EPA-450/5-87-003
NATIONAL AIR TOXICS
INFORMATION CLEARINGHOUSE
oEFA
Office of Air Quality Planning and Standards
Research Triangle Park, North Carolina 27711
State and Territorial Air Pollution Program Administrators
Association of Local Air Pollution Control Officials
Qualitative and Quantitative
Carcinogenic Risk
Assessment
June 1987
-------
DCN No. 87-239-001-13-12
EPA Contract No. 68-02-4330
Work Assignment No. 13
EPA 450/5-87-003
NATIONAL AIR TOXICS INFORMATION CLEARINGHOUSE:
QUALITATIVE AND QUANTITATIVE CARCINOGENIC RISK ASSESSMENT
FINAL REPORT
Prepared for:
Beth M. Hassett
Work Assignment Manager
Strategies and Air Standards Division
Office of Air Quality Planning and Standards
U. S. Environmental Protection Agency
Research Triangle Park, North Carolina 27711
Technical Consultants:
Dr. Ila Cote, Toxicologist
Strategies and Air Standards
Division
Office of Air Quality Planning
and Standards
U. S. Environmental Protection
Agency
Research Triangle Park, NC 27711
Dr. Steven Bayard, Statistician
Mr. Charles Ris, Deputy Director
Carcinogen Assessment Group
Office of Health and
Environmental Assessment
U. S. Environmental Protection
Agency
Washington, D.C. 20460
Prepared by:
Radian Corporation
3200 East Chapel Hill Road/Progress Center
Post Office Box 13000
Research Triangle Park, North Carolina 27709
June 1987
'T.F. Environmental Protection /Lgs
}"••., ion 5, Library (5PL-16)
f'60 S. Dearborn Street, Hoom 1670
Liiuaso, *IL 60G04
-------
DISCLAIMER
This report has been reviewed by the Office of Air Quality Planning and
Standards, U. S. Environmental Protection Agency, and approved for
publication as received from Radian Corporation. Approval does not signify
that the contents reflect the views and policies of the U. S. Environmental
Protection Agency, nor does mention of trade names or commercial products
constitute endorsement or recommendation for use.
-------
PREFACE
The EPA is supporting State and local agency air toxics control efforts
by implementation of an information dissemination center, known as the
National Air Toxics Information Clearinghouse. The EPA established the
Clearinghouse in response to requests for assistance from State and local
agencies concerned about control of toxic air emissions. The Clearinghouse
is composed of a computerized data base which contains indexed information
on toxic and potentially toxic air pollutants, hard copy reports of
information from the data base, several special reports such as this one,
and a quarterly newsletter. The Clearinghouse has been designed and is
being implemented in close coordination with the State and Territorial Air
Pollution Program Administrators (STAPPA) and the Association of Local Air
Pollution Control Officials (ALAPCO).
The purpose of this report is to describe the basic principles and
assumptions associated with a qualitative and quantitative carcinogenic risk
assessment and to illustrate these features using several examples of
quantitative risk assessments done by State and local agencies. The report
is intended to help readers better understand and interpret a risk
assessment rather than to provide instructions that would enable them to
conduct a risk assessment. The report is aimed at managers and staff
members in State and local agencies who are concerned with the use of
qualitative and quantitative carcinogenic risk assessment for evaluating
emissions of toxic air pollutants.
Other Clearinghouse publications include:
t National Air Toxics Information Clearinghouse: Rationale for Air
Toxics Control in Seven State and Local Agencies, EPA 450/5-86-005,
NTIS: PB86 181179/AS, August 1985;
• National Air Toxics Information Clearinghouse: NATICH Data Base
Users Guide for Data Viewing, EPA 450/5-85-008,
NTIS: PB86 123601/AS, September 1985;
-------
National Air Toxics Information Clearinghouse: Ongoing Research
and Regulatory Development Projects, EPA 450/5-86-007,
NTIS: PB86 226396/AS, June 1986;
National Air Toxics Information Clearinghouse: Bibliography of
Selected Reports and Federal Register Notices Related to Air
Toxics, EPA 450/5-86-008; NTIS: PB87 125787/AS, July 1986;
National Air Toxics Information Clearinghouse: How the
Clearinghouse Can Help to Answer Your Air Toxics Questions,
EPA 450/5-86-009; NTIS: PB pending; July 1986;
National Air Toxics Information Clearinghouse: Methods for
Pollutant Selection and Prioritization, EPA 450/5-86-010;
NTIS: PB87 124079/AS, July 1986;
National Air Toxics Information Clearinghouse: NATICH Report on
State and Local Air Toxics Activities, 2 Volumes,
EPA 450/5-86-011A, B; NTIS: PB87 125779/AS, July 1986;
National Air Toxics Information Clearinghouse Database User's
Guide for Data Entry and Editing; EPA 450/5-87-002;
NTIS: PB87 175576/AS; February 1987; and
National Air Toxics Information Clearinghouse Newsletters,
December 1983, February 1984, April 1984, July 1984,
September 1984, December 1984, February 1985, May 1985,
August 1985, December 1985, March 1986, June 1986, September 1986,
December 1986, March 1987, and June 1987.
-------
ABSTRACT
The National Air Toxics Information Clearinghouse has been established
by the EPA Office of Air Quality Planning and Standards (OAQPS) in
coordination with the State and Territorial Air Pollution Program
Administrators (STAPPA) and the Association of Local Air Pollution Control
Officials (ALAPCO) for the purpose of aiding information transfer among
Federal, State, and local air quality management agencies. This report has
been published as part of that effort. The purpose of this report is to
describe the basic principles and assumptions associated with a qualitative
and quantitative carcinogenic risk assessment to help State and local
agencies better understand and interpret a risk assessment. The report
discusses the four steps of risk assessment: hazard identification,
dose-response assessment, exposure assessment, and risk characterization,
focusing primarily on the dose-response assessment. In addition to
describing the basic principles of carcinogenic risk assessment, the report
describes examples of risk assessment work done by EPA and four State/local
agencies.
Vll
-------
TABLE OF CONTENTS
Section Page
1.0 Introduction 1-1
1.1 Purpose 1-1
1.2 Organization 1-1
1.3 Definition of Quantitative Carcinogenic Risk
Assessment 1-2
2.0 Hazard Identification 2-1
2.1 Physical and Chemical Properties 2-1
2.2 Structure/Activity Relationships 2-3
2.3 Pharmacokinetic Interactions 2-3
2.3.1 Absorption 2-4
2.3.2 Distribution 2-4
2.3.3 Metabolism 2-5
2.3.4 Excretion 2-6
2.4 Routes of Exposure 2-6
2.5 Toxicologic Effects 2-7
2.5.1 Short-Term Predictive Tests 2-7
2.5.2 Long-Term Animal Bioassays for Cancer 2-9
2.6 Epidemiologic Data 2-14
2.7 Weight of Evidence of Carcinogenicity for Animal
and Human Studies 2-17
3.0 Dose-Response Assessment 3-1
3.1 The Process of Carcinogenesis 3-4
3.2 The Concept of Thresholds 3-8
-------
Section Page
3.3 Selection of Data From Which to Derive the
Dose-Response Assessment 3-9
3.3.1 Epidemiologic Studies 3-9
3.3.2 Animal Studies 3-11
3.4 Dose-Response Assessment Techniques 3-13
3.4.1 Low Dose Extrapolation Issues 3-13
3.4.2 Mathematical Extrapolation Models for
Animal Studies 3-14
3.4.3 Dose Conversions 3-21
3.4.4 Modeling of Animal Studies Using the
Linearized Multistage Model 3-24
3.4.5 Modeling of Epidemiologic Studies 3-27
4.0 Exposure Assessment 4-1
5.0 Risk Characterization 5-1
5.1 Presentation of Numerical Estimates of Risk 5-1
5.2 Presentation of the Uncertainties in Risk
Assessment 5-3
5.3 Presentation of the Assumptions Used in Risk
Assessment 5-5
6.0 Risk Management 6-1
7.0 Resource Requirements 7-1
8.0 Northeast States for Coordinated Air Use Management -
Ri sk Assessment for Tetrachloroethylene 8-1
8.1 Objectives in Undertaking Risk Assessment 8-1
8.2 Overview of Methodology Used 8-1
8.2.1 Hazard Identification 8-2
8.2.2 Dose-Response Assessment 8-3
8.2.3 Exposure Assessment and Risk
Characterization 8-6
-------
Section
8.3 Resource Requirements 8-6
8.4 Other Risk Assessment Work 8-7
8.5 NESCAUM's Advice to Other Agencies 8-7
9.0 California Department of Health Services 9-1
9.1 Objectives in Undertaking Risk Assessment 9-1
9.2 Overview of Methodology Used 9-1
9.2.1 Hazard Identification 9-2
9.2.2 Dose-Response Assessment 9-4
9.2.3 Exposure Assessment 9-10
9.2.4 CAPCOA Source Assessment Manual 9-11
9.3 Risk Management 9-13
9.4 Resources 9-14
9.5 Other Risk Assessment Work 9-14
9.6 Air Toxics Status 9-14
10.0 Michigan Department of Natural Resources 10-1
10.1 Objectives in Undertaking Risk Assessment 10-1
10.2 General Overview of Methodology Used 10-1
10.2.1 Hazard Identification 10-1
10.2.2 Dose-Response Assessment 10-3
10.2.3 Exposure Assessment 10-4
10.2.4 Risk Characterization 10-7
10.3 Risk Management 10-9
10.4 Resource Requirements 10-10
10.5 Other Risk Assessment Work 10-10
10.6 Advice to Other Agencies 10-10
-------
Section Page
11.0 Clark County Health District 11-1
11.1 Objectives in Undertaking Risk Assessment 11-1
11.2 General Overview of Methodology Used 11-1
11.2.1 Hazard Identification 11-1
11.2.2 Dose-Response Assessment 11-2
11.2.3 Exposure Assessment 11-2
11.2.4 Risk Characterization 11-3
11.3 Ongoing Activities 11-4
11.4 Resource Requirements 11-6
11.5 Advice to Other Agencies 11-6
Glossary G-l
References R-l
Appendix A - EPA Guidelines for Carcinogen Risk
Assessment A-l
Appendix B - International Agency for Research on
Cancer Weight-of-Evidence Classification Scheme B-l
Appendix C - Cancer Information Sources C-l
XII
-------
LIST OF TABLES
Table Page
2-1 General Classification of Tests Available to Determine
Properties Related to Carcinogenicity 2-2
2-2 Illustrative Categorization of Evidence Based on
Animal and Human Data 2-22
3-1 Estimates of Low-Dose Risk to Humans Based on Salivary
Gland Region Sarcomas in Male Rats in the Dow Chemical
Company (1980) Inhalation Study Derived from Four
Different Models 3-28
4-1 Sample Human Exposure Model (HEM) Output 4-4
4-2 Sample from NATICH Data Base of Selected EPA Risk
Analysis Information by Pollutant 4-5
5-1 Summary of Primary Methods for Characterizing
Uncertainty for Estimating Exposures 5-6
9-1 Lifetime Excess Cancer Risk Estimates for Ethylene
Dibromide (EDB) Exposure 9-9
10-1 Maximum Ground Level Concentrations and Associated
Risk for Potential Carcinogens 10-6
10-2 Toxic Equivalency Factors for PCDDs and PCDFs 10-8
10-3 Michigan Division of Air Quality Carcinogenic Chemicals
and Associated Air Concentrations Resulting in a
1 x 10 Cancer Risk 10-11
11-1 Estimated Annual Incidence of Cancers in Las Vegas
Valley Due to Urban Air Pollution 11-5
xm
-------
LIST OF FIGURES
Figure Page
1-1 Overview of Health Risk Assessment 1-3
3-1 Hypothetical Dose-Response Curve 3-2
3-2 Dose-Response Curve Showing Low-Dose Region 3-3
3-3 Log-Log Plot of Risk, P(d), Versus Dose, d, of
Aflatoxin 3-20
9-1 CDHS Algorithm for Performing Dose-Response
Assessments 9-5
xv
-------
1.0 INTRODUCTION
1.1 PURPOSE
The National Air Toxics Information Clearinghouse (the Clearinghouse)
has been established by the EPA Office of Air Quality Planning and Standards
(OAQPS) in coordination with the State and Territorial Air Pollution Program
Administrators (STAPPA) and the Association of Local Air Pollution Control
Officials (ALAPCO) for the purpose of aiding information transfer among
Federal, State, and local air quality management agencies. This report has
been published as part of that effort.
The purpose of this report is to describe the basic principles and
assumptions associated with a qualitative and quantitative carcinogenic risk
assessment and to illustrate its features using several examples of risk
assessment done by EPA and State and local agencies. Risk assessment as it
applies to air pollutants has been emphasized. While the entire risk
assessment process is described, the focus of the report is the
dose-response assessment step of a quantitative risk assessment. The report
is intended to help readers to better understand and interpret a risk
assessment rather than to provide instructions that would enable them to
conduct a quantitative dose-response assessment. The report is aimed at
managers and staff members in State and local agencies who are interested in
understanding the use of quantitative carcinogenic risk assessment for
evaluating emissions of toxic pollutants.
1.2 ORGANIZATION
This report is divided into two parts. Part 1, Sections 1.0 through
7.0, describes general risk assessment methodologies, uses of risk
assessment, and resource requirements. The EPA's approach to quantitative
cancer risk assessment is the main focus of Part 1. Part 2, Sections 8.0
through 11.0, gives four examples of chemical-specific quantitative cancer
risk assessments. The example risk assessments were performed by the
1-1
-------
Northeast States for Coordinated Air Use Management (NESCAUM), the States of
California and Michigan, and the local air pollution control division of
Clark County (Las Vegas), Nevada. Following the text of the report are a
glossary of terms associated with quantitative risk assessment and
appendices containing EPA Guidelines for Carcinogen Risk Assessment, the
weight-of-evidence classification scheme developed by the International
Agency for Research on Cancer, and a list of cancer information sources.
1.3 DEFINITION OF QUANTITATIVE CARCINOGENIC RISK ASSESSMENT
Quantitative carcinogenic risk assessment is a process by which a
factual base of information is used to estimate the probability of
developing cancer due to exposure to a specific chemical. This report
follows the four-component process described in Guidelines for Carcinogen
Risk Assessment developed by EPA (EPA, 1986b). This approach is consistent
with and draws upon the scientific principles of carcinogen risk assessment
developed by the Office of Science and Technology Policy (OSTP, 1985).
The four components of a risk assessment as defined by the guidelines
are:
1. Hazard identification - a review of relevant biological and
chemical information bearing on whether or not a chemical may pose
a human carcinogenic hazard;
2. Dose-response assessment - a definition of the relationship
between the dose of an agent and the magnitude of response,
usually including a quantitative description of the relationship
of dose to response;
3. Exposure assessment - an estimate of the extent of exposure to
which the populations of interest are likely to be subject; and
4. Risk characterization - the integration of hazard identification,
dose-response assessment, and exposure assessment in a framework
to help judge the significance of the risk estimate.
Figure 1-1 illustrates these four steps and lists the main concerns of each
step.
1-2
-------
Pollutant Selection
Pollutant Prloritizatlon
Hazard Identification
• Substances Present in Ambient Air (from emissions,
atmospheric transformation, etc.)
t Substances Associated with Health Effects
• Weight-of-Evidence Evaluation
Dose-Response Assessment
• Qualitative or Quantitative Assessment of Potency
Exposure Assessments
Estimation of Emission or Release Rates
Identification of Exposure Routes
Modeling of Environmental Transport
Evaluation of Environmental Fate
Identification of People Exposed
Estimation of Toxic Substances Intakes
•
t
Risk Characterization/Uncertainty Analyses
Integration of Hazard Identification, Dose-Response
Assessment, and Exposure Assessment
Weight-of-Evidence Evaluation
Evaluation of Uncertainty in Assessment Process
Figure 1-1. Overview of Health Risk Assessment
1-3
-------
This report focuses primarily on the basic processes and assumptions
associated with the dose-response assessment component. Other steps in the
risk assessment process are described in order to place dose-response
assessment in the proper context and to illustrate all of the components of
a complete risk assessment. These other components have been extensively
reviewed elsewhere (OSTP, 1985; EPA, 1985b, 1986a, 1986c). In addition, a
previous Clearinghouse publication entitled "Methods for Pollutant Selection
and Prioritization" reviews in part the hazard identification component of
the risk assessment process (NATICH, 1986a). This report provides examples
of how some State and local agencies have chosen pollutants for risk
assessment work. If readers are familiar with these publications, they may
wish to focus on Section 3.0, Dose-Response Assessment.
Agencies often use quantitative cancer risk assessments in making
decisions about regulating the emissions of known or suspect carcinogens.
These decisions may be necessary based on existing ambient levels of air
toxics or due to proposed new facilities which would increase emissions of
substances of concern. The review of the factual data base undertaken in a
risk assessment is distinctly different from risk management or the process
of considering policy alternatives in order to select the most appropriate
regulatory action that could be taken to reduce the public's exposure to
known or suspect carcinogens. Risk management relies in part on the
scientific results of risk assessment. Section 6.0 discusses risk
management.
1-4
-------
2.0 HAZARD IDENTIFICATION
Hazard identification is the first step in a cancer risk assessment.
The purpose of cancer hazard identification is to determine qualitatively
whether exposure to a given substance is likely to produce a carcinogenic
response (EPA, 1986b). Hazard identification typically includes a review of
several types of information such as the physical and chemical properties of
a chemical, and the results of short-term toxicity tests, long-term
bioassays and epidemiologic studies. Each type of information is discussed
in Sections 2.1 through 2.5. Since the available information on the
carcinogenic potential of a chemical is rarely, if ever, conclusive, results
and conclusions derived from the different types of information are combined
and the judgment concerning potential human carcinogenicity is developed
considering the total weight of evidence. Weight-of-evidence classification
schemes are discussed in Section 2.6. Table 2-1 summarizes the general
types of information used in hazard identification and compares various
features of each type of information.
2.1 PHYSICAL AND CHEMICAL PROPERTIES
The first stage in determining whether or not a chemical is a potential
carcinogen is gathering all of the available information about the chemical.
Often, the most readily available information is on the physical and
chemical properties and the molecular structure. Chemical and physical
properties which are useful in evaluating a chemical's carcinogenic
potential include solubility, stability, sensitivity to pH, and chemical
reactivity (OTA, 1981). These properties are of interest in that they will
affect a large number of factors in the risk assessment (e.g., absorption
into the body; partitioning in various media, such as air, water, soil;
decay rates; etc.).
2-1
-------
UJ
I—I
Of.
UJ «— .
•^™ ^"^
UJ CO
a at
i— i
o
UJ t—
—1 O
CD ^"^
> O
< "-H
Z
00 UJ
1— CD
GO O
UJ Z
o
u. a:
o «t
o
o o
I—I J__
• 1
UJ
1— 1
— 1 h-
S UJ
UJ Q-
z o
UJ O£
CD a.
*
1
1«LJ
CO
t^c
1—
S
<« -H
M *J
- n
B 0
o a.
to n
3 -t
O 4J
§3
0 MV'Qf^ «iu
u« -IB -HtOBU -Id
4 u « O 9 M O
~^B ^00 ^Blt <~l
« -i u no it^nu MB
uBv uB uu«^ o S
*4MX ^>^ E o S « o S S3
0)4JM 01H 0)OUS VX
X«3 Xit XO.3 X
U-QIH 00 0 « n X UK
V «
•J 5 V 5 w IH
^ s •; ti ? °
1J 4J 00 11 • 4JOO*H "0 91
o -j ai ja n -i u o v^u
B uiBB «B UUVB
«l~ O^O« O^» « O > 0)
vntiB auto a o -j c -< TI
-i « > S ^»o»o ^«B op^
J3 O -1 0 «BB At) 0 0! It O
B -O " fl «3S-< •IS'O « >4 to 0
« It^E VltfOO VIl-H «1 V»4
nMoo nuBU TI o o 4MB
«0«> ti -O »«4
M > «l H 00 -1 BU3 -1 t) -1 > u «
3 -J -1 3 0 41O 4 B4B P S u P n
M ^o-i 6«6
VI4IX ndV VI4VO
^M^H ^<*O rH-iff) ^IU*H*^
(« 3 M 4Z0n 43- « -O P
OP4 O O M S OH4>I O U 3 4
-4Or^ -4 39 ^UOB *^VP^
S3-4 S>B"iP BQ § Bo*t3
Sue «P4» « 1 >• 1 « § o-
X P -H X -4 $ ^ -2 3 4 3 X 3 C 0
u n «i o » S " u P a X o o -4 a
v V n
>M » M
X 4 •-> « On
-^ u o n x P «
-i ^ p x e
9 U in B -3
n M n X B X w
n J! VJ440 0 P »
XV C « -O B U B -4 00 M X-l
c V
xx - o
WO « B n n B
tl U 4 -* -H -H
-44 « -1 4 4 -
8 M X v B q n
So o-3 -3 P
XX B C 4
O 4 4 ^ 4 4 M
M M U 4J U » n
nun ii 3 o o- B
a -" P P P 4 400 4
4nn o -i P w- S
tu 4 » 4 3 C BV 3
« « P mo-4 M^> a
00
go
r*
4 u n v X O
r-l 3 -4 U 4 -<
3 p n i n 8
O U X u n « S
«?'-' »4 W 4 "O
O *J 3 .£ V *4 o,
Z n 3 U) U a M
2-2
-------
2.2 STRUCTURE/ACTIVITY RELATIONSHIPS
As mentioned above, in addition to the physical and chemical properties
of a chemical, information about the molecular structure is often readily
available. Comparing the structure of a chemical with those of known
carcinogens and noncarcinogens can give some indication of the likelihood
that the chemical under study will have carcinogenic potential. For
instance, 8 of the first 14 carcinogens regulated by the Occupational Safety
and Health Administration were aromatic amines. Certain molecular
structures or substructures have been associated with carcinogenicity and
structural similarity can be used to suggest which agents are more or less
likely to have a carcinogenic potential. For example, the structural
relationship between chlorinated dibenzo-p-dioxins and chlorinated
dibenzofurans have been used to show a relationship between structure/
activity and carcinogenic potency (EPA, 1987). Carcinogens are found in a
number of chemical classes and, within most classes, chemicals differ
greatly with respect to the nature and extent of carcinogenic activity
(OTA, 1981).
2.3 PHARMACOKINETIC INTERACTIONS
Pharmacokinetics is the study of absorption, distribution, metabolism,
and excretion of chemicals by the body. These mechanisms can all alter the
biological effects of a chemical in both a qualitative and quantitative
manner. Although only a few chemicals have been studied in detail,
pharmacokinetic differences have been shown to be very important in
extrapolating data from test systems (e.g., short-term tests, bioassays) to
possible human effects. Many differences in response between species and
among individuals within a species are due to differences in
pharmacokinetics. Pharmacokinetic interactions can be extremely complex and
lack of specific information on a chemical results in scientific uncertainty
over the true impact of a chemical exposure and requires the use of a
multitude of conservative assumptions in the hazard identification process.
2-3
-------
The following subsections very briefly discuss some possible implications of
pharmacokinetic interactions on the hazard identification process. Further
discussion of pharmacokinetics can be found in Hayes, 1982.
2.3.1 Absorption
Although a chemical exposure may be from a number of different routes,
the amount of chemical absorbed into the body (and subsequently distributed
to the sensitive tissue or organ) is important information. Cancer studies
in animals generally use an exposure route and methodology that maximize
absorption. Information on absorption in the nonlaboratory situation is
very scarce and, for humans, a number of assumptions must frequently be made
regarding potential absorption. When possible, actual estimations of
absorptions should be documented and taken into account in calculating risk.
Factors that control the inhaled dose of a pollutant are related to the
significant mechanisms by which aerosols and gases may be deposited or taken
up in the lung. Extensive discussions of aerosol deposition and gas
absorption appear in EPA, 1982 and EPA, 1986e.
2.3.2 Distribution
Distribution refers to the transport of a chemical through the body by
physical means. The body has several barriers to the free transport of
chemicals (e.g., cell or tissue membranes) and this can alter the
distribution of a chemical and the possible adverse health effects. The
effects of chemical distribution have been best described for pharmaceutical
agents where the lack of distribution to certain organs is relied upon to
limit unwanted side effects. Distribution is altered by the chemical
properties of the agent (e.g., ionic versus nonionic, lipophilic versus
hydrophilic) and to some extent the route of exposure. Some distribution
can still occur after environmental exposure has ceased due to release of
substances stored in the body. For instance, lead can be stored in the bone
and later released under certain physiological conditions related to calcium
balance.
2-4
-------
2.3.3 Metabolism
Metabolism refers to the chemical alteration of a substance by
enzymatic processes within the body. Metabolism Is a normal function of the
body and, In addition to generating energy and/or new chemicals for
physiological processes, is an important component in removing exogenous
chemicals from the body. There are a large number of enzyme systems that
act on different chemical substrates to produce very specific chemical
changes. In general, for exogenous chemicals, these changes tend to make
the compound more hydrophilic (water soluble) which increases the rate at
which it is excreted.
For many chemicals, metabolism is a critical step in generating a
carcinogenic response. While the parent material may have relatively few or
no carcinogenic properties, metabolism can generate an "active" intermediate
chemical which, by being more reactive, can initiate or promote a
carcinogenic response. Many organic chemical carcinogens and possibly some
metal compounds require metabolic activation in order to exert their
cancer-inducing properties (OSTP, 1985). For example, benzo(a)pyrene must
be metabolized to reach its carcinogenic form. Cytochrome P450 enzymes,
integral in the metabolic activation of many compounds, are found primarily
in the liver and to a lesser extent in the lung and other tissues.
Metabolism is also one factor in pharmacokinetics that has been shown
to vary widely between species of animals, to be very dependent upon the
amount of a specific chemical present, and even to show variability between
individuals of the same species. For hazard identification purposes, it is
often assumed that humans react like the most sensitive test species.
However, for risk assessment and for determining the human cancer potential
from chemicals shown to be carcinogenic in animals, intraspecies variability
and alteration of metabolic pathways by saturation of primary pathways are
important considerations in evaluating the usefulness of animal data for
extrapolation to humans. These considerations are discussed further under
Toxicologic Effects (Section 2.5).
2-5
-------
2.3.4 Excretion
Excretion is the removal of exogenous and waste chemicals from the
body. In addition to urine and fecal material, the skin and lungs also
serve to remove waste materials from the body as do tears, milk, and other
secretions. Some materials are excreted unchanged by metabolic processes,
while others are excreted only after being metabolized. Excretion of
chemicals in milk may warrant special consideration in a risk assessment due
to the potential exposure via consumption of dairy products from cattle and
exposure of nursing infants.
2.4 ROUTES OF EXPOSURE
The potential environmental exposure pathways for the chemical under
evaluation may also be important in focusing the hazard identification
process. The carcinogenic response for some chemicals depends on the route
of exposure. Human exposure to environmental carcinogens can occur by
dermal contact, inhalation, ingestion, or a combination of these routes of
exposure. There may be route-dependent differences in molecular,
biochemical, and physical parameters. For example, dermal exposure of
sensitized individuals to nickel can result in dermatitis but is not known
to produce a carcinogenic response (EPA, 1985a). However, studies have
shown inhalation exposure to certain forms of nickel produced a carcinogenic
response (EPA, 1985a). Differences in carcinogenic response between routes
of exposure are often due to pharmacokinetic differences (e.g., absorption,
metabolism). For example, many metals and metal compounds are substantially
more carcinogenic following inhalation exposures versus ingestion because
these agents are not absorbed well from the gastrointestinal tract. Also,
depending on the route of exposure, the effect of an agent can be altered as
a result of interaction with factors that are in association with, but not
actually part of, an organism. For example, studies have shown interactions
between smoking and certain inhaled carcinogens (e.g., asbestos). The
result is that a chemical that shows a carcinogenic response from one route
2-6
-------
of exposure may not show a response from a different route of exposure.
Route of exposure can also alter the tissue or tissues affected by cancer as
well as the potency of the agent.
2.5 TOXICOLOGIC EFFECTS
2.5.1 Short-Term Predictive Tests
As shown In Table 2-1, short-term tests are so named because of the
relatively short length of time needed to complete the experiments - from
less than one day up to about eight months. There has been a growing
interest in short-term tests for genetic toxicity, because of the relatively
shorter time period needed to complete the test and because of the
relatively lower cost compared to long-term bioassays. Many short-term
tests detect chemical interactions with DMA and provide evidence on whether
a chemical may cause mutations. There is evidence that many chemical
carcinogens exhibit mutagenic activity (OTA, 1981), thus, these tests are
useful as screening tools, providing preliminary evidence of carcinogenic
potential.
Short-term tests are usually categorized as either la vitro, a test not
conducted on an entire complex living organism; or in vivo, a test conducted
on an intact living organism. In vitro short-term test systems include gene
mutation, chromosome effects, DNA damage and repair, and cellular
transformation. One of the most widely used in vitro gene mutation tests is
the Ames test, developed by microbiologist Bruce Ames. This test measures
the capacity of a chemical to cause mutations in Salmonella tvphimurium. a
bacterium that is quickly and easily grown in the laboratory and is well
understood genetically. The Ames test involves mixing the chemical under
test with a bacterial culture and then manipulating the culture so that only
mutated bacteria will grow. The number of mutated bacteria 1s a measure of
the potency of the tested material as a mutagen (OTA, 1981).
Some chemicals act as mutagens interacting with DNA only after they are
metabolized, often by enzymes in the liver. Liver extracts are often added
to an Ames test system to provide a mechanism for these metabolic activation
changes to be accomplished (OTA, 1981).
2-7
-------
The Ames test 1s reported to detect known carcinogens as mutagens with
a frequency as high as 90 percent. A positive Ames test shows that an agent
1s a mutagen and suggests that it may be a carcinogen. In tests performed
by Ames and his associates, 90 percent of a group of known carcinogens
tested were found to be mutagenic, giving the test a 10 percent false
negative rate. They also found 88 percent of a group of noncarcinogens were
identified as not mutagenic, giving a false positive rate of 12 percent.
Dr. Ames has shown, however, that the test performs more reliably on certain
classes of compounds. For example, he has shown that his test does not work
well with either halogenated hydrocarbons or metals (OTA, 1981).
Other short-term in vitro tests can detect mutagenesis in bacteria and
bacterial viruses, yeast, and cultured mammalian cells, as well as
interference with chromosomal mechanics, disruption of DNA synthesis and
DNA repair mechanisms in bacteria and other organisms, and transformation of
cultured cells. These tests often involve the use of cell culture systems
in which cells from animal or human tissue are grown and manipulated in the
laboratory. Cell cultures can be manipulated to serve as assays for
mutagens and for chemicals that interfere with chromosomal mechanics
(e.g., chromosomal translocation, sister chromatid exchange, and DNA
damage), but the most directly applicable use of cultured cells for
carcinogen identification involves in vitro transformation. "Transformation"
means that cultured cells exposed to chemical carcinogens display changes in
normal morphology and growth characteristics, resembling tumor cells
(OTA, 1981). This is theoretically a more direct measure of potential
careinogenicity.
Short-term in vivo tests are conducted on an intact living organism.
Such tests include mutagenesis affecting mouse hair color, effects on
chromosomal mechanics in mammals, and tests done by injecting transformed
cells Into an intact organism, most often a rodent (OTA, 1981).
Opinions differ about the use of short-term tests in carcinogen
identification. In 1981, the Office of Technology Assessment addressed this
debate noting that "the majority view is that the [short-term] tests are
most useful as a screen to determine a chemical's potential carcinogenicity"
(OTA, 1981). Generally, a battery of short-term tests can help reduce the
2-8
-------
likelihood of false negatives (carcinogens that are not detected) and false
positives (noncardnogens that are falsely detected) (OTA, 1981). It is
important to note that short-term tests typically focus on an endpoint
different from cancer (e.g., mutations, chromosome aberrations, DNA
damage/repair). The EPA guidelines note that lack of positive results in a
short-term test does not provide the basis for discounting positive results
in long-term animal bioassays (EPA, 1986b). Positive results from
short-term tests for genetic toxicity, however, add to the overall weight of
evidence for carcinogenicity. Short-term tests in themselves are generally
not considered sufficient to determine carcinogenicity and/or support
regulations.
2.5.2 Lona-Term Animal Bioassavs for Cancer
In long-term animal bioassays for cancer, test animals are used as
surrogates for humans since a basic premise of toxicology is that effects
seen in test animals are presumed to be applicable to humans. Noting that
this premise is frequently questioned with regard to human cancer, the
National Research Council (NRC) has explained that cancer in humans and
animals is strikingly similar, adding, "virtually every form of human cancer
has an experimental counterpart, and every form of multicellular organism is
subject to cancer, including insects, fish, and plants" (NRC, 1977).
Although cancer as an endpoint may be similar in humans and test animals,
the notion of test animals as "little humans" is an inappropriate
oversimplification. Many biological differences between animals and humans
must be considered in extrapolating animal test results to possible human
effects. Extrapolation is discussed in Section 3.0.
In long-term cancer bioassays, the chemical under study is administered
to laboratory animals (frequently rats and mice) for their lifetime via a
route that ideally is the same as, or as close as technically possible to,
the one by which human exposure would occur. As the test animals die or are
killed during or at the conclusion of the study, they are examined for the
presence of tumors (OTA, 1981). Data collected from bioassays may also
include precancerous changes, the presence of unusual tumors, time to tumor,
2-9
-------
the presence of benign versus malignant tumors, toxicologic effects other
than those related to cancer, and subchronic data including organ effects.
Guidelines for conducting bioassays have been developed and are described in
Section 3.0. These guidelines are also useful to those who would use data
from a specific bioassay for a risk assessment because they help the user
judge the quality of the methodology.
Compared to short-term tests, animal bioassays take considerably longer
to perform (2 to 5 years) and are much more costly. Short-term tests may
cost from $100 to a few thousand dollars for each test while each long-term
bioassay could range from $400,000 to over $1 million (OTA, 1981). However,
as discussed below, the results from long-term bioassays are considered more
relevant. Also, in contrast to epidemiologic studies (Section 2.6),
multiple variables (e.g., diet, environmental conditions) are easier to
control in an animal study.
Bioassays are extremely useful, but their use is not without
difficulties. Six problem areas are discussed below: (1) biological
similarity and differences between animals and humans, (2) sample size,
(3) super-sensitivity of test animals, (4) the significance of benign versus
malignant tumors, (5) the role of underlying toxicity, (6) overwhelming body
detoxification mechanisms, and (7) multiple pollutant exposure. These
problems are discussed here to make the reader aware that these points
warrant consideration in review of a bioassay rather than to discourage the
use of such studies. It is important to note that all Federal regulatory
agencies accept the use of animal test results as predictors of carcinogenic
risk for humans (OTA, 1981).
In regard to the first problem area listed above, the issue of
biological similarities between human and animals, differences in
pharmacokinetics, size, and patterns of inhalation between rodents and other
test animals and humans, should be considered in interpreting the
significance of the results. Metabolic studies have shown that most
differences between humans and experimental animals are quantitative rather
than qualitative, supporting the idea that animal results can be used to
predict human responses (OTA, 1981).
2-10
-------
The number of test animals used has been the subject of great concern
because of the fact that the test animals may be serving as surrogates for
more than 200 million people in the United States, and potentially for far
more worldwide. While it is desirable to enhance the sensitivity of the
test, it is not feasible to use very many animals. A sufficient number of
animals should be used so that at the end of the study enough animals from
each group are available for thorough pathological evaluation. For such
reasons, it has been recommended that each dose group and concurrent control
group should contain at least 50 animals of each sex. At least one
concurrent untreated control group, identical in every respect to the
exposed groups, except for exposure to the test substance, should be used.
In certain studies, such as with inhalation exposures that require unique
housing conditions, it may also be appropriate to include an additional
concurrent control group housed under conventional conditions (OSTP, 1985).
When careful attention is paid to experimental design, the test is more
likely to achieve the maximum reliability and the results are more amenable
to statistical evaluation.
It is important to consider the impact the use of a limited number of
animals has on the statistical power to detect an effect. If the
spontaneous (background) incidence rates are low, it is generally possible
to detect as little as a 5 to 10 percent increase incidence in an average
bioassay. Alterations of less than 5 percent are not detectable without the
use of historical controls. For example, if the population of the United
States was exposed to an agent which produced a 4.5 percent response (which,
as noted above, is not detectable in a bioassay), approximately 9,000 cancer
cases may be seen. The use of historical controls increases the number of
animals used for comparison and consequently increases the power of the
statistical analyses (i.e., the ability to detect an effect).
Some species or strains of test animals or organs of certain species or
strains of animals are very sensitive to carcinogens and this sensitivity
complicates the use of data from such animals. Many times sensitive species
are used in bioassays because they are sensitive and increase the likelihood
of positive results. Comparative studies have shown that neither rats nor
mice are particularly sensitive species. The possibility of a false result
2-11
-------
can be reduced by the use of two species Instead of one (OSTP, 1985).
Numerous studies suggest that the mouse liver Is a sensitive organ, such
that when mouse liver tumors are the only evidence of carclnogenlclty, test
results are worthy of additional scrutiny (OTA, 1981; OSTP, 1985;
EPA, 1986b). Due to this difficulty, the EPA is currently preparing a
report that discusses and provides guidance in the interpretation of mouse
liver tumors.
The International Agency for Research on Cancer (IARC) considers mouse
liver and lung tumors as only "limited evidence" for carcinogenicity while
OSHA accepts mouse liver tumors as "indicators of carcinogenicity" if
judgment and experience are used in interpreting the data (OTA, 1981). The
EPA Carcinogen Risk Assessment Guidelines explain that EPA would accept the
sole response of mouse liver tumors as "sufficient evidence" of
carcinogenicity (assuming other conditions for this classification are met)
unless, on a case-by-case basis, other factors warranted a downgraded
classification of "limited" evidence. Factors that may warrant a
downgrading of the classification include an increased incidence of tumors
only in the highest dose group and/or only at the end of the study; no
substantial dose-related increase in the proportion of tumors that are
malignant; the occurrence of tumors that are predominantly benign; no
dose-related shortening of the time to the appearance of tumors; negative or
inconclusive results from a spectrum of short-term tests for mutagenic
activity; and the occurrence of excess tumors only in a single sex
(EPA, 1986b). The significance of mouse liver tumors continues to be highly
controversial and the focus of considerable scientific debate.
Related to the condition of sensitivity is the condition of background
incidence. Some species have high background rates of spontaneous tumor
formation. Some varieties of mice have a high background of liver tumor
incidence. This is discussed in Section 3.0.
Benign tumors are tumors that do not spread and invade other tissues or
organs. Malignant tumors, by contrast, spread to other tissues and cause
additional tumors. The issue here is whether benign tumors found in
experimental animals should be taken as evidence that a chemical causes
cancer. The EPA risk assessment guidelines state, "it is recognized that
2-12
-------
chemicals that induce benign tumors frequently also induce malignant tumors,
and that benign tumors often progress to malignant tumors." The EPA
guidelines also add that the Agency will generally combine the incidence of
benign and malignant tumors, unless evidence is available to indicate that
the benign tumors produced by a given chemical do not have the potential to
progress to malignant tumors. If an increased incidence of benign tumors is
observed in the absence of malignant tumors, the evidence will usually be
considered as "limited" evidence of carcinogenicity. It should be noted
that while benign tumors only produce limited evidence of carcinogenicity,
the adverse, potentially life-threatening nature of the tumors should be
considered.
Large doses, usually exceeding human exposure levels, are necessary to
overcome the inherent low statistical sensitivity of bioassays (OSTP, 1984).
Bioassay guidelines state that one treatment group should receive the
maximum tolerated dose (MTD), the highest dose that can be given that would
not alter the animals' normal life span from effects other than cancer
(OTA, 1981). High dose levels are controversial because the high doses "may
themselves produce altered physiologic conditions which can qualitatively
affect the induction of malignant tumors" (OSTP, 1984). OSTP advocates
using "reasonable scientific certainty" that the dose used meets the
objectives of maximum test sensitivity without introducing qualitative
distortions.
The use of high experimental doses presents another problem in
evaluating the significance of animal study results. The animal and human
bodies may handle low and high dose levels in a different manner. If too
much of a particular chemical is present, then a normal metabolic pathway
may become saturated and secondary pathways will begin to be used to a
greater extent. If the secondary metabolic pathway and not the primary
metabolic pathway produces the carcinogenic intermediate, then the high
doses that are used in the experiment are responsible for producing a
disproportionately greater carcinogenic response. At exposure and related
dose levels expected in environmental situations, the carcinogenic
metabolites would be either much lower or nonexistent and the results of the
animal study would grossly overestimate the carcinogenic hazard.
2-13
-------
Alternatively, if the carcinogenic pathway is saturated at high doses, the
effective dose of the carcinogen at a high and low exposure concentration
may be equivalent. In this case, a smaller fraction of the exposure
concentration would be metabolized to the carcinogenic intermediate than at
low doses and linear extrapolation from the high dose exposure may
underpredict the response occurring at a lower exposure concentration. An
example of this scenario is presented in a carcinogenic risk assessment for
1,3-butadiene (EPA, 1985b). Unfortunately, not enough information is
usually available on most chemicals to estimate the effect of altered
metabolic pathways.
The fact that animal studies generally only examine the effect of a
single chemical is a limitation. Single chemical studies are necessitated
by cost considerations and the difficulties of interpreting multiple
chemical study results. The main concern is that the limited data available
on multiple exposures suggest that in certain situations the combined effect
of exposure to two chemicals exceeds the effect expected by a simple
summation of the effects of each chemical alone. In other words, the
combined effects may be synergistic or antagonistic to a carcinogenic
response. In the absence of evidence, EPA uses a summation approach when
considering the impact of multichemical exposures (EPA, 1986c).
Bioassay results will sometimes show toxic effects other than
carcinogenicity (e.g., suppression of immune system, organ damage, endocrine
disturbances) that bear on the evaluation of potential carcinogenicity. The
focus here is to show the alternative mechanisms of carcinogenicity since
the Guidelines for Carcinogen Risk Assessment (EPA, 1986b) primarily focus
upon assumptions that derive from a genotoxic mechanism of action.
2.6 EPIDEMIOLOGIC DATA
Epidemiology is the study of the distribution of disease in human
populations and the factors that influence disease distribution. In the
hazard identification step of cancer risk assessment, epidemiologic studies,
if available, are used to examine the association between human population
exposure to agents and the observed occurrence of cancer. Epidemiologic
2-14
-------
studies examine groups of Individuals unique in exposure to a chemical or
process of interest, and attempt to define differences in cancer rates
between the exposed group and a reference group. EPA and OSTP (EPA, 1986b
and OSTP, 1985) divide epidemiologic studies Into two categories,
descriptive studies and analytical studies.
Descriptive studies are concerned with identifying the distribution or
patterns of disease in populations. Examples of descriptive studies include
identification of high cancer rates in a certain geographical area such as
high bladder cancer rates in New Jersey males and excess mortality rates
from cancer of the mouth and throat, esophagus, colon, rectum, larynx, and
bladder in the industrialized Northeast (OTA, 1981). In descriptive
studies, prevalence, incidence, and mortality rates of cancer define the
levels of risk prevailing in different populations and permit comparisons
between groups. Descriptive studies sometimes use a correlational or
ecological approach, in which the rate of disease is compared with the
spatial or temporal distribution of suspected risk factors (OSTP, 1985).
OSTP and EPA agree that while descriptive studies are useful in
generating hypotheses and providing supporting data, they can rarely be used
to make a causal inference (OSTP, 1985; EPA, 1986b). The primary weakness
is that data are collected on populations rather than individuals.
Information on the exposure status of people who have the disease and those
who do not within each population group is not known (OSTP, 1985).
Analytical studies are based on data derived from observations of
individuals or relatively small groups of people. The OSTP notes that these
types of studies are a principal means of determining human health hazards
of specific environmental exposure and agents (OSTP, 1985). Two types of
common analytical epidemiologic studies are the case-control and cohort
studies. Case-control studies compare individuals with the disease under
study (cases) with a group of similar individuals without the disease
(controls). This type of study is sometimes called "retrospective" because
the presence or absence of the predisposing factor is determined for a time
in the past (OTA, 1981). The carcinogenic properties of diethylstilbestrol
(DES) were identified through case-control studies.
2-15
-------
Cohort studies start by Identifying a group of individuals with a
particular exposure and a similar group of unexposed persons and following
both groups over time to determine subsequent health outcomes (OSTP, 1985).
This type of study 1s sometimes called "prospective" because it looks
forward from exposure to development of the disease characteristic
(OTA, 1981). The link between benzene exposure and leukemia was established
through cohort studies.
The OSTP cites several strengths and limitations of epidemiologic data
to detect a relationship between a specific exposure and an effect.
Epidemiologic studies directly evaluate the experience of human populations
and their response to various environmental exposures. It is often possible
to evaluate the consequences of an environmental exposure in the same manner
in which it occurs in human populations. One of the limitations of
epidemiology is that evidence of an environmental hazard is usually only
obtained from people with high to intermediate levels of exposure, such as
experienced in occupational settings, making the detection of causal
relationships at low exposure levels difficult. Additionally, large numbers
of human subjects are often needed to provide a valid basis for risk
estimates. The EPA guidelines point out that epidemiologic studies are
inherently capable of detecting only comparatively large increases in the
relative risk of cancer (EPA, 1986b). Another problem often encountered in
epidemiology is the lack of all but crude exposure data. In many cases, it
may be difficult to quantify the exposure level. Finally, epidemiologic
studies cannot adjust for all risk factors which may have confounding
influences on the study results (OSTP, 1985). Some possible confounding
factors include the sensitivity of certain subpopulations, genetic makeups,
socioeconomic conditions, and unknown exposure on the job or in hobby
activities.
The EPA Guidelines for Carcinogen Risk Assessment state that, "the
strength of the epidemiologic evidence for carcinogenicity depends, among
other things, on the type of analysis and on the magnitude and specificity
of the response. The weight of evidence increases rapidly with the number
of adequate studies that show comparable results on populations exposed to
the same agent under different circumstances." Criteria for judging the
2-16
-------
adequacy of epidemiologic studies Include factors such as the proper
selection and characterization of exposed and control groups, the adequacy
of duration and quality of follow-up, the proper identifications and
characterization of confounding factors and bias, the appropriate
consideration of latency effects, the valid ascertainment of the causes of
morbidity and death, and the ability to detect specific effects
(EPA, 1986b).
2.7 WEIGHT OF EVIDENCE OF CARCINOGENICITY FOR ANIMAL AND HUMAN STUDIES
The question of how likely an agent is to be a human carcinogen can
only be examined within a framework that accounts for the weight of evidence
of carcinogenicity. This involves considering the quality and adequacy of
the data and the kinds and consistency of responses induced by a suspect
carcinogen. The EPA Guidelines for Carcinogen Risk Assessment identify
three major steps to characterizing the weight of evidence for human
carcinogenicity: (1) characterization of evidence from human and animal
studies individually, (2) combination of these two types of data for an
overall indication of human carcinogenicity, and (3) evaluation of all
supporting information to determine if the overall weight of evidence should
be modified (EPA, 1986b).
The EPA has developed a system for classifying the overall weight of
evidence for carcinogenicity and has developed an adaptation of the IARC
approach for classifying the weight of evidence for human and animal data.
The Agency cautions that classification schemes should not be applied
mechanically, adding that hazard identification should include a narrative
summary of the strengths and weaknesses of the evidence in addition to its
categorization (EPA, 1986b).
Under the IARC classification scheme, evidence of carcinogenicity in
experimental animals is placed in one of the following groups:
1. Sufficient evidence of carcinogenicity is proved when there is an
increased incidence of malignant tumors: (a) in multiple species
or strains; or (b) in multiple experiments (preferably with
2-17
-------
different routes of administration or using different dose
levels); or (c) to an unusual degree with regard to incidence,
site or type of tumor, or age at onset of tumor. Additional
evidence may be provided by data on dose-response effects.
2. Limited evidence of carcinogenicity is determined when the data
suggest a carcinogenic effect but are limited because: (a) the
studies involve a single species, strain, and experiment; or
(b) the experiments are restricted by inadequate dosage levels,
inadequate duration of exposure to the agent, inadequate period of
follow-up, poor survival, too few animals, or inadequate reporting;
or (c) the neoplasms produced often occur spontaneously and, in
the past, have been difficult to classify as malignant by
histological criteria alone (e.g., lung adenomas and
adenocarcinomas and liver tumors in certain strains of mice).
3. Inadequate evidence of carcinogenicity is determined when, because
of major qualitative or quantitative limitations, the studies
cannot be interpreted as showing either the presence or absence of
a carcinogenic effect (IARC, 1982; IARC, 1984).
4. No evidence of carcinogenicity applies when several adequate
studies are available which show that, within the limits of the
tests used, the chemical or complex mixture is not carcinogenic.
(This classification was added by IARC, 1984.)
EPA has made the following changes to the IARC scheme for classifying
animal data (EPA, 1986b):
1. An increased incidence of combined benign and malignant tumors
will be considered to provide sufficient evidence of
carcinogenicity if the other criteria defining the "sufficient"
classification of evidence are met (e.g., replicate studies,
malignancy). Benign and malignant tumors will be combined when
scientifically defensible.
2. An increased incidence of benign tumors alone generally
constitutes "limited" evidence of carcinogenicity.
2-18
-------
3. An Increased Incidence of neoplasms that occur with high
spontaneous background Incidence (e.g., mouse liver tumors and rat
pituitary tumors In certain strains) generally constitutes
"sufficient" evidence of cardnogenicity, but may be changed to
"limited" when warranted by the specific Information available on
the agent.
4. A "no data available" classification has been added.
5. A "no evidence of cardnogenlcity" classification has also been
added. This operational classification would include substances
for which there is no increased incidence of neoplasms in at least
two well-designed and well-conducted animal studies of adequate
power and dose 1n different species. (When saying this
classification was added to the IARC scheme by EPA, EPA referenced
IARC, 1982.)
For classifying evidence of carcinogenicity from studies in humans,
IARC uses the following four groups (see also Appendix B):
1. Sufficient evidence of carcinogenicity Indicates that there 1s a
causal relationship between the exposure and human cancer.
2. Limited evidence of carcinogenicity Indicates that a causal
interpretation is credible, but that alternative explanations,
such as chance, bias, or confounding factors, could not adequately
be excluded.
3. Inadequate evidence, which applies to both positive and negative
evidence, Indicates that one of two conditions prevailed:
(a) there are few pertinent data; or (b) the available studies,
while showing evidence of association, do not exclude chance,
bias, or confounding factors.
4. No evidence applies when several adequate studies are available
which do not show evidence of carcinogenicity. (This
classification was added by IARC in IARC, 1984.)
2-19
-------
EPA has made the following modifications to the IARC approach
classifying evidence from human studies (EPA, 1986b):
1. The observation of a statistically significant association between
an agent and life-threatening benign tumors in humans has been
included in the evaluation of risks to humans.
2. A "no data available" classification has been added.
3. A "no evidence of carcinogenicity" classification has been added.
This classification indicates that no association was found
between exposure and increased risk of cancer in well-conducted,
well-designed, independent analytical epidemiologic studies.
(When saying this classification was added to the IARC scheme, EPA
referenced IARC, 1982.)
The EPA classification system for the characterization of the overall
weight of evidence for carcinogenicity (animal, human, and other supportive
data) of a compound includes the following five groups (EPA, 1986b):
Group A - Human Carcinogens; Sufficient evidence from epidemiologic
studies to support a causal association between exposure to the agents
and cancer.
Group B - Probable Human Carcinogens: Limited evidence of human
carcinogenicity based on epidemiologic studies or sufficient evidence
of carcinogenicity based on animal studies. This group is divided into
two subgroups. Group Bl is reserved for agents for which there is
limited evidence of carcinogenicity from epidemiologic studies. It is
reasonable, for practical purposes, to regard an agent for which there
is "sufficient" evidence of carcinogenicity in animals as if it
presented a carcinogenic risk to humans. Therefore, agents for which
there is "sufficient" evidence from animal studies and for which there
is "inadequate evidence" or "no data" from epidemiologic studies would
usually be categorized under Group B2.
2-20
-------
Group C - Possible Human Carcinogens; Limited evidence of
carcinogenicity in animals in the absence of human data. This group
includes a wide variety of evidence such as (a) a malignant tumor
response in a single well-conducted experiment that does not meet
conditions for sufficient evidence, (b) tumor responses of marginal
statistical significance in studies having inadequate design or
reporting, (c) benign but not malignant tumors with an agent showing no
response in a variety of short-term tests for mutagenicity, and
(d) responses of marginal statistical significance in a tissue known to
have a high or variable background rate.
Group D - Not Classifiable as to Human Carcinoqenicitv; Inadequate
human and animal evidence of carcinogenicity, or no data are available.
Group E - Evidence of Noncarcinoqenicitv for Humans; No evidence for
carcinogenicity in at least two adequate animal tests in different
species or in both adequate epidemiologic and animal studies. The
designation of an agent as being in Group E is based on the available
evidence and should not be interpreted as a definitive conclusion that
the agent will not be a carcinogen under any circumstances.
Table 2-2 illustrates how evidence based on animal and human studies is
combined to yield a tentative assignment to one of the five categories
(EPA, 1986b).
2-21
-------
TABLE 2-2. ILLUSTRATIVE CATEGORIZATION OF EVIDENCE BASED
ON ANIMAL AND HUMAN DATA (EPA, 1986b)a
Human
Evidence
Sufficient
Limited
Inadequate
No Data
No Evidence
Animal Evidence
Sufficient
A
Bl
B2
B2
B2
Limited
A
Bl
C
C
C
Inadequate
A
Bl
D
D
D
No Data
A
Bl
D
D
D
No Evidence
A
Bl
D
E
E
The above assignments are presented for illustrative purposes. There may
be nuances in the classification of both animal and human data indicating
that different categorizations than those given in the table should be
assigned. Furthermore, these assignments are tentative and may be modified
by ancillary evidence. In this regard, all relevant information should be
evaluated to determine if the designation of the overall weight of evidence
needs to be modified. Relevant factors to be included along with the tumor
data from human and animal studies include structure-activity relationships,
short-term test findings, results of appropriate physiological, biochemical,
and toxicological observations, and comparative metabolism and pharmaco-
kinetic studies. The nature of these findings may cause an adjustment of
the overall categorization of the weight of evidence.
2-22
-------
3.0 DOSE-RESPONSE ASSESSMENT
A dose-response assessment is the process of characterizing the
relationship between the exposure to an agent and the incidence of an
adverse health effect in exposed populations (NRC, 1983). Although
dose-response assessments can be prepared for other types of health effects,
this section of the report discusses dose-response assessments in which the
adverse health effect is cancer. In assessments for carcinogens, the
response is normally expressed in terms of a probability or risk estimate,
or as an upper bound of the risk (OSTP, 1985).
Dose-response evaluation is the second part of a complete risk
assessment because it provides the basis for the development of risk
estimates (e.g., a statement that describes the possible magnitude of either
individual or population health impacts). It should be emphasized that
calculation of risk estimates (dose-response assessments) does not require
that the agent be clearly shown to be carcinogenic in humans. The
likelihood that an agent is a human carcinogen is a function of the "weight
of evidence" as described in Section 2.0. It is important to present risk
estimates, appropriately qualified and interpreted, in those circumstances
in which there is a reasonable possibility that the agent is carcinogenic to
humans.
The dose-response assessment is based on data obtained from
epldemiologic studies and/or animal experiments. For pictorial purposes, a
data set may be plotted on a graph to help visualize the dose-response
curve. Figure 3-1 shows hypothetical data and a dose-response curve with
the dose/exposure plotted on the x-axis and percent response (cancer
incidence) on the y-axis. While the curve usually fits the observed data
well, it may not be representative of the data at very low doses. Very low
doses are generally not used in animal experiments because a large number of
animals would be needed in order to detect a carcinogenic response at these
levels. In addition, the occupational exposures found in many
epidemiologic studies display relatively high concentrations. Figure 3-2
3-1
-------
0)
(0
c
O
Q.
(0
O
DC
90-
80-
70-
60-
50-
40-
30-
20-
•
10-
i • "Tr i • i • • • i' •
50 100 200 400 800
10 20
Exposure/Dose
00
f-
Figure 3-1. Hypothetical Data and Dose-Response Curve
3-2
-------
-------
shows another hypothetical dose-response curve that depicts the more
frequent cases in which high doses and responses in an animal study are
plotted. The portion of the dose-response curve associated with low doses
is undefined in this case as shown in the figure by the dotted line. In the
actual ambient environment, humans are more likely to be exposed to much
lower concentrations or doses than are used in experimental studies or
experienced in occupational settings. Therefore, the lower end of the
dose-response curve (bottom left portion in Figure 3-2) is generally the
area of interest in environmental risk assessments. Since there is usually
no experimental or observational dose-response information about that area
of the curve, mathematical models are used to extrapolate the curve from the
observed data range into the low dose region.
Section 3.0 of this report discusses how a dose-response curve is
constructed, extrapolation of animal data to human data, and the various
mathematical models which can be used in extrapolating the dose-response
curve into the low dose region. The discussions of these areas are closely
related to some basic concepts in the current theories of carcinogenesis.
Therefore, a brief description of current theories on cancer, the multistage
process and the threshold/nonthreshold concept is provided. The discussion
of carcinogenesis is presented to give a basic introduction to the concepts
on which dose-response and risk assessment procedures are based, but is not
intended to be a complete treatment of the subject. References are given in
the text which will lead the reader to more detailed discussions of the
topic.
3.1 THE PROCESS OF CARCINOGENESIS
Cancer is a broad term for a group of diseases distinguished by the
uncontrolled proliferation of abnormal cells. Cancers in different body
organs may behave in different ways and are identified by different names,
depending upon the original cell type. For example, malignant tumors of
epithelial cells (cells that line organs or cover organs) are known as
carcinomas, and malignant tumors of connective tissues are known as
3-4
-------
sarcomas. (Other tumor types are defined in the glossary.) In common
usage, the term carcinogen applies to any substance which can cause a
malignant tumor to develop.
A cancerous cell is one that is altered in a largely unknown manner
such that it generates rapidly, increasing numbers of new altered cells to
which the parent cell has transmitted heritable alterations. Groups of
altered cells are tumors. They may also appear as individual foci or
metaplasia.
The causes of cell changes leading to cancer are poorly understood.
Many agents that cause cancer interact with deoxyribonucleic acid (DNA) and
alter a cell's genotype. An agent which has this effect may be called
genotoxic and/or a mutagen. Such an agent produces a mutation. Genotoxic
can also imply other toxic effects as well and thus, in terminology,
mutagenicity is a subset of genotoxicity. Cellular mutation is often
considered to be an early stage in a multistage process leading to cancer.
However, the inheritance of a single mutation may or may not be sufficient
to produce cancer (NRC, 1986). When DNA is damaged, cellular mechanisms can
act to repair the damage, or the cell may be eliminated by actions of the
immune system. Therefore, some damage to DNA appears to be "reversible" and
may not in fact be disconcerting. It is those mutational effects that
predispose a cell to cancer development that are a concern. The "language"
of risk assessment has coined the term "epigenetic" to account for all other
(nonmutational) mechanisms that possibly operate in the carcinogenic
process. Thus, the terms genotoxic, mutagenic, or epigenetic mechanisms are
sometimes used to roughly characterize the mechanisms of carcinogenesis.
There are several theories on the nature of the carcinogenic process.
One favored theory is that carcinogenesis is a multistage process consisting
of at least three distinct steps: initiation, promotion, and progression
(Weinstein, 1985). The multistage nature of the process has been
experimentally demonstrated in cells of some animal tissues, including skin,
lung, liver, and bladder, and is thought to occur in human tissues in a
similar multistage process (NRC, 1986). More complete discussions of the
multistage theory and carcinogenesis may be found in Becker (1981), Farber
(1982), Farber and Cameron (1980), Slaga et al. (1980), Weinstein et al.
(1984), and OSTP (1985).
3-5
-------
The distinctions between three stages now identified as part of the
multistage process (initiation, promotion, progression) are defined
experimentally, yet their exact mechanisms are not well understood
(NRC, 1986). Each stage can be influenced by age, sex, and diet of an
organism as well as hormonal activity and environmental factors. The stages
may involve different cellular and biochemical mechanisms (Weinstein, 1985).
Each stage of the multistage process is described below.
The first step in the multistage process is initiation, which is
thought to involve a heritable change in the cell through a change to its
ONA (IARC, 1982). A single application of some chemicals is sufficient to
initiate the carcinogenic process (Weinstein, 1985). Substances which are
initiators are mutagens that act either directly or indirectly by forming
electrophilic species (metabolites) that modify or damage the DNA structure
(NRC, 1986). Several DNA-carcinogen adducts (products of chemical addition
reactions), formed by the reaction of electrophilic species with
nucleophilic areas in DNA, have been identified in DNA recovered from
reactions of carcinogens in cell cultures and intact organisms treated with
carcinogens (IARC, 1982). The initiation step in the multistage process is
considered reversible only by death of the initiated cell (NRC, 1986) or by
DNA repair mechanisms to correct the damage. The lesion produced by
initiation is thought to persist for an extended period of time.
The second step in the multistage process is promotion of the initiated
cells and results in the production of new, albeit altered cells. This
process is called cellular proliferation. Chemicals called promoters may be
defined as agents that have very weak or no carcinogenic activity by
themselves, but enhance carcinogenic response when they are applied
following a dose of an initiator (Weinstein, 1985; NRC, 1986). This series
of events has only been demonstrated in laboratory experiments (NRC, 1986),
specifically in skin and liver carcinogenesis (OSTP, 1985). Promoters are
generally not believed to interact with DNA. Studies with several promoters
(phorbol esters, teleocidin, and aplysiatoxin) have shown that the site of
action for some promoters is the cell membrane (Weinstein, 1985)., There is
some evidence that promotion involves several stages and, at early stages,
3-6
-------
the actions of a first-stage promoter may be reversible (NRC, 1986).
Actions of second stage promoters are thought to be irreversible (NRC, 1986)
(see also Slaga et al., 1980).
Individuals are continuously exposed to initiators in the ambient
environment. Therefore, environmental exposure to promoters may be
sufficient to yield cancer. Thus, even though promoters may show only weak
carcinogenic activity by themselves, they cannot be ignored when considering
total environmental exposure and risk.
The final stage in the multistage process, progression, is largely
undefined. In this stage, cells become able to form tumors, become
malignant, and have the ability to metastasize (OSTP, 1985). A cancer is
said to metastasize when parts of the cell mass leave the tissue area in
which they are growing and invade surrounding tissue or are transported to
other areas by the circulatory or the lymphatic system (NRC, 1986).
However, not all altered or mutated cells progress to malignant tumors
(OSTP, 1985). Because tumors may continue to increase in their degree of
malignancy, progression is said to be a dynamic process (NRC, 1986).
The classification of agents as initiators or promoters is not always
clear-cut. Some agents can act as both an initiator and a promoter in the
same tissue; these agents are defined as complete carcinogens. In fact,
most chemicals that are initiators are also complete carcinogens at higher
doses (NRC, 1986). Also, some materials act as initiators in one tissue and
as a promoter in others (NRC, 1977).
Examples of agents that are initiators or promoters include
2-acetylaminofTuorene acting as an initiator in rat liver and phenobarbitol
acting as a promoter in that tissue (Weinstein, 1985). In mouse skin,
polycyclic aromatic hydrocarbons act as initiators and phorbol esters act as
promoters (Weinstein, 1985).
Another type of carcinogenic action is cocarcinogenesis. In such
cases, two (or more) compounds, when administered concurrently, increase the
probability of cancer development. The difference between a cocarcinogen
and a promoter is the time frame required for administration of the agent.
Promoters act when applied after an initiator, while cocarcinogens must be
applied concurrently with an initiator.
3-7
-------
While the theory that cancer is a multistage process is relatively well
accepted, an in-depth knowledge of the exact mechanisms of cancer is
unknown. For example, as was discussed earlier, carcinogens are thought to
act directly on cellular genetic material as genotoxins to alter the cell
genome. There is some evidence, however, that some carcinogens may not
affect DNA or may act indirectly on the genome to begin the cancer process
(NRC, 1986; OSTP, 1985). This hypothesis is sometimes referred to as an
epigenetic mechanism of cancer. Asbestos, for example, is thought to not
damage DNA directly (NRC, 1986) although some of the metallic ions in its
complex may.
The exact mechanisms of cancer induction are still not known. It is
generally accepted, however, that carcinogenesis is a multistage process
that may involve the genome directly or indirectly (OSTP, 1985). The change
to malignant tumors may involve oncogene activation or chromosome aberration
(NRC, 1986). Oncogenes are naturally occurring genes that code for factors
that regulate cell growth (NRC, 1986). About 40 of these genes have been
identified in either human or animal tumors. Some oncogenes have been shown
to be activated by chemical carcinogens (NRC, 1986). The role of oncogenes
in the carcinogenic process is not well understood. Initiation may involve
an alteration in DNA that allows the expression or increases the expression
of an oncogene. It has been suggested that chromosomal abberations may
activate oncogenes by causing alterations in genetic information.
Chromosome aberrations are modifications of the normal chromosome complement
due to deletion, duplication, or rearrangement of genetic material. Such
abberrations have been observed in some animal and human tumors (NRC, 1986).
3.2 THE CONCEPT OF THRESHOLDS
For most toxic effects, excluding cancer, there appears to be a
threshold dose below which no effects occur. In these cases, physiological
adaptation or homeostatic mechanisms are able to compensate for any slight
effect, and no toxic effect is observed or, a sufficient dose of the toxic
substance does not reach the target site (organ) and no toxic effect is
observed. If effects did occur, normal repair processes are able to correct
3-8
-------
any damage. If an effect can be caused by a single irreversible molecular
interaction of an agent with its target, then one may expect that there
would be no threshold for such an agent. As discussed in Section 3.1, the
dominant view of carcinogenesis involves the idea that most agents that
cause cancer also cause irreversible damage to DNA (EPA, 1984b). ONA damage
may be induced by very small doses and initiate the carcinogenic process.
Once initiated, this process continues to develop over time after the dose
or exposure is gone. Thus, the assumption upon which many cancer risk
assessments are based is that there is no threshold dose for carcinogens.
The importance of a no threshold assumption is examined in the discussion of
low-dose extrapolation modeling.
Not all scientists, however, agree that a no threshold approach is true
for all carcinogens. Indeed, at the current stage of knowledge, "mechanistic
evidence for DNA repair mechanisms or other biological responses does not
prove the existence of, the lack of, or the location of a threshold for
carcinogenesis" (OSTP, 1985). Also, "the presence or absence of a threshold
for one step in the multistage process does not necessarily determine the
presence or absence of a threshold for the whole process" (OSTP, 1985).
3.3 SELECTION OF DATA FROM WHICH TO DERIVE THE DOSE-RESPONSE ASSESSMENT
Two basic types of data are used in dose-response assessments:
epidemiologic studies of human populations and experimental studies in
animals. These types of studies were discussed in Section 2.0, Hazard
Identification. Both types of data have advantages and disadvantages for
use in quantitative risk assessment.
3.3.1 Epidemioloqic Studies
Epidemiology may be defined as the study of the relationships between
the frequency and distribution of disease(s) in human populations and the
factor(s) that may influence these diseases. For example, an epidemiologic
cohort study may compare disease incidence or mortality within a group
(cohort) of persons exposed to an agent to that of a control group not
3-9
-------
exposed to the agent. Another example is the case-control study.
Case-control studies are those in which the lifestyles and exposures of a
group of persons having a disease (e.g., cancer) are compared to a control
group not having the disease. Thus, in a case-control study, similarities
or differences in past exposures are identified and evaluated.
The EPA, in the Guidelines for Carcinogen Risk Assessment (EPA, 1986b),
states that dose-response assessments based on adequate epidemiologic
studies are preferred over those based on animal studies. One reason is
that in epidemiologic studies, the effects are observed in humans, and the
enormous uncertainty of extrapolation from animal data to humans is
eliminated.
Epidemiologic studies may not, however, contain all of the quantitative
data necessary for a dose-response assessment. For example, past exposures
of cohorts or cases are usually difficult to determine, much less quantify.
If the cohort was exposed to an agent in the workplace, there may be no
quantitative measurements of the amount of the agent in the workplace air,
or there may not be records noting when various types of materials were
used. Furthermore, even when an average cohort exposure is fairly reliable,
individual exposures often vary greatly. If an individual is exposed to an
agent, perhaps through a hobby such as gardening, it is unlikely that
quantitative estimates of exposure are available or that the exposure itself
would be documented. Also, humans are exposed to a variety of substances
and have different lifestyles (e.g., with respect to diet, smoking habits,
alcohol consumption), all of which may complicate interpretation of study
results.
The size of the study group, the selection of a control group, and
ability to document disease/mortality cases also affect the validity of the
epidemiologic study. When an epidemiologic study shows no increased
response, the statistical power to detect an appropriate outcome should be
included in the dose-response assessment (EPA, 1986b). Statistical power is
the probability of detecting an excess risk if it exists (Beaumont and
Breslow, 1981). Thus, a high statistical power for a study decreases the
likelihood of false negative results, but cannot completely rule out the
3-10
-------
possibility of effects occurring (Davis et al., 1985). Negative response
epidemiologic studies or studies which do not show carcinogenic effects
associated with given exposures, may serve to show an upper limit of risk.
Controlling for the effects of smoking are of particular importance for
studies attempting to establish a relationship between chemical exposure and
lung cancer. An example of this importance is found in the EPA health
assessment document for acrylonitrile (EPA, 1983).
In spite of all potential short-comings, well-conducted epidemiologic
studies do provide the most direct evidence linking exposure to carcinogenic
effects in humans. Some of the criteria for evaluating the adequacy of
epidemiological studies are listed in Section 2.5. NRC (1986) may be
consulted for a more detailed discussion on epidemiologic studies, their
use, and their limitations.
3.3.2 Animal Studies
Animal studies or bioassays are widely used to help determine
carcinogenic potency of a chemical (see also Section 2.0, Hazard
Identification). Animal studies have an advantage over epidemiologic
studies in that the exposures are always better controlled and quantified,
animals are exposed only to the agent in question, and disease incidence
(tumor formation) may be more accurately determined (through necropsy and
pathology). The EPA, National Cancer Institute/National Toxicology Program
(NCI/NTP), IARC, and other groups have prepared recommendations for
designing animal studies including the use of (OSTP, 1985):
0 two species of test animals (usually rats and mice of both sexes)
tested at two, or preferably three, dose levels: a high dose
level (roughly the estimated maximum tolerated dose [MTD]) and a
lower dose level (roughly one-half the MTD) as determined in a
90-day subchronic toxicity study;
• a route of exposure similar to the most likely human exposure;
• dosing and observation for toxic effects affecting their health
for most of the animals' natural lifetime, usually 104 weeks for
rodents (this should begin at 6 weeks of age);
3-11
-------
t adequate numbers of animals (at least 50 per sex) in each test
group;
t adequate concurrent controls;
t detailed pathologic examination of tissues; and
• appropriate statistical evaluation of results.
In selecting animal data on which to base a dose-response assessment,
the criteria listed above can serve as a guide for identifying a
well-conducted study. The data set (study results) selected should also
show a statistically significant increase in tumor occurrence or multiple
tumor types and a statistically significant dose-response trend
(EPA, 1986b). Early appearance of tumors in the treated versus control
animals in an analysis that incorporated time-to-tumor data should also be
evaluated. The data set which shows the greatest sensitivity should
generally be given greater emphasis because it is possible that human
sensitivity is as high or higher than the most sensitive responding animal
species (EPA, 1986b). In counting tumors, the EPA guidelines (1986b) state
that benign tumors should generally be combined with malignant tumors,
unless the benign tumors are not considered to have the potential to
progress to malignancies of the same histogenic origin.
There is some debate in the scientific community on the use of data
from tests on certain animal species in preparing dose-response assessments
for carcinogens and the use of maximum tolerated dose in bioassays. A more
complete discussion of these issues is found in OSTP, 1985.
Some animal species have high background rates of spontaneous tumor
formation independent of the administration of a test agent. Including
these tumors with those allegedly caused by exposure to a test substance may
distort the estimate of the risk. High rates of spontaneous tumor
generation increase the sensitivity of the analysis since the spontaneous
tumors are enhanced by the promoting actions of carcinogens given at high
doses. For example, the B6C3F1 male mouse has a high background liver tumor
incidence and the Swiss-Webster female mouse has a high background incidence
of mammary carcinoma. Generally, there is a consensus that a response above
background in B6C3F1 mouse liver, in principle, does have a significance in
3-12
-------
terms of estimating human risk, but the distinction between "benign" or
"hyperplastic" liver nodules and malignant neoplasms is still not clear
(OSTP, 1985). The International Expert Advisory Committee to the Nutrition
Foundation emphasized the need for using scientific judgment on a
case-by-case basis in interpreting mouse liver bioassay results and the
relevance of additional toxicologic data (OSTP, 1985). In the final EPA
guidelines for carcinogen risk assessment, EPA takes the position that when
the only tumor response is in the mouse liver and when other conditions for
a classification of sufficient evidence in animal studies are met, then the
mouse liver data should be considered as sufficient evidence of
carcinogenicity. The EPA also states that the classification could be
changed to a limited evidence category on a case-by-case basis (EPA, 1986b).
3.4 DOSE-RESPONSE ASSESSMENT TECHNIQUES
3.4.1 Low Dose Extrapolation Issues
In the environment, people will generally be exposed to potential
carcinogens at much lower doses than are found either in epidemiologic
studies of workplace exposure or in experimental animal studies. For
example, the doses used in a mouse experiment, included in EPA's risk
assessment of 1,3-butadiene, were 0, 625, and 1250 ppm, given 6 hours per
day, 5 days per week for a lifetime (EPA, 1985b). It is highly unlikely
that long-term concentrations in the ambient environment would ever reach
those test levels. Measured butadiene levels in synthetic rubber facilities
were typically below 1 ppm and nearly always below 20 ppm.
Some scientists believe that the use of the maximum tolerated dose (as
described in bioassay protocols) leads to organ damage which may enhance
background tumor formation. The relatively high doses may overwhelm the
cellular defense mechanisms which may normally provide some measure of
protection for the cell. Also, high doses may alter the normal metabolic
actions of a cell, shifting from the normal, primary metabolic pathway to
one which may produce a metabolite that is actually carcinogenic.
3-13
-------
High doses in experimental studies are used to overcome the inherent
low statistical sensitivity of bioassays (OSTP, 1985). Most bioassays can
detect a cancer incidence of 10 to 15 percent or greater (over background),
but cannot detect lower incidences (OSTP, 1985). Potential problems in the
use of high doses were discussed earlier.
One other way to increase the sensitivity of bioassays is to increase
the number of animals used. One such study, which used 24,000 mice, was
able to detect incidences of only 1 percent or greater but the expense of
conducting the study was considerable (OSTP, 1985). It is unreasonable to
expect that larger-scale studies that can detect increased incidences of
1 percent or less could be economically feasible to conduct. This is of
concern because increased incidences of 0.01 to 0.0001 percent (1 in 10,000
to 1 in 1,000,000) may be of concern in the human environment. Thus,
considering the expense of conducting studies with large numbers of animals,
which do not always provide an useful increase in the ability to detect
disease incidence, it seems likely that use of high doses to increase
sensitivity will continue.
To account for the differences in dose levels used in animal studies
and those concentrations predicted to be found in the ambient environment,
the data set(s) selected for dose-response assessments must be used along
with mathematical models to extrapolate into the low dose range. Several
currently used models are discussed below.
3.4.2 Mathematical Extrapolation Models for Animal Studies
Several different mathematical models are available for low-dose
extrapolation of the dose-response curve. This section of the report
discusses several mathematical models. More detailed discussions of the
various extrapolation models may be found in Doll (1971), Whittemore and
Keller (1978), Brown et al. (1978), Armitage and Doll (1961), and Park and
Snee (1983).
No single mathematical procedure is recognized as the most appropriate
for low dose extrapolation in carcinogenesis (OSTP, 1985). The two general
types of low dose extrapolation models used in carcinogen risk assessment
3-14
-------
are based on either tolerance-distribution or mechanistic assumptions,
although the same model may arise under different assumptions. These can be
listed as follows:
Tolerance-Distribution Models
Probit (log-probit)
Logit (log-logistic)
Multi-hit (gamma-multi-hit)
Wei bull
Mechanistic Models
One-hit
Multistage
Multi-hit (gamma-multi-hit)
Wei bull
Tolerance-distribution models assume that each member of a given
population has a threshold or tolerance level below which that individual
will not respond to the exposure in question and that the variability among
individuals can be expressed as a probability distribution (OSTP, 1985).
Models such as the probit, logit, gamma-multi-hit, and Wei bull can all be
generated by using different probability distributions (OSTP, 1985).
The probit model assumes that sensitivities to a carcinogen among
individuals in a given population are log-normally distributed. The form of
the model is:
P(d) = $ (a + b log d)
Where: P(d) is the probability of response at dose d,
0
Where: P(d) is the probability of response at dose d,
a is the intercept (background incidence), and
b is the measure of potency of a test agent.
3-15
-------
Which, like the probit, is sigmoid and symmetric about the 50 percent
response level, but approaches the extremes more slowly (Brown,, 1982).
There is also a class of models that uses the gamma function to model
the tolerance-distribution. The multi-hit model is a member of this class.
Thus, it is often referred to as the gamma-multi-hit model. It is discussed
under mechanistic models.
The Wei bull model is defined as:
P(d) = 1 - exp - (bdk), b, k > 0
Where: P(d) is the probability of response at dose d,
b is the measure of potency of a test agent, and
k is the number of stages or events.
This model also arises as a mechanistic model from the multi-hit model
applied to multiple target cells.
The probit, logit, gamma, and Weibull distributions all have
potentially similar shapes between tumor frequencies of 2 percent and
98 percent; hence, they often produce essentially identical fits to the
observed data, but differ widely at low doses (Park and Snee, 1983).
A modification of a tolerance-distribution class of models is the
Mantel-Bryan Method, which is based on a probit model. This method was
proposed as a procedure for estimating the lower confidence limits for a
"virtually safe" level of exposure to a carcinogen. (Virtually safe was
- fi -ft
defined as an additional 10" to 10" increase in lifetime cancer risk.)
The Mantel-Bryan procedure uses experimental data to determine the highest
dose that yields no increased response and then calculates the maximum risk
associated with that dose at the 99 percent confidence level. To
extrapolate to low doses, it then assumes a slope of 1 per log dose. Use of
this method in quantitative risk assessment has declined because in the low
dose region it tends to produce relatively high estimates of "safe doses,"
compared to other procedures (OSTP, 1985) and is thought to far overestimate
"true" risk. This class of models is based on a threshold hypothesis and
the models are nonlinear at low doses. They have declined in use with the
development of the hypothesis of a nonthreshold mechanism of action.
3-16
-------
The second class of models which attempts to describe the dose-response
curve in the low dose region is the mechanistic model. This class of models
is based on the presumed mechanism(s) for carcinogenesis (OSTP, 1985).
Examples of these models are the one-hit, multi-hit, and multistage models,
each of which reflects the assumption that a tumor originates from a single
cell that has been damaged (OSTP, 1985).
The one-hit model is the simplest of the mechanistic models and assumes
that a single "hit" or interaction of an agent within a cell will initiate
carcinogenesis. The model was originally derived in relation to
radiation-induced carcinogenesis and a "hit" was defined in terms of a
quantum of radiation. In chemical carcinogenesis, the agent is assumed to
interact with the DMA of a cell. The model takes the form:
P(d) = 1 - exp - (a + bd), a, b > 0
Where: P(d) is the probability of response at dose d,
a is background incidence, and
b is a measure of potency of a test agent.
At low doses, the form becomes P(d) » a + bd; the increase in cancer
frequency, bd, is directly proportional to dose. Because the one-hit model
has only one parameter (other than background), it usually does not fit
experimental data well (OSTP, 1985).
The multi-hit model, a threshold model, assumes that a target cell must
absorb at least "k" chemical hits before a carcinogenic change is induced
(OSTP, 1985), and that the probability of a hit is proportional to dose
(NRC, 1980). The model is shown below:
P(d) -I r (k) dx
Where: P(d) is the probability of response at dose d,
T(k) - (k-1)! for k > 1,
b is a measure of potency of a test agent,
k is the number of chemical "hits," and
x is the expected number of "hits."
3-17
-------
According to OSTP (1985), the multi-hit model may produce conservative
estimates of "safe dose" levels compared with several other models and may
also indicate "safe dose" levels that are higher than the levels which
actually produce deleterious effects.
The multistage model, an extension of the one-hit model, is the most
frequently used of all the low-dose extrapolation models and it reflects the
most prevalent current theory of carcinogenesis. That is, a normal cell
must progress through a series of heritable changes or stages before it can
become malignant. The extension of the one-hit model is that the transition
rates of at least one of the stages is assumed to be dose related
(OSTP, 1985). One version of the multistage model, developed by
Crump et al. (1977), forces a linear term in the estimation of upper
confidence limits. This is the linearized multistage model frequently used
by EPA. The Crump et al. version of the model takes the form:
P(d) = 1 - exp [-(q0 + qjd + q2d2 + ... + qkdk)], k > 1
Where: P(d) is the probability of cancer at dose d,
k is the number of stages, or k may also be assumed to be
equal to the number of dose levels minus one,
q^ are coefficients to be fit to the data, and
i,
d is the applied dose raised to the kth power.
Each of the k terms is believed to be equivalent to a transition between
individual steps in a multistep pathway leading to an altered cell
(NRC, 1986). The Crump et al. version of the multistage model is fairly
conservative in that it will always be linear in the low dose region, since
it forces an upper-limit of q, consistent with the data.
The choice of model to use in a dose-response assessment is
controversial. Different models predict different responses (risk) in the
low dose region. Even though these are "mechanistic" models, their
estimates are derived by curve-fitting and the relationship between the
observed response at high dose levels versus the actual mechanisms involved
3-18
-------
at low levels-remains one of conjecture. Figure 3-3 shows a plot of
response (risk) versus dose of aflatoxin for five dose response models. In
this example, the slope of the dose-response curves for the Weibull,
multi-hit, and Mantel-Bryan procedure using the log-probit models are
steeper than those for the multistage and one hit models, even though the
same data set was used to construct the dose-response curve.
Other, more complex models have been developed to enable incorporation
of more complex phenomena that could not be modeled by simple distribution
models. Time-to-tumor models attempt to relate dose, tumor latency, and
cancer risk (OSTP, 1985). A form of the Weibull model in time (Pike) is an
example of a time-to-tumor model. The Weibull model developed by Pike
(1966) takes the form:
P(t, d) - 1 - exp - [g(d)tk]
Where: P(t, d) is the probability of response at time, t, and
dose, d;
g(d) is a function of dose; and
ic is the number of stages or events.
This model is Weibull in time, but can be other forms in dose. Use of
time-to-tumor models is complicated by the fact that actual response times
are often difficult to determine in an experiment. Some tumors may only be
seen as the animal is examined after it has died. Research on a
hypothetical data base which did contain time-to-tumor information showed
that low-dose risk predicted by time-to-tumor models differed by three
orders of magnitude from risk estimates based on other extrapolation
procedures (OSTP, 1985). Time-to-tumor models may best serve as
enhancements for more common measures of risk such as lifetime probability
of tumors (OSTP, 1985).
An additional class of models incorporate pharmacokinetic modeling to
predict the concentrations of parent compounds and metabolite(s) at the
reactive site(s). Such modeling can be incorporated into either
tolerance-distribution or mechanistic models.
As mentioned earlier, there is no single model which is most
appropriate for identifying "true" risk estimates. EPA (1986b) noted that
in assessments conducted by the Agency, "in the absence of adequate
3-19
-------
P(d)
10-*-
OH MS
I
10-'
MH
r
io-2
MB
10*
Model
OH-One Hit
MS-Multistage
W-Weibull
MH-Multi-Hit
MB - Mantel-Bryan (Log-Probit)
Source: Krewski and Van Ryzin, 1981
S
CD
Figure 3-3. Log-Log Plot of Risk, P(d), vs. Dose, d, of Aflatoxin for
Five Dose-Response Models
3-20
-------
information to the contrary, the linearized multistage model will be
employed" and that a rationale will be included in the assessment to justify
the model that is chosen. EPA guidelines (1986b) state that "when
longitudinal data on tumor development are available, time-to-tumor models
may be used." The Agency further stated their intent to review the
biological and statistical evidence that indicate the suitability of a
particular model, and to present results of various models for comparison to
results of the linearized multistage model, as appropriate.
3.4.3 Dose Conversions
In addition to extrapolating the dose-response curve into the low dose
region, dose-response assessments based on animal studies must derive
equivalent human doses from the animal data. Equivalent doses between
species are defined as those doses that will evoke equal responses. If an
animal study was conducted for less than the animals' lifetime, then the
doses must be converted to equivalent lifetime doses. Both of these
conversions are discussed in this section.
Conversion between species is complicated by differences in humans and
laboratory animals regarding life span, body size, metabolism, route, and
duration of exposures (EPA, 1986a). Usually, scaling factors are used to
make the conversions. Conversions to ambient exposures from epidemiological
study exposures usually require a scaling factor for duration of exposure.
This section describes the types of scaling factors used in both types of
studies. A more detailed discussion of the scaling factors may be found in
EPA (1984b) or other EPA health assessment documents.
Equivalent doses between species (animal to human dose conversions) may
2
be expressed as mg/kg body weight/day, ppm in diet or water, mg/m surface
area per day, or mg/kg body weight/lifetime (EPA, 1986b). The equivalent
2
dose used by EPA, unless there is convincing data to the contrary, is mg/m
surface area/day (EPA, 1986b). The reason for selecting the surface area
conversion is that certain pharmacological effects, namely metabolism,
commonly vary according to surface area (EPA, 1986b). The comparison of an
effect between species is related or proportional to dose/body surface area
3-21
-------
and body surface area is proportional to an animal's weight to the
two-thirds power. This proportion is used in dose conversions because
weight can be determined much more easily than surface area. Thus,
mg/weight ' /day is considered an equivalent dose between mammalian species
in the absence of better information of pharmacokinetic differences between
animals and humans. For example, if a rat is exposed to 100 mg/day, then an
equivalent dose for a human for the same exposure would be:
100/0.35 kg2/3 = X/70 kg2/3
Where: X = equivalent human dose (mg)
0.35 = weight of rat (kg)
70 = weight of human (kg)
Solving for X gives:
100/0.49 = X/17
X - 3500 mg
Often, experimental doses are given in the units other than mg/day;
these doses must then be converted to mg/day. For a study in which test
animals ingested the test agent, conversions require data such as the amount
of food consumed, the concentration of the test agent in the food, and the
absorption fraction and an empirical "food factor" which is the fraction of
an organism's body weight consumed per day as food (EPA, 1984b). The
absorption fraction is assumed to be 1 (assumed to be 100 percent absorbed),
unless data to the contrary are available. Experimental data may be
available which show that the chemical of concern may not be completely
(100 percent) absorbed. For example, a study may show that only half of the
chemical ingested is actually absorbed and the remainder is excreted. For
2/3
experimental exposures via inhalation, the equivalent exposure (mg/w ' ) can
be derived from the exposure concentration and exposure duration, the
relationship between breathing rates and body weight, and absorption
fractions (EPA, 1986b).
In addition to dose conversions, the derivation of exposures must
sometimes be converted to equivalent lifetime exposures. For example, the
test animals may have only been dosed 2 days/week, 6 hours/day for 3/4 of
3-22
-------
their lifetime. If the duration of the experiment (Le) is less than the
natural lifespan of the animal (L), then the slope of the dose-response
curve is multiplied by a factor of (L/Le) . This conversion accounts for
less than lifetime exposure of the test animals and the chance that tumors
occurring at later ages would be undetected in less than lifetime studies.
It is assumed that the age-specific rate of cancer will continue to increase
as a constant function of the background rate, if dose remains constant
(EPA, 1984b). The age-specific rates for humans increase by at least the
second power of age, and often higher powers. Other exposure time
conversions would be used if, in an epidemiologic study in the workplace,
persons were exposed 6 hours/day, 5 days/week for half their expected
lifetime. An example of an equivalent dose and equivalent exposure duration
calculation is shown below.
Example: Rats were exposed via inhalation to 350 ug agent X/m in
particulate form for 7 hours/day, 5 days/week for 78 weeks.
The equivalent lifetime exposure for rats (expected lifetime of 110 weeks
for this species) is:
350 ug/m3 x 7/24 hours x 5/7 days x 78/110 weeks =• 51.7 ug/m3
The equivalent human exposure is calculated by:
d = i W1/3 vr
Where: d - equivalent exposure is ug/W '
i - inhalation rate/body weight; for rats i » 0.64 (or
0.22 m3/0.35 kg), for humans i = 0.29 (or 20 m3/70 kg)
W = weight; for rats 0.35 kg, for humans 70kg
v » concentration of agent X in air, 350 ug/m ; equivalent
lifetime =51.7 ug/m
r - absorption fraction, assumed to be 1 and equal in
both species, unless data that suggest otherwise are
available
3-23
-------
Then: - iW1/3 vr(rat) - iW1/3 vr(human) or
(0.64)(0.35)1/3 (51.7)(1) - (0.29)(70)1/3
Solving for v gives an equivalent lifetime human continuous exposure of
3
20 ug/m (annual average).
Other examples of dose conversions may be found in appropriate chapters of
EPA health assessment documents.
3.4.4 Modeling of Animal Studies Using the Linearized Multistage Model
Dose-response assessments for carcinogens relate the response
(probability or risk of cancer) to exposure of a given dose. Extrapolation
models attempt to predict what the response (risk or probability of cancer)
is in the low dose region of the dose-response curve. The output of an
extrapolation model, then, is an estimate of the probability of a response
(risk) or probability of cancer related to low dose.
Results of the linearized multistage model will be discussed in this
report because the EPA guidelines (1986b) state that the Agency will use
that model in dose-response assessments unless data are available which
indicate other models should be used. The presentation of model output is
taken directly from EPA (1986b).
As shown earlier, the linearized multistage model has the form:
P(d) = 1 - exp [-(qo + qjd + q2d2 + ... + qkdk)]
The point estimate of the coefficients q., i =0, 1, 2, ..., k, and
consequently, the extra risk function, P*(d) or risk above the background
level, at any given dose d, is calculated by maximizing the likelihood
function of the data. When all of the higher order terms in the multistage
model are zero, except for the linear term, the multistage model reduces to
the one-hit model. The model, specifically the curve-fitting methodology,
is discussed by Andersen et al (1983).
3-24
-------
The point estimate and the 95 percent upper confidence limit of the
extra risk, P*(d), (extra risk assumes that tumors induced by the agent
occur independently of spontaneous tumors) are calculated by using the
computer program GLOBAL82, developed by Crump and Watson (EPA, 1984b). At
low doses, upper 95 percent confidence limits on the extra risk and lower
95 percent confidence limits on the dose producing a given risk are
determined from a 95 percent upper confidence limit, qj, on slope parameter
q,. Whenever q, > 0, at low doses the extra risk, Pt(d), has approximately
the form Pt(d) - q, x d. Therefore, q| x d is a 95 percent upper confidence
limit on the extra risk. R/qJ is a 95 percent lower confidence limit on the
dose producing an extra risk of R. In fitting the dose-response model, the
number of terms in the polynomial is chosen equal to (h-1), where h is the
number of dose groups in the experiment, including the control group. Let
LQ be the maximum value of the log-likelihood function. The upper-limit,
q?, is calculated by increasing q, to a value q? such that when the
log-likelihood is remaximized subject to this fixed value qf for the linear
coefficient, the resulting maximum value of the log-likelihood I, satisfies
the equation:
2 (LQ - Lj) - 2.70554
Where: 2.70554 is the cumulative 90 percent point of the chi-square
distribution with one degree of freedom, which corresponds to
a 95 percent upper limit (one-sided).
This approach of computing the upper confidence limit for the extra risk
Pt(d) is an improvement on the Crump et al (1977) model. The upper
confidence limit for the extra risk calculated at low doses is always
linear. This is conceptually consistent with the linear nonthreshold
concept discussed earlier. The slope, q|, is taken as an upper bound of the
potency of the chemical in inducing cancer at low doses.
Whenever the multistage model does not fit the data sufficiently well,
data at the highest dose are deleted and the model is refit to the rest of
the data. This is continued until an acceptable fit to the data is
obtained. To determine whether or not a fit is acceptable, the chi-square
statistic.
3-25
-------
X* - £ (X. - N.P.)2
1 1 1
H1P1 (1 - V
is calculated where:
N. - number of animals in the ith dose group,
X. - number of animals in the ith group with a tumor response,
P. - probability of response in the ith group estimated by
fitting the multistage model to the data, and
h - number of remaining groups.
The fit is predetermined to be unacceptable whenever chi-squared is larger
than the cumulative 99 percent point of the chi-square distribution with f
degrees of freedom, where f equals the number of dose groups minus the
number of non-zero multistage coefficients.
Animal extrapolation estimate upper limit incremental unit risks are
the maximum plausible risks associated with one "unit" of exposure. For
example, if q? - 1.1 x 10 (mg/kg/day) , this means that not more than
3
1.1 cancer cases would be observed per every 1000 (10 ) persons exposed for
70 years to 1 ug/m of the agent in question. An extrapolation model will
2/3
predict the risk associated with a given dose, d mg/kg ' /day. Then, by
ratio (since the model forces the slope of the dose-response curve to be
3
linear), the risk associated with 1 ug/m can be calculated. The standard
conversions of i, W ' , and v must be used and were discussed earlier in
Section 3.4.3.
In addition to the unit risk, the dose-response assessment can yield an
estimate of carcinogenic potency, based on the unit risk. To estimate
potency, the unit risk slope factor for a given chemical is multiplied by
the molecular weight of a chemical and the resulting number is expressed in
terms of (mmol/kg/day)"1 (EPA, 1984b). That value is called the relative
potency index. Suppose that the upper-bound estimate of potency (slope) of
a chemical is 9.9 x 10" (mg/kg/day) and the molecular weight of the
chemical is 92.5. Then the potency index would be 9.9 x 10 (mg/kg/day)
x 92.5, or 9.2 x 10" . The EPA's Carcinogen Assessment Group (CAG) has
3-26
-------
calculated potency indices for many chemicals they have evaluated. The
various potency indices can be used to compare strength or weakness of
carcinogenicity among chemicals.
The computer program of the linearized multistage model also can
provide estimates of the maximum likelihood estimate of risk. Maximum
likelihood is a method of finding good estimates of parameters in models.
If the data are normally distributed, the method of maximum likelihood is
essentially the method of least squares.
An example of the difference in maximum likelihood estimates and
95 percent upper confidence limits generated by four different models is
shown in Table 3-1 (EPA, 1985d). The largest difference in the two types of
risk estimates is seen in those predicted by the multistage model. Maximum
likelihood estimates are extremely sensitive to the data; 95 percent upper
confidence limit estimates are much more stable (NRC, 1986). Consequently,
EPA does not encourage the use of maximum likelihood estimates of risk from
animal data, owing to their statistical instability.
Currently, there is no established procedure for making "most likely"
or "best" estimates of risk within the range of uncertainty defined by the
upper and lower limit estimates (EPA, 1986b). Such an estimate may be most
feasible when human data are available and exposures are in the dose range
of the data (EPA, 1986b).
In some cases, epidemiologic studies can be used to provide an estimate
of the upper bound of risk, when used in conjunction with risk estimates
from animal studies. If an animal study shows a statistically significant
increase in the number of tumors or tumor types and a well-designed and
well-conducted epidemiologic study shows no such statistically significant
evidence, then the risk estimate from the epidemiologic study may indicate
an approximation of the upper limit of risk.
3.4.5 Modeling of Epidemioloqic Studies
Epidemiologic studies can generate data which can be used to derive
quantitative estimates of cancer risk. If there is reason to believe that
the carcinogen acts in a manner to produce a response that is multiplicative
3-27
-------
O >- LU
z a
>- u.
z I-H u-
o z •-<
LU a
Q 3=
LU O Q£
00 3
oo
OU.
i:
LU O
a:
O >
H- OO ft
(—Q£
^ <£ LU
OO OC Q
OC LU >-
—i a
UJ 00
I— O Ol
OO LU .-H
LU DC
00
u
M •
04 *Q
1 O
to X
2
_4
fH ~4
*i
i*
•H F-l
*? -5
5 x
9
U -4
•» V
•r* "6
1*
w
O -4
u •
a x
0
-j
3 «
ft o
«J
f "
O
D
to
+J fl
•J O
_l X
*-N
en
6
to
^
il
I>
O
O
en CM fH «
i i i i
0000
en fH CM fH
o
fH oo 00
fH
Si
ourc<
Vi
3-28
-------
to the background rate, then the cancer experience is reported as relative
risk (NRC, 1986). The measures of relative risk most frequently used are
the Standardized Mortality Ratio (SMR) and the Standardized Incidence Ratio
(SIR) where:
SMR » observed deaths/expected deaths x 100
SIR = observed incidence/expected incidence x 100
Where: observed deaths/incidence are those seen in the study
population and expected deaths/incidence are determined for a
similar population with the same age distribution, but
without the chemical exposure.
Therefore, an SMR or SIR of 100 shows no difference in risk between that
which is expected and that which was observed in the study.
If there is reason to believe that a carcinogen acts in such a manner
as to produce a response that is additive to the background rate, then the
cancer experience is reported as attributable risk. Attributable risk is
defined as the rate of disease (or mortality) in exposed individuals that
can be attributed to the exposure. In general, the attributable risk
measure is used only for cohort studies since it is necessary to know the
person-years of experience of both the exposed and control groups. (For an
additional use in case-control studies, see MacMahon and Pugh, 1970.) The
attributable risk (AR) is defined as:
AR - observed cancers (exposed) - observed cancers (control)
person-years (exposed) person-years (control)
Both the SMRs (or SIRs) and ARs are used to derive quantitative estimates of
risk. SMRs (or SIRs) are used in relative risk models and ARs are used in
additive or excess risk models. These are described in more mathematical
terms below.
The excess additive risk model follows the assumption that the excess
cause-age-specific death rate [hj(t)] due to exposure to a given chemical is
increased in an additive way by an amount proportional to the cumulative
exposure to the chemical up to that age.
3-29
-------
Or: hj(t) = AXt
Where: Xt - cumulative exposure up to age t and
A • proportional increase.
Then, the total cause-age-specific rate h(t) is the sum of the
background cause-specific rate, hQ(t), and h,(t):
h(t) = h0(t) + hj(t)
The parameter A can be estimated by summing the expected death rates:
Where: E. = total number of expected cases in the observation
J period for the group exposed to cumulative exposure X..
EQ. = expected number of cases due to background causes
J (usually derived from county, State, or national death
rates, corresponding to the same age distribution of
the cohort).
X. = cumulative exposure for the jth exposure group.
W. = the number of person-years of observation for the jth
J exposure group.
A m slope of the dose-response model.
To estimate A, the observed number of cause-specific deaths, 0., is
substituted for E-. When there is only one exposure group, the estimate of
J
0. is assumed to be distributed as a Poisson variable with expected value E.
J J
solution proceeds via the method of maximum likelihood (EPA, 1985d). Thus,
the slope, ^ , becomes (Oexposed - °control^XW and the est1mate for tne
lifetime incremental risk is 70 x ^ .
The multiplicative or relative risk model follows the assumption that
the background cause-age-specific death rate at any time is increased by an
amount proportional to the cumulative dose up to that time. The model takes
the form:
3-30
-------
h(t) - h0(t) x (1 + AXt)
The terms in the equation are defined exactly as are those for the additive
model .
To estimate A (the slope of the dose-response model), the observed and
expected mortality experience is summed:
where the terms are defined as for the additive model.
Solution again proceeds via the method of maximum likelihood, with the
maximum likelihood estimates, ^ ,
N O.X.
L [-EQ,X. + J J 3 = 0
j=l OJ J 1 + X..
When there is only one exposure group, the estimate of the slope is:
* - Obi - 1 / X - SMR - 1 / X
A Exp
Lifetime, incremental risk estimates using this model are obtained by
multiplying ^ by the background lifetime risk, designated by PQ, and
obtained from period vital statistics by lifetable methodology. Using
United States cancer death rates, occurring between 1973-1977, the
background risk of death from lung cancer is 0.038 or 38 deaths per
1000 people. Other cancers have lower background risks such as bladder
cancer (0.005).
The multiplicative or relative risk model assumes that the
time-response relationship is constant. Thus, at any time since the start
of exposure (after a latency period), the Standard Mortality Ratio for a set
cumulative exposure is constant. Likewise, in the additive model, the
excess mortality rate for a set cumulative exposure is constant over time.
3-31
-------
Thus, under either model, excess risk (either SMR or mortality rate) should
remain constant once exposure stops. Modification of these models
incorporating such variables as age, time of first exposure, and latency
period have been developed to incorporate additional information. For more
information on these models, see EPA, 1985a.
3-32
-------
4.0 EXPOSURE ASSESSMENT
The third step in the risk assessment process is the exposure
assessment. Since dose-response assessment is the primary focus of this
report, this discussion of exposure assessment is much less detailed than
the discussion of dose-response assessment. A brief description is included
to help readers place exposure assessment in the context of risk assessment
rather than to explore extensively exposure assessment methodologies.
Contact between a pollutant and a human population is called "exposure"
and is measured by the number of people exposed to specific concentrations
of a pollutant for a given time period. An exposure assessment is the
determination or estimation (qualitative or quantitative) of the magnitude,
frequency, duration, and route of exposure. For exposure to carcinogens,
continuous exposure over a lifetime is usually assumed. Exposure estimates
can be coupled with cancer potency data to estimate the potential risk from
exposure to a carcinogen.
The EPA Guidelines for Estimating Exposures outline an exposure
assessment in terms of the following five main topics: sources, exposure
pathways, measured or estimated concentrations and duration, exposed
populations, and integrated exposure analysis. The guidelines also point
out that each exposure assessment must be tailored to meet the needs of the
problem at hand (EPA, 1986d). There are several procedures for estimating
exposure and there is no universally accepted minimum set of specifications
for estimating exposure (OSTP, 1985).
Under EPA's suggested outline of five main topics, the first main area
is the sources of the substance under study. Sources include all points
from which the substance is believed to enter the atmosphere, including
production, distribution, use, and disposal sources. The pathways that need
to be considered will vary depending on the chemical characteristics of the
pollutant, the source of the pollutant, and the land use pattern in the
vicinity of the source. For example, an analysis of a waste-to-energy
4-1
-------
facility in an agricultural region might include modeling of ambient air
concentrations of emissions as well as disposition modeling of water, soil,
and plant concentrations.
The second topic, exposure pathways and environmental fate, examines
how a substance moves from the source to the people exposed. The necessary
level of detail may vary, but such an analysis may look at transport of the
substance through the environment as well as potential physical or chemical
transformation. In other words, an understanding of the environmental
behavior of the substance is important in an exposure assessment
(EPA, 1986d).
Measured or estimated concentrations of releases and environmental
concentrations of the substance are among the main components of an exposure
assessment. If actual measurements are not available, concentrations can be
estimated by various means such as fate models or by analogy to known
substances. Environmental concentrations are generally estimated from
measurements, mathematical models, or a combination of the two. The EPA
guidelines note that if environmental measurements are not limited by sample
size or inaccuracies, then exposure assessments based on measurements have
precedence over estimates based on models. The guidelines also point out
that concentrations must be estimated and presented in a format consistent
with available dose-response information. In some cases, an annual average
concentration estimate will be sufficient while, in other cases, the
temporal distribution of concentrations may be required (EPA, 1986d).
The estimate of the number of people exposed to various concentrations
is the next main part of an exposure assessment. By analyzing the
distribution of the agent, populations and subpopulations that are
potentially subject to a significant exposure can be identified. This will
form the basis for the populations studied. Census and other survey data
can be used to quantify and describe the population exposed. In some cases,
more specific information may be warranted such as information on potential
exposure of sensitive subpopulations (such as pregnant women, children, and
the chronically ill) or of nonhuman populations (EPA, 1986d).
The final step in an exposure assessment is to combine the estimates of
environmental concentrations with the description of the exposed
populations. Specifically, data include the size of the exposed
4-2
-------
populations; the duration, frequency, and intensity of exposure; and the
routes of exposure. The results of exposure calculations should be in a
format consistent with the requirements of the dose-response functions used
in a risk assessment. For example, when lifetime risks are considered,
average daily exposure over a lifetime is usually calculated (EPA, 1986d).
In many exposure assessments for toxic air pollutants, EPA uses the
Human Exposure Model (HEM) to quantify the number of people exposed to air
pollutants emitted by stationary sources. The HEM consists of an
atmospheric dispersion model, including meteorological data; population
distribution data; and a procedure for estimating risks due to the predicted
exposure. The model uses census data for population estimates and an
atmospheric dispersion model for estimates of ambient concentrations at
160 receptor sites surrounding a point source up to 50 km away. The model
matches population estimates with concentration estimates, calculating:
(1) total or aggregate exposure, that is, the summation of the population
exposed times the concentration across all concentrations, and (2) the
population exposed or the number of people exposed to a particular
concentration or higher concentrations. The HEM uses the assumption that
people are exposed to a particular ambient concentration continuously for a
70-year lifetime. Table 4-1 presents an example of HEM output for an
exposure assessment of ethylene dichloride (EDC) from 18 sources
(Kellam, 1986). Results from HEM can be combined with EPA's unit risk
factors to estimate cancer risks both as maximum lifetime risks and annual
incidence (population risk) (EPA, 1986a).
The National Air Toxics Information Clearinghouse (NATICH) data base
contains information on selected EPA risk analysis results calculated using
HEM. These emissions and risk estimates are developed by EPA in support of
decisions concerning possible regulation under Section 112 of the Clean Air
Act. The estimates are made for specific facilities emitting particular
chemicals under study by EPA (NATICH, 1986b). Table 4-2 shows an example of
the NATICH risk information.
The EPA's Office of Pesticides and Toxic Substances has developed two
related exposure modeling systems. The Graphical Exposure Modeling System
(GEMS) is an interactive system being developed for integrated exposure
4-3
-------
.fi J3
U U
^ ^4
M U
T3 Tj
o o
o o
OO
co ci *H -»
iNiHOiiOr-tN vOrHO^OtCOtOOO
cnOOcn*Hi-lfHC4OC>4OOr*-iHO
OOOOOONNOOOOOOO
LU
LU
&
£
oo
oo
oo
oo
oo
oo
o
o
o
o
o
o
o
o
o
o
o
o
o
vo
LU CM
o:
=3 LU
00 O
O
f\ v/
X 00
LU l—l
S
M
S
V
1
o
Q- o:
oo:
I-S^
*-* -4 n
x > -i
x^*
O
a
^ K
O
LU LU
OQ >-
< a:
l— <
00
|
O4
OOOOOOOOOOOOOOOOOO
I t I I I I I ( I I I I I I I I < t
"*^IN<^CO^I»H^»«H»OrH^H**«*r<'«-ICQCO
iHOO«H^«HrHfHtHpH^r-ItOr^iHO »HO
OOOOOOOOOOOOOOOOOO
+ + + + I + + + + •»- + + + + + + + +
f*1 M M H f*T M W 1*1 f'1 r*1 f*1 M M M M f*1 f*1 M
oiiHOicn^atoojtH^moitootfnaitor*
ODNio
-------
<
LftJ
LU
1— 1—
(J Z
LLJ «C
1 ^^
(^•j r^
LU 3
t/> — J
_l
JirO
O O-
LU >-
^
CO Z
< ^2
< 2
°s
Z O
O LL.
Z CO
H-4
Z «/>
QC —1
LU
U
u
H
en
1
1
en
•1
M
0
a
o
M
tH
&
t
ladorf
*
9
u
M
Z
en
i
1
CM
«
CO
o
en
0
o
r*
*H
CM
to
O
CO
•ff
tO
en
CM
o
o
o
o
o
m
o
1
M
to
o
1
u
m
m
CM
gi
•
M
O
4J
M
IH
5
Landing
n
i
^
2
°
X
m
i
t
en CM CM r*
o n
o -* rH o tn
O* O Ot O O ,-1
. . . . . i
•H 0 IO CO Ol -4
H en in CM m *ti
H m o •« . CM »4
CM o in co o
1
CM CM CM CM CM A
O 0 O O O -4
•§
0
«H CM iH ?-4 «H U
O CM O O O
O O O O O B «
O O 0 O O O «
O O O O 0 «J M
v So
r. •» « r« • -i
"t * °! *"! "I o Si1
•0 4 U
p. : §
CM i-l O iH CM • V
tt U 0 JO
I ! i
•* "5
•i *> • T) 3
5 S 3 S •*
U Jj 0 II
on, o • v
*» «J M M
Maun* a 3
fe M • to fe M V «
•eg. So.
S • -S e
O -.40 B
SB M J > Q. S 0-4 3
O X M 5 MO C 4J -4
DM -44 B
fl M ^4 M
-4 M • "*4 JS
W 4 U 3 « W
3 1 "3 ° " S
.s s§ is J 1 .• ; 1
o -i a. 3 -4 -4 «
-------
analyses. This system can model releases in air, surface water, ground
water, soil, and multimedia releases. It contains fate and exposure models,
environmental characteristics data, chemical fate data, population data, and
release source data (OPTS, 1986).
Part of GEMS, the Graphical Atmospheric Modeling Subsystem (GAMS)
allows multiple atmospheric dispersion models to be used for multiple
release sources to examine overlapping exposures. Point and area source
models are used in GAMS to estimate annual average atmospheric
concentrations. The GAMS model integrates the atmospheric concentration
estimates from both models with a population distribution data base in order
to estimate exposure and risk (OPTS, 1985).
The OSTP considers human exposure assessment to be the weak link in
environmental health studies (OSTP, 1985). Many of the OSTP concerns are
also addressed in the EPA guidelines (EPA, 1986d). Some of the issues
leading to this uncertainty include:
• The path a chemical follows from its source to the exposed target
can be quite complex and involve different environmental media.
t There is no universally accepted minimum set of specifications for
the reliable estimate of exposure.
• Exposure assessment requires extrapolation from a limited number
of sites to a large population.
0 Exposure assessments are often unable to reflect all of the
parameters important to determining health effects (e.g., peak
versus average exposure).
Characterization of this uncertainty is discussed in Section 5.0.
4-6
-------
5.0 RISK CHARACTERIZATION
Risk characterization is the final step in risk assessment, in which
information from hazard identification, dose-response assessment, and
exposure assessment are integrated. Two types of information are presented
in risk characterization for a risk assessment. The first piece of
information is a numerical estimate of risk and the second is a framework
which helps judge the significance of risk (EPA, 1986b). The framework
should include weight of evidence information and a description of the
uncertainties in the risk assessment (qualitative and quantitative). The
EPA guidelines (EPA, 1986b) address this framework. This section of the
report discusses various ways in which a numerical estimate of risk can be
presented and describes the ways in which uncertainties in the various
components of a risk assessment can be characterized.
5.1 PRESENTATION OF NUMERICAL ESTIMATES OF RISK
Three basic types of numerical estimates of cancer risk can be
presented in risk characterization: a unit risk, a dose "corresponding to a
given level of risk, and individual or population risks (EPA, 1986b). A
unit risk is the excess lifetime risk due to a continuous, constant lifetime
exposure of one unit of concentration (EPA, 1986b). The unit risk can be
expressed in terms of ppm in diet, mg/kg/day or, most frequently in risk
assessments for air pollutants, micrograms per cubic meter (ug/m ) in the
air. The unit risk approach is based on the assumption that the
dose-response curve is linear at low doses (see also Section 3.0,
Dose-Response Assessment). It is usually expressed as a two-digit number
times a power of ten such as 5.5 x 10 (ug/m )" .
If different dose-response extrapolation models are used, then risk may
best be presented as the dose which is associated with a given level of
risk. For example, if the one-hit model, a linearized multistage model, and
a Weibull model were all used to extrapolate the dose-response curve, each
5-1
-------
model would probably predict different doses that would be associated with a
given level of risk such as 1 x 10" (one case in one million exposed
persons).
Similarly, the National Academy of Science used different extrapolation
models (and different animal to human extrapolation methods) for predicting
the expected number of cancer cases in a general population exposed to
0.12 g/day of saccharin. The modeling results showed a range of between
0.001 cases/million people exposed to 5200 cases/million people exposed
(EPA, 1984a). While some alternative statistical model extrapolation
approaches are of value to a risk manager, in fact, the range of risks
described by using these approaches has little biological significance
unless available evidence of cancer mechanisms can be used to support the
selection of one model over another. In the interest of consistency of
approach and for the purpose of identifying an upper bound estimate on the
potential cancer risk, EPA recommends the use of the linearized multistage
model rather than presenting a range of estimates from various models
unless, on a case-by-case basis, there is reason to do otherwise.
Finally, risks may be reported in terms of risk for an individual or
risk for an exposed population. These presentations are used frequently by
EPA in studies during the development of national emission standards for
hazardous air pollutants (NESHAPs), where a unit risk factor is multiplied
by an exposure estimate to obtain maximum individual risk or aggregate risk.
An example of the different methods of reporting risks is shown in the
sample HEM output in Section 4.0. In the example table, the maximum
individual risk is the risk for the person living in the area of highest
ambient air concentrations. It is determined by multiplying the unit risk
factor for the specific chemical of concern by the highest exposure estimate
in the area under examination. Thus, if the unit risk factor for a chemical
-53-1 3
is 4 x 10 (ug/m ) for a continuous lifetime exposure to 1 ug/m and the
highest predicted exposure concentration is 3 ug/m , then the maximum
individual lifetime risk would be 4 x 10 x 3 or 1.2 x 10. Aggregate
risk, on the other hand, applies to all people within the given area of
analysis. It is expressed as expected incidences of cancer among all people
in the analysis after 70 years of exposure. Frequently, the incidence is
divided by 70 to obtain an incidence per year. An example is shown below.
5-2
-------
2 ua/m
4 x 10"5
(ug/m3)'1
8 x 10'5*
1,000
0.08
1 uq/m
4 x 10'5
(ug/m3)'1
4 x 10"5
10,000
0.4
0.5 ua/m
4 x 10'5
(ug/m3)'1
2 x 10"5
100,000
2.0
-5 3-1
Example: The unit risk factor for chemical X is 4 x 10 (ug/m ) .
The exposure assessment showed ambient air concentrations of 2 ug/m ,
1 ug/m3, and 0.5 ug/m and exposed populations of 1,000, 10,000, and
100,000, respectively. Then the probability (risk) of cancer would be as
follows for the three exposure concentrations:
Unit Risk
Probability of Cancer
Number of Persons
Exposed
After 70 Years of
Exposure (Population
Risk or Aggregate Risk)
Total Aggregate Risk = 2.5
*
Eight cases per 100,000 people exposed.
Thus, the aggregate risk is 2.5 or, expressed as annual incidence,
2.5/70 = 0.04.
Some risk assessments are concerned with population exposures to
multiple chemicals. In these cases, the numerical estimates of risk for
each chemical may be added together, unless there is toxicological evidence
to the contrary (EPA, 1986b). More specific information on risk assessments
for chemical mixtures is found in the EPA Guidelines for the Health Risk
Assessment of Chemical Mixtures (EPA, 1986c).
5.2 PRESENTATION OF THE UNCERTAINTIES IN RISK ASSESSMENT
Uncertainties are inherent in risk assessments. Even though steps are
taken throughout hazard identification, dose-response assessment, and
exposure assessment to reduce the uncertainties, some will still remain in
the final risk assessment. The remaining uncertainties need to be described
5-3
-------
quantitatively (if possible) and qualitatively to provide as much
information as possible for risk managers to use in decision-making. At the
present time, there is no method that can be used to provide an overall
quantitative expression of the uncertainties in a risk assessment.
Therefore, uncertainties are discussed as they occur in each segment of a
risk assessment. The types of uncertainties associated with the first three
components of the risk assessment process (hazard identification,
dose-response assessment, and exposure assessment) are discussed in this
section and methods of describing the uncertainties are shown.
In hazard identification, a major concern is the nature of evidence
that a substance is indeed a human carcinogen. For risk managers to be able
to use the results of a risk assessment, some indication of the belief that
a substance is a human carcinogen must be shown. The EPA has devised a
weight of evidence scheme, similar to that of IARC for use in describing the
likelihood of a substance being a human carcinogen (EPA, 1986b). The system
is described in detail in Section 2.0 of this report. The letter or
letter/number classification of a possible carcinogen should be included in
EPA risk assessments when the numerical estimate of risk is presented. For
example, if the unit risk of a substance is 5 x 10 (ug/m ) and the
weight of evidence for carcinogenicity is B2 (sufficient animal
evidence/inadequate or no human evidence), then in risk characterization,
the risk estimate should be presented as 5 x 10 (ug/m )" [B2]. Note that
in risk characterization, no judgments are made or presented about possible
decisions using the risk estimate. That is, the societal value (or economic
or political implications) possibly associated with the risk estimate is not
part of risk assessment. Those types of decisions or judgments are made as
part of risk management. The weight of evidence notation gives more
information to risk managers about the strength of the evidence (i.e., the
likelihood) for the substance in fact being a carcinogen in humans.
As was shown in Section 3.0, several presumptions are made in preparing
a dose-response assessment. Some uncertainty is associated with these
presumptions and with the extrapolation models used. Most often,
statistical approaches are used to express the uncertainties associated with
dose-response assessment data. First, data sets which show a statistically
5-4
-------
significant increase in tumors in specific organs or tissues should be used
in the dose-response assessment. Negative data sets may also be used. The
appropriate statistical analysis should include at least a statistical te-st
for trend (EPA, 1986b). Second, the extrapolation model(s) used contributes
to uncertainties in the numerical risk estimate. The linearized multistage
procedure, used most frequently by EPA (Section 3.0), leads to an upper
bound of risk, because the model has a feature which estimates the largest
possible linear slope of the dose-response curve (the 95 percent confidence
limit of the data) that fits the data in the experiment (EPA, 1984b). Thus,
the unit risk factor is a plausible bound estimate of the risk. With such
an estimate, the true risk is not likely to be higher than the estimate, but
could be lower (EPA, 1984b).
In summary, there are steps in the dose-response assessment process
which generate uncertainties in the numerical risk estimates. In order to
provide a risk manager with the most information possible, the uncertainties
should be described as fully as possible in risk characterization.
Exposure assessments also generate uncertainties because they are based
on simulation models, measurements, and assumptions about input parameters
for exposure modeling. Table 5-1 summarizes the primary methods of
qualitatively and quantitatively characterizing uncertainty in exposure
estimates (EPA, 1986d). The qualitative methods may include discussions of
the limitations of a sampling program for measuring actual exposures such as
analytical sensitivities and collection efficiencies for sampling equipment.
Discussions of the validity of a given model, and the assumptions made in
selecting model input, are examples of a qualitative statement of the
uncertainties for an exposure assessment based on modeling.
Quantitative expressions of uncertainties include statistical
descriptions such as confidence intervals. More detailed discussions of
these methods are given in EPA (1986d) Guidelines for Exposure Assessment.
5.3 PRESENTATION OF THE ASSUMPTIONS USED IN RISK ASSESSMENT
As can be seen from the discussions on each of the preceding components
of risk assessment, assumptions and scientific judgments must be made in
almost every step to allow the risk assessment to proceed. In risk
5-5
-------
ca
H^
M
N^
QC
UJ
L^
O
• OO
QC UJ
^^
•—i o
QC U.
QL
>•
U. t—
oz
«— 4
>- «c
QC t—
VI
B
-4
VI
M
«
1
a
N
»4
VI
il
y
4
J
U
VI
o
44
VI
Tl
0
J3
VI
£
><
M
1
'E
o.
c
v<
VI
n
^4
VI
V
VI
u
a
V
g
X
0
I
V
4
_
:
a
c
&4
n
•o
|
V
•H
S
VI
«4
VI
*
n
•u
s
itatl
-4
1
•O
«
VI
g
-3
4J
0)
W
1?
t)
(4
i
4
ij
4
Q
*M
0
«J
fl
t»
4J
x
M
1
I
H
•)
V
44 3
. 8-
01 a
ti
3 44
vi O
o
a, v
Sf -!
u n-
Measured '
large sam|
fnembers.
s s
- 1
OB -3
5. v vi
ft • i
01.0 •
s ? t
""JS 6
4J «
<*4 X **
•*< s 5
44
O 44 T) «
•* II 0
n u C
3 vT.3 T>
•gt 3 A
§13 8
o i o. u
. .
M i-l
X
«
I
3
•t
£
vi
44
0
S
o
•4
JJ
4J
1
_J.
«H
JS
VI
44
O
«l
U
«
VI
!
i
4
(fl
el
hi
O
44
«
•
14
3
«
I
s?
t)
•fl
2
3
i
i 8
r 3
« 0 B
• g-:
§ •-
s s ?
a
41 *) * 4
J3 II n ^
U S-43
•9 « v>
h o •O n
o o O o
44 o e a
oi
vi
B
V
|
n
4
§
H
II
V II
•O u
^
V
*-4
*4
VI
B
» «
§ g
U 8.
S •
-4
U H
VI O
V)
-4 B
•a 3
• 1
2 B
3 -
«l •
&:
2 -^
»4
*J
4
~4
3
§•
a
44
o
III
l-l
g,
n n
h
-4 V
-4 J>
g]
« i
n
« O •
2 TU 5
1 - s 2 44 a
•3 334 OB
U Q, 44 -4 U
3J e fa 3 §5
4J O OK -4-4
-4 -4 U -4 O U 4
4 44 iJ O VI 0i 3
£°^ "5 B 3g
» « -4 U -4 • h
VI V 14 -4 14 II VI X*
Bi-4U 44W.O H V
•H -4 VI VI *4 n
tl -1 44 -1 v -OH
g g' °* 5 *•"
SOU w o> .2 ««
•OV3 Slox 3 3 "i
-I a «1 B4B B«-<
44 0 -5-44 5 0 01
Bna on u p. -o
ooSe; 04<<4 «i X o
(J44«l O > -4 UVB
r4 « m
X
« II
!> h
L u 3
3 B vi
« « 0
Jll 1
U 3
n •>
44 4 A
0 I "
• - 44
B -O n o
° * 1 *
*J 6* *J
4 a -4 -! •
u « e TJ ^
-4 »4 5 -4 •
B » O -I 73
•3 • II 40
j -o u > B
.
-4 «
.
rt CM
M
O U
a 3
M 4 O. •
3 VI B X
•1 4 -4 B
0 Tl 0
& .53
5 "5
• M -4
£ 44 0 M
VI O 44 VI
VI
44 •) » -4
O B -4 -O
O n
x -4 4 e
vi vi .a *H
-i • <• -a
•o ^ u u 4
.4 « -4 « -4
-i -o s JS u
4 O 3 iJ 4
> 8 J o >
r4 CM
II
h
3
n
O
&
II
•8
g
x4
U
g
J
«4
14
VI
VI
~4
O
44
0
C *
o n
-4 41
*J r-l
J-3
-4 *4
M VI
VI 4
J >
•O VI
3
•s&
VI -4
It
vi -3
" 5
u i
X
« g
> x -3
-4 El VI 4
vi « a u
"S3 " 3 v, S
c £ 2^5 ? |
0 VI 4 II VI 5 3
-4 1-4 O W
4J 4 4V 4 44 V
s P e LI u o -H
J C 4 O O -4 A
»4O •en44VIB-4
14 COM
VI13 V*Tt4w4«
v> V -4 • « 3 «J O
-4 n .0 M u qr « a
•O 4 4 • 0 N
U3 *4 «J 01 - -4 V
T) M ^- -1 ~ U .O
41 V 4 --* w II
J3 VI II U V) O O
vi ^ vi vi o rt B
o « 3 "4 4 a w
*J D. T3 O>&VIUl«X
niKO B<343.£4
w oi a M -i T) a o s
M T-t
II
4 U
vi 3
4 n
•a o
8 *
5 •
44 5
O vi
S44
0 °
vi &
4 -4 .
VI Tl -^
-4 -1 V
5-4 -a
4 0
J > S
T-* f»*
«
B
« O
Ml ^
B VI
25
1^
4 w
•H
fl"0
JS
X «
1 °
1 g-
- II
I "
S J=
a "
-4 44
Z 0
VI
3
a
fl
»4
^
V
•o
g
VI
o
44
4
VI
4
•O «
«
•O M
01 J3
U 4
*4 *4
35
»
T)
>O
00
O»
rH
<
a.
u
Source :
5-6
-------
characterization, the assumptions should be identified and their effect on
the numerical risk estimate described if possible. Such discussions enhance
the framework with which to help judge the significance of the risk.
Examples of the types of assumptions and judgments which should be
presented and discussed include choice of data sets and extrapolation model,
choice of model(s) used in the exposure assessment, and any pharmacokinetic
or metabolic activities which could influence a numerical risk estimate.
5-7
-------
6.0 RISK MANAGEMENT
Risk management is the decision-making process in which some action is
taken or policy formed concerning a potential risk to the environment and/or
to human health. Risk management differs from risk assessment in that
management of risk usually considers political, economic, and social issues
in the decision-making process. Products of a risk assessment, such as
numerical estimates of risk for an exposed population, are used by risk
managers in deciding, for example, whether or not, or to what extent and at
what cost, a source of toxic pollutants should be controlled. Risk
management may also be considered as a method of setting priorities among
possible actions for various pollutants or sources. Management of risk does
not always deal with decisions on numerical estimates of human health risk
or quantifiable estimates of risk. For example, the value of wilderness
areas is not easily quantified, and yet decisions may have to be made on
whether or not to "preserve" such areas.
Different groups or agencies may choose different tools to manage risk
in different situations. For example, a risk-benefit analysis may be
conducted in which the economic benefits of using a certain chemical
(e.g., increased crop yield) are balanced against the associated risks to
human health or the environment (EPA, 1984a). Additionally, a benefit/cost
analysis, which weighs the cost of control against the monetized benefits of
control, could be performed. Such an approach may work best when all the
factors affected by the decision can be expressed in terms of dollars
(EPA, 1984a). This type of analysis is often difficult for pollution
control agencies to carry out because of the controversy involved with
placing dollar values on a human life. However, a cost-effectiveness
analysis neither expresses monetary benefits nor weighs risks against such
benefits (EPA, 1984a). A cost-effectiveness analysis identifies the
least-cost method for obtaining a stated goal. This technique is the most
frequently used risk management tool at EPA (EPA, 1984a).
6-1
-------
Independent of the type of risk management tool used, risk managers
should be aware of the underlying assumptions and inherent sources of
uncertainty contained in a risk assessment. It is important to consider the
fact that numerical presentations of risk are probabilities, and usually
upper bound risk estimates and not absolute values for numbers of cancer
cases or deaths. Also, each step of the risk assessment process, hazard
identification, dose-response assessment, and exposure assessment, contain
assumptions which allow the risk assessment to proceed, but which must be
understood by the risk manager in making decisions. For example, it is
assumed that toxic effects observed in test animals (when properly
qualified) are applicable to humans (NRC, 1977). But there may be some
cases in which animal models do not respond the same way as humans, due to
metabolic or species differences. In a dose-response assessment, the point
estimates of risk determined by a mathematical extrapolation model may
actually be greater than or less than the true risk. Finally, the estimates
of the magnitude, frequency, and duration of exposures used in an exposure
assessment may not be consistent with each and every type of exposure that
can occur for a given chemical.
The risk management process must take into account that risk assessment
is a continually evolving science that is very dependent on the situation to
which it is applied. New data are constantly being generated that can
assist in decreasing the uncertainty associated with the assumptions that
are made in risk assessment. In most cases, if data are lacking,
assumptions are selected that are "health-conservative." Such stacking of
worst case and conservative assumptions will generally overestimate the true
risk. The goal of a risk assessment should be to present the most accurate
estimate of risk possible. Risk management should encourage the application
of new and better information and assumptions.
In spite of the uncertainties, properly conducted quantitative risk
assessments are valuable tools for risk managers. They provide an estimate
of the probability of the risk to human health. The importance of properly
estimating and describing uncertainties in a risk assessment is made clear
when the uses of risk assessments by risk managers is considered.
6-2
-------
7.0 RESOURCE REQUIREMENTS
Conducting a quantitative risk assessment requires different types of
personnel capabilities and some specialized computer software. This section
of the report describes the types of skills needed and defines the types of
equipment needed to conduct a quantitative risk assessment.
As was shown earlier in the report, a risk assessment includes
information in health sciences (e.g., toxicology, epidemiology,
biostatistics) and exposure modeling (e.g., air dispersion modeling, ground
water modeling). Therefore, staff capability in each of these areas is
needed. A pollution control agency may need to expand the existing staff to
add these capabilities, with the added expense of salaries. Also, because
the field of risk assessment can change quickly, staff skills must be
updated through additional training. One alternative to expanding the staff
.is to rely on assistance from EPA Regional Office personnel. Expert
modelers and toxicologists in EPA Regional Offices may be consulted on a
variety of risk assessment projects. Another alternative to expansion of
staff is to have the work done by an outside group, such as consulting
companies or interstate agencies. An advantage to developing in-house staff
is that the personnel resources will be available in the future. Advantages
of using outside resources include the fact that computer equipment would
not have to be acquired by the agency and agency time would not be
concentrated in conducting the risk assessment.
The computer equipment needed would include copies of the extrapolation
models for a dose-response assessment (such as GLOBAL 83) and any
atmospheric dispersion models or ground water models for exposure
assessments. Also, access to a computer capable of running the models would
be needed. These needs are dependent on the actual types of analysis to be
done.
One possible method an agency could use to quantitatively define risk
for a given exposure scenario would be to use existing risk assessments
developed by EPA or other agencies. In such cases, a unit cancer risk
7-1
-------
factor may already have been calculated. Then the agency would need only to
conduct an exposure assessment and risk characterization to combine the
exposure and dose-response (unit risk) data. To conduct a risk assessment
in this manner would require exposure modeling staff and personnel familiar
enough with the risk assessment process to apply results of previously
conducted dose-response assessments. An example of this case would be one
in which a new facility were to locate in a given region and have the
potential to emit a carcinogen for which a unit risk factor had been
developed. The agency could conduct exposure modeling, perhaps using the
Human Exposure Model (HEM) and then combine the results of HEM with the
appropriate unit risk factor. HEM automatically computes maximum individual
risks and/or aggregate risks. HEM inputs include latitude/longitude of the
source and stack parameters. The user's manual for HEM may be consulted for
more details about this model (EPA, 1986a).
7-2
-------
PART 2
The sections in this part of the report present four examples of how
State and local agencies have used risk assessment in their air toxics work.
The example risk assessments were performed by the Northeast States for
Coordinated Air Use Management (NESCAUM) (Section 8.0), the States of
California (Section 9.0) and Michigan (Section 10.0), and the local air
pollution control division of Clark County (Las Vegas), Nevada
(Section 11.0).
Each agency has taken a somewhat different approach to risk assessment,
often due to the agency's objective for using the risk assessment results.
Many of the assumptions used are agency-specific and may not necessarily be
endorsed by EPA. Similarly, while work by all of the agencies is
characterized as risk assessment, not all the agencies have undertaken the
four-step process described in Part 1 of this report and in the EPA risk
assessment guidelines.
Each section in Part 2 addresses the agency's objectives for
undertaking risk assessment, an overview of the methodology used, and the
use of the results. Each section also addresses topics designed to help
other State and local agency staff who may be deciding how risk assessment
could be done in their agency. These topics include resource requirements
and advantages and disadvantages of the particular approach as seen by the
agency that used it.
-------
8.0 NORTHEAST STATES FOR COORDINATED AIR USE MANAGEMENT -
RISK ASSESSMENT FOR TETRACHLOROETHYLENE
8.1 OBJECTIVES IN UNDERTAKING RISK ASSESSMENT
In March 1985, the Directors of the Northeast States for Coordinated
Air Use Management (NESCAUM) requested that NESCAUM begin to coordinate
assessments of specific toxic air pollutants. Since a comprehensive health
assessment for a toxic air pollutant can be a long and complex process, the
NESCAUM States (Connecticut, Massachusetts, Maine, New Hampshire, New
Jersey, New York, Rhode Island, and Vermont) joined together to share their
expertise. The long term objective of this process is to begin development
of ambient standards for toxic air pollutants. In May 1985,
tetrachloroethylene was chosen as the first toxic pollutant to undergo this
risk assessment process (NATICH, 1985).
8.2 OVERVIEW OF METHODOLOGY USED
After selecting tetrachloroethylene as the pollutant for study, the
NESCAUM member States divided the assessment work among the States and the
EPA Region I and NESCAUM toxics coordinators. General background
information on tetrachloroethylene was assembled including physical and
chemical properties, analytical methods and limits of detection, production,
use, emissions, and environmental fate in air, water, and soil. Data on
ecosystem considerations were also gathered, including aquatic toxicity and
bioconcentration and bioaccumulation. Literature describing exposure via
air, drinking water, and food was reviewed as was literature on
toxicokinetics. In addition, references describing health effects including
acute, subchronic, noncarcinogenic chronic effects as well as fetotoxicity,
teratogenicity, reproductive effects, genetic toxicity, and carcinogenicity
were reviewed.
8-1
-------
NESCAUM's health evaluation for tetrachloroethylene included risk
assessments for both noncarcinogenic toxicity and carcinogenicity. The
noncarcinogenic assessment resulted in an ambient air exposure standard for
chronic noncarcinogenic effects. The cancer risk assessment resulted in an
estimate of the average daily ambient level associated with an one in one
million (1 x 10" ) lifetime excess cancer risk in humans.
8.2.1 Hazard Identification
NESCAUM reviewed literature on both epidemiologic studies, animal
bioassays, mutagenicity, and reproductive and developmental toxicity as well
as information on physical and chemical properties and routes of exposure
before the NESCAUM Air Toxics Committee decided to classify
tetrachloroethylene as a probable human carcinogen.
The NESCAUM committee referenced the results of 12 epidemiologic
studies involving exposure to tetrachloroethylene in dry cleaner workers and
in metal workers. The committee concluded that in the studies done to date,
it is difficult to separate the effects of confounding factors because the
studies involved mixed exposures to petroleum and other solvents and, in
some cases, to metals, and because the effects due to smoking are not clear.
The committee felt that the epidemiologic evidence to date supports an
assessment of carcinogenic potential for tetrachloroethylene, but that this
remains to be defined since many confounders and possible sources of bias
exist (NESCAUM, 1986).
Results from five animal bioassays were reviewed. Two of these
bioassays, one based on exposure via gavage and the other on inhalation,
provided evidence that tetrachloroethylene exposure resulted in a
carcinogenic response in the rodents tested. These bioassays were conducted
by the National Cancer Institute (NCI) and the National Toxicology Program
(NTP). The NTP bioassay corroborated the NCI finding of liver tumors in
mice and also demonstrated that tetrachloroethylene was carcinogenic via the
inhalation route and that it was carcinogenic in more than one species at
more than one site. The other three assays did not show positive evidence.
One of the three assays was not a sensitive indicator of carcinogenicity,
8-2
-------
another used only a 12-month exposure period rather than the rodent lifetime
and used dose levels that may not have been high enough to provide maximum
sensitivity. The third was based on skin painting and it has been
hypothesized that the skin does not have the necessary enzymes to covert
tetrachloroethylene to an active metabolite (NESCAUM, 1986).
According to EPA's classification system for weight of evidence of
carcinogenicity, sufficient animal evidence was present and this evidence
constitutes consideration of a compound as a probable human carcinogen. The
NESCAUM committee concurred with this classification.
8.2.2 Dose-Response Assessment
The NESCAUM committee used data from a 1985 inhalation bioassay
performed by the NTP for low-dose extrapolation. In the NTP test, male and
female rats and mice were exposed to tetrachloroethylene for 6 hours per
day, 5 days per week, for 103 weeks. The rats were exposed to 0, 200, or
400 ppm tetrachloroethylene, and the mice were exposed to 0, 100, and
200 ppm. In male mice, the incidence of hepatocellular carcinomas
(malignant tumors of the liver) was significantly increased at both dose
levels. The incidence of hepatocellular adenomas (benign liver tumors) in
male mice increased at the higher doses. Female mice had increased
incidence of hepatocellular carcinomas at both dose levels. Renal tubular
cell karyomegaly was also observed in both species of treated mice. In male
and female rats, exposure to tetrachloroethylene was associated with
statistically significant increases in mononuclear cell leukemias. It also
produced renal tubular cell karyomegaly in male and female rats, renal
tubular cell hyperplasia in male rats, and increased squamous metaplasia in
the nasal cavities of male rats.
From this NTP study, the male and female mice tumor data were used for
low-dose extrapolation which was performed by New York using the Global 82
model. The Global 82 program uses a linearized multistage model of
carcinogenesis for low-dose extrapolation from animal carcinogenicity data
(see Section 3.0). NESCAUM noted that this model is "reasonably
conservative." The risk estimates made with this model should be regarded
8-3
-------
as representing a plausible upper limit for the risk. In other words, the
true risk is not likely to be higher than the estimate, but it could be
lower (NESCAUM, 1986).
Using the Global 82 model and the mice tumor data from the NTP study,
four dose-response curves were constructed for hepatocellular carcinoma in
male mice, hepatocellular adenoma or carcinoma in male mice, hepatocellular
carcinoma in female mice, and hepatocellular adenoma or carcinoma in female
mice. The chi-square test was applied to determine if the model provided a
reasonable fit to the experimental data in the observable range, and the fit
was found to be acceptable (NESCAUM, 1986).
The linearized multistage model (Global 82) provided an estimate of the
95 percent lower confidence level of the average daily dose associated with
a lifetime excess cancer risk in experimental animals of 1 x 10" lifetime.
These estimates were extrapolated to humans using a conversion factor based
on dose per unit surface area. The NESCAUM committee considered both dose
per unit body weight and dose per unit surface area as interspecies scaling
factors. The dose per unit body weight is based on the assumption that
organ weight, and hence, organ dose are better correlated with body weight
than surface area. The surface area relationship is based on the
proportionality between heat production and body surface area. As weight
increases in warm-blooded animals, the basal heat production per unit body
weight decreases. In other words, the smaller the animal, the faster its
basal metabolic rate (NESCAUM, 1986).
The National Academy of Sciences has noted that compounds are generally
distributed more slowly and tend to persist longer in larger mammals than in
smaller mammals (NRC, 1977). A 1985 EPA report concluded that chlorinated
hydrocarbons persist longer in larger mammals and that, based on pulmonary
excretion data, tetrachloroethylene may persist longer than any other
similar hydrocarbon. The same EPA study noted that tissue half-lives of
tetrachloroethylene appear to follow a surface area relationship
(EPA, 1985c). Another study that compared animal bioassay results with
human epidemiologic data concluded that either the dose per unit body weight
or the dose per unit surface area may be appropriate. The authors added
8-4
-------
that projections based on dose per unit body weight always generated the
lower estimate of human cancer risk and, in some cases, appeared to
underestimate the observed risk.
Taking these studies into consideration, the NESCAUM committee decided
to use the dose per unit surface area approach to interspecies conversion
because this approach is more conservative in the protection of public
health.
Specifically, animal doses were converted to human doses using the
following assumptions:
• body surface area can be expressed as a function of body weight
raised to the 2/3 power, and
t the average human weighs 70 kg and inhales 20 m air per day.
Using these assumptions, NESCAUM calculated the human exposure level
associated with a one-in-one million lifetime excess cancer risk using
various assumptions about the percent tetrachloroethylene metabolized in
mice and humans.
NESCAUM pointed out that it used what are typically regarded as
conservative assumptions. The committee explained that the reason for the
conservative approach stems both from the responsibility of the States to
protect public health and from the lack of adequate data to support any but
those assumptions most protective of public health. Other less conservative
assumptions, such as normalizing dose to body weight rather than surface
area or assuming a lower percentage of the exposure dose is metabolized,
would result in lower unit risk values than those estimated by NESCAUM
(NESCAUM, 1986).
The exposure levels associated with a risk of one-in-one million of an
additional cancer death over a 70-year period ranged from 0.01 ug/m to
0.1 ug/m , depending on the assumptions made about percent metabolism. The
absorption factor used was the same for human and rodents and was assumed to
be at least 70 percent and as high as 100 percent. Conversion of these
human exposure levels to unit risk factors (i.e., the upper bound estimate
of the additional probability that excess cancer risk will result from
8-5
-------
continuous lifetime inhalation exposure to 1 ug/m for a 70-year lifetime)
determines unit risk factors ranging from 1 x 10 to 1 x 10
(NESCAUM, 1986).
During the NESCAUM peer review process, one point raised was whether
100 percent metabolism was a fair estimate of the true dose a human would
receive. After reviewing available data, the Committee concluded that for
exposure to low concentrations, at least 70 percent of the ambient
tetrachloroethylene would be metabolized and possibly as much as
100 percent. Thus, ranges of unit cancer risk factors associated with these
levels of metabolism were presented (NESCAUM, 1986).
8.2.3 Exposure Assessment and Risk Characterization
The goals of the NESCAUM committee were to estimate an acceptable
ambient air concentration protective against adverse noncancerous health
effects and to calculate a unit cancer risk factor for tetrachloroethylene,
and thus, the NESCAUM work was completed after the dose-response assessment.
Since this report discusses the carcinogenic risk assessment process,
NESCAUM's derivative of an air concentration protective against: noncancerous
adverse health effects is not included. The NESCAUM member States are using
the results of the tetrachloroethylene study to formulate control options
for dry cleaners. New York, New Jersey, and Connecticut are in the process
of conducting exposure assessments.
8.3 RESOURCE REQUIREMENTS
Several academic disciplines were important to the NESCAUM air toxics
committee, including toxicology, inhalation toxicology, statistics,
epidemiology, molecular biology, physiology, and molecular physiology. In
its work on tetrachloroethylene, NESCAUM found that molecular physiology was
important because of the need to understand the metabolism of the compound.
Development of the unit cancer risk factor for tetrachloroethylene was
done by a team of ten people from the NESCAUM States, the EPA regional
office, and the NESCAUM staff. Each team member used an average of about
8-6
-------
60 hours for research and analytical work, bringing the total to 600 hours
plus additional time for team meetings. In addition, the NESCAUM staff
member spent about one-half person year on the project. Special resources
devoted to the project included a personal computer and the GLOBAL 82
multistage model software.
8.4 OTHER RISK ASSESSMENT WORK
Similar to the tetrachloroethylene project, NESCAUM will soon publish
results of a study on trichloroethylene and has begun a study of gasoline
vapors.
8.5 NESCAUM'S ADVICE TO OTHER AGENCIES
In evaluating their approach, NESCAUM reported two suggestions for
other agencies. The first was that, although a team of ten people
strengthened the final product, it was difficult for such a large group to
work on this type of project. The second suggestion was the importance of
using toxicity information that has been peer reviewed. It was their
experience that industry sometimes submits toxicity information that has
never been published or peer reviewed.
For additional information on NESCAUM's risk assessment work, readers
can contact Margaret Round, NESCAUM Toxics Coordinator, at (617) 367-8540.
8-7
-------
-------
9.0 CALIFORNIA DEPARTMENT OF HEALTH SERVICES
9.1 OBJECTIVES IN UNDERTAKING RISK ASSESSMENT
According to legislation passed in September 1983, the California Air
Resources Board (CARB) must identify and control toxic air contaminants.
The CARB begins the regulatory process by requesting the California
Department of Health Services (CDHS) to evaluate the health effects of and
to conduct a risk assessment for a candidate chemical or a class of
chemicals. The CARB simultaneously carries out an exposure assessment. The
CARB and CDHS assessments are reviewed by a Scientific Review Panel. If the
Panel finds that the joint report is scientifically adequate, CARB publishes
a report summarizing the findings with respect to whether the substance in
question should be designated as a toxic air contaminant, and, if so,
whether a safe threshold exposure level exists (NATICH, 1984). Where
applicable, the risk assessment will provide an estimate of the added
lifetime cancer risk (CARB, CDHS, April 1985). If CARB declares the
substance a toxic air contaminant, then the results of the risk assessment
are used in risk management decisions regarding recommended control
measures.
9.2 OVERVIEW OF METHODOLOGY USED
Section 9.0 is based on the "Guidelines of Chemical Carcinogen Risk
Assessments and Their Scientific Rationale," published by the California
Department of Health Services in November 1985 (CDHS, 1985), and on the risk
assessment for ethylene dibromide published in April 1985 (CARB,
CDHS, 1985). The guidelines were published by CDHS to clarify internal
procedures their staff usually uses in dealing with certain scientific
decision points characteristic of most risk assessments. The CDHS chose to
publish this information in the form of flexible nonregulatory guidelines
because the "scientific underpinnings of carcinogen risk assessment are
changing too quickly to attempt placing guidelines into law or regulation"
(CDHS, 1985).
9-1
-------
9.2.1 Hazard Identification
In general, CDHS uses the same criteria for evaluating the weight of
evidence of carcinogenicity as does the International Agency for Research on
Cancer (IARC). Specifically, CDHS uses the following ten guidelines for
carcinogen identification (CDHS, 1985):
1. Short-term tests can provide supportive evidence for
carcinogenicity, but will not be considered by themselves as
sufficient evidence.
2. Chemicals that have been shown to have sufficient evidence for
carcinogenicity in test animals will be considered as potential
human carcinogens.
3. Sufficient evidence for carcinogenicity in animals and sufficient
evidence for potential human carcinogenicity can be demonstrated
by positive evidence for carcinogenicity from properly conducted
bioassays in two species of animals or two separate bioassays,
preferably by different routes in the same species. The doses
used should be the maximum tolerated dose (MTD) and some fraction
thereof.
4. In animal bioassays, there must be a statistically significant
increase in the incidence of malignant tumors or a decrease in the
time to development of malignant tumors to constitute sufficient
evidence. In general, benign tumor causation augments the
evidence for carcinogenicity provided by malignant neoplasms.
5. When there is conflicting evidence in several animal bioassays,
the positive and negative results should be weighted by the
adequacy of the study design, the appropriateness of the species
tested, the pharmacokinetics of the species, and the statistical
power of the test. As a risk assessment policy, when choosing
between equally weighted evidence, positive evidence will be
chosen over negative evidence.
6. Assays for mutagenicity and the DNA adduct formation are
considered neither sufficiently reliable nor well enough
understood to influence the decision to list the substance as a
carcinogen, but such information can be used as supportive
evidence. The same is true for the distinction between an
initiator and a promoter. In other words, the distinction between
so called "genetic" and "epigenetic" carcinogens has no
implication for a chemical being listed as a carcinogen.
9-2
-------
7. Properly conducted epidemiological studies (this excludes
so-called "ecological studies" in which individual exposure status
is not recorded) can provide sufficient evidence to warrant
listing as a carcinogen. Unless sufficient evidence from
bioassays also exists, more than one positive epidemiological
study will usually be needed to warrant listing or regulatory
control.
8. A properly conducted epidemiological study with sufficiently long
follow-up, adequate exposure information, and sufficient
statistical power to rule out all but de minimus regulatory risk
could be used to declare a substance as not conveying significant
risk of human carcinogenesis. Such a substance would not be
listed as a carcinogen. It should be noted, however, that no
study or group of studies to date has had these properties. Thus,
for practical purposes, epidemiology can be used to "rule in" a
substance as a potential human carcinogen, but is unlikely to
"rule it out."
9. When there is conflicting evidence between epidemiological
studies, they should be weighted according to the adequacy of
design, length of follow-up, adequacy of exposure information, and
statistical power. As a risk assessment policy, when considering
positive and negative evidence of equal weight, the positive
evidence should be chosen for listing the substance as a
carcinogen.
10. Although minimum protocols and standards for the conduct of
carcinogenicity studies can be specified, scientific judgment is
still needed in the interpretation of results.
In 1985, the CDHS accepted as its list of carcinogens the list of
substances and processes considered by IARC to have sufficient evidence of
carcinogenicity in humans and/or animals. If and when the National
Toxicology Program (NTP) institutes a similar classification system which
rates the sufficiency of the total evidence pertaining to a chemical, CDHS
will add chemicals listed by NTP as having sufficient evidence of
carcinogenicity in animals and/or humans to the CDHS list. If a substance
not listed by NTP or IARC appears to be of sufficient concern in California,
CDHS would request that it be reviewed by NTP or IARC. If this cannot be
done in a timely way, CDHS will use the ten guidelines listed above to
determine if there is sufficient evidence to add the substance to the CDHS
list of carcinogens.
9-3
-------
Ethylene dlbromlde, the example discussed in Section 9.2.2, is listed
by IARC as having sufficient evidence of carcinogenicity in animals
(IARC, 1982).
9.2.2 Dose-Response Assessment
In its guidelines for chemical carcinogen risk assessments, CDHS sought
to develop a flexible dose-response assessment policy so that the Department
would have an algorithm to distinguish between very high, low, and negligible
risk; carry/ out calculations to determine whether a particular exposure is
actionable; develop regulatory standards; and establish simple potency
groupings to assist State agencies as they consider potency along with other
factors in order to set their priorities. To this end, the Department
outlined the following 13 guidelines for dose-response assessment
(CDHS, 1985):
1. Despite the imprecision of available methods, some attempts to
estimate the magnitude of carcinogenic risks to populations are
desirable to improve the basis for setting priorities and to
improve the basis for decision making.
2. Both animal and human data, when available, should be part of the
dose-response assessment and should be used as the basis for
setting regulatory limits and determining the need for action.
3. Development of the comprehensive risk assessment for final
regulatory review will be accompanied by an appropriate statement
of the degrees of mathematical and biological uncertainty.
4. Since neither animal nor cellular biological experiments afford
sufficient evidence of the existence or location of a carcinogenic
threshold, the CDHS will use nonthreshold models.
5. The CDHS will generally follow the algorithm in Figure 9-1 for
carrying out dose-response assessments based on animal bioassay
data. The Department will consider alternative approaches in the
public comment period during peer review of each risk assessment.
6. At present, the basis for distinguishing between "genetic" and
"epigenetic" carcinogens is not sufficiently secure to warrant
separate approaches to dose-response assessment.
9-4
-------
Animal
Bioassay Data
Data on
Competing Causes
of Death
i
Calculate Correction
for Competing Cause
of Death, if Data
Available (Life
Table Methods)
Pharmacokinetic
Data
I
Calculate Active Dose
at Target Site(s),
if Data Available
Time-to-
Tumor Data
Available?
Use Acceptable Time-
to-Tumor Models,
(e.g., Weibull, Time-
Dependent Multistage)
Use Acceptable Quantal
Response Models (e.g.,
Multistage [Crump],
Kodell Method)
I
Assume Dose
Additivity
Assume Dose
Additivity
I
Calculate:
1. Maximum Likelihood
Estimates
2. Upper Confidence
Value
Calculate:
Maximum Likelihood
Estimate
Upper Confidence
Value
Figure 9-1. CDHS Algorithm for Performing Dose-Response Assessments
9-5
-------
7. Pharmacokinetic data on metabolism of dosed substances, effective
'dose at target site, or species differences between laboratory
test animals and humans shall be considered in dose-response
assessments when they are available. When human pharmacokinetic
data are not available, the assumption is made that the human
response is the same as the animal response.
8. Because the dose of a regulated carcinogen may add to the doses
from other carcinogens acting by the same mechanisms, the CDHS
will recommend the use of the linearized 95 percent upper
confidence interval of risk as a dose-response assessment
guideline. Although the Department will provide risk managers
with a range of estimates including the Crump procedure for the
maximum likelihood estimate (MLE), the CDHS will consider
alternative estimates provided during the public comment period.
9. In scaling from animals to humans, the Department will use the
so-called surface area correction (correcting by the 2/3 power of
weight) unless specific evidence is available to the contrary.
10. For the purposes of prioritization carried out by control agencies
to decide the order in which substances should undergo full scale
risk assessment, it will be sufficient to carry out a simpler
procedure of grouping substances into defined high, medium, and
low potency groups based on existing risk assessments.
11. When exposure data from epidemiological studies are sufficient to
establish human dose-response curves, human data should be
included.
12. Properly conducted epidemiological studies that have sufficient
follow-up and that show no statistically significant carcinogenic
effect can be used to estimate the largest effect that is
consistent with the data (the 95 percent upper confidence
interval).
13. As California develops more experience in dose-response
assessment, the CDHS will welcome proposals to standardize
technical details where appropriate for the next revision of the
guidelines.
In its risk assessment for ethylene dibromide (EDB), CDHS assembled
information on the chemical properties of EDB, animal and human toxicology,
pharmacokinetics, animal and human reproductive effects and teratogenicity,
genotoxicity, and animal and human carcinogenicity. This review led to the
conclusion that at ambient levels of EDB found in urban environments in
California, systemic and reproductive effects are unlikely. However, CDHS
9-6
-------
noted that EDB is "a potent carcinogen in more than one animal species, and
could thus be of concern at low levels in the ambient air" (CARS,
CDHS, 1985).
The CDHS staff reviewed the one published epidemiological study of
161 workers. Although this study failed to show a statistically significant
increase in cancer rates, the study authors and CDHS agreed that the study
can neither rule out nor establish EDB as a human carcinogen because of the
small size of the population studied. CDHS agreed with lARC's conclusion
that there is sufficient evidence of carcinogenicity in animals. CDHS
recommended that EDB be considered potentially carcinogenic in humans. The
staff also concluded that there is no evidence to suggest that the
carcinogenicity of EDB would have a safe threshold (CARB, CDHS, 1985).
The CDHS staff based their risk assessment on nasal malignancies
(adenocarcinomas, carcinomas, and squamous cell carcinomas) in male rats and
hemangiosarcomas in female mice (CARB, CDHS, 1985). These data used in the
risk assessment were from two NCI bioassays:
1. an inhalation carcinogenesis bioassay for EDB in which male and
female rats and mice were exposed to 10 and 40 ppm of EOB for
periods from 78 to 103 weeks, and
2. a gavage study in which male and female rats were administered
levels of EDB in corn oil by stomach tube for several months.
The CDHS used three low-dose extrapolation models: the multistage, the
Wei bull-multi stage (a time-dependent multistage model), and the probit
model. The three models were executed using the Crump Global 79 program,
the Howe and Crump Wei bull 82 program and the Kovar and Krewski program
Risk 81, respectively (CARB, CDHS, 1985). Presently, the CDHS also includes
the maximum likelihood estimate and upper 95 percent confidence levels from
the gamma multi-hit and logit-models for low-dose risk assessment to provide
the risk managers with the range of variability due solely to the choice of
the extrapolation model.
The CDHS notes that considerations included in the choice of low-dose
extrapolation models are: simplicity, interpretability, biological
plausibility, sensitivity to differences in the observable range, and
9-7
-------
ability to take into account timing of exposure, latency periods, and
competing risks. The underlying principle behind the use of the multistage
model is its property of being linear at low doses. Additionally, it
provides more flexibility, relative to the one-hit model, in fitting
non-linearities in the observed data. The Wei bull-multi stage model has
these same properties as the simple multistage model and, in addition, it
incorporates a latency period and uses fully the data on survival times
which are available in the NCI carcinogenesis bioassays (CARB, CDHS, 1985).
The CDHS staff examined risk estimates for all three models for nasal
malignancies (a site of first contact in the NCI inhalation study of male
rats) and for hemangiosarcomas in the NCI study of female mice (a
remote-site cancer which appeared in both gavage and inhalation studies).
The results from the risk assessment are summarized in Table 9-1, expressed
as risk estimates for occupational exposure at 20 ppm and community exposure
at 1 ppb using the three low-dose extrapolation models selected by CDHS.
The CDHS recommended the use of an excess lifetime risk value between 102
and 553 per million for each 1 ppb EDB exposure. The CDHS noted that this
lifetime risk from EDB exposure should be viewed in the context of the
overall probability of developing cancer, which is on the order of
250,000 cases per million population (25 percent) over a 70-year lifetime
(CARB, CDHS, 1985). For regulatory considerations, CDHS recommended using a
risk value of 550 per million per 1 ppb EDB.
In discussing their risk estimates, CDHS emphasized that the range
between the maximum likelihood estimate and the 95 percent upper confidence
limit represents only the statistical uncertainty introduced by the
typically small size of the animal studies of carcinogenic effect. Other
important uncertainties are introduced by the choice of a scaling factor
between humans and animals, the choice of extrapolation models, and the
additive, synergistic, or antagonistic effects of other chemicals. The CDHS
noted that synergism was demonstrated between EDB and disulfiram, a
substance which interferes with EDB's metabolism. On the other hand, DNA
repair mechanisms, detoxifying enzymes, and other factors might lower the
risk below what has been calculated. These uncertainties are particularly
9-8
-------
TABLE 9-1. LIFETIME EXCESS CANCER RISK ESTIMATES
FOR ETHYLENE DIBROMIDE (EDB) EXPOSURE
Species/Tumor
Male Rats
Nasal Malignancies
Model
Wei bull -
Multistage
Multistage
Probit
UCLa/MLEb
95% UCL
MLE
95% UCL
MLE
95% UCL
MLE
20 ppm
Occupational
Exposure
985/1000
916/1000
708/1000
627/1000
721/1000
638/1000
1 ppb
Community
Exposure
553/million
285/million
315/million
253/million
51/million
4/mi 1 1 i on
Female Mice
Hemanigiosarcomas
Wei bull -
Multistage
Multistage
Probit
95% UCL
MLE
95% UCL
MLE
95% UCL
MLE
732/1000
549/1000
406/1000
328/1000
438/1000
357/1000
323/million
203/million
134/million
102/million
400/million
34/million
UCL - upper confidence limit
5MLE - maximum likelihood estimate
9-9
-------
to be noted in a case such as that of EDB where the ambient exposures are at
the low parts per trillion level, while the animal experiments occurred at
exposure levels more than ten thousand times higher (CARB, CDHS, 1985).
The CDHS staff compared their risk estimates with results from eight
other risk assessments. Results were similar with the exception of one
study in which CDHS disagreed with the use of combined tumor data from
several studies, a practice which CDHS staff believes dilutes the calculated
risk and is not the most conservative approach from a public health
standpoint.
9.2.3 Exposure Assessment
In a report to the scientific review panel on a specific chemical such
as EDB, the California Air Resources Board (CARB) prepares a review of the
uses, emissions, and public exposure to the particular chemical. The CARB
noted in its report that since EDB is not produced in California and since
nearly all EDB pesticide use is banned, the primary source of EDB emissions
in the State is leaded gasoline. (It is used as a lead scavenger.) The
CARB information on EDB emissions was taken primarily in 1983, prior to the
ban on EDB as a pesticide. Thus, CARB was unable to estimate exposures to
EDB. However, this type of data would be obtained during the risk
management phase of regulation as part of the development of control
measures (CARB, CDHS, 1985).
The CARB has estimated exposure to several other chemicals that have
gone through the toxic air contaminant review process (CARB, CDHS, 1984;
CARB, 1985; CARB, 1986a). In the report to the scientific review panel on
benzene for example, CARB explained how monitoring data on benzene
concentrations in the South Coast Air Basin were used with population data
to estimate the distribution of exposure versus the number of people
exposed. The CARB also estimated benzene concentrations from specific
sources to which people may be locally exposed (CARB, CDHS, 1984).
The CDHS "Guidelines for Chemical Carcinogen Risk Assessments and Their
Scientific Rationale" (CDHS, 1985) cover carcinogen identification and
dose-response assessment. The guidelines do not cover exposure assessment.
9-10
-------
9.2.4 CAPCOA Source Assessment Manual
The local air quality management districts perceive the need to
evaluate proposed projects prior to the full implementation of the State
process for identifying and regulating toxic air contaminants. The
California Air Pollution Control Officers Association (CAPCOA), CDHS, and
CARB, with funding and coordination from EPA Region IX, are working on
completing a source assessment manual for air pollution control districts.
Currently in draft form, the manual provides a step-by-step approach to
estimating and assessing the public health impacts of individual sources of
toxic air contaminants. The manual is intended to give guidance to air
pollution control districts and air quality management districts that must
review permit applications for new or modified sources of pollutants that
have not undergone the complete CARB and CDHS listing process, health
effects review, and study of possible control measures
(Engineering-Science, 1986).
The manual presents two levels of procedures: an iterative screening
technique using progressively more realistic exposure assumptions and a
methodology for a formal source assessment. The iterative screening level
analysis is based on simplified assumptions that ensure the protection of
public health and safety and is designed to simplify evaluation of
applications for permits. Formal assessment is required if the project does
not pass the screening analysis or if the APCD feels a more detailed
assessment is necessary (Engineering-Science, 1986). Both levels of
assessment are presented for description of emission rates, estimation of
ambient air concentrations, description of the exposed population,
estimation of exposure from noninhalation pathways, and assessment of health
risks.
The screening analysis for estimating ambient air concentrations uses
an approach that is very protective of public health, designed to result in
health-conservative estimates of concentrations around the facility. The
screening technique is only applicable to continuous, steady-state releases
that are either neutral or positively buoyant. A simple screening analysis
can be done by hand or a slightly more sophisticated screening analysis can
9-11
-------
be done using a microcomputer. The procedure yields a 1-hour groundlevel
concentration which is a worst-case scenario for screening purposes
(Engineering-Science, 1986).
The formal assessment of ambient concentrations relies on refined
estimates of the facility's impacts on ambient concentrations based on
actual meteorological data. The applicant must be familiar with EPA's
Guideline on Air Quality Models in order to select the most appropriate
dispersion model. After completion of the modeling effort, the manual
recommends that applicants submit the following results for both the
worst-plausible and most-plausible cases: (1) predicted concentration
(short-term and annual average) of each substance at each location
(population-weighted centroid of the smallest census division available),
(2) maximum short-term concentration of each substance at each location
within 2 km of the source where sensitive individuals are located, and
(3) monitored or modeled background concentrations and cumulative impacts
with other sources. The appropriate short-term averaging time would vary
depending on the type of releases and the health effects of concern
(Engineering-Science, 1986).
For the description of the exposed population, the screening analysis
presented in the manual recommends a qualitative description of the location
of the proposed facility. This includes a discussion of whether the area is
urban or rural, densely or sparsely populated, and industrial or
industrial/commercial.in nature. In addition, the manual recommends
identifying any sensitive receptor locations (e.g., schools, hospitals,
retirement communities) within 2 km of the point of maximum concentration.
For the screening assessment, the manual acknowledges that rough estimates
of the exposed population will often suffice. To quantify the inhabitants
within a specific distance, the manual recommends census data at the tract
level (census tracts contain about 4000 people). If the APCD feels it is
warranted, the applicant may also need to estimate the number of workers,
other than those employed at the proposed or modified facility, that would
be exposed. The manual points out that while there may only be a few nearby
residents, many workers may be exposed, especially in the case of industrial
parks (Engineering-Science, 1986).
9-12
-------
A formal assessment of population exposed requires that the applicant
provide a detailed analysis of both residents and off-site workers,
apportioning the populations into smaller geographic areas based on census
tracts (Engineering-Science, 1986).
The manual requires the calculation of the most-plausible and
worst-plausible cases for the excess lifetime carcinogenic risk, the excess
lifetime population cancer burden and the population-weighted excess
lifetime cancer risk for the formal risk assessments. The project
proponents will be encouraged, in the final version of the manual, to
provide the uncertainty associated with each of these six parameters. This
uncertainty in the risk estimates may be provided in either a probabilistic
format (e.g., Monte Carlo methods) or analytically (e.g., sensitivity
analysis) to give the risk managers and the general public an idea of the
potential range of these risks. Additionally, they will be encouraged to
identify and discuss those exposure assumptions that strongly affect the
risk assessment.
9.3 RISK MANAGEMENT
Under California air laws, after a pollutant has undergone a risk
assessment study by CARS and CDHS and has been identified as a toxic air
contaminant, the risk management process begins. Control measures are
investigated and, in cooperation with the APCDs and the public, CARB
prepares a report on the need and appropriate degree of regulation of the
particular contaminant. This was done, for example, for benzene in 1986
(CARB, 1986b). Following a public comment period and a public hearing, CARB
adopts control measures (NATICH, 1984). Sources of emissions determined to
have a biological threshold of action will be required to operate in a
manner that will ensure the threshold level will not be exceeded. For
contaminants with no identifiable threshold (i.e., carcinogens), control
measures must be designed to reduce emissions to the lowest level achievable
through the application of the best available control technology unless an
alternative level of emission reduction is adequate or necessary to prevent
adverse public health effects (NATICH, 1984).
9-13
-------
9.4 RESOURCES
On the CDHS staff, six people in the Air Unit of the Office of
Environmental Health Hazard Evaluation are currently involved in risk
assessment work with air toxics. These include experts in medicine,
toxicology, epidemiology, biostatistics, and law. The CDHS has done risk
assessments for several chemicals (see Sections 9.5 and 9.6) and the
estimated staff time has ranged from about 700 to 2000 person-hours per
chemical. The ethylene dibromide study was one of the shorter risk
assessments, taking an estimated 700 to 800 person-hours on the part of the
CDHS staff.
The CDHS has acquired most of the low-dose extrapolation models in
current use. Many of these models are run on the CDHS IBM mainframe
computer, while others (e.g., the multistage model) are run on personal
computers using the available packaged software programs.
9.5 OTHER RISK ASSESSMENT WORK
In addition to the work on toxic air contaminants, the Air Unit is
required by State law to review the health risk assessments for resource
recovery projects, including municipal waste incinerators, in order to help
local air districts decide whether the facilities will cause any significant
increase in illness or mortality. The unit also consults with local
agencies and individuals about actual or planned air releases of both
carcinogens and noncarcinogens, including potential catastrophic air
releases. Finally, the unit is responsible for review from the health
standpoint of ambient air standards for criteria pollutants such as ozone.
9.6 AIR TOXICS STATUS
The following chemicals for which CDHS, in conjunction with CARB, has
published risk assessments under the toxic air contaminants program, have
been declared to be toxic air contaminants: asbestos, benzene, cadmium and
cadmium compounds, chromium (Cr VI), dioxins and dibenzofurans, ethylene
9-14
-------
dibromide, and ethylene dichloride. As of May 1, 1987, the following
substances are in the process of assessment: arsenic, carbon tetrachloride,
ethylene oxide, methylene chloride, perch!oroethylene, trichloroethylene,
and vinyl chloride. Among the substances currently identified for future
risk assessment work are nickel, chloroform, acetaldehyde, acrylonitrile,
beryllium, 1,3-butadiene, coke-oven emissions, dialkyl-nitrosamines,
1,4-dioxane, epichlorohydrin, formaldehyde, inorganic lead, mercury,
n-nitrosomorpholine, PAHs, PCBs, and radionuclides.
For additional information on the CDHS risk assessment work with air
toxics, readers may contact Dr. James Collins at (415) 540-2669.
9-15
-------
10.0 MICHIGAN DEPARTMENT OF NATURAL RESOURCES
10.1 OBJECTIVES IN UNDERTAKING RISK ASSESSMENT
In Michigan, existing rules state that a person may not emit air
contaminants that cause "injurious effects to human health or safety, animal
life, plant life of significant value, or property." Permit applicants for
sources that would emit any pollutant identified as carcinogenic must plan
to equip that source with the best available control technology and either
show that controlled emissions will not be detectable in the stack by
specified sensitive sampling and analytical methods or, if the controlled
emissions are above the detection limit, show that the emissions are
"environmentally acceptable." The current method of choice for this
demonstration is risk assessment, calculating the lifetime carcinogenic risk
(Wurzel et al., 1984). The Air Quality Division first used risk assessment
in 1981 to evaluate the acceptability of emissions from a pigment
manufacturing plant (Simon, 1987b). Michigan's Department of Natural
Resources (DNR) does both chemical-specific and site-specific risk
assessments. The chemical-specific assessments result in unit risk factors
(Simon, 1986) and the site-specific assessments calculate expected
carcinogenic risk for a specific proposed facility (MDNR, 1986). Risk
assessments have not been mandated by the legislature, nor have specific air
toxics rules been promulgated.
10.2 GENERAL OVERVIEW OF METHODOLOGY USED
10.2.1 Hazard Identification
For the purposes of air use permit review, the DNR considers as
carcinogens "compounds which have sufficient data indicating carcinogenic
potential in animals and compounds which are known to cause an increased
risk of cancer in humans" (Wurzel et al., 1984). This classification is
10-1
-------
made based on review of available studies where the final results indicate a
carcinogenic potential, and the route of exposure and conditions of the
study are appropriate.
The Air Quality Division (AQD) of the MDNR does not have formal
guidelines or rules for carcinogen identification. In general, however, a
chemical will be considered carcinogenic and risk assessment used for
evaluating the emissions if the chemical causes an increased incidence of
benign or malignant neoplasms or a substantial decrease in the latency
period between exposure and onset of neoplasms through oral, dermal, or
inhalation exposure in at least one mammalian species, or man through
epidemiological and/or clinical studies (Simon, 1987b). This approach is
consistent with guidelines and rules adopted by MDNR for other environmental
protection programs. The MDNR has promulgated a rule defining "carcinogen"
in a similar manner in the Part 4 - Water Quality Standard which are rules
related to the discharge of chemicals to the waters of the State. In
addition, the draft criteria revisions of the Michigan Critical Materials
Register define sufficient evidence of carcinogenicity in a similar manner.
The DNR AQD recently developed a unit cancer risk factor for
3-chloro-2-methylpropene. A review of available literature revealed one
chronic animal study. In this study, 3-chloro-2-methylpropene was
administered by gavage to male and female rats and mice five days per week
for 103 weeks. The results showed an increased incidence of squamous cell
neoplasms in the forestomach of both male and female rats and mice. In
addition to the animal bioassay, several short-term mutagenicity tests have
been conducted for this compound. Positive results for mutagenicity have
been shown in four test systems. No human epidemiology studies were
available. Based on this information, the AQD proceeded with a
dose-response assessment (Simon, 1986).
Studies showing a chemical to be carcinogenic from the oral exposure
route will also be used in determining the carcinogenic potential by
inhalation, unless there are specific data that indicate the results seen
from exposure by one route are not appropriate to consider for other routes.
In the case of forestomach tumors in mice by oral exposure, the compound may
be acting directly at the site of application. Thus, exposure by inhalation
10-2
-------
may also produce tumors at the site of application (i.e., respiratory
system). In the case of 3-chloro-2-methylpropene, specific data were not
available that indicated the gavage route was inappropriate to consider for
inhalation exposure. Additionally, although there are some discrepancies in
the mutagenicity data, overall the data indicate that this compound is a
direct-acting mutagen. These data provide additional support that the
compound may produce tumors at the site of application when inhaled
(Simon, 1987b).
10.2.2 Dose-Response Assessment
The DNR acknowledges that "the estimation of risk and, conversely, the
estimation of 'essentially safe' exposures has always been a difficult
problem" mainly because the effects are determined on a relatively small
number of animals at high dose levels. These effects must be translated
into risk estimates for humans at much lower doses. For extrapolation of
test data to the low dose region of the dose-response curve, DNR has adopted
the linearized multistage model. The DNR notes that this model "has the
best, although limited, scientific basis of any of the current mathematical
extrapolation models," adding that risk assessments made with this model are
generally conservative and represent the most plausible upper limit for the
risk. In other words, the risk is not likely to be higher than the
estimate, but could be lower (Wurzel, 1984).
The DNR requires that animal bioassay data used in the model be from
studies that are "conducted with appropriate controls, at known exposure
levels, with sufficient survival to allow statistical analyses to be
completed, and a statistically significant increase in tumor incidence"
(Wurzel et al., 1984). Animal potencies are converted to human potency
values based on the relative surface area rule (see Section 3.0)
(Wurzel et al., 1984).
In the 3-chloro-2-methylpropene risk assessment, the linearized
multistage model (GLOBAL 82) was fit to the data from the gavage study
described above. Unit risk values were determined for male and female mice
and rats. Based on the estimate for male mice, DNR concluded that the unit
10-3
-------
risk value for humans is 3.83 x 10" (ug/m )" . Using this unit risk
factor, DNR estimated that the concentration of 3-chloro-2-methy'lpropene in
air resulting in an increased cancer risk of one in one million is
0.03 ug/m (Simon, 1986). Generally, the results from the animal species
providing the highest estimate of risk will be used to estimate the risks
for humans, since humans may be as sensitive as the most sensitive animal
species (Simon, 1987b).
10.2.3 Exposure Assessment
Wurzel (1984) explained the general approach used by DNR in the past
for exposure assessments by noting:
"The maximum annual ground level concentration should be determined by
a long term dispersion model and the maximum emission rate in pounds per
hour. It should be assumed the maximum emission rate occurs continuously
24 hours per day, 365 days per year, and that the estimated risk is for an
individual who remains at the maximum ground level concentration
continuously for 70 years and absorbs 100 percent of the inhaled compound
(inhaling 20 cubic meters of air per day)."
The DNR's AQD is currently reevaluating this methodology for
noncontinuous, less than lifetime emissions of carcinogenic compounds. As a
screening methodology, the AQD still feels the approach described in
Wurzel et al., 1984 is appropriate. However, in cases where the cancer risk
exceeds one in one million and the emissions are not representative of
continuous exposure, the AQD is attempting to provide an estimate of risk
more representative of the actual exposure situation. The design individual
for the exposure assessment is still a 70 kg person who inhales 20 cubic
meters of air per day (Simon, 1987b).
No exposure assessment was necessary for 3-chloro-2-methylpropene. A
carcinogenic potency value was determined for this compound because a permit
application was received from a company that would be emitting this
compound. It was assumed that the maximum emission rate would occur
continuously, and that a 70 kg person inhaling 20 cubic meters of air per
day would be exposed to the maximum ground level concentration (beyond the
10-4
-------
property line) for a lifetime. Under this exposure scenario, the estimated
risk was less than one in one million, so the emissions were considered
environmentally acceptable.
In the site-specific risk assessment for emissions from a proposed
municipal solid waste-to-energy facility, the AQD analyzed the risks
associated with the emissions of trace metals (cadmium, chromium, and
arsenic) and organics (dioxins and furans). The Division described this as
a "health-conservative analysis." Risk was measured in terms of the maximum
individual excess cancer risk or the individual's additional lifetime
probability of developing cancer due to emissions from the proposed
facility. The risk assessment was based on the assumption that a person
would be exposed to the maximum ambient concentration continuously for an
entire lifetime. The Division noted that the actual risk from the proposed
facility should not exceed this maximum calculated value and is likely to be
much lower (MDNR, 1986).
The AQD assumed that at low doses, carcinogenic risk increases linearly
with dose and that risk equals the exposure level, or dose, multiplied by
the potency. To estimate exposure level, the AQD used emission rates from
similar facilities controlled to a lesser degree than the proposed facility,
noting that such emissions estimates will result in a conservative risk
estimate. The emissions data for the metals were modeled using the Michigan
Long Term dispersion model to estimate the maximum annual ground level
concentration (MDNR, 1986).
The carcinogenic potency was determined for each chemical by a
mathematical extrapolation of animal or human test data. The DNR noted that
the extrapolation models used in this risk assessment provided a rough but
plausible estimate of the upper limit of risk. Table 10-1 lists the results
of this analysis (MDNR, 1986).
Estimation of carcinogenic risks from dioxins and furans was more
difficult due to the large number of compounds in these categories. Since
there is toxicity data for only a very small fraction of the total number of
compounds, the AQD chose an alternate approach to risk assessment. This
method, known as the toxic equivalency factor (TEF) approach, is widely
accepted for assessing risks from dioxins and furans. The TEF method is
10-5
-------
o
UJ
1-
^£
I-H
8
CO '-
CO VO
*f GO
o»
O rH
oe
to z
Z 0
o s.
HH ^"^
l-
CE Z
1- UJ
II
^£ *"~*
O O
^2
1 f_J
ill
> _J
UJ <.
_J rH
(—
a z
Z UJ
Q£ CL
tr
z o
^^ ^L»
~*
o
tJ -"
0 X
^^ 1*^
X
UJ
"(0 r- C
3 0) O
C > -r-
C fl> -P
< _| <0 *^
i- cn
•o -o -P E
vD C C \
•P 3 0) O>
U O U 3
T-
C Q) -P ^
< _j 10 on
E TO -p \
3 C C O)
E 3 CO 3
z c3
(O
U
U)
•r"
ly
•p
C
•p
C
5
3
*o
a.
"~i "I
0 0
in in
i i
0 0
rH rH
X X
rH rH
cn CT>
in cn
cn o
0 rH
*t in
1 1
0 O
rH rH
X X
O* vO
CM CM
•-H cn
rH 00
cn CM
i i
0 0
rH rH
X X
00
U)
-------
based on homologue groups of polychlorinated dibenzo-p-dioxins (PCDD) and
polychlorinated dibenzofurans (PCDF). There are eight homologue groups
based on the degree of chlorination (MDNR, 1986).
The Division explained that these homologues are then further divided
into two subgroups, one consisting of those isomers with chlorine atoms in
the 2,3,7, and 8 positions, and the other subgroup containing all other
isomers. The groups are then assigned a TEF which weighs the toxicity of
this group compared to the most toxic isomer, 2,3,7,8-TCDD. Table 10-2
lists the various TEFs for each group. The TEFs for those isomers having
chlorine atoms in the 2,3,7, and 8 positions are larger, since these are
believed to be the more toxic isomers. The concentration of each PCDD and
PCDF homologue subgroup is then multiplied by its corresponding TEF to
express the toxicity of each group in terms of "equivalent amount of
2,3,7,8-TCDD." The toxic equivalents for each group are then added up to
determine the total 2,3,7,8-TCDD toxic equivalents. This value is then
multiplied by the carcinogenic potency for 2,3,7,8-TCDD to determine the
total carcinogenic risk for the mixture of PCDDs and PCDFs (MDNR, 1986).
Homologue distributions used in this risk assessment were taken from a
compilation of literature sources. Using this emission data, the TEF
approach, and atmospheric dispersion modeling, it was determine that the
maximum ambient ground level concentration of PCDDs and PCDFs in
8 3
2,3,7,8-TCDD toxic equivalents was 2.42 x 10 ug/m . This concentration
was then multiplied by the carcinogenic potency for 2,3,7,8-TCDD to estimate
the excess cancer risk due to the PCDD and PCDF emissions. The resulting
risk is 1.1 in a million. Risks based on expected emission levels are
listed in Table 10-1 (MDNR, 1986).
10.2.4 'Risk Characterization
The risk assessment for the waste-to-energy facility (MDNR, 1986)
included some qualifying explanations that helped characterize the risks
presented. The assessment explained that only exposure via inhalation was
considered. Based on studies that have estimated percent of total risk
attributable to various routes of exposure, the AQD estimated that as a
10-7
-------
TABLE 10-2. TOXIC EQUIVALENCY FACTORS FOR PCDDs AND PCDFs (MDNR, 1986)
Compound
Toxic
Equivalency Factor
Mono through tri CDD
2,3,7,8-TCDD
Other TCDDs
2,3,7,8-PeCDDs
Other PeCDDs
2,3,7,8-HxCDDs
Other HxCDDs
2,3,7,8-HpCDDs
Other HpCDDs
OCDD
1
0.01
0.5
0.005
0.04
0.0004
0.001
0.00001
Mono through tri CDF
2,3,7,8-TCDFs
Other TCDFs
2,3,7,8-PeCDFs
Other PeCDFs
2,3,7,8-HxCDFs
Other HxCDFs
2,3,7,8-HpCDFs
Other HpCDFs
OCDF
0.1
0.001
0.1
0.001
0.01
0.0001
0.001
0.00001
10-8
-------
worse case, other routes of exposure could contribute 50 percent to total
risk. This would make the risk from all routes of exposure twice that
estimated for inhalation only (MDNR, 1986).
The AQD evaluated the significance of the risks by comparing risks from
the proposed facility to common risks people face everyday. This comparison
was included in the AQD report for the general public and others who were
not familiar with risk assessment to provide a better understanding of the
magnitude of the risk numbers for the waste-to-energy facility. These
comparisons included risk of death from motor vehicle accident, drowning,
and accidents in several sports as well as extrapolated cancer risks from
medical X-rays, smoking, peanut butter consumption (aflatoxin) and other
similar activities. From this comparison, the AQD concluded that people are
routinely exposed to risks which greatly exceed those expected from the
proposed facility (MDNR, 1986).
10.3 RISK MANAGEMENT
As mentioned in Section 10.1, the Michigan Air Pollution Control
Commission must verify "environmental acceptability" prior to granting a
permit to a facility that would emit a carcinogen. The Commission reviews
the lifetime carcinogenic risk and has, in the past, deemed emissions
"environmentally acceptable" if the estimated risk is less than one in
one million (Wurzel et al., 1984). Emissions resulting in a risk greater
than one in one million are considered on a case-by-case basis
(Simon, 1987b).
In evaluating the proposed waste-to-energy facility, the AQD determined
this facility would be using state-of-the-art combustion and control
equipment (dry acid gas scrubbers and fabric filter). Based upon all
considerations, the AQD determined the proposed facility would comply with
all applicable State and Federal air quality regulations, even though the
maximum estimated risk was slightly higher than one in one million
(Simon, 1987b).
10-9
-------
10.4 RESOURCE REQUIREMENTS
For risk assessment work, the Air Quality Division has found it
important to have toxicologists on their staff for low-dose extrapolation
analyses as well as dispersion modelers and engineers for estimating
emissions in exposure assessments. The time necessary to complete chemical -
or site-specific risk assessments such as those described in this section
varies with the amount of data that must be reviewed. Development of the
unit cancer risk factor for 3-chloro-2-methylpropene took about three days
on the part of one toxicologist. As for the waste-to-energy facility, much
more time was required. Prior to the specific permit application, a team of
two engineers and a toxicologist spent several months studying similar
facilities. The risk assessment done for the permit application took the
team plus a meteorologist for dispersion modeling* several weeks to complete.
The AQD currently uses the linearized multistage model GLOBAL 82 on
their mainframe computer. In addition, several common air dispersion models
are also used.
10.5 OTHER RISK ASSESSMENT WORK
Table 10-3 lists the pollutants that have been addressed by the
Division. The AQD has no plans or lists of chemicals for which they will be
doing risk assessments. Risk assessments are done on chemicals as the need
arises (e.g., a permit application is received for a compound for which no
previous risk assessment has been done).
10.6 ADVICE TO OTHER AGENCIES
In general, use of risk assessment provides a methodology for
evaluating the public health effects from the emissions of carcinogenic
compounds according to the AQD. With a technology based program, the
expected health impacts are not known, and regulators cannot be sure of
protecting public health. A technology based program may also result in the
use of additional control equipment when this is not necessary to protect
public health (Simon, 1987b).
10-10
-------
TABLE 10-3. MICHIGAN DIVISION OF AIR QUALITY CARCINOGENIC CHEMICALS
AND ASSOCIATED AIR CONCENTRATIONS RESULTING IN A
1 x 10'° CANCER RISK {SIMON, 1987a)
3
Chemical Concentration (ug/m )
Acrylonitrile 0.01
o-Anisidine hydrochloride 0.04
Arsenic 2.3E-04
Benzene 0.14
Benzo(a)pyrene 3.0E-04
Bis(2-chloroethyl)ether 0.003
1,3-Butadiene 0.003
Cadmium 5.6E-04
Carbon tetrachloride 0.04
Chlorodibromomethane 0.04
Chloroform 0.02
3-Chloro-2-methylpropene 0.03
l-Chloro-2-nitrobenzene 0.21
Chromium VI 8.3E-05
DDT 0.003
Dichlorobenzidine 0.002
Diethylhexyl phthalate 0.23
Dimethylvinyl chloride 0.008
1,4-Dioxane 0.18
Epichlorohydrin 0.8
Ethyl acrylate 0.07
Ethylene dichloride 0.09
Ethylene oxide 0.03
Formaldehyde 0.09
Hexachlorobenzene 0.002
Hydrazine 0.003
Methyl chloride 1.6
MBOCA 0.03
10-11
-------
TABLE 10-3. MICHIGAN DIVISION OF AIR QUALITY CARCINOGENIC CHEMICALS
AND ASSOCIATED AIR CONCENTRATIONS RESULTING IN A
1 x 10"5 CANCER RISK (SIMON, 1987a) (Continued)
Chemical Concentration (ug/m )
Methylene chloride 1
2-Naphthylamine 1.3E-04
PCB (Aroclor 1260) 0.001
Propylene oxide 1.6
2,3,7,8-TCDD 2.3E-08
1,1,1,2-Tetrachloroethane 0.07
1,1,2,2-Tetrachloroethane 0.02
Tetrachloroethylene 1.7
Toxaphene 0.003
TRIS 0.002
Vinyl chloride 0.4
2,6-Xylidine 0.78
Date of this revision: November 25, 1986 ,
Unit risk factor - 1 x 10 / concentration (ug/m )
Note; These values are subject to change. The chemicals found in this table
should not be considered an inclusive list of all chemicals considered
carcinogenic by the AQD. This table consists of chemicals that have
previously been reviewed by the AQD, and were considered carcinogenic at the
time of review. Absence of a chemical from this list does not necessarily
mean that chemical would be considered noncarcinogenic by the AQD. Chemicals
may be added to or deleted from this list as the data warrant. The 1 x 10"
cancer risk values listed in this table are not promulgated ambient air
quality standards, and are also subject to change.
The 1 x 10 cancer risk values listed in the table were determined under the
following conditions or assumptions:
1. A linear nonthreshold extrapolation model was used for each risk
assessment. The model used in most cases was the linearized multistage
model.
2. When extrapolating from animal data, doses were assumed to be equivalent
between animals and humans on a relative body surface area basis.
3. The 1 x 10 cancer risk values were calculated for a 70 kilogram person
who inhales 20 cubic meters of air per day.
4. Exposure was assumed to occur through direct inhalation only.
5. Exposure was assumed to occur for 24 hours per day, 7 days per week, for
a lifetime.
10-12
-------
The AQD stressed the need of having an adequate staff to do the
necessary analyses associated with risk assessment. Two of the problems now
facing the AQD are the need for good emissions data and the need for a
monitoring program to determine compliance with designated acceptable
ambient concentrations. A third concern is the designation of an acceptable
risk. It has been the AQD's experience that many members of the public want
no additional risk from toxic emissions, while others argue that the risks
posed by toxic sources are ridiculously low.
For more information on the risk assessment work undertaken by
Michigan's Air Quality Division, readers may contact Catherine Simon at
(517) 373-7023.
10-13
-------
11.0 CLARK COUNTY HEALTH DISTRICT
11.1 OBJECTIVES IN UNDERTAKING RISK ASSESSMENT
In early 1985, after reviewing EPA's 1984 draft report entitled "The
Magnitude and Nature of the Air Toxics Problem in the United States"
(EPA, 1984c), the Clark County Health District (the District) attempted to
address the magnitude and nature of the air toxics problem in Las Vegas.
The draft report estimated that perhaps 1,700 cancers per year nationwide
could be attributed to outdoor air pollution.
11.2 GENERAL OVERVIEW OF METHODOLOGY USED
11.2.1 Hazard Identification
Although, over 50 chemicals had been considered in the draft EPA
report, most of the risk was assigned to fewer than 10 chemical substances
(arsenic, asbestos, benzene, carbon tetrachloride, chloroform, chromium,
perchloroethylene, products of incomplete combustion). For these
substances, the District had some knowledge of their emissions and/or air
quality levels in the Las Vegas Valley. Most air quality measurements were
obtained from an established station in east central Las Vegas which has a
history of high CO and TSP levels, and from a station in the Southeast
Las Vegas Valley which had a history of high ozone levels and complaints of
chlorine odors and eye burning. The toxics data were derived from the
District's efforts to characterize urban haze and to develop specific
hydrocarbon profiles to support Emperical Kinetic Modeling Approach (EKMA)
ozone modeling exercises. The urban haze research provided short-term
(certain hours of the day) data for various metals and carbonaceous
material. Local topsoil was also analyzed to assess crustal contributions.
11-1
-------
11.2.2 Dose-Response Assessment
EPA's draft report included the unit risk factors obtained from CA6 and
others. In reviewing the unit risk factors obtained in the draft report,
the District staff observed that there was no unit risk factor for asbestos
and that the unit risk factor for products of incomplete combustion used a
factor based upon the amount of benzo(a)pyrene present.
For asbestos, the District obtained unit risk factors from the report
by the National Research Council (Committee on Non-Occupational Health
Risks) entitled "Asbestiform Fibers - Non-Occupational Risks." This report
contains risk factors based upon fibers per volume.
For products of incomplete combustion (PICs), the District assumed this
pollutant could be indicated as total carbon and analyzed by a thermal
oxidation technique. The District had an abundance of data for total carbon
particles in the Valley. However, these data were not compatible with risk
data using the specific benzo(a)pyrene substance. Two sources of
information were consulted to obtain a unit risk cancer factor. One was the
article entitled "Health Risks of Diesel Vehicles" published in
Environmental Science Technology. January 1984. This article derived a
range of lifetime unit risk factors of 30 to 60 additional lung cancer
deaths per microgram per cubic meter of particulate per million persons.
The article reviewed bioassay data from several types of fuel combustion and
the District determined that fireplace smoke, gasoline engine smoke, and
diesel soot could all have approximately the same unit risk factor.
Secondly, EPA published technical documentation in 1984 for its proposal to
limit diesel engine particulate emissions. The EPA estimated unit risk
factors ranging from 18 to 98 per microgram per cubic meter per million
persons. The District chose the narrower range of 30 to 60 for their risk
characterizations.
11.2.3 Exposure Assessment
The District used various techniques for estimating the annual average
concentration of each pollutant. The risk estimates assigned to asbestos,
perchloroethylene, and chromium were questionable because the District had
11-2
-------
limited ambient air data for these pollutants. In the case of asbestos, the
only data available were based upon samples analyzed by polarized light
microscopy. The preferred technique is transmission electron microscopy.
The chromium and other heavy metal concentrations were obtained from a haze
study which evaluated only fine particles associated with haze. The
analytical technique was X-ray fluorescence. Ambient levels of
perchloroethylene were estimated from the District's emissions inventory
data.
To determine average annual levels of most volatile organic compounds
and asbestos, the District set up sampling projects designed to sample once
every six days, 24 hours per day. For hydrocarbons, this project spanned a
12-month period from September 1985 to August 1986. Samples were analyzed
for hydrocarbons and chlorinated hydrocarbons by 6C-MS. The updated study
verified the earlier benzene and toluene estimates but revealed much lower
perchloroethylene levels.
Ten 24-hour asbestos samples were collected during the last 6 months of
1986. The results indicated that asbestos fibers were under the detection
limit of 1,000 fibers per cubic meter. This analysis verifies the presence
of non-asbestiform fibers which apparently accounted for higher numbers
reported earlier by the polarized light microscopy method.
Chromium and other metals were collected in a neighborhood with high CO
and woodsmoke and in the vicinity of a busy truckstop. Soils were also
sampled. The chromium levels were about double the detection limit. Levels
of arsenic, cadmium, and nickel were less than their detection limit. Use
of these detection limits in the risk assessment results in significant
upper bounds.
While these follow-up activities were underway, EPA published its final
results in the May 1985 Journal of the Air Pollution Control Association.
This report lowered the estimate of the national incidence of cancer from
1,700 to 1,300.
11.2.4 Risk Characterization
The District initially estimated average annual Valley-wide, levels for
11 chemical substances based on short-term data and multiplied these levels
times the unit risk factors to arrive at an annual cancer incidence per
11-3
-------
million persons in the Valley. Results of this compilation showed that
products of incomplete combustion, asbestos, benzene, perchloroethylene, and
chromium accounted for most of the incidence of nine cancers per million
people per year. This estimated total incidence compared favorably with the
estimate in EPA's draft report.
The District then refined estimates of annual averages of the chemical
substances of interest and recalculated the annual Valley-wide cancer
incidence. Table 11-1 lists the chemical substances, assumed unit risk
factors, the estimated average annual level, and the calculated annual
incidence per chemical. Totaling the chemicals, the District calculated
that the annual incidence is 4.3 to 9.4 cancers per million people per year.
The PICs have the largest incidence. The PICs are generated almost equally
by three sources: cars using leaded gasoline, diesel trucks and buses, and
wood burning fireplaces. Since these particles also impair visibility and
irritate sensitive persons, the District has endeavored to focus on the most
tangible component of PICs: urban haze.
11.3 ONGOING ACTIVITIES
The District has stressed that winter morning haze is caused by older
vehicles using leaded gasoline, vehicles using diesel fuel, and by persons
burning wood in their fireplaces. The staff has continuously monitored haze
with nephelometers at two Valley stations since late 1980. The intensity of
haze correlates well with the concentration of carbon monoxide. The
District has instituted a voluntary "no burn" program for those days when
the pollution index is unhealthy due to CO.
Air toxic regulations have been proposed to be incorporated with New
Source Review. A public hearing was scheduled for March 1987. BACT or LAER
is already required for all new sources emitting particles or VOC. The
District proposes that for 32 additional chemical substances, which are
classed as inorganic gases, BACT will be required for new sources.
Limits on ambient air increases (increments) for asbestos, ammonia,
chlorides, nitrates, and sulfates are also proposed. The asbestos limit
corresponds to the analytical limit of detection. The other limits
correspond to levels associated with visibility impairment.
11-4
-------
IH •
0 8~
S33
J 82
*J M
VI -
W -H <
x 363
85|~
M VI
-IDC
- _ (tOO
CO 3 5 «
S3 3 M
___ Sou
*~" < 84
uj f-. oo "S ° g
O) U « -4
2-* J 83
2 . 3-Sx1
zo 38 S!
_ _| M ft
>-
«/) «t
QC Z
LjlJ **•••*
0
z z c
B
O |B^ C! **
I— -i 5 9
u_=> Si3
O — I S « >.
1 BUD
UJO * 05
OQ. -jg^
uj of * g «
05 1° a
•— • «t 4J 0 •
CJ VI t» >
Z ^ « *
*^~ M n
~g M
_iS •*
«f ~>
c
Z 1—
1. 1 n
Q= -SS^
^° « ?8 S
<^ •» M vjtl
a? uj 3 • n. «
^ *** ft- A
« _j g e »
h- — i J J; o <
to < 3 s ^ w
^^ J! S3 S-
-i ft. X o
•-) M
. -X M W
M 58^
•^•1 1*4 ft
i *
i— i
»M
UJ
.J
GO
n "O o o co -*
O O O r-t O O O
«H
O
V
>O CN -4 O
.0
o o o o ** d
r- e* 5
O O O • O -4 .C
*J U *J 0 *J -4 4J
0 O 0 O «j «
f-l
"s "s
n M
u u
rH A J3
o on »-4
O O tO
t-4
^^
VI
U
IH
a.
VI
•
^i
o «
-4 C
U V
u -I e
« X -5
0. V X -1
T) 4J 14
C (y « 0
O A O *H
S -4 « « MX
3 H
11-5
-------
11.4 RESOURCE REQUIREMENTS
The Clark County analysis was done by the Air Pollution Control
Division staff members with engineering and chemistry backgrounds. The work
requiring toxicological expertise (e.g., development of unit cancer risk
factors) was done by EPA and presented in the EPA report used by Clark
County. The analysis performed by the Division took about two person-weeks
and did not require any special computer resources.
11.5 ADVICE TO OTHER AGENCIES
The main advice the Division stressed to other agencies is the
importance of using all available air quality studies to assess the impact
of toxic emissions. For instance, the Division used data from a number of
studies including studies on particulate matter and benzene emissions. The
Division noted that since the unit cancer risk factors developed by CAG and
listed in the EPA report are conservative estimates, it was not necessary
that emission estimates be highly precise. Combining the information in the
EPA report with existing Clark County data was easy to do in-house because
it required no new research and was of sufficient accuracy.
For more information, please contact Michael Naylor, Clark County
Health District, Air Pollution Control Division, at (702) 383-1276.
11-6
-------
GLOSSARY
adenoma; a benign tumor of a glandular structure or glandular origin.
aneuploidv: the condition in which the chromosome number is not an exact
multiple of the usual haploid number.
benign tumor; not malignant; remaining localized in the territory in which
it arises.
bioassav; a test in living organisms. As used in this report, a test for
carcinogenicity in laboratory animals, generally rats and mice, which
include a near-lifelong exposure to the agent under test.
cancer; a group of diseases characterized by uncontrolled growth of body
cells leading to formation of malignant tumors that tend to grow rapidly and
spread.
carcinogen: an agent capable of inducing a cancer response.
carcinoma: a malignant tumor of epithelial origin (skin, lung, breast).
case-control studv: an epidemiological study in which individuals with the
disease under study (cases) are compared to individuals without the disease
(controls).
chi-sauare test: a test for significant differences between a binomial
population and a multinomial population, where each observation may fall
into one of several classes. The test furnishes a comparison among several
samples instead of just two.
G-l
-------
cohort study; an epidemiological study in which a group of people, a
cohort, is studied over time after exposure to a substance or a personal
attribute or behavior. The group is considered initially free of the
disease under study.
confidence limit; an endpoint of a confidence interval. Confidence
interval is that interval which has a specified probability of containing a
given parameter or characteristic.
diploid; having two sets of chromosomes as found in somatic cells.
dose-response curve; the graphic presentation of the relationship between
the amount of an agent either administered, absorbed, or believed to be
effective and the response of the biological system to that agent. Dose is
plotted on the x-axis and response on the y-axis.
electrophilic (substance); that which accepts an electron pair from another
molecule.
epidemiology; the study of the incidence, distribution and control of a
disease within a population.
eoiqenetic carcinogen; a carcinogen that does not directly involve
interaction with DMA.
foci; the starting point of a disease process.
genetic carcinogen; a substance which exerts its carcinogenic action
through interaction with or affecting of genetic material (DNA).
genome; one haploid set of chromosomes with the genes they contain.
goodness-of-fit; the degree to which the observed frequencies of occurrence
of events in an experiment correspond to the probabilities in a model of the
experiment.
G-2
-------
haploid: possessing half the diploid or normal number of chromosomes found
in somatic or body cells.
hemangiosarcoma: a malignant tumor composed of anaplastic endothelial
cells.
histoqenic origin: the germ cell layer of the embryo from which the adult
tissue developed.
human equivalent dose; the human dose of an agent which is believed to
induce the same magnitude of toxic effect that the known animal dose has
induced.
hvdrophilic: of, relating to, or having a strong affinity for water.
hvperplasia: an abnormal or unusual increase in the elements composing a
part (as tissue cells).
immune system; the apparatus by which a living organism resists and
overcomes disease.
initiator; an agent with the ability to induce a change in a tissue which
leads to the induction of tumors after a second agent, called a promoter, is
administered to the tissue repeatedly.
leukemia; any of several of the diseases of the hematopoietic system
characterized by the uncontrolled proliferation of leukocytes.
linearized multistage model procedure; a sequence of steps in which the
multistage model is fit to the tumor incidence data; the maximum linear term
consistent with the data is calculated; the low dose of the dose-response
function equated to the coefficient of the maximum linear term; the slope is
equated to the upper bound of potency.
G-3
-------
llpoDhilic: having an affinity for fats.
lymphoma; any neoplasm, usually malignant, of the lymphoid tissues.
malignant tumor: a tumor that has invaded neighboring tissue and/or
undergone metastasis to distant body sites, at which point the tumor is
called a cancer and is beyond the reach of local surgery.
maximum likelihood estimate: estimate of a value obtained using a
statistical technique where the likelihood distribution is maximized
(finding the largest value of a function is maximizing it).
metaplasia; conversion of one kind of tissue into a form which is not
normal for that tissue.
metastasis: movement of body cells (e.g., cancer cells) from one part of
the body to another.
metastasize: to invade by metastasis.
mutagen; a chemical or physical agent that interacts with DNA to cause a
permanent, transmissible change in the genetic material of a cell.
mutation; an abrupt change in the genotype of an organism, not resulting
from recombination; genetic material may undergo alteration or
rearrangement.
neoplasm: a new growth of tissue in which growth is uncontrolled and
progressive; a tumor.
95 percent upper confidence limit: confidence limit which states that the
value in question has a 5 percent probability of exceeding the true value.
nucleophilic: having an affinity for atomic nuclei, electron-donating.
G-4
-------
oncogene: naturally occurring genes that code for factors that regulate
cell growth.
oharmacokinetlcs: quantitative study of the metabolic processes of
absorption, distribution, biotransformation, and elimination.
promoter: agent that has very weak or no carcinogenicity by itself, but
enhances carcinogenic response when applied after a dose of an initiator.
g,: the 95 percent upper limit of the risk estimate; the upper bound slope
parameter as determined by the multistage procedure.
sarcoma: a malignant tumor arising in connective tissue and composed
primarily of anaplastic cells that resemble those of supportive tissues.
sister chromatid exchange: an exchange at one locus between the paired
strands of a chromosome which does not result in an alteration of overall
chromosome morphology. The observation of sister chromatid exchanges
induced by chemicals is one of the quickest, easiest, and most sensitive
tests for genetic damage.
squamous cell carcinoma: a carcinoma composed of anaplastic squamous
epithelial cells.
squamous metaplasia: transformation to a squamous form.
standards mortality odds ratio: compares the number of deaths from the
cause at interest to the number of deaths from auxiliary causes in the
exposed population (the odds) to the expected odds derived from a
comparison population.
statistical power: the probability of not overlooking an excess risk.
threshold: the minimum level of a stimulus that will evoke a response.
G-5
-------
translocation: the transfer of a chromosome segment from its usual position
to a new position in the same or different chromosome.
unit cancer risk factor: the incremental upper bound lifetime risk
estimated to result from a lifetime exposure to an agent if it is in the air
at a concentration of 1 ug/m or in the water at a concentration of 1 ug/1.
G-6
-------
REFERENCES
Anderson, E. L. and Carcinogen Assessment Group. Quantitative Approaches in
Use to Assess Cancer Risk. Risk Anal. 3:277-295. 1983.
Armitage, P. and R. Doll. Stochastic Models for Carcinogenesis. (In)
L. Lecam and J. Neyman, eds. Proceedings of the Fourth Berkeley Symposium
on Mathematical Statistics and Probability. University of California Press.
4:19-38. 1961.
Beaumont, James J. and Norman E. Breslow. Power Considerations in
Epidemiologic Studies of Vinyl Chloride Workers. American Journal of
Epidemiology. Vol. 114, No. 5. 1981.
Becker, F. F. Recent Concepts of Initiation and Promotion in
Carcinogenesis. American Journal of Pathology. 105:3-9. 1981.
Brown, C. C. et al. Models for Carcinogenic Risk Assessment. Science.
202:1105. 1978.
Brown, Charles C. High Dose to Low Dose Extrapolation in Animals.
Presented at the American Chemical Socity Symposium on Assessing Health
Risks from Chemicals. Kansas City, Kansas. September 1982.
California Air Resources Board and California Department of Health Services.
Report to the Scientific Review Panel on Benzene. Sacramento, California.
November 1984.
California Air Resources Board and California Department of Health Services.
Report on Ethylene Dibromide to the Scientific Review Panel. Sacramento,
California. April 1985.
California Department of Health Services. Guidelines for Chemical
Carcinogen Risk Assessments and Their Scientific Rationale. Sacramento,
California. November 1985.
California Air Resources Board. Staff Report: Initial Statement of Reasons
for Proposed Rulemaking - Public Hearing to Consider the Adoption of a
Regulatory Amendment Identify!nng Chromium as a Toxic Air Contaminant.
Sacramento, California. December 1985.
California Air Resources Board. Staff Report: Proposed Benzene Control
Plan. Sacramento, California. May 1986b.
California Air Resources Board. Staff Report: Initial Statement of Reasons
for Proposed Rulemaking - Public Hearing to Consider the Adoption of a
Regulatory Amendment Identifying Cadmium as a Toxic Air Contaminant.
Sacramento, California. December 1986a.
R-l
-------
Crump, K. S., H. A. Guess, and L. L. Deal. Confidence Intervals and Test
of Hypotheses Concerning Dose-Response Relations Inferred from Animal
Carcinogenicity Data. Biometrics. 33:437-451. 1977.
Davis, Dervra Lee, Barbara Mandula, and John Van Ryzin. Assessing the Power
and Quality of Epidemiologic Studies of Asbestos - Exposed Populations.
Toxicology and Industrial Health. Vol. 1, No. 4. 1985.
Doll, R. Weibull Distribution of Cancer. Implications for Models of
Carcinogenesis. J. R. Stat. Soc. A13:133-166. 1971.
Engineering-Science. Volumes 1 and 2: Air Toxics Source Assessment Manual
for California Air Pollution Control Districts (Public Review Draft).
Berkeley, California. October 8, 1986.
Farber, E. and R. Cameron. The Sequential Analysis of Cancer Development.
Adv. Cancer Res. 31:125-226. 1980.
Farber, E. Sequential Events in Chemical Carcinogenesis. (In) Cancer: A
Comprehensive Treatise, 2nd Edition. Volume 1 Etiology: Chemical and
Physical Carcinogenesis. F. F. Becker, ed. Plenum Press, New York. 1982.
Hayes, A. W. (editor) Principles and Methods of Toxicology. Raven Press,
New York. 1982.
International Agency for Research on Cancer. IARC Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Humans. Volumes 1 and
2, Supplement 4. World Health Organization. Lyon, France. October 1982.
International Agency for Research on Cancer. IARC Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Humans. Volume 34.
Lyon, France. June 1984.
Kellam, Robert G. Memorandum to Robert E. Rosensteel. Results of Exposure
and Cancer Risk Analyses for EDC Production Facilities. November 28, 1986.
Klassen, C. D., M. 0. Amdur, and J. Doull. Casareth and Doull's Toxicology;
The Basic Science of Poisons. Third Edition. MacMillian Publishing
Company, New York. 1986.
Krewski, D. and C. Brown. Carcinogenic Risk Assessment: A Guide to the
Literature. Biometrics 37, 353-366. June 1, 1981.
MacMahon, B. and T. Pugh. Epidemiology Principles and Methods. Little,
Brown, and Company. Boston, Massachusetts. 1970.
McGaughy, Robert E. Appendix B: EPA Approach for Assessing the Risk of
Environmental Carcinogens. Draft. Carcinogen Assessment Group. U. S.
Environmental. Protection Agency. Washington, D.C. 1986.
R-2
-------
Michigan Department of Natural Resources. Staff Activity Report - Permit to
Install Application No. 451-85. MDNR, Air Quality Division. Lansing,
Michigan. March 18, 1986.
National Air Toxics Information Clearinghouse. National Air Toxics
Information Clearinghouse Newsletter. U. S. Environmental Protection
Agency. Office of Air Quality Planning and Standards. Research
Triangle Park, North Carolina. December 1984.
National Air Toxics Information Clearinghouse. National Air Toxics
Information Clearinghouse Newsletter. U. S. Environmental Protection
Agency. Office of Air Quality Planning and Standards. Research
Triangle Park, North Carolina. December 1985.
National Air Toxics Information Clearinghouse. Methods for Pollutant
Selection and Prioritization. U. S. Environmental Protection Agency.
Office of Air Quality Planning and Standards. Research Triangle Park, North
Carolina. July 1986a.
National Air Toxics Information Clearinghouse. NATICH Data Base Report on
State and Local Agency Air Toxics Activities. Volume 1. Office of Air
Quality Planning and Standards. U. S. Environmental Protection Agency.
Research Triangle Park, North Carolina. July 1986b.
National Research Council. Risk Assessment in the Federal Government:
Managing the Process. Committee on the Institutional Means for Assessment
of Risks to Public Health. National Research Council. Washington, D.C.
1983.
National Research Council, Safe Drinking Water Committee. Drinking Water
and Health. Volume 1. National Academy Press. Washington, D.C. 1977.
National Research Council, Safe Drinking Water Committee. Drinking Water
and Health. Volume 3. National Academy Press. Washingotn, D.C. 1980.
National Research Council, Safe Drinking Water Committee. Drinking Water
and Health. Volume 6. National Academy Press. Washington, D.C. 1986.
Naylor, M. H. Personal Communication with Alice Pelland, Radian
Corporation. February 1987.
Northeast States of Coordinated Air Use Management (NESCAUM). NESCAUM
Regional Health Evaluation Document for Tetrachloroethylene. NESCAUM Air
Toxics Committee. Boston, Massachusetts. 1986.
Office of Pesticides and Toxic Substances (OPTS). GAMS User's Guide -
Incomplete Draft. U. S. Environmental Protection Agency. Washington, D.C.
August 1985.
Office of Pesticides and Toxic Substances (OPTS). Draft Graphical Exposure
Modeling System (GEMS) User's Guide. Volume 1, Core Manual. U. S.
Environmental Protection Agency. Washington, D.C. April 24, 1986.
R-3
-------
Office of Science and Technology Policy (OSTP), Executive Office of the
President. Chemical Carcinogens; A Review of the Science and Its Associated
Principles. February 1985. Washington, D.C. 50 JFR 10372. March 14, 1985.
Office of.Technology Assessment (OTA). Assessment of Technologies for
Determining Cancer Risks from the Environment. Congress of the United
States. Washington, D.C. June 1981.
Park, C. N. and R. D. Snee. Quantitative Risk Assessment: State-of-the-Art
for Carcinogenesis. 1983.
Pike, M. C. A Method of Analysis of a Certain Class of Experiments in
Carcinogenesis. Biometrics. 22:142-162. 1966.
Simon, C. A. Risk Assessment for 3-Chloro-2-Methylpropene. Memorandum to
file. Michigan Department of Natural Resources. Lansing, Michigan.
September 25, 1986.
Simon, C. A. Personal Communication with Alice Pelland, Radian Corporation.
January 6, 1987a.
Simon, C. A. Personal Communication with Alice Pelland, Radian Corporation.
February 17, 1987b.
Slaga, T. J., A. J. P. Klein-Szanto, S. M. Fischer, C. E. Weeks, K. Nelson,
and S. Major. Studies on Mechanism of Action of Anti-Tumor-Promoting
Agents: Their Specificity in Two-Stage Promotion. Proceedings of the
National Academy of Science. USA. 77:2251-2254. 1980.
U. S. Environmental Protection Agency. Air Quality Criteria for Particulate
Matter and Sulfur Oxides - Volume III. EPA 600/8-82-029c. Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office.
Research Triangle Park, North Carolina. 1982.
U. S. Environmental Protection Agency. Health Assessment Document for
Acrylonitrile. Final Report. EPA 600/8-82-007f. Office of Health and
Environmental Assessment. Research Triangle Park, North Carolina. 1983.
U. S. Environmental Protection Agency. Risk Assessment and Management:
Framework for Decision Making. EPA 600/9-85-002. December 1984a.
U. S. Environmental Protection Agency. Health Assessment Document for
Epichlorohydrin, Final Report. EPA 600/8-83-032f. Office of Health and
Environmental Assessment. Research Triangle Park, North Carolina. 1984b.
U. S. Environmental Protection Agency. The Magnitude and Nature of the Air
Toxics Problem in the United States, Draft Report. Office of Air and
Radiation. Washington, D.C. 1984c.
U. S. Environmental Protection Agency. Health Assessment Document for
Nickel. EPA 600/8-83-012f. Office of Health and Environmental Assessment.
Research Triangle Park, North Carolina. 1985a.
R-4
-------
U. S. Environmental Protection Agency. Mutagenicity and Carcinogenicity
Assessment of 1,3-Butadiene. EPA 600/8-85-004f. Office of Health and
Environmental Assessment. Washington, D.C. September 1985b.
U. S. Environmental Protection Agency. Final Health Assessment Document for
Tetrachloroethylene (Perchloroethylene). EPA 600/8-82-005b. Office of
Health and Environmental Assessment. Washington, D.C. 1985c.
U. S. Environmental Protection Agency. Health Assessment Document for
Dichloromethane. EPA 600/8-82-004f. Office of Health and Environmental
Assessment. Research Triangle Park, North Carolina. February 1985d.
U. S. Environmental Protection Agency. User's Manual for the Human Exposure
Model. Office of Air Quality Planning and Standards. Research Triangle
Park, North Carolina. 1986a.
U. S. Environmental Protection Agency. Guidelines for Carcinogen Risk
Assessment. Carcinogen Assessment Group, Office of Health and Environmental
Assessment. Washington, D.C. 51 JF.R 33992. September 24, 1986b.
U. S. Environmental Protection Agency. Guidelines for the Health Risk
Assessment of Chemical Mixtures. Environment of Criteria and Assessment
Office. Cincinnati, Ohio. 51 FR 34014. September 24, 1986c.
U. S. Environmental Protection Agency. Guidelines for Estimating Exposures.
Exposure Assessment Group, Office of Health and Environmental Assessment.
Washington, D.C. 51 £E 34042. September 24, 1986d.
U. S. Environmental Protection Agency. Air Quality Criteria for Ozone and
Other Photochemical Oxidants. EPA 600/8-84-020DF. Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office.
Research Triangle Park, North Carolina. 1986e.
U. S. Environmental Protection Agency. Interim Procedures for Estimating
Risks Associated with Exposure to Mixtures of Chlorinated Dibenzo-p-Dioxins
and Dibenzofurans (CDDs and CDFs). EPA 625/3-87-012. March 1987.
U. S. Environmental Protection Agency. Memorandum from S. Bayard (CAG) to
J. Blancato (EAG) through W. Farland (CAG). 13 pp. Undated.
Weinstein, I. B., S. Gattoni-Celli, P. Kirschmeier, M. Lambert, W. Hsiao,
J. Backer, and A. Jeffrey. Multistage Carcinogenesis Involves Multiple
Genes and Multiple Mechanisms. Pp. 229-237 in A. J. Levine, G. F. Vande
Woude, W. C. Topp, and J. D. Watson, eds. Cancer Cells. 1. The
Transformed Phenotype. Cold Spring Harbor Laboratory. Cold Spring Harbor,
New York. 1984.
Weinstein, I. B. The Relevance of Tumor Promotion and Multistage
Carcinogenesis to Risk Assessment. (In) Banbury Report 19: Risk
Quantitation and Regulatory Policy. D. G. Hoel, R. A. Merrill, and
F. P. Perera, eds. Cold Spring Harbor Laboratory. Cold Spring Harbor,
New York. 1985.
R-5
-------
Whittemore, A. and J. B. Keller. Quantitative Theories of Carcinogenesis.
SAIAM Review. 20(1):1-30. 1978.
Wurzel, K. A., 6. L. Avery, and D. J. Brandt. Technical Methods for
Determining if the Emission of a Non-Criteria Pollutant May Cause Injurious
Effect to Human Health or Safety. Michigan Department of Natural Resources.
Air Quality Division. Lansing, Michigan. January 1984.
R-6
-------
APPENDIX A
EPA GUIDELINES FOR CARCINOGEN RISK ASSESSMENT
-------
51FR 33992
GUIDELINES FOR CARCINOGEN RISK
ASSESSMENT
SUMMARY:On September 24, 1986, the U.S.
Environmental Protection Agency issued the
following five guidelines for assessing the health
risks of environmental pollutants.
Guidelines for Carcinogen Risk Assessment
Guidelines for Estimating Exposures
Guidelines for Mutagenicity Risk Assessment
Guidelines for the Health Assessment of Suspect
Developmental Toxicants
Guidelines for the Health Risk Assessment of
Chemical Mixtures
This section contains the Guidelines for Carcinogen
Risk Assessment
The Guidelines for Carcinogen Risk Assessment
(hereafter "Guidelines") are intended to guide
Agency evaluation of suspect carcinogens in line
with the policies and procedures established in the
statutes administered by the EPA. These Guidelines
were developed as part of an interoffice guidelines
development program under the auspices of the
Office of Health and Environmental Assessment
(OHEA) in the Agency's Office of Research and
Development. They reflect Agency consideration of
public and Science Advisory Board (SAB) comments
on the Proposed Guidelines for Carcinogen Risk
Assessment published November 23, 1984 (49 FR
46294).
This publication completes the first round of risk
assessment guidelines development. These
Guidelines will be revised, and new guidelines will
be developed, as appropriate.
FOR FURTHER INFORMATION CONTACT:
Dr. Robert E. McGaughy
Carcinogen Assessment Group
Office of Health and Environmental Assessment
(RD-689)
401 M Street, S.W.
Washington, DC 20460
202-382-5898
SUPPLEMENTARY INFORMATION: In 1983,
the National Academy of Sciences (NAS) published
its book entitled Risk Attettment in the Federal
Government: Managing the Protest. In that book,
the NAS recommended that Federal regulatory
agencies establish "inference guidelines" to ensure
consistency and technical quality in risk
assessments and to ensure that the risk assessment
process was maintained as a scientific effort
separate from risk management A task force within^
EPA accepted that recommendation and requested"
that Agency scientists begin to develop such
guidelines.
General
The guidelines are products of a two-year
Agencywide effort, which has included many
scientists from the larger scientific community.
These guidelines set forth principles and procedures
to guide EPA scientists in the conduct of Agency risk
assessments, and to inform Agency decision makers
and the public about these procedures. In particular,
the guidelines emphasize that risk assessments will
be conducted on a case-by-case basis, giving full
consideration to all relevant scientific information.
This case-by-case approach means that Agency
experts review the scientific information on each
agent and use the most scientifically appropriate
interpretation to assess risk. The guidelines also
stress that this information will be fully presented
in Agency risk assessment documents, and that
'Agency scientists will identify the strengths and
weaknesses of each assessment by describing
uncertainties, assumptions, and limitations, as well
as the scientific basis and rationale for each
assessment
Finally, the guidelines are formulated in part to
bridge gaps in risk assessment methodology and
data. By identifying these gaps and the importance
of the missing information to the risk assessment
process, EPA wishes to encourage research and
analysis that will lead to new risk assessment
methods and data.
Guidelines for Carcinogen Risk Assessment
Work on the Guidelines for Carcinogen Risk
Assessment began in January 1984. Draft
guidelines were developed by Agency work groups
composed of expert scientists from throughout the
Agency. The drafts were peer-reviewed by expert
scientists in the field of carcinogenesis from
universities, environmental groups, industry, labor,
and other governmental agencies. They were then
proposed for public comment in the FEDERAL
REGISTER (49 FR 46294). On November 9, 1984,
the Administrator directed that Agency offices use
the proposed guidelines in performing risk
assessments until final guidelines become available.
A-l
-------
After the close of the public comment period,
Agency staff prepared summaries of the comments,
analyses of the major issues presented by the
commentors, and proposed changes in the language
of the guidelines to deal with the issues raised.
These analyses were presented to review panels of
the SAB on March 4 and April 22-23, 1985, and to
the Executive Committee of the SAB on April 25-26,
1985. The SAB meetings were announced in the
FEDERAL REGISTER as follows: February 12,
1985 (50 PR 5811) and April 4, 1985 (50 PR 13420
and 13421).
In a letter to the Administrator dated June 19,
1985, the Executive Committee generally concurred
on all five of the guidelines, but recommended
certain revisions, and requested that any revised
guidelines be submitted to the appropriate SAB
review panel chairman for review and concurrence
on behalf of the Executive Committee. As described
in the responses to comments (see Part B: Response
to the Public and Science Advisory Board
Comments), each guidelines document was revised,
where appropriate, consistent with the SAB
recommendations, and revised draft guidelines were
submitted to the panel chairmen. Revised draft
Guidelines for Carcinogen Risk Assessment were
concurred on in a letter dated February 7, 1986.
Copies of the letters are available at the Public
Information Reference Unit, EPA Headquarters
Library, as indicated elsewhere in this section.
Following this Preamble are two parts: Part A
contains the Guidelines and Part B, the Response to
the Public and Science Advisory Board Comments (a
summary of the major public comments, SAB
comments, and Agency responses to those
comments).
The Agency is continuing to study the risk
assessment issues raised in the guidelines and will
revise these Guidelines in line with new information
as appropriate.
References, supporting documents, and
comments received on the proposed guidelines, as
well as copies of the final guidelines, are available
for inspection and copying at the Public Information
Reference Unit (202-382-5926), EPA Headquarters
Library, 401 M Street, S.W., Washington, DC,
between the hours of 8:00 a.m. and 4:30 p.m.
I certify that these Guidelines are not major
rules as defined by Executive Order 12291, because
they are nonbinding policy statements and have no
direct effect on the regulated community. Therefore,
they will have no effect on costs or prices, and they
will
[51 FR 33993]
have no other
significant adverse effects on the economy. These
Guidelines were reviewed by the Office of
Management and Budget under Executive Order
12291.
August 22,1986
Lee M. Thomas,
Administrator
CONTENTS
Part A; Guidelines for Carcinogen Rink Assessment
I. Introduction
llJiatard Idtntification
A. Overview
B. Element* of Hazard Identification
1. Physical-Chemical Properties and Routes and
Patterns of Exposure
2. Structure-Activity Relationships
3. Metabolic and Pharmacokinetic Properties
4. Toxicologic Effect*
5. Short-Term Testa
6. Long-Term Animal Studies
7. Human Studies
C. Weight of Evidence
0. Guidance for Dose-Response Assessment
E. Summary and Conclusion
IU.Dou-Rt*pon»e AtMttment, Expoturt Attutmtnt, ondRitk
Cnarocttraatun
ADose-Response Assessment
1. Selection of Data
2. Choice of Mathematical Extrapolation
Modal
3. Equivalent Exposure Unite Among Species
B. Exposure Assessment
C. Risk Characterization
1. Options for Numerical Risk Estimates
2. Concurrent Exposure
3. Summary of Risk Characterization
IV. SPA Clarification Sytttm for Catagoriting Wtight of
ttuidtnet for Careinogtnieity from Human and Animal
Studitt (Adapttd from IARC)
A. Assessment of Weight of Evidence for Carcinogenicity from
Studies in Humans
B. Assessment of Weight of Evidence for Carcinogenicity from
Studies in Experimental Animals
C. Categorization of Overall Weight of Evidence for Human
Careinogenicity
VJReferences
Part B: Response to Public and Science Advisory Board
Coauaente
1. Introduction
II. Office of Science and Technology Policy Report on
Chemical Carcinogen*
III. Inference Guideline*
TV. Bualuation of Benign Tumors
V. Tnuuplacental and Uultigenerational Animal Bioattayt
VI. Maximum ToUnttd DOM
VII. Mouse Liner Tumors
Vin.Weignt-of-Saidence Categoric*
XI. Quantitative Sttimattt of Risk
A-2
-------
Part A: Guidelines for Carcinogen Risk
Assessment
/. Introduction
This is the first revision of the 1976 Interim
Procedures and Guidelines for Health Risk
Assessments of Suspected Carcinogens (U.S. EPA,
1976; Albert et al., 1977). The impetus for this
revision is the need to incorporate into these1
Guidelines the concepts and approaches td
carcinogen risk assessment that have been
developed during the last ten years. The purpose of
these Guidelines is to promote quality and
consistency of carcinogen risk assessments within
the EPA and to inform those outside the EPA about
its approach to carcinogen risk assessment These
Guidelines emphasize the broad but essential
aspects of risk assessment that are needed by
experts in the various disciplines required (e.g.,
toxicology, pathology, pharmacology, and statistics)
for carcinogen risk assessment Guidance is given in
general terms since the science of carcinogenesis is
in a state of rapid advancement, and overly specific
approaches may rapidly become obsolete.
These Guidelines describe the general
framework to be followed in developing an analysis
of carcinogenic risk and some salient principles to be
used in evaluating the quality of data and in
formulating judgments concerning the nature and
magnitude of the cancer hazard from suspect
carcinogens. It is the intent of these Guidelines to
permit sufficient flexibility to accommodate new
knowledge and new assessment methods as they
emerge. It is also recognized that there is a need for
new methodology that has not been addressed in this
document in a number of areas, e.g., the
characterization of uncertainty. As this knowledge
and assessment methodology are developed, these
Guidelines will be revised whenever appropriate.
A summary of the current state of knowledge in
the field of carcinogenesis and a statement of broad
scientific principles of carcinogen risk assessment,
which was developed by the Office of Science and
Technology Policy (OSTP, 1985), forms an important
basis for these Guidelines; the format of these
Guidelines is similar to that proposed by the
National Research Council (NRC) of the National
Academy of Sciences in a book entitled Risk
Assessment in the Federal Government: Managing
the Process (NRC, 1983).
These Guidelines are to be used within the
policy framework already provided by applicable
EPA statutes and do not alter such policies. These
Guidelines provide general directions for analyzing
and organizing available data. They do not imply
that one kind of data or another is prerequisite for
regulatory action to control, prohibit, or allow the
use of a carcinogen.
Regulatory decision making involves two
components: risk assessment and risk management
Risk assessment defines the adverse health
consequences of exposure to toxic agents. The risk
assessments will be carried out independently from
considerations of the consequences of regulatory
action. Risk management combines the risk
assessment with the directives of regulatory
legislation, together with socioeconomic, technical,
political, and other considerations, to reach a
decision as to whether or how much to control future
exposure to the suspected toxic agents.
Risk assessment includes one or more of the
following components: hazard identification, dose-
response assessment, exposure assessment, and risk
characterization (NRC, 1983).
Hazard identification is a qualitative risk
assessment, dealing with the process of determining
whether exposure to an agent has the potential to
increase the incidence of cancer. For purposes of
these Guidelines, both malignant and benign
tumors are used in the evaluation of the
carcinogenic hazard. The hazard identification
component qualitatively answers the question of
how likely an agent is to be a human carcinogen.
Traditionally, quantitative risk assessment has
been used as an inclusive term to describe all or
parts of dose-response assessment, exposure
assessment, and risk characterization. Quantitative
risk assessment can be a useful general term in
some circumstances, but the more explicit
terminology developed by the NRC (1983) is usually
preferred. The dose-response assessment defines the
relationship between the dose of an agent and the
probability of induction of a carcinogenic effect This
component usually entails an extrapolation from the
generally high doses administered to experimental
animals or exposures noted in epidemiologic studies
to the exposure levels expected from human contact
with the agent in the environment; it also includes
considerations of the validity of these
extrapolations.
The exposure assessment identifies populations
exposed to the agent, describes their composition
and size, and presents the types, magnitudes,
frequencies, and durations of exposure to the agent
[51 PR 339941
In risk characterization, the results of the
exposure assessment and the dose-response
assessment are combined to estimate quantitatively
the carcinogenic risk. As part of risk
characterization, a summary of the strengths and
weaknesses in the hazard identification, dose-
response assessment, exposure assessment, and the
public health risk estimates- are presented. Major
assumptions, scientific judgments, and, to the extent
possible, estimates of the uncertainties embodied in
the assessment are also presented, distinguishing
clearly between fact, assumption, and science policy.
A-3
-------
The National Research Council (NRC, 1983)
pointed out that there are many questions
encountered in the risk assessment process that are
unanswerable given current scientific knowledge.
To bridge the uncertainty that exists in these areas
where there is no scientific consensus, inferences
must be made to ensure that progress continues in
the assessment process. The OSTP (1985) reaffirmed
this position, and generally left to the regulatory
agencies the job of articulating these inferences.
Accordingly, the Guidelines incorporate judgmental
positions (science policies) based on evaluation of the
presently available information and on the
regulatory mission of the Agency. The Guidelines
are consistent with the principles developed by the
OSTP (1985), although in many instances are
necessarily more specific.
//. Hazard Identification
A. Overview
The qualitative assessment or hazard
identification part of risk assessment contains a
review of the relevant biological and chemical
information bearing on whether or not an agent may
pose a carcinogenic hazard. Since chemical agents
seldom occur in a pure state and are often
transformed in the body, the review should include
available information on contaminants, degradation
products, and metabolites.
Studies are evaluated according to sound
biological and statistical considerations and
procedures. These have been described in several
publications (Interagency Regulatory Liaison
Group, 1979; OSTP, 1985; Peto et al., 1980; Mantel,
1980; Mantel and Haenszel, 1959; Interdisciplinary
Panel on Carcinogenicity, 1984; National Center for
Toxicological Research, 1981; National Toxicology
Program, 1984; U.S. EPA, 1983a, 1983b, 1983c;
Haseman, 1984). Results and conclusions
concerning the agent, derived from different types of
information, whether indicating positive or negative
responses, are melded together into a weight-of-
evidence determination. The strength of the
evidence supporting a potential human
carcinogenicity judgment is developed in a weight-
of-evidence stratification scheme.
B. Elements of Hazard Identification
Hazard identification should include a review of
the following information to the extent that it is
available.
1. Physical-Chemical Properties and Routes and
Patterns of Exposure. Parameters relevant to
carcinogenesis, including physical state, physical-
chemical properties, and exposure pathways in the
environment should be described where possible.
2. Structure-Activity Relationships. This section
should summarize relevant structure-activity
correlations that support or argue against the
prediction of potential carcinogenicity.
3. Metabolic and Pharmacokinetic Properties.
This section should summarize relevant metabolic
information. Information such as whether the agent
is direct-acting or requires conversion to a reactive
carcinogenic (e.g., an electrophilic) species,
metabolic pathways for such conversions,
macromolecular interactions, and fate (e.g.,
transport, storage, and excretion), as well as species
differences, should be discussed and critically
evaluated. Pharmacokinetic properties determine
the biologically effective dose and may be relevant to
hazard identification and other components of risk
assessment.
4. Toxico/ogic Effects. Toxicologic effects other
than carcinogenicity (e.g., suppression of the
immune system, endocrine disturbances, organ
damage) that are relevant to the evaluation of
carcinogenicity should be summarized. Interactions
with other chemicals or agents and with lifestyle
factors should be discussed. Prechronic and chronic
toxicity evaluations, as well as other test results,
may yield information on target organ effects,
pathophysiological reactions, and preneoplastic
lesions that bear on the evaluation of
carcinogenicity. Dose-response and time-to-response
analyses of these reactions may also be helpful.
5. Snort-Term Tests. Tests for point mutations,
numerical and structural chromosome aberrations,
DNA damage/repair, and in uitro transformation
provide supportive evidence of carcinogenicity and
may give information on potential carcinogenic
mechanisms. A range of tests from each of the above
end points helps to characterize an agent's response
spectrum.
Short-term in uioo and in uitro tests that can
give indication of initiation and promotion activity
may also provide supportive evidence for
carcinogenicity. Lack of positive results in short-
term tests for genetic toxicity does not provide a
basis for discounting positive results in long-term
animal studies.
6. Long-Term Animal Studies. Criteria for the
technical adequacy of animal carcinogenicity
studies have been published (e.g., U.S. Food and
Drug Administration, 1982; Interagency Regulatory
Liaison Group, 1979; National Toxicology Program,
1984; OSTP, 1985; U.S. EPA, 1983a, 1983b, 1983c;
Feron et al., 1980; Mantel, 1980) and should be used
to judge the acceptability of individual studies.
Transplacental and multigenerational
carcinogenesis studies, in addition to more
conventional long-term animal studies, can yield
useful information about the carcinogenicity of
agents.
It is recognized that chemicals that induce
benign tumors frequently also induce malignant
A-4
-------
tumors, and that benign tumors often progress to
malignant tumors (Interdisciplinary Panel on
Carcinogenicity, 1984). The incidence of benign and
malignant tumors will be combined when
scientifically defensible (OSTP, 1985; Principle 8).
For example, the Agency will, in general, consider
the combination of benign and malignant tumors to
be scientifically defensible unless the benign tumors
are not considered to have the potential to progress
to the associated malignancies of the same
histogenic origin. If an increased incidence of benign
tumors is observed in the absence of malignant
tumors, in most cases the evidence will be
considered as limited evidence of carcinogenicity.
The weight of evidence that an agent is
potentially carcinogenic for humans increases (1)
with the increase in number of tissue sites affected
by the agent; (2) with the increase in number of
animal species, strains, sexes, and number of
experiments and doses showing a carcinogenic
response; (3) with the occurrence of clear-cut dose-
response relationships as well as a high level of
statistical significance of the increased tumor
incidence in treated compared to control groups; (4)
when there is a dose-related shortening of the time-
to-tumor occurrence or time to death with tumor;
and (5) when there is a dose-related increase in the
proportion of tumors that are malignant.
Long-term animal studies at or near the
maximum tolerated dose level (MTD) are used to
ensure an adequate power for the detection of
carcinogenic
[51 PR 33995]
activity (NTP,
1984;'IARC, 1982). Negative long-term animal
studies at exposure levels above the MTD may not be
acceptable if animal survival is so impaired that the
sensitivity of the study is significantly reduced
below that of a conventional chronic animal study at
the MTD. The OSTP (1985; Principle 4) has stated
that.
The carcinogenic effects of agents may be influenced by non-
physiological responses (such as extensive organ damage, radical
disruption of hormonal function, saturation of metabolic
pathways, formation of stones in the urinary tract, saturation of
ON A repair with a functional loss of the system) induced in the
model systems. Testing regimes inducing these responses should
be evaluated for their relevance to the human response to an
agent and evidence from such a study, whether positive or
negative, must be carefully reviewed.
Positive studies at levels above the MTD should be
carefully reviewed to ensure that the responses are
not due to factors which do not operate at exposure
levels below the MTD. Evidence indicating that high
exposures alter tumor responses by indirect
mechanisms that may be unrelated to effects at'
lower exposures should be dealt with on an
individual basis. As noted by the OSTP (1985),
"Normal metabolic activation of carcinogens may
possibly also be altered and carcinogenic potential
reduced as a consequence [of high-dose testingJ."
Carcinogenic responses under conditions of the
experiment should be reviewed carefully as they
relate to the relevance of the evidence to human
carcinogenic risks (e.g., the occurrence of bladder
tumors in the presence of bladder stones and
implantation site sarcomas). Interpretation of
animal studies is aided by the review of target organ
toxicity and other effects (e.g., changes in the
immune and endocrine systems) that may be noted
in prechronic or other lexicological studies. Time
and dose-related changes in the incidence of
preneoplastic lesions may also be helpful in
interpreting animal studies.
Agents that are positive in long-term animal
experiments and also show evidence of promoting or
cocarcinogenic activity in specialized tests should be
considered as complete carcinogens unless there is
evidence to the contrary because it is, at present,
difficult to determine whether an agent is only a
promoting or cocarcinogenic agent. Agents that
show positive results in special tests for initiation,
promotion, or cocarcinogenicity and no indication of
tumor response in well-conducted and well-designed
long-term animal studies should be dealt with on an
individual basis.
To evaluate carcinogenicity, the primary
comparison is tumor response in dosed animals as
compared with that in contemporary matched
control animals. Historical control data are often
valuable, however, and could be used along with
concurrent control data in the evaluation of
carcinogenic responses (Haseman et al., 1984). For
the evaluation of rare tumors, even small tumor
responses may be significant compared to historical
data. The review of tumor data at sites with high
spontaneous background requires special
consideration (OSTP, 1985; Principle 9). For
instance, a response that is significant with respect
to the experimental control group may become
questionable if the historical control data indicate
that the experimental control group had an
unusually low background incidence (NTP, 1984).
For a number of reasons, there are widely
diverging scientific views (OSTP, 1985; Ward et al.,
1979a, b; Tomatis, 1977; Nutrition Foundation,
1983) about the validity of mouse liver tumors as an
indication of potential carcinogenicity in humans
when such tumors occur in strains with high
spontaneous background incidence and when they
constitute the only tumor response to an agent.
These Guidelines take the position that when the
only tumor response is in the mouse liver and when
other conditions for a classification of "sufficient"
evidence in animal studies are met (e.g., replicate
studies, malignancy, see section IV), the data should
be considered as "sufficient" evidence of
carcinogenicity. It is understood that this
classification could be changed on a case-by-case
basis to "limited," if warranted, when factors such as
the following, are observed: an increased incidence
A-5
-------
of tumors only in the highest dose group and/or only
at the end of the study; no substantial dose-related
increase in the proportion of tumors that are
malignant; the occurrence of tumors that are
predominantly benign; no dose-related shortening of
the time to the appearance of tumors; negative or
inconclusive results from a spectrum of short-term
tests for mutagenic activity; the occurrence of excess
tumors only in a single sex.
Data from all long-term animal studies are to be
considered in the evaluation of carcinogenicity. A
positive carcinogenic response in one
species/strain/sex is not generally negated by
negative results in other species/strain/sex.
Replicate negative studies that are essentially
identical in all other respects to a positive study may
indicate that the positive results are spurious.
Evidence for carcinogenic action should be based
on the observation of statistically significant tumor
responses in specific organs or tissues, Appropriate
statistical analysis should be performed on data
from long-term studies to help determine whether
the effects are treatment-related or possibly due to
chance. These should at least include a statistical
test for trend, including appropriate correction for
differences in survival. The weight to be given to the
level of statistical significance (the p-value) and to
other available pieces of information is a matter of
overall scientific judgment. A statistically
significant excess of tumors of all types in the
aggregate, in the absence of a statistically
significant increase of any individual tumor type,
should be regarded as minimal evidence of
carcinogenic action unless there are persuasive
reasons to the contrary.
7. Human Studies. Epidemiologic studies
provide unique information about the response of
humans who have been exposed to suspect
carcinogens. Descriptive epidemiologic studies are
useful in generating hypotheses and providing
supporting data, but can rarely be used to make a
causal inference. Analytical epidemiologic studies of
the case-control or cohort variety, on the other hand,
are especially useful in assessing risks to exposed
humans.
Criteria for the adequacy of epidemiologic
studies are well recognized. They include factors
such as the proper selection and characterization of
exposed and control groups, the adequacy of
duration and quality of follow-up, the proper
identification and characterization of confounding
factors and bias, the appropriate consideration of
latency effects, the valid ascertainment of the causes
of morbidity and death, and the ability to detect
specific effects. Where it can be calculated, the
statistical power to detect an appropriate outcome
should be included in the assessment.
The strength of the epidemiologic evidence for
carcinogenicity depends, among other things, on the
type of analysis and on the magnitude and
specificity of the response. The weight of evidence
increases rapidly with the number of adequate
studies that show comparable results on populations
exposed to the same agent under different
conditions.
It should be recognized that epidemiologic
studies are inherently capable of detecting oi.ly
comparatively large increases in the relative risk of
[51 PR 33996]
cancer. Negative
results from such studies cannot prove the absence
of carcinogenic action; however, negative results
from a well-designed and well-conducted
epidemiologic study that contains usable exposure
data can serve to define upper limits of risk; these
are useful if animal evidence indicates that the
agent is potentially carcinogenic in humans.
C. Weight of Evidence
Evidence of possible carcinogenicity in humans
comes primarily from two sources: long-term animal
tests and epidemiologic investigations. Results from
these studies are supplemented with available
information from short-term tests, pharmacokinetic
studies, comparative metabolism studies, structure-
activity relationships, and other relevant toxicologic
studies. The question of how likely an agent is to be
a human carcinogen should be answered in the
framework of a weight-of-evidence judgment.
Judgments about the weight of evidence involve
considerations of the quality and adequacy of the
data and the kinds and consistency of responses
induced by a suspect carcinogen. There are three
major steps to characterizing the weight of evidence
for carcinogenicity in humans: (1) characterization
of the evidence from human studies and from animal
studies individually, (2) combination of the
characterizations of these two types of data into an
indication of the overall weight of evidence for
human carcinogenicity, and (3) evaluation of all
supporting information to determine if the overall
weight of evidence should be modified.
EPA has developed a system for stratifying the
weight of evidence (see section IV). This
classification is not meant to be applied rigidly or
mechanically. At various points in the above
discussion, EPA has emphasized the need for an
overall, balanced judgment of the totality of the
available evidence. Particularly for well-studied
substances, the scientific data base will have a
complexity that cannot be captured by any
classification scheme. Therefore, the hazard
identification section should include a narrative
summary of the strengths and weaknesses of the
evidence as well as its categorization in the EPA
scheme.
The EPA classification system is, in general, an
adaptation of the International Agency for Research
on Cancer (IARC, 1982) approach for classifying the
A-6
-------
weight of evidence for human data and animal data.
The EPA classification system for the
characterization of the overall weight of evidence for
carcinogenicity (animal, human, and other
supportive data) includes: Group A - Carcinogenic
to Humans; Group B — Probably Carcinogenic to
Humans; Group C - Possibly Carcinogenic to
Humans; Group D — Not Classifiable as to Human
Carcinogenicity; and Group E - Evidence of Non-
Carcinogenicity for Humans.
The following modifications of the IARC
approach have been made for classifying human and
animal studies.
For human studies:
(1) The observation of a statistically significant
association between an agent and life-threatening
benign tumors in humans is included in the
evaluation of risks to humans.
(2) A "no data available" classification is added.
(3) A "no evidence of carcinogenicity"
classification is added. This classificaton indicates
that no association was found between exposure and
increased risk of cancer in well-conducted, well-
designed, independent analytical epidemiologic
studies.
For animal studies:
(1) An increased incidence of combined benign
and malignant tumors will be considered to provide
sufficient evidence of carcinogenicity if the other
criteria defining the "sufficient" classification of
evidence are met (e.g., replicate studies,
malignancy; see section IV). Benign and malignant
tumors will be combined when scientifically
defensible.
(2) An increased incidence of benign tumors
alone generally constitutes "limited" evidence of
carcinogenicity.
(3) An increased incidence of neoplasms that
occur with high spontaneous background incidence
(e.g., mouse liver tumors and rat pituitary tumors in
certain strains) generally constitutes "sufficient"
evidence of carcinogenicity, but may be changed to
"limited" when warranted by the specific
information available on the agent.
(4) A "no data available" classification has been
added.
(5) A "no evidence of carcinogenicity"
classification is also added. This operational
classification would include substances for which
there is no increased incidence of neoplasms in at
least two well-designed and well-conducted animal
studies of adequate power and dose in different
species.
D. Guidance for Dose-Response Assessment
The qualitative evidence for careinogenesis
should be discussed for purposes of guiding the dose-
response assessment. The guidance should be given
in terms of the appropriateness and limitations of
specific studies as well as pharmacokinetic
considerations that should be factored into the dose-
response assessment. The appropriate method of
extrapolation should be factored in when the
experimental route of exposure differs from that
occurring in humans.
Agents that are judged to be in the EPA weight-
of-evidence stratification Groups A and B would be
regarded as suitable for quantitative risk
assessments. Agents that are judged to be in Group
C will generally be regarded as suitable for
quantitative risk assessment, but judgments in this
regard may be made on a case-by-case basis. Agents
that are judged to be in Groups D and E would not
have quantitative risk assessments.
E. Summary and Conclusion
The summary should present all of the key
findings in all of the sections of the qualitative
assessment and the interpretive rationale that
forms the basis for the conclusion. Assumptions,
uncertainties in the evidence, and other factors that
may affect the relevance of the evidence to humans
should be discussed. The conclusion should present
both the weight-of-evidence ranking and a
description that brings out the more subtle aspects of
the evidence that may not be evident from the
ranking alone.
HI. Dote-Retponte Assessment, Exposure
Attettment, and Ritk Characterization
After data concerning the carcinogenic
properties of a substance have been collected,
evaluated, and categorized, it is frequently desirable
to estimate the likely range of excess cancer risk
associated with given levels and conditions of
human exposure. The first step of the analysis
needed to make such estimations is the development
of the likely relationship between dose and response
(cancer incidence) in the region of human exposure.
This information on dose-response relationships is
coupled with information on the nature and
magnitude of human exposure to yield an estimate
of human risk. The risk-characterization step also
includes an interpretation of these estimates in light
of the biological, statistical, and exposure
assumptions and uncertainties that have arisen
throughout the process of assessing risk.
The elements of dose-response assessment are
described in section III.A. Guidance on human
exposure assessment is provided in another EPA
[51 FR 339971
document (U.S.
EPA, 1986); however, section III.B. of these
Guidelines includes a brief description of the specific
type of exposure information that is useful for
carcinogen risk assessment Finally, in section III.C.
on risk characterization, there is a description of the
manner in which risk estimates should be presented
so as to be most informative.
It should be emphasized that calculation of
quantitative estimates of cancer risk does not
A-7
-------
require that an agent be carcinogenic in humans.
The likelihood that an agent is a human carcinogen
is a function of the weight of evidence, as this has
been described in the hazard identification section of
these Guidelines. It is'nevertheless important to
present quantitative estimates, appropriately
qualified and interpreted, in those circumstances in
which there is a reasonable possibility, based on
human and animal data, that the agent is
carcinogenic in humans.
It should be emphasized in every quantitative
risk estimation that the results are uncertain.
Uncertainties due to experimental and
epidemiologic variability as well as uncertainty in
the exposure assessment can be important. There
are major uncertainties in extrapolating both from
animals to humans and from high to low doses.
There are important species differences in uptake,
metabolism, and organ distribution of carcinogens,
as well as species and strain differences in target-
site susceptibility. Human populations are variable
with respect to genetic constitution, diet,
occupational and home environment, activity
patterns, and other cultural factors. Risk estimates
should be presented together with the associated
hazard assessment (section III.C.3.) to ensure that
there is an appreciation of the weight of evidence for
carcinogenicity that underlies the quantitative risk
estimates.
A. Dose-Response Assessment
1. Selection of Data. As indicated in section II.O.,
guidance needs to be given by the individuals doing
the qualitative assessment (toxicologists,
pathologists, pharmacologists, etc.) to those doing
the quantitative assessment as to the appropriate
data to be used in the dose-response assessment.
This is determined by the quality of the data, its
relevance to human modes of exposure, and other
technical details.
If available, estimates based on adequate human
epidemiologic data are preferred over estimates
based on animal data. If adequate exposure data
exist in a well-designed and well-conducted negative
epidemiologic study, it may be possible to obtain an
upper-bound estimate of risk from that study.
Animal-based estimates, if available, also should be
presented.
In the absence of appropriate human studies,
data from a species that responds most like humans
should be used, if information to this effect exists.
Where, for a given agent, several studies are
available, which may involve different animal
species, strains, and sexes at several doses and by
different routes of exposure, the following approach
to selecting the data sets is used: (1) The tumor
incidence data are separated according to organ site
and tumor type. (2) All biologically and statistically
acceptable data sets are presented. (3) The range of
the risk estimates is presented with due regard to
biological relevance (particularly in the case of
animal studies) and appropriateness of route of
exposure. (4) Because it is possible that human
sensitivity is as high as the most sensitive
responding animal species, in the absence of
evidence to the contrary, the biologically acceptable
data set from long-term animal studies showing the
greatest sensitivity should generally be given the
greatest emphasis, again with due regard to
biological and statistical considerations.
When the exposure route in the species from
which the dose-response information is obtained
differs from the route occurring in environmental
exposures, the considerations used in making the
route-to-route extrapolation must be carefully
described. All assumptions should be presented
along with a discussion of the uncertainties in the
extrapolation. Whatever procedure is adopted in a
given case, it must be consistent with the existing
metabolic and pharmacokinetic information on the
chemical (e.g., absorption efficiency via the gut and
lung, target organ doses, and changes in placental
transport throughout gestation for transplacental
carcinogens).
Where two or more significantly elevated tumor
sites or types are observed in the same study,
extrapolations may be conducted on selected sites or
types. These selections will be made on biological
grounds. To obtain a total estimate of carcinogenic
risk, animals with one or more tumor sites or types
showing significantly elevated tumor incidence
should be pooled and used for extrapolation. The
pooled estimates will generally be used in preference
to risk estimates based on single sites or types.
Quantitative risk extrapolations will generally not
be done on the basis of totals that include tumor sites
without statistically significant elevations.
Benign tumors should generally be combined
with malignant tumors for risk estimates unless the
benign tumors are not considered to have the
potential to progress to the associated malignancies
of the same histogenic origin. The contribution of
the benign tumors, however, to the total risk should
be indicated.
2. Choice of Mathematical Extrapolation Moael.
Since risks at low exposure levels cannot be
measured directly either by animal experiments or
by epidemiologic studies, a number of mathematical
models have been developed to extrapolate from
high to low dose. Different extrapolation models,
however, may fit the observed data reasonably well
but may lead to large differences in the projected
risk at low doses.
As was pointed out by OSTP (1985; Principle
26),
No single mathematical procedure it rvcogniaad as the most
appropriate for tow-dose extrapolation in csrcinogenesis. When
relevant biological evidence on mechanism of action eziata (e.g.,
pharmacokinetics, target organ doae), the model* or procedures
A-8
-------
employed should be consistent with the evidence. When data and
information are limited, however, and when much uncertainty
existe regarding the mechanism of carcinogenic action, models or
procedures which incorporate low-dose linearity are preferred
when compatible with the limited information.
At present, mechanisms of the carcinogenesis
process are largely unknown and data are generally
limited. If a carcinogenic agent acts by accelerating
the same carcinogenic process that leads to the
background occurrence of cancer, the added effect of
the carcinogen at low doses is expected to be
virtually linear (Crumpet al., 1976).
The Agency will review each assessment as to
the evidence on carcinogenesis mechanisms and
other biological or statistical evidence that indicates
the suitability of a particular extrapolation model.
Goodness-of-fit to the experimental observations is
not an effective means of discriminating among
models (OSTP, 1985). A rationale will be included to
justify the use of the chosen model. In the absence of
adequate information to the contrary, the linearized
multistage procedure will be employed. Where
appropriate, the results of using various
extrapolation models may be useful for comparison
with the linearized multistage procedure. When
longitudinal data on tumor development are
available, time-to-tumor models may be used.
It should be emphasized that the linearized
multistage procedure leads to •
[51 PR 33998]
a plausible upper
limit to the risk that is consistent with some
proposed mechanisms of carcinogenesis. Such an
estimate, however, does not necessarily give a
realistic prediction of the risk. The true value of the
risk is unknown, and may be as low as zero. The
range of risks, defined by the upper limit given by
the chosen model and the lower limit which may be
as low as zero, should be explicitly stated. An
established procedure does not yet exist for making
"most likely" or "best" estimates of risk within the
range of uncertainty defined by the upper and lower
limit estimates. If data and procedures become
available, the Agency will also provide "most likely"
or "best" estimates of risk. This will be most feasible
when human data are available and when exposures
are in the dose range of the data.
In certain cases, the linearized multistage
procedure cannot be used with the observed data as,
for example, when the data are nonmonotonic or
flatten out at high doses. In these cases, it may be
necessary to make adjustments to achieve low-dose
linearity.
When pharmacokinetic or metabolism data
are available, or when other substantial evidence on
the mechanistic aspects of the carcinogenesis
process exists, a low-dose extrapolation model other
than the linearized multistage procedure might be
considered more appropriate on biological grounds.
When a different model is chosen, the risk
assessment should clearly discuss the nature and
weight of evidence that led to the choice.
Considerable uncertainty will remain concerning
response at low doses; therefore, in most cases an
upper-limit risk estimate using the linearized
multistage procedure should also be presented.
3. Equivalent Exposure Units Among Species.
Low-dose risk estimates derived from laboratory
animal data extrapolated to humans are
complicated by a variety of factors that differ among
species and potentially affect the response to
carcinogens. Included among these factors are
differences between humans and experimental test
animals with respect to life span, body size, genetic
variability, population homogeneity, existence of
concurrent disease, pharmacokinetic effects such as
metabolism and excretion patterns, and the
exposure regimen.
The usual approach for making interspecies
comparisons has been to use standardized scaling
factors. Commonly employed standardized dosage
scales include mg per kg body weight per day, ppm
in the diet or water, mg per m2 body surface area per
day, and mg per kg body weight per lifetime. In the
absence of comparative lexicological, physiological,
metabolic, and pharmacokinetic data for a given
suspect carcinogen, the Agency takes the position
that the extrapolation on the basis of surface area is
considered to be appropriate because certain
pharmacological effects commonly scale according to
surface area (Dedrick, 1973; Freireich et al., 1966;
Pinkel, 1958).
B. Exposure Assessment
In order to obtain a quantitative estimate of the
risk, the results of the dose-response assessment
must be combined with an estimate of the exposures
to which the populations of interest are likely to be
subject. While the reader is referred to the
Guidelines for Estimating Exposures (U.S. EPA,
1986) for specific details, it is important to convey an
appreciation of the impact of the strengths and
weaknesses of exposure assessment on the overall
cancer risk assessment process.
At present there is no single approach to
exposure assessment that is appropriate for all
cases. On a case-by-case basis, appropriate methods
are selected to match the date on hand and the level
of sophistication required. The assumptions,
approximations, and uncertainties need to be clearly
stated because, in some instances, these will have a
major effect on the risk assessment
In general, the magnitude, duration, and
frequency of exposure provide fundamental
information for estimating the concentration of the
carcinogen to which the organism is exposed. These
date are generated from monitoring information,
modeling results, and/or reasoned estimates. An
appropriate treatment of exposure should consider
A-9
-------
the potential for exposure via ingestion, inhalation,
and dermal penetration from relevant sources of
exposures including multiple avenues of intake from
the same source.
Special problems arise when the human
exposure situation of concern suggests exposure
regimens, e.g., route and dosing schedule that are
substantially different from those used in the
relevant animal studies. Unless there is evidence to
the contrary in a particular case, the cumulative
dose received over a lifetime, expressed as average
daily exposure prorated over a lifetime, is
recommended as an appropriate measure of
exposure to a carcinogen. That is, the assumption is
made that a high dose of a carcinogen received over a
short period of time is equivalent to a corresponding
low dose spread over a lifetime. This approach
becomes more problematical as the exposures in
question become more intense but less frequent,
especially when there is evidence that the agent has
shown dose-rate effects.
An attempt should be made to assess the level of
uncertainty associated with the exposure
assessment which is to be used in a cancer risk
assessment This measure of uncertainty should be
included in the risk characterization (section III.C.)
in order to provide the decision-maker with a clear
understanding of the impact of this uncertainty on
any final quantitative risk estimate. Subpopulations
with heightened susceptibility (either because of
exposure or predisposition) should, when possible, be
identified.
C. Risk Characterization
Risk characterization is composed of two parts.
One is a presentation of the numerical estimates of
risk; the other is a framework to help judge the
significance of the risk. Risk characterization
includes the exposure assessment and dose-response
assessment; these are used in the estimation of
carcinogenic risk. It may also consist of a unit-risk
estimate which can be combined elsewhere with the
exposure assessment for the purposes of estimating
cancer risk.
Hazard identification and dose-response
assessment are covered in sections II. and III.A., and
a detailed discussion of exposure assessment is
contained in EPA's Guidelines for Estimating
Exposures (U.S. EPA, 1986). This section deals with
the numerical risk estimates and the approach to
summarizing risk characterization.
1. Options for Numerical Risk Estimates.
Depending on the needs of the individual program
offices, numerical estimates can be presented in one
or more of the following three ways.
a. Unit Risk - Under an assumption of low-dose
linearity, the unit cancer risk is the excess lifetime
risk due to a continuous constant lifetime exposure
of one unit of carcinogen concentration. Typical
exposure units include ppm or ppb in food or water,
mg/kg/day by ingestion, or ppm or ug/m3 in air.
b. Dose Corresponding to a Given Level of Risk -
This approach can be useful, particularly when
using nonlinear extrapolation models where the
unit risk would differ at different dose levels.
c. Individual and Population Risks - Risks may
be characterized either in terms of the excess
individual lifetime risks, the excess number of
cancers
[51 PR 33999]
produced per
year in the exposed population, or both.
Irrespective of the options chosen, the degree
of precision and accuracy in the numerical risk
estimates currently do not permit more than one
significant figure to be presented.
2. Concurrent Exposure. In characterizing the
risk due to concurrent exposure to several
carcinogens, the risks are combined on the basis of
additivity unless there is specific information to the
contrary. Interactions of cocarcinogens, promoters,
and inititators with known carcinogens should be
considered on a case-by-case basis.
3. Summary of Risk Characterization.
Whichever method of presentation is chosen, it is
critical that the numerical estimates not be allowed
to stand alone, separated fcom the various
assumptions and uncertainties upon which they are
based. The risk characterization should contain a
discussion and interpretation of the numerical
estimates that affords the risk manager some
insight into the degree to which the quantitative
estimates are likely to reflect the true magnitude of
human risk, which generally cannot be known with
the degree of quantitative accuracy reflected in the
numerical estimates. The final risk estimate will be
generally rounded to one significant figure and will
be coupled with the EPA classification of the
qualitative weight of evidence. For example, a
lifetime individual risk of 2X10-* resulting from
exposure to a "probable human carcinogen" (Group
B2) should be designated as 2Xl(M [B2] . This
bracketed designation of the qualitative weight of
evidence should be included with all numerical risk
estimates (i.e., unit risks, which are risks at a
specified concentration or concentrations
corresponding to a given risk). Agency statements,
such as FEDERAL REGISTER notices, briefings,
and action memoranda, frequently include
numerical estimates of carcinogenic risk. It is
recommended that whenever these numerical
estimates are used, the qualitative weight-of-
evidence classification should also be included.
The section on risk characterization should
summarize the hazard identification, dose-response
assessment, exposure assessment, and the public
health risk estimates. Major assumptions, scientific
judgments, and, to the extent possible, estimates of
A-10
-------
the uncertainties embodied in the assessment are
presented.
IV. EPA Classification System for Categorizing
Weight of Evidence for Careinogenieity from Human
and Animal Studies (Adapted from I ARC)
A. Assessment of Weight of Evidence for
Careinogenieity from Studies in Humans
Evidence of Careinogenieity from human studies
comes from three main sources:
1. Case reports of individual cancer patients who
were exposed to the agenda).
2. Descriptive epidemiologic studies in which the
incidence of cancer in human populations was found
to vary in space or time with exposure to the
agent(s).
3. Analytical epidemiologic (case-control and
cohort) studies in which individual exposure to the
agent(s) was found to be associated with an
increased risk of cancer.
Three criteria must be met before a causal
association can be inferred between exposure and
cancer in humans:
1. There is no identified bias that could explain
the association.
2. The possibility of confounding has been
considered and ruled out as explaining the
association.
3. The association is unlikely to be due to
chance.
In general, although a single study may be
indicative of a cause-effect relationship, confidence
in inferring a causal association is increased when
several independent studies are concordant in
showing the association, when the association is
strong, when there is a dose-response relationship,
or when a reduction in exposure is followed by a
reduction in the incidence of cancer.
The weight of evidence for Careinogenieity 1 from
studies in humans is classified as:
1. Sufficient evidence of Careinogenieity, which
indicates that there is a causal relationship between
the agent and human cancer.
2. Limited evidence of Careinogenieity, which
indicates that a causal interpretation is credible, but
that alternative explanations, such as chance, bias,
or confounding, could not adequately be excluded.
1 For purposes of public health protection, agents
associated with life-threatening benign tumors in humans are
included in the evaluation.
2 An increased incidence of neoplaama that occur with high
•pontanaoua background incidence (e.g., mouse liver tumors
and rat pituitary tumors in certain strains) generally
constitutes "sufficient'' evidence of Careinogenieity, but may be
changed to "limited" when warranted by the specific
information available on the agent.
3 Benign and malignant tumors will be combined unless
the benign tumors are not considered to have the potential to
progress to the associated malignancies of the same histogenie
origin.
3. Inadequate evidence, which indicates that one
of two conditions prevailed: (a) there were few
pertinent data, or (b) the available studies, while
showing evidence of association, did not exclude
chance, bias, or confounding, and therefore a causal
interpretation is not credible.
4. No data, which indicates that data are not
available.
5. No evidence, which indicates that no
association was found between exposure and an
increased risk of cancer in well-designed and well-
conducted independent analytical epidemiologic
studies.
B. Assessment of Weight of Evidence for
Careinogenieity from Studies in Experimental
Animals
These assessments are classified into five
groups:
1. Sufficient evidence2 of Careinogenieity, which
indicates that there is ah increased incidence of
malignant tumors or combined malignant and
benign tumors:3 (a) in multiple species or strains; or
(b) in multiple experiments (e.g., with different
routes of administration or using different dose
levels); or (c) to an unusual degree in a single
experiment with regard to high incidence, unusual
site or type of tumor, or early age at onset
Additional evidence may be provided by data on
dose-response effects, as well as information from
short-term tests or on chemical structure.
2. Limited evidence of Careinogenieity, which
means that the data suggest a carcinogenic effect
but are limited because: (a) the studies involve a
single species, strain, or experiment and do not meet
criteria for sufficient evidence (see section IV. B.l.e);
(b) the experiments are restricted by inadequate
dosage levels, inadequate duration of exposure to the
agent, inadequate period of follow-up, poor survival,
too few animals, or inadequate reporting: or (c) an
increase in the incidence of benign tumors only.
3. Inadequate evidence, which indicates that
because of major qualitative or quantitative
limitations, the studies cannot be interpreted as
showing either the presence or absence of a
carcinogenic effect.
4. No data, which indicates that data are not
available.
5. No evidence, which indicates that there is no
increased incidence of neoplasms in at least two
well-designed
[51 PR 34000]
and well-
conducted animal studies in different species.
The classifications "sufficient evidence" and
"limited evidence" refer only to the weight of the
experimental evidence that these agents are
carcinogenic and not to the potency of their
carcinogenic action.
A-ll
-------
C. Categorization of Overall Weight of Evidence for
Human Carcinogenicity
The overall scheme for categorization of the
weight of evidence of carcinogenicity of a chemical
for humans uses a three-step process. (1) The weight
of evidence in human studies or animal studies is
summarized; (2) these lines of information are
combined to yield a tentative assignment to a
category (see Table 1); and (3) all relevant
supportive information is evaluated to see if the
designation of the overall weight of evidence needs
to be modified. Relevant factors to be included along
with the tumor information from human and animal
studies include structure-activity relationships;
short-term test findings; results of appropriate
physiological, biochemical, and toxicological
observations; and comparative metabolism and
pharmacokinetic studies. The nature of these
findings may cause one to adjust the overall
categorization of the weight of evidence.
The agents are categorized into five groups as
follows:
Group A — Human Carcinogen
This group is used only when there is sufficient
evidence from epidemiologic studies to support a
causal association between exposure to the agents
and cancer.
Group B — Probable Human Carcinogen
This group includes agents for which the weight
of evidence of human carcinogenicity based on
epidemiologic studies is "limited'* and also includes
agents for .which the weight of evidence of
carcinogenicity based on animal studies is
"sufficient." The group is divided into two
subgroups. Usually, Group Bl is reserved for agents
for which there is limited evidence of carcinogenicity
from epidemiologic studies. It is reasonable, for
practical purposes, to regard an agent for which
there is "sufficient" evidence of carcinogenicity in
animals as if it presented a carcinogenic risk to
humans. Therefore, agents for which there is
"sufficient" evidence from animal studies and for
which there is "inadequate evidence" or "no data"
from epidemiologic studies would usually be
categorized under Group B2.
Group C — Possible Human Carcinogen
This group is used for agents with limited
evidence of carcinogenicity in animals in the
absence of human data. It includes a wide variety of
evidence, e.g., (a) a malignant tumor response in a
single well-conducted experiment that does not meet
conditions for sufficient evidence, (b) tumor
responses of marginal statistical significance in
studies having inadequate design or reporting, (c)
benign but not malignant tumors with an agent
showing no response in a variety of short-term tests
for mutagenicity, and (d) responses of marginal
statistical significance in a tissue known to have a
high or variable background rate.
Group D — Not Classifiable as to Human
Carcinogenicity
This group is generally used for agents with
inadequate human and animal evidence of
carcinogenicity or for which no data are available.
Group E — Evidence of Non-Carcinogenicity for
Humans
This group is used for agents that show no
evidence for carcinogenicity in at least two adequate
animal tests in different species or in both adequate
epidemiologic and animal studies.
The designation of an agent as being in Group E
is based on the available evidence and should not be
interpreted as a definitive conclusion that the agent
will not be a carcinogen under any circumstances.
V. References
Albert, R.E., Train, R.E., and Anderson, E. 11977. Rationale
developed by the Environmental Protection Agency for the
assessmant of carcinogenic risks. J. Natl. Cancer Inst.
58:1537-1541.
Crump, US., Hoel, D.G., Ungley, C.H.. Peto R, 1976.
Fundamental carcinogenic processes and their implications
for low dose risk assessment. Cancer Res. 36:2973-2979.
Dedrick, R-L. 1973. Animal Scale Up. J. Pnwrmacokinec
Biopharm. 1:436-461.
Feron, V J, Grice, H.C., Griesemer, fL, Peto R-, Agthe, C., Althoff,
J., Arnold, D.I~, Blumenthal, H., CabraL JJLP., Delia Porta,
G., Ito, N., Kimmerle, G., Kroes. R., Mohr, U.. Napalkov,
NJ»., Odasbima, S., Page, NJ>., Schrmmm, T., Steinhoff, D.,
Sugar, J.,Tomatis, U Uehleke, H., and Vouk, V. 1980. Basic
requirements for long-term assays for carcinogenicity. In:
Long-term sod short-term screening assays for carcinogens:
a critical appraisal IARC Monographs, Supplement 2. Lyon,
Franca: International Agency for Research on Cancer, pp 21 -
83.
Freireich. E J., Gehan, E.A., Rail, D.P., Schmidt, L.H., and
Skipper, H.E. 1966. Quantitative comparison of toxicity of
anticancer agent* in mouse, rat, hamster, dog, monkey and
man. Cancer Chemother. Rep. 5O-.219-244.
Haseman, U.K. 1984. Statistical issues in the design, analysis and
interpretation of animal carcinogenicity studies. Environ.
Health PerapecL 58:385-392.
Haseman, J.K., Huff. J., and Boonnan.G-A. 1984. Use of
historical control data in carcinogenicity studies in rodents.
Toncol. Pathol. 12:126-135.
Interagency Regulatory Liaison Group (IRLG). 1979. Scientific
basis for identification of potential carcinogens and
estimation of risks. J. Natl. Cancer Inst. 63:245-267.
Interdisciplinary Panel on Carcinogenicity. 1984. Criteria for
evidence of chemical carcinogenicity. Science 225:682-687.
International Agency for Research on Cancer (I ARC). 1982. IARC
Monographs on the
[51 FR 340011
Evaluation of the
Carcinogenic Risk of Chemicals to Humans, Supplement 4. Lyon,
France: International Agency for Research on Cancer.
Mantel, N. 1980. Assessing laboratory evidence for neoplastic
activity. Biometrics 36 381-399.
Mantel, N., and Haenszel, W. 1959. Statistical aspects of the
snalysis of data from retrospective studies of disease. J. Natl.
Cancer Inst 22:719-748.
National Center for Tosicological Research (NCTR). 1981.
Guideline* for statistical tests for carcinogenicity in chronic
bioassays. NCTR Biometry Technical Report 81-001.
Available {ram: National Center for Toxicologies! Research.
A-12
-------
TABLE 1 .-ILLUSTRATIVE CATEGORIZATION OF EVIDENCE BASED ON ANIMAL AND HUMAN DATA'
Sufficient
Limited
Inadequate
No data
No evidence
Animal evidence
Sufficient
A
B1
82
82
B2
•
Limited
A
81
C
C
C
Inadequate
A
81
0
0
0
No data
A
81
0
0
0
No evidence
A
81
0
E
E
1 The above assignments are presented for illustrative purposes. There may be nuances in the classification of both
animal and human data indicating that different categorizations than those given in the table should be assigned.
Furthermore, these assignments are tentative and may be modified by ancillary evidence. In this regard all relevant
information should be evaluated to determine if the designation of the overall weight of evidence needs to be modified.
Relevant factors to be included along with the tumor data from human and animal studies include structure-activity
relationships, short-term test findings, results of appropriate physiological, biochemical, and lexicological observations, and
comparative metabolism and pharmacokinetic studies. The nature of these findings may cause an adjustment of the overall
categorization of the weight of evidence.
National Research Council (NRC). 1983. Risk assessment in the
Federal government: managing the process. Washington,
D.C J National Academy Press.
National Toxicology Program. 1984. Report of the Ad Hoc Panel
on Chemical Carcinogeneais Testing and Evaluation of the
National Toxicology Program, Board of Scientific
Counselors. Available from: US. Government Printing
Office, Washington, D.C. 1984-421-132:4726.
Nutrition Foundation. 1983. The relevance of mouse liver
bepatoma to human carcinogenic risk: a report of the
International Expert Advisory Committee to the Nutrition
Foundation. Available from: Nutrition Foundation. ISBN 0-
935368-37-x.
Office of Science and Technology Policy (OSTP). 1985. Chemical
carcinogens: review of the science and ita associated
principles. Federal Register 50:10372-10442.
Peto, R., Pike, M., Day. N., Gray, R., Lee. P., Pariah. S., Peto, J.,
Richard, S., and Wahrendorf, J. 1980. Guideline* for simple.
sensitive, significant tests for carcinogenic effecta in long-
term animal experiments. In: Monographs on the long-term
and short-term screening assays for carcinogens: a critical
appraisal. I ARC Monographs. Supplement 2. Lyon, France:
International Agency for Research on Cancer, pp. 311 -426.
Pinkel, D. 1958. The use of body surface area as s criterion of drug
doaage in cancer chemotherapy. Cancer Res. 18:853-866.
Tomatis, L. 1977. The value of long-term testing for the
implementation of primary prevention. In: Origins of human
cancer. Hiatt, H.H., Wataon, JJO.. and Winstein, J_A., eds.
Cold Spring Harbor Laboratory, pp. 1339-1357.
US. Environmental Protection Agency (US. EPA). 1976. Interim
procedures and guidelines for health riak and economic
impact assessments of suspected carcinogens. Federal
Register41:21402-21405.
US. Environmental Protection Agency (US. EPA). 1980. Water*
quality criteria document*; availability. Federal Register
45:79318-79379.
US. Environmental Protection Agency (US. EPA). 1983a. Good
laboratory practices standards - toxicology testing. Federal
Register 48:53922.
US. Environmental Protection Agency (US. EPA). 1983b.
Hazard evaluations: humans and domestic animals.
Subdivision F. Available from: NTIS, Springfield, VA. PB 83-
153916.
US. Environmental Protection Agency (US. EPA). 1983c. Health
effecta test guidelines. Available from: NTIS, Springfield,
VA. PB 83-232984.
US. Environmental Protection Agency (US. EPA). 1986, Sept.
24.GuideliiMM for estimating exposures. Federal Register 51
(185): 34042-34054
VS. Food and Drug Administration (US. FDA). 1982.
Toxicological principles for the safety assessment of direct
food additives and color additives used in food. Available
from: Bureau of Foods, US. Food and Drug Administration.
Ward, J.M., Griaaemer, RjC, and Weisburger. E.K. 1979a. The
mouse liver tumor aa an endpoint in carcinogeneaia teats.
ToxicoL AppL PharmacoL 51:388-397.
Ward, J.M., Goodman, D.G., Squire, R-A. Chu, K.C., and Linhart,
MS. 1979b. Neoplastic and oooneoplastic lesions in aging
(CsTBL/eNxCaH/HeN)?! (BedF^ mice. J. Natl. Cancer
lost. 63:849-854.
Part B: Response to Public and Science
Advisory Board Comments
I. Introduction
This section summarizes the major issues raised
during both the public comment period on the
Proposed Guidelines for Carcinogen Risk
Assessment published on November 23, 1984 (49 FR
46294), and also during the April 22-23, 1985,
meeting of the Carcinogen Risk Assessment
Guidelines Panel of the Science Advisory Board
(SAB).
In order to respond to these issues the Agency
modified the proposed guidelines in two stages.
First, changes resulting from consideration of the
public comments were made in a draft sent to the
SAB review panel prior to their April meeting.
Secondly, the guidelines were further modified in
response to the panel's recommendations.
The Agency received 62 sets of comments during
the public comment period, including 28 from
corporations, 9 from professional or trade
associations, and 4 from academic institutions. In
general, the comments were favorable. The
commentors welcomed the update of the 1976
guidelines and felt that the proposed guidelines of
A-13
-------
1985 reflected some of the progress that has occurred
in understanding the mechanisms of carcinogenesis.
Many commentors, however, felt that additional
changes were warranted.
The SAB concluded that the guidelines are
"reasonably complete in their conceptual framework
and are sound in their overall interpretation of the
scientific issues" (Report by the SAB
Carcinogenicity Guidelines Review Group, June 19,
1985). The SAB suggested various editorial changes
and raised some issues regarding the content of the
proposed guidelines, which are discussed below.
Based on these recommendations, the Agency has
modified the draft guidelines.
//. Office of Science and Technology Policy Report on
Chemical Carcinogens
Many commentors requested that the final
guidelines not be issued until after publication of the
report of the Office of Technology and Science Policy
(OSTP) on chemical carcinogens. They further
requested that this report be incorporated into the
final Guidelines for Carcinogen Risk Assessment.
The final OSTP report was published in 1985 (50
PR 10372). In its deliberations, the Agency reviewed
the final OSTP report and feels that the Agency's
guidelines are consistent with the principles
established by the OSTP. In its review, the SAB
agreed that the Agency guidelines are generally
consistent with the OSTP report. To emphasize this
consistency, the OSTP principles have been
incorporated into the guidelines when controversial
issues are discussed.
///. Inference Guidelines
Many commentors felt that the proposed
guidelines did not provide a sufficient distinction
between scientific fact and policy decisions. Others
felt that EPA should not attempt to propose firm
guidelines in the absence of scientific consensus. The
SAB report also indicated the need to "distinguish
recommendations based on scientific evidence from
those based on science policy decisions."
The Agency agrees with the recommendation
that policy, judgmental, or inferential decisions
should be clearly identified. In its revision of the
proposed guidelines, the Agency has included
phrases (e.g., "the Agency takes the position that")
to more clearly distinguish policy decisions.
The Agency also recognizes the need to establish
procedures for action on important issues in the
absence of complete scientific knowledge or
consensus. This need was acknowledged in both the
National Academy of Sciences book entitled Risk
Management in the Federal Government: Managing
the Process and the OSTP report on chemical
carcinogens. As the NAS report states, "Risk
assessment is an analytic process that is firmly
based on scientific considerations, but it also
requires judgments to be made when the available
information is incomplete. These judgments
inevitably draw on both scientific and policy
considerations."
[51 PR 34002]
The judgments of the Agency have been based on
current available scientific information and on the
combined experience of Agency experts. These
judgments, and the resulting guidance, rely on
inference; however, the positions taken in these
inference guidelines are felt to be reasonable and
scientifically defensible. While all of the guidance is,
to some degree, based on inference, the guidelines
have attempted to distinguish those issues that
depended more on judgment. In these cases, the
Agency has stated a position but has also retained
flexibility to accommodate new data or specific
circumstances that demonstrate that the proposed
position is inaccurate. The Agency recognizes that
scientific opinion will be divided on these issues.
Knowledge about carcinogens and
carcinogenesis is progressing at a rapid rate. While
these guidelines are considered a best effort at the
present time, the Agency has attempted to
incorporate flexibility into the current guidelines
and also recommends that the guidelines be revised
as often as warranted by advances in the field.
TV. Evaluation of Benign Tumors
Several commentors discussed the appropriate
interpretation of an increased incidence of benign
tumors alone or with an increased incidence of
malignant tumors as part of the evaluation of the
carcinogenicity of an agent Some comments were
supportive of the position in the proposed guidelines,
i.e., under certain circumstances, the incidence of
benign and malignant tumors would be combined,
and an increased incidence of benign tumors alone
would be considered an indication, albeit limited, of
carcinogenic potential. Other commentors raised
concerns about the criteria that would be used to
decide which tumors should be combined. Only a few
commentors felt that benign tumors should never be
considered in evaluating carcinogenic potential.
The Agency believes that current information
supports the use of benign tumors. The guidelines
have been modified to incorporate the language of
the OSTP report, i.e., benign tumors will be
combined with malignant tumors when
scientifically defensible. This position allows
flexibility in evaluating the data base for each
agent The guidelines have also been modified to
indicate that, whenever benign and malignant
tumors have been combined, and the agent is
considered a candidate for quantitative risk
extrapolation, the contribution of benign tumors to
the estimation of risk will be indicated.
V. Transplacental and Multigenerational Animal
Bioassays
A-14
-------
As one of its two proposals for additions to the
guidelines, the SAB recommended a discussion of
transplacental and multigenerational animal
bioassays for carcinogenicity.
The Agency agrees that such data, when
available, can provide useful information in the
evaluation of a chemical's potential carcinogenicity
and has stated this in the final guidelines. The
Agency has also revised the guidelines to indicate
that such studies may provide additional
information on the metabolic and pharmacokinetic
properties of the chemical. More guidance on the
' specific use of these studies will be considered in
future revisions of these guidelines.
VI. Maximum Tolerated Dose
The proposed guidelines discussed the
implications of using a maximum tolerated dose
(MTD) in b\passays for carcinogenicity. Many
commentors requested that EPA define MTD. The
tone of the comments suggested that the
commentors were concerned about the uses and
interpretations of high-dose testing.
The Agency recognizes that controversy
currently surrounds these issues. The appropriate
text from the OSTP report has been incorporated
into the final guidelines which suggests that the
consequences of high-dose testing be evaluated on a
case-by-case basis.
VII. Mouse Liver Tumors
A large number of commentors expressed
opinions about the assessment of bioassays in which
the only increase in tumor incidence was liver
tumors in the mouse. Many felt that mouse liver
tumors were afforded too much credence, especially
given existing information that indicates that they
might arise by a different mechanism, e.g., tissue
damage followed by regeneration. Others felt that
mouse liver tumors were but one case of a high
background incidence of one particular type of
tumor and that all such tumors should be treated in
the same fashion.
The Agency has reviewed these comments and
the OSTP principle regarding this issue. The OSTP
report does not reach conclusions as to the treatment
of tumors with a high spontaneous background rate,
but states, as is now included in the text of the
guidelines, that these data require special
consideration. Although questions have been raised
regarding the validity of mouse liver tumors in
general, the Agency feels that mouse liver tumors
cannot be ignored as an indicator of carcinogenicity.
Thus, the position in the proposed guidelines has not
been changed: an increased incidence of only mouse
liver tumors will be regarded as "sufficient"
evidence of carcinogenicity if all other criteria, e.g.,
replication and malignancy, are met with the
understanding that this classification could be
changed to "limited" if warranted. The factors that
may cause this re-evaluation are indicated in the
guidelines.
V777. Vteighi-of Evidence Catagorie*
The Agency was praised by both the public and
the SAB for incorporating a weight-of-evidence
scheme into its evaluation of carcinogenic risk.
Certain specific aspects of the scheme, however,
were criticized.
1. Several commentors noted that while the text
of the proposed guidelines clearly states that EPA
will use all available data in its categorization of the
weight of the evidence that a chemical is a
carcinogen, the classification system in Part A,
section IV did not indicate the manner in which EPA
will use information other than data from humans
and long-term animal studies in assigning a weight-
of-evidence classification.
The Agency has added a discussion to Part A,
section IV.C. dealing with the characterization of
overall evidence for human carcinogenicity. This
discussion clarifies EPA's use of supportive
information to adjust, as warranted, the designation
that would have been made solely on the basis of
human and long-term animal studies.
2. The Agency agrees with the SAB and those
commentors who felt that a simple classification of
the weight of evidence, e.g., a single letter or even a
descriptive title, is inadequate to describe fully the
weight of evidence for each individual chemical. The
final guidelines propose that a paragraph
summarizing the data should accompany the
numerical estimate and weight-of-evidence
classification whenever possible.
3. Several commentors objected to the
descriptive title E (No Evidence of Carcinogenicity
for Humans) because they felt the title would be
confusing to people inexperienced with the
classification system. The title for Group E, No
Evidence of Carcinogenicity for Humans, was
thought by these commentors to suggest the absence
of data. This group, however, is intended to be
reserved for agents for which there exists credible
data demonstrating that the agent is not
carcinogenic.
Based on these comments and further
discussion, the Agency has changed the
[51 PR 34003]
title of Group E
to "Evidence of Non-Carcinogenicity for Humans."
4. Several commentors felt that the title for
Group C, Possible Human Carcinogen, was not
sufficiently distinctive from Group B, Probable
Human Carcinogen. Other commentors felt that
those agents that minimally qualified for Group C
would lack sufficient data for such a label.
The Agency recognizes that Group C covers a
range of chemicals and has considered whether to*
subdivide Group C. The consensus of the Agency's
A-15
-------
Carcinogen Risk Assessment Committee, however,
is that the current groups, which are based on the
IARC categories, are a reasonable stratification and
should be retained at present The structure of the
groups will be reconsidered when the guidelines are
reviewed in the future. The Agency also feels that
the descriptive title it originally selected best
conveys the meaning of the classification within the
context of EPA's past and current activities.
5. Some commentors indicated a concern about
the distinction between Bl and B2 on the basis of
epidemiologic evidence only. This issue has been
under discussion in the Agency and may be revised
in future versions of the guidelines.
6. Comments were also received about the
possibility of keeping the groups for animal and
human data separate without reaching a combined
classification. The Agency feels that a combined
classification is useful; thus, the combined
classification was retained in the final guidelines.
The SAB suggested that a table be added to Part
A, section IV to indicate the manner in which
human and animal data would be combined to
obtain an overall weight-of-evidence category. The
Agency realizes that a table that would present all
permutations of potentially available data would be
complex and possibly impossible to .construct since
numerous combinations of ancillary data (e.g.,
genetic toxicity, pharmacokinetics) could be used to
raise or lower the weight-of-evidence classification.
Nevertheless, the Agency decided to include a table
to illustrate the most probable weight-of-evidence
classification that would be assigned on the basis of
standard animal and human data without
consideration of the ancillary data. While it is hoped
that this table will clarify the weight-of-evidence
classifications, it is also important to recognize that
an agent may be assigned to a final categorization
different from the category which would appear
appropriate from the table and still conform to the
guidelines.
IX. Quantitative Estimates of Risk
The method for quantitative estimates of
carcinogenic risk in the proposed guidelines received
substantial comments from the public. Five issues
were discussed by the Agency and have resulted in
modifications of the guidelines.
1. The major criticism was the perception that
EPA would use only one method for the
extrapolation of carcinogenic risk and would,
therefore, obtain one estimate of risk. Even
commentors who concur with the procedure usually
followed by EPA felt that some indication of the
uncertainty of the risk estimate should be included
with the risk estimate.
The Agency feels that the proposed guidelines
were not intended to suggest that EPA would
perform quantitative risk estimates in a rote or
mechanical fashion. As indicated by the OSTP
report and paraphrased in the proposed guidelines,
no single mathematical procedure has been
determined to be the most appropriate method for
risk extrapolation. The final guidelines quote rather
than paraphrase the OSTP principle. The guidelines
have been revised to stress the importance of
considering all available data in the risk assessment
and now state, The Agency will review each
assessment as to the evidence on carcinogenic
mechanisms and other biological or statistical
evidence that indicates the suitability of a particular
extrapolation model." Two issues are emphasized:
First, the text now indicates the potential for
pharmacokinetic information to contribute to the
assessment of carcinogenic risk. Second, the final
guidelines state that time-to-tumor risk
extrapolation models may be used when
longitudinal data on tumor development are
available.
2. A number of commentors noted that the
proposed guidelines did not indicate how the
uncertainties of risk characterization would be
presented. The Agency has revised the proposed
guidelines to indicate that major assumptions,
scientific judgments, and, to the extent possible,
estimates of the uncertainties embodied in the risk
assessment will be presented along with the
estimation of risk.
3. The proposed guidelines stated that the
appropriateness of quantifying risks for chemicals in
Group C (Possible Human Carcinogen), specifically
those agents that were on the boundary of Groups C
and D (Not Classifiable as to Human
Carcinogenicity), would be judged on a case-by-case
basis. Some commentors felt that quantitative risk
assessment should not be performed on any agent in
Group C.
Group C includes a wide range of agents,
including some for which there are positive results
in one species in one good bioassay. Thus, the
Agency feels that many agents in Group C will be
suitable for quantitative risk assessment, but that
judgments in this regard will be made on a case-by-
case basis.
4. A few commentors felt that EPA intended to
perform quantitative risk estimates on aggregate
tumor incidence. While EPA will consider an
increase in total aggregate tumors as suggestive of
potential carcinogenicity, EPA does not generally
intend to make quantitative estimates of
carcinogenic risk based on total aggregate tumor
incidence.
5. The proposed choice of body surface area as an
interspecies scaling factor was criticized by several
commentors who felt that body weight was also
appropriate and that both methods should be used.
The OSTP report recognizes that both scaling factors
are in common use. The Agency feels that the choice
of the body surface area scaling factor can be
A-16
-------
justified from the data on effects of drugs in various
species. Thus, EPA will continue to use this scaling
factor unless data on a specific agent suggest that a
different scaling factor is justified. The uncertainty
engendered by choice of scaling factor will be
included in the summary of uncertainties associated
with the assessment of risk mentioned in point 1,
above.
In the second of its two proposals for additions to
the proposed guidelines, the SAB suggested that a
sensitivity analysis be included in EPA's
quantitative estimate of a chemical's carcinogenic
potency. The Agency agrees that an analysis of the
assumptions and uncertainties inherent in an
assessment of carcinogenic risk must be accurately
portrayed. Sections of the final guidelines that deal
with this issue have been strengthened to reflect the
concerns of the SAB and the Agency. In particular,
the last paragraph of the guidelines states that
"major assumptions, scientific judgments, and, to
the extent possible, estimates of the uncertainties
embodied in the assessment" should be presented in
the summary characterizing the risk. Since the
assumptions and uncertainties will vary for each
assessment, the Agency feels that a formal
requirement for a particular type of sensitivity
analysis would be less useful than a case-by-case
evaluation of the particular assumptions and
uncertainties most significant for a particular risk
assessment.
A-17
-------
APPENDIX B
INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
WEIGHT-OF-EVIDENCE CLASSIFICATION SCHEME
-------
APPENDIX B
INTERNATIONAL AGENCY FOR RESEARCH ON CANCER
WEIGHT-OF-EVIDENCE CLASSIFICATION SCHEME
The text for this appendix is taken directly from IARC, 1984. The term
"Working Group" refers to the IARC Working Group on the Evaluation of the
Carcinogenic Risk of Chemicals to Humans.
7. GENERAL PRINCIPLES APPLIED BY THE WORKING GROUP IN EVALUATING CARCINO-
GENIC RISK OF CHEMICALS OR COMPLEX MIXTURES
The widely accepted meaning of the term 'chemical carcinogenesis', and that used in these
monographs, is the induction by chemicals (or complex mixtures of chemicals) of neoplasms
that are not usually observed, the earlier induction of neoplasms that are commonly observed,
and/or the induction of more neoplasms than are usually found - although fundamentally
different mechanisms may be involved in these three situations. Etymologically, the term
'carcinogenesis' means the induction of cancer, that is, of malignant neoplasms; however, the
commonly accepted meaning is the induction of various types of neoplasms or of a
combination of malignant and benign tumours. In the monographs, the words 'tumour' and
'neoplasm' are used interchangeably. (In the scientific literature, the terms 'tumorigen', 'oncogen'
and 'blastomogen' have all been used synonymously with 'carcinogen', although occasionally
'tumorigen' has been used specifically to denote a substance that induces benign tumours.)
(«) Experimental Evidence
(i) Evidence for carcinogenicity in experimental animals
The Working Group considers various aspects of the experimental evidence reported in the
literature and formulates an evaluation of that evidence.
B-l
-------
IARC MONOGRAPHS VOLUME 34
Qualitative aspects: Both the interpretation and evaluation of a particular study as well as
the overall assessment of the carcinogenic activity of a chemical (or complex mixture) involve
several considerations of qualitative importance, including: (a) the experimental parameters
under which the chemical was tested, including route of administration and exposure, species,
strain, sex, age, etc.; (b) the consistency with which the chemical has been shown to be
carcinogenic, e.g., in how many species and at which target organ(s); (c) the spectrum of
neoplastic response, from benign neoplasm to multiple malignant tumours; (d) the stage of
tumour formation in which a chemical may be involved: some chemicals act as complete
carcinogens and have initiating and promoting activity, while others may have promoting
activity only; and (e) the possible role of modifying factors.
There are problems not only of differential survival but of differential toxicity, which may
be manifested by unequal growth and weight gain in treated and control animals. These
complexities are also considered in the interpretation of data.
Many chemicals induce both benign and malignant tumours. Among chemicals that have
been studied extensively, there are few instances in which the neoplasms induced are only
benign. Benign tumours may represent a stage in the evolution of a malignant neoplasm or
they may be 'end-points' that do not readily undergo transition to malignancy. If a substance
is found to induce only benign tumours in experimental animals, it should nevertheless be
suspected of being a carcinogen, and it requires further investigation.
Hormonal carcinogenesis: Hormonal carcmogenesis presents certain distinctive features:
the chemicals involved occur both endogenously and exogenously; in many instances, long
exposure is required; and tumours occur in the target tissue in association with a stimulation
of non-neoplastic growth, although in some cases hormones promote the proliferation of
tumour cells in a target organ. For hormones that occur in excessive amounts, for
hormone-mimetic agents and for agents that cause hyperactivity or imbalance in the endocrine
system, evaluative methods comparable with those used to identify chemical carcinogens may
be required; particular emphasis must be laid on quantitative aspects and duration of exposure.
Some chemical carcinogens have significant side effects on the endocrine system, which may
also result in hormonal carcinogenesis. Synthetic hormones and anti-hormones can be
expected to possess other pharmacological and toxicological actions in addition to those on
the endocrine system, and in this respect they must be treated like any other chemical with
regard to intrinsic carcinogenic potential.
Complex mixtures: There is an increasing amount of data from long-term carcinogenicity
studies on complex mixtures and on crude materials obtained by sampling in an occupational
environment. The representativity of such samples must be considered carefully.
Quantitative aspects: Dose-response studies are important in the evaluation of carcinoge-
nesis: the confidence with which a carcinogenic effect can be established is strengthened by
the observation of an increasing incidence of neoplasms with increasing exposure.
The assessment of carcinogenicity in animals is frequently complicated by recognized
differences among the test animals (species, strain, sex, age) and route and schedule of
administration; often, the target organs at which a cancer occurs and its histological type may
vary with these parameters. Nevertheless, indices of carcinogenic potency in particular
experimental systems (for instance, the dose-rate required under continuous exposure to halve
the probability of the animals remaining tumourless (9)) have been formulated in the hope that,
at least among categories of fairly similar agents, such indices may be of some predictive
value in other species, including humans.
B-2
-------
PREAMBLE
I carcinogens share many common biological properties, which include metabolism
ctive (electrophilic (10-11)) intermediates capable of interacting with DNA. However, they
t0 differ widely in the dose required to produce a given level of tumour induction. The reason
ma^this variation in dose-response is not understood, but it may be due to differences in
tabolic activation and detoxification processes, in different DNA repair capacities among
"arious organs and species or to the operation of qualitatively distinct mechanisms.
Statistical analysis of animal studies: It is possible that an anima! may die prematurely from
unrelated causes, so that tumours that would have arisen had the animal lived longer may not
be observed; this possibility must be allowed for. Various analytical techniques have been
developed which use the assumption of independence of competing risks to allow for the
effects of intercurrent mortality on the final numbers of tumour-bearing animals in particular
treatment groups.
For externally visible tumours and for neoplasms that cause death, methods such as
Kaplan-Meier (i.e., 'life-table', 'product-limit' or 'actuarial') estimates (9), with associated
significance tests (12,13), have been recommended. For internal neoplasms that are discovered
•incidentally' (12) at autopsy but that did not cause the death of the host, different
estimates (14) and significance tests (12,13) may be necessary for the unbiased study of the
numbers of tumour-bearing animals.
The design and statistical analysis of long-term carcinogenicity experiments were reviewed
in Supplement 2 to the Monographs series (15). That review outlined the way in which the
context of observation of a given tumour (fatal or incidental) could be included in an analysis
yielding a single combined result. This method requires information on time to death for each
animal and is therefore comparable to only a limited extent with analyses which include global
proportions of tumour-bearing animals.
Evaluation of carcinogenicity studies in experimental animals: The evidence of carcinogeni-
city in experimental animals is assessed by the Working Group and judged to fall into one of
four groups, defined as follows:
(1) Sufficient evidence of carcinogenicity is provided when there is an increased incidence
of malignant tumours: (a) in multiple species or strains; or (b) in multiple experiments
(preferably with different routes of administration or using different dose levels); or
(c) to an unusual degree with regard to incidence, site or type of tumour, or age at
onset. Additional evidence may be provided by data on dose-response effects.
(2) Limited evidence of carcinogenicity is available when the data suggest a carcinogenic
effect but are limited because: (a) the studies involve a single species, strain or
experiment; or (b) the experiments are restricted by inadequate dosage levels,
inadequate duration of exposure to the agent, inadequate period of follow-up, poor
survival, too few animals, or inadequate reporting; or (c) the neoplasms produced
often occur spontaneously and, in the past, have been difficult to classify as malignant
by histological criteria alone (e.g., lung adenomas and adenocarcinomas and liver
tumours in certain strains of mice).
(3) Inadequate evidence is available when, because of major qualitative or quantitative
limitations, the studies cannot be interpreted as showing either the presence or
absence of a carcinogenic effect.
(4) No evidence applies when several adequate studies are available which show that,
within the limits of the tests used, the chemical or complex mixture is not
carcinogenic.
B-3
-------
IARC MONOGRAPHS VOLUME 34
It should be noted that the categories sufficient evidence and limited evidence refer only to
the strength of the experimental evidence that these chemicals or complex mixtures are
carcinogenic and not to the extent of their carcinogenic activity nor to the mechanism involved.
The classification of any chemical may change as new information becomes available.
(ii) Evidence for activity in short-term fesfs1
Many short-term tests bearing on postulated mechanisms of carcinogenesis or on the
properties of known carcinogens have been developed in recent years. The induction of cancer
is thought to proceed by a series of steps, some of which have been distinguished
experimentally (16-20). The first step - initiation - is thought to involve damage to DNA,
resulting in heritable alterations in or rearrangements of genetic information. Most short-term
tests in common use today are designed to evaluate the genetic activity of a substance. Data
from these assays are useful for identifying potential carcinogenic hazards, in identifying active
metabolites of known carcinogens in human or animal body fluids, and in helping to elucidate
mechanisms of carcinogenesis. Short-term tests to detect agents with tumour-promoting
activity are, at this time, insufficiently developed.
Because of the large number of short-term tests, it is difficult to establish rigid criteria for
adequacy that would be applicable to all studies. General considerations relevant to all tests,
however, include (a) that the test system be valid with respect to known animal carcinogens
and noncarcinogens; (b) that the experimental parameters under which the chemical (or
complex mixture) is tested include a sufficiently wide dose range and duration of exposure to
the agent and an appropriate metabolic system; (c) that appropriate controls be used; and (d)
that the purity of the compound or, in the case of complex mixtures, that the source and
representative of the sample being tested be specified. Confidence in positive results is
increased if a dose-response relationship is demonstrated and if this effect has been reported
in two or more independent studies.
Most established short-term tests employ as end-points well-defined genetic markers in
prokaryotes and lower eukaryotes and in mammalian cell lines. The tests can be grouped
according to the end-point detected:
Tests of DNA damage. These include tests for covalent binding to DNA, induction of
DNA breakage or repair, induction of prophage in bacteria and differential survival of
DNA repair-proficient/-deficient strains of bacteria.
Tests of mutation (measurement of heritable alterations in phenotype and/or genotype).
These include tests for detection of the loss or alteration of a gene product, and
change of function through forward or reverse mutation, recombination and gene
conversion; they may involve the nuclear genome, the mitochondria! genome and
resident viral or plasmid genomes.
Tests of chromosomal effects. These include tests for detection of changes in
chromosome number (aneuploidy), structural chromosomal aberrations, sister chroma-
tid exchanges, micronuclei and dominant-lethal events. This classification does not
imply that some chromosomal effects are not mutational events.
Tests for cell transformation, which monitor the production of preneoplastic or neoplastic
cells in culture, are also of importance because they attempt to simulate essential steps in
'Based on the recommendations of a working group which met in 1983 (5)
B-4
-------
PREAMBLE
iar carcinogenesis. These assays are not grouped with those listed above since the
nanisms by which chemicals induce cell transformation may not necessarily be the result
of genetic change.
The selection of specific tests and end-points for consideration remains flexible and should
reflect the most advanced state of knowledge in this field.
The data from short-term tests are summarized by the Working Group and the test results
tabulated according to the end-points detected and the biological complexities of the test
systems. The format of the table used is shown below. In these tables, a '+' indicates that
the compound was judged by the Working Group to be significantly positive in one or more
assays for the specific end-point and level of biological complexity; '-' indicates that it was
judged to be negative in one or more assays; and '?' indicates that there were contradictory
results from different laboratories or in different biological systems, or that the result was
judged »o be equivocal. These judgements reflect the assessment by the Working Group of
the quality of the data (including such factors as the purity of the test compound, problems
of metaoolic activation and appropriateness of the test system) and the relative significance
of the component tests.
Overall assessment of data from short-term tests
Genetic activity
DMA damage Mutation Chromosomal
effects
Prokaryotes
Fungi/
Green plants
Insects
Mammalian cells
(in vitro)
Mammals
(in vivo)
Humans
(in vivo)
Cell
transformation
An overall assessment of the evidence for genetic activity is then made on the basis of
the entries in the table, and the evidence is judged to fall into one of four categories, defined
as follows:
(i) Sufficient evidence is provided by at least three positive entries, one of which must
involve mammalian cells in vitro or in vivo and which must include at least two of
three end-points - DNA damage, mutation and chromosomal effects.
B-5
-------
IARC MONOGRAPHS VOLUME 34
(ii) Limited evidence is provided by at least two positive entries.
(HI) Inadequate evidence is available when there is only one positive entry or when there
are too few data to permit an evaluation of an absence of genetic activity or when
there are unexplained, inconsistent findings in different test systems.
(iv) Wo evidence applies when there are only negative entries; these must include entries
for at least two end-points and two levels of biological complexity, one of which must
involve mammalian cells in vitro or in vivo.
It is emphasized that the above definitions are operational, and that the assignment of a
chemical or complex mixture into one of these categories is thus arbitrary.
In general, emphasis is placed on positive results; however, in view of the limitations of
current knowledge about mechanisms of carcinogenesis, certain cautions should be respected;
(i) At present, short-term tests should not be used by themselves to conclude whether or not
an agent is carcinogenic, nor can they predict reliably the relative potencies of compounds as
carcinogens in intact animals, (ii) Since the currently available tests do not detect all classes
of agents that are active in the carcinogenic process (e.g., hormones), one must be cautious
in utilizing these tests as the sole criterion for setting priorities in carcinogenesis research and
in selecting compounds for animal bioassays. (iii) Negative results from short-term tests cannot
be considered as evidence to rule out carcinogenicity, nor does lack of demonstrable genetic
activity attribute an epigenetic or any other property to a substance (5).
(b) Evaluation of Carcinogenicity in Humans
Evidence of carcinogenicity can be derived from case reports, descriptive epidemiological
studies and analytical epidemiological studies.
An analytical study that shows a positive association between an exposure and a cancer
may be interpreted as implying causality to a greater or lesser extent, on the basis of the
following criteria: (a) There is no identifiable positive bias. (By 'positive bias' is meant the
operation of factors in study design or execution that lead erroneously to a more strongly
positive association between an exposure and disease than in fact exists. Examples of positive
bias include, in case-control studies, better documentation of the exposure for cases than for
controls, and, in cohort studies, the use of better means of detecting cancer in exposed
individuals than in individuals not exposed.) (b) The possibility of positive confounding has been
considered. (By 'positive confounding' is meant a situation in which the relationship between
an exposure and a disease is rendered more strongly positive than it truly is as a result of an
association between that exposure and another exposure which either causes or prevents the
disease. An example of positive confounding is the association between coffee consumption
and lung cancer, which results from their joint association with cigarette smoking.) (c) The
association is unlikely to be due to chance alone, (d) The association is strong, (e) There is a
dose-response relationship.
In some instances, a single epidemiological study may be strongly indicative of a
cause-effect relationship; however, the most convincing evidence of causality comes when
several independent studies done under different circumstances result in 'positive' findings.
B-6
-------
PREAMBLE
Analytical epidemiologies! studies that show no association between an exposure and a
cancer ('negative' studies) should be interpreted according to criteria analogous to those listed
above: (a) there is no identifiable negative bias; (b) the possibility of negative confounding has
been considered; and (c) the possible effects of misclassification of exposure or outcome have
been weighed. In addition, it must be recognized that the probability that a given study can
detect a certain effect is limited by its size. This can be perceived from the confidence limits
around the estimate of association or relative risk. In a study regarded as 'negative', the upper
confidence limit may indicate a relative risk substantially greater than unity; in that case, the
study excludes only relative risks that are above the upper limit. This usually means that a
'negative' study must be large to be convincing. Confidence in a 'negative' result is increased
when several independent studies carried out under different circumstances are in agreement.
Finally, a 'negative' study may be considered to be relevant only to dose levels within or below
the range of those observed in the study and is pertinent only if sufficient time has elapsed
since first human exposure to the agent. Experience with human cancers of known etiology
suggests that the period from first exposure to a chemical carcinogen to development of
clinically observed cancer is usually measured in decades and may be in excess of 30 years.
The evidence for carcinogenicity from studies in humans is assessed by the Working Group
and judged to fall into one of four groups, defined as follows:
1. Sufficient evidence of carcinogenicity indicates that there is a causal relationship
between the exposure and human cancer.
2. Limited evidence of carcinogenicity indicates that a causal interpretation is credible,
but that alternative explanations, such as chance, bias or confounding, could not
adequately be excluded.
3. Inadequate evidence, which applies to both positive and negative evidence, indicates
that one of two conditions prevailed: (a) there are few pertinent data; or (b) the
available studies, while showing evidence of association, do not exclude chance, bias
or confounding.
4. No evidence applies when several adequate studies are available which do not show
evidence of carcinogenicity.
(c) Relevance of Experimental Data to the Evaluation of Carcinogenic Risk to Humana
Information compiled from the first*29 volumes of the IARC Monographs (4,21,22) shows
that, of the chemicals or groups of chemicals now generally accepted to cause or probably to
cause cancer in humans, all (with the possible exception of arsenic) of those that have been
tested appropriately produce cancer in at least one animal species. For several of the
chemicals (e.g., aflatoxins, 4-aminobiphenyl, diethylstilboestrol, melphalan, mustard gas and
vinyl chloride), evidence of carcinogenicity in experimental animals preceded evidence obtained
from epidemiological studies or case reports.
For many of the chemicals (or complex mixtures) evaluated in the IARC Monographs for
which there is sufficient evidence of carcinogenicity in animals, data relating to carcinogenicity
for humans are either insufficient or nonexistent. In the absence of adequate data on
humans, it is reasonable, for practical purposes, to regard chemicals for which there is
sufficient evidence of carcinogenicity in animals as if they presented a carcinogenic risk
to humans. The use of the expressions 'for practical purposes' and 'as if they presented a
B-7
-------
IARC MONOGRAPHS VOLUME 34
carcinogenic risk' indicates that, at the present time, a correlation between carcinogenicity m
animals and possible human risk cannot be made on a purely scientific basis, but only
pragmatically. Such a pragmatical correlation may be useful to regulatory agencies in making
decisions related to the primary prevention of cancer.
In the present state of knowledge, it would be difficult to define a predictable relationship
between the dose (mg/kg bw per day) of a particular chemical required to produce cancer in
test animals and the dose that would produce a similar incidence of cancer in humans. Some
data, however, suggest that such a relationship may exist (23,24), at least for certain classes
of carcinogenic chemicals, although no acceptable method is currently available for quantifying
the possible errors that may be involved in such an extrapolation procedure.
B-8
-------
APPENDIX C
CANCER INFORMATION SOURCES
-------
APPENDIX C
CANCER INFORMATION SOURCES
IRIS
The Integrated Risk Information System (IRIS) is being designed and
implemented by the EPA Office of Research and Development. IRIS is a
computer-based information system that provides an introduction to the EPA's
risk assessment and risk management information for specific chemical
substances. Each chemical file may contain one or more of the following:
Oral and/or inhalation reference doses;
Qualitative and quantitative risk assessments for carcinogens
(e.g., weight-of-evidence classification and unit cancer risk
factors);
Drinking water health advisories;
Risk management information (e.g., NESHAPs, reportable quantities,
water quality criteria standards);
Supplementary data (e.g., physical and chemical properties); and
Synonyms for the chemical name.
The reference doses for noncarcinogens and risk assessments for
carcinogens are reviewed, evaluated, and verified by intra-Agency work
groups of scientists.
IRIS will be publicly available by the end of 1987. It will be
accessible through the EPA's electronic mail system as well as through hard
copy reports. For more information on IRIS, contact Rick Picardi, IRIS
Coordinator, (202) 382-7315, (FTS) 382-7315.
Toxic Air Pollutants
The Office of Air Quality Planning and Standards within EPA evaluates
emissions of potentially toxic air pollutants from stationary sources.
Exposure and risk analyses reviewing potential carcinogenic and
C-l
-------
noncarcinogenic risks associated with these emissions are prepared by the
Pollutant Assessment Branch (PAB). For current information on pollutants
being evaluated by PAB or information on conducting an exposure and risk
analysis for a toxic air pollutant, contact the Clearinghouse staff at
(919) 541-0850, (FTS) 629-0850.
Carcinogenic Risk Assessments
The Carcinogen Assessment Group (CAG) within EPA's Office of Research
and Development prepares qualitative and quantitative carcinogenic risk
assessments. As this information is peer-reviewed within the Agency, it
will be incorporated into IRIS. For more information on various activities,
contact CAG at (202) 382-5898, (FTS) 382-5898.
r-2
------- |