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Environ. Sci. Technol. 2009, 43, 8478–8482

LINDA ZICCARDI

Importance of Considering the Framework Principles in Risk Assessment for Metals1 CHARLES A. MENZIE* Exponent, Alexandria, Virginia LINDA M. ZICCARDI YVETTE W. LOWNEY Exponent, Boulder, Colorado ANNE FAIRBROTHER SCOTT S. SHOCK JOYCE S. TSUJI Exponent, Bellevue, Washington DIEM HAMAI DEBORAH PROCTOR Exponent, Irvine, California ELIZABETH HENRY STEAVE H. SU Exponent, New York, New York MICHAEL W. KIERSKI MARGARET E. MCARDLE Exponent, Maynard, Massachusetts LISA J. YOST Exponent, St. Paul, Minnesota

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). In 2007, three documents were published that emphasized important considerations when evaluating exposure to and potential health and environmental effects of metals in the environment. The Metals Environmental Risk Assessment Guidance (MERAG) project was launched by the International Council of Mining and Metals and Eurometraux, with regulatory endorsement provided by the UK Department for Environmental Food and Rural Affairs (DEFRA). The guidance and associated fact sheets were developed to provide scientific and regulatory guidance on the most advanced scientific concepts for metals (1). The guidance document 1 Editor’s Note: To our delight at ES&T, we have started to receive Features and Viewpoints by independent author(s) coincidentally overlapping both in topic and review schedule. Within days of this paper’s acceptance another specifically concerning selenium in the environment was accepted. The choice was thus made to present both manuscripts in the same issue (November 15, 2009; 43[22]). Readers of this piece by Menzie et al. are therefore encouraged to read that by Luoma and Presser (DOI 10.1021/es900828h).

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highlighted the importance of considering background, essentiality, speciation, mobility, and bioavailability when considering the potential adverse health effects of metals. It also addressed issues related to bioaccumulation and biomagnification. A related document focused on how these issues should be considered specifically for human health risk characterization (2). Also in 2007, the U.S. Environmental Protection Agency (EPA) published the Framework for Metals Risk Assessment (3). The Framework is based on a set of principles that are consistent with the scientific considerations set forth in the MERAG guidance and are special attributes of metals. The five Framework principles are 1. Metals are naturally occurring constituents in the environment and vary in concentrations across geographic regions. 2. All environmental media have naturally occurring mixtures of metals, and metals often are introduced into the environment as mixtures. 3. Some metals are essential for maintaining proper health of humans, animals, plants, and microorganisms. 4. The environmental chemistry of metals strongly influences their fate and effects on human and ecological receptors. 5. The toxicokinetics and toxicodynamics of metals depend on the metal, the form of the metal or metal compound, and the organism’s ability to regulate and/ or store the metal. These principles have been increasingly recognized as important for addressing exposure to and risk from metals in the environment. The publications cited above provide a broad technical and regulatory foundation for incorporating the principles into metals risk assessments. Our experience with metals risk assessments indicates that some principles are especially important for some metals and less important for others, and thus, case-specific information is important. This paper provides our view of the relative importance of the Framework principles for exposure and risk assessment of particular metals and metalloids. The ratings of relevant 10.1021/es9006405

 2009 American Chemical Society

Published on Web 08/31/2009

TABLE 1. Relative Importance of Metals Principles in Human Health and Ecological Risk Assessmenta

a Notes: L, low, never or rarely a consideration; M, moderate, sometimes a consideration; H, high, often a consideration; RfD, reference dose; hh, human health; eco, ecological.

importance presented in Table 1 reflect the authors’ experience with both human health and ecological risk assessments for metals associated with mining and manufacturing operations, products, and hazardous waste sites, particularly in North America, but also in other countries. We have developed a thorough understanding of the many factors that influence metal species (e.g., valence states), metal forms (e.g., inorganic and organic), and metal states (phases) (e.g., in solution, or bound to dissolved organic matter or particulates), and the resulting bioavailability of such chemical species. Table 1 incorporates our knowledge that certain forms of metals are more toxic than others, and that regulatory toxicity values are developed for forms of metals that may or may not represent the forms present in the environment. Five Framework Principles. The relative importance of the individual principles for metals most commonly encountered in site-specific risk assessments is summarized in Table 1. Although the Framework focused on inorganic metals and metalloids such as Sb and As that share properties of both metals and nonmetals, we also consider application of the principles to organometallics such as methyl mercury, organoarsenic, and organoselenium where relevant, because these chemicals can be important in a risk assessment context. The information summarized for the metals and metalloids (hereafter collectively referred to as “metals”) listed in Table 1 reflects the cumulative knowledge and risk assessment experience of the authors. We considered the 23 “metals and metalloids of interest” as identified in the Framework, and then selected the chemical species included in Table 1 based on our collective expertise and metals that are known “risk drivers”. In what follows, our intent as metals assessment practitioners was not to provide a comprehensive

review on how each principle influences each metal, but rather, to focus on metals of greatest interest to the risk assessment community and for which our experience has shown that one or more principles are especially important. Principle 1. It is well established (e.g., 4-6) that concentrations of metals in native rocks and soils vary considerably across geographic areas. Table 1 indicates that natural occurrence becomes an increasingly important consideration when risk-based limits approach or fall below the natural background. This can occur because exposure assumptions used to derive the risk-based values, and the actual factors that determine exposure, are inconsistent (e.g., see discussion of bioavailability under Principle 4), or because the riskbased concentrations are based on estimates of theoretical risk extrapolated from toxicity observed at high doses, which may not apply at lower exposure levels. Further, it is important to consider regional variations and that plant and animal populations are shaped, at least in part, by local conditions, including soil and sediment mineralogy (7). We identified the consideration of natural occurrence as highly important for human health and/or ecological risk assessments for Al, As, Ba, Be, Cr(III), Fe, Pb, and Se. Al and As are discussed further, as examples. EPA’s soil screening guidance (8) recognized that Al, the third-most abundant element in the Earth’s crust, is often identified as a chemical of concern in ecological risk assessments because of the conservative nature of the screening benchmarks and toxicity reference values (TRVs) that are based on toxicity tests using Al in solution. Relying on TRVs derived from toxicity studies using soluble forms can result in hazard quotients (HQs) from food-web modeling that indicate risks (i.e., HQs >1) for Al concentrations that VOL. 43, NO. 22, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY

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are below natural background. While Al toxicity is associated with soluble Al, soil and sediment analytical chemistry methods measure total Al, including natural Al, most of which is bound in insoluble mineral complexes such as aluminosilicates which are not bioavailable (8). Based on these considerations, EPA (8)now recommends that Al be identified as a chemical of concern only for sites with soil pH < 5.5, because as pH decreases below this level, Al becomes increasingly soluble, bioavailable, and toxic. An example of a health-based screening level that falls below natural background is provided by As. EPA screening levels for As in soil, based on cancer risk, are 0.39 and 1.6 mg/kg (note that all soil concentrations are in dry weight) for residential and industrial exposure, respectively. Natural background As concentrations in U.S. soils range from 1 to >20 mg/kg, and even higher in naturally mineralized areas (4). Setting health-based criteria below the natural background is a dilemma for As and has resulted in target risks at the upper end of the risk management range, and in the use of state, regional, or local background concentrations in lieu of more stringent health-based criteria. Exposures via environmental media may also be small relative to normal background exposures, because of the ubiquitous presence of inorganic As in the diet and in drinking water. As a result, exposure to inorganic As from incidental soil ingestion is generally lower than intake from background dietary sources until soil concentrations exceed 100 mg/kg (9). Thus, although cancer risk assessments may predict elevated excess risks associated with As in soil, comparison to background dietary exposures helps place such risks in perspective with ordinary exposures. Principle 2. The risks associated with mixtures of metals in the environment depend on the degree to which one metal influences either exposure to or the effects of another. Metals in mixtures may interact to produce antagonistic, additive, or synergistic effects. Table 1 indicates that mixture-related influences on exposure and health effects are moderately to highly important for many of the metals. Additional mixturerelated influences important to metals risk assessments will likely be identified in the future. As indicated in Table 1, consideration of mixtures is of high importance for Cd, Cu, Fe, Pb, Mn, Mo, Ni, Se, Ag, and Zn. Mixture effects have been shown or considered to be important in many human health and ecological risk assessments. For example, populations exposed to elevated levels of As and Cd in China show interactive effects that increase renal toxicity (10). On the other hand, at low doses, exposure and toxicity for metal mixtures may be reduced by interactions in which these constituents form less soluble mineral complexes in the gastrointestinal tract, or compete for metal carrier or binding proteins in the body (e.g., metallothionein). Many interactions among metals at lower doses are thus antagonistic (11-14), with examples including Zn/Cu, Zn/Cd, Fe/Cd, Fe/Co, Mn/Fe, Mn/Al, Mn/Cd, As/Se, and Hg/Sesmixtures of these metals are less toxic than the sum of each of the component metals, individually. For these metals, more accurate estimates of risk are achieved if mixture effects are taken into account. A common example of accounting for mixture effects among metals is the additivity of effects from cationic metals during acute exposures of aquatic organisms. In the case of uptake from solution, the relative potency of cations is determined by differential binding efficiencies at the gill surface (15). Another example of interactions in metals mixtures is that between Se and As, which have been reported to have additive or even synergistic effects in vivo and in vitro (14), as well as some reported antagonistic effects (16). Arsenite may potentiate or attenuate the protective effect of Se against carcinogenicity, depending on the methylation state of the 8480

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FIGURE 1. A simple representation of a “U-shaped” doseresponse curve for an essential metal (EAR ) estimated average requirement; RDA ) recommended dietary allowance; UL ) tolerable upper intake level). Se compound (14). Se is also reported to increase biliary and urinary excretion of As in animal studies, reduce cellular toxicity of As in biological systems, and protect against chromosomal damage by As in cultured human lymphocytes (summarized in (17)). An intervention trial in an As-exposed population in Inner Mongolia reported that 14 months of supplementation with Se reduced hair and blood levels of As and greatly improved various arsenical skin lesions (16). Se’s action is likely related to its role in antioxidant enzymes (17, 18). Principle 3. For risk assessments, the essentiality of a metal becomes an important consideration when risk-based limits fall below concentrations that are essential for maintaining proper health, and also when natural levels of metals fall below those needed for maintaining proper health (deficiency). Finally, essentiality is important when threshold doses for nutrition and toxicity are close to one another. The dose-response curve for essential metals should include low levels at which nutritional deficits occur, as well as the higher levels at which toxic effects occur (resulting in the classic “U”-shaped curve for essential metals; Figure 1). We caution that, because the nutritional and toxic levels of essential metals are specific to organism, sex, and life stage, care should be taken when evaluating dose-response curves of essential metals and when extrapolating from one organism, sex, or life stage to others. Table 1 reflects which essential metals are most likely to cause problems in metals risk assessments due to close threshold doses or other considerations of excess exposure vs deficiency. The importance of considering essentiality when evaluating certain metals has led to proposed new terminology to describe their dose-response features and avoid confusion with the concept of “no-effect levels” used for toxicity at high doses (2). These new terms include “sufficient dietary intake” and “deficiency effect levels.” Because risk assessments typically assess exposures in addition to dietary intake, another boundary term describing effect levels for risk assessment of essential metals is the range of “supplementation levels,” such as those developed by Health Canada (19) for multivitamin/mineral supplements. Similar terms for essential nutrients, including trace metals, in the U.S. include dietary reference daily intakes (RDIs). The parallel development of dose-response relationships for nutrition and toxicity is emerging as a key feature of assessing risks associated with essential metals. Se is an example of a potentially toxic element that is also an essential nutrient in the diet of many wildlife species. In some parts of the world where Se levels are low in soils, Se deficiencies can occur. Conversely, irrigation of soils with higher Se concentrations can mobilize Se due to its relatively high solubility, and produce toxic concentrations in lowlying areas. One of the key challenges to evaluating the risks associated with Se is that there is a fairly narrow range between therapeutic and toxic intake.

Principle 4. Risks of metals and other chemicals depend on exposure concentrations at the site of toxic action, and exposure can be strongly influenced by environmental chemistry. The chemical form of a metal often dictates its environmental fate and transport and its potential for uptake, metabolism, or toxic response. Important and variable environmental factors, such as pH, dissolved oxygen, organic carbon, the presence of sulfides, and cation-exchange capacity, can influence the bioavailability of metals. Thus, relative bioavailability of a metal in the environment compared to the form in toxicity tests is an important consideration in assessing risk. Site-specific bioavailability is important for evaluating exposure to metals such as Pb and Ba. In 2007, EPA released targeted guidance for assessing site-specific oral bioavailability of metals (20). The agency also released a validation of an in vitro method for evaluating the relative bioavailability of lead from soils or soil-like materials. With these new methods and guidance, it is now possible to adjust risk assessments to address Pb bioavailability on a site-specific basis. Ba has received much attention, because it is commonly present in elevated levels in soils, but primarily in forms with low bioavailability. For example, when Ba was assumed to be 100% bioavailable in dust at an Alaskan mining site, foodweb modeling indicated a potential for adverse effects to small mammals (21). However, when site-specific geology and mineral characteristics were reviewed, it was clear that this assumption was likely to be very conservative. An in vitro study was conducted using simulated gastric fluids to evaluate site-specific bioaccessibility of Ba from a variety of soil and tundra materials (22). The relatively low bioaccessibility values confirmed the expectation that the Ba exposure was less significant than exposure to other metals of concern (23), presumably because the environmental form differed from the forms used to establish the benchmark values. Menzie et al. (24) confirmed that the ecological benchmarks for Ba in soil derived from soluble Ba compounds did not reflect exposure to BaSO4, the relatively insoluble form of Ba that is most common in surface soils. Principle 5. Many risk assessments for metals historically have been based on simplified estimates of exposure and effects that too often neglect toxicokinetics (the passage of a toxic agent or its metabolites through an organism) and toxicodynamics (the physiological mechanisms by which toxins are taken up [absorbed], distributed, metabolized, and excreted [ADME]). However, these factors have been critical for some metals and, as new data and assessment methods emerge, will likely increase in importance. The route of exposure and form of metal are important to consider when predicting toxicity, including carcinogenicity. In addition, the sensitivity to and risks from metals vary with age, sex, pregnancy, nutritional status, genetics, and life stage. Toxicokinetics, particularly elimination rates, are important when addressing the potential for metal bioconcentration and bioaccumulation. While certain metals and forms of metals are known to bioaccumulate and transfer to other trophic levels via the food chain, inorganic forms of metals generally do not biomagnify. Many organisms can regulate metal uptake and/or accumulation, or store metals as nonbioavailable granules (25). Our experience suggests that consideration of toxicokinetics and toxicodynamics is important for most metals risk assessments. Cr is an example of a metal for which toxicokinetics are especially important when assessing risks. Trivalent Cr (Cr[III]) and insoluble forms of hexavalent Cr (Cr[VI]) do not readily pass through cellular membranes; therefore, Cr absorption via all pathways of exposure is dependent on metal species and solubility. For example, Cr(VI) generally is not stable in the acidic and reducing conditions of the stomach and is detoxified through reduction to Cr(III) prior

to absorption. Most forms of Cr(III) are not readily bioavailable and are of relatively low toxicity. Only at exposures that overwhelm the reducing capacity of the stomach will significant systemic absorption occur, precipitating an increased risk of adverse health effects. Mn is another metal for which toxicokinetics and toxicodynamics are particularly important to consider. Mn exposure varies significantly by the route of exposure, chemical form, and the nutritional status and developmental stage of the individual. Because it is an essential nutrient, dietary intake of Mn is critical to the maintenance of numerous enzymatic functions and developmental processes. The bioavailability of dietary Mn is tightly controlled by homeostatic mechanisms that maintain relatively steady levels of Mn in the body. These controls can be disrupted by micronutrient imbalances in the individual, resulting in increased absorption of Mn. In contrast to ingested Mn, inhalation delivers a larger bioavailable fraction by facilitating transport to the systemic circulation for distribution to the brain, the target site of Mn-induced neurotoxicity. Therefore, the route of exposure to Mn is especially important in affecting toxicity.

Discussion and Conclusions There are challenges in conducting metals risk assessments given the complexity of factors that influence metals’ chemistry, behavior in the environment, bioavailability, and pharmacokinetics. Emerging metals risk assessment guidance incorporating concepts such as the Framework principles significantly expands on the methods and considerations that have traditionally been applied in the evaluation of risks from exposure to metals. Regulatory agencies within the U.S. and internationally increasingly recognize that it is important to incorporate these principles as the risk assessment process becomes more sophisticated. For example, EPA has issued general guidance that indicates the need to consider such issues as essentiality (26), and very specific guidance regarding evaluation of bioavailability of metals from soils (20). In another example, several states are now recognizing the importance of considering the natural occurrence of metals. For instance, although health-based screening levels for As in soil are based on strict toxicity considerations, many state agencies have recognized that risk-based screening levels for As fall well below natural background, and so have recommended preliminary remedial goals or screening levels targeted at concentrations representative of state-wide background, and several states have implemented guidance that specifically allows for comparison against background on a site-specific basis (e.g., New Jersey (27), New York (28), Georgia (29), and Florida (30), among others). In another regulatory application of the Framework principles, EPA in 2007 revised the aquatic life Water Quality Criteria for Cu to consider site-specific speciation and bioavailability (31), and has a draft strategy for revising other criteria that consider advancements in ecological risk assessment methodology (32). EPA has also developed an approach for estimating the aquatic toxicity of divalent metal cations that considers the bioavailable metal fraction that can be measured in pore water and/or predicted based on the relative sediment concentrations of acid volatile sulfide (AVS), simultaneously extracted metals (SEM), and the total organic carbon (TOC) content of the sediment (33). This paper provides the authors’ view on the relative importance of the Framework principles, based on our collective experience as risk assessors and scientists. Other risk assessors will undoubtedly have additional insights that can contribute to understanding where and how the principles can be effectively applied. Our article is intended to stimulate further consideration and application of the VOL. 43, NO. 22, 2009 / ENVIRONMENTAL SCIENCE & TECHNOLOGY

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principles within regulatory and research arenas. Recognizing where such information has the greatest utility is a starting point that will help focus future work. The authors are from Exponent’s Environmental Sciences and Health Sciences practice groups, which focus on understanding the human health and environmental effects of chemical exposure. The authors’ collective experience in the fate, transport, toxicology, and risk assessment of metals and other chemicals in the environment, products, and food provides broad insight on the potential for and consequences of chemical exposure. Dr. Charles A. Menzie is a Principal Scientist and Director of Exponent’s Ecological Sciences practice. His primary area of expertise is the environmental fate and effects of physical, biological, and chemical stressors on terrestrial and aquatic systems. Dr. Menzie is recognized as one of the leaders in the field of risk assessment and was awarded the Risk Practitioner Award by the Society for Risk Analysis. He chaired the external EPA working group that assisted EPA in the development of the principles discussed in this paper. Please address correspondence regarding this paper to [email protected].

Acknowledgments We acknowledge the extensive work put forth by the International Council of Mining and Metals and Eurometraux in developing the Metals Environmental Risk Assessment Guidance (MERAG), and the U.S. Environmental Protection Agency in the development of the Framework for Metals Risk Assessment.

Supporting Information Available Expanded version of Table 1 that summarizes the relative importance of the metals principles in human health and ecological risk assessment, which includes key considerations. This information is available free of charge via the Internet at http://pubs.acs.org.

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