and isopropanol in concentrations present in hand sanitizers sharply reduce excystation of Giardia and Entamoeba and eliminate oral infectivity of Giardia cysts in gerbils.

Enteric protozoan parasites, which are spread by the fecal-oral route, are important causes of diarrhea (Giardia duodenalis) and amebic dysentery (Entamoeba histolytica). Cyst walls of Giardia and Entamoeba have a single layer composed of fibrils of ß-1,3-linked GalNAc and ß-1,4-linked GlcNAc (chitin), respectively. The goal here was to determine whether hand sanitizers that contain ethanol or isopropanol as the active microbicide might reduce transmission of these parasites. We found that treatment with these alcohols with or without drying in a rotary evaporator (to model rapid evaporation of sanitizers on hands) kills 85 to 100% of cysts of G. duodenalis and 90 to 100% of cysts of Entamoeba invadens (a nonpathogenic model for E. histolytica), as shown by nuclear labeling with propidium iodide and failure to excyst in vitro. Alcohols with or without drying collapsed the cyst walls of Giardia but did not collapse the cyst walls of Entamoeba. To validate the in vitro results, we showed that treatment with alcohols eliminated oral infection of gerbils by 1,000 G. duodenalis cysts, while a commercial hand sanitizer (Purell) killed E. invadens cysts that were directly applied to the hands. These results suggest that expanded use of alcohol-based hand sanitizers might reduce the transmission of Giardia and Entamoeba.

Determination of sevoflurane and isopropyl alcohol in exhaled breath by thermal desorption gas chromatography-mass spectrometry for exposure assessment of hospital staff.

Volatile anaesthetics and disinfection chemicals pose ubiquitous inhalation and dermal exposure risks in hospital and clinic environments. This work demonstrates specific non-invasive breath biomonitoring methodology for assessing staff exposures to sevoflurane (SEV) anaesthetic, documenting its metabolite hexafluoroisopropanol (HFIP) and measuring exposures to isopropanol (IPA) dermal disinfection fluid. Methods are based on breath sample collection in Nalophan bags, followed by an aliquot transfer to adsorption tube, and subsequent analysis by thermal desorption gas chromatography-mass spectrometry (TD-GC-MS). Ambient levels of IPA were also monitored. These methods could be generalized to other common volatile chemicals found in medical environments. Calibration curves were linear (r(2)=0.999) in the investigated ranges: 0.01-1000 ppbv for SEV, 0.02-1700 ppbv for IPA, and 0.001-0.1 ppbv for HFIP. The instrumental detection limit was 10 pptv for IPA and 5 pptv for SEV, both estimated by extracted ion-TIC chromatograms, whereas the HFIP minimum detectable concentration was 0.5 pptv as estimated in SIM acquisition mode. The methods were applied to hospital staff working in operating rooms and clinics for blood draws. SEV and HFIP were present in all subjects at concentrations in the range of 0.7-18, and 0.002-0.024 ppbv for SEV and HFIP respectively. Correlation between IPA ambient air and breath concentration confirmed the inhalation pathway of exposure (r=0.95, p<0.001) and breath-borne IPA was measured as high as 1500 ppbv. The methodology is easy to implement and valuable for screening exposures to common hospital chemicals. Although the overall exposures documented were generally below levels of health concern in this limited study, outliers were observed that indicate potential for acute exposures.

Isopropanol poisoning.

INTRODUCTION: Isopropanol is a clear, colorless liquid with a fruity odor and a mild bitter taste. Most commonly found domestically as rubbing alcohol, isopropanol is also found in numerous household and commercial products including cleaners, disinfectants, antifreezes, cosmetics, solvents, inks, and pharmaceuticals. AIM: The aim of this review is to critically review the epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, diagnosis, and management of isopropanol poisoning. METHODS: OVID MEDLINE and ISI Web of Science were searched to November 2013 using the words "isopropanol", "isopropyl alcohol", "2-propanol", "propan-2-ol", and "rubbing alcohol" combined with the keywords "poisoning", "poison", "toxicity", "ingestion", "adverse effects", "overdose", or "intoxication". These searches identified 232 citations, which were then screened via their abstract to identify relevant articles referring specifically to the epidemiology, toxicokinetics, mechanisms of toxicity, clinical features, diagnosis, and management of isopropanol poisoning; 102 were relevant. Further information was obtained from book chapters, relevant news reports, and internet resources. These additional searches produced eight non-duplicate relevant citations. EPIDEMIOLOGY: The majority of isopropanol exposures are unintentional and occur in children less than 6 years of age. Although isopropanol poisoning appears to be a reasonably common occurrence, deaths are rare. TOXICOKINETICS: Isopropanol is rapidly absorbed following ingestion with peak plasma concentrations occurring within 30 min. It can also be absorbed following inhalation or dermal exposure. Isopropanol is widely distributed with a volume of distribution of 0.45-0.55 L/kg. Isopropanol is metabolized by alcohol dehydrogenase to acetone, acetol and methylglyoxal, propylene glycol, acetate, and formate with conversion of these metabolites to glucose and other products of intermediary metabolism. The elimination of isopropanol is predominantly renal, though some pulmonary excretion of isopropanol and acetone occurs. In one case 20% of the absorbed dose was eliminated unchanged in urine, with the remainder excreted as acetone and metabolites of acetone. The elimination half-life of isopropanol is between 2.5 and 8.0 h, whereas elimination of acetone is slower with a half-life following isopropanol ingestion of between 7.7 and 27 h. MECHANISMS OF TOXICITY: While the exact mechanism of action of isopropanol has not been fully elucidated, brain stem depression is thought to be the predominant mechanism. While the clinical effects are thought to be mostly due to isopropanol, acetone may also contribute. CLINICAL FEATURES: The major features of severe poisoning are due to CNS and respiratory depression, shock, and circulatory collapse. The most common metabolic effects are an increased osmol (osmolal) gap, ketonemia, and ketonuria. Diagnosis. Poisoning can be diagnosed using the measurement of isopropanol serum concentrations, though these may not be readily available. Diagnosis is therefore more typically made on the basis of the patient's history and clinical presentation. An osmol gap, ketonemia, and/or ketonuria without metabolic acidosis, along with a fruity or sweet odor on the breath and CNS depression support the diagnosis. Management. Supportive care is the mainstay of management with primary emphasis on respiratory and cardiovascular support. Hemodialysis enhances elimination of isopropanol and acetone and should be considered in very severe poisoning. CONCLUSIONS: Severe isopropanol poisoning results in CNS and respiratory depression and circulatory collapse. Treatment primarily consists of symptom-directed supportive care. Although hemodialysis increases the elimination of isopropanol and acetone substantially, it should only be considered in severe life-threatening poisonings. Patients usually make a full recovery provided they receive prompt supportive care.

Separating uncertainty and physiological variability in human PBPK modelling: The example of 2-propanol and its metabolite acetone.

Parameter uncertainty and interindividual variability in the predictions of a generic human physiologically based pharmacokinetic (PBPK) model were separated by means of nested Monte Carlo simulations. Separate information on uncertainty and variability can help decision makers to identify whether they should focus on identification of sensitive individuals rather than on additional research to obtain more accurate estimates for particular parameters. In this study, the concentration of acetone in human blood was simulated during and after 4h of exposure to 2-propanol via air. It was shown that the influence of interindividual variability and uncertainty varies over time, from the uptake phase, via a steady-state phase, into the elimination phase. During the uptake phase, interindividual variability played a significant role in the predicted variation of acetone concentrations in blood, with variability up to a factor of 2-3 (90th/10th percentile ratio). After exposure ceased, the parameter uncertainty increased up to a factor of 100 after 16h, whereas variability remained unchanged. Parameter importance analysis indicated that variability in human physiology had the largest influence on predicted acetone concentrations in blood during exposure. Uncertainty in the metabolic rate of acetone was most important after the exposure had ceased and overruled variability.

Synthesis and pharmacological evaluation of 3-amino-1-(5-indanyloxy)-2-propanol derivatives as potent sodium channel blockers for the treatment of stroke.

In investigating potent sodium (Na(+)) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na(+) channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na(+) channels and a significantly low affinity for dopamine D(2) receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na(+) channels, which suggests that 4b would act as a use-dependent Na(+) channel blocker in sustained depolarization during ischemic stroke.

Short-term immunological effects of non-ethanolic short-chain alcohols.

Short-chain alcohols are embedded into several aspects of modern life. The societal costs emanating from the long history of use and abuse of the prototypical example of these molecules, ethanol, have stimulated considerable interest in its general toxicology. A much more modest picture exists for other short-chain alcohols, notably as regards their immunotoxicity. A large segment of the general population is potentially exposed to two of these alcohols, methanol and isopropanol. Their ubiquitous nature and their eventual use as ethanol surrogates are predictably associated to accidental or deliberate poisoning. This review addresses the immunological consequences of acute exposure to methanol and isopropanol. It first examines the general mechanisms of short-chain alcohol-induced biological dysregulation and then provides a tentative model to explain the molecular events that underlie the immunological dysfunction produced by methanol and isopropanol. The time-related context of serum alcohol concentrations in acute poisoning, as well as the clinical implications of their short-term immunotoxicity, is also discussed.

Dermal and pulmonary absorption of propan-1-ol and propan-2-ol from hand rubs.

BACKGROUND: It has been shown that nontoxic concentrations of ethanol are absorbed after hand hygiene using ethanol-based hand rubs. This study investigated whether absorption of propan-1-ol and propan-2-ol from commercially available hand rubs results in measurable concentrations after use. METHODS: The pulmonary and dermal absorption of propanol during hand rubs was investigated. Rubs contained 70% (w/w) propan-1-ol, 63.14% (w/w) propan-2-ol, or 45% (w/w) propan-2-ol in combination with 30% (w/w) propan-1-ol. RESULTS: Peak median blood levels were 9.15 mg/L for propan-1-ol and 5.3 mg/L for propan-2-ol after hygienic hand rubs and 18.0 mg/L and 10.0 mg/L, respectively, after surgical hand rubs. Under actual surgical conditions, the highest median blood levels were 4.08 mg/L for propan-1-ol and 2.56 mg/L for propan-2-ol. The same procedure performed with prevention of pulmonary exposure through the use of a gas-tight mask resulted in peak median blood levels of 1.16 mg/L of propan-1-ol and 1.74 mg/L of propan-2-ol. CONCLUSION: Only minimal amounts of propanols are absorbed through the use of hand rubs. Based on our experimental data, the risk of chronic systemic toxic effects caused by hand rubs is likely negligible. However, our study did not evaluate the consequences of long-term daily and frequent use of hygienic hand rubs.

Enhanced chlorhexidine skin penetration with eucalyptus oil.

BACKGROUND: Chlorhexidine digluconate (CHG) is a widely used skin antiseptic, however it poorly penetrates the skin, limiting its efficacy against microorganisms residing beneath the surface layers of skin. The aim of the current study was to improve the delivery of chlorhexidine digluconate (CHG) when used as a skin antiseptic. METHOD: Chlorhexidine was applied to the surface of donor skin and its penetration and retention under different conditions was evaluated. Skin penetration studies were performed on full-thickness donor human skin using a Franz diffusion cell system. Skin was exposed to 2% (w/v) CHG in various concentrations of eucalyptus oil (EO) and 70% (v/v) isopropyl alcohol (IPA). The concentration of CHG (µg/mg of skin) was determined to a skin depth of 1500 µm by high performance liquid chromatography (HPLC). RESULTS: The 2% (w/v) CHG penetration into the lower layers of skin was significantly enhanced in the presence of EO. Ten percent (v/v) EO in combination with 2% (w/v) CHG in 70% (v/v) IPA significantly increased the amount of CHG which penetrated into the skin within 2 min. CONCLUSION: The delivery of CHG into the epidermis and dermis can be enhanced by combination with EO, which in turn may improve biocide contact with additional microorganisms present in the skin, thereby enhancing antisepsis.

A lethal ingestion of a household cleaner containing pine oil and isopropanol.

This paper presents the case of a woman with a history of schizophrenia found deceased in her residence after she apparently ingested an unknown quantity of a pine oil-containing product. A strong lemon-pine odor emanated from the body. Autopsy revealed a large volume of oily fluid in the stomach. The lungs were heavy, hemorrhagic, and necrotic. There was no evidence of significant recent injury or pre-existing disease. The toxicological screening and quantitation of 1-alpha-terpineol in postmortem fluids was performed by gas chromatography-mass spectrometry. Isopropanol and its metabolite acetone were determined by means of flame-ionization gas chromatography. Postmortem blood, urine, and stomach content levels of 1-alpha-terpineol were 276 mg/L, 0.5 mg/L, and 4.0 g/total contents, respectively, and isopropanol levels were 730 mg/dL, 20 mg/dL, and 1000 mg/dL, respectively. No acetone could be detected. Her death was attributed to the combined toxicity of isopropanol and pine oil.

Assessment of dermal absorption by thermogravimetric analysis: Development of a diffusion model based on Fick's second law.

Recent work in our laboratory shows that it is possible to reproducibly measure the weight change over time of a piece of porcine skin exposed to a chemical vapor by thermogravimetric analysis (TGA), that is, using a microbalance maintained at constant temperature and humidity. Here, we develop a diffusion model by which the TGA skin weight curve can be interpreted. A TGA-specific analytical solution for Fick's second law of diffusion was derived. The solution contains two chemical-dependent parameters; a diffusion coefficient (D) and a skin/air partition coefficient (P). The resulting function was fitted to weight curves from 83 experiments with 4 chemicals; n-butyl acetate, methanol, 2-propanol, and toluene. In most experiments, a single weight function could not adequately describe the shape of the weight curve, therefore up to five parallel compartments, each with its parameter set Di and Pi, were tested. A two-compartment model was adequate for 58% of the experiments according to the Akaike Information Criterion. Dermal penetration of the chemicals was also measured with Franz diffusion cells. The diffusion coefficients obtained by the two methods agreed well.

Transdermal resorption of an ethanol- and 2-propanol-containing skin disinfectant.

BACKGROUND AND AIMS: Ethanol- or 2-propanol-containing disinfectant agents are widely used in medical practice, particularly in the surgical environment. It was the primary objective of this phase I study to comparatively investigate the transdermal resorption of ethanol and 2-propanol within 1 h after dermal application of the two agents as single preparations and a commercial product containing both alcohols in combination, respectively. The secondary objective was to examine whether a mutual influence of the two alcohols in combination exists. MATERIALS AND METHODS: Following the double-blind, randomized, three-times cross-over design for this clinical trial, 20 ml of three different alcohol-containing disinfectants were applied on a 200-cm(2) gauze swab on skin areas, identical in size and location, of 14 healthy volunteers for 10 min to investigate the absorption rate of ethanol and 2-propanol with special focus on the question whether the two alcohols might influence each other's absorption rate when being applied in combination. RESULTS: No clinically relevant enhancement of dermal absorption, with respect to ethanol and 2-propanol, could be observed within 1 h after application, neither when used as single preparations, nor in combination. CONCLUSION: Therefore, the use of ethanol- and 2-propanol-containing disinfectants in the medical environment can be considered as safe.

Poisoning with 1-propanol and 2-propanol.

1-Propanol and 2-propanol are isomers of an alcohol with three carbons. They are colorless liquids with a sweet odor. 1-Propanol is metabolized by alcohol dehydrogenase to propionic acid and presents with metabolic acidosis and elevated anion gap, whereas 2-propanol is metabolized by alcohol dehydrogenase to acetone and presents with rapidly developing (within 3-4 h after exposure) ketosis and ketonuria but without metabolic acidosis. We report a patient who simultaneously ingested a lethal dose of 1-propanol and 2-propanol as a hand disinfectant in hospital. The patient lost consciousness and stopped breathing within half an hour after ingestion. He was intubated and artificially ventilated. Initial laboratory results showed mixed acidosis with elevated anion gap, but ketonuria appeared only 12 h after admission and 6 h following the regaining of consciousness. Therefore, laboratory results in simultaneous poisoning with two isomers of alcohol are not just a sum of laboratory results obtained in isolated poisoning with each isomer because they influence each other's metabolism: 1-propanol retards the metabolism of 2-propanol to acetone. In conclusion, 1-propanol and 2-propanol poisoning presents early with mixed acidosis and elevated anion gap and only later with ketonuria.

Can alcohol-based hand-rub solutions cause you to lose your driver's license? Comparative cutaneous absorption of various alcohols.

We assessed cutaneous ethanol (ETOH) and isopropanol (ISOP) absorption after intensive (30 times per h) use of alcohol-based hand-rub solutions by healthcare workers (HCWs). ETOH was detectable in the breath of 6/20 HCWs (0.001 to 0.0025%) at 1 to 2 min postexposure and in the serum of 2/20 HCWs at 5 to 7 min postexposure. Serum ISOP levels were unrecordable at all time points.

A new technique to assess dermal absorption of volatile chemicals in vitro by thermal gravimetric analysis.

Potential health hazards of dermal exposure, variability in reported dermal absorption rates and potential losses from the skin by evaporation indicate a need for a simple, inexpensive and standardized procedure to measure dermal absorption and desorption of chemical substances. The aim of this study was to explore the possibility to measure dermal absorption and desorption of volatile chemicals using a new gravimetric technique, namely thermal gravimetric analysis (TGA), and trypsinated stratum corneum from pig. Changes in skin weight were readily detected before, during and after exposure to vapours of water, 2-propanol, methanol and toluene. The shape and height of the weight curves differed between the four chemicals, reflecting differences in diffusivity and partial pressure and skin:air partitioning, respectively. As the skin weight is highly sensitive to the partial pressure of volatile chemicals, including water, this technique requires carefully controlled conditions with respect to air flow, temperature, chemical vapour generation and humidity. This new technique may help in the assessment of dermal uptake of volatile chemicals. Only a small piece of skin is needed and skin integrity is not necessary, facilitating the use of human samples. The high resolution weight-time curves obtained may also help to elucidate the characteristics of absorption, desorption and diffusion of chemicals in skin.

Transdermal drug delivery systems of a beta blocker: design, in vitro, and in vivo characterization.

The matrix type transdermal drug delivery systems (TDDS) of metoprolol were prepared by film casting technique using a fabricated stainless steel film casting apparatus and characterized in vitro by drug release, skin permeation, skin irritation, and in vivo pharmacodynamic and stability studies. Four formulations were prepared that differed in the ratio of matrix forming polymers. Formulations M-1, M-2, M-3, and M-4 were composed of Eudragit RL-100 and polyvinyl acetate with the following ratios: 2:8, 4:6, 6:4, and 8:2, respectively. All the four formulations carried 10% (w/w) of metoprolol tartrate, 5% (w/w) of dibutylphthalate, and 5% (w/w) of (+/-) menthol in dichloromethane:isopropyl alcohol (80:20 v/v). Cumulative amount of drug released in 48 hr from the four formulations was 79.16%, 81.17%, 85.98%, and 95.04%. The corresponding values for cumulative amount of drug permeated for the said formulations were 59.72%, 66.52%, 77.36%, and 90.38%. On the basis of in vitro drug release and skin permeation performance, formulation M-4 was found to be better than the other three formulations and it was selected as the optimized formulation. The formulation appeared to be stable when stored at 40 degrees C and 75% RH with negligible degradation of the drug. The TDDS was found to be free of any skin irritation as suggested by skin irritation score of 1.16 (<2.00) under Draize score test. Statistically significant reduction in mean blood pressure (p < .01) was achieved in methyl prednisolone-induced hypertensive rats on treatment with the TDDS.

Evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry.

The physiological and biochemical processes that determine the tissue concentration time courses (pharmacokinetics) of xenobiotics vary, in some cases significantly, with age and gender. While it is known that age- and gender-specific differences have the potential to affect tissue concentrations and, hence, individual risk, the relative importance of the contributing processes and the quantitative impact of these differences for various life stages are not well characterized. The objective of this study was to identify age- and gender-specific differences in physiological and biochemical processes that affect tissue dosimetry and integrate them into a predictive physiologically based pharmacokinetic (PBPK) life-stage model. The life-stage model was exercised for several environmental chemicals with a variety of physicochemical, biochemical, and mode-of-action properties. In general, predictions of average pharmacokinetic dose metrics for a chemical across life stages were within a factor of two, although larger transient variations were predicted, particularly during the neonatal period. The most important age-dependent pharmacokinetic factor appears to be the potential for decreased clearance of a toxic chemical in the perinatal period due to the immaturity of many metabolic enzyme systems, although this same factor may also reduce the production of a reactive metabolite. Given the potential for age-dependent pharmacodynamic factors during early life, there may be chemicals and health outcomes for which decreased clearance over a relatively brief period could have a substantial impact on risk.

Dermal absorption of isopropyl alcohol from a commercial hand rub: implications for its use in hand decontamination.

Isopropyl alcohol-containing hand rubs are widely used in healthcare for hand decontamination. Ten healthy adult volunteers applied a commercially available isopropyl alcohol-containing hand rub to their hands every 10 min over a 4 h period. Blood isopropyl alcohol levels were measured at the beginning and end of the study. At the end of the study, measurable blood isopropyl alcohol levels (range 0.5-1.8 mg/l) were recorded in nine subjects. We confirmed that isopropyl alcohol could be absorbed through the intact skin of adult humans. The social and medical implications are discussed.

Framework for evaluation of physiologically-based pharmacokinetic models for use in safety or risk assessment.

Proposed applications of increasingly sophisticated biologically-based computational models, such as physiologically-based pharmacokinetic models, raise the issue of how to evaluate whether the models are adequate for proposed uses, including safety or risk assessment. A six-step process for model evaluation is described. It relies on multidisciplinary expertise to address the biological, toxicological, mathematical, statistical, and risk assessment aspects of the modeling and its application. The first step is to have a clear definition of the purpose(s) of the model in the particular assessment; this provides critical perspectives on all subsequent steps. The second step is to evaluate the biological characterization described by the model structure based on the intended uses of the model and available information on the compound being modeled or related compounds. The next two steps review the mathematical equations used to describe the biology and their implementation in an appropriate computer program. At this point, the values selected for the model parameters (i.e., model calibration) must be evaluated. Thus, the fifth step is a combination of evaluating the model parameterization and calibration against data and evaluating the uncertainty in the model outputs. The final step is to evaluate specialized analyses that were done using the model, such as modeling of population distributions of parameters leading to population estimates for model outcomes or inclusion of early pharmacodynamic events. The process also helps to define the kinds of documentation that would be needed for a model to facilitate its evaluation and implementation.