EPA-540/1-86-013
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
vvEPA
'HEALTH EFFECTS ASSESSMENT
FOR POLYCYCLIC AROMATIC HYDROCARBONS (PAHs)
U.S. Environmental Protection Agerfcv
Region V, Library
230 South Dearborn Street
Chicago, Illinois 60604
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EPA/540/1-86-013
September 1984
HEALTH EFFECTS ASSESSMENT
FOR POLYCYCLIC AROMAUC HYDROCARBONS (PAHS)
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
Chicago, 1L Ov':''J-i-
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DISCLAIMER
This report has been funded wholly or In part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with polycycllc
aromatic hydrocarbons. All estimates of acceptable Intakes and carcinogenic
potency presented 1n this document should be considered as preliminary and
reflect limited resources allocated to this project. Pertinent toxUologlc
and environmental data were located through on-Hne literature searches of
the Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data
bases. The basic literature searched supporting this document 1s current up
to September, 1984. Secondary sources of Information have also been relied
upon 1n the preparation of this report and represent large-scale health
assessment efforts that entail extensive peer and Agency review. The
following Office of Health and Environmental Assessment (OHEA) sources have
been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria for Acenaphthene.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-015. NTIS PB 81-117269.
U.S. EPA. 1980b. Ambient Water Quality Criteria for Fluoranthene.
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA
440/5-80-049. NTIS PB 81-117608.
U.S. EPA. 1980c. Ambient Water Quality Criteria for Polynuclear
Aromatic Hydrocarbons. Environmental Criteria and Assessment
Office, Cincinnati, OH. EPA 440/5-80-069. NTIS PB 81-117806.
U.S. EPA. 1983a. Review of Tox1colog1c Data 1n Support of Evalua-
tion for Carcinogenic Potential of: Anthracene. Prepared by the
Carcinogen Assessment Group, OHEA, Washington, DC for the Office of
Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1983b. Review of Tox1colog1c Data 1n Support of Evalua-
tion for Carcinogenic Potential of: Benzo[a]anthracene. Prepared
by the Carcinogen Assessment Group, OHEA, ORD, Washington, DC for
the Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1983c. Review of Tox1colog1c Data 1n Support of Evalua-
tion for Carcinogenic Potential of: Benzo[a]pyrene. Prepared by
the Carcinogen Assessment Group, OHEA, ORD, Washington, DC for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1983d. Review of Tox1colog1c Data 1n Support of Evalua-
tion for Carcinogenic Potential of: D1benz[a,h]anthracene. Pre-
pared by the Carcinogen Assessment Group, OHEA, ORD, Washington, DC
for the Office of Solid Waste and Emergency Response, Washington,
DC.
111
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U.S. EPA. 1983e. Review of Toxlcologlc Data 1n Support of Evalua-
tion for Carcinogenic Potential of: Fluorene. Prepared by the
Carcinogen Assessment Group, OHEA, ORD, Washington, DC for the
Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1983f. Reportable Quantity for Acenaphthene. Prepared
by the Environmental Criteria and Assessment Office, Cincinnati, OH
for the Office of Solid Waste and Emergency Response, Washington,
DC.
U.S. EPA. 1983g. Reportable Quantity for Benzo[a]pyrene. Pre-
pared by the Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
The Intent In these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative {I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer 1s not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants In ambient air or water where lifetime exposure 1s
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, 1s similar In concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980d) for a discussion
of this concept]. The AIC 1s route specific and estimates acceptable
exposure for a given route with the Implicit assumption that exposure by
other routes Is Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained 1n U.S. EPA (1983h).
1v
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For compounds for which there 1s sufficient evidence of cardnogenlcHy,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980d). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q]*s have been computed based on oral
and Inhalation data 1f available.
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ABSTRACT
In order to place the risk assessment evaluation 1n proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
The major Issue of the PAH risk assessment 1s the potential cardnogen-
1dty of these compounds. There are limited data available which can be
used for quantitative risk assessment, however, this does not Imply that
there are not adequate qualitative data to consider many of the members of
this class as animal carcinogens. In addition, PAH containing mixtures are
documented to contribute to Increased Incidence of cancer 1n the human popu-
lation. The contribution of Individual chemical species to the carcinogenic
potency of these mixtures and the Interactions of various componets cannot
be adequately addressed at present.
The one PAH, benzo(a)pyrene, for which adequate dose-response data
following exposure by appropriate routes (Inhalation, oral) are available
has been used to develop a cancer-based risk assessment for PAHs. Since
data Indicate that benzo(a)pyrene 1s one of the most potent carcinogens of
the PAHs tested, 1t 1s suggested that cumulative exposures to mixtures
containing PAH concentrations should result 1n a risk that 1s less than that
predicted for benzo(a)pyrene alone. However, H should be kept 1n mind that
many of the PAHs are still Inadequately characterized 1n terms of their
carcinogenic potential; that Interactions of constituents of mixtures are
poorly defined; and that potency ranking has been done using mouse skin
exposure data (data for other routes from which potency comparisons could be
made are not available).
Using data for stomach tumors 1n mice following oral exposure to benzo-
(a)pyrene, a q-|* of 11.53 (mg/kg/day)'1 was computed for oral exposure.
Similarly, using data on Incidence of respiratory tumors 1n hamsters exposed
to benzo{a)pyrene by Inhalation exposure, a q-j* of 6.11 (mg/kg/day)~a
was derived.
v1
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for ERA'S Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was the Project
Officer. The final documents In this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . .
2.1.
2.2.
ORAL
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS
CARCINOGENICITY ,
4.1.
4.2.
4.3.
4.4.
REGULi
HUMAN DATA
4.1.1. Oral ,
4.1.2. Inhalation
BIOASSAYS ,
4.2.1. Oral
4.2.2. Inhalation ,
4.2.3. Mouse Skin Assays
4.2.4. PAH Containing Mixtures
OTHER RELEVANT DATA
WEIGHT OF EVIDENCE
*TORY STANDARDS AND CRITERIA
Page
. . . 1
. . 5
. . 5
. . 5
, . 7
, , 7
. . 7
7
, . . 8
, . . 8
, . . 8
, , 8
, . . 8
. . . 9
. . . 9
, . . 10
. . . 10
. . . 10
. . . 10
. . . 11
. . . 11
. . . 20
. . . 24
26
. . . 26
26
. . . 30
V111
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT 32
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 32
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 32
6.3. CARCINOGENIC POTENCY (q-|*) 32
6.3.1. Oral 33
6.3.2. Inhalation 33
7. REFERENCES 35
APPENDIX A: Summary Table for PAH 46
APPENDIX B: Cancer Data Sheet for Derivation of q-|* 47
APPENDIX C: Cancer Data Sheet for Derivation of q^* 48
1x
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LIST OF TABLES
No. Title Page
1-1 Selected Physical and Chemical Properties and CAS
Numbers of a Few PAHs 2
4-1 CarclnogenlcHy of Benzo[a]pyrene Administered 1n the Diet
to Hale and Female CFW Mice at Levels of 1-250 ppm 12
4-2 Cardnogenldty of Benzo[a]pyrene Administered 1n the Diet
to Male and Female Swiss Mice at Levels of 250-1000 ppm ... 13
4-3 Cardnogenldty of Benzo[a]pyrene Administered In the Diet
to Male and Female Swiss CFW Mice at a Level of 250 ppm ... 14
4-4 Oral Cardnogenldty Testing of Benz[a]anthracene
Administered by Gavage to Male B6AF-] Mice 16
4-5 Oral Cardnogenldty Testing of D1benz[a,h]anthracene
Administered In the Drinking Water to Male and Female
DBA/2 Mice 17
4-6 Cardnogenldty Testing of Fluorene Administered 1n the
Diet to Female Buffalo Rats 18
4-7 Cardnogenldty Testing of Fluorene Administered 1n the
Diet to Albino Rats 19
4-8 Cardnogenldty of Benzo[a]pyrene to Male Syrian Golden
Hamsters by Inhalation 21
4-9 Cardnogenldty of Benzo[a]pyrene 1n Syrian Hamsters
Following Intratracheal Administration of 0.10-1.0 mg/week. . 22
4-10 Cardnogenldty of Benzo[a]pyrene 1n Syrian Golden
Hamsters Following Intratracheal Administration of
18.2-36.4 mg/anlmal 23
4-11 Cardnogenldty Testing of Anthracene 1n Female
Osborne-Mendel Rats by Lung Implantation 25
4-12 Genotoxldty of Selected PAH 27
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
BCF B1oconcentrat1on factor
bw Body weight
CAS Chemical Abstract Service
CS Composite score
GI Gastrointestinal
NOEL No-observed-effect level
ppm Parts per million
TLV Threshold limit value
TWA Time-weighted average
x1
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Polycycllc aromatic hydrocarbons (PAHs) are a class of compounds that
are formed during the Incomplete combustion or pyrolysls of organic mate-
rials containing carbon and hydrogen. Several hundred different PAHs have
been Identified from combustion and pyrolysls sources (Grimmer, 1983). In
this discussion, only a few PAHs compounds (containing 2-6 aromatic rings)
that occur most frequently 1n the environment (Grimmer, 1983) and also
appear on the U.S. EPA's list of priority pollutants will be considered.
The relevant physical and chemical properties and CAS Registry numbers of a
few selected PAHs are given 1n Table 1-1.
The half-lives of PAHs In a particular medium are not known with
certainty. Based on the available experimental data, some speculation about
the half-lives can be made. According to the theoretical predictions of
Cupltt (1980) and the experimental work of Yamasakl et al. (1982), the
majority of naphthalene, phenanthrene, anthracene, fluoranthene and pyrene
should exist 1n the vapor phase 1n the atmosphere. On the other hand, benz-
[a]anthracene, chrysene, benzo[a]pyrene (BaP) and benzo[gh1]perylene should
exist predominantly 1n the partlculate sorbed phase 1n the atmosphere. The
removal of PAHs from the atmosphere can occur through photochemical reac-
tions, chemical reactions (principally with OH radicals, ozone and NO }
and physical removal mechanisms (wet and dry deposition). The PAHs that
exist predominantly 1n the vapor phase In the atmosphere (e.g., naphthalene,
phenanthrene, anthracene, fluoranthene and pyrene) are likely to be removed
primarily through direct or Indirect photochemical reactions (Atkinson et
al., 1984; NAS, 1983; Mabey et al., 1981). The half-life for these com-
pounds 1n the atmosphere should be <1 day. The primary removal mechanism
-1-
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TABLE 1-1
Selected Physical and Chemical Properties and CAS Nunbers of a Few PAHs
Compound
Naphthalene
Phenanthrene
Anthracene
Fluoranthene
Pyrene
i
M Benz[a]anthracene
Chrysene
Benzol a Jpyrene
Benzo(g,h,l]pery1ene
Molecular
Weight
128.16
178.22
178.22
202.24
202.24
228.20
228.20
252.30
276.30
CAS No. Vapor Pressure
(nwHg)
91-20-3 0.082 at 25*C
85-01-8 6. 8x10' • at 20'C
120-12-7 1.95xlO~« at 20'C
206-44-0 5.0x10'* at 25«C
129-00-0 2.5xlO"» at 25»C
56-55-3 101xlO~» at 20*C
218-01-9 6.3xlO'» at 25'C
50-32-8 5,6x10"» at 25*C
191-24-2 1.03x10->« at 25*C
Water Solubility
31.7 mg/l at 25'C
1 mg/kg at 25'C
0.0446 mg/kg at 25*C
0.206 mg/kg at 25*C
0.132 mg/kg at 25'C
9.4 vg/kg at 25 'C
1 .8 vg/kg at 25*C
1.2 yg/kg at 25*C
0.7 vg/kg at 25*C
1*9 *ow3 Bcfb Reference
3.37 146 Mackay et al.. 1980. 1982
4.46 1.230 Wise et al.. 1981;
U.S. EPA, 1980c
4.45 1.210 Wise et al.. 1981;
Mackay ard Shlu. 1977;
U.S. EPA, 1980c
4.90 2.920 Wise et al.. 1981;
U.S. EPA. 1980c;
Mabey et al.. 1981
4.08 2.800 Mabey et al.. 1981;
Wise et al., 1981;
U.S. EPA, 1980c
5.61 11.700 Wise et al.. 1981;
U.S. EPA. 1980c;
Santodonato et al., 1981
5.61 11.700 Wise et al.. 1981;
U.S. EPA. 1980c;
Mabey et al.. 1981
6.06 28.200 Wise et al.. 1981;
U.S. EPA. 1980c;
Mabey et al., 1981
6.51 68.200 Wise et al.. 1981;
U.S. EPA, 1980c;
Mabey et al., 1981
aKow » octanol/water partition coefficient
bBCF - bloconcentratlon factor, values estimated from the equation of Vclth et al., 1979
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for benz[a]anthracene and BaP from the atmosphere 1s likely to be ozonolysls
reactions (NAS, 1983). The expected half-life for this process 1s likely to
be <1 day. It should be remembered that the reactivities of the participate
sorbed portions of the PAHs are strongly dependent on the materials on which
these compounds are sorbed (Korfmacher et al., 1980). Depending on the
nature of partlculate matter, the half-life of partlculate-sorbed PAHs may
be several days to a few weeks. This Increased stability of partlculate-
sorbed PAHs may permit these compounds to participate 1n long distance
transport. In the absence of any chemical reactions, PAHs may stm be
removed from the atmosphere by physical removal mechanisms. In the case of
BaP, the half-life for dry deposition of partlcle-sorbed compound has been
estimated to be -5.5 days (Cupltt, 1980).
Data sufficient for assessing the aquatic fate of PAHs are not available
1n the existing literature. Based on the Information currently available
(Callahan et al., 1979; Mabey et al., 1981), the following conclusions
regarding the aquatic fate of PAHs can be made.
The three likely mechanisms that may be responsible for the removal of
PAHs from aquatic media are volatilization, photochemical reactions and
mlcroblal degradation. With the exception of naphthalene and other PAHs
that have relatively high vapor pressures, volatilization Is not likely to
be a significant removal mechanism. In the case of naphthalene, both
volatilization and adsorption may be quite competitive, with the dominant
process being dictated by the aquatic conditions. High stream and wind
velocities could enhance volatilization, while high organic carbon content
could facilitate sedimentation and the subsequent mlcroblal degradation of
partlcle-sorbed naphthalene.
-3-
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Photolytlc degradation of dissolved PAHs 1s another mechanism by which
PAHs can be removed from aquatic media. However, the sediment-water parti-
tion coefficients (Mabey et a!., 1981) for most PAHs are such that the major
portion of the PAHs are expected to remain 1n a partlculate-sorbed state 1n
water bodies. In view of this, If one considers the light attenuation and
scattering In water bodies occurring with Increased depth and partlculate
content, photolysis does not appear to be a significant removal mechanism
for PAHs.
The predominant mechanism that 1s likely to dictate the fate of most
PAHs 1n aquatic media Is sorptlon onto partlculate matter and subsequent
sedimentation and mlcroblal degradation. Depending on the nature of the PAH
and the characteristics of the aquatic medium, the half-life for mlcroblal
degradation could range from <1 day to several years. Compounds with <4
cyclic rings are more amenable to mlcroblal degradation than compounds with
>4 cyclic rings.
The predominant mechanism for the removal of PAHs from soils 1s likely
to be mlcroblal degradation. Based on the assumption that the potential for
mlcroblal degradation of PAHs 1s greater 1n soils than 1n aquatic systems
(Callahan et al., 1979), the half-life of PAHs 1n soils could range from <1
day to a few years. Considering the soil sorptlon coefficient (Kenaga and
Goring, 1980} and water solubilities, these compounds are not expected to
have high mobility 1n soils. Therefore, significant leaching of these
compounds Into groundwater 1s not expected, particularly from soils with
higher organic carbon content.
-4-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Few quantitative data are available regarding the oral absorption of
PAHs; however, oral absorption of PAHs may be Inferred from the demonstrated
toxldty of PAHs following oral administration (Smyth et a!., 1962; U.S.
EPA, 1980c, 1981; Santodonato et a!., 1981). Polycycllc aromatic hydro-
carbons as a class are highly I1p1d soluble and 1t has been proposed that
they readily absorbed from the GI tract, primarily by passive diffusion
(Rees et al., 1971). In particular, BaP, chrysene, and benz[a]anthracene
are reported to be readily transported across the GI mucosa (Rees et al.,
1971).
A somewhat different assessment of the oral absorption of PAHs was
tendered by Grimmer (1983) who generalized that the mucous layer lining the
GI tract may Impede absorption. Rats given BaP by gavage 1n starch solution
(100 mg) or In the diet (250 mg) absorbed -50% of the administered compound
(Chang, 1943). Regardless of the type of solvent used, BaP readily pene-
trates the forestomach epithelium of mice (Chang, 1943). In the glandular
stomach, however, the type of solvent used plays a decisive role 1n absorp-
tion of BaP (Ekwall et al., 1951; Setala, 1954). HydrophlUc solvents
enhance the absorption of BaP from the glandular stomach, while llpophHU
solvents do not modify BaP absorption. Mitchell and Tu (1979) reported that
an aqueous suspension of pyrene was poorly absorbed from the gut of male
Fischer 344 rats.
2.2. INHALATION
Limited experimental data are available regarding the pulmonary absorp-
tion of PAHs; however, pulmonary absorption of PAHs may be Inferred from the
demonstrated toxldty of PAHs following Inhalation exposure (U.S. EPA,
-5-
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1980c, 1981; Santodonato et al.. 1981). As a class, PAHs are highly I1p1d
soluble and capable of passage across epithelial membranes (U.S. EPA,
1980c). Benzo[a]pyrene, and presumably other PAHs, are readily absorbed
through the lungs (Kotln et al., 1969; Va1n1o et al., 1976). Mitchell and
Tu (1979) reported rapid pulmonary absorption of a pyrene aerosol (300-500
yg/1 of air) by male Fischer 344 rats; widespread tissue distribution
was seen after 60 minutes of exposure.
-6-
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. As reported 1n the abstract of a Polish study, Knobloch et
al. (1969) administered acenaphthylene or acenaphthene orally to rats at a
dose level of 0.6 g acenaphthylene/kg bw 1n olive oil for 40 days or 2 g
acenaphthene/kg bw 1n olive oil for 32 days. Treatment with either compound
resulted 1n considerable body weight loss, unspecified changes 1n the
peripheral blood pattern, changes 1n renal function, and Increased serum
amlnotransferase activities. In addition, rats exposed to acenaphthene had
mild morphological damage to the liver and kidneys, changes consistent with
mild bronchitis, and localized Inflammation of the perlbronchlal tissue.
Genetic differences appear to Influence the subchronlc oral toxlclty of
BaP 1n mice. Specifically, the Ah locus, which determines the IndudblHty
of aryl hydrocarbon hydroxylase, plays a major role In determining the oral
toxlclty of BaP, presumably by Influencing the pathways of blotransforma-
tlon. Robinson et al. (1975) administered BaP 1n the diet at a level of 120
mg/kg bw to nonresponslve (poorly Induclble) AKR/N mice (Ah /Ah type)
and to responsive (markedly Induclble) mice (Ah /Ah type). Nonrespon-
slve mice developed aplastlc anemia and died within 4 weeks, whereas respon-
sive mice remained healthy for at least 6 months.
3.1.2. Inhalation. As reported 1n the abstract of a Russian study,
Reshetyuk et al. (1970) observed chronic nonspecific pneumonia 1n male rats
following exposure to acenaphthylene at a concentration of 18 mg/m3 or
acenaphthene at 12 mg/ma for 4 hours/day, 6 days/week, for 5 months. The
report did not provide details concerning control animals or experimental
protocol (U.S. EPA, 1980c).
-7-
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3.2. CHRONIC
3.2.1. Oral. The only available chronic oral bloassays for PAHs are
Investigations of the carclnogenldty of BaP and d1benz[a,h]anthracene (U.S.
EPA, 1980c). The lack of appropriate protocols (I.e., nontumor pathology)
and detailed reporting of symptoms render these carclnogenldty bloassays
Inadequate for use 1n evaluating other endpolnts.
3.2.2. Inhalation. Pertinent data regarding the nontumor-related chronic
toxldty of PAHs administered by Inhalation could not be located In the
available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Rlgdon and Rennels (1964) fed female rats a diet containing
BaP at a level of 1000 mg/kg (equivalent to 50 mg/kg/day) for up to 3.5
months. Of seven pregnant treated animals, only one dam carried viable
fetuses to term, delivering four pups on the 23rd day of pregnancy. Two of
the four pups were stillborn, one of which was grossly malformed (not
necessarily treatment-related). A third pup was killed for observational
purposes and the fourth pup apparently died of starvation 3 days after
birth, as the dam did not show any signs of lactation. The authors were not
certain 1f this absence of lactation was treatment-related. At autopsy,
four dead fetuses were found 1n the right uterine horn of a second dam.
Signs of toxldty (body weight changes or hlstopathologlcal changes) were
not observed 1n the treated dams.
In a teratogenldty and reproduction study, Rlgdon and Neal (1965) fed
male and female mice diets containing BaP at a level of 0, 250, 500 or 1000
mg/kg over various time spans during mating, gestation and post-partum. No
apparent reproductive, teratogenlc, embryotoxlc or fetotoxlc effects were
observed 1n the experimental animals.
-8-
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Mackenzie and Angevlne (1981) administered BaP orally at a level of 10
mg/kg bw to CD-I mice during pregnancy. There was no effect on fetal body
weights but a marked and specific reduction of gonadal weight occurred.
Also, reduced fertility and reproductive capacity were reported among the
offspring. At a level of 40 mg/kg/day, almost complete sterility was
observed 1n both sexes of offspring (Mackenzie and Angevlne, 1981).
3.3.2. Inhalation. Pertinent data regarding the teratogenlc effects
resulting from Inhalation exposure to PAHs could not be located In the
available literature.
3.4. TOXICANT INTERACTIONS
U.S. EPA (1980c) has extensively described the synerglstk and antago-
nistic Interactions among different PAHs and between PAHs and non-PAHs
chemicals. Briefly, metabolism of PAHs by the mlcrosomal mixed function
oxldase enzyme system yields several types of reactive and potentially
carcinogenic Intermediates. Chemicals that Induce or Inhibit this enzyme
system alter the patterns of PAHs metabolism and, hence, alter their toxic
and carcinogenic properties.
-9-
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4. CARCINOGENICITY
The cardnogenldty of PAHs has been extensively tested by application
to the skin of mice, and been the subject of only limited Investigation by
other routes of administration. The studies discussed below were previously
summarized by U.S. EPA (1983a,b,c,d,e). More complete reviews of the
cardnogenldty bloassays of PAHs are presented by IARC {1973, 1983), U.S.
EPA (1980a,b,c, 1981) and Santodonato et al. (1981).
4.1. HUMAN DATA
Few case reports are available on the direct carcinogenic effects of
PAHs on humans. Cottlnl and Mazzone (1939) applied a 1% solution of BaP 1n
benzene to small areas of exposed and unexposed skin of 26 patients. Up to
120 dally applications were applied over a 4-month period. Regressive
verrucae developed 1n all of the 26 patients within this time. Although
reversible and apparently benign, these changes were thought to represent
early stages of neoplastlc proliferation. Similar cases of epidermal
changes were reported by Rhoads et al. (1954) and Klar (1938) 1n men acci-
dentally exposed to BaP. Numerous epldemlologlc studies of human popula-
tions (primarily worker groups) have shown a clear association between
exposure to PAHs-conta1n1ng mixtures (soots, tars, oils, etc.) and Increased
cancer risk (Santodonato et al., 1981; IARC, 1973, 1983; U.S. EPA, 1981).
4.1.1. Oral. Pertinent data regarding the carc1nogen1c1ty of pure PAHs
to humans following oral exposure could not be located 1n the available
literature.
4.1.2. Inhalation. Pertinent data regarding the cardnogenldty of pure
PAHs to humans following Inhalation exposure could not be located 1n the
available literature.
-10-
-------
4.2. BIOASSAYS
The carcinogenic properties of certain PAHs compounds have been studied
1n animals for more than 50 years. The predominance of testing has been
done with oral, Inhalation exposures, mouse skin assays, Implantations and
subcutaneous Injections.
A.2.1. Oral. Benzo[a]pyrene was administered to mice 1n the diet at
various concentrations to test Us cardnogenlclty (Neal and Rlgdon, 1967;
Rlgdon and Neal, 1966, 1969). These studies are summarized 1n Tables 4-1,
4-2 and 4-3. A dose-response relationship was noted for the Incidence of
stomach tumors (paplllomas and carcinomas) In male and female CFW-Sw1ss mice
treated with 1-250 ppm BaP for up to 197 days (Neal and Rlgdon, 1967).
Stomach tumors were reported 1n animals treated with 20, 40, 45, 50, 100 and
250 ppm BaP (5/23, 1/40, 4/40, 24/34, 19/23 and 66/73, respectively), while
control animals (0/289) and those treated with 1, 10 and 30 ppm BaP (0/25,
0/24 and 0/37, respectively) did not have similar tumors. An Increased
Incidence of lung adenoma and leukemia was noted In mice treated with 250
and 1000 ppm BaP, 1n addition to the Increase In stomach tumors (Rlgdon and
Neal, 1966, 1969).
There 1s no evidence that anthracene 1s an animal carcinogen 1n studies
where administration has been by the oral route. In two studies, Druckrey
and Schmahl (1955) and Schmahl and Relter (unpublished data), there were no
reports of any tumor formation caused by the administration of anthracene.
No tumors were reported 1n 31 rats treated with 4.4 g anthracene (total
dose) during a 33-month study (Schmahl and Relter, unpublished). Druckrey
and Schmahl (1955) reported no tumors 1n 28 rats receiving 4.5 g (total
dose) anthracene.
-11-
-------
TABLE 4-1
Carcinogentelly of Benio[a]pyrene Administered In the Diet to Hale and Female CFW Nice at Levels of 1-250 ppm*
rsj
i
(0.
14.
(B.
(13
(17
(19
(21
(39
(70
Dose
1 ppm
48 mg total dose)
10 p|M
48 mg total dose)
20 ppm
88 mg total dose)
30 ppm
.32 mg total dose)
40 ppm
.76 mg total dose)
45 ppm
.8 mg total dose)
50 ppm
.4-29.4 mg total dose)
100 ppm
.2-48.8 mg total dose)
250 ppm
-165 mg total dose)
0.0 ppm
Duration
of Treatment
110 days
110 days
110 days
110 days
110 days
110 days
107-197 days
98-122 days
70-165 days
NA
Duration
of Study
140 days
140 days
226 days
143-177 days
143-211 days
141-183 days
124-219 days
118-146 days
88-185 days
70-300 days
Purity
of
Compound
NR
NR
NR
NR
NR
NR
NR
NR
NR
NA
Vehicle or
Physical
State
diet
diet
diet
diet
diet
diet
diet
diet
diet
basal diet
only
Target
Organ
stomach
stomach
stomach
stomach
stomach
stomach
stomach
stomach
stomach
stomach
: 1
Tumor Type
paplllomas/carctnomas
paplllomas/carclnomas
papl 1 lomas/carc Inomas
paplllomas/carclnomas
papl 1 lomas/carc Inomas
paplllomas/carctnomas
paplllomas/carclnomas
papt 1 lomas/carc Inomas
paplllomas/carclnomas
paplllomas/carclnomas
Tumor
Incidence
0/25
0/24
5/23
0/37
1/40
4/40
24/34
19/23
66/73
0/289
•Source: Adapted from Neal and Rlgdon. 1967
NA > Not applicable
NR « Not reported
-------
TABIE 4-2
CarcinogenicIty of Benzo[a]pyrene Administered In the Diet to Male and female Swiss Nice at Levels of 200-1000 ppm*
Dose
1000 ppn
(1 mg/g food)
1000 ppm
(1 mg/g food)
250 ppn
(0.25 rog/g food)
250 ppn
(0.25 mg/g food)
0.0 ppra
Duration
of Treatment
73-83 days
127-187 days
72-99 days
147-196 days
NA
Duration
of Study
73-83 days
127-187 days
72-99 days
147-196 days
111-120 days
Purity
of
Compound
NR
NR
NR
NR
NA
Vehicle or
Physical
State
diet
diet
diet
diet
diet only
Target
Organ
stomach
lung
stomach
lung
stomach
lung
stomach
lung
stomach
lung
Tumor Type
paptlloma/carclnoma
adenoma
papll loma/carc Inoma
adenoma
papll loma/carc Inoma
adenoma
papll loma/carc Inoma
adenoma
papll loma/carc Inoma
adenoma
Tumor
Incidence
5/9
7/9
13/13
3/13
12/5?
26/52
9/13
10/13
2/108
25/108
•Source: Adapted from Rldgon and Neal, 1966
NA ~ Not applicable
NR = Not reported
-------
TABLE 4-3
Carctnogentctty of Benzo[a]pyrene Administered In the Diet to Hale and Female Swiss CPU Mice
at a Level of 250 ppma
Dose
250 ppm
(0.25 mg/g
food)
0.0 ppm
Duration
of
Treatment
(days)
80-140
NA
Duration
of Study
(days)
80-140
62-300
Purity
of
Compound
NR
NA
Vehicle or
Physical
State
diet
diet only
Target Organ
stomach
lung
hematopoletlc
system
stomach
lung
hematopoletlc
system
Tumor Type
papllloma/carclnoma
adenoma
leukemia
papllloma/carclnoma
adenoma
leukemia
Tumor
Incidence
69/108
52/108
40/108
2/175°
33/151
0/175°
aSource: Adapted from Rldgon and Neal, 1969
DInc1dence of tumors In a control group reported previously by Rlgdon and Neal (1966)
NA = Not applicable
NR = Not reported
-------
The cardnogenldty of BaP has been Investigated 1n mice following
administration by gavage (Klein, 1963). The compound, administered as a 3%
solution 1n Methocel-Aerosol O.T., was given 1n 0.5 ma doses, 3 times/week
for 5 weeks. The Incidence of lung adenomas and liver hepatomas was
elevated 1n animals terminated at either 444 or 547 days; these tumor
Incidences are summarized 1n Table 4-4.
D1benz[a,h]anthracene was the first pure chemical ever shown to produce
tumors 1n animals. Many early studies showed a carcinogenic effect In
animals when d1benz[a,h]anthracene was administered orally, subcutaneously
or applied to the skin (IARC, 1973; U.S. EPA, 1980c). Snell and Stewart
(1962, 1963) reported on the tumorlgenlc activity of d1benz[a,h]anthracene
after Its oral administration 1n groups of male and female DBA/2 strain
mice. An olive oil emulsion containing 0.2 mg/mi d1benz[a,h]anthracene
was used as a replacement for drinking water. An average dally dose of 0.76
mg d1benz[a,h]anthracene for females and 0.85 mg d1benz[a,h]anthracene for
males was determined from fluid consumption volumes. Among the animals
surviving at 200 days, 27/27 developed pulmonary adenomatosU, 24/27
developed carcinoma of the lung and 16 had hemang1oendothel1omas. Among the
surviving females, 12/13 developed mammary carcinomas. Among 29 controls,
one case of pulmonary adenomatosls was reported. No other tumors were
reported 1n the control group. These tumor Incidences are summarized 1n
Table 4-5.
Chronic administration of fluorene 1n the diet at levels of 0.05-0.5%
did not result 1n a significantly Increased Incidence of tumors 1n rats at
any site (Wilson et al., 1947; Morris et a!., 1960), but the data 1n one
study (Wlson et al., 1947) was Inadequately reported. These studies are
summarized 1n Tables 4-6 and 4-7.
-15-
-------
TABLE 4-4
Oral Carclnogenlclty Testing of Benz[a]anthracene Administered by Gavage to Hale B6AF-) Mice*
Dose or
Exposure
0.5 ml
3X solution
0.5 ml
O.OX solution
0.5 mi
3X solution
0.5 mi
O.OX solution
Duration
of Treatment
5 weeks,
3 doses/week
5 weeks,
3 doses/week
5 weeks,
3 doses/week
5 weeks,
3 doses/week
Duration
of Study
444 days
441 days
547 days
547 days
Purity
of
Compound
NR
NA
NR
NA
Vehicle or
Physical
State
Hethocel-
Aerosol
O.T.
Methocel-
Aerosol
O.T.
Methocel-
Aerosol
O.T.
Methocel-
Aerosol
O.T.
Target
Organ
lung
liver
lung
liver
lung
liver
lung
liver
Tumor
Type
adenoma
hepatoma
adenoma
hepatoma
adenoma
hepatoma
adenoma
hepatoma
Tumor
Incidence
37/39
18/39
10/38
0/38
19/20
20/20
6/20
2/20
*Source: Adapted from Klein, 1963
NA = Not applicable
NR = Not reported
-------
TABLE 4-5
Oral Carclnogenldty Testing of D1benz[a,h]anthracene Administered
In the Drinking Water to Hale and Female DBA/2 M1cea
Dose or Duration
Exposure of
Treatment
0.2 mg/mt 258 days
(0.76-0.85
mg/day)
0.0 mg 259 days
0.48-0.56 167 days
mg/day
Duration Purity Vehicle or
of Study of Physical
Compound State
258 days NR olive oil
emulsion
289 days NA olive oil
emulsion
only
167 days NR olive oil
emulsion
only
Target Organ
lung
mammary gland
mesentery/
pancreas/lymph
lung
mammary gland
mesentery/
pancreas/lymph
lung
mammary gland
mesentery/
pancreas/lymph
Tumor Type
adenoma
carcinoma
mixed
hemangloendothel loma
adenoma
carcinoma
mixed
hemangloendothel loma
adenoma
carcinoma
mixed
hemangloendothel loma
Tumor
Incidence
27/27
24/27
12/13b
16/27
1/35
0/35
0/35
0/35
7/19
15/19
3/9b
6/19
aSource: Adapted from Snell and Stewart. 1962, 1963
blnc1dence of mammary tumors stated for female mice; none occurred In males.
NA = Not applicable
NR = Not reported
-------
TABU 4-6
Carcinogenic Ity Testing of Fluorcne Administered In the Diet to Female Buffalo Rats'
Dose or Duration of
Exposure Treatment
4.6 mg/dayb 18.1 months
(range. 4.1-19.2)
0 ing/day NA
i
00
4.3 mg/dayb 6.1 months
(range. 5.0-6.2)
0 mg/day NA
Duration of Study
19.0
(range.
15.5
(range,
10.2
(range.
13.9
(range.
month
-------
TABLE 4-7
CardnogenlcUy Testing of Fluorene Administered In the Diet to Albino Rats*
Sex
NR
NR
Dose or
Exposure
0.062-1. OX
0.125, 0.25
or 0.5X
Duration
of
Treatment
104 days
453 days
Duration
of Study
104 days
453 days
Purity
of
Compound
NR
NR
Vehicle or
Physical
State
diet
diet
Effects
Organs appeared grossly
hlstologlcally normal
Squamous metaplasia of
bronchial epithelium
and
the
In
three rats. One rat on the
0.125X diet showed a small
kidney tubular adenoma of a
type not seen before In the
rat colony.
'Source: Adapted from Wilson et al., 1947
NR = Not reported
-------
4.2.2. Inhalation. Thyssen et al. (1981) exposed groups of 24 hamsters
by Inhalation to BaP at levels of 2.2, 9.5 or 46.5 mg/m3 for 4.5 hours/day
for 10 weeks, and 3 hours/day thereafter, 7 days/week for up to 675 days.
This study Is summarized 1n Table 4-8. No treatment-related tumors were
observed 1n animals exposed to 2.2 mg/m3. Animals exposed to 9.5 mg/m3,
however, developed tumors of the nasal cavity (12%), larynx (31%), trachea
(4%) and pharynx (2354). Hamsters exposed to BaP at a level of 46.5 mg/m3
also developed tumors of the respiratory tract (13/25) and upper digestive
tract (14/25). No tumors of these types were seen 1n control animals
(Thyssen et al., 1981).
Intratracheal administration of BaP resulted 1n an Increased Incidence
of respiratory tract neoplasms 1n both sexes of Syrian hamsters (Ketkar et
al., 1978; Feron and Kruysse, 1978). These studies are summarized 1n Tables
4-9 and 4-10. A dose-related response was reported for hamsters treated
with 18.2 and 36.4 mg/anlmal (total dose) for 52 weeks, followed by a
29-week latency period. The Incidence of trachea! paplllomas and carcinomas
collectively with lung adenomas was 4/29 and 3/27 for low-dose males and
females, respectively, and 19/30 and 7/24 for high-dose males and females,
respectively (Feron and Kruysse, 1978). Ketkar et al. (1978) reported a
high dose-related mortality 1n hamsters treated at dose levels higher than
those used by Feron and Kruysse (1978). Mean survival times ranged from 40
weeks for male hamsters treated with 0.1 mg BaP/week to 10 weeks for males
treated with 1.0 mg BaP/week. An Increase 1n the Incidence of respiratory
tract carcinoma, adenoma and papHloma was reported 1n treatment groups for
both males and females, but a definite dose-related response was not evident
(Ketkar et al., 1978).
-20-
-------
TABLE 4-8
Carcinogen Icily of Benzol a]pyrene to Hale Syrian Golden Hamsters Via Inhalation*.b
i
rsj
Dose
2.2 mg/m»
(29 mg total dose)
9.5 »g/m»
(127 mg total dose)
46.5 mg/m«
(383 mg total dose)
0.0 mg/m*
Duration Duration
of of Study
Treatment
95.2 weeks 95.2 weeks
96.4 weeks 96.4 weeks
59.5 weeks 59.5 weeks
NA 96.4 weeks
Purity
of
Compound
NR
NR
NR
NA
Vehicle or
Physical
State
NaCl vapor
In air
Had vapor
In air
Nad vapor
In air
NaCl vapor
only
Target Organ
respiratory tract
upper digestive
tract
respiratory tract
upper digestive
tract
respiratory tract
upper digestive
tract
respiratory tract
upper digestive
tract
Tumor
Typec
tumors
tumors
tumors
tumors
tumors
tumors
tumors
tumors
Tumor
Incidence
0/27
0/27
9/26*1
7/26d
13/25«
14/?5e
0/27
0/27
'Source: Adapted from Thyssen et al., 1981
^Exposure was for 4.5 hours/day for the first 10 weeks. 3 hours/day thereafter for 7 days/week.
cTumors were paplllomas, papillary polyps, and squamous cell carcinomas.
^3 nasal cavity. B laryngeal. 1 tracheal, 6 pharyngeal and 1 forestomach tumors
el nasal cavity, 13 laryngeal, 3 tracheal, 14 pharyngeal, 2 esophageal and 1 forestomach tumor
NA - Not applicable
NR - Not reported
-------
TABLE 4-9
Carclnogenlclty of Benzo[a]pyrene In Syrian Hamsters Following Intratrachea! Administration of 0.10-1.0 mg/weeka
OJ
Sex
N
r
N
r
N
F
H
F
Duration Duration Purity
Dose of of of
Treatment" Study0 Compound
0.10 mg/week 40 weeks 40 weeks 97X
0.10 mg/week 34 weeks 34 weeks 97X
0.33 mg/week 24 weeks 24 weeks 97X
0.33 mg/week 28 weeks 28 weeks 97X
1.0 mg/week 10 weeks 10 weeks 97X
1.0 mg/week IS weeks IS weeks 97X
0.0 mg/week 41 weeks 41 weeks NA
0.0 mg/week 35 weeks 3S weeks NA
Vehicle or
Physical
State
bovine
albumin
bovine
albumin
bovine
albumin
bovine
albumin
bovine
albumin
bovine
albumin
bovine
albumin
only
bovine
albumin
only
Target Organ
respiratory tract
respiratory tract
respiratory tract
respiratory tract
respiratory tract
respiratory tract
respiratory tract
respiratory tract
Tumor Typec
various neoplasms
various neoplasms
various neoplasms
various neoplasms
various neoplasms
various neoplasms
various neoplasms
various neoplasms
Tumor
Incidence
5/26
12/30
7/29
10/28
6/27
6/30
0/29
0/30
aSource: Adapted from Ketkar et al.. 1978
t>Hean Survival Time
cCarc1nomas. adenomas, adenocarctnomas and paplllomas were reported.
NA * Not applicable
-------
TABLE 4-10 '
Carclnogenlclty of Benzo[a]pyrene In Syrian Golden Hamsters Following Intratracheal Administration of 18.2-36.4 mg/anlmal*
Sex
N
H
H
F
F
F
Dose
18.2 mg/hamster
total dose
36.4 mg/hamster
total dose
0.0 mg/hamster
total dose
IB. 2 mg/hamster
total dose
36.4 mg/hamsler
total dose
0.0 mg/hamster
total dose
Duration of Duration
Treatment of Study
52 weeks 81 weeks
(1 dose/week)
52 weeks 81 weeks
(1 dose/week)
52 weeks 81 weeks
(1 dose/week)
52 weeks 81 weeks
(1 dose/week)
52 weeks 81 weeks
(1 dose/week)
52 weeks 81 weeks
(1 dose/week)
Purity Vehicle or
of Physical
Compound State
>99X 0.9X NaCl
>99X 0.9X NaCl
>99X saline
vehicle
only
>99X 0.9X NaCl
>99X 0.9X NaCl
>99X saline
vehicle
only
Tumor
Target Organ Typeb
respiratory tract various
respiratory tract various
respiratory tract various
respiratory tract various
respiratory tract various
respiratory tract various
Tumor
Incidence
4/29
19/30
0/30C
3/27
7/24
0/28C
'Source: Adapted from Feron and Kruysse, 1978
bpapniomas and carcinomas of the trachea and pulmonary ademonas were most prevalent.
eCombined tumor Incidence of untreated and vehicle controls.
-------
In a study by Stanton et al. (1972), 0.5 mg anthracene In 0.05 ml warm
soft 1:1 wax-tr1capry!1n was Implanted 1n the lung by a thoracotomy In
Osborne-Mendel female rats (3-6 months old). No epidermal carcinomas were
reported In the 55-week study; however, there was a granulomatous reaction
1n all of the 37 examined animals. No tumors were seen In 10 control
animals. This study 1s summarized 1n Table 4-11.
4.2.3. Mouse Skin Assays. Many of the polycycllc aromatlcs produce
tumors In mouse skin when applied topically alone or 1n combination with a
promoter. As a result of the route of administration, these studies have
limited utility for quantitative risk assessment. However, they provide
useful qualitative data which can be used to estimate relative potency.
U.S. EPA (1982) has used skin painting data on five PAHs [dlbenzo(a.h)-
anthracene; benzo(a)anthracene, 1ndeno(l,2,3-c,d)pyrene; chrysene; benzo(b)-
fluoranthene] tested using similar protocols to qualitatively compare their
potency to BaP. The overall ranking was as follows: BaP > DBA > BbF > BaA >
IP > chrysene. This type of analysis becomes especially Important when risk
assessment estimates for PAHs as a class are attempted. In addition to
these compounds which were tested using similar protocols (anthanthrene),
benzo(1)fluranthene, 7,l2-d1methylbenze(a)anthracene, d1benzo(a,b)pyrene,
d1benzo(a,e)pyrene, d1benzo(a,h)pyrene, d1benzo(a,1)pyrene have all been
shown to have some degree of carcinogenic activity when tested 1n mouse skin
(CRC, 1983) using various protocols (IARC, 1973).
In addition, PAHs containing mixtures have been found to show carcino-
genic acltlvHy In mouse skin Including: crude coal tar, blast furnace tar,
soot extracts, oil shale extracts, cigarette smoke condensates, petroleum
pitch, automobile exhaust (CRC, 1983; IARC, 1973).
-24-
-------
TABLE 4-11
Carclnogenlclty Testing of Anthracene In Female Osborne-Hendel Rats by Lung Implantation*
en
l
Dose or
Exposure
0.5 mg
0.10 mi
vehicle
Duration of
Treatment
single Implant
single Implant
Duration
of Study
55 weeks
81 weeks
Purity of
Compound
refined
recrystalllzed
NA
Vehicle or
Physical
State
1:1 wax-
trlcaprylln
1:1 wax-
trlcaprylln
Target
Organ
trachea
trachea
Tymor Type
eptdermold
carcinoma
epldermold
carcinoma
Tumor
Incidence
0/37
0/10
*Source: Adapted from Stanton et al., 1972
NA = Not applicable
-------
4.2.4. PAH Containing Mixtures. A number of occupational exposure situa-
tions Involving PAH containing mixtures have been linked to Increased Inci-
dence of cancer 1n exposed humars. Exposure of chimney sweeps to soot and
coal tar has been associated with Increased scrotal cancer. Increased Inci-
dence of bronchial carcinoma has been noted 1n gasworkers and coking workers
(CRC, 1983); Increased skin cancer 1n workers 1n the coal tar and pitch
Industry (IARC, 1973). Soots, coal-tars, creosote oils, shale oils and
cutting oils have been shown to be carcinogenic 1n animals following skin
painting or subcutaneous Injection (IARC, 1973). Diesel exhaust condensate
and gasoline engine exhaust condensate have been shown to cause skin tumors
when topically applied to mice (CRC, 1983).
4.3. OTHER RELEVANT DATA
A large number of short-term genotoxlclty tests have been performed with
PAHs. Qualitative Indications of selected PAHs genotoxlclty are summarized
1n Table 4-12. Many of the PAHs that have shown positive results 1n one or
more J[n vitro genotoxlclty screening tests have given negative results In
animal bloassays (Santodonato et al., 1981; IARC, 1973, 1983; U.S. EPA,
1981).
4.4. WEIGHT OF EVIDENCE
Certain PAHs have demonstrated a carcinogenic response by various
routes, while others are considered to be noncarclnogenlc or have not been
tested extensively.
-26-
-------
TABLE 4-12
Genotoxldty of Selected PAHa
PAH
Positive Result 1n at Least One Genotoxldty Assay
Anthanthrene
Anthracene
Benz[c]acr1d1ne
Benz[a]anthracene
Benzo[b]fluoranthene
Benzofbjfluorene
Benzo[g,h,1]perylene
Benzo[a]pyrene
Benzo[e]pyrene
Carbazole
Chrysene
Coronene
Cyclopenta[c,d]pyrene
D1benz[a,h]acr1d1ne
D1benz[a,j]acr1d1ne
D1benz[a,c]anthracene
D1benz[a,h]anthracene
7H-D1benzo[c,g]carbazole
D1benz[a,h]pyrene
D1benzo[a,1]pyrene
1,4~D1methylphenanthrene
Fluoranthene
Fluorene
1-Methylphenanthrene
Perylene
Phenanthrene
Pyrene
Trlphenylene
aSource: Adapted from IARC, 1983
^Positive for cardnogenlclty 1n at least one animal bloassay
cNegat1ve for cardnogenlclty 1n rats fed fluorene In the diet
-27-
-------
IARC (1983) has evaluated selected PAHs based on the overall weight of
evidence of cardnogenlcHy . to humans. These classifications range from
Group 2A (BaP) and 2B meaning that the compound 1s probably carcinogenic 1n
humans to Group 3 which Indicates that there 1s only limited animal evidence
or a paucity of evidence such that the data base 1s Inadequate to assess the
human carcinogenic potential. Some of these classifications are based on
routes of exposure other than oral and Inhalation. As a class, PAH-conta1n-
1ng soots, tars and oils are most appropriately classified as Group 1 {IARC,
1983). Applying the criteria proposed by the Carcinogen Assessment Group of
the U.S. EPA (Federal Register, 1984) for evaluating the overall weight of
evidence for human cardnogenlclty, these chemicals are most appropriately
classified In Group A.
IARC has Judged the following specific PAHs to be probably carcinogenic
In humans, there being sufficient animal evidence and or limited human
evidence. The corresponding U.S. EPA grouping (Federal Register, 1984)
would be Group 81 or B2, depending on the quality of the evidence.
1. benz[a]anthracene
2. benzo[b]fluoranthene
3. benzo[JJfluoranthene
4. benzo[k]fluoranthene
5. benzo[a]pyrene
6. d1benz[a,h]acr1d1ne
7. d1benz[a,j]acr1d1ne
8. d1benz[a,h]anthracene
9. 7H-d1benzo[c,g]carbazole
10. d1benzo[a,e]pyrene
11. d1benzo[a,h]pyrene
12. d1benzo[a,1]pyrene
13. d1benzo[a,l]pyrene
14. 1ndeno[l,2,3-cd]pyrene
-28-
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Further, the following compounds have limited animal evidence for cardno-
genldty, however, the evidence according to IARC 1s Inadequate for making a
definitive statement about the human carcinogenic potential. The appro-
priate U.S. EPA classification (Federal Register, 1984) for these chemicals
1s Group C-Poss1ble Human Carcinogen.
1. anthanthrene
2. benz[c]acr1d1ne
3. carbazole
4. chrysene
5. cyclopenta[c,d]pyrene
6. d1benz[a,c]anthracene
7. d1benz[a,j]anthracene
8. d1benzo[a,e]fluoranthene
9. 2 and 3-methylfluoranthenes
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5. REGULATORY STANDARDS AND CRITERIA
Exposure criteria and TLVs have been developed for PAHs as a class, as
well as for several Individual PAHs. The U.S. Occupational Safety and
Health Administration (OSHA) has set an 8-hour TWA concentration limit of
0.2 mg/m3 for the benzene-soluble fraction of coal tar pitch volatlles
(anthracene, BaP, phenanthrene, acrldlne, chrysene, pyrene) (Code of Federal
Regulations, 1981). NIOSH (1977) recommends a concentration I1ra1t for coal
tar, coal tar pitch, creosote and mixtures of these substances at 0.1
mg/m3 of the cyclohexane-extractable fraction of the sample, determined as
a 10-hour TWA. NIOSH (1977) concluded that these specific coal tar
products, as well as coke oven emissions, are carcinogenic and can Increase
the risk of lung and skin cancer In workers. NIOSH (1977) also recommends a
celling limit for exposure to asphalt fumes of 5 mg airborne partlcu-
lates/m3 of air.
Environmental quality criteria for PAHs have been recommended for
ambient water, which specify concentration limits Intended to protect humans
against adverse health effects. The U.S. EPA (1980c) has recommended a
concentration limit of 28 mg/a. for the sum of all carcinogenic PAHs 1n
ambient water. This value Is based on a mathematical extrapolation of the
results from studies with mice treated orally with BaP, and acknowledges the
conservative assumption that all carcinogenic PAHs are equal 1n potency to
BaP. Dally consumption of water containing 28 mg/8. of carcinogenic PAHs
over an entire lifetime 1s estimated, on the basis of the animal bloassay
data, to keep the lifetime risk of cancer development below one chance In
100,000.
-30-
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The U.S. EPA has not recommended an ambient water quality criterion for
noncardnogenlc PAHs as a class. U.S. EPA (1980b) has recommended, however,
an ambient water quality criterion for fluoranthene of 42 vg/8., which 1s
based on the extrapolation of results from chronic toxlclty tests 1n mice
that received fluoranthene by repeated application to the skin. In deriving
this criterion for fluoranthene, the U.S. EPA (1980b) acknowledged that data
suitable for quantitative risk assessment of noncardnogenlc PAHs are essen-
tially nonexistent. An ambient water quality criterion of 0.02 mg/a for
acenaphthene has been recommended by the U.S. EPA (1980a) on the basis of
organoleptlc properties.
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6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Some Individual PAHs have been shown to be carcinogenic 1n humans and
others to be carcinogenic to animals. Data are available regarding BaP from
which carcinogenic potency can be estimated. It 1s Inappropriate, there-
fore, to calculate an AIS for these chemicals.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Some Individual PAHs have been shown to be carcinogenic 1n humans and
others to be carcinogenic to animals. Data are available regarding BaP from
which carcinogenic potency can be estimated. It 1s Inappropriate, there-
fore, to calculate an AIC for these chemicals.
6.3. CARCINOGENIC POTENCY (q^)
A unit risk for carc1nogen1c1ty 1s presented on the basis that an
assumption (risk management decision) Is made to consider PAHs carcinogenic
to humans as a class of compounds or that Individual compounds are carcino-
gens for humans. This assumption (decision) must be made prior to the use
of the unit risk value. Because of the relative paucity of PAHs data that
1s useful for potency estimation, the estimation of the unit risk Is based
upon the data from a single PAH compound, BaP.
As U.S. EPA (1982) states, on the basis of currently available data, If
the cumulative PAHs exposure 1s less than or equal to the criterion for BaP
the resultant risk should be <10~5. If the cumulative exposure to other
PAHs exceeds the criterion level recommended for BaP, the resultant risk may
exceed 10~5. It should be stated that this approach to risk assessment
Ignores the possibility of carcinogenic synerglsm of PAHs. Practically,
however, 1t seems likely that the potential for synerglsm Is far outweighed
by the difference In carcinogenic potency between BaP and other PAHs.
-32-
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Exposure to any single PAH compound 1n occupational or envronmental
situations Is unlikely to occur. Exposures are expected to be to complex
mixtures with varying PAH constituents. LHtle 1s known at present concern-
Ing potential Interaction of components 1n these complex mixtures.
6.3.1. Oral. To protect for carcinogenic effects of all PAHs, a carcino-
genic potency factor for humans, q *, can be derived from the study of
Neal and Rlgdon (1967), 1n which BaP at dose levels of 1-250 ppm 1n the diet
was fed to strain CFW mice for -110 days. This approach to criterion deri-
vations adopts the conservative assumption that all carcinogenic PAHs are
equal In potency to BaP. The Incidences of stomach tumors (mostly squamous-
cell paplllomas but some carcinomas) were 0/289 for controls, 0/25 at the 1
ppm (0.13 mg/kg/day) level, 0/24 at 10 ppm (1.3 mg/kg/day), 1/23 at 20 ppm
(2,6 mg/kg/day), 0/37 at 30 ppm (3.9 mg/kg/day), 1/40 at 40 ppm (5.2 mg/kg/
day), 4/40 at 45 ppm (5.85 mg/kg/day), 24/34 at 50 ppm (6.5 mg/kg/day),
19/23 at 100 ppm (13.0 mg/kg/day) and 66/73 at 250 ppm (32.5 mg/kg/day).
U.S. EPA (1980c) used these Incidences of stomach tumors to derive a q *
of 11.53 (mg/kg/day)"1, using the multistage model of Crump adopted by the
U.S. EPA (Federal Register, 1980) for computation of carcinogenic potency.
The data base from which this q,* was derived 1s presented 1n Appendix B.
6.3.2. Inhalation. Adopting the same conservative approach as taken
above for oral exposure to carcinogenic PAHs, a carcinogenic potency factor
for humans, q,*, can be derived from the study of Thyssen et al. (1981),
1n which Syrian golden hamsters were exposed to BaP by Inhalation. These
animals were exposed at levels of 0, 2.2, 9.5 or 46.5 mg/m3 for 59.5-96.4
weeks. The Incidences of respiratory tumors were 0/27 for controls, 0/27
for the low-dose group, 9/26 for the mid-dose group, and 13/25 for the high-
dose group. Because of early mortality 1n the highest dose group, these
-33-
-------
data were excluded from the q,* derivation. Based on the respiratory
tumor response of male hamsters, and using the linearized multistage model
adopted by the U.S. EPA (Federal Register, 1980), a carcinogenic potency
factor (q,*) of 6.11 (mg/kg/day)"1 can be derived for humans. The
corresponding dose associated with an Increased lifetime cancer risk of
10~s 1s 2.339xlO~s mg/kg/day or 1.64xlO~« mg/day for a 70 kg human.
Complete data for derivation of the q * are presented 1n Appendix C.
-34-
-------
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Korfmacher, W.A., E.L. Wehry, G. Mamantov and D.F.S. Natusch. 1980. Resis-
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MacKenzle, K.M. and D.M. Angevlne. 1981. Infertility In mice exposed in
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Mitchell, C.E. and K.W. Tu. 1979. Distribution, retention and elimination
of pyrene 1n rats after Inhalation. J. Toxlcol. Environ. Health. 5:
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-40-
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-41-
-------
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-42-
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Carcinogen Assessment Group, OHEA, Washington, DC for the Office of Solid
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-43-
-------
U.S. EPA. 1983e. Review of Tox1colog1c Data 1n Support of Evaluation for
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36: 1040-1048.
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Wise, S.A., W.J. Bonnett, F.R. Guenther and W.E. May. 1981. A relationship
between reversed-phase C,g liquid chromatographlc retention and the shape
of polycycllc aromatic hydrocarbons. J. Chromatogr. Sc1. 19: 457-465.
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ture on aspects of airborne polycycllc aromatic hydrocarbons. Environ. Scl.
Technol. 16: 189-194.
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APPENDIX A
Summary Table for PAH
Carcinogenic
Potency
Inhalation
Oral
Species Experimental
Dose/Exposure
hamsters 2.2-9.5 mg/m»
mice 1-250 ppm
Effect
respiratory
tract tumors
stomach
tumors
Unit Risk or q-|*
6.11
(mg/kg/day)-»a.b
11.53
(mg/kg/day)~ia.b
Reference
Thyssen et al. ,
1981
Neal and
Rlgdon, 1967'
U.S. EPA, 1980c
aUses carcinogenic potency of benzo(a)pyrene
bThese values require that an explicit decision be made which assumes that the compound or compounds are
likely to be human carcinogens Irrespective of the scientific uncertainty 1f any, regarding this assump-
tion.
-------
APPENDIX B
Cancer Data Sheet for Derivation of q-j*
Compound: Benzo[a]pyrene
Reference: Neal and Rlgdon, 1967
Species, strain, sex: mice, CFW, male and female
Body weight: 0.034 kg (assumed)
Length of exposure (le) * 110 days
Length of experiment (Le) = 183 days
Llfespan of animal (L) = 630 days
Tumor site and type: stomach, squamous cell carcinomas and paplllomas
Route, vehicle: oral, diet
Experimental Doses
or Exposures
(ppm)
0
1
10
20
30
40
45
50
100
250
Transformed Dose
(mg/kg/day)
0
0.13
1.3
2.6
3.9
5.2
5.85
6.5
13.0
32.5
Input
Incidence
No. Responding/No. Tested
(or Examined)
0/289
0/25
0/24
1/23
0/37
1/40
4/40
24/34*
19/23*
66/73*
*These data not used because of lack of fit to multistage model.
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APPENDIX C
Cancer Data Sheet for Derivation of q-j*
Compound: Benzo[a]pyrene "'
Reference: Thyssen et a!., 1981
Species, strain, sex: hamsters/Syrian golden/male
Body weight: 0.12 kg (assumed)
Length of exposure (le) = 666.4 days for lower dose and 674.8 days for
higher dose and controls
Length of experiment (Le) = 666.4 days for lower dose and 674.8 days for
higher dose and controls
Llfespan of animal (L) = 666.4 days for lower dose and 674.8 days for higher
dose and controls
Tumor site and type: respiratory tract/paplllomas, papillary polyps and
squamous-cell carcinomas
Route, vehicle: Inhalation/Nad vapor In air
Experimental Doses
or Exposures
0 mg/m3
2.2 mg/m3
9.5 mg/m3
Transformed Dose
(mg/kg/day)
0
0.0892
0.385
Input
Incidence
No. Responding/No. Tested
(or Examined)
0/27
0/27
9/26
See conversions on following page
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CONVERSIONS
0 mg/m3 = 0 mg/kg/day
2.2 mg/m3 x [( "yeefcs x 4.5 hours ^ 85.2 weeks ^_hours
95.2 weeks 24 hours 95.2 weeks 24 hours 7 days
0.037 mVday * 0.12 kg x 666t4 days x <666'4 days) 3 = 0.0892 rag/kg/day
666.4 days 666.4 days
9.5 mg/m3 x [ 10 weeks x 4.5 h0urs} f 86.4 weeks x _3_hpjurs)] 7_dajti
96.4 weeks 24 hours 96.4 weeks 24 hours 7 days
0.037 m'/day * 0.12 kg x 674'8 days x <674'8 days) 3 = 0.385 rog/kg/day
674.8 days 674.8 days
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