Abstract  Abstract Background: This clinical trial evaluated the pharmacokinetics and safety/tolerability of amikacin/fosfomycin solution using a vibrating plate nebulizer, in mechanically ventilated patients with ventilator-associated tracheobronchitis (VAT) or ventilator-associated pneumonia (VAP). Methods: Nine adult patients were consented to receive three escalating doses of a combination of 50 mg/mL amikacin and 20 mg/mL fosfomycin; doses were separated by 24±2 hr. On day 3, patients received two blinded, randomized treatments (amikacin/fosfomycin and volume-matched placebo), separated by 2 hr. All treatments were administered with a single-patient, multitreatment nebulizer (Investigational eFlow(®) Inline Nebulizer System; PARI Pharma GmbH, positioned in the inspiratory limb tubing between the ventilator and the patient. The nebulizer remained in-line until all treatments had been delivered. Concentrations of amikacin and fosfomycin were measured in tracheal aspirate and plasma samples obtained during the 24 hr after each dose. Results: Fifteen minutes after dosing with the 300/120 mg amikacin/fosfomycin combination, tracheal aspirate amikacin concentrations±SD were 12,390±3,986 μg/g, and fosfomycin concentrations were 6,174±2,548 μg/g (n=6). Airway clearance was rapid. Plasma concentrations were subtherapeutic; the highest observed amikacin plasma concentration was 1.4 μg/mL, and the highest observed fosfomycin plasma concentration was 0.8 μg/mL. Administration time was approximately 2 min/mL. No adverse effects on respiratory rate, peak airway pressures, or oxygenation were observed during or following drug or placebo administration. Conclusions: High tracheal aspirate concentrations of amikacin and fosfomycin were achieved in mechanically ventilated patients with VAT or VAP after aerosolized administration with an inline nebulizer system. Airway clearance was rapid. No adverse respiratory effects were noted during or following drug administration.

Abstract  Background: The early biological impact of short-term mechanical ventilation on healthy lungs is unknown. The authors aimed to characterize the immediate tidal volume (V-T)-related changes on lung injury biomarkers in patients with healthy lungs and low risk of pulmonary complications.

Methods: Twenty-eight healthy patients for knee replacement surgery were prospectively randomized to volume-controlled ventilation with V(T)6 (V(T)6) or 10 (V(T)10) ml/kg predicted body weight. General anesthesia and other ventilatory parameters (positive end-expiratory pressure, 5 cm H2O, FIo(2), 0.5, respiratory rate titrated for normocapnia) were managed similarly in the two groups. Exhaled breath condensate and blood samples were collected for nitrite, nitrate, tumor necrosis factor-alpha, interleukins-1 beta, -6, -8, -10, -11, neutrophil elastase, and Clara Cell protein 16 measurements, at the onset of ventilation and 60 min later.

Results: No significant differences in biomarkers were detected between the V-T groups at any time. The coefficient of variation of exhaled breath condensate nitrite and nitrate decreased in the V(T)6 but increased in the V(T)10 group after 60-min ventilation. Sixty-minute ventilation significantly increased plasma neutrophil elastase levels in the V(T)6 (35.2 +/- 30.4 vs. 56.4 +/- 51.7 ng/ml, P = 0.008) and Clara Cell protein 16 levels in the V(T)10 group (16.4 +/- 8.8 vs. 18.7 +/- 9.5 ng/ml, P = 0.015). Exhaled breath condensate nitrite correlated with plateau pressure (r = 0.27, P = 0.042) and plasma neutrophil elastase (r = 0.44, P = 0.001). Plasma Clara Cell protein 16 correlated with compliance (r = 0.34, P = 0.014).

Conclusions: No tidal volume-related changes were observed in the selected lung injury biomarkers of patients with healthy lungs after 60-min ventilation. Plasma neutrophil elastase and plasma Clara Cell protein 16 might indicate atelectrauma and lung distention, respectively.

Abstract  Limited research has examined the association of diet with immigrant status, adjusting for multiple socio-demographic and contextual influences. Among 662 WIC-eligible postpartum women, those who were foreign-born and had lived in the United States for 4 or fewer years consumed 2.5 more fruit and vegetable servings daily than native-born women; this difference diminished with longer US residence. White women consumed 1 serving less than Latinas, and those speaking both English and Spanish at home consumed 1.4 servings more than English-only speakers after adjusting for other covariates.

Abstract  Aim: This study compared the diets of breastfeeding and non-breastfeeding mothers from socioeconomically diverse regions of Melbourne to determine whether breastfeeding is a marker for healthier maternal dietary intakes. Methods: This cross-sectional study obtained information via self-reported questionnaire from 529 first-time Melbourne mothers. Breastfeeding status was determined when the children were 3.9 months. Diet information was obtained using a validated Food Frequency Questionnaire. Maternal diet was assessed by seven indicators: average daily intake of fruit, vegetables, non-core drinks, non-core sweet snacks, non-core savoury snacks, variety of fruit and variety of vegetables eaten in the preceding 12 months. Associations between breastfeeding status and each dietary variable were assessed using linear regression analyses. Socioeconomic position, maternal body mass index and the cluster-based sampling design were controlled for. Results: Of the 529 subjects, 70% were breastfeeding their child. Compared with non-breastfeeding mothers, breastfeeding mothers were found to consume more serves of vegetables (P= 0.001), a greater variety of fruit and vegetables (P= 0.001 and P≤ 0.001 respectively), and sweet snacks were consumed more frequently (P= 0.006). Differences were observed between low and high socioeconomic position mothers for fruit serves (P= 0.003), vegetable serves (P= 0.010) and fruit variety (P= 0.006). These associations persisted after controlling for socioeconomic position and maternal body mass index. Conclusions: The association between infant feeding (breastfeeding) and some aspects of maternal diet provides further evidence suggesting a link between maternal and child diets from a younger age than previously examined.

Abstract  Phthalates are lipophilic and tend to accumulate in adipose tissue, an important regulator of energy balance and glucose homeostasis. The study aimed to determine whether cellular phthalate accumulation influenced fat cell energy metabolism. Following a 3-day treatment with adipogenesis-inducing medium and a 2-day treatment with adipogenesis-maintaining medium, 3T3-L1 cells differentiated into adipocytes in the presence of a phthalate at a clinically relevant concentration (30-300 μM) for another 6 days. Two phthalates, di(2-ethylhexyl)phthalate and di-n-butylphthalate, and their metabolites, mono(2-ethylhexyl)phthalate (MEHP) and mono-n-butylphthalate, were used here. The phthalate treatments caused no marked effect on cytotoxicity and adipogenesis. Only the MEHP-treated adipocytes were found having smaller lipid droplets; MEHP accumulated in cells in a dose- and time-dependent manner. The MEHP-treated adipocytes exhibited significant increases in lipolysis and glucose uptake; quantitative real-time polymerase chain reaction (qPCR) analysis revealed correlated changes in expression of marker genes involved in adipogenesis, lipid metabolism, and glucose uptake. Analysis of oxygen consumption rate (a mitochondrial respiration indicator) and extracellular acidification rate (a glycolysis indicator) indicated a higher energy metabolism in the adipocytes. qPCR analysis of critical genes involved in mitochondrial biogenesis and/or energy metabolism showed that expression of peroxisome proliferator-activated receptor γ coactivator-1α, sirtuin 3, and protein kinase A were significantly enhanced in the MEHP-treated adipocytes. In vitro evidence of MEHP impacts on lipolysis, glucose uptake/glycolysis, and mitochondrial respiration/biogenesis demonstrates that MEHP accumulation disturbs energy metabolism of fat cells.

Abstract  OBJECTIVE: Dust control is recommended as one of the cornerstones of controlling childhood lead exposure; however, the effectiveness of dust control has not been demonstrated for children who have low to mild elevations in blood lead (ie, less than 25 micrograms/dL). The objective of this study was to determine whether dust control, as performed by families, had an effect on children's blood lead levels and dust lead levels in children's homes.

DESIGN: Randomized, controlled trial.

SETTING: Community-based trial in Rochester, NY.

PARTICIPANTS: One hundred four children, 12 to 31 months of age at baseline.

INTERVENTION: Families and children were randomized to one of two groups. Families of children in the intervention group received cleaning supplies, information about cleaning areas that are often contaminated with lead, and a cleaning demonstration. Families in the control group received only a brochure about lead poisoning prevention.

OUTCOME MEASURES: Baseline measurements of lead in blood, house dust, soil, water, and paint were taken from both groups. Seven months after enrollment, a second blood lead assay was obtained, and lead levels in household dust were measured. The main outcome measures were change in blood lead levels and dust lead levels by treatment group.

RESULTS: The median blood lead level of children enrolled in the study was 6.7 micrograms/dL (range, 1.7 to 30.6 micrograms/dL). There was no significant difference in the change of children's blood lead levels or dust lead levels by treatment group. The median change in blood lead levels among children in the intervention group was -0.05 micrograms/dL compared with -0.60 micrograms/dL among those in the control group. There also was no significant difference in the change of dust lead by group assignment, although there was a trend toward a significant difference in the percentage of change in dust lead levels on noncarpeted floors, which was greater among houses in the intervention group.

CONCLUSIONS: These data suggest that an intervention that consists only of providing cleaning supplies and a brief description of dust control is not effective at reducing blood lead levels among urban children with low to mild elevations in blood lead levels at a 7-month follow-up.

Abstract  Surveys were conducted in 4 areas in Wales [UK] with differing degrees of environmental Pb. In 2 areas the source of the Pb was traffic and in 1 it was spoil from Pb mining in the past. The 4th area, which served as a control, was a village remote from heavy traffic, industry and Pb mining. Various environmental samples were taken, and children aged 1-3 yr and their mothers were studied. Blood Pb concentrations were raised in the Pb mining area, and within the areas defined by traffic flow the blood Pb concentrations of the mothers showed a gradient. Pica in the children, assessed by a questionnaire, showed no relation with blood Pb, but the amount of Pb removed from the children's hands with wet wipes was an important contributor to blood Pb concentrations.

Abstract  Georgopoulos and Lioy (1994) presented a theoretical framework for exposure analysis, incorporating multiple levels of empirical and mechanistic information while characterizing/reducing uncertainties. The present review summarizes efforts towards implementing that framework, through the development of a mechanistic source-to-dose Modeling ENvironment for TOtal Risks studies (MENTOR), a computational toolbox that provides various modeling and data analysis tools to facilitate assessment of cumulative and aggregate (multipathway) exposures to contaminant mixtures. MENTOR adopts a "Person Oriented Modeling" (POM) approach that can be applied to either specific individuals or to populations/subpopulations of interest; the latter is accomplished by defining samples of "virtual" individuals that statistically reproduce the physiological, demographic, etc., attributes of the populations studied. MENTOR implementations currently incorporate and expand USEPA's SHEDS (Stochastic Human Exposure and Dose Simulation) approach and consider multiple exposure routes (inhalation, food, drinking water intake; non-dietary ingestion; dermal absorption). Typically, simulations involve: (1) characterizing background levels of contaminants by combining model predictions and measurement studies; (2) characterizing multimedia levels and temporal profiles of contaminants in various residential and occupational microenvironments; (3) selecting sample populations that statistically reproduce essential demographics (age, gender, race, occupation, education) of relevant population units (e.g., census tracts); (4) developing activity event sequences for each member of the sample by matching attributes to entries of USEPA's Consolidated Human Activity Database (CHAD); (5) calculating intake rates for the sample population members, reflecting physiological attributes and activities pursued; (6) combining intake rates from multiple routes to assess exposures; (7) estimating target tissue doses with physiologically based dosimetry/toxicokinetic modeling.

Abstract  The International Programme on Chemical Safety (IPCS) Harmonization Project aims to develop consistent principles for risk assessment that are widely accepted around the world. Experts in exposure assessment (the IPCS Harmonization Project Exposure Assessment Working Group) were invited to identify issues that pose barriers to the harmonization of exposure assessment methods and to develop a plan of action. One issue that was identified is the development and application of exposure models in the exposure assessment process. The Working Group therefore designated a subcommittee to develop a state-of-the-science paper on exposure models.

Abstract  Several authors have considered the importance of exposure timing and how this affects the outcomes observed, but no one has systematically compiled preconceptional, prenatal, and postnatal developmental exposures and subsequent outcomes. Efforts were undertaken to examine the information available and to evaluate implications for risk assessment for several areas: a) respiratory and immune systems, b) reproductive system, c) nervous system, d) cardiovascular system, endocrine system, and general growth, and e) cancer. Major conclusions from a workshop on "Critical Windows of Exposure for Children's Health" included a) broad windows of sensitivity can be identified for many systems but detailed information is limited; b) cross-species comparisons of dose to target tissue and better data on the exposure-dose-outcome continuum are needed; c) increased interaction among scientific disciplines can further understanding by using laboratory animal results in designing epidemiological studies and human data to suggest specific laboratory studies on mechanisms and agent-target interactions; and d) thus far, only limited attention has been given to peripubertal/adolescent exposures, adult consequences of developmental exposures, and genome-environment interactions. More specific information on developmental windows will improve risk assessment by identifying the most sensitive window(s) for evaluation of dose-response relationships and exposure, evaluation of biological plausibility of research findings in humans, and comparison of data across species. In public health and risk management, information on critical windows may help identify especially susceptible subgroups for specific interventions. Key words: children's health, developmental disorders, developmental toxicity, environmental health, risk assessment, teratogen, windows of vulnerability.

Abstract  There has been increased emphasis and effort in recent years to expand the scope of human health risk assessments to more specifically include consideration of children’s environmental health (NRC, 1993; EO, 1997; U.S. EPA, 1995, 2006a). It is important to consider children’s risk because children may experience adverse health effects that are different from adults, in terms of both the nature of the effect and the dose-response relationship, due to growth and development, and the concomitant cellular proliferation and differentiation, which continue through puberty (Selevan et al., 2000). Children may also experience different exposures to environmental hazards due to unique, child-specific behaviors, such as breast feeding, crawling, playing outdoors, and consuming oxygen and nutrients at rates needed by a growing organism (U.S. EPA, 2006b).

Abstract  This paper presents a survey and comparative evaluation of methods which have been developed for the determination of uncertainties in accident consequences and probabilities, for use in probabilistic risk assessment. The methods considered are: analytic techniques, Monte Carlo simulation, response surface approaches, differential sensitivity techniques, and evaluation of classical statistical confidence bounds. It is concluded that only the response surface and differential sensitivity approaches are sufficiently general and flexible for use as overall methods of uncertainty analysis in probabilistic risk assessment. The other methods considered, however, are very useful in particular problems.

Abstract  Residents of a western Pennsylvania community have been using a public groundwater supply known to be contaminated with trichloroethylene (TCE) at concentrations as high as 260 micro-g/L. Volatilization studies were conducted in several homes in this community to assess inhalation exposures received while showering. A newly developed indoor air quality model, MAVRIQ, was used to apply our volatilization models to these measurements. Calibration of MAVRIQ showed that air-exchange rates between the shower stalls and bathrooms are higher than often assumed. Consistent with predictions from our laboratory studies, the inhalation exposures from a six-minute shower in these homes were estimated to be about twice that from direct ingestion of one-liter of contaminated water.

Abstract  This paper presents an approach for characterizing the probability of adverse effects occurring in a population exposed to dose rates in excess of the Reference Dose (RfD). The approach uses a linear threshold (hockey stick) model of response and is based on the current system of uncertainty factors used in setting RfDs. The approach requires generally available toxicological estimates such as No-Observed-Adverse-Effect Levels (NOAELs) or Benchmark Doses and doses at which adverse effects are observed in 50% of the test animals (ED50s). In this approach, Monte Carlo analysis is used to characterize the uncertainty in the dose response slope based on the range and magnitude of the key sources of uncertainty in setting protective doses. The method does not require information on the shape of the dose response curve for specific chemicals, but is amenable to the inclusion of such data. The approach is applied to four compounds to produce estimates of response rates for dose rates greater than the RfD.

Abstract  In recent years, many cases of soil pollution have been unearthed in the Netherlands. The ingestion of soil particles due to mouthing behaviour of young children is an important potential pathway of exposure and may constitute a health risk. For an assessment of these health risks, a reliable estimation of the daily inadvertent ingestion of soil particles is necessary. A method to estimate soil ingestion is the use of titanium (Ti), aluminium (Al) and acid insoluble residue (AIR) content of the soil as a tracer. By measuring these tracers in faeces of children and in soil, an estimate can be made of the amount of soil ingested. This method can be used if the following conditions are met: tracer intake by other routes (food) is low and not too variable; tracer absorption from soil in the gastro-intestinal (GI) tract is negligible; tracer concentrations in soil are high and not too variable. A small pilot study was conducted among 18 children visiting a nursery school and 6 hospitalized children without any possibility of soil contact. The results of the pilot study indicate that each tracer is present in faeces in highly variable amounts, but that a combination of these three tracers produces a useful picture of potential soil ingestion. Quantitatively, a difference between the two populations of 55 mg/d, expressed as soil ingestion, was found. Despite the small numbers involved, this difference was statistically significant as the population standard deviations were small. In a number of different soil types, tracer concentrations were found to be almost equal. Further studies are planned to test the validity of the assumptions, and to investigate larger child populations living in different circumstances.

Abstract  The paper critiques a 1988 dissertation by Wong (1) of soil pica amongst Institutionalized children on the Island of Jamaica. The Wong dissertation presents the most extensive data yet of soil pica with respect to both numbers of children (six) displaying soil pica and the duration of study (4 months). Amongst children of normal mental capabilities with an average age of 3.1 years, 5 of 24 (20.8%) displayed soil pica behavior (i.e., > 1 g soil Ingested/day) on at least one occasion. In addition, 10.5% of all observations of these 24 children Involved soil Ingestion of > 1 gm/day. Emphasis is given to the Wong dissertation because It has essentially escaped notice amongst those researching and critiquing In the area of soil Ingestion most likely because its emphasis was directed toward exposure to parasites having a life‐cycle stage in soil and not chemical contaminants.

Abstract  A standardized, reproducible method of surrogate dermal monitoring was devised to supplement knowledge of the potential transfer of pesticide residues from floor surfaces to persons in contact with the floor. This device was a 12 kg. foam-covered rolling cylinder equipped with stationary handles. The device was rolled over a cotton cloth (the actual collection media) placed over carpet to be sampled. This method transfers between 1 and 3 percent of the potential available pesticide material from nylon carpeting to the collection media. Transfer from carpet to cotton cloth correlates highly with transfer to cotton clothing worn by persons exercising on the carpet.

Abstract  A wide variety of surface materials in buildings can release organic compounds. Examples include building materials, furnishings, maintenance materials, clothing, and paper products. These sources contribute substantially to the hundreds of organic compounds that have been measured in indoor air. Their emissions have been directly connected to complaints of odors or hyperreactivity and are presumed to contribute to the problems in many "sick buildings" where the cause of complaints is uncertain. Significant progress has been made in the past decade in developing procedures for measuring emissions from such materials, in controlled experiments where factors affecting emission rates can be determined and quantified. Emissions data are still limited but are being accumulated gradually by research groups in Europe and North America. It is clear from the recent data gathered in research and modeling studies that one of the most effective ways to limit indoor concentrations of organic compounds is to limit the content of volatile compounds in materials that are used in buildings. Limiting the original residual content of such compounds in the materials, or conditioning such materials prior to use in buildings, or (perhaps) conditioning such materials in place before occupancy of a new or renovated building, are most likely to prevent excessive indoor concentrations. If emissions testing and product certification procedures are available and there is sufficient market demand for low-emitting materials caused by indoor air quality concerns, significant reductions of indoor concentrations of vapor-phase organic compounds could be achieved within the next decade.

Abstract  This paper represents the first quantitative attempt to distinguish the amount of outdoor soil ingestion from indoor dust ingestion in a soil pica child. Based on a methodology using a comparison of differential element ratios it is estimated that the predominant proportion of the fecal tracers were from outdoor soil and not indoor dust origin. The methodology employed can be utilized on a broader scale to assess the relative amounts of soil and dust consumed by individuals.

Abstract  Assessments of doses resulting from exposures to airborne gases and particles are based almost exclusively on inhalation rates that are inconsistent with the quantities of oxygen needed to metabolize dietary intakes of fats, carbohydrates, and protein. This inconsistency leads to erroneous estimates of inhalation exposures and can distort the relative importance of inhalation and ingestion-based exposures to environmental contaminants that are present in foods, air, and water. As a means of dealing with this problem, a new methodology for estimating breathing rates is presented that is based on the oxygen uptake associated with energy expenditures and a ventilatory equivalent that relates minute volume to oxygen uptake. Three alternative energy-based approaches for estimating daily inhalation rates are examined: (1) average daily intakes of food energy from dietary surveys, adjusted for under reporting of foods; (2) average daily energy expenditure calculated from ratios of total daily expenditure to basal metabolism; and (3) daily energy expenditures determined from a time-activity survey. Under the first two approaches, inhalation rates for adult females in different age cohorts ranged from 9.7 to 11 m3 d-1, whereas for adult males the range was 13 to 17 m3 d-1. Inhalation rates for adults determined from activity patterns were higher (i.e., 13 to 18 m3 d-1), however, those rates were shown to be quite sensitive to the energy expenditures used to represent light and sedentary activities. In contrast to the above estimates, the ICRP 23 reference values for adult females and males are 21 and 23 m3 d-1 (Snyder et al. 1975). Finally, the paper provides a technique for determining the short-term breathing rates of individuals based on their basal metabolic rate and level of physical activity.