*>EPA
United States
Environmental Protection
Agency
Derivation of an Acute Reference
Concentration for Inhalation
Exposure to Naphthalene
www.epa.gov/research
Office of Research and Development
Health and Environmental Risk Assessment
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A EPA
EPA/600/R-21/292
www.epa.gov/iris
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
[CASRN 91-20-3]
[May 2022]
Superfund Health Risk Technical Support Center
Chemical and Pollutant Assessment Division
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Washington, DC
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
DISCLAIMER
This document has been reviewed by the U.S. Environmental Protection Agency (EPA), Office of
Research and Development and approved for publication. Any mention of trade names, products, or
services does not imply an endorsement by the U.S. government or the U.S. Environmental Protection
Agency. EPA does not endorse any commercial products, services, or enterprises.
This memorandum contains scientific evaluation provided in response to a request for site technical
support with limited scope. The evaluations herein are intended to address specific scientific questions
posed to researchers and/or consultants with applicable experience. Therefore, the evaluations are
written for a specific scientific audience within EPA Region 2. The observations provided are intended to
assist EPA Region 2 with relevant and innovative science to help meet site-specific environmental goals.
The observations are provided in good faith, and due to the limited scope of technical support requests
include potential uncertainty. This memorandum is not to be considered the only source of information
for decision making, nor should the information provided here be parsed. It would be advisable to
consider this memorandum in conjunction with multiple lines of evidence, including history, experience
of site managers, and other pertinent information available to EPA Regional staff that retain the duties
and responsibilities of all decisions and regulatory actions at the site.
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
CONTENTS
TABLES 4
FIGURES 5
ABBREVIATIONS 6
AUTHORS | CONTRIBUTORS | REVIEWERS 7
1. Background 8
2. Systematic Review Methods 10
2.1. Literature search 10
2.2. Literature screening 10
2.3. Study evaluation 12
2.4. Analysis of dose-response considerations 16
3. Systematic Review Results 16
3.1. Literature search and screening results 16
3.2. Study evaluation results 17
3.3. Summary of available studies 18
4. Description of Physiologically Based Pharmacokinetic Model and Derivation of an Acute
Reference Concentration for Inhalation Exposure to Naphthalene 22
4.1. Study selection for dose-response modeling 22
4.2. Calculation of internal dose metrics using a physiologically based pharmacokinetic
model 22
4.3. Estimation or selection of points of departure 26
4.4. Derivation of acute reference concentration values 28
5. Strengths, Limitations, and Uncertainties 29
Appendix A: Comparison of Naphthalene Inhalation Reference Values from National, State, and
International Agencies and Scientific Organizations 31
Appendix B: Supplemental Information on Systematic Review Methods 36
Appendix C: Dose Response BMD Modeling Results 55
Appendix D: PBPK Model Implementation File 61
Appendix E: Dose Metrics Calculation Script 80
Appendix F: Determination of Respiratory Tract Surface Area Parameters for the Naphthalene
PBPK Model 83
Appendix G: Human Equivalent Concentrations Calculation Script 87
Appendix H: Quality Assurance for the Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene (CASRN 91-20-3) 90
Appendix I: References 91
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
TABLES
Table 1. PECO criteria 11
Table 2. Summary of available naphthalene acute inhalation studies 19
Table 3. Internal dose metrics in rats from the study by Dodd et al. (2010) 26
Table 4. Human equivalent concentrations 28
Table 5. Uncertainty factors for the derivation of the acute RfC for naphthalene 28
Table 6. Acute RfC derivations 29
Table A-l. Details on derivation of the available health effect reference values for inhalation
exposure to naphthalene [from Yost et al. (2021)] 31
Table B-l. Database search strategy 36
Table B-2. Processes used to augment the search of core databases for naphthalene 45
Table B-3. Electronic screening inclusion terms for naphthalene (listed alphabetically by
organ/health system) 51
Table C-l. Incidence of olfactory epithelial necrosis in male and female Sprague-Dawley rats and
Pearson's residuals 56
Table C-2. Incidence of olfactory epithelial necrosis in male and female F344 rats and Pearson's
residuals 56
Table C-3. Incidence of olfactory epithelial necrosis in Sprague-Dawley and F344 rats (combined
sexes) and Pearson's residuals 57
Table C-4. Olfactory epithelial necrosis - male and female Sprague-Dawley and F344 rats. Table
3 in the main text shows the relationship between the nominal doses (ppm) and
actual doses (ppm) applied to the rats and the cumulative metabolite
production in DO tissue values (ug/mL) estimated using the PBPK model. The
latter values appear in the "Dose" column here 58
Table C-5. Benchmark dose results for olfactory epithelial necrosis in male and female Sprague-
Dawley and F344 rats 58
Table F-l. Rat body masses and nasal epithelial surface areas used by various authors. Values in
parentheses indicate sums calculated by us for total surface area of a given
nasal region 84
Table F-2. Respiratory tract surface area parameters used by Campbell et al. (2014) and those
used for current analysis 85
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FIGURES
Figure 1. Available health effect reference values for inhalation exposure to naphthalene
(current through March 2021) 9
Figure 2. Overview of the study evaluation domains and definitions for ratings (i.e., domain and
overall judgments, performed on an outcome-specific basis) 15
Figure 3. Literature flow diagram for identification of naphthalene acute inhalation studies 17
Figure 4. Heat map of animal study evaluation results, listed by author, year, and HERO
identification number 18
Figure 5. Schematic for the naphthalene PBPK model of Kapraun et al. (2020) 24
Figure C-l. Dose-response curve for the Multistage Degree 1 model fit to olfactory epithelial
necrosis in male and female Sprague-Dawley and F344 rats 60
Figure C-2. Dose-response curve for the Multistage Degree 1 model fit (low-dose range) to
olfactory epithelial necrosis in male and female Sprague-Dawley and F344 rats 60
Figure F-l. Optimal power law fit for total olfactory epithelium surface area as a function of
body mass based on data of Gross et al. (1982) 84
Figure F-2. Optimal power law fit for total respiratory epithelium surface area as a function of
body mass based on data of Gross et al. (1982) 85
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Derivation of an Acute Reference Concentration for
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ABBREVIATIONS
AIC Akaike's information criterion UFL
ATSDR Agency for Toxic Substances and Disease UFS
Registry VR
BMD benchmark dose WOS
BMDL benchmark dose lower confidence limit
BMDS Benchmark Dose Software
BMR benchmark response
CASRN Chemical Abstracts Service registry
number
CPAD Chemical and Pollutant Assessment
Division
CPHEA Center for Public Health and
Environmental Assessment
DO dorsal olfactory
DR dorsal respiratory
EPA Environmental Protection Agency
ER extra risk
HAWC Health Assessment Workspace
Collaborative
HEC human equivalent concentration
HERO Health and Environmental Research
Online
IAP IRIS Assessment Plan
IRIS Integrated Risk Information System
LOAEL lowest-observed-adverse-effect level
MeSH Medical Subject Headings
mRNA messenger ribonucleic acid
NIEHS National Institute of Environmental
Health Sciences
NOAEL no-observed-adverse-effect level
OM olfactory mucosa
ORD Office of Research and Development
PBPK physiologically based pharmacokinetic
PECO populations, exposures, comparators,
and outcomes
POD point of departure
PODhec human equivalent concentration point of
departure
RfC inhalation reference concentration
STSC Superfund Health Risk Technical Support
Center
TSCATS Toxic Substances Control Act Test
Submissions
UF uncertainty factor
UFa animal-to-human uncertainty factor
UFc composite uncertainty factor
UFd database deficiencies uncertainty factor
UFh human variation uncertainty factor
LOAEL-to-NOAEL uncertainty factor
subchronic-to-chronic uncertainty factor
ventral respiratory
Web of Science
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
AUTHORS | CONTRIBUTORS | REVIEWERS
Authors
Ingrid Druwe, Ph.D. (Assessment Co-manager)
Erin Yost, Ph.D. (Assessment Co-manager)
J. Allen Davis, M.S.
Dustin Kapraun, Ph.D.
Paul Schlosser, Ph.D.
Executive Direction
Wayne E. Cascio, M.D. (CPHEA Director)
Samantha Jones, Ph.D. (CPHEA Associate Director)
Kristina Thayer, Ph.D. (CPAD Director)
Andrew Kraft, Ph.D. (CPAD Associate Director)
Paul White, Ph.D. (CPAD Senior Science Advisor)
Janice Lee, Ph.D. (CPAD Toxic Effects Assessment Branch Chief)
Contributors
Michelle Angrish, Ph.D. EPA/ORD/CPHEA/CPAD
George Woodall, Ph.D. EPA/ORD/CPHEA/HEEAD
Matthew Wheeler, Ph.D. NIEHS (formerly on-detail to EPA)
Program Management and Production Team
Ryan Jones HERO Director
Maureen Johnson Webmaster
Dahnish Shams Project Management Team
Reviewers
This assessment was peer reviewed by independent, expert scientists external to EPA convened by ERG under
contract EP-C-17-017 (Order No. 68HERH20F0097).
Xinxin Ding, Ph.D.
David C. Dorman, DVM, Ph.D.
Frederick J. Miller, Ph.D.
University of Arizona
North Carolina State University
Fred J. Miller & Associates LLC
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
1. Background
Naphthalene is a volatile organic compound that occurs naturally and is also manufactured for
commercial use. Naphthalene has been detected in ambient air due to industrial emissions, biomass
combustion, and use of fossil fuels, and may be present in indoor air due to wood burning, tobacco
smoking, and use of naphthalene-containing moth repellents (ATSDR, 2005). Respiratory exposure to
naphthalene has been found to induce inflammation and cytotoxicity, with neoplastic lesions resulting
from chronic exposure in animal models (ATSDR, 2005).
A summary of the available inhalation reference values for naphthalene derived by EPA and other
national, state, and international agencies and scientific organizations is depicted in Figure 1 [source:
Yost et al. (2021)1. These values include those intended to assess risk in emergency response scenarios,
occupational exposure scenarios, and the general public (see Appendix A, Table A-l for a tabular
summary of these values and derivation details). In addition to the reference values shown in Figure 1
and Appendix A, the Agency for Toxic Substances and Disease Registry (ATSDR) derived an ad hoc
reference value of 60 ng/m3for acute (<24-hour) inhalation exposure to naphthalene in a Letter Health
Consultation dated March 10, 2014 (ATSDR, 2014). The Letter Health Consultation was prepared by
ATSDR for EPA Region 5 to assess risk to the general public living near the Radiac Abrasives, Inc. facility
in Salem, Illinois. The value derived by ATSDR in the Letter Health Consultation is the only reference
value for acute inhalation exposure to naphthalene in the general public that has previously been
published by a U.S. federal agency.
EPA Region 2 contacted the Superfund Health Risk Technical Support Center (STSC) for assistance in
reviewing the scientific approach used by ATSDR (2014) to derive an acute inhalation reference value for
naphthalene. The principal study used by ATSDR was a 4-hour inhalation study in mice by West; et al.
(2001) that reported a no-observed-adverse-effect level (NOAEL) that was based on a qualitative
histopathological assessment. STSC found that while ATSDR's method of calculating an acute value was
consistent with EPA's Methods of Derivation of Inhalation Reference Concentrations and Application of
Inhalation Dosimetry (U.S. EPA, 1994). the use of a qualitative assessment for a NOAEL may not
represent a state-of-the-science estimate of the toxicity involved with acute exposures. Further,
additional studies on the acute toxicity of naphthalene have been published since the publication of
West; et al. (2001), and physiologically based pharmacokinetic (PBPK) models are available that could
provide a better estimate of toxicity.
Due to these limitations, it was determined that EPA would develop an acute reference concentration
(RfC) for inhalation exposure to naphthalene using Agency guidelines and best practices, including the
use of systematic review methods, the application of a PBPK model for naphthalene (Kapraun et al.,
2020), and the use of benchmark dose modeling to identify and evaluate the available human and
animal health effect studies.
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Derivation of an Acute Reference Concentration for
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Naphthalene Inhalation Reference Values
1.E+04
1.E+03
ACUTE
1.E+02
1.E+01
{
A PAC-3
• NIOSH IDLH*
A PAC-2
NIOSH-STEL*
A PAC-1
ACGIH-STH.-
CD
1.E+00
1.E-01
1.E-02
1.E-03
1.E-04
1.E-05
Avg. of
Short Term
NIOSH-REL (TWA)*
Other State Values |
1
e-
~ MDH HBV (1hr)
| Avg. of Other State Values |
Subchronic
OSHA-PEL (TWA)"
ACGIH-TLV (TWA)*
Cal/OSHA-PEL (TWA)"
Health Canada Indoor RfC
MDH HBV (1yr) -0
Chronic
O
OEHHA REL (Chronic)
ATSDR-MRl (> 1yr) T EPA/IRIS RfC
OEHHA Cancer Risk Range
T
^-| Avg. of
Other State Values
~ PAC-3
A PAC-2
A PAC-1 ,
@ NIOSH IDLH*
O NIOSH-STEL*
O NIOSH-REL (TWA)*
O ACGIH-STEL*
O ACGIH-TLV (TWA)*
O OSHA-PEL (TWA)*
O Cal/OSHA-PEL (TWA)*
* ATSDR-MRL (> 1yr)
~ MDH HBV (1 hr)
~ MDH HBV (1yr)
-it OEHHA REL (Chronic)
EPA/IRIS RfC
-¦—RIVM TCA
-O— Health Canada Indoor RfC
~ Avg. of Other State Values
o OEHHA Cancer Risk Range
Q.
o v>
E ®
.5 rv
10 100 1,000
Duration (hours)
rr| i—r-
10,000 100,000 1,000,000
^2
3
CL
* Indicates an occupational value; expert judgment necessary prior to applying these values to the general public.
Figure 1. Available health effect reference values for inhalation exposure to naphthalene (current
through March 2021).
Source: Yost et al. (2021). See Appendix A of this document for a tabular summary, including information
on how each value was derived. Categories for the reference values based on their intended purpose
are shown in the legend - red for Emergency Response, gold for Occupational, and green for values
applicable to the General Public. Abbreviations: ACGIH = American Conference of Governmental
Industrial Hygienists; ATSDR = Agency for Toxic Substances and Disease Registry; HBV = health-based
value; IDLH = immediately dangerous to life and health; IRIS = Integrated Risk Information System; MDH
= Minnesota Department of Health; MRL = minimal risk level; NIOSH = National Institute for
Occupational Safety and Health; OEHHA = California Environmental Protection Agency's Office of
Environmental Health Hazard Assessment; OSHA = Occupational Safety and Health Administration; PAC
= protective action criteria; PEL = permissible exposure limit; REL = recommended exposure limit
(NIOSH) or reference exposure level (California); RfC = reference concentration; RIVM = Rijksinstituut
voor Volksgezondheid en Milieu, The Netherlands Institute for Public Health and the Environment; STEL
= short-term exposure limit; TCA = tolerable concentration; TLV = threshold limit value; TWA = time-
weighted average.
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Derivation of an Acute Reference Concentration for
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2. Systematic Review Methods
The database of studies identified for EPA's Integrated Risk Information System (IRIS) toxicological
review of naphthalene (available at https://hero.epa.gov/hero/index.cfm/proiect/page/proiect id/367)
served as the starting point to identify acute inhalation toxicity studies. The compilation of this database
was originally described in the IRIS Assessment Plan (IAP) for naphthalene (U.S. EPA, 2018a), and a
systematic evidence map of the complete database was described more recently in a publication by Yost
et al. (2021). Whereas these previous publications used broad PECO (Populations, Exposures,
Comparators, Outcomes) criteria to identify health effect studies for naphthalene for multiple routes of
exposure and any exposure duration, this assessment uses targeted PECO criteria aimed at identifying
acute inhalation exposure studies for naphthalene. Otherwise, the literature search and screening
criteria are the same as those described previously. The studies identified in this assessment are
therefore a subset of those described by Yost et al. (2021).
2.1. Literature search
The database was compiled by conducting literature searches in four online scientific databases
(PubMed, Web of Science [WOS], TOXLINE, and Toxic Substances Control Act Test Submissions [TSCATS])
in February 2013, December 2014, November 2015, January 2017, September 2017, February 2019, and
January 2021, using the search strategy shown in Appendix B, Table B-l. Searches were not restricted by
publication date and no language restrictions were applied. The results of this literature search were
supplemented by the following additional search strategies, which are described in Appendix B,
Table B-2: 1) manual searches of citations from published review articles and national and international
health agency documents, 2) "backward" searches (to identify articles cited by included studies, reviews,
or prior assessments by other agencies), 3) "forward" searches (to identify articles that cite those
studies), 4) searches for a combination of CASRNs and synonyms on chemical assessment-related
websites, and 5) addition of references that had been previously added to the Health and Environment
Online (HERO) database1 as part of an earlier EPA naphthalene review effort.
2.2. Literature screening
PECO criteria (Table 1) were used to guide the identification of relevant studies from the larger database
of studies described above and to determine inclusion or exclusion of human and animal health effect
studies. In addition to PECO criteria, the following exclusion criteria were applied: 1) study materials that
have not been peer reviewed and 2) records that do not contain original data, such as assessments by
government agencies, review articles, editorials, or commentaries.
1EPA's HERO database provides access to the scientific literature behind EPA science assessments. The database includes more
than 3,000,000 scientific references and data from the peer-reviewed literature and contributes to transparent support for
critical agency decision-making.
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Derivation of an Acute Reference Concentration for
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Table 1. PECO criteria.
PECO element
Evidence
Populations
Human: Anv population and lifestage (occupational or general population, including children
and other sensitive populations). The following study designs will be considered most
informative: controlled exposure, cohort, case-control, cross-sectional, and ecological. Case
reports and case series are not included in this analysis.
Animal: Nonhuman mammalian animal species (whole organism) of anv lifestage (including
preconception, in utero, lactation, peripubertal, and adult stages). Transgenic (e.g., knockout)
animals are not included in this analysis.
Exposures
Human: Acute (<24 hours) exposure to naphthalene (CASRN 91-20-3), including occupational
exposures, via inhalation. Exposures quantified by either biomonitoring or occupational
exposure history are preferred.
Animal: Acute (<24 hours) exposure to naphthalene (CASRN 91-20-3) via inhalation. Studies
involving exposures to mixtures will be included only if they include an arm with exposure to
naphthalene alone.
Comparators
Human: A comparison or referent population exposed to lower levels (or no
exposure/exposure below detection limits) of naphthalene.
Animal: A concurrent control group exposed to vehicle-onlv treatment.
Outcomes
All health outcomes. In general, endpoints related to clinical diagnostic criteria, disease
outcomes, histopathological examination, or other apical/phenotypic outcomes will be
prioritized over outcomes such as biochemical measures.
For literature searches conducted through November 2015, all records were first electronically screened
in EndNote with a set of terms intended to prioritize "on-topic" references for title and abstract review
(see Appendix B for a more detailed description of the electronic screening strategy; inclusion/exclusion
terms are listed in Appendix B, Table B-3). For literature searches conducted after November 2015, no
electronic screening was performed due to the smaller number of new records identified, and all studies
underwent manual title/abstract screening.
Title/abstract and full text screening were conducted by two independent reviewers. For title/abstract
screening, reviewers used EndNote (for literature searches conducted between 2013 and 2017), SWIFT-
Active Screener (for literature search conducted in 2019) (https://swift.sciome.com/activescreener), or
DistillerSR (for literature search conducted in 2021)
(https://www.evidencepartners.com/products/distillersr-systematic-review-software/). Screening was
performed manually on all platforms (the machine learning functionality of SWIFT-Active Screener was
not used), and therefore screening results should not have been affected by the type of software used.
For citations with no abstract, articles were screened on the basis of all or some of the following: title
relevance, page numbers (articles one or two pages in length may be assumed to be conference reports,
editorials, or letters and therefore not evaluated further), and PubMed MeSH (Medical Subject
Headings; e.g., a study might not be considered further if no human health or biology- related- MeSH
terms are found). When multiple publications used the same or overlapping data, all publications on the
research were included, with one (generally the publication with the most complete reporting of results)
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Derivation of an Acute Reference Concentration for
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selected for use as the primary record. Non-English studies were tracked during screening but were not
translated or reviewed for this analysis.
An attempt was made to retrieve full texts for all studies not excluded during title/abstract screening,
and full text review was performed to identify the final list of studies meeting PECO criteria. Conference
abstracts and studies for which the full text was found to be unavailable following title/abstract
screening were tracked but not reviewed further. At both the title/abstract and full text screening levels,
screening conflicts were resolved by discussion among the primary screeners with consultation of a third
reviewer or technical advisor (if needed) to resolve any disagreements.
2.3. Study evaluation
Study evaluation was conducted on all studies that met PECO criteria by applying the EPA IRIS study
evaluation method, which is described in the ORD Staff Handbook for Developing IRIS Assessments (U.S.
EPA, 2020a). Each study was assessed by two independent reviewers using EPA's version of Health
Assessment Workspace Collaborative (HAWC, https://hawcprd.epa.gov/portal/), a free and open-source
web-based software application designed to manage and facilitate the process of conducting literature
assessments. Key concerns addressed by the study evaluation were potential sources of bias (factors
that could systematically affect the magnitude or direction of an effect in either direction) and
insensitivity (factors that limit the ability of a study to detect a true effect). This evaluation method
addresses the utility for hazard identification but does not address the usability of a study for dose-
response analysis, which is considered separately (see Section 2.4).
The general approach for evaluating epidemiology and animal toxicology studies is the same (Figure 2)
but the specifics of applying the approach differ. Epidemiology study evaluations consider the following
domains: participant selection, exposure methods sensitivity, outcome measures, confounding, analysis,
selective reporting, and sensitivity. Animal study evaluations consider the following domains: reporting
quality; allocation; observational bias/blinding; confounding; selective reporting and attrition; chemical
administration and characterization; exposure timing, frequency, and duration; endpoint sensitivity and
specificity; and results presentation. Core and prompting questions used to guide the judgment for each
domain for epidemiology and animal studies are described in the ORD Staff Handbook for Developing
IRIS Assessments (U.S. EPA, 2020a).
During study evaluation, in each evaluation domain, reviewers reach a consensus rating regarding the
utility of the study for hazard identification, with categories of Good, Adequate, Deficient, Not Reported
or Critically Deficient. For studies that examine more than one outcome, the evaluation process is
performed separately for each outcome because the utility of a study can vary for different outcomes.
The judgments are defined as follows:
• Good represents a judgment that the study was conducted appropriately in relation to the
evaluation domain, and any deficiencies, if present, are minor and would not be expected to
influence the study results.
• Adequate indicates a judgment that there may be methodological limitations relating to the
evaluation domain, but that those limitations were not likely to be severe or to have a notable
impact on the results.
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• Deficient denotes identified biases or deficiencies that were interpreted as likely to have had a
notable impact on the results or that prevent interpretation of the study findings.
• Not reported indicates that the information necessary to evaluate the domain question was not
available in the study. Generally, this term carries the same functional interpretation as
"deficient" for the purposes of the study confidence classification (described below).
• Critically deficient reflects a judgment that the study conduct introduced a serious flaw that
makes the study uninterpretable. Studies with a determination of critically deficient in an
evaluation domain will almost always be considered overall "uninformative," as described
below. Given this potential for exclusion, this classification is used infrequently and with
extreme care. Serious flaws that do not warrant study exclusion will be classified as "deficient."
Once the evaluation domains have been rated, the identified strengths and limitations are considered as
a whole to reach a study confidence rating of high, medium, low, or uninformative for a specific health
outcome. This rating is based on the reviewer judgments across the evaluation domains and includes
consideration of the impact the noted deficiencies could have on the results. Different outcomes within
the same study can receive different ratings. The ratings, which reflect a consensus judgment between
reviewers, are defined as follows:
• High confidence: A well-conducted study for which no notable deficiencies or concerns were
identified; the potential for bias is unlikely or minimal, and the study used sensitive
methodology. "High" confidence studies generally reflect ratings of "good" across all or most
evaluation domains.
• Medium confidence: A satisfactory (acceptable) study for which deficiencies or concerns were
noted, but for which the limitations are unlikely to discount the overall findings. Generally,
"medium" confidence studies will include "adequate" or "good" judgments across most
domains, with the impact of any identified limitation not being judged as severe.
• Low confidence: A substandard study for which deficiencies or concerns were noted, and the
potential for bias or inadequate sensitivity could have a significant impact on the study results
or their interpretation. Typically, "low" confidence studies would have a "deficient" evaluation
for one or more domains, although some "medium" confidence studies may have a "deficient"
rating in domain(s) considered to have less influence on the magnitude or direction of effect
estimates. Generally, "low" confidence results are not used for derivation of reference values
unless they are the only studies available.
• Uninformative: An unacceptable study for which serious flaw(s) make the study results unusable
for informing hazard identification. Studies with critically deficient judgments in any evaluation
domain will almost always be classified as "uninformative" (see explanation above). Studies with
multiple deficient judgments across domains may also be considered "uninformative."
Uninformative studies are not considered for derivation of reference values.
After the initial evaluation of the studies by level of overall confidence, the next stage is to examine each
group (confidence level) of studies. In this stage, the reviewer rereads the studies and asks:
• Does the separation between the levels of confidence make sense (i.e., are the high confidence
studies distinct from the low confidence studies, and do the medium confidence studies fall in
between these two groups)?
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Derivation of an Acute Reference Concentration for
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• Have the evaluation judgments been consistently applied across the set of studies? (For
example, if a specific limitation was identified in one study and may be applicable to other
studies, the reviewers should go back and make sure the judgment was applied in the same
way.)
All study evaluation ratings, including a brief description of any identified strengths and/or limitations
from the domains and their potential impact on the overall confidence determination, are documented
and retrievable in HAWC (https://hawcprd.epa.gov/summary/visual/100500035/).
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Individual evaluation domains
Animal
Epidemiology
Selection and performance
• Allocation
* Observational bias/blinding
Participant selection
Confounding/variable control
Confounding
Selective reporting and attrition
Selective reporting
Exposure methods sensitivity
* Chemical administration and
characterization
* Exposure timing, frequency, and duration
Exposure measurement
Outcome measures and results display
• Endpoint sensitivity and specificity
¦ Results presentation
Outcome ascertainment
Analysis
Reporting quality
Other sensitivity
Domain judgments
Judgment
Interpretation
0
Good
Appropriate study conduct relating to the domain and
minor deficiencies not expected to influence results.
a
Adequate
A study that may have some limitations relating to the
domain, but they are not likely to be severe or to
have a notable impact on results.
0
Deficient
Identified biases or deficiencies interpreted as likely
to have had a notable impact on the results or
prevent reliable interpretation of study findings.
•
Critically
Deficient
A serious flaw identified that makes the observed
effect(s) uninterpretable. Studies with a critical
deficiency are considered "uninformative" overall.
Overall study rating for an outcome
Rating
Interpretation
High
No notable deficiencies or concerns identified; potential
for bias unlikely or minimal; sensitive methodology.
Medium
Possible deficiencies or concerns noted, but resulting
bias or lack of sensitivity is unlikely to be of a notable
degree.
Low
Deficiencies or concerns were noted, and the potential
for substantive bias or inadequate sensitivity could have
a significant impact on the study results or their
interpretation.
Uninformative
Serious flaw(s) makes study results unusable for hazard
identification or dose response but may be used to
highlight possible research gaps.
Figure 2. Overview of the study evaluation domains and definitions for ratings (i.e., domain and
overall judgments, performed on an outcome-specific basis).
Source: U.S. EPA (2020a)
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Derivation of an Acute Reference Concentration for
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2.4. Analysis of dose-response considerations
For each study that met PECO criteria, an initial assessment was conducted that used the following
considerations to determine whether the data were potentially amenable to dose-response analysis:
• Quantitative exposure-response data are reported and include a measure of variance (individual
animal data preferred).
• Sample size is reported.
• Studies with multiple exposure levels were considered more suitable for dose-response analysis
compared with studies with a single exposure level.
• Studies reporting histopathological data were considered more suitable for dose-response
analysis if they reported dichotomous incidence data (i.e., the number of animals in each dose
group with a lesion). Histopathological data reported as a continuous measurement (e.g., mean
cytotoxicity per dose group) was considered less suitable.
The ultimate selection of studies for dose-response modeling was based on these factors as well as the
other considerations described in Table 12-2 of the ORD Staff Handbook for Developing IRIS Assessments
(U.S. EPA, 2020a). These include study confidence rating (high and medium confidence studies are
preferred over low confidence studies), exposure levels (studies with a broad exposure range near
typical human exposure levels are preferred), study size, and human relevance of the model species.
3. Systematic Review Results
3.1. Literature search and screening results
The literature search and screening strategy identified 10 records of animal toxicology studies that met
PECO criteria and were therefore considered for further evaluation (Figure 3). Two of these records
reported data from the same study: a publication by Dodd et al. (2010) was also published as a
preliminary draft by ConocoPhillips (2007). The publication by Dodd et al. (2010) was selected as the
primary record because it contained a more complete record of the data. The 10 records therefore
corresponded to 9 distinct animal toxicology studies. No studies in humans met PECO criteria.
16
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Database searches (2013 to 2021)
s \
S N
S N
r >
PubMed
wos
TOXLINE
TSCATS
(n = 8,223)
(n = 6,558)
(n = 4,965)
(n = 215)
V J
Total records after deduplication
(n = 17,763)
Title 8i abstract screening
(n= 12,696)
J
Full-text sc
(n = 4
reening
20)
Additional search strategies
(n = 138)
See Appendix Table B2
Not evaluated further (n= 410)
Not relevant to PECO (n = 395); foreign
language or abstract-only (n = 11);
exposure not quantified (animal) (n = 2);
unclear exposure route (animal) (n - 1);
illegible/unclear if data are primary (n =
1)
Excluded by electronic screen
(n = 5,067)
November 2015; see Appendix Table B3
Not evaluated further (n = 12,276)
Not relevant to PECO (n = 12,062);
foreign language, abstract-only, or full
text not available (n = 214)
Studies meeting PECO criteria
• Human health effects studies (n = 0)
• Animal health effect studies [n = 10 records (9 distinct references)]
Figure 3. Literature flow diagram for identification of naphthalene acute inhalation studies.
3.2. Study evaluation results
Study evaluation results for the nine distinct studies that met PECO criteria are shown iri Figure 4. The
hyperlink provided in the figure caption can be used to access interactive versions of these graphics in
HAWC, where readers can click to view the detailed rationale for each study evaluation rating. During
the study evaluation process, study authors were contacted to obtain missing information that could
affect the confidence ratings of the studies or suitability for dose response. Responses were obtained
from the authors of three studies (Kovalchuk et al.. 2017; Cichocki et al.. 2014; West et al.. 2001); a full
record of each correspondence is provided in HAWC.
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Derivation of an Acute Reference Concentration for
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Most of the studies were rated medium confidence (Carratt et al.. 2019; Carratt et al.. 2016; Lee et al..
2005; Phimister et al.. 2004; West et al.. 2001), with two studies rated high confidence (Kovalchuk et al..
2017; Dodd et al.. 2010) and two studies rated low confidence (Cichocki et al.. 2014; Koptagel and Bulut.
1998). Among the low confidence studies, primary concerns were that sample sizes were not reported
(Cichocki et al.. 2014), treatment of control animals was not described (Koptagel and Bulut. 1998), and
exposure characteristics were poorly described (Koptagel and Bulut. 1998). In addition, several studies
did not report whether randomization or normalization procedures were used when allocating animals
to experimental groups, and several studies did not report whether investigators were blinded during
outcome assessment. The two high confidence studies each had concerns noted in a single domain
(allocation and observational bias/blinding, respectively) because these experimental details were not
reported; however, this lack of reporting in a single domain did not substantially reduce confidence in
these otherwise well-designed and well-reported studies. Studies rated medium confidence all had
concerns across multiple domains, but the limitations were judged as unlikely to influence the overall
findings.
Reporting
Allocation
Observational bias/blinding
Confounding/variable control
Selective reporting and attrition
Chemical administration and characterization
Exposure timing, frequency and duration
End point sensitivity and specificity
Results presentation
Overall confidence
Legend
I Good (metric) or High confidence (overall)
Adequate (metric) or Medium confidence (overall)
Delicient (metric) or Low confidence (overall)
Critically deficient (metric) or Umnformatrve (overall]
[NRl Not reported
~ Multiple judgments exist
Figure 4. Heat map of animal study evaluation results, listed by author, year, and HERO identification
number.
An interactive version of this graphic with the ratings rationale is available at the following URL:
https://hawcprd.epa.gov/summarv/visual/assessment/100000053/naphthalene-acute-inhalation-study-
heat-map/.
3.3. Summary of available studies
Table 2 lists the studies that met PECO criteria and provides a brief description of the study designs, a
description of outcomes evaluated, author-reported lowest-observed-adverse-effect level (LOAEL) and
outcomes observed, overall confidence level (from study evaluation, Figure 3), and an initial assessment
of the applicability for dose-response analysis (based on considerations described in Section 2.4).
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Table 2. Summary of available naphthalene acute inhalation studies.
Author/year
Study description
Duration
and doses
tested
Outcome(s)
evaluated
Author-reported LOAEL
and outcome(s) observed
Overall
confidence
level
Applicability for dose-
response
Carratt et al,
(2016)
Male and female B6:129 mice
(n= 3/sex/group)
4-hour
whole-body
exposure;
0, 5,10, 20
ppm
Cytotoxicity in
extrapulmonary and
intrapulmonary
airways, scored using
a damage score
matrix
5 ppm - swollen and
vacuolated epithelial cells in
the extrapulmonary and
intrapulmonary airways;
pattern of increased severity
in females relative to males at
10 and 20 ppm.
Medium
Not suitable. Reported
mean cytotoxicity scores
without measure of
variance.
Carratt et al,
(2019)
Male and female C57BL/6
mice, 7-day-old, 3-week-old, or
adult (n= 5/sex/group)
4-hour
whole-body
exposure;
0, 5,10
ppm
Cytotoxicity in
proximal
intrapulmonary
airways and terminal
bronchioles,
quantified using
stereology
5 ppm - swollen and
vacuolated airway epithelial
Club cells; most severe effects
were observed in proximal
airways of juvenile (3-week-
old) females relative to other
airway levels and age groups.
Medium
Limited suitability.
Histopathology data
reported as a continuous
measurement, rather
than dichotomous
incidence. Quantitative
data (vacuolated cells in
proximal airways)
reported only for one
dose level (10 ppm);
other dose levels only
have qualitative data
reported.
Cichocki et al,
(2014)
Male and female Fischer 344
rats (sample size not reported)
4- or 6-
hour nose-
only
exposure;
0,15, 30
ppm
Cytotoxicity in nasal
tissues, measured as
membrane
permeability to
ethidium
homodimer-1 and
quantified using
stereology
15 ppm - increased
cytotoxicity in respiratory /
transitional mucosa and
olfactory mucosa.
Low
Not suitable.
Histopathology data
reported as a continuous
measurement, rather
than dichotomous
incidence. Reported
quantitative cytotoxicity
data, but sample size not
reported.
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Derivation of an Acute Reference Concentration for
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Author/year
Study description
Duration
and doses
tested
Outcome(s)
evaluated
Author-reported LOAEL
and outcome(s) observed
Overall
confidence
level
Applicability for dose-
response
Dodd et al,
(2010)
Male and female Fischer 344
and Sprague-Dawley rats (n=
5/sex/strain/group in 6-hour
exposure;
n=5/sex/strain/control group
and 10/sex/strain/treatment
group in 5-day exposure)
6-hour
whole-body
exposure;
0, 0.1, 0.3,
1,10, 30
ppm
Histopathological
evaluation of nasal
tissues
0.1 ppm - increased nasal
olfactory epithelium necrosis
in male SD rats (observed at
0.3 ppm for female SD rats,
and 1 ppm for male and
female F344 rats). Increased
nasal respiratory epithelium
necrosis was observed
beginning at 1 ppm. The
extent and severity of necrosis
increased with dose for both
strains and sexes.
High
Suitable. Reported
quantitative incidence
data for necrosis in the
nasal olfactory
epithelium and nasal
respiratory epithelium.
Koptagel and
Bulut (1998)
Male and female Swiss albino
rats (n=12/group)
1-, 3-, or 6-
hour
whole-body
exposure;
0,166 ppm
Histopathological
evaluation of tracheal
mucosa
166 ppm - increased epithelial
damage, lymphocyte
infiltration, hyperemia,
vascular dilation, and
hemorrhage in the lumen.
Low
Not suitable. Reported
semi-quantitative scores
for histopathology.
Kovalchuk et
al. (2017)
Male mice (n= 4-7/control
group; n=5/treatment group)
4-hour
nose-only
exposure;
0, 5,10
ppm
Cytotoxicity in
proximal
intrapulmonary
airways and terminal
bronchioles,
quantified using
stereology
5 ppm - swelling,
vacuolization, and exfoliation
of Club cells; increased
volume fraction of damaged
airway epithelial cells.
Medium
Limited suitability.
Histopathology data
reported as a continuous
measurement, rather
than dichotomous
incidence data. Reported
quantitative data for
volume fraction of
damaged airway
epithelial cells.
Lee et al,
(2005)
Male Sprague-Dawley rats
(n=6/group)
4-hour
whole-body
exposure;
Histopathological
evaluation of nasal
tissues
3.4 ppm - increased regional
patterns of cellular injury in
the olfactory epithelium.
Medium
Limited suitability.
Histopathology data
reported as a continuous
measurement, rather
20
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Author/year
Study description
Duration
and doses
tested
Outcome(s)
evaluated
Author-reported LOAEL
and outcome(s) observed
Overall
confidence
level
Applicability for dose-
response
0, 3.4, 23.8
ppm
than dichotomous
incidence data. Reported
quantitative data for the
percentage of basement
membrane injury in
olfactory epithelia.
Phimister et
al. (2004)
Male Swiss mice (n=minimum
of 3/group)
2- or 4-
hour
whole-body
exposure;
0,1.5,15
ppm
Histopathological
evaluation of lungs
and nasal tissues
15 ppm - cellular injury in
proximal and distal
intrapulmonary airways and in
the olfactory epithelium,
including swelling,
vacuolation, and necrosis of
Clara (Club)a cells.
Medium
Not suitable. Reported
qualitative data.
West et al.
(2001)
Male Swiss Webster mice and
Sprague-Dawley rats (n=3-
4/group, inferred from figures
in publication)
4-hour
whole-body
exposure;
0, 2,10, 30,
75,100
ppm
Histopathological
evaluation of lungs;
Clara (Club)a cell mass
in proximal and
terminal airways
quantified using
morphometry
2 ppm - Cluba cell necrosis in
mice (high degree of
interindividual variability), and
a slight decrease in Club cell
mass in proximal airways.
Effects in distal airways in
mice were observed beginning
at 10 ppm. Extent and severity
of damage in mice increased
with increasing dose. No
changes in airway epithelial
cells were observed in rats at
any concentration.
Medium
Suitable. Reported
quantitative data for Club
cell mass for individual
animals.
aClub cells are referred to as Clara cells (the former name for this cell type) in the publications by Phimjster et al. (2004} and West et al, (2001).
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Derivation of an Acute Reference Concentration for
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4. Description of Physiologically Based Pharmacokinetic Model and Derivation of an Acute Reference
Concentration for Inhalation Exposure to Naphthalene
4.1. Study selection for dose-response modeling
The high confidence study in rats by Dodd et al. (2010) was selected for dose-response modeling.
Although several high or medium confidence studies in rats or mice were found to be potentially
amenable for dose-response analysis (noted as "suitable" or "limited suitability" for dose response in
Table 3.3), Dodd et al. (2010) tested the lowest dose range, identified a LOAEL that was an order of
magnitude lower than other studies, and had no major concerns about study design or reporting. Dodd
et al. (2010) is therefore the only study that was moved forward for dose-response analysis.
Uncertainties regarding the use of rat data to derive an RfC for naphthalene are discussed in Section 5.
In the study by Dodd et al. (2010), Fischer 344 and Sprague-Dawley rats were exposed to naphthalene
vapor in the air at nominal concentrations of 0, 0.1, 0.3, 1.0, 10, and 30 ppm for 6 hours, and the
incidence of nasal olfactory epithelium necrosis and nasal respiratory epithelium necrosis was recorded.
The National Toxicology Program's 2-year inhalation study in rats (NTP, 2000), along with multiple
supporting studies (Carratt et al., 2016; Buckpitt et al., 2002; Greene et al.. 2000; Flowers et al., 1997;
Zheng et al., 1997; Buckpitt et al., 1995; Buckpitt et al., 1992; Xu et al., 1992; Tao et al., 1991b; Tao et al.,
1991a) that found a positive relationship between incidence of olfactory neoplastic lesions and
naphthalene vapors in rats, provide basis for determining that the nasal olfactory epithelium necrosis
data were the most relevant endpoint for this analysis and are used in this assessment. Both strains and
sexes used in the Dodd et al. (2010) study were investigated in this assessment; the male Sprague-
Dawley rats were the most sensitive subpopulation with nasal olfactory epithelium necrosis incidences
of 0/5, 2/5, 3/5, 4/5, 5/5, and 5/5 observed at the above doses, respectively.
4.2. Calculation of internal dose metrics using a physiologically based pharmacokinetic model
Campbell et al. (2.014) developed a computational-fluid-dynamics-informed PBPK model for inhaled
naphthalene in rats and humans. This model can be used to estimate time-course concentrations of
naphthalene in lung, fat, liver, blood, and "lumped compartments" comprising rapidly perfused and
slowly perfused tissues, as well as in specific sections of the upper respiratory tract, including dorsal
respiratory (DR) tissues, dorsal olfactory (DO) tissues, and ventral respiratory (VR) tissues. In the model,
naphthalene enters the body via inhaled air and is absorbed by the various respiratory tract tissues. The
model does not track metabolites of naphthalene but does calculate overall rates of naphthalene
metabolism in liver, lung, DR, DO, and VR tissues. Campbell et al. (2014) assumed metabolism in each of
these compartments to be a saturable (Michaelis-Menten) process and provided sources for the
relevant parameters (maximum metabolic rate and affinity) in each tissue. They demonstrated (through
local sensitivity analyses) that dose metrics related to rates of metabolism were sensitive to the values
of these metabolic parameters, but also to the values of parameters describing cardiac output,
respiration rate, fractional blood flow rates (as proportions of total cardiac output) to the relevant
regions of the respiratory tract, size (thickness) of relevant respiratory tract tissues, and the blood-to-air
partition coefficient for naphthalene.
Kapraun et al. (2020) revised the PBPK model of Campbell et al. (2014) by adding compartments that
allow one to simulate skin exposure. This enhancement allowed Kapraun et al. (2020) to evaluate their
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
PBPK model using data from a controlled skin exposure study in human subjects (Kim et al., 2006) and
demonstrate that model predictions of time-course blood concentrations of naphthalene generally
agree with observed human in vivo data to within a factor of two. Such agreement indicates that PBPK
model dosimetry, rather than allometric scaling or other default approaches, should be preferred for
dosimetry calculations for chemical risk assessment (U.S. EPA, 2020b; IPCS, 2010). Kapraun et al. (2020)
implemented the model using R version 3.6.1 (Team, 2019) and MCSim (Bois, 2009) and applied the
quality assurance guidelines of U.S. EPA (2018b) to verify parameter values and various other aspects of
the software implementation of the model. A complete set of model implementation files for the
Kapraun et al. (2020) PBPK model are available through the U.S. EPA Environmental Dataset Gateway
(https://doi.org/10.23719/1519044). For convenience, the MCSim model implementation file
("naph_pbtk_pde.model") that shows all the primary model equations is provided in Appendix D. Figure
5 provides a schematic depiction of the PBPK model of Kapraun et al. (2020), which was used to perform
dosimetry calculations for this assessment. For all calculations described herein, the skin compartments
of the Kapraun et al. (2020) model were turned "off" (by setting the volumes and blood flow rates for
those compartments to zero) because there was no skin exposure in the study of Dodd et al. (2010);
thus, the PBPK model used for dosimetry was functionally equivalent to the PBPK model of Campbell et
al. (2014).
EPA used the Kapraun et al. (2020) model implementation and applied parameter values for rats given
by Campbell et al. (2014) to compute values of an internal dose metric relevant to the study of Dodd et
al. (2010): the cumulative production of naphthalene metabolites in DO tissue per unit volume (ng/mL)
for a single 6-hour inhalation exposure. EPA chose this dose metric because naphthalene toxicity is
known to be driven by its metabolites, so it can be inferred that necrosis in the DO tissue is likely
correlated more directly with dose of those metabolites (Carratt et al., 2016; Buckpitt et al., 2002;
Greene et al., 2000; Flowers et al., 1997; Zheng et al., 1997; Buckpitt et al., 1995; Buckpitt et al., 1992;
Xu et al., 1992; Tao et al., 1991b; Tao et al., 1991a) than with dose of naphthalene delivered to this
tissue. Because the model does not track metabolites, EPA used the time-integrated (cumulative) rate of
naphthalene metabolism in DO tissue as a surrogate for rate of production of naphthalene metabolites
in DO tissue.
Actual doses (rather than nominal doses) reported by Dodd et al. (2010) were converted into internal
dose metrics (cumulative production of naphthalene metabolites in DO tissue per unit volume) as shown
in Table 3. The R script that performs these calculations ("lnhNTP_dose_metrics_sex_strain_group.R") is
provided in Appendix E. Dose-response analyses were conducted using U.S. EPA's Benchmark Dose
software (Appendix C), with dose levels being these internal dose metrics, to obtain a point of departure
(POD) internal dose metric of 24.2 ng/mL, which was the lower confidence limit estimate of the
benchmark dose (BMDL).
23
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Inhalation
Exhalation
Metabolism
->
Metabolism
Metabolism
Figure 5. Schematic for the naphthalene PBPK model of Kapraun et al. (2020).
The horizontal lines through the box representing the stratum corneum indicate that this compartment
is described using partial differential equations. This description allows for predictions of differing
concentrations at different distances from the exterior surface of the stratum corneum. All other
compartments are described using ordinary differential equations, as is the common practice in PBPK
modeling. For the simulations described herein, the skin compartments (i.e., viable epidermis (exposed),
stratum corneum (exposed), and exposure well) were turned "off."
24
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Consideration was given to whether the rat body mass parameter value used in the Campbell et al.
(2014) model should be changed to reflect the actual body size of the rats in the study by Dodd et al.
(20101. EPA elected not to change the value of the body mass parameter in the model on the basis of
the following observations concerning the publication and model source code of Campbell et al. (2014):
1. Surface areas, and therefore also volumes, for respiratory tract tissue regions are not scaled
with body mass in the Campbell et al. (2014) model. Such scaling is typical in PBPK models,
and is performed in the Campbell et al. (2014) model for volumes of other compartments,
such as liver and fat tissue.2
2. Metabolic parameters (i.e., maximum metabolic rates) for respiratory tract tissues are also
not scaled according to overall body mass because they are scaled by volumes of the
relevant tissues (which are not scaled by overall body mass).3
3. Campbell et al. (2014) used a default body mass of 315 g for rats and this is the default rat
body mass in their model implementation. It is possible that 315 g was chosen by Campbell
et al. (2014) to reflect the size(s) of the rats that were used by Bogdanffy et al. (1999) and
Plowchalk et al. (1997) to determine the (unsealed) dimensions of respiratory tract tissues
that were included in the model of (Campbell et al., 2014).
4. Blood flow rates to the respiratory tract regions are allometrically scaled as body mass to
the % power.
In summary, Campbell et al. (2014) parameterized their model using blood flow rates to respiratory tract
tissue that are allometrically scaled by the value of the body mass parameter but used fixed values
(which are not allometrically scaled by body mass) for surface areas of respiratory tract tissues. Because
Campbell et al. (2.014) indicated the value of the body mass parameter for their rat simulations was
315 g, it was inferred that they determined the fixed values they provided for surface areas of the
respiratory tract tissues were appropriate for a rat of that size. Using a different body mass parameter
(something other than 315 g) in the model would cause values of many calculated parameters (including
blood flow rates to respiratory tract regions) to change but would not cause the surface areas of the
respiratory tract tissues to change by corresponding amounts. EPA was unable to obtain sufficient
information to determine specific values of surface areas of respiratory tract tissues to use for rats other
than the 315 g rats described by the Campbell et al. (2014) model. Because of this, EPA chose not to
change the body mass parameter to a value representative of the rats used in the Dodd et al. (2010)
study (which may have been between 90 and 144 g at the time of exposure based on Figure 3 of Dodd et
al. (2010)).
To investigate how the decision to simulate 315 g rats rather than smaller rats might have affected the
analysis in this assessment, EPA performed additional simulations with 90 g and 144 g rats using
allometrically scaled values for surface areas of respiratory tract tissues. For this analysis (which is not
shown here), it was assumed that surface areas of respiratory tract tissues scale as body mass to the ^
power. The resulting computed dose metrics were all within 3% of the values determined for the 315 g
2Table 2 of Campbell et al. (2014) reveals that parameters describing anatomical details of the respiratory tract are absolute
(not scaled).
-See Table 3 of Campbell et al. (2014).
25
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
rat (i.e., the values shown in Table 3). Therefore, it was concluded that the decision to simulate 315 g
rats (rather than smaller rats) did not greatly affect the results.
In examining this issue of unsealed surface area parameters in the Campbell et al. (2014) model, EPA
investigated references cited by those authors and determined that some of the parameter values they
used needed modification. In particular, the PBPK model in this assessment uses different values for
surface areas of "posterior dorsal olfactory tissue," "posterior ventral respiratory tissue," and
"pulmonary region" tissue than were used by Campbell et al. (2014). Appendix F provides the surface
area parameter values selected and used to obtain the results shown in Table 3, as well as further
explanation of the details of investigations into surface area parameter values. Modifications to the
parameter values proposed by Campbell et al. (2014) resulted in only minor changes (less than 3% in all
cases) to the dose metric values for the relevant simulations.
As demonstrated in the sensitivity analyses of Campbell et al. (2014). the model parameters that exert
the highest degrees of influence on the dose metric used in this assessment (rate of metabolite
production in DO tissue) are those that describe maximum metabolic rate in the DO tissue, metabolic
affinity constant for the DO tissue, cardiac output, respiration rate, (fractional) blood flow rate to the DO
tissue, size (thickness) of the DO tissue, and the blood-to-air partition coefficient for naphthalene. The
sources cited by Campbell et al. (2014) for the values of these model parameters indicate that there is
uncertainty and/or variability in each of these values and that the values used are central estimates.
Nevertheless, the application of uncertainty factors (described in Section 4.4) adequately accounts for
uncertainty in point-of-departure values generated using the PBPK model.
Table 3. Internal dose metrics in rats from the study by Dodd et al. {20101.
Nominal3 dose (ppm)
Cumulative metabolite production in DO tissue (jig/mL)b
0.1
44.19
0.3
134.1
1.0
488.2
10.0
3,721
30.0
5,847
aActual concentrations observed in the exposure chambers (i.e., averages for the mean concentrations observed for
male and female rat chambers) by Dodd et al. (2010) were 0.095, 0.29,1.085,11.95, and 29.6 ppm.
bDose metrics were calculated as the cumulative production of naphthalene metabolites in DO tissue per unit
volume using the Kapraun et al. (2020) model implementation and parameter values for rats given by Campbell
et al. (2014).
4.3. Estimation or selection of points of departure
Consistent with the EPA Benchmark Dose Technical Guidance (U.S. EPA, 2012), the BMD and 95% lower
confidence limit on the BMD (BMDL) were estimated using a benchmark response (BMR) to represent a
minimal, biologically significant level of change. In the absence of information regarding the level of
change considered biologically significant, BMD guidance supported the selection of a BMR of 10% extra
risk (ER) for the incidence of olfactory epithelial necrosis. For this analysis, Benchmark Dose Software
26
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
(BMDS) Version 3.1.2 (U.S. EPA, 2019) was used. Following the EPA Benchmark Dose Technical Guidance
(U.S. EPA, 2012), all maximum likelihood dichotomous models were used. Adequacy of model fit was
judged depending on the x2 goodness-of-fit p-value (p > 0.1), scaled residuals at the data point (except
the control) closest to the predefined benchmark response (absolute value < 2.0), and visual inspection
of the model fit. Among all models providing adequate fit, the BMDL from the model with the lowest
Akaike's information criterion (AIC) was selected as a potential POD when BMDL values were sufficiently
close (within threefold). Otherwise, the lowest BMDL was selected as a potential POD. The primary
metabolites of naphthalene are thought to be the source of necrosis, and the PBPK model described
above in Section 4.1 was used to determine the cumulative production of naphthalene metabolites in
the DO tissue per volume of tissue (ng/mL). This internal dose metric was subsequently used in all dose-
response analyses.
Dodd et al. (2010) used a sample size of five animals/dose group; therefore, any background incidence
of nasal olfactory epithelium necrosis could potentially result in background risk of at least 20%, which is
above the selected BMR of 10% ER. Given the relatively small sample sizes used in this study, it is
possible that background risk was not adequately captured by any one dataset corresponding to a single
stain and sex. To account for this possibility, the practicality of combining individual datasets across sex
(male and female) and strain (Sprague-Dawley and Fisher 344 [F344]) was evaluated using standardized
Pearson's residuals. Standardized Pearson's residuals can be used to compare observed and expected
incidence values for categorical data (of which dichotomous data are a special case). This approach
assumes that the combined data (across male and female rats within a strain and then across F344 and
Sprague-Dawley rats) represents the true proportion of animals expected to respond to exposure to
naphthalene (i.e., the expectation that the same proportion will respond for a given dose in any dataset,
individual or combined). Thus, comparisons to the individual datasets can be made to determine if any
are sufficiently different enough to warrant not combining the data. While the Pearson's residuals were
larger when investigating if it was appropriate to combine across strains compared with differences
between sexes within a single strain, none of the calculated Pearson's residuals indicated that the
observed individual datasets were inconsistent with the corresponding combined datasets (see
Appendix C for full details and results of the analysis).
The rat POD was then converted to a human equivalent concentration (HEC) via the following
procedure:
1. Set the target POD dose metric for humans (i.e., the cumulative production of naphthalene
metabolites in the DO tissue per volume of tissue) to be equal to the POD dose metric for
rats (i.e., the BMDL of the dose-response analysis previously described).
2. Using the PBPK model implementation of Kapraun et al. (2020), calculate the PODhec (ppm)
by determining the continuously applied concentration that would lead to the human POD
obtained in Step 1.
3. Calculate the PODhec (mg/m3) by performing a unit conversion using the molecular weight
of naphthalene.
The HECs calculated via this procedure are shown in Table 4. The R script that performs the relevant
calculations ("HEC_from_DM_new.R") is provided in Appendix G.
27
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Table 4. Human equivalent concentrations.
Endpoint
Scenario
POD
(jig/mL)
PODhec3
(mg/m3)
Olfactory
epithelial
necrosis
1-hour exposure
24.22
19.6
8-hour exposure
1.41
24-hour exposure
0.451
aThe PODhec is the model-predicted air concentration to which a human would need to be exposed for the duration in the
Scenario column so that the human cumulative metabolite production in DO per unit volume is equal to the value in the
POD column.
bAccording to BMD modeling and selection of the Multistage model as the best fitting model; see Appendix C for full BMD
modeling results.
4.4. Derivation of acute reference concentration values
Under EPA's A Review of the Reference Dose and Reference Concentration Processes (U.S. EPA, 2002),
five possible areas of uncertainty and variability are recommended when deriving chronic RfC values.
Given this is a toxicity assessment for acute exposure, however, only four areas of uncertainty and
variability were considered for deriving the acute RfC for naphthalene. The uncertainty in extrapolating
from data obtained in a study with less-than-lifetime exposure to lifetime exposure (i.e., extrapolating
from subchronic to chronic exposure) is not relevant to this acute RfC derivation and was not included.
An explanation of the four possible areas of uncertainty and variability and the values selected for
application to the candidate PODhec values are listed in Table 5.
Table 5. Uncertainty factors for the derivation of the acute RfC for naphthalene.
UF
Value
Justification
UFa
3
A UFa of 3 (10°5 = 3.16 ~ 3) is applied to account for uncertainty in characterizing the toxicokinetic and
toxicodynamic differences between rats and humans following inhalation naphthalene exposure.
Although some of the toxicokinetic uncertainties have been accounted for via the application of a PBPK
model (to convert from animal to human external exposures), residual toxicokinetic uncertainty
remains. Additionally, application of a PBPK model does not account for toxicodynamic uncertainty. In
the absence of chemical-specific data to quantify this residual uncertainty, EPA's guidelines
recommend use of a UF of 3 to account for toxicokinetic and toxicodynamic differences between rats
and humans.
UFh
10
A UFh of 10 is applied for inter-individual variability in the toxicokinetics and toxicodynamics of
naphthalene in humans because the PBPK model used in the analysis does not account for sensitive
or susceptible individuals. Considerable interindividual differences have been observed in the
expression and activity of CYP2A13 in the human respiratory tract (D'Agostino et al,, 2008; Zhang et
al„ 2007; Su et al., 2000), which is active in naphthalene metabolism and bioactivation (Li et al.,
2017; Fukami et al., 2008). The toxicity of inhaled naphthalene has also been demonstrated to differ
as a function of age and sex in mice (Carratt et al., 2019).
ufl
1
A UFl is not needed as the PODhec is based on BMD modeling.
UFd
1
A UFd of 1 is applied because an acute RfC is being derived from acute inhalation toxicity
information. The lack of other types of studies and/or data is immaterial.
UFC
30
Composite uncertainty factor = UFA x UFH x UFL x UFD
28
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
The PODhec estimated using the PBPK model of Kapraun et al. (2020) was divided by a composite
uncertainty factor (UF) of 30 (corresponding to separate UFs of 3 for uncertainty in interspecies
extrapolation and 10 for intraspecies variability) to calculate the acute RfC for naphthalene (see
calculation below). The derivation of the acute RfC for naphthalene was as follows depending on three
common acute exposure scenarios (1-hour, 8-hour, 24-hour) (Table 6):
RfC for naphthalene = PODHEC(mg/m3) h- UFc
Table 6. Acute RfC derivations.
Endpoint
Scenario
PODhec1
(mg/m3)
RfC (mg/m3)
Olfactory epithelial necrosis
1-hour
19.6
7 x 101 (rounded from 6.53 x 10
8-hour
1.41
5 x 10"2 (rounded from 4.70 x 10"2)
24-hour
0.451
2 x 10"2 (rounded from 1.50 x 10"2)
5. Strengths, Limitations, and Uncertainties
The use of rat data for human health assessment of naphthalene is an area of uncertainty because rats
are reported to be less sensitive than mice to naphthalene-induced pulmonary toxicity. For instance,
West et al. (2001) found that rats had no histological changes in lung airway epithelia after 4-hour
exposure to naphthalene concentrations up to 110 ppm, whereas effects were evident in mice at a
concentration of 2 ppm. Rats are, however, sensitive to naphthalene-induced toxicity of nasal cavity
tissues. Nasal olfactory epithelium necrosis from the study by Dodd et al. (2010) was selected for dose-
response analysis in this assessment because it was more sensitive than nasal respiratory epithelium
necrosis in this study and has been demonstrated to be a relevant endpoint in rats; for instance, a 2-year
inhalation study by NTP (2000) found a positive relationship between the incidence of olfactory
neoplastic lesions and exposure to naphthalene vapors. The analysis in this assessment assumes that
naphthalene-induced nasal olfactory epithelium necrosis is a relevant endpoint to humans, which is an
area of uncertainty given the limited amount of human data available on the respiratory toxicity of
naphthalene (Yost et al., 2021) and the relatively small number of animals per dose group in the study
by Dodd et al. (2010). The sample size limitation was, however, mitigated by combining data across
strains and sexes of rats to increase the sample size.
The approach of combining datasets across sexes and strains for the animals in the study by Dodd et al.
(2010) is an area of uncertainty because sex- or strain-related differences have been reported in some
cases for rodent nasal cavity lesions (Brown et al., 1991). For naphthalene, a study that evaluated age-
and sex-related differences in metabolism and lung toxicity in mice (Carratt et al., 2019) reported a
significant sex-related difference in proximal airway toxicity in juvenile but not in adult or neonatal
animals. The study by Cichocki et al. (2014) also reported no consistent sex differences in F344 rats
exposed to 1-30 ppm naphthalene (nose-only exposure) for 4 or 6 hours. Cytotoxicity was observed in
both sexes at the respiratory/transitional mucosa and olfactory mucosa (OM). The authors did report
differences at the messenger ribonucleic acid (mRNA) level of anti-electrophilic genes in the OM in male
mice, but these did not translate to phenotypic differences (i.e., decreased toxicity in these animals).
Further, Dodd et al. (2010) reported that there was no indication of differences in exposure response
29
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
between the sexes and that strain differences were considered minimal following acute exposure to
naphthalene. Hence, the pooling of the animals across sex and strain in the Dodd et al. (2010) study for
this analysis was determined acceptable.
By using systematic review methods, applying a PBPK model for both the experimental and target
species, and employing benchmark dose analysis (characterizing the full range of the data and the
uncertainty in the dose-response relationship), the current approach provides a more robust
quantification of toxicity compared with previous evaluations of the acute toxicity of naphthalene.
Despite the methodological differences used by EPA and ATSDR (2014), the range of RfC values
calculated by EPA for 1-, 8-, and 24-hour exposure scenarios (7 x 10 1 mg/m3 to 2 x 10"2 mg/m3) includes
the acute inhalation value of 6 x 10 2 mg/m3 that was derived by ATSDR (2014).
30
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Appendix A: Comparison of Naphthalene Inhalation Reference Values from National, State, and International Agencies and Scientific
Organizations
Table A-l. Details on derivation of the available healt
h effect reference values for inhalation exposure to naphthalene ffrom Yost et al. (2021)
Reference
value name
Duration
Reference value
Health effect
Point of
departure
Qualifier
Source
Uncertainty
factors3
Notes on
derivation
Review
status
(mg/m3)
(ppm)
Emergency response
PAC-3
1 hour
2,600
500
Adopted
previous IDLH
NA
NA
NIOSH
NA
Adopted
previous
IDLH
Final
(DOE,
2018)
(1994)
PAC-2
1 hour
430
83
Based on PAC-
3
NA
NA
NA
NA
Based on
PAC-3"
PAC-1
1 hour
79
15
Adopted
NIOSH REL-
STEL
NA
NA
NA
NA
Adopted
NIOSH REL-
STEL
Occupational
NIOSH REL
(TWA)
10-hour
TWA
50
10
NR
NR
NR
NR
Final
(NIOSH.
1994)
NIOSH REL-
STEL
15 minutes
75
15
NR
NR
NR
NR
NIOSH IDLH
30 minutes
1,300
250
Acute oral
toxicity
NR
NR
Gerarde
NR
Route-to-
route
extrapolatio
n applied
(1960)
31
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
ACGIHTLV-
TWA [Skin]c
8-hour TWA
52
10
Eye irritation
at 15 ppm,
acute
hemolysis, and
hepatoxicity in
humans
NR
NR
Robbins
(1951)
Hanssler
(1964)
Grigor et
al. (1966);
Irle (1964):
NR
Final
(ACGIH,
2001)
Naiman
and Kosov
(1964):
Valaes et
ACGIHTLV-
STEL [Skin]d
15 minutes
79
15
al. (1963);
Dawson et
al. (1958);
Cock
(1957);
Schafer
(1951)
OSHAPEL
(TWA)e
8-hour TWA
50
10
NR
NR
NR
NR
Final
(OSHA,
Cal-OSHA
PEL (TWA)
8-hour TWA
0.5
0.1
NR
NR
NR
NR
2019)
U.S. EPA
Chronic
0.003
0.0006
Hyperplasia in
10 ppm
LOAEL
NTP (1992)
Total UF = 3,000
Duration
Final
General public
Chronic RfC
(IRIS)f
the respiratory
epithelium and
metaplasia in
the olfactory
epithelium of
adult male and
female mice
9.3 mg/m3
9.3 mg/m3
LOAELadj
LOAELhec
UFA= 10
UFh = 10
UFL= 10
UFdb = 3
adjusted:
(6-h/24-h) x
(5-d/7-d)
HEC
Adjusted8
(U.S. EPA,
1998)
32
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
ATSDR MRL
Chronic
0.0036
0.0007
Nonneoplastic
10 ppm
LOAEL
Abdo et al.
Total UF = 300
Duration
Final
(>1 year)
lesions in nasal
olfactory
1.8 ppm
LOAELadj
(2001);
NTP (2000,
UFA = 3
UFh = 10
adjusted:
(6-h/24-h) x
(ATSDR,
2005)
epithelium and
respiratory
epithelium of
adult male and
female rats
and mice
0.2 ppm
LOAELhec
1992)
UFL= 10
(5-d/7-d)
HEC
Adjustedh
OEHHA REL1
Chronic
0.009
0.002
Nasal
10 ppm
LOAEL
NTP (1992)
Total UF = 1,000
Duration
Final
inflammation,
olfactory
epithelial
metaplasia,
and respiratory
epithelial
hyperplasia in
adult male and
female mice
1.8 ppm
LOAELadj
UFA= 10
UFh = 10
UFL= 10
UFs = 1
adjusted:
(6-h/24-h) x
(5-d/7-d)
(OEHHA,
2000)
MDH HBV
Acute
(1 hour)
0.2
0.038
Respiratory
cell swelling
and sloughing
in rats and
nausea,
vomiting,
abdominal
pain, and
hemolytic
anemia in
humans
204 mg/m3
NOAEL
Buckpitt
and
Richieri
(1984)
Total UF = 1,000
UFA= 10
UFh = 10
UFdb = 10
Final
(MDH,
2004)
Chronic
0.009
0.002
Nasal effects in
10 ppm
LOAEL
NTP (2000.
Total UF = 1,000
Duration
(1 year)
adult rats and
mice
9.3 mg/m3
LOAELadj
1992)
UFA= 10
UFh = 10
UFL= 10
adjusted:
(6-h/24-h) x
(5-d/7-d)
33
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
RIVM TCA
Chronic
0.025
0.0048
Local toxic
effect on the
nasal mucous
membrane in
adult rats
exposed for 28
days
5 mg/m3
LOAEL
Coombs
(1993)
Total UF = 200
UFA= 10
UFh = 10
UFl = 2
No time
extrapolatio
n
Based on EU
Risk
Assessment:
(ECB, 2003)
Final
(Dusseldor
p et al.,
2011)
Health
Canada
Residential
Indoor RfC
Chronic
0.01
0.0019
Nasal epithelial
cytotoxicity in
adult rats
52 mg/m3
9.3 mg/m3
LOAEL
LOAELadj
NTP (2000)
Total UF = 1,000
UFA= 10
UFh = 10
UFdb = 10
Duration
adjusted:
(6-h/24-h) x
(5-d/7-d)
Final
(Health
Canada,
2013)
General public
(other state values)
Rl DEM AAL
24 hours
0.003
0.0006
Adopted IRIS
RfC as 24-hr.
AAL
NA
NA
NA
NA
Adopted
IRIS RfC as
24-hr. AAL
Final
(Ri, 2008)
1 year
0.00003
0.0000056
Cancer
0.000034
(Hg/m3)1
OEHHA
Cancer URF
OEHHA
(2011)
NA
Calculated*
OR DEQ ABC
1 year
0.00003
0.0000056
Cancer
0.000034
(Hg/m3)1
OEHHA
Cancer URF
OEHHA
(2011)
NA
Calculatedk
Final
(Oregon
DEQ,
2018)
CT DEEP HLV
30 minutes
5
1
NR
NR
NR
NR
NA
Final
(2015)
8 hours
1
0.2
NR
52 mg/m3
ACGIH TLV-
TWA
ACGIH
(1992)
Total UF = 50
Details
reported to
NATICH
NDEPBCL
Chronic
(Cancer)
0.0000826
0.000016
Cancer
0.000034
(Hg/m3)1
OEHHA
Cancer URF
OEHHA
(2011)
NA
Calculated1
Final
(NDEP,
2017)
AAL = acceptable ambient level; ABC = ambient benchmark concentration; ACGIH = American Conference of Governmental Industrial Hygienists; ADJ = adjusted; ATSDR = Agency for
Toxic Substances and Disease Registry; BCL = basic comparison level; Cal-OSHA = California Division of Occupational Safety and Health; CT DEEP = Connecticut Department of Energy and
34
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Environmental Protection; DOE = Department of Energy; ECB = European Chemicals Bureau; EU = European Union; HBV = health-based value; HEC = human equivalent concentration;
HLV = hazard limiting value; IDLH = immediately dangerous to life and health; IRIS = Integrated Risk Information System; LOAEL = lowest-observed-adverse-effect level; MDH = Minnesota
Department of Health; MRL = minimal risk level; NA = not applicable; NATICH = National Air Toxics Information Clearinghouse; NDEP = Nevada Division of Environmental Protection;
NIOSH = National Institute for Occupational Safety and Health; NOAEL = no-observed-adverse-effect level; NR = not reported; NTP = National Toxicology Program; OEHHA = California
Environmental Protection Agency Office of Environmental Health Hazard Assessment; OR DEQ = Oregon Department of Environmental Quality; OSHA = Occupational Safety and Health
Administration; PAC = protective action criteria; PEL = permissible exposure limit; REL = recommended exposure limit (NIOSH) or reference exposure level (OEHHA); RfC = reference
concentration; Rl DEM = Rhode Island Department of Environmental Management; RIVM = Rijksinstituut voor Volksgezondheid en Milieu, The Netherlands Institute for Public Health and
the Environment; STEL = short-term exposure limit; TCA = tolerable concentration; TLV = threshold limit value; TWA = time-weighted average; UF = uncertainty factor; UFH = inter-human
variability; UFA = animal to human variability; UFL = LOAEL to NOAEL adjustment; UFS = subchronic to chronic adjustment; UFDb = database uncertainty; URF = unit risk factor; U.S. EPA =
United States Environmental Protection Agency.
a"Uncertainty factors" refer to modifying factors and other adjustment factors used by some organizations or in older EPA assessments.
bPAC-2 = PAC-3 / 6 = 500 ppm / 6 = 83 ppm.
cSupport documentation states: "systemic poisoning following dermal contact and absorption of naphthalene warrants a Skin notation."
Agencies of Ontario, Quebec, Ireland, Australia, New Zealand, Austria, Belgium, Spain, and Singapore report identical values.
dAgencies of Quebec, Australia, New Zealand, Belgium, China, Singapore, South Korea, Spain, Sweden, and the Netherlands report identical values.
0Agencies of Denmark, France, Hungary, Italy, Latvia, China, Romania, South Korea, Sweden, Switzerland, the Netherlands, and Turkey report identical values.
fThe EPA IRIS chronic RfC has been adopted as a state value by the Texas Commission on Environmental Quality, Indiana Department of Environmental Management, Pennsylvania
Department of Environmental Protection, Alaska Department of Environmental Conservation, New Jersey Department of Environmental Protection, and Michigan Department of
Environment, Great Lakes & Energy.
sLOAELhec = LOAELadj x RGDR = 9.3 mg/m3 x 1 = 9.3 mg/m3.
hLOAELHEc = LOAELadj x RGDR = 1.8 ppm x 0.132 = 0.2 ppm.
'The OEHHA REL value has been adopted by New York DEC.
jAAL = 1 / URF / 106 = 1 / 0.000034 (Mg/m3)-1 / 106 = 0.03 Mg/m3.
kABC = 1 / URF / 106 = 1 / 0.000034 (Mg/m3)"1 / 106 = 0.03 Mg/m3.
'BCL = TR x AT / (ET x EF x ED x URF) = (10 6 x 70 yrs. x 365 days/yr. x 24 hrs./day) / [24 hrs./day x 350 days/yr. x 26 yrs. x 0.000034 (Mg/m3)-1] = 0.0826 Mg/m3.
35
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Appendix B: Supplemental Information on Systematic Review Methods
Table B-l. Database search strategy.
Database
Search date
Query string
PubMed
1/28/2021
("naphthalene"[nm] AND 2018/12/01: 2021/01/31[mhda]) OR (("naphthalene"[tw] OR
"albocarbon"[tw] OR "naphthalin"[tw] OR "naphthaline"[tw] OR "naphthene"[tw] OR
"naphtalene"[tw] OR "camphor tar"[tw] OR "tar camphor"[tw] OR "white tar"[tw] OR "moth
balls"[tw] OR "moth flakes"[tw] OR "mothballs"[tw] OR "Naphtalinum"[tw] OR
"Naphthalinum"[tw] OR "Dezodorator"[tw] OR "Mighty 150"[tw] OR "Mighty RDl"[tw]) AND
"Naphthalenes"[mh:noexp] AND 2018/12/01: 2021/01/31 [mhda]) OR ((("naphthalene"[tw] OR
"albocarbon"[tw] OR "naphthalin"[tw] OR "naphthaline"[tw] OR "naphthene"[tw] OR
"naphtalene"[tw] OR "camphor tar"[tw] OR "tar camphor"[tw] OR "white tar"[tw] OR "moth
balls"[tw] OR "moth flakes"[tw] OR "mothballs"[tw] OR "Naphtalinum"[tw] OR
"Naphthalinum"[tw] OR "Dezodorator"[tw] OR "Mighty 150"[tw] OR "Mighty RDl"[tw]) AND
(2018/12/01: 2021/01/31[edat] OR 2018/12/012021/01/31 [crdt])) NOT medline[sb])
2/8/2019
("naphthalene"[nm] AND 2017/10/01: 2019/01/01[mhda]) OR (("naphthalene"[tw] OR
"albocarbon"[tw] OR "naphthalin"[tw] OR "naphthaline"[tw] OR "naphthene"[tw] OR
"naphthalene"[tw] OR "camphor tar"[tw] OR "tar camphor"[tw] OR "white tar"[tw] OR "moth
balls"[tw] OR "moth flakes"[tw] OR "mothballs"[tw] OR "Naphtalinum"[tw] OR
"Naphthalinum"[tw] OR "Dezodorator"[tw] OR "Mighty 150"[tw] OR "Mighty RDl"[tw]) AND
"Naphthalenes"[mh:noexp] AND 2017/10/01: 2019/01/01[mhda]) OR ((("naphthalene"[tw] OR
"albocarbon"[tw] OR "naphthalin"[tw] OR "naphthaline"[tw] OR "naphthene"[tw] OR
"naphtalene"[tw] OR "camphor tar"[tw] OR "tar camphor"[tw] OR "white tar"[tw] OR "moth
balls"[tw] OR "moth flakes"[tw] OR "mothballs"[tw] OR "Naphtalinum"[tw] OR
"Naphthalinum"[tw] OR "Dezodorator"[tw] OR "Mighty 150"[tw] OR "Mighty RDl"[tw]) AND
(2017/10/01: 2019/01/01[edat] OR 2017/10/01: 2019/01/01[crdt])) NOT medline[sb])
9/29/2017
("naphthalene"[nm] AND 2017/02/01: 3000[mhda]) OR (("naphthalene"[tw] OR "albocarbon"[tw]
OR "naphthalin"[tw] OR "naphthaline"[tw] OR "naphthene"[tw] OR "naphtalene"[tw] OR
"camphor tar"[tw] OR "tar camphor"[tw] OR "white tar"[tw] OR "moth balls"[tw] OR "moth
flakes"[tw] OR "mothballs"[tw] OR "Naphtalinum"[tw] OR "Naphthalinum"[tw] OR
"Dezodorator"[tw] OR "Mighty 150"[tw] OR "Mighty RDl"[tw]) AND "Naphthalenes"[mh:noexp]
AND 2017/02/01: 3000[mhda]) OR ((("naphthalene"[tw] OR "albocarbon"[tw] OR
"naphthalin"[tw] OR "naphthaline"[tw] OR "naphthene"[tw] OR "naphtalene"[tw] OR "camphor
tar"[tw] OR "tar camphor"[tw] OR "white tar"[tw] OR "moth balls"[tw] OR "moth flakes"[tw] OR
"mothballs"[tw] OR "Naphtalinum"[tw] OR "Naphthalinum"[tw] OR "Dezodorator"[tw] OR "Mighty
150"[tw] OR "Mighty RDl"[tw]) AND (2014/10/01: 3000[edat] OR 2017/02/01: 3000[crdt])) NOT
medline[sb])
01/04/2017
«524-42-5[rn] OR 130-15-4[rn] OR 7234-04-0[rn] OR 277-50-9[rn]) OR (("l,2-Dihydro-l,2-diketo-
naphthalene"[tw] OR "l,2-Naphthalenedione"[tw] OR "l,2-Naphthaquinone"[tw] OR "beta-
Naphthoquinone"[tw] OR "o-Naphthoquinone"[tw] OR "l,4-Dihydro-l,4-diketonaphthalene"[tw]
OR "l,4-Naphthalenedione"[tw] OR "l,4-Naphthoquinone"[tw] OR "l,4-Naphthylquinone"[tw] OR
"alpha-Naphthoquinone"[tw] OR "p-Naphthoquinone"[tw] OR "l,2-Dihydronaphthalene-l,2-
diol"[tw] OR "l,2-Dihydroxy-l,2-dihydronaphthalene"[tw] OR "l,2-dihydro-l,2-
Naphthalenediol"[tw] OR "Naphthalene-l,2-dihydrodiol"[tw] OR "trans- 1,2-Dihydroxy-1,2-
dihydronaphthalene"[tw] OR "Naphthalene l,2-oxide"[tw] OR "Naphthalene oxide"[tw] OR
"Naphth(l,2-b)oxirene"[tw]) NOT medline[sb])) OR (("naphthalene"[nm] AND 2015/10/01:
3000[mhda]) OR (("naphthalene"[tw] OR "albocarbon"[tw] OR "naphthalin"[tw] OR
36
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Database
Search date
Query string
"naphthaline"[tw] OR "naphthene"[tw] OR "naphtalene"[tw] OR "camphor tar"[tw] OR "tar
camphor"[tw] OR "white tar"[tw] OR "moth balls"[tw] OR "moth flakes"[tw] OR "mothballs"[tw]
OR "Naphtalinum"[tw] OR "Naphthalinum"[tw] OR "Dezodorator"[tw] OR "Mighty 150"[tw] OR
"Mighty RDl"[tw]) AND "Naphthalenes"[mh:noexp] AND 2015/10/01: 3000[mhda]) OR
((("naphthalene"[tw] OR "albocarbon"[tw] OR "naphthalin"[tw] OR "naphthaline"[tw] OR
"naphthene"[tw] OR "naphtalene"[tw] OR "camphor tar"[tw] OR "tar camphor"[tw] OR "white
tar"[tw] OR "moth balls"[tw] OR "moth flakes"[tw] OR "mothballs"[tw] OR "Naphtalinum"[tw] OR
"Naphthalinum"[tw] OR "Dezodorator"[tw] OR "Mighty 150"[tw] OR "Mighty RDl"[tw]) AND
(2015/10/01: 3000[edat] OR 2015/10/01: 3000[crdt])) NOT medline[sb]))
11/06/2015
("naphthalene"[nm] AND 2014/10/01: 3000[mhda]) OR (("naphthalene"[tw] OR "albocarbon"[tw]
OR "naphthalin"[tw] OR "naphthaline"[tw] OR "naphthene"[tw] OR "naphtalene"[tw] OR
"camphor tar"[tw] OR "tar camphor"[tw] OR "white tar"[tw] OR "moth balls"[tw] OR "moth
flakes"[tw] OR "mothballs"[tw] OR "Naphtalinum"[tw] OR "Naphthalinum"[tw] OR
"Dezodorator"[tw] OR "Mighty 150"[tw] OR "Mighty RDl"[tw]) AND "Naphthalenes"[mh:noexp]
AND 2014/10/01: 3000[mhda]) OR ((("naphthalene"[tw] OR "albocarbon"[tw] OR
"naphthalin"[tw] OR "naphthaline"[tw] OR "naphthene"[tw] OR "naphtalene"[tw] OR "camphor
tar"[tw] OR "tar camphor"[tw] OR "white tar"[tw] OR "moth balls"[tw] OR "moth flakes"[tw] OR
"mothballs"[tw] OR "Naphtalinum"[tw] OR "Naphthalinum"[tw] OR "Dezodorator"[tw] OR "Mighty
150"[tw] OR "Mighty RDl"[tw]) AND (2014/10/01: 3000[edat] OR 2014/10/01: 3000[crdt])) NOT
medline[sb])
12/16/2014
("naphthalene"[nm] AND 2012/12/01: 3000[mhda]) OR ("Naphthalenes"[mh:noexp] AND ("91-20-
3"[tw] OR "naphthalene"[tw] OR "albocarbon"[tw] OR "naphthalin"[tw] OR "naphthaline"[tw] OR
"naphthene"[tw] OR "naphtalene"[tw] OR "camphor tar"[tw] OR "tar camphor"[tw] OR "white
tar"[tw] OR "moth balls"[tw] OR "moth flakes"[tw] OR "mothballs"[tw] OR "Naphtalinum"[tw] OR
"Naphthalinum"[tw] OR "Dezodorator"[tw] OR "Mighty 150"[tw] OR "Mighty RDl"[tw]) AND
2012/12/01: 3000[mhda]) OR ((("91-20-3"[tw] OR "naphthalene"[tw] OR "albocarbon"[tw] OR
"naphthalin"[tw] OR "naphthaline"[tw] OR "naphthene"[tw] OR "naphtalene"[tw] OR "camphor
tar"[tw] OR "tar camphor"[tw] OR "white tar"[tw] OR "moth balls"[tw] OR "moth flakes"[tw] OR
"mothballs"[tw] OR "Naphtalinum"[tw] OR "Naphthalinum"[tw] OR "Dezodorator"[tw] OR "Mighty
150"[tw] OR "Mighty RDl"[tw]) AND (2012/12/01: 3000[crdat] OR 2012/12/01: 3000[edat])) NOT
medline[sb])
02/17/2013
(((91-20-3[rn]) OR (("91-20-3"[tw] OR naphthalene[tw] OR albocarbon[tw] OR naphthalin[tw] OR
naphthaline[tw] OR naphthene[tw] OR naphtalene[tw] OR "camph[tw] OR tar"[tw] OR "tar
camphor"[tw] OR "white tar"[tw] OR "moth balls"[tw] OR "moth flakes"[tw] OR mothballs[tw])
AND ("naphthalenes"[mh:noexp]))) AND (("naphthalenes/toxicity"[MeSH Terms] OR
"naphthalenes/adverse effects"[MeSH Terms] OR "naphthalenes/poisoning"[MeSH Terms] OR
"naphthalenes/pharmacokinetics"[MeSH Terms]) OR ("naphthalenes/blood"[MeSH Terms] OR
"naphthalenes/cerebrospinal fluid"[MeSH Terms] OR "naphthalenes/urine"[MeSH Terms]) OR
("naphthalenes/metabolism"[MeSH Terms] AND ("humans"[MeSH Terms] OR "animals"[MeSH
Terms])) OR ("naphthalenes/antagonists and inhibitors"[MeSH Terms]) OR ("chemically
induced"[MeSH Subheading] OR "environmental exposure"[MeSH Terms]) OR ("endocrine
system"[mh] OR "hormones, hormone substitutes, and hormone antagonists"[mh] OR "endocrine
disruptors"[mh]) OR (cancer[sb]) OR ("Computational biology"[mh] OR "Medical lnformatics"[mh]
OR Genomics[mh] OR Genome[mh] OR Proteomics[mh] OR Proteome[mh] OR Metabolomics[mh]
OR Metabolome[mh] OR Genes[mh] OR "Gene expression"[mh] OR Phenotype[mh] OR
genetics[mh] OR genotype[mh] ORTranscriptome[mh] OR ("Systems Biology"[mh] AND
("Environmental Exposure"[mh] OR "Epidemiological Monitoring"[mh] OR analysis[sh])) OR
"Transcription, Genetic "[mh] OR "Reverse transcription"[mh] OR "Transcriptional activation"[mh]
37
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Database
Search date
Query string
OR "Transcription factors"[mh] OR ("biosynthesis"[sh] AND (RNA[mh] OR DNA[mh])) OR "RNA,
Messenger "[mh] OR "RNA, Transfer"[mh] OR "peptide biosynthesis"[mh] OR "protein
biosynthesis"[mh] OR "Reverse Transcriptase Polymerase Chain Reaction"[mh] OR "Base
Sequence"[mh] OR "Trans-activators"[mh] OR "Gene Expression Profiling"[mh]) OR (rat[tw] OR
rats[tw] OR mouse[tw] OR mice[tw] OR muridae[tw] OR rabbit[tw] OR rabbits[tw] OR hamster[tw]
OR hamsters[tw] OR ferret[tw] OR ferrets[tw] OR gerbil[tw] OR gerbils[tw] OR rodent[tw] OR
rodents[tw] OR rodentia[tw] OR dog[tw] OR dogs[tw] OR beagle[tw] OR beagles[tw] OR canine[tw]
OR cats[tw] OR feline[tw] OR pig[tw] OR pigs[tw] OR swine[tw] OR porcine[tw] OR monkey[tw] OR
monkeys[tw] OR macaque[tw] OR macaques[tw] OR baboon[tw] OR baboons[tw] OR
marmoset[tw] OR marmosets[tw] OR "animals, laboratory"[mh]) OR (((pharmacokinetics[mh] OR
metabolism[mh]) AND (humans[mh] OR animals[mh])) OR "dose-response relationship, drug"[mh]
OR risk[mh]))) OR (("91-20-3"[tw] OR naphthalene[tw] OR albocarbon[tw] OR naphthalin[tw] OR
naphthaline[tw] OR naphthene[tw] OR naphtalene[tw] OR "camph[tw] OR tar"[tw] OR "tar
camphor"[tw] OR "white tar"[tw] OR "moth balls"[tw] OR "moth flakes"[tw] OR mothballs[tw])
NOT medline[sb])
Web of Science
1/28/2021
(TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" OR TS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS="mothballs" OR TS="Naphtalinum" OR
TS="Naphthalinum" OR TS="Dezodorator" OR TS="Mighty 150" OR TS="Mighty RD1") AND
((WC=("Toxicology" OR "Endocrinology & Metabolism" OR "Gastroenterology & Hepatology" OR
"Gastroenterology & Hepatology" OR "Hematology" OR "Neurosciences" OR "Obstetrics &
Gynecology" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Respiratory System" OR
"Urology & Nephrology" OR "Anatomy & Morphology" OR "Andrology" OR "Pathology" OR
"Veterinary Sciences" OR "Otorhinolaryngology" OR "Ophthalmology" OR "Pediatrics" OR
"Oncology" OR "Reproductive Biology" OR "Developmental Biology" OR "Biology" OR
"Dermatology" OR "Allergy" OR "Public, Environmental & Occupational Health") OR SU=("Anatomy
& Morphology" OR "Cardiovascular System & Cardiology" OR "Developmental Biology" OR
"Endocrinology & Metabolism" OR "Gastroenterology & Hepatology" OR "Hematology" OR
"Immunology" OR "Neurosciences & Neurology" OR "Obstetrics & Gynecology" OR "Oncology" OR
"Ophthalmology" OR "Pathology" OR "Pediatrics" OR "Pharmacology & Pharmacy" OR "Physiology"
OR "Public, Environmental & Occupational Health" OR "Respiratory System" OR "Toxicology" OR
"Urology & Nephrology" OR "Reproductive Biology" OR "Dermatology" OR "Allergy")) AND
(TS="rat" ORTS-'rats" ORTS="mouse" ORTS="murine" ORTS="mice" ORTS="guinea" OR
TS="muridae" ORTS=rabbit* ORTS=lagomorph* ORTS=hamster* ORTS=ferret* ORTS=gerbil* OR
TS=rodent* ORTS="dog" ORTS="dogs" ORTS=beagle* ORTS="canine" ORTS="cats" OR
TS="feline" OR TS="pig" OR TS="pigs" OR TS="swine" OR TS="porcine" OR TS=monkey* OR
TS=macaque* ORTS=baboon* ORTS=marmoset* ORTS=toxic*) AND (TS="rat" ORTS="rats" OR
TS="mouse" OR TS="murine" ORTS="mice" ORTS="guinea" ORTS="muridae" ORTS=rabbit* OR
TS=lagomorph* ORTS=hamster* ORTS=ferret* ORTS=gerbil* ORTS=rodent* ORTS="dog" OR
TS="dogs" ORTS=beagle* ORTS="canine" ORTS="cats" ORTS="feline" ORTS="pig" ORTS="pigs"
ORTS="swine" ORTS="porcine" ORTS=monkey* ORTS=macaque* ORTS=baboon* OR
TS=marmoset*) OR (TS="child" ORTS="children" ORTS=adolescen* ORTS=infant* OR
TS="WORKER" OR TS="WORKERS" ORTS="HUMAN" OR TS=patient* ORTS="mother" OR
TS="fetal" ORTS="fetus" ORTS="citizens" ORTS="milk" ORTS="formula")) AND PY=(2019-2021)
2/8/2019
(TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" OR TS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" ORTS="moth balls" ORTS="moth flakes" OR TS="mothballs" OR TS="Naphtalinum" OR
38
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Database
Search date
Query string
TS="Naphthalinum" OR TS="Dezodorator" OR TS="Mighty 150" OR TS="Mighty RD1") AND
((WC="Toxicology" OR WC="Endocrinology & Metabolism" OR WC="Gastroenterology &
Hepatology" OR WC="Gastroenterology & Hepatology" OR WC="Hematology" OR
WC="Neurosciences" OR WC="Obstetrics & Gynecology" OR WC="Pharmacology & Pharmacy" OR
WC="Physiology" OR WC="Respiratory System" OR WC="Urology & Nephrology" OR
WC="Anatomy & Morphology" OR WC="Andrology" OR WC="Pathology" OR
WC="Otorhinolaryngology" OR WC="Ophthalmology" OR WC="Pediatrics" OR WC="Oncology" OR
WC="Reproductive Biology" OR WC="Developmental Biology" OR WC="Biology" OR
WC="Dermatology" OR WC="Allergy" OR WC="Public, Environmental & Occupational Health" OR
SU="Anatomy & Morphology" OR SU="Cardiovascular System & Cardiology" OR
SU="Developmental Biology" OR SU="Endocrinology & Metabolism" OR SU="Gastroenterology &
Hepatology" OR SU="Hematology" OR SU="lmmunology" OR SU="Neurosciences & Neurology" OR
SU="Obstetrics & Gynecology" OR SU="Oncology" OR SU="Ophthalmology" OR SU="Pathology" OR
SU="Pediatrics" OR SU="Pharmacology & Pharmacy" OR SU="Physiology" OR SU="Public,
Environmental & Occupational Health" OR SU="Respiratory System" OR SU="Toxicology" OR
SU="Urology & Nephrology" OR SU="Reproductive Biology" OR SU="Dermatology" OR
SU="Allergy") OR (WC="veterinary sciences" AND (TS="rat" ORTS="rats" ORTS="mouse" OR
TS="murine" ORTS="mice" ORTS="guinea" OR TS="muridae" ORTS=rabbit* ORTS=lagomorph*
OR TS=hamster* ORTS=ferret* ORTS=gerbil* ORTS=rodent* ORTS="dog" ORTS="dogs" OR
TS=beagle* ORTS="canine" ORTS="cats" ORTS="feline" ORTS="pig" ORTS="pigs" ORTS="swine"
ORTS="porcine" ORTS=monkey* ORTS=macaque* ORTS=baboon* ORTS=marmoset*)) OR
(TS=toxic* AND (TS="rat" ORTS="rats" ORTS="mouse" ORTS="murine" ORTS="mice" OR
TS="guinea" ORTS="muridae" ORTS=rabbit* ORTS=lagomorph* ORTS=hamster* ORTS=ferret*
OR TS=gerbil* ORTS=rodent* ORTS="dog" ORTS="dogs" ORTS=beagle* ORTS="canine" OR
TS="cats" ORTS="feline" ORTS="pig" ORTS="pigs" ORTS="swine" ORTS="porcine" OR
TS=monkey* OR TS=macaque* OR TS=baboon* OR TS=marmoset*) OR (TS="child" OR
TS="children" ORTS=adolescen* ORTS=infant* ORTS="WORKER" ORTS="WORKERS" OR
TS="HUMAN" ORTS=patient* ORTS=mother ORTS=fetal ORTS=fetus ORTS=citizens ORTS=milk
OR TS=formula)) OR TI=toxic*) AND PY=(2017-2019)
9/29/2017
(TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" OR TS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" ORTS="moth balls" ORTS="moth flakes" OR TS="mothballs" OR TS="Naphtalinum" OR
TS="Naphthalinum" OR TS="Dezodorator" OR TS="Mighty 150" OR TS="Mighty RD1") AND
((WC=("Toxicology" OR "Endocrinology & Metabolism" OR "Gastroenterology & Hepatology" OR
"Gastroenterology & Hepatology" OR "Hematology" OR "Neurosciences" OR "Obstetrics &
Gynecology" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Respiratory System" OR
"Urology & Nephrology" OR "Anatomy & Morphology" OR "Andrology" OR "Pathology" OR
"Otorhinolaryngology" OR "Ophthalmology" OR "Pediatrics" OR "Oncology" OR "Reproductive
Biology" OR "Developmental Biology" OR "Biology" OR "Dermatology" OR "Allergy" OR "Public,
Environmental & Occupational Health") OR SU=("Anatomy & Morphology" OR "Cardiovascular
System & Cardiology" OR "Developmental Biology" OR "Endocrinology & Metabolism" OR
"Gastroenterology & Hepatology" OR "Hematology" OR "Immunology" OR "Neurosciences &
Neurology" OR "Obstetrics & Gynecology" OR "Oncology" OR "Ophthalmology" OR "Pathology" OR
"Pediatrics" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Public, Environmental &
Occupational Health" OR "Respiratory System" OR "Toxicology" OR "Urology & Nephrology" OR
"Reproductive Biology" OR "Dermatology" OR "Allergy")) OR (WC="veterinary sciences" AND
(TS="rat" ORTS-'rats" ORTS="mouse" ORTS="murine" ORTS="mice" ORTS="guinea" OR
TS="muridae" ORTS=rabbit* ORTS=lagomorph* ORTS=hamster* ORTS=ferret* ORTS=gerbil* OR
TS=rodent* ORTS="dog" ORTS="dogs" ORTS=beagle* ORTS="canine" ORTS="cats" OR
39
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Database
Search date
Query string
TS="feline" OR TS="pig" OR TS="pigs" OR TS="swine" OR TS="porcine" OR TS=monkey* OR
TS=macaque* ORTS=baboon* ORTS=marmoset*)) OR (TS=toxic* AND (TS="rat" ORTS="rats" OR
TS="mouse" OR TS="murine" ORTS="mice" ORTS="guinea" ORTS="muridae" ORTS=rabbit* OR
TS=lagomorph* ORTS=hamster* ORTS=ferret* ORTS=gerbil* ORTS=rodent* ORTS="dog" OR
TS="dogs" ORTS=beagle* ORTS="canine" ORTS="cats" ORTS="feline" ORTS="pig" ORTS="pigs"
ORTS="swine" ORTS="porcine" ORTS=monkey* ORTS=macaque* ORTS=baboon* OR
TS=marmoset*) OR (TS="child" OR TS="children" OR TS=adolescen* OR TS=infant* OR
TS="WORKER" OR TS="WORKERS" ORTS="HUMAN" OR TS=patient* OR TS=mother OR TS=fetal OR
TS=fetus OR TS=citizens OR TS=milk OR TS=formula)) OR TI=toxic*) AND PY=(2017-2017)
01/04/2017
(TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" OR TS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" ORTS="moth balls" ORTS="moth flakes" OR TS="mothballs" OR TS="Naphtalinum" OR
TS="Naphthalinum" OR TS="Dezodorator" OR TS="Mighty 150" OR TS="Mighty RD1") AND
((WC=("Toxicology" OR "Endocrinology & Metabolism" OR "Gastroenterology & Hepatology" OR
"Gastroenterology & Hepatology" OR "Hematology" OR "Neurosciences" OR "Obstetrics &
Gynecology" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Respiratory System" OR
"Urology & Nephrology" OR "Anatomy & Morphology" OR "Andrology" OR "Pathology" OR
"Otorhinolaryngology" OR "Ophthalmology" OR "Pediatrics" OR "Oncology" OR "Reproductive
Biology" OR "Developmental Biology" OR "Biology" OR "Dermatology" OR "Allergy" OR "Public,
Environmental & Occupational Health") OR SU=("Anatomy & Morphology" OR "Cardiovascular
System & Cardiology" OR "Developmental Biology" OR "Endocrinology & Metabolism" OR
"Gastroenterology & Hepatology" OR "Hematology" OR "Immunology" OR "Neurosciences &
Neurology" OR "Obstetrics & Gynecology" OR "Oncology" OR "Ophthalmology" OR "Pathology" OR
"Pediatrics" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Public, Environmental &
Occupational Health" OR "Respiratory System" OR "Toxicology" OR "Urology & Nephrology" OR
"Reproductive Biology" OR "Dermatology" OR "Allergy")) OR (WC="veterinary sciences" AND
(TS="rat" ORTS-'rats" ORTS="mouse" ORTS="murine" ORTS="mice" ORTS="guinea" OR
TS="muridae" ORTS=rabbit* ORTS=lagomorph* ORTS=hamster* ORTS=ferret* ORTS=gerbil* OR
TS=rodent* ORTS="dog" ORTS="dogs" ORTS=beagle* ORTS="canine" ORTS="cats" OR
TS="feline" OR TS="pig" OR TS="pigs" OR TS="swine" OR TS="porcine" OR TS=monkey* OR
TS=macaque* OR TS=baboon* OR TS=marmoset*)) OR (TS=toxic* AND (TS="rat" OR TS="rats" OR
TS="mouse" OR TS="murine" ORTS="mice" ORTS="guinea" ORTS="muridae" ORTS=rabbit* OR
TS=lagomorph* ORTS=hamster* ORTS=ferret* ORTS=gerbil* ORTS=rodent* ORTS="dog" OR
TS="dogs" ORTS=beagle* ORTS="canine" ORTS="cats" ORTS="feline" ORTS="pig" ORTS="pigs"
ORTS="swine" ORTS="porcine" ORTS=monkey* ORTS=macaque* ORTS=baboon* OR
TS=marmoset*) OR (TS="child" OR TS="children" OR TS=adolescen* OR TS=infant* OR
TS="WORKER" OR TS="WORKERS" ORTS="HUMAN" OR TS=patient* OR TS=mother OR TS=fetal OR
TS=fetus OR TS=citizens OR TS=milk OR TS=formula)) OR TI=toxic*) AND PY=(2015-2017)
11/04/2015
(TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" OR TS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" ORTS="moth balls" ORTS="moth flakes" OR TS="mothballs" OR TS="Naphtalinum" OR
TS="Naphthalinum" OR TS="Dezodorator" OR TS="Mighty 150" OR TS="Mighty RD1") AND
((WC=("Toxicology" OR "Endocrinology & Metabolism" OR "Gastroenterology & Hepatology" OR
"Gastroenterology & Hepatology" OR "Hematology" OR "Neurosciences" OR "Obstetrics &
Gynecology" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Respiratory System" OR
"Urology & Nephrology" OR "Anatomy & Morphology" OR "Andrology" OR "Pathology" OR
"Otorhinolaryngology" OR "Ophthalmology" OR "Pediatrics" OR "Oncology" OR "Reproductive
Biology" OR "Developmental Biology" OR "Biology" OR "Dermatology" OR "Allergy" OR "Public,
40
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Database
Search date
Query string
Environmental & Occupational Health") OR SU=("Anatomy & Morphology" OR "Cardiovascular
System & Cardiology" OR "Developmental Biology" OR "Endocrinology & Metabolism" OR
"Gastroenterology & Hepatology" OR "Hematology" OR "Immunology" OR "Neurosciences &
Neurology" OR "Obstetrics & Gynecology" OR "Oncology" OR "Ophthalmology" OR "Pathology" OR
"Pediatrics" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Public, Environmental &
Occupational Health" OR "Respiratory System" OR "Toxicology" OR "Urology & Nephrology" OR
"Reproductive Biology" OR "Dermatology" OR "Allergy")) OR (WC="veterinary sciences" AND
(TS="rat" ORTS-'rats" ORTS="mouse" ORTS="murine" ORTS="mice" ORTS="guinea" OR
TS="muridae" ORTS=rabbit* ORTS=lagomorph* ORTS=hamster* ORTS=ferret* ORTS=gerbil* OR
TS=rodent* ORTS="dog" ORTS="dogs" ORTS=beagle* ORTS="canine" ORTS="cats" OR
TS="feline" OR TS="pig" OR TS="pigs" OR TS="swine" OR TS="porcine" OR TS=monkey* OR
TS=macaque* ORTS=baboon* ORTS=marmoset*)) OR (TS=toxic* AND (TS="rat" ORTS="rats" OR
TS="mouse" OR TS="murine" ORTS="mice" ORTS="guinea" ORTS="muridae" ORTS=rabbit* OR
TS=lagomorph* ORTS=hamster* ORTS=ferret* ORTS=gerbil* ORTS=rodent* ORTS="dog" OR
TS="dogs" ORTS=beagle* ORTS="canine" ORTS="cats" ORTS="feline" ORTS="pig" ORTS="pigs"
ORTS="swine" ORTS="porcine" ORTS=monkey* ORTS=macaque* ORTS=baboon* OR
TS=marmoset*) OR (TS="child" OR TS="children" OR TS=adolescen* OR TS=infant* OR
TS="WORKER" OR TS="WORKERS" ORTS="HUMAN" OR TS=patient* OR TS=mother OR TS=fetal OR
TS=fetus OR TS=citizens OR TS=milk OR TS=formula)) OR TI=toxic*) AND PY=(2014-2016)
12/16/2014
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" ORTS="moth balls" ORTS="moth flakes" OR TS="mothballs" ORTS="Naphtalinum" OR
TS="Naphthalinum" OR TS="Dezodorator" OR TS="Mighty 150" OR TS="Mighty RD1") AND
((WC=("Toxicology" OR "Endocrinology & Metabolism" OR "Gastroenterology & Hepatology" OR
"Gastroenterology & Hepatology" OR "Hematology" OR "Neurosciences" OR "Obstetrics &
Gynecology" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Respiratory System" OR
"Urology & Nephrology" OR "Anatomy & Morphology" OR "Andrology" OR "Pathology" OR
"Otorhinolaryngology" OR "Ophthalmology" OR "Pediatrics" OR "Oncology" OR "Reproductive
Biology" OR "Developmental Biology" OR "Biology" OR "Dermatology" OR "Allergy" OR "Public,
Environmental & Occupational Health") OR SU=("Anatomy & Morphology" OR "Cardiovascular
System & Cardiology" OR "Developmental Biology" OR "Endocrinology & Metabolism" OR
"Gastroenterology & Hepatology" OR "Hematology" OR "Immunology" OR "Neurosciences &
Neurology" OR "Obstetrics & Gynecology" OR "Oncology" OR "Ophthalmology" OR "Pathology" OR
"Pediatrics" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Public, Environmental &
Occupational Health" OR "Respiratory System" OR "Toxicology" OR "Urology & Nephrology" OR
"Reproductive Biology" OR "Dermatology" OR "Allergy")) OR (WC="veterinary sciences" AND
(TS="rat" ORTS-'rats" ORTS="mouse" ORTS="murine" ORTS="mice" ORTS="guinea" OR
TS="muridae" ORTS=rabbit* ORTS=lagomorph* ORTS=hamster* ORTS=ferret* ORTS=gerbil* OR
TS=rodent* ORTS="dog" ORTS="dogs" ORTS=beagle* ORTS="canine" ORTS="cats" OR
TS="feline" ORTS="pig" ORTS="pigs" ORTS="swine" OR TS="porcine" ORTS=monkey* OR
TS=macaque* ORTS=baboon* ORTS=marmoset*)) OR (TS=toxic* AND (TS="rat" ORTS="rats" OR
TS="mouse" OR TS="murine" ORTS="mice" ORTS="guinea" ORTS="muridae" ORTS=rabbit* OR
TS=lagomorph* ORTS=hamster* ORTS=ferret* ORTS=gerbil* ORTS=rodent* ORTS="dog" OR
TS="dogs" ORTS=beagle* ORTS="canine" ORTS="cats" ORTS="feline" ORTS="pig" ORTS="pigs"
ORTS="swine" ORTS="porcine" ORTS=monkey* ORTS=macaque* ORTS=baboon* OR
TS=marmoset*) OR (TS="child" ORTS="children" ORTS=adolescen* ORTS=infant* OR
TS="WORKER" OR TS="WORKERS" ORTS="HUMAN" OR TS=patient* OR TS=mother OR TS=fetal OR
TS=fetus OR TS=citizens OR TS=milk OR TS=formula)) OR TI=toxic*)) AND PY=2012-2015
41
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Database
Search date
Query string
02/21/2013
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS="chronic" ORTS=immun* ORTS=lymph* ORTS=neurotox* ORTS=toxicokin* OR
TS=pharmacokin* ORTS=biomarker* OR TS=neurolog* ORTS="subchronic" ORTS="pbpk" OR
TS=epidemiolog* ORTS="acute" ORTS="subacute" ORTS="ld50")
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS="lc50" OR TS=inhal* OR TS=pulmon* OR TS="nasal" OR TS=lung* OR TS=respir* OR
TS=occupation* ORTS="workplace" ORTS=worker* ORTS="oral" ORTS="orally" ORTS=ingest* OR
TS="gavage" ORTS="diet" ORTS="diets" ORTS="dietary" ORTS="drinking" ORTS=gastr* OR
TS=intestin* ORTS=liver* ORTS=hepat* ORTS=kidney* ORTS=nephr*)
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS="gut" ORTS=sensitiz* ORTS=abort* ORTS=abnormalit* ORTS=embryo* OR
TS=cleft* ORTS=fetus* ORTS=foetus* ORTS=fetal* ORTS=foetal* OR TS=fertilit* ORTS=infertil*
ORTS="fertilization" ORTS="fertilisation" ORTS=malform* ORTS="ovum" ORTS="ova" OR
TS="ovary" ORTS="ovaries" ORTS="ovarian" ORTS=placenta* ORTS=pregnan*)
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS=dermal* ORTS="dermis" ORTS="skin" ORTS=epiderm* ORTS="cutaneous" OR
TS=carcinog* ORTS=cocarcinog* OR TS="cancer" OR TS="precancer" ORTS=neoplas* OR
TS=tumor* ORTS=tumour* ORTS=oncogen* ORTS=lymphoma* OR TS=carcinom* OR
TS=genetox* OR TS=genotox* ORTS=mutagen* OR TS=nephrotox* ORTS=hepatotox* OR
TS=endocrin* ORTS=estrogen* ORTS=androgen*)
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS=hormon* ORTS="blood" ORTS="serum" ORTS="urine" ORTS="bone" OR
TS="bones" ORTS=skelet* ORTS="rat" ORTS="rats" ORTS="mouse")
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS="mice" OR TS="guinea" OR TS="muridae" OR TS=rabbit* OR TS=lagomorph* OR
TS=hamster* ORTS=ferret* ORTS=gerbil* ORTS=rodent* ORTS="dog" ORTS="dogs" OR
TS=beagle* ORTS="canine" ORTS="cats" ORTS="feline" ORTS="pig" ORTS="pigs" ORTS="swine"
ORTS="porcine" ORTS=monkey* ORTS=macaque* ORTS=baboon* ORTS=marmoset* OR
TS=toxic* ORTS="adverse" OR TS="poisoning")
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS="prenatal" ORTS="perinatal" ORTS="postnatal" ORTS="reproduce" OR
TS=reproduct* ORTS=steril* OR TS=teratogen* ORTS=sperm* ORTS=neonat* ORTS=newborn*
42
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Database
Search date
Query string
OR TS=development* ORTS=zygote* ORTS="child" OR TS="children" ORTS=adolescen* OR
TS=infant* OR TS=wean* OR TS="offspring" OR TS="age factor" OR TS="age factors")
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS="Genomics" ORTS="Proteomics" OR TS="Metabolic Profile" ORTS="Metabolome"
OR TS="Metabolomics" ORTS="Microarray" ORTS="Nanoarray")
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS="Gene expression" ORTS="Transcript expression" ORTS="transcriptomes" OR
TS="transcriptome" ORTS="Phenotype" OR TS='Transcription" OR TS="Trans-act*" OR
TS="transact*" OR TS="trans act*" OR TS=genetic OR TS="genetics" OR TS="genotype")
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS="lnformatics" OR (TS="lnformation Science" AND TS=Medical ORTS="Systems
biology" OR (TS="Biological systems" AND (TS=monit* ORTS=data ORTS=analysis))))
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS="Genetic transcription" OR TS="Gene transcription" OR TS="Gene Activation" OR
TS="Genetic induction" ORTS="Reverse transcription" ORTS='Transcriptional activation" OR
TS='Transcription factors" OR (TS="Biosynthesis" AND (TS=RNA OR TS=DNA)) ORTS="mRNA")
((TS="naphthalene" ORTS="albocarbon" ORTS="naphthalin" ORTS="naphthaline" OR
TS="naphthene" OR TS="naphtalene" OR TS="camphor tar" OR TS="tar camphor" OR TS="white
tar" OR TS="moth balls" OR TS="moth flakes" OR TS=mothballs) NOT TS="naphthalene acetic
acid") AND (TS="messenger RNA" ORTS="transfer RNA" ORTS="peptide biosynthesis" OR
TS="protein biosynthesis" ORTS="protein synthesis" ORTS="RT-PCR" ORTS="RTPCR" OR
TS="Reverse Transcriptase Polymerase Chain Reaction" OR TS="DNA sequence")
TOXLINE
2/8/2019
@synO+@AND+@OR+(naphthalene+albocarbon+naphthalin+naphthaline+
naphthene+naphtalene+""camphor+tar"+"tar+camphor"+"white+tar"+"moth+balls"
+"moth+flakes"+mothballs+Naphtalinum+Naphthalinum+Dezodorator+
"Mighty+150"+"Mighty+RDl"+@term+@rn+91+20+3)
+@and+@range+yr+2017+2019+@not+@org+pubmed
9/29/2017
@synO+@AND+@OR+(naphthalene+albocarbon+naphthalin+naphthaline+naphthene+naphtalene
+"camphor+tar"+"tar+camphor"+"white+tar"+"moth+balls"+"moth+flakes"+mothballs+Naphtalinu
m+Naphthalinum+Dezodorator+"Mighty+150"+"Mighty+RDl"+@term+@rn+91+20+3)+@and+@r
ange+yr+2017+@not+@org+pubmed
01/04/2017
@synO+@OR+(piscesqcorrection+naphthalene+albocarbon+naphthalin+naphthaline+naphthene+
naphtalene+"camphor tar"+"tar camphor'V'white tar"+"moth balls"+"moth
flakes"+mothballs+Naphtalinum+Naphthalinum+Dezodorator+"Mighty 150"+" Mighty
RDl"+@term+@rn+91-20-
3)+@and+@range+yr+2015+2017+@not+@org+pubmed+pubdart+"nih+reporter"+tscats
43
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Database
Search date
Query string
11/09/2015
@synO+@OR+(piscesqcorrection+naphthalene+albocarbon+naphthalin+naphthaline+naphthene+
naphtalene+"camphor tar'V'tar camphor'V'white tar'V'moth balls"+"moth
flakes"+mothballs+Naphtalinum+Naphthalinum+Dezodorator+"Mighty 150"+" Mighty
RDl"+@term+@rn+91-20-
3)+@and+@range+yr+2014+2016+@not+@org+pubmed+pubdart+"nih+reporter"+tscats
12/16/2014
@OR+(naphthalene+albocarbon+naphthalin+naphthaline+naphthene+naphtalene+mothballs+@te
rm+@rn+91-20-
3)+@AND+@range+yr+2012+2015+@NOT+@org+pubmed+pubdart+"nih+reporter"+tscats
@OR+("camphor+tar"+"tar+camphor"+"white+tar"+"moth+balls"+"moth+flakes")+@AND+@rang
e+yr+2012+2015+@NOT+@org+pubmed+pubdart+"nih+reporter"+tscats
02/18/2013
@OR+(naphthalene+albocarbon+naphthalin+naphthaline+naphthene+naphtalene+mothballs+@te
rm+@rn+91-20-3)+@NOT+@org+pubmed+pubdart+crisp+tscats
@OR+("camphor+tar"+"tar+camphor"+"white+tar"+"moth+balls"+"moth+flakes")+@NOT+@org+
pubmed+pubdart+crisp+tscats
Toxic Substances Control Act Test Submissions (TSCATS) via CDATa
01/04/2017
91-20-3
Mail Received Date Range 10/01/2015 to 01/04/2017
11/04/2015
91-20-3
Mail Received Date Range 01/01/2014 to 11/04/2015
TSCATS 2b
01/04/2017
91-20-3
EPA receipt date 10/01/2015 to date of search
12/16/2014
91-20-3
EPA receipt date 02/01/2013 to date of search
05/01/2013
91-20-3 date limited, 2000 to date of search
TSCATS lc
02/18/2013
@term+@rn+91-20-3+@AND+@org+tscats
TSCA8e/FYI recent submissions'*
01/04/2017
Google: 91-20-3 (8e or fyi) tsca
12/16/2014
Google: 91-20-3 (8e or fyi) tsca
05/01/2013
Google: 91-20-3 (8e or fyi) tsca
aCDAT (Chemical Data Access Tool); formerly available at http://iava.epa.gov/oppt chemical search/. Information from CDAT
has since been incorporated into EPA's ChemView database at https://chemview.epa.gov/chemview.
bTSCATS 2 was searched via the following database URL: https://www.epa.gov/assessing-and-managing-chemicals-under-
tsca/introduction-chemview.
CTSCATS 1 was searched via TOXLINE.
dTSCA section 8e/FYI recent submissions were searched via Google.
44
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Table B-2. Processes used to augment the search of core databases for na
phthalene.
System used
Selected reference(s) or sources
Date
Additional
references
identified
Manual search
of citations
from published
reviews
Bailey et al. (2015). "Hypothesis-based weight-of-evidence
evaluation and risk assessment for naphthalene carcinogenesis."
Critical Reviews in Toxicology: 1-42.
httpsi//doi.org/10.3109/10403444.2015.1061477
Lewis (2012). "Naphthalene animal carcinogenicity and human
relevancy: overview of industries with naphthalene-containing
streams." Regulatory Toxicology and Pharmacology 62(1): 131-
137. https://doi.Org/10.1016/i.vrtph.2011.12.004
Piccirillo et al. (2012). "Preliminary evaluation of the human
relevance of respiratory tumors observed in rodents exposed to
naphthalene." Regulatory Toxicology and Pharmacology 62(3):
433-440. https://doi.Org/10.1016/i.Yrtph.2012.01.008
Magee et al. (2010). "Screening-level population risk assessment
of nasal tumors in the US due to naphthalene exposure."
Regulatory Toxicology and Pharmacology 57(2-3): 168-180.
Rhomberg et al. (2010). "Hypothesis-based weight of evidence: a
tool for evaluating and communicating uncertainties and
inconsistencies in the large body of evidence in proposing a
carcinogenic mode of action-naphthalene as an example."
Critical Reviews in Toxicology 40(8): 671-696.
12/2015
12/2015
12/2015
12/2015
12/2015
12 citations added
1 citation added
0 citations added
0 citations added
0 citations added
Manual search
of citations
from national
and
international
health agency
documents
NTP (2016). Naphthalene (14th ed.). Research Triangle Park, NC:
National Toxicology Program, https://ntp.niehs.nih.gov/ntp/
roc/content/profiles/naphthalene.pdf
ACGIH (2001). Naphthalene. Documentation of the threshold
limit values and biological exposure indices. Cincinnati, OH:
American Conference of Industrial Hygienists.
https://www.acgih.org/science/tlv-bei-guidelines/
ATSDR (2005). Toxicological Profile for Naphthalene, 1-
Methylnaphthalene, and 2-Methylnaphthalene. Atlanta, GA:
Agency for Toxic Substances and Disease Registry.
https://www.atsdr.cdc.gov/toxprofiles/tp67.pdf
IARC (2002). IARC Monographs on the evaluation of the
carcinogenic risk of chemicals to humans: Some traditional herbal
medicines, some mycotoxins, naphthalene, and styrene [IARC
Monograph], Lyon, France.
http://monographs.iarc.fr/ENG/lV1onographs/vol32/niono82.pdf
1/2017
5/2013
5/2013
5/2013
0 citations added
4 citations added
7 citations added
3 citations added
NTP (2011). Naphthalene. In Report on Carcinogens, 12th Edition.
National Toxicology Program.
https://ntp.niehs.nih.gov/whatwestydy/assessments/cancer/roc/
index.html
WHO (1998). Selected non-heterocyclic polycyclic aromatic
hydrocarbons. Environmental Health Criteria, 202. Geneva,
Switzerland, World Health Organization.
https://apps.who.int/iris/handle/10665/41953
5/2013
5/2013
0 citations added
2 citations added
45
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Additional
references
System used
Selected reference(s) or sources
Date
identified
Web of
Abdo et al. (2001). Toxicity and carcinogenicity study in F344 rats
1/2017
0 citations added
Science,
following 2 years of whole-body exposure to naphthalene vapors.
5/2013
0 citations added
"forward"
Inhalation Toxicology 13:931-950.
search3
httDs://doi,org/10,1080/089583701752378179
Dodd et al. (2012). Nasal epithelial lesions in F344 rats following a
1/2017
0 citations added
90-day inhalation exposure to naphthalene. Inhalation Toxicology
5/2013
0 citations added
24:70-79. https://doi.org/10.3109/08958378.2011.636086
Shopp et al. (1984). Naphthalene toxicity in CD-I mice: general
1/2017
0 citations added
toxicology and immunotoxicology. Toxicological Sciences 4:406-
5/2013
0 citations added
419. httDs://doi.org/10.1016/0272-0590(84)90198-2
Web of
Abdo et al. (2001). Toxicity and carcinogenicity study in F344 rats
5/2013
2 citations added
Science,
following 2 years of whole-body exposure to naphthalene vapors.
"backward"
Inhalation Toxicology 13:931-950.
searchb
https://doi.org/10.1080/089583701752378179
Dodd et al. (2012). Nasal epithelial lesions in F344 rats following a
5/2013
0 citations added
90-day inhalation exposure to naphthalene. Inhalation Toxicology
24:70-79. htt»s://doi,org/10,3109/08958378,2011,636086
Shopp et al. (1984). Naphthalene toxicity in CD-I mice: general
5/2013
5 citations added
toxicology and immunotoxicology. Toxicological Sciences 4:406-
419. httDs://doi.org/10.1016/0272-0590(84)90198-2
References
References that had been previously added to the HERO project
3/2017
2 citations added
obtained
page for the naphthalene assessment during the development of
1/2017
9 citations added
during the
earlier draft materials.
12/2015
22 citations added
assessment
5/2013
36 citations added
process
Search of
Searched a combination of CASRNs and synonyms on the
1/2017
1 citation added
Online
following databases:
12/2015
13 citations added
Chemical
American Conference of Governmental Industrial Hygienists
4/2012
19 citations added
Assessment-
(ACGIH): https://www.acgih.org/
Related
American Industrial Hygiene Association (AIHA):
Websites
Workplace Environmental Exposure Levels (WEELs)
(https://www.tera.org/OARS/PDF documents/OARS WEEL T
able.pdf)
Emergency Response Planning Guidelines (ERPGs)
(https://www.aiha.org/get-
involved/AIHAGuidelineFoundation/EmergencyResponsePlan
ningGuidelines/Pages/defaultaspx)
Agency for Toxic Substances and Disease Registry (ATSDR):
https://wwwn.cdc.gov/TSP/index.aspx
CalEPA Office of Environmental Health Hazard Assessment
(OEHHA): http://www.oehha.ca.gov/risk.html
OEHHA Toxicity Criteria Database
(http://www.oehha.ca.gov/tcdb/index.asp)
Biomonitoring California-Priority Chemicals
(https://biomonitoring.ca.gov/chemicals/priority-chemicals)
Biomonitoring California-Designated Chemicals
(https://biomonitoring.ca.gov/chemicals/designated-
chemicals)
46
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
System used
Selected reference(s) or sources
Date
Additional
references
identified
Cal/Ecotox Database (httpsi//ecotox,oehha.ca.gov/)
OEHHA Fact Sheets
(http://www.oehha.ca.gov/pubIic info/facts/index.html)
Non-cancer health effects [reference exposure levels (RELs)]
(http://www.oehha.ca.gov/air/allrels.html)
Cancer Potency Factors (Appendix A and B)
(http://www.oehha.ca.gov/air/hot spots/tsd052909,html)
Consumer Product Safety Commission (CPSC):
http://www.cpsc.gov
Centre for Chemical Safety Assessment (ECETOC):
http://www.ecetoc.org/publications
European Chemicals Agency (ECHA):
General site (http://echa.europa.eu/information-on-
chemicals)
Registered Substances (https://echa.europa.eu/information-
on-chemicals)
Existing Substances Regulation (ESR)
(http://echa.europa.eu/information-on-
chemicals/information-from-existing-substances-regulation)
Environment Canada:
Toxic Substances Managed Under Canadian Environmental
Protection Act (http://www.ec.gc.ca/toxiques-
toxics/Default.asp?lang=En&n=98E80CC6-l)
Final Assessments (http://www.ec.gc.ca/lcpe-
cepa/default,asp?lang=En&xml=09F567A7-BlEE-lFEE-73DB-
8AE6C1EB7658)
Draft Assessments (http://www.ec.gc.ca/lcpe-
cepa/default,asp?lang=En&xml=6892C255-5597-C162-95FC-
4B905320F8C9)
Federal Docket: www.regulations.gov
Health Canada:
Health Canada Drinking Water Documents (http://www.hc-
sc,gc,ca/ewh-semt/pubs/water-eau/index-eng,php#tech doc)
Health Canada First Priority List Assessments (http://www.hc-
sc.gc.ca/ewh-semt/pubs/contaminants/psll-lspl/index-
eng.php)
Health Canada Second Priority List Assessments
(http://www.hc-sc.gc.ca/ewh-semt/pubs/contaminants/psl2-
Isp2/index~eng,php)
International Agency for Research on Cancer (IARC):
http://monographs.iarc.fr/ENG/Monographs/voll01/monol01-
B02-B03.pdf
International Toxicity Estimates for Risk (ITER):
https://iter.tera.org/
Japan Existing Chemical Data Base:
http://dra4.nihs.go.jp/mhlw data/isp/SearchPageENG.jsp
National Academies of Sciences, Engineering, and Medicine
(NASEM): http://www.nap.edu/
47
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
System used
Selected reference(s) or sources
Date
Additional
references
identified
National Cancer Institute (NCI): httpi//www,cancer.gov
National Industrial Chemicals Notification and Assessment
Scheme (NICNAS) (Australia):
Australian Inventory of Chemical Substances (AICS)
(http://www.cirs-
reach.com/lnventorv/Australian Inventory of Chemical Sub
stances AICS.html)
National Institute of Environmental Health Sciences (NIEHS):
http://www.niehs.nih.gov/
National Institute of Occupational Safety and Health (NIOSH):
All Workplace Safety & Health Topics
(http://www.cdc.gov/niosh/topics/)
NIOSHTIC 2 Publications Search:
http://www2a.cdc.gov/nioshtic-2/
Registry of Toxic Effects of Chemical Substances
(https://www.cdc.gov/niosh/rtecs/default.html)
National Institute of Technology and Evaluation Chemical Risk
Information Platform (NITE-CHIRP) (Japan):
http://www.safe.nite.go.ip/english/db.html
National Toxicology Program (NTP):
Report on Carcinogens (RoC)
(https://ntp.niehs.nih.gov/whatwestudy/assessments/cancer
/roc/index.html)
NTP Site Search (https://ntpsearch.niehs.nih.gov/)
Occupational Safety and Health Administration (OSHA):
http://www.osha.gov/dts/chemicalsampling/toc/toc chemsamp.
html
Organisation for Economic Cooperation and Development
(OECD)c:
eChemPortal
(https://www.echemportal.org/echemportal/substance-
search)
OECD Existing Chemicals Database
(https://hpvchemicals.oecd.org/ui/Search.aspx)
U.S. Environmental Protection Agency (EPA):
Acute Exposure Guideline Levels
(https://www.epa.gov/aegl/access-acute-exposure-guideline-
levels-aegls-values#chemicals)
Integrated Risk Information System (IRIS)
(http://www.epa.g0v/i ris/1
National Service Center for Environmental Publications
(NSCEP) (https://www.epa.gov/nscep)
RfD/RfC and Carcinogen Risk Assessment Verification
Endeavor (CRAVE) meeting notes
Science Inventory (http://cfpub.epa.gov/si/)
High Production Volume Information System (HPVIS)
(https://catalog.data.gov/dataset/high-production-volume-
information-system-hpvis)
48
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
System used
Selected reference(s) or sources
Date
Additional
references
identified
Chemical Data Access Tool (formerly available at
http://iava.epa.gov/oppt chemical search/; information
from CDAT has been incorporated into EPA's ChemView
database at https://chemview.epa.gov/chemview)
Office of Pesticide Programs
(http://iaspub.epa.gov/apex/pesticides/f?p=chemicalsearch:l
)
U.S. Food and Drug Administration (FDA): http://www.fda.gov/
National Center for Toxicological Research (NCTR)
(http://www.fda.gov/AboutFDA/CentersOffices/OC/OfficeofS
cientificand Medical Programs/NCTR/default, htm)
a"Forward" search for records that cite included studies.
b"Backward" search for records cited by included studies.
Searched for OECD High Production Volume (HPV) chemicals, Screening Information Dataset (SIDS) International Uniform
Chemicals Information Database (IUCLID), and SIDS United Nations Environment Programme (UNEP).
49
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Electronic screening strategy
For literature searches conducted through November 2015, all identified records were first
electronically screened with a set of terms intended to prioritize "on-topic" references for title and
abstract review. The electronic screening process creates two broad categories: one comprising all
records that contain (in title, abstract, or keywords) at least one inclusion/exclusion term (listed in Table
B-3) related to health outcomes, epidemiological or toxicological study design, toxicokinetics, or
mechanistic information, and one that does not contain any of the terms. Some of the electronic
inclusion/exclusion terms are generic (i.e., not chemical specific) and are intended to capture health
effect studies of any type. Other terms are specific to naphthalene and are based on previous
knowledge of health effects and possible mechanisms of toxicity. Records that contained at least one
inclusion/exclusion term were moved forward for title and abstract screening.
Citations that did not contain at least one inclusion/exclusion term in Table B-3 were subjected to a
quality control check to verify that relevant references are not missed. Specifically, a random sample
(~10%) of the electronically excluded citations were subjected to title/abstract review by a scientist
(toxicologist or epidemiologist) to confirm that the electronic screening process produced acceptable
results (i.e., no relevant citations were inadvertently missed). If the random sample contained at least
one potentially relevant citation, the list of electronic screening terms was revised to add terms
pertaining to the missing citation, and the electronic screening process was repeated. This quality
control and revision process was repeated as many times as necessary to ensure that relevant studies
are retained for title/abstract screening. Citations that did not contain at least one inclusion/exclusion
term were excluded from further review.
50
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Table B-3. Electronic screening inclusion terms for naphthalene (listed alphabetically by organ/health system).
Category
Terms
Organ/health system specific terms
Cardiovascular
angio
blood AND vessel
endotheli
thrombus
aort
capillar
heart
valve
arrhythm
cardiac, cardio, cardium
hypertens
vascular, vaso
artery, arteri
circulat
infarct
vein, venous
blood AND pressure
coronary
myocardi
ventricle
Dermal/
blister
epiderm, epidermal
nail
sweat, perspiration
integumentary
bulla, bullous
erythema
pruritus
tooth, teeth
system
cutaneous
hair
sebaceous
dermal, dermis
keratin, kerato
skin
Developmental
abnormalit
fetal, fetus, foetal, foetus
parturition
terato
abort
gestation
perinatal
uterus, uterine
cleft
implantation
postnatal
viable, viabil
congenital
malform
puberty
visceral
defect
neonat
pregnan
wean
development
newborn
prenatal
zygote
embryo
neural AND tube
resorption
Endocrine
adipokine
hypothalamus
pituitary
thyro
adipocyt
insulin
triiodo
adrenal
pancreas, pancreat
tetraiodo
hormone
pineal
thymus, thymic
Gastrointestinal
abdomen
constipation
gastrointestinal
peptic
anus, anal
diarrhea
ileum, ileal, ileus
rectum, rectal
bucca
digestive
intestin
salivary
bowel
duoden
jejunum, jejunal
stomach
cecum, cecal
esophagus
mouth
tongue
colon
gastric
oral AND cavity
51
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Category
Terms
Organ/health system specific terms
Hematologic
albumin
cytopenia
histamine
RBC (red blood cell)
anemia, anemic, anaemia, anaemic
erythro
hypoxemi
reticulocyt
blood
hemoly, haemoly
granulocyt
serum
cholesterol
hemat
plasma
thrombo
clot
hemocoagulat
platelet
coagulat
hemoglobin
polycythemia
Hepatic
alkaline AND phosphatase
cholesta
glutamyltransferase
liver
aminotransferase
cholangio
hepat
peroxisome
bile, biliary
cirrho
hydropic
portal, periportal
bilirubin
gall AND bladder
Ito
steatosis
centrilobular
glycogen
Kuppfer
stellate
Immune
adenopath
complement
inflamm
monocyt
allerg
dendrocyt, dendritic
interferon
natural AND killer
anaphyla
eosinophil, eosinopenia
leukocyt
neutrophil, neutropenia
antibod
epitope
lymph
phagocyt
antigen
globulin
macrophag
polymorphonuclear
asthma
granuloma
major histocompatibility complex,
sensitize, sensitis
basophil, basopenia
hapten
MHC
sensitivity
B-cell
humoral
marrow
spleen, splenous
cytokine
hypersensit
mast AND cell
WBC (white blood cell)
chemokine
immun
macroglobulin
T-cell
Musculoskeletal
articular
cartilage
muscle, muscul
tendon
bone
collagen
osteo
vertebra
bursa
connective
pyridinoline
calcitonin
ligament
skelet
52
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Category
Terms
Organ/health system specific terms
Nervous
autonomic
efferent
memory
PNS (peripheral nervous
axon
electrophysiol
myelin AND sheath
system)
behavior, behaviour
encephalo
locomotor
Ranvier
brain
fatigue
nerve
Schwann
CNS (central nervous system)
FOB (functional observational
nervous AND system
sensory, sensori
Cognitive
battery)
neuro
spinal AND cord
dendrite
ganglia, ganglio
parasympathetic
sympathetic
synap
Ocular
cataract
harderian
ocular
cornea
lachrymal, lacrimal
ophthalm
eye
lens, lenticular
retina
Reproductive
androgen
fertilit
ova, ovum
seminiferous
breast
follicle
penis
sexual
cervical, cervix
FSH
placenta
sperm
coagulating AND gland
gamete
primordial
sterility
corpora lutea, corpus luteum
gonad
progesterone
testes, testic, testis
endometrium
infertility
prolactin
testosterone
epididym
lacto, lacta
prostate
urogenital
estrogen, estradiol
LH (luteinizing hormone)
reproduct
vagina
estrus, estrous
lordosis
scrotum
vulva
fallopian
mammar
seminal AND vesicle
Respiratory
airway
cough
intratrach
pharyn
alveolar
crackle
laryn
pneumon
BAL (bronchoalveolar lavage)
diffusing AND capacity
lung
pulmonary
bleb
dyspnea
nasal
rale
bronch
FEV, forced AND expiratory
nose
respir
chest
FVC, forced AND vital
olfactory
trach
53
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Category
Terms
Organ/health system specific terms
Urinary
alpha 2u globulin
creatinine
kidney
urethra
anion AND gap
dilation, dilatation
nephro
uria
BUN
genitourinary
proximal AND tubule, distal AND
urinalysis
bladder
glomerul
tubule
urinary
Bowman's
Henle
renal
urine
54
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Appendix C: Dose Response BMD Modeling Results
Standardized Pearson's residuals were calculated to determine whether combining data across sexes
and strains of rats was appropriate. With categorical data (of which dichotomous data are a special
case), Pearson's residuals can be used to compare observed and expected incidence data. Because the
question under consideration is whether individual datasets can be combined, the "expected" counts
can be estimated using the proportion of animals responding in the combined dataset. The Pearson
residual is calculated as:
yt — riiiZi
Pearson residual = e,= ;
UiTTiil - TTi)
where yt is the observed incidence in the individual dataset, n; is the number of animals per dose group
in the individual dataset, and nis the proportion of animals responding per dose group in the combined
dataset. The product of n; and is the expected count within individual dose groups in an individual
dataset. See Tables C-l through C-3 below for Pearson's residuals for combining within and across
strains of rats. When interpreting Pearson's residuals, an absolute value of 2 or 3 (121 or 13 |) indicates
lack of fit (Agresti, 2007), or in this case, provided evidence that the observed data in the individual
datasets is inconsistent with the data in the combined dataset and therefore modeling should not be
conducted using the combined data.
Assuming that the combined data (across male and female rats within a strain and then across F344 and
Sprague-Dawley rats) represents the true proportion of animals expected to respond to exposure to
naphthalene (i.e., the expectation that the same proportion will respond for a given dose in any dataset,
individual or combined), comparisons with the individual datasets can be made to determine whether
any are sufficiently different to warrant not combining the data. Within strains of rats, F344 rats had
lower or equivalent Pearson's residuals compared with Sprague-Dawley rats. Given that the largest
residual when comparing within strains was 10.751 in control Sprague-Dawley rats (based on an
expected value of 1/10 when the observed data were either 0/5 or 1/5) or F344 rats exposed to
0.348 ng/mL/min (based on an expected value of 9/10 when the observed data were either 5/5 or 4/5),
it was deemed appropriate to combine male and female data within strains since no Pearson's residual
had an absolute value exceeding 2. For determining whether it was appropriate to combine the male
and female data across strains (i.e., combine all data together), Pearson's residuals for the combined
Sprague-Dawley and combined F344 rats were compared with the dataset in which all data were
combined. Pearson's residuals were larger for testing combination of datasets across strains than those
testing combination within strains. For comparing Sprague-Dawley or F344 rats with the combined
dataset, none of the absolute Pearson's residuals exceeded 2 (the largest absolute residual being 11.831
in the 0.096 ng/mL/min dose group, based on an expected incidence of 17/20 when the observed data
were either 5/10 for Sprague-Dawley rats or 0/10 for F344 rats). Given that the absolute Pearson's
residuals were less than 2 in all dose groups and that increasing the sample size per dose group allows
for more accurate estimation of model parameters (and therefore BMD and BMDL values), all acute RfC
derivations in this assessment were based on the combined male and female Sprague-Dawley and
F344 data.
55
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Table C-l. Incidence of olfactory epithelial necrosis in male and female Sprague-Dawley rats and
Pearson's residuals.
Dose (ng/mL)
0
45.41
137.7
500.8
3773
5884
Sprague-Dawley males
N
5
5
5
5
5
5
Incidence
0
2
3
4
5
5
Expected3
0.5
1.5
2.5
4
5
5
Residual
-0.7454
0.4880
0.447
0
0
0
Sprague-Dawley females
N
5
5
5
5
5
5
Incidence
1
1
2
4
5
5
Expected3
0.5
1.5
2.5
4
5
5
Residual
0.7454
-0.4880
-0.4472
0
0
0
Combined Sprague-Dawley rats
Nb
10
10
10
10
10
10
Incidence0
1
3
5
8
10
10
Proportion responding01
0.1
0.3
0.5
0.8
1
1
aExpected value = N x proportion responding (from combined dataset).
bSum of dose-group specific Ns for individual datasets.
cSum of dose-group-specific incidence values for individual datasets.
Proportion responding = combined incidence 4- combined N.
Table C-2. Incidence of olfactory epithelial necrosis in male and female F344 rats and Pearson's
residuals.
Dose (|ig/mL)
0
45.41
137.7
500.8
3773
5884
F344 males
N
5
5
5
5
5
5
Incidence
0
0
0
5
5
5
Non-parametric expected3
0
0
0
4.5
5
5
Non-parametric residual
0
0
0
0.7454
0
0
F344 females
N
5
5
5
5
5
5
Incidence
0
0
0
4
5
5
Non-parametric expected3
0
0
0
4.5
5
5
Non-parametric residual
0
0
0
-0.7454
0
0
Combined F344 rats
Nb
10
10
10
10
10
10
Incidence0
0
0
0
9
10
10
Proportion responding01
0
0
0
0.9
1
1
aExpected value = N x proportion responding (from combined dataset).
bSum of dose-group specific Ns for individual datasets.
cSum of dose-group-specific incidence values for individual datasets.
Proportion responding = combined incidence 4 combined N.
56
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Table C-3. Incidence of olfactory epithelial necrosis in Sprague-Dawley and F344 rats (combined sexes)
and Pearson's residuals.
Dose (|ig/mL)
0
45.41
137.7
500.8
3773
5884
Sprague-Dawley combined
N
10
10
10
10
10
10
Incidence
1
3
5
8
10
10
Expected3
0.5
1.5
2.5
8.5
10
10
Residual
0.7255
1.3284
1.8257
-0.4428
0
0
F344 combined
N
10
10
10
10
10
10
Incidence
0
0
0
9
10
10
Expected3
0.5
1.5
2.5
8.5
10
10
Residual
-0.7255
-1.3284
-1.8257
0.4428
0
0
All rats combined
Nb
20
20
20
20
20
20
Incidence0
1
3
5
17
20
20
Proportion responding01
0.05
0.15
0.25
0.85
1
1
aExpected value = N x Proportion responding (from combined dataset).
bSum of dose-group specific Ns for individual datasets.
cSum of dose-group-specific Incidence values for individual datasets.
Proportion Responding = Combined Incidence 4- Combined N.
57
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Table C-4. Olfactory epithelial necrosis - male and female Sprague-Dawley and F344 rats. Table 3 in
the main text shows the relationship between the nominal doses (ppm) and actual doses (ppm) applied
to the rats and the cumulative metabolite production in DO tissue values (ug/mL) estimated using the
PBPK model. The latter values appear in the "Dose" column here.
Dose
N
Incidence
0
20
1
44.19
20
3
134.09
20
5
488.2
20
17
3721
20
20
5847
20
20
Nominal3 dose
(ppm)
Cumulative metabolite production in
DO tissue (jig/mL)
0.1
44.19
0.3
134.1
1.0
488.2
10.0
3721
30.0
5847
aActual doses were 0.095, 0.29,1.085,11.95, and 29.6 ppm.
Table C-5. Benchmark dose results for olfactory epithelial necrosis in male and female Sprague-
Dawley and F344 rats.
Models
Restriction
10% extra risk
P-
value
AIC
BMDS classification
BMDS
notes
BMD
BMDL
BMDU
Dichotomous Hill
Restricted
95.0738
37.9190
295.0051
0.8266
71.1829
Viable-Alternate
Gamma
Restricted
72.1715
26.3725
212.3970
0.8885
70.8664
Viable-Alternate
Log-Logistic
Restricted
95.0440
37.9192
295.0131
0.8266
71.1829
Viable-Alternate
Multistage Degree 5
Restricted
58.6531
27.6433
210.9806
0.9885
70.3741
Viable-Alternate
Multistage Degree 4
Restricted
58.6452
27.6399
210.0405
0.9883
70.3757
Viable-Alternate
Multistage Degree 3
Restricted
59.0147
27.5737
201.0609
0.9274
72.3983
Viable-Alternate
Multistage Degree 2
Restricted
64.3106
27.2461
143.4648
0.9654
70.5148
Viable-Alternate
Multistage Degree 1
Restricted
34.8317
24.1995
53.3809
0.7942
70.0399
Viable - Recommended
Lowest
BMDL
Weibull
Unrestricted
70.6955
26.7373
128.8500
0.9239
70.7125
Viable-Alternate
Logistic
Unrestricted
96.3809
69.2465
133.1277
0.9690
68.8480
Viable-Alternate
Log-Pro bit
Unrestricted
101.1033
35.7685
367.4934
0.7919
71.3009
Viable-Alternate
Probit
Unrestricted
101.4855
78.4935
133.4415
0.4915
71.5232
Viable-Alternate
58
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
User Input
Info
Model
frequentist Multistage degree 1 vl.l
Dataset Name
OlfEpi grouped Jan2022
User notes
[Add user notes here]
Dose-Response Model
P[dose] = g + (l-g)*[l-exp(-bl*doseAl-b2*doseA2 -...)]
Model Options
Risk Type
Extra Risk
BMR
0.1
Confidence Level
0.95
Background
Estimated
Model Data
Dependent Variable
[Custom]
Independent Variable
[Custom]
Total # of Observations
6
Model Results
Benchmark Dose
BMD
34.8316515
BMDL
24.19948893
BMDU
53.38087081
AIC
70.03986512
P-value
0.794223048
D.O.F.
4
r- L.-2
Chi
1.680685597
Slope Factor
0.004132319
Model Parameters
# of Parameters
2
Variable
Estimate
g
0.039218292
bl
0.00302485
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.039218292
0.784365832
1
20
0.2483967
44.19
0.15943094
3.188618809
3
20
-0.1152118
134.09
0.359566619
7.191332372
5
20
-1.021096
488.2
0.780573901
15.61147802
17
20
0.7502165
3721
0.999987571
19.99975142
20
20
0.0157665
5847
0.99999998
19.9999996
20
20
0.0006328
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-32.12537127
6
-
-
NA
Fitted Model
-33.01993256
2
1.78912258
4
0.7744718
Reduced Model
-82.57665765
1
100.902573
5
<0.0001
59
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Frequentist Multistage Degree 1 Model with BMR of 10% Extra Risk for the BMD and
0.95 Lower Confidence Limit for the BMDL
<9-
€>
¦ Estimated Probability
•Response at BMD
» Linear Extrapolation
Data
•BMD
-BMDL
3000
Dose
Figure C-l. Dose-response curve for the Multistage Degree 1 model fit to olfactory epithelial necrosis
in male and female Sprague-Dawley and F344 rats.
Frequentist Multistage Degree 1 Model with BMR of 10% Extra Risk for the BMD and
0.95 Lower Confidence Limit for the BMDL
()
X <
)
Estimated Probability
Response at BMD
• — — Linear Extrapolation
O Data
BMD
BMDL
Dose
Figure C-2. Dose-response curve for the Multistage Degree 1 model fit (low-dose range) to olfactory
epithelial necrosis in male and female Sprague-Dawley and F344 rats.
60
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Appendix D: PBPK Model Implementation File
#
# naph_pbtk_pde.model
#
# Author: Dustin Kapraun, US EPA, November 2018
#
# This code implements a physiologically based pharmacokinetic (PBPK) model for
# naphthalene. It includes all of the components of the computational fluid
# dynamics (CED) and PBPK model of Campbell et al. (2014), but also incorporates
# skin conponents based upon a partial differential equation model for
# diffusion.
#
# The following abbreviations, which were used in the original ACSL code for the
# Campbell et al. (2014) model provided by JL Cambell, are used in variable
# names and in comments throughout this code.
# L = Lumen DO = Dorsal Olfactory
# T = Tissue DR = Dorsal Respiratory
# X = Blood Exchange Region VR = Ventral Respiratory
# L or LI = Liver PP = Poorly Perfused
# PU or LU = Lung RP = Richly Perfused
# FA = Fat AB = Arterial Blood
# VB = Venous Blood
#
# In addition to these, we use the following abbreviations for expressions
# related to skin compartments.
# SC = Stratum Corneum
# VE = Viable Epidermis
#
# Implementation Notes:
# - Setting AEXP to zero ensures skin components of the model are inactive,
# while setting AEXP to a nonzero value ensures skin conponents of the model
# are active.
# - Setting VWELL to zero when AEXP is nonzero ensures skin components of the
# model are active, but enforces a zero flux boundary condition at the outer
# surface of the stratum corneum.
#
# References:
# JL Campbell, ME Andersen, HJ Clewell (2014) , "A hybrid CFD-PBPK model for
# naphthalene in rat and human with IVIVE for nasal tissue metabolism and
# cross-species dosimetry," Inhalation Toxicology 26(6), 333-344.
#
# D Kim, ME Andersen, LA Nylander-French (2006), "A dermatotoxicokinetic model
# of human exposures to jet fuel," Toxicological Sciences 93(1) , 22-23.
#
# D Kim (2006), Toxicokinetic Models of Dermal Exposure to Jet Fuel, PhD
# Dissertation, University of North Carolina at Chapel Hill.
#
# D Kim, ME Andersen, Y-CE Chao, PP Egeghy, SM Rappaport, LA Nylander-French
# (2007), "PBTK Modeling Demonstrates Contribution of Dermal and Inhalation
# Exposure Components to End-Exhaled Breath Concentrations of Naphthalene,"
# Environmental Health Perspectives 115(6), 894-901.
#
# KD McCarley, AL Bunge (2001), "Pharmacokinetic Models of Dermal Absorption,"
# Journal of Pharmaceutical Sciences 90(11), 1699-1719.
#
#
# STATE VARIABLES for the model (for which ODEs are provided in the DYNAMICS
# section).
61
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
States = {
RIV, # Rate of intravenous dosing (nmol/min).
AIV, # Total amount provided intravenously (nmol) .
CIN, # Concentration in ambient air (nmol/mL) .
AWELL, # Total amount in skin exposure well (nmol).
CSC01, # Concentration in stratum corneum at depth 1 (nmol/mL).
CSC02, # Concentration in stratum corneum at depth 2 (nmol/mL).
CSC03, # Concentration in stratum corneum at depth 3 (nmol/mL).
CSC04, # Concentration in stratum corneum at depth 4 (nmol/mL).
CSC05, # Concentration in stratum corneum at depth 5 (nmol/mL).
CSC06, # Concentration in stratum corneum at depth 6 (nmol/mL).
CSC07, # Concentration in stratum corneum at depth 7 (nmol/mL).
CSC08, # Concentration in stratum corneum at depth 8 (nmol/mL).
CSC09, # Concentration in stratum corneum at depth 9 (nmol/mL).
ADERM, # Total amount absorbed through skin (nmol).
ALDR, # Amount in dorsal respiratory lumen (nmol).
AMTDR, # Total amount metabolized in DR tissue (nmol).
ATDR, # Amount in dorsal respiratory tissue (nmol).
AXDR, # Amount in dorsal respiratory blood exchange area (nmol).
ALDOl, # Amount in anterior dorsal olfactory lumen (nmol).
AMTOl, # Total amount metabolized in anterior DO tissue (nmol).
ATDOl, # Amount in anterior dorsal olfactory tissue (nmol).
AXDOl, # Amount in anterior DO blood exchange area (nmol) .
ALD02, # Amount in posterior dorsal olfactory lumen (nmol).
AMT02, # Total amount metabolized in posterior DO tissue (nmol).
ATD02, # Amount in posterior dorsal olfactory tissue (nmol).
AXD02, # Amount in posterior DO blood exchange area (nmol).
ALVR1, # Amount in anterior ventral respiratory lumen (nmol).
AMTV1, # Total amount metabolized in anterior VR tissue (nmol).
ATVR1, # Amount in anterior ventral respiratory tissue (nmol).
AXVR1, # Amount in anterior VR blood exchange area (nmol).
ALVR2, # Amount in posterior ventral respiratory lumen (nmol).
AMTV2, # Total amount metabolized in posterior VR tissue (nmol).
ATVR2, # Amount in posterior ventral respiratory tissue (nmol).
AXVR2, # Amount in posterior VR blood exchange area (nmol) .
ALPL, # Amount in pharynx and larynx lumen (nmol).
ATPL, # Amount in pharynx and larynx tissue (nmol).
AXPL, # Amount in pharynx and larynx blood exchange area (nmol).
ALCA, # Amount in conducting airways lumen (nmol).
ATCA, # Amount in conducting airways tissue (nmol).
AXCA, # Amount in conducting airways blood exchange area (nmol).
AMLPU, # Total amount metabolized in pulmonary tissue (nmol).
ATPU, # Amount in pulmonary tissue (nmol).
AML, # Total amount metabolized in liver tissue (nmol).
ALI, # Amount in liver tissue (nmol).
AFA, # Amount in fat tissue (nmol).
ARP, # Amount in richly perfused tissue (nmol).
APP, # Amount in poorly perfused tissue (nmol).
AVE, # Amount in viable epidermis (nmol).
AAB, # Amount in arterial blood (nmol).
AVB, # Amount in venous blood (nmol).
AIN, # Net amount that has entered the organism (nmol).
AUC_CAB_UG, # AUC for arterial blood concentration(ug/mL*min).
AUC_CTDO_UG, # AUC for DO tissue concentration (ug/mL*min).
CMTDO_UG, # Concentration of metabolite in DO tissue (ug/mL).
AUC_CMTDO_UG, # AUC for metabolite in DO tissue (ug/mL*min).
AUC_RCMTDO_UG, # AUC for rate of production of metabolite in DO per unit
# volume (ug/mL).
CMBODY_UG, # Concentration of metabolite in whole body (ug/mL).
AUC_CMBODY_UG, # AUC for metabolite in whole body (ug/mL*min).
AUC_RCMBODY_UG, # AUC for rate of production of metabolite in whole body per
# unit body mass (ug/kg).
62
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
CTDOALT_UG, # Concentration (alternate) in DO tissue (ug/mL).
AUC_CTDOALT_UG, # AUC for conc. (alt) in DO tissue (um/mL*min).
AUC_RDELDO_UG, # AUC for rate of delivery to DO tissue per unit area
# (ug/cmA2) .
} ;
# End of STATE VARIABILES.
#
#
# OUTPUT VARIABILES for the model (which are computed in the DYNAMICS section
# as analytic functions of state variables, inputs, and parameters).
Outputs
= {
ASC,
# Total amount in stratum corneum (nmol).
CWELL,
#
Concentration in skin exposure well (nmol/mL).
CSCOO,
#
... at outer surface of stratum corneum.
CSC10,
#
... at interface of SC with VE.
CLDR,
# .
.. in dorsal respiratory lumen (nmol/mL).
CTDR,
# .
.. in dorsal respiratory tissue (nmol/mL).
CXDR,
# .
.. in DR blood exchange area (nmol/mL).
CLDOl,
#
... in anterior dorsal olfactory lumen (nmol/mL).
CTDOl,
#
... in anterior dorsal olfactory tissue (nmol/mL).
CXDOl,
#
... in anterior DO blood exchange area (nmol/mL).
CLD02,
#
... in posterior dorsal olfactory lumen (nmol/mL).
CTD02,
#
... in posterior dorsal olfactory tissue (nmol/mL).
CXD02,
#
... in posterior DO blood exchange area (nmol/mL).
CLVR1,
#
... in anterior ventral respiratory lumen (nmol/mL).
CTVR1,
#
... in anterior ventral respiratory tissue (nmol/mL).
CXVR1,
#
... in anterior VR blood exchange area (nmol/mL).
CURT,
#
.. in the upper respiratory tract (nmol/mL).
CLPL,
#
. . in pharynx and larynx lumen (nmol/mL) .
CTPL,
#
.. in pharynx and larynx tissue (nmol/mL).
CXPL,
#
.. in PL blood exchange area (nmol/mL).
CLCA,
#
.. in conducting airways lumen (nmol/mL).
CTCA,
#
.. in conducting airways tissue (nmol/mL).
CXCA,
#
.. in CA blood exchange area (nmol/mL).
CLPU,
#
.. in pulmonary lumen (nmol/mL).
CTPU,
#
.. in pulmonary tissue (nmol/mL).
CvTPU,
#
... in veins leaving pulmonary tissue (nmol/mL).
CLI,
# .
. in liver tissue (nmol/mL).
CvLI,
#
.. in veins leaving liver tissue (nmol/mL).
CFA,
# .
. in fat tissue (nmol/mL).
CvFA,
#
.. in veins leaving fat tissue (nmol/mL).
CRP,
# .
. in richly perfused tissue (nmol/mL).
CvRP,
#
.. in veins leaving richly perfused tissue (nmol/mL).
CPP,
# .
. in poorly perfused tissue (nmol/mL).
CvPP,
#
.. in veins leaving poorly perfused tissue (nmol/mL).
CVE,
# .
. in viable epidermis (nmol/mL).
CvVE,
#
.. in veins leaving viable epidermis (nmol/mL).
CAB,
# .
. in arterial blood (nmol/mL).
CVB,
# .
. in venous blood (nmol/mL).
CAB UG
, # . . . in arterial blood (ug/mL).
JSCOO,
#
... flux at outer surface of SC (nmol/cmA2/min).
JSC10,
#
... flux at interface of SC with VE (nmol/cmA2/min).
AINa,
# Amount in the organism plus cumulative amount that has
#
been
metabolized (nmol) .
CTDO,
# Concentration in DO tissue (nmol/mL).
CTDO_UG, # Concentration in DO tissue (ug/mL).
RCMTDO_UG, # Rate of production of metabolite in DO tissue per unit
# volume (ug/mL/d) .
RCMBODY_UG, # Rate of production of metabolite in whole body per
63
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
# unit body mass (ug/kg/d) .
RDELDO_UG, # Rate of delivery to dorsal olfactory tissue per unit
# area (ug/cmA2/d) .
} ;
# End of OUTPUT VARIABLES.
#
#
# INPUT VARIABLES for the model (which are independent of other variables, and
# which may vary in time).
Inputs = (2015) ;
# End of INPUT VARIABLES.
#
#
# PARAMETERS for the model (which are independent of time). Calculated
# parameters (i.e, parameters that depend on other parameters) are declared and
# initialized to zero here, and the logic for computing their true values is
# then provided in the MODEL INITIALIZATION section.
# NOTE: Default anatomical and physiological values supplied here are for *rat*.
# See Tables 1, 2, and 3 of Campbell et al. (2014). - DFK 2/15/2018
# See also Campbell-supplied source code file "ratparam.m". - DFK 9/26/2019
# Inhalation and intravenous exposure parameters.
# CINPPM =0.0; # Inhaled naphthalene concentration (ppm) .
# CINPPMa =0.0; # Aerosol naphthalene concentration (ppm) .
# IVDOSE =0.0; # Intravenous dose (mg/kg).
# TINF =3.0; # Time for intravenous infusion (min).
# NOTE: CINPPMa and CINa do not appear to be used in any ODEs in the Campbell-
# supplied source code file "napth.csl", so lines involving these terms have
# been commented out in this code. - DFK 2/20/2018
# Also, IVDOSE and TINF are now used externally (in R simulation files) to
# update the new state variable RIV, which describes the instantaneous rate of
# intravenous dosing. - DFK 2/21/2018
# Finally, CINPPM is now used externally (in R simulation files) to update the
# new state variable CIN (which was a calculated a parameter in the Campbell-
# supplied source code file "napth.csl"). - DFK 2/23/2018
# Skin exposure parameters.
AEXP =0.0; # Area of exposed skin (cmA2).
VWELL =1.0; # Volume of material in exposure well (mL).
# Basic anatomical and physiological parameters.
BWinit = 315; # Body mass (g).
QPUc = 1.756; # Cardiac output (mL/min/gA0.75).
MVc = 1.909; # Minute ventilation rate (mL/min/gA0.75).
# Skin parameters.
DSC = 1.0e-8; # Fickian diffusion constant for stratum corneum (cmA2/min).
# NOTES: For the diffusion constant, see the formulas proposed by McCarley &
# Bunge (2001).
TSC = 0.003; # Thickness of stratum corneum (cm) .
TVE = 0.0075; # Thickness of viable epidermis (cm).
# NOTES: TSC should be approximately 0.0015 cm and TVE should be 0.005-0.01 cm
# based on remarks in Sections 1.3.1 and 1.3.2 of Kim (2006). TSC should be
# 0.001-0.005 cm and TVE should be 0.005-0.01 cm according to McCarley & Bunge
# (2001), p. 1700.
64
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
# Blood flows (as fractions of cardiac output) to ...
FBURT = 0.0015; # ... nasal cavity.
FBLI =0.25; # ... liver.
FBFA =0.07; # ... fat.
FBPP = 0.1675; # ... poorly perfused tissue.
FBRP =0.5; # ... richly perfused tissue.
FBCA = 0.011; # ... conducting airways.
# NOTES: These default values sum to 1. Perhaps code should check to ensure
# that values sum to 1 when altered by the user. - DFK 2/16/2018
# Volumes (as fractions of body mass) for
# ... liver.
# ... fat.
. poorly perfused tissue.
richly perfused tissue.
# ... arterial blood.
# ... venous blood,
remaining tissue.
NOTES: All values here (taken from the Campbell-supplied source code file
"ratparam.m") match the values reported by Campbell et al. (2014) , *except*
FTLI = 0.037;
FFAT = 0.065;
FTPP = 0.5618;
FTRP = 0.178;
FTABD = 0.018;
FTVBD = 0.045;
FTREM = 0.09;
#
#
# FTABD, FTVBD, and FTREM, which are not reported by those authors. Also, values
# don't sum to 1. - DFK 2/15/2018
# For rat (i.e, for the parameter values shown here), the total volume (BW) is
# approximately equal to the total body mass (BWinit) after accounting for
# volume of respiratory tract tissue. See comment in MODEL INITIALIZATION
# section below for total body mass. - DFK 2/26/2018
# Partition coefficients for
HBA = 571.0;
# . .
blood:air.
HTB = 3.49;
# . .
general tissue:blood (incl. RP, PP, respiratory)
HLUB = 1.71;
# . .
lung:blood.
HLB = 1.61;
# . .
liver:blood.
HFB = 49.0;
# . .
fat:blood.
HRPB = 2.12;
# . .
richly perfused tissue:blood.
HPPB = 3.49;
# . .
poorly perfused tissue:blood.
# HVEB = 2.8;
#
.. VE:blood (Kim et al., 2007)
HVEB = 2.73;
# . .
VE:blood (Eq. 23 of McCarley & Bunge, 2001)
# HSCVE =1.8
#
.. SC:VE (Kim et al., 2007).
HSCVE = 1.98;
# .
. SC:VE (Eq. 22 of McCarley & Bunge, 2001)
HSCJP8 = 1.0;
# .
. SC:JP8.
# NOTES: For the skin (SC and VE) partition coefficients,
# proposed by McCarley & Bunge (2001).
see the formulas
# NOTES: HTB and HPPB values here (taken from the Campbell-supplied source code
# file "ratparam.m") don't match values reported by Campbell et al. (2014),
# which were both 3.5 (minor discrepancy). HLB value here (taken from
# "ratparam.m") doesn't match value reported by Campbell et al. (2014), which
# was 1.6 (minor discrepancy). HRPB value here (taken from "ratparam.m") doesn't
# match value reported by Campbell et al. (2014), which was 3.5 (substantial
# discrepancy). - DFK 2/15/2018
# Nasal compartment
SADR =0.2; # .
SADOl =0.42; #
SAD02 =6.33; #
SAVR1 =1.8; # .
SAVR2 =4.5; # .
SAPL =1.5; # .
SACA =48.0; # .
SAPU = 3000.0; H
# NOTES: SAPL value
surface areas (cmA2) for ...
dorsal respiratory region.
, anterior dorsal olfactory region.
, posterior dorsal olfactory region,
anterior ventral respiratory region,
posterior ventral respiratory region,
pharynx and larynx,
conducting airways.
,. pulmonary region.
here (taken from the Campbell-supplied source code file
65
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
# "ratparam.m") matches value reported for "nasopharynx" by Campbell et al.
# (2014). SACA and SAPU values here (taken from "ratparam.m") are not defined
# or reported by Campbell et al. (2014). - DFK 2/15/2018
# Epithelial tissue thickness (cm) for ...
WTDR = 0.005; # ... dorsal respiratory region.
WTDO = 0.005; # ... dorsal olfactory regions (anterior & posterior).
WTVR = 0.005; # ... ventral respiratory regions (anterior & posterior).
WTPL = 0.005; # ... pharynx and larynx.
WTCA = 0.005; # ... conducting airways.
WTPU = 0.0004; # ... pulmonary region.
# NOTES: WTPL value here (taken from the Campbell-supplied source code file
# "ratparam.m") does *not* match value reported for "nasopharynx" by Campbell et
# al. (2014), which was 0.0004. WTCA and WTPU values here (taken from
# "ratparam.m") are not defined or reported by Campbell et al. (2014), but value
# reported by those authors for "nasopharynx" matches value provided in
# "ratparam.m" (and here) for *pulmonary region*. - DFK 2/15/2018
posterior).
& posterior).
# Mucus/submucosa thickness (cm) for ...
WMUCUS = 0.001; # ... mucus.
WXDR = 0.002; # ... dorsal respiratory region.
WXDO = 0.002; # ... dorsal olfactory regions (anterior &
WXVR = 0.002; # ... ventral respirator regions (anterior
WXPL = 0.002; # ... pharynx and larynx.
WXCA = 0.002; # ... conducting airways.
# NOTES: The submucosa thicknesses are also referred to as "blood exchange
# region thicknesses" in the Campbell-supplied source code file "napth.csl".
# All values here (taken from the Campbell-supplied source code file
# "ratparam.m") match the value(s) attributed to Plowchalk et al. (1997) by
# Campbell et al. (2014); however, WXCA value is not defined or reported by
# Campbell et al. (2014), and they report a value for "nasopharynx" but nothing
# for "pharynx and larynx". - DFK 2/15/2018
# Lumen volumes (cmA3 or mL) for ...
VLDR = 0.004; # ... dorsal respiratory region.
VLDOl = 0.012; # ... anterior dorsal olfactory region.
VLD02 = 0.054; # ... posterior dorsal olfactory region.
VLVR1 =0.09; # ... anterior ventral respiratory region.
VLVR2 =0.09; # ... posterior ventral respiratory region.
VLPL =0.06; # ... pharynx and larynx.
VLCA =0.53; # ... conducting airways.
# NOTES: All values here (taken from the Campbell-supplied source code file
# "ratparam.m") match the value(s) attributed to Bogdanffy et al. (1999) by
# Campbell et al. (2014); however, VLCA value is not defined or reported by
# Campbell et al. (2014), and they report a value for "nasopharynx" but nothing
# for "pharynx and larynx". - DFK 2/15/2018
# Air-phase mass transfer coefficients (cm/min) for ...
KGDR = 8000.0; # ... dorsal respiratory region.
KGDOl = 7167.0; # ... anterior dorsal olfactory region.
KGD02 = 26667.0; # ... posterior dorsal olfactory region.
KGVR1 = 34680.0; # ... anterior ventral respiratory region.
KGVR2 = 183333.0; # ... posterior ventral respiratory region.
KGPL = 5000.0; # ... pharynx and larynx.
KGCA = 225.0; # ... conducting airways.
# NOTES: All values here (taken from the Campbell-supplied source code file
# "ratparam.m") match the value(s) attributed to Bogdanffy et al. (1999) and/or
# Frederick et al. (1998) by Campbell et al. (2014); however, Campbell et al.
# (2014) report a value for "nasopharynx" but nothing for "pharynx and larynx".
# - DFK 2/15/2018
# Diffusivity constant.
66
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
DIFU = 4.5e-4; # Diffusivity in water (cmA2/min).
# NOTES: Comments in Campbell-supplied source code file "napth.csl" imply this
# value was taken from EPA "Soil Screening Guidance" document at
# http://www.epa.gov/superfund/health/conmedia/soil/pdfs/attachc.pdf.
# That URL cannot be accessed as of 2/16/2018, but there is a "Superfund Soil
# Screening Guidance" page at
# https://www.epa.gov/superfund/superfund-soil-screening-guidance.
# I was unable to easily find the value reported here. NEEDS REVIEW.
# - DFK 2/16/2018
# Molar mass (g/mol) for ...
MW1 = 128.17; # ... naphthalene!
# PPM to nmol/mli conversion. NOTES: First we compute density of gas...
# Density of gas based on Ideal Gas Law. We assume PV = nRT, where P is pressure
# (in atm), V is volume (in L), n is number of moles (mol), R is the ideal gas
# constant (0.08206 L*atm/mol/K), and T is the temperature (in K). At 1 atm and
# 20 deg C (or 293.15 K), the density of gas is n/V = P/RT = 1/(0.08206*293.15)
# = 0.04 mol/L. Now, at this density, 1 part per million (ppm) would be
# 0.04 * le-6 = 4e-8 mol/L = 4e-ll mol/mL = 4e-2 nmol/mL. This value is used
# for conversions from ppm to nmol/mL in the Campbell-supplied source code, but
# is not declared as a variable there. - DFK 2/16/2018
PPMtoNMPML = 0.04;
# Metabolism parameters.
VmaxLI =21.8; # Vmax in liver (nmol/min/mL).
KmLI =6.0; # Km in liver (nmol/mL).
VmaxLU =3.8; # Vmax in lung (nmol/min/mL).
KmLU =40.0; # Km in lung (nmol/mL).
VmaxO = 169.8; # Vmax in DR and DO regions (nmol/min/mL).
KmO =70.0; # Km in DR and DO regions (nmol/mL).
VmaxV =43.5; # Vmax in VR regions (nmol/min/mL).
KmV =11.5; # Km in VR regions (nmol/mL).
# NOTES: All values here (taken from the Campbell-supplied source code file
# "ratparam.m") match the values reported in Table 3 of Campbell et al. (2014),
# *except* they report a value of 11.6 for Km for the ventral respiratory
# regions (minor discrepancy). - DFK 2/15/2018
# Fractional ventilation rates to ...
FADR = 0.15; # ... dorsal respiratory region.
FADO = 0.15; # ... dorsal olfactory regions.
FAVR = 0.85; # ... ventral respiratory regions.
# NOTES: All values here are taken from the Campbell-supplied source code file
# "ratparam.m". The Campbell-supplied source code file "napth.csl" claims these
# values come from the "EPA PK doc". VERIFY. - DFK 2/15/2018
# Parameters to be computed in MODEL INITIALIZATION. The values of these
# parameters depend on values of the parameters already defined.
VTDR = 0.0;
VTDOl = 0.0;
VTD02 = 0.0;
VTVR1 = 0.0;
VTVR2 = 0.0;
VTPL = 0.0;
VTCA = 0.0;
VTPU = 0.0;
VXDR = 0.0;
VXDOl = 0.0;
VXD02 = 0.0;
VXVR1 = 0.0;
VXVR2 = 0.0;
VXPL = 0.0;
67
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
VXCA = 0.0;
VTLUNG = 0.0;
SAURT = 0.0;
VTLI = 0.0;
VFAT = 0.0;
VTSC = 0.0;
VTVE = 0.0;
VTRP = 0.0;
VTPP = 0.0;
VTAB = 0.0;
VTVB = 0.0;
VTREM = 0.0;
SCDX = 0.0;
BW = 0.0;
MV = 0.0;
VPU = 0.0;
VDR = 0.0;
VDO = 0.0;
WR = 0.0;
QPUa = 0.0;
FBDR = 0.0;
FBDOl = 0.0;
FBD02 = 0.0;
FBVR1 = 0.0;
FBVR2 = 0.0;
FBPL = 0.0;
QDR = 0.0;
QDOl = 0.0;
QD02 = 0.0;
QVR1 = 0.0;
QVR2 = 0.0;
QPL = 0.0;
QCA = 0.0;
QLI = 0.0;
QVE = 0.0;
QRP = 0.0;
QPP = 0.0;
QFA = 0.0;
QPU = 0.0;
HTA = 0.0;
MTCDR = 0.0;
MTCDOl = 0.0;
MTCD02 = 0.0;
MTCVR1 = 0.0;
MTCVR2 = 0.0;
MTCPL = 0.0;
MTCCA = 0.0;
KTXDR = 0.0;
KTXDOl = 0.0;
KTXD02 = 0.0;
KTXVR1 = 0.0;
KTXVR2 = 0.0;
KTXPL = 0.0;
KTXCA = 0.0;
# CIN = 0.0;
# CINa = 0.0;
# IVDOSENM = 0.0;
# RIV = 0.0;
# End of PARAMETERS.
#
68
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
#
# MODEL INITIALIZATION section.
Initialize {
# Calculated parameters
# Here we compute values of parameters that depend on constant parameters
# that have already been defined.
# Volumes (mL) of epithelial tissue in ...
VTDR = SADR * WTDR; # ... dorsal respiratory region.
VTDOl = SADOl * WTDO; # ... anterior dorsal olfactory region.
VTD02 = SAD02 * WTDO; # ... posterior dorsal olfactory region.
VTVR1 = SAVR1 * WTVR; # ... anterior ventral respiratory region.
VTVR2 = SAVR2 * WTVR; # ... posterior ventral respiratory region.
VTPL = SAPL * WTVR; # ... pharynx and larynx.
VTCA = SACA * WTCA; # ... conducting airways.
VTPU = SAPU * WTPU; # ... pulmonary region.
# Volumes (mL) of submucosa (or blood exchange areas) in ...
VXDR = SADR * WXDR; # ... dorsal respiratory region.
VXDOl = SADOl * WXDO; # ... anterior dorsal olfactory region.
VXD02 = SAD02 * WXDO; # ... posterior dorsal olfactory region.
VXVR1 = SAVR1 * WXVR; # ... anterior ventral respiratory region.
VXVR2 = SAVR2 * WXVR; # ... posterior ventral respiratory region.
VXPL = SAPL * WXVR; # ... pharynx and larynx.
VXCA = SACA * WXCA; # ... conducting airways.
# Total volume (mL) of respiratory tract tissue.
VTLUNG = VTDR + VTDOl + VTD02 + VTVR1 + VTVR2 + VTPL + VTCA + VTPU
+ VXDR + VXDOl + VXD02 + VXVR1 + VXVR2 + VXPL + VXCA;
# NOTES: Variable name VTLUNG (used here for consistency with Campbell-
# supplied source code files) seems to be misleading, as this quantity
# actually represents total tissue volume of the upper respiratory tract,
# *not* the tissue volume of the lung. - DFK 2/16/2018
# Total surface area (cmA2) of respiratory tract tissue.
SAURT = SADR + SADOl + SAD02 + SAVR1 + SAVR2 + SAPL;
# Volumes (mL) of ...
VTLI = FTLI * BWinit; # ... liver tissue.
VFAT = FFAT * BWinit; # ... fat tissue.
VTSC = AEXP * TSC; # ... (exposed) stratum corneum.
VTVE = AEXP * TVE; # ... (exposed) viable epidermis.
VTRP = FTRP * BWinit - VTVE; # ... richly perfused tissue.
VTPP = FTPP * BWinit; # ... poorly perfused tissue.
VTAB = FTABD * BWinit; # ... arterial blood.
VTVB = FTVBD * BWinit; # ... venous blood.
VTREM = FTREM * BWinit; # ... remaining tissue.
# Discretization thickness for stratum corneum partial differential
# equation discretization.
SCDX = TSC / 10;
# Total body mass (g) .
BW = VTLI + VFAT + VTRP + VTPP + VTAB + VTVB + VTLUNG + VTREM + VTVE;
# NOTES: Using default values (for rat), BWinit is 315 and BW is 315.0013.
# - DFK 2/15/2018
# Minute ventilation rate (mL/min).
MV = MVc * pow(BW, 0.75) ;
69
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
# Ventilation rates
VPU = 0.67 * MV
VDR = FADR * MV
VDO = FADO * MV
WR = FAVR * MV
(mL/min) to ...
alveolar region,
dorsal respiratory region,
dorsal olfactory regions.
ventral respiratory regions.
# Cardiac output (mL/min).
QPUa = QPUc * pow(BW, 0.75);
# Fractional blood flows based on fractional surface areas for...
FBDR = (SADR / SAURT) *
FBDOl = (SADOl / SAURT)
FBD02 = (SAD02 / SAURT)
FBVR1 = (SAVR1 / SAURT)
FBVR2 = (SAVR2 / SAURT)
FBPL = (SAPL / SAURT) *
FBURT; # .
* FBURT; #
* FBURT; #
* FBURT; #
* FBURT; #
FBURT; # .
dorsal respiratory region.
. anterior dorsal olfactory region.
. posterior dorsal olfactory region.
. anterior VR region.
. posterior VR region,
pharynx and larynx.
# Blood flows (mL/min) to
QDR =
FBDR *
QPUa;
# . . .
dorsal respiratory region.
QDOl =
= FBDOl
* QPUa;
# . .
anterior dorsal olfactory region.
QD02 =
= FBD02
* QPUa;
# . .
posterior dorsal olfactory region.
QVR1 =
= FBVR1
* QPUa;
# . .
anterior ventral respiratory region.
QVR2 =
= FBVR2
* QPUa;
# . .
posterior ventral respiratory region
QPL =
FBPL *
QPUa;
# . . .
pharynx and larynx.
QCA =
FBCA *
QPUa;
# . . .
conduction airways.
QLI =
FBLI *
QPUa;
# . . .
liver.
QVE =
FBRP *
(VTVE /
VTRP)
* QPUa; # ... viable epidermis.
QRP =
FBRP *
QPUa -
QVE; #
... richly perfused tissue.
QPP =
FBPP *
QPUa;
# . . .
poorly perfused tissue.
QFA =
FBFA *
QPUa;
# . . .
fat tissue.
# Total blood flow. COMPARE with QPUa. - DFK 2/15/2018
QPU = QDR + QDOl + QD02 + QVR1 + QVR2 + QPL + QCA + QLI + QVE + QRP + QPP
+ QFA;
# Tissue:air partition coefficient.
HTA = HBA * HTB;
# NOTE: Mass transfer coefficient calculations below are based on theory
# similar to total resistance of resistors in parallel. - DFK 4/3/2018
# Mass transfer coefficient (cm/min) for dorsal respiratory region.
MTCDR = 1 / (1 / KGDR + 1 / ((DIFU / (WMUCUS + 0.5 * WTDR) ) * HTA));
# Mass transfer coefficient (cm/min) for anterior dorsal olfactory region.
MTCDOl = 1 / (1 / KGDOl + 1 / ((DIFU /(WMUCUS + 0.5 * WTDO)) * HTA));
# Mass transfer coefficient (cm/min) for posterior dorsal olfactory region.
MTCD02 = 1 / (1 / KGD02 + 1 / ((DIFU / (WMUCUS + 0.5 * WTDO)) * HTA) ) ;
# Mass transfer coefficient (cm/min) for anterior ventral respiratory
# region.
MTCVR1 = 1 / (1 / KGVR1 + 1 / ((DIFU / (WMUCUS + 0.5 * WTVR)) * HTA));
# Mass transfer coefficient (cm/min) for posterior ventral respiratory
# region.
MTCVR2 = 1 / (1 / KGVR2 + 1 / ((DIFU / (WMUCUS + 0.5 * WTVR)) * HTA));
# Mass transfer coefficient (cm/min) for pharynx and larynx.
MTCPL = 1 / (1 / KGPL + 1 / ((DIFU / (WMUCUS + 0.5 * WTPL)) * HTA));
# Mass transfer coefficient (cm/min) for conducting airways.
70
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
MTCCA = 1 / (1 / KGCA + 1 / ((DIFU / (WMUCUS + 0.5 * WTCA)) * HTA));
# Diffusion coefficient (mL/min) for
KTXDR =
KTXDOl
KTXD02
KTXVR1
KTXVR2
KTXPL =
KTXCA =
DIFU * SADR /
= DIFU * SADOl
= DIFU * SAD02
= DIFU * SAVR1
= DIFU * SAVR2
DIFU * SAPL /
DIFU * SACA /
(WTDR /
2
+
WXDR /
2)
;
#
/ (WTDO
/
2
+ WXDO
/
2)
;
#
/ (WTDO
/
2
+ WXDO
/
2)
;
#
/ (WTVR
/
2
+ WXVR
/
2)
;
#
/ (WTVR
/
2
+ WXVR
/
2)
;
#
(WTPL /
2
+
WXPL /
2)
;
#
(WTCA /
2
+
WXCA /
2)
;
#
DR region.
.. anterior OR region.
.. posterior OR region.
.. anterior VR region.
.. posterior VR region,
pharynx and larynx,
conducting airways.
State Variables
# Assign an
RIV = 0.0;
AIV = 0.0;
CIN = 0.0;
AWELL
CSC01
CSC02
CSC03
CSC04
CSC05
CSC06
CSC07
CSC08
CSC09
ADERM
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
ALDR = 0.0;
AMTDR =0.0
ATDR = 0.0;
AXDR = 0.0;
ALDOl =0.0
AMTOl
ATDOl
AXDOl
ALD02
AMT02
ATD02
AXD02
ALVR1
AMTV1
ATVR1
AXVR1
ALVR2
AMTV2
ATVR2
AXVR2
ALPL =
ATPL =
AXPL =
ALCA =
ATCA =
AXCA =
ATPU =
AMLPU
ALI = 0.0;
AML = 0.0;
AFA
ARP
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0;
0.0;
APP = 0.0;
initial value for each state.
# Rate of intravenous dosing (nmol/min).
# Total amount provided intravenously (nmol).
# Concentration in ambient air (nmol/mL).
# Total amount in skin exposure well (nmol).
# Concentration in stratum corneum at depth 1 (nmol/mL)
# Concentration in stratum corneum at depth 2 (nmol/mL)
# Concentration in stratum corneum at depth 3 (nmol/mL)
# Concentration in stratum corneum at depth 4 (nmol/mL)
# Concentration in stratum corneum at depth 5 (nmol/mL)
# Concentration in stratum corneum at depth 6 (nmol/mL)
# Concentration in stratum corneum at depth 7 (nmol/mL)
# Concentration in stratum corneum at depth 8 (nmol/mL)
# Concentration in stratum corneum at depth 9 (nmol/mL)
# Total amount absorbed through skin (nmol).
# Amount in dorsal respiratory lumen (nmol).
# Total amount metabolized in DR tissue (nmol).
# Amount in dorsal respiratory tissue (nmol).
# Amount in dorsal respiratory exchange area (nmol).
# Amount in anterior dorsal olfactory lumen (nmol).
# Total amount metabolized in anterior DO tissue (nmol).
# Amount in anterior dorsal olfactory tissue (nmol).
# Amount in anterior DR blood exchange area (nmol).
# Amount in posterior dorsal olfactory lumen (nmol).
# Total amount metabolized in posterior DO tissue (nmol)
# Amount in posterior dorsal olfactory tissue (nmol).
# Amount in posterior DR blood exchange area (nmol).
# Amount in anterior ventral respiratory lumen (nmol).
# Total amount metabolized in anterior VR tissue (nmol) .
# Amount in anterior ventral respiratory tissue (nmol).
# Amount in anterior VR blood exchange area (nmol).
# Amount in posterior ventral respiratory lumen (nmol).
# Total amount metabolized in post. VR tissue (nmol).
# Amount in posterior ventral respiratory tissue (nmol).
# Amount in posterior VR blood exchange area (nmol).
# Amount in pharynx and larynx lumen (nmol).
# Amount in pharynx and larynx tissue (nmol).
# Amount in PL blood exchange area (nmol).
# Amount in conducting airways lumen (nmol).
# Amount in conducting airways tissue (nmol).
# Amount in CA blood exchange area (nmol).
# Amount in pulmonary tissue (nmol).
# Total amount metabolized in pulmonary tissue (nmol).
# Amount in liver tissue (nmol).
# Total amount metabolized in liver tissue (nmol).
# Amount in fat tissue (nmol).
# Amount in richly perfused tissue (nmol).
# Amount in poorly perfused tissue (nmol) .
71
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
AVE = 0.0; # Amount in viable epidermis (nmol) .
AAB =0.0; # Amount in arterial blood (nmol).
AVB =0.0; # Amount in venous blood (nmol).
AIN =0.0; # Net amount that has entered organism (nmol).
AUC_CAB_UG =0.0; # AUC for arterial blood (ug/mL*min).
AUC_CTDO_UG = 0.0; # AUC for DO tissue (ug/mL*min).
CMTDO_UG =0.0; # Concentration of metabolite in DO tissue (ug/mL).
AUC_CMTDO_UG =0.0; # AUC for metabolite in DO tissue (ug/mL*min).
AUC_RCMTDO_UG =0.0; # AUC for rate of production of metabolite in DO per
# unit volume (ug/mL) .
CMBODY_UG =0.0; # Concentration of metabolite in whole body (ug/mL).
AUC_CMBODY_UG = 0.0;# AUC for metabolite in whole body (ug/mL*min).
AUC_RCMBODY_UG =0.0; # AUC for rate of production of metabolite in whole
# body per unit body mass (ug/kg).
CTDOALT_UG =0.0; # Concentration (alternate) in DO tissue (ug/mL).
AUC_CTDOALT_UG =0.0; # AUC for conc. (alt) in DO tissue (um/mL*min).
AUC_RDELDO_UG =0.0; # AUC for rate of delivery to DO tissue per unit
# area (ug/cmA2).
}
# End of MODEL INITIALIZATION.
#
# DYNAMICS section.
Dynamics {
# Concentrations
# Naphthalene internal concentrations (nmol/mL) in
CLDR =
CTDR =
CXDR =
CLDOl
CTDOl
CXDOl
CLD02
CTD02
CXD02
CLVR1
CTVR1
CXVR1
CLVR2
CTVR2
CXVR2
CURT =
CLPL =
CTPL =
CXPL =
CLCA =
CTCA =
CXCA =
CTPU =
CvTPU
CLPU =
CLI =
CvLI =
CFA =
CvFA =
CRP =
CvRP =
CPP =
CvPP =
ALDR /
VLDR;
#
ATDR /
VTDR;
#
AXDR /
VXDR;
#
= ALDOl
/
VLDOl
#
= ATDOl
/
VTDOl
#
= AXDOl
/
VXDOl
#
= ALD02
/
VLD02
#
= ATD02
/
VTD02
#
= AXD02
/
VXD02
#
= ALVR1
/
VLVR1
#
= ATVR1
/
VTVR1
#
= AXVR1
/
VXVR1
#
= ALVR2
/
VLVR2
#
= ATVR2
/
VTVR2
#
= AXVR2
/
VXVR2
#
(VVR *
CLVR2 +
VDO
= ALPL / VLPL; #
= ATPL / VTPL; #
= AXPL / VXPL; #
= ALCA / VLCA; #
= ATCA / VTCA; #
= AXCA / VXCA; #
= ATPU / VTPU; #
= CTPU / HLUB; #
= CvTPU / HRA; #
ALI / VTLI; #
= CLI / HIiB; #
AFA / VFAT; #
= CFA / HFB; #
ARP / VTRP; #
= CRP / HRPB; H
APP / VTPP; #
= CPP / HPPB; H
dorsal respirator lumen,
dorsal respirator tissue,
dorsal respirator blood exchange area,
anterior dorsal olfactor lumen,
anterior dorsal olfactor tissue,
anterior DO blood exchange area,
posterior dorsal olf actor lumen,
posterior dorsal olfactor tissue,
posterior DO blood exchange area,
anterior ventral respirator lumen,
anterior ventral respirator tissue,
anterior VR blood exchange area,
posterior ventral respirator lumen,
posterior ventral respirator tissue,
posterior VR blood exchange area.
CLD02) / (VVR + VDO); # ... upper resp. tract.
pharnx an£i lar1131 lumen.
pharnx an£i lar11* tissue.
pharnx an£i lar1131 blood exchange area,
conducting airways lumen,
conducting airways tissue,
conducting airways blood exchange area,
pulmonar tissue,
veins leaving pulmonar tissue,
pulmonar lumen,
liver tissue.
veins leaving liver tissue,
fat tissue.
veins leaving fat tissue,
richly perfused tissue.
veins leaving richly perfused tissue,
poorly perfused tissue,
veins leaving poorly perfused tissue.
72
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
CAB = AAB / VTAB; # . . . arterial blood.
CVB = AVB / VTVB; # ... venous blood.
CVE = VTVE > 0 ? AVE / VTVE : 0.0; # ... viable epidermis.
CvVE = CVE / HVEB; # ... veins leaving viable epidermis.
CWELL = VWELL > 0 ? AWELL / VWELL : 0.0; # ... skin exposure well.
CSC00 = VWELL > 0 ? CWELL * HSCJP8 : CSC01; # ... outer surface of SC.
# NOTE: If VWELL is 0, this assignment leads to
# zero flux at the outer surface of the SC.
CSC10 = CVE * HSCVE; # ... interface of SC with VE.
# Naphthalene internal concentrations (ug/mL) in ...
CAB UG = (CAB * MW1) / 1000; # ... arterial blood.
# Naphthalene
FCTDR = CTDR /
FCXDR = CXDR /
FCTDOl = CTDOl
FCXDOl = CXDOl
FCTD02 = CTD02
FCXD02 = CXD02
FCTVR1 = CTVR1
FCXVR1 = CXVR1
FCTVR2 = CTVR2
FCXVR2 = CXVR2
FCTPL = CTPL /
FCXPL = CXPL /
FCTCA = CTCA /
FCXCA = CXCA /
internal
HTB;
HTB;
/ HTB
/ HTB
/ HTB
/ HTB
/ HTB
/ HTB
/ HTB
/ HTB
HTB
HTB
HTB
HTB
concentration (nmol/mL) in blood of
dorsal respiratory tissue,
dorsal respiratory blood exchange area,
anterior dorsal olfactory tissue,
anterior DO blood exchange area,
posterior dorasal olfactory tissue,
posterior DO blood exchange area,
anterior ventral respiratory tissue,
anterior VR blood exchange area,
posterior ventral respiratory tissue,
posterior VR blood exchange area,
pharynx and larynx tissue,
pharynx and larynx blood exchange area,
conducting airways tissue,
conducting airways blood exchange area.
# Amounts (not conputed using ODEs)
# Amount in stratum corneum (nmol) .
ASC = SCDX * (0.5 * CSC00 + CSC01 + CSC02 + CSC03 + CSC04 + CSC05 + CSC06
+ CSC07 + CSC08 + CSC09 + 0.5 * CSC10) * AEXP;
# Fluxes
# Naphthalene fluxes (nmol/cmA2/min) at .
JSC00 = -DSC * (CSC01 - CSC00) / SCDX; #
JSC10 = -DSC * (CSC10 - CSC09) / SCDX; #
outer surface of SC.
interface of SC with VE.
# Time rates of change of state variables (ODEs)
#
# Exposure/Dosing State Variables
#
# Rate of change of intravenous dose rate (nmol/min/min). NOTE: Making RIV
# a state variable allows one to modify it over the course of a simulation
# using the "events" feature of the R package deSolve.. - DFK 2/21/2018
dt(RIV) = 0.0;
# Rate of change of total amount provided intravenously (nmol/min) .
dt(AIV) = RIV;
# Rate of change of concentration in ambient air (nmol/mL/min). NOTE: Making
# CIN a state variable allows one to modify it over the course of a
# simulation using the "events" feature of the R package deSolve.
# - DFK 2/22/2018
dt(CIN) = 0.0;
# Rate of change of total amount absorbed through skin (ug/min).
RADERM = JSC00 * AEXP;
73
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
dt(ADEEM) = RADERM;
#
# Dorsal Respiratory Region (DR)
#
# Rate of change of amount in dorsal respiratory lumen (nmol/min).
RALDR = VDR * (CIN - CLDR) - MTCDR * SADR * (CLDR - CTDR / HTA) ;
dt(AIiDR) = RALDR;
# Rate of change of total amount metabolized in DR tissue (nmol/min).
RMTDR = VTDR * VmaxO * FCTDR / (KmO + FCTDR);
dt(AMTDR) = RMTDR;
# Rate of change of amount in dorsal respiratory tissue (nmol/min).
RATDR = MTCDR * SADR * (CLDR - CTDR / HTA) - KTXDR * (FCTDR - FCXDR)
- RMTDR;
# RATDR = 0.0;
dt(ATDR) = RATDR;
# Rate of change of amount in DR blood exchange area (nmol/min).
RAXDR = KTXDR * (FCTDR - FCXDR) - QDR * (CXDR / HTB - CAB);
dt(AXDR) = RAXDR;
#
# Anterior Dorsal Olfactory Region (DOl)
#
# Rate of change of amount in anterior dorsal olfactory lumen (nmol/min).
RAIiDOl = VDO * (CLDR - CLDOl) - MTCDOl * SADOl * (CLDOl - CTDOl / HTA) ;
dt(ALDOl) = RALDOl;
# Rate of change of amount metabolized in anterior DO tissue (nmol/min).
RMTOl = VTDOl * VmaxO * FCTDOl / (KmO + FCTDOl);
dt(AMTOl) = RMTOl;
# Rate of change of amount in anterior dorsal olfactory tissue (nmol/min).
RATDOl = MTCDOl * SADOl * (CLDOl - CTDOl / HTA) - KTXDOl * (FCTDOl - FCXDOl)
- RMTOl;
dt(ATDOl) = RATDOl;
# Rate of change of amount in anterior DO blood exchange area (nmol/min).
RAXDOl = KTXDOl * (FCTDOl - FCXDOl) - QDOl * (CXDOl / HTB - CAB) ;
dt(AXDOl) = RAXDOl;
#
# Posterior Dorsal Olfactory Region (D02)
#
# Rate of change of amount in posterior dorsal olfactory lumen (nmol/min).
RALD02 = VDO * (CLDOl - CLD02) - MTCD02 * SAD02 * (CLD02 - CTD02 / HTA);
dt(ALD02) = RALD02;
# Rate of change of amount metabolized in posterior DO tissue (nmol/min).
RMT02 = VTD02 * VmaxO * FCTD02 /(KmO + FCTD02);
dt (AMT02) = RMT02;
# Rate of change of amount in posterior dorsal olfactory tissue (nmol/min).
RATD02 = MTCD02 * SAD02 * (CLD02 - CTD02 / HTA) - KTXD02 * (FCTD02 - FCXD02)
74
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
- RMT02;
# RATD02 = 0.0;
dt(ATD02) = RATD02;
# Rate of change of amount in posterior DO blood exchange area (nmol/min) .
RAXD02 = KTXD02 * (FCTD02 - FCXD02) - QD02 * (CXD02 / HTB - CAB);
dt(AXD02) = RAXD02;
#
# Anterior Ventral Respirator Region (VR1)
#
# Rate of change of amount in anterior ventral respiratory lumen (nmol/min).
RALVR1 = WR * (CIN - CLVR1) - MTCVR1 * SAVR1 * (CLVR1 - CTVR1 / HTA) ;
dt(ALVRl) = RALVR1 ;
# Rate of change of amount metabolized in anterior VR tissue (nmol/min).
RMTV1 = VTVR1 * VmaxV * FCTVR1 / (KmV + FCTVR1);
dt(AMTV1) = RMTV1;
# Rate of change of amount in anterior VR tissue (nmol/min).
RATVR1 = MTCVR1 * SAVR1 * (CLVR1 - CTVR1/HTA) - KTXVR1 * (FCTVR1 - FCXVR1)
- RMTV1;
dt(ATVRl) = RATVR1;
# Rate of change of amount in anterior VR blood exchange area (nmol/min).
RAXVR1 = KTXVR1 * (FCTVR1 - FCXVR1) - QVR1 * (CXVR1 / HTB - CAB);
dt(AXVRl) = RAXVR1;
#
# Posterior Ventral Respiratory Region (VR2)
#
# Rate of change of amount in posterior VR lumen (nmol/min).
RALVR2 = VVR * (CLVR1 - CLVR2) - MTCVR2 * SAVR2 * (CLVR2 - CTVR2 / HTA);
dt(ALVR2) = RALVR2;
# Rate of change of amount metabolized in posterior VR tissue (nmol/min).
RMTV2 = VTVR2 * VmaxV * FCTVR2 / (KmV + FCTVR2);
dt(AMTV2) = RMTV2;
# Rate of change of amount in posterior VR tissue (nmol/min).
RATVR2 = MTCVR2 * SAVR2 * (CLVR2 - CTVR2 / HTA) - KTXVR2 *(FCTVR2 - FCXVR2)
- RMTV2;
dt(ATVR2) = RATVR2;
# Rate of change of amount in anterior VR blood exchange area (nmol/min).
RAXVR2 = KTXVR2* (FCTVR2 - FCXVR2) - QVR2 * (CXVR2/HTB - CAB);
dt(AXVR2) = RAXVR2;
#
# Phaiynx and Larynx Region (PL)
#
# Rate of change of amount in pharynx and larynx lumen (nmol/min).
RALPL = MV * (CURT - CLPL) - MTCPL * SAPL * (CLPL - CTPL / HTA);
dt(ALPL) = RALPL;
# Rate of change of amount in pharynx and larynx tissue (nmol/min).
75
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
RATPL = MTCPL * SAPL * (CLPL - CTPL / HTA) - KTXPL * (FCTPL - FCXPL);
dt(ATPL) = RATPL;
# Rate of change of amount in PL blood exchange area (nmol/min).
RAXPL = KTXPL * (FCTPL - FCXPL) - QPL * (CXPL / HTB - CAB);
dt(AXPL) = RAXPL;
#
# Conducting Airways Region (CA)
#
# Rate of change of amount in conducting airways lumen (nmol/min).
RALCA = MV * (CLPL - CLCA) - MTCCA * SACA * (CLCA - CTCA / HTA);
dt(ALCA) = RALCA;
# Rate of change of amount in conducting airways tissue (nmol/min).
RATCA = -KTXCA * (FCTCA - FCXCA) + MTCCA * SACA * (CLCA - CTCA / HTA);
dt(ATCA) = RATCA;
# Rate of change of amount in CA blood exchange area (nmol/min).
RAXCA = KTXCA * (FCTCA - FCXCA) - QCA * (CXCA / HTB - CAB);
dt(AXCA) = RAXCA;
#
# Pulmonary Region (PU)
#
# Rate of change of amount metabolized in pulmonary tissue (nmol/min).
RMLPU = VTPU * VmaxLU * CvTPU / (KmLU + CvTPU);
dt(AMLPU) = RMLPU;
# Rate of change of amount in pulmonary tissue (nmol/min).
RATPU = VPU * (CLCA - CLPU) - QPU * (CvTPU - CVB) - RMLPU;
dt(ATPU) = RATPU;
#
# Liver Tissue (LI)
#
# Rate of change of amount metabolized in liver (nmol/min).
RML = VTLI * VmaxLI * CvLI / (KmLI + CvLI);
dt(AML) = RML;
# Rate of change of amount in liver tissue (nmol/min).
RALI = QLI * (CAB - CvLI) - RML;
dt(ALI) = RALI;
#
# Fat Tissue (FA)
#
# Rate of change of amount in fat tissue (nmol/min).
RAFA = QFA * (CAB - CvFA);
dt(AFA) = RAFA;
#
# Richly Perfused Tissue
#
# Rate of change of amount in richly perfused tissue (nmol/min).
76
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
RARP = QRP * (CAB - CvRP);
dt(ARP) = RARP;
#
# Poorly Perfused Tissue
#
# Rate of change of amount in poorly perfused tissue (nmol/min).
RAPP = QPP * (CAB - CvPP);
dt(APP) = RAPP;
#
# Dermal Exposure Well
#
dt(AWELL) = -JSCOO * AEXP;
#
# Stratum Corneum
#
dt(CSCOl)
=
DSC
*
(CSC00
- 2
*
CSC01
+
CSC02)
(SCDX
*
SCDX)
dt (CSC02)
=
DSC
*
(CSC01
- 2
*
CSC02
+
CSC03)
(SCDX
*
SCDX)
dt (CSC03)
=
DSC
*
(CSC02
- 2
*
CSC03
+
CSC04)
(SCDX
*
SCDX)
dt(CSC04)
=
DSC
*
(CSC03
- 2
*
CSC04
+
CSC05)
(SCDX
*
SCDX)
dt (CSC05)
=
DSC
*
(CSC04
- 2
*
CSC05
+
CSC06)
(SCDX
*
SCDX)
dt (CSC06)
=
DSC
*
(CSC05
- 2
*
CSC06
+
CSC07)
(SCDX
*
SCDX)
dt(CSC07)
=
DSC
*
(CSC06
- 2
*
CSC07
+
CSC08)
(SCDX
*
SCDX)
dt (CSC08)
DSC
*
(CSC07
- 2
*
CSC08
+
CSC09)
(SCDX
*
SCDX)
dt(CSC09)
DSC
*
(CSC08
- 2
*
CSC09
+
CSC10)
(SCDX
*
SCDX)
#
# Viable Epidermis
#
# Rate of change of amount in viable epidermis (nmol/min).
# RAVE = 0.0;
RAVE = JSC10 * AEXP + QVE * (CAB - CvVE);
dt (AVE) = RAVE;
#
# Arterial Blood
#
# Rate of change of amount in arterial blood (nmol/min).
RAAB = QPU * (CvTPU - CAB);
dt(AAB) = RAAB;
#
# Venous Blood
#
# Rate of change of amount in venous blood (nmol/min).
RAVB = QLI * CvLI + QFA * CvFA + QRP * CvRP + QPP * CvPP + QCA * CXCA / HTB
+ QPL * CXPL / HTB + QVR1 * CXVR1 / HTB + QVR2 * CXVR2 / HTB
+ QDOl * CXDOl / HTB + QD02 * CXD02 / HTB + QDR * CXDR / HTB
+ QVE * CvVE - QPU * CVB + RIV;
dt(AVB) = RAVB;
77
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
# Dose metrics
# AUC for concentration in arterial blood (ug/mL*min).
dt(AUC_CAB_UG) = CAB_UG;
# AUC for concentration in dorsal olfactory tissue (ug/mL*min).
CTDO = (ATDOl + ATD02) / (VTDOl + VTD02); # (nmol/mL)
CTDO_UG = (CTDO * MW1) / 1000; # (ug/mL)
dt(AUC_CTDO_UG) = CTDO_UG;
# Concentration of metabolite in dorsal olfactory tissue (ug/mL).
dt(CMTDO_UG) = (RMTOl + RMT02) * (MW1 / 1000) / (VTDOl + VTD02) -
CMTDO_UG * 1.0 * pow(VTDOl + VTD02, 0.75);
# AUC for concentration of metabolite in DO tissue (~ug/mL*min).
dt(AUC_CMTDO_UG) = CMTDO_UG;
# AUC for rate of production of metabolite in DO per unit volume (ug/mL).
RCMTDO_UG = (RMTOl + RMT02) * (MW1 / 1000) / (VTDOl + VTD02);
dt(AUC_RCMTDO_UG) = RCMTDO_UG;
# Concentration of metabolite in whole body (ug/mL).
dt(CMBODY_UG) = (RMTDR + RMTOl + RMT02 + RMTV1 + RMTV2 + RMLPU + RML) *
(MW1 / 1000) / BW - CMBODY_UG * 1.0 * pow(BW, 0.75);
# AUC for concentration of metabolite in whole body (~ug/mL*min).
dt(AUC_CMBODY_UG) = CMBODY_UG;
# AUC for rate of production of metabolite in whole body per unit body mass
# (ug/kg).
RCMBODY_UG = (RMTDR + RMTOl + RMT02 + RMTV1 + RMTV2 + RMLPU + RML) *
(MW1 / 1000) / BW;
dt(AUC_RCMBODY_UG) = RCMBODY_UG;
# Concentration (alternate) in dorsal olfactojry tissue (~ug/mL).
dt(CTDOALT_UG) = (MTCDOl * SADOl * (CLDOl - CTDOl / HTA) +
MTCD02 * SAD02 * (CLD02 - CTD02 / HTA)) * (MW1 / 1000) /
(VTDOl + VTD02) - CTDOALT_UG * 1.0 * pow(VTDOl + VTD02, 0.75);
# AUC for concentration (alternate) in dorsal olfactory tissue (~ug/mL*min).
dt(AUC_CTDOALT_UG) = CTDOALT_UG;
# AUC for rate of deliver to dorsal olfactojry tissue per unit area
# (ug/cmA2) .
RDELDO_UG = (MTCDOl * SADOl * (CIiDOl - CTDOl / HTA) +
MTCD02 * SAD02 * (CLD02 - CTD02 / HTA)) * (MW1 / 1000) /
(SADOl + SAD02);
dt(AUC RDELDO UG) = RDELDO UG;
# Balance checks
# Rate of change of *net* amount moving into the organism (nmol/min) via
# inhaled air, intravenous injection, and skin exposure.
RAIN = MV * (CIN - CLCA) + VPU * (CLCA - CLPU) + RIV + RADERM;
dt(AIN) = RAIN;
# Total amount in the organism plus cumulative amount that has been
# metabolized (nmol) .
AINa = ALDR + ATDR + AXDR + AMTDR + ALDOl + ATDOl + AXDOl + AMTOl
+ ALD02 + ATD02 + AXD02 + AMT02 + ALVR1 + ATVR1 + AXVR1
+ AMTV1 + ALVR2 + ATVR2 + AXVR2 + AMTV2 + ALPL + ATPL + AXPL
78
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
+ ALCA + ATCA + AXCA + ATPU + AMLPU + AAB + AVB + All + AML
+ AFA + ARP + APP + ASC + AVE;
}
# End of DYNAMICS.
#
End.
79
-------
Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Appendix E: Dose Metrics Calculation Script
#
# InhNTP_dose_metrics.R
#
# Author: Dustin Kapraun, US EPA, June 2018
#
# This code simulates the National Toxicology Program (NTP) study involving
# naphthalene dosing of rats via inhalation as described by Campbell et al.
# (2014). Running this code simulates an inhalation exposure scenario and
# calculates dose metrics, such as average blood concentration and average
# concentration in the dorsal olfactory region. This script requires the MCSim
# naphthalene model implementation ("naph_pbtk_pde").
#
# Reference:
# JL Campbell, ME Andersen, HJ Clewell (2014) , "A hybrid CFD-PBPK model for
# naphthalene in rat and human with IVIVE for nasal tissue metabolism and
# cross-species dosimetry," Inhalation Toxicology 26(6): 333-344.
#
# DE Dodd, EA Gross, RA Miller, BA Wong (2010), "Nasal olfactory epithelial
# lesions in F344 and SD rats following 1- and 5-day inhalation exposure to
# naphthalene vapor," International Journal of Toxicology 29(2).
#
# Set working directory to the directory containing this file.
script_dir = dirname(sys.frame(1)$ofile)
setwd(script_dir)
# Load the model "naph_pbtk_pde". When using the default parameters for this
# model the dermal compartments will be disabled and the model behavior should
# be equivalent to that of the Campbell et al. (2014) model for rats,
source("init_naph_pbtk_pde.R")
# Specify the simulation duration.
# TSTOP =24 * 60 # Simulation time of 1 day (min).
TSTOP = 10 * 24 * 60 # Simulation time of 10 days (min).
CINT =6 # Frequency with which solver should report results (min).
times = seq(from=0, to=TSTOP, by=CINT)
nt = length(times)
times_d = times / 60 / 24
# Set parameters to their default values as given in the ".model" file, and
# then calculate values of those parameters that depend on other parameters.
# Note that default parameter values in the ".model" file are for rats,
parms = initParms()
# Modify default PPMtoNMPL parameter from Campbell et al. (2014) to use two
# significant figures.
parms["PPMtoNMPML"] = 0.0416 # nmol/mL per ppm
# Strain/sex codes for F344 rats (male and female) and Sprague-Dawley rats
# (male and female).
acode = c("F344m", "F344f", "SDm", "SDf")
# Mean body mass values for various rat strains and sexes. These were digitally
# extracted from Figure 3 of Dodd et al. (2010) by Allen Davis on 2/4/2020.
# F344 F: 91.3
# F344 M: 108.5
# SD F: 142
# SD M: 144
BW vec = c(108.5, 91.3, 144, 142)
80
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Derivation of an Acute Reference Concentration for
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# Use a fixed body mass and scale surface areas of nasal epithelial tissues.
# Gross et al. (1982) found that the total surface areas for respiratory
# epithelium and olfactory epithelium were 3.524 cmA2 and 4.185 cmA2,
# respectively, for a 115-g rat; they also found that these surface areas were
# 6.231 cmA2 and 6.752 cmA2, respectively for a 288-g rat. We used regression
# to obtain power law formulas of the form
# S = a*MAb,
# where S is surface area (cmA2), M is body mass (g), and a and b are scalar
# parameters. For total respiratory epithelium surface area, a=0.18522 and
# b=0.6208. For total olfactory epithelium surface area, a=0.35317 and b=0.521.
# We used these formulas to calculate total surface areas for respiratory
# epithelium and olfactory epithelium for a 315-g rat as 7.073 cmA2 and 6.586
# cmA2, respectively. We then computed the surface areas of the sub-components
# of these tissues using previously estimated values for some and calculating
# differences from the total for the others.
parms["BWinit"] = 315
SA_respiratory_total = 6.586 # Total respiratory tissue surface area (cmA2).
SA_olfactory_total = 7.073 # Total olfactory tissue surface area (cmA2).
parms["SADR"] =0.2 # Frederick et al. (1998).
parms["SAVR1"] =1.8 # Frederick et al. (1998).
parms["SAVR2"] = SA_respiratory_total - (parms[["SADR"]] + parms[["SAVR1"]])
parms["SADOl"] =0.42 # Frederick et al. (1998).
parms["SAD02"] = SA_olfactory_total - parms[["SADOl"]]
parms["SAPL"] =1.5 # Campbell et al. (2014). Original source unknown,
parms["SACA"] =48.3 # Sarangapani et al. (2002).
parms["SAPU"] = 3400 # Sarangapani et al. (2002).
parms = initParms(parms)
# Set ambient concentration(s) at the beginning of the simulation and specify
# the duration of the inhalation exposure. These values are taken from Table 1
# of Dodd et al. (2010).
CINPPM_nom = c(0.1, 0.3, 1, 10, 30) # Inhalation exposure nominal dose (ppm) .
CINPPM_male = c(0.09, 0.30, 1.10, 11.6, 28.5) # ... male rats (ppm) .
CINPPM_female = c(0.10, 0.28, 1.07, 12.3, 30.7) # ... female rats (ppm) .
TCHNG1 = 360 # Inhalation exposure duration (min).
TCHNG1 =372 # Inhalation exposure duration including
# "T90" (min).
# Retrieve model parameters to be used in dose calculations below.
PPMtoNMPML = parms[["PPMtoNMPML"]] # Conversion factor for ppm to nmol/mL.
# Set up data structure to hold results.
nc = length(CINPPM_nom) # Number of concentrations.
ng = length(acode) # Number of groups (sexes x strains) of rats.
# DM_mat = matrix(data=NA, nrow=nc, ncol=ng)
# Set concentrations to averages of actual observed concentrations.
CINPPM_vec = (CINPPM_male + CINPPM_female) / 2
# Print information for this set of simulations.
cat("For all rats, body mass is", parms[["BWinit"]],
"g and actual doses are", CINPPM_vec, "ppm.\n")
# Set default initial values of states.
Y0 = initStates(parms)
# Convert ppm to nmol/mL.
CIN_vec = CINPPM_vec * PPMtoNMPML # Inhalation exposure dose (nmol/mL).
idx = 0
for (CIN in CIN_vec) {
idx = idx + 1
81
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
# Implement inhalation dosing using deSolve "events". Assume a single 6-h
# exposure.
t_inh_on = c(0)
t_inh_off = t_inh_on + TCHNG1
df_inh_on = data.frame(var=rep("CIN", length(t_inh_on)), time=t_inh_on,
value=rep(CIN, length(t_inh_on)),
method=rep("replace", length(t_inh_on)))
df_inh_off = data.frame(var=rep("CIN", length(t_inh_off)), time=t_inh_off,
value=rep(0, length(t_inh_off) ) ,
method=rep("replace", length(t_inh_off)))
df_inh = rbind(df_inh_on, df_inh_off)
df_inh = df_inh[order(df_inh$time),]
# Run simulation.
out = run_model (model_name, times, YO=YO , pa2nTLS=pa2nris,
event_list=list(data=df_inh))
# Dose Metric: Cumulative Production of Metabolites in DO per Unit Volume.
# Generate a figure that shows cumulative production of metabolite in DO.
rop = out[, "RCMTDO_UG"]
cum_prod = out[nt, "AUC_RCMTDO_UG"]
plot(times_d, rop, type="l", lwd=2, lty=l, col="blue",
xlab="Time (day)", ylab="Rate of Metabolite Production in DO Tissue (ug/mL/min)")
# Print a message about the cumulative production of metabolites.
cat(" ", CINPPM_nom[idx], "ppm -> Cumulative metabolite production in DO tissue:",
cum_prod, "ug/mL\n")
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Derivation of an Acute Reference Concentration for
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Appendix F: Determination of Respiratory Tract Surface Area Parameters for the Naphthalene
PBPK Model
The values originally used by Kapraun et al. (2020) for respiratory tract surface area parameters in their
PBPK model were identical to the values used by Campbell et al. (2014) in their antecedent model as
reported in Table 2 of Campbell et al. (2014). Campbell et al. (2014) cited Bogdanffv et al. (1999) as the
source of these surface area parameters, and, indeed, those authors used many of the same surface
area parameters in their own inhalation model for naphthalene. However, Bogdanffv et al. (1999) used
the surface area parameters, which are not scaled by body mass, for simulations of a 250 g rat, whereas
Campbell et al. (2.014) (and subsequently Kapraun et al. (2020)) used the values for a 315 g rat.
Furthermore, Campbell et al. (2014) did not cite references for surface areas of the "nasopharynx"
(which actually represents the pharynx and the larynx in their model), the conducting airways, and the
pulmonary region compartments of their PBPK model, and the Bogdanffv et al. (1999) model did not
include these compartments at all.
Bogdanffv et al. (1999) cited Gross et al. (1982) and DeSesso (1993) as the sources of the values they
used for their respiratory tract surface area parameters. DeSesso (1993) provided values for total
surface area of the olfactory and respiratory nasal epithelial tissues, but Campbell et al. (2014) used sub-
components of those regions. The sum of the values used by Campbell et al. (2014) and Bogdanffv et al.
(1999) for the anterior dorsal olfactory and posterior dorsal olfactory surface areas is equal to the total
olfactory surface area reported by DeSesso (1993), which was 6.75 cm2; however, DeSesso (1993) used
this total surface area for simulating a 250 g rat whereas Campbell et al. (2014) assumed this value for a
315 g rat. Furthermore, DeSesso (1993) attributed their total olfactory surface area value to Gross et al.
(1982), who reported a more exact value of 6.752 cm2. However, Gross et al. (1982) indicate that a 288 g
rat was used for their measurements.
The total surface area for the respiratory nasal epithelial tissue, which comprises three sub-
compartments in the models of Campbell et al. (2014) and Bogdanffv et al. (1999), was 6.5 cm2. Again,
Campbell et al. (2.014) cited Bogdanffv et al. (1999) and Bogdanffv et al. (1999) cited Gross et al. (1982)
and DeSesso (1993) for the values. DeSesso (1993) used a value of 6.23 cm2 for a 250 g rat and Gross et
al. (1982) determined a value of 6.231 cm2 for a 288 g rat. DeSesso (1993) cited Gross et al. (1982) for
their surface area values, so it appears that the original source of all the values used for nasal epithelial
tissue surface areas was the 288 g rat of Gross et al. (1982). Although not cited by Campbell et al. (2014)
as a source for surface areas, it appears that many of the nasal epithelial tissue surface areas reported
by Frederick et al. (1998) were used by Campbell et al. (2014). The rat body masses and nasal epithelial
surface areas used by various authors are summarized in Table F-l.
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
Table F-l. Rat body masses and nasal epithelial surface areas used by various authors. Values in
parentheses indicate sums calculated by us for total surface area of a given nasal region.
Gross et al.
(1982)
DeSesso
(1993)
Frederick et
al. (1998)
Bogdanffv et
al. (1999)
Campbell et
al. (2014)
Body mass (g)
115
288
250
315
250
315
Anterior Dorsal Olfactory (cm2)
0.42
0.42
0.42
Posterior Dorsal Olfactory (cm2)
6.33
6.33
Olfactory Total (cm2)
4.185
6.752
6.75
(6.75)
(6.75)
Dorsal Respiratory (cm2)
0.2
0.2
0.2
Anterior Ventral Respiratory (cm2)
1.8
1.8
1.8
Posterior Ventral Respiratory (cm2)
4.5
4.5
4.5
Respiratory Total (cm2)
3.524
6.231
6.5
(6.5)
(6.5)
Gross et al. (1982) measured and reported total surface areas of respiratory epithelium and olfactory
epithelium (as well as squamous epithelium, which was not used by the later authors of PBPK models)
for both 115 g rats (7 weeks old) and 288 g (16 weeks old) rats. EPA calibrated simple power law
empirical models for surface area as a function of body mass to the Gross et al. (1982) data and
determined that the total surface areas for olfactory nasal epithelial tissue and respiratory nasal
epithelial tissue should be 7.07 and 6.59 cm2, respectively, for a 315 g rat. See Figures F-l and F-2 and
Table F-2.
y:
= 0.3532X0-52
f •
0 50 100 150 200 250 300 350
Body Mass (g)
Figure F-l. Optimal power law fit for total olfactory epithelium surface area as a function of body
mass based on data of Gross etal.(1982).
84
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
250 300 350
Figure F-2. Optimal power law fit for total respiratory epithelium surface area as a function of body
mass based on data of Gross etal.(1982).
Table F-2. Respiratory tract surface area parameters used by Campbell et al. (2014) and those used for
current analysis.
Campbell et al. (2014)
Current analysis
Body mass (g)
315
315
Anterior dorsal olfactory (cm2)
0.42
0.42
Posterior dorsal olfactory (cm2)
6.33
6.65
Olfactory total (cm2)
(6.75)
7.07
Dorsal respiratory (cm2)
0.2
0.2
Anterior ventral respiratory (cm2)
1.8
1.8
Posterior ventral respiratory (cm2)
4.5
4.59
Respiratory total (cm2)
(6.5)
6.59
Pharynx + larynx (cm2)
1.5
1.5
Conducting airways (cm2)
48
48
Pulmonary region (cm2)
3,000
3,400
Frederick et al. (1998) reported surface areas estimated for dorsal olfactory, anterior dorsal respiratory,
anterior ventral respiratory, and posterior ventral respiratory epithelial tissues determined for a 315 g
male F344 rat by Kimbell et al. (1993) and Kimbell et al. (1997). As shown in Table F-l, the surface area
values used by Campbell et al. (2014) match those used by Frederick et al. (1998) for these specific nasal
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0 50 100 150 200
Body Mass (g)
85
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
epithelial tissues. For this analysis, EPA used the difference of the total surface area for olfactory nasal
epithelial tissue computed here, 7.07 cm2, and the surface area for the anterior dorsal olfactory region
used by Campbell et al. (2014). 0.42 cm2 (apparently based on Frederick et al. (1998). Kimbell et al.
(1993), and Kimbell et al. (1997)), to estimate a surface area of 6.65 cm2 for the posterior dorsal
olfactory tissue as shown in Table F-2. EPA also used the difference of the total surface area for
respiratory nasal epithelial tissue computed by us, 6.59 cm2, and the surface area for the dorsal
respiratory and anterior ventral respiratory regions used by Campbell et al. (2014), 0.2 cm2 and 1.8 cm2,
respectively (again based on Frederick et al. (1998). Kimbell et al. (1993). and Kimbell et al. (1997)). to
estimate a surface area of 4.59 cm2 for the posterior ventral respiratory tissue as shown in Table F-2.
Campbell et al. (2.014) did not provide references for the values they used for surface areas of the
"nasopharynx," conducting airways, and pulmonary region compartments of their PBPK model. EPA
used the same surface area value reported by Campbell et al. (2014) for the "nasopharynx," 1.5 cm2,
although the compartment in their model and the surface area value appear both to represent the
pharynx and larynx rather than the nasopharynx. EPA also used the same surface area value reported by
Campbell et al. (2.014) for the conducting airways, 48 cm2, which matches the value reported by
Sarangapani et al. (2002). Finally, EPA used a value of 3,400 cm2 for the surface area of the pulmonary
region epithelial tissue. This value was used by Sarangapani et al. (2002) and agrees with the value
reported by U.S. EPA (1994). but differs from the value used by Campbell et al. (2014).
The values of the respiratory tract surface area parameters shown in Table F-2 were used to obtain the
dose metric results shown in Table 3.
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Appendix G: Human Equivalent Concentrations Calculation Script
#
# HEC_from_DM.R
#
# Author: Dustin Kapraun, US EPA, September 2018
#
# Given a specific value for an animal dose metric, this code calculates a
# human equivalent concentration (HEC). (That is, for a specified internal
# concentration or tissue rate of delivery, this code will compute the human
# inhalation exposure, or inhalation concentration, that will result in the
# same internal concentration.) Running this code simulates inhalation exposure
# scenarios in a human and uses optimization to find the HEC. This script
# requires the MCSim naphthalene model implementation ("naph_pbtk_pde").
#
# Reference:
# JL Campbell, ME Andersen, HJ Clewell, "A hybrid CFD-PBPK model for
# naphthalene in rat and human with IVIVE for nasal tissue metabolism and
# cross-species dosimetry," Inhalation Toxicology 26(6): 333-344, 2014.
#
# Set working directory to the directory containing this file.
script_dir = dirname (sys.frame (1)$ofile)
setwd(script_dir)
# Load the model "naph_pbtk_pde".
source("init_naph_pbtk_pde.R")
# Define functions to calculate various dose metrics.
dose_metric <- function(CINPPM, dmid, parms, Y0, times)
# Set inhalation concentration.
PPMtoNMPML = parms[["PPMtoNMPML"]] # Conversion factor
CIN = CINPPM * PPMtoNMPML # Inhalation exposure dose
Y0["CIN"] = CIN
#
# Implement inhalation dosing using deSolve "events".
# pattern based on the original study design (i.e., x
# Create a data frame containing the dosing events.
x = 24
TCHNG1 = x * 60 # Inhalation exposure duration (i
# Implement inhalation dosing using deSolve "events".
# that lasts x hours.
t_inh_on = c(0)
t_inh_off = t_inh_on + TCHNG1
df_inh_on = data.frame(var=rep("CIN", length(t_inh_on)), time=t_inh_on,
value=rep(CIN, length(t_inh_on)) ,
method=rep("replace", length(t_inh_on)))
df_inh_off = data.frame(var=rep("CIN", length(t_inh_off)), time=t_inh_off,
value=rep(0, length(t_inh_off)),
method=rep("replace", length(t_inh_off)))
df_inh = rbind(df_inh_on, df_inh_off)
df_inh = df_inh[order(df_inh$time),]
# Run simulation.
out = run_model (model_name, times, Y0=Y0 , pa2nTLS=pa2nris,
event_list=list(data=df_inh))
#
{
for ppm to nmol/mL.
(nmol/mL).
Assume an exposure
h/day, 5 day/week).
in) .
Assume a single exposure
87
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Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene
nt = length(times)
# Calculate specified dose metric,
if (dmid == 1) {
# Dose Metric 1: average naphthalene concentration in DO tissue (ug/mL).
avg_conc = out[, "AUC_CTDO_UG"] / times
dmval = avg_conc[nt]
} else if (dmid = 2) {
# Dose Metric 2: average rate of delivery of naphthalene to DO tissue
# (ug/cmA2/min).
avg_rod = out[, "AUC_RDELDO_UG"] / times
dmval = avg_rod[nt]
} else if (dmid = 3) {
# Dose Metric 3: average rate of production of metabolite in DO tissue
# (ug/mL/min).
avg_rop = out[, "AUC_RCMTDO_UG"] / times
dmval = avg_rop[nt]
} else if (dmid = 4) {
# Dose Metric 4: average blood concentration (ug/mL).
avg_conc = out[, "AUC_CAB_UG"] / times
dmval = avg_conc[nt]
} else if (dmid = 5) {
# Dose Metric 5: average rate of production of metabolite in whole body
# (ug/kg/min).
avg_rop = out[, "AUC_RCMBODY_UG"] / times
dmval = avg_rop[nt]
} else if (dmid = 6) {
# Dose Metric 6: cumulative metabolite production in DO tissue (ug/mL).
cum_prod = out[, "AUC_RCMTDO_UG"]
dmval = cum_prod[nt]
}
return (dmval)
}
cost_fun <- function(CINPPM_hum, DM_hum, dmid, parms, YO, times) {
DM_hum_calc = dose_metric(CINPPM_hum, dmid, parms, YO, times)
return((DM_hum_calc - DM_hum) ** 2)
}
# Specify the simulation duration.
# TSTOP =365 *24* 60 # Simulation time of 1 year (min).
# TSTOP =1*24* 60 # Simulation time of 1 day (min)
TSTOP = 10 * 24 * 60 # Simulation time of 10 days (min).
CINT =6 # Frequency with which solver should report results (min).
times = seq(from=0, to=TSTOP, by=CINT)
# Load human model parameters into "parms".
parms = get_human_parms()
# Modify default PPMtoNMPL parameter from Campbell et al. (2014) to use two
# significant figures.
parms["PPMtoNMPML"] = 0.0416 # nmol/mL per ppm
# Get values of human parameters.
BW_hum = parms [ ["BW" ] ] # Body mass (g) .
DO_vol_hum = parms[["VTDOl"]] + parms[["VTD02"]] # DO volume (mL).
# Set default initial values of states.
Y0 = initStates(parms)
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Derivation of an Acute Reference Concentration for
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# # BMD values (ug/mL) values shared by Allen Davis on 7/20/2020.
# DM_rat_vec = c(24.8, # BMDL
# 35.7, # BMD
# 54.8) # BMDU
# BMD values (ug/mL) values shared by Allen Davis on 1/3/2022.
DM_rat_vec = c(24.2, # BMDL
34.8, # BMD
53.4) # BMDU
for (DM_rat in DM_rat_vec) {
DM_hum = DM_rat
# DM3_hum = DM3_rat * (BW_rat / BW_hum)
# DM3_hum = DM3_rat * (BW_hum / BW_rat)
# DM3 hum = DM3 rat * (DO vol rat / DO
** 0.25
** 0.75 * (DO_vol_rat / DO_vol_hum)
vol hum) ** 0.25
# Find human equivalent concentration that will yield the specified dose
# metric.
opt_result = optimize(cost_fun, c(0, le6), DM_hum, 6, parms, Y0, times)
CINPPM_hum = opt_result$minimum
CINMGPM3_hum = CINPPM_hum * parms [[" PPMtoNMPML"] ] * parms [["MW1"] ]
# cat("DM_rat =", DM_rat, "ug/mL/min => HEC =", CINPPM_hum, "ppm",
# "=", CINMGPM3_hum, "mg/mA3\n")
cat("DM_rat =", DM_rat, "ug/mL => HEC =", CINPPM_hum, "ppm",
"=", CINMGPM3_hum, "mg/mA3\n")
}
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Derivation of an Acute Reference Concentration for
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Appendix H: Quality Assurance for the Derivation of an Acute Reference Concentration for
Inhalation Exposure to Naphthalene (CASRN 91-20-3)
This assessment is prepared under the auspices of the U.S. Environmental Protection Agency (EPA)
within the Office of Research and Development (ORD) in the Center for Public Health and Environmental
Assessment (CPHEA). EPA has an agency-wide quality assurance (QA) policy that is outlined in the EPA
Quality Manual for Environmental Programs (see CIO 2105-P-01.1) and follows the specifications
outlined in EPA Order CIO 2105.1.
As required by CIO 2105.1, ORD maintains a Quality Management Program, which is documented in an
internal Quality Management Plan (QMP). The latest version was developed in2013 using Guidance for
Developing Quality Systems for Environmental Programs (QA/G-1). An NCEA/CPHEA-specific QMP was
also developed in 2013 as an appendix to the ORD QMP. QA for products developed within CPHEA is
managed under the ORD QMP and applicableappendices.
This work was conducted under the U.S. EPA Quality Assurance program to ensure data are of known
and acceptable quality to support their intended use. Surveillance of the work by the assessment
managers and programmatic scientific leads ensured adherence to QA processes and criteria, as well as
quick and effective resolution of any problems. The QA manager, assessment managers, and
programmatic scientific leads have determined under the QA program that this work meets all U.S. EPA
quality requirements. This assessment was written with guidance from the CPHEA Quality Assurance
Project Plans (QAPPs; see table below). As part of the QA system, a quality product review is conducted
prior to management clearance. A Technical Systems Audit may be performed at the discretion of the
QA staff. During the assessment development, this project underwent one quality audit on October 15,
2021, with no major findings. All assessments receive internal peer review by at least two CPHEA
scientists and an independent external peer review by at least three scientific experts. The reviews focus
on whether all studies have been correctly selected, interpreted, and adequately described for the
purposes of deriving a reference value. The reviews also cover quantitative and qualitative aspects of
the value development and address whether uncertainties associated with the assessment have been
adequately characterized. ERG, Inc. conducted a contractor-led peer review of this report under
contract EP-C-17-017 (Order No. 68HERH20F0097).
Title
Document number
Latest approval date
Superfund Health Risk Technical Support
Center (STSC) and Related Technical
Support Activities
L-CPAD-0033105-QP
March 2021
Quality Assurance Project Plan (QAPP) for
Enhancements to Benchmark Dose
Software (BMDS)
L- H E EAD-0032189-QP
September 2020
Umbrella Quality Assurance Project Plan
(QAPP) for Dosimetry and Mechanism-
Based Models
L-CPAD-0032188-QP
December 2020
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Derivation of an Acute Reference Concentration for
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Appendix I: References
Hazardous air pollutants, 1-31 (2015).
https://eregulatioris.ct.gov/eRegsPortal/Browse/getDocumerit7guid ={00D6A654-0300-CC47-
9B95-397D2AD21304}
Abdo, KM; Grumbein, S; Chou, BJ; Herbert, R. (2001). Toxicity and carcinogenicity study in F344 rats
following 2 years of whole-body exposure to naphthalene vapors. Inhal Toxicol 13: 931-950.
http://dx.doi.org/10.1080/0895837Q1752378179
ACGIH. (1992). Documentation of the threshold limit values and biological exposure indices
Naphthalene (6th ed.). Cincinnati, OH.
ACGIH. (2001). Documentation of the threshold limit values and biological exposure indices
Naphthalene. Cincinnati, OH.
Agresti, A. (2007). An introduction to categorical data analysis (2nd ed.). Hoboken, NJ: John Wiley and
Sons.
ATSDR. (2005). Toxicological profile for naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene.
(PB2006100004). Atlanta, GA.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults.xhtml?searchCluerv=PB2006100004
ATSDR. (2014). Letter health consultation: Radiac Abrasives, Inc. Chicago, Illinois. Atlanta, GA.
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