Guidance for Evaluating the Oral Unavailability of Metals in Soils
for Use in Human Health Risk Assessment
United States OSWER 9285.7-80
Environmental
Protection Agency
' Guidance for Evaluating the Oral Bioavailability of
J Metals in Soils for Use in Human Health Risk
Assessment
MAY 2007
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
for Use in Human Health Risk Assessment
TABLE OF CONTENTS
1. Purpose 1
2. Introduction 1
3. Scope 2
4. Definition of Bioavailability 2
5. Existing Pertinent EPA Guidance on Use of Site-Specific Bioavailability Factors 3
6. Medium-Specific Default Values for Bioavailability of Metals 4
7. Recommended Decision Framework for Data Collection and Utilization of Oral
Bioavailability Data for Metals in Human Health Risk Assessment 5
8. TRW Review of Bioavailability Assessments 13
9. Implementation of Bioavailability Guidance 16
10. Cited References 16
FIGURES
1. Recommended Decision Framework for Assessing Oral Bioavailability of Metals at Contaminated
Sites
TABLES
1. Recommended Criteria for Validation of Test Methods (adapted from ICCVAM, 1997) 14
2. Recommended Criteria for Regulatory Acceptance of Toxicological Test Methods (adapted from
ICCVAM, 1997) 15
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
for Use in Human Health Risk Assessment
Guidance for Evaluating the Oral Unavailability of Metals in Soils
for Use in Human Health Risk Assessment
1. Purpose
The purpose of this document is to provide guidance to Regional risk assessors on how to
assess site-specific oral bioavailability of metals in soils for use in human health risk
assessments. Specifically, this guidance document provides: 1) a recommended process for
deciding when to collect site-specific information on the oral bioavailability of metals in soils for
use in human health risk assessments; 2) a recommended process for documenting the data
collection, analysis, and implementation of a validated method that would support site-specific
estimates of oral bioavailability; and 3) general criteria that EPA normally will use to evaluate
whether a specific bioavailability method has been validated for regulatory risk assessment
purposes. This guidance is focused on media-specific relative bioavailability and does not
address adjustments to default absolute bioavailability values. Also, this guidance addresses
human health risk assessment and may not be necessarily useful for evaluating ecological
receptors. Finally, the guidance document provides information on methodologies for directly
assessing bioavailability and does not pertain to indirect methods for predicting bioavailability
(e.g., speciation).
This document provides technical and policy guidance to the U.S. Environmental
Protection Agency (EPA) staff on making risk management decisions for contaminated sites. It
also provides information to the public and to the regulated community on how EPA intends to
exercise its discretion in implementing its regulations at contaminated sites. It is important to
understand, however, that this document does not substitute for statutes that EPA administers or
their implementing regulations, nor is it a regulation itself. Thus, this document does not impose
legally-binding requirements on EPA, states, or the regulated community, and may not apply to a
particular situation based upon the specific circumstances. Rather, the document suggests
approaches that may be used at particular sites, as appropriate, given site-specific circumstances.
2. Introduction
In most cases, the toxicity of an ingested chemical depends, in part, on the degree to
which it is absorbed from the gastrointestinal tract into the body. Because oral reference doses
(RfDs) and cancer slope factors (CSFs) are generally expressed in terms of ingested dose (rather
than absorbed dose), accounting for potential differences in absorption between different
exposure media can be important to site risk assessments (U.S. EPA, 1989). This is true for all
chemicals, but is of special importance for metals. This is because metals can exist in a variety
of chemical and physical forms, and not all forms of a given metal are absorbed to the same
extent. For example, a metal in contaminated soil may be absorbed to a greater or lesser extent
than when ingested in drinking water or food. Thus, if the oral RfD or CSF for a metal is based
on studies using the metal administered in water or food, risks from ingestion of the metal in soil
might be underestimated or overestimated. Even a relatively small adjustment in oral
bioavailability can have significant impacts on estimated risks and cleanup goals.
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
for Use in Human Health Risk Assessment
3. Scope
This guidance document is limited to evaluating the bioavailability of metals ingested in
soil or other soil-like media, for the purpose of assessing human health risks. The basic concepts
and principles discussed here are, however, generally applicable, and may also have relevance
for other exposure routes (dermal, inhalation), other media (sediment, diet), other receptors
(ecological species), and other chemical classes (certain types of organic compounds). This
document is not intended to be a state of the science review on bioavailability. Additional
information on bioavailability of soil contaminants is available from other sources (e.g., Hrudey
etal., 1996; Kelley etal, 2002; NRC, 2003).
This guidance document addresses sites where human health risks from ingestion of
chemical contaminants in soil or soil-like media are evaluated under the Comprehensive
Environmental Response, Compensation, and Liability Act (CERCLA) process or under the
Resource Conservation and Recovery Act (RCRA) Corrective Action process. This document
supplements the guidance in Appendix A of the Risk Assessment Guidance for Superfund
(RAGS), Part A, regarding adjustments to absorption (U.S. EPA, 1989). In addition, this
document provides guidance on how to consider bioavailability in metals risk assessments,
which is one of the many key guiding principles outlined in the Framework for Metals Risk
Assessment (U.S. EPA, 2007b).
4. Definition of Bioavailability
The term bioavailability (BA) has many different meanings across various disciplines of
toxicology and pharmacology. For the purposes of this guidance document, the term
bioavailability means:
The fraction of an ingested dose that crosses the gastrointestinal epithelium and
becomes available for distribution to internal target tissues and organs.
As defined above, bioavailability and oral absorption fraction are equivalent terms. This
definition does not consider the case of metals that may act directly upon the gastrointestinal
epithelium (e.g., irritants and corrosives), although the same factors that influence bioavailability
may also be important in influencing the magnitude of direct effects of a chemical at the portal of
entry.
Bioavailability expressed as a fraction (or percentage) of a dose is commonly referred to
as absolute bioavailability. The term relative bioavailability refers to a comparison of absolute
bioavailabilities. Relative bioavailability generally is important in risk assessment because we
are often most interested in knowing the extent to which the absolute bioavailability of a metal
increases or decreases in context with the exposure matrix (e.g., food vs. water vs. soil), or with
the physical or chemical form(s) of the metal to which humans are exposed. Often, it is more
feasible to assess relative bioavailability than absolute bioavailability (an example of this for lead
is demonstrated in U.S. EPA, 2007a). Thus, for the purposes of this guidance document, relative
bioavailability means:
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
for Use in Human Health Risk Assessment
The ratio of the bioavailability of a metal in one exposure context (i.e., physical
chemical matrix or physical chemical form of the metal) to that in another
exposure context.
While absolute bioavailability can never exceed 1.0 (or 100%), relative bioavailability
may be either greater than or less than 1. In this guidance document, relative bioavailability is
abbreviated as KB A; however, it has been referred to in other reports that are cited in this
guidance document as the relative absorption fraction (RAF) or the relative bioavailability
adjustment (KBA).
A related term, pertaining to bioavailability assessment, is bioaccessibility. This usually
refers to a measure of the physiological solubility of the metal at the portal of entry into the body
(NRC, 2003). Since solubilization is usually required for absorption across membranes, poorly
soluble forms of metals, with low bioaccessibility, may also have low bioavailability. In certain
circumstances, if solubility is the major determinant of absorption at the portal of entry,
bioaccessibility may be a predictor of bioavailability. Lead is an example of this, as is discussed
in U.S. EPA(2007a).
5. Existing Pertinent EPA Guidance on Use of Site-Specific Bioavailability Factors
Risk Assessment Guidance for Superfund (RAGS) Part A
Under appropriate circumstances, reliable site-specific data may be used in place of
default (non-site specific) exposure and toxicity factors. For example, RAGS Part A (U.S. EPA,
1989) states:
The specific values [exposure parameters] identified should be regarded as
general recommendations, and could change based on site-specific information.
Supplemental guidance for Superfund (U.S. EPA, 1991) reinforces the appropriate use of
site-specific parameter values as follows:
...exposure parameters presented in this document [i.e., the defaults] are
generally considered appropriate and should be used in baseline risk assessments
unless alternate or site-specific values can be clearly justified by supporting data.
RAGS Part A (U.S. EPA, 1989) Appendix A specifically addresses the consideration of
medium-specific bioavailability information in site-specific risk assessments, which are referred
to as adjustments for absorption efficiency. In particular, Appendix A of RAGS states:
Adjustments also may be necessary for different absorption efficiencies depending
on the medium of exposure (e.g., contaminants ingested with food or soil might be
less completely absorbed than contaminants ingested with water).
If the medium of exposure in the site exposure assessment differs from the medium
of exposure assumed by the toxicity value (e.g., RfD values usually are based on
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
for Use in Human Health Risk Assessment
or have been adjusted to reflect exposure via drinking water, while the site
medium of concern may be soil), an absorption adjustment may, on occasion, be
appropriate. For example, a substance might be more completely absorbed
following exposure to contaminated drinking water than follow ing exposure to
contaminated food or soil (e.g., if the substance does not desorbfrom soil in the
gastrointestinal tract).
RAGS (U.S. EPA, 1989) also emphasizes the need for reliable information in support of
quantitative relative bioavailability adjustments:
In the absence of a strong argument for making this adjustment or reliable
information on relative absorption efficiencies, assume that the relative
absorption efficiency between food or soil and water is one.
The absolute bioavailability of the metal in the exposure medium of concern at the site
may be greater or less than that in the exposure medium used in the critical toxicity study that
formed the basis of the RfD or CSF. Thus, assuming a relative bioavailability of 1.0 for the
medium of concern could result in either an underestimate or an overestimate of risk at the site.
When a reliable site-specific RBA value is available, the exposure estimate (i.e., intake)
is adjusted when calculating the hazard quotient (HQ):
HQ = (PI x RBA} Eq. 1
RfD
where DI is the daily oral intake (mg/kg-day), RfD is the reference dose, HQ is the hazard
quotient, and RBA is the relative bioavailability. Similarly, the exposure estimate is adjusted
when estimating cancer risk (CR):
CR = (DI x RBA) x CSF Eq. 2
where CSF is the cancer slope factor and CR is the cancer risk.
6. Medium-Specific Default Values for Bioavailability of Metals
As noted above, Agency guidance (U.S. EPA, 1989) recommends that, in the absence of
data to the contrary, the bioavailability of a chemical should be assumed to be equal in soil, diet,
and water (i.e., RBA = 1.0). However, the Agency recognizes that some cases may exist where
sufficient data are available for a chemical to support development of medium-specific default
absorption factors for that chemical. The purpose of these medium-specific and chemical-
specific default values is to increase the accuracy of exposure and risk calculations even when
site-specific studies are not available. These default absorption factors are determined by EPA
based on national data.
Lead is an example of a chemical for which the Agency has established recommended
medium-specific default absorption factors for both children and adult populations. The
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
for Use in Human Health Risk Assessment
Integrated Exposure Uptake Biokinetic Model for Lead in Children (IEUBK model) predicts
geometric mean blood lead (PbB) concentrations for a hypothetical child or population of
children (birth to 84 months of age) resulting from exposure to environmental sources of lead,
including soil, dust, air, drinking water, and diet (U.S. EPA, 1994a,b; White et a/., 1998). An
assumption in the model is that the absolute bioavailability of lead in soil and dust for children,
at low intake rates, is 0.3 (30%) and the absolute bioavailability of soluble lead in water and food
for children is 0.5 (50%). This corresponds to a relative bioavailability of 0.6 (60%) for lead in
soil (or dust) compared to soluble lead in water or food for children. The model also allows for
the input of site-specific values.
The Agency has developed the Adult Lead Methodology (ALM) for assessing lead risks
in adult populations (U.S. EPA, 1996). An assumption in the ALM is that the absolute
bioavailability of lead in soil for adults is 0.12 (12%)\ This value is based on assumptions that
the absolute bioavailability of soluble lead in water for adults is 0.2 (20%) and that the relative
bioavailability of lead in soil, compared to soluble lead, for adults is 0.6 (60%).
The Agency has also derived RfDs that are specific for an exposure medium based on
consideration of bioavailability or other factors that might suggest unique dose-response
relationships in that medium. For example, separate RfDs for cadmium in food and drinking
water have been derived based on the rationale that the bioavailability of cadmium in water is
greater than that of cadmium in food by a factor of 2 (i.e., 5% vs. 2.5%, respectively [U.S. EPA,
2003a]). Similarly, the Agency recommends that a modifying factor of three be applied to the
chronic oral RfD for manganese when the RfD is used to assess risks from drinking water or soil
to account, in part, for potential differences in bioavailability of manganese in water and soil
compared to food (U.S. EPA, 2003b).
However, even in cases where sufficient data exist to support default medium-specific
absorption factors for a chemical, site-specific data collection may also be important. Important
factors that can affect the bioavailability of metals in soil can be expected to vary from site to
site, or within a given site. These include the physical and chemical forms of the metal, as well
as the physical and chemical characteristics of the association between the metal and soil
particles. Default values for bioavailability may not reflect these factors (e.g., chemistry, particle
size, matrix effects) at any given site. Therefore, use of default values should not substitute for
site-specific assessments of bioavailability, where such assessments are deemed feasible and
valuable for improving the characterization of risk at the site (see Recommended Decision
Framework, below).
7. Recommended Decision Framework for Data Collection and Utilization of Oral
Bioavailability Data for Metals in Human Health Risk Assessment
While existing Agency risk assessment guidance (U.S. EPA, 1989, 1994b, 1996)
recommends default oral bioavailability values and also supports the use of site-specific
bioavailability information in human health risk assessments, these documents do not provide
guidance on how to assess site-specific bioavailability or on how to decide if such assessments
1 Lead absorption is generally lower in adults than in children, hence the default bioavailability of lead is lower in
the ALM than in the IEUBK model.
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
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should be pursued in support of site risk assessments. This document addresses these issues by
outlining a recommended decision framework on how to evaluate and incorporate site-specific
oral bioavailability information into risk-based decision-making.
The recommended decision framework is intended to improve risk estimates at specific
sites where the framework is applied, as well as to encourage the expansion of a knowledge base
that can be applied to future assessments of bioavailability of metals in soil at all sites. Thus, the
need for site-specific data collection may ultimately be decreased as the knowledge base
expands.
The decision framework recommended below uses evaluation criteria and an ordered
process for considering these criteria in the assessment of site-specific bioavailability of metals.
A flowchart of the recommended framework is presented in Figure 1. This recommended
decision framework is intended to help ensure that: (1) decisions about when to collect site-
specific data are well thought out and documented; and, (2) that when data are collected, these
data will be of appropriate quality to support site-specific risk assessment and risk management
decision-making.
As noted above, the recommended decision framework is intended for the collection of
data to inform site-specific risk-based decisions. The framework is not intended to address the
collection of data for research purposes that may serve to expand scientific knowledge for future
assessments (e.g., evaluation or development of methods for assessing bioavailability). In
practice, the collection of samples for site characterization may provide opportunities to collect
samples for research.
A discussion of the main steps in the recommended decision framework follows.
Step 1. Estimate risk using default values for bioavailability.
The first recommended step is to estimate the current and potential future human health
risk based on default values for bioavailability that have been recommended in EPA guidance.
As noted earlier, in most cases, the default relative bioavailability factor is 1.0 (U.S. EPA, 1989),
although medium-specific default values are available for lead, cadmium, and manganese. If
risks predicted using the default bioavailability assumptions are below a level of concern at all
parts of the site, and if there is no reason to believe the default bioavailability value has been
substantially underestimated, it is generally appropriate to conclude that no further investigation
of site-specific bioavailability is needed (although the information may be useful for
characterizing uncertainty). This conclusion, however, is predicated on the assumption that the
default bioavailability value is an upper bound, health-protective estimate (e.g., default KB A is
1.0). One potential exception is lead, where the default KB A for lead in soil (60%) is intended to
be a central tendency value rather than an upper bound value. Hence, it is possible that the actual
KB A at the site could be higher or lower than the default. If there is reason to believe that the
lead KB A at a site might be substantially higher than the default value (e.g., lead carbonate
[EPA, 1994b, 2007a]), it is suggested that the initial assessment (Step 1) be re-run using a higher
assumed KBA value (see Step 3bl). If risks predicted using default bioavailability assumptions
are above a level of concern at part or all of the site, then collection of site-specific
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
for Use in Human Health Risk Assessment
bioavailability data may be of value for refining risk estimates and/or for determining the extent
of remediation. The assessment could proceed to Step 2.
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
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FIGURE 1 Recommended Decision Framework for Assessing
Oral Unavailability (BA) of Metals at Contaminated Sites2
Step 1
Estimate risk using
default BA values
Yes
Are all risks below a level of concern?
No
Is default BA
adequately protective?
Yes
Step 2*
Has EPA identified a validated method
available for estimating site-specific BA?
No
STOP: There is no
acceptable approach for
obtaining reliable data
Yes
StepS
Cost comparison
Step 3a
Estimate the costs for obtaining RBA data
Step 3b1
Estimate the range of BA values that might occur
Step 3b2
Estimate the added value
z
STOP: Collection of site-
specific BA data not
recommended
No
Step 3c
Does the added value exceed the costs of
obtaining the bioavailability data?
Yes
Step 4
Document site-specific implementation of
the validated method
StepS
Collect samples and assess BA
TRW REVIEW
(OPTIONAL) of sampling
and implementation of the
validated method
Step 6
Integrate results of BA estimates into risk characterization
*The process of EPA identification of a validated method is independent of the site evaluation
process and should occur before a method is used at a contaminated site.
2 This is not intended to address the collection of samples for research.
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
for Use in Human Health Risk Assessment
Note that if the assessment does proceed beyond Step 1, completing the process and
reaching a decision regarding the collection of site-specific bioavailability information should be
made early in the site-specific evaluation process. This is important to help avoid substantial
delays that might arise from a delayed or late decision to collect additional site-specific
information in support of a site-specific bioavailability assessment. It should be apparent very
early in the risk assessment process whether any metals may be risk drivers and where additional
bioavailability information could have a significant impact.
Step 2. Determine whether or not EPA has identified one or more validated methods for
estimating site-specific bioavailability.
Step 2 of the recommended procedure evaluates whether or not EPA has identified one or
more validated methodologies for estimating the absolute or relative bioavailability of the metal
of concern at the site. Several organizations have addressed the validation of toxicological test
methods (ICCVAM, 1997; NRC, 2003). The Agency believes that these regulatory validation
approaches are generally applicable to the assessment of bioavailability methods. Across United
States federal agencies, the Interagency Coordinating Committee for Validation of Alternative
Methods (ICCVAM) typically provides for review and assessment of the validity of
toxicological test systems (http://iccvam.niehs.nih.gov). ICCVAM has developed validation
criteria and regulatory acceptance criteria for test methods used to generate information to
support regulatory decisions. Validation can be achieved by demonstrating that a method is
reliable and relevant for its proposed use, while regulatory acceptance can be accomplished when
a regulatory (e.g., EPA) or research agency determines that it fills a specific need. Using the
ICCVAM criteria as a general guide, the Technical Review Workgroup for Metals and Asbestos
(TRW) will evaluate new test methods and determine whether they are suitable for regulatory
risk assessment purposes. These criteria (modified from ICCVAM) are presented in greater
detail in Section 8.
If EPA has not identified a validated methodology, we recommend that further pursuit of
site-specific values generally not proceed without the development and validation of a suitable
method. The latter efforts usually would not be undertaken as part of site-specific risk
assessment efforts, but original research on the development of alternative bioavailability
methods is encouraged, where resources are available.
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
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Step 3. Evaluate the costs and potential value added by obtaining the data.
Step 3a. Estimate the costs.
In this recommended step, information is collected on the cost (including both time and
money) that would be required to obtain reliable site-specific bioavailability data. This should
include the level of effort that would be needed to plan for and collect appropriate site samples
for analysis, the time and cost of performing the bioavailability measurements using the
validated method(s), and the effort needed to summarize, evaluate, and apply the results to the
risk assessment process.
Step 3b. Estimate the potential value added by obtaining the data.
Step 3bl. Estimate the range of bioavailability values that are plausible.
In this recommended step, information should be assembled from the site under
consideration, or from other similar sites, that may be useful in judging whether the
bioavailability of the metal in soil at the site could be substantially different from the default
value used in the screening-level calculations performed in Step 1. Examples of the types of
information that may be relevant include:
a) Bioavailability values obtained using validated methods at other sites that are thought
to be similar to the site under consideration.
b) Data on the chemical forms of the metal in the soil. These data might have been
derived from measurements made at the site or from knowledge about the sources of soil
contamination.
c) Data on the soil types at the site may also be assembled, with specific attention to
those characteristics that are known or suspected to affect reactivity and solubility with
the metal. In general, these would include the organic content and the nature of the
organic fraction (e.g., fulvic acid, humic acid), mineral composition, and the physical
characteristics of the metal-soil particles (e.g., particle size, chemical phase, extractability
of the metal).
The specific types of information that would be relevant for a particular metal of concern should
be assessed from the available scientific literature. A recent review of these topics can be found
in NRC (2003).
Based on the available information, the range of bioavailability values that might be
plausible at the site should be estimated. These estimates may be based, in large part, on
observations at other sites and on professional judgment applied to extrapolations to the site of
interest. The objective is to provide plausible bounds on the absolute or relative bioavailability
of the metal at the site, which may then be used in estimating costs and potential value added by
collecting site-specific bioavailability data.
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Guidance for Evaluating the Oral Unavailability of Metals in Soils
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Step 3b2. Estimate the added value.
Step 3b2 of the recommended decision framework estimates the added value that might
be realized if reliable site-specific bioavailability data were obtained. For example, cost savings
could be realized if the site-specific bioavailability values were in the lower part of the plausible
range. This estimation could be accomplished by first using the plausible range of
bioavailability values to estimate the current and potential future human health risk. Then one
could determine the extent of the site soils that would fall above a level of concern using the
default bioavailability assumption, and compare that to the area that would be above a level of
concern based on the potential alternative (lower) assumed value. The difference in areas of
concern is then multiplied by the estimated cost of remediation per unit area, and the result is a
crude estimate of the potential cost savings from reduced remediation. Collection of site-specific
bioavailability data could also provide additional value through improved confidence in the
estimate and enhanced information for risk communication.
Step 3c. Cost comparison.
In the final part of recommended Step 3, the estimated costs (time and money) of
obtaining the data are compared to the added value that may be realized, and a decision is
reached based on the cost comparison. For example, at a site where the area of concern based on
default bioavailability assumptions is relatively small, the cost of cleanup might be the same or
less than the cost of obtaining the data. Conversely, at a large site, the potential cost savings
might outweigh the cost of data collection if collection of site-specific bioavailability data
resulted in even a small decrease in the extent of the site determined to be above a level of
concern. In the absence of cost savings, the value of continuing with the bioavailability study
may still be worth the added expense (e.g., in order to improve confidence in the estimate and
provide additional information for risk communication). It is also important to consider whether
additional data collection activities can be completed within an adequate time frame. Depending
upon the type of information needed, data collection could take a few weeks to several months.
If additional collection of site-specific bioavailability data is not feasible, either due to resource
or schedule constraints, then the plausible range of bioavailability values and their potential
impacts on risk estimates should be discussed in the uncertainty section of the human health risk
assessment. However, if the cost comparison and feasibility evaluation support collection and
analysis of additional data, then the assessment could proceed.
Step 4. Document site-specific implementation of validated method.
In this recommended step, a site-specific risk assessment should document the 1)
rationale for use of the selected validated method at the site; 2) the basis for the selection of soil
samples assayed for the purpose of predicting bioavailability at each area of concern; and 3) the
approaches (conceptual and quantitative) used to integrate the site bioavailability information
into the risk characterization. We also recommend that the risk assessment document the basis
for selecting the appropriate sample size needed to ensure that the bioavailability assay yields a
reliable estimate of bioavailability (or relative bioavailability). Additionally, the risk assessment
should describe how the estimates of bioavailability are used in the risk characterization, such as
whether the bioavailability estimates were used to adjust an exposure or risk term in the risk
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estimation algorithm; or, if a biokinetic model is being used in the risk assessment (e.g., IEUBK
Model), what specific parameters in the model were adjusted based on the bioavailability
information collected.
The first part of the site-specific documentation (i.e., rationale) should address the basis
for relying on data from the selected method for predicting bioavailability (relative or absolute)
for receptors of concern at the site (note, this documentation should address site-specific issues,
not already addressed in existing generic guidance for use of the selected method). This site-
specific documentation should satisfy the data quality objectives and methodology validation for
acceptance. The site-specific documentation should also summarize the pertinent results of these
evaluations and why they support the use of the method for the assessment of site-specific
bioavailability. Limitations of the selected method for the intended application, in comparison to
alternatives, should be documented as well.
The second part of the site-specific documentation should address the approach used to
translate the results from bioavailability assays into estimates of absolute or relative
bioavailability of the metal in the receptors of concern at the site. For example, if statistical
transformations of the data, such as regression models, were used in translating the data output
from the methodology into bioavailability estimates, these statistical models should be
documented (see U.S. EPA, 2007a, for an example of a regression model applied to the output of
an in vitro solubility assay for lead).
The third part of the documentation should address selection and procuring of samples
that allow prediction of bioavailability at each area of concern. The ultimate goal of the
bioavailability assessment is to arrive at a bioavailability adjustment(s) that can be applied to risk
estimations for all or part of the site. In some cases, the bioavailability of the metal of concern
may be similar across the entire site, and a single sample (usually a composite sample) may be
adequate for derivation of a site-specific KB A estimate. In other cases, the bioavailability of the
metal of concern may vary within or between sub-areas of the site due to differences in soil
characteristics, metal concentrations, form of metal, aging, land use, or other factors. In these
cases, bioavailability should be assessed in representative samples collected from each sub-area
of potential concern. In all cases, the documentation for the selection of samples to be assessed
should address the adequacy of the sample size and sample locations for assessing both within-
area and between-area variability, and explain how the estimates of variability will be integrated
into the bioavailability assessment at each area. The TRW is available for consultation and
review of site-specific implementation plans as needed. For additional information on sampling,
see U.S. EPA Site Assessment Guidance (U.S. EPA, 2001b).
Step 5. Collect soil samples and assess bioavailability.
Step 5 of the recommended process is the collection of the soil samples and measurement
of bioavailability in those samples using the selected methodology. Sample collection,
laboratory procedures, data handling, and archiving should be consistent with Agency guidance
for data quality objectives and assurance (U.S. EPA, 2000a,b,c; 2002a,b,c). A report on the
methodology used and results of the assessment, including a thorough discussion and, where
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possible, a quantitative assessment of confidence in the bioavailability estimates should be
developed for inclusion in documents supporting the risk assessment.
In the case that a validated in vitro method is used to estimate bioavailability, it is
recommended that the protocol specified in the methodology be followed for making the
extrapolation from in vitro data to in vivo values. That is, there is no a priori assumption that all
validated in vitro methods must yield results that are identical to in vivo values. Rather, it is
assumed that a mathematical equation will exist such that the in vitro result (entered as input)
will yield an estimate of the in vivo value (as output).
In general, the mathematical equation that links in vitro results to in vivo results will yield
an estimate of the expected (average) value of the in vivo bioavailability value. However, some
range of uncertainty or variability in actual KB A values around this average value can be
expected, due either to authentic inter-sample variability in RBA and/or to measurement error in
in vitro bioaccessibility or RBA. Thus, the true in vivo bioavailability value may be either lower
or higher than the best estimate predicted from the in vitro value. Risk assessors and risk
managers should exercise their judgment in deciding whether to use the average value, a range of
values, or a conservative point estimate when applying the results to the risk assessment.
Step 6. Integrate results of bioavailability estimates into risk characterization.
In Step 6 of the recommended procedure, the results of the site-specific bioavailability
assessment should be incorporated into the characterization of the site risks. This approach is
consistent with other EPA risk assessment guidance (U.S. EPA, 1989, 1991) which recommends
that, in general, reliable site-specific parameter values are preferred over default values that may
not represent site-specific conditions. The uncertainty assessment section of the risk
characterization should discuss the basis for confidence in the site-specific estimates of
bioavailability, the limitations in the estimates, and any issues related to extrapolating these
values over time (i.e., whether the value measured at present is likely to change over time due to
potential physical or chemical changes in the test material over time). The uncertainty
assessment should also provide at least a qualitative, but preferably a quantitative, assessment of
uncertainty in the site-specific bioavailability estimates, as well as the potential impacts of this
uncertainty on the risk characterization. Guidance regarding approaches to quantitative
uncertainty assessment of site risk estimates can be found in RAGS Volume 3 (U.S. EPA,
200 la).
8. TRW Review of Bioavailability Assessments
Review by the Technical Review Workgroup for Metals and Asbestos (TRW) may be
sought at any point in the process described above, when new methods or novel applications of
existing methods are implemented. In particular, the TRW normally will use the "method
validation" and "regulatory acceptance" criteria modified from ICCVAM (1997) to evaluate new
bioavailability test methods in determining whether they are suitable for regulatory risk
assessment purposes. Table 1 provides the general criteria that EPA typically considers to
determine if a specific bioavailability method has been validated for regulatory risk assessment
purposes (adapted from ICCVAM, 1997). Generally, a test methodology may be accepted for
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regulatory use (i.e., is a regulatory methodology) only after it has been adequately evaluated,
documented, and undergone independent review. Some examples of the general criteria that
EPA will typically use for evaluating the regulatory acceptance of a test methodology are
provided in Table 2 (adapted from ICCVAM, 1997). The Agency does not expect that all of the
recommended criteria in Tables 1 and 2 will need to be addressed to the same extent for each
alternative bioavailability methodology. Rather, EPA intends to evaluate the recommended
criteria on a case-by-case basis.
TABLE 1 Recommended Criteria for Validation of Test Methods (adapted from
ICCVAM, 1997)
U.S. EPA typically will consider the following criteria in evaluating whether a new or revised test
method may be considered validated for regulatory risk assessment purposes. The extent to which
these criteria are relevant typically will vary with the method and its proposed use.
• The scientific and regulatory rationale for the test method, including a clear statement of its
proposed use.
• The relationship of the test method endpoint(s) to the biologic effect of interest.
• A detailed protocol for the test method, including a description of the materials needed, a
description of what is measured and how it is measured, acceptable test performance
criteria (e.g., positive and negative control responses), a description of how data will be
analyzed, a list of the species for which the test results are applicable, and a description of
the known limitations of the test including a description of the classes of materials that the
test can and cannot accurately assess.
• The extent of within-test variability and the reproducibility of the test within and among
laboratories, including the degree to which biological variability affects this test
reproducibility.
• The test method performance using reference chemicals or test agents representative of the
types of substances to which the test method will be applied, including both known positive
and known negative agents.
• Sufficient data to permit a comparison of the performance of a proposed substitute test with
that of the test it is designed to replace.
• Data supporting the validity of a test method and reported in accordance with Good
Laboratory Practices (GLPs).
• Data supporting the assessment of the validity of the test method.
• The methodology and results have been subjected to independent scientific review.
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TABLE 2 Recommended Criteria for Regulatory Acceptance
of Toxicological Test Methods (adapted from ICCVAM, 1997)
A test method proposed for regulatory acceptance generally should be supported by the following
attributes:
Has undergone independent scientific peer review by disinterested persons who are experts in the field,
knowledgeable in the method, and financially unencumbered by the outcome of the evaluation.
Has a detailed protocol with standard operating procedures (SOPs), a description of operating
characteristics, and criteria for judging test performance and results.
Data generated adequately measure or predict the toxic endpoint of interest and demonstrate a linkage
between either the new test and an existing test or the new test and effects in the target species.
Adequate test data for chemicals and products representative of those administered by the regulatory
program or agency and for which the test is proposed.
Generate data useful for risk assessment purposes, i.e., for hazard identification, dose-response
assessment, and/or exposure assessment. Methods may be useful alone or as part of a battery or
leveled approach.
The specific strengths and limitations are clearly identified and described.
Be robust (relatively insensitive to minor changes in protocol) and transferable among properly
equipped and staffed laboratories.
Be time and cost effective.
Can be harmonized with similar testing requirements of other agencies and international groups.
Suitable for international acceptance.
Provide adequate consideration for the reduction, refinement, and replacement of animal use.
It is strongly recommended that both "method validation" and "regulatory acceptance"
criteria be met before the quantitative use of a method in site-specific risk assessments. Such
methods would generally be identified by EPA as regulatory methodologies, in contrast to
research methodologies that may have been explored for assessing bioavailability, but may not
be appropriate for applications to site risk assessments. In support of this guidance document,
the Agency intends to identify regulatory methodologies for assessing bioavailability of metals
in soils as it has already done for lead (e.g., see U.S. EPA, 2007a).
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The TRW is available to review the plans for incorporation of the site-specific
bioavailability data (generated by a validated method) into the site assessment. Interested parties
also have the option of submitting for TRW review the proposed sampling plan for input on
whether the plan adequately captures spatial variability in metal species or soil types across the
site.
9. Implementation of Bioavailability Guidance
The Agency recognizes that conducting a bioavailability assessment is complex and
crosses several scientific disciplines (geochemistry, toxicology, etc.). Using this guidance often
will involve considerable scientific judgment and expertise. As a result, EPA believes it is
important to provide technical support to those engaged in human health risk assessment at
contaminated sites and has established a "Bioavailability Committee" which will operate under
EPA's Technical Review Workgroup for Metals and Asbestos (TRW). This committee will be
composed of EPA staff with expertise in bioavailability assessment and its application to site-
specific risk assessments. The Bioavailability Committee of the TRW will act as the primary
point of contact, information archive, and repository of outreach materials for the methods
recommended in the guidance document. It will meet on an as-needed basis to review site-
specific applications, provide assistance to the Regions, and issue additional guidance as
necessary. Moreover, the Committee will review new methods for assessing bioavailability of
inorganic soil contaminants (new method validation). Additional information, technical
assistance, and future bioavailability guidance will be provided on the following website:
http://www.epa.gov/superfund/bioavailability.
10. Cited References
Hrudey, S.E., W. Chen, and C.G. Rousseaux. 1996. Bioavailability in Environmental Risk
Assessment. CRC Press, Boca Raton, FL, USA.
ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods).
1997. Validation and Regulatory Acceptance of Toxicological Test Methods: A Report of the
Ad Hoc Coordinating Committee on the Validation of Alternative Methods. NIH Publication 97-
3981. National Institute of Environmental Health Sciences, Research Triangle Park, N.C.
Kelley, M.E., S.E. Brauning, and R.A. Schoof 2002. Assessing Oral Bioavailability of Metals
in Soil. Battelle Press, Columbus, OH, USA.
National Research Council. 2003. Bioavailability of Contaminants in Soils and Sediments :
Processes, Tools, and Applications. National Academies Press: Washington, DC.
http://www.nap.edu/openbook/0309086256/html/
U.S. EPA. 1986. Air Quality Criteria for Lead Volume I-IV. Environmental Criteria and
Assessment Office, Office of Research and Development, RTF, NC. EPA 600/8-83-028 a-d.
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U.S. EPA. 1989. Risk Assessment Guidance for Superfund. Volume I. Human Health
Evaluation Manual (Part A). EPA/540/1-89/002.
U.S. EPA. 1991. Human Health Evaluation Manual, Supplemental Guidance: Standard Default
Exposure Factors. OSWER Directive 9285.6-03.
U.S. EPA. 1993. Data Quality Objectives Process for Superfund. EPA540-R-93-071.
U.S. EPA. 1994a. Technical Support Document: Parameters and Equations Used in the
Integrated Exposure Uptake Biokinetic Model for Lead in Children (v. 0.99d). EPA/540/R-
94/040, PB94-963505.
U.S. EPA. 1994b. Guidance Manual for the Integrated Exposure Uptake Biokinetic Model for
Lead in Children. EPA/540/R-93/081, PB93-963510.
U.S. EPA. 1996. Recommendations of the Technical Review Workgroup for Lead for an
Interim Approach to Assessing Risks Associated with Adult Exposures to Lead in Soil. U.S.
Environmental Protection Agency Technical Review Workgroup for Lead.
U.S. EPA. 1999. US Submission to Meeting of OECD Working Party on Existing Chemicals.
February, 1999 HPV Chemical Human Health Testing: Animal Welfare Issues and Approaches.
U.S. EPA. 2000a. Guidance for the Data Quality Objectives Process (G-4). EPA600/R-96/055
U.S. EPA. 2000b. Guidance for the Data Quality Objectives Process for Hazardous Waste Sites
(G-4HW). EPA/600/R-00/007.
U.S. EPA. 2000c. Guidance for Data Quality Assessment: Practical Methods for Data Analysis
(G-9). EPA/600/R-96/084.
U.S. EPA. 200la. Risk Assessment Guidelines for Superfund: Volume III - Part A. Process for
Conducting Probabilistic Risk Assessment. EPA 540-R-02-002.
U.S. EPA. 2001b. Site Assessment Guidance CD. Available online:
http://www.epa.gov/oerrpage/superfund/sites/phonefax/descript/siteassess.htm.
U.S. EPA. 2002a. Guidance on Quality Assurance Project Plans (G-5). EPA/600/R-02/009.
U.S. EPA. 2002b. Guidance on Choosing a Sampling Design for Environmental Data
Collection (G-5S). EPA/600/R-02/005.
U.S. EPA. 2002c. Guidance on Environmental Data Verification and Validation (G-8).
EPA/240/R-02/004.
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U.S. EPA. 2003a. Reference Dose for Chronic Oral Exposure: Cadmium. IRIS.
http://www.epa.gov/iris/.
U.S. EPA. 2003b. Reference Dose for Chronic Oral Exposure: Manganese. IRIS.
http://www.epa.gov/iris/.
U.S. EPA. 2007a. Estimation of Relative Bioavailability of Lead in Soil and Soil-like Materials
Using in Vivo and in Vitro Methods. OSWER 9285.7-77.
U.S. EPA. 2007b. Framework for Metals Risk Assessment. EPA 120/R-07/001.
White P.O., P. Van Leeuwen P., B.D. Davis, M. Maddaloni, K.A. Hogan, A.H. Marcus, and
R.W. Elias. 1998. The conceptual structure of the Integrated Exposure Uptake Biokinetic
Model for Lead in Children. Environ. Health Perspect. 106(Suppl 6):1513-1530.
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