Retrospective exposure reconstruction using approximate Bayesian computation: A case study on perfluorooctanoic acid and preeclampsia.

BACKGROUND: In environmental epidemiology, measurements of toxicants in biological samples are often used as individual exposure assignments. It is common to obtain only one or a few exposure biomarkers per person and use those measurements to represent each person's relevant toxicant exposure for a given health outcome, even though most exposure biomarkers can fluctuate over time. When the timing of the exposure reflected by the biomarker measurement is misaligned with disease development especially if it occurs after the disease outcome, results could be subject to reverse causality or exposure measurement error. OBJECTIVE: This study aimed to use an approximate Bayesian computation (ABC) method to improve PFOA exposure estimates and characterize the effects of PFOA on preeclampsia in the C8 Studies. METHODS: Serum PFOA concentrations were measured in blood samples collected during 2005-2006 in West Virginia and Ohio (the C8 Studies), and residential and water use histories and pregnancy outcomes were obtained from self-reports. Our previous results may have been influenced by the choice of methods for characterizing PFOA exposures. Here we use an ABC method to combine measured PFOA serum concentrations and environmentally modeled PFOA concentrations to reconstruct historical PFOA exposures. We also expanded our previous work by assuming more realistic lognormal distributions for key input parameters in the exposure and pharmacokinetic models. RESULTS: Compared to using fixed values of model parameters and Monte Carlo simulations, ABC produced similar Spearman correlations between estimated and measured serum PFOA concentrations, yet substantially reduced the mean squared error by over 50%. Based on ABC, compared to previous studies, we found a similar adjusted odds ratio (AOR) for the association between PFOA and preeclampsia. CONCLUSIONS: Bayesian combination of modeled exposure and measured biomarker concentrations can reduce exposure measurement error compared to modeled exposure.

Characterization of asbestos exposures associated with the use of facial makeups.

There has been renewed interest in the safety of cosmetics that may contain asbestos or other elongate mineral particles at very low levels as a naturally occurring contaminant. The authors evaluated asbestos exposure during the application of facial makeups in a constructed chamber simulating a bathroom space. The facial makeups tested included products previously found to have very low or "trace" asbestos content by governmental and commercial laboratories using a variety of bulk analysis methods. Tremolite asbestos was detected in five of 54 personal air samples and three of 72 area air samples in 18 simulations. The calculated geometric mean and 95th percentile task-based asbestos concentration associated with personal facial makeup use in this study, incorporating censored data, is 0.0015 and 0.0018 fiber per cubic centimeter (f/cc), respectively, with a corresponding 95th percentile 24-h time-weighted average (TWA) asbestos concentration of 0.00008 f/cc for three applications per day in a simulated bathroom with no active ventilation. Based on these results, cumulative non-occupational asbestos exposures confer a less than one in 1,000,000 risk of asbestos-related disease based on many typical usage patterns and less than 1/100,000 risk with upper-end lifetime usage patterns, using the US Environmental Protection Agency asbestos risk model.

Assessment of formaldehyde exposures under contemporary embalming conditions in U.S. funeral homes.

The funeral service profession has used formaldehyde-containing embalming solutions for the preparation of decedents since the early 1900s. The available literature regarding funeral director exposure to formaldehyde largely consists of data collected prior to 2000, with most studies reporting task-length exposure concentrations rather than full-shift time-weighted average concentrations. As formaldehyde undergoes review in the U.S. Environmental Protection Agency Toxic Substances Control Act (TSCA) risk evaluation process, accurately characterizing long-term exposure potential in this profession is critical. This study presents passive badge sampling and air change rate measurement results conducted at 13 funeral home locations across the United States. Full-shift (approximately 8-hr) samples were collected on one embalmer per day in each funeral home and on one occupational non-user (ONU), e.g., a receptionist. Additionally, task-length samples were collected during each embalming that occurred during the shift, were one to occur. Full-shift concentrations ranged from 0.007 to 1.1 ppm and 0.007 to 0.042 ppm for embalmers and ONUs, respectively. Task-length formaldehyde concentrations ranged from 0.058 to 1.4 ppm, with the average embalming taking 72.8 min to complete. Air change rates in the preparation rooms ranged from 2.8 to 28.3 air changes per hour; however, no correlation between task-length formaldehyde concentrations and air change rate was observed. Following empirical data collection, a Monte Carlo analysis of estimated annual 8-hr time-weighted average (TWA) exposure was conducted to determine the potential exposure distribution for embalmers employed at private funeral homes. Inputs to the simulation were derived from responses to a National Funeral Directors Association survey and from empirical measurements collected during the study. With respect to the reconstructed 8-hr TWAs, the median 8-hr TWA was 0.037 ppm, with 93.6% of the predicted concentrations below 0.1 ppm. This study provides a robust characterization of contemporary formaldehyde exposures in the funeral service profession. Further, it provides a strategy for interpreting the results along with surveyed responses regarding embalming frequency to better inform risks associated with formaldehyde exposure in this profession.

Human biomonitoring of bisphenol A along pregnancy: An exposure reconstruction of the EXHES-Spain cohort.

This study was aimed at reconstructing the exposure to bisphenol (BPA) of 60 pregnant women from the EXHES-Spain cohort. A biomonitoring study was conducted by determining BPA levels in urine samples over the three trimesters of pregnancy. Moreover, the correlations between BPA levels and the role of different potential exposure sources, with special emphasis on the dietary intake, were also studied. Urine samples were subjected to dispersive liquid-liquid microextraction and the subsequent analysis via gas chromatography-mass spectrometry. BPA was detected in 76% of the urine samples. A significant decrease of urinary BPA levels was observed along pregnancy, as mean concentrations of creatinine-adjusted BPA were 4.64, 4.84 and 2.51 µg/g in the first, second and third trimester, respectively. This decrease was essentially associated with changes in the dietary habits of the pregnant women, including a lower intake of canned food and drinks. However, the potential role of other pregnancy-related biochemical or physiological factors should not be disregarded. Very interestingly, significant differences in urine BPA levels were found according to the fruit consumption pattern, as women who ate more citrus fruits showed lower BPA concentrations in urine. The reconstructed exposure to BPA was estimated in 0.072, 0.069 and 0.038 µg BPA/kg of body weight/day in the first, second and third trimesters, respectively. These values are far below the temporary tolerable daily intake (t-TDI) established by the EFSA.

Modeled prenatal exposure to per- and polyfluoroalkyl substances in association with child autism spectrum disorder: A case-control study.

BACKGROUND/OBJECTIVE: Per- and polyfluoroalkyl substances (PFAS) display neurobehavioral toxicity in laboratory animal studies. We examined associations of modeled prenatal maternal exposure to PFAS with child diagnosis of autism spectrum disorder (ASD). METHODS: Participants were 453 mother-child pairs from CHARGE (CHildhood Autism Risk from Genetics and Environment), a population-based case-control study. Children underwent psychometric testing and were clinically confirmed for ASD (n = 239) or typical development (TD, n = 214). At the end of the clinic visit, maternal blood specimens were collected. We quantified nine PFAS in maternal serum samples collected when their child was 2-5 years old. As surrogate in utero exposure, we used a model built from external prospective data in pregnancy and 24 months post-partum and then reconstructed maternal PFAS serum concentrations during pregnancy in this case-control sample. We used logistic regression to evaluate associations of modeled prenatal maternal PFAS concentrations with child ASD. RESULTS: Modeled prenatal maternal perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) were borderline associated with increased odds of child diagnosis of ASD (per nanogram per milliliter increase: odds ratio [OR] = 1.46; 95% confidence interval [CI]: 0.98, 2.18 for PFHxS, OR = 1.03; 95% CI: 0.99, 1.08 for PFOS). When compared to the lowest quartile (reference category), the highest quartile of modeled prenatal maternal PFHxS was associated with increased odds of child diagnosis of ASD (OR = 1.95; 95% CI: 1.02, 3.72). CONCLUSIONS: In analyses where modeled prenatal maternal PFAS serum concentrations served as in utero exposure, we observed that prenatal PFHxS and PFOS exposure, but not other PFAS, were borderline associated with increased odds of child diagnosis of ASD. Further studies in which PFAS concentrations are prospectively measured in mothers and children at a range of developmental stages are needed to confirm these findings.

Risk characterization of bisphenol-A in the Slovenian population starting from human biomonitoring data.

The current study aims to characterize exposure and risk associated to bisphenol-A (BPA) exposure in Slovenia, starting from biomonitoring data. Based on the urinary data, daily intake for the individuals was back-calculated using a physiology based biokinetic (PBBK) model properly parameterized for BPA, coupled with an exposure reconstruction algorithm. Re-running the PBBK model in forward mode allowed the estimation of biologically effective dose (free plasma BPA) and the respective daily area under the curve (AUC). Finally, risk characterization ratio was derived using both external and internal dose metrics. The urinary BPA levels were found low, with GM of 0.79, 1.51 and 0.20 µg/g creatinine for mothers, children and fathers respectively, similar to the levels of other European countries. Based on the above and accounting for the dynamics of exposure and biokinetics, daily intake was estimated, median exposure levels have been estimated equal to 0.019, 0.035 and 0.005 µg/kg_bw/d for mothers, fathers and children respectively. The highest estimated intake level was found in a child, equal to 0.87 µg/kg_bw/d, while the maximum intake for mothers and fathers were 0.7 and 0.8 µg/kg_bw/d respectively. The respective RCR levels using the EFSA t-TDI of 4 µg/kg_bw/d were 2 magnitudes of order lower below 1, independently of the selected method. It has to be noted that had daily intake been estimated solely based on the urinary concentrations mass balance, the estimated intake would be lower, as a result of the oversimplification on exposure and elimination time dynamics. This highlights the importance for using PBBK modelling based exposure reconstruction schemes for rapidly metabolized and excreted compounds such as BPA, as well as the study design of efficient sampling for rapidly metabolized compounds.

Potential Airborne Asbestos Exposure and Risk Associated with the Historical Use of Cosmetic Talcum Powder Products.

Over time, concerns have been raised regarding the potential for human exposure and risk from asbestos in cosmetic-talc-containing consumer products. In 1985, the U.S. Food and Drug Administration (FDA) conducted a risk assessment evaluating the potential inhalation asbestos exposure associated with the cosmetic talc consumer use scenario of powdering an infant during diapering, and found that risks were below levels associated with background asbestos exposures and risk. However, given the scope and age of the FDA's assessment, it was unknown whether the agency's conclusions remained relevant to current risk assessment practices, talc application scenarios, and exposure data. This analysis updates the previous FDA assessment by incorporating the current published exposure literature associated with consumer use of talcum powder and using the current U.S. Environmental Protection Agency's (EPA) nonoccupational asbestos risk assessment approach to estimate potential cumulative asbestos exposure and risk for four use scenarios: (1) infant exposure during diapering; (2) adult exposure from infant diapering; (3) adult exposure from face powdering; and (4) adult exposure from body powdering. The estimated range of cumulative asbestos exposure potential for all scenarios (assuming an asbestos content of 0.1%) ranged from 0.0000021 to 0.0096 f/cc-yr and resulted in risk estimates that were within or below EPA's acceptable target risk levels. Consistent with the original FDA findings, exposure and corresponding health risk in this range were orders of magnitude below upper-bound estimates of cumulative asbestos exposure and risk at ambient levels, which have not been associated with increased incidence of asbestos-related disease.

Reconstructing historical exposures to elongate mineral particles (EMPs) in the taconite mining industry for 1955-2010.

As part of ongoing epidemiological studies for assessing the association between exposure to dust from taconite operations and the development of respiratory diseases, the goal of this study was to reconstruct the exposures of workers to elongate mineral particle (EMP) in the Minnesota taconite mining industry from 1955-2010. Historical NIOSH-7400 and equivalent EMP personal exposure data were extracted from two sources: (1) the Mine Safety and Health Administration (MSHA) online database recorded for all inspection results since 1978 with 655 EMP monitoring records from 1978-2010 for 13 MSHA Mine IDs associated with this study; and (2) the mining companies' internal monitoring reports contained 96 personal EMP exposure records. NIOSH-7400 EMP personal exposures were measured for workers in different jobs in all active mines in 2010 by obtaining 1,285 personal samples. After data treatment, all data were grouped into seven mines and eight departments. Within each mine-department, the yearly EMP mean concentration in f/cc for each year of operation was predicted using two approaches. The performance of two approaches varied by situation. The assumptions underlying each approach described in this article have limitations. A linear regression based on limited historical measurements and those made in 2010-2011 (Approach 1) does not yield reasonable and plausible values of the slope. Approach 2 assumes that the EMP and the respirable dust in the same department share the same historical time trend. This approach allowed us to avail of the more reasonable slope estimates from the historical respirable dust data set and yielded more plausible historical exposure estimates for most locations. This work with two different job exposure matrix (JEMs) provides a unique research opportunity to study the potential impact of exposure assessment to epidemiological results. Both JEMs are being used to assess associations between EMP and respiratory disease in epidemiological studies.

A Bayesian Model and Stochastic Exposure (Dose) Estimation for Relative Exposure Risk Comparison Involving Asbestos-Containing Dropped Ceiling Panel Installation and Maintenance Tasks.

Assessing exposures to hazards in order to characterize risk is at the core of occupational hygiene. Our study examined dropped ceiling systems commonly used in schools and commercial buildings and lay-in ceiling panels that may have contained asbestos prior to the mid to late 1970s. However, most ceiling panels and tiles do not contain asbestos. Since asbestos risk relates to dose, we estimated the distribution of eight-hour TWA concentrations and one-year exposures (a one-year dose equivalent) to asbestos fibers (asbestos f/cc-years) for five groups of workers who may encounter dropped ceilings: specialists, generalists, maintenance workers, nonprofessional do-it-yourself (DIY) persons, and other tradespersons who are bystanders to ceiling work. Concentration data (asbestos f/cc) were obtained through two exposure assessment studies in the field and one chamber study. Bayesian and stochastic models were applied to estimate distributions of eight-hour TWAs and annual exposures (dose). The eight-hour TWAs for all work categories were below current and historic occupational exposure limits (OELs). Exposures to asbestos fibers from dropped ceiling work would be categorized as "highly controlled" for maintenance workers and "well controlled" for remaining work categories, according to the American Industrial Hygiene Association exposure control rating system. Annual exposures (dose) were found to be greatest for specialists, followed by maintenance workers, generalists, bystanders, and DIY. On a comparative basis, modeled dose and thus risk from dropped ceilings for all work categories were orders of magnitude lower than published exposures for other sources of banned friable asbestos-containing building material commonly encountered in construction trades.

Characterizing and Communicating Risk with Exposure Reconstruction and Bayesian Analysis: Historical Locomotive Maintenance/Repair Associated with Asbestos Woven Tape Pipe Lagging.

Our reconstructed historical work scenarios incorporating a vintage 1950s locomotive can assist in better understanding the historical asbestos exposures associated with past maintenance and repairs and fill a literature data gap. Air sampling data collected during the exposure scenarios and analyzed by NIOSH 7400 (PCM) and 7402 (PCME) methodologies show personal breathing zone asbestiform fiber exposures were below the current OSHA exposure limits for the eight-hour TWA permissible exposure limit (PEL) of 0.1 f/cc (range <0.007-0.064 PCME f/cc) and the 30-minute short-term excursion limit (EL) of 1.0 f/cc (range <0.045-0.32 PCME f/cc) and orders of magnitude below historic OSHA PEL and ACGIH TLVs. Bayesian decision analysis (BDA) results demonstrate that the 95th percentile point estimate falls into an AIHA exposure category 3 or 4 as compared to the current PEL and category 1 when compared to the historic PEL. BDA results demonstrate that bystander exposures would be classified as category 0. Our findings were also significantly below the published calcium magnesium insulations exposure range of 2.5 to 7.5 f/cc reported for historic work activities of pipefitters, mechanics, and boilermakers. Diesel-electric locomotive pipe systems were typically insulated with a woven tape lagging that may have been chrysotile asbestos and handled, removed, and reinstalled during repair and maintenance activities. We reconstructed historical work scenarios containing asbestos woven tape pipe lagging that have not been characterized in the published literature. The historical work scenarios were conducted by a retired railroad pipefitter with 37 years of experience working with materials and locomotives.

Reconstructing exposures from biomarkers using exposure-pharmacokinetic modeling--A case study with carbaryl.

Sources of uncertainty involved in exposure reconstruction for short half-life chemicals were characterized using computational models that link external exposures to biomarkers. Using carbaryl as an example, an exposure model, the Cumulative and Aggregate Risk Evaluation System (CARES), was used to generate time-concentration profiles for 500 virtual individuals exposed to carbaryl. These exposure profiles were used as inputs into a physiologically based pharmacokinetic (PBPK) model to predict urinary biomarker concentrations. These matching dietary intake levels and biomarker concentrations were used to (1) compare three reverse dosimetry approaches based on their ability to predict the central tendency of the intake dose distribution; and (2) identify parameters necessary for a more accurate exposure reconstruction. This study illustrates the trade-offs between using non-iterative reverse dosimetry methods that are fast, less precise and iterative methods that are slow, more precise. This study also intimates the necessity of including urine flow rate and elapsed time between last dose and urine sampling as part of the biomarker sampling collection for better interpretation of urinary biomarker data of short biological half-life chemicals. Resolution of these critical data gaps can allow exposure reconstruction methods to better predict population-level intake doses from large biomonitoring studies.

An analysis of historical exposures of pressmen to airborne benzene (1938-2006).

Benzene is an aromatic hydrocarbon that, with sufficient cumulative lifetime doses, can cause acute myelogenous leukemia. Because of its volatility and solvent properties, it was used in the printing industry in inks, ink solvents, and cleaning agents from the 1930s to the 1970s. This analysis represents the first known attempt to gather and synthesize the available data on historical airborne benzene concentrations in printing facilities and exposures to pressmen. The sources of fugitive benzene vapors from printing operations have been identified as evaporation from ink fountains, exposed sections of the printing cylinder, the paper web, the paper post exit, and spilled ink. In addition, specific activities that could lead to benzene exposure, such as filling the fountains, using solvents to clean the press, and using solvents as personal cleaning agents, potentially occurred multiple times per work period. Eighteen studies were identified that reported workplace airborne concentrations in printing facilities between 1938 and 2006. Typical benzene air concentrations, considering both personal and area samples of various durations, were as high as 200 p.p.m. in the 1930s through the 1950s, 3-35 p.p.m. in the 1960s, 1.3-16 p.p.m. in the 1970s, 0.013-1 in the 1980s, and far less than 1 p.p.m. in the 1990s and 2000s. The decrease in benzene air concentrations by the late 1970s was likely to be linked to the decreased benzene content of printing materials, increased engineering controls, and to more stringent occupational exposure limits.

Occupational Exposure and Health Impact Assessment of Diisocyanates in Finland.

Diisocyanates are a group of chemicals widely used in different industrial applications. The critical health effects related to diisocyanate exposure are isocyanate sensitisation, occupational asthma and bronchial hyperresponsiveness (BHR). Industrial air measurements and human biomonitoring (HBM) samples were gathered in specific occupational sectors to examine MDI, TDI, HDI and IPDI and the respective metabolites from Finnish screening studies. HBM data can give a more accurate picture of diisocyanate exposure, especially if workers have been exposed dermally or used respiratory protection. The HBM data were used for conducting a health impact assessment (HIA) in specific Finnish occupational sectors. For this purpose, exposure reconstruction was performed on the basis of HBM measurements of TDI and MDI exposures using a PBPK model, and a correlation equation was made for HDI exposure. Subsequently, the exposure estimates were compared to a previously published dose-response curve for excess BHR risk. The results showed that the mean and median diisocyanate exposure levels and HBM concentrations were low for all diisocyanates. In HIA, the excess risk of BHR from MDI exposure over a working life period was highest in the construction and motor and vehicle industries and repair sectors, resulting in estimated excess risks of BHR of 2.0% and 2.6%, and 113 and 244 extra BHR cases in Finland, respectively. Occupational exposure to diisocyanates must be monitored because a clear threshold for DI sensitisation cannot be established.

Reconstructing Historical Exposures to Respirable Dust and Respirable Silica in the Taconite Mining Industry for 1955-2010.

The goal of this study was to reconstruct the historical respirable silica (RS) and respirable dust (RD) exposures of workers in the Minnesota taconite industry from 1955 to 2010 as part of several epidemiological studies for assessing the association between exposure to components of taconite dusts and the development of respiratory diseases. A job-exposure matrix (JEM) was developed that uses 9127 RS and 19 391 RD occupational hygiene historical measurements. Historical RS and RD data were extracted from several sources and were grouped into seven mines and then into eight departments [Concentrating, Crushing, Janitor, Mining, Office/control room, Pelletizing, Shop (mobile), and Shop (stationary)]. Within each department, we applied a two-level random-intercept regression model which assumes that the natural log of Y (RD or RS concentration) changes over time at a constant rate. Among all predicted RD and RS values, we found that larger RD values were located in the following departments: Crushing, Concentrating, Pelletizing, and Shop (mobile). Larger RS values were located only in either Crushing or Shop (mobile). The annual rates of change for historical RD and RS exposures were between -3.3 and 3.2%. The silica percentage in the dust varied by mine/department with the highest value of 29.3% in Mine F (Crushing) and the lowest value of 2.1% in Mine B (Pelletizing). The predicted historical RD and RS arithmetic mean exposures ranged between <0.075 and 3.14 mg m-3, and between <0.005 and 0.36 mg m-3, respectively. The result of this study is a JEM by mine, department, and year for RD and RS for epidemiological studies.

Population physiologically based pharmacokinetic modeling for the human lactational transfer of PCB-153 with consideration of worldwide human biomonitoring results.

BACKGROUND: One of the most serious human health concerns related to environmental contamination with polychlorinated biphenyls (PCBs) is the presence of these chemicals in breast milk. OBJECTIVES: We developed a physiologically based pharmacokinetic model of PCB-153 in women, and predict its transfer via lactation to infants. The model is the first human, population-scale lactational model for PCB-153. Data in the literature provided estimates for model development and for performance assessment. METHODS: We used physiologic parameters from a cohort in Taiwan and reference values given in the literature to estimate partition coefficients based on chemical structure and the lipid content in various body tissues. Using exposure data from Japan, we predicted acquired body burden of PCB-153 at an average childbearing age of 25 years and compared predictions to measurements from studies in multiple countries. We attempted one example of reverse dosimetry modeling using our PBPK model for possible exposure scenarios in Canadian Inuits, the population with the highest breast milk PCB-153 level in the world. RESULTS: Forward-model predictions agree well with human biomonitoring measurements, as represented by summary statistics and uncertainty estimates. CONCLUSION: The model successfully describes the range of possible PCB-153 dispositions in maternal milk, suggesting a promising option for back-estimating doses for various populations.

Pulmonary injury associated with spray of a water-based nano-sized waterproofing product: a case study.

BACKGROUND: In most reported cases of lung trauma with water proofing products, volatile organic compounds (VOC) have a prominent role. Here we report on a case involving ten workers exposed to a sprayed product containing nanoparticles in a water solution with only a few percent VOC. CASE PRESENTATION: Ten workers suffered from respiratory symptoms following spray impregnation of hardwood furniture using a waterproofing product that contained positively charged fluorinated acrylate copolymer solid cores with a median diameter of 70 nm (1.3 w%) in aqueous suspension with 3.3 w% VOC and 0.3 w% quaternary ammonium. The worker who applied one liter of the product in a wood workshop, using an air mix spray gun, did not report any health complaints. Another worker, who entered the workshop 3 h later and had rolled and smoked two cigarettes, was hospitalized with severe chemical pneumonitis. A chest X-ray (CXR) showed bilateral infiltrative impairment in the lower lobe regions. On the next day a second CXR showed increased patchiness marking in all fields. A high-resolution Computer Tomography (CT)-scan demonstrated extensive bilateral areas of ground-glass opacities predominantly in the lower regions of the upper lobes, the right middle lobe and the apical regions of the lower lobes, compatible with severe chemical pneumonitis. On the following morning, nine workers in an adjacent workplace in the same building, experienced dry cough, chest tightness and substernal pain upon physical exercise. Reconstruction of the spray application in a climate chamber confirmed trimethyl silanol, glycol ethers and fluoroalkenes in the gas phase. Immediately after the spray application, aerosols were observed at a maximum concentration of 6.3 × 104 cm-3. Mass concentrations were 0.095 and 10 mg/m3 in the size ranges 5.6-560 nm and 0.22-30 µm, respectively, decreasing to less than 10 µg/m3 in both size ranges after 15 h. CONCLUSION: The hospitalized worker had smoked cigarettes contaminated with fluoropolymers which is a plausible explanation for the lung trauma. Respiratory symptoms in the nine workers may be caused by inhalation of particles that became airborne by resuspension from surfaces when workers entered the adjacent workplace the next day. A contribution from VOC appears less likely because measurements and modelling showed that concentrations in the mg/m3 range could have occurred only if the building was assumed to be completely airtight.