Toxicological
Profile
for
BENZO [a] PY REN E
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry
-------
ATSDR /TP-88/05
TOXICOLOGICAL PROFILE FOR
BENZO(a]PYRENE
Date Published - May 1990
Prepared by:
ICF-Clement
under Contract No. 68-02-4235
for
U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry (ATSDR)
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. 1857-B026-A1
-------
DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry.
-------
FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans."
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
iii
-------
Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
0 < AuxJ>o
James 0. Mason, M.D., Dr. P.H.
Assistant Surgeon General
Administrator, ATSDR
iv
-------
CONTENTS
FOREWORD ill
LIST OF FIGURES Ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS BENZO[a] PYRENE? 1
1.2 HOW MIGHT I BE EXPOSED TO BENZO[a] PYRENE? 1
1.3 HOW DOES BENZO [a] PYRENE GET INTO MY BODY? 2
1.4 HOW CAN BENZO[a]PYRENE AFFECT MY HEALTH? 2
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I
HAVE BEEN EXPOSED TO BENZO [a] PYRENE? 2
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 2
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH? 4
2. HEALTH EFFECTS SUMMARY 5
2.1 INTRODUCTION 5
2.2 LEVELS OF SIGNIFICANT EXPOSURE 6
2.2.1 Key Studies and Graphical Presentations 6
2.2.1.1 Inhalation exposure 6
2.2.1.2 Oral exposure 9
2.2.1.3 Dermal exposure 13
2.2.2 Biological Monitoring 13
2.2.3 Environmental Levels as Indicators of Exposure
and Effects 18
2.2.3.1 Levels found In the environment 18
2.2.3.2 Human exposure potential 18
2.3 ADEQUACY OF DATABASE 19
2.3.1 Introduction 19
2.3.2 Health Effect End Points 19
2.3.2.1 Introduction and graphic summary 19
2.3.2.2 Description of highlights of graphs 22
2.3.2.3 Summary of relevant ongoing research .... 23
2.3.3 Other Information Needed for
Human Health Assessment 23
2.3.3.1 Toxicokinetics and mechanisms
of action 23
2.3.3.2 Adequacy of data on biological
monitoring 24
2.3.3.3 Environmental considerations 24
v
-------
Contents
3. CHEMICAL AND PHYSICAL INFORMATION 27
3.1 CHEMICAL IDENTITY 27
3.2 PHYSICAL AND CHEMICAL PROPERTIES 27
4. TOXICOLOGICAL DATA 31
4.1 OVERVIEW 31
4.2 TOXICOKINETICS 32
4.2.1 Overview 32
4.2.2 Absorption 32
4.2.2.1 Inhalation 32
4.2.2.2 Oral 34
4.2.2.3 Dermal 34
4.2.3 Distribution 35
4.2.4 Metabolism 36
4.2.5 Excretion 39
4.3 TOXICITY 40
4.3.1 Lethality and Decreased Longevity 40
4.3.1.1 Overview 40
4.3.1.2 Inhalation 40
4.3.1.3 Oral 40
4.3.1.4 Dermal 41
4.3.1.5 General discussion 41
4.3.2 Systemic/Target Organ Toxicity 41
4.3.2.1 Overview 41
4.3.2.2 Hematopoietic toxicity 42
4.3.2.3 Dermal toxicity 42
4.3.3 Reproductive and Developmental Toxicity 44
4.3.3.1 Overview 44
4.3.3.2 Inhalation 45
4.3.3.3 Oral 45
4.3.3.4 Dermal 47
4.3.3.5 General discussion 47
4.3.4 Genotoxicity 48
4.3.4.1 Overview 48
4.3.4.2 General discussion 48
4.3.5 Carcinogenicity 54
4.3.5.1 Overview 54
4.3.5.2 Inhalation 54
4.3.5.3 Oral 57
4.3.5.4 Dermal 60
4.3.5.5 General discussion 66
4.4 INTERACTIONS WITH OTHER CHEMICALS 67
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL 73
5.1 OVERVIEW 73
5.2 PRODUCTION 73
5.3 IMPORT 74
5.4 USE 74
5.5 DISPOSAL 74
6. ENVIRONMENTAL FATE 75
6.1 OVERVIEW 75
6.2 RELEASES TO THE ENVIRONMENT 75
6.3 ENVIRONMENTAL FATE 76
vi
-------
Contents
7. POTENTIAL FOR HUMAN EXPOSURE 79
7.1 OVERVIEW 79
7.2. LEVELS MONITORED IN THE ENVIRONMENT 79
7.2.1 Air 79
7.2.2 Water 80
7.2.3 Soil 80
7.2.4 Food 80
7.2.5 Tobacco Products and Tobacco Smoke 81
7.3 OCCUPATIONAL EXPOSURES 81
7.4 POPULATIONS AT HIGH RISK 81
8. ANALYTICAL METHODS 83
8.1 ENVIRONMENTAL SAMPLES 83
8.2 BIOLOGICAL SAMPLES 85
9. REGULATORY AND ADVISORY STATUS 89
9.1 INTERNATIONAL 89
9.2 NATIONAL 89
9.2.1 Regulatory Standards 89
9.2.2 Advisory Levels 91
9.2.2.1 Air advisory levels 91
9.2.2.2 Water advisory levels 91
9.2.2.3 Food advisory levels 92
9.2.2.4 Non-media-specific levels 92
9.2.2.5 Other guidance 92
9.3 STATE 92
10. REFERENCES 93
11. GLOSSARY 121
APPENDIX: PEER REVIEW 125
vii
-------
LIST OF FIGURES
1.1 Health effects from ingesting benzo[a]pyrene 3
2.1 Effects of benzo[a]pyrene--inhalation exposure 7
2.2 Levels of significant exposure for benzo[ajpyrene--
inhalation 8
2.3 Effects of benzo[a]pyrene--oral exposure 10
2.4 Levels of significant exposure for benzo[ajpyrene--oral 11
2.5 Effects of benzo[a]pyrene--dermal exposure 14
2.6 Levels of significant exposure for benzo[ajpyrene--dermal .... 15
2.7 Benzo[a]pyrene binding to mouse skin DNA and hemoglobin 17
2.8 Availability of information on health effects of
benzo[a]pyrene (human data) 20
2.9 Availability of information on health effects of
benzo[a]pyrene (animal data) 21
4.1 Metabolic fate of benzo [a] pyrene 33
4.2 Stereoselective metabolism of benzo[a]pyrene to an ultimate
carcinogenic metabolite by rat liver microsomes 38
ix
-------
LIST OF TABLES
3.1 Chemical Identity of benzo[a]pyrene 28
3.2 Physical and chemical properties of benzo[a]pyrene 29
4.1 Genetic toxicity of benzo[a]pyrene (in vitro) 49
4.2 Genetic toxicity of benzo[a]pyrene (in vivo) 52
4.3 Dose-response relationship between inhaled benzo[a]pyrene
and respiratory tract tumors in hamsters 55
4.4 Tumor dose-response relationships for benzo[a]pyrene
injected into rat lungs 58
4.5 Forestomach tumors in mice fed benzo[a]pyrene 59
4.6 Tumor incidence in mice fed benzo[ajpyrene 61
4.7 Benzo[a]pyrene-induced skin tumor rates in mice 63
4.8 Tumor incidence following dermal exposure of mice
to benzo [a]pyrene 64
4.9 Carcinogenic activity of benzo[ajpyrene on mouse skin--l .... 65
4.10 Carcinogenic activity of benzo[a]pyrene on mouse skin--II ... 65
4.11 Relative tumor-initiating potency of various emission
extracts and benzo[a]pyrene 68
4.12 Carcinogenic activity of automobile emission
condensate (AEC), diesel emission condensate (DEC),
and PAHs on mouse skin 70
8.1 Methods for analysis of benzo[a]pyrene in
environmental media 84
8.2 Methods for analysis of PAHs in biological samples 86
9.1 Regulatory standards and advisory levels 90
xi
-------
1
1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS BENZO[a]PYRENE?
Benzo[a]pyrene (B[a]P) is one of the polycyclic aromatic
hydrocarbon (PAH) compounds. Because it is formed when gasoline,
garbage, or any animal or plant material burns, it is usually found in
smoke and soot. This chemical combines with dust particles in the air
and is carried into water and soil and onto crops. Benzo[ajpyrene is
found in the coal tar pitch that industry uses to join electrical parts
together. It is also found in creosote, a chemical used to preserve
wood.
1.2 HOff MIGHT I BE EXPOSED TO BENZO[a]PYRENE?
People may be exposed to B[a]P from environmental sources such as
air, water, and soil and from cigarette smoke and cooked food. Vorkers
who handle or are involved in the manufacture of PAH-containing
materials may also be exposed to B[a]P. Typically, exposure for workers
and the general population is not to B[a]P alone but to a mixture of
similar chemicals.
The general population may be exposed to dust, soil, and other
particles that contain B[a]P. The largest sources of B[a]P in the air
are open burning and home heating with wood and coal. Factories that
produce coal tar also contribute small amounts of B[a]P to the air.
People may come in contact with B[a]P from soil on or near hazardous
waste sites, such as former gas-manufacturing sites or abandoned wood-
treatment plants that used creosote. At this time, B[a]P has been found
at 110 out of 1,117 sites on the National Priorities List (NPL) of
hazardous waste sites in the United States. As more sites are evaluated
by the Environmental Protection Agency (EPA), this number may change.
The soil near areas where coal, wood, or other products have been burned
is another source of exposure. Exposure to B[a]P and other PAHs may also
occur through skin contact with products that contain PAHs such as
creosote-treated wood, asphalt roads, or coal tar.
People may be exposed to B[a]P by drinking water from the drinking
water supplies in the United States that have been found to contain low
levels of the chemical. Foods grown in contaminated soil or air may
contain B[a]P. Cooking food at high temperatures, as occurs during
charcoal grilling or charring, can increase the amount of B[a]P in the
food. Benzo[a]pyrene has been found in cereals, vegetables, fruits,
meats, beverages, chewing tobacco, and in cigarette smoke.
The greatest exposure to B[a]P is likely to take place in the
workplace. People who work in coal tar-production plants; coking plants;
asphalt-production plants; coal-gasification sites; smoke houses;
municipal trash incinerators; and facilities that burn wood, coal, or
-------
2 Section 1
oil may be exposed to B[a]P in the workplace air. Benzo[a]pyrene may
also be found in areas where high-temperature food fryers and broilers
are used.
1.3 HOW DOES BENZO[ a ]PYRENE GET INTO MY BODY?
The most common way B[a]P enters the body is through the lung when
a person breathes in air or smoke containing it. It also enters the body
through the digestive system when substances containing it are
swallowed. Although B[a]P does not normally enter the body through the
skin, small amounts could enter if contact occurs with soil that
contains high levels of B[a]P (for example, near a hazardous waste site)
or if contact is made with heavy oils containing B[a]P.
1.4 HOff CAN BENZO[a]PYRENE AFFECT MY HEALTH?
Benzo[a]pyrene causes cancer in laboratory animals when applied to
their skin. This finding suggests that it is likely that people exposed
in the same manner could also develop cancer.
Because studies of B[a]P are not complete, we don't know if B[a]P
that is breathed in or swallowed could cause cancer.
Mice fed high levels of B[a]P during pregnancy had trouble
reproducing, and so did their offspring. The newborn animals of pregnant
mice fed B[a]P also had other harmful effects (for example, birth
defects and lower-than-normal body weight). It is possible that similar
effects could happen to people exposed to B[a]P.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO BENZO[a]PYRENE?
Very few tests are available that can tell whether exposure to
B[a]P has taken place. In the body, B[a]P is changed to related chemical
substances called metabolites. The metabolites can bind with DNA, the
genetic material of the body, and with hemoglobin, the oxygen-carrying
protein in red blood cells. The body's response after exposure can be
measured in the blood. However, this test is still being developed.
Benzo[a]pyrene can also be found in the urine and blood of individuals
exposed to PAHs. It is not possible to know from these tests how much
B[a]P a person was exposed to or to predict what health effects may
happen at certain levels. Also, none of these tests have been used in
exposure situations outside the workplace.
1.6 VHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
No information has been found about specific levels of B[a]P that
have caused harmful effects in people after breathing, swallowing, or
touching the substance.
Figure 1.1 shows the amount of B[a]P found to cause harmful health
effects in laboratory animals after eating B[a]P for short and long
periods. Short- and long-term exposures to B[a]P caused death in
experimental animals fed the chemical. The offspring of animals that ate
10 milligrams of B[a]P per kilogram of body weight (mg/kg) during
pregnancy had trouble reproducing. Some of the offspring weighed less
than normal at birth and had birth defects.
-------
Public Health Statement 3
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
EFFECTS
IN
ANIMALS
DOSE
(mg/kg/day)
EFFECTS
IN
HUMANS
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
DOSE
(mg/kg/day)
EFFECTS
IN
HUMANS
130
DEATH-
-120
1
100
I
90
I
80
I
70
I
60
I
50
I
40
I
30
I
20
REPRODUCTIVE/ |
DEVELOPMENTAL —10
EFFECTS |
0
QUANTITATIVE
DATA WERE
NOT AVAILABLE
DEATH-
130
I
¦120
I
110
I
100
I
90
I
80
I
70
I
60
I
50
I
40
I
30
I
20
I
10
1
T
0.03
I
0.02
I
0.01-
I
0
¦ MINIMAL RISK FOR
EFFECTS OTHER THAN
CANCER
Fig. 1.1. Health effects from Ingesting benzobfeyrene.
-------
4 Section 1
A Minimal Risk Level (MRL) is also included in Fig. 1.1. This MRL
is based on experiments in animals, as described in Sect. 2. The MRL
provides a basis for comparison with levels that people might be exposed
to in food. If a person is exposed to PAHs at an amount less than the
MRL, harmful (noncancer) health effects are not expected to occur.
Because this level is based only on information currently
available, some uncertainty is always associated with it. Also, because
the method for deriving MRLs does not use any information about cancer,
an MRL does not imply anything about the presence, absence, or level of
risk for cancer.
1.7 VHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH?
Based on information from another PAH chemical, the federal
government has developed standards and guidelines to protect individuals
from the potential health effects of PAHs, including B[a]P, in drinking
water. The U.S. Environmental Protection Agency (EPA) has provided
estimates of levels of total cancer-causing PAHs in lakes and streams
associated with various risks of developing cancer in people. EPA has
also determined that any release of PAHs of more than 1 pound should be
reported to the National Response Center.
Pure B[a]P is produced in the United States only as a laboratory
chemical. However, B[a]P is a PAH, and PAHs are found in coal tar and in
the creosote oils and pitches formed from the production of coal tar.
The government's goal has been to protect workers involved with the
production of coal tar products. These regulations are for exposure to
B[a]P in workplace air. Although government standards are not B[a]P
alone, they are useful in controlling exposure to total PAHs.
The National Institute for Occupational Safety and Health (NIOSH)
has determined that workplace exposure to coal products can increase the
risk of lung and skin cancer in workers and suggests a workplace
exposure limit for coal tar products of 0.1 milligram of PAHs per cubic
meter of air (0.1 mg/m^) for a 10-hour workday, 40-hour workweek. NIOSH
has not suggested a specific workplace limit for B[a]P. The Occupational
Safety and Health Administration (OSHA) has set a legal limit of 0.2
milligram of all PAHs per cubic meter of air (0.2 mg/m-*) .
-------
5
2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to B[a]P. The purpose of this section is to present
levels of significant exposure for B[a]P based on key toxicological
studies, epidemiological investigations, and environmental exposure
data. The information presented in this section is critically evaluated
and discussed in Sect, 4, Toxicologic Data, and Sect. 7, Potential for
Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of B[a]P; and (2) a
summarized depiction of significant exposure levels associated with
various adverse health effects. This section also includes information
on the levels of B[a]P that have been monitored in human fluids and
tissues and information about levels of B[a]P found in environmental
media and their association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt clinical findings in exposed
persons or with the identification of persons with the potential to
develop such disease may be interested in levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health officials
and project managers concerned with response actions at Superfund sites
may want information on levels of exposure associated with more subtle
effects in humans or animals (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse - Effect ^evel, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels) are of interest to
health professionals and citizens alike.
Adequacy of Database (Sect 2.3) highlights the availability of key
studies on exposure to B[a]P in the scientific literature and displays
these data in three-dimensional graphs consistent with the format in
Sect. 2.2. The purpose of this section is to suggest where there might
be insufficient information to establish levels of significant human
exposure. These areas will be considered by the Agency for Toxic
Substances and Disease Registry (ATSDR), EPA, and the National
Toxicology Program (NTP) of the U.S. Public Health Service in order to
develop a research agenda for benzo[a]pyrene.
-------
6 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
2.2.1 Key Studies and Graphical Presentations
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of exposure--
inhalation, ingestion, and dermal--and then by toxicological end points
that are categorized into six general areas--lethality, systemic/target
organ toxicity, developmental toxicity, reproductive toxicity, genetic
toxicity, and carcinogenicity. The data are discussed in terms of three
exposure periods--acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type is
a "thermometer" graph. It provides a graphical summary of the human and
animal toxicological end points and levels of exposure for each exposure
route for which data are available. The ordering of effects does not
reflect the exposure duration or species of animal tested. The second
kind of graph shows Levels of Significant Exposure (LSE) for each route
and exposure duration. The points on the graph showing NOAELs and LOAELs
reflect the actual dose (levels of exposure) used in the key studies. No
adjustments for exposure duration or intermittent exposure protocol were
made.
Adjustments reflecting the uncertainty of extrapolating animal data
to man, intraspecies variations, and differences between experimental
versus actual human exposure conditions were considered when estimates
of levels posing minimal risk to human health were made for noncancer
end points. Those minimal risk levels were derived for the most
sensitive noncancer end point for each exposure duration by applying
uncertainty factors. These levels are shown on the graphs as a broken
line starting from the actual dose (level of exposure) and ending with a
concave-curved line at its terminus. Although methods have been
established to derive these minimal risk levels (Barnes et al. 1987),
shortcomings exist in the techniques that reduce the confidence in the
projected estimates. Also shown on the graphs under the cancer end point
are low-level risks (10"^ to 10" ^) reported by EPA if available. In
addition, the actual dose (level of exposure) associated with the tumor
incidence is plotted.
2.2.1.1 Inhalation exposure
No information on the effects of short-term or intermediate
inhalation exposure to B[a]P are available. The induction of cancer
appears to be the key end point of toxicity following long-term exposure
to B[a]P. This conclusion is based on observations of experimental
animals since no data are available for human exposure. Available data
are displayed in Figs. 2.1 and 2.2.
Lethality and decreased longevity. No information is available.
Systemic toxicity. No information is available.
Developmental toxicity. No information is available.
-------
Health Effects Summary 7
ANIMALS
(mg/m3)
10,000 [-
1,000
100
10
0.1
0.01
HAMSTER, CANCER,
3.147 HOURS/DAY,
7 DAYS/WEEK, CHRONIC,
CONTINUOUS
HUMANS
QUANTITATIVE DATA
WERE NOT
AVAILABLE
• LOAEL
Fig. 2.1. Effects of benzo(a]pyraM—inhalation exposure.
-------
8 Section 2
ACUTE
(<14 DAYS)
mg/rrr
INTERMEDIATE
(15-364 DAYS)
CHRONIC
(>365 DAYS)
CANCER
10,000 r QUANTITATIVE DATA
WERE NOT
AVAILABLE
1,000
100
10
0.1
0.01
QUANTITATIVE DATA
WERE NOT
AVAILABLE
• s
0.001 u
s HAMSTER (SYRIAN) • LOAEL
Fig. 2.2. Levels of significant exposure for benzojajpyrene—inhalation.
-------
Health Effects Summary 9
Reproductive toxicity. No information is available.
Genotoxicity. Only one study cited inhalation as a possible
secondary route of exposure to B[a]P. Oral exposure of B[a]P to
Drosophila melanogaster was the primary route and resulted in no
mutagenic activity in the sex-linked recessive lethal test (Valencia and
Houtchens 1981).
Carcinogenicity. No information directly correlating human
inhalation exposure to B[a]P and cancer induction is available, although
reports of lung tumors in individuals exposed to mixtures of polycyclic
aromatic hydrocarbons containing B[a]P lend some qualitative support to
its potential for human carcinogenicity (Lloyd 1971, Redmond et al.
1972, Mazumdar et al. 1975, Hammond et al. 1976, Wynder and Hoffmann
1967, Maclure and MacMahon 1980, Schottenfeld and Fraumeni 1982).
Studies in experimental animals have demonstrated the ability of
B[a]P to induce respiratory tract tumors following long-term inhalation
exposure. In Syrian golden hamsters exposed throughout their lives to
B[a]P as an aerosol, concentrations above 9.5 mg/m^ B[a]P produced an
excess of respiratory tract tumors (Thyssen et al. 1981). Although EPA
previously published an inhalation cancer risk estimate for B[a]P based
on data from this study, this number is currently under review and was
not included here pending recalculation.
2.2.1.2 Oral exposure
Short-term and intermediate oral exposure to very high levels of
B[a]P resulted in death in experimental animals fed B[a]P in the diet.
Deaths appeared to be caused by bone marrow depression. The results of
oral studies conducted in mice and rats provide evidence that In utero
exposure to B[a]P is associated with adverse reproductive and
developmental effects. The induction of cancer appears to be the key end
point of toxicity following intermediate and long-term oral exposure to
B[a]P. Lower doses are required to induce tumors than other end points
of toxicity. This conclusion is based on observations of experimental
animals since no data are available for human exposure. Available data
are summarized in Figs. 2.3 and 2.4.
Lethality and decreased longevity. No information is available on
lethality and decreased longevity in humans following oral exposure to
B[a]P. Subchronic oral exposure of mice to B[a]P (120 mg/kg/day B[a]P)
for up to 6 months resulted in decreased survival time in
"nonresponsive" strains [i.e., strains whose hepatic aryl hydrocarbon
hydroxylase activity is not induced by PAH when compared to unexposed
controls (Robinson et al. 1975)]. Half of the deaths occurred within 15
days of dosing. Death appeared to be caused by bone marrow depression
that led to hemorrhage or infection.
Systemic toxicity. No information is available on the systemic
toxicity of B[a]P in humans following oral exposure. Hematopoietic
effects (e.g., aplastic anemia, pancytopenia) of B[a]P have been
reported in a "nonresponsive" strain of mice following subchronic oral
exposure to 120 mg/kg/day for up to 6 months (Robinson et al. 1975).
-------
10 Section 2
ANIMALS
(mg/kg/day)
10,000 r
1,000
100
10
0.1
0.01
MOUSE, DEATH,
b 9 >15-180 DAYS,
CONTINUOUS
MOUSE, REPRODUCTIVE/
DEVELOPMENTAL, GESTATION
• (7-16 DAYS), CONTINUOUS
m MOUSE, CANCER,
CHRONIC, CONTINUOUS
HUMANS
QUANTITATIVE DATA
WERE NOT
AVAILABLE
• LOAEL ® FEL
Fig. 13. Effects of benzoUlpyrene—oral exposure.
-------
Health Effects Summary 11
ACUTE
(<14 DAYS)
INTERMEDIATE
(15-364 DAYS)
CHRONIC
(>365 DAYS)
DEVELOP- REPRO-
mg/kg/day LETHALITY MENTAL DUCTIVE
DECREASED
LONGEVITY CANCER
10,000 i-
0.001 >-
» m
m MOUSE
m • m
• LOAEL
® FEL
9 m
QUANTITATIVE
DATA WERE NOT
AVAILABLE
m
I MINIMAL RISK FOR EFFECTS
vv OTHER THAN CANCER
Fig. 2.4. Levels of significant exposure for betizo{a)pyrene—oral.
-------
12 Section 2
Only one dose was tested. At the single dose tested, the hematopoietic
effects resulted in death; therefore, this study can not be used to
identify a LOAEL.
Developmental toxicity. No information is available on the
developmental toxicity of B[a]P in humans following oral exposure.
Results of a modified two-generation oral study in mice indicated that
in utero exposure to B[a]P throughout days 7 to 16 of gestation was
associated with developmental toxicity (MacKenzie and Angevine 1981).
The mean pup weight from rats that received 10, 40, or 160 mg/kg/day
during pregnancy was significantly different from controls. Furthermore,
prenatal exposure to B[a]P resulted in dramatic alterations in gonadal
development by disrupting gonadal morphology and germ cell development
in both males and females. Results from other rodent studies in which
B[a]P was administered orally or by injection provide additional
evidence that B[a]P may produce adverse reproductive/developmental
effects (Rigdon and Rennels 1964, Legraverend et al. 1984, Shum et al.
1979, Hoshino et al. 1981, Swartz and Mattison 1985, Urso and Gengozian
1980, Bulay and Wattenberg 1971, Nikonova 1977).
Reproductive toxicity. No information is available on the
reproductive toxicity of B[a]P in humans following oral exposure. The
results of a modified two-generation oral study in mice indicated that
B[a]P was associated with adverse reproductive effects (MacKenzie and
Angevine 1981). The reproductive toxicity of B[a]P included a decreased
fertility index and a high incidence of sterility in progeny. The
impaired reproductive capacity resulted from in utero exposure to B[a]P
administered throughout gestation (days 7-16) at doses of 10, 40, or 160
mg/kg/day. Results from other rodent studies in which B[a]P was
administered orally or by injection provide additional evidence that
B[a]P may produce adverse reproductive/developmental effects (Rigdon and
Rennels 1964, Legraverend et al. 1984, Shum et al. 1979, Hoshino et al.
1981, Swartz and Mattison 1985, Wolfe and Bryan 1939, Barbieri et al.
1986).
Genotoxicity. Positive results in somatic mutations and heritable
gene mutations have been reported in mice and Drosophila melanogaster,
following oral exposure to B[a]P. Positive mutagenic activity has been
reported in the mouse spot test (Davidson and Dawson 1977) and the
somatic mutation and sex-linked recessive lethal mutation assays with
Drosophila melanogaster (Fahmy and Fahmy 1980, Nguyen et al. 1979, Vogel
et al. 1983). However, negative results have been reported in similar
studies with Drosophila (Valencia and Houtchens 1981, Zijlstra and Vogel
1984). Mixed results have been reported for aneuploidy studies with
Drosophila melanogaster via feeding (Vogel et al. 1983, Valencia et al.
1984, Fabian and Matoltsy 1946).
Carcinogenicity. No information is available on the potential for
human carcinogenicity of B[a]P following oral exposure.
Studies in experimental animals have demonstrated the ability of
ingested B[a]P to induce leukemia and tumors in the forestomach and lung
following intermediate-term exposure. In mice receiving B[a]P in the
diet for 110 days, dose levels of 5.2 mg/kg/day and above produced an
excess of forestomach tumors (Neal and Rigdon 1967). Although EPA
previously published an oral cancer risk estimate for B[a]P based on
-------
Health Effects Summary 13
data from this study, this number is currently under review and was not
included here pending recalculation.
2.2.1.3 Dermal exposure
No information is available on the effects of short-term dermal
exposure of humans to B[a]P. There are reports on the effects of B[a]P
following short-term dermal exposures in animals and intermediate-term
dermal exposure to B[a]P in hunans and experimental animals. These
studies suggest that B[a]P has adverse effects on the skin; however,
these studies fail to employ control groups, and, therefore, definitive
conclusions concerning the dermal toxicity of B[a]P cannot be made.
The induction of cancer appears to be the key end point of toxicity
following long-term dermal exposure to B[a]P. This conclusion is based
on observations of experimental animals because no data are available
for human exposure to B[a]P alone; results are summarized in Figs. 2.5
and 2.6. The potential for dermal carcinogenicity in humans from B[a]P
is supported by observations of skin cancer resulting from exposure to
complex mixtures of PAHs that include B[a]P.
Lethality and decreased longevity. No information is available.
Systemic toxicity. There are no reports in the literature
concerning the systemic toxicity of B[a]P following dermal exposures.
There are reports in the literature, however, concerning the dermal
toxicity of B[a]P following subchronic applications to human and animal
skin (Cotti.nl and Mazzone 1939, Elgjo 1968); however, these studies did
not provide adequate quantitative information and failed to employ
control groups, and, therefore, cannot be used to develop a significant
human exposure level for the dermal toxicity of B[a]P.
Developmental toxicity. No information is available.
Reproductive toxicity. No information is available.
Genotoxicity. No information is available.
Carcinogenicity. No information directly correlating human dermal
exposure to B[a]P and cancer induction is available, although reports of
skin tumors among individuals exposed to mixtures of polycyclic aromatic
hydrocarbons containing B[a]P lend some qualitative support to its
potential for human carcinogenicity (Pott 1775, Purde and Etlin 1980).
Studies in experimental animals have demonstrated the ability of
B[a]P to induce skin tumors following long-term dermal exposure. Mice
receiving doses of 1.7 pg/day and above applied to their skin developed
an excess of skin tumors following long-term exposure (Habs et al.
1980). No estimate of human risk has been calculated.
2.2.2 Biological Monitoring
The available biological monitoring techniques can be useful in
predicting whether exposure to B[a]P or other PAHs has occurred, but
they may not be useful in estimating body doses because there have been
no population-based studies to determine normal body levels of PAHs
(e.g., in smokers). Individual variability, confounding effects of drugs
or cigarettes, and specificity of the techniques are likely to
-------
14 Section 2
ANIMALS
(mg/kg/day)
HUMANS
10,000 r
QUANTITATIVE DATA
WERE NOT
AVAILABLE
1,000
100
10
1 -
• MOUSE, CANCER,
2 TIMES/WEEK,
CHRONIC, INTERMITTENT
0.01
• LOAEL
Fig. 2.5. Effects of benzo(a]pyrene—dermal exposure.
-------
Health Effects Summary
ACUTE
(<14 DAYS)
mg/kg/day
INTERMEDIATE
(15-364 DAYS)
CHRONIC
(>365 DAYS)
CANCER
10,000
r QUANTITATIVE DATA
WERE NOT
AVAILABLE
1,000
100
10
0.1
0.01
QUANTITATIVE DATA
WERE NOT
AVAILABLE
• m
0.001 •-
m MOUSE
Fig. 1.6.
• LOAEL
Levels of significant exposure for benzo(a]pyrene—dermal.
-------
16 Section 2
complicate the association between B[a]P metabolites In the body and
environmental exposure. The most common tests for determining exposure
to B[a]P include examination of tissues, blood, and urine for the
presence of B[a]P metabolites. Currently available biological monitoring
techniques are discussed in detail in Sect. 8.
Modica et al. (1982) and Bartosek et al. (1984) used gas-liquid
chromatography to determine the presence of PAHs in blood, mammary and
adipose tissue, and liver and brain of rats. However, examples of
examination of human tissue samples using this method were not located
in the available literature.
In the tissues, B[a]P can be rapidly converted by specific cellular
enzymes to a dihydrodiol and further metabolized to diol epoxides which
can bind to DNA and form DNA adducts. A tissue sample can be taken from
an exposed individual, and DNA from the exposed cells can be digested
and labeled with radioactive phosphorus (32P). Thin-layer chromatography
is then used to determine the presence of altered DNA and scintillation
counting used to quantify the adducts (Randerath et al. 1985). In
another technique, the diol epoxides are removed from the DNA and
quantified by fluorescence spectroscopy (Rahn et al. 1982, Vahakangas et
al 1985 Shugart 1985, 1986). It has recently been reported that these
diol epoxides also form adducts with hemoglobin in the red blood cells,
and the presence of these diol epoxide adducts can be determined in
blood using fluorescence spectroscopy (see Fig. 2.7) (Shugart 1985,
1986). Although the presence of both DNA and hemoglobin adducts is
directly associated with exposure to B[a]P, this technique of analyzing
adducts is limited in its usefulness to predict body dose from
environmental exposure because individual biochemistry may affect the
conversion of B[a]P to diol epoxides and because of the limited
specificity of fluorescence spectroscopy. A technique has been developed
that tests for the presence of antibodies to the PAH-DNA adducts in
blood using immunoassays (Perera et al. 1982, Harris 1985, Harris et al.
1985, Santella et al. 1985, Harris et al. 1986, Haugen et al. 1986). A
patent has been submitted for a method and kit for detecting antibodies
in human sera to B[a]P diol epoxide-DNA adducts using an immunoassay
(Harris 1985) . This method has been examined in occupationally exposed
individuals and smokers.
The urine of exposed individuals has also been examined using
chromatography for the presence of B[a]P and B[a]P metabolites (Becher
and Bjorseth 1983, Becher et al. 1984, Jongeneelen et al. 1985, 1986,
Clonfero et al. 1986).
A recent technique using an antibody-based fiber-optic biosensor is
being tested to detect benzo[a]pyrene. This technique has been
investigated in sample solutions containing B[a]P and may be useful for
assessing the exposure of an individual to B[a]P or other PAHs, provided
appropriate antibodies are used (Vo-Dinh et al. 1987).
-------
Health Effects Summary 17
Fig. 2.7. Benzo{a]pyrene binding to mouse skin DNA and hemoglobin. Log-log plot relates the
log dose of B[a]P binding and the log dose of B[a]P applied to mouse skin. (O): B[a]P binding
hemoglobin expressed as pg Tetrol 1-1 /mg hemoglobin; and (•): B[a]P binding to DNA expressed
as ng Tetrol 1-1 /g DNA. Each data point represents the average values from 2 mice. Source:
Shugart 1985.
-------
18 Section 2
2.2.3 Environmental Levels as Indicators of Exposure and Effects
2.2.3.1 Levels found in the environment
B[a]P has been detected in air, water, and soils. B[a]P
concentrations in urban air are up to 10 to 100 times greater than the
concentrations in rural areas. Reported urban air concentrations range
between 0.2 and 19.3 ng/m^ (Pucknat 1981). Ambient B[a]P concentrations
in nonurban areas ranged from 0.1 to 1.2 ng/m^ (Pucknat 1981).
B[a]P has been detected in U.S. groundwater and surface water used
as drinking water sources, but the data are limited. B[a]P
concentrations in untreated water have been reported to range between
0.6 and 210 ng/L (EPA 1980). In treated waters, the concentrations have
been reported to range between 0.3 and 2.0 ng/L.
In soils, limited data indicate B[a]P concentrations in the range
of 40 to 1,300 fig/kg in relatively rural areas of the United States
(Blumer 1961).
B[a]P may occur in the soil and on particulate matter in the air
surrounding waste sites, such as former manufactured-gas plants and
creosote wood treatment plants. However, exposure levels at these sites
have not yet been published.
Data are not available that relate environmental levels to
significant health effects in humans following exposures.
2.2.3.2 Human exposure potential
Humans may be exposed to B[a]P in air, water, soil, and food, each
of which constitutes a normal route of background exposure. Much higher
exposure concentrations are associated with tobacco smoke and with some
occupational environments. At hazardous waste sites, humans will most
likely be exposed to B[a]P via contact with soil or inhalation of
particulate matter in air. Estimates of body doses or tissue levels
associated with B[a]P intake require (1) information on the chemical
concentrations in soil and air, (2) certain assumptions about factors
controlling intake, and (3) information on absorption of B[a]P from soil
or particulate matter.
Information on the first two of these data needs is relatively
site-specific and cannot be generalized across all sites. Quantitative
toxicological information on the absorption of B[a]P from soil or
particulate matter is limited, although absorption is expected to be low
(Becher et al. 1984). Consequently, estimates of dose following exposure
to B[a]P in soil or air are based on limited toxicological data and on
assumptions regarding dermal absorption of B[a]P from soil and
absorption of incidentally ingested B[a]P on soil or inhaled B[a]P on
particulate matter. Any risk assessment of potential health effects
following environmental exposures has some degree of uncertainty in view
of the necessary assumptions.
-------
Health Effects Summary 19
2.3 ADEQUACY OF DATABASE
2.3.1 Introduct ion
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of
significant human exposure for the substance and the
associated acute, subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and
chronic health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans."
This sectLon identifies gaps in current knowledge relevant to
developing levels of significant exposure for B[a]F. Such gaps are
identified for certain health effect end points (lethality,
systemic/target organ toxicity, developmental toxicity, reproductive
toxicity, and carcinogenicity) reviewed in Sect. 2.2 of this profile in
developing levels of significant exposure for B[a]P and for other areas
such as human biological monitoring and mechanisms of toxicity. The
present section briefly summarizes the availability of existing human
and animal data, identifies data gaps, and summarizes research in
progress that may fill such gaps.
Specific research programs for obtaining data needed to develop
levels of significant exposure for B[a]P will be developed by ATSDR,
NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs, 2.8 and 2.9, respectively.
The bars of full height indicate that there are data to meet at
least one of the following criteria;
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or "probable human carcinogen" by both EPA
-------
HUMAN DATA
SUFFICIENT
INFORMATION*
SOME
INFORMATION
NO
INFORMATION
dermal
LETHALITY ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOGENICITY
Z / TOXICITY TOXICITY
SYSTEMIC TOXICITY
* Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
NOTE: The adequacy of the database for the carcinogenicity of benzo[a]pyrene by the inhalation and dermal
routes of exposure has been assessed on the basis of human exposure to complex mixtures of chemicals
containing this compound, not on the basis of the compound alone.
Fig. 2.8. Availability of information on health effects of benzo{a]pyrene (human data).
-------
ANIMAL DATA
V SUFFICIENT
C INFORMATION*
SOME
INFORMATION
NO
INFORMATION
INHALATION
DERMAL
LETHALITY ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOGENICITY
Z / TOXICITY TOXICITY
SYSTEMIC TOXICITY
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
Fig. 2.9. Availability of informatioB on health effects of beuzoUJpyrene (animal data).
-------
22
Section 2
and the International Agency for Research on Cancer (IARC)
(qualitative), and the data are sufficient to derive a cancer
potency factor (quantitative).
3. For animal carcinogenicity, a substance causes a statistically
significant number of tumors in at least one species and the data
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause this
health effect via this exposure route.
Bars of half height indicate that "some" information for the end
point exists, but does not meet any of these criteria.
The absence of a column indicates that no information exists for
that end point and route.
2.3.2.2 Description of highlights of graphs
Figure 2.8 indicates that no data are available to establish
significant exposure levels for humans. Regressive verrucae were
reported following subchronic dermal application to human skin (Cottini
and Mazzone 1939); however, this study was seriously flawed, and the
dermal effects reported cannot be definitively linked to B[a]P. No other
data concerning the toxicity of B[a]P alone in humans following
inhalation, oral, or dermal exposures were located in the available
literature. Although reports of adverse health effects such as
carcinogenicity do exist for inhalation and dermal exposure to mixtures
of chemicals that include B[a]P, they provide inadequate information to
assess quantitatively the role of B[a]P alone and have, therefore, been
indicated as providing "some" data.
Figure 2.9 indicates the data available to establish significant
exposure levels for animals. A subchronic mouse study provided some but
inadequate data to establish a significant exposure level for the lethal
effects of B[a]P following oral exposure. In this study, 120 mg/kg/day
of B[a]P administered in the diet decreased survival time in a
"nonresponsive" strain of mice (Robinson et al. 1975). Half of the
deaths occurred within 15 days of dosing. However, only a single dose
was tested, and information is not available on the effects of lower
doses on survival times. No data are available concerning the effect of
B[a]P on lethality following dermal or inhalation exposures.
No data are available on the systemic toxicity of B[a]P following
inhalation or dermal exposures. Data are available in animals that
suggest that B[a]P may adversely affect the skin following acute and
subchronic dermal application (Bock and Mund 1958, Suntzeff et al. 1955,
Elgjo 1968). Because these studies failed to evaluate control groups,
conclusions concerning the dermal toxicity of B[a]P cannot be made. Some
data are available to suggest that intermediate oral exposures to B[a]P
adversely affected the hematopoietic system In a "nonresponsive" strain
of mice leading to death due to hemorrhage or infection (Robinson et al.
1975). Only one dose was tested, which resulted in death; therefore,
this study cannot be used to identify a LOAEL. No other data are
available concerning the systemic toxicity of B[a]P following dermal or
oral exposures. There are reports in the literature concerning B[a]P-
induced immune suppression following Intraperitoneal and subcutaneous
-------
Health Effects Summary 23
Injection of mice. However, reports concerning the inanunotoxlclty of
B[a]P following inhalation, oral, or dermal exposure could not be
located in the available literature.
Some (albeit inadequate) data are available to establish a
significant exposure level for the reproductive/developmental effects of
B[aJP following oral exposures. Based on a modified two•generation study
in mice, a LOAEL of 10 mg/kg/day was identified (MacKetizie and Angevine
1981). However, it must be emphasized that this study did not identify a
NOAEL. Therefore, the LOAEL may actually be lower than 10 mg/kg/day. The
fact that B[a]P causes developmental/reproductive effects is supported
by results from other studies conducted in rodents in which B[a]P was
administered orally or by injection. Ho information is available
concerning these effects following inhalation or dermal exposure.
Adequate data are available to assess the carcinogenicity of B[a]P
in animals. B[a]P is a well-studied, moderately potent carcinogen in
animals, for which dose-response data are adequate for all three routes
of exposure.
2.3.2.3 Summary of relevant ongoing research
Research is ongoing in the areas of B[a]P's molecular dosimetry as
well as its biological mechanisms of action for carcinogenesis including
DNA adduct formation and repair and potential for oncogene activation.
B[a]P has been listed in NTP's Fiscal Year 1986 Annual Plan and Review
of Current Department of Health and Human Services (DHHS), Department of
Energy (DOE), and EPA Research Related to Toxicology. B[a]P will be
tested by the following agencies: National Institute of Environmental
Health Sciences; the Food and Drug Administration (FDA) National Center
for Toxicological Research; National Institute of Arthritis, Diabetes,
and Digestive and Kidney Diseases; and EPA's Office of Research and
Development. A comparative potency method to assess quantitatively the
carcinogenic effects for PAHs is under development by the Carcinogen
Assessment Group, the Office of Solid Waste, the Office of Drinking
Water, and the Office of Air Quality Planning and Standards of the EPA
(EPA Contract Number 68-02-4403) and is being applied to the data
available for B[a}P.
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Toxicokinetics and mechanisms of action
The metabolism of B[a]P has been studied extensively in human
cells, tissue homogenates, and microsomal preparations. The
toxicokinetics profiles for inhalation exposure to B[a]P in animals have
been established. The role of metabolism in the absorption process has
been delineated. There is no information on the tissue distribution of
&[a]7 after oral administration, although the information available on
the toxicokinetics of B[a]P suggests that significant quantitative
differences in tissue distribution are not expected as a result of
different routes of administration.
B[a]P requires metabolic activation to exert its mutagenic and
carcinogenic effects. The initial steps in the proposed mechanism of
action of B[a]P-induced carcinogenesis involve metabolic formation of
-------
24 Section 2
bay-region diol epoxides followed by covalent interaction of these
reactive metabolites with DNA (Conney 1982).
2.3.3.2 Adequacy of data on biological monitoring
The biological monitoring techniques for quantifying DNA adducts or
hemoglobin adducts are limited, because inborn factors, environmental
chemistry, and drugs can alter the activity of the enzymes responsible
for converting B[a]P to the diol epoxides that bind to DNA or
hemoglobin. In addition, fluorescence spectrometry may measure other
compounds that can adduct to DNA or hemoglobin. There is a lack of
information concerning the use of these techniques in occupationally or
environmentally exposed individuals. Additional research should include
further investigation of the quantitative relationship between
hemoglobin adducts and DNA adducts and an examination of the formation
of adducts following occupational exposure.
The techniques that use immunoassays to determine the presence of
antibodies to adducts in blood have been tested in experimental animals
and humans (Perera et al. 1982, Harris 1985, Harris et al. 1985, Harris
et al. 1986, Haugen et al. 1986). This technique has shown an
association between sera positive for antibodies and occupational
exposure or smoking. The reliability of this method should be further
examined in other, nonoccupational, exposure situations.
The presence of B[a]P or B[a]P metabolites in urine is an
indication that exposure has occurred. However, in occupational studies,
the amount of B[a]P concentrated in the urine did not adequately reflect
environmental B[a]P concentrations (Becher and Bjorseth 1983). This
discrepancy was reported to result from the nonbioavailability of
particle-bound PAHs; therefore, this method should be further examined
for its applicability in other exposure situations (Becher et al. 1984).
In addition, the smoking of cigarettes results in human exposure to
PAHs, and the determination of biological levels of PAHs in smokers and
in the general population must be further examined to properly assess
environmental or occupational exposure.
2.3.3.3 Environmental considerations
The accuracy and precision of the analytical methods used to
measure ambient B[a]P are somewhat limited. But the current methods, if
properly conducted, are sufficient to record ambient levels of B[a]P.
However, some analytical methods are of limited sensitivity.
Information on the fate of B[a]P sorbed onto particulate matter in
air is, at present, unclear. The role of photochemical oxidation in the
removal of B[a]P from air needs to be elucidated. Also, additional
information on biodegradation processes and rates in terrestrial systems
is needed.
Only limited information is available on the interactions of B[a]P
with other chemicals typically found in the environment and at hazardous
waste sites. Consequently, risks associated with exposure to B[a]P in
the environment are not completely understood.
-------
Health Effects Suimnatry 25
Recent studies on the fate of B[a]P in the environment have been
published (e.g., Coover and Sims 1987, Bossert and Bartha 1986). It is
likely that additional research in this area is continuing.
-------
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
The chemical formula, structure, synonyms, and Identification
numbers for B[a]P are listed in Table 3.1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Important physical and chemical properties of B[a]P are given in
Table 3.2.
-------
28 Section 3
Table 3.1. Chemical identity of benzo[a]pyreiie
Chemical name: Benzofajpyrene (IARC 1983)
Synonyms: Benzo[def]chrysene; 3,4-benzopyrene, 3,4-benzpyrene;
benz[a]pyrene; BP; B[a]P (IARC 1983)°
Trade name: Not applicable
Chemical formula: C20H)j (IARC 1983)
Wiswesser line notation: L D6 B6666 2AB TJ (HSDB 1987)
Chemical structure:
Identification numbers:
CAS Registry No.: 50-32-8
NIOSH RTECS No.: DJ3675000
EPA Hazardous Waste No.: U022
OHM-TADS No.: 8200129
DOT/UN/NA/IMCO Shipping No.: Not available
STCC No.: Not available
Hazardous Substances Data Bank No.: 2554
National Cancer Institute No.: Not available
"Confusion exists in the literature concerning the naming of
this compound, mainly because two different systems (Richter
and IUPAC) of numbering the pyrene ring structure have been
used; the IARC reference, unfortunately, does not acknowledge
that this confusion exists and that the nomenclature of some of
the synonyms listed is incorrect.
-------
Chemical and Physical Information
Table 3.2. Physical and chemical properties of benzofajpyrene
Property
Value
References
Molecular weight
252,3 g/mol
IARC 1983
Color
Pale yellow; fluoresces
yellow-green in ultraviolet
light
IARC 1983,
CRC 1987
Physical state
Plates or needles
(recrystallized from
benzene/ligroin)
CRC 1987
Odor
Unknown
Melting point
179-179.3°C
CRC 1987
Boiling point
310-312°C (at 10 mm Hg)
495°C (at 760 mm Hg)
CRC 1987,
Aldrich 1986
Autoignition temperature
Unknown
Solubility
Water
3.8 X lO'6 g/L
EPA 1982,
Organic solvents
Sparingly soluble in
ethanol and methanol;
soluble in benzene,
toluene, xylene, acetone,
DMSO, and ether
IARC 1983
Biological fluids
Unknown
Density
1.351
Partition coefficients
Octanol-water (Kow)
1.15 X 106
EPA 1982
Log Kow
6.06
Soil-organic carbon-water
(*oc>
5.5 X 106
EPA 1982
Vapor pressure (25°C)
5.6 X 10"9 mm Hg
EPA 1982
Henry's law constant
4.9 X 10"7 atm-m3/mol
EPA 1982
Flash point
Unknown
Flammability limits
Unknown
Conversion factors0
1 ppm = 10.32 mg/m3
Verschueren 1983
"Calculated based on the ideal gas law, PV = nRT at 25°C.
-------
31
4. TOXICOLOGICA.L DATA
4.1 OVERVIEW
B[a]P ts readily absorbed by all routes of exposure. Absorbed Bla]P
is distributed rapidly throughout the body, metabolized to conjugated
derivatives, and eliminated.
B[a]P is a well-studied, well-established experimental carcinogen.
Its carcinogenicity has been demonstrated in laboratory animals by all
routes for which humans would normally expect to be exposed. In
addition, it has elicited tumors by several experimental routes of
exposure. B[a]P's carcinogenic mechanism of action is thought to result
from its metabolism to a reactive diol epoxide derivative prior to
conjugation and elimination. This derivative can interact with DNA. As a
result, B[a]P has been demonstrated to cause mutations in many
experimental systems. Mutation is considered a necessary (albeit
insufficient) step for the carcinogenic activity of B[a]F.
Few reports are available on the noncarcinogenic systemic effects
of B[a.|P in humans or experimental animals following inhalation, oral,
or dermal exposures. Occupational exposures to conrplex mixtures and
Industrial processes that incude PAHs have been evaluated by IARC
(1973). Toxic effects include a variety of skin lesions and noncancer
lung diseases such as bronchitis. However, It is not possible to
determine from those studies the effect of individual PAHs.
Lethality and decreased longevity have been reported in a
"nonresponsive" strain of mice (i.e., strains whose hepatic aryl
hydrocarbon hydroxylase activity is not induced by PAH) that were
exposed orally to high levels of B[a]P (120 mg/kg/day). Death appeared
to be caused by bone marrow depression leading to hemorrhage or
infection.
There are reports in the literature concerning the dermal toxicity
of B[a]P following acute applications to animal skin and subchronic
applications to human and animal skin. Because these studies failed to
employ control groups, definitive conclusions concerning the dermal
toxicity of B[a]P cannot be made.
Although there are no studies available on the reproductive/
developmental effects of B[a]P in humans, results from studies in
rodents Indicate that in utero exposure to B[a]P either by the oral
route or by injection is associated with developmental toxicity and
adverse reproductive effects. Adverse reproductive/developmental effects
resulted from oral exposures to doses of B[a]P as low as 10 mg/kg/day.
fi[a]P-induced immune suppression has been reported in mice and in
the offspring of mice treated intraperitoneally with B[a]P. However,
-------
32 Section 4
similar reports could not be located in the available literature
following inhalation, oral, or dermal exposures.
4.2 TOXICOKINETICS
4.2.1 Overview
B[a]P is readily absorbed by inhalation, oral, and dermal routes of
administration. Metabolism plays an important role in the absorption of
B[a]P via the lungs and the skin; intestinal absorption appears to be
less dependent on metabolic factors.
Absorbed B[a]P is rapidly distributed to several tissues.
Benzo[a]pyrene metabolites are subject to enterohepatic circulation as
evidenced by time-dependent increases in the intestinal tissue
concentrations of these intermediates.
The metabolism of B[a]P is complex and includes the formation of
proposed ultimate carcinogens, that is, B[a]P 7,8-diol-9,10-epoxide
(Fig. 4.1). A unified concept to explain and predict the carcinogenic
potential of polycyclic aromatic hydrocarbons has been proposed, based
on this mechanism of activation of B[a]P. This concept, the "bay-region"
theory, postulates that specific structural features may be used as an
indicator to predict the formation of diol epoxide metabolites and,
thus, the potential carcinogenicity of an aromatic hydrocarbon. The
"bay-region" theory does not preclude other activation mechanisms that
may result in the initiation of cancer but simply identifies a likely
pathway for activation. The formation of other reactive metabolites of
B[a]P generated under specific situations (i.e., free radical
intermediates) has also been demonstrated, although these pathways have
not been shown to be relevant to the in vivo toxicity of B[a]P.
4.2.2 Absorpt ion
4.2.2.1 Inhalation
Human. No quantitative information on the absorption of B[a]P via
the respiratory tract was found for human subjects. Absorption of B[a]P
via this route is inferred from the isolation of urinary metabolites of
B[a]P in subjects exposed to polycyclic aromatic hydrocarbons in an
industrial environment (Becher and Bjorseth 1983).
Animal. The biological fate and mechanisms of absorption of
inhaled B[a]P adsorbed on particles were studied in the rat (Sun et al.
1982). A [%] -benzo[a]pyrene concentration of 0.6 j*g/L adsorbed on
ultrafine Ga203 particles (diam -0.1 pm) was administered to rats as an
aerosol. A parallel study was conducted with a pure [^H]-B[a]P aerosol
(no carrier) at a concentration of 1 fig/L. Total exposure time for both
groups was 30 min. The amount of aerosol particles deposited in the lung
after termination of exposure was -20% for Ga203 (corresponding to 3%
[^H]-B[a]P) and -10% for the pure hydrocarbon aerosol. These values
represent the percentage of the total inhaled mass that was actually
deposited in the lungs. The excretion of hydrocarbon was monitored for
over 2 weeks at which time a nearly quantitative recovery of
radioactivity was obtained, indicating complete absorption of the
initially deposited hydrocarbon. Consistent with administration of B[a]P
-------
Toxicological Data 33
GSH conjugates
GLUCURONIDES
AND
SULPHATE ESTERS
GSH conjugates
7 6 5
BENZO [a] PYRENE
1° ^
t 0 X
GSH conjugates
©
o
PHENOLS
4.5-
7,8-
9.10-
©
©
t® e I,
V 7-
3- 9-
6-
O
0
QUINQNES
1.6
3.6-
6.12-
@
I
4.5-
7.8-
9.10-
9-OH-4.5-diol
6-OH-7,8-diol
t-(3-)OH-9,10-diol
GLUCURONIDES
ANO
SULPHATE ESTERS
| © ©
DIOL EPOXIDES
TETRAOLS
78-diol-9.C-epoxide
9, 'C-diol-7.8-epoxide
Fig. 4.1. Metabolic fate of benzofajpyrene. Source: IARC 1983.
-------
34 Section 4
by other routes, inhaled hydrocarbon was excreted predominantly in the
feces (94% for B[a]P on Ga203 particles and 86% for the pure aerosol).
Significant differences in the clearance times of Ga203-adsorbed and
pure B[a]P strongly suggested that a substantial amount of B[a]P coated
on Ga203 particles was cleared from the lungs by mucociliary clearance
and subsequent ingestion. The pure B[a]P aerosol particles retained by
the lungs were cleared by absorption into the blood stream. In contrast,
particle association of B[a]P increased its retention in the lung and
increased the relative amount of B[a]P that was cleared by mucociliary
action and subsequently ingested. This resulted in an increased
absorption of B[a]P in the alimentary tract and thereby increased the
dose of this compound and its metabolites to the stomach, liver, and
kidneys relative to pure B[a]P. Similar observations have been reported
by other workers (Creasia et al. 1976, Tornquist et al. 1985).
The effect of dose on the pulmonary clearance of B[a]P in the rat
was studied by intratracheal instillation of [^C]-B[a]P (16, 90, and
6,400 fig of hydrocarbon). Clearance was determined to be biphasic with a
fast component (half-life :£ 1 day) and a slow component (half-life ^ 1
day). As dose increased (16 to 6,400 pg B[a]P), an increased percentage
(from 89 to 99.76%) was cleared with a half-life < 1 day and a decreased
percentage (from 11 to 0.24%) with a half-life > 1 day (Medinsky and
Kampcik 1985). The slower component is clearly subject to saturation at
the high dose levels.
4.2.2.2 Oral
Human. No data on the absorption of B[a]P via the gastrointestinal
tract in human subjects were identified.
Animal. The gastrointestinal tract absorption of B[a]P was studied
in the rat. Carbon-14-labeled B[a]P (0.04 /anol, 0.4 jimol and 4,0 ;imol),
dissolved in peanut oil, was administered to rats by gavage (Hecht et
al. 1979). Absorption of hydrocarbon was determined by measuring
radioactivity in feces and urine. Total excretion of label in feces
averaged 74 to 79% from 0 to 48 h and 85% from 0 to 168 h; excretion in
urine was significantly less (1 to 3% of administered dose). The role of
metabolism in the excretion of B[a]P was briefly explored. The amount of
unchanged B[a]P excreted decreased as dose increased (13, 7.8, and 5.6%,
respectively) for the three doses studied.
The absorption of B[a]P from the gastrointestinal tract has been
reported to be enhanced in mice and cats when solubilized in vehicles
possessing both lipophilic and hydrophilic properties (Setala and Ekwall
1950, Ermalla et al. 1951). These vehicles can solubilize and stabilize
fat-soluble B[a]P in aqueous solution. Once B[a]P has entered the small
intestine it is solubilized by the bile salts and absorbed by the
epithelial cells of the small intestine (Laher and Barrowman 1983).
4.2.2.3 Dermal
Human. Dermal absorption of B[a]P through human skin (leg skin)
was determined under in vitro conditions (Kao et al. 1985). The extent
of permeation after 24 h was established as 3% of an applied dose of
[l^C] benzo[a]pyrene (10 jtg/cm^).
-------
Toxicological Data 35
Animal. The percutaneous absorption of l^C-B[a]P was studied in
adult Swiss Webster mice (Sanders et al. 1986). Absorption was measured
by analyzing radioactivity in excreta (feces and urine) and by analysis
of residual label at the site of application. Disappearance of
radiolabel from the application site was rapid: 6% (of an applied dose)
in 1 h and 40% in 24 h. After 7 days, 93% of the radioactivity was
recovered in excreta, mostly in the feces.
The skin penetration of an applied dose of [^C] B[a]P (10 pg/cw?-)
was determined in several mammalian species under in vitro conditions
(Kao et al. 1985). Dorsal skin from marmoset, guinea pig, rabbit, rat,
and mouse were used for the permeation experiments. The mouse showed the
highest permeation at 10% (24 h), followed by the rat, rabbit, and
marmoset (1 to 3%); the guinea pig exhibited the lowest permeation at
0.1%. The authors (Kao et al. 1985) suggested that first-pass cutaneous
metabolism was an important factor in determining the extent of B[a]P
penetration through the skin. They consider that, in addition to
diffusion, metabolic pathways play a decisive role in the percutaneous
absorption of B[a]P.
4.2.3 Distribution
Absorbed B[a]P is rapidly and widely distributed among several
tissues. Hydrocarbon levels in the various tissues reflect the influence
of the route of administration, vehicle formulation (if any), and
metabolism.
There is no quantitative information available concerning the
distribution of B[a]P after oral administration. Indirect evidence is
available from inhalation experiments on rats for which a significant
contribution from ingestion of B[a]P (coated or particles) was
established (Sun et al. 1982).
Absorption and distribution of inhaled B[a]P is rapid; maximum
levels of radioactivity found in the liver, esophagus, small intestine,
and blood were detected 30 min after exposure. After 12 h, maximum
levels of radioactivity were detected in the cecum, stomach, and large
intestine.
The distribution pattern for inhaled Ga203 particles coated with
B[a]P was similar. However, there were significant differences in the
levels of B[a]P delivered to the different tissues. In most cases,
absorption of B[a]P from Ga203 particles led to higher levels of
hydrocarbon. An explanation advanced to explain these differences was
that inhalation of B[a]P adsorbed on insoluble particles is cleared
predominantly by mucociliary transport and ingestion. This latter
mechanism of absorption leads to the increased levels in the liver and
kidneys. An additional conclusion is that B[a]P absorbed via the
intestinal tract is distributed in an analogous pattern to inhaled
B[a]P.
The disposition of [3H]-B[a]P in rats following intratracheal
instillation was reported by Weyand and Bevan (1986). The percentages of
dose detected in various tissues were: at 5 min, lungs (59%), carcass
(14%), liver (12.5%), blood (3.9%), and intestines (1.9%); at 60 min,
lungs (15%), carcass (27%), liver (17%), blood (1.6%), and intestines
-------
36 Section 4
(9.9%); and at 360 min, lungs (5%), carcass (21.5%), liver (4.6%), blood
(1.7%), and intestines (14.9%). The percentages include both parent
hydrocarbons and metabolites. The systemic availability of unchanged
B[a]P administered intratracheally was lower relative to B[a]P delivered
intravenously. The reduction was attributed to a significant
contribution of lung enzymes to metabolism of B[a]P.
The data in this study (Weyand and Bevan 1986) and others (Sun et
al. 1982, Mitchell 1982) provide evidence for the enterohepatic
circulation of B[a]P metabolites. The concentration of B[a]P metabolites
in the intestines increases with time, suggesting active intestinal
reabsorption.
4.2.4 Metabolism
Mammalian metabolism of B[a]P follows the general scheme
established for smaller aromatic hydrocarbons (Williams 1959). This
general scheme involves initial oxidative and hydrolytic steps,
collectively known as Phase I metabolism, and subsequent conjugation of
Phase I metabolites with glutathione, sulfate, or glucuronic acids to
form Phase II metabolites. Typically, for PAH, Phase I
biotransformations are considered activating steps because of the
reactive nature of the metabolites that can be formed; Phase II
transformations are considered detoxifying steps, since these conjugated
metabolites are suitable for excretion and are removed from the system
(Cooper et al. 1983, Levin et al. 1982, Thakker et al. 1985).
The metabolism of B[a]P has been studied both in vitro and in vivo
(Sims and Grover 1974). The use of in vitro systems was justified by
comparing the profiles of Phase I metabolites excreted in vivo with
those generated under in vitro conditions and noting the similarities.
The observed differences are due to the absence of conjugating systems
under in vitro conditions. The most commonly used in vitro system is the
rat liver microsomal fraction, although numerous other species have been
used (Sims and Grover 1974). More recently, the use of cells and
cultured tissues has allowed the study of both Phase I and Phase II
metabolism under in vitro conditions.
The metabolism of B[a]P in human tissues has received considerable
attention. Studies have been conducted using bronchus (Cohen et al.
1976), colon (Autrup et al. 1978), kidney (Prough et al. 1979), liver
(Selkirk et al. 1975a), lung (Prough et al. 1979, Mehta et al. 1979),
lymphocytes (Selkirk et al. 1975b), macrophages (Marshall et al. 1979),
skin epithelium (Fox et al. 1975), tracheobronchial tissue (Autrup et
al. 1980), mammary epithelial cells (Bartley and Stampfer 1985), bladder
(Selkirk et al. 1983), and esophagus (Harris et al. 1979).
In general, similar metabolites are formed from B[a]P in the many
microsomal, cell, and cultured tissue preparations that have been
examined. There are differences in the relative levels and rates of
formation of specific metabolites among tissues and cell preparations
used and among animal species and strains. These differences are
susceptible to change as a result of pretreatment of the animals with
either inducers or inhibitors of particular enzymes. The metabolism of
B[a]P is summarized in Fig. 4.1. B[a]P is metabolized initially by the
microsomal cytochrome P-450 monoxygenase system to several arene oxides
-------
ToxicoLogical Data 37
(reaction 1, Fig. 4.1). Once formed, these arene oxides may rearrange
spontaneously to phenols (reaction 3), undergo hydration to the
corresponding trans-dihydrodiols in a reaction catalyzed by microsomal
epoxide hydrolase (reaction 4), or react covalently with glutathione,
either spontaneously or in a reaction catalyzed by cytosolic glutathione
5-transferases (reaction 5). Phenols may also be formed by the
cytochrome P-450 monooxygenase system by direct oxygen insertion
(reaction 2), although unequivocal proof for this mechanism is lacking.
6-Hydroxybenzo[a]pyrene is further oxidized either spontaneously or
metabolically to the 1,6-, 3,6-, or 6,12-quinones (reaction 6), and this
phenol is also a presumed intermediate in the oxidation of B[a]P to the
three quinones catalyzed by prostaglandin endoperoxide synthetase.
Evidence exists for the further oxidation metabolism of two additional
phenols: 3-hydroxybenzo[a]pyrene is metabolized to the 3,6-quinone
(reaction 6), and 9-hydroxybenzo[a]pyrene is oxidized to the K-region
4,5-oxide, which is hydrated to the corresponding 4,5-dihydrodiol
(reaction 7). The phenols, quinones, and dihydrodiols can all be
conjugated to glucuronides and sulphate esters (reactions 8-10); the
quinones also form glutathione conjugates (reaction 11).
In addition to being conjugated, the dihydrodiols undergo further
oxidative metabolism. The cytochrome P-450 monooxygenase system
metabolizes B[a]P 4,5-dihydrodiol to a number of uncharacterized
metabolites, while the 9,10-dihydrodiol is metabolized predominantly to
its 1- and/or 3-phenol derivative (reaction 12) with only minor
quantities of a 9,10-diol, 7,8-epoxide being formed (reaction 14). In
contrast to 9,10-dihydrodiol, metabolism of B[a]P 7,8-dihydrodiol is to
a 7,8-diol, 9,10-epoxide (reaction 14), and phenol-diol formation is a
relatively minor pathway. The diol epoxides can be conjugated with
glutathione either spontaneously or by glutathione S-transferase-
catalyzed reaction (reaction 15). They may also hydrolyze spontaneously
to tetraols (reaction 16, although epoxide hydrolase does not catalyze
the hydration).
The primary oxidative metabolites of B[a]P are substrates for
further oxidative metabolism by the cytochrome P-450 dependent
monooxygenase system (Levin et al. 1982, Cooper et al. 1983, Ribeiro et
al. 1985). B[a]P 7,8-diol-9,10-epoxide has been established as an
ultimate carcinogen. The conversion of B[a)P oxides to trans-
dihydrodiols is catalyzed by epoxide hydrolase (Jerina and Daly 1974,
Sims and Grover 1974); the stereochemistry of the steps leading to the
formation of dihydrodiols has been elucidated and plays an important
role in their toxicity. The sequence of reactions leading to B[a]P 7,8-
diol-9,10-epoxide from B[a]P proceeds with varying degrees of
stereoselectivity (Thakker et al. 1977). The pathways leading to
stereoisomeric diol epoxides of B[a]P are shown in Fig. 4.2. There are
significant differences in the mutagenic and carcinogenic activities of
diastereomeric and enantiomeric intermediates. (+)-Diol epoxide-2 is the
major stereoisomer formed by rat liver microsomes (Jerina et al. 1980,
1976). The significance of this finding is that this isomer has high
tumorigenic activity (Levin et al. 1982) and gives rise to the major
adduct formed upon reaction with DNA. The structure of this adduct has
been established as a diol epoxide-deoxyguanosine adduct where
alkylation takes place at the exocyclic nitrogen (N-2) of
-------
38 Section 4
M-BP 7.8-OXDC
{ ~ ) - BP 7.0 - DIHYOROOIOL
(~-BP 7 0-DOL fi.fj EPOXIDE-?
o
(-}»BP 7,0-DOL B O CPOXKJf
°>
OH
(~)-BP 78-OOL ft © FPOXiDf -f
OH
H*BP 7.8-DtOL 9 O tPOXf)F-2
ADAPTED FROM LEVIN ET AL. (1960) 94 (ARC (1983). Absolute stereochemistry of all metabolites is as shown. Heavy arrows indicate
the predominant pathways. Dlo4 epoxides exist as diastereoisomeric pairs in which the benzyKc hydroxyl group and the epoxide oxygen are
either da (variously called did epoxide 1, dkX epoxide 2, or syrvdiol epoxide) or trans (variously called dioi epoxide 2, did epoxide 1, or
anti-did epoxide).
Fig. 4.2. Stereoselective metabolism of benzo[a]pyreiie to an ultimate carcinogenic metabolite by
rat liver microsomes.
-------
Toxicological Data 39
deoxyguanosine. This diol epoxide-deoxyguanosine has been isolated from
several animal species (Horton et al. 1985, Autrup and Seremet 1986) and
human tissue preparations (Harris et al. 1979).
The formation of Phase II metabolites from epoxides, dihydrodiols,
phenols, and diol epoxides is generally believed to constitute a
detoxication step leading to the elimination of the hydrocarbon
metabolites. Enzyme systems active in the conjugative metabolism of
B[a]P include the UDP-glucuronyl transferase (Cooper et al. 1983),
sulfate transferase (Moore and Cohen 1979), and glutathione transferase
(Grover 1977, Hernandez et al. 1980).
The formation of B[a)P 7,8-diol-9,10-expoxide from B[a]P 7,8-diol
can also be catalyzed by the prostaglandin synthetase system. In the
presence of arachidonic acid, this microsomal enzyme catalyzes the
formation of diol epoxide-2 from racemic 7,8-dihydrodiol (Panthanickal
and Marnett 1981). The activity of the prostaglandin is low in the
liver, but significant levels are found in the lung; the highest
activity is found in seminal vesicles. The importance of this pathway in
the in vivo metabolic formation of tumorigenic diol epoxides from 7,8-
diol remains an open question.
Elucidation of the mechanistic aspects of the metabolic steps
leading to the formation of B[a]P 7-8-diol-9,10-epoxide and the
identification of this intermediate as an ultimate carcinogen suggested
a unified concept to explain and predict the carcinogenic potential of
other polycyclic aromatic hydrocarbons. This concept, known as the "bay
region" theory (Jerina et al. 1980), stipulates that epoxides on
saturated angular benzo-rings (bay region or phenanthrene-like
structure) should exhibit high chemical reactivity if the epoxide is
located in the bay region. This premise is supported by molecular
orbital calculations that predict the ease of formation of carbonium
ions by ring opening of bay-region epoxides (Jerina and Lehr 1977,
Mohammad 1985). This chemical reactivity is reflected in biological
activity, and thus bay-region diol epoxides are likely candidates as
ultimate carcinogens of a series of polycyclic aromatic hydrocarbons.
4.2.5 Excretion
Metabolism of B[a]P is a prerequisite for hepatobiliary excretion
and elimination through the feces, regardless of the route of
administration. The rate-determining step in the biliary excretion of
B[a]P administered intravenously has been shown to be metabolism and not
biliary transport (Schlede et al. 1970). Because of "first-pass"
metabolism in the liver, orally administered B[a]P would be expected to
show an enhanced rate of excretion relative to other administration
routes. B[a]P and its metabolites are reabsorbed by enterohepatic
circulation (Chipman et al. 1982). The time required to recover
administered B[a]P in the feces roughly follows the sequence according
to route of administration: dermal ^ lung 2: oral.
-------
40 Section 4
4.3 TOXICITY
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Overview
Pertinent data about lethality and decreased longevity in humans
following exposure to B[a]P could not be found in the available
literature.
Lethality data for experimental animals acutely exposed to B[a]P by
the inhalation, oral, and dermal routes could not be found in the
available literature. The effects of subchronic oral exposure to B[a]P
were a decreased survival time in "nonresponsive" strains of mice (i.e.,
strains whose hepatic aryl hydrocarbon hydroxylase activity is not
induced by PAH when compared with corresponding controls) (Robinson et
al. 1975). Half of the deaths occurred within 15 days of dosing. Death
appeared to be caused by bone marrow depression, leading to hemorrhage
or infection.
4.3.1.2 Inhalation
Pertinent data about lethality and decreased longevity resulting
from inhalation exposure of humans or experimental animals to B[a]P
could not be found in the available literature.
4.3.1.3 Oral
Human. Pertinent data about lethality and decreased longevity
resulting from oral exposure of humans to B[a]P could not be found in
the available literature.
Animal. Pertinent data about the acute oral toxicity of B[a]P in
experimental animals could not be found in the available literature.
Robinson et al. (1975) investigated the effects of oral
administration of B[a]P on the life spans of several inbred strains of
mice. Strains of mice were classified as either "responsive" or
"nonresponsive," based on the strain's susceptibility to the induction
of cytochrome P-450 and associated enzymes by PAHs. The strains tested
differed at a gene site generally described as the Ah locus. The
responsive strains tested were C57B1/6, C3H/HeN, and BALB/CAnN. The
nonresponsive strains were DBA/2 and AKR/N. Treatment groups, consisting
of 30 animals/strain, were fed a laboratory diet ad libitum, which had
been soaked in corn oil containing B[a]P; the estimated oral dose was
-120 mg/kg/day. Responsive and nonresponsive control groups, each
consisting of 30 animals, were fed the same diet which had been soaked
in unadulterated corn oil. The number of deaths were observed for a
180-day period. Following oral administration of 120 mg/kg/day B[a]P for
up to 6 months, survival time of all nonresponsive mice was shortened
significantly when compared to corresponding controls, while survival
time of treated responsive mice was not significantly different from
their corresponding paired control. Among the "nonresponsive" strains,
all of the mice in the treatment groups died, with at least half the
deaths occurring within 15 days. Only two mice died in the
"nonresponsive" control group (DBA/2) over the same period of time.
-------
Toxicological Data 41
Death appeared to be caused by bone marrow depression (aplastic anemia;
pancytopenia) leading to hemorrhage or infection. The authors concluded
that decreased survival was associated with a single gene difference in
aromatic hydrocarbon responsiveness.
4.3.1.4 Dermal
Pertinent data about lethality and decreased longevity resulting
from dermal exposure of humans or experimental animals to B[a]P could
not be found in the available literature.
4.3.1.5 General discussion
Pertinent data about lethality and decreased longevity in humans
exposed to B[a]P could not be found in the available literature.
Lethality and decreased longevity have been reported in "nonresponsive"
strains of mice following subchronic oral exposure to 120 mg/kg body
weight B[a]P and in "responsive" mice following a single intraperitoneal
dose of 500 mg/kg body weight B[a]P (Robinson et al. 1975). No LD50
values have been reported for experimental animals exposed by the oral
or dermal routes of exposure, nor have LC50 values been reported for
experimental animals exposed to B[a]P by inhalation. The acute lethality
of B[a]P has been investigated following intraperitoneal injection. The
LD5O for B[a]P administered intraperitoneally to male B6C3F1 mice is
-250 mg/kg body weight (Salamone 1981).
4.3.2 Systemic/Target Organ Toxicity
4.3.2.1 Overview
Few reports are available on the systemic effects of B[a]P in
humans or experimental animals. Occupational exposures to complex
mixtures and industrial processes that include PAHs have been evaluated
by IARC (1973); however, it is not possible to determine from these
studies the effects of individual PAHs. In addition, systemic toxicity
associated with B[a]P exposure is generally not evident, except at doses
sufficient to produce a high tumor incidence in experimental animals.
Regressive verrucae were reported following subchronic dermal
application of B[a]P to human skin (Cottini and Mazzone 1939). However,
this study was seriously flawed in that B[a]P was dissolved in benzene
and a benzene control was not evaluated. Therefore, the dermal effects
reported in this study may have been due to the benzene vehicle.
In a subchronic oral animal study, B[a]P adversely affected the
hematopoietic system of a "nonresponsive" strain of mice leading to
death due to hemorrhage or infection (Robinson et al. 1975). Alterations
in epidermal cell growth following subchronic dermal application of
B[a]P to the skin of hairless mice have also been reported (Elgjo 1968).
However, the latter experiment was flawed in that no acetone-vehicle
control was evaluated. Therefore, the dermal effects reported in this
study may in fact be due to the acetone vehicle, rather than the B[a]P.
There are a number of older reports in the literature that show that
topical application of B[a]P for an acute exposure period (e.g., 4 days)
suppresses sebaceous glands in mouse skin (Bock and Hund 1958, Suntzeff
et al. 1955). These studies also did not employ control groups;
-------
42 Section 4
therefore, it is not possible to determine if the effects seen were due
to the solvent and/or the preparation procedures.
There are reports in the literature concerning the immunotoxicity
of B[a]P following intraperitoneal and subcutaneous injection. B[a]P-
induced immune suppression was reported in male B6CF1 mice (Lyte and
Bick 1985) and in the offspring of C3H/Anf mice treated
intraperitoneally with B[a]P (Urso and Gengozian 1980). Subcutaneous
injections of B[a]P in female B6C3F1 mice produced a dose-related
suppression of antibody production to both T-cell-independent and T-
cell-dependent antigens (White and Holsapple 1984). Reports concerning
the immunotoxicity of B[a]P following inhalation, oral, or dermal
exposure could not be found in the available literature.
No other reports were found in the available literature concerning
the systemic toxicity of B[a]P.
4.3.2.2 Hematopoietic toxicity
Overview. Hematopoietic effects (e.g., aplastic anemia,
pancytopenia) of B[a]P have been reported in a "nonresponsive" strain of
mice following subchronic oral exposure to 120 mg/kg body weight B[a]P
(Robinson et al. 1975). Hematopoietic effects of B[a]P have not been
reported in humans.
Inhalation. Pertinent data about the hematopoietic toxicity of
B[a]P in humans or experimental animals following inhalation exposure
could not be found in the available literature.
Oral. Pertinent human data about the hematopoietic toxicity of
B[a]P resulting from oral exposure could not be found in the available
literature.
As stated (see Sect. 4.3.1.3 on oral toxicity), aplastic anemia and
ultimately death in experimental animals have been linked to subchronic
oral exposures to 120 mg/kg body weight B[a]P (Robinson et al. 1975).
Dermal. Pertinent data about the hematopoietic toxicity of B[a]P
following dermal exposure of humans or experimental animals could not be
found in the available literature.
General discussion. Results from one experiment suggest that
decreased survival in a "nonresponsive" strain of mice following
subchronic oral exposure to B[a]P appeared to be caused by bone marrow
depression (i.e., aplastic anemia, pancytopenia). The investigators
concluded that decreased survival in "nonresponsive" versus "responsive"
mice was associated with a single gene difference in aromatic
hydrocarbon responsiveness reflected as ability to induce aryl
hydrocarbon hydroxylase and consequently activate B[a]P to its reactive
metabolite. No other data regarding the hematopoietic toxicity of B[a]P
in humans or in experimental animals were found in the available
literature, regardless of the route of exposure.
4.3.2.3 Dermal toxicity
Overview. There are reports in the literature concerning the
dermal toxicity of B[a]P following acute applications to animal skin and
subchronic applications to human and animal skin. However, these studies
-------
Toxicological Data 43
failed to employ control groups, and, therefore, definitive conclusions
concerning the dermal toxicity of B[a]P cannot be made. No data on oral
and inhalation exposures of humans or experimental animals to B[a]P were
found in the literature.
Inhalation. Pertinent data about the dermal toxicity of B[a]P
following inhalation exposure of humans or experimental animals could
not be found in the available literature.
Oral. Pertinent data about the dermal toxicity of B[a]P following
oral exposure could not be found in the available literature.
Dermal. Cottini and Mazzone (1939) applied a 1% solution of B[a]P
in benzene to small areas of exposed and unexposed skin in 26 human
patients. Up to 120 daily applications were applied in 4 months.
Regressive verrucae developed in all 26 patients within this time.
Although reversible and apparently benign, the changes were thought to
represent early stages of neoplastic proliferation. Similar cases of
epidermal changes were reported by Rhoads et al. (1954) and Klar (1938)
in men accidentially exposed to B[a]P. However, it should be emphasized
that the experiment conducted by Cottini and Mazzone (1939) is seriously
flawed in that B[a]P was applied as a 1% solution in benzene and no
benzene control was evaluated. In addition, due to the lack of adequate
information regarding dose quantification, significant human exposure
levels cannot be developed from these studies.
Effects of B[a]P on the skin of patients with preexisting dermal
conditions of periphigus vulgaris and xeroderma pigmentosum were also
tested by Cottini and Mazzone (1939). Following 20 applications of
B[a]P, patients with periphigus developed local bullous eruptions
characteristic of the disease. The patients having xeroderma pigmentosum
were exposed to 85 applications. Only pigmentary and slight verrucous
effects were exhibited. Additional tests were conducted on patients with
preexisting active skin lesions due to squamous cell cancer. Initial
results indicated a general improvement and/or retardation of the
lesion; in one case, an actual analgesic effect was observed. The
severity of the manifestation on abnormal skin appeared to be related to
age. That is, those in the lowest age range exhibited fewer and less
severe effects than those in the mid-range groups, and so on. No such
age relationship on effects involving those patients with normal or
preexisting skin lesions was noted.
In a number of older investigations, topical application of B[a]P
has been reported to suppress or even destroy sebaceous glands in mouse
skin (Bock and Mund 1958). Bock and Mund (1958) applied 0.2 mL of B[a]P,
twice daily, to two-thirds of the shaved backs of Swiss mice. Four days
after the last application, the mice were sacrificed. The treated skin
was then subjected to an elaborate preparation and staining procedure
and was qualitatively examined. B[a]P was reported to suppress sebaceous
glands. However, controls were not employed; therefore, it is not
possible to determine if the effects seen were due to the solvent and/or
the preparation procedures. In vitro preparations of mouse skin have
also been reported to undergo degeneration of sebaceous glands following
exposure to B[a)P (Suntzeff et al. 1955). These studies also failed to
employ control groups.
-------
44 Section 4
Alterations in epidermal cell growth after dermal application in
mice of B [ajP were reported by Elgjo (1968). In this study 0.05 mL of a
1% B[a)P solution was demally applied to the interscapular area of
hairless mice. Groups of eight mice were sacrificed 1, 2, 4, 7, and 14
days following application. Increases in cellular mitotic rates, mitotic
counts, and mitotic duration that, according to the authors, were
indicative of a regenerative reaction were observed. All values for
these parameters were higher than normal values supplied by the author;
however, concurrent controls were not utilized. The authors concluded
that the alterations in the kinetics of epidermal cell growth produced
by B[a]P were more sustained than after application of croton oil. The
study by Elgjo (1968) is limited for drawing conclusions concerning the
dermal toxicity of &[a]P in that (1) experimental data were compared
with historical controls only, (2) no acetone-vehicle control was
evaluated, and (3) the statistical significance of the increased values
was not determined. Therefore, a LOAEL for dermal effects cannot be
identified from this study.
General discussion. No data on oral and inhalation exposures to
B[a]P producing toxic effects in humans or experimental animals were
found in the literature. Conclusions concerning the dermal toxicity of
B[a]P following dermal exposures cannot be made. Regressive verrucae
were noted to have occurred in 26 patients within a 4-month period when
they were given daily applications of a 1% solution of B[a]P (Cottini
and Mazzone 1939). This study did not employ a control group; therefore,
definitive conclusions concerning the dermal toxicity of B[a]P cannot be
made. However, occupational exposures to complex mixtures and industrial
processes that include PAHs have been evaluated by IARC (1973). Toxic
effects included a variety of skin lesions and noncancer lung diseases
such as bronchitis. However, it is not possible to determine from these
studies the effect of individual PAHs.
A single subchronic dermal study conducted in hairless mice
suggests that dermal application of 0.05 mg of a 1% B[a]P solution had
adverse effects on the skin (Elgjo 1968). This study did not employ a
control group; therefore, definitive conclusions concerning the dermal
toxicity of B[a]P cannot be made. In a number of older investigations,
acute topical application (e.g., 4 days) of B[a]P has been reported to
suppress or even destroy sebaceous glands in mouse skin (Bock and Mund
1958, Suntzeff et al. 1955). These studies also did not employ control
groups; therefore, it is not possible to determine If the effects seen
were due to solvent and/or the preparation procedures.
No other studies were identified in the literature concerning the
dermal toxicity of B[a]P by any other routes of administration.
4.3.3 Reproductive and Developmental Toxicity
4.3.3.1 Overview
There are no studies available on the reproductive/developmental
effects of B[a]P in hunans. The reproductive/developmental toxicity of
B[a]P following inhalation or dermal exposure has not been investigated
in experimental animals. The results of two oral studies in mice
(MacKenzie and Angevine 1981, Legraverend et al. 1984) and one In rats
-------
Toxicological Data 45
(Rigdon and Rennels 1964) indicate that in utero exposure to B[a]P is
associated with developmental toxicity and adverse reproductive effects.
A modified two-generation oral study in mice demonstrated the
reproductive toxicity of B[a]P, which included a decreased fertility
index and a high incidence of sterility in progeny (Mackenzie and
Angevine 1981). Developmental toxicity was also observed; the mean pup
weight of mice was significantly different from the controls. Other
investigators have reported an increased incidence of stillbirths,
resorptions, and malformations in selected mouse strains occurring
following oral exposure (Legraverend et al. 1984). These investigators
indicated that B(a]P-induced in utero toxicity and teratogenicity are
directly related to the maternal and/or embryonal genotype controlled by
the Ah locus (Legraverend et al. 1984).
4.3.3.2 Inhalation
Pertinent data about the reproductive and developmental toxicity of
B[a]P in humans or experimental animals following inhalation exposure
could not be found in the available literature.
4.3.3.3 Oral
Pertinent data about the reproductive and developmental toxicity of
B[a]P in humans following oral exposure could not be found in the
available literature.
Rigdon and Rennels (1964) conducted two series of experiments in
rats to examine the effect of dietary B[a]P on reproductive
consequences. The studies are suggestive of a reproductive effect of
B[a]P; however, the small numbers of animals used in this experiment do
not permit any firm conclusions. In the first experiment, 8 male and 8
female rats were administered 1 mg of B[a]P per gram of food. Control
groups consisting of 6 males and 6 females were fed a standard diet.
Treated females were mated with control males, and control females were
mated with B[a]P-treated males. Vaginal smears were taken during a 28-
day period beginning with the first day of B[a]P feeding. No treatment-
related effects on estrus were observed. Of the treated females, 5
became pregnant compared to 3 pregnant controls. However, only 1 of the
treated females delivered; it delivered a total of 4 pups. Two of the 4
pups were stillborn; one was grossly malformed. The pups born alive died
3 days postpartum, presumably of starvation. In the second experiment, 7
control male and female rats were mated as were 7 B[a]P-fed males and
females. Control rats had normal pregnancies. Only 2 B[a]P-fed females
of 7 mated became pregnant. An autopsy revealed that 1 dam carried 4
dead fetuses and that fetal resorption occurred in the other. Rigdon and
Neal (1965) did not find deleterious reproductive/developmental effects
in Swiss mice fed diets containing 0.25, 0.50, or 1.0 mg B[a]P per gram
of food over various time spans during mating, gestation, and
postpartum.
Sheveleva (1978) administered B[a]P by gavage to rats at doses of
0, 0.05, 0.5, or 5 mg/kg/day on days 1-15, 3-4, or 9-10 of pregnancy.
The dams receiving 0.5 and 5 mg/kg on days 1-15 showed signs of maternal
toxicity including decreased weight gain and hematological changes. At
these doses there were dose-related increases in preimplantation and
-------
46 Section 4
postimplantation losses, decreased live fetuses/dam, and decreased fetal
weights on day 20. At all dose groups, fetuses shoved hydronephrosis and
bladder dilation. When Bfa]P was administered on days 3-4 and 9-10,
postimplantation losses and decreased fetal weights were reported. It is
not clear if those results applied to all three dose levels. These
experiments provide suggestive evidence that B[a]P produces adverse
reproductive/developmental effects in rats at doses that are not
associated with maternal toxicity. However, no quantitative data were
reported; therefore, the results cannot be validated.
Mackenzie and Angevine (1981) investigated the effects of B[a]P on
pregnancy maintenance and on fetal development and survival. Groups of
CD-I mice were administered daily oral (intubation) B[a]P doses of 0,
10, 40, or 160 mg/kg maternal body weight from the 7th to 16th days of
gestation. There were 30 to 60 females per dose group. No maternal
toxicity was observed at any dose tested. The mean litter size was
comparable among groups, and all litters appeared normal by gross
observation. The percentage of pregnant females and viable litters at
parturition was significantly reduced in the 160 mg/kg/day dosage group.
The mean pup weight by 42 days of age was significantly different from
controls in all three groups administered B[a]P. The Fl progeny were
bred to untreated animals and further studied for postnatal development
and reproductive function. The fertility index was significantly
decreased for Fl males and females in all treatment groups. Total
sterility was observed in Fl males from the 160 mg/kg/day treatment
group and in Fl females from both the 40 and 160 mg/kg/day treatment
groups. Fertility was severely reduced in animals in the 10 mg/kg/day
dose group; the mean number of litters and litter size of Fl females in
this group were significantly lower than in the controls. This
infertility was associated with significant alterations in gonadal
morphology and germ-cell development. There was a significant decrease
in testicular weight, atrophic seminiferous tubules, and germ-cell
aplasia. Host of the females had no ovaries or only remnants of ovarian
tissue. Ovarian tissue in females exposed to 10 mg/kg/day was
hypoplastic with reduced follicles and corpora lutea. There were no
gross abnormalities in the F2 offspring from the Fl breeding studies and
no significant differences among treatment groups in the F2 offspring
body weights at 4 and 20 days of age. The authors concluded that in
utero exposure to B[a]P at doses of 10 mg/kg/day throughout the period
of major organogenesis resulted in impaired reproductive capacity and
developmental effects in male and female mice. Based on this study, a
L0AEL for reproductive toxicity and developmental effects of 10
mg/kg/day was determined. The study by Mackenzie and Angevine (1981) was
generally well conducted, and the data were appropriately analyzed;
however, treated fetuses were not examined for skeletal effects and
effects on other internal organs. A NOAEL could not be identified.
The effect of genetic differences in B[a]P metabolism on in utero
toxicity and teratogenicity has been evaluated by the oral route
(Legraverend et al. 1984). B[a]P metabolism occurs more readily in mice
that are genetically Ah-responsive than in those that are Ah-
nonresponsive. Legraverend et al. (1984) fed pregnant mice, either
B6AKF1 Ah-responsive or AKR/J Ah-nonresponsive, -120 mgAg/day B(a]P on
days 2 through 10 of gestation. Control mice received food soaked in the
-------
Toxicologlcal Data 47
corn oil vehicle alone. /)-Naphthoflavone was given intraperitoneally on
day 16 of gestation in order to help distinguish between fetuses of
different Ah-genotypes. Oral B[a]P treatment in the AKR/J mouse resulted
in more stillbirths, resorptions, and malformations among Ah-
nonresponsive compared with the Ah-responsive embryos. No differences in
in utero toxicity or teratogenicity were observed in Ah-genetically
different litter mates from an Ah-responsive mother. Legraverend et al.
(1984) concluded that the differences are specific to the route of
administration and can be attributed to "first-pass" liver metabolism
occurring with oral dosing. Although this was a well-designed and well-
conducted experiment, only one dose group was evaluated in this study,
and no quantitative comparisons between treated groups and corresponding
control animals were presented for any of the reported in utero toxic or
teratogenic effects.
4.3.3.4 Dermal
Pertinent data about the reproductive and developmental toxicity of
B[a]P in humans or experimental animals following dermal exposure could
not be found in the available literature.
4.3.3.5 General discussion
There are no studies available on the reproductive/developmental
effects of B[a]P in humans. Placental transfer of B[a]P has been shown
in the mouse (Shendrikova et al. 1974, Shendrikova and Aleksandrov 1974)
following intravenous injection and oral administration, respectively.
The results of two oral studies in mice (Mackenzie and Angevine 1981,
Legraverend et al. 1984) and one in rats (Rigdon and Rennels 1964)
indicate that in utero exposure to B[a]P is associated with
developmental toxicity and adverse reproductive effects. Adverse
developmental/reproductive effects resulted from oral exposure to doses
of B[a]P of 10 mg/kg/day (Mackenzie and Angevine 1981). Investigations
by Legraverend et al. (1984) suggest that it is B[a]P and not a
metabolite of B[a]P which is responsible for these adverse effects. No
data were available in experimental animals regarding the reproductive
and developmental effects of B[a]P following inhalation or dermal
exposures. However, adverse reproductive/developmental effects were
observed in several injection studies. Adverse effects observed
following intraperitoneal injection of B[a]P in mice included:
stillbirths, resorptions, and malformations (Shum et al. 1979, Hoshino
et al. 1981); decreases in follicular growth and corpora lutea (Swartz
and Mattison 1985, Payne 1958); testicular changes (i.e., atrophy of
seminiferous tubules with absent spermatids and spermatozoa,
interstitial cell tumors) (Payne 1958); immunosuppression (Urso and
Gengozian 1980); and tumor induction (Bulay and Vattenberg 1971).
Adverse effects observed following subcutaneous injection of B[a]P
include increased fetal resorptions in rats (Wolfe and Bryan 1939) and
tumor induction in mice (Nikonova 1977). Decreased fetal survival was
reported in Swiss mice following direct embryonal injection of B[a]P
(Barbieri et al. 1986).
-------
48 Section 4
4.3.A Genotoxicity
4.3.4.1 Overview
The genetic toxicity of B[a]P has been evaluated experimentally in
a variety of short-term genetic toxicology assays. B[a]P has been tested
extensively in vivo in rodents and insects, measuring genotoxic effects
at various genetic end points in both germ cells and somatic cells. In
addition, B[a]P has been tested extensively in several bacterial and
mammalian cell systems and has been chosen as a positive control or
model test compound for the validation of some of these test systems.
The test systems used to evaluate B[a]P's genotoxicity and the results
of each are summarized in Tables 4.1 and 4.2.
B[a]P undergoes metabolism to form reactive electrophilic
intermediates capable of interacting with nucleophilic macromolecules
within the target cell, most notably, binding covalently to DNA
(Williams and Weisburger 1986, Miller 1970, Lutz 1979), These reactive
metabolites form bulky DNA adducts, which are generally regarded as an
important determinant in mutagenesis and in clastogenesis (Brendel and
Ruhland 1984, Fahl et al. 1981). The genotoxicity of B[a]P is dependent
on metabolic activation, either exogenously supplied or endogenously
present.
4.3.4.2 General discussion
B[a]P has been tested for in vivo heritable genetic effects. The
most extensively used test for the induction of heritable mutations is
the mouse-specific locus test. B[a]P exposure via injection produced
negative results in this assay (Russell and Russell 1978, Russell 1978,
Russell et al. 1981). Mixed results have been reported in mutation
studies with Drosophila melanogaster. Positive results were reported for
sex-linked recessive lethal mutations (Nguyen et al. 1979, Vogel et al.
1983) and dominant lethal mutations (Nguyen et al. 1979), as well as
somatic mutations (Fahmy and Fahmy 1973, 1980) in this insect species.
However, negative results were reported for sex-linked recessive lethal
mutations in Drosophila by other researchers (Valencia and Houtchens
1981, Zijlstra and Vogel 1984).
B[a]P has also been tested in vivo for other genetic end points in
both germ cells and somatic cells. B[a]P exposure via injection produced
negative results in the mouse germ cell heritable translocation assay
(Generoso et al. 1982), but positive results were observed in the mouse
germ cell dominant-lethal mutation test (Generoso et al. 1982, Epstein
et al. 1972, Epstein and Shafner 1968). In vivo B[a]P exposure has
resulted in aneuploidy (male sex chromosome loss) in Drosophila
melanogaster (Vogel et al. 1983), chromosomal aberrations in hamster
spermatogonia (Basler and Rohrborn 1978), morphological abnormality in
mouse spermhead (Bruce and Heddle 1979, Topham 1980, Wyrobek et al.
1981) , and unscheduled DNA synthesis (UDS) in male mouse germ cells
(Sega 1979). There is no evidence to indicate that the occurrence of UDS
in germ cells of male mice affect mutation frequencies in these cells.
Generally, positive genotoxic responses have been reported in somatic
cells. Positive results were observed in the mouse somatic mutation or
spot test following oral exposure (Davidson and Dawson 1976, 1977;
-------
Table 4.1. Geeetic toxicity of beazo(*feyreae (h 1K10)
End. paints
Species (test systems}
Results w or w/o activation'
DNA damage
Mitotic recombination
DNA damage/repair (UDS)
Escherichia coli K12
(prophage induction)
Escherichia coli
(pol A—/pol A+)
Escherichia coli
(rec-h/rec—)
Bacillus subtilis
(rec+/rec—)
Rat bepatocytes
(DNA single strand breaks)
Saccharomyces cererisiae
Syrian hamster embryo cells
Rat tracheal epithelial cells
Primary rat bepatocytes
Positive w activation
Positive w activation
Positive w activation
Positive w activation
Positive w/o activation
Negative w activation
Positive w/o activation
Positive w/o activation
Positive w/o activation
Human fibroblasts
Positive w activation
Gene mutations
Human amnion cells
Human foreskin epithelial
cells
HeLa cells
Salmonella typhtmurium,
strain TM677 (RAGs/SAGr)
Salmonella typhtmurium
(his+/his—):
strains TA98, TA100, TA1538
Positive w activation
Positive w activation
Positive w activation
Positive w activation
Positive w activation
Salmonella typhtmurium
(rodent body fluids)
TA98, TA100, TA1538
Positive w/o activation
References
Ho and Ho 1981, Moreau et al. 1976
Rosenkranz and Poirier 1979
Mamber et al. 1983, Ichinotsubo et al.
1977, Tweats 1981
McCarroll et al. 1981
Sina et al. 1983
Simmon 1979b, Kassinova et aL 1981
Casto et al. 1977
Ide et al. 1981
Probst et al. 1981; Tong et aL
1981a,b; Williams et al. 1982
Agrelo and Amos 1981, Agrelo and
Severn 1981, Robinson and Mitchell
1981
Yu et al. 1983
Lake et al. 1978
Martin et aL 1978, Martin and McDennid
1981 §
Kadenet al. 1979 g
K-t
0
GUtt et aL 1981, HollsleLn e< al. <£
1979, Probst et al. 1981, Rosenkranz O
and Poirier 1979, Simmon 1979a, ^
WLslocki et al. 1976, Bruce and Heddle _
1979 to
a
Connor et al. 1979, Battzinger et al. 01
1978
•P-
vO
-------
Table 4.1 (coatiawd)
End points
Species (test systems)
Results w or w/o activation*
Gene mutations
(continued)
Salmonella typhimurium
host-mediated assay
Chinese hamster lung cells
(V79)/APRT (8-AG)
V79/HGPRT (6-TG)
V79/Na+,K+ ATPase
(Ouabain)
Chinese hamster ovary
(CHO)/HGPRT
CHO/Na+ ,K+ ATPase
(Ouabain)
C3H 10Tl/2/Na+,K+ ATPase
(Ouabain)
Mouse lymphoma L5178Y/TK + / -
Negative w/o activation
Positive w activation
Positive w activation
Positive w activation
Positive w activation
Positive w activation
Positive w activation
Positive w activation
Adult rat liver (ARL)/HGPRT
Human fibroblasts/HGPRT
Human fibroblasts
(diphtheria toxin)
Human EUE epithelial-like
cells (diphtheria toxin)
Sister chromatid exchange V79
Don cells
CHO
Syrian hamster cells
ARL
H4-IJ-E (rat hepatoma cells)
Positive w/o activation
Positive w activation
Positive w activation
Positive w/o activation
Positive w activation
Positive w/o activation
Positive w activation
Positive w/o activation
Positive w/o activation
Positive w/o activation
References
u»
o
Glatt et al 1985, Simmon et al. 1979 ^
(b
O
Huberman 1975, Wislocki et aL 1976, £
Kuroki et aL 1979 O
*3
Jones et aL 1983, Krahn and
Heidelberger 1977
Bradley ct aL 1981, Hsu et aL 1979,
Langenbach et aL 1978,
Kuroki et aL 1979
Bennudez et aL 1982, Li 1982,
Gupta and Singh 1982,
Machanoff et aL 1981
Li 1982, Gupta and Singh 1962
Gehly et aL 1982
Amacher and Paillet 1982, 1983;
Clrve et aL 1979; Jotz and Mitchell
1981; Thornton et al. 1982
Tong et al. 1980, 1981b
Tong et aL 1981c
Gupta and Goldstein 1981
Rocchi et aL 1980
Popescu et aL 1977, Wojciechowski
et al. 1981
Baker et aL 1983
Hopkins and Ferry 1980, Pal et aJ. 1978
Popescu et aL 1981
Tong et al. 1981a
Dean et al. 1983
-------
Table 4.1 (corine*)
End points
Species (test systems)
Results w or w/o activation*
References
Sister chromatid exchange
(continued)
HTC (rat hepatic tumor cells)
Positive w/o activation
Dean et aL 1980
Human hepatoma cells
(C-HC-4 and C-HC-20)
Positive w/o activation
Abe et aL 1983a,b
Human lymphocytes
Positive w activation
Hopkins and Perry 1980, Rudiger et aL
1976
Human lymphocytes
Positive w/o activation
Craig-Holmes and Shaw 1977
Chromosomal aberrations
V79
Positive w activation
Matsuoka et aL 1979, Popescu et aL
1977
V79
Positive w/o activation
Kocchar 1982
Moose C3H 10T1/2 fibroblasts
Positive w activation
Gehly et aL 1982
Rat cells
Positive w/o activation
Dean 1981
CHO
Positive w activation
Whitehead et aL 1983
Cellular transformation
Syrian hamster embryo cells
(clonal assay)
Positive w/o activation
DiPaoto et aL 1969, 1971; Popescu
et aL 1981; Huberman 1975; Pienta
et aL 1977; Amacher and Zelljadt 1983
Syrian hamster embryo cells
(focal assay)
Positive w/o activation
Casto et al 1977
RLV/Fischer rat embryo cells
Positive w activation
Mishra et aL 1978, Dunkel et aL 1981,
Rhim et aL 1972
Mouse embryo AKR
Positive w/o activation
Rhim et aL 1972, 1973, 1974
Mouse BALB/C3T3 cells
Positive w/o activation
Sivak et al. 1980, Dunkel et aL 1981
Mouse C3H10T1/2 cells
Positive w/o activation
Lubet et al. 1983
Mouse C3H10T1/2 fibroblasts
Positive w activation
Gehly et aL 1982
SA7/Syrian hamster embryo cells
Positive w/o activation
Casto et al. 1977
SA7/rat embryo cells
Positive w/o activation
DiPaoto and Casto 1976
Mouse C3H/M2 prostate cells
Positive w/o activation
Marquardt et aL 1976
The results presented in Tables 4.1 and 4.2 are based on the activity profiles prepared by Waters et aL (1987), Gene-Tox listings from John £
S. Wassom, and/or personal review of the original citation.
-------
52 Section <4
Table 4.2. Genetic toxicity of benzol»)pyTMtt (!¦ iV»o)
End points
Species (test systems)
Results"
References
DKA damage (UDS)
Gene mutations
Rat hepatocytes
Mouse germ cells (male)
Drosophila melanogaster
(somatic mutation)
Drosophila melanogaster
(sex-linked recessive lethal)
Drosophila melanogaster
(sex-linked dominant lethal)
Drosphila melanogaster
(sex-linked recessive lethal)
Mouse somatic ceil
(spot test)
Mouse-specific locus test
Sister chromatid exchange Mouse bone marrow cells
C3H mouse diffusion chamber
(V79 - target cell)
Chinese hamster bone marrow cells
Chromosomal aberrations
Drosophila melanogaster (aneuploidy:
male sex chromosome loss)
Drosophila melanogaster (aneuploidy:
female germ cell chromosome gain)
Chinese hamster bone marrow cells
Chinese hamster bone marrow cells
Hamster spermatogonia
Long Evans rat bone marrow cells
Mouse micranuclei
Mouse mictonuclei
Mouse germ cell dominant lethal
Mouse germ cell heritable
translocation
Morphological abnormality Mouse sperm head
Negative Mirsalis et al. 1982
Positive Sega 1979
Positive Fahmy and Fahmy 1973, 1980
Positive Vogel et al. 1983, Nguyen et al. 1979
Positive Nguyen et al. 1979
Negative Valencia and Houtchens 1981,
Zijlstra and Vogel 1984
Positive Brusick 1980; Russell 1977, 1978;
Davidson and Dawson 1976, 1977
Negative Russell and Russell 1978, Russell 1978,
Russell et al. 1981
Positive Schreck and Latt 1980, Paika et al. 1981
Positive Sirianni and Huang 1978
Positive Bayer and Bauknecht 1977, Basler et al.
1979, Roszinaky-Kocher et al. 1979
Positive Vogel et aL 1983
Negative Valencia et al. 1984,
Fabian and Matollsy 1946
Positive Roszinsky-Kocher et al. 1979
Negative Basler et al. 1979
Positive Barier and Rohrborn 1978
Positive Rees et al. 1970
Positive Kirkhart 1981, Salamone et al. 1981
Negative Bruce and Heddle 1979
Positive Epstein and Shafner 1968, Epstein et al.
1972, Generoso et al. 1982
Negative Generoso et al. 1982
Positive Bruce and Heddle 1979,
Topham 1980, Wyrobek et al. 1981
"The results presented in Tables 4.1 and 4.2 are based on the activity profiles prepared by Waters et al. (1987), Gene-
Ton listings from John S. Wassom, and/or personal review of the original citation.
-------
Toxicological Data 53
Russell 1977, 1978). B[a]P has been chosen as a positive control in the
mouse spot test (Brusick 1980, Russell 1977). The induction of sister
chromatid exchange (SCE) by B[a]P in bone narrow cells of mice (Schreck
and Latt 1980, Paika et al. 1981) and Chinese hamsters (Basler et al.
1979, Bayer and Bauknecht 1977, Roszinsky-Kocher et al. 1979) has been
demonstrated. Mixed results have been reported for chromosomal
aberrations in Chinese hamster bone marrow cells (Basler et al. 1979,
Roszinsky-Kocher et al. 1979) and mouse micronuclei (Bruce and Heddle
1979, Kirkhart 1981, Salamone et al. 1981).
B[a]P shows positive mutagenic activity in vitro in several strains
of Salmonella typhimurium in the presence of either rodent microsomes or
hepatocytes for exogenous metabolic activation. Negative results were
reported for host-mediated activation (Glatt et al. 1985, Simmon et al.
1979). Body fluids from rodents exposed in vivo to B[a]P showed positive
mutagenic activity in three strains of Salmonella typhimurium (Batzinger
et al. 1978, Connor et al. 1979). Generally, B[a]P shows positive
genotoxic activity in in vitro mammalian cell systems with either
exogenous or endogenous metabolic activation.
Several established cell lines, both rodent and human, have
recently been shown to possess endogenous bioactivating capabilities for
many agents, along with providing targets for measures of genotoxicity.
For example, the induction of point mutations at the HGPRT locus and/or
SCEs in intact cell systems of adult rat-liver (ARL) epithelial cells
(Tong et al. 1981a,b) and rat hepatoma (HTC and H4-II-E) cells (Dean et
al. 19B0, 1983) has been demonstrated following in vitro B[a]P exposure.
Metabolic activation of £[a]P has been demonstrated by several cultured
human hepatoma cell lines. Two of these human hepatoma cell lines, CHC-4
and CHC-20, acted as targets for genotoxic action (e.g., SCE induction)
(Abe et al. 1983a,b), while the other human cell lines served as
mediators of activation, resulting in SCE induction in human fibroblasts
(Huh et al. 1982) and point mutations in V79 cells (Diamond et al.
1980) . Other human cells and tissues have also been shown to metabolize
B[a]P (Huh et al. 1982).
There is sufficient evidence from short-term in vivo and in vitro
genetic toxicology tests to prove that B[a]P is a potent genotoxic agent
when metabolically activated. There is sufficient evidence that B[a]P
interacts with mammalian gonads or germ cell DNA and it induces such end
points as unscheduled DNA synthesis (Sega 1979), chromosomal aberrations
(Basler and Rohrborn 1978), and morphological abnormalities (Wyrobek et
al. 1981). However, B[a]P is present as a component of the total content
of PAHs in the environment. How interactions among various PAHs affect
their potential for human genotoxicity is uncertain. Other components of
PAH mixtures also demonstrate genotoxicity. Therefore, it is reasonable
to assume that exposure to genotoxic components of PAH mixtures will
present a risk to humans by inducing heritable genetic damage and
potential human carcinogenesis.
-------
54 Section 4
4.3.5 Carcinogenicity
4.3.5.1 Overview
B[a]P is a moderately potent experimental carcinogen in many
species by many routes of exposure (IARC 1983). There are no reports
directly correlating human B[a]P exposure and tumor development,
although humans are likely to be exposed by all routes. There are a
number of reports associating human cancer and exposure to mixtures of
PAHs that include B[a]P. In view of these observations and its well-
established carcinogenic activity in laboratory animals, it is
reasonable to conclude that B[a]P would be expected to be carcinogenic
in humans by all routes of exposure.
4.3.5.2 Inhalation
Human. No studies on the carcinogenicity of B[a]P in humans
following inhalation exposure were found in the available literature.
However, epidemiologic studies have shown an increased incidence of lung
cancer in humans exposed to coke oven emissions (Lloyd 1971, Redmond et
al. 1972, (tazumdar et al. 1975), roofing tar emissions (Hammond et al.
1976), and cigarette smoke (TJynder and Hoffmann 1967, Maclure and
MacMahon 1980, Schottenfeld and Fraumeni 1982). Each of these mixtures
contains B[a]P as well as other carcinogenic PAHs and other potentially
carcinogenic chemicals, such as nitrosamines. It is thus impossible to
evaluate the contribution of B[a]P to the total carcinogenicity of these
mixtures in humans because of their complexity and the presence of other
carcinogens. Reports of this nature provide qualitative evidence of the
potential for B[a]P-induced carcinogenicity nonetheless.
Animal. B[a]P has elicited lung tumors in several bioassay systems
following inhalation exposure or intratracheal Instillation. Its
carcinogenic potency is enhanced by coadministration of particulate
matter or some gases (IARC 1983).
Few studies have investigated the carcinogenicity of B[a)P alone by
the inhalation route of exposure; most of these have obtained negative
results (Laskin et al. 1970). A notable exception is the study of
Thyssen et al. (1981) that provides clear-cut evidence of a dose-
response relationship between inhaled B[a]P and respiratory tract
tumorigenesis. The protocol and results of this key study are summarized
in Table 4.3. Respiratory tract tumors were induced in the nasal cavity,
larynx, and trachea of animals in the two highest dose groups; lung
tumors were absent, although there is some evidence that hamster lung
tissue can activate Bta]P as well as tine other respiratory tract tissues
(Dahl et al. 1985). Tumors related to exposure also occurred in the
pharynx, esophagus, and forestomach (presumably as a consequence of
mucociliary particle clearance) and were papillomas, papillary polyps,
and squamous cell carcinomas. Length of survival decreased with
increasing B[a]P concentration.
In another experiment, respiratory tract tumors were observed In
rats using a combination of B[a]P and the atmospheric irritant sulfur
-------
Toxicological Data
Table 4.3. Dose-response relationship between Inhaled benzo(a}pyrene
and respiratory tract tumors in hamsters0
Exposure
Average
Effective
rate (x)
survival (t)
number
Number of respiratory
(mg/m3 B[a]P)
(weeks)
exposed
tract tumors observed
0.0
96.4
27
0
2.2
95.2
27
0
9.5
96.4
26
9
46.5
59.5
25
13
'Groups of 24 male Syrian golden hamsters each were exposed
throughout their lives to B[a]P in a sodium chloride aerosol for 4.5
h/day, 7 days/week for 10 weeks and then 3 h/day thereafter at
dose levels of 2.2, 9.5, or 45.6 mg/m} air. Animals that died during
the first year of the experiment were replaced, which may account
for the discrepancy between the authors' statement that there were
24 hamsters per group and their reported "effective number
exposed."
Source: Thyssen et al. 1981.
-------
56 Section 4
dioxide (S02); sulfur dioxide by itself was not carcinogenic (Laskin et
al. 1970). Rats were exposed to 10 mg/m^ B[a]P for 1 h/day for 1 year in
the presence or absence of 10 ppm S02 for an additional 6 h/day.
Squamous cell carcinomas developed in the lungs of 2/21 rats exposed to
B[a]P alone and 5/21 rats exposed to both.
In contrast, intratracheal instillation experiments have produced
greater yields of B[a]P-induced lung tumors. Vehicles used, and their
effects on tumorigenicity, have varied widely. For example, a number of
studies have demonstrated the effects of intratracheal instillation of
B[a]P-coated Fe203 particles (Saffiotti et al. 1972, Stenback et al.
1975) and MgO dust (Stenback et al. 1975) in hamsters, although each of
these studies failed to include a group receiving B[a]P alone, negating
an evaluation of the extent of cocarcinogenie activity of the dusts used
(if any). Sellakumar et al. (1976), however, showed that
coadministration of Fe203 and B[a]P by intratracheal instillation in
hamsters increased the percentage of respiratory tract tumor-bearing
animals from 15 to 71%, as compared to administration of B[a]P alone. In
this experiment, administering Fe203 either prior to or following B[a]P
treatment had no effect, supporting the contention that Fe203 is a
cocarcinogen. Harris et al. (1971) reported basal cell hyperplasia of
the upper respiratory tract when Fe203 was administered; the induction
of hyperplasia is consistent with one of the proposed mechanisms of
action of cocarcinogens. Stenback et al. (1976) and Stenback and Rowland
(1979) observed pulmonary interstitial cell proliferation and bronchial
epithelial alterations following intratracheal instillation of several
dusts in hamsters, including titanium dioxide, aluminum oxide, carbon,
ferric oxide, silicon dioxide, manganese dioxide, and agar gelatin. In
these experiments, B[a]P alone induced few tumors, while
coadministration of B[a]P and dusts elicited a variety of benign and
malignant respiratory tract tumors, depending on the dust used. A
significant proportion of forestomach tumors were also observed,
indicating that ingestion exposure occurred following the mucociliary
clearance of particles. Henry et al. (1973) produced tumors in the
respiratory tracts of hamsters with a colloidal suspension of B[a]P and
gelatln/NaCl; Feron et al. (1973) observed a dose-response relationship
with B[a]P and a NaCl solution. In another experiment, coadministration
of noncarcinogenic furfural resulted In the earlier appearance of
epithelial metaplasia and a shorter latency period for tracheobronchial
tumors (Feron 1972). Other experiments with hamsters have failed to
demonstrate dose-response relationships, presumably due to excess
toxlclty-related mortality in higher dose groups (Ketkar et al. 1979,
1978). Dose-response relationships were demonstrated for B[a]P and lung
tumor formation following intratracheal instillation with and without
coadministration of carbon black in Wistar rats (Davis et al. 1975). In
a preliminary report, intratracheal instillation of B[a]P and ferric
oxide induced squamous carcinoma of the lung in subhuman primates
(lesser bush babies, Galago crassicaudatus) (Crocker et al. 1970).
Deutsch-Wenzel et al. (1983) tested B[a]P for carcinogenicity by
direct injection of a single dose (0.1-1.0 mg) in a trioctanoin/beeswax
vehicle into the lungs of female Osborne-Mendel rats. Upon Injection,
the mixture congealed into a pellet, from which B[a]P diffused over time
into the surrounding lung tissue. Epidermoid carcinomas and pleomorphic
-------
ToxLcological Data 57
sarcomas were observed, and dose-response relationships were obtained.
The treatment method involved some trauma to the animals. Tumor
induction times were difficult to observe, so survival time and the
number of tumor-bearing animals were the responses evaluated. Table 4.4
shows the results. The reduced survival rates of the higher dose groups
probably reduced the tumor incidences observed.
There are several possible reasons why inhalation bioassays of
B[a]P have failed to produce lung tumors in contrast to intratracheal
instillation or injection:
1. Sufficient doses of B[a]P may not have been deposited and retained
following inhalation exposure (Harris and Autrup 1983) .
2. Elution of B[a]P from carrier particles or wax may be slow,
maximizing exposure duration in the case of intratracheal
instillation or injection.
3. Mucociliary clearance mechanisms may be impaired by toxicity
resulting from direct instillation, thus increasing exposure
duration.
4. Direct instillation or injection involves some trauma and necrotic
activity, which can result in regenerative hyperplasia. Increasing
the number of proliferating cells (as in the case of hyperplasia)
can increase the number of cells at risk of B[a]P-induced mutagenic
and potentially carcinogenic events (Hirakawa et al. 1979).
5. B[a]P is only a moderately potent respiratory tract carcinogen.
The inhalation study of Thyssen et al. (1981) is the least likely
to be confounded by artifacts of intratracheal instillation or injectLon
procedures and can be extrapolated more directly to human routes of
exposure.
4.3.5.3 Oral
Human. No studies on the carcinogenicity of B[a]P in humans
following oral exposure were found in the available literature.
Animal. B[a]P ingestion has been associated with tumor development
in both mice and rats. Dietary B(a]P elicited papillomas and carcinomas
in the forestomach of male and female Swiss mice in a series of
experiments in which doses of 0-250 ppm B[a]P in the diet were consumed
for 1-197 days and animals were observed for 70-300 days (Neal and
Rigdon 1967). The details and results of this key study are depicted in
Table 4.5. The lack of a consistent protocol in these experiments and
other factors, such as variable age of first exposure, a duration of
exposure that only lasted -1/7 of a lifetime, and an observation period
that was <1/5 of a lifetime, make it difficult to reliably quantitate a
dose-response relation. Furthermore, tumors were reported as combined
papillomas and carcinomas, so that no distinction between these benign
and malignant tumors can be made. The same authors found an association
between dietary B[a]P at concentrations of 0, 250, and 1000 ppm
-------
Section 4
Table 4.4. Tumor dose-response relationships for benzo{a]pyrene
injected into rat lungs"
Compound
Dose
(mg)
Number
of
animals
Median
survival time
(weeks) (95%
confidence
interval)
Number of animals
bearing epidermoid
carcinomas/number
of animals bearing
pleomorphic sarcomas
Tumor
incidence
(%)
B[a]P
0.1
35
111 (95-120)
4/6
28.6
B[a)P
0.3
35
77 (68-99)
21/2
65.7
B[a]P
1.0
35
54 (46-64)
33/0
94.3
BW-TC4
35
104 (91-121)
0/0
0.0
Untreated
control
35
118 (104-133)
0/0
0.0
"Single doses of B[a]P were injected into the left lung of female Osborne-Mendel
rats in a vehicle of molten trioctanoin/beeswax, which congealed and permitted gra-
dual diffusion of B[a]P into lung tissue over time.
^Beeswax and trioctanoin (vehicle).
Source: Deutsch-Wenzel et al. (1983).
-------
Toxicological Data
Table 4.5. Forestomach tumors in mice fed benzo(a]pyrene0
Age first
Concentration of
Number
Number with
exposed
B[a]P in food
of days
Age killed
forestomach tumors/
(days)
(mg/g)
fed B[a]P
(days)
number of mice
0.0
300
0/289
30
0.001
110
140
0/25
30
0.01
110
140
0/24
116
0.02
110
226
1/23
33-67
0.03
110
143-177
0/37
33-101
0.04
110
143-211
1/40
31-71
0.045
110
143-183
4/40
17-22
0.05
107-197
124-219
24/34
20-24
0.10
98-122
118-146
19/23
18-20
0.25
70-165
88-185
66/73
49
0.25
1
155
0/10
56
0.25
2
162
1/9
49
0.25
4
155
1/10
62
0.25
5
168
4/9
49
0.25
7
155
3/10
91
0.25
30
198
26/26
74
0.10
7
182
0/10
48
0.10
30
156
12/18
98-180
5.0
1
209-294
17/33
"Male and female Swiss mice received B[a]P in the diet for varying lengths
of time. The sizes of the treatment groups were apparently the same as the
numbers of mice reported in this table; treatment-related effects on survival
thus cannot be evaluated.
Source: Adapted from Neal and Rigdon (1967).
-------
60 Section 4
administered to mice for different lengths of time and the development
of leukemia and forestomach and lung tumors (Rigdon and Neal 1966,
1969). The results of these experiments are shown in Table 4.6. Tumor
incidence was related to both dose and length of exposure (except in the
case of leukemia). These studies have the same limitations as the Neal
and Rigdon (1967) study. The Neal and Rigdon (1967) study provides the
best dose-response information available for the oral route of exposure,
despite the irregular protocol employed, although the relevance of
forestomach tumors in rodents to human cancer is the subject of some
controversy.
Mammary tumors have been induced by intragastric doses of B[a]P in
female LEW/Mai rats (McCormick et al. 1981). Rats receiving a single
dose of 50 mg B[a]P had a 77% incidence of mammary tumors after 90
weeks, whereas rats receiving 8 weekly doses of 6.25 mg had an incidence
of 67%. The control rats had a high spontaneous mammary tumor rate of
30%, indicating that B[a]P can increase the rate at which spontaneous
tumors develop, which is thought in some cases to occur via mechanisms
other than direct mutation/initiation, possibly by affecting oncogene
expression (Goldsworthy and Pitot 1985).
Intragastric doses of B[a]P have also been shown to elicit
pulmonary adenomas and forestomach papillomas in female ICR/Ha, A/J, and
A/HeJ mice (Sparnins et al. 1986, Wattenberg and Leong 1970, Wattenberg
and Bueding 1986) . As parts of experiments designed to evaluate the
effectiveness of various inhibitors of carcinogenesis, B[a]P was
administered by gavage to mice in the presence or absence of suspected
inhibitors. For example, A/HeJ mice received two doses of 3 mg B[a]P in
0.25 mL sesame oil 2 h apart, which was repeated twice at approximately
2-week intervals (Wattenberg and Leong 1970); the pulmonary tumor count
was found to rise from 0.3 ± 0.5 per mouse in the control group to
16.6 ± 7.7 in the treated group at 30 weeks of age. Of A/J mice
receiving 2 mg B[a]P in 0.2 mL corn oil three times at 2-week intervals,
100% developed forestomach tumors (Sparnins et al. 1986); no controls
were included, however.
4.3.5.4 Dermal
Human. No studies on the carcinogenicity of B[a]P in humans
following dermal exposure were found in the available literature. As
with inhalation exposure, however, there are reports of skin cancer
among individuals exposed dermally to mixtures of PAHs containing B[a]P.
The earliest of these is the report of Pott (1775) of scrotal cancer
among chimney sweeps. More recently, skin cancer among those exposed
dermally to shale oils has been reported (Purde and Etlin 1980). These
reports provide only qualitative evidence of the carcinogenic potential
of B[a]P in humans, however, because of the presence of other putative
carcinogens in the mixtures.
Animal. B[a]P is a moderately potent experimental skin carcinogen,
and it is often used as a positive control in bioassays of other agents.
B[a]P was first reported to induce skin tumors in mice in 1933 (Cook et
al. 1933, Cook 1933), although mixtures of PAHs that include B[a]P (such
as coal tar) were shown to be dermal carcinogens in animals as early as
-------
Toxicological Data
Table 4.6. Tumor incidence in mice fed benzofrlpyrene"
Dose
(ppm)
Duration of
treatment
(days)
Tumor type
Tumor
incidence"
0
38-210+
Forestomach papilloma/carcinoma
Lung adenoma
Leukemia
2/175 (1)
33/151 (19)
0/175 (0)
250
80-140
Forestomach papilloma/carcinoma
Lung adenoma
Leukemia
69/108 (64)
52/108 (48)
40/108 (37)
250
72-99
Stomach papilloma/carcinoma
Lung adenoma
12/52 (23)
26/52 (50)
250
147-196
Stomach papilloma/carcinoma
Lung adenoma
9/13 (69)
10/13 (77)
1000
73-83
Stomach papilloma/carcinoma
Lung adenoma
5/9 (56)
7/9 (78)
1000
127-187
Stomach papilloma/carcinoma
Lung adenoma
13/13 (100)
3/13 (23)
"Male and female Swiss mice received B[a]P in the diet for varying
lengths of time. The sizes of the treatment groups were apparently the same
as the numbers of mice reported in this table; treatment-related effects on
survival thus cannot be evaluated. In each case, the duration of the treat-
ment was equal to the duration of the study.
*Data within parentheses indicate percentages.
Source: Adapted from Rigdon and Neal 1966, 1969.
-------
62 Section 4
1918 (Yamagiwa and Ichikawa 1918). B[a]P is active both as a "complete"
carcinogen and as an initiator using initiation/promotion protocols. In
its role as a positive control, B[a]P is usually administered at a
single dose level, so that quantitative evaluation of dose-response
relationships is not possible. For this reason, this discussion will be
limited to key experiments employing more than one dose level.
In mice, the tumorigenic dose of B[a]P is dependent on the solvent
used for delivery and on the strain of mice (IARC 1983). For example,
Habs et al. (1980) tested B[a]P in acetone in order to determine its
dose-response relationships as a carcinogen when topically applied,
using a syringe, to the interscapular region of groups of 40 female NMRI
mice twice weekly throughout their lifetimes. Table 4.7 lists the doses
used and results obtained. A clear-cut dose-response relationship was
seen for B[a]P and the induction of tumors, although the authors do not
specify whether papillomas were considered to be tumors as well as
carcinomas (however, this protocol usually produces only the latter).
This strain of mice has a high (-70%) background incidence rate of
systemic tumors, so an evaluation of the effects of B[a]P on any organ
other than the site of administration was not possible.
Bingham and Falk (1969) applied graded concentrations of B[a]P
topically to the backs of C3H/He mice (sex unspecified) three times per
week for 50 weeks and quantitated local tumors. B[a]P was dissolved in
decalin or a solution of n-dodecane and decalin (50:50 by weight), and
50 mg by weight of solution was administered at each dosing; however,
the method of application was not specified. Table 4.8 shows the results
of this experiment. Sample sizes were small and no decalin solvent
controls were included; however, decalin is not considered to be
carcinogenic. Use of the n-dodecane and decalin solvent mixture enhanced
the potency of B[a]P significantly at lower doses in comparison with
decalin alone.
Hoffmann and Wynder (1966) tested B[a]P for activity as a
carcinogen or as a tumor initiator on mouse skin. For the
carcinogenicity evaluations, female Ha/ICR/mil Swiss albino mice
received three weekly topical applications of 0.05 or 0.1% solutions in
dioxane for 1 year. The number of animals with papillomas observed at
each dose is shown in Table 4.9. No tumors were observed in the dioxane
vehicle controls. For the initiation/promotion experiments, ten doses of
the B(a]P were applied in dioxane 2 days apart to the backs of mice for
a total dose of 0.25 mg per mouse and followed by 2.5% croton oil in
acetone. The frequency and duration of croton oil administration were
unclear. Twenty-four of 30 animals (80%) developed tumors in the treated
group, while 2 of 30 control animals (7%; croton oil alone) developed
tumors. B[a]P was applied to mouse skin in both of these experiments
using a brush; as a result, accurate dose quantitation is not possible.
As part of a study of the carcinogenicity of tobacco and its
constituents, B[a]P was tested as a complete carcinogen on the skin of
mice (Wynder and Hoffmann 1959). Groups of 20 to 30 female Swiss mice
received concentrations of 0.001 to 0.01% of the test substances
dissolved in acetone three times a week applied to their backs with a
brush throughout their lifetimes. Table 4.10 shows the results of this
experiment. No solvent control group was reported; however, no
-------
Toxicological Data
Table 4.7. Benzo(a]pyrene-induce
-------
Section 4
Table 4.8. Tumor incidence following dermal exposure
of mice to benzoUJpyrene13
Dose
Tumor incidence''
Percent
Vehicle concentration* mg/kg/da/ Malignant Benign
Decalin
0.02
4.8
5/12 (42)
1/12(8)
Decalin
0.002
0.48
0/20 (0)
0/20 (0)
Decalin
0.0002
0.048
0/21 (0)
0/21 (0)
Decalin
0.00002
0.0048
0/18 (0)
0/18 (0)
n-Dodecane
+
decalin4
0.02
5.4
10/16 (63)
5/16(31)
n-Dodecane
+
decalin
0.002
0.54
7/26 (27)
2/26 (8)
n-Dodecane
+
decalin
0.0002
0.054
3/23 (13)
3/23 (13)
n-Dodecane
+
decalin
0.00002
0.0054
5/24 (21)
0/24 (0)
n-Dodecane
+
decalin
0.000002
0.00054
0/24 (0)
0/24 (0)
n-Dodecane
+
decalin
0
0
0/30 (0)
0/30(0)
"Solutions of B[a]P were applied to the backs of C3H/He mice three times per
week for 50 weeks. Approximately 50 mg of solution was applied at each dosing by
an unspecified method.
*As determined by authors.
"Calculated by assuming that the density of decalin is 0.9 and the density of
n-dodecane and decalin is 0.8, and adjusting for intermittent exposure by multiplying
by 3/7.
''Data within parentheses indicate percentages.
'50:50 by weight.
Source: Bingham and Falk (1969).
-------
Toxicological Data
Table 4.9. Carcinogenic activity of benzo[a]pyrene
on moose skin—1°
Number of Tumor
Dose tumor-bearing animals/ incidence
Compound (percent concentration)* number of animals (%)
B[a]P 0.05 17/20 85
0.0 L 19/20 95
Dioxane 0/20 0
"B[a]P in dioxane was applied to the backs or groups of 20 female
Ha/ICR/mil Swiss mice three times weekly for one year.
^Equivalent to 50 and 10 mg B[a]P per dose, respectively
(D. Hoffmann, personal communication).
Source: Hoffmann and Wynder (1966).
Table 4.10. Carcinogenic activity of benzo{a]pyrene
on mouse skin—II"
Dose
(percent concentration)6
Incidence
of papillomas'-''
Incidence
of carcinomas0-''
0.001
13/24 (54)
1/24 (4)
0.005
22/22(100)
19/22 (86)
0.01
19/20 (95)
19/20 (95)
flB[a]P in acetone was applied to the backs of groups of
20 to 30 female Swiss mice three times weekly throughout
their lives.
^Equivalent to 1, 5, and 10 mg B[a]P per dose, respec-
tively (D. Hoffmann, personal communication).
These numbers differ from those reported by the
authors, who did not account for survival.
^Data within parentheses indicate percentages.
Source: Wynder and Hoffmann (1959).
-------
66 Section 4
papillomas or carcinomas were obtained for several other PAHs tested in
the same experiment. A solvent control group would most likely have been
negative as well. Again, dose quantitation is difficult due to the
method of application. Dose-response relationships for B[a]P and skin
tumors in mice were also demonstrated by Wynder et al. (1957, 1960).
Some of the dermal carcinogenicity experiments described in this
section may have underestimated the potency of B[a]P because the ability
of this compound to induce the enzymes responsible for its metabolic
detoxication can reduce its carcinogenicity (Slaga and diGiovanni 1984),
Levin et al. (1976) showed that doses of 0.1 nmol B[a]P (25 mg)
administered to the backs of female C57B1/6J mice as infrequently as
once every 2 weeks produced a 94% tumor incidence after 60 weeks of
treatment. More frequent administration would have been expected to
reduce tumor incidence (Slaga and diGiovanni 1984, Weibel 1980).
B[a]P has also produced skin tumors in rats, rabbits, and guinea
pigs (IARC 1973), although mice appear to be the most sensitive species.
4.3.5.5 General discuss ion
The most sensitive (occurs at the lowest doses) and well-studied
end point of B[a]P-induced intermediate- and long-term toxicity is
cancer. B[a]P has been shown to cause cancer in laboratory animals by
all routes of exposure by which humans can expect to be exposed
(inhalation, oral, dermal). In addition, B[a]P has elicited tumors in
animals by several experimental routes of exposure such as
intraperitoneal, intrapulmonary, and subcutaneous injection, as well as
transplacentally (IARC 1973, 1983).
A series of steps is involved between exposure to B[a]P and tumor
development; these involve metabolic activation and genotoxicity, as
described in previous sections. Target tissues for B[a]P-induced
carcinogenesis possess the ability to metabolically activate B[a3P to
its reactive epoxide derivative. Covalent binding of reactive
metabolites of B[a]P to DNA can occur and results in the formation of
DNA adducts. This step appears to be essential for the production of
B[a]P-induced neoplasia (Gelboin 1980, Weinstein et al. 1978).
B{a]P metabolites have been found to bind to DNA in every tissue
that has been examined, regardless of species, dose, or route of
administration. The physical nature of the adducts formed, the levels at
which they occur, and the extent to which they persist unrepaired appear
to be similar in various tissues, whether or not those tissues are
likely to develop tumors (Stowers and Anderson 1985). Thus, the
formation of B[a]P-DNA adducts is a necessary but not sufficient step
for B[a]P-induced carcinogenesis; another step is also required.
B[a]P-induced mutation can result when a DNA adduct remains
unrepaired and cell proliferation occurs. Mutations that result at sites
critical to the regulation of cell differentiation or growth control may
lead to malignancy. Marshall et al. (1984) have shown that reaction of
B[a]P diol epoxide in vitro can lead to the activation of a transforming
oncogene which, when Introduced into the DNA of mammalian cells, can
lead to mutation and transformation. The difference between the oncogene
before and after activation is that of a single base-pair substitution.
-------
Toxlcological Data 67
Tissues that have higher rates of cell turnover, such as the skin
and lung, appear to be target tissues for B[a]P-induced tumor formation,
while those with slower rates, such as the liver, are not. The rate of
cell proliferation can have an important influence on the rate at which
mutation occurs and may account for the differences in susceptibility
among tissues. For example, B[a]P does not usually cause liver tumors in
rats. Performing partial hepatectomy on rats leads to a high rate of
hepatic cell turnover. If partial hepatectomy is performed prior to
B[a]P administration, tumors will occur in that organ (Hirakawa et al.
1979).
B[a]P is thus a moderately potent tumor initiator; its potency is
related to the extent to which it is metabolized to its reactive epoxide
metabolite, the extent to which that metabolite reacts with DNA, and the
rate at which cell proliferation occurs in a potential target tissue.
4.4 INTERACTIONS WITH OTHER CHEMICALS
Most human exposures to B[a]P are not to the pure compound but to
particle-bound B[a]P; the presence of particles is likely to affect its
pharmacokinetics and carcinogenicity. Sun et al. (1982) showed that when
B[a]P was particle-bound, it was cleared from hamster lungs much more
slowly than a pure B[a]P aerosol, thus increasing the length of time the
lungs were exposed and increasing the dose to the gastrointestinal tract
as a result of mucociliary clearance. Respirable B[a]P-containing
particulates such as diesel exhaust, when coated with the phospholipid
component of a pulmonary surfactant, are genotoxic (Wallace et al.
1987). Dusts can increase the rates of pulmonary cell proliferation
(Harris et al. 1971, Stenback et al. 1976, Stenback and Rowland 1979),
which in turn increases the susceptibility of these cells to an
initiation event in the presence of a carcinogen. Coadministration of
B[a]P and particles greatly increases respiratory tract tumor yields in
experimental animals (Stenback et al. 1976, Stenback and Rowland 1979).
The effects of particles on B[a]P's potential human carcinogenicity is
likely to be similar.
Human exposure to B[a]P in the environment occurs seldom, if ever,
to B[a]P alone but to B[a]P as a component of complex mixtures of PAHs
and other chemicals. Interactions between B[a]P and other mixture
components are likely to occur. In particular, interactions may play a
large part in carcinogenesis resulting from experimental exposure to
PAHs. For example, tfahlum et al. (1984) have shown that different
temperature-range distillates of coal liquids have different skin-
tumor- initiating activities in mice, despite the fact that they contain
similar levels of known carcinogenic PAHs. This difference is believed
to be due to the modifying effects of the spectrum of noncarcinogenic
PAHs obtained at different temperatures. Most of the PAH components of
coal liquid fractions obtained at different temperatures will vary both
qualitatively and quantitatively, and consequently their abilities to
modify carcinogenesis will vary accordingly. Other experiments have
shown that most PAH mixtures are considerably less potent than B[a]P
alone. For example, various kinds of combustion emissions and B[a]P were
tested for potency as tumor initiators on the skin of SENCAR mice (Slaga
et al. 1980). Table 4.11 shows that the PAH mixtures were much less
potent as tumor initiators than B[a]P. The authors calculated relative
-------
Section 4
Table 4.11. Relative tumor-initiating potency
of various emission extracts and benzo{a]pyrene
Relative potency4
[based on
Substance" papillomas/(mouse-mg)]
Benzo[a]pyrene
1.0
Roofing-tar emission extract
0.004
Coke-oven emission extract
0.007
Caterpillar diesel exhaust extract
0C
Oldsmobile diesel exhaust extract
0.002
Nissan diesel exhaust extract
0.007
Mustang gasoline exhaust extract
0.002
Cigarette-smoke condensate
0'
"Material was applied to Senear mice once as initiator.
Phorbol myristate acetate (2 fig), twice a week, was used as
promoter. Emission exposures that were used in the relative
potency calculations were restricted to the linear portion of
the dose-response curve.
aAs calculated by authors.
These entries refer to potencies that were not signifi-
cantly different from zero at P = 0.05.
Sources: Slaga et al. (1980) and NAS (1983).
-------
Toxicological Data 69
potency estimates that ranged from 0.007 for coke oven emissions extract
to less than 0.002 for diesel engine exhaust extract, using papillomas
per mouse per milligram as the end point. In another study, the
tumorigenicity of an automobile emission condensate (AEC), a diesel
emission condensate (DEC), a representative mixture of carcinogenic
PAHs, and B[a]P were tested for carcinogenicity by chronic application
to mouse skin (Misfeld 1980). The results are shown in Table 4.12.
Relative potencies were calculated by the authors to be 0.00011, 0.0053,
and 0.36 for DEC, AEC, and the PAH mixture, respectively, as compared
with B[a]P. The relative roles of the PAH components of each of these
mixtures are unknown, however, so that quantitative evaluation is not
possible. Since human exposure occurs to mixtures of PAHs, and not
individual components, quantitative evaluation of the toxicity of
individual PAHs is probably insufficient.
Human exposure to complex mixtures of PAHs has been extensive;
some adverse effects are well-documented, particularly carcinogenic
effects following long-term exposure. The extent of human exposures to
well-defined PAH mixtures that are responsible for producing excess
disease is generally not known in quantitative terms. Coke oven
emissions and related substances such as coal tar have probably been the
most widely studied. Coal tar derivatives were most likely responsible
for the first observation of occupational cancer, that of scrotal cancer
among London chimney sweeps, made by Pott (1775). More recent mortality
studies have demonstrated strong associations between human exposure to
coke oven emissions and excess disease; specifically, significant
increases in lung and genitourinary cancer mortality have been observed
(IARC 1983). The earliest of these reports was made in 1936 by
investigators in Japan and England (Kennaway and Kennaway 1936) who were
studying lung cancer mortality among persons employed in coal
carbonization and gasification processes. Subsequent studies conducted
in the United States clearly demonstrated substantial increases in lung
and genitourinary system cancer mortality among coke oven workers (Lloyd
1971, Redmond et al. 1972, IARC 1984). Human tumorigenicity has also
been reported to result from exposure to creosote. Creosote is a generic
term that refers to wood preservatives derived from coal tar, creosote,
or coal tar neutral oil and includes extremely complex mixtures of
liquid and solid aromatic hydrocarbons. Workers who engaged in
activities such as dipping timbers in creosote were reported to have
developed malignant and premalignant skin lesions of the face, arms, and
scrotum (0'Donovan 1920, Cookson 1924, Henry 1947, Lenson 1956). Many of
the individual PAH components of creosote have been shown to be both
mutagenic and carcinogenic in laboratory bioassays, supporting the
evidence of its human carcinogenicity (IARC 1983).
Exposures to many other complex chemical mixtures that include
PAHs, such as the use of tobacco products and exposure to roofing tar
emissions and shale oils, have been associated with human disease
incidence. Although this discussion falls short of providing a thorough
review of the extensive literature available on the experimental and
epidemiological observations of the toxicity of PAH mixtures, its
purpose has been to provide examples wherein such toxicity has been
documented, in order to emphasize that human exposure occurs to multiple
PAHs.
-------
70 Section 4
Table 4.12. Carcinogenic activity of automobile emission
condensate (AEC), diesel emission condensate (DEC),
and PAHs on mouse skin
Treatment
Percent
mice with tumors
Relative
potency"
Solvent control
0
Benzofajpyrene
3.86 fig
7.69 Mg
15.4 fig
32.8
60.9
89.1
1
AEC"
290 fig
880 fig
2,630 fig
10.3
44.3
83.3
0.0053
DEC6
4,300 ng
8,600 fig
17,150 Mg
0
2.6
12.7
0.00011
Mixture of PAHs
3-5 fig
10.5 fig
1.3
38.7
0.36
"As calculated by authors.
^Obtained with leaded fuel.
Sources: Misfeld (1980) and NAS (1983).
-------
Toxicological Data 71
Predicting the toxicity of a complex mixture on the basis of one or
several of its components may be misleading because interactions among
the components may modify toxicity. For example, both carcinogenic and
noncarcinogenic PAHs may compete for the same metabolic activating
enzymes and thereby reduce the toxicity of carcinogenic PAHs. Exposure
to other PAHs can induce enzyme levels leading to more rapid
detoxication of B[a]P, reducing its carcinogenicity (Levin et al. 1976).
Interactions between B[a]P and benzo[e]pyrene have been shown to have
both synergistic and antagonistic effects on mutagenicity (Hass et al.
1981). Naturally occurring compounds have been found to induce the
enzymes that metabolize PAHs, leading to either increased or decreased
toxicity. For example, plant flavonoids can induce microsomal
monooxygenases and reduce the carcinogenicity of B[a]P (tfeibel 1980).
Environmental contaminants such as TCDD can also increase microsomal
enzyme activity and consequently affect PAH toxicity (Kouri et al.
1978) . Interactions can thus play important modulating roles in PAH
toxicity that may not be adequately reflected in the identification of
significant human exposure levels based on the toxicity of single PAHs,
since human exposure occurs to mixtures of PAHs.
-------
73
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL
5 • 1 OVERVIEW
B[aJP is on the Toxic Substances Control Act (TSCA) Chemical
Inventory (EPA 1979b), which lists chemicals (as defined by TSCA) that
have been manufactured, imported, or processed for a commercial purpose
in the United States since January 1, 1975. Data from the TSCA inventory
indicates that the aggregate production of BfaJP is <1 million lb. B[a]P
also occurs in fossil fuels and as a result o£ the incomplete combustion
of fuel and wood. B[a]P is available as a research chemical from some
specialty chemical firms. B|a]P and other polycyclic aromatic
hydrocarbons are found In coal tar and in the creosote oils and pitches
formed from the distillation of coal tars. Coal tar pitch is primarily
used as a binder for electrodes. Creosote is primarily used as a wood
preservative. Coal tar is also used as a therapeutical treatment for
skin diseases (e.g., psoriasis). PAHs are also found in limited amounts
in bitumens and asphalt.
5•2 PRODUCTION
The primary current source of B[a]? In air is combustion of wood
for residential heating (EPA 1965). The production of B{a]P from this
source is a consequence of incomplete combustion and uncontrolled
release Into the air. As a product of combustion, an estimated 1.8
million lb of BfaJP is released from stationary sources. The sources for
96% of this amount are refuse piles, outcrops, abandoned coal mines,
coke manufacture, and residential external combustion of bituminous and
anthracite coal.
Crude coal tar is produced as a by-product in the formation of coke
from coal. Hot gases and vapors that are released from the conversion of
coal to coke are collected in a scrubber that condenses these gases Into
araetonia, water, crude tar, and other by-products. A typical coke oven
produces 80% coke, 12% coke-oven gas, 3% coal tar, and 1% crude benzene.
The coal tar is then distilled to yield a number of chemical oils,
creosote, and coal tar pitch. The coal tar pitch residue is 40.5% of the
crude tar; creosote is -11.5%. Heavy and light creosote also make up a
small percentage of distillate (NIOSH 1977). Coal Car contains -30 mg/kg
B[a]P; coal tar pitch contains -10 ag/kg B[a]P; and creosote oil
contains <0.01 mg/kg B[a]P (EPA 1985).
As of 1981, the world output of crude coal tar was 1.8 x 107 metric
tons; 1.4 x 107 metric tons was of coke-oven origin. In 1980, the U.S.
production of crude tar was 2.4 x 106 metric tons. Creosote oil
production in the United States in 1981 was estimated to be 5.1 x 105
metric tons. The coal tar pitch production in the United States in 1974
was estimated to be 1 x 10° metric tons (McHeil 1983).
-------
74 Section 5
Bitumens and asphalt are derived from crude oils. Asphalt is a
mixture of bitumen with mineral materials (IARC 1985). Bitumen samples
have been reported to contain between 0.1 and 27 mg/kg B[a]P (IARC
1985).
5.3 IMPORT
In 1985, the United States imported a total of almost 12 million
gal of creosote oil from the Netherlands, France, West Germany, and
other countries and almost 185 million lb of coal tar pitch, blast
furnace tar, and oil-gas tar from Canada, Mexico, West Germany, Asian
countries, Australia, and other countries (USDOC 1986).
5.4 USE
B[a]P has some use as a research chemical. It is available from
some specialty chemical firms in quantities of 100 mg to 1 g (Aldrich
Chemical Co. 1986).
Coal tar pitch is removed from the tar still as a residue. The rate
of feeding and firing of the still regulates the viscosity of the tar.
Coal tar pitch is primarily used as a binder for electrodes in the
aluminum reduction process; it is used to bind the carbon electrodes
used in the reduction pots (NIOSH 1977). In North America, coal tar
pitch is also used as the adhesive in membrane roofs (McNeil 1983).
Almost 99% of creosote produced is sold to wood preservation
plants; from 0.1 to 0.2% is sold to individual customers (NIOSH 1977).
Creosote is used in the preservation of railroad ties, marine pilings,
and telephone and telegraph poles. Some creosote is also consumed as
fuel by steel producers (NIOSH 1977).
Coal tar is also used in the clinical treatment of skin disorders
(e.g., eczema, dermatitis, and psoriasis). The use of dermatological
coal tar preparations is extensive (NIOSH 1977).
Bitumens and asphalt are primarily used for paving roads,
waterproofing and roofing, electrical insulation, sound Insulation, and
pipe coating (IARC 1985).
5.5 DISPOSAL
Following small input of B[a]P from coal-tar creosote, 0.36 mg/L
B[a]P has been found in water raw discharge from timber product
industries in 1978 (EPA 1985).
Total B[a]P wastewater discharge in 1978 from coke-making
operations was reported as 3 metric tons (EPA 1985).
-------
75
6. ENVIRONMENTAL FATE
6.1 OVERVIEW
B[a]P in the environment is derived from both natural (e.g.,
volcanoes, wildfires) and man-made sources, but B[a]P originating from
man-made sources is quantitatively the most significant. B[a]P is formed
during high-temperature pyrolytic processes; consequently, natural and
man-induced combustion are the major sources of environmental B[a]P.
Virtually all direct releases of B[aJP into the environment are to the
air. Small and approximately equal amounts are released to water and
land. B[a]P is removed from the atmosphere primarily by photochemical
oxidation and dry deposition to land or water. B[a]P that reaches the
surface will likely remain and will be partitioned primarily to soil and
sediment, where it is very persistent. The dominant degradation process
for BfaJP in soil/sediment is biodegradation. Biodegrad&tion is a slow
process, with a half-life of 290 days being estimated for Bta]P in soil.
6.2 RELEASES TO THE ENVIRONKENT
Incomplete combustion of carbonaceous material is the major source
of B[a]P formation in the environment, and residential heating is the
single largest combustion source. The large quantity of B[a]P released
during home heating is primarily a consequence of inefficient combustion
processes and uncontrolled emissions. Historically, the greatest amount
of residential B[a]P releases has been attributed to home combustion of
coal (Edwards 1983, Pucknat 1981, Perera 1981, Suess 1976, NAS 1972).
However, current trends in energy consumption indicate a diminishing
reliance on coal as a residential heating source and an increased
reliance on heating oil, electricity, gas, and wood (Census 1981). Of
all home heating sources, wood heating is by far the greatest
contributor to Bta]P emissions. In fact, Harkov and Greenberg (1985)
estimated that over 95% of all B[a]P emissions in New Jersey are from
home wood combustion. In a recent assessment of B[a]P sources and
release volumes across the United States, EPA (1985) also estimated that
home wood combustion is the single largest B[a]P source, contributing 72
metric tons, or 40% of all released volumes. Combustion sources overall
are responsible for 154 metric tons, or over 90% of total B[a]P
releases. All other sources (e.g., coal tar, creosote, asphalt, and
bitumen production and use) individually contribute 2% or less to total
B[a]P releases.
Ninety-eight percent of all estimated environmental releases of
B[a]P are to air. Of the remaining 2%, approximately equal amounts of
B[a]P are released to water and land.
Although they contribute small amounts of B[a]P and other PAHs to
the environment on a national scale, hazardous waste sites may
-------
76 Section 6
constitute concentrated sources of B[a]P and PAHs on a local scale. For
example, abandoned wood treatment plants are sources of high
concentrations of creosote; former manufactured-gas plants (town gas
sites) are sources of high concentrations of coal tar. Both creosote and
coal tar are composed of a variety of PAHs, including B[a]P. PAHs at
these sites are likely to occur on the soil and on suspended particulate
matter in the air.
6.3 ENVIRONMENTAL FATE
The environmental fate of B[a]P is determined, to a large degree,
by the chemical's low water solubility (3.8 fig/L at 20°C) and high
propensity for binding to particulate or organic matter. As a result,
B[a]P in the atmosphere is associated primarily with particulate matter,
especially soot, whereas the majority of B[a]P in aquatic systems is
strongly bound to suspended particles or bed sediments. Likewise, B[a]P
is strongly sorbed to soils. Dispersion of particle-bound B[a]P is the
primary transport process within air, water, and land. B[a]P can leach
through soils, but low water solubility and strong sorption to soil
limit the relative importance of this intramedia transport process.
Dry deposition of particle-bound B[a]P is the most significant
transport process between air and land or water. Approximately 52% of
B[a]P released into the atmosphere will reach the surface via dry
deposition; wet deposition is less significant by a factor of from 3 to
5 (EPA 1985). Because of a very low vapor pressure, B[a]P that reaches
the surface will likely remain, and will be partitioned to
soil/sediment. Soil/particle adsorption or biotic uptake are the primary
transport processes for the removal of waterborne B[a]P. Desorption into
water from soil is very unlikely, and erosion of contaminated soils by
surficial runoff is the most probable process for transport of soil-
bound B[a]P to aquatic systems.
Information about the fate of particulate B[a]P released to the
atmosphere is unclear. It is generally assumed, however, that
photochemical oxidation processes play an important role. Atmospheric
half-lives on the order of hours or days have been suggested (NAS 1972).
B[a]P strongly absorbs solar radiation at wavelengths above 300 nm, and
there is sufficient evidence to indicate that B[a]P undergoes
photooxidation in solution, as the pure solid, and when adsorbed onto
certain solid substrates (e.g., alumina) (NAS 1972). Singlet oxygen has
been implicated as the primary oxidant, and endoperoxides (and,
ultimately, quinones) as the reaction products (NAS 1972).
It has been inferred that similar processes take place when the
compounds are adsorbed on airborne particles. However, the data in
support of this view are somewhat limited. Thomas et al. (1968) reported
that B[a]P adsorbed on soot was readily photooxidized, with 40% of the
B[a]P destroyed within the first 40 mln of Illumination. Peters and
Seifert (1980) reported that B[a]P deposited from liquid solution onto
dust-coated glass fiber filters underwent rapid photodegradation when
exposed to unfiltered halogen lamp light. However, Korfmacher et al.
(1980a,b) found that B[a]P will rapidly photooxidize in liquid solution
but is highly resistant when adsorbed on fly ash. Additional research is
needed to elucidate the exact fate of atmospheric B[a]P.
-------
Environmental Fate 77
Within aquatic systems, B[a]P accumulates in the sediment and is
transported with suspended sediment. B[a)P in the water column also
accumulates in aquatic organisms. However, many organisms metabolize and
excrete B[a]P rapidly, so that bioaccumulation is a short-term process.
For example, in bluegill sunfish, an 89% loss of B[a]P was recorded 4 h
after exposure (Leversee et al. 1981). Lee et al. (1972) reported rapid
elimination of B[a]P in three species of California marine teleosts.
Depuration rates in invertebrate species vary more widely. Some species
(e.g., hard-shell clams) show little or no depuration, while others
(e.g., oysters) eliminate virtually all PAHs following exposure (Eisler
1987).
Aquatic organisms also can assimilate B[a]P and other PAHs from
food. For example, crustaceans and fish have been reported to readily
assimilate PAHs from contaminated food (Eisler 1987). However, in many
cases where assimilation of PAHs has been demonstrated, metabolism and
excretion of PAHs were rapid (Eisler 1987). In laboratory aquatic
ecosystem studies in which radiolabeled B[a]P was used, Lu et al. (1977)
found that B[a]P can be accumulated through the food to high levels in
mosquito fish. After 3 days of exposure, the intact parent compound
comprised over 50% of the extractable radiolabeled carbon in fish.
However, after 33 days of exposure, the intact parent compound comprised
only 7% of the total extractable radiolabeled carbon, indicating
metabolism of B[a)P. The tendency of fish to metabolize B[a]P may
explain why B[a]P is frequently undetected, or only detected in low
concentrations in the livers of fish from environments heavily
contaminated with B[a]P and other PAHs.
A minimal amount of B[a]P is dissolved and degraded rapidly by
direct photolysis. Smith et al. (1978) calculated a half-life of 1.2 h
for midday direct photolysis of dissolved B[a]P. Chemical oxidation may
be a significant fate process for B[a]P degradation in water when
chlorine or ozone (both oxidants) exist in sufficient concentrations
(EPA 1979a).
The major fate of sediment-bound B[a]P is biodegradation. In
general, biodegradation processes are quite slow; a half-life of
21,000 h has been reported for B[a]P (EPA 1979a). Biodegradation half-
lives in contaminated streams can be from 10 to 400 times longer. These
long half-lives indicate that B(a]P is relatively persistent in
sediments and aquatic systems.
Within terrestrial systems also, biodegradation is the probable
fate process. However, this process is very slow and, consequently,
B[a]P is very persistent in soils. Bossert and Bartha (1986) reported
that 72% of the original amount of B[a]P applied to soils existed after
16 months of incubation with bacteria. Coover and Sims (1987) estimated
a half-life of B[a]P in soil of 290 days.
At hazardous waste sites half-lives may be longer, as other
contaminants present at the site may be toxic to the degrading
microorganisms. Bossert and Bartha (1986) reported reduced
biodegradation of B[a]P in soil containing a chemical toxic to
microorganisms.
-------
79
7. POTENTIAL FOR HUMAN EXPOSURE
7.1 OVERVIEW
As the previous discussions indicate, the greatest portion of
environmental B[a]P releases are directly into the atmosphere.
Consequently, inhalation is the primary route of background human
exposure to B[a]P in the environment. Approximately 52% of the B[a|P in
the atmosphere returns to the surface via dry deposition. This input, in
addition to small direct releases by industry and publicly owned
treatment works, leads to B[a]P in soil and water to which humans may be
exposed. Humans may also be exposed to B[a]P in food, tobacco smoke, and
some occupational environments, and through contact with PAH-containing
products (e.g., coal tar, coal tar-based shampoos, asphalt, and
creosote-treated wood). At hazardous waste sites, humans will most
likely be exposed to B[a]P in the soil and on particulate matter in air.
7.2. LEVELS MONITORED IN THE ENVIRONMENT
7.2.1 Air
B[a]P has been detected in both urban and rural atmospheres, but a
concentration of industrial activities and transportation in and around
cities has led to a substantial difference between B[a]P concentrations
in urban and nonurban areas. B[a]P concentrations reported for urban air
are up to 10 to 100 times greater than concentrations in rural areas.
Pucknat (1981) summarized 1970 data from the National Air Sampling
Network (NASN) and reported B[a]P concentrations in 120 U.S. cities of
between 0.2 and 19.3 ng/m^. Ambient BTa]P concentrations in nonurban
areas ranged between 0.1 and 1.2 ng/m*.
Other investigators (Edwards 1983, Perera 1981, Sawicki 1976) have
reported similar ambient air concentrations for U.S. urban and rural
areas, using data derived largely from the 1960s and early 1970s. More
recent data, however, indicate that ambient levels may be decreasing.
Faoro and Manning (1981) analyzed a limited sample of NASN data updated
through 1977 and indicated that B[a]P concentrations have shown
consistent sizeable declines during the period from 1967 to 1977 at 26
urban sites and 3 background sites studied (data not provided). However,
this trend was described based on a limited sample size and, therefore,
cannot be regarded as definitive.
In addition to historical trends, seasonal variations in B[a]P air
levels also have been demonstrated. Harkov and Greenberg (1985) studied
B[a]P emissions during the heating season (November-March) and the non-
heating season, and estimated (based on monitoring data) that 97% of the
annual B[a]P emissions in New Jersey occurred during the 5-month heating
-------
80 Section 7
season. This emission pattern is consistent with reports by other
authors (Edwards 1983, Pucknat 1981).
7.2.2 Water
B[a]P has been detected in U.S. groundwaters and in surface waters
used as drinking water sources, but minimal data limit the degree to
which background levels can be adequately characterized.
EPA (1980) reported B[a]P concentrations in groundwater in one site
in Indiana and one site in Ohio to be 4.0 and 0.3 ng/L, respectively.
Concentrations of B[a]P in treated surface waters used as drinking water
sources ranged between 0.3 and 2.0 ng/L. Untreated water concentrations
ranged between 0.6 and 210 ng/L (EPA 1985, 1980; Sorrell 1981).
Because of a high propensity to bind to organic matter, it is
unlikely that B[a]P will occur to any appreciable extent in surface
water or groundwater at hazardous waste sites or other areas.
7.2.3 Soil
Very few data are available on B[a]P levels in U.S. soils. Blumer
(1961) reported concentrations between 40 and 1300 Mg/kg in the soil
from relatively rural areas of the eastern United States. Soil
concentrations in more populated and industrialized areas may be higher.
Butler et al. (1984) have demonstrated much higher soil B[a]P
concentrations near complex road interchanges than at areas more
distant. Typical concentrations of B[a]P in soils of the world are
between 100 and 1,000 fig/kg, although values as high as 650,000 fig/kg
(10 m from a German soot plant) have been reported (Edwards 1983). Soils
near waste sites (e.g., former manufactured-gas plants and creosote wood
treatment plants) can be expected to contain B[a]P and other PAHs in the
soil.
7.2.4 Food
B[a]P has been detected in unprocessed cereal, potatoes, grain,
flour, bread, vegetables, and fruits, and in a variety of processed
foods and beverages (Grimmer 1983). EPA (1985) estimated a daily B[a]P
intake from food of 50 ng. The method of preparation of certain foods
can increase the B[a]P intakes. In meat or fish, the amount of B[a]P
present depends to some degree on the method of cooking; time of
exposure, distance from the heat source, and the disposal of fat during
cooking all influence B[a]P content. Charcoal broiling increases the
amount of B[a]P in meat. Lijinsky and Shubik (1965) measured an average
of 9 /ig/kg B[a]P in charcoal-broiled steak. B[a]P also has been detected
in vegetables and fruits grown in B[a]P-contaminated soil near areas
with high vehicular traffic (Wang and Meresz 1982). Thus, consumption of
food grown near hazardous waste sites and areas of high vehicular
traffic may contribute to human exposure to B[a]P.
Humans also may be exposed to B[a]P in aquatic organisms (e.g.,
fish, clams, and oysters) that are typical components of the diet. PAHs,
including B[a]P, have been detected in bivalve mollusks (i.e., clams,
oysters, mussels), crabs, and lobsters (Eisler 1987). PAHs also have
-------
Potential for Human Exposure 81
been detected in fish, but fish levels are usually low, probably because
this group rapidly metabolizes PAHs.
7.2.5 Tobacco Products and Tobacco Smoke
B[a]P has been reported to occur in chewing tobacco (Hoffman et al.
1986) and in mainstream and sidestream tobacco smoke. Concentrations in
cigarette mainstream smoke between 5 and 78 ng/cigarette have been
reported (IARC 1983). Concentrations in sidestream smoke have been
reported to be even higher. Undiluted sidestream smoke of four types of
commercial cigarettes contained more B[a]P (44.8 to 67.0 ng/cigarette)
than the mainstream smoke of the same cigarette (2.2 to 26.2
ng/cigarette) (Adams et al. 1987).
Today there is an increasing concern about indoor air pollution by
environmental tobacco smoke. A report by the U.S. Surgeon General (1986)
concluded that environmental tobacco smoke can be a substantial
contributor to the level of indoor air pollution concentrations of
respirable particles. These higher concentrations of sidestream smoke
constituents (e.g., B[a]P), in conjunction with the fact that many
people spend many hours in indoor polluted atmospheres, may lead to
increased health risks to individuals passively exposed to cigarette
smoke.
7.3 OCCUPATIONAL EXPOSURES
B[a]P has been isolated in numerous occupational situations,
including coal-tar production and coking plants, coal gasification
sites, smoke houses, aluminum production plants, bitumen and asphalt
production plants, road and roof tarring operations, and around
municipal incinerators. Within these environments, B[a]P occurs with a
complex mixture of other PAHs. Thus, exposure to B[ajp alone does not
occur. Historically, the highest level of human exposure to B[a]P
occurred in industrial situations; B[a]P concentrations ranging from 800
to 23,100 ng/m^ have been reported to occur in the workroom air of coke
oven operations in the United Kingdom (Davies et al. 1986). Similarly
high values have been reported by Lindstedt and Solenberg (1982) in
Swedish industries.
7.4 POPULATIONS AT HIGH RISK
At highest risk for cancer by B[a]P are those people who are
exposed to high levels of B[a]P. Examples of high-risk populations
include: workers in certain occupations that have elevated B[a]P
concentration in the ambient work environment; smokers and involuntary
(passive) smokers who receive elevated B[a]P intake in tobacco smoke;
and populations living near industries (e.g., creosote and coal tar
manufacturers) that generate B[a]P as a by-product of production.
Individuals in these high-exposure groups may have varying
susceptibility to PAH toxicity. Some of the available data on PAH
carcinogenicity suggest a relationship between aryl hydrocarbon
hydroxylase (AHH) activity and cancer risk. Genetic variation in AHH
inducibility has been implicated as a determining factor for
susceptibility to lung and laryngeal cancer (EPA 1980). Attempts have
been made to demonstrate that persons with lung cancer have higher
-------
82 Section 7
inducibillty of AHH in cultured lymphocytes. A review by Calabrese
(1984) indicates that several studies support this hypothesis, find some
genetic data indicate that the human population can be segregated based
on this trait (EPA 1980). Thus, individuals that are AHH-inducible may
constitute a high-risk population. However, the data regarding genetic
susceptibility are not conclusive.
-------
83
8. ANALYTICAL METHODS
8.1 ENVIRONMENTAL SAMPLES
The procedures used to sample and extract B[a]P In different media
are very similar. In air and tobacco smoke, PAHs, including B[a]P, are
adsorbed predominantly on particulate matter, and the particulate matter
is collected on a filter. In water and soil, PAHs are extracted without
filtration.
The extraction of PAHs from the filter can be accomplished by a
variety of techniques with or without solvents. The following extraction
techniques are the most commonly used: soxhlet, sublimation at elevated
temperatures, ultrasonic, and polytron extraction (Sawicki 1976, Swanson
and Walling 1981).
A cleanup step is necessary to separate B[a]P and PAHs from other
chemicals. Typically, this step involves liquid-liquid extraction of the
dry organic particulate extract, followed by adsorption chromatography
using silica gel or alumina columns (Sawicki 1976, Riggin and Strup
1984). These adsorbents selectively remove interfering compounds. In
addition, thin-layer chromatography can be used as a cleanup method
(Sawicki 1976) but may not yield a B[a]P peak free of interference
(Tomkins et al. 1985).
The most commonly used analytical methods for determining B[a]P in
environmental samples are column gas chromatography (GC) and high-
performance liquid chromatography (HPLC). Table 8.1 summarizes common
analytical methods, detection limits, and accuracy (percent recovery)
for the determination of B[a]P in air, water, soil, cigarette smoke, and
food.
Column gas chromatography (GC) is an analytical technique in which
components of a sample are separated by differential distribution
between a gaseous mobile phase and a solid or liquid stationary phase
(EPA 1983). Complete separation of B[a]P from other PAHs is difficult
using gas chromatography. When B[a]P is present in the sample with
perylene or benzo[e]pyrene, separation of B[a]P is insufficient because
of problems in resolution (Sawicki 1976). Following separation in the GC
column, sample components are identified and quantified by a detection
system [e.g., flame ionization detection (FID) or mass spectrometry
(MS)]. These techniques are detailed in NIOSH (1984) and EPA (1983,
1984a).
HPLC is an analytical method in which components are separated
based on their polarity (EPA 1983). Reverse-phase HPLC, which is used
more widely for the analysis of PAHs, uses a nonpolar stationary phase
and a polar mobile phase; hydrophilic components are eluted earlier than
-------
84 Section 8
Table 8.1. Methods for uilyiis of benzofafeyreae 1b earironiiienUl media
Media
Sample preparation
Analytical
method"
Detection limit
Accuracy
References
Air
Ultrasonic extraction with
cyclohexane
HPLC
3 ng/m3
(1500-m3 sample)
NA*
NIOSH 1984
(Method 5506)
Ultrasonic extraction with
benzene, pentane, or dichloro-
methane
HPLC/FS
5 PS
NA
Andersson et al.
1983
Soxhlet extraction with
benzene-methanol
GC/MS
0.05 ng/m1
NA
Matsumoto and
Kashimoto 1985
Extraction with solvent
GC/MS
NA
NA
NIOSH 1984
(Method 5515)
Soxhlet extraction with
dichloromethane
TLC/FS
0.1 ng/g suspended
particulate matter
NA
Katz 1979
Soxhlet extraction with
petroleum benzene
TLC/QLL
0,05 rtg/mL extract
NA
Yanjrsheva and
Kireeva 1979
Water
Extraction with methylene
chloride
HPLC/FS
0.023 ng/L
~56%
EPA 1984a
(Method 610)
UV
4»»g/L
76-135%
Riggin and Strap
1984
Extraction with dichloro-
methane
HPLC/UV
2.5 pg/L
NA
Ogan et aL 1979
Extraction with methylene
chloride at pH < 2
and pH > 11
GC/MS
2.5 Mg/L
-90%
EPA 1984a
(Method 625)
GC/MS
NA
NA
EPA 1986a
Extraction with methylene
chloride at pH 12-13 and
pH < 2
GC/MS
10 Mg/L
NA
EPA 1984a
(Method 1625)
Extraction with cyclohexane
TLC/FS
0.5-1 ng/L
NA
Borneff and Kunte
1979
Not specified
TLC/QLL
0.03 ng/L
(10-L sample)
NA
Ya Khesina 1979
Soil
Extraction with n-pentane
TLC/UV
NA
NA
Butler et al.
1984
Soxhlet extraction with
benzene
TLC/UV
NA
NA
Blumer 1961
Extraction with methylene
chloride
GC/MS
NA
NA
EPA 1986a
Cigarette tmoke
Ultrasonic extraction with
benzene
HPLC/FS
<1 ng/cigarette
95%
Tomfcins et al.
1985
Food
Extraction with isooctane
TLC/UV
0.2 Mg/kg
NA
Howard 1979
'Abbreviation!: HPLC, high-performance liquid chromatography, TLC, thin-layer chromatography; FS. fluorescence
spectroscopy; QLL, quasi-Linear luminescence; GO, column gas chromatography; MS, mass spectrometry; UV, ultraviolet
absorption spectroscopy.
*NA — Not available.
-------
Analytical Methods 85
are hydrophobic components. HPLC can separate B[a]P from other PAHs
(Sawicki 1976). The detection systems most appropriate for HPLC analysis
of B[a]P are UV absorption spectroscopy (UV) and fluorescence
spectroscopy (FS) (EPA 1983). Fluorescence spectroscopy is useful for
extremely dilute solutions; therefore, pretreatment and cleanup of the
sample before HPLC may not be necessary (Das and Thomas 1978).
Thin-layer chromatography (TLC) has also been used to analyze for
PAHs. One-dimensional TLC cannot separate B[a]P from other PAHs;
however, B[a]P can be separated using a two-dimensional alumina-
cellulose acetate TLC (Sawicki 1976). With quasi-linear luminescence
methods (QLL), quasi-linear spectra can be obtained for PAHs at liquid
nitrogen temperatures (Sawicki 1976).
GC and HPLC are the chromatographic methods routinely used for the
determination of 10 to 20 of the major PAHs in air and water samples.
Detailed analysis of major and minor PAHs in a complex PAH mixture
requires a combination of chromatographic techniques (Wise et al. 1986).
GC/MS has a detection limit of >10 pg; HPLC has an approximate detection
limit for PAHs of 25 to 50 pg (Santodonato et al. 1981). TLC/FS has been
used for analysis of PAHs in air, water, and soil. It is useful for the
analysis of one or two compounds and has a detection limit of 1 to 2 ng
(Santodonato et al. 1981).
HPLC (5506) or GC/MS (5515) are the methods recommended by NI0SH
for analyzing PAHs in workplace air (NIOSH 1984). These methods
incorporate a sampling train consisting of a filter and a solid sorbent
(NIOSH 1984). The use of a high-volume sampler to sample a large
quantity of air allows for detection of small amounts of B[a]P. The
analytical methods required by EPA (1984a) for the analysis of B[a]P in
water are procedures 610 (HPLC/FS), 625 (GC/MS), and 1625 (GC/MS). These
are required test procedures for municipal and industrial wastewater-
discharging sites under the Clean Water Act. GC/MS is the method
required by the EPA Contract Laboratory Program (CLP) for analysis of
B[a]P and other PAHs in water and soil. The Contract Required
Quantitation Limit (CRQL) for B[a]P in water is 10 /ig/L, and that in
soil/sediment is 330 Mg/kg (EPA 1986a).
8.2 BIOLOGICAL SAMPLES
The available biological monitoring techniques are useful for
detecting whether occupational or environmental exposure to PAHs has
occurred, but because there have been no population-based studies to
determine normal body levels of PAHs, it is not yet possible to predict
environmental exposure from body PAH levels or to predict what health
effects are likely to be associated with these levels. In general,
techniques that measure PAH or PAH metabolite concentration in the urine
are most appropriate for use in determining occupational exposure, since
a high level of PAH exposure is necessary to result in the presence of
these compounds in the urine. Methods that detect diol epoxide-DNA
adducts are more sensitive to low exposure levels and are most
appropriate for use in determining environmental exposure. The
techniques presently available for determining exposure to PAHs are
summarized in Table 8.2 and discussed in detail in this subsection.
-------
86
Section 8
Table 8.2. Methods for analysis of PAHs
in biological samples
Medium
Technique
Measured
parameter
Reference
Tissue
Gas chromatography
PAH concentration
Modica et al. 1982,
Bartosek et al. 1984
Postlabeling of DNA
Diol epoxide-DNA
adducts
Randerath et al. 1985,
1986
High-performance
liquid chromatography
Diol epoxide-DNA
adducts
Shugart 1985, 1986;
Haugen et al. 1986
Liquid chromatography
Diol epoxide-
hemoglobin adducts
Shugart 1985, 1986
Blood
Immunoassay
Antibodies to diol
epoxide-DNA adducts
Harris 1985,
Harris et al. 1985,
Harris et al. 1986
Urine
Gas chromatography
PAH concentration
Clonfero et al. 1986
High-performance
liquid chromatography
PAH concentration
Becher and Bjorseth
1983, Becher et al.
1984
-------
Analytical Methods 87
Modica et al. (1982) and Bartosek et al. (1984) examined PAHs
(specifically chrysene and benz[a]anthracene) present in blood, mammary,
adipose, liver, and brain tissue from rats orally exposed to PAHs, using
gas-liquid chromatography and FID. PAHs were determined in all tissues
examined. Examples of PAH concentrations in human tissue samples using
this technique were not located in the available literature. The
detection units for this method were not reported.
In mammalian systems, B[a]P can be converted by specific cellular
enzymes to trans-B[a]P-7,8-dihydrodiol. This metabolite is further
converted to two isomeric diol epoxides (anti- and syn-B[a]PDE). These
diol epoxides are capable of binding to DNA (Ueinstein et al. 1976). The
degree of DNA adduct formation can be used as a measure of dose in
target tissues or organs (Phillips et al. 1979; Perera et al. 1982; Rahn
et al. 1982; Randerath et al. 1985; Vahakangas et al. 1985; Shugart
1985, 1986). Randerath et al. (1985, 1986) examined PAH-DNA adducts in
skin tissue from mice dermally treated with cigarette smoke condensate
and placenta, bronchus, and larynx tissue from smokers. In this
technique, radioactivity (^P) is incorporated into the DNA removed from
the exposed cells and the digested DNA is separated using TLC.
Quantitation of the adducts is achieved by scintillation counting. Small
amounts of DNA are needed for analysis. In another technique, B[a]PDE-
DNA adducts obtained from mice dermally exposed to or subcutaneously
injected with B[a]P were isolated and acid hydrolyzed, and the liberated
tetrols were analyzed by HPLC/FS (Shugart 1985, 1986).
Shugart (1985, 1986) also reported that there is a dose-response
relationship between the amount of B[a]P and the occurrence of B[a]P
adducts to hemoglobin in mice exposed dermally or by subcutaneous
injection. The B[a]PDE adducts with hemoglobin can be Isolated and acid
hydrolyzed, and the liberated tetrols can be analyzed by HPLC/FS.
Further, Shugart (1985, 1986) reported that the amount of anti-B[a]PDE
binding to DNA and hemoglobin at various doses of B[a]P appears to be
qualitatively similar. The anti-diol epoxide is the carcinogenic form
that interacts with both hemoglobin and DNA in the target tissue
(Shugart 1985). Therefore, a measure of the stable hemoglobin adducts in
blood may be suitable for estimating carcinogenic risk of B[a]P
exposure.
Procedures are currently available that examine the presence of
antibodies to DNA adducts in the blood using enzymatic immunoassays
(Perera et al. 1982; Santella et al. 1985; Harris 1985; Harris et al.
1985, 1986; Haugen et al. 1986). Perera et al. (1982) injected mice
intraperitoneally with B[a]P and reported a dose-related increase in DNA
adducts as determined by immunoassay. Harris (1985, Harris et al. 1985)
developed a technique for determining human exposure to PAHs by
detecting antibodies in sera to diol epoxide-DNA adducts using an
immunoassay. The technique was tested on coke oven workers exposed to
substantial amounts of B[a]P and other PAHs in the work atmosphere,
smokers, and nonsmokers. Antibodies to B[a]P diol epoxide-DNA adducts
were quantified by enzyme-1inked iramunosolvent assay (ELISA). Higher
proportions of sera positive for antibodies were found in a group of
smokers and in the occupationally exposed group.
-------
88 Section 8
The urine of exposed animals or humans has been examined for the
presence of B[a]P and B[a]P metabolites. PAHs and their metabolites were
extracted from human urine and analyzed using HPLC/FS or GC/MS following
occupational exposure or therapeutic coal tar application (Becher and
Bjorseth 1983, Becher et al. 1984, Jongeneelen et al. 1985, 1986;
Clonfero et al. 1986). Occupationally exposed individuals were found to
have a higher concentration of PAHs in the urine than unexposed
individuals. However, high environmental concentrations of PAHs in the
workplace were not found to be reflected to the same extent in excretion
of PAHs in the urine (Becher and Bjorseth 1983, Becher et al. 1984).
This was suggested to result from the nonbioavailability of
particulate-bound B[a]P, and this method may still be applicable in
other exposure situations. Clonfero et al. (1986) reported that B[a]P
was found in the urine of individuals dermally treated with therapeutic
coal tar, but only high levels of PAHs in the coal tar resulted in a
measurable urine concentration. Quantification of the urinary metabolite
of B[a]P, 3-hydroxy-benzo[a]pyrene, by HPLC/FS can also be used as an
indication of exposure to B[a]P (Jongeneelen et al. 1986). Detection
limits for chromatographic techniques used in urine analysis were not
reported.
Vo-Dinh et al. (1987) have developed an antibody-based fiber-optic
biosensor that can be used to detect B[a]P or other PAHs in sample
solutions. In this technique, antibodies to B[a]P are covalently bound
to the tip of the sensing probe. A helium-cadmium laser excites the
molecules of B[a]P bound to the antibodies, and the resulting
fluorescence of these molecules is recorded by a photomultiplier. The
intensity of the fluorescence signal is proportional to the amount of
antigen bound to the sensor tip. The fiber-optics device can detect
1 femtomole (fmol; one-quadrillionth of a mole) B[a]P in a 5-jiL sample
drop. This technique can be useful in the assessment of an individual's
exposure to B[a]P and other PAHs, provided appropriate antibodies are
used.
-------
89
9. REGULATORY AND ADVISORY STATUS
Regulatory standards and advisory levels have been developed for
the carcinogenic PAHs and for B[a]P specifically. The present regulatory
(enforceable) standards and advisory (nonenforceable) levels for air and
water exposures are presented in Table 9.1 and discussed in detail in
this section.
B[a]P has been shown to be carcinogenic in experimental animals and
undergoes metabolism to reactive electrophiles capable of binding
covalently to DNA and inducing bacterial mutation and DNA damage. IARC
(1983) has classified B[a]P in Group 2B, because of sufficient evidence
of carcinogenicity in experimental animals. IARC (1985) has also
concluded that there is sufficient evidence of carcinogenicity of coal
tars, creosote, and coal tar pitches in experimental animals. In
addition, IARC (1985) concluded that there is sufficient evidence that
occupational exposure to coal tar and coal tar pitch is associated with
skin cancer and that there is limited evidence of the carcinogenicity of
creosote in occupationally exposed individuals.
Applying the classification criteria for weight of evidence
developed by the Carcinogen Assessment Group of EPA, B[a]P is classified
by EPA (1984b) In Group B2--probable human carcinogen. This category
applies to agents for which there is sufficient evidence of
carcinogenicity from animal studies and inadequate evidence of
carcinogenicity from epidemiologic studies.
9.1 INTERNATIONAL
The World Health Organization (WHO 1971) set an upper limit of 0.2
jig/L for the total concentration of the PAHs B[a]P, fluoranthene,
benzo[g,h,i]perylene, benzo[b]fluoranthene, benzo[k]fluoranthene, and
indeno[l,2,3-cd]pyrene in domestic waters. This limit was not chosen on
the basis of potential health effects.
9.2 NATIONAL
9.2.1 Regulatory Standards
Coal tar, coal tar pitch, and creosote are considered by NIOSH and
EPA to be human carcinogens (NIOSH 1977; EPA 1978, 1981, 1986b). NIOSH
reviewed epidemiologic and experimental toxicological evidence and
concluded that inhalation exposure to these coal products, which contain
a number of PAHs including B[a]P, increases the risk of lung and skin
cancer in workers (NIOSH 1977). The Secretary of Labor has taken the
position that no safe occupational exposure can be established for a
carcinogen.
-------
Section 9
Table 9.1. Regulatory standards and advisory levels
Regulatory standard
or advisory level
Basis
Concentration or
risk coefficient
Reference
Air
Regulatory standard:
8-h Time-
weighted average
permissible
exposure limit
(PEL)
Benzene-soluble frac-
tion of coal tar
pitch volatiles
0.2 mg/m3
OSHA 1985a
Advisory levels:
8-h Time-
weighted average
PEL
B[a]P
0.2 Mg/m3
OSHA 1985b
8-h Time-
weighted average
threshold limit
value
Benzene-soluble frac-
tion of coal tar
pitch volatiles
0.2 mg/m3
ACGIH 1986
10-h Time-
weighted average
threshold limit
value
Cyclohexane-soluble
fraction of coal tar
pitch volatiles
Water
0.1 mg/m3
NIOSH 1977
Advisory levels:
Ambient water
quality criterion
Total carcinogenic
PAHs
0 (28, 2.8, and
0.28 ng/L)°
EPA 1980
"The EPA recommended concentration for ambient water is zero. However,
because attainment of this level may not be possible to achieve, the EPA estimated
concentrations of total carcinogenic PAHs for ambient water corresponding to a
10'5, 10'6, and 10'7 upper-bound lifetime excess risk estimate, respectively, are
presented.
-------
Regulatory and Advisory Status 91
The current workroom air standard determined by OSHA is an 8-h
time-weighted average permissible exposure limit (PEL) of 0.2 mg/m^ for
the benzene-soluble fraction of coal tar pitch volatiles. The PEL was
established to minimize exposure to those volatiles believed to be
carcinogens; these include B[a]P as well as anthracene, phenanthrene,
acridine, chrysene, and pyrene (OSHA 1985a, 1986).
9.2.2 Advisory Levels
9.2.2.1 Air advisory levels
Proposed OSHA permissible exposure limit. In 1974, OSHA
established the Standards Advisory Committee on Coke Oven Emissions. The
Committee recommended a time-weighted average PEL of 0.2 for
occupational exposure to B[a]P (OSHA 1985b).
ACGIH time-weighted average threshold limit value. The American
Conference of Governmental Industrial Hygienists (ACGIH 1986)
recommended a time-weighted average threshold limit value (TLV) for
occupational exposure to coal tar pitch volatiles based on an 8-h
workday and a 40-h week. The ACGIH time-weighted average TLV of 0.2
mg/m^ was recommended for the benzene-soluble fraction of coal tar pitch
volatiles (including B[a]P as well as anthracene, phenanthrene,
acridine, chrysene, and pyrene). The TLV is based upon the ACGIH
conclusion that, at concentrations below 0.2 mg/m^, any increase in the
incidence of lung and other tumors caused by occupational exposure to
coal tar pitch volatiles should be minimal.
NIOSH time-weighted average threshold limit value. NIOSH examined
the epidemiologic and experimental toxicological evidence on coal tar,
coal tar pitch, and creosote and concluded that they are carcinogenic to
experimental animals and potentially humans (NIOSH 1977) . Polynuclear
hydrocarbons such as B[a]P have been identified in coal tar products.
Because of the carcinogenic potential of these compounds, NIOSH
recommended that the permissible exposure limit be set at the lowest
concentration detected by the NIOSH-recommended method of environmental
monitoring, 0.1 mg/m^ (NIOSH 1977). NIOSH proposed this time-weighted
average threshold limit value to reduce the risk of cancer associated
with exposure to coal tar products in the workplace.
9.2.2.2 Water advisory levels
Ambient water quality criterion. EPA (1980) developed an ambient
water quality criterion (AWQC) to protect human health from the
potential carcinogenic effects caused by exposure to carcinogenic PAHs
through ingestion of contaminated water and contaminated aquatic
organisms.
Benzo[a]pyrene is a known animal carcinogen. Because there is no
recognized safe concentration for a human carcinogen, EPA (1980)
recommended that the sum of the concentrations of total carcinogenic
PAHs in ambient water be zero. However, EPA (1980) recognized that a
zero concentration level may not be possible to attain. The present
criterion for total carcinogenic PAHs was developed using the
carcinogenicity assay reported by Neal and Rigdon (1967), in which
stomach tumors developed in CFtf-Swiss mice exposed to doses of
-------
92 Section 9
1 to 250 ppm B[a]P in the diet with a statistically higher incidence
than In controls. Assuming that an individual consumes 2 L of water and
6.5 g of fish and shellfish each day, the sun of the concentrations of
total carcinogenic PAHs corresponding to upper-bound lifetime excess
cancer risks of 10'^, 10~®, and 10"7 are 28, 2.8, and 0.2B ng/L,
respectively.
9.2.2.3 Food advisory levels
No food advisory levels for B[a}P were located in the available
literature.
9.2.2>4 Non-media-specific levels
Although EPA previously published Inhalation and oral cancer risk
estimates for B[a]P based on the studies of Thyssen et al. (1981) and
Neal and Rigdon (1967), these numbers are currently under review and
have not been included here pending recalculation.
9.2.2.5 Other guidance
Sections 103(a) and 103(b) of the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA) require that
persons in charge of vessels or facilities from which a hazardous
substance has been released in quantities that are equal to or greater
than its reportable quantity (RQ) immediately notify the National
Response of the release. Potential carcinogens are grouped into high-,
medium-, or low-hazard categories on the basis of biological information
available. The reportable quantity for B[a]P is 1 lb (EPA 1987).
9.3 STATE
The State of Mew York has recommended a guidance level of 0.2 /ig/L
for the sum of benz[a]anthracene, benzofluoranthene, B(a]P, chrysene,
fluoranthene, indeno[l,2,3-cd]pyrene, methylbenz[a]anthracene, and
pyrene in ambient water (NYSDEC 1984). (Regulations and advisory
guidance from the states were still being compiled at the time of
printing.)
-------
93
10. REFERENCES
Abe S, Nemoto N, Sasaki M. 1983a. Sister-chromatid exchange induction by
indirect mutagens/carcinogens, aryl hydrocarbon hydroxylase activity,
and B[a]P metabolism in cultured human hepatoma cells. Mutat Res
109:83-90.
Abe S, Nemoto N, Sasaki M. 1983b. Comparison of aryl hydrocarbon
hydroxylase activity and inducibility of sister-chromatid exchanges by
polycyclic aromatic hydrocarbons in mammalian cell lines. Mutat Res
122:47-51.
Adams J, O'Mara K, Hoffman D. 1987. Toxic and carcinogenic agents in
undiluted mainstream smoke and sidestream smoke of different types of
cigarettes. Carcinogenesis 8:729-731.
Agrelo C, Amos H. 1981. DNA repair in human fibroblasts. Prog Mutat
Res 1 (Eval Short-Term Tests Carcinog: Rep Int Collab Program)
1:528-532.
Agrelo CE, Severn BJ. 1981. A simplified method for measuring scheduled
and unscheduled DNA synthesis in human fibroblasts. Toxicology
21:151-158.
Aldrich Chemical Company. 1986. Catalog of Fine Chemicals. Aldrich
Chemical Co., Milwaukee, Wis.
Amacher DE, Paillet SC. 1982. Hamster hepatocyte-mediated activation of
procarcinogens to mutagens in the L5178Y/TK mutation assay. Mutat Res
106:305-316.
Amacher DE, Paillet SC. 1983. The activation of procarcinogens to
mutagens by cultured rat hepatocytes in the L5178Y/TK mutation assay.
Mutat Res 113:77-88.
Amacher DE, Zelljadt I. 1983. The morphological transformation of Syrian
hamster embryo cells by chemicals reportedly nonmutagenic to Salmonella
typhimurlwn. Carcinogenesis 4:291-295.
ACGIH (American Conference of Governmental Industrial Hygienists). 1986.
Threshold Limit Values and Biological Exposure Indices. 5th ed. ACGIH,
Cincinnati, Ohio.
*Key studies.
-------
94 Section 10
Andersson K, Levin J-O, Nilsson C-A. 1983. Sampling and analysis of
particulate and gaseous polycyclic aromatic hydrocarbons from coal tar
sources in the working environment. Chemosphere 12:197-207.
Autrup H, Harris CC, Trump BF, Jeffrey AM. 1978. Metabolism of B[a]P and
identification of the major B[a]P adducts in cultured human colon.
Cancer Res 38:3689.
Autrup H, Wefald WC, Jeffrey AM, et al. 1980. Metabolism of
benzo[a]pyrene by cultured tracheobronchial tissues from mice, rats,
hamsters, bovines, and humans. Int J Cancer 25:293-300.
Autrup H, Seremet T. 1986. Excretion of benzola]pyrene-Gua adduct in the
urine of benzo[a]pyrene-treated rats. Chem Biol Interact 60:217-226.
Baker RSU, Mitchell GA, Meher-Homji KM, Podobna E. 1983. Sensitivity of
two Chinese hamster cell lines to SCE induction by a variety of chemical
mutagens. Mutat Res 118:103-116.
Barbieri 0, Ognio E, Rossi 0, Astigiano S, Rossi L. 1986. Embryotoxicity
of benzo[a]pyrene and some of its synthetic derivatives in Swiss mice.
Cancer Res 46:94-98.
Barnes D et al. 1987. Reference dose (RfD): Description and use in
health risk assessments. Appendix A in Integrated Risk Information
System Supportive Documentation. Vol. 1. Office of Health and
Environmental Assessment, Environmental Protection Agency, Washington,
D.C., EPA/600/8-86/032a.
Bartley JC, Stampfer MR. 1985. Factors influencing B[a]P metabolism in
human mammary epithelial cells in culture. Carcinogenesis 6:1017-1022.
Bartosek I, Guaitani A, Modica R, Fiume M, Urso R. 1984. Comparative
kinetics of oral benz[a]anthracene, chrysene, and triphenylene in rats:
Study with hydrocarbon mixtures. Toxicol Lett 23:333-339.
Basler A, Bachmann U, Roszinsky-Kocher G, Robrborn G. 1979. Effects of
caffeine on slster-chromatid exchanges (SCE) in vivo. Mutat Res
59:209-214.
Basler A, Rohrborn G. 1978. Mutagenicity of polycyclic hydrocarbons. IV.
Correlated studies with anthracene, benzo[a)anthracene, B[a]P, chrysene,
and phenanthrene. Proc Perugia Qudrenn Int Conf Cancer 6:843-849.
Battzinger RP, Ou SL, Bueding E. 1978. Antimutagenic effects of 2(3)-
tert-butyl-4-hydroxyanisole and of antimicrobial agents. Cancer Res
38:4478-4485.
Bayer U, Bauknecht T. 1977. Dose-dependence of sister-chromatld
exchanges induced by 3 hydrocarbons in the in vivo bone marrow test with
Chinese hamsters. Experientia 33:25.
-------
References 95
* Becher G, Bjorseth A. 1983. Determination of exposure to polycyclic
aromatic hydrocarbons by analysis of human urine. Cancer Lett
17:301-311.
Becher G, Haugen A, Bjorseth A. 1984. Multimethod determination of
occupational exposure to polycyclic aromatic hydrocarbons in an aluminum
plant. Carcinogenesis 5:647-651.
Bermudez E, Couch DB, Tillery D. 1982. The use of primary rat
hepatocytes to achieve metabolic activation of promutagens in the
Chinese hamster ovary/hypoxanthine-guanine phosphoribosyl transferase
mutational assay. Environ Mutagenesis 4:55-64.
* Bingham E, Falk HL. 1969. The modifying effect of carcinogens on the
threshold response. Arch Environ Health 19:779-783.
* Blumer M. 1961. Benzpyrenes in soil. Science 134:474-475.
Bock FG, Mund R. 1958. A survey of compounds for activity in suppression
of mouse sebaceous glands. Cancer Res 18:887-892.
Borneff J, Kunte H. 1979. Analysis of polycyclic aromatic hydrocarbons
in water using thin layer chromatography and spectrofluorometry. In:
Egan H, ed. Environmental Carcinogens: Selected Methods of Analysis.
Vol. 3. Analysis of Polyaromatic Hydrocarbons in Environmental Samples.
International Agency for Research on Cancer, Lyon, France, pp. 129-139.
* Bossert ID, Bartha R. 1986. Structure biodegradability relationships
of polycyclic aromatic hydrocarbons in soil. Bull Environ Contain Toxicol
37:490-495.
Bradley MO, Bhuyan B, Francis MC, Langenbach R, Peterson A, Huberman E.
1981. Mutagenesis by chemical agents in V79 Chinese hamster cells: A
review and analysis of the literature. Mutat Res 87:81-142.
Brendel M, Ruhland A. 1984. Relationships between functionality and
genetic toxicology of selected DNA-damaging agents. Mutat Res 133:51-85.
Bruce tf, Heddle JA. 1979. Mutagenic activity of 61 agents as determined
by the micronucleus, Salmonella, and sperm abnormality assays. Can J
Genet Cytol 21:319-334.
Brusick D. 1980. Principles of Genetic Toxicology. Plenum Press, New
York.
Bulay OM, Uattenberg LW. 1971. Carcinogenic effects of polycyclic
hydrocarbon carcinogen administration to mice during pregnancy on the
progeny. J Nat Cancer Inst 46:397-402.
Butler JD, Butterworth V, Kellow C, Robinson HG. 1984. Some observations
on the polycyclic aromatic hydrocarbon (PAH) content of surface soils in
urban areas. Sci Total Environ 38:75-85.
-------
96 Section 10
Calabcese EJ. 1984. Ecogenetics: Genetic Variation in Susceptibility to
Environmental Agents. John Wiley and Sons, New York.
Casto BC, Janosko N, DiPaola JA. 1977. Development of a focus assay
model for transformation of hamster cells in vitro by chemical
carcinogens. Cancer Res 37:3508-3515.
Census. 1981. Housing Survey: 1981 General Housing Characteristics. Part
A, United States and Regions. Bureau of the Census, Washington, D.C.
Chipman JK, Hirom PC, Front GS, Millburn P. 1982. Benzo[a]pyrene
metabolism and enterohepatic circulation in the rat. In: Synder R et al.
eds. Biological Reactive Intermediates. II. Chemical Mechanisms and
Biological Effects, Part A. Plenum Press, New York, pp. 761-768.
Clive D, Johnson KO, Spector JFS, Batson AG, Brown MMM. 1979. Validation
and characterization of the L5178Y/TK+1-mouse lymphoma mutagen assay
system. Mutat Res 59:61.
Clonfero E, Zordan M, Cottica D, et al. 1986. Mutagenic activity and
polycyclic aromatic hydrocarbon levels in urine of humans exposed to
therapeutical coal tar. Carcinogenesis 7:819-823.
Cohen GM, Haws SM, Moore BP, Bridges Jtf. 1976. Benzo[a]pyrene-3-yl
hydrogen sulfate, a major ethyl acetate-extractable metabolite of B[a]P
in human, hamster, and rat lung cultures. Biochem Pharmacol
25:2561-2570a.
Conney AH. 1982. Induction of microsomal enzymes by foreign chemicals
and carcinogenesis by polycyclic aromatic hydrocarbons: G.H.A. Clowes
Memorial Lecture. Cancer Res 42:4875-4917.
Connor TH, Forti GC, Sitra P, Legator MS. 1979. Bile as a source of
mutagenic metabolites produced in vivo and detected by Salmonella
typhlmurium. Environ Mutagenesis 1:269-276.
Cook JW. 1933. The production of cancer by pure chemical compounds. In:
Torre Balnco J, Wissmann SC, eds. Congreso Intemacional de Lucha
Cientifica y Social contra el Cancer, Madrid. Vol. 2. Madrid, Blass,
p. 373.
Cook JW, Hewett CL, Hieger I. 1933. The isolation of a cancer-producing
hydrocarbon from coal-tar. J Chem Soc:395.
Cookson HA. 1924. Epithelioma of the skin after prolonged exposure to
creosote. Br Med J 68(1):368.
Cooper CS, Grover PL, Sims P. 19B3. The metabolism and activation of
benzo[a]pyrene. In: Bridges JW, Chase LF eds. Progress in Drug
Metabolism. Vol. 7. John Wiley and Sons, New York, pp. 295-395.
-------
References 97
* Coover MP, Sims RC. 1987. The effect of temperature on polycyclic
aromatic hydrocarbon persistence in an unacclimated agricultural soil.
Haz Waste Haz Mat 4:69-82.
* Cottini GB, Mazzone GB. 1939. The effects of 3,4-benzpyrene on human
skin. Am J Cancer 37:186-195.
CRC Handbook of Chemistry and Physics (CRC). 1987. 67th ed. CRC Press,
Boca Raton, Fla.
Craig-Holmes AP, Shaw MW. 1977. Effects of six carcinogens on SCE
frequency and cell kinetics In cultured human lymphocytes. Mutat Res
46:375-384.
Creasia DA, Poggenburg JK, Jr., Netteshelm P. 1976. Elutlon of
benzo[a]pyrene from carbon particles in the respiratory tract of mice.
J Toxicol Environ Health 1:967-975.
Crocker TT, Chase JE, Veils SA, Nunes LL. 1970. Preliminary report on
experimental squamous carcinoma of the lung in hamsters and in a primate
(Galago CrassLcaudatus). In: Nettesheim P, Hanna MG, Deatherage JW, eds.
Morphology of Experimental Respiratory Carcinogenesis. U.S. Atomic
Energy Commission Symposium Series 21, p. 317.
Dahl AR, Coslett DC, Bond JA, Hesseltine GR. 1985. Metabolism of
benzo[a]pyrene on the nasal mucosa of Syrian hamsters: Comparison to
metabolism by other extrahepatic tissues and possible role of nasally
produced metabolites in carcinogenesis. J Natl Cancer Inst 75:135-139.
Das BS, Thomas GH. 1978. Fluorescence detection in high performance
liquid chromatographic determination of polycyclic aromatic
hydrocarbons. Anal Chem 50:967-973.
Davidson GE, Dawson GWP. 1976. Chemically induced presumed somatic
mutations in the mouse. Mutat Res 38:151-154.
Davidson GE, Dawson GWP. 1977. Induction of somatic mutations in mouse
embryos by benzo[a]pyrene. Arch Toxicol 38:99-103.
* Davies GM, Hodkinson A, Divetta. 1986. Measurement and analysis of
occupational exposures to coke oven emissions. Ann Occup Hyg 30:51-62.
Davis BR, Whitehead JK, Gill ME, Lee PN, Butterworth AD, Roe FJR. 1975.
Response of rat lung to 3,4-benzpyrene administered by intratracheal
instillation infusine with or without carbon black. Br J Cancer
31:443-461.
Dean BJ. 1981. Activity of 27 coded compounds in the RL1 chromosome
assay. Prog Mutat Res 1 (Eval Short-Term Tests Carcinog: Rep Int Collab
Program): 570-579.
-------
98 Section 10
Dean R, Bynum G, Kram D, Schneider EL. 1980. Sister chromatid exchange
induction by carcinogens in HTC cells. An in vitro system which does not
require addition of activating factors. Mutat Res 74:477-483.
Dean RG, Bynum G, Jacobson-Kram D, Hadley E. 1983. Activation of
polycyclic hydrocarbons in Reuber H4-II-E hepatoma cells. Mutat Res
111:419-427.
* Deutsch-Wentzel RP, Brune H, Grimmer 0, Dettbarn G, Misfield J. 1983.
Experimental studies in rat lungs on the carcinogenicity and dose-
response relationships of eight frequently occurring environmental
polycyclic aromatic hydrocarbons. J Natl Cancer Inst 71:539-544.
Diamond L, Kruszewski F, Knowles BB, Baird WM. 1980. Metabolic
activation of B[a]P by a human hepatoma cell line. Carcinogenesis
1:871-875.
DiPaolo JA, Casto BC. 1976. In vitro transformation - Interaction of
chemical carcinogens with viruses and physical agents. Int Agency Res
Cancer Sci Publ 12:415-432.
DiPaolo JA, Donovan JP, Nelson RL. 1969. Quantitative studies of in
vitro transformation by chemical carcinogens. J Natl Cancer Inst
42:867-874.
DiPaolo JA, Donovan JP, Nelson RL. 1971. Transformation of hamster cells
in vitro by polycyclic hydrocarbons without cytotoxicity. Proc Natl Acad
Sci USA 68:2958-2961.
Dunkel VC, Pienta R-J, Sivak A, Traul KA. 1981. Comparative neoplastic
transformation responses of BALb 3T3 cells, Syrian hamster embryo cells,
and Rauscher murine leukemia virus-infected Fischer 344 rat embryo cells
to chemical carcinogens. J Natl Cancer Inst 67:1303-1315.
Edwards NT. 1983. Polycyclic aromatic hydrocarbons (PAHs) in the
terrestrial environment - A review. J Environ Qual 12:427-441.
Eisler R. 1987. Polycyclic Aromatic Hydrocarbon Hazards to Fish,
Wildlife, and Invertebrates: A Synoptic Review. Biological Report 85.
Contain Haz Rev Rep 11. U.S. Fish and Wildlife Service, U.S. Department
of the Interior, Washington, D.C.
* Elgjo K. 1968, Growth kinetics of the mouse epidermis after a single
application of 3,4-benzopyrene, croton oil, or 1,2-benzopyrene. Acta
Path Microbiol Scand 73:183-190.
EPA (Environmental Protection Agency). 1978. Notices of Rebuttable
Presumption Against Registration and Continued Registration (RPAR) of
Pesticide Products Containing Coal Tar Creosote and Coal Tar Neutral
Oils. Position Document (PD) 1. Office of Pesticide Programs,
Washington, D.C.
-------
References 99
* EPA (Environmental Protection Agency). 1979a. Water-Related
Environmental Fate of 129 Priority Pollutants. Washington, D.C.,
December, EPA 440/4-79-029.
EPA (Environmental Protection Agency). 1979b. Toxic Substances Control
Act. Chemical Substances Inventory. Volume E. Office of Toxic
Substances, Washington, D.C., EPA-TSCA-/CSE-VI.
* EPA (Environmental Protection Agency). 1980. Ambient Water Quality
Criteria for Polynuclear Aromatic Hydrocarbons. Office of Water
Regulations and Standards, Washington, D.C., EPA 440/5-80-069, NTIS
PB81-117806.
EPA (Environmental Protection Agency). 1981. Wood Preservative
Pesticides. Creosote, Pentachlorophenol, and the Inorganic Arsenicals
(Wood Uses). Position Document (PD) 2/3. Office of Pesticide Programs,
Washington, D.C.
EPA (Environmental Protection Agency). 1982. Aquatic Fate Process Data
for Organic Priority Pollutants. Office of Water Regulations and
Standards, Washington, D.C., EPA 40/4-81-014.
EPA (Environmental Protection Agency). 1983. Technical Assistance
Document for Sampling and Analysis of Toxic Organic Compounds in Ambient
Air. Environmental Monitoring Systems Laboratory, Research Triangle
Park, N.C., June, EPA 600/4-83-027.
EPA (Environmental Protection Agency). 1984a. Guidelines establishing
test procedures for the analysis of pollutants under the Clean Water
Act; final rule and interim final rule and proposed rule. Fed Regist
49:1-210 (Oct. 26, 1984).
EPA (Environmental Protection Agency). 1984b. Health Effects Assessment
for Benzo[a]pyrene. Environmental Criteria and Assessment Office,
Cincinnati, Ohio, September, EPA 540/1-86-022.
* EPA (Environmental Protection Agency). 1985. An Exposure and Risk
Assessment for Benzo[a]pyrene and Other Polycyclic Aromatic
Hydrocarbons. Vol. IV. Office of Water, Washington, D.C., EPA 440/4-85-
020-V4.
EPA (Environmental Protection Agency). 1986a. Statement of Work for
Organics Analysis. EPA Contract Laboratory Program. Attachment A.
EPA (Environmental Protection Agency). 1986b. Creosote,
pentachlorophenol, and inorganic arsenicals: Amendment of notice of
intent to cancel registrations. Fed. Regist 51:1334 (Jan. 10, 1986).
EPA (Environmental Protection Agency). 1987. 40 CFR Parts 117 and 302.
Reportable quantity adjustments. Fed. Regist 52:8140-8153 (Mar. 16,
1987).
-------
100 Section 10
Epstein SS, Arnold E, Andrea J, Bass W, Bishop Y. 1972. Detection of
chemical mutagens by the dominant lethal assay in the mouse. Toxicol
Appl Pharmacol 23:288-325.
Epstein SS, Shafner H. 1968. Chemical mutagens in the human environment.
Nature (London) 219:385-387.
Ermala P, Stela K, Ekwall P. 1951. Gastric absorption of 3,4-benzpyrene.
The effect of physiological processes on absorption. Cancer Res
11:753-757.
Fabian G, Matoltsy G. 1946. Test of a carcinogenic substance in respect
to the "non-disjunction" frequency of the X-chromosome in Drosophila.
Nature (London) 158:911-912.
Fahl WE, Scarpelli DS, Gill K. 1981. Relationship between B[a]P-induced
DNA base modification and frequency of reverse mutations in mutant
strains of Salmonella typhimurlum. Cancer Res 41:3400-3406.
Fahmy MJ, Fahmy OG. 1973. Mutagenic properties of benzo[a]pyrene and its
methylated derivatives in relation to the molecular mechanisms of
hydrocarbon carcinogenesis. Cancer Res 33:302-309.
Fahmy MJ, Fahmy OG. 1980. Altered control of gene activity in the soma
by carcinogens. Mutat Res 72:165-172.
Faoro RB, Manning JA. 1981. Trends in B[a]P, 1966-77. JAPCA 31:62-64.
Feron VJ. 1972. Respiratory tract tumors in hamsters after intratracheal
instillations of benzo[a]pyrene alone and with furfural. Cancer Res
32:28-36.
Feron VJ, deJong D, Emmelot P. 1973. Dose-response correlation for the
induction of respiratory-tract tumours in Syrian golden hamsters by
intratracheal instillations of benzo[a]pyrene. Eur J Cancer 9:387-390.
Fox CH, Selkirk JK, Price FM, Croy RG, Sanford KK, Cottier-Fox M. 1975.
Metabolism of benzo[a]pyrene by human epithelial cells in vitro. Cancer
Res 35:3551.
Gehly EB, Landolph JR, Heidelberger C, Nagasawa H, Little JB. 1982.
Induction of cytotoxicity, mutation, cytogenetic changes, and neoplastic
transformation by B[a]P and derivatives in C3H110T1/2 Clone 8 mouse
fibroblasts. Cancer Res 42(5):1866-1875.
Gelboin HW. 1980. Benzo[a]pyrene metabolism, activation, carcinogenesis:
Role and regulation of mixed-function oxidases and related enzymes.
Physiol Rev 60:1107-1166.
Generoso WM, Cain KT, Hellwig CS, Cacheiro NL. 1982. Lack of association
between induction of dominant-lethal mutations and induction of
heritable translocations with benzo[a]pyrene in postmeiotic germ cells
of male mice. Mutat Res 94:155-163.
-------
References 101
Glatt HR, Billings R, Piatt KL, Oesch F. 1981. Improvement of the
correlation of bacterial mutagenicity with carpinogenicity of B[a]P and
four of its major metabolites by activation with intact liver cells
instead of cell homogenate. Cancer Res 41(1):270-277.
Glatt H, Buecker M, Piatt KL, Oesch F. 1985. Host-mediated mutagenicity
experiments with benzo[a]pyrene and two of its metabolites. Mutat Res
156:163-169.
GoIdsworthy TL, Pitot HC. 1985. An approach to the development of a
short-term whole-animal bioassay to distinguish initiating agents
(incomplete carcinogens), promoting agents, complete carcinogens, and
noncarcinogens in rat liver. J Toxicol Environ Health 16:389-402.
Grimmer G. 1983. Foodstuffs in environmental carcinogens. In: Grimmer G,
ed. Polycyclic Aromatic Hydrocarbons. CRC Press, Boca Raton, Fla.
Grover PL, 1977. In: Parte DV, Smith RL, eds. Drug Metabolism--From
Microbe to Man. Taylor and Francis, London.
Gupta RS, Goldstein S. 1981. Mutagen testing in the human fibroblast
diphtheria toxin resistance (HF DIPR) system. Prog Mutat Res 1 (Eval
Short-Term Tests Carcinog: Rep Int Collab Program): 614-625.
Gupta RS, Singh B. 1982. Mutagenic responses of five independent genetic
loci in CHO cells to a variety of mutagens: Development and
characteristics of a mutagen screening system based on selection for
multiple drug-resistant markers. Mutat Res 94:449-466.
* Habs M, Schmahl D, Misfeld J. 1980. Local carcinogenicity of some
environmentally relevant polycyclic aromatic hydrocarbons after lifelong
topical application to mouse skin. Arch Geschwulstforsch 50:266-274.
Hammond ED, Selikoff IJ, Lawther PO, Seidman H. 1976. Inhalation of
B[a]P and cancer in man. Ann NY Acad Sci 271:116-124.
* Harkov R, Greenberg A. 1985. Benzo[a]pyrene in New Jersey--Results
from a twenty-seven-site study. JAPCA 35:238-243.
Harris CC, Autrup H. 1983. Human Carcinogenesis. Academic Press, New
York.
* Harris C. 1985. Method and Kit for Detecting Human Exposure to
Genotoxic Agents. U.S. Department of Health and Human Services,
Washington, D.C., PAT-APPL-6-778 669, PB86-131620.
Harris C, Vahakangs K, Newman MJ, et al. 1985. Detection of
benzo[a]pyrene diol epoxlde-DNA adducts In peripheral blood lymphocytes
and antibodies to the adducts in serum from coke oven workers. Proc Natl
Acad Sci 82:6672-6676.
-------
102 Section 10
* Harris CC, Newman MJ, Weston A, Mann DL. 1986. Identification of human
antibodies to polycyclic aromatic hydrocarbon-DNA adducts. Clin Res
34:690A
Harris CC, Autrup H, Stoner GD, et al. 1979. Metabolism of B[a]P, N-
nitrosodimethylamine, and N-nitrosopyrrolidine and identification of the
major carcinogen-DNA adducts formed in cultured human esophagus. Cancer
Res 39:4401-4406.
Harris CC, Sporn MB, Kaufman DG, Smith JM, Baker MS, Saffiotti V. 1971.
Acute ultrastructural effects of benzo(a)pyrene and ferric oxide on the
hamster tracheobronchial epithelium. Cancer Res 31:1977.
Hass BS, Brooks EE, Schumann KE, Dornfield SS. 1981. Synergistic
additive and antagonistic mutagenic responses to binary mixtures of
benzo[a]pyrene and benzo[e]pyrene as detected by strains TA98 and TA100
in the Salmonella/microsome assay. Environ Mutagenesis 3:159-166.
* Haugen A, Becher G, Benestad C, et al. 1986. Determination of
polycyclic aromatic hydrocarbons in the urine, benzo[a]pyrene diol
epoxide-DNA adducts in lymphocyte DNA, and antibodies to the adducts in
sera from coke oven workers exposed to measured amounts of polycyclic
aromatic hydrocarbons in the work atmosphere. Cancer Res 46:4178-4183.
Hazardous Substances Databank (HSDB). 1987. Benzo[a]pyrene. National
Library of Medicine, Toxicology Information Program.
Hecht SS, Grabowski W, Groth K. 1979. Analysis of faeces for B[a]P after
consumption of charcoal-broiled beef by rats and humans. Food Cosmet
Toxicol 17:223-227.
Henry MC, Port DC, Bates RR, Kaufman DG. 1973. Respiratory tract tumors
in hamsters induced by benzo[a]pyrene. Cancer Res 33:1585-1592.
Henry SA. 1947. Occupational cutaneous cancer attributable to certain
chemicals in industry. Br Med Bull 4:398-401.
Hernandez 0, Walker M, Cox RH, Foureman GL, Smith BR, Bend JR. 1980.
Regiospecificity and stereospecificity in the enzymatic conjugation of
glutathione with (+)-benzo[a]pyrene 4,5-oxide. Biochem Biophys Res
Commun 96:1494-1502.
Hirakawa T, Ishikawa T, Nimoto N, Takayama S, Kitagawa T. 1979.
Induction of enzyme-altered islands in rat liver by a single treatment
with B[a]P after partial hepatectomy. Gann 70:373-394.
Ho YL, Ho SK. 1981. Screening of carcinogens with the prophage lambda
CLTS857 induction test. Cancer Res 41:532-536.
Hoffmann D, Harley NH, Fisenne I, Adams JD, Brunnemann KD. 1986.
Carcinogenic agents in snuff. J Natl Cancer Inst 76:435-437.
-------
References 103
* Hoffmann D, Wynder EL. 1966. Beitrag zur carcinogenen Virkung von
Dibenzopyrenen. Z Krebsforsch 68:137-149.
Hollstein M, McCann J, Angelosanto FA, Nichols WW. 1979. Short-term
tests for carcinogens and mutagens. Mutat Res 65:133-226.
Hopkins JM, Perry PE. 1980. Benzo[a]pyrene does not contribute to the
SCE's induced by cigarette smoke condensate. Mutat Res 77:377-381.
Horton JK, Rosenior JC, Bend JR, Anderson MW. 1985. Quantitation of
B[a]P metabolite: DNA adducts In selected hepatic and pulmonary cell
types isolated from [^H]benzo[a]pyrene-treated rabbits. Cancer Res
45:3477-3481.
Hoshino K, Hayashi Y, Takehira Y, Kameyama Y. 1981. Influences of
genetic factors on the teratogenicity of environmental pollutants:
Teratogenic susceptibility to benzo[a]pyrene and Ah locus in mice. Cong
Anom 21:97-103.
Howard J. 1979. Analysis of B[a]P and other polycyclic aromatic
hydrocarbons in food. In: Egan H, ed. Environmental Carcinogens:
Selected Methods of Analysis, Vol. 3. Analysis of Polyaromatic
Hydrocarbons in Environmental Samples. International Agency for Research
on Cancer, Lyon, France, pp. 175-191.
Hsu I, Harris CC, Yamaguchi M, Trump BF, Schafer PW. 1979. Induction of
ouabain-resistant mutation and sister chromatid exchanges in Chinese
hamster cells with chemical carcinogens mediated by human pulmonary
macrophages. J Clin Invest 64(5):1245-1252.
Huberman E. 1975. Mammalian cell transformation and cell-mediated
mutagenesis by carcinogenic polycyclic hydrocarbons. Mutat Res
29:285-291.
Huh N, Nemoto N, Utakoji T. 1982. Metabolic activation of
benzo[a]pyrene, aflatoxin Bl, and dimethylnitrosaaine by a human
hepatoma cell line. Mutat Res 94:339-348.
Ichinotsubo D, Mower HF, Setliff J, Mandel M. 1977. Use of rec bacteria
for testing of carcinogenic substances. Mutat Res 46:53-62.
Ide F, Ishikawa T, Takayama S. 1981. Detection of chemical carcinogens
by assay of unscheduled DNA synthesis in rat tracheal epithelium in
short-term organ culture. J Cancer Res Clin Oncol 102:115-126.
IARC (International Agency for Research on Cancer). 1973. IARC
Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man.
Vol. 3. Certain Polycyclic Aromatic Hydrocarbons and Heterocyclic
Compounds. IARC, Lyon, France.
* IARC (International Agency for Research on Cancer). 1983. IARC
Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to
Humans. Vol. 32. IARC, Lyon, France.
-------
104 Section 10
IARC (International Agency for Research on Cancer). 1984. IARC
Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to
Humans. Vol. 34. Polynuclear Aromatic Compounds, Part 3, Industrial
Exposures in Aluminum Production, Coal Gasification, Coke Production,
and Iron and Steel Founding. IARC, Lyon, France.
IARC (International Agency for Research on Cancer). 1985. IARC
Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to
Humans. Vol. 34. Polynuclear Aromatic Compounds, Part 4, Biturnins,
Coal-tars and Derived Products, Shale Oils, and Soots. IARC, Lyon,
France.
Jerina DM, Daly JW. 1974. Arene oxides: A new aspect of drug metabolism.
Science 185:573-582.
Jerina DM, Lehr RE, Yagi H, et al. 1976. Mutagenicity of B[a]P
derivatives and the description of a quantum mechanical model which
predicts the ease of carbonium ion formation from diol epoxides. In: de
Serres FJ, Fouts JR, Bend JR, Philpot RM, eds. In Vitro Metabolic
Activation in Mutagenesis Testing, Elsevier/North Holland, Amsterdam,
pp. 159-178.
Jerina DM, Lehr RE. 1977. The bay region theory: A quantum mechanical
approach to aromatic hydrocarbon-induced carcinogenicity. In: Ullrich V,
Roots I, Hildebrandt AG, Estabrook RW, Conney AH, eds. Microsomes and
Drug Oxidations. Pergamon Press, Oxford, p. 709.
Jerina DM, Sayer JM, Thakker DR, et al. 1980. Carcinogenicity of
polycyclic aromatic hydrocarbons: The bay-region theory. In: Pullman B,
Ts'O POP, Gelboin H, eds. Carcinogenesis: Fundamental Mechanisms and
Environmental Effects, D. Reidel Publishing Co., Hingham, Mass., pp. 1-
12.
Jones CA, Santella RM, Huberman E, Selkirk JK, Grunberger D. 1983. Cell
specific activation of B[a]P by fibroblasts and hepatocytes.
Carcinogenesis 4(11):1351-1357.
Jongeneelen FJ, Leijdekkers C-M, Bos RP, Theuws JLG, Henderson PT. 1985.
Excretion of 3-hydroxy-benzo[a]pyrene and mutagenicity in rat urine
after exposure to B[a]P. J Appl Toxicol 5:277-282 (as cited in
Jongeneelen et al. 1986).
* Jongeneelen FJ, Bos RP, Anzion RBM, Theuws JLG, Henderson PT. 1986.
Biological monitoring of polycyclic aromatic hydrocarbons; metabolites
in urine. Scand J Work Environ Health 12:137-143.
Jotz MM, Mitchell AD. 1981. Effects of 20 coded chemicals on the forward
mutation frequency at the thymidine kinase locus in L5178Y mouse
lymphoma cells. Prog Mutat Res 1 (Eval Short-Term Tests Carcinog: Rep
Int Collab Program):580-593.
-------
References 105
Kaden DA, HiCes RA, Thilly WG. 1979. Mutagenicity of soot and associated
polycyclic aromatic hydrocarbons to Salmonella typhimurium. Cancer Res
39:4152-4159.
Kao JK, Patterson FK, Hall J. 1985. Skin penetration and metabolism of
topically applied chemicals in six mammalian species, including man: An
in vitro study with benzo[a]pyrene and testosterone. Toxicol Appl
Pharmacol 81:502-516.
Kassinova GV, Kovaltsova SV, Harfin SV, Zakharov IA. 1981. Activity of
40 coded compounds in differential inhibition and mitotic crossing-over
assays in yeast. Prog Mutat Res 1 (Eval Short-Term Tests Carcinog: Rep
Int Collab Program):434-455.
Katz M. 1979. Analysis of polycyclic aromatic hydrocarbons in
atmospheric suspended particulate matter. In: Egan H, ed. Environmental
Carcinogens: Selected Methods of Analysis. Vol. 3. Analysis of
Polyaromatic Hydrocarbons in Environmental Samples. International Agency
for Research on Cancer, Lyon, France, pp. 193-213.
Kennaway NM, Kennaway EL. 1936. Study of the incidence of cancer of the
lung and larynx. J Hyg 36:236-267.
Ketkar M, Green V, Schneider P, Mohr V. 1979. Investigations on the
carcinogenic burden by air pollution in man. Intratracheal instillation
studies with benzo[a]pyrene in a mixture of Tris buffer and saline in
Syrian golden hamsters. Cancer Lett 6:279-284.
Ketkar M, Resnick G, Schneider P, Mohr U. 1978. Investigations on the
carcinogenic burden by air pollution in man. Intratracheal instillation
studies with benzo[a]pyrene in bovine serum albumin in Syrian hamsters.
Cancer Lett 4:235-239.
Kirkhart B. 1981. Micronucleus test on 21 compounds. Prog Mutat Res 1
(Eval Short-Term Tests Carcinog: Rep lilt Collab Program):698-704.
Klar E, 1938. Tiber die entstehung eines epithelloms beim menshem nach
experimentellan arbeiten mit benzypren. Klin Wschr 17:1279 (abstract in
English).
Kochhar TS. 1982. Effects of polycyclic hydrocarbons on the induction of
chromosomal aberrations In absence of an exogenous metabolic activation
system in cultured hamster cells. Experientia 38:845-846.
* Korfmacher WA, Natusch DFS, Taylor DR, Mamantov G, Wehry EL. 1980a.
Oxidative transformation of polycyclic aromatic hydrocarbons adsorbed on
coal fly ash. Science 207:763-765.
* Korfmacher WA, Wehry EL, Mamantov G, Natusch DFS. 1980b. Resistance to
photochemical decomposition of polycyclic aromatic hydrocarbons vapor
adsorbed on coal fly ash. Environ Sci Technol 14:1094-1099.
-------
106 Section 10
Kouri RE, Rude TH, Joglekar R, et al. 1978. 2,3,7,8-Tetrachloro-
dibenzo-p-dioxin as cocarclnogen causing 3-methylcholanthrene initiated
subcutaneous tumors In mice genetically 'nonresponsive' at Ah locus.
Cancer Res 38:2777-2783.
Krahn D, Heidelberger C. 1977. Liver homogenate mediated mutagenesis in
Chinese hamster V-79 cells by polycyclic aromatic hydrocarbons and
aflatoxins. Mutat Res 46:27-44.
Kuroki T, Malaveille C, Drevon C, Piccoli C, Macleod M, Selkirk JK.
1979. Critical importance of microsome concentration in mutagenesis
assay with V79 Chinese hamster cells. Mutat Res 63:259-272.
Laher JM, Barrowman JA. 1983. Polycyclic hydrocarbon and polychlorinated
biphenyl solubilization in aqueous solutions of mixed micelles. Lipids
18:216-222.
Lake RS, Kropko ML, Pezzutti MR, Shoemaker RH, Ingel HJ. 1978. Chemical
induction of unscheduled DNA synthesis in human skin epithelial cell
cultures. Cancer Res 38:2091-2098.
Langenbach R, Freed HF, Raveh D, Huberman E. 1978. Cell specificity in
metabolic activation of aflatoxin B1 and benzo[a]pyrene to mutagens for
mammalian cells. Nature (London) 276:277-280.
Laskin S, Kuschner M, Drew RT. 1970. Studies in pulmonary
carcinogenesis. In: Hanna MG, Nettesheim P, Gilbert J, eds. Inhalation
Carcinogenesis. AEC Symposium Series 18. Oak Ridge Division of Technical
Information, U.S. Atomic Energy Commission, pp. 321-351.
Lenson N. 1956. Multiple cutaneous carcinoma after creosote exposure. N
Engl J Med 254:520-523.
Lee RF, Sauerheber R, Dobbs GD. 1972. Uptake, metabolism, and discharge
of polycyclic aromatic hydrocarbons by marine fish. Mar Biol 17:201-208
(as cited in Eisler 1987).
* Legraverend C, Guenther TM, Nebert DW. 1984. Importance of the route
of administration for genetic differences in benzo[a]pyrene-induced in
utero toxicity and teratogenicity. Teratology 29:35-47.
Leversee GJ, Geisy JP, Landrum PF, et al. 1981. Disposition of
benzo[a]pyrene in aquatic systems components: periphyton, chironomids,
daphnia, fish. In: Cooke M, Dennis AJ, eds. Chemical Analysis and
Biological Fate: Polynuclear Aromatic Hydrocarbons. Fifth International
Symposium. Battelle Press, Columbus, Ohio, pp. 356-366 (as cited in
Eisler 1987).
Levin ff, Buening MK, Wood AW, et al. 1980. An enantiomeric interaction
In the metabolism and tumorigenicity of (+)- and (-)-benzo[ajpyrene
7,8-oxide. J Biol Chem 255:9067-9074.
-------
References 107
* Levin W, Wood A, Chang RL, et al. 1982. Oxidative metabolism of
polycyclic aromatic hydrocarbons to ultimate carcinogens. Drug Metab Rev
13:555-580.
Levin W, Wood AW, Yagi H, Dansette PM, Jerina DM, Conney AH. 1976.
Carcinogenicity of benzo[a]pyrene 4,5-, 7,8-, 9 and 10-oxides on mouse
skin. Proc Natl Acad Sci 73:243-247.
Li AP. 1982. Quantification of mutations at the Na+-K+-ATPase and
hypoxanthine-guanine phosphoribosyl transferase (HGPRT) gene loci in
Chinese hamster ovary cells. J Tiss Cult Meth 7(l):22-32.
Lindstedt G, Sollenberg J. 1982. Polycyclic aromatic hydrocarbons in the
occupational environment. Scan J Work Environ Health 8:1-19.
Lloyd JW. 1971. Long-term mortality study of steelworkers. V.
Respiratory cancer in coke plant workers. J Occup Med 13:53-68.
Lu P-Y, Metcalf RL, Plummer N, Mandel D. 1977. The environmental fate of
three carcinogens: Benzo[a]pyrene, benzidine, and vinyl chloride
evaluated in laboratory model ecosystems. Arch Environ Contam Toxicol
6:129-142.
Lubet RA, Kiss E, Gallagher MM, Dively C, Kouri RE, Schecht IM. 1983.
Induction of neoplastic transformation and DNA single strand breaks in
C3H-10T1/2 Clone 8 cells by polycyclic hydrocarbons and alkylating
agents. J Natl Cancer Inst 71(5):991-997.
* Lutz WK. 1979. In vivo covalent binding of organic chemicals to DNA as
a quantitative indicator in the process of chemical carcinogenesis.
Mutat Res 65:289-356.
Lyte M, Bick PH. 1985. Differential immunotoxic effects of the
environmental chemical benzo[a]pyrene in young and aged mice. Mech Age
Develop 30:333-341.
Machanoff R, O'Neill JP, Hsie AW. 1981. Quantitative analysis of
cytotoxicity and mutagenicity of benzo[a]pyrene in mammalian cells
(CHO/HGPRT system). Chem Biol Interact 34:1-10.
* Mackenzie KM, Angevine DM. 1981. Infertility in mice exposed in utero
to benzo[a]pyrene. Biol Reproduc 24:183-191.
Maclure KM, MacMahon B. 1980. An epidemiologic perspective of
environmental carcinogenesis. Epidemiol Rev 2:19-48.
Mahlum DD, Wright CW, Chess EK, Wilson BW. 1984. Fractionation of skin
tumor-initiating activity in coal liquids. Cancer Res 44:5176-5181.
Mamber SW, Bryson V, Katz SE. 1983. The Escherichia coll wp2/wpl00 rec
assay for detection of potential chemical carcinogens. Mutat Res
119:135-144.
-------
108 Section 10
Marquardt H, Grover PL, Sims P. 1976. In vitro malignant transformation
of mouse fibroblasts by non-K-region dihydrodiols derived from 7-
methylbenz[a]anthracene, 7,12-dimethylbenz[a]anthracene, and
benzo[a]pyrene. Cancer Res 36:2059-2064.
* Marshall MV, McLemore TL, Martin RR, et al. 1979. Patterns of
benzo[alpha]pyrene metabolism in normal human pulmonary alveolar
macrophages. Cancer Lett 8:103-109.
Marshall CJ, Vousden KH, Phillips DH. 1984. Activation of c-Ha-ras-1
proto-oncogene by in vitro modification with a chemical carcinogen,
benzolajpyrene diol-epoxide. Nature 310:586-589.
Martin CN, McDermid AC, Garner RC. 1978. Testing of known carcinogens
and non-carcinogens for their ability to induce unscheduled DNA
synthesis in HeLa cells. Cancer Res 38:2621-2627.
Martin CN, McDermid AC. 1981. Testing of 42 coded compounds for their
ability to induce unscheduled DNA repair synthesis in HeLa cells. Prog
Mutat Res 1 (Eval Short-Term Tests Carcinog: Rep Int Collab
Program):533-537.
Matsuoka A, Hayashi M, Isidate M, Jr. 1979. Chromosomal aberration tests
on 29 chemicals combined with S9 mix in vitro. Mutat Res 66:277-290.
Matsumoto H, Kashimoto T. 1985. Average daily respiratory intake of
polycyclic aromatic hydrocarbons in ambient air determined by capillary
gas chromatography. Bull Environ Contain Toxicol 34:77-83.
Mazumdar S, Redmond CK, Sollecito VI, Sussman N. 1975. An epidemiological
study of exposure to coal tar pitch volatiles among coke oven workers. J
Air Pollut Control Assoc 25:382-389.
McCarroll NE, Keech BH, Piper CE. 1981. A microsuspension adaptation of
the Bacillus subtllis rec assay. Environ Mutagenesis 3:607-616.
McCormick D et al. 1981. Inhibition of benzo[a]pyrene-induced mammary
carcinogenesis by retinyl acetate. J Natl Cancer Inst 66:559-564 (cited
In EPA 1982).
McNeil D. 1983. Tar and pitch. In: Kirk-Othmer Encyclopedia of Chemical
Technology. Vol. 22. 3rd ed. John Wiley and Sons, New York, pp. 564-600.
Medinsky MA, Kampcik SJ. 1985. Pulmonary retention of [^C]
benzo[aJpyrene in rats as influenced by the amount instilled. Toxicol
35:327-336.
Mehta R, Meredith-Brown M, Cohen CM. 1979. Metabolism and covalent
binding of benzo[a)pyrene in human peripheral lung. Chem Biol Interact
28:345-348.
Miller JA. 1970. Carcinogenesis by chemicals: An Overview. G.H.A. Clowes
Memorial Lecture. Cancer Res 30:559-576.
-------
.References 109
Mlrsalis JC, Tyson C, Butterworth BE. 1982. Detection of genotoxlc
carcinogens in the in vivo-in vitro hepatocyte DNA repair assay. Environ
Mutagenesis 4:553-562.
Misfeld J. 1980. The tumor-producing effects of automobile exhaust
condensate and of diesel exhaust condensate. In: Pepelko WE, Danner RM,
Clarke NA, eds. Health Effects of Diesel Engine Emissions: Proceedings
of an International Symposium. Vol. 2. Environmental Protection Agency,
Cincinnati, Ohio, EPA 600/9-80-057b, pp. 1012-1025.
Mishra NK, Wilson CM, Pant KJ, Thomas FO. 1978. Simultaneous
determination of cellular mutagenesis and transformation by chemical
carcinogens in Fischer rat embryo cells. J Toxicol Environ Health
4:79-91.
Mitchell CE. 1982. Distribution and retention of benzo [ajpyrene in rats
after inhalation. Toxicol Lett 11:35-42.
Modica R, Fiume M, Bartosek I. 1982. Gas-liquid chromatographic assay of
polycyclic aromatic hydrocarbon mixtures: Specifically modified method
for rat tissues. J Chromatogr 24:352-355.
Mohammad SN. 1985. Relative roles of K region and bay region towards
determining the carcinogenic potencies of polycyclic aromatic
hydrocarbons. Cancer Biochem Biophys 8:41-46.
Moore BP, Cohen GM. 1979. Metabolism of benzo[a]pyrene and its major
metabolites to ethyl acetate-soluble and water-soluble metabolites by
cultured rodent trachea. Cancer Res 38:3066.
Moreau P, Bailone A, Devoret R. 1976. Prophage lambda induction in
Escherichia coli K12 envA uvrB: A highly sensitive test for potential
carcinogens. Proc Natl Acad Sci USA 73:3700-3704.
* NAS (National Academy of Sciences). 1972. Particulate Polycyclic
Organic Matter. National Academy of Sciences, Washington, D.C.
NAS (National Academy of Sciences). 1983. Polycyclic Aromatic
Hydrocarbons: Evaluation of Sources and Effects. National Academy Press,
Washington, D.C.
NIOSH (National Institute for Occupational Safety and Health). 1977.
Criteria for a Recommended Standard ... Occupational Exposure to Coal
Tar Products. Department of Health, Education, and Welfare, NIOSH
Publication 78-107.
NIOSH (National Institute for Occupational Safety and Health). 1984.
NIOSH Manual of Analytical Methods. 3rd ed. NIOSH, Cincinnati, Ohio.
* Neal J, Rigdon RH. 1967. Gastric tumors in mice fed benzo[ajpyrene: A
quantitative study. Tex Rep Biol Med 25:553-557.
-------
110 Section 10
NYSDEC (New York State Department of Environmental Conservation). 1984.
Ambient Water Quality Criteria. Memo to Regional Water Engineers, Bureau
Directors and Section Chiefs, May 10, 1984.
Nguyen TD, Boyd JB, Green MM. 1979. Sensitivity of Drosophila mutants to
chemical carcinogens. Mutat Res 63:67-77.
Nikonova TV. 1977. Transplacental action of benzo[a]pyrene and pyrene.
Bull Exp Biol Med 84:1025-1027.
0'Donovan WJ. 1920. Epitheliomatous ulceration among tar workers. Br J
Dermatol Syph 32:215-252.
0SHA (Occupational Safety and Health Administration). 1986. Occupational
Safety and Health Standards Subpart Z -- Toxic and Hazardous Substances.
OSHA (Occupational Safety and Health Administration). 1985a. Permissible
Exposure Limits. Code of Federal Regulations 29:1910.1002.
OSHA (Occupational Safety and Health Administration). 1985b. Permissible
Exposure Limits. Code of Federal Regulations 29:1910.1029.
Ogan K, Katz E, Slavin W. 1979. Determination of polycyclic aromatic
hydrocarbons in aqueous samples by reversed phase liquid chromatography.
Anal Chem 51:1315-1320.
Paika IJ, Beauchesne MT, Randall M, Schreck RR, Latt SA. 1981. In vivo
SCE analysis of 20 coded compounds. Prog Mutat Res 1 (Eval Short-Term
Tests Carcinog: Rep Int Collab Program):673-681.
Pal K, Tierney B, Grover PL, Sims P. 1978. Induction of sister chromatid
exchanges in Chinese hamster ovary cells treated in vitro with non-K-
region dihydrodiols of 7-methylbenz[a]anthracene and benzo[a]pyrene.
Mutat Res 50:367-375.
Panthanickal A, Marnett LJ. 1981. Arachidonic acid-dependent metabolism
of (+/-)-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene to polyguanylic acid-
binding derivatives. Chem Biol Interact 33:239-252.
Payne S. 1958. The pathological effects of the intraperitoneal injection
of 3:4-benzopyrene into rats and mice. Br J Cancer 12:65-74.
Perera F. 1981. Carcinogenicity of airborne fine particulate
benzo[a]pyrene: An appraisal of the evidence and the need for control.
Environ Health Perspect 42:163-185.
* Perera FP, Poirer MC, Yuspa SH, et al. 1982. A pilot project in
molecular cancer epidemiology: Determination of benzo[a]pyrene-DNA
adducts in animal and human tissues by immunoassays. Carcinogenesis
3:1405-1410.
Peters J, Seifert B. 1980. Losses of benzo[a]pyrene under the conditions
of high volume sampling. Atmos Environ 14:117-120.
-------
References 111
Pienta RJ, Poiley JA, Lebherz WB, III. 1977. Morphological
transformation of early passage golden Syrian hamster embryo cells
derived from cryopreserved primary cultures as a reliable in vitro
biossay for identifying diverse carcinogens. Int J Cancer 19:642:655.
Phillips DH, Grover PL, Sims P. 1979. A quantitative determination of
the covalent binding of a series of polycyclic hydrocarbons to DNA in
mouse skin. Int J Cancer 23:201-208.
Popescu NC, Turnball D, DiPaolo JA. 1977. Sister-chromatid exchange and
chromosome aberration analysis with the use of several carcinogens and
non-carcinogens: Brief communication. J Natl Cancer Inst 59(1):289-293.
Popescu NC, Amsbaugh SC, Dipaolo JA. 1981. Relationship of carcinogen-
induced sister chromatid exchange and neoplastic cell transportation.
Int J Cancer 28:71-77.
Pott P. 1775. Surgical observations relative to the cancer of the
scrotum. London. Reprinted in Natl Cancer Inst Monog 10:7-13 (1973).
Prough RA, Patrizi VW, Okita RT, Masters RSS, Jakobsson SW. 1979.
Characteristics of benzo[a]pyrene metabolism by kidney, liver, and lung
microsomal fractions from rodents and humans. Cancer Res 39:1119-1206.
Probst GS, McMahon RE, Hill LE, Thompson CZ, Epp JK, Neal SB. 1981.
Chemically-induced unscheduled DNA synthesis in primary rat hepatocyte
cultures: A comparison with bacterial mutagencity using 218 compounds.
Environ Mutagenesis 3:11-32.
Pucknat AW. 1981. Characteristics of PNA in the environment. In: Pucknat
AW, ed. Health Impacts of Polynuclear Aromatic Hydrocarbons. Noyes Data
Corp., Park Ridge, N.J., pp. 78-122.
Purde M, Etlin S. 1980. Cancer cases among workers in the Estonia oil
shale processing industry. In: Rom WN, Archer VE, eds. Health
Implications of New Energy Technologies. Ann Arbor Science, Ann Arbor,
Mich., pp. 527-528.
* Rahn RO, Chang SS, Holland JM, Shugart LR. 1982. A fluorometric-HPLC
assay for quantitating the binding of benzo[a]pyrene metabolites to DNA.
Biochem Biophys Res Commun 109:262-268.
* Randerath K, Randerath E, Agrawal HP, Gupta RC, Schurdak ME, Reddy KV.
1985. Postlabeling methods for carcinogen-DNA adduct analysis. Environ
Health Perspect 62:57-65.
Randerath E, Avitts TA, Reddy MV, Miller RH, Everson RB, Randerath K.
1986. Comparative ^P-analysis Qf cigarette smoke-induced DNA damage in
human tissues and mouse skin. Cancer Res 46:5869-5877.
Redmond CK, Ciocco A, Lloyd JW, Rush HW. 1972. Long-term mortality study
of steelworkers. VI. Mortality from malignant neoplasms among coke oven
workers. J Occup Med 14:621-629.
-------
112 Section 10
Rhim JS, Cho HY, Joglekar MH, Huebner RJ. 1972. Camparison of the
transforming effect of benzo[ajpyrene in mammalian cell lines in vitro.
J Natl Cancer Inst 48:949-957.
Rhim JS, Gordon RJ, Bryan RJ, Huebner RJ. 1973. Transformation of mouse
cells injected with AKR leukemia virus by benzene extract fractions of
city air particles. Int J Cancer 12:485-492.
Rhim JS, Park DK, Weisburger EK, Weisburger, JH. 1974. Evaluation of an
in vitro assay system for carcinogens based on prior infection of rodent
cells with nontransforming RHA tumor virus. J Natl Cancer Inst
52:1167-1171.
Rhoads CP, Smith UE, Cooper NS, Sullivan RD. 1954. Early changes in the
skin of several species including man, after painting with carcinogenic
materials. Proc Am Assoc Cancer Res 1:40.
Ribeiro 0, Kirkby CA, Hirom PC, Milburn P. 1985. Secondary metabolites
of benzo[a]pyrene:3-hydroxy trans-7,8-dthydro-7,8-dihydroxy-
benzo[a]pyrene, a biliary metabolite of 3-hydroxybenzo[a]pyrene in the
rat. Carcinogenesis 10:1507-1511.
Rigdon RH, Rennels G. 1964. Effect of feeding benzpyrene on reproduction
in the rat. Experientia 20:224-226.
Rigdon RH, Neal J. 1965. Effects of feeding benzo[a]pyrene on fertility,
embryos, and young mice. J Natl Cancer Inst 34:297-305.
* Rigdon RH, Neal J. 1966. Gastric carcinomas and pulmonary adenomas in
mice fed benzo[a]pyrene. Tex Rep Biol Med 24:195-207.
* Rigdon RH, Neal J. 1969. Relationship of leukemia to lung and stomach
tumors in mice fed benzo[a]pyrene. Proc Soc Exptl Biol Med NY, 130:146-
148.
Riggin R, Strup PE. 1984. Screening Methods for PAH Priority Pollutants
in Wastewater. Prepared for the Environmental Monitoring Support
Laboratory, Environmental Protection Agency, Cincinnati, Ohio, March,
EPA 600/S4-84-007.
Robinson DC, Mitchell AD. 1981. Unscheduled DNA synthesis response of
human fibroblasts, WI-38 cells, to 20 coded chemicals. Prog Mutat Res 1
(Eval Short-Term Tests Carcinog: Rep Int Collab Program):517-527.
* Robinson JR, Felton JS, Levitt RC, Thorgeirsson SS, Nebert DW. 1975.
Relationship between "aromatic hydrocarbon responsiveness" and the
survival times in mice treated with various drugs and environmental
compounds. Mol Pharm 11:850-865.
Rocchi P, Ferreri AM, Borgia R, Prodi G. 1980. Polycyclic hydrocarbons
induction of diptheria toxin-resistant mutants in human cells.
Carcinogenesis 1:765-767.
-------
References 113
Rosenkranz HS, Poirler LA. 1979. Evaluation of the mutagenicity and
DNA-modifying activity of carcinogens and non-carcinogens in microbial
systems. J Natl Cancer Inst 62(4):873-891.
Roszinsky-Kocher G, Basler A, Rohrborn G. 1979. Mutagenicity of
polycyclic hydrocarbons. V. Induction of sister-chromatid exchanges in
vivo. Mutat Res 66:65-67.
Rudiger HW, Kohl F, Mangels W, et al. 1976. Benzo[a]pyrene induces
sister chromatid exchanges in cultured human lymphocytes. Nature
(London) 262:290-292.
Russell LB. 1977. Validation of the in vivo somatic mutation method in
the mouse as a prescreen for germinal point mutations. Arch Toxicol
38:75-85.
Russell LB, Shelby PB, Von Halle E, Sheridan W, Valcovic L. 1981. The
mouse specific-locus test with agents other than radiations.
Interpretation of data and recommendations for future work. Mutat Res
86:329-354.
Russell WL. 1978. Specific-locus test for mutagenicity of benzo[a]pyrene
in the mouse. Program and Abstracts, 9th annual meeting, EMS.
Russell VL, Russell LB. 1978. Use of the mouse specific-locus method to
quantify the gene mutation hazard from mutagens associated with non-
nuclear energy technologies. EPA 3-year summary.
Saffiotti U, Montesano R, Sellakumar AR, Kaufman DG. 1972. Respiratory
tract carcinogenesis induced in hamsters by different dose levels of
benzo[a]pyrene and ferric oxide. J Natl Cancer Inst 49:1199-1204 (cited
in EPA 1980d).
Salamone MF. 1981. Toxicity of 41 carcinogens and noncarcinogenic
analogs. Prog Mutat Res 1 (Eval Short-Term Tests Carcinog: Rep Int
Collab Program):682-685.
Salamone MF, Hedde JA, Katz M. 1981. Mutagenic activity of 41 compounds
in the in vivo micronucleus assay. Prog Mutat Res 1 (Eval Short-Term
Tests Carcinog: Rep Int Collab Program):686-697.
Sanders CL, Skinner C, Gelman RA. 1986. Percutaneous absorption of 7,10
14C-benzo[a]pyrene and 7,12 14C-dimethylbenz[a]anthracene in mice. JEPTO
2:25-34.
Santella RM, Hsieh L-L, Lin C-D, Viet S, Weinstein IB. 1985.
Quantitation of exposure to benzo[a]pyrene with monoclonal antibodies.
Environ Health Perspect 62:95-99.
Santodonato J, Howard P, Basu D. 1981. Health and ecological assessment
of polynuclear aromatic hydrocarbons. J Environ Pathol Toxicol 5:51-75.
-------
114 Section 10
Savlcki E. 1976. Analysis of Atmospheric Carcinogens and their
Cofactors. INSERM Symposia Series. Vol. 52, pp. 297-354.
Schlede E, Kuntzman R, Haber S, Conney AH. 1970. Effect of enzyme
induction on the metabolism and tissue distribution of benzo[a]pyrene.
Cancer Res 30:2893-2897.
Schottenfeld D, Fraumani J., ed. 1982. Cancer Epidemiology and
Prevention. W.B. Sanders Co., Philadelphia, Pa.
Schreck RR, Latt SA. 1980. Comparison of benzo[a]pyrene metabolism and
sister chromatid induction in mice. Nature (London) 288:407-408.
Sega GA. 1979. Unscheduled DNA synthesis (DNA repair) in the germ cells
of male mice: Its role in the study of mammalian mutagenesis. Genetics
92:S49-S58.
Selkirk JK, Croy RG, Gelboin HV. 1975a. Isolation by high pressure
liquid chromatography and characterization of benzo[a]pyrene-4'5-epoxide
as a metabolite of benzo[a]pyrene. Arch Biochem Biophys 168:322.
Selkirk PK, Croy RG, Whitlock KP, Gelboin HV. 1975b. In vitro metabolism
of benzo[a]pyrene by human liver microsomes and lymphocytes. Cancer Res
35:3651.
Selkirk JK, Nikbakht A, Stoner GD. 1983. Comparative metabolism and
macromolecular binding of benzo[a]pyrene in explant cultures of human
bladder, skin, bronchus, and esophagus of eight individuals. Cancer Lett
18:11-19.
Sellakumar A, Stenback F, Rowland J. 1976. Effects of different dusts on
respiratory carcinogenesis in hamsters induced by benzo(a)pyrene and
diethylnitrosamine. Europ J Cancer 12:313-319.
Setala D, Ekwall P. 1950. Penetration of benzo[a]pyrene Into the stomach
wall of mouse. Science 112:229-231.
Shendrikova IA, Aleksandrov VA. 1974. Comparative penetration of
polycyclic hydrocarbons through rat placenta into the fetus. Bull Exp
Biol Med (USSR) 77:169-171.
Shendrikova IA, Ivanov-Golitsyn MN, Likchachev AY. 1974. The
transplacental penetration of benzo[ajpyrene In mice. Voprosy Onkologii
20:53-56.
Sheveleva GA. 1978. On the effect of 3,4-benzpyrene on the development
of the foetus applied at different stages of gestation. Gigiena Truda I
Professional nye Zabolevaniya 7:54.
* Shugart L. 1985. Quantitating exposure to chemical carcinogens: In
vivo alkylation of hemoglobin by benzo[a]pyrene. Toxicology 34:211-220.
-------
References 115
* Shugart L. 1986. Quantifying adductive modification of hemoglobin from
mice exposed to benzo[a]pyrene. Anal Biochem 152:365-369.
Shum S, Jensen NM, Nebert DW. 1979. The murine Ah locus: In utero
toxicity and teratogenesis associated with genetic differences in
benzo[a]pyrene metabolism. Teratology 20:365-376.
Simmon VF. 1979a. In vitro mutagenicity of chemical carcinogens and
related compounds with Salmonella typhimurium. J Natl Cancer Inst
62(4):893-899.
Simmon VF. 1979b. In vitro assays for recombinogenie activity of
chemical carcinogens and related compounds with Saccharomyces cerevisiae
D3. J Natl Cancer Inst 62:901-909.
Simmon VF, Rosenkranz HS, Zeiger E, Poirier LA. 1979. Mutagenic activity
of chemical carcinogens and related compounds in the intraperitoneal
host-mediated assay. J Natl Cancer Inst 62:911-918.
* Sims P, Grover PL. 1974. Epoxides in polycyclic aromatic hydrocarbon
metabolism and carcinogenesis. Adv Cancer Res 20:165.
Sina JF, Bean CL, Dysart GR, Taylor VI, Bradley MO. 1983. Evaluation of
the alkaline elution/rat hepatocyte assay as a predictor of
carcinogenic/mutagenic potential. Mutat Res 113:357-391.
Sirianni SR, Huang CC. 1978. Sister chromatid exchange induced by
promutagen/carcinogens in Chinese hamster cells cultured in diffusion
chambers in mice. Proc Soc Exp Biol Med 158:269-274.
Sivak A, Charest MC, Rudenko L, Silveira DM, Simons I, Wood AM. 1980.
BALB/C-3T3 cells as target cells for chemically induced neoplastic
transformation. In: Mishra N, Dunkel V, Mehlman M, eds. Advances in
Modern Environmental Toxicology. Mammalian Cell Transformation by
Chemical Carcinogens. Senate Press, Princeton Junction, N.J., pp. 133-
160.
Slaga TJ, diGiovanni J. 1984. Inhibition of chemical carcinogenesis. In:
Searle CE, ed. Chemical Carcinogens. 2nd ed. Vol. 2. ACS Monograph 182.
Washington, D.C.
Slaga TJ, Triplett LL, Nesnow S. 1980. Mutagenic and carcinogenic
potency of extracts of diesel and related environmental emissions: Two-
stage carcinogenesis in skin tumor sensitive mice (SENCAR). In: Pepelko
WE, Danner RM, Clarke NA, eds. Health Effects of Diesel Engine
Emissions. Proceedings of an International Symposium. Vol. 2.
Environmental Protection Agency, Cincinnati, Ohio, EPA 600/9-80-057b,
pp. 874-897.
Smith JH, Mabey WR, Bohonos N, et al. 1978. Environmental Pathways of
Selected Chemicals in Freshwater Systems, Part II: Laboratory Studies.
Environmental Protection Agency, Athens, GA. EPA-600/7-78-074, p. 432
(as cited in EPA 1979a).
-------
116 Section 10
Sorrell RK, Brass HJ, Reding R. 1981. A Review of Occurrences and
Treatment of Polynuclear Aromatic Hydrocarbons. EPA-600/0-81-066.
Sparnins VL, Mott AW, Baraney G, Wattenberg LW. 1986. Effects of allyl
methyl trisulfide on glutathione-S-transferase activity. Nutr Cancer
8:211-215.
Stenback F, Sellakuaar A, Shubik P. 1975. Magnesium oxide as carrier
dust in benzo[aJpyrene-induced lung carcinogenesis in Syrian hamsters. J
Natl Cancer Inst 54:861-867.
Stenback F, Rowland J, 1979. Experimental respiratory carcinogenesis in
hamsters: Environmental, physicochemical, and biological aspects. Oncol
36:63-71.
Stenback F, Rowland J, Sellakuaar A. 1976. Carcinogenicity of
benzo(a)pyrene and dusts in the hamster lung (instilled intratracheally
with titanium oxide, aluminum oxide, carbon, and ferric oxide). Oncol
33:29-34.
Stowers SJ, Anderson MW. 1985. Formation and persistence of
benzo[a]pyrene metabolite-DNA adducts. Environ Health Perspect 62:31-39.
Suess MJ. 1976. The environmental load and cycle of polycyclic aromatic
hydrocarbons. Sci Total Environ 6:239-250.
Sun JD, Wolff RK, Kanapilly GM. 1982. Deposition, retention, and
biological fate of inhaled benzo[aJpyrene adsorbed onto ultrafine
particles and as a pure aerosol. Toxicol Appl Pharmacol 65:231-244.
Suntzeff VA, Lowdry EV, Cronizer A. 1955. Microscopic visualization of
the degeneration of sebaceous glands caused by carcinogens. Cancer Res
15:637-640.
Swanson DH, Walling JF. 1981. Use of ultrasonics in the rapid extract of
ht-vol filters for benzo[a]pyrene (B[a]P) analysis. Chrooatogr
Newsletter 9:25-26.
Swartz WJ, Mattison DR. 1985. Benzo[aJpyrene inhibits ovulation in
C57BL/6N mice. Anatomical Record 212:268-276.
Thakker DR, Yagi H, Akagi H, et al. 1977. Metabolism of benzo[a]pyrene.
VI. Stereoselective metabolism of benzo[a]pyrene and benzo[a]pyrene
7,8-dihydrodiol to diol epoxides. Chem Biol Interact 16:281-300.
Thakker DR, Yagi H, Levin W, Wood AW, Conney AH, Jerina DM. 1985.
Polycyclic aromatic hydrocarbons: Metabolic activation to ultimate
carcinogens. In: Anders MW, ed. Bioactivation of Foreign Compounds.
Academic Press, pp. 178-242.
Thomas JF, Mukai M, Teggens BD. 1968. Fate of airborne benzo[ajpyrene.
Environ Sci Technol 2:33-39.
-------
References 117
Thornton SC, Diamond L, Hite M, Balrd WM. 1982. The effect of liver
homogenate (S20) concentration on polycyclic aromatic hydrocarbon
activation and mutation induction in the L5178Y mouse lymphoma mutation
assay. Mutat Res 106:101-112.
* Thyssen J, Althoff J, Kimmerle G, Mohr U. 1981. Inhalation studies
with benzo[a]pyrene in Syrian golden hamsters. J Natl Cancer Inst
66:575-577.
Tomkins BA, Jenkins RA, Griest WH, Reagan RR, Holladay SK. 1985. Liquid
chromatographic determination of benzo[a]pyrene in total particulate
matter of cigarette smoke. J Assoc Off Anal Chem 68:935-940.
Tong C, Fazio M, Williams GM. 1980. Cell cycle-specific mutagenesis at
the hypoxanthine phosphoribosyltransferase locus in adult rat liver
epithelial cells. Proc Natl Acad Sci 77:7377.
Tong C, Ved Brat S, Williams GM. 1981a. Sister-chromatid exchange
induction by polycyclic aromatic hydrocarbons in an intact cell system
of adult rat-liver epithelial cells. Mutat Res 91:467-473.
Tong C, Laspia MF, Telang S, Williams GM. 1981b. The use of adult rat
liver cultures in the detection of the genotoxicity of various
polycyclic aromatic hydrocarbons. Environ Mutagenesis 3:477-487.
Tong C, Fazio M, Williams GM. 1981c. Rat hepatocyte-mediated mutagenesis
of human cells by carcinogenic polycyclic aromatic hydrocarbons but not
organochlorine pesticides. Proc Soc Exp Biol Med 167:572-575.
Topham JC. 1980. Do induced sperm-head abnormalities in mice
specifically identify mammalian mutagens rather than carcinogens? Mutat
Res 74:379-387.
Tornquist A, Wiklund L, Toftgard R. 1985. Investigation of absorption,
metabolism kinetics, and DNA-binding of intratracheally administered
benzo[a]pyrene in the isolated, perfused rat lung: A comparative study
between microcrystalline and particulate absorbed benzo[a]pyrene. Chem
Biol Interact 54:185-198.
Tweats DJ. 1981. Activity of 42 coded compounds in a differential
killing test using Escherichia coli strains wp2, wp67 (uvrA polA), and
cm871, (uvra lexa reca). Prog Mutat Res 1 (Eval Short-Term Tests
Carcinog: Rep Int Collab Program):199-209.
Urso P, Gengozian N. 1980. Depressed humoral immunity and increased
tumor incidence in mice following in utero exposure to benzo[a]pyrene. J
Toxicol Environ Health 6:569-576.
USDOC (U.S. Department of Commerce). 1986. U.S. Imports for Consumption
and General Imports. FT 246/Annual 1985.
-------
118 Section 10
U.S. Surgeon General. 1986. The Health Consequences of Involuntary
Smoking. U.S. Department of Health and Human Services. DHHS (CDC) 87-
839B, pp. 118-174.
* Vahakangas K, Trivers G, Rowe M, Harris CC. 1985. Benzo[a]pyrene
diolepoxide-DNA adducts detected by synchronous fluorescence
spectrophotometry. Environ Health Perspect 62:101-104.
Valencia R, Abrahamson S, Lee WR, et al. 1984. Chromosome mutation tests
for mutagenesis in Drosophila melanogaster: A report of the U.S.
Environmental Protection Agency Gene-Tox Program. Mutat Res 134:61-88.
Valencia R, Houtchens K. 1981. Mutagenic activity of 10 coded compounds
in the Drosophila sex-linked recessive lethal test. Prog Mutat Res 1
(Eval Short-Term Tests Carcinog: Rep Int Collab Program):651-659.
Verschueren K. 1983. Handbook of Environmental Data on Organic
Chemicals. 2nd ed. Van Nostrand Reinhold, New York.
* Vo-Dinh T, Tromberg BJ, Griffin GD, Ambrose KR, Sepaniak MJ,
Gardenhire EM. 1987. Antibody-based fiberoptics biosensor for the
carcinogen benzo[a]pyrene. Appl Spectrosc 41:735-738.
Vogel EW, Zijlstra JA, Blijleven WGH. 1983. Mutagenic activity of
selected aromatic amines and polycyclic hydrocarbons in Drosophila
melanogaster. Mutat Res 107:53-77.
Wallace WE, Keane MJ, Hill CA, Xu J, Ong T. 1987. Mutagenicity of diesel
exhaust particles and oil shale particles dispersed in lecithin
surfactant. J Toxicol Environ Health 21:163-171.
* Wang DT, Meresz 0. 1982. Occurrence and potential uptake of
polynuclear aromatic hydrocarbons of highway traffic origin by
proximally grown food crops. In: Cooke M, Dennis AS, Fisher GL, eds.
Polynuclear Aromatic Hydrocarbons: Physical and Biological Chemistry.
Sixth International Symposium. Battelle Press, Columbus, Ohio, pp. 885-
896.
Waters MD, Stack HF, Brady AL, Lohman PH, Haroun L, Vainio H. 1987. Use
of computerized data listings and activity profiles of genetic and
related effects in the review of 195 compounds. Genetic Toxicology
Division, Health Effects Research Laboratory, EPA, Research Triangle
Park, N.C.
Wattenberg LW, Bueding E. 1986. Inhibitory effects of 5-(2-pyrazinyl)-
4-methyl-l,2-dithiol-3-thione (Oltipraz) on carcinogenesis induced by
benzo[a]pyrene, diethylnitrosamine, and uracil mustard. Carcinogenesis
7:1379-1381.
Wattenberg LW, Leong JL. 1970. Inhibition of the carcinogenic action of
benzo[a]pyrene by flavones. Cancer Res 30:1922-1925.
-------
References 119
Weibel FJ. 1980. Activation and inactivation of carcinogens by
microsomal monooxygenases: Modification by benzoflavones and polycyclic
aromatic hydrocarbons. In: Slaga TJ, ed. Carcinogenesis. Vol. 5:
Modifiers of Chemical Carcinogenesis. Raven Press, New York.
Weinstein IB, Jeffrey AM, Leffler S, Pulkrabek P, Yamasaki H, Grunberger
D. 1978. Interactions between polycyclic aromatic hydrocarbons and
cellular macromolecules. In: Ts'O POP, Gelboin HV, eds. Polycyclic
Hydrocarbons and Cancer. Vol. 2: Molecular and Cell Biology. Academic
Press, New York, pp. 3-36.
Weinstein IB, et al. 1976. Benzo[a]pyrene diol epoxides as intermediates
in nucleic acid binding in vitro and In vivo. Science 193:592-595.
Veyand EH, Bevan DR. 1986. Benzo[a]pyrene disposition and metabolism in
rats following Intratracheal instillation. Cancer Res 46:5655-5661.
White KL Jr, Holsapple MP. 1984. Direct suppression of in vitro antibody
production by mouse spleen cells by the carcinogen benzo[a]pyrene but
not by the congener benzo[ejpyrene. Cancer Res 44(8):3388-3393.
Whitehead FW, San RHC, Stich HF. 1983. An intestinal cell-mediated
chromosome abberration test for the detection of genotoxic agents, Mutat
Res 111:209-217.
Williams GM, Laspia MF, Dunkel VC. 1982. Reliability of the hepatocyte
primary culture/DNA repair test in testing of coded carcinogens and
noncarcinogens. Mutat Res 97:359-370.
Williams GM, Weisburger JH. 1986. Chemical carcinogens. In: Klaasson CD,
Amdur MO, Doull J, eds. Toxicology: The Basic Science of Poisons. 3rd
ed. Macmlllan Publishing Co., New York, pp. 99-173.
Williams RT. 1959. Detoxication Mechanisms. 2nd ed. Chapman and Hall,
London.
Wislocki PG, Wood AW, Change RL, et al. 1976. Mutagenicity and
cytotoxicity of benzo[a]pyrene, arene oxides, phenols, quinones, and
dihydrodiols In bacterial and mammalian cells. Cancer Res 36:3350-3357.
Wise SA, et al. 1986. Characterization of the polycyclic aromatic
hydrocarbons from two standard reference material air particulate
samples. Anal Chem 58:3067-3077.
Wojciechowski JP, Kaur P, Sabharwal PS. 1981. Comparison of metabolic
systems required to activate pro-mutagens/carcinogens in vitro for
sister-chromatid exchange studies. Mutat Res 88:89-97.
Wolfe JM, Bryan WR. 1939. Effects induced in pregnant rats by injection
of chemically pure carcinogenic agents. Am J Cancer 36:359-368.
WHO (World Health Organization). 1971. International Standards for
Drinking Water. 3rd ed. World Health Organization, Geneva, Switzerland.
-------
120 Section 10
* Wynder EL, Hoffman D. 1959. A study of tobacco carcinogenesis. VII.
The role of higher polycyclic hydrocarbons. Cancer 12:1079-1086.
Wynder EL, Hoffmann D. 1967. Tobacco and Tobacco Smoke. Academic Press,
New York.
Wynder EL, Fritz L, Furth N. 1957. Effect of concentrations of
benzopyrene in skin carcinogenesis. J Natl Cancer Inst 19:361-370.
Wynder EL, Spranger JW, Fark MM. 1960. Dose-response studies with
benzo[a]pyrene. J Natl Cancer Inst 13:106-110.
Wyrobek A, Gordon L, Watchmaker G. 1981. Effect of 17 chemical agents
including 6 carcinogen/noncarcinogen pairs on sperm shape abnormalities
in mice. Prog Mutat Res 1 (Eval Short-Term Tests Carcinog: Rep Int
Collab Program):712-717.
Yamagiwa K, Ichikawa K. 1918. Experimental study of the pathogenesis of
carcinoma. J Cancer Res 3:1-29.
Ya Khesina A. 1979. Determination of benzo[a]pyrene in extracts by
spectroluminescence. In: Egan H, ed. Environmental Carcinogens: Selected
Methods of Analysis. Vol. 3. Analysis of Polyaromatic Hydrocarbons in
Environmental Samples. IARC, Lyon, France, pp. 215-229.
Yanysheva N Ya, Kireeva IS. 1979. Determination of benzo[a]pyrene in air
using quasi-linear luminescence. In: Egan H, ed. Environmental
Carcinogens: Selected Methods of Analysis. Vol. 3. Analysis of
Polyaromatic Hydrocarbons in Environmental Samples. IARC, Lyon, France,
pp. 231-240.
Yu Y, Ding C, Li Q, Chen X. 1983, A modified method of uds detection in
vitro suitable for screening the DNA-damaging effects of chemicals.
Mutat Res 122:377-384.
Zijlstra JA, Vogel EW. 1984. Mutagenicity of 7,12-dimethylbenz(a)-
anthracene and some other aromatic mutagens in DrosophLla melanogaster.
Mutat Res 125:243-261.
-------
121
11. GLOSSARY
Acute Exposure--Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Bioconcentration Factor (BCF)--The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Carcinogen--A chemical capable of inducing cancer.
Ceiling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure--Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
Frank Effect Level (FEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
EPA Health Advisory--An estimate of acceptable drinking water levels for
a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH)--The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-impairing symptoms or irreversible
health effects.
-------
122 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxicity--The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro--Isolated from the living organism and artificially maintained,
as in a test tube.
In vivo--Occurring within the living organism.
Key Study--An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentration(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(50) (LCso)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(50) (LDso)--The dose of a chemical which has been calculated
to cause death in 50% of a defined experimental animal population.
Lovest-Observed-Adverse-Effect Level (LOAEL)--The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
Lowest-Observed-Effeet Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
Malformations--Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level--An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen--A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
-------
Glossary 123
Neurotoxicity--The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL)--That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
No-Observed-Effect Level (NOEL)--That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL)--An allowable exposure level in
workplace air averaged over an 8-h shift.
qj*--The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The q^* can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually #ig/L for water, mg/kg/day for
food, and ng/xo? for air).
Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ)--The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are: (1) 1 lb
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Toxicity--The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL)--The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
-------
124 Section 11
Target Organ Toxicity--This term covers a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
Teratogen--A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV)--A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA)--An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF)--A factor used in operationally deriving the RfD
from experimental data. TJFs are intended to account for (1) the
variation in sensitivity among the members of the human population,
(2) the uncertainty in extrapolating animal data to the case of humans,
(3) the uncertainty in extrapolating from data obtained in a study that
is of less than lifetime exposure, and (4) the uncertainty in using
LOAEL data rather than NOAEL data. Usually each of these factors is set
equal to 10.
-------
125
APPENDIX: PEER REVIEW
A peer review panel was assembled for benzo[a]pyrene. The panel
consisted of the following members: Dr. Alexander Wood, Hoffmann-
La Roche, Inc.; Dr. Dietrich Hoffmann, American Health Foundation; and
Dr. Roger McClellan, Lovelace Institute for Inhalation Toxicology. These
experts collectively have knowledge of B[a]P's physical and chemical
properties, toxicokinetics, key health end points, mechanisms of action,
human and animal exposure, and quantification of risk to humans. All
reviewers were selected in conformity with the conditions for peer
review specified in the Superfund Amendments and Reauthorization Act of
1986, Sect. 110.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
------- |