Recommended Reference Values for Risk Assessment of Oral Exposure to Copper.

The U.S. Environmental Protection Agency's (EPA) Integrated Risk Information System (IRIS) database, the authoritative source of U.S. risk assessment toxicity factors, currently lacks an oral reference dose (RfD) for copper. In the absence of such a value, various health-based reference values for copper are available for use in risk assessment. We summarize the scientific bases and differences in assumptions among key reference values for ingested copper to guide selection of appropriate values for risk assessment. A comprehensive review of the scientific literature best supports the oral RfD of 0.04 mg/kg body weight/day derived by EPA from their Drinking Water Action Level. This value is based on acute gastrointestinal effects but is further supported by broader analysis of copper deficiency and toxicity.

Essential concepts for interpreting the dose-response of low-level arsenic exposure in epidemiological studies.

Scientifically robust selections of epidemiological studies and assessments of the dose-response of inorganic arsenic in the low-dose range must consider key issues specific to arsenic in order to reduce risk of bias. The abundance of toxicological, mechanistic, and epidemiological evidence on arsenic enables a nuanced assessment of risk of bias in epidemiological studies of low-level arsenic, as opposed to a generic evaluation based only on standard principles. Important concepts in this context include 1) arsenic metabolism and mode of action for toxicity and carcinogenicity; 2) effects of confounding factors such as diet, health status including nutritional deficiencies, use of tobacco and other substances, and body composition; 3) strengths and limitations of various metrics for assessing relevant exposures consistent with the mode of action; and 4) the potential for bias in the positive direction for the observed dose-response relationship as exposure increases in the low-dose range. As an example, evaluation of a recent dose-response modeling using eight epidemiological studies of inorganic arsenic and bladder cancer demonstrated that the pooled risk estimate was markedly affected by the single study that was ranked as having a high risk of bias, based on the above factors. The other seven studies were also affected by these factors to varying, albeit lesser, degrees that can influence the apparent dose-response in the low-dose range (i.e., drinking water concentration of 65 µg/L or dose of approximately ≤1 µg/kg-day). These issues are relevant considerations for assessing health risks of oral exposures to inorganic arsenic in the U.S. population, and setting evidence-based regulatory limits to protect human health.

Critical Review of Exposure and Effects: Implications for Setting Regulatory Health Criteria for Ingested Copper.

Decades of study indicate that copper oral exposures are typically not a human health concern. Ingesting high levels of soluble copper salts can cause acute gastrointestinal symptoms and, in uncommon cases, liver toxicity in susceptible individuals with repeated exposure. This focused toxicological review evaluated the current literature since the last comprehensive reviews (2007-2010). Our review identified limitations in the existing United States and international guidance for determining an oral reference dose (RfD) for essential metals like copper. Instead, an alternative method using categorical regression analysis to develop an optimal dose that considers deficiency, toxicity, and integrates information from human and animal studies was reviewed for interpreting an oral RfD for copper. We also considered subchronic or chronic toxicity from genetic susceptibility to copper dysregulation leading to rare occurrences of liver and other organ toxicity with elevated copper exposure. Based on this approach, an oral RfD of 0.04 mg Cu/kg/day would be protective of acute or chronic toxicity in adults and children. This RfD is also protective for possible genetic susceptibility to elevated copper exposure and allows for background dietary exposures. This dose is not intended to be protective of patients with rare genetic disorders for copper sensitivity within typical nutritional intake ranges, nor is it protective for those with excessive supplement intake. Less soluble mineral forms of copper in soil have reduced bioavailability as compared with more soluble copper in water and diet, which should be considered in using this RfD for risk assessments of copper.

Dose-response for assessing the cancer risk of inorganic arsenic in drinking water: the scientific basis for use of a threshold approach.

The biologic effects of inorganic arsenic predominantly involve reaction of the trivalent forms with sulfhydryl groups in critical proteins in target cells, potentially leading to various toxicologic events including cancer. This mode of action is a threshold process, requiring sufficient concentrations of trivalent arsenic to disrupt normal cellular function. Nevertheless, cancer risk assessments for inorganic arsenic have traditionally utilized various dose-response models that extrapolate risks from high doses assuming low-dose linearity without a threshold. We present here an approach for a cancer risk assessment for inorganic arsenic in drinking water that involves considerations of this threshold process. Extensive investigations in mode of action analysis, in vitro studies (>0.1 µM), and in animal studies (>2 mg/L in drinking water or 2 mg/kg of diet), collectively indicate a threshold basis for inorganic arsenic-related cancers. These studies support a threshold for the effects of arsenic in humans of 50-100 µg/L in drinking water (about 65 µg/L). We then evaluate the epidemiology of cancers of the urinary bladder, lung, and skin and non-cancer skin changes for consistency with this calculated value, focusing on studies involving low-level exposures to inorganic arsenic primarily in drinking water (approximately <150 µg/L). Based on the relevant epidemiological studies with individual-level data, a threshold level for inorganic arsenic in the drinking water for these cancers is estimated to be around 100 µg/L, with strong evidence that it is between 50 and 150 µg/L, consistent with the value calculated based on mechanistic, in vitro and in vivo investigations. This evaluation provides an alternative mode of action-based approach for assessing health-protective levels for oral arsenic exposure based on the collective in vitro, in vivo, and human evidence rather than the use of a linear low-dose extrapolation based on default assumptions and theories.

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.

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.

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.

Association of low-level arsenic exposure in drinking water with cardiovascular disease: a systematic review and risk assessment.

The U.S. Environmental Protection Agency (EPA) is developing an integrated assessment of non-cancer and cancer risk assessment of inorganic arsenic (iAs). Cardiovascular disease (CVD) in association with iAs exposure has been examined in a number of studies and provides a basis for evaluating a reference dose (RfD) for assessing potential non-cancer health risks of arsenic exposure. In this systematic review of low-level iAs exposure (i.e., <100-150µg/L arsenic water concentration) and CVD in human populations, 13 cohort and case-control studies from the United States, Taiwan, Bangladesh, and China were identified and critically examined for evidence for derivation of a RfD. Eight cross-sectional and ecological studies from the United States were also examined for additional information. Prospective cohort data from Bangladesh provided the strongest evidence for determining the point of departure in establishing a candidate RfD based on a combined endpoint of mortality from "ischemic heart disease and other heart diseases." This study as well as the overall literature supported a no-observed-adverse-effect level of 100µg/L for arsenic in water, which was equivalent to an iAs dose of 0.009mg/kg-day (based on population-specific water consumption rates and dietary iAs intake). The study population was likely sensitive to arsenic toxicity because of nutritional deficiencies affecting arsenic methylation and one-carbon metabolism, as well as increasing CVD risk. Evidence is less clear on the interaction of CVD risk factors in the United States (e.g., diabetes, obesity, and hypertension) with arsenic at low doses. Potential uncertainty factors up to 3 resulted in a RfD for CVD in the range of 0.003-0.009mg/kg-day. Although caution should be exercised in extrapolating these results to the U.S. general population, these doses allow a margin of exposure that is 10-30 times the current RfD derived by EPA (based on skin lesions in Southwest Taiwan). These findings suggest that the current EPA RfD is protective of CVD.

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.

Modeling of blood lead levels in astronauts exposed to lead from microgravity-accelerated bone loss.

INTRODUCTION: Most astronauts experiencing prolonged microgravity undergo accelerated bone loss at a whole-body rate of 0.5-1% per month, with some load-bearing bones losing mass at normalized rates up to about 2.6% per month. The accompanying release of lead (Pb) stored in bones would increase the concentration of Pb in the blood (PbB), thereby complicating efforts to set acceptable Pb concentrations for spacecraft drinking water (PbW). METHODS: A physiologically based pharmacokinetic (PBPK) model was modified to permit modeling the effects on PbB of temporarily increased rates of bone loss and various PbW concentrations. RESULTS: The model predicts that, for the average American astronaut, the increase in PbB due to Pb released from bones would be more than offset by decreases in ingested or inhaled spacecraft environmental Pb, so that calculated PbB levels actually decrease in microgravity when PbW < about 9 microg Pb x L(-1). Measured PbB in astronauts before and immediately after 6-mo stays on the International Space Station (ISS) support these results. Currently, PbW on the ISS averages 0.6 microg Pb x L(-1) and PbW on Earth at the Johnson Space Center averages about 5 microg Pb x L(-1). CONCLUSIONS: Most astronauts on long spaceflights will not be adversely affected by the release of lead from bones into the blood. A small percentage of astronauts (assuming there could be any who would have high concentrations of lead in their bones) could be at risk of experiencing elevated levels of PbB due to microgravity-accelerated release of Pb from their bones, depending on their individual rate of bone loss.

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).

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.

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.

Use of background inorganic arsenic exposures to provide perspective on risk assessment results.

Background exposures provide perspective for interpreting calculated health risks associated with naturally occurring substances such as arsenic. Background inorganic arsenic intake from diet and water for children (ages 1-6 years) and all ages of the U.S. population was modeled stochastically using consumption data from USDA, published data on inorganic arsenic in foods, and EPA data on arsenic in drinking water. Mean and 90th percentile intakes for the U.S. population were 5.6 and 10.5 microg/day, assuming nationwide compliance with the 10 microg/L U.S. drinking water standard. Intakes for children were slightly lower (3.5 and 5.9 microg/day). Based on the current EPA cancer slope factor for arsenic, estimated lifetime risks associated with background diet and water at the mean and 90th percentile are 1 per 10,000 and 2 per 10,000, respectively. By comparison, reasonable maximum risks for arsenic in soil at 20 (higher typical background level) and 100mg/kg are 4 per 100,000 and 2 per 10,000, using EPA default exposure assumptions. EPA reasonable maximum estimates of arsenic exposure from residential use of treated wood are likewise within background intakes. These examples provide context on how predicted risks compare to typical exposures within the U.S. population, thereby providing perspective for risk communication and regulatory decision-making on arsenic in the environment and in consumer products.

Research strategies for safety evaluation of nanomaterials, part IV: risk assessment of nanoparticles.

Nanoparticles are small-scale substances (<100 nm) with unique properties and, thus, complex exposure and health risk implications. This symposium review summarizes recent findings in exposure and toxicity of nanoparticles and their application for assessing human health risks. Characterization of airborne particles indicates that exposures will depend on particle behavior (e.g., disperse or aggregate) and that accurate, portable, and cost-effective measurement techniques are essential for understanding exposure. Under many conditions, dermal penetration of nanoparticles may be limited for consumer products such as sunscreens, although additional studies are needed on potential photooxidation products, experimental methods, and the effect of skin condition on penetration. Carbon nanotubes apparently have greater pulmonary toxicity (inflammation, granuloma) in mice than fine-scale carbon graphite, and their metal content may affect toxicity. Studies on TiO2 and quartz illustrate the complex relationship between toxicity and particle characteristics, including surface coatings, which make generalizations (e.g., smaller particles are always more toxic) incorrect for some substances. These recent toxicity and exposure data, combined with therapeutic and other related literature, are beginning to shape risk assessments that will be used to regulate the use of nanomaterials in consumer products.

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 microg/L, respectively) and older participants (3.8, 1.9, 0.91-19.9 microg/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.

Health effect levels for risk assessment of childhood exposure to arsenic.

Health risks to children from chemicals in soil and consumer products have become a regulatory focus in the U.S. This study reviews short-term health effect levels for arsenic exposure in young children (i.e., 0-6 years old). Acute health effects are described mostly in adults in case reports of arsenic poisoning from water or food and in studies of medicinal arsenic treatment. Several epidemiological studies report health effects from subchronic arsenic exposure in children primarily from drinking water in developing countries. Acute health effects typically include gastrointestinal, neurological, and skin effects, and in a few cases facial edema and cardiac arrhythmia. Dermatoses are most consistently reported in both adults and children with subchronic exposure. With low exposure, the prevalence and severity of disease generally increases with age (i.e., length of exposure) and arsenic dose. The available data collectively indicate a lowest-observed-adverse-effect level around 0.05mg/kg-day for both acute and subchronic exposure. At low doses, children do not appear to be more sensitive than adults on a dose-per-body-weight basis, although data for acute exposures are limited and uncertainties exist for quantifying potential neurological or vascular effects at low-level subchronic exposures. Based on these data, possible reference levels for acute and subchronic exposure in young children are 0.015 and 0.005mg/kg-day, respectively.