Kent Thomas

Exposure Assessment in the National Children’s Study: Introduction

The science of exposure assessment is relatively new and evolving rapidly with the advancement of sophisticated methods for specific measurements at the picogram per gram level or lower in a variety of environmental and biologic matrices. Without this measurement capability, environmental health studies rely on questionnaires or other indirect means as the primary method to assess individual exposures. Although we use indirect methods, they are seldom used as stand-alone tools. Analyses of environmental and biologic samples have allowed us to get more precise data on exposure pathways, from sources to concentrations, to routes, to exposure, to doses. They also often allow a better estimation of the absorbed dose and its relation to potential adverse health outcomes in individuals and in populations. Here, we make note of various environmental agents and how best to assess exposure to them in the National Children’s Study—a longitudinal epidemiologic study of children’s health. Criteria for the analytical method of choice are discussed with particular emphasis on the need for long-term quality control and quality assurance measures.

Mortality in the agricultural health study, 1993-2007.

Comparing agricultural cohorts with the general population is challenging because the general healthiness of farmers may mask potential adverse health effects of farming. Using data from the Agricultural Health Study, a cohort of 89,656 pesticide applicators and their spouses (N = 89, 656) in North Carolina and Iowa, the authors computed standardized mortality ratios (SMRs) comparing deaths from time of the enrollment (1993-1997) through 2007 to state-specific rates. To compensate for the cohorts overall healthiness, relative SMRs were estimated by calculating the SMR for each cause relative to the SMR for all other causes. In 1,198,129 person-years of follow-up, 6,419 deaths were observed. The all-cause mortality rate was less than expected (SMR(applicators) = 0.54, 95% confidence interval (CI): 0.52, 0.55; SMR(spouses) = 0.52, 95% CI: 0.50, 0.55). SMRs for all cancers, heart disease, and diabetes were significantly below 1.0. In contrast, applicators experienced elevated numbers of machine-related deaths (SMR = 4.15, 95% CI: 3.18, 5.31), motor vehicle nontraffic accidents (SMR = 2.80, 95% CI: 1.81, 4.14), and collisions with objects (SMR = 2.12, 95% CI: 1.25, 3.34). In the relative SMR analysis for applicators, the relative mortality ratio was elevated for lymphohematopoietic cancers, melanoma, and digestive system, prostate, kidney, and brain cancers. Among spouses, relative SMRs exceeded 1.0 for lymphohematopoietic cancers and malignancies of the digestive system, brain, breast, and ovary. Unintentional fatal injuries remain an important risk for farmers; mortality ratios from several cancers were elevated relative to other causes.

Design strategy for assessing multi-pathway exposure for children: the Minnesota Children's Pesticide Exposure Study (MNCPES).

Although children are exposed to a variety of environmental hazards, including pesticides, there is a scarcity of information available to estimate exposures realistically. This article reports on one of the first attempts to measure multi-pathway pesticide exposures in a population-based sample of urban and non-urban children. A design strategy was developed to assess multi-pathway pesticide exposures in children using personal exposure measurements in combination with complimentary measurements of biological markers of exposure, concentrations in relevant environmental media, and time spent in important microenvironments and participating in exposure-related activities. Sample collection and analysis emphasized measurement of three insecticides (i.e., chlorpyrifos, diazinon, and malathion) and one herbicide (i.e., atrazine). These compounds were selected because of their frequent use, presence in multiple environmental media, expected population exposures, and related hazard/toxicity. The study was conducted during the summer of 1997 in Minnesota and involved a stratified sample of households with children ages 3–12 years. Participants resided in either (a) the cities of Minneapolis and St. Paul (urban households), or (b) Rice and Goodhue Counties just south of the metropolitan area (non-urban households). Results from a residential inventory documenting storage and use of products containing the target pesticides were used to preferentially select households where children were likely to have higher exposures. The study successfully obtained pesticide exposure data for 102 children, including measurements of personal exposures (air, hand rinse, duplicate diet), environmental concentrations (residential indoor/outdoor air, drinking water, residential surfaces, soil), activity patterns (obtained by questionnaire, diary, videotaping), and internal dose (metabolites in urine).

Population-based dietary intakes and tap water concentrations for selected elements in the EPA Region V National Human Exposure Assessment Survey (NHEXAS)

A National Human Exposure Assessment Survey (NHEXAS) field study was performed in U.S. Environmental Protection Agency (EPA) Region V, providing population-based exposure distribution data for selected elements in several personal, environmental, and biological media. Population distributions are reported for the 11 elements that were measured in water and dietary samples. Dietary intakes and home tap water concentrations of lead, arsenic, and cadmium were further examined for intermedia associations, for differences between dietary exposure for adults and children, and to estimate the proportion of the population above health-based reference values (dietary) or regulatory action levels or maximum contaminant levels (water). Water lead and arsenic concentrations were significantly associated with dietary intake. Intake of all elements was higher from solid foods than from liquid foods (including drinking water). Dietary intakes of Pb, As, and Cd were greater than those calculated for intake from home tap water or inhalation on a µg/day basis. Median dietary intakes for the Region V population for Pb, As, and Cd were 0.10, 0.13, and 0.19 µg/kg bw/day, respectively. While Pb, As, and Cd concentrations in the foods consumed by 0 to 6-year-old children were similar to or lower than those for adults, dietary intakes calculated on a body weight basis were 1.5 to 2.5 times higher for young children. Intrapersonal intake differences accounted for most of the variance in short-term (daily) dietary intakes for Pb and As, while interpersonal differences accounted for more of the intake variance for Cd. Only small percentages of the population exceeded health-based intake reference values or concentrations equal to regulatory levels in water for Pb, As, and Cd.

Biomonitoring of exposure in farmworker studies.

Although biomonitoring has been used in many occupational and environmental health and exposure studies, we are only beginning to understand the complexities and uncertainties involved with the biomonitoring process—from study design, to sample collection, to chemical analysis—and with interpreting the resulting data. We present an overview of concepts that should be considered when using biomonitoring or biomonitoring data, assess the current status of biomonitoring, and detail potential advancements in the field that may improve our ability to both collect and interpret biomonitoring data. We discuss issues such as the appropriateness of biomonitoring for a given study, the sampling time frame, temporal variability in biological measurements to nonpersistent chemicals, and the complex issues surrounding data interpretation. In addition, we provide recommendations to improve the utility of biomonitoring in farmworker studies.

The challenge of assessing children's residential exposure to pesticides

In implementing the Food Quality Protection Act (FQPA) the U.S. Environmental Protection Agency (USEPA) has adopted a policy that the exposure factors and models used to assess and predict exposure to pesticides should generally be conservative. Some elements of exposure assessments for FQPA are screening level — they are both uncertain and conservative. If more realistic assessments are to be conducted, then research is required to reduce uncertainty associated with the factors and models used in the exposure assessments. To develop the strategy for conducting this research, critical exposure pathways and factors were identified, and the quality and quantity of data associated with default assumptions for exposure factors were evaluated. Then, based on our current understanding of the pathways that are potentially most important and most uncertain, significant research requirements were identified and prioritized to improve the data available and assumptions used to assess childrens aggregate exposure to pesticides. Based on the results of these efforts, four priority research areas were identified: (1) pesticide use patterns in microenvironments where children spend time, (2) temporal and spatial distribution of pesticides following application in a residential setting, (3) dermal and nondietary ingestion exposure assessment methods and exposure factors, (4) dietary exposure assessment methods and exposure factors for infants and young children. The National Exposure Research Laboratory (NERL) research strategy in support of FQPA is designed to address these priority research needs.

Assessment of a pesticide exposure intensity algorithm in the agricultural health study

The accuracy of the exposure assessment is a critical factor in epidemiological investigations of pesticide exposures and health in agricultural populations. However, few studies have been conducted to evaluate questionnaire-based exposure metrics. The Agricultural Health Study (AHS) is a prospective cohort study of pesticide applicators who provided detailed questionnaire information on their use of specific pesticides. A field study was conducted for a subset of the applicators enrolled in the AHS to assess a pesticide exposure algorithm through comparison of algorithm intensity scores with measured exposures. Pre- and post-application urinary biomarker measurements were made for 2,4-D (n=69) and chlorpyrifos (n=17) applicators. Dermal patch, hand wipe, and personal air samples were also collected. Intensity scores were calculated using information from technician observations and an interviewer-administered questionnaire. Correlations between observer and questionnaire intensity scores were high (Spearmans r=0.92 and 0.84 for 2,4-D and chlorpyrifos, respectively). Intensity scores from questionnaires for individual applications were significantly correlated with post-application urinary concentrations for both 2,4-D (r=0.42, P<0.001) and chlorpyrifos (r=0.53, P=0.035) applicators. Significant correlations were also found between intensity scores and estimated hand loading, estimated body loading, and air concentrations for 2,4-D applicators (r-values 0.28–0.50, P-values<0.025). Correlations between intensity scores and dermal and air measures were generally lower for chlorpyrifos applicators using granular products. A linear regression model indicated that the algorithm factors for individual applications explained 24% of the variability in post-application urinary 2,4-D concentration, which increased to 60% when the pre-application urine concentration was included. The results of the measurements support the use of the algorithm for estimating questionnaire-based exposure intensities in the AHS for liquid pesticide products. Refinement of the algorithm may be possible using the results from this and other measurement studies.

Adult and children's exposure to 2,4-D from multiple sources and pathways

In this study, we investigated the 2,4-dichlorophenoxyacetic acid (2,4-D) herbicide exposures of 135 preschool-aged children and their adult caregivers at 135 homes in North Carolina (NC) and Ohio (OH). Participants were randomly recruited from six NC and six OH counties. Monitoring was performed over a 48-h period at the participants’ homes. Environmental samples included soil, outdoor air, indoor air, and carpet dust. Personal samples collected by the adult caregivers concerning themselves and their children consisted of solid food, liquid food, hand wipe, and spot urine samples. All samples were analyzed for 2,4-D (free acid form) by gas chromatography/mass spectrometry. 2,4-D was detected in all types of environmental samples but most often in carpet dust samples, with detection frequencies of 83% and 98% in NC and OH, respectively. The median level of 2,4-D in the carpet dust samples was about three times higher in OH homes compared to NC homes (156 vs. 47.5 ng/g, P<0.0002). For personal samples, 2,4-D was more frequently detected in the hand wipe samples from OH participants (>48%) than from NC participants (<9%). Hand wipe levels at the 95th percentile were about five times higher for OH children (0.1 ng/cm2) and adults (0.03 ng/cm2) than for the NC children (0.02 ng/cm2) and adults (<0.005 ng/cm2). 2,4-D was detected in more than 85% of the child and adult urine samples in both states. The median urinary 2,4-D concentration was more than twice as high for OH children compared to NC children (1.2 vs. 0.5 ng/ml, P<0.0001); however, the median concentration was identical at 0.7 ng/ml for both NC and OH adults. The intraclass correlation coefficient of reliability for an individuals urinary 2,4-D measurements, estimated from the unadjusted (0.31–0.62) and specific gravity-adjusted (0.37–0.73) values, were somewhat low for each group in this study. The variability in urinary 2,4-D measurements over the 48-h period for both children and adults in NC and OH suggests that several spot samples were needed to adequately assess these participants’ exposures to 2,4-D in residential settings. Results from this study showed that children and their adult caregivers in NC and OH were likely exposed to 2,4-D through several pathways at their homes. In addition, our findings suggest that the OH children might have been exposed to higher levels of 2,4-D through the dermal and nondietary routes of exposure than the NC children and the NC and OH adults.

Sampling design, response rates, and analysis weights for the National Human Exposure Assessment Survey (NHEXAS) in EPA Region 5:

For the Phase I field test of the National Human Exposure Assessment Survey (NHEXAS) in U.S. Environmental Protection Agency (EPA) Region 5, this paper presents the survey sampling design, the response rates achieved, and the sample weighting procedure implemented to compensate for unit nonresponse. To enable statistically defensible inferences to the entire region, a sample of about 250 members of the household population in EPA Region 5 was selected using a stratified multistage probability-based survey sampling design. Sample selection proceeded in four nested stages: (1) sample counties; (2) area segments based on Census blocks within sample counties; (3) housing units (HUs) within sample segments; and (4) individual participants within sample households. Each fourth-stage sample member was asked to participate in 6 days of exposure monitoring. A subsample of participants was asked to participate in two rounds of longitudinal follow-up data collection. Approximately 70% of all sample households participated in household screening interviews in which rosters of household members were developed. Over 70% of the sample subjects selected from these households completed the Baseline Questionnaire regarding their demographic characteristics and potential for exposures. And, over 75% of these sample members went on to complete at least the core environmental monitoring, including personal exposures to volatile organic compounds (VOCs) and tap water concentrations of metals. The sample weighting procedures used the data collected in the screening interviews for all household members to fit logistic models for nonresponse in the later phases of the study. Moreover, the statistical analysis weights were poststratified to 1994 State population projections obtained from the Bureau of the Census to ensure consistency with other statistics for the Region.

Non-hodgkin lymphoma risk and insecticide, fungicide and fumigant use in the agricultural health study.

Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. A total of 523 cases occurred among 54,306 pesticide applicators from enrollment (1993–97) through December 31, 2011 in Iowa, and December 31, 2010 in North Carolina. Information on pesticide use, other agricultural exposures and other factors was obtained from questionnaires at enrollment and at follow-up approximately five years later (1999–2005). Information from questionnaires, monitoring, and the literature were used to create lifetime-days and intensity-weighted lifetime days of pesticide use, taking into account exposure-modifying factors. Poisson and polytomous models were used to calculate relative risks (RR) and 95% confidence intervals (CI) to evaluate associations between 26 pesticides and NHL and five NHL-subtypes, while adjusting for potential confounding factors. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Our results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were associated with an elevated risk of NHL or NHL subtypes. These findings are among the first to suggest links between DDT, lindane, permethrin, diazinon and terbufos with NHL subtypes.