EPA/690/R-22/006F | September 2022 | FINAL
United States
Environmental Protection
Agency
xvEPA
Provisional Peer-Reviewed Toxicity Values for
The Aromatic High Carbon Range Total Petroleum
Hydrocarbon (TPH) Fraction (Cancer)
(various CASRNs)
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
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A United Stiles
WtirV Protection
EPA/690/R-22/006F
September 2022
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
The Aromatic High Carbon Range Total Petroleum
Hydrocarbon (TPH) Fraction (Cancer)
(various CASRNs)
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGERS
Glenn E. Rice, ScD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Allison L. Phillips, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
CONTRIBUTORS
M. Margaret Pratt, PhD
Center for Public Health and Environmental Assessment, Washington, DC
Karen Hogan, Retired
Center for Public Health and Environmental Assessment, Washington, DC
Jeff Swartout (deceased)
Center for Public Health and Environmental Assessment, Cincinnati, OH
Jacqueline Weinberger, Student Services Contractor
Oak Ridge Associated Universities
Charlotte Moreno, Student Services Contractor
Oak Ridge Associated Universities
Emily Noeske, Student Services Contractor
Oak Ridge Associated Universities
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Jeffry L. Dean II, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
M. Margaret Pratt, PhD
Center for Public Health and Environmental Assessment, Washington, DC
PRIMARY EXTERNAL REVIEWERS
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
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PPRTV PROGRAM MANAGEMENT
Teresa L. Shannon
Center for Public Health and Environmental Assessment, Cincinnati, OH
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) Center for Public Health and Environmental
Assessment (CPHEA) website at https://ecomments.epa.gov/pprtv.
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS vi
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
1. INTRODUCTION 3
1.1. DEFINITION OF THE AROMATIC HIGH CARBON RANGE FRACTION 3
1.2. OVERVIEW OF PHYSICOCHEMICAL PROPERTIES AND ENVIRONMENTAL
FATE 4
1.3. OVERVIEW OF MIXTURE ASSESSMENT METHODS 7
1.3.1. Indicator Chemical Approach 8
1.3.2. Relative Potency Factor Approach 9
1.3.3. Integrated Addition Approach 10
1.3.4. Limitations and Uncertainties Associated with Component Methods 11
1.4. REVIEW 01 AVAILABLE ASSESSMENTS 11
1.5. DOCUMENT OVERVIEW 11
2. INDICATOR CHEMICAL METHOD 13
2.1. CONSIDERATIONS FOR INDICATOR CHEMICAL SELECTION FOR THE
AROMATIC HIGH CARBON HYDROCARBON FRACTION CANCER
ASSESSMENT 13
2.1.1. Indicator Chemical Selection 13
2.1.2. Estimating Cancer Risk Using Indicator Chemical 17
3. RELATIVE POTENCY FACTORS APPROACH FOR POLYCYCLIC AROMATIC
HYDROCARBONS IN THE AROMATIC HIGH CARBON RANGE FRACTION 18
3.1. SELECTION OF BENZO[A]PYRENE AS AN INDEX CHEMICAL 18
3.2. U.S. EPA'S RELATIVE POTENCY FACTOR APPROACH FOR POLYCYCLIC
AROMATIC HYDROCARBONS 20
3.2.1. Estimating Cancer Risk Using the Relative Potency Factor Approach 21
4. USING INTEGRATED ADDITION TO ESTIMATE CANCER RISKS POSED BY
POLYCYCLIC AROMATIC HYDROCARBONS AND OTHER CARCINOGENS IN THE
AROMATIC HIGH CARBON FRACTION 23
4.1. 1.1-BIPI H:\ YI. ORAL CANCER ASSESSMENT 23
4.2. 1 -METHYLNAPHTHALENE CANCER ASSESSMENT 24
4.3. APPLYING THE INTEGRATED ADDITION METHOD TO ESTIMATE CANCER
RISK FROM THE AROMATIC HIGH CARBON FRACTION 24
5. CONCLUSION 26
APPENDIX A. REFERENCES 27
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
IRIS
Integrated Risk Information System
ACGIH
American Conference of Governmental
IVF
in vitro fertilization
Industrial Hygienists
LC50
median lethal concentration
AIC
Akaike's information criterion
LD50
median lethal dose
ALD
approximate lethal dosage
LOAEL
lowest-observed-adverse-effect level
ALT
alanine aminotransferase
MN
micronuclei
AR
androgen receptor
MNPCE
micronucleated polychromatic
AST
aspartate aminotransferase
erythrocyte
atm
atmosphere
MOA
mode of action
ATSDR
Agency for Toxic Substances and
MTD
maximum tolerated dose
Disease Registry
NAG
7V-acetyl-P-D-glucosaminidase
BMC
benchmark concentration
NCI
National Cancer Institute
BMCL
benchmark concentration lower
NOAEL
no-observed-adverse-effect level
confidence limit
NTP
National Toxicology Program
BMD
benchmark dose
NZW
New Zealand White (rabbit breed)
BMDL
benchmark dose lower confidence limit
OCT
ornithine carbamoyl transferase
BMDS
Benchmark Dose Software
ORD
Office of Research and Development
BMR
benchmark response
PBPK
physiologically based pharmacokinetic
BUN
blood urea nitrogen
PCNA
proliferating cell nuclear antigen
BW
body weight
PND
postnatal day
C#
carbon number
POD
point of departure
CA
chromosomal aberration
PODadj
duration-adjusted POD
CAS
Chemical Abstracts Service
QSAR
quantitative structure-activity
CASRN
Chemical Abstracts Service registry
relationship
number
RBC
red blood cell
CBI
covalent binding index
RDS
replicative DNA synthesis
CHO
Chinese hamster ovary (cell line cells)
RfC
inhalation reference concentration
CL
confidence limit
RfD
oral reference dose
CNS
central nervous system
RGDR
regional gas dose ratio
CPHEA
Center for Public Health and
RNA
ribonucleic acid
Environmental Assessment
SAR
structure-activity relationship
CPN
chronic progressive nephropathy
SCE
sister chromatid exchange
CYP450
cytochrome P450
SD
standard deviation
DAF
dosimetric adjustment factor
SDH
sorbitol dehydrogenase
DEN
diethylnitrosamine
SE
standard error
DMSO
dimethylsulfoxide
SGOT
serum glutamic oxaloacetic
DNA
deoxyribonucleic acid
transaminase, also known as AST
EC
equivalent carbon
SGPT
serum glutamic pyruvic transaminase,
EPA
Environmental Protection Agency
also known as ALT
ER
estrogen receptor
SSD
systemic scleroderma
FDA
Food and Drug Administration
TCA
trichloroacetic acid
FEVi
forced expiratory volume of 1 second
TCE
trichloroethylene
GD
gestation day
TWA
time-weighted average
GDH
glutamate dehydrogenase
UF
uncertainty factor
GGT
y-glutamyl transferase
UFa
interspecies uncertainty factor
GSH
glutathione
UFc
composite uncertainty factor
GST
glutathiones-transferase
UFd
database uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFh
intraspecies uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFl
LOAEL-to-NOAEL uncertainty factor
HEC
human equivalent concentration
UFS
subchronic-to-chronic uncertainty factor
HED
human equivalent dose
U.S.
United States of America
i.p.
intraperitoneal
WBC
white blood cell
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV document.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR THE AROMATIC
HIGH CARBON RANGE TOTAL PETROLEUM HYDROCARBON (TPH)
FRACTION (CANCER)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund program. PPRTVs are derived after a review of the relevant
scientific literature using established U.S. Environmental Protection Agency (U.S. EPA)
guidance on human health toxicity value derivations.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
Currently available PPRTV assessments can be accessed on the U.S. EPA's PPRTV
website at https://www.epa.gov/pprtv. PPRTV assessments are eligible to be updated on a 5-year
cycle and revised as appropriate to incorporate new data or methodologies that might impact the
toxicity values or affect the characterization of the chemical's potential for causing adverse
human-health effects. Questions regarding nomination of chemicals for update can be sent to the
appropriate U.S. EPA's eComments Chemical Safety web page
(https ://ecomments epa. gov/chemical safety/).
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) 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 PPRTV was written
with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP), the QAPP
titled Program Quality Assurance Project Plan (PQAPP) for the Provisional Peer-Reviewed
Toxicity Values (PPRTVs) and Related Assessments/Documents (L-CPAD-0032718-QP), and the
PPRTV development contractor QAPP titled Quality Assurance Project Plan—Preparation of
Provisional Toxicity Value (PTV) Documents (L-CPAD-0031971-QP). As part of the QA
system, a quality product review is done prior to management clearance. A Technical Systems
Audit may be performed at the discretion of the QA staff.
All PPRTV 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 provisional reference value. The reviews also cover quantitative and
qualitative aspects of the provisional value development and address whether uncertainties
associated with the assessment have been adequately characterized.
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1 DISCLAIMERS
2 The PPRTV document provides toxicity values and information about the adverse effects
3 of the chemical and the evidence on which the value is based, including the strengths and
4 limitations of the data. All users are advised to review the information provided in this document
5 to ensure that the PPRTV used is appropriate for the types of exposures and circumstances at the
6 site in question and the risk management decision that would be supported by the risk
7 assessment.
8 Other U.S. EPA programs or external parties who may choose to use PPRTVs are
9 advised that Superfund resources will not generally be used to respond to challenges, if any, of
10 PPRTVs used in a context outside of the Superfund program.
11 This document has been reviewed in accordance with U.S. EPA policy and approved for
12 publication. Mention of trade names or commercial products does not constitute endorsement or
13 recommendation for use.
14 QUESTIONS REGARDING PPRTVS
15 Questions regarding the content of this PPRTV assessment should be directed to the
16 U.S. EPA ORD CPHEA website at https://ecomments.epa.gov/pprtv.
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1. INTRODUCTION
This Provisional Peer-Reviewed Toxicity Value (PPRTV) assessment supports a
fraction-based approach to risk assessment for mixtures of petroleum hydrocarbons U.S. EPA
(2022a. 2009). In this approach, total petroleum hydrocarbon (TPH) fractions are defined based
on expected transport in the environment and analytical methods used to quantify environmental
contamination by TPH mixtures. TPH components were first classified into aromatics and
aliphatics, and each of these two major fractions were further separated into low, medium, and
high carbon range fractions. This PPRTV assessment describes the cancer assessment approach
for the aromatic high carbon range fraction of TPH. The toxicity values described herein are used
in the assessment of Complex Mixtures of Petroleum Hydrocarbons that is intended to replace
current approaches used at TPH-contaminated sites U.S. EPA (2022a. 2009).
In general, fraction-based approaches involve: (1) dividing a complex mixture into
groups based on similarities in their chemical structures or chemical properties; (2) measuring
the concentrations of these groups (or the components within the group) in environmental media
or estimating the rates of human exposure in mg/kg-day to these groups; (3) selecting an
approach to characterize a dose-response relationship for the group; (4) combining the
dose-response approach and the exposure estimates for all members of the group to estimate
health risks from the group; and (5) estimating risks or hazards posed by exposure to the
complex mixture using the risk characterization information from the individual groups [adapted
from Atsdr (2018)1.
1.1. DEFINITION OF I II I AROMATIC HIGH CARBON RANGE FRACTION
The aromatic high carbon range fraction includes aromatic hydrocarbons with a carbon
(C) range of C10-C32 (contains between 10 and 32 carbons, inclusive) and an equivalent carbon
(EC)1 number index range of EC11-EC35 that occur in, or co-occur with, petroleum
contamination. It should be noted that the aromatic medium carbon range fraction of the TPH
mixture assessment also includes C10 compounds but, unlike the aromatic high carbon range
fraction, is restricted to those with EC9-EC < ll.2 The EC index is equivalent to the retention
time of the compound on a boiling point gas chromatography (GC) column (nonpolar capillary
column), normalized to //-alkanes NJ PEP (2010; Sternberg et al. (1962). As such, EC numbers
are the physical characteristic that underpin analytical separation of petroleum components. EC
numbers are useful because they are more closely related to environmental mobility than carbon
number. Grouping based on EC numbers provides a consistent basis for logically placing
petroleum hydrocarbon compounds into fractions, because EC measures correlate with
physicochemical properties such as water solubility, vapor pressure, Henry's law constant, and
soil adsorption coefficient (log Koc). Individual compounds in this fraction have a backbone
consisting of one or more aromatic rings, which can be substituted with alkane, alkene, and other
nonaromatic ring structures. Example compounds include 1,2,4-triethylbenzene,
1-methylnaphthalene, 1,1-biphenyl, fluorene, and benzo[a]pyrene (BaP).
1 Based on an empirical relationship, the EC value can be estimated from a compound's boiling point (BP; °C) using
the following equation: EC = 4.12 + 0.02 (BP) + 6.5 x 10~5 (BP)2; see Gustafson et al. (1997a).
2The "EC criterion" avoids placing the generally less toxic substituted benzenes (C9-C10) withPAHs,
naphthalenes, and 1,1-biphenyl in the same fraction.
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The aromatic high carbon range fraction as described above is further subdivided for the
purposes of this document as follows. Unsubstituted polycyclic aromatic hydrocarbons (PAHs)
consist of aromatic hydrocarbons comprised of two to six fused aromatic hydrocarbon rings and
exclude all compounds with alkyl or other substituents on the ring as well as compounds with
anything other than carbon and hydrogen in their composition (i.e., exclude heterocyclic
compounds). Substituted PAHs (subPAHs) include alkyl-substituted PAH derivatives such as
1,4-dimethylphenanthrene, 1-methylnaphthalene, and 5-methylchrysene. Carcinogenic fraction
members that cannot be classified as either PAH or subPAH include all other aromatic
hydrocarbons within the C10-C32 and EC11-EC35 ranges that occur in petroleum
contamination, such as 1,1-biphenyl.
1.2. OVERVIEW OF PHYSICOCHEMICAL PROPERTIES AND ENVIRONMENTAL
FATE
The systematic chemical names, synonyms [following guidance in Nist (2020bVI.
CASRNs, chemical abbreviations, and chemical structures for 1,1-biphenyl,
1-methylnaphthalene, and the seven PAHs in this document are listed in Table 1 and in
Appendix B of U.S. EPA (2022a). The physicochemical properties for these chemicals, compiled
from the CompTox Chemicals Dashboard U.S. EPA (2021), are provided in Table 2. As
indicated by the octanol-water partition coefficient (log Kow) and octanol-air partition coefficient
(log Koa) values, PAHs are generally solids at room temperature; they have moderate to low
water solubility and vapor pressure. Members of this fraction generally are expected to have little
to no mobility in soil, based on measured log Koc data.
Table 1. Synonyms and Abbreviations for Chemicals in this PPRTV
Assessment"
Chemical (common synonymsb)
CASRN
Abbreviation
Structure
Benzo [a]pyrene
(benzo [pgr] tetraphene;
benzol tfe/lchrvscnc:
1,2-benzpyrene;
3.4-benzopyren;
4.5-benzpyrene;
6,7 -benzopyrene)
50-32-8
BaP
Benz [a] anthracene
(tetraphene;
benzo\h |phcnanthrcnc:
1,2-benzanthracene;
2,3 -benzophenanthrene;
1,2-benzanthrene;
naphthanthracene)
56-55-3
BaAC
Benz [e] acephenanthrylene
(b c n /o | /> | fl no ra n t lie nc:
benzo [e]fluoranthene;
benzo [e] acephenanthrylene;
3,4-benz[e]acephenanthrylene;
2.3 -benzofluoranthene;
3.4 -benzofluoranthene)
205-99-2
BeAPE
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Table 1. Synonyms and Abbreviations for Chemicals in this PPRTV
Assessment"
Chemical (common synonymsb)
CASRN
Abbreviation
Structure
Benzo [A]fluoranthcnc
(bibenzo [b,jk] fluorene;
8,9-benzofluoranthene;
11,12-benzofluoranthene;
2,3:1 ',8'-biaphthylene)
207-08-9
BkFA
ocx8
Chrysene
(benzo [ajphenanthrene;
1,2-benzophenanthrene)
218-01-9
CH
Dibenz[a, h] anthracene
(benzo [k\ tetraphene;
1,2:5,6-dibenzoanthracene;
1,2:5,6-benzanthracene;
1,2:5,6-benz[a] anthracene)
53-70-3
DBahAC
Indeno[l,2,3-c,
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Table 2. Physicochemical Properties of Selected Aromatic High Carbon Range Compounds"
Chemical
BaP
BaAC
BeAPE
BkFA
CH
DBahAC
I123cdP
BH
lMeNPT
BeP
Structure
OCcQ
CK3
CASRN
50-32-8
56-55-3
205-99-2
207-08-9
218-01-9
53-70-3
193-39-5
92-52-4
90-12-0
192-97-2
Molecular formula
C20H12
C18H12
C20H12
C20H12
C18H12
C22H14
C22H12
C12H10
C11H10
C20H12
EC numberb
30.0
25.3
25.0
28.7
26.1
32.5
32.6
13.5
12.7
27.80
Molecular weight
(g/mol)
252.316
228.294
252.316
252.316
228.294
278.354
276.338
154.212
142.201
252.316
Melting point (°C)
111
159
166
217
255
268
164
69.8
-3.10
178
Boiling point (°C)
495
437
434*
480
448
524
536
255
242
469*
Vapor pressure
(mm Hg at 25°C)
5.48 x 10-9
2.10 x 10-7
5.00 x 10-'
9.65 x 10-10
6.23 x 10-9
9.55 x 10-10
7.05 x 10-10*
8.93 x 10-3
6.70 x 10-2
5.70 x 10-9
Henry's law constant
(atm-m3/mol at
25°C)
4.57 x 10~7
1.20 x 10-5
6.57 x 10-7
5.84 x 10 7
5.23 x 10-6
9.24 x 10 7*
3.48 x 10 7
3.08 x 10~4
5.14 x 10~4
1.07 x 10-6*
Water solubility
(mg/L at 25°C)
8.4 x 10~9
5.23 x 10-8
9.4 x 10-9
3.2 x 10-9
1.22 x 10-s
4.31 x 10-9
6.9 x 10-10
4.60 x 10 5
1.95 x 10~4
1.89 x 10-8
Log Kow
6.13
5.6
5.78
6.11
5.81
6.63
6.74*
4.01
3.87
6.44
Log Koa
9.61*
9.37*
8.64*
9.38*
9.37*
11.7*
11.7*
6.15
5.01*
10.3*
Log Koc
5.95
5.30
5.42*
4.34
5.20*
6.22
6.20
3.27
3.36
5.67*
'Data arc presented as experimental averages from the U.S. EPA CompTox Chemicals Dashboard unless otherw ise stated; https://eomptox.epa.gov/dashboard: updated
02-03-2021 U.S. EPA (20211.
bEC number was developed by the TPHCWG and is proportional to the BP of a chemical. EC number is analogous to an //-paraffin retention time index and can be
estimated using the following equation: EC = 4.12 + 0.02 (BP) + 6.5 x 10~5 (BP)2 NIST (2020a: Edwards et at (1997: Gustafson et at (1997b).
*Predicted value.
BaAC = benz[a]anthracene; BaP = benzo[a]pyrene; BeAPE = benz[e]acephenanthrylene; BeP = benzo[e]pyrene; BH = 1,1-biphenyl; BP = boiling point;
BkFA = ben/o|/i'|flnorantlienc: CH = chrysene; DBahAC = dibenz[a,/z]anthracene; EC = equivalent carbon; I123cdP = indcno| 1.2.3-6,c/|pyrcnc: Koa = octanol-air
partition coefficient; Koc = soil adsorption coefficient; Kow = octanol-water partition coefficient; lMeNPT = 1-methylnaphthalene; TPHCWG = Total Petroleum
Hydrocarbon Criteria Working Group; U.S. EPA = U.S. Environmental Protection Agency.
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Volatilization of members of this fraction from water and moist soil will be moderate
based upon the measured Henry's law constant values. Volatilization from dry soil surfaces is
expected to be low to moderate based upon the measured vapor pressure values. Measured
aerobic and anaerobic biodegradation data are available for the representative compounds. Under
aerobic conditions, some PAHs are expected to have slow removal by biodegradation in
unacclimated systems and more rapid biodegradation in acclimated systems. Acclimation periods
(days to months) have been observed prior to the onset of microbial degradation in tests using
soil not previously exposed to PAHs. It is thought that this occurs because small population(s) of
organisms capable of PAH degradation must attain sufficient densities before detectable PAH
reduction is observed Mihelcic and Luthv (1988). 1,1-Biphenyl undergoes biodegradation more
readily than many PAHs, as demonstrated in a modified test where 1,1-biphenyl achieved 66%
of its theoretical biochemical oxygen demand (BOD) after 14 days ECHA (2019; Oecd (2009).
Under anaerobic conditions, biodegradation reactions are believed to occur slowly for all fraction
members. Members of the aromatic high carbon range fraction do not contain hydrolysable
functional groups; therefore, the rate of hydrolysis is expected to be negligible for all fraction
members. In the atmosphere, the rate of photooxidation is expected to be moderate for fraction
members. Many of the fraction members, except, for example, 1,1-biphenyl, contain
chromophores that absorb at wavelengths >290 nm, and are therefore expected to be susceptible
to direct photolysis by sunlight NLM (2017a. b, c, d, e, f, g, 2015a. b, 2014. 2005). When the
fraction members occur in the atmosphere in the particulate phase, they will be physically
removed by wet and dry deposition.
1.3. OVERVIEW OF MIXTURE ASSESSMENT METHODS
A number of different approaches have been developed and used to estimate risks and
hazards posed by exposures to chemical mixtures encountered in the environment. The three
utilized in this PPRTV assessment are the indicator chemical approach, the relative potency
factor approach, and integrated addition. The choice of approaches is based on the available
analytical chemistry.
The simplest of these approaches to implement is the indicator chemical approach Atsdr
(2018). The indicator chemical approach estimates the risk or hazard of a mixture by evaluating
the dose-response assessment developed for a component of the mixture to the exposure rate of
the entire mixture. The indicator chemical approach is used when there are only measures of the
concentrations of this fraction (i.e., no information is available on the concentrations of
individual chemicals in this fraction).
In addition to the indicator approach, the U.S. Environmental Protection Agency (EPA)
Supplementary Guidance for Conducting Health Risk Assessment of Chemical Mixtures (U.S.
EPA (2000. 1986) describes the following two broad categories of approaches for assessing
human health risks and health hazards associated with environmental exposures to chemical
mixtures: component methods and whole mixture methods. Component-based approaches, which
involve analyzing the toxicity of a mixture's individual components, have more inherent
uncertainty and are recommended when appropriate toxicity data on a mixture of concern, or on
a sufficiently similar mixture (discussed below), are unavailable U.S. EPA (2000. 1986). In this
PPRTV assessment, two component approaches are described for assessing cancer risks posed
by exposures to the aromatic high carbon range fraction, when there are sufficient component
exposure and toxicity data: (1) the relative potency factor (RPF) approach is used to evaluate
cancer risks posed by selected PAHs and (2) a general integrated addition approach is used to
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assess cancer risks posed by the aromatic high carbon range fraction. This includes a group of
PAHs that mediate carcinogenicity through a mutagenic mode of action (MOA), as well as two
other non-PAH carcinogens (i.e., 1,1-biphenyl and 1-methylnaphthalene) placed in separate
groups because their carcinogenicity does not appear to be mediated through a mutagenic MOA.
These component-based approaches are pursued and described in subsequent sections of this
assessment.
Chemical mixture assessments are conducted most appropriately with quantitative dose-
response information resulting from comparable exposures to the mixture of concern. If the dose-
response data are insufficient to develop a health reference value for the specific mixture of
concern in the environment, the second option that the U.S. EPA Supplementary Guidance for
Conducting Health Risk Assessment of Chemical Mixtures U.S. EPA (2000) recommends is a
"sufficient similarity" approach that uses a health reference value from a characterized surrogate
mixture to estimate the hazard or risk associated with exposures to the mixture of concern. This
method requires chemistry and toxicity data on both the potential surrogate mixture and the
mixture of concern (e.g., an in vitro endpoint that is related to the apical endpoint observed in an
epidemiological study or whole animal study), and a health reference value (e.g., from an in vivo
study) on the surrogate mixture. If the chemistry and toxicity data indicate that the mixtures are
"sufficiently similar" to one another, then the health reference value for the surrogate mixture
can be used as a proxy for the mixture of concern. No data were identified that were suitable to
implement a whole mixture approach.
The choice of a chemical mixtures risk assessment method is driven by the available data.
Starting with the method requiring the least information and then discussing methods requiring
more information, the following subsections summarize the indicator chemical approach, the
RPF approach, and the integrated addition approach.
1.3.1. Indicator Chemical Approach
When the chemical composition of a mixture or a mixture fraction is not known, or
toxicity measures are only available for a few individual chemicals in a mixture, the toxicity of
an individual chemical can be used as an indicator for the toxicity of a mixture or a mixture
fraction Atsdr (2018). Atsdr (2018) describes an indicator chemical as "a chemical . . . selected
to represent the toxicity of a mixture because it is characteristic of other components in the
mixture and has adequate dose-response data." Indicator chemical approaches are typically
implemented to assess risks in a health-protective manner; the chemical chosen as an indicator is
among the best characterized toxicologically and likely among the most toxic components of the
mixture. The indicator chemical needs to have adequate dose-response data to indicate hazard
potential or dose-response relationship for cancer, depending on the purpose of the assessment.
The health risk value of the indicator chemical is integrated with exposure estimates for the
mixture or mixture fraction to estimate health risk from the group (i.e., calculate fraction-specific
hazard index or a fraction-specific cancer risk estimate for a specific exposure pathway). This
approach does not scale for the potency of individual constituents; instead, it assumes that
toxicity of all measured members of the fraction can be adequately estimated, given the purpose
of the risk assessment, by the indicator chemical.
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1.3.2. Relative Potency Factor Approach
The RPF approach is a component-based approach that assumes components in a mixture
act in a toxicologically similar manner. Such an assumption can be made when toxicologic data
on all components of a mixture are not available, and when the class of chemicals comprising the
mixture shares a known or suspected common MOA. Implementing an RPF approach requires a
quantitative dose-response assessment for an index chemical (IC) and pertinent scientific data
that allow the toxic potency of the mixture components to be meaningfully compared to that of
the IC.
Under the assumption of dose addition, the health risk associated with exposure to a
mixture can be estimated as follows: initially, the chemical component doses are scaled relative
to the potency of an IC, and then these scaled doses are summed and expressed as an index
chemical equivalent dose (ICED) for the mixture. For any given mixture, the general equation
below highlights the steps involved in estimating the ICED.
ICED = V RPF. D. +%
i—t
where
IC = index chemical
ICED = index chemical equivalent dose of the mixture (e.g., mg/kg-day)
RPFj = relative potency factor of the Mi PAH detected
in the mixture (unitless)
Dt = dose of the Mi chemical detected in the mixture (mg/kg-day)
DIC = dose of index chemical in the mixture (mg/kg-day), given that
the value of the RPF for the IC is 1
RPFs for individual components can be estimated using the slope factors of the Mi
components.
RPFj = slopej -h slope,c
= R/BMDR_j R/BMDr_ic
= BMl)R-iC -h BMl)R_j
where
BMD = benchmark dose
R = response
Next, a plausible upper bound on cancer risk can be estimated by multiplying the ICED
by the cancer risk estimate for the IC (e.g., oral slope factor [OSF] in [mg/kg-day ] oral unit
risk in [mg/L] or inhalation unit risk (IUR) in [mg/m3]-1).
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1.3.3. Integrated Addition Approach
Many mixture exposures, including the aromatic high carbon range fraction, contain
component chemicals that cause cancer in toxicologically dissimilar ways. This recognition of
the different bioactivities associated with complex mixtures led the U.S. EPA to develop a hybrid
general additivity approach that incorporated both dose addition and response addition, yielding
the probabilistic risk of the toxicologically relevant endpoint of concern—in this case,
carcinogenic risk of the mixture. While an RPF approach may be most applicable to an
assessment of cancer risk posed by P A Us comprised of the aromatic high carbon TPH fraction,
other TPH members of this fraction (e.g., 1-methylnaphthalene and 1,1-biphenyl) may cause
cancer through different MO As. For exposures to mixtures composed of such components and
when needed data are available, the U.S. EPA recommends the use of an integrated addition
approach.
For chemicals eliciting a common endpoint, the integrated addition approach begins with
separation of the mixture components into dose-additive groups % ^ \ ,2003) based on
similar MO As (i.e., "similarity groups"). Next, the assumptions of similarity within groups, and
then of toxicological independence across groups, are evaluated. If there are interactions [defined
by the U.S. EPA as a deviation from results predicted using an additivity model with individual
component exposure and dose-response data U.S. EPA. (2000): e.g., synergism or antagonism],
other mixture assessment methods would be preferred. Otherwise, within each similarity group,
the RPF approach is used to estimate the health risk associated with exposures to the group of
chemicals. The similarity group risks are then combined across all groups using response
addition to estimate the risk posed by the entire mixture U.S. EPA. (2000). In this assessment, the
MO As of chemicals such as 1,1-biphenyl are assumed to be independent from the MO As of the
PAHs. The specific steps of the integrated addition approach include:
• Forming toxicological similarity groups based on available information on MO A
(e.g., two similarity groups could cause the same effect through different MO As);
similarity groups can vary in size from a single member to many members.
• Selecting an IC for each similarity group.
• Developing RPFs for each similarity group, reflecting intragroup potency differences,
and exposure estimates.
• Calculating an ICED for each similarity group, based on the RPFs and component
exposure estimates.
• Calculating each similarity group mixture risk (as probability) for the common effect(s)
using the IC dose-response function.
• Estimating the total mixture risk using response addition across the similarity group risk
estimates using the following equation:
where
R-mix = risk posed by the mixture
Rj = risk posed by thejth subgroup (unitless)
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1.3.4. Limitations and Uncertainties Associated with Component Methods
Component methods involve substantial uncertainties that should be considered prior to
their application. In particular, component methods can be misinterpreted to reflect
well-characterized risk, due to knowledge of chemical component concentrations. In fact, a poor
understanding of the magnitude and nature of toxicological interactions can limit the confidence
of calculated risk. In addition, information is often lacking on the identity of some mixture
components, and mixture composition is often affected by fate and transport processes. As a
result, real-world mixture exposures may not always be reflective of unweathered mixtures
tested in laboratory settings. The IC and/or indicator chemical is selected based on the best
available data, even though all components of the fraction have not been structurally
well-characterized or tested for carcinogenic potential.
1.4. REVIEW OF AVAILABLE ASSESSMENTS
The U.S. EPA relied on the literature search described in a separate PPRTV assessment
that evaluates noncancer hazards associated with exposures to the aromatic high carbon range
fraction of TPH mixtures U.S. EPA (2022b); in addition, in June of 2020 and August of 2021,
U.S. EPA searched the literature to identify constituents of the fraction having existing cancer
risk values or relative potency estimates in the Integrated Risk Information System [IRIS],
PPRTV assessments, and U.S. EPA documents. These cancer risk values and relative potency
estimates are used in the approaches described below.
1.5. DOCUMENT OVERVIEW
The remainder of the document is divided into three sections. Each section describes, in
detail, the application of the approach to the assessment of cancer risk posed by exposure to the
aromatic high carbon fraction, including the information needed to implement each approach.
Section 2 addresses the indicator chemical approach and the selection of BaP as an indicator
chemical for the assessment of cancer risks posed by inhalation and oral route exposures to the
aromatic high carbon range fraction. Section 3 describes the U.S. EPA's RPFs for some PAHs, a
group of chemicals assumed to be toxicologically similar within the aromatic high carbon range
fraction. It also describes the selection of BaP as the IC. Section 4 details the integrated addition
approach as implemented for carcinogens in the aromatic high carbon range fraction including
those that are and are not PAHs. Figure 1 summarizes the three approaches and indicates
preference order for each approach.
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Available Exposure l)a(u
Fraction Measure
Aromatic high corbonfraetton
Approaches
Approach
Indicator C hemical Approach
BaP is indicator chemical
Individual
PAH Measures
Hal', ftti4C BeAPE, Bkl'A,
at, DiiahAC andII2JctS>
RPF Approach
Rf*Fx btixfvl wi a femitmm mufagrnic \K)A;
jBaP ts iruttx chwiirni
PA] I + non-PAI 1
Carcinogen
Measures
BaP, BfiAC, BeAPE, BkFA,
CH, DIM,AC. arid IntrrtP:
BH and 1-MeNPT
Integrated Addition Approach
RPFs based on a common mutagenic \fQA;
Cancer risks for BH and l-SSeSPT
calculated indnniutilh became of
mmmftagmtc MOAs
~
Three approaches are available to estimate the cancer risk associated with exposure to chemicals in the
aromatic high carbon range fraction. Approach selection should be driven by the available exposure data.
Increased analytical characterization of fraction components allows for more refined risk estimates with
less inherent uncertainty. Approach preference is inversely correlated with approach uncertainty.
BaAC = benz[o] anthracene: BaP = benzo[a]pyrene; BeAPE = benz[e]acephenantlirylene;
BH = 1,1 -biphenyl; BkFA = benzo[A]fluoranthene; CH = clirysene; DBaliAC = dibenzo[o,/?]antliracene;
I123cdP = indeno| L2.3-c,J|p_\rcne; 1-MeNPT = I-methylnaphthalene; MOA = mode of action;
PAH = polycyclic aromatic hydrocarbon; RPF = relative potency factor; TPH = total petroleum
hydrocarbon.
Figure 1. Provisional Peer-Reviewed Toxicity Approaches for the Aromatic High Carbon
Range TPH Fraction Cancer Assessment
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2. INDICATOR CHEMICAL METHOD
For some sites that are contaminated with TPH mixtures, only the mass of the aromatic
high carbon range fraction is measured; the concentrations of the individual components within
the fraction are not known. In this case, an indicator chemical can be selected to represent the
toxicity of the fraction. The cancer dose-response estimate for the indicator chemical can be
integrated with the exposure data for the entire mass of the fraction to estimate cancer risk posed
by exposure to the fraction. This approach can be considered a health-protective default approach
used to evaluate potential cancer risks from exposures to the aromatic high carbon hydrocarbon
fraction. The primary assumption is that the cancer OSF and IUR of the indicator chemical
provide a reasonable or health-protective estimate of those for the entire fraction. Sections 2.1
and 2.1.1 describe the criteria for selecting an indicator chemical.
2.1. CONSIDERATIONS FOR INDICATOR CHEMICAL SELECTION FOR THE
AROMATIC HIGH CARBON HYDROCARBON FRACTION CANCER
ASSESSMENT
The criteria suggested for selecting chemicals for potential use as indicator chemicals for
the aromatic high carbon range fraction cancer assessment are as follows:
• The indicator chemical should occur in the aromatic high carbon range (i.e., within the
C and EC number range of the hydrocarbon fraction).
• The health effect(s) of the indicator chemical must be similar to what is observed from
exposures to the fraction or what is anticipated based on available studies of the identified
components of the fraction. For this cancer assessment, the carcinogenicity associated
with potential indicator chemicals needed to be characterized (i.e., for a cancer
assessment, it should be characterized as a carcinogen).
• The indicator chemical should have available cancer risk estimates (e.g., OSF or
provisional oral slope factors [p-OSFs]) from the U.S. EPA or another appropriate
source, or adequate data for the direct derivation of cancer risk estimates.
• The carcinogenic potency of the indicator chemical should be similar to, or greater than,
those of the other likely fraction components.
2.1.1. Indicator Chemical Selection
BaP was selected as the indicator chemical for the fraction following consideration of
other chemicals in the fraction. Initially, the U.S. EPA considered 17 chemicals that occur in this
fraction that the Agency for Toxic Substances and Disease Registry (ATSDR) evaluated in their
PAH profile Atsdr (1995); see Table 3. ATSDR"s rationale for choosing these 17 chemicals
included: (1) more information was available on these than on the others; (2) they were
suspected to be more harmful than some of the others; and (3) there was documentation of
effects that were known to be characteristic of PAHs. Of these 17 PAHs, BaP was the only PAH
with an existing U.S. EPA OSF or IUR. Additional information that explains how BaP met the
considerations articulated in Section 2.1 is summarized below.
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Table 3. Chemicals Considered in the ATSDR PAH Toxicological Profile"
Acenaphthene
Be nzo |c/| pyre nc
Benzo [&]fluoranthene
Fluorene
Acenaphthylene
Benzo [e]pyrene
Chrysene
Indeno [1,2,3 -c, c/|pyrcne
Anthracene
Be n/o | w, /?, /1 pc ry lene
Dibenz [a, /?|anthracene
Phenanthrene
Benz[a]anthracene
Benzo [/]fluoranthene
Fluoranthene
Pyrene
Benz [e] acephenanthry lene
aAtsdr (1995).
ATSDR = Agency for Toxic Substances and Disease Registry; PAH = polycyclic aromatic hydrocarbon.
1 BaP has 20 carbons, within the carbon range (C10-C32) for this fraction. The EC for
2 BaP is 30.0, also within the range of EC 1 1-EC35 for the fraction ATSDR (1999).
3 BaP has been characterized as carcinogenic to humans by international health
4 organizations including U.S. EPA (2017) and IARC (2010); see also Straif et al. (2005). BaP has
5 been shown to induce tumors in animal studies both at the site of administration Culp et al.
6 (1998; Gavlor et al. (1998; Wevand et al. (1995) and at distal sites Wevand et al. (2004; Kroese
7 et al. (2001). Table 4 lists other PAHs that have been characterized by the International Agency
8 for Research on Cancer (IARC) as Group 1 (carcinogenic to humans), Group 2A (probably
9 carcinogenic to humans), or Group 2B (possibly carcinogenic to humans) IARC (2010).
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Table 4. PAHs Classified by the IARC as Group 2B or Greater Human
Carcinogens"
Common Name
Group
Benz [/'] aceanthry lene
2B
Benz[a]anthraceneb
2B
Benzo[/>]fluorantheneb (benz[e]acephenanthrylene in this assessment)
2B
Benzo [/]fluoranthene
2B
Benzo [&]fluorantheneb
2B
Benzo [c]phenanthrene
2B
Benzo [a]pyreneb
1
Chryseneb
2B
Cyclopcnta|«/|pyrcnc
2A
Dibenz [a, /?|anthraccnc'
2A
Dibenzo [a, /?|pvrcne
2B
Dibenzo [a, /]pyrene
2B
Dibenzo [a, l\pyrene
2A
Indeno [ 1,2,3 -c,
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cavity. In a study using B6C3F1 female mice exposed to BaP in the diet Behind and Gulp (1998;
Gulp et al. (1998). the study authors reported portal-of-entry tumors, including papillomas and/or
carcinomas of the forestomach, esophagus, tongue, and larynx. Dermal exposure studies using
BaP with several strains of mice demonstrated dose-response trends for skin tumors across a
range of doses and study durations Sivak et al. (1997; Grimmer et al. (1984; Habs et al. (1984;
Grimmer et al. (1983; Habs et al. (1980; Schmaht et al. (1977; Schmidt et al. (1973; Roe et al.
(1970; Poel (1963. 1959).
In comparison to the data available for oral and dermal routes of exposure, BaP
dose-response data are more limited for the inhalation route. The only inhalation carcinogenicity
study of BaP Thvssen et al. (1981) was limited by an atypical delivery method (adsorption onto
salt crystals), but clearly demonstrated upper respiratory tract tumors following BaP exposure in
hamsters and supported estimation of an IUR U.S. EPA (2017). Positive responses were also
reported in several studies employing intratracheal instillation of BaP Fcron and Kruvsse (1978;
Fcron et al. (1973; Henry et al. (1973; SatTiotti et al. (1972).
Although the exact composition of complex PAH mixtures varies, BaP is routinely
detected in many occupational and urban settings IPCS (1998; Petrv et al. (1996; Atsdr (1995;
Hecht et al. (1974) and in environmental media contaminated with PAH mixtures Shen (2016;
Delgado et al. (2005). Given the frequency of detection and its relative carcinogenic potency
among PAHs routinely detected in the environment, BaP has therefore been proposed to
contribute significantly to the overall carcinogenicity of a PAH mixture, even when present in
low concentrations Petrv et al. (1996; U.S. EPA (1993).
Finally, in 2017, the U.S. EPA concluded that under U.S. EPA's Guidelines for
Carcinogen Risk Assessment U.S. EPA (2005). BaP is "Carcinogenic to Humans" based on
strong and consistent evidence in animals and humans U.S. EPA (2017). The U.S. EPA also
published a cancer OSF and an IUR for BaP on IRIS. The OSF was 1 per mg/kg-day based on
forestomach, esophagus, tongue, and larynx tumors observed in Wistar rats and in female
B6C3F1 mice in the Kroese et al. (2001) and Behind and Gulp (1998) studies, respectively. The
IUR was 6 x 10_1 per mg/m3 based on elevated incidences of squamous cell neoplasia in the
larynx, pharynx, trachea, nasal cavity, esophagus, and forestomach in Wistar rats observed by
Thvssen et al. (1981). BaP is a known carcinogen in test animals following exposures through
the oral, inhalation, and dermal routes of exposure. Studies in multiple animal species
demonstrate that BaP is carcinogenic at multiple tumor sites (alimentary tract, liver, kidney,
respiratory tract, pharynx, and skin) by all routes of exposure. Exposure to other PAH members
of the aromatic high carbon fraction has been reported to promote tumorigenesis in similar target
tissues. For example, increased incidences of hepatomas and pulmonary adenomas were
observed in mice orally exposed to benz[a]anthracene Klein (1963). Forestomach papillomas
were found in mice orally exposed to dibenz[a,h]anthracene and croton oil Berenblum and Haran
(1955). Much like BaP, chrysene induces melanocytes in derm ally exposed mice Iwata et al.
(1981). In addition, benz[a]anthracene, benz[c]acephenanthrylene, benzo[/]fluoranthene,
dibenz [a, h] anthracene, and indeno[ 1 ,2,3-c,6/]pyrene have been shown to induce skin tumors in
studies with laboratory animals Atsdr (1995). Although tumorigenesis has been observed in
similar target tissues for aromatic high carbon range PAH members, BaP is among the most
potent characterized carcinogens in this fraction. Thus, it is assumed that this approach will be
health-protective because the carcinogenic potency of BaP is assigned to the entire fraction. In
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summary, BaP meets the considerations for selection as an indicator chemical for carcinogenicity
associated with this fraction U.S. EPA (2017. 1993).
2.1.2. Estimating Cancer Risk Using Indicator Chemical
Based on increased incidences of alimentary tract tumors observed in both the Kroese et
al. (2001) rat bioassay and the Behind and Gulp (1998) mouse bioassay, U.S. EPA (2017)
estimated that the OSF for BaP was 1 per mg/kg-day. Based on increased incidences of
gastrointestinal (GI) tract and respiratory tract tumors observed in the Thvssen et al. (1981)
hamster bioassay, U.S. EPA (2017) estimated an IUR of 6 10 1 per mg/m3. If an indicator
chemical approach is used, these health reference values can be integrated with estimates of the
exposure rates for the aromatic high carbon range fraction to estimate the oral or inhalation
cancer risk.
Rmix = OSFBaP X /RF
where
Rmix = risk posed by the mixture
OSFBaP = oral slope factor for benzo[a]pyrene (per mg/kg-day)
IRp = oral intake rate of aromatic high carbon fraction (mg/kg-day)
Rmix = IURbop x Cf
where
Rmix = risk posed by the mixture
WRBaP = inhalation unit risk for benzo[a]pyrene (per (J,g/m3)
Cp = concentration of aromatic high carbon fraction in air ([j,g/m3)
Of the three approaches described in this assessment, the indicator chemical method
requires the least analytical characterization of the aromatic high carbon fraction, but has the
most inherent uncertainty; as such, this approach is preferred only when exposure data on
fraction components are unavailable. Uncertainty arises in this method because the indicator
chemical is used to represent the toxicity of an untested portion of the mixture.
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3. RELATIVE POTENCY FACTORS APPROACH FOR POLYCYCLIC AROMATIC
HYDROCARBONS IN THE AROMATIC HIGH CARBON RANGE FRACTION
For some sites that are contaminated with TPH mixtures, the mass of the aromatic high
carbon fraction and the concentrations of some individual PAHs3 are measured. This section
discusses the selection of BaP as the IC (see Section 3.1) and the use of Estimated Order of
Potential Potency (EOPP) factors for seven PAHs developed in the U.S. EPA's 1993 Provisional
Guidance for Quantitative Risk Assessment ofPolycyclic Aromatic Hydrocarbons U.S. EPA
(1993) to estimate cancer risk associated with PAHs in the aromatic high carbon TPH fraction
(see Section 3.2). EOPPs are conceptually and quantitatively consistent with RPFs. RPFs are
based on an assumption of dose addition. The RPF method assumes that component chemicals
are toxicologically similar. It also assumes that component doses can be added when toxic
potency is scaled relative to the potency of an IC. Component exposure data are required for this
approach.
3.1. SELECTION OF BENZO[A]PYRENE AS AN INDEX CHEMICAL
The U.S. EPA's Mixtures Guidance U.S. EPA (2000) characterizes an appropriate IC as
typically the best-studied member of the chemical class, having the largest body of high-quality
data describing exposure and health effects. Further, an appropriate IC is expected to have toxic
effects similar to the rest of the members of the class (i.e., effects progress to the apical endpoint
via a similar MO A), and to have quantitative dose-response assessments of acceptable scientific
quality, including those that allow meaningful comparison of the toxic potencies of the
component chemicals and the IC. This section reviews these characteristics as they apply to BaP
within the aromatic high carbon fraction.
BaP is the most suitable PAH to use as an IC for carcinogenic PAHs identified in the
aromatic high carbon range TPH fraction. As described in Section 2, in addition to its structural
similarity to the PAHs in this chemical class, BaP is well-studied, and has a robust evidence base
of both bioassay data and MO A information.
Evidence suggests that the PAHs of the aromatic high carbon fraction (including BaP)
exhibit similar structures. The carcinogenic activity of PAH compounds is influenced by specific
structural features, and the relationship between these structural features and mechanistic events
related to PAH carcinogenesis has been evaluated Bruce et al. (2008; Viiavalakshmi and Suresh
(2008). Bostrom et al. (2002) reported that PAHs having four or more benzene rings generally
exhibit greater carcinogenic potency than PAHs with two or three benzene rings. In addition,
there is evidence that the carcinogenic activity of PAHs is also related to the specific
arrangement of the benzene rings; PAHs with at least four rings and a classic bay or fjord region
(see Figure 2) display a greater tendency towards bioactivation, particularly to diol epoxide
metabolites, relative to other PAHs lacking these features I ARC (2010). Some PAHs with these
structural features have been thoroughly studied, and there is extensive documentation describing
their tumorigenic potency Harvey (1991). The more highly reactive diol epoxide stereoisomers
readily bind to cellular macromolecules to form protein and deoxyribonucleic acid (DNA)
adducts, the latter being associated with genotoxicity. As discussed in IARC (2010) and
3As noted earlier in this document, the U.S. EPA defined PAHs as unsubstituted compounds with two to six fused
aromatic rings made up only of carbon and hydrogen atoms. The definition of the PAHs excludes their alkyl-
substituted derivatives.
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elsewhere, there is a body of epidemiology literature documenting the detection of PAH-derived
diol epoxide-DNA adducts in human populations exposed to complex PAH mixtures.
Fjord region
Bay region
Chrysene
Dibenzo[def,p]chrysene
Figure 2. Bay and Fjord Regions of Polycyclic Aromatic Hydrocarbons
Those PAHs classified by the U.S. EPA as probable human carcinogens (see Table 4),
are known to form PAH DNA adducts and are considered mutagenic I ARC (2010). Given the
mutagenic MOA for these PAHs, the dose-additive approach described in this section assumes
that carcinogenic PAHs within this TPH fraction act in a toxicologically similar manner; that is,
it is assumed that these PAHs promote carcinogenesis by a mutagenic MOA. Such an
assumption is consistent with implementation of the RPF approach, which assumes toxicologic
similarity when toxicity data are missing on some components of a mixture.
The various mutagenic mechanisms, as well as the existence of numerous pathways
through which tumor initiation and progression may proceed, are briefly summarized below and
discussed in much more detail in assessments conducted by IARC (20101 the World Health
Organization IPCS (1998). Atsdr (1995). and Bostrom et al. (2002). Biological perturbations that
have been observed to occur in response to PAH exposure and can be plausibly linked to
carcinogenesis include:
• Oxidative metabolism to reactive intermediates that covalently bind to DNA, ribonucleic
acid (RNA), and proteins (diol epoxide, radical cation, and o-quinone pathways).
• Formation of PAH DNA adducts (stable and/or depurinating adducts).
• Mutations in cancer-related genes (e.g., TP53 tumor suppressor genes or RAS oncogenes)
resulting in carcinogenesis.
• Enhancement of tumor promotion and progression via alteration of gene expression and
cell signaling pathways; some of these alterations are mediated through aryl hydrocarbon
receptor (AhR) activation and others are elicited in response to cytotoxicity and cell
signaling perturbations in the presence of BaP derived metabolic products.
At least three distinct mutagenic mechanisms have been identified by which carcinogenic
PAHs are believed to act: (1) formation of diol epoxides (via cytochrome P450 [CYP450] and
epoxide hydrolase metabolism) leading to stable and unstable DNA adducts, mainly at guanine
and adenine sites, which can lead to mutations in protooncogenes and tumor suppressor genes;
(2) radical cation (via CYP450 peroxidase metabolism) formation, leading to generation of
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unstable adducts at guanine and adenine sites, and ultimately to apurinic sites and mutation in the
RAS oncogenes; and (3) o-quinones with generation of reactive oxygen species (ROS) (via
metabolism by aldo-keto reductase enzymes), leading to stable and unstable DNA adducts, and
induction of mutations, including in tumor suppressor gene, TP53 Atsdr (2018; Xu et al. (2009;
Jiang et al. (2007; Jiang et al. (2005; Xue and Warshawskv (2005; Bolton et al. (2000; Penning et
al. (1999; Harvey (1996; Cavatieri and Rogan (1995).
Oncogene and/or tumor suppressor gene mutations, including mutations in TP53 and the
KRAS oncogene, have been observed in human lung tumors following exposure to smoky coal
emissions known to contain complex mixtures of PAHs DeMarini et al. (2001). The mutation
spectrum from these lung tumors appears to be unique and consistent with exposure to PAHs in
the absence of cigarette smoke. In experimental animal models, KRAS and HRAS oncogenes
and/or TP53 tumor suppressor gene mutations in forestomach, lung, and skin tumors have also
been observed following PAH exposure Chakravarti et al. (2008; Connev et al. (2001; Gulp et al.
(2000; Smith et al. (2000; Nesnow et al. (1998; Nesnow et al. (1996. 1995; Mass et al. (1993).
Cellular proliferation following PAH exposure has been associated with several distinct
key events including AhR activation, cytotoxicity, and inflammation. Some, but not all, PAHs
bind to the AhR, which leads to upregulation of genes related to growth and differentiation
Bostrom et al. (2002). AhR-null mice were found to be completely resistant to BaP-induced
complete skin carcinogenesis Shimizu et al. (2000). Some PAHs are metabolized to o-quinones,
which can generate cytotoxic ROS Bolton et al. (2000; Penning et al. (1999; Flowers-Geary et al.
(1996; Flowers-Geary et al. (1993). with the resulting inflammation potentially contributing to
the tumor promotion process. Other mechanisms by which PAHs affect cell survival, growth,
and differentiation, thus contributing to tumor promotion and progression, include sustained
alterations of cell cycle processes (e.g., activation of epidermal growth factor receptor,
ra.s/ra//mitogen-activated protein kinase, and cyclooxygenase-2-generated prostaglandin
E2 signaling), elevated polyamine synthesis through ornithine decarboxylase induction,
resistance to apoptosis, inhibition of gap junctional intracellular communication, and suppression
of the immune system I ARC (2010; Rundhaug and Fischer (2010).
3.2. U.S. EPA'S RELATIVE POTENCY FACTOR APPROACH FOR POLYCYCLIC
AROMATIC HYDROCARBONS
In 1993, the U.S. EPA published the Provisional Guidance for Quantitative Risk
Assessment of Polycyclic Aromatic Hydrocarbons, a component-based approach to assessing
cancer risks posed by PAH mixtures in the environment, that recommended RPFs termed
"estimated order of potential potency" (EOPP) factors for seven PAHs [see Table 5; U.S. EPA
(1993)1. The seven un substituted PAHs included: BaP, benz[a]anthracene,
benz[e]acephenanthrylene (synonym, benzo[A]fluoranthene), benzo[Ł]fluoranthene, chrysene,
dibenz[a,h]anthracene, and indeno[ 1,2,3-c,c/]pyrene. U.S. EPA (1991) previously categorized
these seven PAHs as Group B2,probable human carcinogens under the 1986 U.S. EPA Cancer
Guidelines U.S. EPA (1986). This RPF approach focused on un substituted PAHs that had three
or more fused aromatic rings containing only carbon and hydrogen atoms. In addition to
structural similarity, these well-studied PAHs demonstrate the formation of DNA-reactive
metabolites that are associated with the induction of DNA damage and tumorigenesis, which
appears to be mediated through a mutagenic MOA. The underpinning of the RPF approach is the
concept of dose additivity, which follows from an assumption of toxicological similarity.
Specifically, the toxicodynamic response pathways of dose-additive chemicals share at least one
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1 common key event (i.e., biochemical process) that links a molecular initiating event to an apical
2 outcome (or multiple related apical health outcomes). The doses or their resulting products "add"
3 at this key event. Given that all PAHs in this approach are assumed to be carcinogenic via a
4 mutagenic MO A, the estimation of cancer risks posed by PAH mixtures in the aromatic high
5 carbon range fraction relies on an assumption of dose addition among component chemicals.
Table 5. RPFs for PAH Carcinogenicity in the U.S. EPA 1993 Provisional
Guidance"
PAH (abbreviation)
RPF
Data Source(s)
Benzo|c/|pyrenc (BaP)
1
NA
Benz[a]anthracene (BaAC)
0.1
Bingham and Fa Ik (1969)
Benz[e]acephenanthrylene (BeAPE)b
0.1
Habs etal. (1980)
Be n/o | k | fliio ra ntlic nc (BkFA)
0.01
Habsetal. (1980)
Chrysene (CH)
0.001
Wvnder and Hoffmann (1959)
D ibe n/1 o, /? |a n111racenc (DbahAC)
1
Wvnder and Hoffmann (1959)
I ride no 11.2.3-6,c/|pyrcnc (I123cdP)
0.1
Habs et al. (1980); Hoffmann and Wvnder (1966)
aU.S. EPA (1993).
bFormerly bcnzo | h | fluoranthcnc.
NA = not applicable; PAH = poly cyclic aromatic hydrocarbon; RPF = relative potency factor;
U.S. EPA = U.S. Environmental Protection Agency.
6 The assessment in U.S. EPA (1993) focused on the structurally similar PAHs that have
7 tumor incidence data from in vivo animal skin painting bioassays. This RPF approach
8 acknowledges the complexity of the tumor development process and the likely differences in
9 other key events among different PAHs. Most importantly, it avoids the excessive uncertainty of
10 basing PAH relative potency on specific precursor events having uncertain quantitative
11 relationships with actual tumor formation. The EOPP values were all calculated from lifetime
12 "skin painting" bioassays and were rounded to the closest order of magnitude.
13 3.2.1. Estimating Cancer Risk Using the Relative Potency Factor Approach
14 If an RPF approach is used, the BaP OSF and IUR estimates can be integrated with
15 estimates of the individual PAH exposure rates (or concentrations) to estimate the oral or
16 inhalation cancer risk associated with exposure to the fraction.
17 Rmix = OSFBaP X ICED
18 where
19 Rmix = risk posed by the mixture
20 OSFBaP = oral slope factor for benzo[a]pyrene (per mg/kg-day)
21 ICED = index chemical equivalent dose (mg/kg-day)
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1 The doses of the individual components are scaled by the RPFs found in Table 5, and
2 then summed to yield the ICED of the entire mixture (ICEDmk).
3 !CED,,;, = V d- - RPF-;
n '
4 where
5 d = dose of the individual mixture component (mg/kg-day)
6 RPF = relative potency factor associated with the individual mixture
7 component (unitless)
8 An identical approach can be applied to inhalation concentrations as applied to exposure
9 via oral exposure.
10 Rmx = IURBap X ICEC
11 where
12 Rmix = risk posed by the mixture
13 IURBaP = inhalation unit risk for benzo[a]pyrene (per jig/m3)
14 ICEC = index chemical equivalent concentration (jig/m3)
15 iŁEŁ*.m = V r, x RPF;
i—i
16 where
17 c = concentration of the individual mixture component (jig/m3)
18 RPF = relative potency factor associated with individual mixture
19 component (unitless)
20 Of the three approaches described in this assessment, the RPF approach requires
21 analytical characterization of some carcinogenic PAH components of the aromatic high carbon
22 fraction; as such, this approach is preferred when component exposure data for carcinogenic
23 P A Us, but not non-PAH carcinogens, are available. Uncertainty exists in the RPF approach
24 because it does not use direct toxicity and dose-response data for every member of its chemical
25 class.
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4. USING INTEGRATED ADDITION TO ESTIMATE CANCER RISKS POSED BY
POLYCYCLIC AROMATIC HYDROCARBONS AND OTHER CARCINOGENS IN
THE AROMATIC HIGH CARBON FRACTION
For some sites that are contaminated with TPH mixtures, the mass of the aromatic high
carbon range fraction and the concentrations (or exposure rates) of some individual PAHs and
other carcinogens that are not PAHs and occur in this fraction are measured. This section
describes the use of an integrated addition model to estimate cancer risks posed by PAHs,
subPAHs, and other carcinogenic fraction members measured in the aromatic high carbon
fraction. For chemicals eliciting a common endpoint, the integrated addition approach begins
with identification of different dose-additive groups based on suspected or known MO As for
chemicals identified in the fraction, and then the mixture components are assigned into these
dose-additive groups based on toxicological similarity U.S. EPA (2003). Next, the assumptions
of similarity within groups and then of toxicological independence across groups are evaluated.
If there are interactions [e.g., U.S. EPA (2000) explains that interactions are departures from
what would be expected under some form of additivity, such as synergism)], other mixture
assessment methods would be preferred. Otherwise, within each similarity group, the RPF
approach is used to estimate the group risk. The similarity group risks are then combined across
all groups using response addition to estimate mixture risk U.S. EPA (2000).
This assessment assumes that the carcinogenic MO As of the PAHs are independent of the
subPAH, 1-methylnaphthalene, and the other carcinogenic fraction member, 1,1-biphenyl. As
explained in Section 3.1, the PAHs, distinct from the subPAH and the other carcinogenic fraction
members, appear to mediate their carcinogenic activity through a mutagenic MOA. The
carcinogenicity of 1,1-biphenyl does not appear to be related to mutagenicity; metabolites of this
compound may induce genetic damage through oxidative damage and cytotoxicity, leading to
carcinogenic responses (see Section 4.1). For 1-methylnaphthalene, the MOA data from a small
number of genotoxicity tests suggest equivocal evidence of a mutagenic MOA (see Section 4.2).
4.1. 1,1-BIPHENYL ORAL CANCER ASSESSMENT
Published in 2013, the IRIS assessment for 1,1-biphenyl (CASRN 92-52-4) concluded
that, under U.S. EPA's Guidelines for Carcinogen Risk Assessment U.S. EPA (2005), the
database for 1,1-bi phenyl provides "Suggestive Evidence of Carcinogenic PotentiaF U.S. EPA
(2013). This was based on an increased incidence of urinary bladder tumors in male F344 rats
Umeda et al. (2002) and liver tumors in female BDF1 mice Umeda et al. (2005) exposed to
1,1-biphenyl in the diet for 104 weeks, as well as information on mode of carcinogenic action.
U.S. EPA (2013) concluded that the in vitro evidence did not indicate that 1,1-bi phenyl was
mutagenic; however, biphenyl metabolites may induce genetic damage through oxidative
damage and cytotoxicity.
The U.S. EPA derived a screening OSF of 8 10~3 per mg/kg-day U.S. EPA (2013). This
is based on an analysis of liver adenomas or carcinomas that occurred in female BDF1 mice
following oral exposures to 1,1-bi phenyl Umeda et al. (2005). U.S. EPA (2013) did not derive an
IURfor 1,1-biphenyl.
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4.2. 1-METHYLNAPHTHALENE CANCER ASSESSMENT
The 2005 PPRTV assessment for 1-methylnaphthalene (CASRN 90-12-0) concluded that,
under the U.S. EPA's Guidelines for Carcinogen Risk Assessment U.S. EPA (2005), the database
for 1 -methylnaphthalene provides "Suggestive Evidence of Carcinogenic PotentiaT U.S. EPA
(2008). U.S. EPA (2008) reported that the database of information regarding the carcinogenicity
of 1-methylnaphthalene in laboratory animals was limited to a single carcinogenicity study. In
this study, male and female B6C3F1 mice (50/sex/group) were administered
1 -methylnaphthalene in the diet for 81 weeks Murata et al. (1993). Under the conditions of the
study, statistically significant increased incidences of lung adenomas and combined lung
adenomas and adenocarcinomas were observed in exposed male mice, but not female mice.
MO A data for 1-methylnaphthalene-induced lung tumors in the male mice are limited to results
of a few genotoxicity tests that provide equivocal evidence of a mutagenic MOA.
U.S. EPA (2008) derived a p-OSF of 2.9 x 10 2 per mg/kg-day. This is based on lung
adenoma or carcinoma (combined) observed in male mice from the Murata et al. (1993) 81-week
oral study. U.S. EPA (2008) concluded that there were no appropriate human or animal data
from which to derive an IUR for 1-methylnaphthalene and the updated literature search
conducted in August of 2021 by U.S. EPA found no other inhalation studies of this compound
that evaluated cancer outcomes.
4.3. APPLYING THE INTEGRATED ADDITION METHOD TO ESTIMATE CANCER
RISK FROM THE AROMATIC HIGH CARBON FRACTION
The U.S. EPA assumes that the MO As for carcinogenicity associated with the PAHs,
1,1-biphenyl, and 1-methylnaphthalene exposures are toxicologically independent. In
Section 1.3.2, the U.S. EPA summarized evidence that PAHs cause cancer through a mutagenic
MOA. U.S. EPA (2013) concluded that 1,1-biphenyl does not appear to be mutagenic and U.S.
EPA (2008) concluded that the evidence for a mutagenic MOA for 1 -methylnaphthalene was
equivocal. It seems reasonable to conclude that the PAHs (as defined in this assessment),
1,1-biphenyl, and 1-methylnaphthalene are toxicologically independent. At this time,
1,1-biphenyl and 1-methylnaphthalene are the only chemicals identified as having carcinogenic
activity within the aromatic high carbon fraction that are not defined as PAHs in this document.
The U.S. EPA assumes that the PAHs form one subgroup exhibiting a common mutagenic MOA
within this fraction and that 1,1-biphenyl, with a likely nonmutagenic MOA, and
1-methylnaphthalene, with an uncertain MOA, are the only chemicals in a second group and a
third group, respectively.
Given these data, the U.S. EPA suggests using an integrated addition model to evaluate
carcinogenic risks. To implement such a model, the cancer risks from 1-methylnaphthalene,
1,1-biphenyl, and the PAHs need to be estimated separately.
Initially, multiplying the 1-methylnaphthalene p-OSF by its intake rate results in an
estimate of the cancer risk associated with 1-methylnaphthalene. Similarly, multiplying the
1,1-biphenyl OSF by its intake rate generates an estimate of the 1,1-biphenyl cancer risk. Then,
multiplying the ICED of the PAHs by the BaP OSF results in an estimate of the cancer risk
associated with the PAHs. The aromatic high carbon fraction cancer risk (RMix) can be estimated
by summing the calculated cancer risks from 1-methylnaphthalene, 1,1-biphenyl, and the seven
PAHs.
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Rj = OSFj X ICEDj
where
Rj = risk posed by thejth chemical group (unitless)
OSFj = oral slope factor of the index compound of the jth chemical
group (per mg/kg-day)
ICEDj = index chemical equivalent dose of the jth chemical
group (mg/kg-day)
The inhalation risk equation for the PAH described in Section 3.2.1 can be used to
estimate the cancer risk associated with the inhalation of this fraction.
Of the three approaches described in this assessment, the integrated addition approach
requires the most analytical characterization of the aromatic high carbon fraction, but has the
least inherent uncertainty; as such, this is the preferred approach for estimating the risk posed by
this fraction when data are available. However, response addition of known carcinogens may
yield incorrect risk estimates when there are toxicologic interactions that can enhance or inhibit
the cancer potency.
where
Rmix = risk posed by the fraction
Rj = risk posed by the jth subgroup (unitless)
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5. CONCLUSION
This PPRTV assessment provides three approaches for evaluating the cancer risk
associated with exposures to the aromatic high carbon range fraction. The selection of a specific
approach depends on the available data. The application of the indicator chemical method
requires concentration or exposure rate data for the fraction. This is the least preferred of the
three approaches because of the assumption that the entire fraction is as carcinogenic as BaP.
The application of the RPF method requires concentration or exposure rate data for up to seven
individual PAHs. The application of the integrated addition method requires exposure rate or
concentration data on individual PAHs that mediate their carcinogenicity through a mutagenic
MOA and other compounds that are unlikely to mediate their carcinogenicity through a
mutagenic MOA of the fraction. This is the preferred method of the three approaches presented
in this PPRTV assessment.
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dependent differences in the profile of mutations induced by carcinogenic (R,S,S,R) bay-
and fjord-region diol epoxides of polycyclic aromatic hydrocarbons [Review], Adv Exp
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Culp. SJ; Gavlor. DW; Sheldon. WG; Goldstein. LS; Beland. FA. (1998). A comparison of the
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Gulp. SJ; Warbritton. AR; Smith. BA; Li. EE; Behind. FA. (2000). DNA adduct measurements,
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P; Gao, W; Olivier, M; Hainaut, P; Mumford, JL. (2001). Lung tumor KRAS and TP53
mutations in nonsmokers reflect exposure to PAH-rich coal combustion emissions.
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ECHA (European Chemicals Agency). (2019). Substance evaluation conclusion as required by
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evaluating member state(s): Portugal. https://echa.europa.eu/documents/10162/5795770e-
ba49-26d6-2ac4-57fbe2408459.
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Youngren. SH; Nakles. DV. (1997). Total petroleum hydrocarbon criteria working group
series: Volume 4: Development of fraction specific reference doses (RFDs) and reference
concentrations (RFCs) for total petroleum hydrocarbons (TPH). Amherst, MA: Amherst
Scientific Publishers.
Feron, VJ; de Jong, D; Emmelot, P. (1973). Letter: Dose-response correlation for the induction
of respiratory-tract tumours in Syrian golden hamsters by intratracheal instillations of
benzo(a)pyrene. Eur J Cancer 9: 387-390. http://dx.doi.org/10.1016/0Q14-
2964(73)90057-1.
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