Exposure-response Studies Research Articles

Household air pollution and respiratory health in Africa: persistent risk and unchanged health burdens.

Despite evidence emerging from the Global Burden of Disease studies that biomass use and household air pollution are declining globally, with important positive health impacts for households in low- and middle-income countries, these trends have not been equally documented in African countries. This review describes the state of household air pollution exposure and its relationship with respiratory disease in Africa. African studies on this topic are limited, and generally focus on respiratory infections. Most evidence emerge from models based on the Global Burden of Disease data, and from limited individual epidemiological studies across the continent. More than 80% of the African population is exposed to household air pollution. Women and children continue to bear the substantial burden of exposure. Evidence from limited exposure-response studies strongly points to household air pollution being the major driver of acute and chronic respiratory diseases on the continent. Respiratory infections, particularly in children, and other chronic respiratory diseases, are strongly attributable to household air pollution. Elimination of such exposures through interventions such as cleaner fuels and preferably, electricity, is critical to improving respiratory health on the continent.

Early infliximab trough levels in paediatric IBD patients predict sustained remission.

Exposure-response studies have shown that higher infliximab concentrations are associated with better outcomes in inflammatory bowel disease. There is little agreement about the optimal time to measure infliximab levels in children. We aimed to evaluate whether trough levels at week 6 or week 14 predict sustained remission. The secondary aim was to define target trough levels at weeks 6 and 14. We used routinely collected electronic healthcare data of 70 anti-tumour necrosis factor naïve children with inflammatory bowel disease treated with a standard infliximab induction- and variable maintenance scheme. Trough levels and blood and faecal markers for disease activity were measured before every infliximab administration. Sustained remission was defined as the absence of symptoms and low inflammatory markers between weeks 26 and 52 after the start of infliximab therapy. Optimal infliximab levels at weeks 6 and 14 were determined using the receiver operating characteristic curve. The median infliximab level at week 6 was not significantly higher in children who achieved sustained remission compared to those who did not (16.9 mg/L versus 12.0 mg/L; p = 0.058) but the median infliximab level at week 14 was significantly higher in those with sustained remission (7.7 mg/L versus 3.8 mg/L; p = 0.006). The area under the receiver operating characteristics curves at weeks 6 and 14 to predict sustained remission was 0.67 (95% CI 0.51-0.83) and 0.75 (95% CI 0.60-0.90), respectively. Target trough levels at weeks 6 and 14 were ⩾13.2 and ⩾6.9 mg/L, respectively. An infliximab measurement at week 14 with a target through level ⩾6.9 mg/L best predicted sustained remission.

The screening and prioritization of contaminants of emerging concern in the marine environment based on multiple biological response measures

There is ample evidence that a range of anthropogenic chemicals occur in the aquatic environment, some of which have the potential to cause harm. Contaminants of Emerging Concern (CECs) are a subset of anthropogenic compounds that are poorly characterized in terms of effects and occurrences, and that are generally unregulated. Due to the sheer number of chemicals used, it is necessary to identify and prioritize those that may cause biological impacts.A key challenge of doing so is the lack of traditional ecotoxicological information. The utilization of in vitro exposure-response studies or benchmarks based on in vivo data can provide a basis for developing threshold values for evaluation of potential impacts. There are challenges, including understanding the accuracy and range of application for modeled measures and translating in vitro response information from receptor models to apical endpoints. Despite this, the use of multiple lines of evidence increases the range of available information, and supports a weight-of-evidence approach to inform the screening and prioritization of CECs in the environment.The objective of this work is to perform an evaluation of CECs detected in an urban estuary, and to identify those that are most likely to elicit a biological response. Monitoring data from marine water, wastewater, and fish and shellfish tissue samples from 17 different campaigns combined with multiple biological response measures were compared with appropriate threshold values. CECs were categorized based on their potential to elicit a biological response; the uncertainty, based on consistency of lines of evidence, was also evaluated. Two-hundred-fifteen CECs were detected. Fifty-seven were identified as High Priority (likely to cause a biological effect), and 84 as Watch List (potential to cause biological effects). Due to the extent of the monitoring and range of the lines of evidence, this approach and results are applicable to other urbanized estuarine systems.

Determination of plasma protein binding of dalbavancin

Dalbavancin is a lipoglycopeptide with a long half-life, making it a promising treatment for infections requiring prolonged therapy, such as complicated Staphylococcus aureus bacteraemia. Free drug concentration is a critical consideration with prolonged treatment, since free concentration-time profiles may best correlate with therapeutic effect. In support of future clinical trials, we aimed to develop a reliable and reproducible assay for measuring free dalbavancin concentrations. The ultracentrifugation technique was used to determine free dalbavancin concentrations in plasma at two concentrations (50 and 200 mg/L) in duplicate. Centrifuge tubes and pipette tips were treated for 24 h before use with Tween 80 to assess adsorption. Dalbavancin concentrations were analysed from the plasma samples (total) and middle layer samples (free) by LC/MS/MS with isotopically labelled internal standard. Warfarin served as a positive control with known high protein binding. Measurement of free dalbavancin was sensitive to adsorption onto plastic. Treatment of tubes and pipette tips with ≥2% Tween 80 effectively prevented drug loss during protein binding experiments. By the ultracentrifugation method, dalbavancin's protein binding was estimated to be approximately 99%. Dalbavancin has very high protein binding. Given dalbavancin's high protein binding, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure-response studies, especially clinical trials. Future investigations should confirm if the active fraction is best predicted by the free or total fraction.

Geospatial Modelling for Estimation of PM2.5 Concentrations in Two Megacities in Peninsular India

Airborne particles finer than 2.5 microns (PM2.5) constitute a major public health risk in India. Therefore, extensive scientific studies must be conducted to assess the PM2.5 exposures of Indians and determine the “exposure-response function” specific to India. While Peninsular India includes three megacities with populations exceeding 10 million each, there are very few studies on air quality modelling in this region compared to North India. In this paper, the authors describe a Linear Mixed Effects (LME) model to estimate monthly-average PM2.5 concentrations at a spatial resolution of 1 km2 between 2016 and 2019 in the megacities of Bengaluru and Hyderabad with a total population of 23 million. This model is based on covariates such as aerosol optical depth (AOD), meteorological parameters, and Land-use-Land-cover (LULC) variables and is validated with extensive datasets from continuous and manual air quality monitoring stations through a 10-fold cross-validation process. The final LME model can explain more than 60 percent of the variation in the PM2.5 concentrations in Bengaluru and Hyderabad. This model is then used to predict the monthly-average grid-wise PM2.5 concentrations in more than 800 grids in each of these two cities to study the spatial and temporal patterns in PM2.5 concentrations between 2016 and 2019. These spatiotemporal maps of PM2.5 concentration are critical to overcoming the misclassification of exposure and will form a crucial input to much-needed PM exposure-response studies in these two megacities. This paper can serve as a useful framework for similar studies by showing the way to bridge the gaps in the current air quality monitoring network in Peninsular India.

Occupational inhalant allergy in food handling occupations.

Review article on recent developments on inhalant food allergens associated with occupational respiratory allergy and asthma. This review has found that occupational inhalant allergy in food handling occupations is a common and recognisable clinical entity (class 3 food allergy) in high-risk food occupations such as bakeries and seafood processing. Aerosolised food proteins from plant or animal food sources, additives and biological food contaminants cause occupational sensitization, rhinitis and asthma. The risk of allergy may be enhanced across the food value chain as a result of food processing techniques including the introduction of new food allergens in the food matrix. Occupational food allergy and asthma can be prevented by improved health-based exposure standards, workplace control measures, education and training activities, and early diagnosis accompanied with exposure reduction. Future studies need to focus on exposure-response studies to establish improved exposure limits especially for flour dust, the relevance of cooked vs raw foods in influencing risk, identifying and characterising major inhalant food allergens accompanied with component resolved diagnostic approaches, and evaluating the effectiveness of interventions for common high-risk food sensitizers causing occupational rhinitis and asthma.

1094. Determination of Plasma Protein Binding of Dalbavancin

Abstract Background Dalbavancin is a semi-synthetic glycopeptide with a long half-life, making it a promising alternative for infections requiring prolonged therapy such as complicated Staphylococcus aureus bacteremia. A critical pharmacokinetic consideration with prolonged treatment is the unbound or “free” concentration-time profile, as free antibiotic concentrations may correlate with tissue penetration and therapeutic effects better than total drug. Dalbavancin’s plasma protein binding (PB) remains poorly studied and has been reported to range between 93-99%. A reliable and validated free drug assay is needed to link dalbavancin concentrations with patient outcomes. Methods The ultracentrifugation technique was used to determine free dalbavancin concentrations in plasma at two concentrations (50 and 200 µg/mL) in duplicate. Centrifuge tubes and pipette tips were treated for 24 hours before use with Tween 80 to assess adsorption. PB centrifugation conditions: 400,000 g (106,000 RPM in TLA-120.1 rotor) for 4 hours at 37°C. Dalbavancin concentrations were analyzed from the plasma samples (total) and middle layer samples (free) by liquid chromatography – tandem mass spectrometry (LC/MS/MS) with isotopically labeled internal standard. Warfarin served as a positive control with known high protein binding. Results Measurement of free dalbavancin was sensitive to adsorption onto plastic. Treatment of tubes and pipette tips with ≥2% Tween 80 effectively prevented drug loss during PB experiments (Figure 1). Addition of 2% Tween 80 did not affect PB results of warfarin. In PB experiments with 2% Tween 80 coated tubes, the free fraction of dalbavancin was 0.96% (95% CI: 0.94-0.98) at 50 µg/mL and 1.11% (95% CI: 1.08-1.13) at 200 µg/mL. Figure 1. Percent Free Dalbavancin vs Varying Concentrations of Tween 80 for Pretreatment of Tubes Conclusion By the ultracentrifugation method, dalbavancin’s PB was estimated to be approximately 99%. Given dalbavancin’s high PB, accurate measurement of free dalbavancin concentrations should be a key consideration in future exposure-response studies, especially clinical trials. Future investigations should also determine if the active fraction is best predicted by the free or total fraction, as this remains a subject of debate. Supported by NIAID/NIH grant UM1AI104681. Content is solely the authors’ responsibility and does not represent official NIH views. Disclosures Thomas L. Holland, MD, Aridis (Consultant)Basilea Pharmaceutica (Consultant)Lysovant (Consultant) Thomas L. Holland, MD, Aridis (Individual(s) Involved: Self): Consultant; Basilea Pharmaceutica (Individual(s) Involved: Self): blinded adjudication, Consultant, Other Financial or Material Support; Genentech (Individual(s) Involved: Self): Consultant; Lysovant (Individual(s) Involved: Self): Consultant; Motif Bio (Individual(s) Involved: Self): Consultant Thomas Lodise, Jr., PharmD, PhD, Astra-Zeneca (Consultant)Bayer (Consultant)DoseMe (Consultant, Advisor or Review Panel member)ferring (Consultant)genentech (Consultant)GSK (Consultant)Melinta (Consultant)merck (Consultant, Independent Contractor)nabriva (Consultant)paratek (Consultant, Advisor or Review Panel member, Speaker’s Bureau)shionogi (Consultant, Advisor or Review Panel member, Speaker’s Bureau)Spero (Consultant)tetraphase (Consultant)Venatrox (Consultant) Thomas Lodise, Jr., PharmD, PhD, Melinta Therapeutics (Individual(s) Involved: Self): Consultant; Merck (Individual(s) Involved: Self): Consultant, Scientific Research Study Investigator; Paratek (Individual(s) Involved: Self): Consultant; Shionogi (Individual(s) Involved: Self): Consultant, Speakers’ bureau; Spero (Individual(s) Involved: Self): Consultant; Tetraphase Pharmaceuticals Inc. (Individual(s) Involved: Self): Consultant

Integrating monitor wearing to estimate household air pollution exposure parameters in the Ghana Randomized Air Pollution and Health Study (GRAPHS)

BACKGROUND AND AIM: Personal monitoring can enhance exposure-response studies. Prior studies employ a wearing compliance minimum threshold to reduce exposure misclassification. Leveraging the full range of device wearing data illuminates important exposure outcomes in the context of a large household air pollution cookstove intervention study with three arms (control, liquified petroleum gas (LPG), and improved biomass). METHODS: Evaluating the association between accelerometer-derived device wearing and mean 48-hr personal exposures in generalized estimating equations yields three parameters: (1) the y-intercept (0% device wearing) estimates community air pollution per study arm; (2) the difference between estimated concentrations per study arm at maximum device wearing is the effect of the cooking interventions on overall personal exposure; (3) estimated concentrations at maximum device wearing minus the y-intercept concentration estimates the average direct contribution of cooking events to personal exposure. RESULTS:Median device wearing during waking hours was 7- 8 hrs/day across study arms (range 0 - 15.9 hrs). Estimated community-level PM₂.₅ concentrations were similar across study arms (37-48 μg/m³). On average, the overall exposure was estimated at 108 ± 14 μg/m³ for the control arm and 53 ± 23 μg/m³ for LPG, suggesting a 50% reduction from this intervention. We estimate the direct contribution of individual cooking activities to exposure to be 60 ± 14 μg/m³ in the control arm and 6.2 ± 22.6 μg/m³ in the LPG arm (90% less). The improved biomass stove had negligible impact on reducing personal air pollution exposure. Using only data from cooking hours provided relatively similar % reductions for the LPG intervention (45% for overall; 85% for direct cooking impact). CONCLUSIONS:The association between device wearing and personal exposure allows quantification of important household air pollution exposure assessment outcomes, two of which previously could not be obtained without additional monitoring. KEYWORDS: Air pollution, Particulate matter, Modeling, Exposures

A feasibility study of metabolic phenotyping of dried blood spot specimens in rural Chinese women exposed to household air pollution.

Exposure-response studies and policy evaluations of household air pollution (HAP) are limited by current methods of exposure assessment which are expensive and burdensome to participants. We collected 152 dried blood spot (DBS) specimens during the heating and non-heating seasons from 53 women who regularly used biomass-burning stoves for cooking and heating. Participants were enrolled in a longitudinal study in China. Untargeted metabolic phenotyping of DBS were generated using ultra-high performance liquid chromatography coupled with mass spectrometry to exemplify measurement precision and assessment for feasibility to detect exposure to HAP, evaluated by season (high pollution vs. low pollution) and measured personal exposure to fine particulate matter <2.5 μm diameters (PM2.5) and black carbon (BC) in the 48-h prior to collecting the DBS specimen. Metabolites e.g., amino acids, acyl-carnitines, lyso-phosphorylcholines, sphinganine, and choline were detected in the DBS specimens. Our approach is capable of detecting the differences in personal exposure to HAP whilst showing high analytical reproducibility, coefficient of variance (CV) <15%, meeting the U.S. Food and Drug Administration criteria. Our results provide a proof of principle that high-resolution metabolic phenotypic data can be generated using a simple DBS extraction method thus suitable for exposure studies in remote, low-resource settings where the collection of serum and plasma is logistically challenging or infeasible. The analytical run time (19 min/specimen) is similar to most global phenotyping methods and therefore suitable for large-scale application.

Bayesian network-based framework for exposure-response study design and interpretation

Conventional environmental-health risk-assessment methods are often limited in their ability to account for uncertainty in contaminant exposure, chemical toxicity and resulting human health risk. Exposure levels and toxicity are both subject to significant measurement errors, and many predicted risks are well below those distinguishable from background incident rates in target populations. To address these issues methods are needed to characterize uncertainties in observations and inferences, including the ability to interpret the influence of improved measurements and larger datasets. Here we develop a Bayesian network (BN) model to quantify the joint effects of measurement errors and different sample sizes on an illustrative exposure-response system. Categorical variables are included in the network to describe measurement accuracies, actual and measured exposures, actual and measured response, and the true strength of the exposure-response relationship. Network scenarios are developed by fixing combinations of the exposure-response strength of relationship (none, medium or strong) and the accuracy of exposure and response measurements (low, high, perfect). Multiple cases are simulated for each scenario, corresponding to a synthetic exposure response study sampled from the known scenario population. A learn-from-cases algorithm is then used to assimilate the synthetic observations into an uninformed prior network, yielding updated probabilities for the strength of relationship. Ten replicate studies are simulated for each scenario and sample size, and results are presented for individual trials and their mean prediction. The model as parameterized yields little-to-no convergence when low accuracy measurements are used, though progressively faster convergence when employing high accuracy or perfect measurements. The inferences from the model are particularly efficient when the true strength of relationship is none or strong with smaller sample sizes. The tool developed in this study can help in the screening and design of exposure-response studies to better anticipate where such outcomes can occur under different levels of measurement error. It may also serve to inform methods of analysis for other network models that consider multiple streams of evidence from multiple studies of cumulative exposure and effects.

A Sensitive Assay for Proteases in Bioaerosol Samples: Characterization and Quantification of Airborne Proteases in Salmon Industry Work Environments.

Proteases are probably underestimated exposure agents in bioaerosols. Their roles as barrier disrupters in allergic sensitization and activators of innate inflammation call for more attention in exposure-response studies. The main objectives of this study was (i) to establish a suitable method for detection of small quantities of proteases in filtered air samples and (ii) to utilize the method to characterize exposure to proteases in a salmon industry work environment. Analysis of proteases in filtered air samples was based on zymography, using sodium dodecyl sulfate-polyacrylamide gel electrophoresis with 0.1% gelatin as substrate added in the polyacrylamide gel. Gelatinase activity was evident as cleared (unstained) regions. The area of these regions was quantified using image analysis (UVP Vision Works®). Standard curves with known amounts of active porcine trypsin were added to each gel. Validation of 11 non-linear standard curves showed R2 (range) = 0.8989-0.9882, limit of detection = 0.056 nM, lower limit of quantification = 0.161 nM, and coefficients of variations (range) = 20-28%. Sampling of bioaerosols in salmon industry was performed using polytetrafluoretylene filters with an airflow of 3 l min-1. All samples contained visible bands close to the size of porcine trypsin (23.3 kDa). The bands did not disappear in the presence of EDTA but abolished by Pefabloc, demonstrating that the enzyme is a serine protease, most likely salmon trypsin. Airborne levels of active protease were below the statistical detection limit in the filleting department but quantifiable in extract samples from the slaughter department. Three filtered air samples from the slaughter department showed air concentrations of 6.2, 16.5, and 27.0 ng m-3 air. We conclude that zymography is a sensitive and reliable method for exposure assessment of active proteases in indoor environmental samples. We recommend this assay for use in occupational studies to characterize and quantify exposure to active proteases in bioaerosols.

Urinary biomarkers of polycyclic aromatic hydrocarbons in pre- and peri-pubertal girls in Northern California: Predictors of exposure and temporal variability

BackgroundPolycyclic aromatic hydrocarbons (PAHs), a class of chemicals produced as combustion by-products, have been associated with endocrine disruption. To understand exposure in children, who have been less studied than adults, we examined PAH metabolite concentrations by demographic characteristics, potential sources of exposure, and variability over time, in a cohort study of pre- and peri-pubertal girls in Northern California. MethodsUrinary concentrations of ten PAH metabolites and cotinine were quantified in 431 girls age 6–8 years at baseline. Characteristics obtained from parental interview, physical exam, and linked traffic data were examined as predictors of PAH metabolite concentrations using multivariable linear regression. A subset of girls (n = 100) had repeat measures of PAH metabolites in the second and fourth years of the study. We calculated the intraclass correlation coefficient (ICC), Spearman correlation coefficients, and how well the quartile ranking by a single measurement represented the four-year average PAH biomarker concentration. ResultsEight PAH metabolites were detected in ≥ 95% of the girls. The most consistent predictors of PAH biomarker concentrations were cotinine concentration, grilled food consumption, and region of residence, with some variation by demographics and season. After adjustment, select PAH metabolite concentrations were higher for Hispanic and Asian girls, and lower among black girls; 2-naphthol concentrations were higher in girls from lower income households. Other than 1-naphthol, there was modest reproducibility over time (ICCs between 0.18 and 0.49) and the concentration from a single spot sample was able to reliably rank exposure into quartiles consistent with the multi-year average. ConclusionsThese results confirm diet and environmental tobacco smoke exposure as the main sources of PAHs. Controlling for these sources, differences in concentrations still existed by race for specific PAH metabolites and by income for 2-naphthol. The modest temporal variability implies adequate exposure assignment using concentrations from a single sample to define a multi-year exposure timeframe for epidemiologic exposure-response studies.

Fungal Fragments and Fungal Aerosol Composition in Sawmills.

Assessment of exposure to fungi has commonly been limited to fungal spore measurements that have shown associations between fungi and development or exacerbation of different airway diseases. Because large numbers of submicronic fragments can be aerosolized from fungal cultures under laboratory conditions, it has been suggested that fungal exposure is more complex and higher than that commonly revealed by spore measurements. However, the assessment of fungal fragments in complex environmental matrix remain limited due to methodological challenges. With a recently developed immunolabeling method for field emission scanning electron microscope (FESEM), we could assess the complex composition of fungal aerosols present in personal thoracic samples collected from two Norwegian sawmills. We found that large fungal fragments (length >1 µm) dominated the fungal aerosols indicating that the traditional monitoring approach of spores severely underestimate fungal exposure. The composition of fungal aerosols comprised in average 9% submicronic fragments, 62% large fragments, and 29% spores. The average concentrations of large and submicronic fragments (0.2–1 µm) were 3 × 105 and 0.6 × 105 particles m−3, respectively, and correlated weakly with spores (1.4 × 105 particles m−3). The levels of fragments were 2.6 times higher than the average spore concentration that was close to the proposed hazardous level of 105 spores per m3. The season influenced significantly the fungal aerosol concentrations but not the composition. Furthermore, the ratio of spores in the heterogeneous fungal aerosol composition was significantly higher in saw departments as compared to sorting of green timber departments where the fungal fragments were most prevalent. Being the dominating particles of fungal aerosols in sawmills, fungal fragments should be included in exposure-response studies to elucidate their importance for health impairments. Likewise, the use of fungal aerosol composition in such studies should be considered.

Kriging-Based Design of Experiments for Multi-Source Exposure–Response Studies in Nanotoxicology

For the sustainable development of nanomaterials (NMs), it is critical to assess the toxic potency of NMs. One of the major challenges with toxicology studies of NMs, compared to traditional materi...

Development of Helisoma trivolvis pond snails as biological samplers for biomonitoring of current-use pesticides.

Nontarget aquatic organisms residing in wetlands are commonly exposed to current-use pesticides through spray drift and runoff. However, it is frequently challenging to measure exposure because of rapid dissipation of pesticides from water and reduced bioavailability. The authors' hypothesis is that freshwater snails can serve as bioindicators of pesticide exposure based on their capacity to passively accumulate tissue residues. Helisoma trivolvis snails were evaluated as biomonitors of pesticide exposure using a fungicide formulation that contains pyraclostrobin and metconazole and is frequently applied to crops surrounding depressional wetlands. Exposure-response studies indicate that H. trivolvis are tolerant of pyraclostrobin and metconazole at concentrations >10 times those lethal to many aquatic species, with a median lethal concentration based on pyraclostrobin of 441 μg/L (95% confidence interval of 359-555 μg/L). Bioconcentration factors ranged from 137 mL/g to 211 mL/g and from 39 mL/g to 59 mL/g for pyraclostrobin and metconazole, respectively. Elimination studies suggested one-compartmental elimination and snail tissue half-lives (t50 ) of approximately 15 h and 5 h for pyraclostrobin and metconazole, respectively. Modeling derived toxicokinetic parameters in the context of an environmentally relevant pulsed exposure suggests that residues can be measured in snails long after water concentrations fall below detection limits. With high fungicide tolerance, rapid accumulation, and slow elimination, H. trivolvis may be viable for biomonitoring of pyraclostrobin and should be investigated for other pesticides. Environ Toxicol Chem 2016;35:2320-2329. © 2016 SETAC.

Clinical pharmacokinetic properties of magnesium sulphate in women with pre-eclampsia and eclampsia.

BackgroundThe pharmacokinetic basis of magnesium sulphate (MgSO 4) dosing regimens for eclampsia prophylaxis and treatment is not clearly established.ObjectivesTo review available data on clinical pharmacokinetic properties of MgSO 4 when used for women with pre‐eclampsia and/or eclampsia.Search strategy MEDLINE, EMBASE, CINAHL, POPLINE, Global Health Library and reference lists of eligible studies.Selection criteriaAll study types investigating pharmacokinetic properties of MgSO 4 in women with pre‐eclampsia and/or eclampsia.Data collection and analysisTwo authors extracted data on basic pharmacokinetic parameters reflecting the different aspects of absorption, bioavailability, distribution and excretion of MgSO 4 according to identified dosing regimens.Main resultsTwenty‐eight studies investigating pharmacokinetic properties of 17 MgSO 4 regimens met our inclusion criteria. Most women (91.5%) in the studies had pre‐eclampsia. Baseline serum magnesium concentrations were consistently <1 mmol/l across studies. Intravenous loading dose between 4 and 6 g was associated with a doubling of this baseline concentration half an hour after injection. Maintenance infusion of 1 g/hour consistently produced concentrations well below 2 mmol/l, whereas maintenance infusion at 2 g/hour and the Pritchard intramuscular regimen had higher but inconsistent probability of producing concentrations between 2 and 3 mmol/l. Volume of distribution of magnesium varied (13.65–49.00 l) but the plasma clearance was fairly similar (4.28–5.00 l/hour) across populations.ConclusionThe profiles of Zuspan and Pritchard regimens indicate that the minimum effective serum magnesium concentration for eclampsia prophylaxis is lower than the generally accepted level. Exposure–response studies to identify effective alternative dosing regimens should target concentrations achievable by these standard regimens.Tweetable abstractMinimum effective serum magnesium concentration for eclampsia prophylaxis is lower than the generally accepted therapeutic level.

The National Environmental Respiratory Center (NERC) experiment in multi-pollutant air quality health research: II. Comparison of responses to diesel and gasoline engine exhausts, hardwood smoke and simulated downwind coal emissions

The NERC Program conducted identically designed exposure–response studies of the respiratory and cardiovascular responses of rodents exposed by inhalation for up to 6 months to diesel and gasoline exhausts (DE, GE), wood smoke (WS) and simulated downwind coal emissions (CE). Concentrations of the four combustion-derived mixtures ranged from near upper bound plausible to common occupational and environmental hotspot levels. An “exposure effect” statistic was created to compare the strengths of exposure–response relationships and adjustments were made to minimize false positives among the large number of comparisons. All four exposures caused statistically significant effects. No exposure caused overt illness, neutrophilic lung inflammation, increased circulating micronuclei or histopathology of major organs visible by light microscopy. DE and GE caused the greatest lung cytotoxicity. WS elicited the most responses in lung lavage fluid. All exposures reduced oxidant production by unstimulated alveolar macrophages, but only GE suppressed stimulated macrophages. Only DE retarded clearance of bacteria from the lung. DE before antigen challenge suppressed responses of allergic mice. CE tended to amplify allergic responses regardless of exposure order. GE and DE induced oxidant stress and pro-atherosclerotic responses in aorta; WS and CE had no such effects. No overall ranking of toxicity was plausible. The ranking of exposures by number of significant responses varied among the response models, with each of the four causing the most responses for at least one model. Each exposure could also be deemed most or least toxic depending on the exposure metric used for comparison. The database is available for additional analyses.

0183 Face validity and inter-rater agreement between expert assessments of occupational mechanical exposures in a lower body job exposure matrix

ObjectivesWe constructed a lower body job exposure matrix (JEM) based on five experts’ assessments of occupational mechanical exposures. The aim of this study was to evaluate the face validity of...

Wintertime Factors Affecting Contaminant Distribution in a Swine Farrowing Room

An estimated 200,000 to 500,000 U.S. workers in concentrated animal feeding operations (CAFOs) are at risk of adverse respiratory outcomes from exposures to indoor contaminants. In the wintertime, general ventilation is minimized in the Midwest due to high heating costs required to maintain indoor temperatures optimal for animal production. Pit fans typically operate to exhaust under-floor manure pits, but little other fresh air intake exists. Many operators believe that these systems are sufficient to reduce contaminant concentrations within the building during winter. Investigating whether these pit fans provide sufficient protection against classic CAFO contaminants during minimal wintertime ventilation was warranted. Direct-reading instruments were used to measure and record concentrations of multiple contaminants using both fixed-area and mobile contaminant mapping in a farrowing room during a Midwest winter. With the exception of CO, concentrations were significantly (p < 0.001) higher with the pit fan off compared with those with the pit fan on. Additional analyses identified that significant changes (p < 0.001) in mean room concentrations of respirable dust (decreased, 77% with pit fan off and 87% with pit fan on) and CO2 (increased, 24%) over the 5-hr study periods and that multiple fixed-area monitors rather than the much-used, single center-of-room monitor provided a more conservative (e.g., protective) assessment of room concentrations. While concentrations did not exceed occupational exposure limits from OSHA or ACGIH for individual contaminants, recommended agricultural health limits from exposure-response studies suggested in the literature were exceeded for respirable dust, CO2, and NH3, indicating a need to consider personal exposures and control options to reduce contaminant concentrations in farrowing rooms. Pit fans reduced NH3 and H2S concentrations, but these fans may not be sufficient to control dust and eliminate the need for secondary exposure prevention methods.

Critical Review of Scientific Basis for Lowering Coal Mine Dust Exposure Level. iii. Exposure-Response Studies of Radiographic CWP

Implementation of the coal mine dust (“CMD”) interim standard of 3.0 milligrams per cubic meter (“mg/m 3 ”) in 1970 was reduced to 2.0 mg/m3 in 1972 and produced a steady decline in dust levels and prevalence of coal workers pneumoconiosis (“CWP”). Beginning in the mid-1990s, an apparent increase was reported in what was thought to be severe and rapidly progressive CWP and PMF despite stability in CMD levels. These “sentinel health” events led to further investigation and stimulated the 2010 MSHA proposal to lower the current CMD standard from 2.0 mg/m 3 to 1.0 mg/m 3 . The purpose of this study is to summarize exposure-response associations between CMD and CWP to evaluate evidence for a revised standard. There are five cohorts of UK and US coalminers with exposure-response analyses useful for assessing a proposed coal mine dust standard. Two major biases confound such an evaluation. Exposure misclassification bias occurs for exposures occurring before standards and before sampling surveillance was initiated. This bias is most obvious in the US studies where sample results collected after initiation of the standard were back-extrapolated to pre-standard time periods. The bias introduced produces a spurious steeper exposure-response slope due to overestimation of risk at higher exposure levels (>4 mg/m 3 ) and under-estimation of risk at lower exposures. Participation bias occurs in one of the US studies when survey participation rates dropped below 50% in rounds 1-4. Exposure-response evidence suggests a coal mine dust standard of 2 mg/m 3 appears to be protective from occurrence of CWP ≥2 for low rank coals. However there is excess CWP ≥2 in miners exposed to high rank coal, suggesting a lower exposure standard is needed to protect these miners.