Joyce S. Tsuji

Low-level arsenic exposure in drinking water and bladder cancer: a review and meta-analysis.

Although exposure to high levels of arsenic in drinking water is associated with excess cancer risk (e.g., skin, bladder, and lung), lower exposures (e.g., <100-200 microg/L) generally are not. Lack of significant associations at lower exposures may be attributed to methodologic issues (e.g., inadequate statistical power, exposure misclassification), or to differences in the dose-response relationship at high versus low exposures. The objectives of this review and meta-analysis were to evaluate associations, examine heterogeneity across studies, address study design and sample size issues, and improve the precision of estimates. Eight studies of bladder cancer and low-level arsenic exposure met our inclusion criteria. Meta-analyses of never smokers produced summary relative risk estimates (SRREs) below 1.0 (highest versus lowest exposure). The SRRE for never and ever smokers combined was elevated slightly, but not significantly (1.11; 95% CI: 0.95-1.30). The SRRE was somewhat elevated among ever smokers (1.24; 95% CI: 0.99-1.56), and statistical significance was observed in some subgroup analyses; however, heterogeneity across studies was commonly present. Although uncertainties remain, low-level arsenic exposure alone did not appear to be a significant independent risk factor for bladder cancer. More studies with detailed smoking history will help resolve whether smoking is an effect modifier.

Arsenic exposure and bladder cancer: Quantitative assessment of studies in human populations to detect risks at low doses

While exposures to high levels of arsenic in drinking water are associated with excess cancer risk (e.g., skin, bladder, and lung), exposures at lower levels (e.g., <100-200 µg/L) generally are not. Lack of significant associations may result from methodological issues (e.g., inadequate statistical power, exposure misclassification), or a different dose-response relationship at low exposures, possibly associated with a toxicological mode of action that requires a sufficient dose for increased tumor formation. The extent to which bladder cancer risk for low-level arsenic exposure can be statistically measured by epidemiological studies was examined using an updated meta-analysis of bladder cancer risk with data from two new publications. The summary relative risk estimate (SRRE) for all nine studies was elevated slightly, but not significantly (1.07; 95% confidence interval [CI]: 0.95-1.21, p-Heterogeneity [p-H]=0.543). The SRRE among never smokers was 0.85 (95% CI: 0.66-1.08, p-H=0.915), whereas the SRRE was positive and more heterogeneous among ever smokers (1.18; 95% CI: 0.97-1.44, p-H=0.034). The SRRE was statistically significantly lower than relative risks predicted for never smokers in the United States based on linear extrapolation of risks from higher doses in southwest Taiwan to arsenic water exposures >10 µg/L for more than one-third of a lifetime. By contrast, for all study subjects, relative risks predicted for one-half of lifetime exposure to 50 µg/L were just above the upper 95% CI on the SRRE. Thus, results from low-exposure studies, particularly for never smokers, were statistically inconsistent with predicted risk based on high-dose extrapolation. Additional studies that better characterize tobacco use and stratify analyses of arsenic and bladder cancer by smoking status are necessary to further examine risks of arsenic exposure for smokers.

Low-level arsenic exposure and developmental neurotoxicity in children: A systematic review and risk assessment.

UNLABELLED Risk assessments of arsenic have focused on skin, bladder, and lung cancers and skin lesions as the sensitive cancer and non-cancer health endpoints, respectively; however, an increasing number of epidemiologic studies that can inform risk assessment have examined neurodevelopmental effects in children. We conducted a systematic review and risk assessment based on the epidemiologic literature on possible neurodevelopmental effects at lower arsenic exposures. Twenty-four cross-sectional, case-control, and cohort studies were identified that report on the association between low-level arsenic exposure (i.e., largely <100 μg/L of arsenic in drinking water) and neurological outcomes in children. Although the overall evidence does not consistently show a causal dose-response relationship at low doses, the most rigorously conducted studies from Bangladesh indicate possible inverse associations with cognitive function, predominantly involving concurrent arsenic exposure as measured by biomarkers (i.e., arsenic in urine or blood) and raw verbal test scores at ages 5-11 years. Issues such as non-comparability of outcome measures across studies; inaccuracies of biomarkers and other measures of inorganic arsenic exposure; potential effect modification by cultural practices; insufficient adjustment for nutritional deficiencies, maternal IQ, and other important confounders; and presence of other neurotoxicants in foreign populations limit generalizability to U.S. POPULATIONS Of the few U.S. studies available, the most rigorously conducted study did not find a consistent dose-response relationship between arsenic concentrations in tap water or toenails and decrements in IQ scores. Assuming that the strongest dose-response relationship from the most rigorous evidence from Bangladesh is generalizable to U.S. populations, possible reference doses were estimated in the range of 0.0004-0.001 mg/kg-day. These doses are higher than the U.S. Environmental Protection Agency reference dose for chronic lifetime exposure, thus indicating protectiveness of the existing value for potential neurotoxicity in children. This reference dose is undergoing revision as EPA considers various health endpoints in the reassessment of inorganic arsenic health risks.

Evaluation of Exposure to Arsenic in Residential Soil

In response to concerns regarding arsenic in soil from a pesticide manufacturing plant, we conducted a biomonitoring study on children younger than 7 years of age, the age category of children most exposed to soil. Urine samples from 77 children (47% participation rate) were analyzed for total arsenic and arsenic species related to ingestion of inorganic arsenic. Older individuals also provided urine (n = 362) and toenail (n = 67) samples. Speciated urinary arsenic levels were similar between children (geometric mean, geometric SD, and range: 4.0, 2.2, and 0.89–17.7 μg/L, respectively) and older participants (3.8, 1.9, 0.91–19.9 μg/L) and consistent with unexposed populations. Toenail samples were < 1 mg/kg. Correlations between speciated urinary arsenic and arsenic in soil (r = 0.137, p = 0.39; n = 41) or house dust (r = 0.049, p = 0.73; n = 52) were not significant for children. Similarly, questionnaire responses indicating soil exposure were not associated with increased urinary arsenic levels. Relatively low soil arsenic exposure likely precluded quantification of arsenic exposure above background.

Importance of Considering the Framework Principles in Risk Assessment for Metals

The recent EPA Framework for Metals Risk Assessment provides the opportunity for contextual risk assessment for sites impacted by metals (such as the depicted Dauntless Mine in Colorado).

The SHEDS-Wood Model: Incorporation of Observational Data to Estimate Exposure to Arsenic for Children Playing on CCA-Treated Wood Structures

Background Lumber treated with chromated copper arsenate (CCA) compounds has been used in residential outdoor wood structures and public playgrounds. The U.S. Environmental Protection Agency (EPA) has conducted a probabilistic assessment of children’s exposure to arsenic using the Stochastic Human Exposure and Dose Simulation model for the wood preservative scenario (SHEDS-Wood). The assessment relied on data derived from an experimental study conducted using adult volunteers and designed to result in maximum hand and wipe loadings to estimate the residue–skin transfer efficiency. Recent analyses of arsenic hand-loading data generated by studies of children actively involved in playing on CCA-treated structures indicate that the transfer efficiency coefficient and hand-loading estimates derived from the experimental study significantly overestimate the amount that occurs during actual play. Objectives Our goal was to assess the feasibility of using child hand-loading data in the SHEDS-Wood model and their impact on exposure estimates. Methods We used data generated by the larger of the studies of children in SHEDS-Wood, instead of the distributions used by U.S. EPA. We compared our estimates of the lifetime average daily dose (LADD) and average daily dose (ADD) with those derived by the U.S. EPA. Results Our analysis indicates that data from observational studies of children can be used in SHEDS-Wood. Our estimates of the mean (and 95th percentile) LADD and ADD were 27% (10%) and 29% (15%) of the estimates derived by U.S. EPA. Conclusion We recommend that the SHEDS-Woods model use data from studies of children actively playing on playsets to more accurately estimate children’s actual exposures to CCA.

Separating potential source exposure from background exposure in subsistence populations in developing countries.

Risk assessment methods of developed countries have prescribed exposure assumptions for calculating health risks that are generally inappropriate for developing countries because of population, cultural, and social differences. For example, populations in developing countries are often subsistence users of natural resources with a more outdoor-oriented lifestyle. Assessments should thus measure specific dietary intake rates and contact rates with environmental media. Chemical analyses of food, environmental media, and any biomarkers of exposure should include a carefully matched reference population to distinguish between exposures due to naturally occurring metals in more mineralized areas and potential anthropogenic sources. Without a reference group, one might predict excess risk associated with the external source, even though exposure is due to background levels. For example, subsistence populations often have a simple diet with high ingestion rates of a few food types (e.g. 200 g/day wet weight of fish; 500 g/day of rice). These foods can be naturally elevated in arsenic (fish and rice) and mercury (fish). Conservative risk assessments that extrapolate toxicity from high to low doses can predict elevated risks for these naturally occurring elements (e.g. greater than 1 in 10,000 cancer risk for arsenic). Whether the calculated risks are actually indicative of harm to subsistence populations should be considered in light of the beneficial properties of the diet and the lack of alternative food choices.

Utilizing a Combination of TGA and GC-MS to Estimate Health-Based Risks from Off-Gassed Volatile Compounds

Off-gassed compounds emitted from various materials can, in some instances, present health risks. In order to assess the potential health risks, off-gassed compounds must be identified, quantified, and evaluated relative to known health-based exposure guidance levels. We present a simple screening method for doing this that combines thermogravimetric analysis with thermal desorption–gas chromatography–mass spectrometry. The masses of particular volatile compounds are estimated over the course of a short-term, acute exposure. Assumptions (or measurements) of a room size can be used to convert these mass estimates to estimated concentrations, which can then be compared with readily available health-based exposure thresholds.

Considerations when using longitudinal cohort studies to assess dietary exposure to inorganic arsenic and chronic health outcomes.

Dietary arsenic exposure and chronic health outcomes are of interest, due in part to increased awareness and data available on inorganic arsenic levels in some foods. Recent concerns regarding levels of inorganic arsenic, the primary form of arsenic of human health concern, in foods are based on extrapolation from adverse health effects observed at high levels of inorganic arsenic exposure; the potential for the occurrence of these health effects from lower levels of dietary inorganic arsenic exposure has not been established. In this review, longitudinal cohort studies are evaluated for their utility in estimating dietary inorganic arsenic exposure and quantifying statistically reliable associations with health outcomes. The primary limiting factor in longitudinal studies is incomplete data on inorganic arsenic levels in foods combined with the aggregation of consumption of foods with varying arsenic levels into a single category, resulting in exposure misclassification. Longitudinal cohort studies could provide some evidence to evaluate associations of dietary patterns related to inorganic arsenic exposure with risk of arsenic-related diseases. However, currently available data from longitudinal cohort studies limit causal analyses regarding the association between inorganic arsenic exposure and health outcomes. Any conclusions should therefore be viewed with knowledge of the analytical and methodological limitations.

Establishment of exposure guidelines for lead in spacecraft drinking water.

BACKGROUND Setting Spacecraft Water Exposure Guidelines (SWEGs) for lead (Pb) in spacecraft drinking water has special challenges related to estimating the increase in blood lead levels (PbB) due to the release of lead to systemic circulation via microgravity-induced bone loss. METHODS The effects on the PbB of lead in drinking water (PbW) and lead released from bones, and changes in lead exposure before, during, and after spaceflight, were evaluated using a physiologically based pharmacokinetic model that incorporated environmental lead exposure on Earth and in flight and included temporarily increased rates of osteoporosis during spaceflight. RESULTS The model predicts that in 2030 (the earliest potential launch date for a long-duration mission), the average American astronaut would have a PbB of 1.7 microg x dl(-1) at launch and that, while in microgravity, PbB levels would decrease at PbW values less than about 9 microg L(-1) because of reduced exposure within the spacecraft to environmental lead. Astronauts with high concentrations of lead stored in bones could experience increases in PbB due to microgravity-accelerated release of lead from bones. While the resultant in-flight PbB would depend on their preflight bone lead levels, their PbB will not be significantly further elevated (< 1 microg x dl(-1)) by consuming water with a PbW of < or = 9 microg x dl(-1). Selection of a SWEG that would not result in an increase in blood lead is prudent given uncertainties about health effects at low exposures. CONCLUSION A SWEG of 9 microg x L(-1) would protect astronauts on long-duration spaceflights by ensuring that PbB values will not exceed prelaunch levels.