vvEPA
EPA/635/R-17/330
IRIS Assessment Plan
www.epa.gov/iris
IRIS Assessment Plan for Chloroform
[CASRN 67-66-3]
September 2017
Integrated Risk Information System
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency

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IRIS Assessment Plan for Chloroform
DISCLAIMER
This document is a preliminary draft for review purposes only. This information is
distributed solely for the purpose of pre-dissemination review under applicable information quality
guidelines. It has not been formally disseminated by EPA. It does not represent and should not be
construed to represent any Agency determination or policy. Mention of trade names or commercial
products does not constitute endorsement or recommendation for use.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Chloroform
CONTENTS
AUTHORS | CONTRIBUTORS	v
1.	INTRODUCTION	1
2.	SCOPING AND INITIAL PROBLEM FORMULATION	2
2.1.	BACKGROUND	2
2.2.SCOPING SUMMARY	3
2.3. PROBLEM FORMULATION	5
3.	OVERALL OBJECTIVE, SPECIFIC AIMS AND DRAFT POPULATIONS, EXPOSURES,
COMPARATORS, AND OUTCOMES (PECO) FRAMEWORK	6
3.1.SPECIFIC AIMS	6
3.2.	DRAFT PECO FRAMEWORK	7
3.3.	ASSESSMENT APPROACH	9
3.4.	KEY SCIENCE ISSUES	9
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Chloroform
TABLES
Table 1. EPA program or regional office interest in an updated chloroform assessment	4
Table 2. Draft PECO framework for the chloroform assessment	8
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This document is a draft for review purposes only and does not constitute Agency policy.

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IRIS Assessment Plan for Chloroform
AUTHORS | CONTRIBUTORS
Assessment Team
Ted Berner (Assessment Manager)
Ainina Wilkins
Jenny Li
Amanda Persad
Audrey Galizia
U.S. EPA/ORD/NCEA
Executive Direction
Tina Bahadori
Mary Ross
Kris Thayer
Vincent Cogliano
Emma Lavoie
Samantha Jones
NCEA Center Director
NCEA Deputy Center Director
IRIS Division Director
IRIS Division Director (2010-2017)
Assistant Center Director for Scientific Support
NCEA Associate Director for Health (acting)
Contributors and Production Team
Hillary Hollinger
Ryan Jones
Vicki Soto
Dahnish Shams
Maureen Johnson
HERO Librarian
HERO Director
Project Management Team
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Chloroform
1. INTRODUCTION
The Integrated Risk Information System (IRIS) Program is undertaking a reassessment of the health
effects of chloroform via inhalation. IRIS assessments provide high quality, publicly available information
on the toxicity of chemicals to which the public might be exposed. These assessments are not regulations,
but provide a critical part of the scientific foundation for decisions made in EPA program and regional
offices to protect public health.
Before beginning an assessment, the IRIS Program consults with EPA program and regional offices
to define the scope of the assessment, including the nature of the hazard characterization needed,
identification of the most important exposure pathways, and level of detail needed to inform program and
regional office decisions. Based on the scope defined by EPA, the IRIS Program undertakes problem
formulation activities to frame the scientific questions that will be the focus of the assessment, which is
conducted using systematic review methodology.
This document presents the draft assessment plan for chloroform, including a summary of the IRIS
Program's scoping and initial problem formulation conclusions, objectives and specific aims of the
assessment; draft PECO (Populations, Exposures, Comparators, and Outcomes) framework that outlines the
evidence considered most pertinent to the assessment; and identification of key areas of scientific
complexity. Brief background information on uses and potential for human exposure is provided for
context.
This document is a draft for review purposes only and does not constitute Agency policy.
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2.SCOPING AND INITIAL PROBLEM FORMULATION
2.1. BACKGROUND
Chloroform (trichloromethane) is a colorless, volatile liquid with a distinct odor. Chloroform is
nonflammable. It is slightly soluble in water and is readily miscible with most organic solvents. Because
chloroform is relatively volatile, it tends to escape from contaminated environmental media (e.g., water or
soil) into air and may also be released in vapor form from some types of industrial or chemical operations.
Therefore, humans may be exposed to chloroform not only by ingestion of chloroform in drinking water,
food, or soil, but also by dermal contact with contaminated media (especially water) and by inhalation of
vapor (especially in indoor air).
An assessment of chloroform is available on the IRIS website and consists of (1) an inhalation
assessment, (2) an oral assessment, and (3) a mode of action (MOA) analysis for cancer
(https://cfpub.epa.gov/ncea/iris2/chemicalLanding.cfm7substance nmbr=25). The inhalation assessment
(posted in 1987) derived an inhalation unit risk (IUR) for chloroform of 2.3 x 10 5 per |ig/m3. This IUR was
based on an oral gavage study in mice that employed a route-to-route extrapolation without the use of a
physiologically based pharmacokinetic (PBPK) model.1 That assessment did not include the derivation of a
reference concentration (RfC) for chloroform. The oral assessment (posted in 2001) yielded a reference
dose (RfD) of 1 x 10 2 mg/kg-day. Also posted in 2001, the MOA analysis concluded that chloroform is
likely carcinogenic to humans by all routes of exposure only under high-exposure conditions that lead to
cytotoxicity and regenerative hyperplasia in susceptible tissues. Based on this MOA analysis, the RfD was
determined to be protective with respect to cancer because, at the RfD, cytotoxicity—a key event in the
MOA for cancer—was not observed. The inhalation assessment posted in 1987 was never updated to
address the route-to-route extrapolation approach or the more recent MOA analysis.
As a result, the methodology used to derive the IUR posted in 1987 has two shortcomings: (1) it
utilized a route-to-route extrapolation approach that did not employ a PBPK model, and (2) it incorporated
a linear extrapolation approach for dose-response that implicitly assumes a risk of cancer at all nonzero
exposures to chloroform (i.e., no threshold). The MOA analysis added in 2001, however, concluded that for
cancer, chloroform exhibits a "threshold" by all routes of exposure, and thus a chloroform dose that does
not elicit cytotoxicity presents no cancer risk. Therefore, the assumption underlying the IUR dose-response
approach (linear extrapolation with no threshold) is inconsistent with the MOA analysis.
'Conducting a route-to-route extrapolation without the use of a PBPK model is no longer advocated because of the
potential inaccuracy of this methodology, especially when converting doses from the oral to the inhalation route of
exposure.
This document is a draft for review purposes only and does not constitute Agency policy.
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2.2. SCOPING SUMMARY
The chloroform inhalation assessment will be updated by deriving an RfC based on available
inhalation data from human or animal studies and evaluating this RfC in light of the MOA analysis posted in
2001. During scoping, the IRIS Program met with EPA program and regional offices that had interest in an
updated IRIS assessment for chloroform to discuss specific assessment needs. Table 1 provides a summary
of input from this outreach. EPA's Office of Land and Emergency Management (OLEM), EPA's Office of Air
and Radiation (OAR), and Region 4 expressed a specific need for an inhalation reference value for
chloroform. Derivation of an RfC will address these program and regional office needs. In addition, the
MOA analysis posted in 2001 will be used to determine whether this newly derived RfC is protective with
respect to cancer. Finally, the derivation of the RfD and the analysis that determined the RfD was protective
with respect to cancer will not be reevaluated as part of this update to the chloroform assessment because
EPA program and regional offices did not express a specific need for an updated oral reference value for
chloroform.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Chloroform
Table 1. EPA program or regional office interest in an updated chloroform
assessment
Program or
regional
office1
Inhalation
Statutes/Regu lations
Description of Authority/Regulation
Anticipated Uses/Interest
OLEM
V
Comprehensive
Environmental
Response,
Compensation and
Liability Act (CERCLA) -
Section 102
Authorizes EPA to promulgate regulations
designating chemicals as hazardous
substances which, when released into the
environment, may present substantial danger
to public health or welfare or the
environment.
Up-to-date toxicity values (i.e.,
an RfC) are needed to set risk-
based screening levels, derive
baseline risks, establish clean-
up levels, and evaluate clean-
up progress at contaminated
sites, many of which
experience chloroform vapor
intrusion.
Region 4
V
Chloroform is present as a
volatile contaminant at many
industrial sites. Up-to-date
toxicity values (i.e., an RfC) are
needed to conduct regional
risk assessment-related
activities at these
contaminated sites.
OAR
V
Clean Air Act (CAA) -
Section 112
Section 112 (b) defines the original list of 189
hazardous air pollutants (HAP). Under Section
112(c) of the CAA, EPA must identify and list
source categories that emit HAP and then set
emission standards for those listed source
categories under CAA Section 112(d). CAA
Section 112(b)(3)(A) specifies that any person
may petition the Administrator to modify the
list of HAP by adding or deleting a substance.
Section 112(d) states that the EPA must
establish NESHAPs for each category or
subcategory of major sources and area
sources of HAPs [listed pursuant to Section
112(c)], The standards must require the
maximum degree of emission reduction that
the EPA determines to be achievable by each
particular source category. Different criteria
for maximum achievable control technology
(MACT) apply for new and existing sources.
Less stringent standards, known as generally
available control technology (GACT)
standards, are allowed at the Administrator's
discretion for area sources.
Chloroform is classified as a
hazardous air pollutant (HAP)
under the Clean Air Act (CAA).
OAR is mandated under CAA to
periodically conduct risk and
technology reviews (RTRs) for
HAPs in which up-to-date
toxicity values are needed to
evaluate residual risk.
1OLEM (Office of Land and Emergency Management); OAR (Office of Air and Radiation); Region 4 serves Alabama, Florida,
Georgia, Kentucky, Mississippi, North Carolina, South Carolina, Tennessee and 6 tribes.
1
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Chloroform
1	2.3. PROBLEM FORMULATION
2	This assessment will consider all adverse effects elicited by inhalation exposure to chloroform for
3	which data are available. The IRIS Program anticipates there will be fewer than 30 PECO-relevant studies,
4	and the following health effects are likely to warrant inclusion in this assessment: nasal cavity effects,
5	nervous system effects, liver and kidney effects, immune system effects, and reproductive/developmental
6	effects.
7
This document is a draft for review purposes only and does not constitute Agency policy.
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3.OVERALL OBJECTIVE, SPECIFIC AIMS AND DRAFT
POPULATIONS, EXPOSURES, COMPARATORS, AND
OUTCOMES (PECO) FRAMEWORK
The overall objective of this assessment is to identify adverse health effects and characterize
exposure-response relationships for these effects of chloroform to support development of toxicity values.
More specifically, the objective of this assessment is to derive an RfC for chloroform without the need for
route-to-route extrapolation by using inhalation dose-response data from human or animal studies. In
addition, the MOA analysis for cancer for chloroform posted on the IRIS website in 2001 will be used to
determine whether this newly derived RfC is protective with respect to cancer. If so, the current IUR for
chloroform will be removed from the IRIS website. If not, the available inhalation data will be evaluated to
determine whether they can be used to derive a revised IUR for chloroform that would then replace the
existing IUR. This assessment will use systematic review methods to evaluate the epidemiological and
toxicological literature for chloroform, including consideration of relevant mechanistic evidence. The
evaluations conducted in this assessment will be consistent with relevant EPA guidance.2 The systematic
review protocol will be disseminated after review of the draft assessment plan and will reflect changes
made to the specific aims and PECO framework in response to public input
3.1. SPECIFIC AIMS
•	Identify epidemiological (i.e., human) and toxicological (i.e., experimental animal) literature
reporting effects of exposure to chloroform via inhalation as outlined in the PECO framework.
•	Use an iterative approach to determine which mechanistic studies are most important to
summarize, based on factors such as robustness of the evidence in humans and animals, likelihood
to impact evidence synthesis conclusions for human health, and directness or relevance of the model
systems for understanding potential human health hazards. For chloroform, evaluating individual
mechanistic studies for cancer-related outcomes is not anticipated to be critical because of the
existing MOA analysis. So, for mechanistic information, this assessment will rely on other published
authoritative sources, such as public health agency reports and expert review articles.
2EPA guidance documents: http://www.epa.gov/iris/basic-information-about-integrated-risk-information-
svstem# guidance /
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Chloroform
•	Conduct study evaluations (risk of bias and sensitivity) for individual epidemiological and
toxicological studies. Studies with critical deficiencies will be considered uninformative and not
considered further.
•	Extract data on relevant health outcomes from epidemiological and toxicological studies included
based on study evaluation.
•	Synthesize the evidence across studies, assessing similar health outcomes using a narrative
approach or meta-analysis (if appropriate).
•	For each health outcome, express confidence in conclusions from across studies (or subsets of
studies) within human and animal evidence streams, evaluating each evidence stream (human and
animal) separately.
•	For each health outcome, integrate results across evidence streams (human and animal) to
conclude whether a substance is hazardous to humans. Identify and discuss issues concerning
potentially susceptible populations and life stages. Biological support provided from mechanistic
studies and non-mammalian model systems will be considered based on the iterative prioritization
approach outlined in the PECO framework.
•	Derive an RfC, as supported by the available data.
•	Subsequent to RfC derivation, evaluate the protectiveness of the RfC against cancer based on the
2001 MOA analysis. If the RfC is protective against cancer, the IUR posted in 1987 would be
removed from the IRIS website. If not, the available inhalation data will be evaluated to see if they
are amenable to deriving a revised IUR for chloroform that would then replace the existing IUR.
•	Characterize uncertainties and identify key data gaps and research needs such as limitations of the
evidence base, limitations of the systematic review, and consideration of dose-relevance and
pharmacokinetic differences when extrapolating findings from higher-dose animal studies to lower
levels of human exposure.
3.2. DRAFT PECO FRAMEWORK
A PECO (Populations, Exposures, Comparators, and Outcomes) framework is used as an aid to focus
the research question(s), search terms, and inclusion/exclusion criteria in a systematic review. The draft
PECO framework for chloroform (Table 2) was based on (1) nomination of the chemical for assessment, (2)
discussions with scientists in EPA program and regional offices to determine the scope of the assessment
that will best meet Agency needs, and (3) preliminary review of the health effects literature for chloroform
(primarily reviews and authoritative health assessment documents) to identify the major health hazards
associated with exposure to chloroform via inhalation and key areas of scientific complexity.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Chloroform
Table 2. Draft PECO framework for the chloroform assessment
PECO element
Evidence
Populations
Human: Anv DODulation and life stage (e.g.. children, general DODulation. occuDational. or high exDosure
from an environmental source). The following study designs will be considered most informative:
controlled exposure, cohort, case-control, cross-sectional, and ecological. Note: Case reports and case
series will be tracked during study screening, but are not the primary focus of this assessment. They may
be retrieved for full-text review and subsequent evidence synthesis if no or few informative study designs
are available. Case reports also can be used as supportive information to establish biologic plausibility for
some target organs and health outcomes.
Animal: Nonhuman mammalian animal SDecies (whole organism) of anv life stage (including
preconception, in utero, lactation, peripubertal, and adult stages).
Nonmammalian model svstems/in vitro/in silico: Nonmammalian model systems (e.g.. fish. amDhibians.
birds, Caenorhabditis elegans); human or animal cells, tissues, or biochemical reactions (e.g., ligand
binding assays) with in vitro exposure regimens; bioinformatics pathways of disease analysis; or high
throughput screening data. These studies are tagged during title and abstract screening and an iterative
approach is used to prioritize their inclusion for full-text retrieval and evidence synthesis based on
likelihood to impact evidence synthesis conclusions for human health3
Exposures
Human: ExDosure to chloroform (CASRN 67-66-3). including occuDational exDosures. via inhalation.
Exposures quantified by either actual exposure measurements or occupational exposure history are
preferred.
Animal: Anv exDosure to chloroform via inhalation. Studies emDloving chronic exDosures or short-term
developmental-only exposures will be considered the most informative. Studies involving exposures to
mixtures will be included only if they include an arm with exposure to chloroform alone.
Nonmammalian model svstems/in vitro/in silico: Exposure via growth or assay medium.
Comparators
Human: A comDarison or reference DODulation exDosed to lower levels (or no exDosure/exDosure below
detection limits) of chloroform, or exposed to chloroform for shorter periods of time.
Animal: A concurrent control grouD exDosed to vehicle-onlv treatment.
In vitro: Mammalian cells, bacterial strains for mutagenicity assays or cell-free assay corrmonents
(targets) exposed to an appropriate control.
Outcomes
All health outcomes (both cancer and noncancer). In general, endpoints related to clinical diagnostic
criteria, disease outcomes, histopathological examination, or other apical/phenotypic outcomes will be
prioritized for evidence synthesis over outcomes such as biochemical measures. As discussed above,
based on preliminary screening work, EPA anticipates that a systematic review for health effect
categories other than those identified (i.e., nasal cavity effects, nervous system effects, liver and kidney
effects, immunotoxic effects, and reproductive/developmental effects) will not be undertaken unless a
significant amount of new evidence is found upon review of references during the comprehensive
literature search.
aNote: An iterative approach is used to prioritize evidence from nonmammalian model systems (e.g., fish, amphibians, birds, C. elegans),
in vitro, in silico, and other types of mechanistic studies based on likelihood to impact evidence synthesis conclusions for human health.
Evidence from these studies will be tagged preliminarily during title/abstract screening as "Other Informative Studies" or "Supplemental
Information" according to hazard categories or types of mechanistic outcomes/pathways. These studies are prioritized for full-text
retrieval and evidence synthesis to focus on those studies most important to summarize, based on factors such as robustness of the
evidence in humans and animals, directness or relevance of the model systems, and concentrations tested. For example, if robust
epidemiological or nonhuman mammalian evidence is available, the need to conduct a thorough assessment of individual nonmammalian
and mechanistic studies could be diminished unless controversial issues need to be resolved, e.g., issues related to applicability of animal
evidence to humans or shape of the dose-response relationship at low exposure levels.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan for Chloroform
1	3.3. ASSESSMENT APPROACH
2	The chloroform inhalation assessment will be updated by deriving an RfC based on available
3	inhalation data in human or animal studies and evaluating this RfC in light of the MOA analysis posted on
4	the IRIS website in 2001. The newly derived RfC will inform whether the current IUR will be updated or
5	removed.
6	3.4. KEY SCIENCE ISSUES
7	No specific key science issues have been identified outside of those described in the background and
8	scoping summary.
This document is a draft for review purposes only and does not constitute Agency policy.
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