Debra Walsh

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.

DNA adducts and chronic degenerative diseases. Pathogenetic relevance and implications in preventive medicine

Chronic degenerative diseases are the leading causes of death in developed countries. Their control is exceedingly difficult due to their multiplicity and diversity, the interconnection with a network of multiple risk factors and protective factors, the long latency and multistep pathogenesis, and the multifocal localization. Adducts to nuclear DNA are biomarkers evaluating the biologically effective dose, reflecting an enhanced risk of developing a mutation-related disease more realistically than the external exposure dose. The localization and accumulation of these promutagenic lesions in different organs are the composite result of several factors, including (a) toxicokinetics (first-pass effect); (b) local and distant metabolism; (c) efficiency and fidelity of DNA repair; and (d) cell proliferation rate. The last factor will affect not only the dilution of DNA adducts but also the possible evolution towards either destructive processes, such as emphysema or cardiomyopathies, or proliferative processes, such as benign or malignant tumors at various sites. They also include heart tumors affecting fetal myocytes after transplacental exposure to DNA-binding agents, blood vessel tumors, and atherosclerotic plaques. In this article, particular emphasis is given to molecular alterations in the heart, which is the preferential target for the formation of DNA adducts in smokers, and in human aorta, where an extensive molecular epidemiology project is documenting the systematic presence of adducts to the nuclear DNA of smooth muscle cells from atherosclerotic lesions, and their significant correlation with known atherogenic risk factors. Exocyclic DNA adducts resulting from lipid peroxidation, and age-related indigenous adducts (I-compounds) may also originate from endogenous sources, chronic infections and infestations, and inflammatory processes. Type II I-compounds are bulky DNA lesions resulting from oxidative stress, whereas type II-compounds are presumably normal DNA modifications, which display positive correlations with median life span and are decreased in cancer and other pathological conditions. Profiles of type II-compounds strongly depend on diet and are related to the antidegenerative effects of caloric/ dietary restriction. Even broader is the possible meaning of adducts to mitochondrial DNA, which have been detected in rodents exposed to genotoxic agents and complex mixtures, as well as in untreated rodents, in larger amounts when compared to the nuclear DNA of the same cells. Mutations in mitochondrial DNA increase the number of oxidative phosphorylation-defective cells, especially in energy-requiring postmitotic tissues such as brain, heart and skeletal muscle, thereby playing an important role in aging and a variety of chronic degenerative diseases. A decreased formation of DNA adducts is an indicator of reduced risk of developing the associated disease. Therefore, these molecular dosimeters can be used as biomarkers in the prevention of chronic degenerative diseases, pursued either by avoiding exposure to adduct-forming agents or by using chemopreventive agents. Interventions addressed to the human organism by means of dietary measures or pharmacological agents have encountered a broad consensus in the area of cardiovascular diseases, and are deserving a growing interest also in cancer prevention. The efficacy of chemopreventive agents can be assessed by evaluating inhibition of nuclear DNA or mitochondrial DNA adduct formation in vitro, in animal models, and in phase II clinical trials in high-risk individuals.

Air pollution exposure–DNA adduct dosimetry in humans and rodents: evidence for non-linearity at high doses

The impact of air pollution exposure on the level of total DNA adducts in human white blood cells (WBCs) was evaluated in two populations in the Czech Republic and compared to the exposure-DNA adduct relationship in other populations in the US and China in human lung cells and rodent lung tissue. The human populations examined were exposed to respirable particles (< 2.5 microm) (PM2.5) in urban, rural, and occupational settings where the particles originated from coal and petroleum fuel combustion, coke production, and other coal-tar aerosols (e.g., used in aluminum production). These particles contain carcinogenic polycyclic aromatic hydrocarbons (PAHs) that are known to form DNA adducts through covalent binding. Personal exposure to PM2.5 and PAHs were measured prior to collection of blood samples for DNA adduct analysis by 32P-postlabeling. Coke oven workers (n = 76), in 10 job categories on the top and side of a coke oven in Ostrava, CZ, were studied and compared to a different population exposed to environmental levels of PAHs from air pollution in Teplice, CZ. Personal exposures to airborne particles ranged from < 1 to more than 15,000 microg/m3 and carcinogenic PAHs exposure ranged from < 5 to > 200,000 ng/m3. At low to moderate environmental exposures to carcinogenic PAHs, DNA adduct levels in the WBCs were significantly correlated with exposure. However, at the higher occupational levels found on the coke oven, the exposure-DNA adduct relationship became non-linear. Under these high exposure conditions, the relative DNA adduct level per unit of exposure (DNA-binding potency) was significantly lower than measured at environmental exposures. This finding is consistent with observations in lung cells from bronchoalveolar lavage of humans exposed to a wide range of PAH. This same high exposure-dose non-linearity was also observed in lung DNA from rats exposed by inhalation to a coal-tar pitch aerosol. DNA adduct levels in all these cases show evidence of a form of non-linearity at high doses that has been described by Lutz (W.K. Lutz, Dose-response relationship and low dose extrapolation in chemical carcinogenesis, Carcinogenesis, 11 (1990) 1243-1247) as a superlinear dose response. This superlinear response may be due to saturation of metabolic activation enzymes, induction of either DNA repair processes or detoxification enzymes, or other mechanisms. Regardless of the mechanism, this decrease in the DNA-binding potency at moderate to high doses of PAH has important implications for dose-response extrapolation in risk assessment.

Use of a continuous nephelometer to measure personal exposure to particles during the U.S. Environmental Protection Agency Baltimore and Fresno panel studies

ABSTRACT In population exposure studies, personal exposure to PM is typically measured as a 12- to 24-hr integrated mass concentration. To better understand short-term variation in personal PM exposure, continuous (1-min averaging time) nephelometers were worn by 15 participants as part of two U.S. Environmental Protection Agency (EPA) longitudinal PM exposure studies conducted in Baltimore County, MD, and Fresno, CA. Participants also wore iner-tial impactor samplers (24-hr integrated filter samples) and recorded their daily activities in 15-min intervals. In Baltimore, the nephelometers correlated well (R2 = 0.66) with the PM25 impactors. Time-series plots of personal nephelometer data showed each participants PM exposure to consist of a series of peaks of relatively short duration. Activities corresponding to a significant instrument response included cooking, outdoor activities, transportation, laundry, cleaning, shopping, gardening, moving between microenvironments, and removing/putting on the instrument. On average, 63-66% of the daily PM exposure occurred indoors at home (about 2/3 of which occurred during waking hours), primarily due to the large amount of time spent in that location (an average of 7277%). Although not a reference method for measuring mass concentration, the nephelometer did help identify PM sources and the relative contribution of those sources to an individuals personal exposure.

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.

An analysis by chemical class of Salmonella mutagenicity tests as predictors of animal carcinogenicity

For a number of years, investigators have recognized that humans potentially are exposed to large numbers of genotoxicants. Many efforts have attempted to validate various short-term bioassays for use as rapid, inexpensive screens for genotoxicants--especially carcinogens. In this analysis, we examine Salmonella mutagenicity as an indicator of potential carcinogenicity by comparing published (and when possible, evaluated) Salmonella results with the evaluated Gene-Tox animal carcinogen data base. The Salmonella bioassay does especially well in those cases where the level of evidence for carcinogenicity is the strongest. Analysis shows that except for specific classes of compounds, the plate-incorporation protocol and the preincubation protocol are equally efficient at detecting mutagens. This paper also demonstrates how validation values (sensitivity, specificity, etc.) vary with chemical class. Overall, this analysis demonstrates that when used and interpreted in a meaningful chemical class context, the Salmonella bioassay remains extremely useful in identifying potential animal carcinogens.

Gas chromatographic analysis of chlorophenylmercapturic acid lindane metabolites

An analytical method for phenols has been adapted for the analysis of chlorophenylmercapturic acids in rat urine. Chlorothiophenols were produced from the mercapturic acids by hydrolytic cleavage with sodium hydroxide. Acetate esters of the chlorothiophenols were formed by addition of acetic anhydride to the aqueous alkaline solution. After acylation, the acetate derivatives were extracted into hexane. Forming the acetate esters of the chlorothiophenols prevented their oxidation to disulfides and significantly improved their chromatographic properties. Electron-capture gas chromatographic analysis of the stable acetate esters was performed on a mixed phase column, 4% SE-30 + 6% OV-210. Recoveries of four chlorothiophenols ranged from 82 to 93%. This method required no sample transfer steps; therefore, sample loss and analysis time were minimized.

A pilot study of global positioning system/geographical information system measurement of residential proximity to agricultural fields and urinary organophosphate metabolite concentrations in toddlers

This pilot study enrolled 20 children between the ages of 11 and 17 months in Imperial County, California to assess childrens pesticide exposure and residential proximity to agricultural fields. We compared parental self-report of residential proximity to agricultural fields to measurements using global positioning system/geographical information system (GPS/GIS) technology, and we assessed the relationship between residential proximity to agricultural fields and a biomarker of organophosphate (OP) pesticide exposure. Questionnaires were administered twice, 4 weeks apart, to determine self-reported residential proximity to agricultural fields. Urine samples were collected at each contact to measure OP metabolites. Actual residential proximity to the closest agricultural field and number of fields was within 1 mile to the west were measured using GPS/GIS. Self-report of living proximity to agricultural fields agreed with GPS/GIS measurement 75% of the time during the initial interview, compared to 66% agreement during the second interview. Presence of urinary metabolites suggests that OP exposure was ubiquitous: creatinine-adjusted total urinary dimethyl values ranged from 1.60 to 516.00 μg/g creatinine, and total diethyl ranged from 2.70 to 134.84 μg/g creatinine. No association was found between urinary OP metabolites and residential to field proximity. These results suggest that initial self-report of living proximity to agricultural fields may be more accurate than follow-up self-report. Limitations in this pilot study prevent determination of whether self-report is an accurate measure of proximity.

The 1999 Fresno Particulate Matter Exposure Studies: Comparison of Community, Outdoor, and Residential PM Mass Measurements

ABSTRACT 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 par-ticulate 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

GIS-Modeled Indicators of Traffic-Related Air Pollutants and Adverse Pulmonary Health Among Children in El Paso, Texas

Investigators examined 5,654 children enrolled in the El Paso, Texas, public school district by questionnaire in 2001. Exposure measurements were first collected in the late fall of 1999. School-level and residence-level exposures to traffic-related air pollutants were estimated using a land use regression model. For 1,529 children with spirometry, overall geographic information system (GIS)-modeled residential levels of traffic-related ambient air pollution (calibrated to a 10-ppb increment in nitrogen dioxide levels) were associated with a 2.4% decrement in forced vital capacity (95% confidence interval (CI): -4.0, -0.7) after adjustment for demographic, anthropomorphic, and socioeconomic factors and spirometer/technician effects. After adjustment for these potential covariates, overall GIS-modeled residential levels of traffic-related ambient air pollution (calibrated to a 10-ppb increment in nitrogen dioxide levels) were associated with pulmonary function levels below 85% of those predicted for both forced vital capacity (odds ratio (OR) = 3.10, 95% CI: 1.65, 5.78) and forced expiratory volume in 1 second (OR = 2.35, 95% CI: 1.38, 4.01). For children attending schools at elevations above 1,170 m, a 10-ppb increment in modeled nitrogen dioxide levels was associated with current asthma (OR = 1.56, 95% CI: 1.08, 2.50) after adjustment for demographic, socioeconomic, and parental factors and random school effects. These results are consistent with previous studies in Europe and California that found adverse health outcomes in children associated with modeled traffic-related air pollutants.