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Background: Identifying baseline inflammatory biomarkers that predict susceptibility to size-specific particulate matter (PM) independent of gaseous pollutants could help us better identify asthmatic subpopulations at increased risk for the adverse health effects of PM., Objective: To evaluate whether the association between lung function and exposure to ambient levels of PM less than 2.5 microm in diameter (PM2.5) (fine) and 10 to 2.5 microm in diameter (PM(10-2.5)) (coarse) in children with persistent asthma differed across baseline measures of inflammation and innate immune activation., Methods: We performed a panel study on a local population of 16 children with persistent asthma and evaluated daily pulmonary function (percentage of predicted peak expiratory flow and forced expiratory volume in 1 second) while concurrently measuring daily PM2.5 and PM(10-2.5) exposure from a central site in Chapel Hill, North Carolina. The children underwent a baseline medical evaluation that included assessment of several immunoinflammatory biomarkers in peripheral blood., Results: Children without measurable CD14 expression on circulating neutrophils had significantly reduced pulmonary function (forced expiratory volume in 1 second and peak expiratory flow) with each interquartile range (IQR) increase in PM2.5 (IQR = 8.5 microg/m3) and PM(10-2.5) (IQR = 4.1 microg/m3) concentration, unlike children with measurable CD14 expression (P < .001 for interaction)., Conclusions: Asthmatic children with muted surface expression of CD14 on circulating neutrophils may have a decreased capacity to respond to bacterial components of PM.

The primary objective of this study is to characterize the genotoxic potential of the ambient air aerosols collected within an air shed impacted primarily by wood smoke and automotive emissions. The study also examines the relative merits of a microsuspension assay and the standard plate assay for monitoring the presence of airborne particle-bound mutagens. Wintertime ambient air particulate samples collected from Boise, Idaho, USA, were shown to contain extractable organic matter that is mutagenic in the Salmonella typhimurium microsuspension and plate-incorporation assays. Differences in the results from the primary sites, auxiliary sites and the background site demonstrate that the particle-bound mutagens are not evenly distributed within the air shed and are more associated with the location of sampling than with the time of sampling or the type of bioassay used to evaluate the samples. This study also demonstrates that the bioassay protocol used in such studies should depend upon the characteristics of the air shed's mutagens and the purpose of the study. For example, the microsuspension assay gave somewhat more variable results between samples but was approximately threefold more sensitive than the plate assay. When strain TA98 was used in the microsuspension assay, the mutagenic response was greater without an exogenous activation system. The reverse was true for the plate assay in which the use of an exogenous activation system increased the mutagenicity response. TA100 in the microsuspension assay provided results comparable to those with TA98. This is important because TA100 can also be used to bioassay semivolatile and volatile organics associated with ambient air mutagenicity. This, in turn, allows a comparison of the mutagenicity of organics collected by differing methods due to their volatility. Future studies should be directed toward correlation of mutagenicity results with other analytical results in order to further develop methods for better characterization of the genotoxicity of ambient air.

This study investigates the relationship between ambient fine particle pollution and impaired cardiac autonomic control in the elderly. Heart rate variability (HRV) among 56 elderly (mean age 82) nonsmoking residents of a retirement center in Baltimore County, Maryland, was monitored for 4 weeks, from July 27 through August 22, 1998. The weather was seasonally mild (63-84 degrees F mean daily temperature) with low to moderate levels of fine particles (PM2.5 < 50 micrograms/m3). Two groups of approximately 30 subjects were examined on alternate days. A spline mixed-effects model revealed a negative relationship between outdoor 24-h average fine particulate matter (PM2.5) and high-frequency (HF) HRV that was consistent with our earlier Baltimore study for all but 2 days. These 2 days were the only days with significant precipitation in combination with elevated PM2.5. They were also unusual in that back-trajectory of their air masses was distinctly different from those on the other study days, emanating from the direction of rural Pennsylvania. Mixed-effects analysis for all 24 study days showed a small negative association of outdoor PM2.5 with HF HRV (-0.03 change in log[HF HRV] for a 10 micrograms/m3 increment in PM2.5) after adjustment for age, sex, cardiovascular status, trend, maximum temperature, average dew point temperature, random subject intercepts, and autocorrelated residuals. After excluding study days 4 and 5, this association was strengthened (-0.07 change in log[HF HRV] for 10 micrograms/m3 PM2.5, 95% CI -0.13 to -0.02) and was similar to that obtained in an earlier study (-0.12 change in log[HF HRV] for a 10 micrograms/m3 increment in outdoor PM2.5, 95% CI -0.24 to -0.00) [Liao D., Cai J., Rosamond W.D., Barnes R.W., Hutchinson R.G., Whitsel E.A., Rautaharju P., and Heiss G. Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study. The ARIC Study. Atherosclerosis Risk in Communities Study. Am J Epidemiol 1997: 145 (8): 696-706]. Acute (1 to 4 h) previous PM2.5 exposure did not have a stronger impact than the 24-h measure. A distributed lag model incorporating the six preceding 4-h means also did not indicate any effect greater than that observed in the 24-h measure. This study is consistent with earlier findings that exposures to PM2.5 are associated with decreased HRV in the elderly.

Personal exposures, indoor and outdoor concentrations, and questionnaire data were collected in three retirement center settings, supporting broader particulate matter (PM)--health studies of elderly populations. The studies varied geographically and temporally, with populations studied in Baltimore, MD in the summer of 1998, and Fresno, CA in the winter and spring of 1999. The sequential nature of the studies and the relatively rapid review of the mass concentration data after each segment provided the opportunity to modify the experimental designs, including the information collected from activity diary and baseline questionnaires and influencing factors (e.g., heating, ventilation, and air-conditioning (HVAC) system operation, door and window openings, air exchange rate) measurements. This paper highlights both PM2.5 and PM10 personal exposure data and interrelationships across the three retirement center settings, and identifies the most probable influencing factors. The current limited availability of questionnaire results, and chemical speciation data beyond mass concentration for these studies, provided only limited capability to estimate personal exposures from models and apportion the personal exposure collections to their sources. The mean personal PM2.5 exposures for the elderly in three retirement centers were found to be consistently higher than the paired apartment concentrations by 50% to 68%, even though different facility types and geographic locations were represented. Mean personal-to-outdoor ratios were found to 0.70, 0.82, and 1.10, and appeared to be influenced by the time doors and windows were open and aggressive particle removal by the HVAC systems. Essentially identical computed mean PM2.5 personal clouds of 3 micrograms/m3 were determined for two of the studies. The proposed significant contributing factors to these personal clouds were resuspended particles from carpeting, collection of body dander and clothing fibers, personal proximity to open doors and windows, and elevated PM levels in nonapartment indoor microenvironments.

Two collaborative studies have been conducted by the U.S. Environmental Protection Agency (EPA) National Exposure Research Laboratory (NERL) and National Health and Environmental Effects Research Laboratory to determine personal exposures and physiological responses to particulate matter (PM) of elderly persons living in a retirement facility in Fresno, CA. Measurements of PM and other criteria air pollutants were made inside selected individual residences within the retirement facility and at a central outdoor site on the premises. In addition, personal PM exposure monitoring was conducted for a subset of the participants, and ambient PM monitoring data were available for comparison from the NERL PM research monitoring platform in central Fresno. Both a winter (February 1-28, 1999) and a spring (April 19-May 16, 1999) study were completed so that seasonal effects could be evaluated. During the spring study, a more robust personal exposure component was added, as well as a more detailed evaluation of physical factors, such as air-exchange rate, that are known to influence the penetration of particles into the indoor environment. In this paper, comparisons are made among measured personal PM exposures and PM mass concentrations measured at the NERL Fresno Platform site, outside on the premises of the retirement facility, and inside selected residential apartments at the facility during the two 28-day study periods. The arithmetic daily mean personal PM2.5 exposure during the winter study period was 13.3 micrograms/m3, compared with 9.7, 20.5, and 21.7 micrograms/m3 for daily mean overall apartment, outdoor, and ambient (i.e., platform) concentrations, respectively. The daily mean personal PM2.5 exposure during the spring study period was 11.1 micrograms/m3, compared with 8.0, 10.1, and 8.6 micrograms/m3 for the daily mean apartment, outdoor, and ambient concentrations, respectively.

An extensive PM monitoring study was conducted during the 1998 Baltimore PM Epidemiology-Exposure Study of the Elderly. One goal was to investigate the mass concentration comparability between various monitoring instrumentation located across residential indoor, residential outdoor, and ambient sites. Filter-based (24-h integrated) samplers included Federal Reference Method Monitors (PM2.5-FRMs), Personal Environmental Monitors (PEMs), Versatile Air Pollution Samplers (VAPS), and cyclone-based instruments. Tapered element oscillating microbalances (TEOMs) collected real-time data. Measurements were collected on a near-daily basis over a 28-day period during July-August, 1998. The selected monitors had individual sampling completeness percentages ranging from 64% to 100%. Quantitation limits varied from 0.2 to 5.0 microg/m3. Results from matched days indicated that mean individual PM10 and PM2.5 mass concentrations differed by less than 3 microg/m3 across the instrumentation and within each respective size fraction. PM10 and PM2.5 mass concentration regression coefficients of determination between the monitors often exceeded 0.90 with coarse (PM10-2.5) comparisons revealing coefficients typically well below 0.40. Only one of the outdoor collocated PM2.5 monitors (PEM) provided mass concentration data that were statistically different from that produced by a protoype PM2.5 FRM sampler. The PEM had a positive mass concentration bias ranging up to 18% relative to the FRM prototype.

GeneTox Manager (GTM) is a data capture, data management, and statistical analysis program used for microbial mutagenicity data. Its main purpose is to provide a homogeneous environment for the collection, organization, and analysis of data generated in the laboratory while also supporting a quality assurance program. The complete system consists of both a personal computer (PC) system and a minicomputer (VAX) system. The joint PC/VAX version of the system is designed to function with both the PC and VAX FOCUS databases so that the VAX can be used for long-term storage, archiving of files, and the analysis of large groups of data. Because of the highly specialized use and nature of the PC/VAX version, this discussion is focused upon the PC stand-alone version. The user-friendly system uses a structured menu system, screen entry helps, and other help screens. GTM provides tabular and graphical summaries of the data and performs specialized statistical analyses. This public domain software was written primarily using Clipper. The manuals and programs are now available through the government's National Technical Information Service.

A factorial experimental design was used within this study to evaluate the influence of multiple metabolic activation system concentrations on the dose-response exhibited by promutagens (indirect-acting mutagens) in the Salmonella spiral and plate assays. The mutagenic activity of the three compounds used spanned three orders of magnitude. The mutagenic activity of the compounds ranged from 10 to 100 revertants/micrograms for acetylaminofluorene (2AAF) to more than 1000 revertants/micrograms for 2-aminoanthracene (2AA). Benzo [a] pyrene (BaP) activity was within an intermediate range (100-1000 revertants/micrograms). During a single experiment, a mutagen was tested in TA100 at 13 doses plus a negative control dose. Each dose was tested at 10 S9 concentrations. The S9 concentrations ranged from 0.1 mg protein/plate to 4 mg protein/plate in the standard plate assay and from 0.25 to 4.90 mg-equivalents in the spiral assay. The spiral Salmonella assay, an automated version of the standard assay, generates dose-response data from a concentration gradient on a single agar plate, thereby providing a straightforward approach to this type of study. This study demonstrates not only that even small differences in S9 concentrations can affect the measurement of mutagenic potency but that S9/compound interactions cannot be generalized through the use of interaction studies. This study also shows that spiral assay data and plate assay data for promutagens cannot be compared directly unless the S9 concentrations for all chemical doses are also comparable.

Two experiments were conducted to determine the effects of hypothermia and pentobarbital anesthesia, alone and in combination, on the brain-stem auditory evoked responses (BAERs) of rats. In experiment I, unanesthetized rats were cooled to colonic temperatures 0.5 and 1.0 degrees C below normal. In experiment II, 2 groups of rats were cooled and tested at 37.5, 36.0, 34.5 and 31.5 degrees C. One group was anesthetized during testing and the other group was awake. The rat BAER was sensitive to cooling of 1 degree C or less. Peak latencies were prolonged and peak-to-peak amplitudes were increased by hypothermia alone. The effect on amplitude may be related to the time course of temperature change or to stimulus level. Pentobarbital significantly affected both latencies and amplitudes over and above the effects of cooling. The specific effects of pentobarbital differed by BAER peak and by temperature. The findings point up the importance of the potential confound of anesthetic drugs in most of the evoked potential literature on hypothermia and, for the first time, quantify the complex interactions between pentobarbital and temperature which affect the BAER wave form.

2,6-Dinitrotoluene (2,6-DNT) and pentachlorophenol (PCP) are used for industrial purposes and are found in the environment as hazardous contaminants. Because concurrent exposure to both compounds can occur, it is of interest to determine if organochlorine compounds potentiate the effect of nitroaromatic chemicals. CD-1 mice were treated with PCP (42.8 mg/kg) for 4 weeks. On weeks 1, 2, and 4 after the initial PCP dose, mice were treated p.o. with 2,6-DNT (75 mg/kg) and 24 hr urines were collected. After concentration, the urines were tested for their mutagenic activity in Salmonella typhimurium strain TA98 without metabolic activation in a microsuspension bioassay. A significant increase (P less than .05) in mutagenicity was observed in urines from mice treated with 2,6-DNT alone and in combination with PCP. By week 4, mice that received both 2,6-DNT and PCP excreted urine that was more mutagenic than that from animals which received only 2,6-DNT. At weeks 2 and 4, mice were sacrificed and intestinal enzyme activities (nitroreductase, azo reductase, beta-glucuronidase, dechlorinase, and dehydrochlorinase) were quantitated. The enhanced genotoxicity observed in urines from 2,6-DNT/PCP-treated mice coincided with a decrease in nitroreductase and an increase in beta-glucuronidase activities in the small intestine.

A variety of linear and nonlinear mathematical models have been proposed to characterize Salmonella mutagenicity data sets, but no systematic procedure has been suggested for comparing two or more data sets across experiments, laboratories, occasions, mutagens or treatment conditions. In this paper, a general method for data-set comparison is provided. Nonlinear regression techniques are applied to real data sets. Data-set and parameter equivalence are described in depth. Confidence-band construction for nonlinear models and other graphical techniques are presented as auxiliary tools. Key Statistical Analysis System (SAS) code programs are provided.

Mathematical modeling of the kinetics of nickel absorption, distribution, and elimination was performed in healthy human volunteers who ingested NiSO4 drinking water (Experiment 1) or added to food (Experiment 2). Nickel was analyzed by electrothermal atomic absorption spectrophotometry in serum, urine, and feces collected during 2 days before and 4 days after a specified NiSO4 dose (12 micrograms of nickel/kg, n = 4; 18 micrograms of nickel/kg, n = 4; or 50 micrograms of nickel/kg, n = 1). In Experiment 1, each of the subjects fasted 12 hr before and 3 hr after drinking one of the specified NiSO4 doses dissolved in water; in Experiment 2, the respective subjects fasted 12 hr before consuming a standard American breakfast that contained the identical dose of NiSO4 added to scrambled eggs. Kinetic analyses, using a compartmental model, provided excellent goodness-of-fit for paired data sets from all subjects. Absorbed nickel averaged 27 +/- 17% (mean +/- SD) of the dose ingested in water vs 0.7 +/- 0.4% of the same dose ingested in food (a 40-fold difference); rate constants for nickel absorption, transfer, and elimination were not significantly influenced by the oral vehicle. The elimination half-time for absorbed nickel averaged 28 +/- 9 hr. Renal clearance of nickel averaged 8.3 +/- 2.0 ml/min/1.73 m2 in Experiment 1 and 5.8 +/- 4.3 ml/min/1.73 m2 in Experiment 2. This study confirms that dietary constituents profoundly reduce the bioavailability of Ni2+ for alimentary absorption; approximately one-quarter of nickel ingested in drinking water after an over-night fast is absorbed from the human intestine and excreted in urine, compared with only 1% of nickel ingested in food. The compartmental model and kinetic parameters provided by this study will reduce the uncertainty of toxicologic risk assessments of human exposures to nickel in drinking water and food.

The spatial variation of site-specific cancer mortality rates at the county or state economic area level can provide a) insights into possible etiologic factors and b) the basis for more detailed epidemiologic studies. One difficulty with such studies, especially for rare cancer types, is that unstable local area rate estimates, resulting from small population sizes, can obscure the underlying spatial pattern of disease risk. This paper presents a methodology for producing more stable rate estimates by statistically weighting the local area rate estimate toward the experience at the national level. The methodology is illustrated by the analysis of the spatial variation of two cancer types, bladder and lung, for U.S. white males over the three decades 1950-79.

The effects of alterations in body temperature on flash and pattern reversal evoked potentials (FEPs and PREPs) were examined in hooded rats whose thermoregulatory capacity was compromised with lesions of the preoptic/anterior hypothalamic area and/or cold restraint. Body temperature, measured with a rectal thermometer, was manipulated via exposure to different ambient temperatures. To describe the data, a model was used in which both linear and quadratic relationships could be estimated. PREP amplitudes were not significantly influenced by body temperature over the range of 27-42 degrees C, although in one experiment FEP amplitudes did show a linear decline as temperatures fell below approximately 30 degrees C. Both FEP and PREP latencies were strongly influenced by temperature and became progressively longer as body temperature was lowered. The non-linear component affecting latencies became more prominent as body temperature decreased. These data demonstrate the temperature dependence of FEP and PREP latencies independent of anesthetic or other drugs.

Compartment model approaches have been proposed for the analysis of the age incidence of specific types of cancer. These models represented the age increases in incidence as the result of a compound hazard function where individual level risks were described by the Weibull hazard function and where the population level hazard rate is a continuous mixture of the Weibull hazards. These formulations assumed that the mixing function, which described differences in risk due to different exposure histories, was constant after the age at which the model was first applied. In this paper we show how the mixing distribution can be allowed to change with time reflecting changing exposures. The model is fitted to U.S. lung cancer mortality data where for recent male cohorts there appear to be changing patterns of exposure possibly related to recent declines in male smoking. The implications for future lung cancer mortality trends in the United States are discussed.

Previous studies have revealed that trace element concentrations in hair can reflect exposure in cases of frank poisoning and deficiency. This study reports significant correlations within a single metropolitan area between trace-element content of hair and exposure (as measured by analyses for the corresponding elements in dustfall or housedust) for Ba, Cr, Pb, Hg, Ni, Sn, and V. Age, sex, hair color, and smoking habits were factors included in the statistical evaluation. Several metals increase and decrease together in the hair specimens, in agreement with trends reported for other human tissues.

Despite the value and widespread use of the Ames test, little attention has been focused on standardizing quantitative methods of analyzing these data. In this paper, a realistic and statistically tractable model is developed for the evaluation of Ames-type data. The model assumes revertant colony formation at any dose follows a Poisson process, while the mean number of revertants per plate is a nonlinear function of up to 4 parameters. An exponential decay term can be included in the model to adjust for toxicity. The resultant system of nonlinear equations is solved using a modified Gauss-Newton iterative scheme to obtain maximum likelihood estimates of the model parameters. Significance of the key parameters is tested by fitting reduced models and using likelihood ratio tests. The model's performance is demonstrated on data from organic extracts of various environmental contaminants. Among the advantages of the proposed model are (1) no data is discarded in the parameter estimation process, (2) no arbitrary constants need to be added to zero counts or doses, and (3) no mathematical transformation of the data is required.

"The geographic mapping of age-standardized, cause-specific death rates is a powerful tool for identifying possible etiologic factors, because the spatial distribution of mortality risks can be examined for correlations with the spatial distribution of disease-specific risk factors. This article presents a two-stage empirical Bayes procedure for calculating age-standardized cancer death rates, for use in mapping, which are adjusted for the stochasticity of rates in small area populations. Using the adjusted rates helps isolate and identify spatial patterns in the rates. The model is applied to sex-specific data on U.S. county cancer mortality in the white population for 15 cancer sites for three decades: 1950-1959, 1960-1969, and 1970-1979. Selected results are presented as maps of county death rates for white males.", (excerpt)

The effects of the formamidine pesticide chlordimeform (CDM), and the carbamate carbaryl (CAR) were compared using a functional observational battery (FOB). The FOB, a series of observations and measurements that can be rapidly administered to toxicant-treated rats, includes home-cage and open-field observations, neuromuscular and sensorimotor tests, and physiological measures. Evaluations were made according to U.S. Environmental Protection Agency testing guidelines so as to determine dose-, time-, and sex-related toxicant effects. Long-Evans hooded rats of both sexes were tested initially and then dosed ip with either vehicle, CDM (1, 25, 56 mg/kg) or CAR (3, 10, 30 mg/kg), and tested at various times after dosing (for CDM 1, 5, 24 hr; for CAR 0.5, 3, 24, 48 hr). Both compounds affected general activity (home-cage and open-field), equilibrium, CNS excitability, and sensory responsiveness. Whereas similar decreases were obtained on rearing, gait, and arousal, there were important qualitative differences in the effects of CAR and CDM on reactions to handling and the reflex tests in that CDM increased excitability and enhanced responses to several stimuli but CAR either had no effect or decreased these measures. Only CDM produced an increase in muscle tone as measured by grip strength, and only CAR produced cholinergic autonomic signs of intoxication. Body weight and temperature were decreased by both compounds. Thus, the profiles of effect produced by these two pesticides could be clearly differentiated using the FOB.