John P. Creason

Comparison of chlordimeform and carbaryl using a functional observational battery

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.

Particulate matter and heart rate variability among elderly retirees: the Baltimore 1998 PM study.

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°F mean daily temperature) with low to moderate levels of fine particles (PM2.5 <50 μg/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-trajectoryof 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 μg/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 μg/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 μg/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.

Coarse particulate matter (PM2.5- 10) affects heart rate variability, blood lipids, and circulating eosinophils in adults with asthma

Introduction We investigated whether markers of airway and systemic inflammation, as well as heart rate variability (HRV) in asthmatics, change in response to fluctuations in ambient particulate matter (PM) in the coarse [PM with aerodynamic diameter 2.5–10 μm (PM2.5–10)] and fine (PM2.5) size range. Methods Twelve adult asthmatics, living within a 30-mile radius of an atmospheric monitoring site in Chapel Hill, North Carolina, were followed over a 12-week period. Daily PM2.5–10 and PM2.5 concentrations were measured separately for each 24-hr period. Each subject had nine clinic visits, at which spirometric measures and peripheral blood samples for analysis of lipids, inflammatory cells, and coagulation-associated proteins were obtained. We also assessed HRV [SDNN24HR (standard deviation of all normal-to-normal intervals in a 24-hr recording), ASDNN5 (mean of the standard deviation in all 5-min segments of a 24-hr recording)] with four consecutive 24-hr ambulatory electrocardiogram measurements. Linear mixed models with a spatial covariance matrix structure and a 1-day lag were used to assess potential associations between PM levels and cardiopulmonary end points. Results For a 1-μg/m3 increase in coarse PM, SDNN24HR, and ASDNN5 decreased 3.36% (p = 0.02), and 0.77%, (p = 0.05) respectively. With a 1-μg/m3 increase in coarse PM, circulating eosinophils increased 0.16% (p = 0.01), triglycerides increased 4.8% (p = 0.02), and very low-density lipoprotein increased 1.15% (p = 0.01). No significant associations were found with fine PM, and none with lung function. Conclusion These data suggest that small temporal increases in ambient coarse PM are sufficient to affect important cardiopulmonary and lipid parameters in adults with asthma. Coarse PM may have underappreciated health effects in susceptible populations.

Modeling the Ames test

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 models 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.

Nickel absorption and kinetics in human volunteers

Abstract 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 μg of nickel/kg, n = 4; 18 μg of nickel/kg, n = 4; or 50 μg 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 1998 Baltimore Particulate Matter Epidemiology-Exposure Study: Part 1. Comparison of Ambient, Residential Outdoor, Indoor and Apartment Particulate Matter Monitoring

A combined epidemiological–exposure panel study was conducted during the summer of 1998 in Baltimore, Maryland. The objectives of the exposure analysis component of the 28-day study were to investigate the statistical relationships between particulate matter (PM) and related co-pollutants from numerous spatial boundaries associated with an elderly population, provide daily mass concentrations needed for the epidemiological assessment, and perform an extensive personal exposure assessment. Repeated 24-h integrated PM2.5 (n=394) and PM10 (n=170) data collections corresponding to stationary residential central indoor, individual apartment, residential outdoor and ambient monitoring were obtained using the same sampling methodology. An additional 325 PM2.5 personal air samples were collected from a pool of 21 elderly (65+ years of age) subjects. These subjects were residents of the 18-story retirement facility where residential monitoring was conducted. Mean daily central indoor and residential apartment concentrations were approximately 10 µg/m3. Outdoor and ambient PM2.5 concentrations averaged 22 µg/m3 with a daily range of 6.7–59.3 µg/m3. The slope of the central indoor/outdoor PM2.5 mass relationship was 0.38. The average daily ratio of PM2.5/PM10 mass co ncentrations across the measurement sites ranged from 0.73 to 0.92. Both the central indoor and mean apartment PM2.5 mass concentrations were highly correlated with the outdoor variables (r>0.94). The lack of traditionally recognized indoor sources of PM present within the facility might have accounted for the high degree of correlation observed between the variables. Results associated with the personal monitoring effort are discussed in depth in Part 2 of this article.

The 1998 Baltimore Particulate Matter Epidemiology–Exposure Study: Part 2. Personal exposure assessment associated with an elderly study population

An integrated epidemiological–exposure panel study was conducted during the summer of 1998 which focused upon establishing relationships between potential human exposures to particulate matter (PM) and related co-pollutants with detectable health effects. The study design incorporated repeated individual 24-h integrated PM2.5 personal exposure monitoring. A total of 325 PM2.5 personal exposure samples were obtained during a 28-day study period using a subject pool of 21 elderly (65+ years of age) residents of an 18-story retirement facility near Baltimore, Maryland. Each sample represented a unique 24-h breathing zone measurement of PM2.5 mass concentration. PM2.5 and PM10 mass concentrations collected from the apartments of the subjects as well as residential and ambient sites were compared to individual and mean PM2.5 personal exposures. Daily PM2.5 personal exposure concentrations ranged from 2.4 to 47.8 µg/m3 with an overall individual study mean of 12.9 µg/m3. Mean PM2.5 personal exposures were determined to be highly correlated to those representing the central indoor (r=0.90) and ambient sites (r=0.89). Subjects reported spending an average of 92% of each day within the confines of the retirement center. Based upon measured and modeled exposures, a mean PM2.5 personal cloud of 3.1 µg/m3 was estimated. Data collected from these participants may be unique with respect to the general elderly population due to the communal lifestyle within the facility and reported low frequency of exposure to sources of PM.

Temperature-dependent changes in visual evoked potentials of rats☆

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.

The relationships between personal PM exposures for elderly populations and indoor and outdoor concentrations for three retirement center scenarios

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 μg/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.

Data Evaluation and Statistical Analysis of Functional Observational Battery Data Using a Linear Models Approach

Statistical analysis of functional observational battery (FOB) data presents special problems in that there are three different types of data collected (continuous, count, and categorical), all of which are measured in a repeated manner across time. Initial measurements are made before any treatment is applied, and proper use of these individual control values must be determined. A coherent structure for the analysis of such data is laid out, and examples of applications are presented. Rationale for the approaches used are described. Behavioral characteristics of the statistical tests are summarized for one FOB experiment to show that the tests indeed perform properly. The availability and ease of use of the SAS statistical software employed, including the key analysis procedures PROC CATMOD and PROC GLM, and of the SASGRAPH graphics procedures and their importance to data evaluation in the FOB are fully described. Cautions about these procedures and further statistical research and development needs are summarized.