UnitedStatesEPA740‐R17‐001|June2017
EnvironmentalProtectionAgencyOfficeofChemical
SafetyandPollutionPrevention
Guidance to Assist Interested Persons
in Developing and Submitting
Draft Risk Evaluations
Under the
Toxic Substances Control Act
June 2017
06/22/2017
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DISCLAIMER
This Guidance does not constitute rulemaking by the United States Environmental Protection
Agency (U.S. EPA), and cannot be relied on to create a substantive or procedural right enforceable
by any party in litigation with the United States. As indicated by the use of non-mandatory
language such as “may” and “should,” it provides recommendations and does not impose any
legally binding requirements.
The TSCA statutory provisions and EPA regulations described in this document contain legally
binding requirements. This document is not a regulation itself, nor does not it change or substitute
for those provisions and regulations. While EPA has made every effort to ensure the accuracy of the
discussion in this guidance, the obligations of EPA and the regulated community are determined by
statutes, regulations, or other legally binding requirements. In the event of a conflict between the
discussion in this document and any statute or regulation, this document would not be controlling.
The guidance is not applicable to risk evaluations developed to support other EPA statutes or
programs. Interested persons are free to raise questions and objections about the substance of this
guidance and the appropriateness of the application of this guidance to a particular situation. EPA
may take action that is at variance with the recommendations in this document and may change
them at any time without public notice.
This is a living document and may be revised periodically. EPA welcomes public input on this
document at any time.
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TABLE OF CONTENTS
TABLE OF CONTENTS ..................................................................................................................... 3
AUTHORS, CONTRIBUTORS, AND REVIEWERS ....................................................................... 4
GLOSSARY OF TERMS AND ABBREVIATIONS ......................................................................... 4
1 PURPOSE OF THIS GUIDANCE ............................................................................................... 5
2 BACKGROUND AND STATUTORY FRAMEWORK ............................................................ 6
2.1 Statutory Requirements for Risk Evaluations under TSCA .................................................. 6
2.2 Definitions ............................................................................................................................. 7
3 SCIENTIFIC STANDARDS FOR TSCA RISK EVALUATIONS .......................................... 10
3.1 Best Available Science ........................................................................................................ 10
3.2 Weight of Evidence ............................................................................................................. 11
3.2.1 Systematic Review ....................................................................................................... 12
3.3 Data Quality ........................................................................................................................ 13
4 TSCA RISK EVALUATION PROCESS .................................................................................. 13
4.1 Scope ................................................................................................................................... 15
4.1.1 Conceptual Model ........................................................................................................ 15
4.1.2 Analysis Plan ............................................................................................................... 15
4.2 Exposure Assessment .......................................................................................................... 16
4.3 Hazard Assessment ............................................................................................................. 18
4.4 Risk Characterization .......................................................................................................... 20
5 RISK DETERMINATION IN TSCA RISK EVALUATIONS ................................................. 22
6 REFERENCES ........................................................................................................................... 23
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
This guidance document was developed by the U.S. EPA, Office of Chemical Safety and
Pollution Prevention, Office of Pollution Prevention and Toxics.
GLOSSARY OF TERMS AND ABBREVIATIONS
AOP Adverse Outcome Pathway
CFR Code of Federal Regulations
EPA Environmental Protection Agency
IRIS Integrated Risk Information System
MOA Mode of action
NRC National Research Council
OECD Organization for Economic Cooperation and Development
OPPT Office of Pollution Prevention and Toxics
TSCA Toxic Substances Control Act
U.S. United States
U.S.C United States Code
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1 PURPOSE OF THIS GUIDANCE
On June 22, 2016, the “Frank R. Lautenberg Chemical Safety for the 21st Century Act” was
signed into law, thereby amending the 1976 Toxics Substances Control Act. The amended Toxic
Substances Control Act is referred to as TSCA hereafter. One of the key features of the amended
law is the requirement that EPA prioritize and assess existing chemicals, and manage identified
risks. Through a combination of new authorities, a risk-based assessment mandate, deadlines for
action, and minimum throughput requirements, TSCA effectively creates a “pipeline” by which
EPA will conduct risk evaluation and management of existing chemicals.
The law also requires EPA to develop guidance, which is presented in this document, to assist
interested persons (referred as external parties hereafter) in submitting draft risk evaluations
which shall be considered by EPA. In accordance with TSCA, the guidance shall, at a minimum,
address the quality of the information submitted and the process to be followed in developing
draft risk evaluations for consideration by EPA.
This guidance avoids being prescriptive as EPA’s approaches – and consequently the guidance
that EPA would provide to external parties ‒ will likely evolve over time, and new relevant
guidance documents will be developed. EPA’s goal is to ensure that external parties have
flexibility to use the best available science by adapting and keeping current with changing
science. Its contents may be refined, updated, or superseded in the future to capture the latest
changes to the risk evaluation process resulting from Agency experience, advances in science,
and future guidance which may be developed or updated.
EPA’s expectation is that external party draft risk evaluations will be of the same high quality as
those developed by EPA. To that end, this guidance discusses the science standards, data quality
considerations, and the steps of the risk evaluation process that external parties should follow
when developing draft TSCA risk evaluations. Having the key factors and risk evaluation
process laid out in this guidance will foster predictability by transparently communicating EPA’s
expectations.
EPA’s vision is to have a sustainable TSCA program that ismeaningfully informed by high-
quality risk evaluations conducted by external parties. EPA will continue to consider other
approaches to ensure that external parties are provided with sufficient information to provide
high quality draft risk evaluations to the Agency. For example, EPA may consider the
development of a voluntary consensus standard for the conduct of risk evaluations that would be
consistent with the requirements in TSCA and would also meet the EPA quality standards
EPA values the opportunity for public involvement to strengthen the guidance document for
external party draft risk evaluations. External parties should contact EPA atTSCA-
[email protected] to discuss any questions about the contents of this guidance document
including plans to submit draft risk evaluations for consideration by EPA. Furthermore, the
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public can provide comments on the guidance at www.regulations.gov, docket # EPA-HQ-
OPPT-2017-0341.
Concomitant with this guidance, EPA is issuing final rules to establish the procedures EPA will
use to prioritize chemical substances and conduct risk evaluations for existing chemicals (40
CFR Part 702). External parties are encouraged to read the final rules, including preambles to
both rules, to familiarize themselves with the TSCA prioritization and risk evaluation processes.
Please visit the EPA website for more information on the TSCA implementation activities.
2 BACKGROUND AND STATUTORY FRAMEWORK
2.1 Statutory Requirements for Risk Evaluations under TSCA
EPA’s Office of Pollution Prevention and Toxics (OPPT) is responsible for health and
environmental risk evaluations of existing chemicals under TSCA. These risk evaluations are
conducted to determine whether a chemical substance or category of chemicals, under the
conditions of use, presents an unreasonable risk of injury to health or the environment. The risk
evaluations have to be conducted without consideration of costs or other non-risk factors, and
must evaluate risks to potentially exposed or susceptible subpopulations that EPA identifies as
relevant to the risk evaluation.
TSCA section 6(b) identifies the minimum components EPA must include in all chemical risk
evaluations. For each risk evaluation, EPA must publish a document that outlines the scope of
the risk evaluation that will be conducted, and that includes the hazards, exposures, conditions of
use, and the potentially exposed or susceptible subpopulations the EPA expects to consider. The
statute provides that the scope of the risk evaluation must be published no later than six months
after the initiation of the risk evaluation. The statute also requires that EPA allow for at least one
30-day public comment period on the draft risk evaluation, prior to publishing a final risk
evaluation. Furthermore, there are statutory time limits for completing TSCA risk evaluations.
TSCA requires EPA to complete the final risk evaluation within three years from initiation, with
a possible six-month extension. External parties are encouraged to go to 40 CFR Part 702 for
more information about the procedures for chemical risk evaluations under TSCA.
Each risk evaluation must: (1) “integrate and assess available information on hazards and
exposure for the conditions of use of the chemical substance, including information on specific
risks of injury to health or the environment and information on potentially exposed or susceptible
subpopulations identified as relevant by the Administrator;” (2) “describe whether aggregate or
sentinel exposures were considered, and the basis for that consideration;” (3) “not consider costs
or other nonrisk factors”; (4) “take into account, where relevant, the likely duration, intensity,
frequency, and number of exposures under the conditions of use;” and (5) “describe the weight
of scientific evidence for the identified hazards and exposure.” When conducting risk evaluations
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of metals or metal compounds, EPA must use the March 2007 Framework for Metals Risk
Assessment of the Office of the Science Advisor (U. S. Environmental Protection Agency, 2007)
or a successor document that addresses metals risk assessment and is peer-reviewed by the
Science Advisory Board.
Moreover, the statute requires that EPA adhere to specific provisions regarding Scientific
Standards and Weight of the Scientific Evidence (herein after referred to as weight of the
evidence). Chapter 3 of this guidance document addresses the science standards for draft risk
evaluations as articulated in Section 26 (h) and (i) of TSCA [15 U.S.C. 2625(h) and (i)] and 40
CFR Part 702.
Pursuant to TSCA section 26(j) [15 U.S.C. 2625(j)], and subject to TSCA section 14, 40 CFR
Part 702 specifies that EPA will provide public access to the following information, as
applicable, for a particular risk evaluation: (1) the draft scope, final scope, draft risk evaluation,
and final risk evaluation; (2) all notices, determinations, findings, consent agreements, and
orders; (3) any information required to be provided to the Agency under 15 U.S.C. 2603; (4) a
nontechnical summary of the risk evaluation; (5) a list of the studies, with the results of the
studies, considered in carrying out each risk evaluation; (6) the final peer review report,
including the response to peer review and public comments received during peer review; and (7)
response to public comments received on the draft scope and the draft risk evaluation.
EPA will review this guidance document according to the statutory timeframes set forth in
section 26(l)(2) of TSCA, and revise it as EPA determines to be necessary to reflect new
scientific developments or understandings.
2.2 Definitions
This section defines key terms that are important to understand when developing a draft risk
evaluation. The following definitions are codified in TSCA (15 U.S.C. 2602) or 40 CFR Part
702.33. EPA recommends that external parties consult with the preamble of 40 CFR Part 702 for
EPA’s interpretation of those definitions that were established in the final rule establishing the
procedures for chemical risk evaluations under TSCA.
1. Aggregate exposure means the combined exposures to an individual from a single chemical
substance across multiple routes and across multiple pathways.
2.
Best available science means science that is reliable and unbiased. Use of best available
science involves the use of supporting studies conducted in accordance with sound and
objective science practices, including, when available, peer reviewed science and supporting
studies and data collected by accepted methods or best available methods (if the reliability of
the method and the nature of the decision justifies use of the data). Additionally, as stated in
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EPA’s Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances
Control Act, under 40 CFR Part 702.33, EPA will consider as applicable:
The extent to which the scientific information, technical procedures, measures,
methods, protocols, methodologies, or models employed to generate the information
are reasonable for and consistent with the intended use of the information;
The extent to which the information is relevant for the Administrator’s use in making
a decision about a chemical substance or mixture;
The degree of clarity and completeness with which the data, assumptions, methods,
quality assurance, and analyses employed to generate the information are
documented;
The extent to which the variability and uncertainty in the information, or in the
procedures, measures, methods, protocols, methodologies, or models, are evaluated
and characterized; and
The extent of independent verification or peer review of the information or of the
procedures, measures, methods, protocols, methodologies or models.
3. Chemical substance means any organic or inorganic substance of a particular molecular
identity, including any combination of such substances occurring in whole or in part as a
result of a chemical reaction or occurring in nature, and any element or uncombined radical.
Chemical substance does not include
any mixture;
any pesticide (as defined in the Federal Insecticide, Fungicide, and Rodenticide Act)
when manufactured, processed, or distributed in commerce for use as a pesticide,
tobacco or any tobacco product;
any source material, special nuclear material, or byproduct material (as such terms are
defined in the Atomic Energy Act of 1954 and regulations issued under such Act);
any article the sale of which is subject to the tax imposed by section 4181 of the
Internal Revenue Code of 1954 (determined without regard to any exemptions from
such tax provided by section 4182 or 4221 or any other provision of such Code), and
any food, food additive, drug, cosmetic, or device (as such terms are defined in
section 201 of the Federal Food, Drug, and Cosmetic Act) when manufactured,
processed, or distributed in commerce for use as a food, food additive, drug,
cosmetic, or device.
4. Conditions of use means the circumstances, as determined by the Administrator, under which
a chemical substance is intended, known, or reasonably foreseen to be manufactured,
processed, distributed in commerce, used, or disposed of.
5. Guidance: any significant written guidance of general applicability prepared by the EPA
Administrator.
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6. Pathways means the mode through which one is exposed to a chemical substance, including
but not limited to: food, water, soil, and air.
7. Potentially exposed or susceptible subpopulation means a group of individuals within the
general population identified by the Agency who, due to either greater susceptibility or
greater exposure, may be at greater risk than the general population of adverse health effects
from exposure to a chemical substance or mixture, such as infants, children, pregnant
women, workers, or the elderly.
8. Reasonably available information means information that EPA possesses or can reasonably
generate, obtain, and synthesize for use in risk evaluations, considering the deadlines
specified in TSCA section 6(b)(4)(G) for completing such evaluation. Information that meets
the terms of the preceding sentence is reasonably available information whether or not the
information is confidential business information, that is protected from public disclosure
under TSCA section 14.
9. Routes means the particular manner which a chemical substance may contact the body,
including absorption via ingestion, inhalation, or dermally (integument).
10. Sentinel exposure means the exposure from a single chemical substance that represents the
plausible upper bound of exposure relative to all other exposures within a broad category of
similar or related exposures.
11. Uncertainty means the imperfect knowledge or lack of precise knowledge of the real world
either for specific values of interest or in the description of the system.
12. Variability means the inherent natural variation, diversity, and heterogeneity across time
and/or space or among individuals within a population.
13. Weight of evidence means a systematic review method, applied in a manner suited to the
nature of the evidence or decision, that uses a pre-established protocol to comprehensively,
objectively, transparently, and consistently, identify and evaluate each stream of evidence,
including strengths, limitations, and relevance of each study and to integrate evidence as
necessary and appropriate based upon strengths, limitations, and relevance.
The terms “risk assessment” and “risk evaluation” are commonly used interchangeably in the
scientific literature and in certain EPA technical guidance documents. Risk assessment evaluates
available scientific information on the properties of an agent and its effects in biological systems
to provide an evaluation of the potential for harm as a consequence of environmental exposure
(EPA, 2005).
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On the other hand, the term “risk evaluation” is used exclusively in this guidance, consistent
with the specialized meaning of “risk evaluation” under TSCA. “Risk evaluation” is the process
specified under section 6(b)(4)(A) of determining whether a chemical substance presents an
unreasonable risk of injury to health or the environment under the conditions of use. A risk
evaluation has to be conducted without consideration of costs or other non-risk factors, and must
evaluate risks to potentially exposed or susceptible subpopulations that EPA identifies as
relevant to the risk evaluation. Risk assessment does not necessarily imply all aspects of TSCA
risk evaluation as specified under section 6(b)(4)(A).
3 SCIENTIFIC STANDARDS FOR TSCA RISK
EVALUATIONS
TSCA requires that, to the extent that EPA makes a decision based on science under TSCA
sections 4, 5, or 6, EPA must use certain scientific standards and make those decisions consistent
with the best available science and based on the weight of the scientific evidence [15 U.S.C.
2625(h) and (i)]. In addition, TSCA section 6(b)(4) establishes specific substantive requirements
for EPA-conducted risk evaluations [15 U.S.C 2605 (b)(4)].
Given these TSCA requirements, EPA recommends that external parties, in preparing a draft risk
evaluation, adhere to the same scientific standards and other substantive requirements that apply
to EPA in the course of implementing TSCA section 6(b) and preparing risk evaluations.
External-party draft risk evaluations will be of little or no value to EPA if they do not explain
how they conform to the TSCA provisions mentioned above. Also, although it will be within
EPA’s purview to determine that the information received meets the TSCA scientific standards,
EPA will be more able to effectively utilize the information provided if external parties
understand and apply their best judgment in conforming to the standards in draft risk evaluations.
3.1 Best Available Science
EPA recommends that external parties prepare draft risk evaluations using the best available
science as described in 15 U.S.C. 2625(h) and defined in 40 CFR Part 702.33, establishing the
procedures for chemical risk evaluations under TSCA.
In determining that best available science is an integral component of section 6 risk evaluations,
EPA defined, by rulemaking, best available science as “science that is reliable and unbiased.
Use of best available science involves the use of supporting studies conducted in accordance
with sound and objective science practices, including, when available, peer reviewed science and
supporting studies and data collected by accepted methods or best available methods (if the
reliability of the method and the nature of the decision justifies use of the data).”
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As defined in 40 CFR Part 702.33, implementing the best available science also means “…to
consider, as applicable:
The extent to which the scientific information, technical procedures, measures, methods,
protocols, methodologies, or models employed to generate the information are reasonable
for and consistent with the intended use of the information;
The extent to which the information is relevant for the Administrator’s use in making a
decision about a chemical substance or mixture;
The degree of clarity and completeness with which the data, assumptions, methods,
quality assurance, and analyses employed to generate the information are documented;
The extent to which the variability and uncertainty in the information, or in the
procedures, measures, methods, protocols, methodologies, or models, are evaluated and
characterized; and
The extent of independent verification or peer review of the information or of the
procedures, measures, methods, protocols, methodologies or models."
EPA’s Procedures for Chemical Risk Evaluation Under the Amended Toxic Substances Control
Act, under 40 CFR Part 702.45, require EPA to peer review the risk evaluations. If EPA were to
use parts of a draft risk evaluation submitted by an external party, those parts would become part
of the EPA’s risk evaluation and would undergo the required peer review, regardless of the
source of the information.
EPA is not suggesting that external parties need to have their draft risk evaluation peer reviewed
before submission to EPA. Therefore, EPA has not described a peer review process for these
submissions in this guidance document. However, if an external party wanted to have an
assessment peer reviewed before submission to EPA, nothing would preclude those activities and
EPA would likely consider any peer review record that was provided with the submission.
3.2 Weight of Evidence
TSCA risk evaluations are required to rely on the weight of the scientific evidence [15 U.S.C.
2625 (i)]. EPA recommends that external parties use weight of the evidence approaches in the
draft risk evaluation. In accordance with the final rule (40 CFR Part 702.33), weight of evidence
is defined as “a systematic review method, applied in a fit-for-purpose manner, that uses a pre-
established protocol to comprehensively, objectively, transparently, and consistently, identify
and evaluate each stream of evidence, including strengths, limitations, and relevance of each
study and to integrate evidence as necessary and appropriate based upon strengths, limitations,
and relevance.”
Application of weight of the evidence analysis is an integrative and interpretive process. It is
more than simply tallying of the number of positive and negative studies and is applicable to
both human health and ecological risk evaluations.
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There are certain principles of weight of the evidence evaluations that are universal, including
foundational considerations such as objectivity and transparency, and the general process. This
process starts with assembling the relevant information, evaluating the information for quality
and relevance, and finally the synthesizing and integrating the different lines of evidence to
support conclusions (EPA, 2016). EPA recommends that interested persons explain the evidence
integration process and methods used to support the weight of evidence analysis in the draft risk
evaluation.
3.2.1 SYSTEMATIC REVIEW
EPA intends to use systematic review when conducting TSCA risk evaluations for existing
chemicals. As defined by the Institute of Medicine, systematic review “is a scientific
investigation that focuses on a specific question and uses explicit, pre-specified scientific
methods to identify, select, assess, and summarize the findings of similar but separate studies”
(Institute of Medicine, 2011). The goal of systematic review methods is to ensure that the review
is complete, unbiased, reproducible, and transparent (Bilotta, Milner, & Boyd, 2014).
The principles of systematic review have been well developed in the context of evidence-based
medicine (e.g., evaluating efficacy in clinical trials) (Higgins & Green, 2011) and are being
adapted for use across a more diverse array of systematic review questions, including answering
important public health questions. The National Academies’ National Research Council (NRC)
has encouraged EPA to move towards systematic review processes to enhance the transparency
of scientific literature review that support chemical-specific risk assessments to inform
regulatory decision making (National Research Council, 2011, 2014).
Key elements of systematic review include (Hoffmann et al., 2017; Stephens et al., 2016):
A clearly stated set of objectives (defining the question)
Developing a protocol which describes the specific criteria and approaches that will be
used throughout the process
Applying the search strategy criteria in a literature search
Selecting the relevant papers using predefined criteria
Assessing the quality of the studies using predefined criteria
Analyzing and synthesizing the data using the predefined methodology
Interpreting the results and presenting a summary of findings
EPA/OPPT plans to integrate systematic review into the TSCA risk evaluations to meet the
statutory requirements of TSCA. EPA strongly recommends that external parties use systematic
review approaches when developing draft TSCA risk evaluations. EPA also recommends that
external parties develop a pre-established systematic review protocol at the beginning of the draft
risk evaluation development process to ensure that the review is complete, unbiased,
reproducible, and transparent. The protocol should describe the pre-specified criteria,
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approaches, methods and/or procedures to identify, select, assess, and summarize the findings of
studies including strengths, limitations, and relevance of each study. The protocol should also
address how the evidence will be integrated, as necessary and appropriate, based upon strengths,
limitations and relevance. Expert judgement is often used throughout the process of evaluating
the studies. However, benchmarking interpretations to clear criteria for study quality will help
improve the transparency and objectivity of the evaluation.
3.3 Data Quality
Prior to developing a draft risk evaluation, EPA recommends that external parties implement a
data quality system that ensures that the draft risk evaluation uses quality data intended for risk
assessment purposes consistent with the requirements of TSCA [15 U.S.C. 2625(h) and (i); 2605
(b)(4)]. EPA encourages external parties to read EPA’s Guidelines for Ensuring and Maximizing
the Quality, Objectivity, Utility, and Integrity of Information Disseminated by the Environmental
Protection Agency. EPA will use the approaches set forth in the rule at 40 CFR Part 702 and the
accompanying preamble to prepare the various sections of TSCA risk evaluations. Thus, EPA
recommends that external parties familiarize themselves with those documents. In addition,
EPA’s Assessment Factors provides a summary of general assessment factors that the public
should consider when generating and documenting the quality of their information products
(EPA, 2003). Moreover, EPA strongly recommends that external parties disclose and make
publicly available all raw data used to support the draft risk evaluation, if not previously reported
in the literature.
4 TSCA RISK EVALUATION PROCESS
Since EPA's inception, human health and ecological risk assessment has informed decisions
made to protect humans and the environment. EPA uses risk assessment as a tool to integrate
exposure and health effects or ecological effects information into a characterization of the
potential for health hazards in humans or other hazards to our environment (U. S. Environmental
Protection Agency, 2004).
According to 40 CFR Part 702, the steps of the TSCA risk evaluation process include scope,
hazard assessment, exposure assessment, risk characterization and finally a risk determination.
The steps are applicable for both human health and environmental risk evaluations and rely on
EPA’s risk assessment frameworks described in the Framework for Ecological Risk Assessment
(EPA, 1992a), the Guidelines for Ecological Risk Assessment (EPA, 1998) and the Framework
for Human Health Risk Assessment to Inform Decision Making (EPA, 2014). External parties
should consider these frameworks when developing fit-for-purpose draft risk evaluations that are
consistent with the best available science and based on the weight of the evidence within the
context of TSCA. While EPA is ultimately most interested in the quality of the submitted
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external party draft risk evaluation, not the specific process by which the evaluation was
developed, EPA believes following these steps help to ensure a high-quality product.
TSCA includes an explicit requirement for EPA to publish the scope for any risk evaluation it
will conduct. Further, TSCA requires this scope to include the hazards, exposures, conditions of
use, and the potentially exposed or susceptible subpopulations that EPA expects to consider. In
the TSCA Risk Evaluation Rule (40 CFR Part 702), EPA has included the conceptual model and
an analysis plan as required components of the scope for a risk evaluation. As defined in EPA’s
guidance, problem formulation captures the exposure pathways, receptors and health endpoints
that would be included in the risk evaluations (EPA, 1992a; 1998; 2014). Furthermore, EPA’s
risk assessment frameworks explain that the outcome of problem formulation is a conceptual
model(s) and an analysis plan (EPA, 1992a; 1998; 2014). Hence, problem formulation has
essentially the same function as scoping under the amended TSCA, thereby aligning the
requirements of the scope for a TSCA risk evaluation with the components of a problem
formulation in EPA guidance (EPA, 1992a; 1998; 2014). Thus, EPA guidance on problem
formulation will be relevant and useful to external parties in scoping TSCA risk evaluations.
TSCA provides that external parties may submit to EPA a draft risk evaluation. EPA does not
expect that external parties would provide a separate scope to EPA. However, EPA recommends
that external party draft risk evaluations document problem formulation in the form of a
conceptual model and analysis plan.
Furthermore, since each risk evaluation is based on the specific circumstances surrounding the
chemical being assessed, this guidance does not single out of any specific guidance, method or
model for routine use, to ensure that there is flexibility to address the specific questions of the
TSCA risk evaluation. When conducting risk evaluations, EPA will take advantage of existing
guidance, tools, models and/or approaches that are relevant and available for use in conducting a
risk evaluation under TSCA as long as they are consistent with the various requirements of
section 26 of TSCA, including conforming to the best available science and weight of the
evidence requirements. A compendium of existing guidance typically consulted by EPA can be
found at the following websites:
EPA’s Risk Assessment Portal
EPA’s Pesticide Science and Assessing Pesticide Risks
1
EPA’s Predictive Models and Tools for Assessing Chemicals under TSCA
OECD’s Assessment of Chemicals
1
Some of the risk assessment guidance for pesticides may be useful to address risk assessment issues in TSCA risk
evaluations.
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4.1 Scope
As stated above, the scoping step of a TSCA risk evaluation identifies the hazards, exposures,
conditions of use and potentially exposed or susceptible subpopulations that EPA expects to
consider in a risk evaluation. EPA recommends that, in scoping a draft risk evaluation, external
parties follow the principles and approaches laid out in 40 CR Part 702 and the accompanying
preamble.
In addition, consistent with Part 702, EPA recommends that the outcome of the scoping phase of
the draft risk evaluation includes a conceptual model(s) and an analysis plan which are further
discussed in 4.1.1 and 4.2.2. In addition, it is also important to identify previous assessments and
regulatory history during scoping as this information may frame the draft risk evaluation by
understanding (1) what elements of the life cycle of the chemical substance are regulated by
EPA, other federal agencies, States, local governments, Tribes and other international
organizations; (2) how they are regulated; (3) the rationale for the regulation, and (4) how the
chemical substance has been evaluated in the past (e.g., previous risk assessments). Previous
assessments generally provide useful information about exposure, hazards and risks and any
potentially exposed or susceptible subpopulations that have been considered by others.
4.1.1 CONCEPTUAL MODEL
An important outcome of the scoping phase is a conceptual model that:
Describes actual or predicted relationships between the chemical substance, the
conditions of use and human and environmental receptors.
Identifies human and ecological health hazards expected to be evaluated in the draft risk
evaluation.
Considers the life cycle of the chemical substance, including manufacture, processing,
distribution in commerce, storage, use, and disposal, relevant to the conditions of use
expected to be considered in the draft risk evaluation.
The conceptual model also addresses those aspects that might not be analyzed in the draft risk
evaluation (e.g., excluded exposure pathways), the recognition of which sometimes is important
in the overall decision-making process (EPA, 2014). Additional details and examples are
provided in EPA’s risk assessment guidance (EPA, 1998; 2014).
4.1.2 ANALYSIS PLAN
The analysis plan describes the analytical intentions for the TSCA risk evaluation (EPA, 2014).
During analysis planning, the relationships described in the conceptual model are evaluated to
determine how they will be assessed using available and new data. Although the conceptual
model may identify a larger set of pathways and relationships, the analysis plan focuses on the
pathways and relationships that will be pursued in the risk assessment. The rationale for selecting
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or omitting pathways and relationships is incorporated into the plan, as is acknowledgement of
data gaps and uncertainties.
The analysis plan may include these components: (1) the assessment design and rationale for
selecting specific pathways to include in the risk assessment; (2) a description of the data,
information, methods and models to be used in the analyses (including uncertainty analyses), as
well as intended outputs (e.g., risk metrics); (3) associated data gaps and limitations. The
analysis plan may describe the extent or aspects of the assessment that are qualitative rather than
quantitative. In all cases, the analysis plan addresses the quality of data to be used (EPA, 1998;
2014).
4.2 Exposure Assessment
Pursuant to TSCA section 6(b)(4)(F), EPA, “where relevant, will take into account the likely
duration, intensity, frequency, and number of exposures under the conditions of use in an
exposure assessment”. Consistent with TSCA, the exposure assessment evaluates, where
relevant, the likely duration, intensity, frequency and number of exposures to human populations
(e.g., general population, consumer, worker), including potentially exposed or susceptible
subpopulations, and ecological receptors (e.g., aquatic, terrestrial species) for the conditions of
use of the chemical substance. TSCA also requires that a risk evaluation describe whether
aggregate or sentinel exposures are considered in the exposure assessment and the basis for that
consideration.
An exposure assessment includes some discussion of the size, nature, and types of individuals or
populations exposed to the chemical substance, as well as discussion of the uncertainties in this
information. Exposure can be measured directly, but when data are unavailable, it is estimated
indirectly through consideration of measured concentrations in the environment, consideration of
models of chemical transport and fate in the environment, and/or estimates of human intake or
environmental exposure over time.
Using reasonably available information, exposures are estimated (usually quantitatively) for the
identified conditions of use. For human health exposure, the assessment would consider all
relevant potentially exposed or susceptible subpopulation(s) and utilize any combination, as
available, of population-based epidemiological studies, information related to geographic
location of susceptible subpopulations, models representing exposures to the population,
measurements in human tissues or relevant environmental or exposure media, and any other
relevant, scientifically valid information or methodology. In an environmental health exposure
assessment, the interaction of the chemical substance with ecological receptors is characterized
and evaluated.
EPA recommends that external parties document all aspects of the exposure scenarios being
evaluated in the draft risk evaluation (e.g., workers, general population, consumers). This also
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includes documentation for scenarios for relevant potentially exposed or susceptible
subpopulations. EPA also recommends that external parties document use of aggregate or
sentinel exposure analyses (if applicable). EPA recommends including the following information
in the exposure assessment:
Chemical-specific factors including, but not limited to: physical- chemical properties and
environmental fate and transport parameters.
Characterization of exposure information relevant to exposure scenarios under evaluation
including a discussion of the overall quality and main limitations of the exposure data,
data sources and underlying principles and assumptions using weight of evidence
approaches.
Disclosure of all data used for the calculations (modeled and measured).
If applicable, model framework and its scientific basis, including rationale for why the
model is selected for risk assessment purposes, utilizes the proper modeling relationships,
results in reasonable approximations, and meets the objectives of the evaluation in terms
of acceptable levels of uncertainty and variability.
Discussion of available exposure evidence on factors that may make potentially exposed
or susceptible subpopulations more vulnerable to the exposure of the chemical of interest.
Basis for selecting key and/or supporting exposure studies in the exposure assessment;
List of equations and explanation of each input and output parameter that are used to
calculate the exposure estimates.
Where relevant, estimates of human exposure by pathway that consider likely duration,
intensity, frequency, and number of exposures under the conditions of use under
evaluation, including potentially exposed or susceptible subpopulations, in a manner
appropriate for the intended risk characterization.
If considered, aggregate and/or sentinel exposure estimates under the conditions of use
and the basis for their estimation.
Results of the sensitivity analysis when modeling is used (if applicable).
Integrative discussion based on the best available science and the weight of the evidence.
Discussion should include the strengths and limitations of the exposure evidence, along
with a discussion on the uncertainties, variability, degree of confidence, and underlying
assumptions including science policy assumptions supporting the exposure estimates.
Further discussion of these elements can be found in EPA’s Guidelines for Exposure Assessment
(EPA, 1992b). In addition, EPA encourages interested persons to consult EPA guidance on
various issues related to exposure assessment and exposure to susceptible subpopulations. The
guidance can be found at EPA’s Risk Assessment Portal, Protecting Children’s Environmental
Health web page or EPA’s ExpoBox. Other applicable policy for susceptible subpopulations can
be found in Executive Orders 12898 and 13045 and EPA guidance on evaluating health risks to
children (1995, 2006).
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EPA recommends that external parties use tables, figures, and appendices to increase
transparency and clarity of the exposure assessment.
4.3 Hazard Assessment
In compliance with TSCA section 6(b)(4)(F), EPA will conduct a hazard assessment on each
chemical substance or category, under the conditions of use as identified by the Administrator. A
hazard assessment identifies the types of adverse health or environmental effects or hazards that
can be caused by exposure to the chemical substance in question, and characterizes the quality
and weight of the evidence supporting this identification.
The hazard assessment has two components: the hazard identification and the dose-response
assessment. Hazard identification is the process of determining whether exposure to a chemical
substance or category can cause an increase in the incidence of specific adverse health or
environmental effects (e.g., cancer, developmental toxicity, reduced growth in aquatic
organisms). All hazard information is reviewed in a manner consistent with best available
science and weight of the evidence. This includes the identification, evaluation, and synthesis of
information to describe the potential health and environmental hazards of the chemical, under the
conditions of use, and documentation of all assessment methods.
As part of the hazard identification assessment, EPA typically reviews and summarizes all
available and relevant data. Specifically, for human health hazards, the assessment considers all
relevant potentially exposed or susceptible subpopulation(s). Potential information sources that
may support the health hazard assessment include, but are not limited to: population based
epidemiological studies that identify risk factors and susceptible subpopulations; information
related to geographic location of subpopulations; models that represent health effects of relevant
subpopulation; in vivo and/or in vitro laboratory studies; and mechanistic or kinetic studies in a
variety of test systems including, but not limited to, mode of action (MOA), adverse outcome
pathways (AOP)], toxicokinetics, toxicodynamics, and computational toxicology (e.g., high-
throughput assays, genomic response assays). The hazard identification will also include an
evaluation of the strength, limitations, and uncertainties associated with the available
information. Similarly, field or laboratory data and modeling strategies may be used in the
environmental hazard assessment.
In some cases, computer models using structure-activity relationships (i.e., predictions of
toxicological activity based on analysis of chemical structure) also may be used as supporting
evidence for both the human health and environmental hazard assessment. Read-across and
chemical category approaches can be used when data gaps occur in the hazard database of the
chemical of interest.
Dose-response assessment describes dose-response relationships in the hazard information, in
other words how the likelihood and severity of adverse health or environmental effects (the
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responses) are related to the amount and condition of exposure to a chemical substance (the dose
provided). The same principles generally apply for studies where the exposure is to a
concentration of the chemical substance (e.g., airborne concentrations applied in inhalation
exposure studies or water or other media concentrations for ecological exposure studies), and the
resulting information is referred to as the concentration-response.
EPA recommends that external parties document all aspects of the environmental and human
health hazard identification and dose-response assessments including the following information:
Characterization of nature and severity of human health and ecological effects and their
respective dose or concentration responses including a discussion of the overall quality
and main limitations of the hazard data, data sources and underlying principles and
assumptions.
Disclosure of all data used for the calculations of hazard values (modeled and measured).
If applicable, for any model used, the model framework and its scientific basis (e.g.,
physiologically-based pharmacokinetic modeling), including rationale for why the model
is selected for risk assessment purposes, utilizes the proper modeling relationships,
results in reasonable approximations, and meets the objectives of the evaluation in terms
of acceptable levels of uncertainty and variability.
Incorporation of mechanistic data, if available, to inform the biological or chemical
events associated with toxic effects (i.e., MOA/AOP) and guide the synthesis and
integration of the effects evidence for both hazard identification and dose-response.
Discussion of available hazard evidence on factors that may make potentially exposed or
susceptible populations more vulnerable to adverse effects (e.g., life stages, windows of
developmental susceptibility).
If applicable, a discussion of the adequacy and robustness of data-gap filling approaches
(e.g., analog data through read-across, category approaches, models based on structure-
activity relationships) and basis for use.
Integrative discussion based on the best available science and the weight of the evidence.
Discussion should include the strengths and limitations of the hazard evidence, along
with a discussion on the uncertainties, variability, degree of confidence, and underlying
assumptions including science policy assumptions supporting the hazard values.
The correspondence between the expected route(s) of exposure and the exposure route(s)
utilized in the studies forming the basis of the dose-response assessment, as well as the
interrelationships of potential effects from different exposure routes.
Model(s) used to develop the dose-response curve and the basis for selecting the model,
their strengths and limitations and underlying assumptions.
Extrapolation methods and the basis for selecting them, including their strengths and
limitations and underlying assumptions.
The basis for selecting interspecies dose scaling factors to account for extrapolating doses
from experimental animals to humans.
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Rationale for route-to-route extrapolations, including strengths and limitations
Discussion if the dose-response values are adopted from other sources (e.g., EPA’s
Integrated Risk Information System (IRIS) assessments).
Applicability of dose-response values (i.e., point of departures) and critical effects to
susceptible populations,
Basis for selecting key and/or supporting studies and corresponding human health and
ecological hazards (or effects) including their basis and hazard values for pertinent
exposure scenarios.
List of equations and explanation of each input and output parameter that are used to
calculate the hazard values.
Major assumptions and uncertainties in the dose-response values affecting their
confidence.
Basis for the selection of uncertainty factors for estimating hazard values for the variety
of scenarios under examination.
EPA’s Weight of Evidence in Ecological Assessment may provide useful information for
planning and using the weight of the evidence for the ecological component of the hazard
assessment (EPA, 2016). EPA recommends that external parties use tables, figures, and
appendices to increase transparency and clarity of the human health and environmental hazard
assessments.
4.4 Risk Characterization
According to EPA’s Risk Characterization Handbook, “the risk characterization integrates
information for the preceding components of the risk assessment and synthesizes an overall
conclusion about risk that is complete, informative, and useful for decision makers” (EPA,
2000). It should be prepared according to the Risk Characterization Principles of transparency,
clarity, consistency and reasonableness (EPA, 2000).
Transparency ensures that any reader understands all the steps, logic, key assumptions,
limitations, and decisions in the risk evaluation, and comprehends the supporting
rationale that lead to the outcome (EPA, 2000).
Clarity ensures that the risk characterization is clear and easy to understand (EPA, 2000),
Consistency ensures that the content of the risk characterization is in harmony with
statutory requirements, program precedents, and EPA’s assessment guidelines including
science policy, and deviations are explained if need be (EPA, 2000).
Reasonableness ensures that the integrative analysis of the risk characterization is
scientifically sound and based on the best available science by following an acceptable
logic and retaining common sense in applying relevant guidance (EPA, 2000).
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EPA recommends that external parties develop a risk characterization section that addresses the
following:
Discussion of the risk estimation approach, including equations and pertinent
assumptions.
Discussion of how the hazard and exposure assessments are integrated into the
quantitative and/or qualitative estimates of risk for the identified human and ecological
receptors under the conditions of use of the chemical substance (e.g., exposure scenarios,
hazard values and rationale for their selection, effects of concern based on weight of
evidence approach).
Summary of the magnitude of the human health and environmental risk estimates (in
tabular form) for the various exposure scenarios assessing the conditions of use of the
chemical substance, including risk estimates for aggregate or sentinel exposures (if
applicable).
Discussion of the major issues associated with determining the nature and extent of the
risk in potentially exposed or susceptible populations, including data needs.
Discussion of the overall characterization and/or analysis of the impact of the uncertainty
and variability on estimated risks. This should include considerations regarding
uncertainty and variability in each of the risk evaluation components (e.g., use of default
assumptions such as uncertainty factors, exposure scenarios, choice of models and
information used for quantitative analysis). It should also include discussion about data
quality issues in the data/information supporting the risk characterization and the level of
confidence in the human health and environmental hazard and exposure values used to
estimate risks.
If appropriate and relevant, discussion of plausible alternative interpretations of the data
and analyses used in the draft risk evaluation.
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5 RISK DETERMINATION IN TSCA RISK EVALUATIONS
The final step of a risk evaluation is for EPA to determine whether the chemical substance, under
the conditions of use, presents an unreasonable risk of injury to health or the environment.
Determinations will specify whether a chemical substance does or does not present an
unreasonable risk of injury to health or the environment under the conditions of use. In general,
EPA may weigh a variety of factors in determining unreasonable risk and include, but not limited
to: the effects of the chemical substance on health and human exposure to such substance under
the conditions of use (including cancer and non-cancer risks); the effects on the chemical
substance on the environment and environmental exposure under the conditions of use; the
population exposed (including any susceptible populations); the severity of hazard (the nature of
the hazard, the irreversibility of hazard); and uncertainties.
TSCA expressly reserves to EPA the final determination of whether risk posed by a chemical
substance is “unreasonable.” External parties have the option of including their unreasonable risk
judgment in their draft risk evaluation, with the clear understanding that EPA reserves the
authority to determine and issue the final determination.
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6 REFERENCES
1. 15 U.S. Code Chapter 53, Subchapter I. Toxics Substances Control Act.
http://uscode.house.gov/view.xhtml?path=/prelim@title15/chapter53&edition=prelim
2. Bilotta, G. S., Milner, A. M., & Boyd, I. (2014). On the use of systematic reviews to inform
environmental policies. Environmental Science & Policy, 42, 67-77.
3. Executive Order 12898. (1994). Federal actions to address environmental justice in minority
populations and low-income populations. Federal Register, 59(32), 7629-7633.
4. Executive Order 13045. (1997). Protection of children from environmental health risks and
safety risks. Federal Register, 62(78), 19885-19888.
5. Higgins, J. P., & Green, S. (2011). Cochrane handbook for systematic reviews of
Interventions (Electronic version 5.1.0 updated March 2011 ed.).
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Tsaioun, K. (2017). A primer on systematic reviews in toxicology. Arch Toxicol. doi:
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8. National Research Council. (2011). Review of the Environmental Protection Agency's Draft
IRIS Assessment of Formaldehyde Division on Earth and Life Studies. Washington, DC.
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(IRIS) Process. Board on Environmental Studies and Toxicology. Washington, DC.
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Risk Assessment Forum. Washington, DC.
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quality, objectivity, utility and integrity of information disseminated by the Environmental
Protection Agency. Office of Environmental Information. Washington, DC.
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principles and practices. Office of the Science Advisor. Washington, DC.
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18. U. S. Environmental Protection Agency. (2005). Guidelines for carcinogen risk assessment.
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assessment. Office of Research and Development. Washington, DC.
