United States
Environmental Protection
1=1 m m Agency
EPA/690/R-12/017F
Final
12-27-2012
Provisional Peer-Reviewed Toxicity Values for
Fluoranthene
(CASRN 206-44-0)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Dan D. Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
Nina Ching Y. Wang, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Anuradha Mudipalli, MSc, PhD
National Center for Environmental Assessment, Research Triangle Park, NC
Paul G. Reinhart, PhD, DABT
National Center for Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS Ill
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVS I
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 4
HUMAN STUDIES 6
Oral Exposures 6
Inhalation Exposures 6
ANIMAL STUDIES 6
Oral Exposure 6
Subchronic Studies 6
Chronic Studies 9
Developmental and Reproductive Studies 10
Carcinogenic Studies 10
Inhalation Exposure 10
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 10
Tests Evaluating Carcinogenicity and Genotoxicity 15
Other Toxicity Tests 19
Metabolism Studies 20
Mechanistic Studies 20
DERIVATION 01 PROVISIONAL VALUES 22
DERIVATION 01 ORAL REFERENCE DOSE 23
Derivation of Subchronic Provisional RfD (Subchronic p-RfD) 23
Derivation of Chronic RfD (Chronic RfD) 25
DERIVATION OF INHALATION REFERENCE CONCENTRATION 25
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 25
MUTAGENICITY INFORMATION 27
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 27
Derivation of Provisional Oral Slope Factor (p-OSF) 27
Derivation of Provisional Inhalation Unit Risk (p-IUR) 27
APPENDIX A. PROVISIONAL SCREENING VALUES 28
APPENDIX B. DATA TABLES 29
APPENDIX C. BMD MODELING OUTPUTS FOR FLUORANTHENE 31
APPENDIX D. REFERENCES 48
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
FLUORANTHENE (CASRN 206-44-0)
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 Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
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.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa.gov/iris), the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents and appropriate use of this PPRTV assessment should
be directed to the EPA Office of Research and Development's National Center for
Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
Fluoranthene occurs as pale yellow needles or crystals (Hazardous Substance Database,
HSDB, 2005) and is a polycyclic aromatic hydrocarbon (PAH) of nonalternant type. An
alternant PAH is a conjugated hydrocarbon that has only 6-membered (hexagonal) rings (e.g.,
benzo[a]pyrene), while nonalternant PAHs are those that have a mixture of 6- (hexagonal) and
lower-membered rings. Fluoranthene is a 4-ring (tetracyclic) structure wherein a benzene and a
naphthalene unit (both are hexagonal) are conjugated to a five-membered (pentagonal) ring.
Fluoranthene occurs in a number of products including (i) as a natural constituent of coal tar and
petroleum-derived asphalt, which can be used as lining material for the interior of steel and
ductile-iron potable water pipes and storage tanks; (ii) in research; (iii) in the production of
fluorescent dyes; (iv) as a stabilizer in epoxy resin adhesives; (v) in electrical insulating oils; and
(vi) as a parent compound for pharmaceutical drugs. Fluoranthene is found in polluted urban air,
water, diesel and gasoline engine exhaust, cigarette smoke, and other products of incomplete
combustion of organic matter (International Agency for Research on Cancer, IARC, 1983;
Grimmer and Pott, 1983). Its presence is an indicator of less efficient or lower-temperature
combustion, as nonalternant PAHs are less preferred in formation than alternant PAHs. It is one
of the most prevalent dietary PAHs; a dietary intake of 1-2 |ig/day was estimated in one study
(de Vos et al., 1990). The empirical formula for fluoranthene is Ci6Hi0, and the molecular
structure of fluoranthene is presented in Figure 1. Some physicochemical properties of
fluoranthene are provided in Table 1.
Figure 1. Fluoranthene Structure
Table 1. Physicochemical Properties Table for Fluoranthene (CASRN 206-44-0)a
Property (unit)
Value
Boiling point (°C)
384
Melting point (°C)
111
Density (g/cm3 at 0°C)
1.252
Vapor pressure (mm Hg at 20°C)
0.01
pH (unitless)
NA
Solubility in water (mg/L at 25°C)
0.20-0.26
Relative vapor density (air = 1)
NA
Molecular weight (g/mol)
202.26
Octanol/water partition coefficient (log Kow, unitless)
5.16
aValues were obtained from HSDB (2005).
NA = Not available.
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A noncancer oral RfD of 0.04 mg/kg-day for fluoranthene is included in the U.S. EPA
IRIS database (U.S. EPA, 1990). The study used to derive this value is an EPA
subchronic-toxicity study (U.S. EPA, 1988), in which CD-I mice (20/sex/group) were
administered gavage doses of fluoranthene at 0, 125, 250, or 500 mg/kg-day for 13 weeks. An
additional group of 30 mice/sex was used for baseline blood evaluations. The lowest-observed-
adverse-effect-level (LOAEL) was selected based on nephropathy, increased liver weights,
hematological alterations, increased liver enzymes, and clinical signs in the mid- and high-dose
groups. An uncertainty factor (UF) of 3000 was applied to the no-observed-adverse-effect-level
(NOAEL) value of 125 mg/kg-day from this study to derive the RfD value. When values were
developed by other regulatory agencies, this study was also cited as the principal study. No data
were available to allow for the calculation of a RfC for IRIS (U.S. EPA, 1990). No RfD, RfC, or
cancer assessment for fluoranthene is included in the Drinking Water Standards and Health
Advisories List (U.S. EPA, 2009). A subchronic RfD value of 0.4 mg/kg-day is reported in the
HEAST (U.S. EPA, 2010). This RfD value is based on nephropathy, liver-weight changes, and
hematological changes. The Chemical Assessments and Related Activities (CARA) list
(U.S. EPA, 1994) does not include a Health and Environmental Effects Profile (HEEP) for
fluoranthene. The toxicity of fluoranthene has not been reviewed by the ATSDR (2010), but it is
included in the review of PAHs (ATSDR, 1995). The ATSDR specifies a recommended oral
minimum risk level (MRL) of 0.4 mg/kg-day for intermediate-duration exposure (15 to
364 days); no inhalation MRL values are reported for any PAHs. A World Health Organization
(IPCS, 1998) Environmental Health Criteria (EHC) document on PAHs reports the NOAEL and
LOAEL values cited by IRIS (125 and 250 mg/kg-day, respectively); no separate EHC document
exists for fluoranthene. The CalEPA (2008) has not derived toxicity values for exposure to
fluoranthene. No occupational exposure limits for fluoranthene have been derived by the
American Conference of Governmental Industrial Hygienists (ACGIH, 2010), the National
Institute of Occupational Safety and Health (NIOSH, 2010), or the Occupational Safety and
Health Administration (OSHA, 2010). OSHA does provide standards for coal tar pitch volatiles;
however, those regulations apply to a mixture of compounds.
A PPRTV document for fluoranthene also exists (i.e., U.S. EPA, 2002), which states that
no OSF can be derived for fluoranthene due to inadequate human and animal data. In a previous
IRIS assessment (U.S. EPA, 1990), fluoranthene was categorized in Group D ('Wo/ Classifiable
as to Human Carcinogenicity"). The HEAST (U.S. EPA, 2010) does not report a U.S. EPA
(1986) cancer weight-of-evidence (WOE) classification for fluoranthene. The IARC (2010)
determined that there is "limited evidence in animals" and that fluoranthene is "not classifiable"
with respect to carcinogenicity in humans (Group 3). Fluoranthene is not included in the
12th Report on Carcinogens (NTP, 2011). CalEPA (2008) has not prepared a quantitative
estimate of carcinogenic potential for fluoranthene.
Literature searches were conducted on sources published from 1900 through April 2012
for studies relevant to the derivation of provisional toxicity values for fluoranthene
(CAS No. 206-44-0). Searches were conducted using EPA's Health and Environmental
Research Online (HERO) database of scientific literature. HERO searches the following
databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library; DOE: Energy
Information Administration, Information Bridge, and Energy Citations Database; EBSCO:
Academic Search Complete; GeoRef Preview; GPO: Government Printing Office;
Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics
& Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National
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Service Center for Environmental Publications [NSCEP] and National Environmental
Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases;
SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network):
ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search,
NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and TSCATS; Virtual Health Library; Web
of Science (searches Current Content database among others); World Health Organization; and
Worldwide Science. The following databases outside of HERO were searched for relevant
health information: ACGM, AT SDR, CalEPA, EPA IRIS, EPA HEAST, EPA HEEP, EPA OW,
EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides an overview of the relevant database for fluoranthene and includes all
potentially relevant repeated short-term-, subchronic-, and chronic-duration studies. The entry
for the principal study is bolded.
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Table 2. Summary of Potentially Relevant Data for Fluoranthene (CASRN 206-44-0)
Number of
Male/Female,
Species, Strain,
Study Type, Study
BMDL/
Category
Duration
Dosimetry3
Critical Effects at LOAEL
NOAEL3
BMCL3
LOAEL3
Reference
Notesb
Human
1. Oral (mg/kg-day)3
None
2. Inhalation (mg/m3)3
None
Animal
1. Oral (mg/kg-day)3
Subchronic
40/40, rat, F344,
0, 150, 750, 1500
Renal tubular casts (male)
NA°
Not
NA°
Knuckles et al.
PR
dietary, 7 days/week,
performed
(2004)
up to 90 days
20/20 mouse, CD-I,
0,125, 250,500
Nephropathy, increased liver weights,
125
124
250
U.S. EPA
PS,
gavage, 13 weeks
hematological alterations, and clinical
(1988)
PR,
effects
IRIS
Chronic
None
Developmental
None
Reproductive
None
Carcinogenic
None
2. Inhalation (mg/m3)a
None
""Dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-day) for oral noncancer effects. All long-term exposure
values (4 weeks and longer) are converted from a discontinuous to a continuous (weekly) exposure.
bIRIS = utilized by IRIS, date of last update, PS = principal study, NPR = not peer reviewed, PR = peer reviewed.
°The study authors stated that the NOAEL was 150 mg/kg-day, based upon renal tubular casts and hematological changes observed at 750 mg/kg-day; however, due to
numerous deficiencies in this study, a NOAEL and LOAEL cannot be established.
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HUMAN STUDIES
Oral Exposures
No oral studies on the subchronic, chronic, developmental, or reproductive toxicity or on
the carcinogenicity of fluoranthene in humans were identified.
Inhalation Exposures
No inhalation studies on the subchronic, chronic, developmental, or reproductive toxicity
or on the carcinogenicity of fluoranthene in humans were identified.
ANIMAL STUDIES
Oral Exposure
The effects of oral exposure of animals to fluoranthene have been evaluated in two
subchronic studies: U.S. EPA (1988) and Knuckles et al. (2004).
Subchronic Studies
In the study by Knuckles et al. (2004), fluoranthene (98% purity) was administered in the
diet at doses of 0, 150, 750, or 1500 mg/kg-day to male and female F344 rats for approximately
90 days. Although not explicitly stated in the study report, 40 rats/sex were apparently used for
each dose group. Stability of the test compound in the diet and homogeneity was stated to be
acceptable. Animal husbandry was adequate, conforming with the National Institutes of Health
Guidelines for the Care and Use of Laboratory Animals. Animals were weighed twice weekly,
and food consumption was recorded. Hematology and clinical chemistry were performed on
blood samples obtained at sacrifice, and the following parameters were determined: erythrocyte
count, total leukocyte count, hematocrit, hemoglobin, mean corpuscular volume, mean
corpuscular hemoglobin, mean corpuscular hemoglobin concentration, alanine aminotransferase,
aspartate aminotransferase, and blood urea nitrogen (BUN). During Days 29, 59, and 89, urine
was collected over approximately 24 hours from 10 rats/sex/group, and urinalysis was
determined for following parameters: urinary glucose, bilirubin, ketone, specific gravity, pH,
protein, urobilinogen, nitrite, blood, and leukocytes.
Animals were euthanized on Day 30, 60, or 90, with 10 rats/sex/dose group sacrificed at
each time point (Knuckles et al., 2004). The number of animals examined for renal tubular casts
were apparently 6-8 rats/sex/dose group; two 1500-mg/kg-day males and one 750-mg/kg-day
female died (Ramesh, personal communication, July 27, 2010). The methods did not report
which organs were weighed and examined grossly and histologically. Based on the results, the
stomach, liver, kidney, testes, prostate, and ovaries were excised and prepared routinely for
histological examination; it is assumed that organs from all animals were examined, and that
these organs were also weighed and examined grossly. (It is noted that the study authors used
the words "such as" in their listing of organs examined histologically; therefore, it cannot be
confirmed that this is a complete listing.) It is also unknown whether a full necropsy was
performed. An acute study was also performed, but it is not pertinent to this assessment.
Organ-weight and toxicity data were initially analyzed by analysis of variance
(ANOVA), followed by the Bonferroni multiple-range test (Knuckles et al., 2004). Pathology
data were reportedly analyzed with Fisher's Exact Test and the Cochran-Armitage test for linear
trends. A two-way ANOVA was used for the determination of statistical differences in toxicity
on the basis of duration of dose and dose level and to assess the interactions among these
variables. The criterion for statistical significance wasp < 0.05.
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Considering the various toxicological endpoints noted in the study (Knuckles et al.,
2004), the occurrence of renal tubular casts in males provided the most sensitive endpoint. The
incidences of renal tubular casts for the subchronic study were presented graphically in Figure 9
in the study; however, the study did not adequately describe the methodology used in obtaining
the data presented in Figure 9. The study also did not explain whether the data in Figure 9 were
dichotomous or continuous in nature. Figure 9 of the study depicts "percent tubular casts"
(y-axis label) as a bar graph with mean and standard deviation (as specified in the caption),
suggesting that the data are continuous, but the data seem to be dichotomous. Although the
Figure 9 caption specifies that the "percentage incidence of renal casts in F344 rats" was
measured, it is unclear if the authors were referring to percentage incidence of casts on multiple
slides (inappropriate methodology) or the percentage incidence in the groups of animals. This
confusion was continued in the report's text, which stated that "tubular casts were observed in
40%, 80%, and 100% of kidney tissues of male rats..The very next sentence stated "only 10%
of the female rats at the two highest dose levels showed significant kidney tubular casts," and
further in the text it was stated that "this was especially true in the kidney, where 80% and 100%
of the male rats at dosages of 750 or 1500 mg/kg/day developed abnormal tubular casts after
90 days." These latter statements suggest that analysis was conducted on dichotomous data.
The report also did not clearly explain how the data in Figure 9 were statistically
analyzed (Knuckles et al., 2004). In the figure, all male dose groups were denoted as increased
(p < 0.05) compared to controls; however, the abstract specified that only the two highest dose
groups were significantly (p < 0.05) affected at 90 days. The methods indicated that histology
data were analyzed by Fisher's Exact Test and the Cochran-Armitage test for linear trends.
Fisher's Exact Test is not appropriate for the analysis of multiple dose groups of continuous data.
A "step-down" approach using the Cochran-Armitage trend test can be used to indicate
significance in particular groups, but the methods did not indicate that technique was used.
Additionally, there was a lack of corroborating evidence of an adverse effect in the
kidney (Knuckles et al., 2004). Aside from the renal tubular casts, the only other mention of an
adverse effect in the male kidney was noted in the report's abstract: "Only BUN in males was
significantly increased in the high-dose group (1500-mg FLA/kg BW/day) at the 90-day time
point." The data were not presented, and the magnitude difference between treatment groups
was not reported. Because of the confusion related to the renal casts, independent verification
(via BUN) was desirable, but not possible, and without the data on the magnitude of change, it is
unknown if the effect is biologically significant by EPA definitions. Except for a possible
negative effect at the high dose due to increased BUN, the gross and histological pathology,
organ weight-, and clinical chemistry data provided no additional evidence of a negative effect
on the kidney.
Food consumption and body weights were each decreased (p < 0.05) by 15% in the
1500-mg/kg-day males; however, neither summary data nor individual animal data were reported
for independent verification (Knuckles et al., 2004). Despite some uncertainties with the data
analysis, 1500 mg/kg-day is an appropriate adverse effect level in this study. It was also stated
that the liver/body-weight ratios were significantly increased by 20% in the 1500-mg/kg-day
males, but data were not reported for independent verification. Although these data are sufficient
to establish an adverse effect, according to NCEA policy, there was no corroborative evidence of
an adverse effect on the liver, which suggests that increased liver weight was an adaptive
response.
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Other possible toxicological endpoints presented in this study do not clearly establish an
adverse effect level (Knuckles et al., 2004). Two high-dose males and one mid-dose female
were sacrificed moribund; however, cause-of-death was not determined, and it is unclear if the
deaths were treatment related. Erythrocyte and leukocyte counts, hematocrit percentages, and
hemoglobin concentrations were reported graphically (x-y plots). However, the standard
deviation associated with each mean was often unclear. In the findings reported in these plots,
the variation was often large in magnitude, a clear trend in response with time was not apparent
(transient effects), the mean values at Day 0 often differed considerably (significantly decreased
erythrocyte count in the 150-mg/kg-day females, p < 0.05), and it is uncertain if the effects were
dose dependent. Therefore, interpretation of these findings is problematic. The one finding that
is possibly treatment related and adverse, by EPA definitions, was the decrease in leukocyte
counts in the 1500-mg/kg-day male and female rats. However, due to the large numbers of
deficiencies noted in this study, no LOAEL is established.
A chronic RfD value is available in the IRIS database (U.S. EPA, 1990) based on
data from the study by the U.S. EPA (1988). This study is also selected as the principal
study for deriving the subchronic p-RfD herein. This study is unpublished but is considered
peer reviewed and was conducted according to Good Laboratory Practices (GLP). It was
conducted by a contract laboratory, Toxic Research Laboratories, Ltd for the Dynamac
Corporation and is dated 1987.
Fluoranthene (>97% purity) was administered once each day in corn oil by gavage to
20 CD-I mice/sex/dose group at doses of 0, 125, 250, or 500 mg/kg-day for 13 weeks
(U.S. EPA, 1988). A group of 30 mice/sex was used to assess clinical chemistry and hematology
parameters prior to treatment. Mice were obtained from Charles River Laboratories (Portage,
MI), and animal husbandry was performed appropriately. The mice were observed twice daily
for mortality and signs of adverse effects. Body weights and food consumption were recorded
weekly. The eyes of all mice were examined prior to treatment and during Week 13. Blood was
collected from the treated groups at sacrifice, but urine was not collected. The following
hematology and clinical chemistry parameters were measured or calculated: erythrocyte count,
total and differential leukocyte count, hemoglobin, erythrocyte packed cell volume, mean
corpuscular volume, mean corpuscular hemoglobin and hemoglobin concentration, glucose, urea
nitrogen, cholesterol, total bilirubin, albumin, globulin, albumin/globulin ratio, alkaline
phosphatase, serum glutamate oxalacetate and pyruvate transaminase, lactate dehydrogenase,
sodium, potassium, chloride, and total carbon dioxide.
On Days 91-93, all surviving mice were euthanized. All mice—including decedents—
were subjected to necropsy (U.S. EPA, 1988). Tissue samples were prepared routinely and
examined microscopically. The following tissues were collected and examined microscopically:
salivary glands, esophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, liver,
gall bladder, pancreas, trachea, lungs, aorta, heart, bone marrow, mesenteric lymph node, spleen,
thymus, kidneys, urinary bladder, testes, epididymides, prostate, seminal vesicles, ovaries,
uterus, mammary gland, brain, peripheral nerve (sciatic), spinal cord, pituitary, eyes with optic
nerve, adrenal gland, parathyroids, thyroids, sternum, skeletal muscle, skin, femur bone with
marrow and joint, and all gross lesions and masses. Additionally, liver, heart, spleen, kidneys,
testes, and brain were weighed (paired organs were weighed together).
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All tissues were processed routinely, and samples of the following tissues were examined
microscopically: (i) all tissues from the control and 500-mg/kg-day groups and all decedents;
(ii) liver, lungs, and kidneys from all groups; and (iii) all gross lesions (U.S. EPA, 1988). The
severity grades of the histological lesions were not reported but may have been included in
Appendix J (P.A.I. Histopathology Report; unavailable). The data were tested for homogeneity
of variance by using Bartlett's Test. If the data were homogeneous, Dunnett's test was
performed; otherwise, a modified Dunnett's test was used. Significance at/? < 0.05 and 0.01 was
reported. No treatment-related effects were noted on mortality, clinical signs, body weights,
body-weight gains, food consumption, food efficiency, ophthalmology, hematology, clinical
chemistry, or gross pathology (U.S. EPA, 1988).
Increased incidences of nephropathy were observed in the 500-mg/kg-day males (55%)
and 250- and 500-mg/kg-day females (25-55%) compared to controls (5%, each sex; U.S. EPA,
1988). Severity of the histological lesions was minimal to mild except for one high-dose male
that exhibited nephropathy with moderate severity.
The significant hematology and clinical chemistry findings are presented in Table B.l
and included the following: (i) decreases of 7—8% in packed cell volume in the 250- and
500-mg/kg-day females; (ii) decrease of 28% in absolute lymphocytes in the 500-mg/kg-day
males; (iii) decreased percentage of eosinophils in the 500-mg/kg-day females (0.6% decrease in
treated group vs. 2.0% in controls); (iv) increase of 11% in globulin in the 500-mg/kg-day males;
(v) decrease of 10% in albumin/globulin ratio in the 250- and 500-mg/kg-day males; and
(vi) increase of 40-54% in serum glutamate pyruvate transaminase at 250 and 500 mg/kg-day in
both sexes (U.S. EPA, 1988). These findings are not considered significantly harmful to the
animals' health due to the low magnitude of change (not considered biologically significant) and
because a toxicological syndrome could not be identified to support a WOE approach.
Liver weights relative to body weights were increased (p < 0.01) by 1-32% in all treated
male groups and by 12—26% in the 250- and 500-mg/kg-day females (see Table B.2; U.S. EPA,
1988). According to NCEA policy, a change in liver organ weight of at least 10% is considered
adverse; therefore, an adverse effect was observed at 250 mg/kg-day and is determined to be a
LOAEL. Also, increased incidences of liver pigment accumulation were noted in the 250- and
500-mg/kg-day males and females (55-100%) of mice in treated groups vs. 0% in controls; see
Table B.3). The brown, granular, anisotropic pigment was generally found in a centrilobular
distribution primarily contained within Kupffer cells; however, the composition of the pigment
was not determined.
This study (U.S. EPA, 1988) was conducted in compliance with the EPA Pesticide
Assessment Guidelines, Subdivision F, Section 158.82-1 and the EPA Toxic Substance Control
Act Testing Guidelines for Ninety Day Subchronic Toxicity Studies (40 CFR 798.2650).
IRIS stated that the LOAEL was 250 mg/kg-day for the study (U.S. EPA, 1988) based on
nephropathy, increased liver weights, hematological alterations, and clinical effects and selected
the 125-mg/kg-day dose as the NOAEL.
Chronic Studies
No studies regarding the effects of chronic oral exposure to fluoranthene in animals were
identified.
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Developmental and Reproductive Studies
No studies regarding the effects of oral exposure to fluoranthene in animals on
developmental and reproductive parameters were identified.
Carcinogenic Studies
No studies regarding the effects of oral exposure to fluoranthene on carcinogenicity in
animals were identified.
Inhalation Exposure
No inhalation studies on the subchronic, chronic, developmental, or reproductive toxicity
or carcinogenicity of fluoranthene in animals were identified.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Other studies that are not appropriate for selection of a POD for fluoranthene and the
determination of p-RfD, p-RfC, p-OSF, or p-IUR values may provide supportive data that
supplement a WOE approach to risk assessment. These studies include carcinogenicity study
designs other than standard 18-month or 24-month chronic studies in the mouse and rat,
respectively, as well as genotoxicity, immunotoxicity, neurobehavioral toxicity, metabolism, and
mechanistic studies. These studies are summarized briefly in Table 3, and further details and
discussion are presented in the accompanying text.
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Table 3. Other Fluoranthene Studies
Tests
Materials and Methods
Results
Conclusions
References
Tests evaluating carcinogenicity and genotoxicity
Carcinogenicity
Twenty female CD rats/dose group were treated by
subcutaneous injection withFDE (fluoranthene metabolite,
10 |imol). FDE (2 |imol). BcPDE (positive control,
2 |imol). or DMSO (negative control) under each of
3 nipples on the left, and DMSO was injected under
3 nipples on the right.3 The procedure was repeated on the
second day. Palpation for mammary tumors was
conducted weekly. Termination occurred after 41 weeks.
Mammary adenomas were increased with
FDE treatment at both doses, and
adenocarcinomas were increased at the high
FDE dose.
FDE, a metabolite of
fluoranthene, may result
in mammary tumors.
Hecht et al.
(1995)
Carcinogenicity
Newborn CD-I mice were treated by intraperitoneal
injection of fluoranthene on Days 1, 8, and 15 (total doses
of 0, 0.7, 1.75, or 3.5 mg), and 18-23 or
14-24 mice/sex/dose were euthanized at 6 or 9 months,
respectively. Lung and liver tumors were counted.
The incidence of lung tumors was increased in
both sexes at 6 and 9 months at both doses,
and liver tumors were increased at 9 months in
males at both doses.
Fluoranthene treatment
in the newborn mouse
assay results in lung and
liver tumors.
Wang and
Busby (1993)
Carcinogenicity
DNA was isolated from the tissues of animals in the study
above (Wang and Busby, 1993). DNA adducts were
isolated and quantified from various tissues.
A positive correlation was noted between
DNA adduct level and persistence in relation
to target organ specificity for tumor formation.
Fluoranthene treatment
in the newborn mouse
assay results in DNA
adducts.
Wang et al.
(1995)
Carcinogenicity
Newborn CD-I mice were treated by intraperitoneal
injection of fluoranthene on Days 1, 8, and 15 (total doses
of 0, 3.46 |imol (approx. 70 mg/kg), or 17.3 |imol (approx.
350 mg/kg), and 16-34 mice/sex/dose were euthanized at
52 weeks. Lung and liver tumors were counted.
At both doses of fluoranthene, the incidence
of lung tumors was increased in both sexes,
and liver tumors were increased in males.
Fluoranthene treatment
in the newborn mouse
assay results in lung and
liver tumors.
LaVoie et al.
(1994)
Carcinogenicity
Fluoranthene was applied withbenzo[a]pyrene (B[a]P) to
mouse skin, and tumor yield was compared to application
of B |o | P or fluoranthene alone. The tumor promoter
potential of fluoranthene was also tested using B[a]P as an
initiator.
The cocarcinogenic response was an
approximate 3-fold increase in tumor yield
and a reduction in the tumor latency period by
at least half. Fluoranthene alone was not
carcinogenic.
Fluoranthene was a
cocarcinogen in this
study.
Van Duuren
and
Goldschmidt
(1976)
Carcinogenicity
Various studies are discussed that were performed prior to
1990 in animals. Six studies involved dermal application
of fluoranthene to mice, and an additional study involved
subcutaneous injection of fluoranthene in mice.
No increase in tumor incidence was noted in
the fluoranthene-treated groups.
Fluoranthene was not
carcinogenic in these
studies.
U.S. EPA
(1990)
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Table 3. Other Fluoranthene Studies
Tests
Materials and Methods
Results
Conclusions
References
Genotoxicity
Male S-D rats were treated with radiolabeled fluoranthene
by intraperitoneal injection or were treated with unlabeled
fluoranthene by dietary administration. DNA adducts
were isolated in the blood and organ tissues.
Hemoglobin adducts and DNA adducts in
many organs were isolated, and the major
DNA adduct was identified.
Fluoranthene
administration resulted
in DNA adducts.
Gorelick et
al. (1989)
Genotoxicity
Fluoranthene (110 nmol [22 ug]) was applied with (or
without) |3H|B|o|P (11 nmol) to CD-I mouse skin, and
DNA adduct level and metabolite profile in skin were
compared to application of [3H]B[a]P alone.
The presence of fluoranthene increased the
levels of B[a]P-DNA binding but did not
affect the B[a]P metabolite profile.
Fluoranthene was a
cocarcinogen in this
study.
Rice et al.
(1988)
Genotoxicity
In vivo mouse bone marrow micronucleus and rat liver
unscheduled DNA synthesis tests were performed.
No evidence of genotoxicity was noted.
Fluoranthene was not
genotoxic in this study
Stacker et al.
(1996)
Genotoxicity
Various mutagenicity tests were reviewed.
Positive and negative results were observed in
several of the same types of tests.
IRIS concluded that the
evidence for
mutagenicity is
equivocal
U.S. EPA
(1990)
Other toxicity tests
Immunotoxicity
A series of experiments were performed using murine
bone marrow cultures obtained from C57BL/6 mice.
Fluoranthene treatment can result in apoptosis
in the pre-B cells or alter their growth and
survival characteristics.
Fluoranthene treatment
can suppress B-cell
lymphopoiesis.
Hinoshita et
al. (1992)
Immunotoxicity
BDF1 mice were immunized with Japanese cedar pollen
antigen (JCPA). Various chemicals were used as
adjuvants, including fluoranthene, and the mice were
challenged with JCPA. IgE antibody levels and antibody
response were measured. Intraperitoneal macrophages
obtained from unimmunized mice were incubated with
fluoranthene or other chemicals, and the
chemiluminescence response and interleukin-la (IL-la)
production to JCPA were measured.
Fluoranthene increased the production of IgE
antibody to JCPA and IgE antibody response,
and modulated the secretion of IL-la.
Exposure to
fluoranthene can
increase the immune
system response.
Kanoh et al.
(1996)
Developmental
S-D rat embryos were incubated with fluoranthene and rat
hepatic S-9. C57/B6 mice were injected intraperitoneally
with fluoranthene on one of GDs 6-9.
Adverse effects were noted on embryos
in vitro, and embryo resorption occurred
in vivo.
Fluoranthene can be a
developmental toxicant.
Irvin and
Martin (1987)
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Table 3. Other Fluoranthene Studies
Tests
Materials and Methods
Results
Conclusions
References
Neurobehavioral
toxicity
F344 rats were treated with a single gavage dose of
fluoranthene at doses of 0, 100, 200, or 400 mg/kg. Motor
activity assessment and the functional observational
battery (FOB) were performed.
At 200 and 400 mg/kg, activity was decreased
after treatment, and abnormal findings were
observed in the FOB, such as increased
urination, decreased grip strength, etc.
Fluoranthene can affect
neurobehavior
adversely.
Saunders et
al. (2003)
Metabolism studies
Metabolism
Microsomes isolated from the small intestine and liver of
various animals and humans were each incubated with
fluoranthene in order to compare the metabolic rates and
profiles.
Metabolic rate and metabolite profile for
fluoranthene varied with species. The
metabolic rate in humans was much higher
than in rodents, and a greater amount of the
parent was converted to a detoxification
product in humans.
Fluoranthene toxicity
studies in rodents may
lead to conservative
estimates of toxicity in
humans.
Walker et al.
(2006)
Metabolism
Radiolabeled fluoranthene was incubated with DNA. The
DNA adducts were isolated and characterized using
high-performance liquid chromatography (HPLC) and
mass spectroscopy (MS).
DNA adducts were isolated and characterized.
It was determined that a single DNA adduct
accounted for approximately 70% of the total
modified deoxyribonucleosides.
The primary DNA
adduct was determined,
providing insight into an
important metabolic
pathway.
Babson et al.
(1986)
Mechanistic studies
Mechanistic
The effects of six PAHs on gene expression in rat liver
were examined.
PAHs generally induce a compound-specific
response on gene expression. Carcinogenic
PAHs induce the oxidative stress pathway.
Fluoranthene does not induce oxidative stress.
Discrimination of
carcinogenic potential
may be possible by
evaluating gene
expression.
Staal et al.
(2007)
Mechanistic
The effects of four PAHs on estrogenic activity in in vivo
uterine assays in Wistar rats were examined.
Three of the four (including fluoranthene)
exhibited estrogenic activity. Fluoranthene
did not induce P450 monooxidases at the
doses used.
Fluoranthene possess
estrogenic activity
Kummer et
al. (2008)
Mechanistic
The effects of 12 PAHs on gap junctional intracellular
communication (GJIC) in WB-F344 rat liver epithelial
cells were assayed.
PAHs containing bay or bay-like regions
(including fluoranthene) inhibited GJIC more
than linear PAHs.
This finding suggests
that fluoranthene may
act as a tumor promoter.
Weis et al.
(1998)
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Table 3. Other Fluoranthene Studies
Tests
Materials and Methods
Results
Conclusions
References
Mechanistic
The effects of 14 PAHs on the induction of CYP1A1 and
IB 1 mRNA were examined using genetically engineered
C57BL/6J mice.
Activation of the PAHs to mutagenic species
correlated with induction of CYP1A1 and
IB 1. Fluoranthene induction of these P450s
was very low or nonexistent.
Carcinogenicity potency
may relate to the
potential of the PAHs to
induce CYP1A1 and
1B1.
Shimada et
al. (2002)
aFDE (a«ft'-2,3-dihydroxy-l,10b-eopxy-10b,l,2,3-tetrahydrofluoranthene), BcPDE (a«//'-3,4-dihydroxy-l,2-epoxy-l,2,3,4-tetrahydrobenzo[c]phenanthrene; used as a
positive control), DMSO (dimethyl sulfoxide; used as a negative control).
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Tests Evaluating Carcinogenicity and Genotoxicity
Although a long-term study has not been performed in animals to evaluate the
carcinogenic potential of fluoranthene, the results from several studies suggest that fluoranthene
may be carcinogenic. Three of these studies (Hecht et al., 1995; Wang and Busby, 1993 and
Wang et al., 1995; and LaVoie et al., 1994) were performed after the last carcinogenicity
assessment for fluoranthene by IRIS. The IRIS document for fluoranthene (U.S. EPA, 1990)
summarized the carcinogenicity and mutagenicity data available up to 12/01/1990. The
cocarcinogenic potential of fluoranthene was evaluated in vivo by Van Duuren and Goldschmidt
(1976) and by Rice et al. (1988). Gorelick et al. (1989) performed studies that demonstrate the
formation of fluoranthene-DNA adducts in vivo and characterized the major DNA adduct.
Stocker et al. (1996) performed two in vivo genotoxicity tests.
Hecht et al. (1995) evaluated the potential of a diol epoxide metabolite of fluoranthene
(FDE; £//7//-2,3-dihydroxy-!, 1 Ob-epoxy-1 Ob, 1,2,3-tetrahydrofluoranthene) to induce mammary
carcinogenicity. FDE is a metabolite of fluoranthene produced by human liver microsomes.
FDE was previously shown to be a mutagen in S. typhimurium and to form DNA adducts in
in vivo and in vitro tests. The DNA adduct was shown to be stable enough to be transported to
other tissues after formation in human liver. Twenty female CD rats/dose group were treated
with FDE, BcPDE (c/////-3,4-dihydroxy-! ,2-epoxy-1 ,2,3,4-tetrahydrobenzo[c']-phenanthrene;
positive control), or DMSO (negative control). The animals were treated by subcutaneous
injection with FDE (10 (amol; >99% purity), FDE (2 |imol), BcPDE (2 |imol; >99% purity), or
DMSO under each of 3 nipples on the left, and DMSO was injected under 3 nipples on the right.
The procedure was repeated on the second day. Palpation for mammary tumors was conducted
weekly. Termination occurred after 41 weeks, and gross and histological examinations of the
mammary glands were performed. Mammary adenomas were increased (p < 0.05) with FDE
treatment (39-42 tumors in treated vs. 2 tumors in controls) at both doses, and adenocarcinomas
were increased (not statistically significant) at the high dose of FDE (10 tumors in treated vs.
2 tumors in controls). Findings of this study indicate that treatment with FDE may result in
mammary tumors.
Another carcinogenicity study was performed and was reported in two parts: the initial
report presented the tumorigenicity data from this study (Wang and Busby, 1993), and the
second report presented data regarding the formation and persistence of DNA adducts
(Wang et al., 1995). Newborn VAF/Plus CD-I mice were treated by intraperitoneal injection of
fluoranthene (>99% purity). The total dosages were 0-, 0.7-, 1.75-, or 3.5-mg fluoranthene. The
newborn mice were injected on Day 1 with 1/7 of the dose, Day 8 with 2/7 of the dose, and
Day 15 with 4/7 of the dose. Mice were euthanized by CO2 asphyxiation at 6 or 9 months of age
and necropsied. Tissues for DNA adduct analysis were collected from animals euthanized at
2 hours, 1, 3, 7, 14, 30, 75, or 165 days after the last injection. Lungs, heart, liver, kidneys,
spleen, and thymus were excised, rinsed, flash frozen in liquid nitrogen, and stored at -100°C.
DNA from the tissue samples was isolated, hydrolyzed to nucleotides, enriched for modified
nucleotides, 32P-postlabeled, and chromatographed using a high-performance liquid
chromatography (HPLC) system with a C18 column. At 6 months, 18-23 mice/sex/dose were
examined, and 14-24 mice/sex/dose were examined at 9 months. Tumors in lung and liver were
quantified. At 6 months, total lung tumor (adenoma and adenocarcinoma) incidences were
increased (p < 0.03) in the combined sexes at 1.75 and 3.5 mg (10—44% in treated vs. 0% in
controls), and the number of lung tumors/mouse was increased at 3.5 mg/kg (0.56 in treated vs.
0 in controls). The following increases in the incidences of tumors (p < 0.03) were observed at
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9 months: incidences of liver tumors in all treated male groups (22-57% in treated vs. 0% in
control); total lung tumors in the combined sexes of all dose groups (24-42% in treated vs.
5% in controls); and number of lung tumors/mouse in the combined sexes of all dose groups
(0.27-0.68 in treated vs. 0.05 in controls). The study authors stated,
When FA was activated in vitro by rat liver microsomes in the presence of calf
thymus DNA, the major DNA adduct formed was identified as anti-10b-N2-
deoxyguanosin-l, 2,3-trihydroxy-l, 2,3,1 Ob-tetrahydrofluoranthene (anti-FADE
adduct) (Babson et al., 1986). Subsequently, anti-FADE adduct was identified by
32
an HPLC- P-postlabeling method as the major FA-DNA adduct in tissues of
Spr ague-Daw ley rats chronically fed FA in the diet (Gorelick et al., 1989). We
also demonstrated that anti-FADE adduct was the major FA-DNA adduct in
tissues of Blu:Ha mice andfurther that the highest level of adduct formation was
in the lung 24 h after a tumorigenic dose of FA (Wang et al., 1995).
The study authors also concluded that,
Lung, the target organ for FA tumor igenicity, contained higher levels of anti-
FADE adduct than other tissues from 1 165 days after treatment. The anti-
FADE adduct level decreased in a biphasic manner after reaching maximum
values at 2 h in heart and spleen plus thymus and 3 days in lungs, liver, and
kidneys. About 10% of the maximum amount of anti-FADE adduct remained in
lung, liver, and heart 165 days after final FA treatment, at which time 44% of
animals had developed lung adenomas. Significant inter-litter variations, but no
sex differences in adduct levels, were observed. These results indicated a positive
correlation between anti-FADE adduct level and persistence in relation to target
organ specificity for tumor formation.
Busby et al. (1984) also noted lung tumors in a similarly performed newborn-mouse
assay in the BLU:Ha (ICR) strain. Wang and Busby (1993) stated that this mouse strain is no
longer commercially available.
LaVoie et al. (1994) also investigated fluoranthene tumorigenicity in the newborn-mouse
assay. Newborn CD-I mice (64-79 pups/sex/dose group) were treated by intraperitoneal
injection of fluoranthene (>99.5% purity) on Days 1, 8, and 15, receiving total doses of 3.46 or
17.3 |iinol (approximately70 and 350 mg/kg). 2-Methylfluoranthene (2MeFA) and
3-methylfluoranthene (3MeFA) were tested at the same doses. B[a]P was included as the
positive control at a dose of 1.10 |imol, and DMSO was included as the vehicle control. Mice
(16-34 mice/sex/dose group) were euthanized at 52 weeks of age. The percentages of mice with
lung tumors were increased in all fluoranthene-treated animals (35—86%) and the high-dose
2MeFA group (69-96%) compared to vehicle control (12—17%). The percentages of mice with
hepatic tumors were increased in all treated males in the fluoranthene, 2MeFA, and 3MeFA
groups (33-100%)) compared to vehicle control (17%>), and increased in the high-dose 2MeFA
and 3MeFA females (11-31%) compared to vehicle control (6%).
Van Duuren and Goldschmidt (1976) observed that fluoranthene was a potent
cocarcinogen when applied together with B[a]P to mouse skin. Fluoranthene (40-[j,g/application)
was applied to mouse skin (50 female ICR/Ha Swiss mice/group) three times weekly with B[a]P
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(5-[j,g/application). Animals were euthanized after 440 days. The cocarcinogenic response
resulted in an approximate 3-fold increase in tumor yield and reduced the tumor latency period
by at least half. Fluoranthene, when applied alone to the backs of mice at the same dose, was not
tumorigenic. Fluoranthene's potential as a tumor promoter was also evaluated. B[a]P
(150-[j,g/application) was applied to mouse skin (50 animals). Fourteen days after the primary
treatment, animals were given applications of fluoranthene (40-[j,g/application) three times
weekly and were euthanized on Day 448. This treatment resulted in only one mouse having a
single papilloma, indicating that fluoranthene had weak or no promoter ability in this test.
IRIS (U.S. EPA, 1990) summarized the animal carcinogenicity data that was observed
prior to December 1, 1990, as follows:
Suntzeff et al. (1957) administered a 10% solution of fluoranthene in acetone by
topical application 3 times/week to unspecified numbers of CAF, Jackson, Swiss
and Miller ton mice. No tumors were found by 13 months. Wynder and Hoffmann
(1959) administered a 0.1% solution of fluoranthene in acetone onto the backs of
20 female Swiss (Millerton) mice 3 times/week for life. No tumors were found.
Hoffmann et al. (1972) administered 50 /uL of a 1% fluoranthene solution to the
backs of 20 female Swiss-albino Ha/ICR/Mill mice 3 times/week for 12 months.
All treated mice survived and no tumors were observed. As part of the same
study, 30 mice received 0.1 mg fluoranthene in 50 /uL acetone every second day
for a total of 10 doses. Promotion by dermal application of 2.5% croton oil in
acetone was initiated 10 days later and continuedfor 20 weeks. A single
papilloma was noted in 29 surviving mice. Horton and Christian (1974)
administered 50 mg fluoranthene in decalin or in decalimn-dodecane (50:50) to
the backs of 15 male C3H mice. The mice were treated 2 times/week for
82 weeks. No skin tumors were observed. Barry et al. (1935) administered
300 mg fluoranthene in benzene by dermal application (number of applications
not stated) to 20 mice (type unspecified). The survival rate was 35% after
6 months and 20% at 1 year. No tumors were found by 501 days. Shear (1938)
administeredfour doses of 10 mg fluoranthene in glycerol by subcutaneous
injection to strain A mice. Six out of 14 mice survivedfor 18 months; no tumors
were found by 19 months. In a skin-painting assay fluoranthene (100 ug) was
administered to 20 Swiss albino Ha/ICR mice, 3 times/week for 1 year; 3.3% of
the mice in both this group and in a similar acetone-control group tumors were
observed in 3.3% of the mice in both the treated and acetone-control groups
(LaVoie etal., 1979).
Gorelick et al. (1989) performed experiments that suggest the fluoranthene-hemoglobin
adducts may be useful as biomarkers. Male S-D rats (2-3/dose) were treated with one dose of
"3
[8- H] fluoranthene by intraperitoneal injection at doses of 2-177,000 nmol/kg. In a separate
experiment, male S-D rats (n = 21) were treated with fluoranthene in the diet for 37 days to
achieve an average daily intake of 80 mg/kg. Animals were fed uncontaminated diets 3 days
before termination. In addition to the fluoranthene-containing diet, 6 of the 21 animals were also
"3
treated with [8- H] fluoranthene by intraperitoneal injection as a tracer (total of 8 doses). Blood
and tissue samples were collected at sacrifice from all animals. The authors stated "Fluoranthene
binding to globin was proportional to dose over the range of 2 nmol/kg to 177 |imol/kg, and the
adducted protein was cleared at the same rate as unmodified hemoglobin, indicating that the
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adducts are stable in vivo." Fluoranthene-DNA adduct formation was found in most tissues after
chronic administration. The major DNA adduct was identified as the product of
£//7//-2,3-dihydroxy- l, 10/?-epoxy-l,2,3-trihydro-fluoranthene andN -deoxyguanosine. This diol
epoxide exhibited an unusual stability at physiological pH, suggesting that hemoglobin adducts
could be useful for biomonitoring exposure to fluoranthene.
Rice et al. (1988) treated female CD-I mice (9/time point/dose group) by applying
11 nmol [3H]B[a]P (99.4% radiochemical purity) or 11 nmol [3H]B[a]P with 110-nmol
fluoranthene (>99% purity) in acetone to their shaved backs. The mice were euthanized at 4, 8,
24, or 48 hours post-treatment, and their skin was removed, frozen, and powdered. DNA was
isolated from the skin and quantified. DNA hydrolysis and adduct isolation was accomplished
by HPLC or Affi-Gel 601 column chromatography. Additionally, two groups of 35 female CD-I
mice were treated with 12 nmol [3H]B[a]P or 12 nmol [3H]B[a]P with 120-nmol fluoranthene in
acetone to their shaved backs and animals (5/time point/dose group) were euthanized at 0.5, 1, 2,
4, 8, 24, or 48 hours. The skin was removed, frozen, powdered, homogenized in
phosphate-buffered saline, and extracted with acetone and ethyl acetate. Aliquots were treated
with P-glucuronidase or arylsulfatase, and B[a]P metabolites were isolated and quantified by
HPLC. The level of B[a]P-DNA binding increased in the presence of fluoranthene at each time
interval (36-76%), The B[a]P metabolite profile, including P-glucuronide and sulfate
conjugates, was similar in the ethyl acetate skin extracts in the presence or absence of
fluoranthene cotreatment. This finding suggests that fluoranthene affects B[a]P carcinogenicity
at some point after B[a]P has been activated to an ultimate carcinogen.
Babson et al. (1986) incubated 3-[3H] fluoranthene with calf thymus DNA in the
presence of rat liver microsomes and isolated and characterized the major DNA adducts using
HPLC and mass spectrometry. Identity of the DNA adduct was further established by
comparison with the DNA adduct formed by incubating a synthesized reactive metabolite with
DNA. It was determined that c//7//-2,3-dihydroxy-l, l 0/?-epoxy- l ,2,3-trihydrofluoranthene
binding to the N-2 position of deoxyguanosine is responsible for approximately 70%> of the total
modified deoxyribonucleosides.
Stocker et al. (1996) performed mouse bone marrow micronucleus and rat liver
unscheduled DNA synthesis in vivo mutagenicity test systems. Fluoranthene did not show any
evidence of genotoxicity in either of these assays following acute oral administration at levels of
up to 2000 mg/kg.
IRIS (U.S. EPA, 1990) summarized the evidence for mutagenicity of fluoranthene as
equivocal:
The results of mutagenicity assays offluoranthene in several strains of
Salmonella typhimurium have been positive and not positive. Evidence for
mutagenicity in mammalian cells is also equivocal: results of tests for
chromosomal effects in Chinese hamster cells have been both positive and not
positive. A test for gene mutations in human lymphoblast cells was not positive,
whereas results of tests in different mutant Chinese hamster ovary cell lines have
been both positive and not positive.
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Other Toxicity Tests
Other toxicity studies were located, including immunotoxicity studies (Hinoshita et al.,
1992; Kanoh et al., 1996), a developmental toxicity study (Irvin and Martin, 1987), and a
neurobehavioral toxicity study (Saunders et al, 2003).
Hinoshita et al. (1992) conducted a series of in vitro experiments using murine bone
marrow cultures obtained from C57BL/6 mice. It was stated that
Data presented herein indicate that: (i) fluoranthene suppresses B lymphopoiesis
within 2 days in bone marrow cultures; (ii) fluoranthene suppresses
lymphopoiesis at least in part by direct interactions with preB cells;
(Hi) fluoranthene lymphotoxicity is mediated by rapid induction ofDNA
fragmentation characteristic of programmed cell death (apoptosis), and (iv) preB
cell populations surviving the initial death signal or preB cell populations
exposed to lower doses offluoranthene (0.5-5 ug mL) exhibit altered growth and
survival characteristics. These data suggest several levels at which fluoranthene
could compromise B lymphopoiesis.
Kanoh et al. (1996) immunized five female BDF1 mice seven times at 2-week intervals
by the intranasal route with Japanese cedar pollen antigen (JCPA, 10 |ig; containing 0.05 |ig of
the major allergen, Cry j 1) with 400-|ig fluoranthene dissolved in 10-|iL DMSO. The animals
were boosted with JCPA alone at 9 weeks after the final immunization. Anthracene and B[a]P
were also tested, as well as a JCPA-only control. Passive cutaneous anaphylaxis (PCA) titers
were measured in the mice. Additionally, the intraperitoneal macrophages obtained from
unimmunized mice were incubated with fluoranthene in vitro, and the chemiluminescence
response profiles and interleukin (IL)-la production of the macrophages were measured.
Fluoranthene increased the production of IgE antibody to JCPA and IgE antibody response, but
this increase was weak compared to the increase produced by alum or diesel exhaust particles.
The authors concluded that fluoranthene also modulated the secretion of IL-la.
Irvin and Martin (1987) incubated S-D rat embryos (Day 10) with fluoranthene in the
presence of rodent hepatic S-9 fractions and reported the following findings: "decreased
crown-rump length and somite development, deformities of the telencephalon, and absence of
red blood cell circulation through the yolk sac." Administration of fluoranthene via
intraperitoneal injection to C57/BL-6 mice on one of GDs 6-9 resulted in increased rates of
embryo resorption. The data were reported in an abstract, but a complete report was not located.
Saunders et al. (2003) treated F344 rats with a single gavage dose of fluoranthene in
peanut oil at doses of 0, 100, 200, or 400 mg/kg. The animals were subjected to a motor activity
assessment and a functional observational battery (FOB). Activity (horizontal, vertical, total
distance, and stereotypic) was decreased at doses of 200 and 400 mg/kg. The following findings
were reported at 400 mg/kg, and many of these findings were also observed at 200 mg/kg:
"dysfunction, including ataxia, decreased grip strengths, increased landing foot splay, loss of
aerial righting, increased urination and defecation, and decreased responses to sensory stimuli in
both sexes. Neurological deficits in the FOB peaked at 6 hours and lasted for 48 hours
posttreatment." Males were more sensitive to these effects than females.
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Metabolism Studies
The metabolism of fluoranthene is briefly described in the following study by
Walker et al. (2006).
Walker et al. (2006) isolated microsomes from the small intestine and liver of rat, mouse,
hamster, goat, sheep, pig, dog, cow, monkey, and humans (obtained commercially), and
incubated these microsomes with fluoranthene in order to compare the metabolic rates and
profiles. Postincubation, samples were extracted with ethyl acetate and analyzed for the parent
and metabolites by reverse-phase HPLC with fluorescent detection. The results demonstrated
that the metabolic rates and profiles varied greatly with species. Parent compound was not
present in any sample after incubation. The mean concentration of total metabolites formed in
liver microsomes was lowest in the rat and mouse (approximately 0.25-0.4 pmoles/mL/mg
protein) and highest in human (approximately 2.6 pmoles/mL/mg protein). Similar results were
observed in intestinal microsomes, but concentrations were approximately a tenth of the
concentrations observed in liver microsomes. The fluoranthene metabolites generated in
intestinal and liver microsomes were identified as fluoranthene 2,3-diol, trans-2,3-dihydroxy-
1,10/?-epoxy- l ,2,3,10b tetrahydro fluoranthene (2,3D fluoranthene), 3-hydroxy fluoranthene, and
8-hydroxy fluoranthene. The rodent intestinal and hepatic microsomes produced a considerably
higher proportion of 2,3D fluoranthene than human microsomes. Conversely, intestinal and
hepatic microsomes from humans converted a greater proportion of fluoranthene to 3-hydroxy
fluoranthene, the detoxification product.
Mechanistic Studies
Possible mechanisms or modes of action of fluoranthene as a carcinogen or cocarcinogen
are briefly described in the following three studies: Staal et al. (2007), Weis et al. (1998), and
Shimada et al. (2002).
Staal et al. (2007) examined the effects of six PAHs (including fluoranthene) on gene
expression in precision-cut liver slices from male Wistar rats using DNA microarray technology.
The results indicated that PAHs generally induce a compound-specific response on gene
expression and that discrimination of carcinogenic from noncarcinogenic compounds is partly
feasible with the oxidative stress response pathway. Fluoranthene induced the expression of
77 genes including those involved in mitochondrial fatty acid beta-oxidation and formed DNA
adducts above background level. Only carcinogenic PAHs (which did not include fluoranthene)
induced the oxidative stress pathway.
Kummer et al. (2008) examined the effects of four PAHs on estrogenic activity in in vivo
uterine assays in Wistar rats. Three of the four (including fluoranthene) exhibited estrogenic
activity. Fluoranthene did not induce P450 monooxidases at the doses used. The authors
concluded that fluoranthene possessed estrogenic activity
Weis et al. (1998) assayed the effects of 12 PAHs on gap junctional intracellular
communication (GJIC) in WB-F344 rat liver epithelial cells. GJIC was used as an epigenetic
biomarker for structure-activity (tumor promotion) relationships of the 12 PAHs. Previous
research indicates that epigenetic events play a part in tumor promotion, and that
down-regulation of GJIC contributes to the uncontrolled cellular growth that leads to tumor
development. Results indicated that PAHs containing bay or bay-like regions (like fluoranthene)
inhibited GJIC more than did linear PAHs.
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Shimada et al. (2002) evaluated the effects of 14 PAHs (including fluoranthene) on the
induction of CYP1A1 and 1B1 mRNA. The effects were evaluated in genetically-engineered
C57BL/6J arylhydrocarbon receptor knock-out mice, AhR (-/-), compared to wild-type, AhR
(+/+). The authors concluded that, "Liver microsomal activities of 7-ethoxyresorufin and
7-ethoxycoumarin O-deethylations and of mutagenic activation of (±)-trans-7,8-dihydroxy-
7,8-dihydro-B[a]P to DNA-damaging products were found to correlate with levels of CYP1 Al
and 1B1 mRNAs in the liver." The authors stated that their findings suggest that the
carcinogenicity potencies of PAHs may relate to their potential to induce CYP1A1 and 1B1.
Fluoranthene induction of these P450 isozymes was very low or nonexistent.
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DERIVATION OF PROVISIONAL VALUES
Table 4 presents a summary of noncancer reference values. Table 5 presents a summary of cancer values. No cancer values could be
derived. For the oral subchronic studies, the average daily dose was provided.
Table 4. Summary of Noncancer Reference Values for Fluoranthene (CASRN 206-44-0)
Toxicity Type (Units)
Species/
Sex
Critical Effect
Reference
Value
POD Method
POD
UFC
Principal Study
Subchronic p-RfD
(mg/kg-day)
Mouse/M+F
Renal nephropathy
1 x KT1
BMDL
124
1000
U.S. EPA (1988)
Chronic RfD (IRIS)
(mg/kg-day)
Mouse/M+F
Nephropathy, increased liver weights,
hematological alterations, and clinical
effects
4 x 10~2
NOAEL
125
3000
U.S. EPA (1988)
Subchronic p-RfC
(mg/m3)
None
Chronic p-RfC
(mg/m3)
None
Table 5. Summary of Cancer Reference Values for Fluoranthene (CASRN 206-44-0)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
None
p-IUR
None
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DERIVATION OF ORAL REFERENCE DOSE
Derivation of Subchronic Provisional RfD (Subchronic p-RfD)
IRIS (U.S. EPA, 1990) based its chronic RfD on a mouse subchronic toxicity study,
where the critical effects were nephropathy, increased liver weights, hematological alterations,
and clinical effects (U.S. EPA, 1988).
Since 1990, an additional subchronic toxicity study using rats was performed with
fluoranthene by Knuckles et al. (2004). Although, this study used dietary exposure, which is
more relevant to human exposure than gavage dosing, it has numerous deficiencies which are
noted in the study summary. The deficiencies in the study preclude its consideration for the
derivation of the subchronic p-RfD.
Consequently, the subchronic toxicity study (U.S. EPA, 1988) used by IRIS was selected
as the principal study to derive the subchronic p-RfD. The standard deviations for group organ
weights were not reported in the available documentation nor were the individual data.
Therefore, liver organ-weight data could not be modeled. The nephropathy endpoint is,
however, the most sensitive of the two organ endpoints. A BMDLio of 124 mg/kg-day, based on
nephropathy, was determined for the female mouse (more sensitive sex). Results from these
modeling efforts are presented in Appendix C.
Adjusted for daily exposure:
The following dosimetric adjustments were made for each dose in the principal study for
dietary treatment.
DOSEadj = DOSE x [conversion to daily dose]
= 125 mg/kg-day x (days of week dosed ^ 7 days in week)
= 125 mg/kg-day x 7 ^ 7
= 125 mg/kg-day
Among the dichotomous models for incidence of nephropathy (see Table 6), the Probit
model was chosen as it had the lowest AIC, resulting in a BMDLio of 124 mg/kg-day for a POD.
Visual inspection of the curves for each model did not result in the rejection of any model for
problems such as supralinearity or compromised low-dose fitting due to modeling of the
high-dose range. The range of the BMDL values from models meeting the goodness-of-fit
criteria is <3-fold.
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Table 6. Goodness-of-Fit Statistics, BMDio, and BMDLio Values for Dichotomous Models
for Nephropathy in Female Mice Dosed with Fluoranthene"
Model (in order of
lowest BMDL)
Goodness-of-Fit
p-V alueb
AIC
BMD10
(mg/kg-day)
BMDL10
(mg/kg-day)
Probit
0.94
75.078°
164
124
Quantal Linear
0.49
76.492
87.8
58.2
Multistage
0.81
77.018
164
66.0
Gamma
0.92
76.974
166
66.3
Logistic
0.91
75.156
177
133
Log-Logistic
0.94
76.968
167
63.4
Log-Probit
0.96
76.966
168
103
Weibull
0.86
76.996
163
66.1
aU.S. EPA (1988).
bValues >0.1 meet conventional goodness-of-fit criteria.
°Lowest AIC.
After considering all treatment-related endpoints, the subchronic p-RfD for fluoranthene,
based on the BMDLio of 124 mg/kg-day from the incidences of renal nephropathy in female
mice (U.S. EPA, 1988), is derived as follows:
Subchronic p-RfD = BMDLio UFc
= 124 mg/kg-day ^ 1000
= 1 x 10-1 mg/kg-day
Table 7 summarizes the UFs for the subchronic p-RfD for fluoranthene, and the
confidence descriptors for the subchronic p-RfD are provided in Table 8.
Table 7. Uncertainty Factors for Subchronic p-RfD for Fluoranthene"
UF
Value
Justification
ufa
10
A UFa of 10 is applied for interspecies extrapolation to account for potential toxicokinetic
and toxicodynamic differences between mice and humans. There are no data to determine
whether humans are more or less sensitive than mice to the nephrotoxicity of fluoranthene.
ufd
10
A UFd of 10 is applied because there are no acceptable two-generation reproduction studies
or developmental studies.
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially susceptible
individuals in the absence of information on the variability of response in humans.
ufl
1
A UFl of 1 is applied for using a POD based on a BMDL.
UFS
1
A UFS of 1 is applied because a subchronic study was utilized as the principal study.
UFC
1000
aU.S. EPA (1988).
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Table 8. Confidence Descriptor for Subchronic p-RfD for Fluoranthene"
Confidence Categories
Designation1"
Rationale
Confidence in Study
M
The study was given a medium confidence level, as it is a
well-designed study that identified both a LOAEL and a NOAEL
for several sensitive endpoints using an adequate number of
animals. The data from this study, such as histological severity
data for each finding, were not available for independent review.
Confidence in Database
L
The database was given a low confidence level because only two
subchronic studies were located; no reproductive or developmental
studies were located.
Confidence in Subchronic
p-RfD°
L
The overall confidence in the subchronic p-RfD is low due to a lack
of confidence in the database.
aU.S. EPA (1988).
bL = Low, M = Medium, H = High.
The overall confidence cannot be greater than the lowest entry in table.
Derivation of Chronic RfD (Chronic RfD)
A chronic RfD of 4 x 1CT2 mg/kg-day is available on IRIS (U.S. EPA, 1990) based on the
same mouse subchronic study that is used as the principal study for the subchronic p-RfD above,
where the critical effects were nephropathy, increased liver weights, hematological alterations,
and clinical effects (U.S. EPA, 1988). The UFc was reported as 3000. The confidence factors
were reported as follows: study (medium), database (low), and RfD (low). The IRIS database
should be checked to determine if any changes have been made.
DERIVATION OF INHALATION REFERENCE CONCENTRATION
No published studies investigating the effects of subchronic or chronic inhalation
exposure to fluoranthene in humans or animals were identified that were acceptable for use in
risk assessment.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 9 identifies the cancer WOE descriptor for fluoranthene. IRIS (U.S. EPA, 1990)
evaluated the overall WOE for carcinogenicity to humans using the Guidelines for Carcinogen
Risk Assessment (U.S. EPA, 1986) and designated fluoranthene under the category of
"Group D—Not Classifiable as to its Human Carcinogenicity." The IRIS document stated that
there are no human data and only inadequate data from animal bioassays.
As of April 2012, it is concluded that there is "inadequate information to assess
carcinogenic potential" of fluoranthene. No studies could be located regarding the effects of
chronic oral, inhalation, or dermal exposure to fluoranthene in animals. No epidemiological
study was located that evaluates the effect of fluoranthene in humans.
Many studies, summarized above, suggest that fluoranthene is a cocarcinogen and may be
a weak complete carcinogen (Hecht et al., 1995; Wang and Busby, 1993; Wang et al, 1995;
LaVoie et al., 1994; Van Duuren and Goldschmidt, 1976; U.S. EPA, 1990; Rice et al., 1988;
Gorelick et al., 1989; Stocker et al., 1996).
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Newborn mice assays suggest that fluoranthene may be a complete carcinogen, although
a weak carcinogen compared to B[a]P. DNA adducts were isolated in rat tissues, which suggests
the possibility that fluoranthene may be involved in carcinogenic initiation. Conversely, skin
painting tests were routinely negative, and four subcutaneous injections in mice did not induce
tumors. Also, it was found that fluoranthene did not induce oxidative stress, in contrast to
known PAH carcinogens. Fluoranthene does not induce CYP1A1 and 1B1; whereas, one study
suggested that the carcinogenic potential of PAHs may correlate with the induction of these
isozymes. Fluoranthene was not genotoxic in the mouse bone marrow micronucleus and rat liver
unscheduled DNA synthesis in vivo mutagenicity test systems. IRIS concluded that evidence for
mutagenicity of fluoranthene was equivocal.
There is more substantial evidence that fluoranthene is a cocarcinogen. When applied
with B[a]P to mouse skin, the cocarcinogenic response resulted in an approximate 3-fold
increase in tumor yield and reduced the tumor latency period by at least half. B[a]P-DNA
binding was increased in the presence of fluoranthene by 36-76%. Fluoranthene was found to
inhibit GJIC, which can lead to tumor promotion. However, in a mouse skin initiator-promoter
test, fluoranthene had weak or no promoter ability. Exposure to other PAHs (such as B[a]P) may
also occur when a person is exposed to fluoranthene. Human exposure to both fluoranthene and
B[a]P occurs primarily through the smoking of tobacco, inhalation of polluted air, and by
ingestion of food and water contaminated by combustion effluents (IARC, 1983). Consequently,
the possibility of concurrent exposure to B[a]P is important if fluoranthene acts as a
cocarcinogen.
Table 9. Cancer WOE Descriptor for Fluoranthene (CASRN 206-44-0)
Possible WOE
Descriptor
Designation
Route of Entry (Oral,
Inhalation, or Both)
Comments
"Carcinogenic to
Humans "
N/A
N/A
There is no acceptable carcinogenicity study in
animals or human studies.
"Likely to be
Carcinogenic to
Humans "
N/A
N/A
There is no acceptable carcinogenicity study in
animals or human studies.
"Suggestive
Evidence of
Carcinogenic
Potential"
N/A
N/A
There is no acceptable carcinogenicity study in
animals or human studies.
"Inadequate
Information to
Assess Carcinogenic
Potential"
Selected
Both
There is inadequate human and animal evidence of
carcinogenicity. An acceptable chronic
toxicity/carcinogenicity study has not been
performed by either oral or inhalation routes of
exposure.
"Not Likely to be
Carcinogenic to
Humans "
N/A
N/A
No strong evidence of noncarcinogenicity in humans
is available.
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MUTAGENICITY INFORMATION
Fluoranthene was not genotoxic in the mouse bone marrow micronucleus and rat liver
unscheduled DNA synthesis in vivo mutagenicity test systems. IRIS (U.S. EPA, 1990)
concluded that evidence for mutagenicity of fluoranthene was equivocal. There are no adequate
studies on the carcinogenic potential of fluoranthene in humans or animals.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of Provisional Oral Slope Factor (p-OSF)
No human or animal studies examining the carcinogenicity of fluoranthene following oral
exposure were identified. Therefore, derivation of a p-OSF is precluded.
Derivation of Provisional Inhalation Unit Risk (p-IUR)
No human or animal studies examining the carcinogenicity of fluoranthene following
inhalation exposure were identified. Therefore, derivation of a p-IUR is precluded.
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APPENDIX A. PROVISIONAL SCREENING VALUES
There are no provisional screening values for fluoranthene.
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APPENDIX B. DATA TABLES
Table B.l. Means ± SD of Selected Hematology and Clinical Chemistry Findings
in Mice Administered Fluoranthene by Gavage for 13 Weeksa,b
Parameter
Dose group (mg/kg-day)
0
125
250
500
Males
Absolute lymphocytes (/ 107|iL)
6.1 ± 1.70
5.7 ± 1.12
6.9 ± 1.64
4.4 ± 1.20° (J.28)
Globulin (g/dL)
2.62 ±0.18
2.73 ±0.16
2.74 ±0.21
2.90 ± 0.29° (fll)
Albumin/globulin ratio
1.20 ± 0.11
1.11 ± 0.10
1.08±0.11c(|10)
1.08 ± 0.10° (|10)
Serum glutamate pyruvate
transaminase (U/L)
21.9 ±5.79
24.4 ±4.65
30.7 ± 9.20° (|40)
33.6 ± 9.22d (|53)
Females
Packed cell volume (%)
47.9 ±2.73
46.9 ±3.30
44.3 ± 2.55° (J.8)
44.6 ± 1.98° (4,7)
Eosinophils (%)
2.0 ±0.82
1.5 ± 1.08
1.2 ± 1.03
0.6 ± 0.70d (4,70%)
Serum glutamate pyruvate
transaminase (U/L)
20.2 ±4.62
22.6 ±4.62
31.1 ± 10.06d (|54)
28.2 ± 5.03° (|40)
aU.S. EPA (1988). Data were obtained from Tables 3-4 on pages 49-60 of the cited publication.
Percent difference from control, calculated from the cited data, is listed in parentheses.
Significantly different (p < 0.05) from the control group.
dSignificantly different (p < 0.01) from the control group.
Table B.2. Mean of Selected Organ Weights in Mice Administered Fluoranthene
by Gavage for 13 Weeksa,b
Parameter
Dose group (mg/kg-day)
0
125
250
500
Males
Terminal body weight (g)
33.9
33.3
33.9
34.7
Absolute liver weight (g)
1.74
1.84
1.99° (f 14)
2.36° (t35)
Liver weight relative to body weight (%)
5.14
5.52d (|7)
5.88° (f 14)
6.78° (t32)
Females
Terminal body weight (g)
27.7
27.9
27.4
28.9
Absolute liver weight (g)
1.44
1.53
1.60° (fll)
1.91° (t32)
Liver weight relative to body weight (%)
5.22
5.48
5.83° (t 12)
6.59° (t26)
aU.S. EPA (1988). Data were obtained from Table 8 on pages 103-104 of the cited publication.
bPercent difference from control, calculated from the cited data, is listed in parentheses. Standard deviation was not
reported.
Significantly different (p < 0.01) from the control group.
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Table B.3. Selected Nonneoplastic Lesions (# Affected/20) in C57/BL-6 Mice Administered
Fluoranthene by Gavage for 13 Weeksa
Dose group (mg/kg-day)
Parameter
0
125
250
500
Males
Nephropathy
1
2
1
11
Liver pigment
0
1
15
20
Females
Nephropathy
1
2
5
11
Liver pigment
0
2
11
15
aU.S. EPA (1988). Data were obtained from Table 9 on pages 105-110 of the cited publication.
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APPENDIX C. BMD MODELING OUTPUTS FOR FLUORANTHENE
627575_Nephropathy_F_Gamma_l
Gamma Multi-Hit Model with 0.95 Confidence Level
0 100 200 300 400 500
dose
09:01 07/28 2010
Gamma Model. (Version: 2.15; Date: 10/28/2009)
Input Data File: C:/BMDS/627575_Nephropathy_F_Gamma_l.(d)
Gnuplot Plotting File: C:/BMDS/627575_Nephropathy_F_Gamma_l.pit
Wed Jul 28 09:01:22 2010
[add_notes_here]
The form of the probability function is:
P[response]= background+(1-background)*CumGamma[siope*dose,power],
where CumGamma(.) is the cummulative Gamma distribution function
Dependent variable = DichPerc
Independent variable = Dose
Power parameter is restricted as power >=1
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial (and Specified) Parameter Values
Background = 0.0909091
Slope = 0.00357867
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Power =
2.11169
Asymptotic Correlation Matrix of Parameter Estimates
Background
Background 1
Slope 0.36
Power 0.45
Slope
0.36
1
0.98
Power
0. 45
0. 98
1
Interval
Variable
Limit
Background
0.140028
Slope
0.0110768
Power
5 .27156
Estimate
0. 0489334
0.00414311
2.28944
Parameter Estimates
Std. Err.
0.0464776
0. 00353766
1.52152
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
-0.042161
-0.00279057
-0.692686
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood)
-35.4814
-35.487
-43.8545
76.974
# Param's Deviance Test d.f. P-value
4
3 0.0110862 1 0.9161
1 16.7461 3 0.000797
Goodness of Fit
Scaled
Dose
Est. Prob.
Expected
Observed
Size
Residual
0.0000
0. 0489
0.979
1.000
20
0. 022
125.0000
0.1047
2.094
2.000
20
-0.069
250.0000
0.2431
4.8 62
5.000
20
0. 072
500.0000
0.5529
11.058
11.000
20
-0.026
Chi^2 = 0.01
d.f. = 1
P-value = 0.9162
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 165.748
BMDL = 66.296
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627575_Nephropathy_F_Logistic_l
Logistic Model with 0.95 Confidence Level
dose
09:01 07/28 2010
Logistic Model. (Version: 2.13; Date: 10/28/2009)
Input Data File: C:/BMDS/627575_Nephropathy_F_Logistic_l.(d)
Gnuplot Plotting File: C:/BMDS/627575_Nephropathy_F_Logistic_l.pit
Wed Jul 28 09:01:22 2010
[add_notes_here]
The form of the probability function is:
P[response] = 1/[1+EXP(-intercept-slope*dose)]
Dependent variable = DichPerc
Independent variable = Dose
Slope parameter is not restricted
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
background = 0 Specified
intercept = -2.58499
slope = 0.00563257
Asymptotic Correlation Matrix of Parameter Estimates
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the user,
intercept
slope
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
and do not appear in the correlation matrix )
intercept slope
1 -0.87
-0.87 1
Interval
Variable
Limit
intercept
1.64758
slope
0.00941306
Estimate
-2.82119
0.00614982
Parameter Estimates
Std. Err.
0.598794
0. 00166495
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
-3.9948
0. 00288658
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Log(likelihood)
-35.4814
-35.5777
-43. 8545
75.1555
# Param's
4
2
1
Deviance Test d.f.
0.1926
16.7461
P-value
0.9082
0.000797
Dose
Goodness of Fit
Est._Prob. Expected Observed Size
Scaled
Residual
0.0000
125.0000
250.0000
500.0000
Chi^2 = 0.20
0.0562
0.1138
0.2169
0.5631
d.f. = 2
1.124 1.000 20 -0.120
2.276 2.000 20 -0.194
4.338 5.000 20 0.359
11.262 11.000 20 -0.118
P-value = 0.9071
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
0.1
Extra risk
0. 95
177.413
132.974
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627575_Nephropathy_F_LogLogistic_l
Log-Logistic Model with 0.95 Confidence Level
dose
09:01 07/28 2010
Logistic Model. (Version: 2.13; Date: 10/28/2009)
Input Data File: C:/BMDS/627575_Nephropathy_F_LogLogistic_l.(d)
Gnuplot Plotting File: C:/BMDS/627575_Nephropathy_F_LogLogistic_l.pit
Wed Jul 28 09:01:22 2010
[add_notes_here]
The form of the probability function is:
P[response] = background+(1-background)/[1+EXP(-intercept-siope*Log(dose))]
Dependent variable = DichPerc
Independent variable = Dose
Slope parameter is restricted as slope >= 1
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background = 0.05
intercept = -13.3006
slope = 2.16096
35 Fluoranthene
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Asymptotic Correlation Matrix of Parameter Estimates
background intercept slope
background 1 -0.45 0.42
intercept -0.45 1 -1
slope 0.42 -1 1
Parameter Estimates
Interval
Variable
Limit
background
intercept
slope
Estimate
0.0491162
-12.9785
2.10694
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Indicates that this value is not calculated.
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-35.4814
-35.484
-43. 8545
Param's
4
3
1
Deviance Test d.f.
0.00511695
16.7461
P-value
0. 943
0.000797
AIC:
76.968
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0.0491
0.982
1.000
20
0. 018
125.0000
0.1033
2.067
2.000
20
-0.049
250.0000
0.2456
4.913
5.000
20
0. 045
500.0000
0.5519
11.038
11.000
20
-0.017
Chi^2 = 0.01 d.f. = 1 P-value = 0.9430
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 166.844
BMDL = 63.3727
36
Fluoranthene
-------
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12-27-2012
627575_Nephropathy_F_LogProbit_l
LogProbit Model with 0.95 Confidence Level
dose
09:01 07/28 2010
Probit Model. (Version: 3.2; Date: 10/28/2009)
Input Data File: C:/BMDS/627575_Nephropathy_F_LogProbit_l.(d)
Gnuplot Plotting File: C:/BMDS/627575_Nephropathy_F_LogProbit_l.pit
Wed Jul 28 09:01:22 2010
[add_notes_here]
The form of the probability function is:
P[response] = Background
+ (1-Background) * CumNorm(Intercept+Slope*Log(Dose)),
where CumNormf .) is the cumulative normal distribution function
Dependent variable = DichPerc
Independent variable = Dose
Slope parameter is restricted as slope >= 1
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial (and Specified) Parameter Values
background = 0.05
intercept = -7.50078
37 Fluoranthene
-------
FINAL
12-27-2012
slope =
1.2161
Asymptotic Correlation Matrix of Parameter Estimates
background intercept
background 1 -0.4 8
intercept -0.48 1
slope 0.45 -1
slope
0. 45
-1
1
Interval
Variable
Limit
background
0.14462
intercept
1.51059
slope
2.25691
Estimate
0. 0506433
-7.60328
1.23325
Parameter Estimates
Std. Err.
0.0479481
3.10857
0.522285
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
-0.0433333
-13.696
0.209586
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood)
-35.4814
-35.4828
-43. 8545
76.9657
# Param's Deviance Test d.f. P-value
4
3 0.00280448 1 0.9578
1 16.7461 3 0.000797
Goodness of Fit
Scaled
Dose
Est. Prob.
Expected
Observed
Size
Residual
0.0000
0.0506
1.013
1.000
20
-0.013
125.0000
0.0977
1.955
2.000
20
0. 034
250.0000
0.2534
5.069
5.000
20
-0.035
500.0000
0.5484
10.967
11.000
20
0. 015
Chi^2 = 0.00
d.f. = 1
P-value = 0.9577
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 168.358
BMDL = 102.629
38
Fluoranthene
-------
FINAL
12-27-2012
627575_Nephropathy_F_Multi_l
Multistage Model with 0.95 Confidence Level
dose
09:01 07/28 2010
Multistage Model. (Version: 3.2; Date: 05/26/2010)
Input Data File: C:/BMDS/627575_Nephropathy_F_Multi_l.(d)
Gnuplot Plotting File: C:/BMDS/627575_Nephropathy_F_Multi_l.pit
Wed Jul 28 09:01:22 2010
[add_notes_here]
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*dose/sl-beta2*dose/s2-beta3*dose/s3)]
The parameter betas are restricted to be positive
Dependent variable = DichPerc
Independent variable = Dose
Total number of observations = 4
Total number of records with missing values = 0
Total number of parameters in model = 4
Total number of specified parameters = 0
Degree of polynomial = 3
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
39
Fluoranthene
-------
FINAL
12-27-2012
Default Initial Parameter Values
Background = 0.0437984
Beta(1) = 0.000327276
Beta(2) = 2.36901e-006
Beta(3) = 0
the user,
Background
Beta (1)
Beta (2)
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Beta(3)
have been estimated at a boundary point, or have been specified by
and do not appear in the correlation matrix )
Background Beta(l) Beta(2)
1 -0.7 0.53
-0.7 1 -0.94
0.53 -0.94 1
Parameter Estimates
Interval
Variable
Limit
Background
Beta(1)
Beta(2)
Beta(3)
Estimate
0.0483278
0. 000207744
2.63786e-006
0
Std. Err.
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
Indicates that this value is not calculated.
Model
Full model
Fitted model
Reduced model
Analysis of Deviance Table
#
Log(likelihood)
-35.4814
-35.5089
-43.8545
Param's
4
3
1
Deviance Test d.f.
0.0549934
16.7461
P-value
0.8146
0.000797
AIC:
77.0179
Dose
Goodness of Fit
Est. Prob.
Expected
Observed
Size
Scaled
Residual
0.0000
125.0000
250.0000
500.0000
Chi^2 = 0.05
0.0483
0.1102
0.2338
0.5564
d.f. = 1
0.967 1.000 20 0.035
2.203 2.000 20 -0.145
4.676 5.000 20 0.171
11.128 11.000 20 -0.058
P-value = 0.8148
Benchmark Dose Computation
Specified effect = 0.1
40
Fluoranthene
-------
FINAL
12-27-2012
Risk Type = Extra risk
Confidence level = 0.95
BMD = 164.319
BMDL = 65.9789
BMDU = 301.233
Taken together, (65.9789, 301.233) is a 90 % two-sided confidence
interval for the BMD
41 Fluoranthene
-------
FINAL
12-27-2012
627575_Nephropathy_F_Probit_l
Probit Model with 0.95 Confidence Level
dose
09:01 07/28 2010
Probit Model. (Version: 3.2; Date: 10/28/2009)
Input Data File: C:/BMDS/627575_Nephropathy_F_Probit_l.(d)
Gnuplot Plotting File: C:/BMDS/627575_Nephropathy_F_Probit_l.pit
Wed Jul 28 09:01:22 2010
[add_notes_here]
The form of the probability function is:
P[response] = CumNorm(Intercept+Slope*Dose) ,
where CumNormf .) is the cumulative normal distribution function
Dependent variable = DichPerc
Independent variable = Dose
Slope parameter is not restricted
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial (and Specified) Parameter Values
background = 0 Specified
intercept = -1.61379
slope = 0.00351017
42
Fluoranthene
-------
FINAL
12-27-2012
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background
have been estimated at a boundary point, or have been specified by
the user,
and do not appear in the correlation matrix )
intercept slope
intercept 1 -0.84
slope -0.84 1
Interval
Variable
Limit
intercept
1.03422
slope
0.0054239
Estimate
-1.64939
0.00359211
Parameter Estimates
Std. Err.
0.31387
0.000934601
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
-2.26457
0. 00176033
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
AIC:
Log(likelihood)
-35.4814
-35.5388
-43. 8545
75.0777
# Param's Deviance Test d.f. P-value
4
2 0.114776 2 0.9442
1 16.7461 3 0.000797
Dose
Goodness of Fit
Est. Prob.
Expected
Observed
Size
Scaled
Residual
0.0000
125.0000
250.0000
500.0000
Chi^2 = 0.11
0.0495
0.1150
0.2262
0.5583
d.f. = 2
0.991 1.000 20 0.010
2.300 2.000 20 -0.210
4.524 5.000 20 0.254
11.166 11.000 20 -0.075
P-value = 0.9444
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
0.1
Extra risk
0. 95
164.089
123.818
43
Fluoranthene
-------
FINAL
12-27-2012
627575_Nephropathy_F_Quantal_l
Quantal Linear Model with 0.95 Confidence Level
dose
09:01 07/28 2010
Quantal Linear Model using Weibull Model (Version: 2.15; Date: 10/28/2009)
Input Data File: C:/BMDS/627575_Nephropathy_F_Quantal_l.(d)
Gnuplot Plotting File: C:/BMDS/627575_Nephropathy_F_Quantal_l.pit
Wed Jul 28 09:01:22 2010
[add_notes_here]
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(-slope*dose)]
Dependent variable = DichPerc
Independent variable = Dose
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial (and Specified) Parameter Values
Background = 0.0909091
Slope = 0.00138629
Power = 1 Specified
Asymptotic Correlation Matrix of Parameter Estimates
44
Fluoranthene
-------
FINAL
12-27-2012
the user,
Background
Slope
( *** The model parameter(s) -Power
have been estimated at a boundary point, or have been specified by
and do not appear in the correlation matrix )
Background Slope
1 -0.33
-0.33 1
Interval
Variable
Limit
Background
0.104942
Slope
0.00185316
Estimate
0.0363917
0.0012007
Parameter Estimates
Std. Err.
0.0349751
0.000332899
95.0% Wald Confidence
Lower Conf. Limit Upper Conf.
-0.0321583
0.000548226
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance Table
Log(likelihood)
-35.4814
-36.2459
-43. 8545
76.4917
# Param's
4
2
1
Deviance Test d.f.
1.52885
16.7461
P-value
0.4 65 6
0.000797
Dose
Goodness of Fit
Est. Prob.
Expected
Observed
Size
Scaled
Residual
0.0000
125.0000
250.0000
500.0000
Chi^2 = 1.44
0.0364
0.1707
0.2863
0.4713
d.f. = 2
0.728 1.000 20
3.414 2.000 20
5.725 5.000 20
9.427 11.000 20
P-value = 0.4875
0.325
-0.840
-0.359
0.705
Benchmark Dose Computation
Specified effect
Risk Type
Confidence level
BMD
BMDL
0.1
Extra risk
0. 95
87.7496
58.235
45
Fluoranthene
-------
FINAL
12-27-2012
627575 Nephropathy F Weibull_l
Weibull Model with 0.95 Confidence Level
dose
09:01 07/28 2010
Weibull Model using Weibull Model (Version: 2.15; Date: 10/28/2009)
Input Data File: C:/BMDS/627575_Nephropathy_F_Weibull_l.(d)
Gnuplot Plotting File: C:/BMDS/627575_Nephropathy_F_Weibull_l.pit
Wed Jul 28 09:01:22 2010
[add_notes_here]
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(-slope*dose/spower)]
Dependent variable = DichPerc
Independent variable = Dose
Power parameter is restricted as power >= 1.000000
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial (and Specified) Parameter Values
Background = 0.0909091
Slope = 2.73771e-005
Power = 1.63153
Asymptotic Correlation Matrix of Parameter Estimates
46
Fluoranthene
-------
FINAL
12-27-2012
Background Slope Power
Background 1 -0.4 6 0.44
Slope -0.46 1 -1
Power 0.44 -1 1
Parameter Estimates
Interval
Variable
Limit
Background
0.137314
Slope
0.000132446
Power
3.24146
95.0% Wald Confidence
Estimate Std. Err. Lower Conf. Limit Upper Conf.
0.0480752 0.0455308 -0.0411635
1.32888e-005 6.07955e-005 -0.000105868
1.7622 0.75474 0.282933
Analysis of Deviance Table
Model
Full model
Fitted model
Reduced model
Log(likelihood)
-35.4814
-35.4979
-43. 8545
# Param's
4
3
1
Deviance Test d.f.
0.0329838
16.7461
P-value
0.8559
0.000797
AIC:
76.9959
Goodness of Fit
Scaled
Dose Est._Prob. Expected Observed Size Residual
0.0000
0. 0481
0.962
1.000
20
0. 040
125.0000
0.1088
2.175
2.000
20
-0.126
250.0000
0.2387
4 .773
5.000
20
0.119
500.0000
0.5539
11.077
11.000
20
-0.035
Chi^2 = 0.03 d.f. = 1 P-value = 0.8564
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 163.188
BMDL = 66.1369
47
Fluoranthene
-------
FINAL
12-27-2012
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51
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