ENDANGERMENT ASSESSMENT HANDBOOK .
Errata
Certain changes have been made to the draft Endangerment Assessment Guidance
since this Handbook was written. These changes should be kept in mind while
reading the Handbook, especially Sections 2.0 and 4.0:
• The endangerment assessment is not necessary.to support cost recovery
for CERCLA Section 104 remedial actions.
• The endangerment assessment is normally developed as part of an
enforcement lead RI/FS.
• In evaluation of public health impacts, human health standards and
criteria should be included.
• At remedial sites subsequently targeted for CERCLA Section 106 or RCRA
Section 7003 enforcement action, all of the elements of an endangerment
assessment will be provided by completing the contamination assessment,
public health assessment and environmental assessment during the RI/FS
process.
Specific changes to this Handbook include the following:
1. Page 4-11, Se'ction 4.3.2, Paragraph 2
Delete the third sentence which reads: "Intermedia transport
processes . . . characterized in the Level 1 endangerment assessment.1
Delete the last sentence which reads: "An overview . . . Figure
4-2."
2. Page 4-13. Figure 4-13
Change the title of the figure to read: "Figure 4-2 Overview of
Environmental Fate and Transport Analysis for Level 2 Endangerment
Assessments."
3. Page 4-14, First Line
Add this sentence following the first line: "An overview of the
environmental fate and transport analysis for Level 2 endangerment
assessments is shown in Figure 4-2."
4. Page 4-14, First Full Paragraph, First Sentence
Add this sentence after the first full sentence: "Intermedia
transport processes (e.g., adsorption, volatilization, infiltration,
bioaccumulation) and intramedia transformation processes (e.g.,
-------
photolysis, hydrolysis, oxidation and biodegration) which potentially
affect migration of the contaminants of concern are identified and
characterized in the Level 2 and 3 endangerment assessments."
5. Page 4-22, Section 4.4.1., Paragraph 2
Add these sentences at the end of the second paragraph: "How
extensive the toxicity profiles are will depend on the amount of
time available to prepare the profile and the level of detail of the
endangerment assessment. Thus, the toxicity profiles prepared for
Level 1 endangerment assessments may not be as extensive as the
profiles prepared for Level 2 or 3 endangerment assessments. A
Level 1 toxicity profile would include, at a minimum, identification'
of applicable standards and guidelines for the contaminants of
concern. Table 4-8 provides guidance for the preparation of toxicity
profiles for endangerment assessments of varying levels of detail."
6. Page 4-28, Table 4-8
Change Step 2.1 to read: "Estimate 'Acceptable Levels'"
7. Page 4-39, Section 4.5.2, Paragraph 1
Change the first sentence to read: "One method that toxicologists
use to characterize noncarcinogenic risks involves comparing the
expected exposure level_. (E) to the "acceptable level" (AL) (USE.PA
198-5a). This proposed method has not been adopted as official EPA
policy."
8. Page 4-39, Section 4.5.3, Paragraph 2
Replace the final sentence ("As within . . . risks increases.") wi^h
the following: "This is an oversimplification of the procedures
used to estimate noncarcinogenic risks associated with exposure to
multiple chemicals. There are many assumptions made in developing
these calculation procedures which the user should be aware of.
These assumptions are detailed in the mixture guidelines in Appendix
3 of this Handbook (USEPA 1985a)."
9. Page 4-40, Paragraph 2
Add this sentence at the end of the second paragraph: "Qualitative
risk characterization methods include a comparison of actual or
potential exposure levels to background levels, analytical detection
limits, technically based criteria and standards and health based
criteria and standards. Quantitative risk characterization methods
include all of the above in addition to a quantitative estimation of
the actual or potential risks at the site."
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pro
PRC Engineering
Suite 600
303 East Wacker Drive
Chicago, IL 60601
312-938-0300
TWX 910-2215112
Cable CONTOWENG
Planning Research Corporation
THE ENDANGERMENT ASSESSMENT HANDBOOK
Prepared For
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office Of Waste Programs Enforcement
Washington, D.C. 20460
Work Assignment No.
Contract No.
PRC No.
Prepared By
Telephone No.
EPA Primary Contact
Telephone No.
136
68-01-7037
15-1360-00
Life Systems, Inc.
(Timothy E. Tyburski)
216/464-3291
R. Charles Morgan
202/475-6113
August, 1985
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£ife Systems, JHC.
Submitted to:
Office of Waste Programs Enforcement
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Attention: Chief, Health Sciences Section, R. Charles Morgan (2 copies).
TR-693-24B
ENDANGERMENT ASSESSMENT HANDBOOK
Prepared Under
Program No. 1393
for
Subcontract No. TES EMI-LS
Under
Contract No. 68-01-7037
PRC, Environmental Management, Inc.
Prime Contractor
PRC Work Assignment No. 136
ICAIR Work Assignment No. 12
Contact: Timothy E. Tyburski
Telephone: (216) 464-3291
August, 1985
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DISCLAIMER
This document has not undergone final review within EPA and is for internal
Agency use/distribution only.
There has been an EPA Workgroup review of the development of this document
prior to this draft. This final draft is being distributed to EPA personnel
for a six-month review period after which changes will be made based on the
comments received.
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£ife Systems, JHC.
FOREWORD
This Endangerment Assessment Handbook was prepared by ICAIR, Life Systems,
Inc., under U.S. Environmental Protection Agency (EPA) Contract 68-01-7037
during the period February 1, 1985 to August 16, 1985. The program was
directed by Mr. Timothy E. Tyburski. The handbook was compiled by Ms. Lee Ann
Smith with technical support from Mr. Kevin Gleason, Ms. Yvonne Hales and
Mr. Jon Hellerstein.
Mr. R. Charles Morgan and Ms. Kathleen Plourd, Health Sciences Section,
Technical Support Branch, Office of Waste Programs Enforcement (OWPE) were the
lead EPA Technical Contacts. ICAIR would also like to acknowledge the contri-
butions of the EPA Workgroup members to this program: Cheryl Peterson,
Compliance Branch, OWPE; Linda Southerland, Guidance and Oversight Branch,
OWPE; Libby Clemens, Resource Conservation and Recovery Act (RCRA) Enforcement
Division, OWPE; Kurt Lamber, Physical Sciences Section, Technical Support
Branch, OWPE; Craig Zamuda, Office of Emergency and Remedial Response (OERR);
John Schaum, Exposure Assessment Group, Office of Health and Environmental
Assessment (OHEA); Jim Kohanek, Office of Enforcement and Compliance Monitor-
ing (OECM); Ralph Jennings, EPA Region 4; and Sally Edwards, EPA Region 1.
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TABLE OF CONTENTS
PAGE
LIST OF FIGURES iv
LIST OF TABLES iv
LIST OF ACRONYMS v
GLOSSARY vi
1.0 INTRODUCTION 1-1
1.1 Purpose and Scope of the Endangerment Assessment Handbook . 1-1
1.2 Handbook Organization 1-2
2.0 LEGISLATIVE AND PROGRAMMATIC FRAMEWORK 2-1
2.1 Applicable Legislation 2-1
2.2 Role of the Endangerment Assessment in Enforcement Cases . 2-1
2.2.1 When to Perform an Endangerment Assessment .... 2-1
2.2.2 Who Performs an Endangerment Assessment ...... 2-4
2.2.3 Confidentiality of an Endangerment Assessment . . . 2-4
2.3 Relationship of Enforcement Actions to Superfund Actions . 2-4
2.3.1 The RI and FS Processes 2-5
2.3.2 Relationship of the Endangerment Assessment
Process to the RI and FS Assessment Processes . . . 2-8
3.0 OVERVIEW OF THE ENDANGERMENT ASSESSMENT PROCESS 3-1
3.1 Contaminant Identification . . '. 3-3
3.2 Exposure Assessment 3-3
3.3 Toxicity Assessment 3-4
3.4 Risk Characterization 3-6
4.0 GUIDELINES FOR CONDUCTING ENDANGERMENT ASSESSMENTS 4-1
4.1 Level of Detail 4-1
4.1.1 Level 1 ("Qualitative") 4-1
4.1.2 Level 2 ("Semi-Quantitative") 4-3
4.1.3 Level 3 ("Quantitative") 4-3
4.2 Contaminant Identification Guidelines 4-4
continued-
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Table of Contents - continued
PAGE
4.3 Exposure Assessment Guidelines 4-8
4.3.1 Contaminant Release Analysis 4-10
4.3.2 Environmental Fate and Transport Analysis 4-11
4.3.3 Exposed Population Analysis 4-14
4.3.4 Calculation of Exposure Level and Dose Incurred . . 4-17
4.3.5 Exposure Assessment References 4-19
4.4 Toxicity Assessment Guidelines 4-21
4.4.1 Toxicological Evaluation 4-22
4.4.2 Dose-Response Assessment 4-31
4.4.3 Toxicity Assessment References 4-35
4.5 Risk Characterization Guidelines 4-36
4.5.1 Characterize Carcinogenic Risks 4-37
4.5.2 Characterize Noncarcinogenic Risks 4-39
4.5.3 Characterize Environmental Risks • • • 4-40
4.5.4 Characterize Public Health Risks 4-40
4.5.5 Risk Characterization References . . 4-40
5.0 PREPARATION OF THE ENDANGERMENT ASSESSMENT DOCUMENT 5-1
5.1 Section 1.0 Introduction 5-3
5.1.1 Section 1.1 Site Description and History 5-5
5.1.2 Section 1.2 Contaminants Found at the Site .... 5-5
5.2 Section 2.0 Environmental Fate and Transport 5-6
5.3 Section 3.0 Exposure Evaluation 5-6
5.4 Section 4.0 Toxicity Evaluation 5-7
5.5 Section 5.0 Risk and Impact Evaluation 5-7
5.6 Section 6.0 Conclusions 5-8
6.0 SOURCES OF INFORMATION AND ASSISTANCE 6-1
6.1 Endangerment Assessment Process 6-1
6.2 RI and FS Processes . 6-1
6.3 Toxicity Profiles 6-2
6.4 EPA Risk and Exposure Assessment Guidelines 6-2
7.0 REFERENCES 7-1
continued-
ii
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Table of Contents - continued
PAGE
APPENDIX
1 Draft Endangerment Assessment Guidance Ai-i
2 Examples of Endangerment Assessments A2-1
Part 1. Level 1 Endangerment Assessment A2-4
Part 2. Level 2 Endangerment Assessment A2-5
Part 3. Level 3 Endangerment Assessment A2-6
3 EPA's Proposed Assessment Guidelines A3-1
Part 1. Carcinogenic Risk Assessment A3-2
Part 2. Exposure Assessment A3-3
Part 3. Mutagenicity Risk Assessment A3-4
Part 4. Health Assessment of Suspect Developmental
Toxicants A3-5
Part 5. Health Risk Assessment of Chemical Mixtures . . A3-6
4 Test Protocol Criteria for Animal Assays A4-1
5 Definition of Toxicological Endpoints A5-1
iii
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LIST OF FIGURES
FIGURE PAGE
2-1 Role of the Endangerment Assessment in CERCLA Enforcement
Cases 2-3
2-2 The Remedial Investigation Process . 2-6
2-3 The Feasibility Study Process 2-7
2-4 The Interrelationship of the Endangerment Assessment
Document, Remedial Investigation Report and Feasibility
Study Report 2-9
3-1 The Endangerment Assessment Process 3-2
3-2 The Exposure Assessment Process 3-5
3-3 The Toxicity Assessment Process 3-7
3-4 The Risk Characterization Process 3-9
4-1 Overview of Contaminant Release Analysis 4-12
4-2 Overview of Environmental Fate and Transport Analysis for
Level 1 Endangerment Assessments 4-13
4-3 Overview of Environmental Fate and Transport Analysis for
Level 2 and 3 Endangerment Assessments 4-16
4-4 Overview of Exposed Population Analysis 4-18
4-5 Overview of Process for Calculating Exposure Levels and
Dose Incurred 4-20
LIST OF TABLES
TABLE • PAGE
4-1 Relationship Between the Endangerment Assessment Handbook
and the Superfund Public Health Assessment Manual (SPHAM) . . 4-2
4-2 Guidelines for Level of Detail in Endangerment Assessments . 4-5
4-3 Site-Specific Documentation Available for the Preparation of
Endangerment Assessments - ... 4-7
4-4 Exposure Assessment Steps 4-9
4-5 Components of EPA's Graphical Exposure Modeling System (GEMS) 4-15
4-6 Toxicity Profiles Prepared Specifically for Use at Hazardous
Waste Sites 4-23
4-7 EPA Sources of Toxicity Profiles . 4-26
4-8 Toxicity Assessment Steps 4-28
4-9 Guidelines for Selection of Uncertainty Factors 4-33
4-10 Risk Characterization Steps 4-38
5-1 Endangerment Assessment Document Outline 5-2
5-2 Factors to be Considered in Endangerment Assessments .... 5-4
iv
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LIST OF ACRONYMS
ADI Acceptable Daily Intake
AO Administrative Order
ATSDR Agency for Toxic Substances and Disease Registry
CASR Chemical Activities Status Report
CERCLA Comprehensive Environmental Response,
Compensation and Liability Act
ECAO Environmental Criteria and Assessment Office
EPA Environmental Protection Agency
FS Feasibility Study
GEMS Graphical Exposure Modeling System
HI Hazard Index
LOAEL Lowest-Observed-Adverse-Effect Level
NCP National Contingency Plan
NEIC National Enforcement Investigations Center
NOAEL No-Observed^Adverse-Effect Level
NOEL No-Observed-Effect Level
OAQPS Office of Air Quality Planning and
Standards
ODW Office of Drinking Water
OECM Office of Enforcement and Compliance Monitoring
OERR Office of Emergency and Remedial Response
OHEA Office of Health and Environmental
Assessment -__
ORD Office of Research and Development
OSW Office of Solid Waste
OTS Office of Toxic Substances
OWPE Office of Waste Programs Enforcement
OWRS Office of Water Regulations and
Standards /'
QA/QC Quality Assurance/Quality Control
RCRA Resource Conservation and Recovery Act
REM/FIT Remedial Planning/FieId Investigation Team
RI Remedial Investigation
SPHAM Superfund Public Health Assessment Manual
TAT Technical Assistance Team
TES Technical Enforcement Support
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GLOSSARY
Acceptable Dally Intake - The amount of toxicant, in mg/kg body weight/day,
that will not cause adverse effects after chronic exposure to the general
human population.
Administrative Action - Any action that a statute or regulation authorizes EPA
to take, but does not involve filing papers with a court and is not part of
prosecuting a case already filed. Examples of administrative actions are
issuance of orders under Section 106 of CERCLA and Section 7003 of RCRA.
Dose-Response Assessment - The second step in the toxicity assessment process
which involves defining the relationship between the exposure level (dose) of
a chemical and the incidence of the adverse effect (response) in the exposed
populations.
Endangerment Assessment - A site-specific assessment of the actual or
potential danger to public health or welfare or the environment from the
threatened or actual release of a hazardous substance or waste from a site.
The endangerment assessment document is prepared in support of an enforcement
action under CERCLA or RCRA.
Enforcement Action - Any action taken pursuant to Section 106 of CERCLA or
Section 7003 of RCRA to compel responsible parties to respond to hazardous
conditions'. An enforcement action may include administrative actions and/or
judicial actions.
Exposure Assessment - One of the components of the endangerment assessment
process, the exposure assessment is a four-step process to identify actual or
potential routes of exposure, characterize populations exposed and determine
the extent of the exposure. /•
Exposure Evaluation - The section of the endangerment assessment document
which reports the results of the exposure assessment process.
Judicial Action - Any action that involves filing papers with a court or is
part of prosecuting a case already filed. Examples of judicial actions are
actions taken to seek injunctive relief or actions taken when a party fails to
comply with an administrative order.
LC - Lethal concentration at which 50% of the test organisms die.
—~j(j
LD - Lethal dose at which 50% of the test organisms die.
Lowest-Observed-Adverse-Effect Level (LOAEL) - The lowest dose of a chemical
in a study that produces statistically or biologically significant increases
in the frequency or severity of adverse effects between the exposed population
and an appropriate control.
vi
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No-Observed-Adverse-Effect Level (NOAEL) - That dose of a chemical at which
there are no statistically or biologically significant increases in the
frequency or severity of adverse effects between the exposed population and an
appropriate control.
No-Observed-Effect Level (NOEL) - That dose of a chemical at which there are
no statistically or biologically significant increases in the frequency or
severity of effects between the exposed population and an appropriate control.
Risk Characterization - The final component of the endangerment assessment
process which integrates all of the information developed during the exposure
and toxicity assessments to yield a complete characterization of the actual or
potential risk at a site.
Risk and Impact Evaluation - The section of the endangerment assessment
document which reports the results of the risk characterization process.
Toxicity Assessment - One of the components of the endangerment assessment
process, the toxicity assessment is a two-step process to determine the nature
and extent of health and environmental hazards associated with exposure to
contaminants of concern present at the site. It consists of toxicological
evaluations and dose-response assessments for contaminants of concern.
Toxicity Evaluation - The section of the endangerment assessment document
which reports the results of the toxicity assessment process.
Toxicity Profile - A summary of the available human health or environmental
toxicity data on a contaminant. This document considers doses used, routes of
exposure, types of adverse effects manifested and definitive statements of
quantitative indices of toxicity.
Toxicological Evaluation - The first step in the toxicity assessment process /
which is a qualitative evaluation of the scientific data to determine the
nature and severity of actual or potential health and environmental hazards
associated with exposure to a chemical substance. The end product of the
toxicolpgical evaluation is a toxicity profile for each of the contaminants of
concern.
Unit Cancer Risk - Excess lifetime risk of cancer due to a continuous lifetime
exposure of one unit of carcinogen concentration.
vii
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1.0 INTRODUCTION
Current U.S Environmental Protection Agency (EPA) policy states that an
endangerment assessment is required to support all administrative and judicial
enforcement actions under Section 106(a) of the Comprehensive Environmental
Response, Compensation and Liability Act of 1980 (CERCLA) and Section 7003 of
the Resource Conservation and Recovery Act of 1976 (RCRA).
This Handbook makes a distinction between:
• The endangerment assessment process which evaluates the collective
demographic, geographic, physical, chemical and biological factors
at a site to determine whether there is a significant risk to public
health or welfare or the environment as a result of a threatened or
actual release of a hazardous substance or waste; and
• The endangerment assessment document which summarizes the findings
of the assessment process in a concise format and documents EPA's
assertion that an imminent and substantial endangerment to public
health or welfare or the environment may exist at a site targeted
for enforcement actions.
1.1 Purpose and Scope of the Endangerment Assessment Handbook
This Handbook provides guidance to EPA regional, state and contractor personnel
on conducting endangerment assessments and preparing the necessary documentation.
Its primary purpose is to assist individuals in the preparation of endangerment
assessment documents which will satisfy the enforcement needs of each case.
This Handbook is intended only as a supplement to the "Draft Endangerment
Assessment Guidance" prepared and distributed by EPA's Office of Waste Programs
Enforcement (OWPE) (USEPA 1985d) and should be used in conjunction with that
document, which is included in its entirety in Appendix 1 to this Handbook.
The Handbook explains the use of the endangerment assessment as an enforcement
tool and its relationship to the remedial investigation (RI) and feasibility
study (FS) processes at a site. It provides guidance on how to develop an
endangerment assessment and discusses the timing, scope and level of detail
that are required and how these factors may be affected by site-specific
enforcement concerns.
The Handbook also describes the relationship of the endangerment assessment
document to other documents generated for a site and provides instructions for
preparing the document. Finally, it identifies key references and other
sources of information and assistance.
A distinction between the endangerment assessment process and endangerment
assessment document is made throughout this Handbook to clarify the difference
between the complex, multi-disciplinary assessment process and the fairly
straightforward task of preparing a document which reports the conclusions of
the assessment process.
1-1
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EPA has recently completed guidance documents for planning and performing RI
and FS studies at Superfund sites:
• Guidance on Remedial Investigations Under CERCLA (USEPA 1985c)
• Guidance on Feasibility Studies Under CERCLA (USEPA 1985b)
A detailed instruction manual is being developed, designed to accompany the RI
and FS guidance documents, for conducting public health assessments at Super-
fund sites:
• Superfund Public Health Assessment Manual (ICF 1985)
Since the endangerment assessment process is similar to the public health and
environmental assessments which are conducted as part of the RI and FS, this
manual should be used as a technical reference when performing endangerment
assessments. To avoid unnecessary duplication of technical detail provided in
the Superfund manual, this Handbook directs the reader to this manual for
additional information where appropriate.
1.2 Handbook Organization
This Handbook is divided into six sections and five appendices in addition to
this Introduction:
2.0 Legislative and Programmatic Framework
3.0 Overview of the Endangerment Assessment Process
4.0 Guidelines for Conducting Endangerment Assessments
5.0 Preparation of the Endangerment Assessment Document
6.0 Sources of Information and Assistance
7.0 References
Appendix 1 Draft Endangerment Assessment Guidance
Appendix 2 Examples of Endangerment Assessments
Appendix 3 EPA's Proposed Assessment Guidelines
Appendix 4 Test Protocol Criteria for Animal Assays
Appendix 5 Definition of Toxicological Endpoints
Section 2.0 provides an overview of the legislative and programmatic framework
in which the endangerment assessment fits. It summarizes the legislative
background of the endangerment assessment process and discusses when an
endangerment assessment should be prepared and who should prepare it. The
relationship of the endangerment assessment process to the RI and FS processes
and the role of the endangerment assessment document in enforcement cases is
also discussed in this section.
Section 3.0 provides an overview of the.endangerment assessment process and
its components: contaminant identification, exposure assessment, toxicity
assessment and risk characterization. This section briefly describes the
objectives of each component and the information needed to complete each of
the assessments.
1-2
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Section 4.0 provides guidelines for conducting endangerment assessments. It
contains a discussion of the levels of detail required in an endangerment
assessment and discusses the steps required to complete the contaminant
identification, exposure assessment, toxicity assessment and risk characteriza-
tion components introduced in Section 3.0.
Section 5.0 describes the format, scope and content of the endangerment
assessment document. It provides specific instructions for completing each
required section of the document, sources of information and factors to be
addressed.
Section 6.0 provides information on the points of contact at EPA Headquarters
for additional information on the endangerment assessment process and the
requirements of an endangerment assessment document.
Section 7.0 is a list of references cited in this Handbook.
1-3
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2.0 LEGISLATIVE AND PROGRAMMATIC FRAMEWORK
2.1 Applicable Legislation
Section 106(a) of CERCLA states that "... when the President determines that
there may be an imminent and substantial endangerment to public health or
welfare or the environment because of an actual or threatened release of a
hazardous substance from a facility, he may . . . secure such relief as may be
necessary to abate such danger and threat,. . . ."
Section 7003 of RCRA states that "... upon receipt of evidence that the
handling, storage, treatment, transportation or disposal of any solid waste or
hazardous waste may present an imminent and substantial endangerment to health
or the environment, the Administrator may bring suit ... to immediately
restrain any person contributing to such handling, storage, treatment, transporta-
tion, or disposal or to take such other action as may be necessary."
Thus, Section 106(a) of CERCLA authorizes EPA to take judicial or administrative
action to compel responsible parties to respond to hazardous conditions
resulting from an actual or threatened release of a hazardous substance.
Likewise, Section 7003 of RCRA may be used as the authority under which EPA
may issue orders or file civil actions to compel responsible parties to
respond to hazardous conditions resulting from the handling, storage, treatment,
transportation or disposal of solid wastes or hazardous wastes.
2.2 Role of the Endangerment Assessment in Enforcement Cases
Before taking enforcement actions (i.e., judicial actions, administrative
actions) under Section 106(a) of CERCLA or Section 7003 of RCRA, EPA must be
able to properly document and justify its assertion that an imminent and
substantial endangerment to public health or welfare or the environment may
exist. The endangerment assessment provides this justification and docu-
mentation.
It is important to note at this juncture that "imminent" does not mean immediate
harm, rather, it means an impending risk of harm. Sufficient justification
for a determination of an imminent endangerment may exist if harm is threatened;
no actual injury need have occurred or be occurring. Similarly, "endangerment"
means something less than actual harm (USEPA 1985d).
The data collected at a site (i.e., contaminants present, quantities present,
environmental media affected, etc.) does not stand on its own; it must be
interpreted. The endangerment assessment document provides an interpretation
of the data which supports the "Findings of Fact" sections in the administra-
tive or judicial enforcement documents that may be prepared for a site.
2.2.1 When to Perform an Endangerment Assessment
The endangerment assessment document must be prepared before a CERCLA Section
106(a) or RCRA Section 7003 action is filed or issued. Therefore, the
endangerment assessment process should be initiated as soon as a site is
2-1
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£ife Systems, JHC.
identified as an enforcement site and administrative or judicial actions are
considered. The requirement for an endangerment assessment document should
not slow down the enforcement process at a site.
Only one endangerment assessment document should be prepared for a site. The
original document may then be revised, updated or amended throughout the site
development process as additional data become available.
Figure 2-1 illustrates the points in time when an enforcement action under
CERCLA, and the required endangerment assessment, may be initiated at a site.
The endangerment assessment may be performed:
1. Before issuance of an administrative order (AO) for removal actions;
2. As part of the RI/FS;
3. Before issuance of an AO or consent decree for responsible party
RI/FS or cleanup (i.e., remedial actions);
4. Before issuance of an AO to a Federal facility for cleanup; or
5. Before any judicial action is taken (i.e., case is filed).
Figure 2-1 also illustrates what site documentation may be available to
provide input to the endangerment assessment. Finally, since the endangerment
assessment may be performed at varying points in time to support different •-•-
enforcement actions, the level of detail in the document will vary on a
case-by-case basis. Figure 2-1 indicates what level of detail may be appro-
priate for endangerment assessments supporting CERCLA enforcement actions
performed at different points of time. The concept of varying levels of
detail in endangerment assessments is discussed more fully in Section 4.0.
While an endangerment assessment document must be prepared to support both
RCRA Section 7003 actions and CERCLA Section 106 actions, the circumstances
when Section 7003 orders are used and endangerment assessments must be pre-
pared differ under RCRA and CERCLA. Whereas the CERCLA Section 106 authority
initially relies on the discovery or notification of a release of hazardous
substances, the RCRA Section 7003 authority can be activated when the
Administrator possesses evidence "that the past or present handling, storage,
treatment, transportation or disposal of any solid waste or hazardous waste
may present (emphasis added) an imminent and substantial endangerment to
health or the environment" (42 USC Section 6973). Additionally, the Section
7003 authority extends to imminent hazards presented by a wider range of
hazardous constituents than CERCLA Section 106 authority. Section 7003 orders
cover constituents that fall under the definition of "solid wastes" (RCRA
Section 1004(27)) and "hazardous wastes" (RCRA Section 1004(5)) while CERCLA
Section 106 orders cover "hazardous substances" (CERCLA Section 104(14)).
Endangerment assessments must be prepared to support the issuance of an
administrative order or before judicial action is taken under RCRA Section
7003. But, unlike the CERCLA program, the RCRA program does not have a
2-2
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Discovery Or Notification
Of Release
ti£*&&&&&&^ —.~ ,
Preliminary Assessment And
Site Inspection
No Release Or
Threat Of Release
Terminate Activities
Removal
Not Required But
Remedial Action May
Be Necessary
*X Hazard Ranking
~ System (HRS)
. No Further
Action Necessary
1or2
National Priorities List (NPL)
Scoping of Response Actions
1or2
2\
2or3\
Remedial
Action Necessary
Remedial Investigation/
Feasibility Study
Remedial Actions
Implemented
1 \. Points At Which Endangerment Assessment May
^^j Be Performed (No. Indicates Level of Detail)
Site Documentation That May Provide
Input To Endangerment Assessment
£ife Systems, Jnc.
Removal Action
Appropriate
Removal Actions
Removal Action
Necessary
FIGURE 2-1 ROLE OF THE ENDANGERMENT ASSESSMENT IN CERCLA ENFORCEMENT CASES
2-3
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formalized RI/FS study process. Hence, the detailed information contained in
an RI/FS study that is available for use in the CERCLA endangerment assessment
may not be readily available to include in an endangerment assessment for
supporting Section 7003 orders.
For more information on Section 7003 orders, please see the "Final Revised
Guidance Memorandum on the Use and Issuance of Administrative Orders under
Section 7003 of the Resource Conservation and Recovery Act (RCRA)," dated
September 26, 1984.
2.2.2 Who Performs an Endangerment Assessment
Agency policy states that the Regions have the responsibility to assure that
endangerment assessments are performed. For assistance in performing
endangerment assessments, the Regions can draw on technical expertise avail-
able in their Regional offices, OWPE's Technical Support Branch, the Office of
Research and Development (ORD), the Agency for Toxic Substances and Disease
Registry (ATSDR) and/or contractor personnel available through the Technical
Enforcement Support (TES), Remedial Planning/Field Investigation Team (REM/FIT)
or Technical Assistance Team (TAT) contracts.
The only exception to EPA (Regions) performing the endangerment assessment is
if the responsible parties elect to perform the RI/FS pursuant to an AO. In
these cases, they will also, in effect, perform an endangerment assessment
because they will develop many or all of the elements of an endangerment
assessment as part of the RI/FS. Since 'subsequent enforcement actions (i.e.,
AOs requiring responsible parties to perform cleanup) rely on this endanger-
ment assessment for justification, close Regional oversight should be given to
this responsible party work.
2.2.3 Confidentiality of an Endangerment Assessment
The endangerment assessment document, and all supporting documentation, must
be considered enforcement confidential as long as an enforcement action is
pending. Document control procedures which should be implemented may include:
• Marking the cover page of all documents as "Privileged Work Product
Prepared in Anticipation of Litigation"
• Marking each page of all documents as "Enforcement Confidential"
• Limiting the distribution of all documentation
• Limiting the number of copies distributed
• Utilizing standard chain-of-custody procedures for the documents per
the National Enforcement Investigations Center (NEIC) manual
The endangerment assessment is no longer considered confidential when the
finalized document is distributed to the public.
2.3 Relationship of Enforcement Actions to Superfund Actions
The Hazardous Substance Response Trust Fund, commonly known as Superfund, was
established by CERCLA to finance the discovery of actual or threatened
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releases of hazardous substances into the environment and the development and
implementation of response actions at these uncontrolled hazardous waste
sites. To ensure that Superfund is used as effectively as possible, proce-
dures for use of the fund were incorporated into the revised National Contin-
gency Plan (NCP) (USEPA 1985c).
Section 104 of CERCLA authorizes EPA to initiate Superfund-financed response
actions as soon as an actual or threatened release of a hazardous substance is
discovered. All Superfund-financed response actions must be in accord with
the NCP.
As discussed previously, Section 106(a) of CERCLA authorizes EPA to take any
necessary enforcement actions to compel responsible parties to respond to
hazardous conditions resulting from an actual or threatened release of a
hazardous substance. Thus, if a potentially responsible party is identified
at any time during the development and implementation of Superfund-financed
response actions at a site, enforcement actions may be taken to compel the
potentially responsible party to conduct the cleanup itself or provide funds
for the government-conducted cleanup (i.e., reimburse Superfund costs). Any
response actions or remedies resulting from enforcement actions at Superfund
sites must be in accord with the procedures outlined in the NCP.
2.3.1 The RI and FS Processes
The NCP requires that a detailed RI and FS be conducted at each site targeted
for remedial response action under Sections 104 and 1.06 of CERCLA. The goal
of the RI is to obtain the necessary site data so the potential impacts on
public health or welfare or the environment can be evaluated and remedial
alternatives can be developed and selected. The goal of the FS is to develop
and evaluate alternative remedial actions (including the no-action alter-
native) in terms of cost, effectiveness and their engineering feasibility.
Thus, the RI emphasizes data collection and site characterization while the FS
emphasizes data analysis and an evaluation of alternative remedial actions.
For Superfund-financed sites, the NCP requires an analysis of impacts on
public health, welfare and the environment. Therefore, the RI and FS pro-
cesses require an assessment of the contamination at the site and the
potential impacts on public health or the environment from that contamination.
The RI assessments focus on the existing conditions at the site in performing
a baseline assessment or complete site characterization. Figure 2-2 illus-
trates when the site characterization assessments are performed in the RI
process. The FS assessments evaluate the potential impacts at the site
associated with each remedial alternative, including the no-action alter-
native. The no-action alternative analysis is, essentially, a baseline
assessment at the site against which all remedial alternatives are compared.
Figure 2-3 illustrates when this analysis of alternatives is performed in the
FS process.
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Scoping Remedial
Investigation
Sampling
Plan Development
Health And
Safety Planning
Institutional
Issues
>| Site Characterization
•.-I • Contamination Assessment
y • Public Health Assessment
?^ • Environmental Assessment
Bench/Pilot-Scale
Studies
Remedial
Investigation Report
Data and information required
for this assessment process
should be used in the preparation
of the endangerment assessment.
Adapted from EPA 1985c
FIGURE 2-2 THE REMEDIAL INVESTIGATION PROCESS
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Characterize Problem
and Identify
General Response
Actions
Formulate &
Develop
Alternatives &
Technologies
Technical
Screening
Environmental, Public
Health & Institutional
Cost Screening
Technical Analysis
Identify Alternative
Remedial Actions
Cost Analysis
±
Summary of
Alternatives
i
Institutional
Analysis
I Environmental.-,;'
>,',, Analysis ' /-;'
' yyy f*f'-* r, ff*fjj.f •. -.'' '
Data and information required
for this assessment process
should be used in the preparation
of the endangerment assessment.
Adapted from EPA 1985b
Final Feasibility
Report
FIGURE 2-3 THE FEASIBILITY STUDY PROCESS
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2.3.2 Relationship of the Endangerment Assessment Process to the RI and FS
Assessment Processes
The assessments performed during the RI and FS processes are very similar to
the endangerment assessment. Although the assessments are performed for
different reasons, the information requirements are similar and the assessment
methods used should be consistent. Therefore, in addition to this Handbook,
the guidance documents and instruction manuals prepared in support of the RI
and FS processes should be utilized when performing endangerment assessments.
Since a Superfund-financed site may become an enforcement site at any time
during the development and implementation of remedial response actions (see
Figure 2-1), documentation prepared for each program (e.g., Superfund and
Enforcement) should be complementary. Thus, if the RI and FS are essentially
complete when an enforcement action is initiated, the requirement for an
endangerment assessment may be fulfilled by the "Site Characterization" and
"Analysis of No-Action Alternative" sections of the RI and FS reports,
respectively. In this situation no separate endangerment assessment document
is required. Conversely, if an endangerment assessment is prepared prior to
completion of the RI and FS reports, it should address all the issues that are
required in the assessment sections of the RI and FS reports. The objective
should always be to reduce duplication of assessment efforts and documentation
at any given site. Figure 2-4 illustrates the interrelationship of the
endangerment assessment document required at enforcement sites and the RI and
FS reports required at Superfund sites.
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REMEDIAL
INVESTIGATION
Site
Characterization
• Contamination
Assessment
• Public Health
Assessment
• Environmental
Assessment
ENDANGERMENT
ASSESSMENT
Enforcement
Document
• Exposure Evaluation
• Toxicity Evaluation
• Risk and Impact
Evaluation
FEASIBILITY
STUCV
Analysis of
No Action Alternative
• Public Health
Analysis
• Environmental
Analysis
FIGURE 2-4 THE INTERRELATIONSHIP OF THE ENDANGERMENT ASSESSMENT DOCUMENT,
REMEDIAL INVESTIGATION REPORT AND FEASIBILITY STUDY REPORT
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REMEDIAL
INVESTIGATION
Site
Characterization
• Contamination
Assessment
• Public Health
Assessment
• Environmental
Assessment
ENDANGERMENT
ASSESSMENT
Enforcement
Document
• Exposure Evaluation
• Toxicity Evaluation
• Risk and Impact
Evaluation
FEASIBILITY
STUD/
Analysis of
No Action Alternative
• Public Health
Analysis
• Environmental
Analysis
FIGURE 2-4 THE INTERRELATIONSHIP OF THE ENDANGERMENT ASSESSMENT DOCUMENT,
REMEDIAL INVESTIGATION REPORT AND FEASIBILITY STUDY REPORT
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3.0 OVERVIEW OF THE ENDANGERMENT ASSESSMENT PROCESS
The overall objective of an endangerment assessment is to provide a determination
of the magnitude and probability of actual or potential harm to public health
or welfare or the environment by the threatened or actual release of a hazardous
substance (for a CERCLA action) or a hazardous waste (for a RCRA action). Tr.
general, this objective may be attained by identifying and characterizing the
following:
1. Hazardous substances and/or hazardous wastes present in all relevant
media (e.g., air, water, soil, sediment, biota);
2. Environmental fate and transport mechanisms within specified environ-
mental media, such as physical, chemical and biological degradation
processes and hydrogeological evaluations and assessments;
3. Exposure pathways and extent of expected exposure;
4. Populations at risk;
5. Intrinsic toxicological properties of specified hazardous substances
or hazardous wastes; and
6. Extent of expected harm and the likelihood of such harm occurring
(i.e., risk characterization).
An endangerment assessment is an evaluation and interpretation of the collective
demographic, geographic, physical, chemical and biological factors at a site
which describe the extent of the potential or actual harm. Thus, the process
of evaluating endangerment is multi-disciplinary, requiring the expertise of
scientists in several technical areas.
The endangerment assessment process is comprised of four separate components
which, collectively, address each of the six key areas identified above. The
endangerment assessment process is divided into these four components based on
the areas of technical expertise required to perform each. The four components
of the endangerment assessment process are:
1. Contaminant Identification
2. Exposure Assessment
.3. Toxicity Assessment
4. Risk Characterization
Figure 3-1 illustrates the endangerment assessment process and its four
components. The following sections provide a brief overview of each compon-
ent. Section 5 of this handbook describes how the information developed
during each component of the endangerment assessment process is presented in a
concise endangerment assessment document.
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i
Exposure
Assessment
Identify Contaminants
of Concern
Risk Characterization
-Endaogenrneot
Assessment
Document
Toxicity
Assessment
FIGURE 3-1 THE ENDANGERMENT ASSESSMENT PROCESS
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3.1 Contaminant Identification
The objective of this component is to screen the information available on
hazardous substances or wastes present at the site and identify contaminants
of concern. This screening process is necessary in order to focus subsequent
efforts in the endangerment assessment process on a few, selected contaminants.
Contaminants of concern may be selected based on their intrinsic toxicological
properties or because they are present in large quantities or because of
potentially critical exposure routes (i.e., being released into a drinking
water supply).
"Indicator chemicals" may have been selected as part of the RI/FS. In this
case, the endangerment assessment should focus on those chemicals. If "indi-
cator chemicals" have not yet been selected, the enforcement team must select
the contaminants of concern. The enforcement team may choose to select the
contaminants based on the methodology for selecting "indicator chemicals"
discussed in Chapter 4 of the SPHAM (2 CF 1985). The goal of the selection
process is to select the contaminants which encompass all of the relevant
physiochemical and toxicological properties of the contaminants present at the
site.
3.2 Exposure Assessment
The objectives of an exposure assessment are to identify actual or potential
routes of exposure, characterize the exposed populations and determine the
extent of the exposure. These objectives may be attained by performing the
following four steps:
1. Analyze contaminant release
2. Analyze environmental fate and transport
3. Analyze exposed populations
4. Estimate or calculate expected exposure levels (or doses incurred)
The first step, an analysis of contaminant releases from the hazardous waste
site, involves characterizing the contaminants of concern at the site and
determining the amount of each contaminant released to each environmental
medium.
In the second step the environmental fate and transport of the contaminants
are analyzed. The results of these analyses provide information on the
magnitude and extent of environmental contamination. The exposure routes
identified during this step will have varying levels of proof supporting their
evaluation, depending on the amount of field data available at the time the
exposure assessment is being performed.
The third step of an exposure assessment involves an analysis of exposed
populations. Exposed populations may include human populations, sensitive
subsets of the human population and/or fish and wildlife populations which may
be at risk. This analysis yields data on the magnitude of exposure and
identifies potential high-risk populations (i.e., children, women of child-
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bearing age, endangered or threatened wildlife populations, etc.). This step
may also involve the application of exposure coefficients. An exposure
coefficient combines information on the frequency, mode and magnitude of
exposure to yield a value representative of the amount of contaminated medium
contacted per day.
The final s,tep in an exposure assessment integrates the results of the pre-
ceding three steps to yield a qualitative or quantitative estimate of the
expected exposure levels resulting from actual or potential releases of
contaminants from the site. Figure 3-2 illustrates the exposure assessment
process.
3.3 Toxicity Assessment
The objectives of the toxicity assessment are to determine the nature and
extent of health and environmental hazards associated with exposure to contami-
nants present at the site. It is a two-step process consisting of:
1. Toxicological Evaluation
2. Dose-Response Assessment
The first step in the toxicity assessment, the toxicological evaluation, is a
qualitative evaluation of the scientific data to determine the nature and
severity of actual or potential health and environmental hazards associated .
with exposure to a chemical substance. The toxicological evaluation involves
a critical evaluation and interpretation of toxicity data from epidemiological,
clinical, animal and jLn vitro studies and results in a toxicity profile for
each contaminant of concern. Toxicity profiles present a review of the
primary literature on the types of adverse effects manifested (e.g., chronic,
acute, carcinogenic, etc.), doses employed, routes of administration (e.g.,
oral, dermal, inhalation, etc.), the quality and extent of test data, the
reliability of the test data and other factors. Toxicity profiles provide the
weight-of-evidence that the contaminants of concern pose potential hazards to
human health or the environment.
Once the toxicological evaluation determines that a chemical is likely to
cause a particular adverse effect, the next step is to determine the potency
of the chemical. The second step in the toxicity assessment, the dose-response
assessment, is a quantitative estimation of risk from exposure to a toxic
chemical. It defines the relationship between the dose of a chemical and the
incidence of the adverse eff'ect.
The dose-response assessment for noncarcinogenic chemicals utilizes the
quantitative indices of toxicity (e.g., NOEL, NOAEL, LOAEL, LC^, etc.), which
were identified during the toxicological evaluation, and their respective
margins of safety to determine "acceptable levels" for the contaminants of
concern. "Acceptable levels" are defined as exposure levels which are not
anticipated to cause adverse effects. These "acceptable levels" may be
expressed in a variety of ways such as Acceptable Daily Intakes (ADIs),
Ambient Air Standards, Water Quality Criteria, etc.
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Contaminant Release
Analysis
Environmental Fate
and Transport
Analysis
Exposed Populations
Analysis
Calculation of
Exposure Levels
and Dose Incurred
Exposure
Assessment
FIGURE 3-2 THE EXPOSURE ASSESSMENT PROCESS
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The dose-response assessment for carcinogenic chemicals provides estimates of
the probability that a specific adverse effect will occur (e.g., unit cancer
risk or carcinogenic potency values). These estimates of probability are
derived using mathematical models of the dose-response relationship.
The end-product of a toxicity assessment is a qualitative description of thr
toxic properties of the contaminants of concern at the site and a quantitative
index of the toxicity for each contaminant at the site, if the data are
sufficient for such an assessment.
EPA has developed toxicity profiles on a large number of the contaminants that
are found at hazardous waste sites (see Section 4.4 of this Handbook for a
discussion of the available toxicity profiles). These toxicity profiles
characterize the adverse health and environmental effects that are anticipated
to result from exposure to these contaminants. Additionally, these profiles
define the "acceptable levels" for noncarcinogenic chemicals and the estimates
of unit cancer risk for carcinogenic chemicals. Endangerment assessments
should always utilize existing EPA toxicity profiles when they are available.
If there are no appropriate toxicity profiles available for-the contaminants
and exposure routes of concern, then the members of the endangerment assess-
ment team with the appropriate expertise will have to develop toxicity
profiles based on the current scientific literature.
Figure 3-3 illustrates the toxicity assessment process.
3.4 Risk Characterization
•
The final component of the endangerment assessment process, risk characteri-
zation, is the process of estimating the incidence of an adverse health or
environmental effect under the various conditions of exposure defined in the
exposure assessment. This objective is attained by integrating all of the
information developed during the exposure and toxicity assessments to yield a
complete characterization of potential or actual risk. The risk characteriza-
tion should address all types of potential or actual risks at the site
including:
1. Carcinogenic risks
2. Noncarcinogenic risks
3. Environmental risks
4. Risks to public welfare
The final assessment should include a summary of the risks associated with a
site and such factors as the weight-of-evidence associated with each step of
the process, the estimated uncertainty of the component parts, the distrib-
ution of risk across various sectors of the population, the assumptions
contained within the estimates, etc.
For carcinogens where risk estimation data are available (e.g., carcinogenic
potency values), crude estimates of the excess cancer risk at a site can be
obtained by multiplying the carcinogenic potency value by the current and
projected chronic exposure levels. The estimated excess cancer risks are then
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Route of Administration
(Inhalation, dermal, etc.)
Dose
(Acute, subchronic, chronic)
Types of Effects
(Local, systemic, etc.)
Reliability of Data
(Clinical studies versus
animal studies, etc.)
Mixture Effects
(Synergism, antagonism, etc.)
Toxicity
Assessment
1. Toxicological
Evaluation
2. Dose-Response
Assessment
FIGURE 3-3 THE TOXICITY ASSESSMENT PROCESS
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compared to acceptable risk levels defined in regulatory legislation and
guidelines.
For noncarcinogenic effects, projected exposure levels are compared to "accep-
table levels" (e.g., ADI values or established criteria and standards)
identified during the toxicity assessment. Any time there is an actual or
projected exposure level which exceeds an "acceptable level" for that contam-
inant and exposure route, the risk at the site is considered unacceptable.
The risk characterization should evaluate the risks associated with each
projected exposure route for each contaminant of concern at a site.
Characterization of the environmental risks involves identifying the toxic
effects of exposures to the chemicals of concern to fish or wildlife popu-
lations. The environmental risk evaluation should also discuss what the
effects of exposure will be on indigenous species, on the food chain .and on
the habitat, since all of these factors affect the environmental quality at a
site.
The risk characterization should also include an evaluation of the potential
or actual risks to public welfare. Welfare risks may include adverse effects
on property values, future land uses, recreational and commercial activities,
public perception and opinion, quality of life, etc.
Figure 3-4 illustrates the risk characterization process.
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Toxicity
Assessment
Qualitative
or Quantitative
Indices of Toxicity
Exposure
Assessment
Predicted Exposure
Levels, Doses or
Environmental
Levels
Risk
Characterization
1. Carcinogenic risk
2. Non-carcinogenic risk
3. Environmental risk
4. Risk to public welfare
FIGURE 3-4 THE RISK CHARACTERIZATION PROCESS
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4.0 GUIDELINES FOR CONDUCTING ENDANGERMENT ASSESSMENTS
This section provides guidelines for conducting the few components of an
endangerment assessment, beginning with a discussion of the level of detail
required for each type of enforcement action. Although the steps required for
conducting the exposure and toxicity assessments and risk characterization are
identified, the details of how they are to be performed are not included in
this Handbook. The "Superfund Public Health Assessment Manual" (ICF 1985),
currently under development as an instruction manual to accompany the RI and
FS guidance documents, will provide details for performing the components of
the endangerment assessment process.
The endangerment assessment process is very similar to the baseline assessments
performed during the RI and FS process. Although the assessments at Superfund
and enforcement sites are performed for different reasons, the information
requirements for each type of assessment are similar and the assessment methods
used should be consistent. Therefore, the assessment methodologies detailed
in the RI and FS instruction manuals cited above should be utilized, in
conjunction with this Handbook, when performing endangerment assessments..
Table 4-1 outlines the relationship between the endangerment assessment steps
identified in this Handbook and the appropriate chapters in the RI and FS
instruction manuals.
4.1 Level of.Detail
It is EPA policy that endangerment assessments should be undertaken only to
the extent "necessary and sufficient" to fulfill the requirements of legal
enforcement proceedings. The endangerment assessment level of detail should
be limited to the amount of information needed to sufficiently demonstrate an
actual or potential imminent and substantial endangerment.
The level of detail required to sufficiently demonstrate endangerment will
vary depending on:
1. Type of enforcement action (e.g., AO for removal versus litigation)
2. Type of response action (e.g., removal versus remedial action)
3. Stage of response action (e.g., RI/FS workplan versus RI/FS
completed)
The level of detail required to support a particular enforcement action will
ultimately be determined on a case-by-case basis by the litigation team.
The levels of detail required actually represent a continuum from the quali-
tative to the quantitative. For simplicity's sake, however, three succinct
levels of detail have been defined: Level 1 (qualitative), Level 2 (semi-
quantitative) and Level 3 (quantitative).
4.1.1 Level 1 ("Qualitative")
Level 1 endangerment assessments are generally prepared to support AOs for
removal actions, a responsible party RI/FS or preliminary scoping activities.
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TABLE 4-1 RELATIONSHIP BETWEEN THE ENDANGERMENT ASSESSMENT
HANDBOOK AND THE SUPERFUND PUBLIC HEALTH
ASSESSMENT MANUAL (SPHAM)
Steps Identified in the
Endangerment Assessment Handbook
1.0 CONTAMINANT IDENTIFICATION
2,.0 EXPOSURE ASSESSMENT
2.1 Contaminant Release Analysis
2.2 Environmental Fate Analysis
2.3 Exposed Population Analysis
2.4 Calculation of Dose Incurred
3.0 TOXICITY ASSESSMENT
3.1 Toxicological Evaluation
3.2 Dose-Response Assessment
4.0 RISK CHARACTERIZATION
4.1 Noncarcinogenic Risks
4.2 Carcinogenic Risks
4.3 Environmental Risks
4.4 Public Welfare Risks
Chapters in the
in which the Steps are Discussed
5
5
5
6
7
7
8
8
(a) SPHAM = Superfund Public Health Assessment Manual (ICF 1985)
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Level 1 endangerment assessments are also applicable for those cases when time
becomes a factor in the enforcement action. An example of a situation in
which a "quick and dirty" assessment may be necessary is a case where the
responsible party is going to declare bankruptcy and EPA must file an enforce-
ment action very quickly in order to assure the financial liability of the
responsible party.
Basically, the information to satisfy the requirements for a Level 1 endangerment
assessment can be covered by the Action Memorandum developed by the regions to
support emergency removal actions. It is based entirely on existing data
which may include the Hazard Ranking System evaluation, preliminary site
assessment and site inspection report (if available). The "Findings of Fact"
in an AO for remedial actions may serve as a Level 1 endangerment assessment
and vice versa.
A Level 1 endangerment assessment must characterize the physical description
of the site and identify contaminants detected or suspected to be at the site.
A brief discussion of the toxic properties of the contaminants present should
be sufficient to justify EPA's contention that imminent and significant risk
of harm to human life or health or the environment may exist or exists.
4". 1. 2 Level 2 ("Semi-Quantitative")
A Level 2 endangerment assessment may be developed to support an AO or consent
decree for responsible party cleanup. It will be based on existing information
on the site, including the Hazard Ranking System evaluation, preliminary site
assessment and site inspection reports. Additional information that may be
available include the RI/FS workplan and preliminary health effects and
exposure studies.
A Level 2 endangerment assessment must completely characterize, the site
contamination and provide preliminary exposure and toxicity assessments. The
toxicity assessment will generally rely on existing standards and guidelines
for the contaminants of concern at the site. The risk characterization will
be "semi-quantitative" in nature and should identify any data gaps and recommend
additional studies, if necessary.
4.1.3 Level 3 ("Quantitative")
A Level 3 endangerment assessment is required for sites targeted for litigation
after completion of the RI/FS and will be used to support any subsequent AOs
or judicial actions seeking design and construction remedies.
It will be based on all existing data gathered during the RI/FS. For sites
with enforcement potential, EPA regions should review the RI/FS workplan to
ensure that information developed as part of the RI/FS will be sufficient to
perform a-quantitative endangerment assessment.
A Level 3 endangerment assessment must provide a. detailed characterization of
the site and, when possible, quantitative exposure and toxicity assessments
for the contaminants present. The Level 3 endangerment assessment differs
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from the Level 2 in that actual exposure levels should be developed, using
state-of-the-art modeling techniques. Likewise, in the absence of existing
standards and guidelines for the contaminants of concern, the Level 3 en-
dangerment assessment should generate quantitative indices of toxicity (e.g.,
"acceptable levels," unit cancer risk estimates, etc.) for use in the charac-
terization of risks at the site. The risk characterization will be a
quantitative evaluation of the risk assessment values for each probable
exposure scenario.
A Level 3 endangerment assessment may be performed concurrently with the FS
evaluation of the no-action alternative. The FS may provide input to the
endangerment assessment although the purposes and objectives of the two
documents are different. In some cases, a quantitative assessment will still
not be possible at the RI/FS stage due to data limitations.
Table 4-2 presents a summary of guidelines for determination of the levels of
detail required for each type of enforcement action. The guidelines are
flexible and may shift on a case-by-case basis as required to support a
particular enforcement action. The matrix should help determine what consti-
tutes an adequate endangerment assessment for a particular enforcement action.
Table 4-3 summarizes the site-specific documentation that may be available to
prepare the endangerment assessment document for each level of detail.
4.2 Contaminant Identification Guidelines
The first component of the endangerment assessment process is the identifi-
cation of contaminants of concern.. The objective of this component is to
narrow the field of contaminants at the site to those that either pose the
greatest potential of release or the greatest toxic threats.
Identification of contaminants of concern is an informal screening process
performed with the input of all members of the endangerment assessment team.
The best professional judgment of the endangerment assessment team results in
selection of contaminants of concern which represent a range of the physio-
chemical and toxicological properties of the contaminants at the site.
This screening process corresponds to the "Selection of Indicator Chemicals"
process described in the Superfund Public Health Assessment Manual (SPHAM)
(ICF 1985). The Superfund process for selecting indicator chemicals is a
four-step process which evaluates the environmental concentrations and toxi-
cological properties of the contaminants. The steps of this process are:
1. Identify contaminants present at the site.
2. Record environmental concentrations from site sampling data.
3. Calculate indicator scores for all chemicals (based on concentration
and toxicity).
4. Select indicator chemicals (based on indicator scores).
If indicator chemicals have been selected at a site (i.e., site was a Super-
fund site prior to the initiation of enforcement actions), they should be used
as the contaminants of concern for the endangerment assessment. If indicator
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TABLE 4-2 GUIDELINES FOR LEVEL OF DETAIL IN ENDANGERMENT ASSESSMENTS
(a)
Level of
Detail
Level 1
Enforcement
* Action
AQ for removal
action, AO for
PRP RI/FS, pre-
liminary
scoping.
Data Base
-P-
i
Ln
Level 2
Issuance of AO
or consent
decree for
responsible
party cleanup.
May be limited, probably
consisting of information
from the Preliminary Site
Assessment, Site Inspec-
tion Report, and Hazard
Ranking System evalua-
tion, if completed. No
health studies available;
no demographic studies
available. Preliminary
sampling data will
probably be available on
pollutants present. Data
on extent of release or
concentrations of
materials at the point of
exposure may be
available.
Remedial Investigation
complete or other quan-
titative data available
on nature/extent of
release. Data available
on magnitude and demo-
graphics of population at
risk. Possibly some
preliminary health
effects studies. Sources
and specific materials
associated with release
are identified.
Type of Assessment
Qualitative assessment of
exposure routes, popula-
tion at risk and
probability
of harm. Critical.
pollutants and their
toxicological properties
can be readily identified
and quantity of pollu-
tants estimated.
Reasonable and prudent to
conclude that an exposure
may exist because of the
release.
Remarks
Semi-quantitative apprais-
al considering specific
exposure routes and
critical pollutants. The
assessment should
identify any data gaps
and recommend additional
studies, if necessary.
For removal actions where
the normal site ranking
process has not been
completed or undertaken,
information for the
assessment may be
available from record
searches, State-sponsored
investigations, written
reports from inspections
by Government authorities
and notification in
accordance with CERCLA
Section 103.
This assessment must be
able to support legal
action in the event it is
challenged by a recalci-
trant responsible party.
Should be conclusive
enough that responsible
parties will be encour-
aged to make a firm
commitment to complete
remedial action.
continued-
(a) The guidelines are flexible and may shift on a case-by-case basis as required to support a particular
enforcement action.
-------
Table 4-2 -.continued
Level of
Detail
Level 3
Enforcement
Action
Litigation
(site-by-site
basis).
Data Base
RI and FS complete. All
required geological and
hydrogeological studies
complete. Health studies
may be available.
Type of Assessment
Detailed, quantitative
review to identify
potential health effects,
critical exposure levels
and necessary follow-up
health studies. Critical
pollutants and exposure
routes identified and
existing exposure levels
defined or estimated.
Constitutes an appraisal
based on the best
expertise and knowledge
and an estimate of the
uncertainty.
Remarks
This assessment must be
able to support legal
action in the event it is
challenged by a recalci-
trant responsible party.
Should be conclusive
enough that responsible
parties will be encour-
aged to make a firm
commitment to complete
remedial action.
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TABLE 4-3 SITE-SPECIFIC DOCUMENTATION AVAILABLE FOR THE
PREPARATION OF ENDANGERMENT ASSESSMENTS
Availability for Levels of Detail
Site-Specific Documentation
Preliminary Site Assessment
Site Inspection Report
Hazard Ranking System
Evaluation
Remedial Investigation/
Feasibility Study
Epidemiological Studies
Demographic Studies
Sampling Studies
Exposure Studies
Health Effects Studies
Geological Studies
Hydrogeological Studies
Qualitative
(Level 1)
Probable
Probable
Probable
No
Semi-
Quantitative
(Level 2)
Yes
Yes
Yes
Possible
Quantitative
(Level 3)
Yes-
Yes
Yes
Yes
No
No
Possible
Possible
No
Possible
Possible
Possible
Possible
Probable
Probable
Possible
Probable
Probable
Possible
Yes
Yes
--.- Yes
Possible
Yes
Yes
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chemicals have not been selected, the endangerment assessment team will select
the contaminants of concern, possibly based on the methodology discussed in
Chapter 4 of the SPHAM (ICP 1985).
4.3 Exposure Assessment Guidelines
This section of the Handbook is intended to serve as a guide for individuals
responsible for conducting exposure assessments. It identifies and describes
the necessary steps in an exposure assessment and provides general information
for performing each of the required steps. This section is not intended to
serve as a definitive guide on how to perform specific exposure assessment
procedures. For this type of information, the reader is referred to the
SPHAM (IGF 1985). Additional guidance documents for performing exposure
assessments include Callahan et al. (1983), McNeils et al. (1984), Schultz et
al. (1984) and USEPA (1984).
The exposure assessment should evaluate all existing exposure routes and those
which may reasonably be anticipated to exist in the future. For example, if
land use development documents indicate that a site located in a currently
rural or industrial area is scheduled for residential development, then the
exposure assessment should develop exposure scenarios evaluating the current
risk, as well as the risks associated with predicted residential use patterns.
The exposure scenarios developed will depend on site-specific technical and
legal considerations. Generally, an exposure assessment for an endangerment
assessment should present the "worst probable case" exposure scenarios. The
exposure assessment at a site prior to any removal~or remedial actions may be
significantly different from an exposure assessment at the same site following
completion of the RI/FS (i.e., a removal action at the site may have altered
the exposure routes). Thus, the exposure assessment should always consider
the type of enforcement action the endangerment assessment is intended to
support. The best professional judgment of the experts on the endangerment
assessment team will be the basis for establishing whicli exposure scenarios
should be developed for each site.
The objectives of an exposure assessment are to identify actual or potential
routes of exposure, characterize the populations exposed and determine the
extent of the exposure. These objectives may be attained by performing the
following four steps:
1. Analyze contaminant release
2. Analyze environmental fate and transport
3. Analyze exposed populations
4. Estimate or calculate expected exposure levels (or doses incurred)
This section presents information on conducting each of these analyses.
Table 4-4 identifies the individual steps required to 'complete an exposure
assessment, the endangerment assessment level of detail to which they apply
and the locations in this Handbook where they are discussed.
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TABLE 4-4 EXPOSURE ASSESSMENT STEPS
Exposure Assessment Step
1.0 Contaminant Release Analysis
1.1 Identify Information Required
1.2 Evaluate Contaminant Release to
Environmental Media
1.3 Quantify Contaminant Release to
Environmental Media
2.0 Environmental Fate and Transport
Analysis
2.1 Identify Potential Points of
Environmental Contamination
2.2 Evaluate Environmental Fate and
Transport Processes
2.3 Quantify Environmental Fate and
Transport Processes
3.0 Exposed Population Analysis
3.1 Identify Exposed Populations
3.2 Characterize Populations
3.3 Analyze Population Activity
3.4 Identify/Develop Exposure
Coefficients
4.0 Calculation of Dose Incurred
4.1 Determine Population Exposure
Level
4.2 Estimate Dose Incurred
Level of .
Detailta)
1 2 3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Applicable
Handbook Sections
4.0
4.3.1
4.3.2
4.3.3
4.3.4
5.0
5.1
5.2
5.3
5.3
(a) X indicates the level of endangennent assessment (e.g., Level 1, 2 or 3)
for which this step must be performed.
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4.3.1 Contaminant Release Analysis
The contaminant release analysis involves the identification of each on-site
source of release for the contaminants of concern. The results of this
analysis provide the basis for the next step in the exposure assessment
process, environmental fate analysis.
In order to evaluate the probability and extent of contaminant releases from a
hazardous waste site, the following information is required:
1. Identity of contaminants at the site
2. Physical/chemical properties of the contaminants
3. Climatological site parameters
4. Hydrogeological site parameters
5. Location and manner of waste placement
Each potential source of contaminants must be identified and evaluated to
determine its likely contribution to overall contaminant release. The nature
of the contaminants involved and the probable magnitude of release are also
evaluated.
Contaminant release analysis for Level 1 endangerment assessments consists of
identifying and characterizing the information identified above. A qualitative
description of the sources of contaminants and the relative importance of each
source is sufficient for a Level 1 endangerment assessment.
Quantitative analyses of'contaminant releases from hazardous waste sites (for
Level 2 and 3 endangerment assessments) are initiated by an evaluation of the
available data to determine their accuracy and completeness. Following this
initial evaluation, each source of contaminant release is analyzed and total
releases (i.e., mass loadings) to each environmental medium (e.g., atmosphere,
surface water, soil, ground water) are evaluated and quantified. Potential
sources of contaminant release to each medium are outlined below:
1. Atmospheric Contamination - Emissions of contaminated fugitive dusts
(airborne wastes and contaminated soil particles) and volatilization
of contaminants are the most likely sources of atmospheric contamination
2. Surface-Water Contamination - Contaminated runoff and overland flow
of contaminants (from leaks, spills, etc.) are the most likely
sources of surface water contamination.
3. Ground-Water Contamination - The leaching of toxic contaminants from
contaminated soils or vertical migration of toxics from lagoons and
ponds are the most likely sources of ground-water contamination.
4. Soil Contamination - Sources of surface soil contamination include
intentional placement of waste on or in the ground, or as a result
of spills, lagoon failure or contaminated runoff. Toxic contami-
nants can also be leached from surface soils to subsurface layers.
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Schultz et al. (1984) discusses the methods available to evaluate and quantify
each of these factors (e.g., atmospheric, surface-water, ground-water and soil
contamination).
Level 2 endangerment assessments should report the results of any monitoring
studies available for each of these factors. If there are insufficient
monitoring data available to quantify contaminant releases to these media, the
Level 2 endangerment assessment should present a discussion of the site
characteristics which affect the probability or likelihood of contamination of
each media occurring at the site.
Level 3 endangerment assessments may utilize computer modeling techniques to
arrive at estimates of the average and'maximum contaminant release to each
media. These quantitative estimates are required for the subsequent calculations
of actual and projected exposure levels at the site.
An overview of the contaminant release analysis process is shown in Figure 4-1.
4.3.2 Environmental Fate and Transport Analysis
The purpose of the environmental fate and transport analysis is to determine
the potential for off-site migration of contaminants from on-site sources
identified during the qualitative release analysis. The analysis of environ-
mental fate and transport results in identification of probable points of '
contamination associated with a hazardous waste site. The results of this
analysis provide the basis for the next step in the exposure assessment
process, the exposed population analysis.
A qualitative environmental fate and transport analysis (i.e., Level 1 endanger-
ment assessment) is based on information on the physical/chemical properties
of the contaminants, the manner of their placement at the site and relevant
climatological and hydrogeological site parameters. This information was
identified during the contaminant release analysis. Intermedia transport
processes (e.g., adsorption, volatilization, infiltration, bioaccumulation)
and intramedia transformation processes (e.g., photolysis, hydrolysis, oxidation
and biodegradation) which potentially affect migration of the contaminants of
concern are identified and characterized in the Level 1 endangerment assessment.
This information is used to identify potential points of environmental contami-
nation. An overview of the environmental fate and transport analysis for
Level 1 endangerment assessments is shown in Figure 4-2.
Level 2 and 3 endangerment assessments require a more quantitative environmental
fate and transport analysis to generate estimates of the direction of movement
of contaminants and the ambient concentrations of contaminants in various
environmental media. The average release rate estimates derived during the
contaminant release analyses are used as input.
**
In general, the environmental fate and transport analysis for Level 2 endanger-
ment assessments evaluates the transport pathways within each medium but does
not take into consideration transfer and transformation processes. The Level
2 endangerment assessment should report any ambient monitoring data and
4-11
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Identify Information
Required (Level 1)
Evaluate Releases to
Environmental
Media (Level 2)
Quantify Releases to
Environmental
Media (Level 3)
Contaminant
Identity
Physical/
Chemical
Properties Data
Hydrogeological/
Climatological
Parameters
Waste
Placement
Data
«
Atmospheric ;
Evaluation
Surface Water
Evaluation
Ground Water
Contamination
Evaluation
Soil
Evaluation
Quantify Average
and Maximum Releases
to Atmosphere
Quantify Average
finri Maximum Rplpa^p^
to Surface Water
Quantify Average
and Maximum Releases
to Ground Water
Quantify Average
and Maximum Releases
to Soil
Environmental
Fate and
Transport
Analysis
FIGURE 4-1 OVERVIEW OF CONTAMINANT RELEASE ANALYSIS
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Contaminant Release
Analysis
Intermedia Transport
Processes
(Adsorption, volatilization,
infiltration, bioaccumulation)
Intramedia Transformation
Processes
(Photolysis, hydrolysis,
oxidation, biodegradation)
Identification of
Points of
Environmental
Contamination
FIGURE 4-2 OVERVIEW OF ENVIRONMENTAL FATE AND TRANSPORT ANALYSIS FOR
LEVEL 1 ENDANGERMENT ASSESSMENTS
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provide conservative estimates of final ambient concentrations and the extent
of hazardous substance migration.
Level 3 endangerment assessments require more in-depth assessments of environ-
mental fate and transport. Modeling procedures usually must be applied to
quantify atmospheric fate, surface-water fate, ground-water fate and biotic
pathways. One relevant set of models for this purpose is the Graphic Exposure
Modeling System (GEMS) (USEPA 1982). GEMS provides access to models capable
of assessing the fate of contaminants in air, surface water, ground water and
soil. Table 4-5 identifies the current components of GEMS. Schultz et al.
(1984) discuss further the available methods for quantitative environmental
fate and transport analyses.
An overview of the environmental fate and transport analysis process for Level
2 and 3 endangerment assessments is shown in Figure 4-3.
4.3.3 Exposed Population Analysis
The exposed population analysis provides an evaluation of the expected degree
of human population contact with contaminants emanating from the site. The
results of this analysis are used in estimating or calculating exposure levels
and doses incurred by the exposed populations.
The exposed population analysis involves the following four steps:
1. Identification of exposed populations
2. Characterization of population
3. Analyses of population activities
4. Development of exposure coefficients
The first step requires comparing data on environmental contamination with
population data in order to identify and enumerate those populations (human
and environmental) that will potentially or actually be exposed to the contami-
nant (s) of concern. The second step, population characterization, involves
identifying those groups (e.g., infants, elderly, women of child-bearing age,
endangered or sensitive wildlife species) within the exposed populations which
may experience a greater risk than the average population as a result of a
given exposure level. The third step, activity analysis, involves an examina-
tion of the activities (e.g., employment, recreation) of potentially or
actually exposed populations in order to define the extent or level of expo-
su're of the previously identified and characterized populations.
The final step of the exposed population analysis is the identification of
exposure coefficients. The exposure coefficient combines information on the
frequency and magnitude of contact with contaminants to yield a quantitative
value of the amount of contaminated medium contacted per day. Exposure
coefficients are developed for each exposure route and are used as input in
calculating the dose incurred. An example of an exposure coefficient would be
the .average daily intake of drinking water or pounds of fish consumed in a
week, etc. Schultz et al. (1984) provide lists of exposure coefficients that
may be required for exposure assessments at hazardous waste sites.
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TABLE 4-5 COMPONENTS OF EPA's GRAPHICAL EXPOSURE MODELING SYSTEM (GEMS)
Models
ATM/SECPOP:
PTMAX:
PTDIS:
BOXMOD:
EXAMS:
SESOIL:
ENPART:
Atmospheric transport model (ATM) and a population
distribution retrieval program (SECPOP).
Produces analysis of maximum atmospheric concentration
as a function of wind speed and atmospheric stability.
Calculates downwind atmospheric concentration at ground
level at various downwind distances.
Interactive simple atmospheric box model for screening
chemicals.
Evaluates behavior of synthetic organic chemicals in
aquatic ecosystems.
Long-term environmental fate simulation model for
water, sediment and pollutant transport/transformation.
Environmental partitioning model.
Physiochemical Property Estimation Programs
SFILES: Molecular structure diagrams.
CLOGP: Estimates octanol-water partition coefficient (log P)
CHEMEST: Estimates physiochemical properties of organics.
Data Files
GEOECOLOGY DATA BASE: County-level data on a variety of environmental
parameters.
IFD/GAGE:
Point source discharges and stream gaging stations.
MASTER AREA REFERENCE U.S. Census data for small geographic areas.
FILE 1980 CENSUS:
METEOROLOGICAL DATA: Stability Tubular Array (STAR) data for >300
first-order weather stations.
ZIP CODE FILE:
CANONICAL ENVIRON-
MENTS DATA:
Associates zip codes with Federal Information Processing
System (FIPS) codes.
Model input parameters for major U.S. river systems,
lakes and reservoirs.
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Average Atmospheric
Release Data
Average Surface Water
Release Data
Average Ground Water
Release Data
Average Soil Release
Data
Atmospheric
Fate
Analysis
Surface Water
Fate
Analysis
Ground Water/
Soil Fate
Analysis
Biotic
Pathways
Analysis
Quantify Average and
Maximum Atmospheric
Concentration
Quantify Average and
Maximum Surface
Water Concentration
Quantify Average and
Maximum Ground Water/
Soil Concentration
Quantify Biotic
Concentrations
of Contaminants
Exposed
Population
Analysis
FIGURE 4-3 OVERVIEW OF ENVIRONMENTAL FATE AND TRANSPORT ANALYSIS FOR
LEVEL 2 AND 3 ENDANGERMENT ASSESSMENTS
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jCifc Systems, Jnc.
Level 1 endangerment assessments should identify the exposed populations and
provide a brief characterization of the population. This is a descriptive
analysis which should not require quantitative census or survey data. Level 2
and 3 endangerment assessments will utilize available census and survey data
to provide quantitative assessments of the exposed populations.
An overview of the exposed population analysis process is shown in Figure 4-4.
4.3.4 Calculation of Exposure Level and Dose Incurred
Schaum (1984) presents a discussion of the specific exposure assessment
methods that should be used in estimating the dose incurred. The following
discussion outlines the general steps that are required in performing this
ultimate step in an exposure assessment.
The term "exposure" may be defined as the amount of a contaminant that contacts
the boundaries of an organism (e.g., skin, lungs, or gastrointestinal tract),
while "dose" may be defined as the amount of that contaminant absorbed by the
organism. The fourth and final step in conducting an exposure assessment
requires a quantitative determination of the dose of contaminants incurred by
receptor populations. Accomplishing this task involves integrating the
results obtained during the first three steps of the exposure assessment
(Contaminant Release Analysis, Environmental Fate Analysis and Exposed Population
Analysis) to determine the cumulative dose of each contaminant incurred by
each population segment.
In calculating the dose incurred, an exposure coefficient is multiplied by the
chemical-specific environmental concentration values derived during the Contami-
nant Release Analysis. This calculation provides a route-specific estimate of
the total amount of each contaminant to which the population is exposed on a
daily basis. Summing the exposures for each exposure route yields a total
daily exposure level for each contaminant.
This exposure value must be adjusted to account for the extent to which each
chemical is transferred across the membranes of the exposed organism (i.e., the
extent of absorption). This adjustment is accomplished by multiplying total
daily exposure values by an absorption factor. Absorption factors are generally
available in the toxicity profiles discussed in Section 4.4 of this Handbook.
When empirically derived absorption factors are not available, an absorption
factor of unity is applied, thereby generating a conservative, worst-case
estimate of the dose incurred. Finally, this whole-body dose estimate (mg/day)
is converted to terms of mg of contaminant/kg of body mass/day by dividing it
by the body mass representative of the receptor population. EPA's Exposure
Assessment Group has prepared a report which contains ranges of standard
factors (i.e., body mass, surface area, etc.) for use in performing exposure
assessments. Use of these standard factors promotes consistency among all
exposure assessment activities (Anderson et al. 1984).
Since the risk characterization portion of a quantitative (Level 3) endangerment
assessment requires the development of average daily dose and maximum daily
dose estimates, two calculations of dose incurred must be performed. Estimates
4-17
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Data on Environmental
Concentrations of
Contaminants
I
I—'
oo
Available
Population
Data
Identification/
Enumeration of
Exposed
Populations
Population
Characteri-
zation
Activity
Analysis
Exposure
Coefficient
Development
Calculation
of Dose
Incurred
FIGURE 4-4 OVERVIEW OF EXPOSED POPULATION ANALYSIS
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£ife Systems, Jnc.
of average daily dose are calculated by multiplying the exposure coefficients
derived during the exposed populations analysis by the average environmental
concentration values. Estimates of maximum daily dose are calculated by
multiplying the exposure coefficients by the maximum environmental concentration
values.
Level 1 endangerment assessments are qualitative assessments which do not
require a calculation of estimated exposure levels or doses incurred. Level 2
and 3 endangerment assessments require an integrated exposure assessment which
quantifies exposure via all routes of exposure (inhalation, ingestion and
dermal) and all exposure pathways (e.g., surface water, atmosphere, ground
water, etc.). The uncertainty associated with the exposure values is a
fuaction of the input parameters throughout the exposure assessment process.
Level 2 and 3 exposure assessments must characterize the uncertainty associ-
ated with the final exposure and dose calculations. Whitmore (1984) provides
a methodology for characterizing the uncertainty in exposure assessments. All
exposure calculations for the endangerment assessment must be adequately
documented. Assumptions made in support of these calculations require justi-
fication in writing as part of the endangerment assessment.
An overview of the process for calculating the dose incurred is shown in
Figure 4-5.
4.3.5 Exposure Assessment References
Anderson E, Browne N, Duletsky~S et al. GCA Corporation. 1984. Development
of statistical distributions or ranges of standard factors used in exposure
assessment. Revised Draft Final Report. Washington, DC: U.S. Environmental
Protection Agency, Office of Health and Environmental Assessment, Exposure
Assessment Group. Contract No. 68-02-3510.
Callahan MA, Johnson RH, McGinnity JL et al. 1983. Handbook for performing
exposure assessments. Draft. Washington, DC: U.S. Environmental Protection
Agency, Office of Health and Environmental Assessment.
ICF Incorporated. 1985. Superfund public health assessment manual. Draft.
Washington, DC: U.S. Environmental Protection Agency, Office of Emergency and
Remedial Response. Contract No. 68-01-6872.
McNeils DN, Earth DC, Khare M et al. Environmental Research Center, Univer-
sity of Nevada at Las Vegas. 1984. Exposure assessment methodologies for
hazardous waste sites. Las Vegas, NV: Office-of Research and Development.
Environmental Monitoring Systems Laboratory. CR810550-01.
Schaum J. 1984. Short course on integration of exposure and risk assessment.
Part 3. Exposure assessment methods. Paper presented at the Annual Meeting
of the Society for Environmental Toxicology and Chemistry, Arlington, VA.
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Exposure Coefficient
Environmental Concentration
of Contaminant
Population Exposure
Level
Absorption Factor
Estimate of Dose
Incurred
FIGURE 4-5 OVERVIEW OF PROCESS FOR CALCULATING POPULATION
EXPOSURE LEVELS AND DOSE INCURRED
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Schultz HL, Palmer WA, Dixon GH et al. Versar Inc. 1984. Superfund exposure
assessment manual. Final Draft. Washington, DC: U.S. Environmental Protec-
tion Agency, Office of Toxic Substances, Office of Solid Waste and Emergency
Response. Contract Nos. 68-01-6271 and 68-03-3149.
USEPA. 1984. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for exposure assessment. Fed.
Regist., Nov. 23, 1984, 49 46314.
USEPA. 1982. U.S. Environmental Protection Agency. Office of Pesticides and
Toxic Substances. Graphical exposure modeling system (GEMS) user's guide.
Draft. Washington, DC: U.S. Environmental Protection Agency.
Whitmore RW. Research Triangle Institute. 1984. Methodology for character-
ization of uncertainty in exposure assessments. Washington, DC: U.S. Environ-
mental Protection Agency, Office of Health and Environmental Assessment,
Exposure Assessment Group. Contract No. 68-01-6826.
4.4 Toxicity Assessment Guidelines
This section of the Handbook is intended to serve as a guide for individuals
responsible for conducting toxicity assessments. It identifies and describes
the necessary steps required in a toxicity assessment and provides general
information on performing each of the required steps. The toxicity assessment
process is discus'sed briefly in the SPHAM (ICF 1985) . A more detailed
"diseuyylun of the—components of- the toxicity assessment process is provided in
"Toxicology Handbook: Principles Related to Hazardous Waste Site
Investigations" (ICAIR 1985) which is currently being prepared under the
direction of the Health Sciences Section, OWPE.
The objectives of the toxicity assessment are to determine the nature and
extent of health and environmental hazards associated with exposure to con-
taminants present at the site. The end-product is a toxicity profile for each
contaminant of concern. The toxicity profile is derived from current
toxicological literature on a contaminant. The profile includes consider-
ations of doses used, routes of exposure, types of adverse effects manifested
and definitive statements on quantitative indices of toxicity for the
contaminant.
The Office of Emergency and Remedial Response (OERR) and OWPE have prepared
toxicity profiles specifically for use in assessing toxicological risk at
hazardous waste sites. The Chemical Profiles prepared by OWPE briefly sum-
marize .the chemical and physical properties, fate and transport, health
effects and environmental toxicity levels for chemicals found most often at
hazardous waste sites. There are currently 183 Chemical Profiles available in
draft form from OWPE. OERR is preparing Health Effects Assessments on the
most commonly occurring chemicals at hazardous waste sites. The Health
Effects Assessments, being prepared for OERR by EPA's Environmental Criteria
and Assessment Office (ECAO), contain information on acceptable intake levels
for sub-chronic and chronic exposure from both ingestion and inhalation
pathways of exposure. There are currently 58 Health Effects Assessments
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available in draft form from OERR. Table 4-6 lists the chemicals for which
Chemical Profiles and Health Effects Assessments are currently available.
Other EPA offices have also prepared toxicity profiles on numerous chemicals.
The EPA Chemical Activities Status Report (CASK), a guide to EPA activities on
specific chemical substances, provides information on the status of the
activities and a point-of-contact in the appropriate EPA program office
responsible for the preparation of the toxicity profile (USEPA 1984f). The
types of toxicity profiles included in CASR are listed in Table 4-7. For
information on the availability of specific toxicity profiles, contact the
program office identified in Table 4-7.
If an acceptable EPA toxicity profile exists for a contaminant at the site in
question, it is unnecessary to re-create one for the Toxicity Assessment. The
existing profile should be briefly summarized and referenced in the endangerment
assessment document. However, if the existing profile focuses on a different
exposure route, or is more than three years old, it should be supplemented
with a search of the current literature.
When no toxicity profile is available, or the existing toxicity profile is
inadequate, the toxicologist on the endangerment assessment team must review
the current toxicological literature on the contaminant of concern and prepare
a suitable toxicity profile. This toxicological review and evaluation process
is known as the toxicity assessment. It is a two-step process consisting of a ,
toxicological evaluation and a dose-response assessment. Table 4-8 summarizes
the steps in the toxicity assessment process and identifies the endangerment
assessment level of detail to which they apply and the locations in this
Handbook where they are discussed.
4.4.1 Toxicological Evaluation
The toxicological evaluation is the first step in the toxicity assessment
process. It is a qualitative evaluation of the scientific data to determine
the nature and severity of potential health and environmental hazards associated
with exposure to a chemical substance.
The toxicological evaluation involves a critical evaluation and interpretation
of toxicity data from epidemiological, clinical, animal and j.n vitro studies
when human health effects are of concern and of ecotoxicity studies when
environmental effects are of concern. The toxicological evaluation results in
either a health or environmental toxicity profile (or both) for each contaminant
of concern. The toxicity profile presents a review of the primary literature
on the types of adverse effects manifested (e.g., chronic, acute, carcinogenic,
etc.), routes of administration (e.g., dermal, oral, inhalation, etc.), dose
employed, the quality and extent of test data, the reliability of the test
data and other factors.
The toxicity profile also identifies any quantitative indices of toxicity
reported in the literature, such as NOEL (no-observed-effect level), NOAEL
(no-observed-adverse-effect level), LOAEL (lowest-observed-adverse-effect
level), LC (concentration at which 50 percent of the test organisms die),
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TABLE 4-6 TOXICITY PROFILES PREPARED SPECIFICALLY FOR USE
AT HAZARDOUSE WASTE SITES
Chemical
OWPE
Chemical Profile
OERR Health
Effects Assessment
Acenaphthene
Acenaphthylene
Acetic acid
Acetone
Acrolein
Acrylonitrile
Aldrin
Anthracene
Antimony
Arsenic
Asbestos
Barium
Benzene
Benzidine
Benzo (a) anthracene
Benzo(a)pyrene
Benzothiazole
Beryllium
alpha-BHC
beta-BHC
gamma-BHC (lindane)
delta-BHC
Butanol
Butyl 'acetate
Cadir.iuir
Carbon tetrachloride
cls-Chlordane
trans-Chlordane ._.
Chlorine
Chlorobenzene
Chlorobenzilate
Chloroethane
Chloroform
p-Chloro-m-cresol
l-Chloro-3-nitrobenzene
bis ( 2-Chloroethoxy) ethane
•Chromium (total)
Chromium (hexavalent)
Chromium (trivalent)
Chrysene
Coal tars
Cobalt
Copper
Cresol
Cyanides
Cyanuric acid
p,p'-DDD
o,p'-DDD
p.p'-DDE
p,p'-DDT
o.p'-DDT
Dibromochloropropane
1 ,2-Dichlorobenzene
1 ,3-Dichlorobenzene
1 , 4-Dichlorobenzene
1 , 1-Dichloroethane
1 ,2-Dichloroethane
1 , i-Dichloroethylene
1 ,2-cis-Dichloroethylene
1 , 2-trans-Dichloroethylene
2 , 4-Dichlorophenol
2,4-Dichlorophenoxyacetlc acid
1 , 2-Dichloropropane
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
. X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
continued-
4-23
-------
Oft'Systems, Jnc.
Table 4-6 - continued
Chemical
OWPE
Chemical Profile
OERR Health
Effects Assessment
1 ,3-Dlchloropropane
1 ,3-Dichloropropene
Dicofol
Dleldrin
Diethyl benzene
Diethylene glycol
Diethyl phthalate
Dllsobutyl ketone
Dimethylaminoethyl methacrylate
Dimethyl aniline
Dimethylnltroaamine
2,4-Dimethyl pentane
2,4-Dimethylphenol
n-Dloctyl phthalate
1 , 4-Dioxane
Diphenyl ethane
End r in
Ethanol
bis(2-Chloroethyl) ether
Ether
Ethyl acetate
Ethylbenzene
Ethylene glycol
Ethyl hexanedlol
bis-2-Ethylhexyl phthalate
Ethyl toluene
Fluoranthene
Formaldehyde
Glycol ethers
Heptachlor
Heptane
Hexachlorobenzene
Hexachlorobutadiene
Hexachlorocyclohexane
Hexachlorocyclopentadiene
Hexachloroe thane
Hexachlorophene
Hexane
Iron
Isobutyl alcohol
Isopropyl benzene
Isopropyl ether
Lead
Lithium
Magnesium
Manganese
Mercury
Methacrylic acid
Methanol
Methyl chloride
2-Methyl dodecane
Methylene chloride
Methyl ethyl benzene
Methyl ethyl ketone
3-Methyl hexane
Methyl isobutyl ketone
Methyl methacrylate
Methyl parathion
2-Methyl pentane
3-Methyl pentane
2-Methyl- 1-pentene
2-Methyl tetradecane
2-Methyl trldecane
X
X
X.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
. X
X
x •
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
continued-
4-24
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jjfe Systems, JHC.
Table 4-6 - continued
OWE OERR Health
Chemical Chemical Profile Effects Assessment
Monethanolamine
Naphthalene
Nickel
Nitrocellulose
2-Nltrophenol
Pentachlorophenol
Pentadecane
Phenanthrene
Phenol
Phenyl ether
Phosphoric acid
Phosphorus
Picric acid
Polychlorinated blphenyls (PCBs)
Polychlorinated dibenzo-p-dioxin
Polycyclic aromatic hydrocarbons (PAHs)
Pyrene
Selenium
Silver
Sodium chlorate
Sodium cyanide
Sodium
Stoddard solvent
Sulfuric acid
1 ,2,4,5-Tetrachlorobcnzene
2 , 3 , 7 , 8-Te trachloro-
dihenzo-p-dioxin (TCDD)
1 , J ,2,2-Tetrachloroethane
Tetrachloroethylene .
Tetraethyl lead
Te t rahydro f uran
Tetramethyl benzene
Thallium
Titanium
Toluene
Toxaphene
1 ,?,3-Trichlorobenzene
1 ,2,4-Trichlorobenzene
1 >3,5-Trlchlorobenzene
2,3,6-Trichlorobenzoic acid
1,1,1 -Trlchloroethane
1 ,1,2-Trichloroe thane
Trichloroethylene
Trichlorof luorome thane
2,4, 5-Trichlorophenol
2,4,6-Trichlorophenol
2,4,5-Trichlorophenoxyacetic acid
2,4,5-Trichlorophenoxy propionic acid
Trlmethylbenzene
1,3, 5-Trimethylbenzene
1 ,2,4-Trimethylbenzene
tris ( 2 , 3-Dibromopropy 1 ) phosphate
Undecane
Vanadium
Vinyl chloride
Xylene
m-Xylene
o-Xylene
p-Xylene
Zinc
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
4-25
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TABLE 4-7 EPA SOURCES OF TOXICITY PROFILES
Document
Criteria Document
Air
Criteria Document
Drinking Water
Availability
Office of Air Quality
Planning and Standards
(OAQPS)
Office of Drinking Water
(ODW)
Description
i
IsJ
Criteria Document -
Ambient Water Quality
Office of Water Regula-
tions and Standards (OWRS)
Chemical Hazard
Information Profile
(CHIP)
Chemical Profile
Office of Toxic Substances
(OTS)
Office of Waste Programs'
Enforcement (OWPE)
i
Summary of the latest scientific knowledge on the
effects of varying quantities of a substance in the
air. Usually prepared for OAQPS by the Office of
Health and Environmental Assessment (OHEA).
Summary of important experimental results from the
literature relevant to the chemistry and health
effects of a specific drinking water contaminant.
Serves as a foundation to support regulatory standards
or guidelines for the acceptable concentration of the
contaminant in the drinking water.
Information on the type and extent of identifiable
toxic effects on health and welfare expected from the
presence of pollutants in any body of water.
Objective of document is to protect most species in a
balanced and healthy aquatic community. To date, 65
have been completed, covering all priority pollutants.
Summary of readily available information concerning
the health and environmental effects and potential
exposure to a chemical.
Brief summary of the chemical/physical properties,
fate and transport, health effects and environmental
toxicity levels for 202 chemicals identified at
hazardous waste sites. Currently 183 of the planned
Chemical Profiles are available in draft form.
continued-
-------
Table 4-7 - continued
Document
Health Advisory
Availability
Description
ODW
Health Assessment
Document
.P-
i
N>
Health and Environ-
mental Effects
Profile
Health Effects
Assessments
Office of Health and
Environmental Assessment
(OHEA)
Office of Solid Waste
(OSW)
Office of Emergency and
Remedial Response (OERR)
Develops toxicological analyses to establish an
acceptable level in drinking water for unregulated
contaminants for various exposure durations. Used in
transient situations (spills, accidents) therefore,
does not consider chronic exposure data (e.g.,
carcinogenicity).
Inventories the scientific literature and evaluates
key studies. Discusses dose-response relationships so
that the nature of the adverse health response is
evaluated in perspective with observed environmental
levels. Usually prepared by OHEA for another office.
Profiles are "mini-" criteria documents prepared
usually as summaries of existing water quality
criteria documents. They serve as a support for the
listing of hazardous wastes in the RCRA program.
Summary of the pertinent health effects information on
58 chemicals found most often at hazardous waste sites,
Developed by the Environmental Criteria and Assessment
Office (ECAO) for OERR.
-------
TABLE 4-8 TOXICITY ASSESSMENT STEPS
£ife Systems, Jnc.
Toxicity Assessment Step
1.0 Toxicological Evaluation
1.1 Prepare Health Toxicity Profile
a. Conduct literature search
b. Evaluate adequacy of each
study
c. Review studies to obtain
information on dose, bio-
logical end points and
exposure
d. Summarize information on
each contaminant
1.2 Prepare Environmental Toxicity
Profile
a. Conduct literature search
b. Evaluate adequacy of each
study
c. Review studies to obtain~
information on dose, toxic
effects and thoroughness
of study
d. Summarize information on
each contaminant
2.0 Dose-Response Assessment
2.1 Estimate ADI levels
a. Select appropriate quantita-
tive index of toxicity (e.g.,
NOEL, NOAEL, LOAEL, etc.)
b. Determine uncertainty factor
c. Calculate ADI
2.2 Estimate unit cancer risks
a. High-to-low dose extrapolation
b. Interspecies extrapolation
Level of.
Detail™
X
X
X
X
X
X
X
X
Applicable
Handbook Sections
4.0
4.4.1
4.4.1.1
4.4.1.2
X(b) X 4.4.2
X 4.4.2.1
4.4.2.2
5.0
5.4
5.4
5.4
5.4
5.4
(a) X indicates the level of endangerment assessment (e.g., Level 1, 2 or 3)
for which this step must be performed.
(b) Generally, a Level 2 endangerment assessment will utilize ADI and unit
cancer risk values calculated in existing toxicity profiles. Only a
Level 3 endangerment assessment will require calculation of new values.
4-28
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£ife Systems, JHC.
etc. It also reports data on mixture effects and discusses the limitations,
if any, of each study that could potentially impact its selection as the basis
for deriving an ADI and unit cancer risk (for humans) or determination of
levels of environmental concern (for aquatic and terrestrial organisms). In
the development of an endangerment assessment, it may be necessary to use an
interim ADI value (or other index of toxicity) with caveats indicating it may
require updating in the future if the Agency revises the value.
4.4.1.1 Health Toxicity Profile
The first step in preparing a health toxicity profile is to conduct a thorough
search of the current health effects literature on the contaminants of concern
and to identify and acquire candidate studies for the profile. The next step
is an evaluation of the adequacy of each study for the toxicity assessment.
It is imperative that studies contain sufficient quantitative data to provide
the basis for risk characterization. Accordingly, the studies should follow
established test protocol criteria for determining biological or toxicological
endpoints. Parameters to be considered include: (1) dose levels, (2) duration
and frequency of compound administration, (3) route of compound exposure, (4)
species selection, (5) the number of test animals, etc. Guidelines for
evaluating test protocol criteria for specific endpoints have been established
by EPA. These guidelines are summarized in Appendix 4.
The next step in preparing a toxicity profile is to review the studies which
have been determined to be adequate to obtain the following data: (1) specific
dose levels used, (2) all biological endpoints manifested, (3) route of
exposure or (4) any limitations of the study which may compromise positive or
negative outcomes. Important data to be considered when reviewing the studies
include the following:
1. Dose; Studies of noncarcinogenic effects should report (a) the dose
of the test substance at which there are no statistically or bio-
logically significant increases in the frequency or severity of
adverse effects between the exposed animals and an appropriate
control (NOAEL) or (b) the lowest dose of the test substance that
produces a statistically or biologically significant increase in the
frequency or severity of adverse effects between the exposed animals
and an appropriate control (LOAEL). These values provide the basis
for deriving the ADI for noncarcinogenic effects.
Studies' of carcinogenic effects should report the frequency of tumor
formation as a function of exposure level (dose). From this dose-
response data, mathematical models are employed to predict cancer
frequency rates at very low exposure'levels.
2. Biological Endpoints; Results of a variety of studies report a wide
range of adverse effects manifested. These include hepatotoxicity,
renal toxicity, blood toxicity, neurotoxicity, behavioral toxicity,
reproductive toxicity, teratogenicity, mutagenicity and carcinogen-
icity. Appendix 5 defines these biological endpoints.
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3. Route of Exposure; The most relevant routes of exposure are oral,
dermal and inhalation. Those studies which include the route of
major concern for human exposure are the most useful.
The final step in the preparation of a toxicity profile is to briefly summarize
the toxicological information on each contaminant of concern at a site. This
summary should focus on those studies examining the exposure routes of concern
at the site (i.e., oral dose if -contaminants are expected to be found in the
drinking water).
4.4.1.2 Environmental Toxicity Profile
The first step in preparing an environmental toxicity profile is to conduct a
search of the environmental literature on the contaminants of concern and to
identify and acquire candidate toxicity studies on fish and wildlife for the
profile. The next step is an evaluation of the adequacy of each study for an
environmental toxicity evaluation. An adequate study includes considerations
of dose levels tested and toxic effects manifested, as well as thoroughness of
reporting environmental parameters (e.g., temperature, photoperiod, dissolved
oxygen concentration and pH).
The next step is to review the studies which have been determined to be
adequate to obtain the data that should be summarized in the profile. Important
data to be considered when reviewing the studies include the following:
1. Dose; The studies should report quantitative indices of environmental
toxicity such as the NOAEL, LOAEL, LC , etc. These toxicity values
may be used in deriving various levels of environmental concern.
2. Types of Effects; Environmental effects include effects of contami-
nants on growth, reproduction or survival which would either
temporarily or permanently alter population levels of wild plants
and animals. Accordingly, hazardous waste discharges may result in
fish kills or other deleterious effects such as decreased reproduc-
tive potential, abnormal larval growth, systemic pathological
effects or tumorigenesis. Environmental effects on birds can be
manifested in three major forms: direct mortality/morbidity (via
bioconcentration in the food chain or volatilization), indirect
mortality/morbidity (via elimination of food sources such as phyto-
plankton) and reproductive effects (such as eggshell thinning).
Behavioral changes can occur as well (e.g., migratory patterns,
feeding habits and social population size) . Other effects include
bioconcentration in aquatic species all along the food chain (e.g.,
fat soluble compounds) and aesthetic considerations such as
impartation of unpleasant taste to water and edible fish/shellfish.
The final step in the preparation of an environmental toxicity profile is to
briefly summarize the toxicological information on each contaminant of concern
at a site. This summary should focus on those studies examining ecosystems
and/or species which are present at the site.
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£ifc Systems, Jnc.
4.4.2 Dose-Response Assessment
Once the toxicological evaluation determines that a chemical is likely to
cause a particular adverse effect, the next step is to determine the potency
of the chemical. The second step, then, in the toxicity assessment, the
dose-response assessment, is a quantitative estimation of risk from exposure
to a chemical. It defines the relationship between the dose of a chemical and
the incidence of the adverse effect.
The objective of the dose-response assessment is to use the quantitative
indices of toxicity (e.g., NOEL, NOAEL, LOAEL, LC5Q, etc.) presented in the
toxicity profiles to determine ADI levels (for noncarcinogens) and unit cancer
risk (for carcinogens) or levels of environmental concern (for aquatic and .
terrestrial organisms).
4.4.2.1 Estimation of Acceptable Daily Intake Levels
The dose-response assessment for noncarcinogenic chemicals produces an estima-
tion of the NOEL, NOAEL or LOAEL and the margin of safety associated under the
prescribed conditions of exposure. These quantitative indices of toxicity may
be used to derive an exposure level which is considered "acceptable" or which
is not expected to cause adverse effects. This exposure level may be ex-
pressed in a variety of ways such as the ADI, Ambient Air Standard, Water
Quality Criteria, etc. .The term "acceptable level" will be used in this
Handbook to indicate any such derived criteria, standard or advisory level.
The toxicity profile should identify any quantitative indices of toxicity as
well as any derived "acceptable levels" for noncarcinogens. A Level 2 endanger-
ment assessment should utilize only available values in characterizing the
risks at a site. A Level 3 endangerment assessment may require the estimation
of an "acceptable level" for contaminants present at the site. Following is a
brief discussion of the methodology for deriving an ADI.
A widely accepted procedure for evaluating noncarcinogenic toxic endpoints is
to estimate the ADI. An ADI is defined as the amount of toxicant, in mg/kg
body weight/day (or in mg/day for a 70-kg person) that is not expected to
result in any adverse effects following chronic exposure to the general human
population. Adverse effects are considered to be functional impairment or
pathological lesions that may affect the biological integrity of the whole
organism or that reduce an organism's ability to respond to an additional
toxic insult. It is assumed in an ADI estimation that there are threshold
doses below which no adverse effects will occur. The ADI is calculated by
dividing the quantitative index of toxicity (e.g., NOEL, NOAEL, LOAEL, etc.)
derived from human or animal toxicity studies, by one or more uncertainty
factors. The parameters for calculation of the ADI are defined as follows:
1. The NOEL (No-Observed-Effect Level) is defined as that dose of a
chemical at which there are no statistically or biologically signif-
icant increases in the frequency or severity of effects between the
exposed population and an appropriate control.
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jCife Systems, Jnc.
2. The NOAEL (No-Observed-Adverse-Effect Level) is defined as that dose
of a chemical at which there are no statistically or biologically
significant increases in the frequency or severity of adverse effects
between the exposed population and an appropriate control. Effects
are produced at this dose, but they are not considered to be adverse.
3. The LOAEL (Lowest-Observed-Adverse-Effect Level) is defined as the
lowest dose of a chemical in a study or group of studies that
produces statistically or biologically significant increases in the
frequency or severity of adverse effects between the exposed popu-
lation and an appropriate control.
Either the NOEL, NOAEL or the LOAEL may be used in estimating the ADI. The
formula for calculating the ADI is shown below:
= NOEL x Body Weight
Uncertainty Factor
If the NOEL is taken to be a safe dose for the species tested, an uncertainty
factor must then be applied to allow for the potentially higher sensitivity of
exposed humans and differences in sensitivity among exposed individuals.
Uncertainty factors are adjustments of the NOEL, NOAEL, or LOAEL reported for
small populations of humans or experimental animals in order to estimate the
comparable NOEL from chronic exposure to a chemical by a large human population
that includes sensitive subgroups. The size of the uncertainty factor used .
depends on the severity of the biological effects observed in toxicolpgical
studies. For example, an uncertainty factor of «iOO might be used for a revers-
ible effect, while an uncertainty factor of 1,000 might be employed if a chemical
causes an irreversible effect such as teratogenicity.
Several considerations that influence the selection of an .uncertainty factor
are the species and strain of the test animals, the quality and sensitivity of
the experimental data, the availability of comparative pharmacokinetic data
and information on the absorption, distribution, biotransformation, binding
and excretion of the test chemical in the animal species and in man.
Table 4-9 summarizes several uncertainty factors currently in use by the EPA
to estimate ADI's for toxicants.
4.4.2.2 Estimation of Unit Cancer Risk
The dose-response assessment for carcinogenic chemicals should provide an
estimation of the probability or range of probabilities that a specific adverse
effect (i.e., tumor growth) will occur under the prescribed conditions of
exposure. These estimates of probability are derived using mathematical models
of the dose-response relationship. One way of expressing this numerical estimate
of risk is as a "unit cancer risk" which is defined as the excess risk due to
a continuous lifetime exposure to one unit of carcinogen concentration.
The toxicity profile should identify any numerical estimates of risk which
have been derived. Level 2 endangerment assessments should utilize only
4-32
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£ife Systems, JHC.
TABLE 4-9 GUIDELINES FOR SELECTION OF UNCERTAINTY FACTORS
. Uncertainty Factor ^a> ' .
1. Use a 10-fold factor when extrapolating from valid experimental results
from studies on prolonged ingestion by man. This 10-fold factor protects
the sensitive members of the human population estimated from data
garnered on average healthy individuals.
2. Use a 100-fold factor when extrapolating from valid results of long-term
feeding studies on experimental animals with results of studies of human
ingestion not available or scanty (e.g., acute exposure only). This
represents an additional 10-fold uncertainty factor in extrapolating data
from the average animal to the average man.
3. Use a 1,000-fold factor when extrapolating from less than chronic results
on experimental animals with no useful long-term or acute human data.
This represents an additional 10-fold uncertainty factor in extrapolating
from less-than-chronic to chronic exposures.
4. Use an additional uncertainty factor of between 1 and 10 depending on the;
sensitivity of the adverse effect when deriving an ADI from LOAEL. This '
uncertainty factor drops the LOAEL into the range of a NOAEL.
(a) In calculating an ADI when no indication of carcinogenicity of a chemical
exists, these factors are to be applied to the highest valid NOAEL or NOEL
that does not have a valid LOAEL equal to or below it. In some cases, an
additional variable uncertainty factor should be applied. The EPA has
recommended that this variable uncertainty factor reflect a scientific
judgment of the difference between the observed LOAEL and the hypothesized
NOAEL. This difference will not necessarily be the same from experiment to
experiment. In lieu of specific data, the value of this additional
uncertainty factor utilized by the EPA ranges from one through ten, based
on the severity of the adverse effect at the LOAEL.
(b) Uncertainty factors one and two are supported by the FDA and the WHO/FAO;
uncertainty factors one through three have been established by the NAS
and are used in a similar form by the FDA; uncertainty factors one through
four are recommended by the EPA.
4-33
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£ife Systems, Jnc.
established risk estimates. Level 3 endangerment assessments may require the
derivation of a quantitative risk estimate for carcinogenic contaminants of
concern at a site. The following is a brief discussion of the estimation of
unit cancer risk. For further details on quantitative carcinogenic risk
assessment, the reader is referred to EPA's Proposed Guideline for Carcinogen
Risk Assessment (USEPA 1984). These Guidelines are attached in their entirety
as Appendix 3, Part 1.
There are three main types of evidence which may be used to determine whether
a substance poses a carcinogenic hazard: (1) epidemiologic data from exposed
human populations, (2) experimental evidence derived from long-term bioassays
of animals and (3) supportive or suggestive evidence derived from studies of
chemical structure or from other short-term tests. Ideally, this assessment
would be based on epidemiological studies of human populations. However,
epidemiological studies are often unsatisfactory because it is difficult to
measure individual exposure patterns, it may be impossible to eliminate the
confounding effects of other factors and the time between exposure and occur-
rence of an observable effect may be very long (up to several decades). Conse-
quently, it is often necessary to rely on tests carried out on laboratory
animals exposed to much higher levels of the toxic agent than humans are
expected to experience. The results of such tests have to be subjected to two
types of extrapolation:
1. The results obtained for laboratory animals at relatively high expo-
sure levels have to be extrapolated down to predict the effects of
relatively low exposure on those animals (high-to-low dose extrapo-
lation) .
2. The resulting predicted effects of low-level exposure on laboratory
animals are then used to predict the effects on human health (inter-
species extrapolation).
The experimental results are extrapolated from the high, observed doses to
low, expected doses by fitting a mathematical model to the data and using the
model to predict the low-dose response. The Proposed Guidelines for Carcinogen
Risk Assessment (USEPA 1984b) recommends the use of the linearized multistage
model for high-to-low dose extrapolation unless there is mechanistic, statis-
tical or other biological evidence that indicates the greater suitability of
an alternative extrapolation model or statistical'or biological evidence that
excludes the use of the multistage model. The point estimate and the 95%
upper confidence limit of excess risk are calculated by using the computer
program GLOBAL 79, developed by Crump and Watson (1979). This model approxi-
mates the dose-response curve by a straight line with slope determined by the
linear term of the model. The linearized multistage model estimates a plaus-
ible upper limit to risk and is consistent with some mechanisms of carcino-
genesis. However, it should be emphasized that such an estimate does not
necessarily represent the actual risk. USEPA (1984b) provides a discussion of
the application of this model as well as a list of additional references on
quantitative risk assessment.
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£ife Systems, JHC.
The results of animal studies, having been extrapolated from high to low dose,
then have to be extrapolated to humans. Differences in the metabolism of
chemicals between species often creates the greatest problem in obtaining
meaningful extrapolations. Methods of scaling animal doses to equivalent
human doses have been based on body weight, concentration in the diet and body
surface area. Additional uncertainty is introduced when the route of
exposures differs from one species to another.
High-to-low dose and interspecies extrapolation involves a series of assumptions.
some of which are impossible to verify, and necessarily involves a high degree
of uncertainty. Nevertheless, it is important to obtain as realistic an
estimate as possible so that appropriate decisions can be made regarding the
risk of exposure to toxic substances.
4.4.2.3 Interpretation of Unit Cancer Risk
t
For several reasons, the unit cancer risk estimate based on animal bioassays
is only an approximate indication of the absolute risk in populations exposed
to known carcinogen concentrations. First, there are important species
differences in uptake, metabolism and organ distribution of carcinogens, as
well as species differences in target site susceptibility, immunological
responses, hormone function, dietary factors and disease. Second, the concept
of equivalent doses for humans compared to animals on a mg/surface area basis
is virtually without experimental verification regarding carcinogenic response.
Finally, human populations are variable with respect to genetic constitution
and diet, living environment, activity patterns and other cultural factors.
The unit cancer risk estimate can give a rough indication of the relative
potency of a given agent compared with other carcinogens. The comparative
potency of different agents is more reliable when the comparison is based on
studies in the same test species, strain and sex and by the same route of
exposure, preferably by inhalation. However, it should be recognized that the
estimation of cancer risks to humans at low levels of exposure is uncertain.
At best, the linear extrapolation model recommended by EPA provides a rough,
but plausible, estimate of the upper-limit of risk (i.e., it is not likely
that the true risk would be much higher than the estimated risk, but it could
very well be considerably lower).
4.4.3 Toxicity Assessment References
ICAIR, Life Systems, Incorporated. 1985. The hazardous waste site toxicology
handbook. Draft. Washington, DC: U.S. Environmental Protection Agency,
Office of Waste Programs Enforcement. Contract No. 68-01-7037.
ICF Incorporated. 1985. Superfund public health assessment manual. Draft.
Washington, DC: U.S. Environmental Protection Agency, Office of Emergency and
Remedial Response. Contract No. 68-01-6872.
ICF Incorporated. 1983a. Scientific support document: the scientific basis
for the risk evaluation process. Draft. Washington, DC: U.S. Environmental
Protection Agency, Office of Emergency and Remedial Response.
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£ife Systems, Jnc.
ICF Incorporated. 1983b. Superfund feasibility study guidance, chapter 4,
risk evaluation. Washington, DC: U.S. Environmental Protection Agency, Office
of Emergency and Remedial Response.
USEPA. 1985a. U.S. Environmental Protection Agency. Environmental Criteria
and Assessment Office. Proposed guidelines for the health risk assessment ol
chemical mixtures. Fed. Regist., Jan. 9, 1985, 50 1170.
USEPA. 1984b. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for carcinogen risk assessment.
Fed. Regist., Nov. 23, 1984, 49 46294.
USEPA. 1984d. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for mutagenicity risk assessment.
Fed. Regist., Nov. 23, 1984, 49 46314.
USEPA. 1984e. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for the health assessment of
suspect developmental toxicants. Fed. Regist., Nov. 23, 1984, 49 46324.
4.5 Risk Characterization Guidelines
'The final component of the endangerment assessment process is risk characteriza-
tion. The objective of risk characterization is to estimate the incidence of
an adverse health or environmental effect under the various conditions of
exposure defined in the exposure assessment. It is performed by integrating
information developed during the exposure and toxicity assessments to yield a
complete characterization of risk at the site. Four discrete steps are required
to develop this information:
1. Characterize carcinogenic risks at the site
2. Characterize noncarcinogenic risks at the site
3. Characterize environmental risks at the site
4. Characterize public welfare risks at the site
The final assessment should include a summary of the risks associated with a
site and such factors as the weight-of-evidence associated with each step of
the process, the estimated uncertainty of the component parts, the distribution
of risk across various sectors of the population, the assumptions contained
within the estimate, etc.
Typically, releases from a hazardous waste site result in exposure to a mixture
of chemicals rather than a single compound. This phenomenon occurs when a
series of unrelated compounds, placed in the same area for disposal or storage,
eventually come in contact with each other and are released to the environment
as a mixture. The EPA has published "Proposed Guidelines for Health Risk
Assessment of Chemical Mixtures" (USEPA 1985a) which provide guidelines for
assessing the effects of multiple toxicant or multiple carcinogen exposure.
The preferred approach for predicting the effects of exposure to mixtures is
to use health effects data on the mixture of concern or on a similar mixture
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(i.e., same components but in slightly different proportions) and adapt the
same assessment procedures as used for single compounds. Most frequently, the
toxicological properties of the mixtures are poorly characterized. When
health effects data are not available on an identical or similar mixture, the
risk assessment may be based on the toxic or carcinogenic properties of the
individual components of the mixture. The use of dose additive models is
recommended by EPA for combining the risk estimates for individual chemicals
in the mixture to estimate the risk for the mixture.
The methodology for risk characterization is based on existing and proposed
guidelines for performing carcinogenic, mutagenic, teratogenic and mixture
risk assessments (USEPA 1984b,d,e=; 1985a). These guidelines are included in
their entirety as Appendix 3 of this Handbook. Additional guidance on risk
characterization at hazardous waste sites is contained in the SPHAM (ICF
1985). Further information on risk assessment in general is available in the
following publications.: ICF 1983a,b, NAS 1982, Schaum 1984 and USEPA 1984a.
Table 4-10 lists the steps required to complete the risk characterization and
identifies the endangerment assessment level of detail to which they apply and
the locations in this Handbook where they are discussed.
4.5.1 Characterize Carcinogenic Risks
In order to obtain a quantitative estimate of carcinogenic risk, the results
of the dose-response assessment must be"combined with an estimate of the
exposures to which the population is subject. Depending on the needs of the
endangerment assessment, quantitative estimates of risk can be presented in
one or more of the following ways:
1. Unit Cancer Risk - Under an assumption of low-dose linearity the
unit cancer risk is the excess lifetime risk due to a continuous
lifetime exposure of/one unit of carcinogen concentration.
2. Dose Corresponding to a Given Level of Risk - This approach is use-
ful when using nonlinear extrapolation models where the unit risk
differs at various dose levels.
3. Individual Risks - Risk is characterized in terms of excess indi-
vidual lifetime risks.
4. Population Risks - Risk is characterized in terms of the excess
number of cancers produced per year in the exposed population.
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 (USEPA 1985a). Interactions with enzyme inducers
or inhibitors, cocarcinogens, promoters and initiators should be considered on
a case-by-case basis.
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TABLE 4-10 RISK CHARACTERIZATION
1.0
2.0
3.0
4.0
Risk Characterization Step
Characterize carcinogenic risk
1.1 Compare site-specific exposure
levels to estimates
1.2 Compare site-specific exposure
levels to existing regulatory
guidelines and standards for
carcinogens
1.3 Characterize uncertainties asso-
ciated with risk estimates
Characterize noncarcinogenic risk
2.1 Compare site-specific exposure
levels to "Acceptable Levels"
2.2 Compare site-specific exposure
levels to existing regulatory
guidelines and standards for
noncarcinogens
2.3 Characterize uncertainties
Characterize environmental risk
3.1 Compare site-specific exposure
levels to ecotoxicity data
3.2 Compare estimated environmental
concentrations to existing
environmental concern levels and
regulatory guidelines and stand-
ards
3.3 Characterize uncertainties
Characterize public welfare risk
Level o
Detail
1 2
X X
X
X
X
X X
X
X
X X
X
X
X
X X
STEPS
I)
3
X
X
X
X
X
X
X
X
X
X
X
X
Applicable
Handbook Sections
4.0 5
4.5.1 5
4.5.1 5
4.5.1 5
4.5.1 5
4.5.2 5
4.5.2 5
4.5.2 • 5
4.5.3 5
4.5.3 5
4.5.3 5
4.5.3
4.5.4 5
.0
.5
.5
.5
.5
.5
.5
.5
.5
.5
.5
.5 •
(a) X indicates the level of endangerment assessment (e.g., Level 1, 2 or 3)
for which this step must be performed.
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The results of every risk estimation are subject to uncertainties. These
uncertainties may be due to limitations in the human and animal studies, lack
of adequate exposure data, and the assumptions of the high-to-low dose and
interspecies extrapolation procedures used. Risk estimates should be pre-
sented together with a summary of the toxicity and exposure assessments to
ensure that the weight-of-evidence that provides a basis for site-specific
risks is adequately described. All of the key findings of the qualitative
assessment and the interpretative rationale that forms the basis for conclu-
sions should be summarized. In addition, uncertainties in the evidence as
well as factors that affect the relevance of animal studies to humans should
be discussed.
To characterize carcinogenic risks at the site, compare site-specific exposure
levels for each contaminant at the site to quantitative estimates of risk
identified or developed during the dose-response assessment. Exposure levels
should also be compared to existing regulatory guidelines and standards for
carcinogens. The risk characterization should be accompanied by a discussion
of the uncertainties associated with the risk estimate used.
A method for determining incremental risk at a site resulting from exposure to
carcinogens is proposed. by ICF (1985). Site-specific exposure levels (chronic
daily intake) are multiplied by the quantitative risk estimates (carcinogenic .
potency factors) to obtain an estimate of incremental risk for each chemical.
Total incremental risk at the site is obtained by summing this incremental
risk estimate for each chemical.
4.5.2 Characterize Noncarcinogenic Risks
Characterizing risks from noncarcinogenic compounds involves comparing the
expected exposure level (E) to the "acceptable level" (AL) (USEPA 1985a) . The
resultant ratio (referred to as the Hazard Index (HI) provides a numerical
indicator of the transition between acceptable and unacceptable exposure levels.
(Note: When making this comparison (E/AL) , it is important to ensure that the
units for the exposure level and the "acceptable level" are the same. It may
be necessary to apply a scaling factor or exposure coefficient to the esti-
mated exposure level, as appropriate, to standardize the units in the ratio.)
Thus, when HI >1 (where HI = E/AL), there is a potential health risk to the
exposed populations.
EPA guidelines assume dose additivity for exposure to multiple noncarcinogens.
Therefore, the HI of a mixture may be defined as:
HI = EI/ALI + E2/AL2 + . . . E±/AL±
As with single chemicals, any time the HI approaches unity, concern for potential
risks increases.
This assumption of additivity is most properly applied to compounds that induce
the same effect by the same mechanism. Thus, it may be desirable to group the
compounds by type of critical effect and derive a separate HI for each group
to avoid overestimating risk at a site.
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For the purposes of the endangennent assessment, an HI should be estimated for
each contaminant of concern and each exposure scenario using all "acceptable
levels" identified in the toxicity profile. The resulting HI scores (or sum
of HI scores) characterizes the risk to human populations from the noncarcin-
ogenic chemicals at the site. ICF (1985) proposes a similar methodology for
characterizing noncarcinogenic risk.
The noncarcinogenic risk characterization should include an explanation of the
"acceptable levels" which were used, a determination of the "acceptability" of
the risks and a discussion of the uncertainties associated with the assessment.
4.5.3 Characterize Environmental Risks
For ecological risks, the ecotoxicity assessment and the environmental exposure
assessment are integrated to quantify the probability that adverse effects may
occur, will occur or are occurring as a result of exposure. The methods used
to integrate such information can vary from a simple comparison of exposure
and toxicity data (quotient or ratio approach) to more complex methods, which
utilize comparative toxicology/exposure and effects models. Estimated environ-
mental concentrations of contaminants at the site should be compared to existing
environmental .concern levels and existing regulatory guidelines and standards.
The ecological risk characterization should include an explanation of the
extrapolations that have been made, a determination or estimation of the
ecological significance of any adverse effects and a discussion of the uncer-
tainties associated with the assessment.
4.5.4 Characterize Public Welfare Risks
Risks to public welfare are not easily quantifiable. Obvious impacts would
include a decrease in property values, adverse impacts on recreational facilities
(i.e., lakes, streams, wildlife areas, etc.), decreases in commercial fisheries,
etc. Health and environmental risks could, directly or indirectly, have adverse
effects on the public welfare. Risks to public welfare should be a considered
throughout the endangerment assessment process and characterized in the endanger-
ment assessment document.
4.5.5 Risk Characterization References
ICF Incorporated. 1985. Superfund public health assessment manual. Draft.
Washington, DC: U.S. Environmental Protection Agency, Office of Emergency and
Remedial Response. Contract No. 68-01-6872.
ICF Incorporated. 1983a. Scientific support document: the scientific basis
for the risk evaluation process. Draft. Washington, DC: U.S. Environmental
Protection Agency, Office of Emergency and Remedial Response.
ICF Incorporated. 1983b. Superfund feasibility study guidance, Chapter 4,
risk evaluation. Washington, DC: U.S. Environmental Protection Agency,
Office of Emergency and Remedial Response.
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NAS. 1982. National Academy of Sciences, National Research Council. Risk
and decision making: perspectives and research. Washington, DC: National
Academy Press.
Schaum J. 1984. Short course on integration of exposure and risk assessment.
Part 3. Exposure assessment methods. Paper presented at the Annual Meeting
of Society for Environmental Toxicology and Chemistry, Arlington, VA.
USEPA. 1985a. U.S. Environmental Protection Agency. Environmental Criteria
and Assessment Office. Proposed guidelines for the health risk assessment of
chemical mixtures. F.ed. Regist., Jan. 9, 1985, 50 1170.
USEPA. 1984a. U.S. Environmental Protection Agency. Risk assessment and
management: framework for decision making. Washington, DC: U.S. Environmental
Protection Agency.
USEPA. 1984b. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for carcinogen risk assessment.
Fed. Regist., Nov. 23, 1984, 49 46294.
USEPA. 1984d. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for mutagenicity risk assessment.
Fed. Regist., Nov. 23, 1984, 49 46314.
USEPA. 1984e. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for the health assessment of
suspect developmental toxicants. Fed. Regist., Nov. 23, 1984, 49 46324.
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5.0 PREPARATION OF THE. ENDANGERMENT ASSESSMENT DOCUMENT
This section presents and discusses the content and recommended format for the
endangerment assessment document. This format has been designed to:
1. Ensure that all major issues are adequately addressed.
2. Ensure adequate documentation and support for EPA's enforcement
actions.
3. Produce comparable documents from different sites.
4. Promote high-quality documents.
The recommended format consolidates information from the individual assess-
ments into a single, concise document. Thus, the endangerment assessment
document is an "executive summary" of the endangerment assessment process
which fully characterizes the site and supports the EPA's contention that an
endangerment may exist at the site.
The endangerment assessment document should not repeat site information
reported elsewhere. The author should reference existing documents, such as
the RI and FS reports, which contain detailed site or assessment information,
and maintain complete records and notes during the assessment process. These
can be used, if necessary, to substantiate the conclusions reported in the
endangerment assessment document. Referencing existing documents should aid
in keeping the endangerment assessment document brief. The length of the
document will vary depending on the site characteristics and the point in time
the assessment is being made (i.e., the-amount of data available). As a rule,
the average endangerment assessment document should not exceed 20 typewritten
pages excluding Appendices. Appendix 2 provides examples of Level 1, 2 and 3
endangerment assessment documents.
Table 5-1 presents the recommended endangerment assessment document outline.
This outline should be followed when preparing all endangerment assessments,
no matter what level of detail. Obviously, a Level 1 document will not be as
lengthy as a Level 2 or 3; however, all data requirements must be addressed.
The endangerment assessment document should contain seven major sections:
Section 1.0' is an introduction briefly describing the site, site history
and contaminants found at the site.
Section 2.0 identifies the environmental fate and transport of contami-
nants at the site.
Section 3.0 evaluates the results of the exposure assessment.
Section 4.0 evaluates the results of the toxicity assessment.
Section 5.0 evaluates the results of the risk characterization of the
site.
Section 6.0 draws conclusions based on expected exposures and toxic
properties of contaminants of concern at the site.
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TABLE 5-1 ENDANGERMENT ASSESSMENT DOCUMENT OUTLINE
Disclaimer
1.0 Introduction
1.1 Site description and history
1.2 Contaminants found at site
2.0 Environmental Fate and Transport
2.1 Factors affecting migration
2.2 Movement and environment fate
3.0 Exposure Evaluation
3.1 Routes of exposure
3.2 Populations exposed
3.3 Extent of exposure
4.0 Toxicity Evaluation
5.0 Risk and Impact Evaluation
5.1 Human Health
5.2 Environmental
5.3 Public Welfare
6.0 Conclusions
7.0 References
Appendices (documentation)
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Section 7.0 is a list of references used in preparing the endangennent
assessment document. Appendices should consist of any support documenta-
tion.
Table 5-2 presents a summary of the key factors that should be addressed in
each section of the document at each level of detail.
All draft endangennent assessment documents should include a Disclaimer
indicating that the document has not yet been approved by EPA and is not
available for public distribution. The disclaimer may read:
"This document has not been peer and administratively reviewed within EPA
and is for internal Agency use/distribution only"
Draft endangerment assessments should also be clearly marked as being "Enforce-
ment Confidential." When the endangerment assessment is final (i.e., EPA and
responsible parties have agreed to release it to the public or the litigation
is settled) the Disclaimer and "Enforcement Confidential" should be removed
from the document.
The following are instructions for preparing each of the major sections of the
endangerment assessment document.
5.1 Section 1.0 Introduction
The" purpose of this section of the endangerment assessment document is to~
acquaint the reader with the site characteristics and contaminants present at
the site.
Sections 1.0 and 2.0 are important in establishing the "point in time" at
which the endangerment assessment was performed. Since an endangerment
assessment may be performed at varying points in time, the degree of endanger-
ment may vary. It is helpful to illustrate, to the best extent possible
(based on the information available at the time the endangerment assessment is
being performed) what types of chemicals and what quantities were disposed of
at the site, the manner of disposal, and any prior actions taken at the site,
to help provide a setting for the "point in time" concept. This setting
should also be carefully segregated from other parts of the endangerment
assessment in a separate introductory section. Care should also be taken not
to mix the manner of disposal information with exposure scenarios. Environ-
mental fate information and any removal actions must be taken into account in
order to clearly set forth exposure to chemicals being evaluated.
Preparation of the Introduction and subsequent sections of the endangerment
assessment document begins with a thorough review of the available documen-
tation on the site. Notes should be taken as the documents are reviewed,
focusing on the pertinent factors identified on Table 5-2. This section
contains two subsections: Site Description and Site History and Contaminants
Found at the Site.
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TABLE 5-2 FACTORS TO BE CONSIDERED IN ENDANGERMENT ASSESSMENTS
Level 1
Level of Detail
Level 2
Level 3
Cn
1.0 Introduction
1.1 Site Description and Site History
a. geographic location
b. management practices/site use/site modifications
c. chronological survey
d. facility description/containment systems
e. substances brought on site (identity, quantity, form manner
of disposal
1.2 Contaminants found at site
a. identity of substances detected
2.0 Environmental Fate and Transport
a. identity of possible transport pathways
3.0 Exposure Evaluation
a. identity of potential exposure routes
b. identity of populations at risk
4.0 Toxicity Evaluation
a. characterize key toxicological properties
5.0 Risk and Impact Evaluation
a. risk may exist because of potential exposure to toxic
chemicals
6.0 Conclusions
7.0 References
1.0 Introduction
1.1 Site Description and Site History
a. geographic location
b. management practices/site use/site modifications
c. chronological survey
d. facility description/containment systems
e. substances brought on site (identity, quantity, form and
manner of disposal)
1.2 Contaminants found at site
a. identity of substances detected
b. concentration of substances detected
c. analytical methodology and QA/QC
2.0 Environmental Fate and Transport
a. physical-chemical properties of specified
chemicals/substances (e.g., soil/sediment adsorption
coefficients, vapor pressures, solubility, etc.) [preliminary]
b. photodegradation rates, decomposition rates, hydrolysis
rates, chemical transformations, etc. (preliminary]
c. local topography [preliminary]
d. description of the hydrological setting and flow system
[preliminary]
e. soil analyses [preliminary]
f. climatic factors, other factors affecting fate and transport
[preliminary]
3.0 Exposure Evaluation
a. demographic profile of populations at risk including
subpopulation at special risk [preliminary]
b. background chemical exposures [preliminary]
c. life style and occupation histories [preliminary]
d. population macro- and micro-environments [preliminary]
e. exposure routes [preliminary)
f. magnitude, source, and probability of exposure to specified
substances [preliminary]
4.0 Toxicity Evaluation
a. metabolism [preliminary]
b. acute toxicity [preliminary]
c. subchronic toxicity [preliminary]
d. chronic toxicity [preliminary]
e. carcinogenicity [preliminary]
f. mutagenicity [preliminary]
g. teratogenicity/reproductive effects [preliminary]
h. other health effects as relevant including neurotoxicity,
immuno-depressant activity, allergic reactions, etc.
[preliminary]
i. epidemiological evidence (chemical specific or site specific)
[preliminary] i
j. aquatic/non-human terrestrial species
toxicity/environmental quality impairment [preliminary]
5.0 Risk and Impact Evaluation
a. qualitative description of risk to public health, welfare and
the environment
6.0 Conclusions
7.0 References
1.0 Introduction
1.1 Site Description and Site History
a. geographic location
b. management practices/site use/site modifications
c. chronological survey
d. facility description/containment systems
e. substances brought on site (identity, quantity, form and
manner of disposal
1 .2 Contaminants found at site
a. identity of substances detected
b. concentration of substances detected
c. analytical methodology and QA/QC
d. survey of environmental monitoring studies (detailed
discussion of environmental media and contamination
levels)
2.0 Environmental Fate and Transport
a. physical-chemical properties of specified
chemicals/substances (e.g., soil/sediment adsorption
coefficients, vapor pressures, solubility, etc.) [final]
b. photodegradation rates, decomposition rates, hydrolysis
rates, chemical transformations, etc. (final)
c. local topography [final]
d. description of the hydrological setting and flow system
[final]
e. soil analyses [final]
f. climatic factors, other factors affecting fate and transport
[final]
g. prediction of fate and transport (where necessary using
-modeling methods)
3.0 Exposure Evaluations
a. demographic profile of populations at risk including
subpopulation at special risk [final]
b. background chemical exposures [final]
c. life style and occupation histories [final]
d. population macro- and micro-environments [final)
e. exposure routes [final]
f. magnitude, source, and probability of exposure to specified
substances [final]
4.0 Toxicity Evaluation
a. metabolism (final]
b. acute toxicity [final]
c. subchronic toxicity (final]
d. chronic toxicity [final]
e. carcinogenicity [final]
f. mutagenicity [final]
g. teratogenicity/reproductive effects [final]
h. other health effects as relevant including neurotoxicity,
immuno-depressant activity, allergic reactions, etc. [final]
i. epidemiological evidence (chemical specific or site specific)
[final]
j. aquatic/non-human terrestrial species
toxicity/environmental quality impairment (final)
5.0 Risk and Impact Evaluation
a. carcinogenic risk assessment
b. probability of non-carcinogenic human health effects
c. non-human species risk assessment
d. environmental impacts/ecosystem alterations
6.0 Conclusions
7.0 References
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5.1.1 Section 1.1 Site Description and Site History
This subsection should summarize background site description and history
information. The purpose of this section is to provide a framework in time
and place for the endangerment assessment. A map of the site should also be
included in this introductory section.
Review the background material on the site, being alert for chronological
events, such as removal actions, which may have significantly altered the site
characteristics or probable exposure routes. Refer to the available documents
(i.e., RI and FS reports) for detailed information and maps of the site.
The site history information presented in this subsection must be clearly
referenced. Identify and cite any affidavits, inspection reports, surveys,
etc. that have been previously prepared on this site. This documentation of
previous events is critical in an enforcement document, especially if it is to
support a judicial action.
5.1.2 Section 1.2 Contaminants Found at the Site
This subsection should identify and, to the extent possible, quantify the
contaminants present at the site. A primary objective of this section is to
focus the remaining sections of the endangerment assessment document on the
contaminants of concern which are present in significant quantities.
To complete this section, review all available monitoring reports. Level 1
assessments will probably not have monitoring data available so contaminant
identification information must be developed from the disposal logs at the
site. Level 2 assessments will have preliminary monitoring data available
from the RI, and Level 3 assessments should have the complete RI to work from.
A critical evaluation of the analytical methodology and QA/QC (quality assur-
ance/quality control) procedures for the sampling effort should be included in
all Level 3 assessments.
The QA/QC procedures that were used during the data collection and analysis
phases must be discussed in Level 3 endangerment assessments because the
existence of, or lack of, QA/QC data is .very important in determining how
valid the conclusions based on the sampling data are. If the QA/QC procedures
are known, they should be documented; if the QA/QC procedures are not known or
the data are unavailable, this should be stated. This discussion and evalu-
ation of the QA/QC procedures is in keeping with the concept that the
endangerment assessment is an interpretive document. It provides a critical
evaluation of the available site information in order to reach a justifiable
conclusion regarding the potential for endangerment at a site.
This section should contain information on the identity, quantity and form of
contaminants present at the site and the concentrations of contaminants in the
environmental media. Level 1 assessments will typically identify contaminants
present and, possibly, quantities disposed of. Level 2 and 3 assessments will
provide more quantitative information on the concentrations of contaminants at
the site.
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5.2 Section 2.0 Environmental Fate and Transport
The purpose of this section is to describe the potential for off-site migra-
tion of contaminants and provide estimates of the direction of movement of
contaminants and ambient concentrations of contaminants in various environ-
mental media. This section of the endangerment assessment should summarize
the results of the environmental fate analysis portion of the exposure
assessment.
The discussion should include information on any factors which may signifi-
cantly affect the environmental fate and transport of contaminants released
from the site. The assumptions upon which the environmental fate analysis was
based should be stated, as well as any limitations of the environmental fate
analysis. Again, bear in mind that if the environmental fate and transport
characteristics at the site have been fully characterized in existing docu-
mentation, it is not necessary to repeat that information in this document.
Cross-referencing existing documents will satisfy the requirements of this
section.
A Level 1 environmental fate and transport analysis may only go as far as
identifying possible transport pathways. A Level 2 analysis should char-
acterize the physical and chemical and properties of the contaminants, trans-
formation processes (e.g., photodegradation, decomposition and hydrolysis) and
site factors which affect transport such as local topography, the hydrological
setting, climatological setting and geological setting of the site. A Level 3
analysis will continue this characterization through a prediction of fate and
transport pathways, using modeling methods when necessary. This level of
detail is necessary to provide input to the quantitative Exposure Evaluation
characteristic of a Level 3 endangerment assessment.
5.3 Section 3.0 Exposure Evaluation
The purpose of this section is to identify actual or potential routes of
exposure, characterize the populations exposed and determine the extent of the
exposure. Section 3.0 should.evaluate the results of the exposure assessment
and may contain up to three separate subsections: Populations Exposed, Routes
of Exposure and Extent of Exposure. The information presented should basic-
ally be a summary of the results of the Exposed Population Analysis and
Estimation/Calculation of Dose Incurred steps of the exposure assessment.
Information on expected doses incurred should include a summation of the total
dose of each contaminant received as a result of exposures by multiple routes.
This section should also identify anticipated or potential pathways of expo-
sure. The exposure routes should be presented in the order of those routes
with the highest amount of proof first (i.e., most field data supporting the
exposure route, highest level of confidence, etc.). This assures that EPA
presents its strongest, most defensible case first in the endangerment assess-
ment document.
The Exposure Evaluation for a Level 1 endangerment assessment will identify
potential exposure routes and populations at risk. It is not necessary to
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quantify the exposure or populations in a Level 1 endangerment assessment. A
Level 2 Exposure Evaluation will compile all the demographic data available on
the site; this information will have been collected during the RI and FS
studies, Based on this data, a s.eries of exposure estimates may be presented.
The Level 3 Exposure Evaluation may use available modeling methods to predict
the extent of future exposure at the site. It is important that this section
include a discussion of all the assumptions upon which the calculations of
exposure were based. Data limitations should also be discussed.
A summary table identifying exposed populations, exposure routes and extent of
exposure is an ideal way to summarize the exposure assessment information.
Keep in mind that the Exposure Evaluation should define as many of the factors
listed in Table 5-2 as possible. If a factor cannot be defined, identify the
data gap but do not attempt to collect additional data for the sole purpose of
completing the endangerment assessment. Such original data collection is
beyond the scope of the endangerment assessment effort.
5.4 Section 4.0 Toxicity Evaluation
The purpose of Section 4.0 is to provide the toxicological weight-of-evidence
that the contaminants at the site pose actual or potential risks to public
health or the environment. This section, which evaluates the results of the
toxicity assessment, will comprise the bulk of the endangerment assessment
document, since the toxic properties of contaminants are usually not com-
pletely characterized in any other documents prepared for the site.
Toxicological factors identified in Table 5-2 should be defined for each of
the contaminants of concern. If there are a large number of contaminants
being evaluated, then a tabular summary of the toxic properties of each
contaminant, is appropriate. As discussed previously, this information should
be derived from existing toxicity profiles or the primary literature.
The Toxicity Evaluation for a Level 1 assessment should be a brief character-
ization of the key toxicological properties for the contaminants at the site
with the greatest risk of potential exposure. The Level 2 and 3 assessments
should identify any quantitative indices of toxicity (e.g., NOEL, NOAEL, LC Q,
etc.), derived "acceptable levels" (e.g., ADIs, recommended standards, cri-
teria, etc.) or unit cancer risk estimates available from the literature. A
Level 3 assessment may go on to calculate ADIs and unit cancer risk estimates
for contaminants at the site when these values are not available in the
current literature. The studies that provide the basis for the quantitative
indices of toxicity and risk estimations should be identified and discussed in
this section as well as any assumptions or data gaps.
5.5 Section 5.0 Risk and Impact Evaluation
The purpose of this section is to integrate the findings of the exposure and
toxicity assessments to estimate site-specific risks. Section 5.0 evaluates
and summarizes the information developed during the risk characterization
process.
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The results of the exposure assessment should be summarized in a tabular form
for each medium, population group and route of exposure for which dose esti-
mates have been calculated. The risk estimates are then tabulated in dupli-
cate tables that report the probability of harm or margins of safety. These
data should be accompanied by a statement of the nature and severity of the
risks, the major assumptions used, the uncertainties that result and the
guidelines and standards that may be exceeded by potential exposure values and
the associated risks.
It may be sufficient for a Level 1 Risk and Impact Evaluation to simply state
that risk may exist because of potential exposure to toxic chemicals. A Level
2 Risk and Impact Evaluation should contain a qualitative description of
potential adverse effects and a quantitative estimate of risk based on exist-
ing guidelines and standards (e.g., Ambient Water Quality Criteria, Drinking
Water Standards, etc.). A Level 3 Risk and Impact Evaluation should provide a
quantitative risk assessment for all carcinogenic and noncarcinogenic chemi-
cals and an evaluation and summary of the adverse effects on public health or
welfare or the environment.
5.6 Section 6.0 Conclusions
The purpose of Section 6.0 is to present the results of the entire endanger-
-ment assessment process in a very brief statement of the problems that could
occur at a sdte if no action is taken. This section should also contain a
clear explanation as to whether the site may present an endangerment based on
the risk assessment that was-performed.
Data gaps, assumptions and uncertainties that affect the risk assessment
should be fully qualified in the conclusion section. The endangerment assess-
ment document should not address risk management options at the site. Rather,
this document should clearly and objectively state the existing and potential
risks to public health or welfare or the environment that may exist at the
site.
5-8
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£ife'Systems, Jnc.
6.0 SOURCES OF INFORMATION AND ASSISTANCE
The bibliographies provided at the end of Sections 4.3, 4.4 and 4.5 of this
Handbook are a primary source of information on the endangerment assessment
process and its component parts. Additional guidance and assistance may be
obtained from the points of contact identified in this section.
6.1 Endangerment Assessment Process
The primary points of contact for specific questions on the endangerment
assessment process and the enforcement requirements at a site are:
R. Charles Morgan, Chief
Health Sciences Section
Office of Waste Programs Enforcement
USEPA
401 M Street, SW
Washington, DC 20460
Telephone: (202) 382-5611
Kathleen Plourd
Health Sciences Section
Office of Waste Program Enforcement
401 M Street, SW
USEPA
Washington, DC 20460
Telephone: (202) 382-5646
Additional questions or comments on the endangerment assessment process or
this Handbook may be directed to:
Lee Ann Smith or
Timothy E. Tyburski
ICAIR Life Systems, Inc.
24755 Highpoint Road
Cleveland, OH 44.122
Telephone: (216) 464-3291
6.2 RI and FS Processes
The primary point of contact for specific questions on Superfund requirements
at a site and the RI and FS guidance documents and instruction manuals is:
Craig Zamuda
Office of Emergency and Remedial Response
USEPA
401 M Street, SW
Washington, DC 20460
Telephone: (202) 382-2470
6-1
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£ife Systems, Jnc.
6.3 Toxicity Profiles
Questions on the availability of toxicity profiles prepared specifically for
use at hazardous waste sites should be addressed to the OWPE and OERR contacts
identified above. Mr. R. Charles Morgan or Ms. Kathleen Plourd should be
contacted for information on the OWPE Chemical Profiles; Craig Zamuda is the
point of contact for the OERR Health Effects Assessments.
6.4 EPA Risk and Exposure Assessment Guidelines
The EPA has recently published a series of draft guidelines for risk and
exposure assessment. These draft guidelines are reproduced in their entirety
as Appendix 3 of this Handbook. Each of the draft guidelines contain a
complete reference list as well as a point of contact at EPA for questions on
the individual assessment processes. The point of contact at EPA for each set
of assessment guidelines is identified below:
Carcinogen Risk Assessment
Dr. Robert McGaughy
Carcinogen Assessment Group (RD-689)
Office of Health and Environmental Assessment
USEPA
401 M Street, SW
Washington, DC 20460
(202) 382-5952
Exposure Assessment
Dr. James W. Falco
Exposure Assessment Group (RD-689)
Office of Health and Environmental Assessment
USEPA
401 M Street, SW
Washington, DC 20460
(202) 475-8909
Mutagenicity Risk Assessment
Dr.'David Jacobson-Kram
Reproductive Effects Assessment Group (RD-689)
Office of Health and Environmental Assessment
USEPA
401 M Street, SW
Washington, DC 20460
(202) 382-7336
6-2
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£ife Systems, Jnc.
Health Assessment of Suspect Developmental Toxicants
Dr. Carole A. Kiimnel
Reproductive Effects Assessment Group (RD-689)
Office of Health and Environmental Assessment
USEPA
401 M Street, SW
Washington, DC 20460
(202) 382-7331
Health Risk Assessment of Chemical Mixtures
Dr. Richard Hertzberg
Environmental Criteria and Assessment Office
USEPA
26 West St. Clair
Cincinnati, OH 45268
(513) 684-7531
6-3
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£ifc Systems, Jnc.
7.0 REFERENCES
Anderson E, Browne N, Duletsky S et al. GCA Corporation. 1984. Development
of statistical distribution or ranges of standard factors used in exposure
assessment. Revised Draft Final Report. Washington, DC: U.S. Environmental
Protection Agency, Office of Health and Environmental Assessment, Exposure
Assessment Group. Contract No. 68-02-3510.
Callahan MA, Johnson RH, McGinnity JL et al. 1983. Handbook for performing
exposure assessments. Draft. Washington, DC: U.S. Environmental Protection
Agency, Office of Health and Environmental Assessment.
ICAIR, Life Systems, Inc. 1985. Toxicology handbook: Principles related to
hazardous waste site investigations. Draft. Washington, DC: U.S. Environ-
mental Protection Agency, Office of Waste Programs Enforcement. Contract No.
68-01-7037.
ICF Incorporated. 1985. Superfund public health assessment manual. Draft.
Washington, DC: U.S. Environmental Protection Agency, Office of Emergency and
Remedial Response. Contract No. 68-01-6872.
ICF Incorporated. 1983a. Scientific support document: the scientific basis
for the risk evaluation process. Draft. Washington, DC: U.S. Environmental
Protection Agency, Office of Emergency and Remedial Response.
ICF~~Tnc6rporate"d. " 1983b. Superfund feasibility study guidance, chapter 4,
risk evaluation. Washington, DC: U.S. Environmental Protection Agency,
Office of Emergency and Remedial Response.
McNeils DN, Earth DC, Khare M et al. Environmental Research Center, Univer-
sity of Nevada at Las Vegas. 1984. Exposure assessment methodologies for
hazardous waste sites. Las Vegas, NV: Office of Research and Development.
Environmental Monitoring Systems Laboratory. CR810550-01.
Morgan RC, Clemens R, Davis BD et al. 1984. Endangerment assessments for
superfund enforcement actions. Washington, DC: U.S. Environmental Protection
Agency, Office of Waste Programs Enforcement.
NAS. 1982. National Academy of Sciences, National Research Council. Risk
and decision making: perspectives and research. Washington, DC: National
Academy Press.
Nisbet ICT. Clement Associates, Inc. 1984. Seminar presentation on endan-
germent assessment. Final Report. Washington, DC: U.S. Environmental
Protection Agency, Office of Waste Programs Enforcement. Contract No.
68-01-6769.
Schaum J. 1984. Short course on integration of exposure and risk assessment.
Part 3. Exposure assessment methods. Paper presented at the Annual Meeting
of Society for Environmental Toxicology and Chemistry, Arlington, VA.
7-1
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JCifc Systems, Jnc.
Schultz HL, Palmer WA, Dixon GH et al. Versar Inc. 1984. 'Superfund exposure
assessment manual. Final Draft. Washington, DC: U.S. Environmental Protec-
tion Agency, Office of Toxic Substances, Office of Solid Waste and Emergency
Response. Contract Nos. 68-01-6271 and 68-03-3149.
USEPA. 1985a. U.S. Environmental Protection Agency. Environmental Criteria
and Assessment Office. Proposed guidelines for the health risk assessment of
chemical mixtures. Fed. Regist., Jan. 9, 1985, 50 1170.
USEPA. 1985b. U.S. Environmental Protection Agency. Office of Emergency and
Remedial Response. Guidance on feasibility studies under CERCLA. Draft.
Washington, DC: U.S. Environmental Protection Agency.
USEPA. 1985c; U.S. Environmental Protection Agency. Office of Emergency and
Remedial Response. Guidance on remedial investigations under CERCLA. Final
Draft. Washington, DC: U.S. Environmental Protection Agency.
USEPA. 1985d. U.S. Environmental Protection Agency. Office of Waste Pro-
grams Enforcement. Draft endangerment assessment guidance. Memorandum from
Jack W. McGraw. Washington, DC: U.S. Environmental Protection Agency.
May 28, 1985.
USEPA. 1984a. U.S. Environmental Protection Agency. Risk assessment and
management: framework for decision making. Washington-, DC: U.S. Environ-
mental Protection Agency.
USEPA. 1984b. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for carcinogen risk assessment.
Fed. Regist., Nov. 23, 1984, 49 46294.
USEPA. 1984c. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for exposure assessment. Fed.
Regist., Nov. 23, 1984, 49 46304.
USEPA. 1984d. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for mutagenicity risk assess-
ment. Fed. Regist., Nov. 23, 1984, 49 46314.
USEPA. 1984e. U.S. Environmental Protection Agency. Office of Health and
Environmental Assessment. Proposed guidelines for the health assessment of
suspect developmental toxicants. Fed. Regist., Nov. 23, 1984, 49 46324.
USEPA. 1984f. U.S. Environmental Protection Agency. Office of Pesticides
and Toxic Substances. Chemical activities status report, fourth edition,
volume 2. Washington, DC: U.S. Environmental Protection Agency. EPA 560/
TIIS-84-0016.
USEPA. 1982. U.S. Environmental Protection Agency. Office of Pesticides and
Toxic Substances. Graphical exposure modeling system (GEMS) user's guide.
Draft. Washington, DC: U.S. Environmental Protection Agency.
7-2
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£ife Systems, Jnc.
Whitmore RW. 1984. Research Triangle Institute. Methodology for character-
ization of uncertainty in exposure assessments. Washington, DC: U.S.
Environmental Protection Agency, Office of Health and Environmental Assess-
ment, Exposure Assessment Group. Contract No. 68-01-6826.
7-3
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£ifc Systematic.
APPENDIX 1
DRAFT ENDANGERMENT ASSESSMENT GUIDANCE
Al-1
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
DRAFT
SEP 2 0 1985
OFFICE OF
SOLID WASTE AND EMERGENCY RESPONSE
MEMORANDUM
SUBJECT: Endangerment Assessment Guidance
FROM: J. Winston Porter
Assistant Administrator
TO: Addressees
PURPOSE
This memorandum clarifies the requirement that an
endangerment assessment be developed to support all administra-
tive and judicial enforcement actions under Section 106 of the
Comprehensive Environmental Response, Compensation, and Liability
Act (CERCLA) and Section 7003 of the Resource Conservation and _
Recovery Act (RCRA). Before taking enforcement action under
these provisions t<5 abate the hazards or potential hazards at a
site, the Environmental Protection Agency (EPA) must be able to
properly document and justify its assertion that an imminent and
substantial endangerment to public health cr welfare or the
environment may exist. The' endangerment a; .essment provides this
documentation and justification. The endancjerment assessment is
not necessary to support cost recovery for Section 104 remedial
actions.
This memorandum also provides guidance on the content,
timing, level of detail, format, and resources required for the
preparation of endangerment assessments.
WHAT IS AN ENDANGERMENT ASSESSMENT
An endangerment assessment is a determination of the
magnitude and probability of actual or potential harm to public
health or welfare or the environment by the threatened or actual
.release of a hazardous substance (for a CERCLA action) or a
hazardous waste (for a RCRA action).
An endangerment assessment evaluates the collective
demographic, geographic, physical, chemical, and biological
factors which describe the extent of the impacts of a potential
or actual release of a hazardous substance and/or hazardous
waste.
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-2-
DRAFT
In general, the endangerment assessment should identify and
characterize:
(a) Hazardous substances and/or hazardous wastes present
in all relevant environmental media (e.g., air, water,
soil, sediment, biota);
(b) Environmental fate and transport mechanisms within
specified environmental media, such as physical, chemical
and biological degradation processes and hydrogeological
evaluations and. assessments;
(c) Intrinsic toxicological properties or human health
standards and criteria of specified hazardous substances
or hazardous wastes;
(d) Exposure pathways and extent of expected or potential
exposure;
(e) Populations at risk; and,
(f) Extent of expected harm and the likelihood of such harm
occurring (i.e., risk characterization).
WHY PERFORM AN ENDANGERMENT ASSESSMENT
Under Section 106(a) of CERCLA, if the President determines
that there may be an imminent and substantial endangerment to
public health or welfare or the environment from an actual or-
threatened release of a hazardous substance, the President may
secure such relief as may be necessary to abate such danger or
threat* Such relief may be in the form of a judicial action or
an administrative order to compel responsible parties to respond
to hazardous conditions.
Before an order can be issued under §106 of CERCLA, EPA
must be able to document and justify its assertion that an
imminent and substantial endangerment to public health or welfare
or the environment may exist. The endangerment assessment
provides this documentation and justification. It is the basis
for the findings of fact in administrative orders, consent
decrees, and complaints.
•In situations dealing with hazardous wastes or solid wastes
under RCRA, rather than hazardous substances under CERCLA, Section
7003 of RCRA may be used as the authority under which EPA may
issue orders or file civil actions !_/'. Section 7003 of RCRA
requires a similar finding of imminent and substantial endanger-
ment and, therefore, EPA must also document and justify such an
assertion with an endangerment assessment before taking enforcement
action.
I/ "Final Revised Guidance Memorandum on the Use and Issuance of
Administrative Orders Under Section 7003 of the Resource Conserva-
tion and Recovery Act", September 26, 1984 signed by Courtney Price
and Lee Thomas.
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-3-
DRAFT
It is important to note that "imminent" does not mean immediate
harm. Rathor/.it means an impending risk of harm. Sufficient.
justification for a determination of an imminent endangerment may
exist if harm is threatened; no actual injury need have occurred
or be occurring. Similarly, "endangerment" means something less
than actual harm.
WHEN TO PERFORM AN ENDANGERMENT ASSESSMENT
At remedial sites subsequently targeted for CERCLA §106 or
RCRA §7003 enforcement action, all of the elements of an endanger-
ment assessment will be provided by completing the contamination
assessment, public health evaluation, and environmental assessment
during the RI/FS process. As such, these assessments are equivalent
to the endangerment assessment for enforcement sites. The informa-
tion from the contamination assessment, public health evaluation,
and environmental assessment will be considered sufficient to
issue an order although additional work may be needed prior to
litigation (See Attachment 1 and the RI/FS guidance documents
referenced on Page 6 of this guidance).
Where an RI/FS has not been initiated or completed, an
endangerment assessment must be prepared to justify an adminis-
trative order or judicial action under CERCLA §106 or RCRA §7003.
For example, orders issued to govern responsible party conduct of
an RI/FS or to compel responsible party performance of immediate
response actions will require an endangerment assessment prior to
issuance. In both cases, the endangerment assessments will demon-
strate that there may be an imminent and substantial endangerment
which justifies either further investigative action to determine
the appropriate remedy for a site or an immediate response action.
In isolated cases, EPA has negotiated with potentially
responsible parties for the site remedy.before it has developed
the RI/FS. In these few cases, an endangerment assessment must be
developed independently of the RI/FS and completed prior to issuance
of the order or decree for remedial action.
An endangerment assessment is required for all future RCRA
§7003 actions, as well as older RCRA §7003 cases to which CERCLA
§106 authority has been or will be added. An endangerment assess-
ment is not required for older RCRA §7003 cases already filed by
.the Department of, Justice without an endangerment assessment. The
litigation team, however, may determine on a case-by-case basis
that the preparation of an endangerment assessment or its equivalent
would substantially strengthen the government's case.
Endangerment assessments must be prepared for all RCRA §7003
or CERCLA §106 orders issued to another Federal agency for cleanup
of a Federally-owned facility. Normally, EPA will seek response
action at a Federal facility through a site-specific compliance
agreement with the appropriate Federal agency or other responsible
parties. If, however, a compliance agreement is not complied with
by Federal owners or responsible parties, EPA may issue an order.
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-4-
WHAT LEVEL OF DETAIL
DRAFT
The determination that an imminent and substantial »ndanger-
ment to public health or welfare or the environment may exist is
a legal prerequisite that must be met before an order can be
issued. It is EPA policy that endangerment assessments should
be undertaken only to the extent "necessary and sufficient" to
fulfill th<3 requirements of lc-::al enforcement proceedings. At
any site, there is the potential for conducting studies beyond
the level of detail needed for enforcement actions. The level
of detail of the endangerment assessment should be limited to
the amount of information needed to sufficiently demonstrate an
actual or potential im-ninent and substantial endangerment. The
level of detail to sufficiently demonstrate endangerment will
vary from case to case based on the following factors:
0 the type of enforcement action (e.g., AO for removal
vs litigation);
0 the type of response action (e.g., removal vs remedial);
and
0 the stage of response action (e.g., RI/FS workplan vs
RI/FS completed).
The level of detail required to support a particular enforce-
ment action will ultimately be determined on a cas.e-by-case
basis by Regional program personnel in consultation with Regional.
Counsel. As a general guide, the matrix on page 5 defines these
levels of detail based on the factors listed above. The matrix
•should help the Regions to both (1) determine what constitutes an *
adequate endangerment assessment for a particular enforcement
action, and (2) plan their intramural and extramural resources
accordingly.
When endangerment assessments are developed to support
administrative orders for private party RI/FS or immediate
removal actions, information already available about the site
will generally be sufficient. Where sites are targeted for
enforcement action after completion of an RI/FS, the endangerment
assessments developed as part of the RI/FS will be more detailed
and generally more quantitative as they will be based on informa-
tion obtained from the remedial investigation. Such endangerment
assessments will be used to support any subsequent CERCLA §106
orders or judicial actions seeking design and construction of
site remedies.
The information gathered in an RI/FS is generally similar
to the type of information needed for an endangerment assessment.
However, RI/FS and endangerment assessments are developed for
different purposes. RI/FS are used to determine appropriate
response actions under CERCLA §104, while endangerment assessments
are used for enforcement actions under CERCLA §106 or RCRA §7003.
For sites with CERCLA §106 or RCRA §7003 enforcement potential,
Regions should review the RI/FS workplan to determine whether
information developed as part of the RI/FS will be sufficient
for an endangerment assessment. In certain complex cases,
additional information may be needed and a separate enOangerment
assessment workplan may be required.
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GUIDELINES FDR LEVELS Ob1 L
Complexity
T,evel 1
Level II
Level III
ffile:—
Type of
Action
.AO for removal
action, AO for
private party
RI/FS, prelimi-
nary .scoping
Issuance of AO
or consent decree
for pri'Mte party
cleanup
Litigation
(site-by-site
basis)
Data Base
May bo United, probably
consisting of information
from the Preliminary Site
Assessment, Site Inspection
Report, and Hazard Ranking
System evaluation, if completed.
No health studies available;
no demographic studies avail-
able. Preliminary sampling
data will probably be available
on pollutants present. Data on
extent of release or concentra-
tions of materials at the point
of exposure may be available.
Remedial Investigation complete
or other quantitative data
available on nature/extent of
release. Data may be available
on magnitude and demographics
of population at risk. . '
Possibly some preliminary
health effects studies.
Sources and specific
materials associated with
release are identified.
RI and FS complete. All
required geological, hydro-
geological, and health
studies complete.
Type of Assessment
Qualitative assessment
of exposure routes, popu-
lation at risk, and
probability of harm occurring.
Critical pollutants and
their toxicological pro-
perties can be readily
identified and quantity
of pollutants estimated.
Reasonable and prudent to
conclude that an exposure
may exist because' • the
release.
Semi-quantitative appraisal
considering specific exposure
routes and critical pollu-
tants. The assessment should
be able to identify any data
gaps anl recommend additional
studies, if necessary.
basis as
flexible and may shift on a case-by-case
ired to ^support a particular enforcement
Detailed, quantitative
review to identify potential .
health effects, critical
exposure levels, and necessary
follow-up health studies.
Critical pollutants and routes
identified, and existing expo-
sures defined or estimated.
This will constitute an
appraisal to the best of
expertise and knowledge and an
estimate of the uncertainty.
UKAn
Remarks
For removal actions
where the normal site
ranking process has
not been completed
or undertaken, in-
formation for the
assessment may be
available from record
searches, State spon-
sored investigations,
written reports from
inspections by
government authori-
ties, and notifica-
tion in accordance
with CERCLA §103.
This assessment must
be able to support
legal action in the
event that it is
challenged by a
recalcitrant PRP.
Should be conclusive
enough that PRPs will
be encouraged to make
a firm commitment to
complete remedial
action, but not
necessarily detailed
and complete if
based on RI/FS.
May require endanger-
ment assessment work
in addition to infor-
mation generated
during RI/FS.
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-6-
DRAFT
The endangerment assessment should evaluate the adequacy,
accuracy, precision, comprehensiveness, reliability, and overall
quality of identified information and data.
Emergency actions do not require the same depth of. assess-
ment as planned or remedial activities. By definition, an
immediate and significant risk of harm to human life or health
or the environment will be present in an emergency, making
the assessment of endangerment easier to prepare. Further,
EPA is justifying only the need for immediate action, not the
long-terra remedial solution. Thus, th-3 endangerment assessment
may be much briefer, although the P.=gions should attempt to
use as much available information as feasible. The Action
Memorandum supporting the emergency action will normally be
considered adequate to serve as an endangerment assessment in
support of an enforcement action under §106 of CERCLA for an
immediate response.
Attachment 2 is an abstract of a detailed paper on "Endan-
germenjt Assessments for Superfund Enforcement Actions", prepared
by. Technical" Support Branch, CERCLA Enforcement Division, the
Office of Waste Programs Enforcement (OWPE). This paper,
previously distributed to the Regions, will provide technical
assistance in preparing qualitative and quantitative assessments.
OWPE is also preparing a handbook on preparation of endangerment
assessments.
Methodologies used for performance of such aspects of the
endangerment assessment as exposure and risk assessment should
be consistent with the concepts and methods currently in use by
the EPA Office of Research and Development (ORD).
Attachment 3 shows how the various toxicity, exposure, and
risk evaluations.are used to define the overall problems and
hazards (endangerment) at a site. Although the use of these
evaluations is possible at every sitet the need for a detailed
analysis, as outlined, is likely to be appropriate at only a
limited number of sites to sufficiently demonstrate an actual
or potential imminent and substantial endangerment.
The Office of Emergency and Remedial Response (OERR) has
developed guidance manuals covering the performance of remedial
investigations and feasibility studies. The chapters listed
below from these documents and the OWPE handbook will provide
guidance in preparing endangerment assessments:
Guidance on Remedial Investigations Under CERCLA (OERR, May 1985)
Chapter 7 - Site Characterization
Chapter 9 - Remedial Investigation Report Format
Guidance on Feasibility Studies Under CERCLA (OERR, April 1985)
Chapter 5 - Evaluate Protection of Public Health Requirements
Handbook on Preparation of Endanqerment Assessments (OWPE -
Technical Support Branch, Summer 1985)
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DRAFT
-7-
At.tachiuent 4 is a list of references that can be ussd in
preparation of the endangerment assessment.
FORMAT
The endangerment assessment generally should follow a
standard framework as provided in Attachment 5 and use qualitative
and/or quantitative terms as appropriate.
The Action Memorandum will normally be considered adequate
to serve as the endangerment assessment document in support of an
order under §106 for an emergency action.
The endangerment assessment document may be the order itself
(where the order contains all of the elements of an endangerment
assessment) or a separate document. In deciding whether to
develop a separate document or to include the elements of the
endangerment assessment in the order, Regions should consider the
following factors:
1. Are the responsible parties more likely to consent to
an order if the endangerment assessment is part of the body of
the order, or a separate document?
2. Is the order likely to be issued unilaterally or on
consent? A separate document will, of course, be more important
in "adversarial settings. ~"~
We strongly urge that the endangerment assessment in support
of an administrative order for private party c.;. :-anup be a separate
document. Where all of the elements of an endangerment assessment
are in the RI/FS documents, a separate document may consist simply
of a brief statement cross-referencing the appropriate elements
of the RI/FS.
WHO SHOULD PERFORM AN ENDANGERMENT ASSESSMENT
The Regions have the responsibility to assure that endanger-
ment assessments are performed. The Regions can draw on technical
expertise available in their Regional offices, OWPE - Technical
Support Branch, ORD, the Agency for Toxic Substances and Disease
Registry (see MOU between ATSDR and EPA), and/or contractor
personnel available through the Technical Enforcement Support
(TSS) or REM/FIT and TAT contracts.
Endangerment assessments used to justify administrative
orders or judicial actions issued or filed before development
of the RI/FS should normally be drafted by Regional personnel
with the assistance of the TES contractor. The Regions and TES
contractor also have the lead in preparation of endangerment
assessments for older cases where an RI/FS has not been completed.
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-8-
DRAFT
If responsible parties elect to perform the RI/FS, they:will,
in effect, perform an endangerment assessment because they will
develop many or all of the elements of an endangerment assessment
as part of the RI/FS. Regions should review the RI/FS workplan to
determine whether information developed as part of the RI/FS will
be suffici-ent to show that an imrriio.e.-it and substantial endangerment
may exist. Because subsequent enforcenent actions will rely on
the endangerment assessment developed as part of the RI/FS, close
Regional oversight should be given to. this responsible party work.
The authority for determinations of imminent and substantial
endangerment relating to emergency response actions costing up to
one million dollars has been delegated to the Regions, subject to
the directives issued by the Office of Solid Waste and Emergency
Response. (See Delegation 14-1-A, Selection and Performance of
Removal Actions Costing Up to $1,000,000 and the Memorandum
"Waiver of Advance Concurrence Requirements for Certain Consent
Administrative Orders, Gene A. Lucero, January 3, 1985).
When exercising the authority to determine that an imminent
and substantial endangerment exists for the purposes of taking
enforcement action, the Region must consult with OWPE as outlined
in the November 30, 1984 Regional Assignment Memo (also see the
Memorandum "Superfund Delegations of Authority - ACTION MEMORANDUM",
Howard Messner, April 4, 1984). In contacting OWPE, Regional
staff should be prepared to discuss the .details of the endangerment
assessment for each determination. In certain cases involving
complex health and environmental endangerment issues, OWPE may
request a copy of .the draft endangerment assessment for review.
OWPE will complete a review of this document within 14 days of
receipt, to ensure consistent, timely response.
USE OF THIS GUIDANCE
The policy and procedures set forth here, and internal
office procedures adopted in conjunction with this document,
are intended for the guidance of staff personnel, attorneys,
and other employees of the U.S. Environmental Protection Agency.
They do not constitute rulemaking by the Agency, and may not be
relied upon to create a right or benefit, substantive or
procedural, enforceable at law or in equity, by any person.
The Agency may take any action at variance with the policies or
procedures contained in.this memorandum or which are not in
compliance with internal office procedures that may be adopted
pursuant to those materials.
If you have^any -questions or concerns regarding this guidance,
please have your "staff contact Chuck Morgan (FTS-475-6690), Chief
of the Environmental Health Sciences Section of OWPE or Linda
Southerland (FTS-382-2035) of the Guidance and Oversight Branch.
-------
schment 1
RI/FS Process
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Attachment 2
ENDANGERMENT ASSESSMENTS FOR SUPL'RFUND 'ENFORCEMENT
R. Charles Morgan2
Robert Clemens
Thomas T. Evans
Jerald A. Fagliano
Joseph A. LiVolsi, Jr.
Abraham L. Mittelman
J. Roy Murphy
Jean C. Parker
Kenneth Partymiller
Support Branch, Office of Waste Programs Enforcement, U.S. EPA
ABSTRACT
The Comprehensive Environmental Response, Compensation and
Liablity Act of 1980 (CERCr\) gave the Environmental Protection Agency
(EPA) new responsibilities md powers to take actions in response
to releases of hazardous substances into the environment which may '
present an imminent and substantial endangerment to the._environrnent,
or the public health or welfare.
In an action to abate an endangerment, an assessment is made
of the hazards or potential hazards at a site according to methods
outlined in the National Contingency Plan. Information needed
to perform an endangerment assessment includes the site history '
and management practices, identification and quantification of
hazardous substances at a site, and their likely transport and
fate. Estimates of actual or potential human and environmental
exposures are compared to toxicological data to describe the kind
and degree of endangerment.
This paper discusses the many factors that should be considered
in an endangerment assessment and streses the need for strict
quality assurance and sound scientific judgment.
The information presented in the paper is based on the technical
enforcement case development experiences of the authors.
Contact to whom comments should be addressed:
(WH-527), 401 M. Street, S.W. Washington, D.C. 20460
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Attachment 3
Data Collection/Problem Characterization
Data Collection/Problem Characterization
I. Site Characterization
A. physical description of the site
B. geographical location
C. demographic surroundings
D. type of facility (landfill, incinerator, impoundment)
E. management practices
II. Contaminants Found at the Site
A. identity/type
B. quantity
C. form
D. manner of disposal
E. ambient levels
III. Factors Affecting Migration
A. topography
B. soil parameters
C. geological parameters
D. hydrological characteristics
E. climate
IV. Environmental Fate of Contaminants
A. physical and chemical degradation'characteristics
B. movement between environmental media
C. hydrogeological/geochemical characteristics
D. evidence migration
V. Hazard Identification (site/population specific)
A. Toxicological evaluation, e.g.
- organ toxicity, carcinogenic
- mutagenic, teratogenic
- neurotoxic, etc.
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B. Impact Evaluation (actual)
•^» .
1. Environmental impacts
a. determination of need
b. literature searches
c. lab tests
d. food chain studies
e) environmental effect observation
- stressed vegetation
- wildlife or aquatic life morbidity/mortality
- domestic animal morbidity/mortalilty
f) natural resource damages
2. Public Health Impacts (actual)
a) health assessment/advisory (short-term)
1. determination of need?
2. literature searches
3. lab tests, pi"~>t biological testing
4. testing of fo "i chain contamination
5. health assessment document
6. health advisories
b) human health studies (long-term)
- epidemiological studies
- clinical studies
- registries
c) human health standards and criteria
Data Interpretation
I. Dose-Response Assessment (predictive")
A. quantitative component of cancer mathematical
modeling- probability
B. ADI calculations for non-carcinogens
II. Exposure Assessment
A. locate potential populations at risk of exposure
B. determine routes and pathways of exposure
for each in various environmental media,
and environmental transport and fate data
C. calculate maximum short-term dose and average
dose expected over a lifetime
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III. Risk Characterization (predictive)
.•> .
A. combining exposure, hazard and dose-response
assessments for a specific site
B. estimation of the magnitude of the public health
problem at a particular site including Medical
Panel concerns.
Risk Management
process of evaluating and selecting options; environmental,
economic, social and political consequences may be considered
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Attachment 4
BIBLIOGRAPHY
Proposed Guidelines for Carcinogen Risk Assessment, EPA, 49
FR 84-30724 November 23, 1984.
Proposed Guidelines for Exposure Assessment, EPA, 49 FR 84-30723
November 23, 1984.
Proposed Guidelines for Mutagenicity Risk Assessment, EPA, 49
FR 84-30722 November 23, 1984.
Proposed Guidelines for the Health Assessment of Suspect Develop-
mental Toxicants, EPA, 49 FR 84-30721 November 23, 1984.
Proposed Guidelines for the Health Risk Assessment of Chemical
Mixtures, EPA, 50 FR 85-589 January 9, 1985.
Remedial Investigations Guidance Document, February 1985.
Interim Procedures and Guidelines for Health Risk and Economic
Impact Assessments for Suspected Carcinogens, EPA, 41
FR 24102 May 25, 1976.
Scientific Bases for Identification of Potential Carcinogens
and Estimation of Risks, Report by the Work Group on
Risk Assessment of the Interagency Regulatory Liaison
Group, 44 FR 39858 July 6, 1979.
Guidelines and Methodology Used in the Preparation of Health
Assessment Chapters of the Consent Decree Water Criteria
Documents, Appendix C of Water Quality Criteria Documents:
EPA, 45 FR 79347 November 28, 1980.
Appendix £: Response to Comments on the Human Health Effects
Methodology for Deriving Ambient Water Quality Criteria,
45 FR 79368.
Endangerment Assessments for Superfund Enforcement Actions,
HMCRI Compendium of Papers, November, 1984.
Risk Assessment and Management: Framework for Decision Making
U.S. EPA, December 1984.
* Further references are forthcoming in the Feasibility Study
Guidance Document, the Superfund Exposure Assessment Manual,
the Superfund Public Health Evaluation Process: Procedures
Manual, the Superfund Risk Evaluation Manual, and the Office
of Research and Development Handbook for Performing Exposure
Assessments.
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APPENDIX 2
EXAMPLES OF ENDANGERMENT- ASSESSMENT
Part 1 - Level 1 Endangerment Assessment
Part 2 - Level 2 Endangerment Assessment
Part 3 - Leyel 3 Endangerment Assessment
A2-1
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PREFACE
The following examples of Level 1, 2 and 3 endangennent assessments are based
on data from a real enforcement case. They were prepared exclusively for
illustrative purposes and are not intended to definitively reflect current
endangerment posed by the site. It was necessary to selectively include
information from a substantial number of documents in the EPA's case files to
reflect the scope and type of information that typically would be available at
the times Level 1, 2 or 3 assessment documents are prepared. As a result,
some data were considered not to exist during preparation of the Level 1 or 2
examples which were subsequently used to prepare the Level 3 example. Some
descriptions and information in these example documents may not fully reflect
actual site conditions at the present time but are intended to represent
conditions that may have existed at the time each assessment would have been
prepared.
Although a substantial information base was available, some key information
was still not available. The' example endangerment assessment documents
illustrate several approaches to deal with an incomplete or a less than ideal
data base. The scope, quality and type of information available and site
specific features influenced the level of detail, content, length and focus of
the example endangerment assessment documents.. The example endangerment
assessments focused on a single.chemical (dioxin) due to its extreme toxicity.
The type of monitoring data available and existing exposure assessment and
risk assessment documents precluded addressing multiple chemicals in the
example endangerment assessments. More information on other contaminants may
become ,available to enable expansion of the scope of these assessments.
Future revisions of these examples endangerment assessments or preparation of
real endangerment documents on other sites may require addressing several
chemicals of concern. These documents should contain correspondingly less
detailed toxicity information for individual chemicals (relative to the amount
of information provided on dioxin in the example documents) to keep the entire
document's length of a manageable size.
The Vertac site is probably more complex than the typical site since it
contains several landfill areas, drum storage areas, discharges to surface
waters, spill areas, drainage ditches and adjacent residences. Several
removal and remedial actions implemented at the site further complicate the
example.
Existing exposure evaluation documents for the Vertac site have focused on
dioxin exposures via consumption of contaminated fish or inhalation of
airborne dioxin contaminated dust. Assessments of direct dermal exposures,
direct ingestion (i.e. pica in children) and ingestion of contaminated
drinking water were limited by the available information and the resources
available and the schedule for completion of the examples. Future revisions
of the example endangerment assessments may address these routes in more
detail (i.e., in the Levels 2 and 3 example) and possibly consider exposures
to other contaminants as appropriate. This may include rough exposure
calculations in the Level 2 example and some original exposure modeling for
the Level 3 example as appropriate data become available.
A2-2
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The risk and impact evaluation may require expansion in future revisions
pending results of the exposure evaluations. This is especially relevant for
the Level 3 example which should ideally provide quantitative assessments for
direct dermal and ingestion exposures, and ingestion of contaminated drinking
water. The risk and impact evaluation may also need to address adverse
effects posed by other contaminants from'the site.
A2-3
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PART 1 - LEVEL 1 ENDANGERMENT ASSESSMENT
A2-4
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Submitted to:
Office of Waste Programs Enforcement
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Attention: Chief, Health Sciences Section, R. Charles Morgan (2 copies)
VERTAC SITE ENDANGERMENT ASSESSMENT
(Level 1 Example)
Prepared Under
•Program No. 1393
for
Contract No. 68-01-7037
Work Assignment No. 12
PRC Work Assignment No. 136
Contact: Timothy E. Tyburski
Telephone: (216) 464-3291
July 25, 1985
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DISCLAIMER
This document has not been peer and administratively reviewed within EPA and
is for internal Agency use/distribution only.
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TABLE OF CONTENTS
PAGE
1.0 INTRODUCTION 1
1.1 Site Description and History 1
1.2 Contaminants Found On-Sire 1
2.0 ENVIRONMENTAL FATE AND TRANSPORT 1
3.0 EXPOSURE EVALUATION ' 3
3.1 Routes of Exposure 3
3.2 Populations Exposed 4
4.0 TOXICITY EVALUATION 5
5.0 RISK AND IMPACT EVALUATION 6
6.0 CONCLUSIONS 6
7.0 REFERENCES. '.7
LIST OF FIGURES
FIGURE PAGE
1 Vertac Site Map ' . 2
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1.0 INTRODUCTION
The disposal of chemical waste and discharges of process wastewater at the
Vertac hazardous waste site over a 30-year period has resulted in contami-
nation of soils, groundwater and surface waters. This contamination may
endanger human health, welfare and the environment.
1.1 Site Description and History
The Vertac site (about 93 acres), located in Jacksonville, AR, is currently
used to manufacture the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D).
Munitions and numerous pesticides including DDT, aldrin, dieldrin, toxaphene,
2,4-D, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4,5-trichlorophenoxy-
propionic acid (Silvex or 2,4,5-TP) and Agent Orange have been previously
manufactured on site. The site is bounded by the Rocky Branch Creek and the
East Branch of the Rocky Branch Creek, an old artillery booster line and an
adjacent housing subdivision (see Figure 1). The creek flows to Bayou Meto, a
tributary of the Arkansas River.
1.2 Contaminants Found On-Site
The site contains about 30,000 yd of chlorinated phenols, benzene and toluene
wastes in the Reasor-Hill Landfill, 20,000 yd of materials (containing
dioxin) in the equalization basin, 100,000 yd of toluene still bottoms in the
Hercules-Transvaal Landfill and 3,000 drums of 2,4,5-T still bottoms and
contaminated soils .in a roofed and diked warehouse. Discharges of process
wastewaters, disposal of pesticide manufacturing wastes, reactor spills and
other plant operations have caused the actual or potential release of the
following contaminants:
• 2,3,7,8-TCDD • Chlorophenols
• 2,4,5-T • Chlorobenzenes
• 2,4-D • Toluene.
• 2,4,5-TP • Methanol
This endangerment assessment focuses on dioxin because it is the most highly
toxic substance at this facility and is very persistent in soils and aquatic
systems. Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin or 2,3,7,8-TCDD) has
been detected as an impurity in waste products from the manufacture 'of 2,4,5-T
and Agent Orange, in soils on-site and in sediments and fish tissues from
ad-jacent surface waters.
2.0 ENVIRONMENTAL FATE AND TRANSPORT
Dioxin is very persistent (estimated half-life of 10 years) in the environment
and resists biodegradation, photodegradation, oxidation and hydrolysis (USEPA
1984). Dioxin is adsorbed on particles (suspended or sediments) and soils and
is only slightly soluble (0.2 ug/L) in water (USEPA 1984). Since dioxin tends
to remain bound to soils, the vertical migration of dioxin in soil is usually
minimal. The primary route of transport is via horizontal transfer of dioxin
adsorbed to soils and dust particles. Wind erosion and surface runoff erosion
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ROOFED DRUM
STORAGE AREA
OLD DRUM
STORAGE SIT
HERCULES-TRANSVAAL
COOLING
POND
BLOW-OUT AREA
n
Barrier Walls
ASOR-HILL
ANOF1LL
Barrier Walls
x
General Drainage Ditch
—French Drai
Interceptor Dice
BRAOEN STREET
Adapted from Walton 1982 as cited in JRB (1983)
FIGURE 1 VERTAC SITE MAP
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processes are anticipated to be the primary mechanisms of natural horizontal
transport. Vertical migration of dioxin through the soil is unlikely to occur
unless the capacity of the soils are saturated or dioxin is solvated by
organic solvents (NRCC 1981). Dioxin solvated by organic solvents may be more
readily transported through soil to the groundwater.
Dioxin released to aquatic systems bioaccumulates in a number of species and
may accumulate up to four orders of magnitude above environmental concentra-
tions (Isensee and Jones 1975) . Bioaccumulation and bioconcentration factors
for dioxin are being reassessed by the U.S. Environmental Protection Agency.
Anthropogenic activities involving disturbance of soils and frequent vehicular
movement (associated with routine on-site land fill operations) are expected
to cause emission of dust potentially bearing dioxin. Wet and dry deposition
of this dust may contaminate surface soils and surface water bodies (Rocky
Branch Creek, Bayou Meto and Lake Dupree) adjacent to the site.
The direct discharge of process wastewaters to the cooling pond and transport
of dioxin on suspended particles has caused substantial contamination of the
Rocky Branch Creek and Bayou Meto. Flooding of the Rocky Branch Creek south
of the Vertac site has potentially transported dioxin-particulate to Lake
Dupree, a man-made recreational lake about 1.3 miles south of Vertac.
3.0 EXPOSURE EVALUATION
3.1 Routes of Exposure
The potential routes of exposure are:
1. Consumption of contaminated fish from the Bayou Meto and Rocky
Branch Creek.
2. Consumption of groundwater or surface water downgradient of the
Vertac site.
3. Inhalation of dust-contaminated with dioxin that becomes airborne
due to wind erosion or anthropogenic activities.
4. Direct contact with waters, sediments or soils adjacent to the site
that have been contaminated by surface runoff, erosion processes and
direct releases. Direct contact includes direct dermal exposures as
well as direct ingestion exposures (i.e. pica in children).
The route of primary concern is anticipated to be consumption of contaminated
fish from the Bayou Meto because of the probability for dioxin to bioaccumulate
in fish (as indicated by the high bioconcentration factors). Preliminary
environmental monitoring data has detected high concentrations of dioxin in
fish from Lake Dupree (810 ppt) and Bayou Meto (300 ppt) (Schaum and Faico
1982). Bayou Meto was classified as a warm water fishery according to the
1975 .Arkansas Water Quality Standards and was considered suitable for desir-
able species of fish, wildlife and other aquatic and semi-aquatic life and
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potentially as raw water source for public water supplies. However, pollution
problems in Bayou Meto and its tributaries (including the Rocky Branch Creek)
date back to 1955 when massive fish kills were first reported to be associated
with releases of contaminants from the Vertac site.
3.2 Populations Exposed
The population that consumes fish caught from the Bayou Meto is potentially
exposed to high concentrations (about 300 ppt) of dioxin (Schaum and Falco
1982). Individuals who may consume large (5 to 16 Ib/year) amounts of fish
from the Bayou have the highest exposure potential. Complaints of "medicinal"
taste and odor problems in fish caught from the Bayou registered with the
Arkansas Game and Fish Commission indicate that there have been chronic
pollutional problems and provide evidence of real exposure potential via this
route. Further complaints about taste and odor of fish from the Bayou regis-
tered in 1963 and in 1965 were also traced to contaminants released from the
Vertac site. '
Insufficient data on the prevailing wind direction, wind speed and geograph-
ical features affecting wind patterns are available to determine which
populations are at an increased exposure potential for airborne dust. The
population living in the subdivision to the south of the Vertac site is
potentially at risk for exposure to dioxin-dust emissions. The size of the
population living near the site has not been determined. It is assumed that
the proximity of the population to the site subjects the nearest residents to
an~increased risk of exposure, to dioxin since~~airborne dust concentrations are
expected to be greatest close to the site and to diminish with increasing
distance from the site. People that are homebound during the daytime, and
especially those that are outside during site activities that create dust
emissions are expected to be at highest risk; however, the concentration
indoors and outdoors may equalize over time.
Preliminary contacts with state and local permitting agencies have not identi--
fied a substantial number of domestic or industrial wells within the vicinity
of the site. Populations that consume groundwater may be at increased risk of
exposure to dioxin or other contaminants that may percolate into the water
table and migrate off-site.
Off-site migration via wind and water erosion processes or direct releases
creates the potential for direct contact exposures. Populations that are in
close proximity to the site (i..e., in the housing subdivision) and/or people
that may use the area for recreation are expected to be at higher risk for
direct contact exposures.
Aquatic organisms, avian species and terrestrial organisms may be exposed to
dioxin and other contaminants released from the site. Preliminary monitoring
data on fish indicate substantial dioxin exposures have occurred and resulted
in bioaccumulation of high dioxin levels in tissues. Aquatic species that are
benthic feeders are expected to be at higher risk due to high concentrations
of dioxin detected in sediments of the Rocky Branch Creek, Bayou Meto and Lake
Dupree.
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4.0 TOXICITY EVALUATION
Dioxin is a highly toxic compound which causes liver damage, skin lesions
(chloracne), renal function impairment, hematologic effects, adrenal atrophy,
reproductive system damage, immunosuppression, fetotoxicity, teratogenicity
and cancer in laboratory animals. The effects of greatest concern associated
with exposure to dioxin are liver damage, thymic atrophy, fetotoxicity,
teratogenicity and carcinogenicity. McConnell et al. (1978a,b) observed that
orally administered dioxin induced mortality in various laboratory animals at
doses (LD50) ranging from 0.6 Ug/kg to about 280 ug/kg.
Chronic toxicity studies identify the live:r as the primary organ affected by
dioxin (Kociba et al. 1978, 1979, NTP 1980). Oral administration of dioxin
doses in less than 0.1 ug/kg/day produced hepatitis in rodents.
Dioxin has been experimentally shown to produce fetal abnormalities and
teratologic effects in mice, rats and rabbits. Cleft palet and kidney abnor-
malities were observed in offspring from dams (mice) receiving very low doses
of dioxin (0.1 ug/kg/day) for nine to ten days during gestation (Smith et al.
1976). Hemorrhages edema and kidney abnormalities have also been reported in
fetal rats (Courtney and Moore 1971) and bone and soft tissue malformations in
fetal rabbits (Giavini et al. 1982) following maternal exposure to dioxin. A
study in rhesus monkeys observed a statistically significant increase in early
abortions in animals exposed to dioxin (McNulty 1978).
Conflicting evidence is available '^roncerning the potential teratogenicity of
dioxin in humans. Some epidemiological studies show a positive association"
between exposures to the herbicide 2,4,5-T (which contains dioxin as an
impurity) and the occurrence of birth defects or abortions while other studies
have found no association.
Numerous studies in laboratory animals 'indicate that dioxin is a potent
carcinogen when administered via ingestion or dermal exposure (Van Miller
1977, Toth et al. 1978, Kociba et al. 1978 and NTP 1980a,b). The U.S. EPA
Carcinogen Assessment Group has identified dioxin as the most potent chemical
carcinogen evaluated to date using animal tumorigenesis models.
A substantial number of studies indicate an association between expo-
s.ure to dioxin and development of cancer in humans, however, human data are
not available to definitively demonstrate that dioxin causes cancer. Most of
the studies examined people who were occupationally exposed to dioxin along
with phenoxyherbicides (2,4-D, 2,4,5-T and chlorophenols). Soft-tissue
carcinomas were observed in workers exposed to phenoxy acids (Hardell 1977)
and malignant lymphomas in workers exposed to phenoxy acids and chlorophenols
(Hardell et al. 1981). Other epidemiological studies (Zack and Suskind 1980,
Cook et al. 1980, Smith 1982, 1983) also found increased tumor frequencies in
dioxin exposed populations. However, since dioxin was usually a contaminant
of pheynoxy acids and/or chlorophenols, human exposures were always to multi-
ple chemicals. Therefore, the evidence for human carcinogenicity is only
suggestive due to problems associated with the evaluation of risks from
chemical mixtures.
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The toxic properties of the other site contaminants, 2,4,5-T, 2,4-D, Silvex,
chlorophenols, chlorobenzenes, toluene and methanol, are summarized in NAS
(1977, 1980, 1983).
5.0 RISK AND IMPACT EVALUATION
Contamination from the Vertac site presents endangerment to human health and
the environment due to exposure potential and toxicity. Consumption of
contaminated fish from the Bayou Meto may substantially increase the cancer
risks in humans due co dioxin exposures. Preliminary data indicate an
apparent lack of exposure potential via groundwater; however, groundwater
contamination with dioxin or more environmentally mobile chemicals is probable
and may preclude future use of groundwater as a drinking water resource.
Residents adjacent to the Vertac site in the housing subdivision are poten-
tially subjected to dioxin exposure via inhalation of contaminated dust and
are therefore subjected to an increased risk of cancer. Potential exposures
via direct contact with contaminated soils and sediments caused by offsite
erosion and/or release of dioxin presents increased risks of cancer and
various acute and chronic effects, such as chloracne, to populations that may
garden, play or be in contact with soils or sediments.
Release of dioxin from the Vertac site also poses potential risks to aquatic
and terrestrial species because of its tendency to bioaccumulate in aquatic
organisms. Contaminant releases from the Vertac facility have caused massive
fish kills (acute toxicity) and may potentially cause chronic toxicity.
Contamination from the Vertac site also has a major impact on the public
welfare since it is probable that surface waters may not be useable for
fishing and/or recreation. Additionally, properties adjacent to the site
which are contaminated or may be contaminated will potentially have decreased
values.
6.0 CONCLUSIONS
On-site disposal of large quantities of pesticide manufacturing waste, dis-
charges of process wastewaters, spills and other plant operations at the
Vertac site have caused substantial chemical contamination both on-site and
off-site. The actual or potential release of dioxin and other toxicants to-
the environment may present a substantial endangerment to humans, aquatic
organisms, terrestrial organisms and avian species. The most significant
threat to human health may be due to the potential consumption of dioxin that
accumulates in fish caught from the Bayou Meto, although other routes may be
important for other individuals. Potential dioxin exposures via direct
contact (direct dermal exposure on direct ingestion) with contaminated soils
and sediments may potentially endanger human health. The contamination of
groundwater may preclude its use as a drinking water resource. Residents
adjacent Co the site n:ay be exposed to dioxin via inhalation of dust—emissions
from anthropogenic activities at the site or from wind erosion. Adverse
health effects including cancer have or potentially may occur in populations
exposed to dioxin from the Vertac site'. The release of dioxin to aquatic
systems and soils may lead to bioaccumulation in organisms throughout the food
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chain and present risk to the environment. The potential loss of fishing in
the Bayou Meto, decrease in value of property adjacent to the site and the
loss of groundwater as a potential drinking water resource impact the public
welfare.
•7.0 REFERENCES
Cook RR, Townsend JC, Ott MG, Silverstein LG. 1980. Mortality experience of
employees exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). J. Occup.
Med. 22:530-532. .
Courtney KD, Moore JA. 1971. Teratology studies with 2,4,5-T and 2,3,7,8-TCDD.
Toxicol. Appl. Pharmacol. 20:396-403.
Falco J, Schaum J. 1984. Assessment of risk caused by remedial actions
considered for Vertac Chemical Corporation site, Jacksonville, Arkansas.
Washington, DC: U.S. Environmental Protection Agency. EPA-600-X-84-351,
pp. 1-35. December 1984.
Giavini E, Prati M, Vismara C. 1982. Rabbit teratology study with
2,3,7,8-tetrachlorodibenzo-p-dioxin. Environ. Res. 29:74-78.
Hardell L. 1977. Soft-tissue sarcomas and exposure to phenoxy acids: A
clinical observation. Lakartidningen 74:2753-5754.
Hardell L, Eriksson M. 1981. Soft-tissue sarcomas, phenoxy herbicides and
chlorinated phenols. Lancet ii:250.
Isensee AR, Jones GE. 1975. Distribution of 2,3,7,8-tetrachlorodibenzo-p-
dioxin (TCDD) in aquatic model ecosystem. Environ. Sci. Technol. 9:668-672.
Kociba RJ, Keyes DG, Beyer JE, et al. 1978. Results of a two-year chronic
toxicity and oncogenicity study of 2,3,7,8-tetrachlorodibenzo-p-dioxin in
rats. Toxicol. Appl. Pharmacol. 46(2):279-303.
Kociba RJ, Keyes DG, Beyer JE, Carreon RM, Gehring PJ. 1979. Long-term
toxicologic studies of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in
laboratory animal's. Ann. NY Acad. Science 320:397-404.
McConnell EE, Moore JA, Dalgard DW. 1978a. Toxicity of 2,3,7,8-tetrachloro-
dibenzo-p-dioxin in rhesus monkeys (Macacas mulatta) following a single oral
dose. Toxicol. Appl. Pharmacol. 43:175-187.
McConnell EE, Moore JA, Baseman JK, Harris MW. 1978b. The comparative
toxicity of chlorinated dibenzo-p-dioxins in mice and guinea pigs. Toxicol.
Appl. Pharmacol. 44:335-356.
McNulty W. 1978. Direct testimony before the administrator, U.S. Environ-
mental Protection Agency, FIFRA Docket No. 415, et al., EPA Exhibit No. 106.
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NAS. 1977. National Academy of Sciences. Drinking water and health, Vol. 1.
Washington, DC: National Academy of Sciences.
NAS. 1980. National Academy of Sciences. Drinking water and health, Vol. 3.
Washington, DC: National Academy Press.
NAS. 1983. National Academy of Sciences. Drinking water and health, Vol. 5.
Washington, DC: National Academy Press.
NTP. 1982a. National Toxicology Program. Carcinogenesis bioassay of
2,3,7,8-tetrachlorodibenzo-p-dioxin in Osborne-Mendel rats and B6C3F1 mice
(Gavage Study). Tech. Rpt. Ser. No. 209. NIH. Pub. No. 82-1765.
NTP. 1982b. National Toxicology Program. Carcinogenesis bioassay of
2,3,7,8-tetrachlorodibenzo-p-dioxin in Swiss-Webster mice (dermal study).
Tech. Rpt. Ser. No. 201. NIH Pub. No. 82-1757.
NTP. 1980. National Toxicology Program. Bioassay of l.,2,3,7,8- and
1,2,3,7,8,9-hexachlorodibenzo-p-dioxin (gavage) for possible carcinogenicity.
DHHS Publication No. (NIH) 80-1754. Research Triangle Park, NC: National
Toxicology Program.
NRCC. 1981. National Research Council of Canada. Polychlorinated
dibenzo-p-dioxins: Criteria for their effects on man and his environment.
Pub. No. NRCC 18574, ISSN 0316-0114.. Ottawa, .Canada: NRCC/CNRC Assoc*. Com, .
Scientific Criteria for Environ. Qual. pp. 251. •—
Schaum J, Falco J. 1982. Exposure analysis of Vertac facility. Washington,
DC: U.S. Environmental Protection Agency. OHEA-E-50. pp. 1-38. April 5.
Smith AH, Fisher DO, Pearce N, Teague CA. 1982. Do agricultural chemicals
cause soft-tissue sarcoma? Initial findings of a case-control study in New
Zealand. Community Health Studies 6:114-119.
Smith AH, Fisher DO, Giles HJ, Pearce N. 1983. The New Zealand soft tissue
sarcoma case-control study: Interview findings concerning phenoxy-acetic acid
exposure. Chemosphere 12:565-571.
Smith FA, Schwetz BA, Nitschke KD. 1976. Teratogenicity of 2,3,7,8-tetra-
chlorodibenzo-p-dioxin' in CF-1 mice. Toxicol. Appl. Pharmacol. 38:517-523.
Toth K, Sugar J, Somfai-Relle S, Bence J. 1978. Carcinogenic bioassay of the
herbicide, 2,4,5-trichlorophenoxyethanol (TCPE) with different 2,3,7,8-tetra-
chlorodibenzo-p-dioxin (dioxin) content in Swiss mice. Prog. Biochem. Pharmacol.
14:82-93.
JSEPA. 1984. U.S. Environmental Protection Agency. 'Office of water
Regulations and Standards. Ambient water quality criteria for 2,3,7,8-tetra-
chloro-dibenzo-p-dioxin. Washington, DC: U.S. Environmental Protection
Agency. EPA/440/5-84-007. February 1984.
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£ifc Systems, Jnc.
Van Miller JP, Lalich JJ, Allen JR. 1977. Increased incidence of neoplasms
in rats exposed to low levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin.
Chemosphere 6:537-544.
Zack JA, Suskind RR. 1980. The mortality experience of workers exposed to
tetrachlorodibenzodioxin in a trichlorophenol process accident.
J. Occup. Med. 22:11-14.
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tifeSystems.Jnc.
PART 2 - LEVEL 2 ENDANGERMENT ASSESSMENT
A2-5
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Submitted to:
Office of Waste Programs Enforcement
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Attention: Chief, Health Sciences Section, R. Charles Morgan (2 copies)
VERTAC SITE ENDANGERMENT ASSESSMENT
(Level 2 Example)
Prepared Under
Program No. 1393
for
Contract No. 68-01-7037
Work Assignment No. 12
PRC Work Assignment No. 136
Contact: Timothy E. Tyburski
Telephone: (216) 464-3291
July 25, 1985
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&fe Systems, Jnc.
DISCLAIMER
This document has not been peer and administratively reviewed within EPA and
is for internal Agency use/distribution only.
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TABLE OF CONTENTS
PAGE
LIST OF FIGURES iii
LIST OF TABLES iii
1.0 INTRODUCTION 1-1
1.1 Site Description and History 1-1
1.2 Contaminants Found at the Site 1-3
2.0 ENVIRONMENTAL FATE AND TRANSPORT 2-1
2.1 Factors Affecting Migration 2-1
2.1.1 Geology 2-1
2.1.2 Hydrology 2-1
2.1.3 Hydrogeology 2-2
2.1.4 Climatology . . . 2-3
2.2 Environmental Fate and Transport of Dioxin 2-3
2.2.1 Environmental Fate 2-3
2.2.2 Environmental Transport . . . . . 2-4
2.3 Contaminant Movement On Site and Off Site 2-5
3.0 EXPOSURE EVALUATION 3-1
3.1 Routes of Exposure 3-1
3.1.1 Fish Consumption 3-1
3.1.2 Groundwater 3-1
3.1.3 Airborne Dust 3-1
3.1.4 Direct Contact with Contaminated Soils/Sediment . . 3-2
3.2 Populations Exposed 3-2
3.2.1 Fish Consumption 3-2
3.2.2 Groundwater 3-2
3.2.3 Airborne Dust 3-2
3.2.4 Direct Contact 3-3
3.3 Extent of Exposure 3-3
3.3.1 Fish Consumption 3-3
3.3.2 Groundwater 3-4
continued-
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Table of Contents - continued
PAGE
3.3.3 Airborne Dust 3-4
3.3.4 Direct Contact 3-^
4.0 TOXICITY EVALUATION 4-1
4.1 Pharmacokinetics 4-1
4.2 Acute Toxicity 4-1
4.2.1 Toxicity in Humans 4-1
4.2.2 Toxicity in Laboratory Animals 4-2
4.2.3 Toxicity in Aquatic Species "..... 4-4
4.3 Subchronic and Chronic Toxicity 4-4
4.3.1 Toxicity in Humans 4-4
4.3.2 Toxicity in Laboratory Animals .• 4-4
4.3.3 Toxicity in Aquatic Species 4-6
4.4 Teratogenicity, Reproductive Effects and Fetotoxicity . . . 4-7
4.4.1 Effects of Humans 4-7
4.4.2 Effects in Laboratory Animals 4-7
4.5 Mutagenicity 4-8
4.6 Carcinogenicity .• 4-8
4.6.1 Carcinogeni.city in Humans 4-8
4.6.2 Carcinogenicity in Laboratory Animals 4-10
4.7 Quantitative Indices of Toxicity 4-14
4.7.1 Noncarcinogenic Effects Indices 4-14
4.7.2 Carcinogenic Effects Indices 4-14
5.0 RISK AND IMPACT EVALUATION . 5-1
5.1 Human Health 5-1
5.2 Environmental 5-3
5.3 Public Welfare 5-1
6.0 CONCLUSIONS 6-1
7.0 REFERENCES .7-1
ii
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FIGURE
LIST OF FIGURES
PAGE
1-1
Vertac Site Map 1-2
LIST OF TABLES
TABLE
1-1
4-1
4-2
4-3
PAGE
Ranges of Dioxin Contamination Detected On-Site at
the Vertac Facility and in Adjacent Water Bodies 1-5
Effects of Dioxin in Animals Following Acute Exposure
. 4-3
NOAEL and LOAEL'Values Obtained From Subchronic and
Chronic Oral Toxicity Studies of Dioxin 4-5
Summary of Carcinogenic Effects of Dioxin .' 4-11
iii
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1.0 INTRODUCTION
Disposal of chemical wastes and discharges of process wastewater over a
30-yr period has resulted in contamination of soils, groundwater and surface
waters at the Vertac Chemical Corporation herbicide manufacturing facility in
Jacksonville, AR. The release or potential release of contaminants from tMs
site may endanger human health, welfare and the environment. Human health is
at risk due to the potential for consumption of contaminated fish, inhalation
of airborne contaminants, direct contact with contaminanted soils/sediments
and ingestion of contaminated groundwatar. Contaminants relaased to surface
waters have been bioaccumulated to substantial levels in fish and other
aquatic species.
1.1 Site Description and History
The Vertac hazardous waste site is located in northwest Jacksonville, AR
(Pulaski County), approximately 20 mi northeast of Little Rock. The site
(about 93 acres in size) is bounded by Marshall Road to the east and the
Missouri-Pacific Railroad to the west. The old artillery booster line is on
the northern boundary and an adjacent housing development is to the south.
The Rocky Branch Creek flows along the western edge of the site and the East
Branch of the Rocky Branch Creek flows to the east of the site. The cooling
pond located along the western edge of the site was formed by construction of
an earthen dam across the Rocky Branch Creek. The Rocky Branch Creek flows
into Bayou Meto (a tributary o,f the Arkansas River) about two miles south of
the Vertac site. There is a fence around the entire site with a main gate
facing Marshall Road. Figure 1-1 demonstrates, the site features and •
boundaries.
The site is a herbicide manufacturing plant owned by the Vertac Chemical
Corporation which currently produces 2,4-dichlorophenoxyacetic acid (2,4-D).
The site has been used since the 1930s by a variety of companies for the
manufacture of munitions and pesticides including DDT, aldrin, dieldrin,
toxaphene, 2,4-D, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 2,4,5-tri-
chlorophenoxypropionic acid (Silvex or 2,4,5-TP) and Agent Orange (a mixture
of 2,4-D and 2,4,5-T). The herbicides 2,4,5-T and Agent Orange are known to
contain 2,3,7,8-tetrachlorodibenzo-p-dioxin (hereafter referred to as dioxin,
2,3,7,8-TCDD or TCDD) as an impurity. Waste disposal, cooling water dis-
charges and other plant operations apparently resulted in on-site and off-site
releases of pesticides and herbicides manufactured on site, chemicals used in
manufacturing processes and manufacturing impurities/by-products, including
TCDD.
Estimates of the quantity and types of contaminated materials at the Vertac
site were reported (JRB 1983) as follows:
3 3
!. Thirty thousand (30,000) yd (22,300 m ) of chlorinated phenols,
benzene and toluene wastes within the Reasor-Hill landfill.
3 3
2. Twenty thousand (20,000) yd (15,200 m ) of still bottoms, contam-
inated with 2,3,7,8-TCDD, presently contained in the equalization
1-1
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ROOFED DRUM
STORAGE AREA
OLD DRUM
STORAGE SIT
HERCULES-TRANSVAAL
COOLING
POND
BLOW-OUT AREA
O
Central Drainage Ditch
Interceptor
BRAOEN STREET
Adapted from Walton 1982 as cited in JRB (1983)
FIGURE 1-1 VERTAC SITE MAP
1-2
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basin wastewater treatment system. This amount includes the clay
cap placed on the basin at closure.
3 3
3. One hundred thousand (100,000) yd (76,000 m ) of material, includ-
ing toluene still bottoms, in the Hercules-Transvaal landfill area.
4. Three thousand (3,000) drums (55 gallons each) of 2,4,5-T still
bottoms (repacked in 85 gallon overpack drums) and contaminated
soils from the former above-ground storage area, stored in the
concrete diked warehouse.
The U.S. Environmental Protection Agency (USEPA) has initiated enforcement
actions against the site owners and required a number of remedial actions to
be implemented. The major remedial actions completed as of 1984 are
summarized below:
1. The Reasor-Hill landfill was capped with clay, covered with soil
and seeded with grass. Clay barrier walls were installed on three
sides and the downgradient side was left open.
\
2. The Hercules-Transvaal landfill was capped with clay, covered with
soil and seeded with grass. No barrier walls were installed.
3. The former above-ground drum storage area was capped with clay,
covered with soil and seeded. The old dcums were repacked and
placed in the roofed storage_ warehouse.
•
4. Two-thirds of the blow-out area (where spills from reactors had
occurred) was paved with asphalt and the remainder was capped with
clay, covered with soil and seeded.
5. The equalization basin has been ^subjected to extensive remedial
actions including dewatering and "lime solidification of sludges,
installation of clay barrier walls, installation of a "French drain"
on the downgradient side, capping with clay, covering with soil and
seeding.
Under the proposed remedial action (Alternative IV), the Reasor-Hill Landfill
and North Burial Area (includes old drum storage sites and Hercules-Transvaal
Landfill) will be excavated and contaminated materials/soils will be redis-
posed of in a new on-site secure landfill in an area to the north of and over-
lapping with the North Burial Area. This proposed remedial action will
involve excavation of 50,000 yd of soil from the Reasor-Hill Landfill and
100,000 yd from North Burial Areas.
1.2 Contaminants Found at the Site
Contaminants found at the site include pesticides and herbicides manufactured
on site, chemicals used in the manufacture of DDT, aldrin, dieldrin, toxaphene,
2,4-D, 2,4,5-T, 2,4,5-TP (Silvex) and Agent Orange (2,4-D and 2,4,5-T mixture).
Dioxin, an impurity resulting from synthesis of 2,4,5-T, is also present at
1-3
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£ife Systems, Jnc.
the Vertac facility. Environmental monitoring surveys from the period of 1978
to 1983 have detected chemical contaminants in groundwater, surface water,
soils and sediments. The USEPA Office of Waste Programs Enforcement has
identified the following "indicator" chemicals for the Vertac site on the
basis of their toxic properties, presence in large quantities or potential and
actual releases to the environment:
• 2,3,7,8-TCDD • Chlorophenols
• 2,4,5-T • Chlorobenzenes
• 2,4-D • Toluene
• 2,4,5-TP • Methanol
This endangerment assessment will focus on dioxin because it is the most
highly toxic substance at the facility and is very persistent in soils and
aquatic systems. Dioxin has been detected in waste products, groundwater and
soils on site and in sediments and fish tissue in adjacent surface waters (see
Table 1-1). Refer to CH2M Hill (1984a), JRB (1983) and Walton et al. (1982)
for data on individual sampling sites, dates and maps indicating sampling
locations and groundwater monitoring wells. A site map showing these
locations (which is normally provided in an endangerment assessment) is not
included because of the complexity of the several monitoring studies performed
at this site. The values presented in Table 1-1 are a composite of the
available monitoring data from the period 1979 to 1983.
These data have not been subjected to a comprehensive quality assurance and
quality control review but a preliminary -review of available data reports
indicates tha-t quality control and quality assurance procedures were
implemented. These procedures included the chain of custody, split samples,
replicate analyses, sample spiking with an internal radiolabelled dioxin
standard, routine instrument calibration, methodological (extraction) blanks,
adherence to recommended sample holding times and storage temperature, etc.
1-4
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TABLE 1-1 RANGES OF DIOXIN CONTAMINATION DETECTED ON-SITE
AT THE VERTAC FACILITY AND IN ADJACENT WATER BODIES
i
Ul
Sample Type
Sediments
Soils
Surface
Waters
Ground
Water
Wastes
Fish
Location/Description
Equalization basin
Cooling pond
Drainage ditches, on-slte
On-slte groundwater monitoring
well
Rocky Branch Creek
Rocky Branch Creek, on-slce
Sewer and Interceptors off-site
Creek bed adjacent to private
residences
Lake Dupree
Surface soils on-slte
,
Hercules-Transvaal area/surface
dirt
Reasor Hill landfill/dirt
Reaaor Hill landfill/mud
Reasor Hill landfill area
Blow-out area
Rocky Branch Creek, on-slte
Discharge In combined sewer
at Braden and Alta Lane
Monitoring wells down gradient
of Hercules-Transvaal
Landfill
Monitoring wells, on-slte
Toluene still bottoms disposed
on-alte
Seeps from Reasor Hill
Equalization basin liquid
Equalization basin discharge
Caught In Bayou Meto
Caught in Lake Dupree
Dloxln
Concentration, ppb
0.061 to 1.200
0.216 to 102.0
0.800 to 14.1
NDIB' to 12.1
0.500
0.216 to 17.4
18.4 to 11.4
1
0.150
ND<">
100 Co 14 000
559
1.42
0.505
NR1 '
0.99 to 45
ND
0.017
"High"
ND to <0.03
17.000
0.045 to 5.5
445
<10
<0.025 to 0.100
0.810
,
Total Number of
Samplea Analyzed
5
18
6
4
NA'C' '
5
1
NA
1
NA
NA '
i
i
i
NA
2
1
1
NA
15
NA
1
1
1
6
1
Nunbcr
with Dloxin
Not Detected
0
0
0
2
NA(C)
0
0
NA
0
NA
NA
0
0
0
NA
0
1
0
NA
21
NA
0
0
0
0
0
Detected Dloxln
Concentrations, ppb
Mean 1 SD(n)(a)
460.2 t 459.1 (5)
18.2 t 24.2 (18)
16.1 ! 12.9 (6)
10.0 1 1.0 (2)
NA
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2.0 ENVIRONMENTAL FATE AND TRANSPORT "
2.1 Factors Affecting Migration
2.1.1 Geology
The Vertac site is situated very near or possibly on the fall line of the
Interior Highlands and Coastal Plain physiographic regions. The geologic maps
show that the Vertac site is slightly to the west of the fall 1'ine suggesting
that it is in the Interior Highlands but evidence (the northern part of the
site contains clays of the Midway Group which are present in the Coastal
Plain) suggests it is also in the Coastal Plain or in the transition zone.
The surface soils near the eastern portion of the site are sedimentary. The
subsoils are part of the Atoka Formation characteristics of the Interior
Highlands.
The site is underlain by the consolidated rock of the Atoka Formation which
surfaces in the Interior Highlands and underlies the sediments of the Coastal
Plain. The Vertac site is located on the south flank of a. westward plunging
syncline. The bedrock is alternating gray to black shales and sandstones of
the Atoka Formation which dips to the northeast at a rate of about 30 degrees.
There are many discrepancies regarding the strike and dip of the rock strata
on-site since the site is so close to the fall line. The overlying unweathered
bedrock in ascending order is weathered bedrock approximately five feet thick,
clays and alluvium.
The soil is classified as a Leadvale-Urban land complex with a 1 to 3% slope.
The Leadvale Urban land complex are areas of Leadvale soils that have been
modified by urban development. The Leadvale soils are moderately well-drained,
nearly level and gentle-sloping soils in valleys. They are formed mainly of
loamy sediment washed from uplands composed of sandstone, shale and in some
areas from weathered siltstone. The Leadvale soils have moderately low
permeability and maintain a medium level of available water capacity. The
level of runoff from the Leadvale Urban land complex is medium and the erosion
hazard is moderate if the soils are not protected by vegetation. Soil borings
indicate the presence of yellowish brown silty sands in the northeast corner
of the site and yellowish brown or tan silty clays in the southeast portion of
the site (CH2M HilL 1984a).
2.1.2 Hydrology
Surface drainage patterns.at the Vertac site are predominantly westerly and
easterly. The western 55 acres drain directly to the Rocky Branch Creek. The
Rocky Branch Creek enters the Vertac site at the northwest boundary and flows
into a man-made cooling pond. About 700,000 gallons/day of process waste-
waters enter the cooling pond. Waters from the cooling pond flow out a
concrete outlet structure at the southwest extremity of the pond. A central
ditch (no longer present) acted as a surface drainage channel from the plant
production area and flowed into the cooling pond. The combined flow of
surface runoff and process waters enters Rocky Branch Creek and flows south
about two miles to Bayou Meto.
2-1
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The eastern 38 acres of the site drain east to numerous small ditches caused
by natural erosion. Along adjacent driveways and roads are a few man-made
ditches. The catch basins located on the eastern portion of the site drain to
a storm sewer which empties into an open ditch near the main plant entrance.
All surface runoff east of the drainage divide eventually flows into the East
Branch, of the Rocky Branch Creek. Most of this runoff is carried by the "E*si-
Ditch" to the East Branch. The East Branch flows into Rocky Branch Creek
south of the Vertac Site.
During heavy spring rains it is not uncommon for the Rocky Branch Creek to
flood the area south of the Vertac Site. This is important because there is a
manmade recreational lake (Lake Dupree) 1.3 mi south of the Vertac site. Lake
Dupree and the Rocky Branch Creek are not normally connected but, the low
terrain and tendency for flooding in the area potentially enables contaminants
discharged into Rocky Branch Creek to be deposited in Lake Dupree (JRB 1983).
2.1.3 Hydrogeology
The Interior Highlands are hilly and underlain by consolidated sediments which
dip slightly in £. southeasterly direction. The consolidated rock of the
Interior Highlands underlies unconsolidated sediments of the Coastal Plain.
Above the lowest level of the water table, the consolidated rock of the
Highlands has been weathered. Soil and "rotten rock" (i.e., weathered rock)
in this region are present to a.total depth of about 20 ft (maximum). This
weathered rock area is more permeable and porous chan unweathered rock. Water
is present in intergranular voids of "rotten rocks" and soil while water is-
only present in joints, fractures and other secondary openings in unweathered
rock.
The sediments of the Coastal Plain vary from high plasticity clays to sands
and gravels with varying permeabilities. There are three units within the
sediments which are major water sources in some areas of Pulaski County.
Beds of claystone, calcareous sandstone, sandy limestone, marl and conglomerate
(about 7 to 60 ft) comprise one aquifer unit. Fine to medium sand with some
interbedded clay lenses (about 320 ft thick) comprise another aquifer unit.
Terrace deposits and alluvium (deposited by the Arkansas and Mississippi
rivers) composed of fine-grain top stratum and deeper coarser stratum (about
120 ft) -is the third aquifer unit. Refer to Walton et al. (1982), CH2M Hill
(1984a) and JRB (1983) for further hydrogeologic information and a
diagram of the locations of aquifers in .the Coastal Plain and Interior High-
land regions.
The general horizontal groundwater flow is from north to south (CH2M Hill
1984a). Two groundwater divides are evident on site with one running from the
northeast boundary of the site along the east side, across the plant and then
due south. The second divide runs from the northwest along the western edge
of the cooling pond and south along Rocky Branch. The contaminated wacer
table flows toward the cooling pond and the Rocky Branch Creek at a rate of
<1 to 10 in/yr (CH2M Hill 1984a). The vertical groundwater flow rates in
bedrock were calculated to range from 2 x 10~ in/yr to 6.0 in/yr (CH2M Hill
1984a) which indicates potential downward migration of contaminants.
2-2
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£ife Systems, Jnc.
Little is known about the hydrogeology of bedrock deposits at the Vertac site
and the structure of bedrock has not been evaluated.
The Rocky Branch Creek receives groundwater inflows from the water table from
both the east and west. These flows have passed under or through the
Reasor-Hill area. Contaminants entering the groundwater east of.the divide
may eventually enter the Coastal Plain aquifers (off-site) (CH2M Hill 1984a).
The recharge and inflow upgradient of contaminant sources flows toward western
surface water bodies and are conveyed off-site above ground or in the water
table.
2.1.4 Climatology
Precipitation is fairly well distributed throughout the year; however, May is
normally the wettest month. The annual precipitation averages about 48 in and
about 31% of total precipitation occurs from March through May. August
through October are the driest months with a total of 3 in of rain.
Winters are mild with average winter temperatures of 41 F and an average
annual snowfall of 5.7 in. The greatest monthly snowfall reported was 12 in
in January 1966. The summers are hot with an average daily temperature of
82 F and maximum temperatures of over 100 F occurring frequently in July and
August.
2.2 Environmental Fate and Transport of Dioxin
2.2.1 Environmental Fate
Dioxin is not readily biodegraded. Dioxin is persistent in freshwater aquatic
environments with a half-life of 550 to 590 days in sediment containing lake
waters (Ward and Matsumufa 1977)'. The biodegradation half-life of dioxin was
estimated to be greater than one year based on theoretical biotransformation
rate values and assumed concentrations of microorganisms (USEPA 1984). The
biodegradation half-life of 0.5 yr for dioxin in soils was based on data from
a rural Missouri incident involving accidental spraying of dioxin contaminated
oils (IARC 1977). Recent data suggest that the half-life may be closer to
10 yr (USEPA 1984).
Dioxin in the presence of organic solvents (Crosby et al. 1971) or other
hydrogen donators is photodegraded (Crosby and Wong 1977). Insufficient
information is available on reactions of dioxin in aquatic media under
environmental conditions to predict the photodegradation half-life in natural
waters. Assessment of photodegradation in natural waters is complicated by
the tendency for dioxin to be strongly adsorbed on particles in sediments that
are not exposed to ultraviolet (UV) light.
Information on photodegradation of airborne dioxin adsorbed on particulates is
conflicting. The importance of photodegradation relative to deposition (dry
or wet) in the fate of airborne dioxin is uncertain but may be important.
Dioxin sorbed to solid surfaces and exposed to the atmosphere yielded negligible
2-3
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£ife Systems, Jnc.
photodegradation (Crosby et al. 1971), while photolysis was evident for dioxin
in a condensed phase on glass or silica.
The photodecomposition of dioxin on wet or dry soils under artificial and
natural sunlight (UV radiation) was observed to be negligible in soils (Crosby
et al. 1971). However, photodecomposition may occur when dioxin and other
pesticides (hydrogen donators) are present as a mixture in soils (Crosby and
Wong 1977).
No information on the oxidation of dioxin in aquatic systems was available but
its strong electropositive nature suggests it may be more resistant than
nonchlorinated or less chlorinated aromatics. The potential for oxidation of
dioxin (sorbed on airborne particulates) by atmospheric compounds (NO , 0-,
etc.) is unknown. Hydrolysis is unlikely to occur under environmental condi-
tions in aquatic systems (USEPA 1984).
Quantitative information on volatilization of dioxin from aquatic systems is
not available although several references have mentioned volatilization as a
possible loss process (Callahan et al. 1979). The validity of these estimates
has not been assessed with experimental data. Volatilization of dioxin
adsorbed on soils is expected to be at a very slow rate due to the extremely
low vapor pressure of dioxin (Falco and Schaum 1984).
Sorption on particles (suspended or sediments) and in microorganisms appears
to be an important fate for dioxin in aqueous environments. Isenee and Jones
(1975) observed t-ha\—a-g-% -ro-9.9.%—LL^UjMEfcFt^r(Mnq-in*4 adsorbed on. sediments in an
aquatic system and the majority of dioxin not on sediments was in aquatic
organisms. Ward and Matsumura (1978) observed that more than 90% of dioxin in
aquatic medium remained bound to sediments. The low water solubility and high
octanol/water partition coefficient of dioxin support these observations.
Many aquatic species bioaccumulate dioxin. In a static experimental test
chamber, the accumulation appeared to be dependent upon initial dioxin con-
centrations. The bioconcentration factors (determined experimentally in a
static system) vary with species and may range frpm about 2,000 (algae or
snail) to 9,000 (catfish) to 26,000 (mosquitofish) (Isenee and Jones 1975,
Isenee 1978).
2.2.2 Environmental Transport
Kearney et al. (1973) examined the mobility of dioxin in five soil types and
observed that decreased mobility was associated with increased organic content
of soils. Dioxin was relatively immobile in all test soils and Kearney et al.
(1973) concluded that leaching to underground water supplies would be unlikely,
Matsumura and Benezet (1973) postulated that dioxin transport would be via
horizontal transfer of contaminated soils and dust particles.
Dioxin does not readily migrate vertically in soils (USEPA 1984). Nash and
Beall (1980) observed that 80% of dioxin applied to soils in a microagroeco-
system remained in the upper 2 cm of soils and that only trace amounts were
detected at 8 to 15 cm. The NRCC (1981) suggested that vertical migration of
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dioxin may result when the sorption capacity of soils are saturated or as a
result of biotic mixing (i.e., action of earthworms or other soil
invertebrates). Dioxin solvated by organic solvents may be more readily
transported through soils to the groundwater.
Wet and dry deposition of particulate-bound dioxins appear to be.an important
fate-determining process in the transport of airborne dioxins.
2.3 Contaminant Movement On Site and Off Site
The summary of the Vertac site history indicates that contaminants (dioxin and
others) were discharged in untreated wastewaters and process wastes, trans-
ported and released to the Rocky Branch Creek possibly as early as 1955
(JRB 1983). Dioxin and other contaminants were also released by
seepage from underground burial areas and by erosion of contaminated surface
soils.
Contaminants from the Hercules-Transvaal Landfill have migrated to the process
cooling pond. The central drainage ditch and surface runoff also transported
dioxin to the cooling pond. Contaminants that leaked into the cooling pond
and/or settled there probably flowed into the Rocky Branch Creek since the
pond is in its steam course. Spills and/or valve ruptures of the trichloro-
phenol reactor in the "blow-out" area or other areas released dioxin which may
have percolated underground or have been transported via surface runoff to the
East Branch. Leachates from the equalization basin along the western edge
of the site also contributed to contamination of the Rocky Branch Creek.
Transport of dioxin to Dupree Lake probably occurred as a result of flooding*
of the Rocky Branch Creek during periods of heavy spring rains.
Implementation of remedial actions involving disturbance of soils and vehi-
cular movement may have promoted contaminant transport particularly during
remediation of the equalization basin. The remedial actions implemented (clay
caps, barrier walls, French drain, etc.) may reduce the potential for further
contamination by. preventing infiltration of surface .precipitation, runoff and
wind erosion.
There is some uncertainty about the vertical migration of contaminants to
groundwaters. • Unexpectedly, "high" concentrations of dioxin were detected in
groundwater monitoring wells downgradient from the Hercules-Transvaal Landfill
area (JRB 1983). There is potential for lateral subsurface movement
in this landfill since no barrier walls have been installed. The closure of
the equalization.basin appears to contain lateral leachate seeps but the
effectiveness over time is uncertain since the French drain and barrier walls
were constructed over weathered rock (with fissures). Installation of the
above-grade neutralization wastewater treatment system and discharge to the
local wastewater treatment plant has reduced or eliminated the potential for
further release of process waste to the Rocky Branch Creek.
The proposed remedial action (Alternative IV) which involves excavation of
contaminated soils/materials and redisposal in a secure landfill on-site) will
disturb soils and create the ootential release of contaminants as dust
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emissions. Primary sources of dust emissions are expected to be from vehicle
travel over contaminated soils, loading/unloading operations and spreading
excavated soil in the new landfill. The release and movement of contaminated
dust may be reduced by implementation of dust control measures. It is assumed
that "clean-dirt" will be applied to roadways between the excavation sites and
the secure landfill and covered trucks will be 'used to reduce contaminant
releases. The wind-only generated dust emissions are expected to be negli-
gible compared to mechanically generated dusts occurring during truck travel,
loading/unloading and spreading operations.
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3.0 EXPOSURE EVALUATION
This section will identify actual and potential routes of exposure, characterize
the populations exposed and determine extent of the exposure to dioxin.
3.1 Routes of Exposure
Potential exposure routes are as follows:
1. Consumption of fish from the Bayou Meto and Rocky Branch Creek.
2. Consumption of groundwater downgradient of the Vertac site.
3. Inhalation of dust-contaminated with dioxin that may become airborne
due to implementation of remedial action Alternative IV.
4. Direct contact with waters, sediments or soils adjacent to the site
that have been contaminated by surface runoff or erosion processes.
Direct contact includes direct dermal exposures as well as direct
ingestion exposures (i.e., pica in children).
3.1.1 Fish Consumption
Consumption of contaminated fish from Bayou Meto is an^exposure route of
primary concern since dioxin readily bioaccumulates in fish. Environmental
monitoring data indicate that high concentrations of dioxin are found in fish
(<25 to 300 ppt) and sediments (500 ppt) of Bayou Meto (see Table 1-1).
Dioxin released from the site via transport on suspended solids in overland
runoff or sorbed to airborne dust is of particular concern. Dioxin-bearing
particles accumulate in sediments of receiving waters and bioaccumulate in
fish. Significant potential human health threats may result from consumption
of contaminated fish from Bayou Meto. Arkansas officials have banned fishing
on the Bayou Meto; however, the fishing ban is not easily enforced (Falco
1982). Thus, there appears to be a real potential for dioxin exposure.
3.1.2 Groundwater
Concentrations ranging from ND 0.03 ppb (with a mean ± standard deviation of
0.005 ± 0.010 ppb) of dioxin were detected in groundwater monitoring wells
downgradient from the Hercules-Transvaal landfill area; however, no existing
domestic or industrial wells were reported to be located in areas that are
immediately downgradient from the Vertac site (JRB 1983, Schaum and Falco
1982). Potential consumption of contaminated groundwater may result in
exposures to dioxin and other contaminants that are both more mobile in the
subsurface soils and more soluble in water.
3.1.3 Airborne Dust
Inhalation exposure to dioxin is likely to be via contaminanted dust rather
than via vapors since dioxin in soils does not volatilize appreciably.
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Potential exposure to dioxin via inhalation of contaminated dust is not
expected to be substantial since remedial actions implemented (clay capping of
disposal areas and covering the blow-out area) will diminish wind erosion.
However, the potential for exposure to dioxin is substantially increased by
the proposed remedial action (Alternative IV) which will disturb the soil and
create emissions of dioxin-contaminated dust.
3.1.4 Direct Contact with Contaminated Soils/Sediment
Dioxin in contaminated soils may be adsorbed across the skin. The concentra-
tion in soils and type of soils are expected to affect dermal adsorption. The
direct contact with contaminated soils,is dependent upon the degree of outdoor
activities such as gardening or playing. The degree of dermal exposure
depends upon the amount of skin exposure, duration of contact and soil condi-
tions .
Exposure due to direct ingestion depends on age with children aged two to six
years having the greatest exposure potential. Seasonal variation in weather,
soil conditions and activity patterns affect the amount of exposure via direct
ingestion of contaminated soils/sediments.
3.2 Populations Exposed
3.2.1 Fish Consumption
Populations with high fish consumption from affected water bodies are at an
increased risk of dioxin exposure. Data on fish consumption rates and the
number of people that consume fish caught from Bayou Meto were not available.
Human exposure via consumption of fish should not be occurring since there is
a fishing ban for the Bayou Meto; however, there is evidence that the ban is
not easily enforced. Complaints of "medicinal" taste and odor problems of
fish from Bayou Meto registered with the Arkansas Game and Fish Commission
indicate the there has been chronic pollutional problems, and that people may
have been exposed to dioxin and other contaminants.
Assuming that most fish from Bayou Meto are likely to be consumed by local
residents, the number of exposed people is probably less than the local
population. Approximately 476,000 people are in counties that are at least
partially drained by Bayou Meto according to census data.
3.2.2 Groundwater
Data on the size (if any) of the population utilizing wells or consuming
groundwater from other sources contaminated by the site were unavailable.
Walton et al. (1982) state that no domestic or industrial water wells were
located in areas that are immediately downgradient from the Vertac site.
Contacts with state and local permitting agencies identified only two domestic
wells within the vicinity of the site (Walton et al. 1982). One well (50 ft
deep) was 1.5 mi west of Vertac and the other well (15 ft deep) was about
1.5 mi southeast of the site. There is insufficient data on groundwater
contamination and off-site flows to determine when the plume may reach these
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wells, the expected concentrations and the size of the population that may be
exposed.
3.2.3 Airborne Dust
Insufficient data are available to determine the no action endangerment lev=l
and the size of the exposed population. Monitoring data on ambient concen-
trations of dioxin-contaminated dust emissions from the site are unavailable.
The population at greatest risk of exposure to dioxin via airborne dust would
be workers/observers on-site during the proposed remedial action if an ade-
quate personal protection program was not implemented. It is recommended that
an adequate personal protection program will be required under the Remedial
Action Plan to eliminate or substantially reduce potential exposures to
on-site personnel.
Insufficient data on prevailing wind direction, wind speed and geographical
features affecting wind patterns are available to determine which populations
are at increased exposure potential-for airborne dust. Residents of the
subdivision to the south of the site are the nearest potentially exposed
off-site population. The proximity of this population to the site subjects
this population to an increased risk of exposure to dioxin since airborne dust
concentrations are expected to be greatest near the site and to decrease with
increasing distance from the site. People that stay at home during the
daytime and especially those that are frequently outside for'long periods-are
expected-to have higher exposures. This group-may include young children,
nonworking parents and the elderly. It is assumed that dioxin-contaminated
dust concentrations will tend to be higher outdoors relative to inside a
house. No quantitative information on the number of residents near the site
and specific behavior patterns is available.
3.2.4 Direct Contact /
No quantitative data are available on the size of the population potentially
exposed to dioxin via direct contact with contaminated soils or sediments
on-site or off-site. The fence around the facility limits accessibility and
reduces potential accidental direct contact exposures on-site. Detection
of dioxin in surface soils in the subdivision south of Vertac (Braden Street,
West Lane and Alta Cove) (CH2M Hill 1984) suggests that residents may be at
risk for dioxin exposure. People who garden and play outdoors are expected to
be at higher risk for direct contact exposures. Since the highest
concentrations of dioxin off-site are found in sediments of the Rocky Branch
Creek, it is anticipated that people who swim, wade or play in and around the
creek may be at increased risk. Likewise, people who use Lake Dupree for
recreational activities may have increased exposure.
3.3 Extent of Exposure .•
3.3.1 Fish Consumption
No estimates of actual fish consumption based on local surveys of the Rocky
Branch Creek and Bayou Meco are available. Limited monitoring data on the
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dioxin content of fish in the Rocky Branch Creek, Bayou Meto and Lake Dupree
are available. Detection of <25 to 300 ppt of dioxin in fish from Bayou Meto
and 810 ppt in a fish from Lake Dupree suggest that dioxin exposures may
result if such fish were consumed (Schaum and Falco 1982) . Estimation of the
extent of exposure is difficult because of limited data on dioxin content of
fish and consumption rates. This is further complicated by the fact that
fishing on Bayou Meto is currently banned.
Using the range of reported dioxin concentrations in Bayou Meto (<25 to
300 ppt), exposures, could be estimated as follows:
300 ng/kg2.37 kg/yr =
1Q>1 ng/kg/yr
where :
300 ng/kg = maximum content of dioxin detected in fish from Bayou Meto
5.2 Ib/yr (2.37 kg/yr or 6.5 g/day) = assumed consumption rate based on
the national average consumption
rate of freshwater fish
70 kg = assumed body weight of adult
Thus, dioxin exposures from fish consumption may range from <0.85 to
10.1 ng/kg/yr for Bayou Meto to 27.4 ng/kg/yr for Lake Dupree, assuming that a
70-kg adult consumes 5.2 Ib/yr of fish and that preliminary monitoring data on
fish tissue are representative of the actual content of dioxin in fish. These
exposure values are based on limited_4ata and much more extensive data are
required to precisely define the magnitude and extent of actual exposures via
contaminated fish consumption.
3.3.2 Groundwater
The extent of dioxin exposure via groundwater has not been determined. Due to
the apparent lack of water wells and the low solubility of dioxin in water,
it is expected that exposure potential will be minimal. Using the highest
reported concentration of 0.03 ppb dioxin in groundwater on-site (CH2M Hill
1984a) and assuming a 70-kg adult would consume two liters of water per day, a
maximum potential exposure could be calculated as follows:
= °-°009 ^/k8/day (0.9 ng/kg/day)
(70-kg)
This is a worst case scenario. Insufficient data on groundwater flows,
dilution rates and the extent of contamination are available to calculate
reasonable conservative exposure estimates. Using the mean concentration of
dioxin detected in wells (0.005 ppb) and the above equation, the exposure may
be estimated as 0.0001 yg/kg/day. Recent monitoring data have not detected
dioxin in any wells on-site and therefore suggests that potential exposure
levels may be less.
In addition, actual exposure at this level is unlikely since Walton et al.
(1982) and CH2M Hill (1984a) state that data indicate that no existing wells
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are located within two miles of the site and there is no contamination in any
wells beyond two miles. Future contamination or installation of new drinking
water wells downgradient of the site may increase the potential and magnitude
of exposures.
3.3.3 Airborne Dust
The extent of the exposure to dioxin via inhalation of contaminated dust from
wind erosion is not anticipated to be significant because of remedial actions
implemented. No data are available to estimate exposure for no action level
or present endangerment level. However, data on the actual content of air-
borne dioxin contaminated dust are not available to substantiate this
conclusion. In addition to air concentrations of dioxin, information on
absorption/retention of dioxin dust particulates in the lung, a respiration
rate (20 m /day usually assumed) and duration of daily exposure would be
required to estimate exposure via dioxin dust inhalation.
Prediction of potential exposures for the proposed remedial action will
require emission modeling to predict air concentrations. The magnitude of
exposure is anticipated to be greatest on-site at locations in closest
proximity to the remedial action involving excavation, loading/unloading,
transporting and spreading operations. Dust control measures and personnel
protection programs may eliminate or reduce worker exposure during remedi-
ation. The-residents closest to the site are expected to potentially be the
off-site population with the greatest extent of exposures.
3.3.4 Direct Contact
No quantitative estimates of the extent of dioxin exposure via direct contact
are available. Future exposure assessments should address specific subpopu-
lations suspected of having increased exposures due to their behavior or
activities. For example, children playing in contaminated soils or sediments
of adjacent waterways are probably exposed to dioxin via direct dermal contact
or ingestion. People who garden in residential areas with dioxin-contaminated
soils also have increased exposure potential via direct contact. The lack of
information on the dermal absorption, amount of direct soil contact, dioxin
content of soils/sediments, quantity of soil directly ingested and other
factors currently preclude performance of quantitative exposure estimates.
Direct contact is an important route that should be addressed in future
exposure assessments. The Kimbrough et al. (1977) report on toxicity in six
children dermally exposed to dioxin-contaminated soils in horse-arenas in
eastern Missouri confirms the potential .significance of this route.
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4.0 TOXICITY EVALUATION
Exposure to dioxin can cause thymic atrophy, decreased body weight, liver
damage, skin lesions (chloracne), renal function .impairment, hematologic
effects, adrenal atrophy, reproductive system damage, immunosuppression,
fetotoxic, teratogenic and mutagenic effects and cancer. Dioxin is an
extremely toxic substance, with an LDrQ value reported as low as 0.6 yg/kg
(guinea pig) following oral administration (Schwetz et al. 1973).
4.1 Pharmacokinetics
The available information on the pharmacokinetics of dioxin in several mam-
malian species of laboratory animals is summarized by Neal et al. (1982),
Manara et al. (1982), Gasiewicz et al. (1983), Olson (1983) and USEPA (1984).
The absorption of dioxin via oral and dermal exposure routes has been studied
but data on absorption via inhalation are not available (USEPA 1984). About
70% to 83% of a single oral (gavage) dose of radiolabeled dioxin (1 Ug/kg or
50 yg/kg) was absorbed when administered by gavage to Sprague-Dawley rats
(Rose et al. 1976, Piper et al. 1973). With repeated gavage administration of
1 yg/kg/day, absorption was about 80%. Olson (1983) observed about 74%
absorption in hamsters.receiving a large sublethal dose (650 yg/kg) of radio-
labeled dioxin in corn oil. Fries and Marrow (1975) reported about 50% to 60%
absorption of dioxin administered to rats in the diet (7 or 20 ppb) for
42 days. Poiger and Schlatter (1980) studied the dermal absorption of dioxin
(raethanol vehicle) and estimated (based on hepatic content of dioxin) that the
amount absorbed from dermal application was about 40% of the amount absorbed
from, an equivalent oral dose. Application of a soil/water paste decreased
hepatic dioxin content to about 2% of the administered dose.
Dioxin is lipophilic and is predominantly distributed to the liver and adipose
tissues (USEPA 1984) in most laboratory animal species. Dioxin appears to be
distributed throughout the body without metabolic alteration (Olson et al.
1980). However, six metabolites of dioxin in the dog (Poiger et al. 1982) and
two metabolites in the rat (Sawahata et al. 1982) have been identified.
Excretion and metabolism of dioxin are relatively slow processes in the body
resulting in biological half-lives ranging from 10 days in hamsters to 43 days
in guinea pigs. Dioxin accumulates .in tissues with high adipose content
(Nolan et al. 1979, Olson et al. 1980).
4.2 Acute Toxicity
4.2.1 Toxicity in Humans
Acute exposure of humans to dioxin results in nausea and vomiting, headache,
and irritation of the eyes, skin and respiratory tract. The initial skin
reaction is a cutaneous reaction resembling a chemical burn, followed several
days-to-weeks after by chloracne (Taylor 1979). Chloracne, the typical human
dermal reaction to dioxin, is a cutaneous eruption of comedones (blackheads),
cysts, and in severe cases, pustules. These usually occur on the face and
shoulders as a result of squamous metaplasia (transformation of glandular or
mucosal epithelium into stratified squamous epithelium) of the dermal glands
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(Crow 1978, Pass! et al. 1981). Most of the documented acute exposures to
dioxin have been the result of chemical industry accidents involving 2,4,5-T,
which is contaminated with dioxin (Holmestedt 1980, May 1973, Gianotti 1977,
Garattini 1982, Taylor 1979, Crow 1981 and Zack and Suskind 1980).
There are data regarding the health effects of dioxin on children and adults
following accidental releases of the chemical from a plant in Seveso, Italy
(Pochiari et al. 1979). Reduced peripheral nerve conduction velocities
occurred in both adults and children, with a correlation between the incidence
and the distance from the plant. Total serum complement activity, lymphocyte
blastogenic response and peripheral blood lymphocytes were elevated in
children exposed in the accident (Tognoni and Bonaccorsi 1982). The limited
number of studies regarding the immunological effects of dioxin in adults have
not revealed any reduction in immunocapability (May 1982).
Six children dermally exposed to dioxin-contaminated soil (30 ppm, 30 mg/kg
soil) in horse-arenas in eastern Missouri developed headaches, skin lesions
and polyarthralgia (pain in joints) (Kimbrough et al. 1977). In the most
severe case, epistaxis (nosebleeds) and lethargy were reported.
Numbness of the extremities, skin rashes and irritation, liver dysfunction,
weakness, loss of sex drive and psychological changes have been associated -
with exposure to 2,3,7,8-TCDD and other dioxins, which occur as contaminants.
in Agent Orange, in veterans and residents of Vietnam. The relationship
between exposure to dioxin and the development .of these symptoms is unknown •
(Holden 1979, Bogen 1979). . ' .... --
4.2.2 Tbxicity in Laboratory Animals
McConnell et al. (1978 a,b) observed that dioxin induced mortality in a
variety of laboratory animals (rat, guinea pig, mouse, rabbit, monkey) at dose
(LD._) levels between 0.6 Ug/kg and 283.7 Mg/kg following oral administration.
The dermal LD_ value in rabbits was 270 Ug/kg (Schwetz et al. 1973).
A summary of studies providing data on the sub-lethal effects of acute expo-
sure to TCDD is presented in Table 4-1. The effects were reported to occur
following single exposures ranging from 0.1 to 300 Ug/kg in four animal
species (rat, guinea pig, chicken, mouse). Liver damage is the most consis-
tently reported effect in most species. Rats receiving a single dose of
100 yg/kg of TCDD showed severe liver damage, thymic atrophy and jaundice
(Gupta et al. 1973). In the same study, thymic and liver damage of lesser
severity occurred at lower dose levels (25 and 50 Ug/kg). In another study
(Greig et al. 1973), rats exposed to TCDD (300 Ug/kg) exhibited jaundice,
multinucleated parenchymal cells of the liver and gastric hemorrhage. Histo-
pathologic liver changes were observed five weeks after single oral doses of
TCDD as low as 50 Ug/kg were administered to male and female CD rats, and one
week after a single dose of 50 Ug/kg was administered to female CD-I mice
(Harris et al. 1973). Increased liver weights were found in male Wistar rats
seven days after single intraperitoneal doses of 0.1 Ug/kg (Cunningham and
Williams 1972).
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TABLE 4-1 EFFECTS OF DIOXIN IN ANIMALS FOLLOWING ACUTE EXPOSURE
i
u>
Species
Rat
Guinea Pig
Rat
Chicken
Rat
Rat *
Rat
Mouse
Rat
Rat
Dose (pg/kg) Route
25, 50 or 100
100
3.0
300
25 - 50
10 Oral
0.1 i.p.
50 Oral
50 Oral
10
10, 25, or 50
Effects
Reference
Liver damage, thymic atrophy
Jaundice, 43% mortality
Hemorrhage, adrenal atrophy,
cellular depletion of lymphoid
organs, 90% mortality
Weight loss, gastric hemorrhage,
liver damage (cellular changes),
jaundice
Pericardial edema
Hematologic efiects
Increased liver weights
Liver damage
Liver damage
Decreased renal function
Decreased rena}. function
Gupta et al. (1973)
Gupta et al. (1973)
Greig et al. (1973)
Greig et al. (1973)
Weissburg and Zinkl (1973)
Cunningham and Williams (1972)
Harris et al. (1973)
Harris et al. (1973)
Anaizi and Cohen (1978)
Hook et al. (1978)
Adapted from NAS (1977), NTP (1982 a,b) and Esposito et al. .(1980).
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4.2.3 ' Toxicity in Aquatic Species
The USEPA (1984) summarizes the available information on the acute toxicity of
dioxin to aquatic organisms. The 96-hr lethal concentrations (LC5Q) reported
by Miller et al. (1973) and Norris and Miller (1974) were >0.2 yg/L for
Paranais sp. (worm), Physa sp. (snail) and Aedes aegypti (mosquito larvae),
>1 yg/L for Oncorhychus kisutch (coho salmon), >10 yg/L for Poecilia reticulata
(guppy) and >0.24 yg/L for Ictalurus punctatus (fingerling channel catfish).
Helder (1980, 1981 and 1982) observed that the LC«-0 is >0.01 ug/L for Esox
lucius (northern pike embryos) and Salmo gairdneri (rainbow trout yolk-sac
fry) and >0.1 yg/L for the juvenile rainbow trout.
4.3 Subchronic and Chronic Toxicity
4.3.1 Toxicity in Humans
Several epidemiologic studies and case reports involving dioxin exposure in
human subjects have been reported (Esposito et al. 1980). Effects observed
include skin lesions (chloracne, prophyria cutanea tarda), liver function
impairment and neurological disorders (polyneuropathy, peripheral nerve
damage). An International Agency for Research on Cancer (IARC 1982) evalua-
tion of human exposure data concluded that these studies are inadequate since
they involve multiple chemical exposures.
4.3.2 Toxicity in Laboratory Animals
Longer exposures to dioxin caused effects similar to those reported "following
acute exposure including thymic atrophy, liver damage, renal function impair-
ment, hematological effects, hormonal alterations, immunosuppression, nervous-
ness and irritability. Chronic and subchronic studies in many different
strains of laboratory mice and rats indicate that the liver is the primary
organ affected by long-term exposure (Kociba et al. 1973, 1979, NTP 1980a). A
summary of major studies providing dose-response effects is presented in
Table 4-2. Studies providing dose-response data indicating the greatest
sensitivity to dioxin are described below.
Doses as low as 0.1 yg/kg/day caused a slight degree of liver degeneration in
rats in a subchronic 13-wk (5 doses per week) study (Kociba et al. 1976).
Dose levels of 1.0 yg/kg/day increased levels of serum bilirubin and alkaline
phosphatase and caused pathologic changes in the livers of rats. A no-
observed-adverse-effect level (NOAEL) of 0.01 yg/kg dioxin was reported for
for noncarcinogenic effects in rats.
Increased mortality was observed in female Sprague-Dawley rats maintained for
two years on a diet that provided a dioxin dose of 0.1 yg/kg/day, while no
increased mortality was observed in male rats at this dose or in animals
receiving doses of 0.01 or 0.001 yg/kg/day (Kociba et al. 1978, 1979). At
termination of the study, gross and histologic examination indicated that the
liver was the most severely affected organ, with degenerative, necrotic and
inflammatory changes observed. Increases in urinary excretion rates of the
metabolites, coproporphyrin and uroporphyriri, in the high and middle dose
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TABLE 4-2 NOAEL AND LOAEL VALUES OBTAINED FROM SUBCHRONIC AND CHRONIC ORAL
TOXICITY STUDIES OF DIOXIN
Species
Rat
Rat
Rat
Rat
.P. Mouse
i
Ol
Monkey
Rat
Rat
Mouse
Duration.
of Exposure
13 wk
13 wk
16 wk
28 wk
13 wk
36 wk
104 wk
104 wk
104 wk
Endpoints
Decreased body weight,
liver pathology
Toxic hepatitis
Elevated porphyrin
levels
Fatty changes in the
liver, decreased body
weight
Toxic hepatitis
Pancytopenia
Degenerative and necrotic
changes in the liver
Toxic hepatitis
Dermatitis and amyloidosis
NOAEL
yig/kg/day
0.01
0.07
0.0014
ND«"
ND
ND
0.001
0.0014
ND
LOAEL '
Mg/kg/day
0.1
0.14
0.014
0.014
0.014
2
0.01
0.007
0.001
Reference
Kociba et al
NTP (1980a)
Goldstein et
. (1976)
al. (1982)
King and Roesler (1974)
NTP (1980a)
Allen et al.
Kociba et al
NTP (1980a)
NTP (1980a)
(1977)
. (1978, 1979)
(a) ND = Not determined.
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females were consistent with the observed liver damage. Primary liver injury
was dose-related with the lowest dose representing a NOAEL for noncarcinogenic
effects.
When dioxin was administered by gavage (by stomach tube) in corn oil-acetone
(9:1) at dose levels of 0, 0.01, 0.05 or 0.5 yg/kg/wk (0.0, 0.001, 0.007 ar.-i
0.07 yg/kg/day), toxic hepatitis was observed in male Osborne-Mendel rats at
incidences of none out of 74 tested (0/74), 1/50, 0/50 and 14/50 and in female
rats at incidences of 0/75, 0/50, 1/50 and 32/49(NT? 1980a). Other non-
neoplastic lesions were not observed, even though extensive histologic examina-
tions were performed. The two preceding studies of noncarcinogenic effects
support a NOAEL for rats of sQ.OOl yg/kg/day and a lowest-observed-adverse-
effect level (LOAEL) of 0.05 yg/kg/day.
Non-neoplastic effects.of chronic dioxin exposures were described in studies
investigating the carcinogenic potential of dioxin in mice. In a National
Toxicology Program (NTP 1980a) bioassay, histologic examinations were per-
formed on B6C3F1 mice treated biweekly with dioxin by gavage in corn oil-
acetone (9:1) for 104 wk followed by an additional 3-wk observation period.
The doses for male animals were 0.0, 0.01, 0.05 and 0.5 pg/kg/wk, and for
female animals, 0.0, 0.04, 0.2 and 2.0 yg/kg/wk. The only non-neoplastic
adverse effect observed was toxic hepatitis, which occurred in males at
incidences of 0/73, 5/49, 3/49 and 44/50, and in "females at incidences of
0/73, 1/50, 2/48 and 34/47, respectively, in the control, low, medium and high
dose groups. In another study, weekly administration of .dioxin by gavage at
doses of 0.0, 0.007, 0:7 or 7.0 yg7kg/wk for one year resulted in amyloidosis
(deposition of amyloid, a complex proteinaceous material) of the kidney,
spleen and liver, and dermatitis at the time of death in male Swiss mice (Toth
et al. 1978, 1979). The incidences of these effects in the control, low,
medium and high dose groups, respectively, were 0/38, 5/44, 10/44 and 17/43.
In the high dose group, the amyloidosis was extensive and considered to be the
cause of early mortality. Severe toxic effects were observed at doses of
1 yg/kg/day (early mortality) and 0.28 to 0.07 yg/kg/day (toxic hepatitis),
while a LOAEL for dermatitis and amyloidosis of 0.001 yg/kg/day was reported.
4.3.3 Toxicity in Aquatic Species
No standard chronic toxicity assays of dioxin in aquatic species were located
in the available literature (USEPA 1984) but several studies provide informa-
tion indicative of chronic toxicity values. In a static bioassay, Miller
et al. (1973) indicated that 0.2 yg/L may cause chronic toxicity in Paranais
sp. (worm). Based on the 55% mortality in coho salmon within 60 days follow-
ing acute (96-hr) exposures to 0.0056 yg/L (Miller et al. 1979), the USEPA
(1984) suggests that 0.0056 yg/L may cause chronic toxicity coho salmon.
Similarly the USEPA (1984) concludes that chronic toxicity values such as
0.001 ug/L (rainbow trout) and 0.01 yg/L (northern pike, coho. salmon, mosquite
fish and channel catfish) can be inferred based on results of acute assays by
Helder (1980, 1981, 1982), Yockim et al. (1978) and Branson et al. (1983). A
concentration of 1.3 yg/L may not cause chronic toxicity in Daphnia magna or
Physa (USEPA 1984).
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Limited data are available on the toxicity of dioxin to aquatic plants.
Isensee and Jones (1975) and Isensee (1978) observed no adverse effects in
algae (Oedogonium cardiacum) or duckweek (Lemna minor) exposed to 1.3 yg/L and
0.71 ug/L (respectively) for 30 days. Yockim et al. (1978) has also observed
no adverse effects on 0_^ cardiacum exposed to 0.0024 to 0.0042 yg/L of dioxin
for 32 days.
4.4 Teratogenicity, Reproductive Effects and Fetotoxicity
4.4.1 Effects of Humans
Epidemiological studies have attempted to investigate health effects of dioxin
in humans by indirectly evaluating health effects in populations exposed to
2,4,5-T (which commonly contains dioxin as an impurity). A positive associa-
tion between 2,4,5-T exposures and increases in birth defects or abortions has
been reported in human populations in Oregon (USEPA 1979), New Zealand (Hanify
et al. 1981) and Australia (Field and Kerr 1979). A lack of any such associa-
tion has been reported .in human populations in Arkansas (Nelson et al. 1979),
Hungary (Thomas 1980), New Zealand (Dept. of Health, New Zealand 1980, McQueen
et al. 1977) and Australia (Aldred 1978).
4.4.2 Effects in Laboratory Animals
Dioxin has been reported to be fetotoxic and teratogenic when administered
alone or in combination with other chemicals. Several studies have been
identified in- the available literature based on dioxin exposure alone.
Effects observed were kidney anomalies, intestinal hemorrhage, general edema,
cleft palate and fetal death. Adverse effects on reproduction were also
reported.
Intestinal hemorrhage, general edema and a reduction in fetal weights were
reported in rats following tne administration of 0.125 ug/kg/day in studies by
Sparschu et al. (1971). In the same studies, the number of fetuses was
reduced and fetal death increased at 0.5 yg/kg/day. No structural malforma-
tions were reported at 0.03 yg/kg/day. Courtney and Moore (1971) reported
cleft palate and kidney abnormalities in mice borne by dams administered
dioxin at doses of 1.0 yg/kg or 3.0 yg/kg. Similarly, kidney malformations
were reported by the same authors"in offspring from rats which received
subcutaneous injections of 0.5 ug/kg/day on day 9, 10, or 13 and 14 of
gestation.
Murray et al. (1979) completed a three-generation reproduction study using
Sprague-Dawley rats fed dioxin continuously in the diet (at levels of 0,
0.001, 0.01, and 0.1 yg/kg/day). Significant decreases were observed in
fertility, litter size, gestation survival, postnatal survival, and postnatal
body weight for the 0.01 and 0.1 yg/kg groups. No apparent adverse effect on
reproduction was seen at the 0.001 yg/kg dose level.
Although Murray et al. (1979) considered the lowest dose tested, 0.001 yg/kg,
to be a NOEL (noncarcinogenic), reevaluation of these data by Nisbet and
Paxton (1982) using different statistical methods indicated that there was a
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reduction in the gestation index, decreased fetal weight, increased liver-
to-body weight ratio, and increased incidence of dilated renal pelvis at the
0.001 JJg/kg dose. The reevaluation of data suggests that equivocal adverse
effects were seen at the lowest dose (0.001 yg/kg/day) and that this dose
should, therefore, represent a LOAEL.
Schantz et al. (1979) found reductions in fertility and various other toxic
effects in rhesus monkeys fed 55 ppt dioxin in the diet for 20 mo. This
corresponds to a calculated daily dioxin dose of 0.0015 ug dioxin/kg/day.
These results suggest that monkeys may be somewhat more sensitive than rats,
since the effects in monkeys were more severe and not equivocal.
Luster et al. (1980) examined bone marrow* immunologic parameters, and host
susceptibility in B6C3F1 mice following pre- and postnatal exposure to TCDD.
Doses of 0, 1.0, 5.0 and 15.0 yg/kg bw of dioxin were given to dams on day 14
of gestation and to offspring on days 1, 7, and 14 following birth. Neonatal
body, liver, spleen, and thymus weights were decreased and bone marrow
toxicity occurred in the 5.0 and 15.0 yg/kg groups. Red blood cell counts,
hematocrits, and hemoglobin were decreased at the highest dose tested.
4.5 Mutagenicity
Studies on the mutagenicity of dioxin have produced conflicting results.
Dioxin reportedly produces mutagenic effects in Escherichia Coli and " .
Salmonella typhimurium TA 1532 (Russian et al. (1972) but not in-£.
typhimurium test strains TA1535, TA100, TA1538, TA98, and TA1537 with or
without metabolic activation (Geiger and Neal 1981). Green et al. (1977)
observed an increased incidence of chromosomal breaks in female rats dosed
with 4 yg/kg and in males dosed with 2 yg/kg or 4 yg/kg of dioxin twice weekly
for 13 weeks.
4.6 Carcinogenicity /
4.6.1 Carcinogenicity in Humans
Epidemiologic studies of industrial workers and herbicide applicators suggest
that dioxin may be a human carcinogen. However, since dioxin is usually a
contaminant of phenoxy acids and/or chlorophenols, human exposure is usually
to multiple chemicals. Therefore, the evidence for human Carcinogenicity from
these studies is only suggestive due to the difficulty of evaluating the risk
of dioxin exposure in the presence of the confounding effects of the other
chemicals (USEPA 1984).
Hardell (1977) observed an unusual occurrence of relatively rare soft-tissue
sarcomas (STS) in 7 of 87 patients seen from 1970 to 1976 at the Department of
Oncology, University Hospital, Umea, Sweden. All seven had had occupational
exposure to phenoxy acids 10 to 20 yr earlier. The clustering of these rare
tumors among these patients prompted the author to suggest that epidemio-
logical studies be designed to determine if exposure to phenoxy acids and
their impurities (i.e., dioxins) are related to the occurrence of STS.
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A few occurrences of STS have also been reported among chemical industry
workers in the United States who were exposed to varying levels of 2,4,5-
chlorophenols with dioxin contaminants (Cook et al. 1980, Moes and Selikoff
1981). Honchar and Halperin (1981) reported that 3 of 105 deaths among
phenoxy acid workers reported by two chemical companies were from STS.
Zack and Suskind (1980) reported a STS death in a cohort study of workers
exposed to dioxin in a trichlorophenol process accident in West Virginia.
This tumor, a fibrous histiocytoma, was considered as a rare event.
In a cohort mortality study of 61 male employees of a trichlorophenol manu-
facturing area who exhibited chloracne following a 1964 exposure incident,
Cook et al. (1980) noted four deaths by the end of his study period, one of
which was due to a fibrosarcoma.
There are numerous other studies reported regarding STSs. For example, Smith
et al. (1982) conducted an initial case-control study of 102 males identified
from the New Zealand Cancer Registry as having STSs (ICD 171) between 1976 and
1980. For each case, three controls each with another form of cancer were
matched by age and year of registration. The selection of cancer controls
from the same registry was done to eliminate recall bias or interviewer bias
or both.
The distribution of tumor types differed considerably from the Hardell and
Eriksson et al. (1981) study to the Smith et al. (1982) study. 'Leiomyo-
sarcomas;- malignant histocytomas, neurogenic sarcomas and myxosarcoma seem to
predominate in the Hardell and Eriksson (1981) study, whereas fibrosarcbmas
and liposarcomas appear prominently in the Smith et al. (1982) study.
Smith et al. (1983) conducted another case-control study of STSs in males that
were reported to the New Zealand Cancer Registry by Public Hospitals between
1976 and 1980. Smith et al. (1983) remarked that it was surprising that he
found no STS victim who had ever worked full-time in phenoxyacetic acid
herbicide spraying. Perhaps they have not yet been observed for a long enough
period. As was pointed out by the author, the findings do not support the
hypothesis that exposure to phenoxyacetic acid herbicides causes STS; however,
neither do they support a negative finding without better documentation
regarding actual exposure and time of actual exposure.
The Michigan Department of Public Health (1983) recently conducted an ecologi-
cal study of soft and connective tissue cancer mortality rates in Midland and
other selected Michigan counties. They found that mortality rates for this
cancer were 3.8 to 4.0 times the national average for the periods 1960 to 1969
and 1970 to 1978, respectively, for white females in Midland. These estimates
are based upon five deaths and seven deaths, respectively. No excess risk was
reported among white males, however. The Michigan Department of Health
concluded that because of the occurrence of these two sucgessive elevated
rates, it is unlikely to be a chance happening. At the same time the age-
adjusted male and female cancer mortality rates for Midland were below that of
the State of Michigan for the period 1970 to 1979. Midland County is the home
of a major chemical company that produced phenoxyacetic acid herbicides until
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recently. The authors stated that a detailed review of death certificates,
hospital records, residency and occupational histories of the 20 male and
female cases revealed no "commonalities" suggesting a "single causative
agent," although a majority of their spouses had worked at this chemical
facility. They recommended that a case-control study should be instituted to
evaluate possible influences, such as lifestyles, occupation or location of
residences, on the risk of STS.
4.6.2 Carcinogenicity in Laboratory Animals
The carcinogenic potential of dioxin has been studied extensively in labora-
tory animals. A summary of the results of selected comprehensive studies is
presented in Table 4-3. The results of these studies show that dioxin-exposed
animals exhibited malignant lesions involving multiple organ systems including
accessory digestive organs (liver), endocrine (thyroid, adrenal), renal,
reproductive (testes), and nasal structures. Representative studies are
described below.
Groups of ten male Sprague-Dawley rats were fed a diet containing dioxin for
78 wk at concentrations ranging from 1 ppt to 500 ppt or 1 ppb to 1,000 ppb
(Van Miller et al. (1977). These dietary levels represent approximate weekly
dose levels of 0.0003 to 0.1 yg/kg or 0.4 to 500 yg/kg. Animals exposed at
5 ppt, 50 ppt, 500 ppt or 5 ppb showed an overall incidence of neoplasms of
38%-(23/60). No neoplasms.were reported or observed following exposure to
1 ppt dioxin. In the 5 ppt group, 5/10 animals had six neoplasms (earduct
carcinoma, lymphocytic leukemia, adenocarcinoma, malignant histiocytoma (with
metastases), angiosarcoma and Leydig-cell adenoma). Neoplasms were also
observed in the following groups: at 50 ppt, three in 3/10; at 500 ppt,
four in 4/10; at 1 ppb, five in 4/10; at 5 ppb, ten in 7/10. Neoplasms were
not observed in the controls. Rats administered dioxin at 50, 500 or 1,COO ppb
exhibited 100% mortality by the fourth week.
In another study (Kociba et al. 1978), groups of 100 Sprague-Dawley rats
(50 males and 50 females) received diets containing dioxin at 0, 22, 210, or
2,220 ppt (equivalent to a daily dose of 0.0, 0.001, 0.01 and 0.1 yg/kg bw)
for two years. - Administration of 0.01 yg/kg/day increased the incidence of
hepatocellular hyperplastic nodules (female: 18/50 versus 8/86 controls) and
focal alveolar hyperplasia in the lungs (P<0.05). Dietary intake of
0.1 yg/kg/day increased the incidence of hepatocellular carcinomas (female:
11/49 versus 1/86) and squamous cell carcinomas of the lung (female: 7/49
versus 0/86), hard palate/nasal turbinates (male: 4/50 versus 0/85; female:
4/49 versus 0/86), and tongue.(male: 3/50 versus 0/85) (P<0.05). Also in-
creased in frequency by the 0.1 yg TCDD/kg/day were adenoma of the adrenal
cortex (male) and hepatocellular hyperplastic nodules (female).
The NTP (1982a) conducted a study for 104 wk using Osborne-Mendel rats and
B6C3F1 mice. The rats and male mice were administered TCDD at 0, 0.01, 0.05
or 0.5 yg/kg/wk by gavage in two divided doses, and the female mice were given
0, 0.04, 0.2, or 2.0 yg/kg/wk. Incidences of follicular cell thyroid adenomas
in male rats (P<0.001) and of neoplastic nodules in livers of female rats
(P=0.006) increased significantly. Dioxin increased the numbers of hepato-
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TABLE 4-3 SUMMARY OF CARCINOGENIC EFFECTS OF DIOXIN
Species/Sex
(Number)
Rat/
M (50)
F (50)
Dose
Rat/M (10) 1 ppt
Rat/M (10) 5-500 ppt
Rat/M (10) 1-5 ppb
0.001 Ug/kg
0.01 Ug/kg
0.1 pg/kg
Duration
78 wk
2 yr
Route
Diet
Diet
Effects
Reference
No neoplasm.
Van Miller et al.
(1977)
Ear duct carcinoma, benign tumor
of the kidney and testes,
lymphocytic leukemia, skin
carcinomas and benign muscle
tumors.
Cholangiocarcinoma of liver,
squamous cell tumor of lung,
angiosarcoma in skin, glioblas-
toma in brain, malignant histio-
cytomas in peritoneum.
No significant increase in tumors. Kociba et al. (1978)
Liver cancer.
Liver cancer, squamous cell car-
cinoma of the lung, hard palate/
nasal turbinates, or tongue
(P=0.05).
Mouse/F (30) 0.015 ug/kg/wk 99-104 wk Dermal
Mouse/M (30) 0.003 pg/kg/wk 99-104 wk Dermal
Rat/M (50) 0.5 pg/kg/wk 104 wk
Rat/F (50) 0.5 pg/kg/wk 104 wk
Gavage
Gavage
Fibrosarcoma in integumentary
system (8/27, P=0.007).
Fibrosarcoma in integumentary
system (6/28, P=0.08)
Follicular cell adenomas of
thyroid (10/50, P=0.001).
Neoplastic nodules of the liver
(12/49, P=0.006).
NTP (1982b)
NTP (1982a)
continued-
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Table 4-3 - continued
Species/Sex
(Number)
Dose
Duration Route
Mouse/M&F 2.0 yg/kg/wk 104 wk
Mouse/F
2.0 yg/kg/wk 104 wk
Mouse/M (39) 0.007 ug/kg/wk 52 wk
Mouse/M (44) 0.7 ug/kg/wk 52 wk
Mouse/M (44) 7.0 yg/kg/wk 52 wk
Gavage
Gavage
Gavage
Gavage
Gavage
Effects
Hepatocellular carcinoma
(17/50. P=0.002 in M);
(6/47, P=0.14 in F).
Follicular cell adenomas of the
thyroid (5/46, P=0.009)
!
Liver tumors (13/44, P not
specified
Li
Li
Adapted from Esposito et al. (1980), NTP (1982a,b).
er tumors (21/44, P<0.01)
er tumors (13/43, P=0.11)
Reference
NTP (1982a)
Toth et al. (1979)
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cellular carcinomas in male mice (P=0.002) and in females (P=0.014). The
total liver tumors (carcinomas and adenomas) were increased in males (P<0.001)
and females (P=0.002). In addition, female mice had increased incidence of
follicular cell thyroid adenomas. These studies indicate that TCDD is an
animal carcinogen.
Toth et al. (1979) administered doses of 0, 0.007, 0.7 and 7.0 yg/kg/wk of
dioxin to male mice by gavage in a study to determine whether 2,4,5-trichloro-
phenoxyethanol (2,4,5-TCPE), its contaminant (dioxin) or both were carcino-
genic. The incidence of liver tumors was significantly increased in the dose
group receiving dioxin at the 0.7 yg/kg/wk level. No significant increased
incidence in liver tumors was observed in the 7.0 yg/kg/wk dose group although
increased mortality in this group probably precluded detection of tumors with
longer latent periods.
The NTP (1982b) conducted a skin painting cancer bioassay of dioxin on Swiss-
Webster mice (50 of each sex/dose). A dose of 0.001 yg/application (males)
and 0.005 tig/application (females) in acetone suspension was painted on the
skin 3 days/wk for 104 wk. The vehicle control group (45 mice/sex) was
painted with 0.1 mL acetone 3 times/wk for 104 wk. The incidence of fibro-
sarcoma in the integumetary system was significantly increased in females
(8/27, P=0.007) but not in males (6/28, P=0.08) compared to the incidence
respective controls (2/41 and 3/42).
DiGiovanni et al. (1977) reported tha-t dioxin was a-tumor initiator in mouse
skin. However-j—the ro-le of dioxin-as—an initiator needs to be confirmed since
appropriate vehicle and prpmotion-only controls were not included in this
assay.. Several assays (NTP 1982b, Berry et al. 1978, 1979) demonstrated that
dioxin was not a tumor-promoter when applied to mouse skin after unknown
initiator (DMBA).
Poland and Knutson (1982) reported that dioxin was a tumor promoter when
tested on the skin of mice homozygous for the "hairless" trait but not in mice
heterozygous for this recessive trait. Pitot et al. (1980) also reported that
dioxin was a promoter for DEN-initiated hepatocarcinogenesis in rats following
parenteral administration of the compounds. On mouse skin, dioxin was a
complete -carcinogen and possibly a tumor initiator, while no tumor-promoting
activity could be attributed to dioxin in the assays. In rat liver initiated
with DEN, dioxin was a tumor promoter.
In the mouse skin bioassay, initiation with simultaneous administration of
dioxin and DMBA, however, did not affect tumor yield (DiGiovanni et al. 1977).
Similarly no effect was observed when dioxin was administered either immedi-
ately before (five minutes) or one day after DMBA initiation (Berry et al.
1979, DiGiovanni et al. 1977, Cohen et al. 1979). When treatment with dioxin
occurred one to ten days before DMBA initiation, dioxin demonstrated a potent
anticarcinogenic action. Although one to five days prior exposure to dioxin
inhibited tumor initiation by BaP, 3-MC, and BaP-diol-epoxide, the tumor-
initiating ability of the latter compound was also inhibited when dioxin
exposure occurred either five minutes before or one day after initiation
(DiGiovanni et al. 1980). The increased AHH activity resulting from dioxin
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exposure may account for the anticarcinogenic activity by altering the
metabolism of the initiating compound; however, DiGiovanni et al. (1980)
suggests that the initiation of the initiating activity of BaP-diol-epoxide
one day after initiation indicates that more than one mechanism participates
in the anticarcinogenic activity of dioxin.
4.7 Quantitative Indices of Toxicity
4.7.1 Noncarcinogenic Effects Indices
Recommended exposure limits to dioxin to ensure human safety have been
established by several agencies. The National Academy of Sciences (NAS 1977),
before TCDD was considered to be a carcinogen, suggested an ADI for dioxin of
0.0001 yg/kg/day based on a 13-wk feeding study in rats (Kociba et al. 1976).
The reported NOEL in that study (0.01 yg/kg) was divided by an uncertainty
factor of 100 to determine the ADI. The NAS then calculated a suggested-
no-adverse-effeet-level (SNARL) in drinking water of 0.0007 yg/L, based on the
average weight of a human adult (70 kg) and an average daily intake of water
of two liters, with water representing 20% of total intake.
The USEPA (1984) has calculated an ADI of 10~~ yg/kg/day based on noncarcino-
genic toxicity for comparison to the carcinogenic risk assessment value. A
LOAEL based on noncarcinogenic toxic effects and reduced fertility of
0.001 ug/kg/day and an uncertainty factor of 1,000 were used in the cal-
culations. Using a bioaccumulation factor of 5,000, and assuming a daily
consumptioir-of 6.5 g of fish, a water concentration of 2.0 x 10 Ug/L was
derived. It was noted thac this value may not be sufficiently low Co protect
against the carcinogenic effects of dioxin (USEPA 1984). The USEPA is
currently reevaluating the bioconcentration factor for dioxin.
The USEPA (1984) concluded that insufficient data were available concerning
adverse effects of dioxin on aquatic life to allow derivation of ambient water
quality criterion. Limited information in freshwater species indicate acute
values may be >0.1 ug/L and chronic values may be <0.01 yg/L (northern pike,
coho salmon, mosquito fish and channel catfish) and <0.001 yg/L (rainbow
trout).
-4.7.2 Carcinogenic Effects Indices
Since there is no recognized safe concentration for a human carcinogen, and
dioxin is a suspected human carcinogen, the recommended concentration of
dioxin in water is zero (USEPA 1984). The USEPA calculated a range_o>f _fi
concentrations for dioxin corresponding to cancer risk levels of 10 , 10
and 10 . These calculations used a linearized multistage model and were
based on animal bioassay data. -The recommended criteria which may result in
an increased cancer risk of 10 , 10 or 10 are 1.3 x 10~ , 1.3 x 10~ and
1.3 x 10 ' yg/L, respectively. These criteria are beiow the limit of
detection of TCDD in water (approximately 3 x 10~ yg/L) by current analytical
methods.
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The Food and Drug Administration (FDA) issued a health advisory stating that
fish with residues of dioxin ^50 ppt should not be consumed, but fish with
residues of < 25 ppt pose no serious health concern (USEPA 1984). The Centers
for Disease Control (CDC) has established 1 ppb as a level of concern for
dioxin in residential soils at Times Beach, MO.
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5.0 RISK AND IMPACT EVALUATION
5.1 Human Health
Dioxin contamination from the Vertac site presents endangerment to human
health. Ingestion of fish from Bayou Meto or Lake Dupree that have bio-
accumulated dioxin will substantially increase cancer risks in humans.
Limited monitoring data indicate that dioxin has bioaccumulated in fish to
levels that are up to 16 times greater than the FDA's health advisory value of
^50 ppt for dioxin residue in fish. Thus, fish are considered unsafe for
human consumption. The efficacy of the fishing ban on Bayou Meto is uncertain
since it is not easily enforced. : Individuals that may consume large quanti-
ties of fish from Lake Dupree, Bayou Meto or the Rocky Branch Creek are
considered at higher risk.
Groundwater contaminated with dioxin potentially poses an unacceptable cancer
risk to humans. The actual risk via the groundwater route is probably minimal
due to an apparent lack of exposure potential. However, this route could
result in substantial carcinogenic risk if groundwater contaminated at 0.03 ppb
dioxin (the highest detected level in groundwater on-site) were consumed.
Assuming the 70-kg human would consume two liters of water per day then the
dose would be 0.0009 yg/kg/day (0.9 ng/kg/day). Consumption of a dioxin dose
of 0.9 ng/kg/day over a lifetime poses unacceptable carcinogenic risk exceed-
ing the 10~ risk associated with consumption of water with a dioxin concen-
tration of 1.3 x 10 ug/L (3.7 x 10 Og/kg/day or 0.0000037 ng/kg/day).
Consumption of drinking wa-t-er containing 0.005 ppb dioxin (the mean detected
concentration) would result in a dose of 0.0001 ug/kg/day (0.1 ng/kg/da_y)
which would also pose unacceptable carcinogenic risk exceeding the 10 level.
The lower bound estimate of induced cancers is zero since consumption may not
occur and because recent analyses have not detected dioxin in groundwater
monitoring wells.
/'
Other potential risks to human health may result from inhalation exposures to
dioxin-contaminated dust from natural wind erosion and/or from the proposed
remedial action (Alternative IV) involving excavation, loading/unloading,
transporting and spreading dioxin-contaminated soils and materials at the
Vertac site. Monitoring data on wind-generated dioxin contaminated dust
emissions were not available to estimate exposures and to assess human health
risks for a no action alternative or the present endangerment level. The
health risk associated with exposures via wind-erosion is anticipated to be
minimal relative to that associated with the remedial action (Falco and Schaum
1984). The residents to the south of the site are expected to be at greatest
risk due to their proximity to the site (Falco and Schaum 1984). The risk
associated with inhalation of dioxin-contaminated dusts will decline with
distance from the site.
The potential for direct contact with contaminated soils and sediments poses
human health risks. Monitoring data indicate that levels of dioxins in soils
and sediments off-site exceed the CDC's 1 ppb level of concern for residential
soils established for Times Beach, MO.
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5.2 Environmental
There are potential risks to aquatic and terrestrial species related to dioxin
releases from the Vertac site. The absence of benthic life, several massive
fish kills and reported "medicinal" taste and odor of fish caught from Bayou
Meto (receiving waters of the Rocky Branch Creek) reflect the impact of
contaminants released from the Vertac site on aquatic life (JRB. 1983). The
limited environmental monitoring data for sediments in the Rocky Branch Creek,
Bayou Meto and Lake Dupree indicate substantial dioxin contamination has
occurred. Analyses of- fish tissues demonstrates that dioxin has been bio-
accumulated to substantial levels (up to 300 ppt in Bayou Meto and 810 ppt in
Lake Dupree) but the health significance of such tissue levels and potential
impact on survival, growth, development and reproduction of aquatic life
remains unknown. The absence of ambient water quality criteria and especially
criteria for dioxin levels in sediments impedes performance of a quantitative
assessment of potential effects on aquatic organisms.
There is a paucity of monitoring data on the concentration of dioxin in
surface waters offsite. The only data available indicate that dioxin was not
detected in water from the Rocky Branch Creek. Therefore, it is not possible
to compare dioxin concentrations in receiving water to levels causing acute
toxicity (>1.0 ppb) in certain freshwater species or chronic toxicity in the
rainbow trout (<0.001 ppb) or in several other fish species (<0.01 ppb).
The high content of dioxin in" sediments (500 ppt ave) in the Rocky Branch
Creek and poten-6-ial for release to the water column suggests 'that aquatic
organisms may be at risk. No existing guidelines or standards are available -.
to determine risks to avian or terrestrial organisms. The potential impact of
contamination on such species is of concern since the Bayou Meto area serves
as an important water fowl resting area and contains about 70,000 acres of
wetlands. Limited data are available on the avian species and terrestrial
species present in the area. Contamination of the Bayou Meto and accumulation
of dioxin in the aquatic food chain may endanger predator (avian or terres-
trial) species.
5.3 Public Welfare
The major socioeconomic impact of the release of dioxin from the Vertac site
has been the loss of adjacent surface waters for fishing and recreation. For
example, the release of dioxin to the Rocky Branch Creek and Bayou Meto and
transport to Lake Dupree during flooding has caused fish to accumulate
(810 ppt) dioxin in excess of the FDA health advisory value of ^50 ppt. Thus,
fish from Lake Dupree may be unfit for human consumption. This contamination
of fish has required the Arkansas public health officials to issue a fishing
ban for the Bayou Meto area. An additional impact on public .welfare may be a
potential decrease of property values immediately adjacent to the site (i.e.,
especially residential property values) and the loss of groundwater aquifers
as a potential source of drinking water.
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6.0 CONCLUSIONS
The most significant endangerment of human health is due to the potential
consumption of dioxin-contaminated fish from Bayou Meto. Limited environ-
mental monitoring data indicate that residues of dioxin in fish from Bayou
Meto and Lake Dupree may exceed the FDA's health advisory value of ^50 ppt
dioxin by about 16 times. Populations that consume large quantities of fish
from Bayou Meto, Rocky Branch or Lake Dupree are expected to have increased
cancer risk. The fishing ban for Bayou Meto may reduce this threat to human
health, but its efficacy is unknown since it is not easily enforced.
The contamination of groundwater represents another substantial potential
threat to human health. There is a real potential for offsite migration of
contaminants to groundwater. A maximum concentration of 0.03 ppb and a mean
of 0.005 ppb of dioxin have been detected in onsite groundwater monitoring
wells. Actual exposures to humans via this route is currently considered
unlikely since no permitted domestic and industrial wells were located in the
area immediately downgradient of the site. Human health may be endangered if
water wells are drilled in the future and used for drinking water purposes.
Assuming humans may potentially consume groundwater in the future, the result-
ing dose of dioxin would increase risk of cancer substantially above the 10
level. Further groundwater monitoring data are necessary to verify and
characterize the magnitude and extent of any offsite contamination.
Exposure to dioxin via inhalation of dust-emissions from .the proposed remedial
action is anticipated to present_an increased cancer jrisk for residents near
the Vertac site. Risks associated with inhalation of dioxin-contaminated dust
will diminish with distance from the site. Demographic information on the
size of this population was unavailable. Risks associated with wind-generated
dust emissions are expected to be minimal due to remedial actions already
implemented. Detection of dioxin in soils and sediments in excess of the
CDC's 1 ppb health concern level for residential soils (established for Times
Beach, MO) indicates potential risks associated with direct contact (dermal
and ingestion) exposures.
Assessment of risks to aquatic and terrestrial organisms was difficult due to
limited environmental monitoring data and the unavailability of established
ambient water criteria. Massive fish kills, dioxin bioaccumulated in fish and
the absence of benthic life suggest potential impacts on aquatic life.
Loss of fishing in the Bayou Meto area impacts the public welfare. Addi-
tionally decrease of property values adjacent to the site or along the bayou
may impact the economic stability of the area. Contamination of groundwater
may prevent its future use as a drinking water resource.
6-1
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Zack JA, Suskind RR. 1980. The mortality experience of workers exposed to
tetrachlorodibenzodioxin in a trichlorophenol process accident.
J. Occup. Med. 22:11-14.
7-10
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Attachment 5
1. Physical Description of the Site and Site History
a. geographic location
b. management practices/site use/site modifications
c. chronological survey
d. facility description/containment systems
e. substances brought on site (identity, quantity, form
manner of disposal)
2. Site Contamination/Off-Site Contamination
a. identity of substances detected
b. concentration of substances detected
c. analytical methodology and QA/QC
. d. survey of environmental monitoring studies (detailed
discussion of environmental media and contamination
levels)
3. Environmental Fate and Transport
a. physical-chemical properties of specified chemicals/
substances (e.g., soil/sediment adsorption coefficients,
vapor pressures, solubility, etc.) .
b. photodegradation rates, decomposition rates, hydrolysis' rates,
chemical-transformations, etc. •
c. local topography
d. description of the hydrological setting and flow system
e. soil analyses
f. climatic factors, other factors affecting fate and
transport
. g. prediction of fate and transport (where necessary using
modeling methods)
4. Toxicological Properties (hazard identification)
a. metabolism
b. acute toxicity
c. subchronic toxicity
d. chronic toxicity
e. carcinogenicity
f. mutagenicity
g. teratogencity/reproductive effects
h. other health effects as relevant including neurotoxicity,
immuno-depressant activity, allergic reactions, etc.
i. epidemiological evidence (chemical specific or site
specific)
j. aquatic/non-human terrestrial species toxicity/
environmental quality impairment
k. human health standards and criteria
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-2-
5. Exposure Assessment
a. demographic profile of populations at risk including
subpopulation at special risk
b. background chemical exposures
c. life style and occupation histories
d. population macro-and micro-environments
e. exposure routes
f. magnitude, source, and probability of exposure
to specified substances
6. Risk Evaluation and.Impact Evaluation
a. carcinogenic risk assessment
b. probability of non-carcinogenic human health
effects
c. non-human species risk assessment
d. environmental impacts/ecosystem alterations
7. Conclusions
8. Documentation (Appendices)
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iCife Systems, Jnc.
PART 3 - LEVEL 3 ENDANGERMF.NT ASSESSMENT
A2-6
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£ift Systems, JHC.
Submitted to:
Office of Waste Programs Enforcement
U.S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Attention: Chief, Health Sciences Section, R. Charles Morgan (2 cop-ies)
VERTAC SITE ENDANGERMENT ASSESSMENT
(Level 3 Example)
Prepared Under
Program No.-1S93-
for
Contract No. 68-01-7037
Work Assignment No. 12
PRC Work Assignment No. 136
Contact: Timothy E. Tyburski
Telephone: (216) 464-3291
July 25, 1985
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JLifc bystems, M.
DISCLAIMER
This document has not been peer and administratively reviewed within EPA and
is for internal Agency use/distribution only.
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£ife Systems, Jnc.
TABLE OF CONTENTS
PAGE
LIST OF FIGURES - ill
LIST OF TABLES ' . iii
1.0 INTRODUCTION 1-1
1.1 Site Description and History 1-1
1.2 Contaminants Found at the Site , . 1-3
2.0 ENVIRONMENTAL FATE AND TRANSPORT 2-1
2.1 Factors Affecting Migration 2-1
2.1.1 Geology .......... 2-1
2.1.2 Hydrology • 2-1
2.1.3 Hydrogeology 2-2
2.1.4 Climatology . 2-3
2.2 Environmental Fate and Transport of Dioxin 2-3
2.2.1 Environmental Fate 2-3
2.2.2 Environmental Transport ... —T . . . . 2-5
2.3 Contaminant Movement On Site and Off Site 2-6
3.0 EXPOSURE EVALUATION 3-1
3.1 Routes of Exposure /. . . 3-1
3.1.1 Fish Consumption 3-1
3.1.2 Groundwater 3-1
3.1.3 Airborne Dust 3-2
3.1.4 Direct Contact with Contaminated Soils/Sediment . . 3-2
3.2 Populations Exposed 3-2
3.2.1 Fish Consumption 3-2
3.2.2 Groundwater 3-3
3.2.3 Airborne Dust 3-3
3.2.4 Direct Contact 3-5
3.3 Extent of Exposure 3-5
3.3.1 Fish Consumption 3-5
3.3.2 Groundwater 3-5
continued-
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£ife Systems, Jnc.
Table of Contents - continued
PAGE
3.3.3 Airborne Dust 3-7
3.3.4 Direct Contact 3-7
4.0 TOXICITY EVALUATION 4-1
4.1 Pharmacokinetics 4-1
4.2 Acute Toxicity 4-1
4.2.1 Toxicity in Humans . . 4-1
4.2.2 Toxicity in Laboratory Animals 4-2
4.2.3 Toxicity in Aquatic Species 4-3
4.3 Subchronic and Chronic Toxicity 4-3
4.3.1 Toxicity in Humans . • -. . 4-3
4.3.2 Toxicity in Laboratory Animals 4-3
4.3.3 Toxicity in Aquatic Species 4-7
4.4 Teratogenicity, Reproductive Effects and Fetotoxicity .-. . 4-7
4.4.1 Effects of Humans •.*.... 4-7
-—4-;-4-. 2 Effects in Laboratory Animals . —»- 4-8
4.5 Mutagenicity 4-9
4.6 Carcinogenicity 4-9
4.6.1 Carcinogenicity in Humans- 4-9
4.6.2 Carcinogenicity in Laboratory Animals/ ....... 4-11
4.7 Quantitative Indices of Toxicity 4-15
4.7.1 Noncarcinogenic Effects Indices 4-15
4.7.2 Carcinogenic Effects Indices 4-15
5.0 • RISK AND IMPACT EVALUATION "... 5-1
5.1 Human Health .5-1
5.1.1 QRA for Consumption of Contaminated Fish 5-1
5.1.2 QRA for Contaminated Groundwater 5-1
.5.1.3 QRA for Airborne Dust 5-3
5.1.4 QRA for Direct Contact 5-3
5.2 Environmental 5-3
5.3 Public Welfare 5-5
6.0 CONCLUSIONS 6-1
7.0 REFERENCES 7-1
ii
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ttfcSystems, JMC.
. LIST OF FIGURES
FIGURE . PAGE
1-1 Vertac Site Map 1-2
3-1 Minimum and Maximum Accumulative Exposure (ng/kg/day)
Immediately South of the Vertac Property (Resulting
From the Combination of Phases 1 and 2 Activities) 3-8
5-1 Minimum and Maximum Accumulative Upper .Bound Risk
Estimate Immediately South of the Vertac Property
(Resulting from the Combination of Phase 1 and 2
Activities 5-4
LIST OF TABLES
TABLE ' . PAGE
1-1 Ranges of Dioxin Contamination Detected On-Site at
the Vertac Facility and in Adjacent Water Bodies 1-5
3-1 Estimates of Population Size Exposed and Effects
of Assumptions Regarding Fish Consumption Rate
and .Fish Catch Rate 3-4
3-2 Dioxin Concentration in Sediment, Dioxin Concentration
in Fish and Human Exposure by River Mile 3-6
4-1 Effects of Dioxin in Animals Following Acute Exposure . . . 4-4
4-2 NOAEL and LOAEL Values Obtained From Subchronic and
Chronic Oral Toxicity Studies of Dioxin 4-5
4-3 „ Summary of Carcinogenic Effects of Dioxin '. . 4-12
5-1 Human Exposure and Upper-Limit Cancer Risk Estimates
by River Mile 5-2
iii
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jCife Systems, JMC.
1.0 INTRODUCTION
Disposal of chemical wastes and discharges of process wastewater over a
30-yr period has resulted in contamination of soils, groundwater and surface
waters at the Vertac Chemical Corporation herbicide manufacturing facility in
Jacksonville, AR. The release or potential release of contaminants from this
site may endanger human health, welfare and the environment. Human health is
at risk due to the potential for consumption of contaminated fish, inhalation
of airborne contaminants, direct contact with contaminanted soils/sediments
and ingestion of contaminated groundwater. Contaminants released to surface
waters have been bioaccumulated to substantial levels in fish and other
aquatic species.
1 • 1 Site Description and History
The Vertac hazardous waste site is located in northwest Jacksonville, AR
(Pulaski County), approximately 20 mi northeast of Little Rock. The site
(about 93 acres in size) is bounded by Marshall Road to the east and the
Missouri-Pacific Railroad to the west. The old artillery booster line is on
the northern boundary and an adjacent housing development is to the south.
The Rocky Branch Creek flows along the western edge of the site and the East
Branch of the Rocky Branch Creek flows to the east.of the site. The cooling
pond located along the western edge of the site was formed by construction of
an earthen dam across the Rocky Branch Creek. The Rocky Branch Creek flows
into Bayou Meto (a tributary of the Arkansas River) about two miles south of
"the Vertac site. There is a fence around the entire site with a main gate
facing Marshall Road.". Figure 1-1 demonstrates the site features and
boundaries.
The site is a herbicide manufacturing plant owned by the Vertac Chemical
Corporation which currently produces 2,4-dichlorophenoxyacetic acid (2,4-D).
The site has been used since the 1930s by a variety of companies for the
manufacture of munitions and pesticides including DDT, aldrin, dieldrin,
toxaphene, 2,4-D, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 2,4,5-tri-
chlorophenoxypropionic acid (Silvex or 2,4,5-TP) and Agent Orange (a mixture
of 2,4-D and 2,4,5-T). The herbicides 2,4,5-T and Agent Orange are known to
contain 2,3,7,8-tetrachlorodibenzo-p-dioxin (hereafter referred to as dioxin
2,3,7,8-TCDD or TCDD) as an impurity. Waste disposal, cooling water dis-
charges and other plant operations apparently resulted in on-site and off-site
releases of pesticides and herbicides manufactured on site, chemicals used in
manufacturing processes and manufacturing impurities/by-products, including
TCDD.
Estimates of the quantity and types of contaminated materials at the Vertac
site were reported (JRB 1983) as follows:
3 3
1. Thirty thousand (30,000) yd (22,800 m ) of chlorinated phenols,
benzene and toluene wastes within the Reasor-Hill landfill.
Twenty thousand (20,000) yd (15,200 m ) of still bottoms, contau
nated with 2,3,7,8-TCDD, presently contained in the equalization
1-1
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£ifc Systems, Jnc.
ROOFED DRUM
STORAGE AREA
OLD DRUM
STORAGE SIT
HERCULES-TRANSVAAL
COOLING
POND
BLOW-OUT AREA
n
Barrier Walls
ASOR-HILL
ANOFILL
Barrier Walls
Central Drainage Dicch
French Drai
Interceptor Dice
BRAOEN STREET
Adapted from Walton 1982 as cited in JRB (1983)
FIGURE 1-1 VERTAC SITE MAP
1-2
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£ife Systems, Jnc.
basin wastewater treatment system. This amount includes the clay
cap placed on the basin at closure.
3 3
3. One hundred thousand (100,000) yd (76,000 m ) of material, includ-
ing toluene still bottoms, in the Hercules-Transvaal landfill area.
4. Three thousand (3,000) drums' (55 gallons each) of 2,4,5-T still
bottoms (repacked in 85 gallon overpack drums) and contaminated
soils from the former above-ground storage area, stored in the
concrete diked warehouse.
The U.S. Environmental Protection Agency (USEPA) has initiated enforcement
actions.against the site owners and required a number of remedial actions to
be implemented. The major remedial actions completed as of 1984 are
summarized below:
1. The Reaspr-Hill landfill was capped with clay, covered with soil
and seeded with grass. Clay barrier walls were installed on three
sides and the downgradient side was left open.
2. The Hercules-Transvaal landfill was capped with clay, covered with
soil and seeded with grass. No barrier walls were -installed.
3. The former above-ground drum storage area was capped with clay,
covered with soil and seeded. The old drums were repacked and
placed in the roofed storage warehouse.
4-. Two-thirds of the blow-out area (where spills from reactors had
occurred) was paved with asphalt and the remainder was capped with
clay, covered with soil and seeded.
5. The equalization basin has been subjected to extensive remedial
actions including dewatering and lime solidification of sludges,
installation of clay barrier walls, installation of a "French drain"
on the downgradient side, capping with clay, covering with soil and
seeding.
Under the proposed remedial action (Alternative IV), the Reasor-Hill Landfill
and North Burial Area (includes old drum storage sites and Hercules-Transvaal
Landfill) will be excavated and contaminated materials/soils will be redis-
posed of in a new on-site secure landfill in an area to the north of and over-
lapping with the North Burial Area. This proposed remedial action will
involve excavation of 50,000 yd of soil from the Reasor-Hill Landfill and
100,000 yd from North Burial Areas.
1.2 Contaminants Found at the Site
•«
Contaminants found at the site include pesticides and herbicides manufactured
on site, chemicals used in the manufacture of DDT, aldrin, dieldrin, toxaphene,
2,4-D, 2,4,5-T, 2,4,5-TP (Silvex) and Agent Orange (2,4-D and 2,4,5-T mixture).
Dioxin, an impurity resulting from synthesis of 2,4,5-T, is also present at
1-3
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Jjfe Systems, Jnc.
the Vertac facility. Environmental monitoring surveys from the period of 1978
to 1983 have detected chemical contaminants in groundwater, surface water,
soils and sediments. The USEPA Office of Waste Programs Enforcement .has
identified the following "indicator" chemicals for the Vertac site on the
basis of their toxic properties, presence in large quantities or potential and
actual releases to the environment:
• 2,3,7,8-TCDD • Chlorophenols
• 2,4,5-T • Chlorobenzenes
• 2,4-D • Toluene.
• 2,4,5-TP • Methanol
This endangerment assessment will focus on dioxin because it is the most
highly toxic substance at the facility and is very persistent in soils and
aquatic systems. Dioxin has been detected in waste products, groundwater and
soils on site and in sediments and fish tissue in adjacent surface waters (see
Table 1-1). Refer to CH2M Hill (1984a), JRB (1983) and Walton et al. (1982)
for data on individual sampling sites and dates and maps indicating sampling
locations and groundwater monitoring wells. .A site map showing these
locations (which is normally provided in an endangerment assessment) is not
included because of the complexity of the several monitoring studies performed
at this site. The values presented in Table 1-1 are a composite of the
available monitoring data from the period 1979 to 1983.
These data have not been subjected to a comprehensive quality assurance and
quality control review but a preliminary review .of available data reports
indicates that quality control and quality assurance procedures were
implemented. These procedures included the chain of custody, split samples,
replicate analyses, sample spiking with an internal radiolabelled dioxin.
standard, routine instrument calibration, methodological (extraction) blanks,
adherence to recommended sample holding times and storage temperatures, etc.
1-4
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TABLE 1-1 RANGES OF DIOXIN CONTAMINATION DETECTED ON-SITE
AT THE VERTAC FACILITY AND IN ADJACENT WATER BODIES
i
Ln
Sample Type
Sediment n
Soils
Surface
Waters
Ground
Water
Wastes
Fish
Locat ion/Description
Equalization basin
Cooling pond
Drainage ditches, on-slte
On-slte groundwater monitoring
we.ll
Rocky Branch Creek
Rocky Branch Creek, on-slte
Sewer and interceptors off-site
Creek bed adjacent to private
residences
Lake Dupree
Surface soils on-slte
Surface soils on-slte
Hercules-Transvaal area/surface
dirt
Reasor Hill landfill/dirt
Reasor Hill landfill/mud
Reasor Hill landfill area
Blow-out area
Rocky Branch Creek, on-slte
Discharge in combined sewer
at Braden and Alta Lane
Monitoring wells down gradient
of Hercules-Transvaal
Landfill
Monitoring wells, on-slte
Toluene still bottoms disposed
on-slte
Seeps from Reasor Hill
Equalization basin liquid
Equalization basin discharge
Caught In Bayou Meto
Caught in Lake Dupree
Dloxln
Concentration, ppb
0.063 to 1,200
0.236 to 102.0
0.800 to 34.1
NDID' to 12.1
0.500
0.236 to 17.4
18.4 to 33.4
1
0.150
ND(d>
100 to 14.000
559
3.42
0.505
NR1*'
0.99 to 45
ND
0.017
"High"
ND to <0.03
37,000
0.045 to 5.5
445
<10
<0.025 to 0.300 '
0.810
Total Number of
Samplea Analyzed
5
18
6
4
NA(c)
5
3
NA
1
NA
NA
1
1
1
NA1
2
1
1
NA
35
*
NA
3
1
1
6
1
Number
with JJloxin
Not Detected
0
0
0
2
NA(c)
0
0
NA
0
NA
NA
0
0
0
NA
0
|
0
NA
21
NA
0
0
0
0
0
Detected Dloxln
Concentratlona, ppb
/ \
Mean t SD(nr
460.2 t 459.1 (5)
18.2 i 24.2 (18)
16.1 t 12.9 (6)
10.0 i 3.0 (2)
NA(C>
4.1 i 7.5 (5)
28.3 i 8.6 (3)
NA
NA
NA
NA
NA
NA
NA
NA
22.5 t 31.7 (2)
NA
NA
NA
0.005 t 0.010 (13)
NA
2.4 1 2.7 (3)
NA
NA
0.087 1 0.110 (6)
NA
Reference
CH2M Hill (I984a)
CH2M Hill (1984a)
CH2M Hill (I984a)
CH2H Hill (1984a)
Falco (1982)
CH2M Hill (1984a)
CH2M Hill (1984a)
JRB (1983)
Schaum and Falco
(1982)
JRB (1983)
Falco anJ Schaum
(1984)
CH2M Hill (1984a)
CH2M Hill (1984a)
CII2H Hill (1984a)
JRB (1983)
CH2M Hill (1984a)
CH2M Hill (I984a)
CH2M Hill (1984a)
JRB (1983)
CH2M Hill (1984a)
JRB (1983)
CH2M Hill (1984a)
CH2M Hill (1984a)
CH2M Hill (I984a)
Schaum and Falco
(1982)
Schaum and Falco
(1982)
(a) The mean and standard deviation of samples with detected levels of dloxln were calculated. Samplea with
"not detected" (ND) levels of dloxln were not used in the calculations. The value in parentheses Is the
number of samples with detected dloxln levels used In the calculations.
(b) ND » Not detected. Detection limit was not reported.
(c) NA • Not applicable due to insufficient information.,
(d) Not detected in measurable quantity. Detection limits 50 to 100 ppt.
(e) NR •• detected but concentration not reported.
£>
fr
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£ife Systems, Jnc.
2.0 ENVIRONMENTAL FATE AND TRANSPORT
2.1 Factors Affecting Migration
2.1.1 Geology
The Vertac site is situated very near or possibly on the fall line of the
Interior Highlands and Coastal Plain physiographic regions. The geologic maps
show that the Vertac site is slightly to the west of the fall line suggesting
that it is in the Interior Highlands but evidence (the northern part of the
site contains clays of the Midway Group which are present in the Coastal
Plain) suggests it is also in the Coastal Plain or in the transition zone.
The surface soils near the eastern portion of the site are sedimentary. The
subsoils are part of the Atoka Formation characteristics of the Interior
Highlands.
The site is underlain by the consolidated rock of the Atoka Formation which
surfaces in the Interior Highlands and underlies the sediments of the Coastal
Plain. The Vertac site is located on the south flank of a westward plunging
syncline. The bedrock is alternating gray to black shales and sandstones of
the Atoka Formation which dips to the northeast at a rate of about 30 degrees.
There are many discrepancies regarding the strike and dip of the rock strata
on-site since the site is so close to the fall line. The overlying unweathered
bedrock in ascending order is weathered bedrock approximately five feet thick,
clays and alluvium.
The soil is classified as a Leadvale-Urban land complex with a 1 to 3% slope.
The Leadvale Urban land complex are areas of Leadvale soils that have been
modified by urban development. The Leadvale soils are moderately well-drained,
nearly level and gentle-sloping soils in valleys. They are formed mainly of
loamy sediment washed from uplands composed of sandstone, shale and in some
areas from weathered siltstone. The Leadvale soils have moderately low
permeability and maintain a medium level of available water capacity. The
level of runoff from the Leadvale Urban land complex is medium and the erosion
hazard is moderate if the soils are not protected by vegetation. Soil borings
indicate the presence of yellowish brown silty sands in the northeast corner
of the site and yellowish brown of tan silty clays in the southeast portion of
the site (CH2M Hill 1984a).
2.1.2 Hydrology
Surface drainage patterns at the Vertac site are predominantly westerly and
easterly. The western 55 acres drain directly to the Rocky Branch Creek. The
Rocky Branch Creek enters the Vertac site at the northwest boundary and flows
into a man-made cooling pond. About 700,000 gallons/day of process waste-
waters enter the cooling pond. Waters from the cooling pond flow out a
concrete outlet structure at the southwest extremity of the pond. A cantrsl
ditch (no longer present) acted as a surface drainage channel from the plant
production area and flowed into the cooling pond. The combined flow of
surface runoff and process waters enters Rocky Branch Creek and flows south
about two miles to Bayou Meto.
2-1
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£ife Systems, Jnc.
The eastern 38 acres of the site drain east to numerous small ditches caused
by natural erosion. Along adjacent driveways and roads are a few man-made
ditches. The catch basins located on the eastern portion of the site drain to
a storm sewer which empties into an open ditch near the main plant entrance.
All surface runoff east of the drainage divide eventually flows into the East
Branch of the Rocky Branch Creek. Most of this runoff is carried by the "K?.r.t
Ditch" to the East Branch. The East Branch flows into Rocky Branch Creek
south of the Vertac Site.
During heavy spring rains it is not uncommon for the Rocky Branch Creek to
flood the area south of the .Vertac Site. This is important because there is a
manmade recreational lake (Lake Dupree) 1.3 mi south of the Vertac site. Lake
Dupree and the Rocky Branch Creek are not normally connected but, the low
terrain and tendency for flooding in the area potentially enables contaminants
discharged into Rocky Branch Creek to be"deposited in Lake Dupree (JRB 1983).
2.1.3 Hydrogeology
The Interior Highlands are hilly and underlain by consolidated sediments which
dip slightly in a southeasterly direction. The consolidated rock of the
Interior Highlands underlies unconsolidated sediments of the Coastal Plain.
Above the lowest level of the water table, the consolidated rock of the
Highlands has been weathered. Soil and "rotten rock" (i.e., weathered rock)
in this region are present to a total depth of about 20 ft (maximum). This
weathered rock.area is more permeable and porous than unweathered rock. Water
Is prpsent -tji -intprgrannlar voids of "rotten rocks" and soil, while water is
only present in joints, fractures and other secondary openings in unweathered
rock.
The sediments of the Coastal Plain vary from high plasticity clays to sands
and gravels with varying permeabilities. There are three units within the
sediments which are major water sources in some areas of Pulaski County.
Beds of claystone, calcareous sandstone, sandy limestone, marl and conglomerate
(about 7 to 60 ft) comprise one aquifer unit. Fine to medium sand with some
interbedded clay lenses (about 320 ft thick) comprise another aquifer unit.
Terrace deposits and alluvium (deposited by the Arkansas and Mississippi
rivers) composed of fine-grain top stratum and deeper coarser stratum (about
120 ft) is the third aquifer unit. Refer to Walton et al. (1982), CH2M Hill
(1984a) and JRB (1983) for further hydrogeologic information and a diagram of
the locations of aquifers in the Coastal Plain and Interior Highland regions.
The general horizontal groundwater flow is from north to south (CH2M Hill
1984a). Two groundwater divides are evident on site with one running from the
northeast boundary of the site along the east side, across the plant and then
due south. The second divide runs from the northwest along the western edge
of the cooling pond and south along Rocky Branch. The contaminated water
cable flows toward the cooling pond and the Rocky Branch Creek at a rate of
<1 to 10 in/yr (CH2M Hill 1984a). The vertical groundwater flow rates in
bedrock were calculated to range from 2 x 10 in/yr to 6.0 in/yr (CH2M Hill
1984a) which indicates potential downward migration of contaminants. Little
2-2
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£ife Systems, J
is known about the hydrogeology of bedrock deposits at the Vertac site and the
structure of bedrock has not been evaluated.
The Rocky Branch Creek received groundwater inflows from the water table from
both the east and west. These flows have passed under or through the
Reasor-Hill area. Contaminants entering the groundwater east of the divide
may eventually enter the Coastal Plain aquifers (off-site) (CH2M Hill 1984a).
The recharge and inflow upgradient of contaminant sources flows toward western
surface water bodies and are conveyed off-site above ground or in the water
table.
2.1.4 Climatology
Precipitation is fairly well distributed throughout the year; however, May is
normally the wettest month. The annual precipitation averages about 48 in and
about 31% of total precipitation occurs from March through May. August
through October are the driest months with a total of 3 in of rain.
Winters are mild with average winter temperatures of 41 F and an average
annual snowfall of 5.7 in. The greatest monthly snowfall reported was 12 in
in January 1966. The summers are hot with an average daily temperature of
82 F and maximum temperatures of over 100 F occurring frequently in July and
August.
2.2 Environmental Fate and Transport of Dioxin
2.2.1 Environmental Fate •
2.2.1.1 Biodegradation
Dioxin is not readily biodegraded. Few microbial strains (5/100) capable of
degrading persistent pesticides could degrade dioxin slightly (USEPA 1980).
Dioxin is persistent in freshwater aquatic environments with a half-life of
550 to 590 days in sediment containing lake waters (Ward and Matsumura 1977).
The biodegradation half-life of dioxin was estimated to be greater than one
year based on theoretical biotransformation rate values and assumed concentra-
tions of microorganisms (USEPA 1984). The biodegradation half-life of 0.5 yr
for dioxin in soils was based on data from a rural Missouri incident involving
accidental spraying of dioxin contaminated oils (IARC 1977). Recent data
suggest that the half-life may be closer to -10 yr (USEPA 1984).
2.2.1.2 Photodegradation
Dioxin is in the presence of organic solvents (Crosby et al. 1971) or other
hydrogen donatprs is photodegraded (Crosby and Wong 1977). Insufficient
information is available on reactions of dioxin in aquatic media under environ-
mencai'conditions to predict the photodegradation half-life in natural waters.
However, photolysis is expected to be an important fate process when hydrogen
donating substrates are present (USEPA 1984). Assessment of photodegradation
in natural waters is complicated by the tendency for dioxin to be strongly
2-3
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Ofc Systems, Jnc.
adsorbed on particles in sediments that are not exposed to ultraviolet (UV)
light.
Information on photodegradation of airborne dioxin adsorbed on particulates is
conflicting. The importance of photodegradation relative to deposition (dry
or wet) in the fate of airborne dioxin is uncertain but may be important.
Dioxin sorbed to solid surfaces and exposed to the atmosphere yielded neglig-
ible photodegradation (Crosby et al. 1971), while photolysis was evident for
dioxin in a condensed phase on glass or silica.
The photodecomposition of dioxin on wet or dry soils under artificial and
natural sunlight (UV radiation) was observed to be negligible in soils (Crosby
et al. 1971). However, photodecomposition may occur when dioxin and other
pesticides (hydrogen donators) are present as a mixture in soils (Crosby and
Wong 1977).
2.2.1.3 Oxidation and Hydrolysis
No information on the oxidation of dioxin in aquatic systems was available but
its strong electropositive nature suggests it may be more resistant than
nonchlorinated or less chlorinated aromatics. The potential for oxidation of
dioxin (sorbed on airborne particulates) by atmospheric compounds (NO , 0_,
etc.) is unknown. Hydrolysis is unlikely to occur under environmental condi-
tions in aquatic systems (USEPA 1984).
2.2.1.4 Volatilization ' .__
•
Quantitative information on volatilization of dioxin from aquatic systems is
not available although several references have mentioned volatilization as a
possible loss process (Callahan et al. 1979). Matsumura et al. (1983) ob-
served that dioxin may undergo water-mediated evaporation in an aquatic
system. Based on theoretical models, the volatilization half-life was pre-
dicted, to be about 5.5 yr from a pond and 12 yr from a lake. The validity of
these estimates has not been assessed with experimental data. Volatilization
of dioxin adsorbed on soils is expected to be at a very slow rate due to the
extremely low'vapor pressure of dioxin (Falco and Schaum 1984).
2.2.1.5 Sorption
Sorption on particles (suspended or sediments) and in microorganisms appears
to be an important fate for dioxin in aqueous environments. Isenee and Jones
(1975) observed that 85% to 99% of dioxin remained adsorbed on sediments in an
aquatic system and the majority of dioxin not on sediments was in aquatic
organisms. Ward and Matsumura (1978) observed that more than 90% of dioxin in
aquatic medium remained bound to sediments. The low water solubility and high
octanol/water partition coefficient of dioxin support these observations.
The half-life of dioxin in soils has been reported to be 1 to 3 yr (Kearney et
al. 1972), about 330 days (dry conditions), 190 days (wet conditions) (U.S.
Air Forces study cited in USEPA 1984) and 10 yr (Young 1983).
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2.2.1.6 Bioaccumulation
Many aquatic species bioaccumulate dioxin. In a static experimental test
chamber, the accumulation appeared to be dependent upon initial dioxin con-
centrations. The bioconcentration factors (determined experimentally in a
static system) vary with species and may range from about 2,000 (algae or
snail) to 9,000 (catfish) to 26,000 (mosquitofish) (Isenee and Jones 1975,
Isenee 1978).
Schaum and'Falco (1982) derived a fish-sediment distribution coefficient (Kps)
to reflect bioaccumulation of dioxin in fish and enable calculation of
potential concentrations in fish from sediment concentrations. Coefficients
were derived on the basis of actual monitoring data and on the basis of
biota-water and organic matter-water distribution equations from published
literature. 'Limited data on dioxin concentrations in fish (810 ppt in a bass)
and in sediments (150 ppt) in Lake Dupree were used to calculate the
distribution coefficient as follows:
810
*
TS 150 ppt <
This KS value probably underestimates the K. in the .catfish population
inhabiting the Bayou, since catfish and other benthic feeders tend to bioac-
cumulate dioxin to a greater extent than nonbenthic feeders. The alternative
KF of 550 was calculated based on an assumed organic carbon content (0.5%) in
accordance with the relationships defined by Perwak et al. (1980) and Hamaker
(1978). The discrepancy .between the K values based on monitoring data (5.4)
and that derived from biota-water and organic matter-water distribution
relationships (550) may be explained by uncertainty in actual organic content
of sediments, species differences, insufficient residence time for fish or
dioxin to reach equilibrium, or non-equilibrium due to dynamic flow conditions
in the Bayou. Thus, the uncertainty regarding the K__ coefficient adds great
uncertainty to estimates of human exposure levels.
2.2.2 Environmental Transport
Schaum and Falco (1982) calculated the dioxin load to Bayou Meto based on an
environmental transport model. The estimated mean sediment yield rate for the
upper Bayou Meto water shed of 0.63/yr/acre was assumed to be constant throughout
the watershed and applicable to the Rocky Branch Creek. The assumption was
considered valid because factors (rainfall,- slope steepness, cover, etc.)
affecting erosion appear roughly the same throughout the area. The trapping
efficiency of the cooling pond was calculated to range from 0.46 to 0.71.
Minimum and maximum sediment loads of 550 tons/yr and 620 tons/yr were calcu-
lated. Using the 500 ppt dioxin concentration of sediments near the mouth of
Rocky Branch Creek, the minimum and maximum dioxin loads to Bayou Meto were
calculated co be 2.7 x 10~7 and 3.1 x 10 tons/yr. Nonpoint source pollution
data and U.S. Geological Service (USGS) data on the Arkansas River basin
sediment loads were used were used to calculate dioxin concentrations at seven
different points along Bayou Meto. Calculations assumed steady-state sediment
movement since data on the variability of sediment storage and removal rates
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in the bayou were unavailable. The uncertainty associated with variations in
sediment storage/removal rates were considered insignificant relative to
uncertainties associated with the fish-sediment distribution coefficient.
Kearney et al. (1973) examined the mobility of dioxin in five soil types and
observed that decreased mobility was associated with increased organic content
of soils. Dioxin was relatively immobile in all test soils and Kearney et al.
(1973) concluded that leaching to underground water supplies would be unlikely.
Matsumura and Benezet (1973) postulated that dioxin transport would be via
horizontal transfer of contaminated soils and dust particles. Dioxin does not
readily migrate vertically in soils (USEPA 1984). Nash and Beall (1980)
observed that 80% of dioxin applied to soils in a microagroecosystem remained
in the upper 2 cm of soils and that only trace amounts were detected at 8 to
15 cm. The NRCC (1981) suggested that vertical migration of dioxin may result
when the sorption capacity of soils are saturated or as a result of biotic
mixing (i.e., action of earthworms or other soil invertebrates). Dioxin
solvated by organic solvents may be mo.re readily transported through soils to
the groundwater.
Wet and dry deposition of particulate-bound dioxins appear to be an important
fate-determining process in the transport of airborne dioxins.•
2.3 -Contaminant Movement On Site and Off Site
The summary of the Vertac site history indicates that contaminants (dioxin and
others) were discharged in untreated wastewaters and process wastes, trans-
ported and released to the Rocky Branch Creek possibly as early.as 1955
(JRB 1983). Dioxin and other contaminants were also released by seepage from
underground burial areas and by erosion of contaminated surface soils.
Contaminants from the Hercules-Transvaal Landfill have migrated to the process
/ cooling pond. The central drainage ditch and surface runoff also transported
dioxin to the cooling pond. Contaminants that leaked into the cooling pond
and/or settled there probably flowed into the Rocky Branch Creek since the
pond is in its steam, course. Spills and/or valve ruptures of the trichloro-
phenol reactor in the "blow-out" area or other areas released dioxin which may
have percolated underground or have been transported via surface runoff to the
East Branch. Leachates from the equalization basin along the western edge
of the site also contributed to contamination of the Rocky Branch Creek.
Transport of dioxin to Dupree Lake probably occurred as a result of flooding
of the Rocky Branch Creek during periods of heavy spring ra.ins.
Implementation of remedial actions involving disturbance of Soils and vehi-
cular movement may have promoted contaminant transport particularly during
remediation of the equalization basin. The remedial actions implemented (clay
caps, barrier walls, French drain, etc.) may reduce the potential for further
contamination by preventing infiltration of surface precipitation, runoff and
wind erosion. There is some uncertainty about the vertical migration of
contaminants to groundwaters. Unexpectedly, "high" concentrations of dioxin
were detected in groundwater monitoring wells downgradient from the Hercules-
Transvaal Landfill area (JRB 1983) . There is potential for lateral subsurface
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movement in this landfill since no barrier walls have been installed. The
closure of the equalization basin appears to contain lateral leachate seeps
but the effectiveness over time is uncertain since the French drain and
barrier walls were constructed over weathered rock (with fissures). Installa-
tion of the above-grade neutralization wastewater treatment system and dis-
charge to the local wastewater treatment plant has reduced or eliminated the
potential for further release of process waste to the Rocky Branch Creek.
The proposed remedial action (Alternative IV) which involves excavation of
contaminated soils/materials and redisposal in a secure landfill on-site) will
disturb soils and create the potential release of contaminants as dust emis-
sions. The release and movement of contaminated dust may be reduced by
implementation of dust control measures. Falco and Schaum (1984) determined
that primary sources of dust emissions would result from vehicle travel over
contaminated soils, loading/unloading operations and spreading excavated soil
in the new on-site secure landfill. A front-end loader will be used to
excavate material and load it into dump trucks. Material will be transported
in the trucks on existing roadways where materials will be dumped and spread
with a bulldozer in the secure landfill on site. It is assumed that "clean-
dirt" will be applied to roadways between the excavation sites and the secure
landfill and covered trucks will be used to reduce contaminant releases. The
wind-only generated dust emissions were assumed to be negligible compared to
mechanically generated dusts occurring during truck travel, loading/unloading
and spreading operations. The estimated duration of the proposed excavation/
remedial actions and associated dust emissions is 190 days for the Reasor-Hill.
site and 380 days for the North Burial Area.
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3.0 EXPOSURE EVALUATION
This section will identify actual and potential routes of exposure, characterize
the populations exposed and determine extent, of the exposure to dioxin. The
results of exposure assessments for the proposed on-site remedial action and
for consumption of fish from off-site contamination of receiving waters are
summarized.
3.1 Routes of Exposure
Potential exposure routes are as follows:
1. Consumption of fish from the Bayou Meto and Rocky Branch Creek.
2. Consumption of groundwater downgradient of the Vertac site.
3. Inhalation of dust-contaminated with dioxin that may become airborne
due to implementation of remedial action Alternative IV.
4. Direct contact with waters, sediments or soils adjacent to the site
that have been contaminated by surface runoff or erosion processes.
Direct contact includes direct dermal exposures as well as direct
ingestion exposures (i.e. pica in children).
3.1.1 Fish Consumption
Environmental monitoring data indicate that the high concentrations of dioxin
are found in fish (<25 to 300 ppt) and sediments (500 ppt) of Bayou Meto
(Schaum and Falco 1982). Significant potential human health threats may
result from consumption of contaminated fish from Bayou Meto. Arkansas
officials have banned fishing on the Bayou Meto; however, the fishing ban is
not easily enforced (Falco 1982). Thus, there appears to be a real potential
for dioxin exposure. Schaum and Falco (1982) concluded that consumption of
dioxin contaminated fish represented the most important potential exposure
route and estimated the amount of dioxin bioaccumulating in fish at various
distances downstream from the site. This exposure assessment calculated
bioaccumulation in fish, estimated potential human consumption rates and
derived the resulting exposure levels.
Dioxin released from the site via transport on suspended solids in overland
runoff or sorbed to airborne dust is of particular concern. Dioxin-bearing
particles accumulate in sediments of receiving waters and bioaccumulate in
fish. Monitoring data indicate that 500 ppt of dioxin are present in the
Rocky Branch Creek sediments. Schaum and Falco (1982) have calculated the
dioxin load to Bayou Meto based on this concentration (500 ppt), modeled
sediment redistribution to Bayou Meto and applied the fish-sediment distri-
bution coefficient to calculate dioxin concentrations in fish.
* • *
3.1.2 Croundwater
Concentrations ranging from ND to 0.03 ppb (with a mean ± standard deviation
of 0.005 ± 0.010 ppb) of dioxin were detected in grour.dwater monitoring wells
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downgradient from the Hercules-Transvaal landfill area; however, no existing
domestic or industrial wells were reported to be located in areas that are
immediately downgradient from the Vertac site (JRB 1983, Schaum and Falco
1982). The exposure assessment by Schaum and Falco (1982) did not evaluate
human exposure via consumption of contaminated groundwater but noted that this
route may represent a long-terra threat and should be analyzed further.
Subsequent groundwater exposure assessments should consider dioxin and other
contaminants, that are both more mobile in the subsurface soils and more
soluble in water, to characterize the importance of this route.
3.1.3 Airborne Dust
Schaum and Falco (1982) recognized that dioxin would probably be present on
dust particles but would be unlikely to volatilize appreciably and be detected
as a vapor in ambient air offsite. This potential exposure route was not
•examined by Schaum and Falco (1982) since remedial actions implemented (clay
capping of disposal areas and covering the blow-out area) were expected to
diminish releases of dioxin-contaminated dust via wind erosion.
The potential for exposure to dioxin via inhalation of contaminated dust is
increased by the proposed remedial action (Alternative IV). Falco and Schaum
(1982) assessed the exposure potential associated with remedial actions that
disturb the soil and create potential dust emissions.
3.1.4 Direct Contact with Contaminated Soils/Sediment
Dioxin in contaminated soils may be adsorbed across the skin. The concentra-
tion in soils and type of soils are expected to affect dermal adsorption. The
direct contact with contaminated soils is dependent upon the degree of outdoor
activities such as gardening or playing. The degree of dermal exposure
depends upon the amount of skin exposure, duration of contact and soil condi-
tions.
/
Exposure due to direct ingestion depends on age with children aged two to six
years having the greatest exposure potential. Seasonal variation in weather,
soil conditions and activity patterns affect the amount of exposure via direct
ingestion of contaminated soils/sediments.
3.2 Populations Exposed
3.2.1 Fish Consumption
Populations with high fish consumption from affected water bodies are at an
increased risk of dioxin exposure. Schaum and Falco (1982) stated that the
number of people exposed to dioxin via consumption of fish caught from Bayou
Meto cannot be estimated precisely. Exposure via consumption of fish should
not be occurring since there is a fishing ban for Che Bayou Meto; however,
there is evidence that the ban is not easily enforced. Schaum and Falco
(1982) estimated the number of people potentially exposed if such a ban was
not in effect. The predicted fish catch from the Bayou Meto was divided by an
estimate of the individual's consumption rate to estimate the size of
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population exposed. Both the fish catch and consumption rates were difficult
to assess accurately. The national average consumption of nonmarine fish (5.2
Ib/yr) was used in the calculations; however, fish consumption rates may vary
by up to threefold between the average and the 95th percentile. The consump-
tion rate of fish from the Bayou Meto (only) is probably less than the amount
predicted since the 5.2 Ib/yr statistic represents the individual's total
consumption which is likely to reflect fish caught from many sources. The
mean catch rate (62 Ib/acre/yr) was based on the rate from an off-stream
reservoir which may differ from that in the Bayou Meto. The total catch
(160,000 Ib/yr) was estimated by multiplying the mean catch rate by the river
surface area (2,600 acres based on an assumed mean width of 150 ft and length
of 144 mi). Schaum and Falco (1982) illustrate how the exposed population
size may vary according to assumptions made regarding the consumption and
catch rates (see Table 3-1).
Assuming that most fish from Bayou Meto are likely to be consumed by local
residents, Schaum and Falco (1982) concluded that the number of exposed people
is probably less than the local population. Approximately 476,000 people are
in counties, that are at least partially drained by Bayou Meto according to
census data.
3.2.2 Groundwater
Walton et al. (1982) states that no domestic or industrial water wells were
located in areas that are immediately downgradient from the Vertac site.
Contacts with state and local permitting agencies identified only two domestic
wells within the .vicinity of the site (Walton et al. 1982).
One well (50 ft deep) was 1.5 mi west of Vertac and the other well (15 ft
deep) was about 1.5 mi southeast of the site. Data on the size (if any) of
the population utilizing these wells or consuming groundwater from other
sources contaminated by the site was unavailable. There are insufficient data
on groundwater contamination and off-site flows to determine when the plume
may reach these wells and the expected concentrations.
3.2.3 Airborne Dust
The population at greatest risk to exposure to dioxin via airborne dust would
be workers/observers on-site during the proposed remedial action .if an ade-
quate personal protection program was not implemented. It is assumed that an
adequate personal protection program will be required under the Remedial
Action Plan to eliminate or substantially reduce potential exposures to
on-site personnel.
Insufficient data on prevailing wind direction, wind speed and geographical
features affecting wind patterns are available to determine which populations
are at an increased exposure potential for airborne dust'. Residents of the
subdivision to the south of the site are the nearest potentially exposed
off-site population (Falco and Schaum 1984). The proximity of this population
to the site is assumed to subject this population to an increased risk of
exposure to dioxin since airborne dust concentrations are expected to be
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TABLE 3-1 ESTIMATES OF POPULATION SIZE EXPOSED AND
EFFECTS OF ASSUMPTIONS REGARDING FISH
CONSUMPTION RATE AND FISH CATCH RATE
Consumption Rate,
Ib/individual/year
2.5
5.2
7.5
10.0
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greatest near the site and to decrease with increasing distance from the site.
People that stay at home during the daytime and especially those that are
frequently outside for long periods are expected to have higher exposures.
This group may include young children, nonworking parents and the elderly. It
is assumed that dioxin-contaminated dust concentrations will tend to be higher
outdoors relative to inside a house. No quantitative information on the
number of residents near the site and specific behavior patterns is available.
3.2.4 Direct Contact
No quantitative data are available on the size of the population potentially
exposed to dioxin via direct contact with contaminated soils or sediments
on-site or off-site. The fence around the facility limits accessibility and
reduces potential accidental direct contact exposures on-site. Detection
of dioxin in surface soils in the subdivision south of Vertac (Braden Street,
West Lane and Alta Cove) (CH2M Hill 1984) suggests that residents may be at
risk for dioxin exposure. People who garden and play outdoors are expected to
be at higher risk for direct contact exposures. Since the highest
concentrations of dioxin off-site are found in sediments of the Rocky Branch
Creek, it is anticipated that people who swim, wade .or play in and around the
creek may be at increased risk. Likewise, people who use Lake Dupree for
recreational activities may have increased exposure.
3.3 Extent of Exposure
3.3.1 -Fish Consumption
No estimates of actual fish consumption based on local surveys of the Rocky
Branch Creek and Bayou Meto are available. Schaum and Falco (1982) estimated
that the annual human exposures to dioxin from consumption of contaminated
fish could range from 110 ng/kg of body weight (bw) for fish caught near the
confluence of Bayou Meto and the Rocky Branch Creek to as low as 0.09 ng/kg/bw
for fish caught from Bayou Meto (mouth). Table 3-2 identifies ranges of
predicted dioxin exposures from consuming fish caught at various points along
the Bayou Meto as presented by Schaum and Falco (1982). The concentration of
dioxin in sediment (C ) was calculated by dividing dioxin load by total
sediment load. The range of values reflects the assumed range of trapping
efficiencies (0.41 to 0.71). The concentration of dioxin in fish was cal-
culated by multiplying C by the sediment fish distribution coefficient
(assumed range of 5.4 toS550). The calculated human exposure assumes a 70-kg
human consumes 5.2 Ib (6.5 g/day) of fish per year. Estimates of human
exposure based on the available monitoring data are in agreement with pre-
dictions based on the environmental transport model. There is much uncer-
tainty associated with the predicted exposures. Factors previously discussed
(such as utilization of an estimated dioxin sediment load, fish-sediment
distribution coefficients, unavailability of actual fish consumption rates,
etc.) contribute to the uncertainty. This uncertainty is compounded by the
fact that fishing on Bayou Meto is currently banned.
The Schaum and Falco (1982) exposure assessment provides a means to bound the
possible range of exposure but the limited data are not sufficient to produce
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TABLE 3-2 DIOXIN CONCENTRATION IN SEDIMENT, DIOXIN CONCENTRATION
IN FISH, AND HUMAN EXPOSURE BY RIVER MILE
Concentration of
Dioxin In Sediment (C ppt)
u>
i
River .
Mileta)
132
100
75
54
34
16
0
Based on
Calculations
5.2-6.0
3.1-3.5
2.6-3.0
0.83-0,94
0.71-0.80
0.62-0.70
0.49-0.56
Based on ^
Monitoring ( }
500
<70
<85
<80
<30
<2?c)
NA^ '
Concentration of
Dioxin in Fish (C,, ppt)
Based on
Calculations
28-3,300
17-1,900
14-1,600
4.5-520
3.8-440
3.3-390
2.6-310
Based on
Monitoring
300
112
30
<30
<25
<25
NA
(b)
Estimated
Human Exposure, ng/kg/yr
Based on Based on
Calculations Monitoring
0.96-110
0.56-65
0.48-56
0.15-18
0.13-15
0.11-13
0.09-10
10.1
3.79
1.0
NA
NA
NA
NA
(a) River mile defined as the number of miles upstream from the mouth of Bayou Meto.
(b) All C_ and C monitoring data were gathered by Arkansas Department of Pollution Control and Ecology
in 1981.
(c) NA = No data available.
Adapted froiu Schaum and Falco (1982).
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a statistically valid estimate of the error range. The predicted exposure
values are based on very limited data and much more extensive data are
required to precisely define the magnitude and extent of dioxin exposure via
contaminated fish consumption.
3.3.2 Groundwater
The extent of dioxin exposure via groundwater has not been determined. Due to
the apparent lack of water wells and the low solubility of dioxin in water, it
is expected that exposure potential will be minimal. Using the highest
reported concentration of 0.03 ppb dioxin in groundwater on-site (CH2M Hil]
1984a) and assuming a 70-kg adult would consume two liters of water per day, a
maximum potential exposure could be calculated as follows:
2 = °-°009
(70-kg)
This is a worst case scenario. Insufficient data on groundwater flows,
dilution ra-tes and the extent of contamination are available to calculate
reasonable conservative exposure estimates. Using the mean concentration of
dioxin detected in wells (0.005 ppb) and the above equation, the exposure may
be estimated as OiOOOl yg/kg/day. Recent monitoring data have not detected
dioxin in any wells on-site and therefore suggest that exposure levels may be
less.
In addition, -actual exposure at _this -level is unlikely since Walton et al.
(1982) and CH2M Hill (1984a) state that data indicate that no existing wells
are located within two miles of the site and there is no contamination in any
wells beyond two miles. Future contamination or installation of new drinking
water wells downgradient of the site may increase the potential and magnitude
of exposures .
3.3.3 Airborne Dust
Falco and Schaum (1984) assessed potential exposures to dioxin via inhalation
of dust^emissions associated with the proposed remedial action (Alternative
IV) . The two phased remedial action involves excavation initially, at Reasor-
Hill Landfill (Phase 1) and finally at the North Burial area (Phase 2). The
exposure assessment predicted possible off-site emission rates, used disper-
sion models to determine resulting off -site air concentrations of dioxin and
calculated inhalation exposures. The range of exposure estimates is due to
the uncertainty in the concentration of dioxin in the material (soil) to be
excavated (assumed to range from 0.1 to 14 ppm) . Exposure estimates assume
that no dust control measures are implemented during remediation.
Falco and Schaum (1984) used standard equations to predict dust emissions
resulting from vehicular travel, loading/unloading and spreading operations.
Assumptions regarding the silt content of soils, soil moisture content,
particulate size, number of precipitation days, average wind speed and vehicle
characteristicsqwere required. ? The predicted emission rates for dioxin ranged
from 1.55 x 10 to 2.17 x 10 g/sec for Phase 1 and from 2.3 x 10~ to 3.8 x
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JO for Phase 2. The ambient air concentrations of dioxin were calculated
with the method developed by Cowherd et al. (1984) for specific ground-level
area sources of particulate emissions. Implementation of the model relied on
assumptions of comparability between meteorological conditions at the Vertac
site and conditions used to develop the model and comparability between size
of the source in the model and the size of the source at Vertac. Falco and
Schaum (1984) determined the average air concentrations and plotted isopleths
for the site. The average lifetime exposure levels (via inhalation) were
calculated for each dioxin-concentration isopleth based on assumed respiration
rate, exposure duration, body weight and lifetime expectancy. This assessment
also assumed that all inhaled dioxin-particulate inhaled into the body is
retained and absorbed. Since the exposure concentrations reflect respirable
dust-sized particulates (<10 u), virtually all inhaled particulates will be
retained by the lung. Figure 3-1 illustrates isopleths for the combined phase
exposure levels for the area outside the site's southern boundary where the
nearest residents are located.
3.3.4 Direct Contact
No quantitative estimates of the extent of dioxin exposure via direct contact
are available. Future exposure assessments should address specific subpopu-
lations suspected of having increased exposures due to their behavior or
activities. For example, children playing in contaminated soils or sediments
of adjacent waterways are. probably exposed to dioxin via direct dermal contact
or ingestion. People who garden in residential areas with dioxin-contaminaced
soils also have increased exposure potential via direct contact. The lack of
information on the dermal absorption, amount of direct soil contact, dioxin
content of soils/sediments, quantity of soil directly ingested and other
factors currently preclude performance of quantitative exposure estimates.
Direct contact is an important route that should be addressed in future
exposure assessments. The Kimbrough et al. (1977) report on toxicity in six
children dermally exposed to dioxin-contaminated soils in horse-arenas in
eastern Missouri confirms the potential significance of this route.
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(Crow 1978, Passi et al. 1981). Most of the documented acute exposures to
dioxin have been the result of chemical industry accidents involving 2,4,5-T,
which is contaminated with dioxin.
The first cases of chloracne associated with exposure to dioxins occurred
following an explosion in a chemical plant producing 2,4,5-T in 1949 (Holm-
stedt 1980). Zack and Suskind (1980) reported nausea, headaches, fatigue,
muscular aches and pains, and chloracne as the frequent complaints among the
228 workers exposed. Chemical tests revealed elevated lipid levels and
prolonged prothrombin times. Residual chloracne, peripheral neuropathy,
fatigue and severe aches and pains persisted for up to two years. Other
reports of adverse effects in humans following acute exposure to. dioxin as a
result of industrial accidents are provided by Holmestedt (1980), May (1973,
Gianotti (1977), Garattini (1982), Taylor (1979) and Crow (1981).
The Lombardy Regional Authority has compiled extensive data regarding the
health effects of dioxin on children and adults following accidental releases
of the chemical from a plant in Seveso, Italy (Pochiari et al. 1979). Reduced
peripheral nerve conduction velocities occurred in both adults and children,
with a correlation between the incidence and the distance from the plant.
Total serum complement activity, lymphocyte blastogenic response and
peripheral blood lymphocytes were elevated in children exposed in the accident
(Tognoni and Bonaccorsi 1982). The limited number of studies regarding the
immunological effects of dioxin in adults have not revealed any reduction in
immunocapability (May 1982).
Caramaschi et al. (1981) reported an increase in the frequency of headaches,
eye irritation, gastrointestinal tract symptoms and abnormal g-GT, serum GPT
and aminolevulinic acid levels in children living in the Seveso area who
developed chloracne. Increased urinary glucaric acid levels, indicative of
increased microsomal enzyme activity, were found in children three years after
the accident (Ideo et al. 1982).
Six children dermally exposed to dioxin-contaminated soil (30 ppm, 30 mg/kg
soil) in horse-arenas in eastern Missouri developed headaches, skin lesions
and polyarthralgia (pain in joints) (Kimbrough et al. 1977). In the most
severe case, epistaxis (nosebleeds) and lethargy were reported.
Numbness of the extremities, skin rashes and irritation, liver dysfunction,
weakness, loss of sex drive and psychological changes have been associated
with exposure to 2,3,7,8-TCDD and other dioxins, which occur as contaminants
in Agent Orange, in veterans and residents of Vietnam. The relationship
between exposure to dioxin and the development of these symptoms is unknown
(Holden 1979, Bogen 1979).
4.2.2 Toxicity in Laboratory Animals
McConnell et al. (1978 a,b) observed that dioxin induced mortality in a
variety of laboratory animals (rat, guinea pig, mouse, rabbit, monkey) at dose
(LD 0) levels between 0.6 ug/kg and 283.7 ug/kg following oral administration.
The dermal LD value in rabbits was 270 Ug/kg (Schwetz et al. 1973).
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A summary of studies providing data on the sub-lethal effects of acute expo-
sure to TCDD is presented in Table 4-1. The effects were reported to occur
following single exposures ranging from 0.1 to 300 yg/kg in four animal
species (rat, guinea pig, chicken, mouse). Liver damage is the most consis-
tently reported effect in most species. Rats receiving a single dose of
100 yg/kg of TCDD showed severe liver damage, thyraic atrophy and jaundice
(Gupta et al. 1973). In the same study, thymic and liver damage of lesser
severity occurred at lower dose levels (25 and 50 yg/kg). In another study
(Greig et al. 1973), rats exposed to TCDD (300 yg/kg) exhibited jaundice,
multinucleated parenchymal cells of the liver and gastric hemorrhage. Histo-
pathologic liver changes were 'observed five weeks after single oral doses of
TCDD as low as 50 yg/kg were administered to male and female CD rats, and one
week after a single dose of 50 yg/kg was administered to female CD-I mice
(Harris et al. 1973). Increased liver weights were found in male Wistar rats
seven days after single intraperitoneal doses of 0.1 yg/kg (Cunningham and
Williams 1972).
4.2.3 Toxici'ty in Aquatic Species
The USEPA (1984) summarizes the available information on the acute toxicity of
dioxin to aquatic organisms. The 96-hr lethal concentrations (LC5n) reported
by Miller et al. (1973) and Norris and Miller (1974) were >0.2 yg7L for.
Paranais sp. (worm), Physa sp. (snail) and Aedes aegypti (mosquito larvae),
>1 yg/L for Oncorhychus kisutch (coho salmon), >10 yg/L for Poecilia reticulata
(guppy) and >0.24 yg/L for.Ictalurus punctatus (fingerling channel catfish).
Helder (1980, 1981 and 1982) observed that the LC5Q is >0.01 yg/L for Esox
lucius (northern pike embryos) and Salmo gairdneri (rainbow trout yolk-sac
fry) and >0.1 yg/L for the juvenile rainbow trout.
4.3 Subchronic and Chronic Toxicity
4.3.1 Toxicity in Humans
Several epidemiologic studies and case reports involving dioxin exposure in
human subjects have been reported (Esposito et al. 1980). Effects observed
include skin lesions (chloracne, prophyria cutanea tarda), liver function
impairment and neurological disorders "(polyneuropathy, peripheral nerve
damage). An International Agency for Research on Cancer (IARC 1982) evalua-
tion of human exposure data concluded that these studies are inadequate since
they involve multiple chemical exposures.
4.3.2 Toxicity in Laboratory Animals
Longer exposures to dioxin caused effects similar to those reported following
acute exposure including thymic atrophy, liver damage, renal function impair-
ment, hematological effects, hormonal alterations, immunosuppression, nervous-
ness and irritability. Chronic'and subchronic.. studies in many different
strains of laboratory mice and rats indicate that the liver is the primary
organ affected by long-term exposure (Kociba et al. 1973, 1979, NTP 1980a). A
summary of major studies providing dose-response effects is presented in
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TABLE 4-1 EFFECTS OF DIOXIN IN ANIMALS FOLLOWING ACUTE EXPOSURE
-e-
Species
Rat
Guinea Pig
Rat
Chicken
Rat *
Rat
Rat
Mouse
Rat
Rat
Dose (tJg/kg) Route
25, 50 or 100
100
3.0
300
25 - 50
10 Oral
0.1 i.p.
50 , Oral
50 Oral
10
10, 25, or 50
Effects
Reference
Liver damage, thymic atrophy
Jaundice, 43% mortality
Hemorrhage, adrenal atrophy,
cellular depletion of lymphoid
organs, 90% mortality
Weight loss, gastric hemorrhage,
liver damage (cellular changes),
jaundice
Pericardial edema,
Hematologic effects
Increased liver weights
Liver damage
Liver damage
Decreased renal function
Decreased renal function
Gupta .et al. (1973)
Gupta et al. (1973)
Greig et al. (1973)
Greig et al. (1973)
Weissburg and Zinkl (1973)
Cunningham and Williams (1972)
Harris et al. (1973)
Harris et al. (1973)
Anaizi and Cohen (1978)
Hook et al. (1978)
Adapted from NAS (1977), NTP (1982 a,b) and Esposito et al. (1980).
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Table 4-2. Studies providing dose-response data indicating the greatest
sensitivity to dioxin are described below.
Doses as low as 0.1 yg/kg/day caused a slight degree of liver degeneration in
rats in a subchronic 13-wk (5 doses per week) study (Kociba et al. 1976).
Dose levels of 1.0 yg/kg/day increased levels of serum bilirubin and alkaline
phosphatase and caused pathologic changes in the livers of rats. A no-
observed-adverse-effect level (NOAEL) of 0.01 yg/kg dioxin was reported for
noncarcinogenic effects in rats.
Increased mortality was observed in female Sprague-Dawley rats maintained for
two years on a diet that provided a dioxin dose of 0.1 yg/kg/day, while no
increased mortality was observed in male rats at this dose or in animals
receiving doses of 0.01 or 0.001 yg/kg/day (Kociba et al. 1978, 1979). At
termination of the study, gross and histologic examination indicated that the
liver was the most severely affected organ, with degenerative, necrotic and
inflammatory changes observed. Increases in urinary excretion rates of the
metabolites, coproporphyrin and uroporphyrin, in the high and middle dose
females were consistent with the observed liver damage. Primary liver injury
was dose-related with the lowest dose representing a NOAEL (noncarcinogenic).
When dioxin was administered by gavage (by stomach tube) in corn oil-acetone
(9:1) at dose levels of 0, 0.01, 0.05 or 0.5 yg/kg/wk (0.0, 0.001, 0.007 and
0.07 lag/kg/day), toxic hepatitis was observed in male Osborne-Mendel rats at
incidences of none out of Ik tested (0/74), 1/50, 0/50 and 14/50 and in female
rats at incidents nf 0/75, 0/5CU-..1/50. and 32/4~9(NTP 1980a) . Other non-
neoplastic lesions were not observed, even though extensive histologic examina-
tions were performed. The two preceding studies support a NOAEL for noncar-
cinogenic effects in rats of sO.001 yg/kg/day and a lowest-observed-adverse-
effect level (LOAEL) of 0.05 yg/kg/day.
Non-neoplastic effects of chronic dioxin exposures were described in studies
investigating the carcinogenic potential of dioxin in mice. In a National
Toxicology Program (NTP 1980a) bioassay, histologic examinations were per-
formed on B6C3F1 mice treated biweekly with dioxin by gavage in corn oil-
acetone (9:1) for 104 wk followed by an additional 3-wk observation period.
The doses for male animals were 0.0, 0.01, 0.05 and 0.5 yg/kg/wk, and for
female animals, 0.0, 0.04, 0.2 and 2.0 yg/kg/wk. The only non-neoplastic
adverse effect observed was toxic hepatitis, which occurred in males at
incidences of 0/73, 5/49, 3/49 and 44/50, and in females at incidences of
0/73, 1/50, 2/48 and 34/47, respectively, in the control, low, medium and high
dose groups. In another study, weekly administration of dioxin by gavage at
doses of 0.0, 0.007, 0.7 or 7.0 yg/kg/wk for one year resulted in amyloidosis
(disposition of amyloid, a complex proteinaceous material) of the kidney,
spleen and liver, and dermatitis at the time of death in male Swiss mice (Toth
et al. 1978, 1979). The incidences of these effects in the control, low,
medium and high dose groups, respectively, were 0/38, 5/44, iO/44 and 17/43.
In the high dose group, the amyloidosis was extensive and considered to be the
cause of early mortality. Severe toxic effects were observed at doses of
1 yg/kg/day (early mortality) and 0.28 to 0.07 yg/kg/day (toxic hepatitis),
while a LOAEL for dermatitis and amyloidosis of 0.001 yg/kg/day was reported.
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TABLE 4-2 NOAEL AND LOAEL VALUES OBTAINED FROM SUBCHRONIC AND CHRONIC ORAL
TOXICITY STUDIES OF DIOXIN
Species
Rat:
Rat
Rat:
Rat
Mouse
Monkey
Rat
Rat
Mouse
Duration
of Exposure
13 wk
13 wk
16 wk
28 wk
13 wk
36 wk
104 wk
104 wk
104 wk
Endpoints
Decreased body weight,
liver pathology
Toxic hepatitis
Elevated porphyrin
levels
i
NOAEL
ug/kg/day
0.01
0.07
0.0014
Fatty changes in the ND
liver, decreased body
weight
t
Toxic hepatitis ND
Pancytopenia ND
Degenerative and necrotic 0.001
changes in the liver
Toxic hepatitis 0.0014
Dermatitis and amyloldosis ND
LOAEL
ug/kg/day
0.1
0.14
0.014
0.014
0.014
2
0.01
0.007
0.001
Reference
Kociba et al
NTP (1980a)
Goldstein et
. (1976)
al. (1982)
King and Roesler (1974)
NTP (1980a)
Allen et al.
Kociba et al
NTP (1980a)
NTP (1980a)
(1977)
. (1978, 1979)
(a) ND = Not determined.
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4.3.3 Toxicity in Aquatic Species
No standard chronic toxicity assays of dioxin in aquatic species were located
in the available literature (USEPA 1984) but several studies provide informa-
tion indicative of chronic toxicity values. In a static bioassay, Miller
et al. (1973) indicated that 0.2 yg/L may cause chronic toxicity in Paranais
sp. (worm). Based on the 55% mortality in coho salmon within 60 days follow-
ing acute (96-hr) exposures to 0.0056 yg/L (Miller et al. 1979), the USEPA
(1984) suggests that 0.0056 yg/L may cause chronic toxicity coho salmon.
Similarly the USEPA.(1984) concludes that chronic toxicity values such as
0.001 yg/L (rainbow trout) and 0.01 yg/L (northern pike, coho salmon, mosquite
fish and channel catfish) can be inferred based on results of acute assays by
Helder (1980, 1981, 1982), Yockim et al. (1978) and Branson et al. (1983). A
concentration of 1;3 yg/L may not cause chronic toxicity in Daphnia magna or
Physa (USEPA 1984).
Limited data are available on the toxicity of dioxin to aquatic plants.
Isensee and Jones (1975) and Isensee (1978) observed no adverse effects in
algae (Oedogoriium cardiacum) or duckweek (Lemna minor) exposed to 1.3 yg/L and
0.71 yg/L (respectively) for 30 days. Yockim et al. (1978) has also observed
no adverse effects on £._ cardiacum exposed to 0.0024 to 0.0042 yg/L of dioxin
for 32 days.
4.4 Teratogenicity, Reproductive Effects and Fetotoxicity
4.4.1 Effects.of Humans —
Epidemiological studies have attempted to investigate health effects of dioxin
in humans by indirectly evaluating health effects in populations exposed to
2,4,5-T (which commonly contains dioxin as an impurity). A positive associa-
tion between 2,4,5-T exposures and increases in birth defects or abortions has
been reported in human populations in Oregon (USEPA 1979), New Zealand (Hanify
et al. 1981) and Australia (Field and Kerr 1979). A lack of any such associa-
tion has been reported in human populations in Arkansas (Nelson et al. 1979),
Hungary (Thomas 1980), New Zealand (Dept. of Health, New Zealand 1980, McQueen
et al. 1977) and Australia (Aldred 1978).
Thomas (1980) used an approach similar to that of Field and Kerr (1979) for
analyzing data from Hungary. One major difference, however, is that Thomas
(1980) compared the incidence of stillbirths, cleft lip, cleft palate, spina
bifida, anencephalus and cystic kidney disease in all of Hungary between 1976
and 1980 with 2,4,5-T use in all of Hungary in 1975. Because Hungary requires
compulsory notification of malformations diagnosed from birth to age one year;
because a relatively large percentage (55%) of the Hungarian population lives
in rural areas where 2,4,5-T exposure may be expected to be greatest; and
because annual use of 2,4,5-T in Hungary had risen from 46,000 kg in 1969 to
1,200,000 kg in 1975, Thomas (1980) considered Hungary to be "...probably che
best country in which to examine possible health effects of this herbicide."
In any event, all indices of birth defect rates decreased or remained stable
over the period of study.
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Epidemiologic studies to determine the reproductive effects in individuals
exposed to dioxin and 2,4,5-T following the accidental contamination of a
populated area around Seveso, Italy, have not been completed.
4.4.2 Effects in Laboratory Animals
Dioxin has been reported to be fetotoxic and teratogenic when administered
alone or in combination with other chemicals. Several studies have been
identified in the available literature based on dioxin exposure alone.
Effects observed were kidney anomalies, intestinal hemorrhage, general edema,
cleft palate and fetal death. Adverse effects on reproduction were also
reported.
Intestinal hemorrhage, general edema and a reduction in fetal weights were
reported in rats following the administration of 0.125 yg/kg/day in studies by
Sparschu et al. (1971). In the same studies, the number of fetuses was
reduced and fetal death increased at 0.5 yg/kg/day. No structural malforma-
tions were reported at 0.03 ug/kg/day. Courtney and Moore (1971) reported
cleft palate and kidney abnormalities in mice borne by dams administered
dioxin at doses of 1.0 yg/kg or 3.0 yg/kg. Similarly, kidney malformations
were reported by the same authors in offspring from rats which received
subcutaneous injections of 0.5 yg/kg/day on day 9, 10, or 13 and 14 of
gestation.
Murray et al. (1979) completed a three-generation reproduction study using
Sprague-Dawley rats fed dioxin-continuously in the diet (at levels of 0,
0.001, 0.01, and 0.1 yg/kg/day). . Significant decreases were observed in
fertility, litter size, gestation survival, postnatal survival, and postnatal
body weight for the 0.01 and 0.1 yg/kg groups. No apparent adverse effect on
reproduction was seen at the 0.001 yg/kg dose level.
Although Murray.et al. (1979) considered the lowest dose tested, 0.001 yg/kg,
to be a NOEL (noncarcinogenic), reevaluation of these data by Nisbet and
Paxton (1982) using different statistical methods indicated that there was a
reduction in the gestation index, decreased fetal weight, increased liver-
to-body weight ratio, and increased incidence of dilated renal pelvis at the
0.001 yg/kg dose. The reevaluation of data suggests that equivocal adverse
effects were seen at the lowest dose (0.001 yg/kg/day) and that, this dose
should, therefore, represent a LOAEL.
Schantz et al. (1979) found reductions in fertility and various other toxic
effects in rhesus monkeys fed 55 ppt dioxin in the diet for 20 mo. This
corresponds to a calculated daily dioxin dose of 0.0015 yg dioxin/kg/day.
These results suggest that monkeys may be somewhat more sensitive than rats,
since the effects in monkeys were more severe and not equivocal.
Luster et al. (1980) examined bone marrow, immunologic parameters, and host
susceptibility in B6C3F1 mice following pre- and postnatal exposure to TCDD.
Doses of 0, 1.0, 5.0 and 15.0 yg/kg bw of dioxin were given to dams on day 14
of gestation and to offspring on days 1, 7, and 14 following birth. Neonatal
body, liver, spleen, and thymus weights were decreased and bone marrow
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toxicity occurred In the 5.0 and 15.0 Ug/kg groups. Red blood cell counts,
hematocrits, and hemoglobin were decreased at the highest dose tested.
4.5 Mutagenicity
Studies on the mutagenicity of dioxin have produced conflicting results.
Dioxin reportedly produces mutagenic effects in various bacterial systems.
However, results were negative in tests employing other indicator test
systems, including cytogenetic (chromosome analysis) tests and dominant lethal
assays. Hussain et al. (1972) reported that dioxin (2 ug/mL) increased the
incidence of reverse mutations in Escherichia coli. Similarly, dioxin (dose
not specified) was reported to be mutagenic without metabolic activation in
Salmonella typhimurium test strain TA 1532. Green et al. (1977) gave 0.25,
0..5, 1.0, 2.0, or 4.0 Ug/kg of dioxin (dissolved in 1 part acetone: 9 parts
corn oil) by gavage to male and female Osborne-Mendel rats twice weekly for
13 wk and observed an increased incidence of chromosomal breaks in female rats
dosed with 4 ug/kg and in males dosed with 2 Ug/kg or 4 ug/kg.
Mutagenic effects (with or without metabolic activation) were not detected
when Geiger and Neal (1981) examined the mutagenicity of dioxin (up to
20 ug/plate) using the £. typhimurium test strains TA1535, TA100, TA1538,
TA98, and TA1537.
4.6 Carcinogenicity
4.6.1 Carcinogenicity in Humans . _-
•
Epidemiologic studies of industrial workers and herbicide applicators suggest
that dioxin may be a human carcinogen. However, since dioxin is usually a
contaminant of phenoxy acids and/or chlorophenols, human exposure is usually
to multiple chemicals. Therefore, the evidence for human carcinogenicity from
these studies is only suggestive due to the difficulty of evaluating the risk
of dioxin exposure in the presence of the confounding effects of the other
chemicals (USEPA 1984).
Observations of an unusual occurrence of relatively rare soft-tissue sarcomas
(STSs) were first made by Hardell (1977). Of some 87 patients seen from 1970
to 1976 at the Department of Oncology, University Hospital, Umea, Sweden,
seven individuals with soft-tissue sarcomas were identified. All seven had
had occupational exposure to phenoxy acids 10 to 20 yr earlier. The tumors
were two leiomyosarcomas;-one liposarcoma; one rhabdomyosarcoma; one myxofibro-
sarcoma; and .two additional sarcomas of which the histopathology was uncertain,
but one was probably a neurofibrosarcoma and the other a rhabdomyosarcoma.
The clustering of this rare tumor type among these patients prompted the
author to suggest that epidemiological studies be designed to determine if
exposure to phenoxy acids and their impurities (i.e., dioxins) are related to
the occurrence of STS.
A few occurrences of soft tissue sarcoma have also been reported among
chemical industry workers in the United States who were exposed to varying
levels of 2,4,5-chlorophenols with dioxin contaminants (Cook et al. 1980, Moes
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and Selikoff 1981). Honchar and Halperin (1981) reported that 3 of 105 deaths
among phenoxy acid workers reported by two chemical companies were from STS.
Zack and Suskind (1980) reported a STS death in a cohort study of workers
exposed to dioxin in a trichlorophe-nol process accident in West Virginia.
This tumor, a fibrous histiocytoma, was considered as a rare event.
In a cohort mortality study of 61 male employees of a trichlorophenol manu-
facturing area who exhibited chloracne following a 1964 exposure incident,
Cook et al. (1980) noted four deaths by the end of his study period, one of
which was due to a fibrosarcoma.
There are numerous other studies reported regarding STSs. For example, Smith
et al. (1982) conducted an initial case-control study of 102 males identified
from the New Zealand Cancer Registry as having STSs (ICD 171) between 1976 and
1980. For each case, three controls each with another form of cancer were
matched by age and year of registration. The selection of cancer controls
from the same registry was done to eliminate recall bias or interviewer bias
or both.
The distribution of tumor types differed considerably from the Hardell and
Eriksson et al. (1981) study to the Smith et al. (1982) study. Leiomyo-
sarcomas, malignant histocytomas, neurogenic sarcomas and myxosarcoma seem to
predominate in the Hardell and Eriksson (1981) study, whereas fibrosarcomas .
and.liposarcomas appear prominently.in the Smith et al. (1982) study.
Smith et al. (1983) conducted another case-control study of STSs in males that
were reported to the New Zealand Cancer Registry by Public Hospitals"between
1976 and 1980. Smith et al. (1983) remarked that it was surprising that he '
found no STS victim who had ever worked full-time in phenoxyacetic acid
herbicide spraying. Perhaps they have not yet been observed for a long enough
period. As was pointed out by the author, the findings do not support the
hypothesis that exposure to phenoxyacetic acid herbicides causes STS; however,
neither do they support a negative finding without better documentation
regarding actual exposure and time of actual exposure.
The Michigan Department of Public Health (1983) recently conducted an ecological
study of soft and connective tissue cancer mortality rates in Midland and
other selected Michigan counties. They found that mortality rates for this
cancer were 3,8 to 4.0 times the national average for the periods 1960 to 1969
and 1970 to 1978, respectively, for white females in Midland. These estimates
are based upon five deaths and seven deaths, respectively.- No excess risk was
reported among white males, however. The Michigan Department of Health
concluded that because of the occurrence of these two successive elevated
rates, it is unlikely to be a chance happening. At the same time the age-
adjusted male and female cancer mortality rates for Midland were below that of
the Scate of Michigan for the period 1970 to 1979. Midland County is the home
of a major chemical company that produced phenoxyacetic acid herbicides until
recently. The authors stated that a detailed review of death certificates,
hospital records, residency and occupational histories of the 20 male and
female cases revealed no "commonalities" suggesting a "single causative
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agent," although a majority of their spouses had worked at this chemical
facility. They recommended that a case-control study should be instituted to
evaluate possible influences, such as lifestyles, occupation or location of
residences, on the risk of STS.
4.6.2 Carcinogenicity in Laboratory Animals
The carcinogenic potential of dioxin has been studied extensively in labora-
tory animals. A summary of the results of selected comprehensive studies is
presented in Table 4-3. The results of these studies show that dioxin-exposed
animals exhibited malignant lesions involving multiple organ systems including
accessory digestive organs (liver), endocrine (thyroid, adrenal), renal,
reproductive (testes), and nasal structures. Representative studies are
described below.
Groups of ten male Sprague-Dawley rats were fed a diet containing dioxin for
78 wk at concentrations ranging from 1 ppt to 500 ppt or 1 ppb to 1,000 ppb
(Van Miller et al. (1977). These dietary levels represent approximate weekly
dose levels of 0.0003 to 0.1 yg/kg or 0.4 to 500 yg/kg. Animals exposed at
5 ppt, 50 ppt, 500 ppt or 5 ppb showed an overall incidence of neoplasms of
38% (23/60). No neoplasms were reported or observed following exposure to
1 ppt dioxin. In the 5 ppt group, 5/10 animals had six neoplasms (earduct
carcinoma, lymphocytic leukemia, adenocarcinoma, malignant histiocytoma (with
metastases), angiosarcoina and Leydig-cell adenoma). Neoplasms were also.
observed in the following groups: at 50 ppt, three in 3/10; at. 500 ppt,
four in 4Y10; at 1 ppb, five in 4/1.0; at 5 ppb, ten in 7/10. Neoplasms were
not observed in the controls. Rats administered dioxin at 50, 500 or 1,000 ppb
exhibited 100% mortality by the fourth week.
In another study (Kociba et al. 1978), groups of 100 Sprague-Dawley rats
(50 males and 50 females) received diets containing dioxin at 0, 22, 210, or
2,220 ppt (equivalent to a daily dose of 0.0, 0.001, 0.01 and 0.1 yg/kg bw)
for two years. Administration of 0.01 yg/kg/day increased the incidence of
hepatocellular hyperplastic nodules (female: 18/50 versus 8/86 controls) and
focal alveolar hyperplasia in the lungs (P<0.05). Dietary intake of
0.1 yg/kg/day increased the incidence of hepatocellular carcinomas (female:
11/49 versus 1/86) and squamous cell carcinomas of the lung (female: 7/49
versus 0/86), hard palate/nasal turbinates (male: 4/50 versus 0/85; female:
4/49 versus 0/86), and tongue (male: 3/50 versus 0/85) (P<0.05). Also in-
creased in frequency by the 0.1 yg TCDD/kg/day were adenoma of the adrenal
cortex (male) and hepatocellular hyperplastic nodules (female).
The NTP (1982a) conducted a study for 104 wk using Osborne-Mendel rats and
B6C3F1 mice. The rats and male mice were administered TCDD at 0, 0.01, 0.05
or 0.5 yg/kg/wk by gavage in two divided doses, and the female mice were given
0, 0.04, 0.2, or 2.0 yg/kg/wk. Incidences of follicular cell thyroid adenomas
in male rats (F<0.001) and of neoplastic nodules in livers of female rats
(P=0.006) increased significantly. Dioxin increased the numbers of hepato-
cellular carcinomas in male mice (P=0.002) and in females (P=0.014). The
total liver tumors (carcinomas and adenomas) were increased in males (P<0.001)
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TABLE 4-3 SUMMARY OF CARCINOGENIC EFFECTS OF DIOXIN
Species/Sex
(Number)
Rat/
M (50)
I- (50)
Dose
Rat/M (10) 1 ppt
Rat/M (10) 5-500 ppt
Rac/M (10) 1-5 ppb
0.001 pg/kg
0.01 Kg/kg
0.1 Mg/kg
Duration Route
78 wk
2 yr
Effects
Reference
Diet No neoplasm.
Van Miller et al.
(1977)
Ear duct carcinoma, benign tumor
of the kidney and testes,
lymphocytic leukemia, skin
carcinomas and benign muscle
tumors.
Cholangiocarcinoma of liver,
squamous cell tumor of lung,
angiosarcoma in skin, glioblas-
toma in brain, malignant histio-
cytomas in peritoneum.
*
Diet No significant increase in tumors. Kociba et al. (1978)
Liver cancer.
Liver cancer, squamous cell car-
cinoma of the lung, hard palate/
nasal turbinates, or tongue
(P=0.05).
Mouse/F (30) 0.015 pg/kg/wk 99-104 wk Dermal
Mouse/M (30) 0.003 pg/kg/wk 99-104 wk Dermal
Rat/M (50) 0.5 pg/kg/wk 104 wk
Rat/F (50) 0.5 pg/kg/wk 104 wk
Gavage
Gavage
Fibrosarcoma in integumentary
system (8/27, P=0.007).
Fibrosarcoma in integumentary
system (6/28, P=0.08)
Follicular cell adenomas of
thyroid (10/50, P=0.001).
Neoplastic nodules of the liver
(12/49, P=0.006).
NTP (1982b)
NTP (1982a)
continued-
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Table 4-3 - continued
.£>
i
Species/Sex
(Number)
Dose
Duration Route
Mouse/M&F 2.0 pg/kg/wk 104 wk
Mouse/F
2.0 pg/kg/wk 104 wk
Mouse/M (39) 0.007 pg/kg/wk 52 wk
Mouse/M (44) 0.7 pg/kg/wk 52'wk
Mouse/M (44) 7.0 pg/kg/wk 52 wk
Gavage
Gavage
Gavage
Gavage
Gavage
Effects
Hepatocellular carcinoma
(17/50, P=0.002 in M);
(6/47, P=0.14 in F).
Follicular cell adenomas of the
thyroid (5/46,. P=0.009)
Liver tumors (13/44, P not
specified
Liver tumors (21/44, P<0.01)
Liver tumors (13/43, P=0.11)
Reference
NTP (1982a)
Toth et al. (1979)
Adapted from Esposito et al. (1980), NTP (1982a,b).
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and females (P=0.002). In addition, female mice had increased incidence of
follicular cell thyroid adenomas. These studies indicate that TCDD is an
animal carcinogen.
Toth et al. (1979) administered doses of 0, 0.007, 0.7 and 7.0 yg/kg/wk of
dioxin to male mice by gavage in a study to determine whether 2,4,5-trichlor.->-
phenoxyethanol (2,4,5-TCPE), its contaminant (dioxin) or both were carcino-
genic. The incidence of liver tumors was significantly increased in the dose
group receiving dioxin at the 0.7 pg/kg/wk level. No significant increased
incidence in liver tumors was observed in the 7.0 pg/kg/wk dose group although
increased mortality in this group probably precluded detection of tumors with
longer latent periods.
The NTP (1982b) conducted a skin painting cancer bioassay of dioxin on Swiss-
Webster mice (50 of each sex/dose). A dose of 0.001 pg/application (males)
and 0.005 pg/application (females) in acetone suspension was painted on the
skin 3 days/wk for 104 wk. The vehicle control group (45 mice/sex) was
painted with 0.1 mL acetone 3 times/wk for 104 wk. The incidence of fibro-
sarcoma in the integumetary system was significantly increased in females
(8/27, P=0,007) but not in males (6/28, P=0.08) compared to the incidence
respective controls (2/41 and 3/42).
DiGiovanni et al. (1977) reported that dioxin was a tumor initiator in mouse
skin. However, the role of dioxin as an initiator needs to be confirmed since
appropriate vehicle and promotion-only controls were not included in this
assay. 'Several assays (NTP 1982b, Berry et al. 1978, 1979) demonstrated that
dioxin was not a tumor-promoter when applied to mouse skin after unknown
initiator (DMBA).
Poland and Knutson (1982) reported that dioxin was a tumor promoter when
tested on the skin of mice homozygous for the "hairless" trait but not in mice
heterozygous for this recessive trait. Pitot et al. (1980) also reported that
dioxin was a promoter for DEN-initiated hepatocarcinogenesis in rats following
parenteral administration of the compounds. On mouse skin, dioxin was a
complete carcinogen and possibly a tumor initiator, while no tumor-promoting
activity could be attributed to dioxin in the assays. In rat liver initiated
with DEN, dioxin was a tumor promoter.
In the mouse skin bioassay, initiation with simultaneous administration of
dioxin and DMBA, however, did not affect tumor yield (DiGiovanni et al. 1977).
Similarly no effect was observed when dioxin was administered either immedi-
ately before (five minutes) or one day after DMBA initiation (B,erry et al.
1979, DiGiovanni et al. 1977, Cohen et al. 1979). When treatment with dioxin
occurred one to ten days before DMBA initiation, dioxin demonstrated a potent
anticarcinogenic action. Although one to five days prior exposure to dioxin
inhibited tumor initiation by BaP, 3-MC, and BaP-diol-epoxide, the tumor-
initiating ability of the latter compound was also inhibited when dioxin
exposure occurred either five minutes before or one day after initiacion
(DiGiovanni et al. 1980). The increased AHH activity resulting from dioxin
exposure may account for the anticarcinogenic activity by altering the
metabolism of the initiating compound; however, DiGiovanni et al. (1980)
4-14
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£ife Systems, Jttc.
suggests that the initiation of the initiating activity of BaP-diol-epoxide
one day after initiation indicates that more than one mechanism participates
in the anticarcinogenic activity of dioxin.
4.7 Quantitative Indices of Toxicity.
4.7.1 Noncarcinogenic Effects Indices
Recommended exposure limits to dioxin to ensure human safety have been
established by several agencies. The'National Academy of Sciences (NAS 1977),
before TCDD was considered to be a carcinogen, suggested an ADI for dioxin of
0.0001 ug/kg/day based on a 13-wk feeding study in rats (Kociba et al. 1976).
The reported NOEL in that study (0.01 ug/kg) was divided by an uncertainty
factor of 100 to determine the ADI. The NAS then calculated a suggested-
no-adverse-effeet-level (SNARL) in drinking water of 0.0007 ug/L, based on the
average weight of a human adult (70 kg) and an average daily intake of water
of two liters, with water representing 20% of total intake.
The USEPA (1984) has calculated an ADI of 10~ ug/kg/day based on noncarcino-
genic toxicity for comparison to the carcinogenic risk assessment value. A
LOAEL based on noncarcinogenic toxic effects and reduced fertility of
0.001 ug/kg/day and an uncertainty factor of 1,000 were used in the calcula-
tions. Using a bioaccumulation factor of 5,000, and assuming a_daily
consumption of 6.5 g of fish, a water concentration of 2.0 x 10 Ug/L was
derived. It was noted that this value'may not be sufficiently low to protect
against the carcinogenic effects of dioxin (USEPA 1984). The USEPA is cur-
rently reevaluating the bioconcentration factor for dioxin.
The USEPA (1984) concluded that insufficient data were available concerning
adverse effects of d.ioxin on aquatic life to allow derivation of ambient water
quality criterion. Limited information in freshwater species indicate acute
values may be >0.1 ug/L and chronic values may be <0.01 Ug/L (northern pike,
coho salmon, mosquito fish and channel catfish) and <0.001 Ug/L ,(rainbow
trout).
4.7.2 Carcinogenic Effects Indices
Since there is no recognized safe "concentration for a human carcinogen, and
dioxin is a suspected human carcinogen", the recommended concentration of
dioxin in water is zero (USEPA 1984). The USEPA calculated a range_pf _,
concentrations for dioxin corresponding to cancer risk levels of 10 ; 10
and 10 . These calculations used a linearized multistage model and were
based on animal bioassay data. ..The recommended criteria which may result in
an increased cancer risk of 10 , 10~ or 10~ are 1.3 x 10~ , 1.3 x 10 and
1.3 x 10 Ug/Lj respectively. These criteria are below the limit of
detection of TCDD in water (.approximately 3 x 10~ ug/L) by current analytical
methods.
The Food and Drug Administration (FDA) issued a health advisory stating that
fish with residues of dioxin >50 ppt should not be consumed, but fish with
residues of < 25 ppt pose no Serious health concern (USEPA 1984). The Centers
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for Disease Control (CDC) has established 1 ppb as a level of concern for
dioxin in residential soils at Times Beach, MO.
-4-16
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£ife Systems, JHC.
5.0 RISK AND IMPACT EVALUATION
5.1 Human Health
Quantitative risk assessments (QRA) for exposures to dioxin via consumption of
contaminated fish and via inhalation of air-borne dust have focused on carrir.c -
genie effects (Falco 1982, Falco and Schaum 1984). Both risk assessments are
based on limited data and required numerous assumptions (previously discussed
in Section 3.0) to address data gaps. Falco (1982) emphasizes that the
limited data -are not sufficient to produce a statistically valid estimate of
errors but the assessments provide a means to bound possible exposures and
associated risks.
5.1.1 QRA for Consumption of Contaminated Fish
Falco (1982) estimated the upper limit individual cancer risk to range from
10 to 10 due to consumption of dioxin contaminated fish from Bayou Meto.
These cancer risks are based on potential exposures which were estimated to
range from 0.09 ng/kg/yr to 110 ng/kg/yr. The QRA was based on the Kociba
et al. (1978) study in which dioxin induced a statistically significant
increase in the incidence of tumors in the liver, lung and hard palate or
nasal turbinates. The linerized multi-staged model was employed with an
assumed continuous exposure during the course of a lifetime (70 yr). The
upper lifetime cancer risks were estimated for consumption of fish-caught from
various distances from the site along the length of Bayou Meto. The upper
limit cancer risk estimate is greater than 10 for consumption of fish from
the mouth of Bayou Meto which is approximately 130 mi downstream from the
Vertac site. Falco (1982) emphasized that the actual risk may range anywhere
between 0 (the lower bound) to upper limit risk estimates presented in Table 5-1
Consumption of fish at a rate greater than the assumed average rate (5.2 Ib/yr)
increases the upper limit of individual cancer risk. For example, individuals
with consumption rates at the expected,upper ,95th percentile (16 Ib/yr) would
have cancer risks ranging from 3 x 10~ to 3.2 x 10 corresponding to the
range of estimated contamination levels (2.6 to 3,300 ppt dioxin) in fish from
Bayou Meto.
Falco and Schaum (1982) estimated that the number of people potentially
exposed annually would be 30,000 if one assumes an average consumption rate
and average catch rate. Since the upper cancer risk for this group ranges
from 10 to 10 (depending upon the range of dioxin contamination levels in
fish), the corresponding upper bound estimate of induced cancers under this
scenario could range from 3 cases (1 case every 25 yr) to 3,000 cases
(43 cancers/yr) (assuming continuous exposure for 70 yr).
5.1.2 QRA for Contaminated Groundwater
No QRA for dioxin exposures due to contaminated groundwater has been per-
formed. The actual risk via the groundwater route is probably minimal due to
the apparent lack of exposure potential. However, this route may pose unac-
ceptable carcinogenic risk if groundwater contaminated at 0.03 ppb dioxin (the
highest detected level in groundwater on-site) were consumed. Assuming the
5-1
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&fe Systems, JHC.
TABLE 5-1 HUMAN EXPOSURE AND UPPER-LIMIT CANCER RISK
ESTIMATES BY RIVER MILE
River
Mile
132
100
75
54
34
16
0
Exposure, ng/kg/yr
Based on
Calculations
(b)
0.96-110
0.56-65
0.48-56
0.15-18
0.13-15
0.11-13
0.09-10
Based on
Monitoring
(c)
10.1
3.79
1.0
Upper-Limit Lifetime ,
Cancer Risk Estimates
Based on
Monitoring
Based on
Calculations
0.0012
0.00065
0.00056
0.00017
0.00015
0.00013
0.00010
0.122
0.073
0.063
0.021
0.017
0.015
0.012
0.01
0.0044
0.0012
(a) Calculated Exposure = (C x
where C
concentration of T
^,-
CDD
x consumption rate)/70 kg body weight
in sediment and
(b)
-,,
sediment fish
distribution coefficient. Consumption rate assumed"3 5.2 Ib/yr
(2.37 kg/yr); low values assume K = 5.4; high values assume K,,,, = 550.
K
(C
Exposures based on monitoring = (C" x consumption rate)/70 kg body
r
weight where C^ = measured concentration of TCDD in fish (only available at
river miles 132, 100 and 75). Consumption rate assumed = 5.2 Ib/yr
(2.37 kg/yr).
(c) Upper Limit Risk = 1 - e x exposure) where exposure is in
units of ng/kg/day. The risk could always approach-zero as a lower bound.
5-2
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JCifc Systems, JHC.
70-kg human would consume two liters of water per day then the dose would be
0.0009 yg/kg/day (0.9 ng/kg/day) . Consumption of a dioxin dose of 0.9,-ng/kg/day
over a lifetime poses unacceptable carcinogenic risk exceeding the 10 risk ,
associated withqconsumption of water with a dioxin concentration of 1.3 x 10
yg/L (3.7 x 10~ yg/kg/day or 0.0000037 ng/kg/day). Consumption of drinking
water containing 0.005 ppb dioxin (the mean detected concentration) would
result in a dose of 0.0001 yg/kg/day (0.1 ng/kg/day) which would also pose
unacceptable carcinogenic risk exceeding the 10 level. The lower bound
estimate is zero since consumption may not occur and because recent analyses
have not detected dioxin in groundwater monitoring wells.
5.1.3 QRA for Airborne Dust
Falco and Schaum (1984) performed a QRA for inhalation exposure to dust
(sorbed on dioxin) associated with the proposed remedial action (Alterna-
tive IV) . The predicted upper bound cancer risk associated with the remedial
action ranges from 5 x 10 to 7.4 x 10 for the nearest residents to the
Vertac site. This risk estimate assumes no dust control measures are
implemented^ The wide range of risk estimates is due to uncertainty in the
concentration of dioxin in materials to be excavated (0.1 to 14 ppm). Falco
and Schaum (1984) calculated cancer risk with an adjusted cancer potency
factor. The cancer potency factor (95% upper limit of the linear coefficient
in the dose response model) of 0.156 (ng/kg/day)~ was adjusted to account for
differences in absorption via oral exposure versus inhalation exposure routes.
Assuming an approximate oral absorption rate of about 50%, the potency factor
based on a dose administered in feed.was multiplied by a facto_r of two to
yield the potency 0.312 (ng/kg/day) based on an absorbed dose.. Based on
predicted exposure levels, carcinogenic risk levels were calculated and
plotted (see Figure'5-1) for the nearest residents of the Vertac site. There
is no demographic information available on the number of residents within the
isopleths on Figure 5-1. The upperbound estimates of risk associated with
inhalation of dioxin-contaminated dust will decline with distance from the
site. Sources of uncertainty are associated with parameter value assumptions
such as the dioxin concentration in soils, silt content, volume of excavated
soil, moisture content of soils, % dioxin absorption in lungs versus gastro-
intestinal tract and the cancer potency estimates. In addition emission
factor equations and dispersion models have associated uncertainties. Thus,
information necessary to analyze uncertainty on a statistical basis is
unavailable but the estimated range of risks appears representative of these
type of calculations (Falco and Schaum 1984).
5.1.4 QRA for Direct Contact
No QRA for dioxin exposures via direct contact with contaminated soils and
sediments is available. However, the levels of dioxin in soils and sediments
offsite exceed the CDC's 1 ppb level of concern for residential soils
established for Times Beach, MO.
5.2 Environmental
No QRA for aquatic or terrestrial life in the environment adjacent to or
contaminated by the Vertac site is available. There are potential risks to
5-3
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£ife Systems, Jnc.
2.3 x 10 to 6.1 x 10
4.5 x 10 to 6.8 x 10
5 x 10~8 to 7.4 x 10"6
Scale: 1 in = 145 meters
Center of Dust Emission Source
= Property Line
Adapted from Falco and Schaum (1984)
FIGURE 5-1 MINIMUM AND MAXIMUM ACCUMULATIVE UPPER BOUND RISK ESTIMATE
IMMEDIATELY SOUTH OF THE VERTAC PROPERTY (RESULTING FROM THE
COMBINATION OF PHASE 1 AND 2 ACTIVITIES)
5-4
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£ifc Systems, JHC.
aquatic and terrestrial species related to dioxin releases from the Vertac
site. The absence of benthic life, several massive fish kills and reported
"medicinal" taste and odor of fish caught from Bayou Meto (receiving waters
of the Rocky Branch Creek) reflect the impact of contaminants released from
the Vertac site on aquatic life (JRB 1983). The limited environmental moni-
toring data for sediments in the Rocky Branch Creek, Bayou Meto and Lake
Dupree indicate substantial dioxin contamination has occurred. Analyses of
fish tissues demonstrates that dioxin has been bioaccumulated to substantial
levels (up to 300 ppt in Bayou Meto and 810 ppt in Lake Dupree) but the health
significance of such tissue levels and potential impact on survival, growth,
development and reproduction of aquatic life remains unknown. The absence of
ambient water quality criteria and especially criteria for. dioxin levels in
sediments impedes performance of a QRA for aquatic organisms.
There is a paucity of monitoring data on the concentration of dioxin in
surface waters offsite. The only data available indicate that dioxin was not
detected in water from the Rocky Branch Creek. Therefore, it is not possible
to compare dioxin concentrations in receiving water to levels causing acute
toxicity (>1.0 ppb) in certain freshwater species or chronic toxicity in the
rainbow trout (<0.001 ppb) or in several other fish species (<0.01 ppb).
The high content of dioxin in sediments (500 ppt ave) in the Rocky Branch
Creek and potential for release to the water column suggests that aquatic
organisms may be at risk. No existing guidelines or standards are available
'to determine risks to avian 'or terrestrial organisms-, The potential impact of
.contamination on such species is of concern since the Bayou Meto area serves
as an important water fowl resting area and contains about 70,000 acres of
wetlands. Limited data are available on the avian species and terrestrial
species present in the area. Contamination of the Bayou Meto and accumulation
of dioxin in the aquatic food chain may endanger predator (avian or
terrestrial) species.
5.3 Public Welfare
The major socioeconomic impact of the release of dioxin from the Vertac site
has been the loss of adjacent surface waters for fishing and recreation. For
example, the release of dioxin to the Rocky Branch Creek and Bayou Meto and
transport to Lake Dupree during flooding has caused fish to accumulate (810 ppt)
dioxin in excess of the FDA health advisory value of ^50 ppt. Thus, fish from
Lake Dupree may be unfit for human consumption. This contamination of fish
has required the Arkansas public health officials to issue a fishing ban for
the Bayou Meto area. An additional impact on public welfare may be a poten-
tial decrease of property values immediately adjacent to the site (i.e.,
especially residential property values) and the loss of groundwater aquifers
as a potential source of drinking water.
5-5
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JttfcSystems,
6.0 ' CONCLUSIONS
The most significant endangerment of human health is due to the potential
consumption of dioxin-contaminated fish from Bayou Meto. Falco and Schaum
(1982) estimated that chronic (lifetime) consumption of contaminated fish from
Bayou Meto may lead to an upper limit individual cancer risk ranging from
1/10,000 to 1/10. Under this scenario (assuming 30,000 people are exposed
based on an average catch rate and an average consumption rate) the estimated
upper bound of induced cancers may range from 3 cases (1 case/25 yr) to
3,000 cases (43 cases/yr). However, the lower, bound estimate of induced
cancers is zero regardless of consumption rate and fish catch size. The
fishing ban for Bayou Meto may reduce this threat to human health, but its
efficacy is unknown since it is not:easily enforced.
The contamination of groundwater represents another substantial potential
threat to human health. There is a real potential for offsite migration of
contaminants to groundwater. A maximum of 0.03 ppb and a mean of 0.005 ppb of
dioxin have been detected in on-site groundwater monitoring well. Actual
exposures to humans via this route is currently considered unlikely since no
permitted domestic and industrial wells were located in the area immediately
downgradient of the site. Human health may be endangered if water wells are
drilled in the future and used for drinking water purposes. However * assuming
humans may potentially consume groundwater in the future, the resulting dose
of dioxin would increase risk of cancer substantially above the 10 level.
Further groundwater monitoring data are necessary to verify and characterize
the magnitude and extent of any offsite contamination.
Exposure to dioxin via dust-emissions from the proposed remedial action
(Alternative IV) was estimated to present an upperbound cancer risk ranging
from 5.8 x 10~ to 7.4 x 10 for residents near the Vertac site (within about
300 meters). Demographic information on the size of this population was un-
available and therefore, an estimate of number of excess cancers is not
possible. /
The potential for direct contact with contaminated soils and sediments poses
human health risks. Monitoring data indicate that levels of dioxins in soils
and sediments off-site exceed the CDC's 1 ppb level of concern for residential
soils (established for Times Beach, MO).
No quantitative assessment of risk to aquatic and terrestrial organisms was
available. Limited environmental'monitoring data and the unavailability of
established ambient water criteria preclude such an assessment. The data
demonstrate that dioxin is present in the sediments and bioaccumulates in fish
above the FDA's health advisory value of ^50 ppt.
Loss of fishing in the Bayou Meto area impacts the public welfare. Addi-
tionally decrease of property values adjacent to the site or along the bayou
may impact the economic stability of the area. Contamination of groundwater
may prevent its future use as a drinking water resource.
6-1
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£ife Systems, fac.
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Kimbrough RD, Carter CD, Liddle JA, Cline RE. 1977. Epidemiology and
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King ME, Roesler AR. 1974. Subacute intubation study on rats with the
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Kociba RJ, Keeler PA, Park CN, Gehring PJ. 1976. 2,3,7,8-tetrachloro-
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Toxicol. Appl. Pharmacol. 35:553-574.
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Kociba RJ, Keyes DG, Beyer JE, et al. 1978. Results of a two-year chronic
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Kociba RJ, Keyes DG, Beyer JE, Carreon RM, Gehring PJ. 1979. Long-term
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Luster MI, Boorman GA, Dean JH, et al. 1980. Examination of bone marrow,
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Miller RA, Norris LA, Hawkes CL. 1973. Toxicity of 2,3,7,8-tetrachlorodibenzo-
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Miller RA, Norris LA, Loper BR. 1979. The response of coho. salmon and
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Moore JA, Gupta BN, Vos JG. 1976. Toxicity of 2,3,7,8-tetrachlorodibenzo-
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Neal RA,' Olson JR, Gasiewicz TA, Geiger LE. 1982. The toxicokinetics of
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13:355-385. __
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2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The Toxicologist 3:103.
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metabolism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the Golden Syrian
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2,3,7,8-TCDD. Interim draft report. Washington, DC: U.S. Environmental
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Piper WN, Rose RQ, Gehring PJ. 1973. Excretion and tissue distribution of
2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. Environ. Health Perspect.
5:241-244.
Pitot HC, Goldsworthy T, Poland H. 1980. Promotion by 2,3,7,8-tetrachloro-
dibenzo-p-dioxin of hepatocarcinogenesis from diethylnitrosamine. Cancer Res.
40:3616-3620.
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accidental release of tetrachlorodibenzo-p-dioxin (TCDD) at Seveso, Italy.
Ann. NY Acad. Sci. 320:311-320.
Poiger H, Schlatter C. 1980. Influence of solvents and adsorbents on dermal
and intestinal absorption of TCDD. Food Cosmet. Toxicol. 18:477-481.
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7-7
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2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) formed an incubation with isolated
rat hepatocytes. Biochem. Biophys., Res. Commun. 105:341-346.
*
Shantz SL, Barsotti DA, Allen JR. 1979. Toxicological effects produced in
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Smith AH, Fisher DO, Pearce N, Teague CA. 1982. Do agricultural chemicals
cause soft-tissue sarcoma? Initial findings of a case-control study in New
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2,3,7,8-tetrachlorodibenzo-p-dioxin in the rat. Food. Cosmet. Toxicol.
9:405-412.
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»
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7-10
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APPENDIX 3
EPA's PROPOSED ASSESSMENT GUIDELINES
Part 1 - Carcinogen Risk Assessment
Part 2 - Exposure Assessment
Part 3 - Mutagenicity Risk Assessment
Part 4 - Health Assessment of Suspect
Developmental Toxicants
Part 5 - Health Risk Assessment
Chemical Mixtures
A3-1
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PART 1 - CARCINOGEN RISK ASSESSMENT
A3-2
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Friday
November 23, 1984
Part VII
Environmental
Protection Agency
Proposed Guidelines for Carcinogen Risk
Assessment; Request for Comments
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46294
Federal Register / Vol. 49. No. 227 / Friday. November 23, 1984 / Notices
ENVIRONMENTAL PROTECTION
AGENCY
1FRL-2706-4]
Proposed Guidelines for Carcinogen
Risk Assessment
AGENCY: Environmental Protection
Agency (EPA).
ACTION: Proposed Guidelines for
Carcinogen Risk Assessment and
Request for Comments.
SUMMARY: The U.S. Environmental
Protection Agency is proposing
Guidelines for Carcinogen Risk
Assessment (Guidelines). These
Guidelines are proposed for use within
the policy and procedural framework
provided by the various statutes that
EPA administers to guide Agency
analysis of carcinogenicity data. We
solicit public comment and will take
public comment into account in revising
these Guidelines. These Guidelines will
be reviewed by the Science Advisory
Board in meetings now tentatively
scheduled for April 1985.
These proposed Guidelines were
developed as part of a broad guidelines
development program under the
auspices of the Office of Health and
Environmental Assessment (OHEA),
located in the Agency's Office of
Research and Development. Consonant
with the role of OHEA's Carcinogen
"Assessment Group (GAG) as the
Agency's senior health committee for
carcinogenicity assessment, the
Guidelines were developed by an
Agency-wide working group chaired by
the Chairman of GAG.
DATE: Comments must be postmarked
by January 22.1985.
ADDRESS: Comments may be mailed or
delivered to: Dr. Robert McGaughy.
Carcinogen Assessment Group (RD-
689), Office of Health and
Environmental Assessment, U.S.
Environmental Protection Agency, 401 M.
Street SW., Washington. D.C. 20460.
FOR FURTHER INFORMATION CONTACT.
Dr. Robert McGaughy, Telephone: 202-
382-5952.
SUPPLEMENTARY INFORMATION: This is
the first proposed revision of the 1976
Interim Procedures and Guidelines for
the Health Risk Assessment of
Suspected Carcinogens (Federal
Register 41:21402-21405, 1976). This
revision incorporates concepts and
approaches to carcinogen assessment
that have been developed during the last
eight years. These proposed revised
Guidelines describe salient principles
for evaluating the nature and magnitude
of the cancer hazard from suspect
carcinogens and general framework to
be followed in developing analyses of
carcinogenic risk.
These Guidelines were sent to 38
scientists in the field of carcinogenesis
from universities, environmental groups,
industry, labor, and governmental
agencies. We have decided to delay
incorporating suggestions from the 26
reviewers who submitted comments into
the Guidelines published here until
comments submitted during this public
comment period are received.
References and supporting documents
used in the preparation of these
Guidelines as well as comments
received are available for inspection
and copying at the Public Information
Reference Unit (202-382-5926). EPA
Headquarters Library. 401 M Street SW..
Washington, DC, between the hours of
8:00 and 4:30 p.m.
Dated: November 9,1984.
William D. Ruckelshaus,
Administrator.
Contents
I. Introduction
II. Hazard Identification (Qualitative Risk
Assessment)
A. Overview
B. Elements of Hazard Identification
1. Physical-Chemical Properties and
Routes and Patterns of Exposure
2. Structure-Activity Relationships
3. Metabolic and Pharmacokinetic
Properties
4. Toxicologic Effects
5. Short-Term Tests
6. Long-Term Animal Studies
7. Human Studies
C. Weight of Evidence
D. Guidance for Quantitative Assessment
E. Summary and Conclusion
III. Dose-Responsive Assessment, Exposure
Assessment, and Risk Characterization
A. Dose-Responsive Assessment
1. Selection of Data
2. Choice of Mathematical Extrapolation
Model
3. Equivalent Exposure Units Among
Species
B. Exposure Assessment
C. Risk Characterization '
1. Options for Numerical Risk Estimates
2. Concurrent Exposure
3. Summary of Risk Characterization
IV. Appendix EPA Classification System for
Evidence of Carcinogencity From Human
Studies and From Animal Studies
V. References
I. 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 these
Guidelines the concepts and approaches
to carcinogen risk assessment that have
been deveioped during the iast eight
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 the experts in the various
disciplines required (e.g., toxicology.
pathology, pharmacology, and statisucsi
for carcinogen 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.
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, 1984), 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 report entitled "Risk
Assessment in the Federal Government"
(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 a prerequisite for
regulatory action to control, prohibit, or
allow the use of a carcinogen. The •
analysis of carcinogenic risks will be
carried out independently from
considerations of the socioeconomic
consequences of regulatory action.
Regulatory decisionmaking involves
two components: Risk assessment and
risk management. Risk assessment
defines the adverse health consequences
of exposure to toxic agents; risk
management combines the risk
assessment with the directives of the
enabling 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
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Federal Register / VoL 49. No. 227 / Friday. November 23. 1964 / Notices
46295
assessment, exposure assessment and
risk characterization (NRC, 1983).
«azard identification is a qualitative
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, 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 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
^fc/ironment: it also includes
^Pisiderations 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.
In risk characterization, the outputs of
the exposure assessment and the dose-
response assessment are combined to
estimate quantitatively some measure of
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.
II. Hazard Identification (Qualitative
Risk Assessment)
A. Overview
The qualitative assessment or hazard
itification part of risk assessment
tains a review of the relevant
logical land chemical information
bearing on whether or not an ageni 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
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. 1984; Peto et
al., 1980; Mantel I960; 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). 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
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.
2. Structure-Activity Relationships
This section should summarize
relevant structure-activity correlations
that support 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
padiways for such conversions,
macromolecular interactions, and
transport in, fate in. and excretion from
the body as well as species differences
in metabolism should be discussed.
4. Toxicologic Effects
Toxicologic effects other than
carcinogenicity (e.g., suppression of the
immune system, endocrine disturbances,
organ damage), which are relevant to
the evaluation of carcinogenicity, should
be summarized. Prechronic and chronic
toxicity evaluations, as well as other
test results, may yield information on
target organ eifecis, pathopnyaioiogicai
reactions, and preneoplastic lesions that
bear on the evaluation of
carcinogeniciry. Dose-response and
time-to-response analyses of these
reactions may also be helpful.
5. Short-Term Tests
Tests for point mutations, numerical
and structural chromosome aberrations.
DNA damage/repair, and in vitro
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 vivo and in vitro tests
that can give indication of initiation and
promotion activity may also provide
supportive evidence for carcinogenicity.
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. 1984; U.S. EPA, 1983a; 1983b;
1983« Feron et al., I960; Mantel, 1980)
and should be used to judge the
acceptability of individual studies.
The-strength of the evidence that an
agent is carcinogenic increases~with the
increase in number of tissue sites
affected by the agent; the increase in
number of animal species, strains, and
sexes showing a carcinogenic response;
the occurrence of clear-cut dose-
response relationships as well as a high
level of statistical significance of the
increased tumor incidence is treated
with respect to control groups; the dose-
related shortening of the time-to-tumor
occurrence or time to death with tumor,
and 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
activity. Negative long-term animal
studies at exposure levels above the
MTD or partial lifetime exposures at the
MTD may not be acceptable because of
toxicity, or 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. Positive studies ai 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-dose
icsting produces tumor responses by
indirect mechanisms that may be
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unrelated to effects at lower does should
be dealt with on an individual basis.
The mechanism of the carcinogenic
responses under conditions of the
experiment should be reviewed
carefully as it relates to the relevance of
the evidence to human carcinogenic
risks (e.g.. the occurrence of bladder
tumors in the presence of bladder stones
and injection 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
toxicological studies. Time and dose-
related changes in the incidence of
preneoplastic lesions may also be
helpful in interpreting animal studies.
Historical control data are often
valuable and could be used along with
concurrent control data in the
evaluation of carcinogenic responses.
For the evaluation of rare tumors, even
small tumor responses may be
significant compared to historical data.
In the case of tumors with relatively
high spontaneous rates, a response that
is significant with respect to the
experimental control group becomes
questionable if the historical control
data indicate that the experimental
control group had an unusually low
background incidence.
Agents that are positive in long-term
animal experiments and also show
evidence of promoting or cocarcingenic
activity in specialized tests should be
considered as complete carcinogens
unless there is evidence to the contrary.
Agents that show positive results in
special tests for initiation, promotion, or
cocarcingenicity and no indication of
tumor response in well-conducted and
well-designed long-term animal studies
should be dealt with on an individual
basis.
There are widely diverging scientific
views (OSTP, 1984; Ward et al. 1979a;
1979b; Tomatis; 1977; Nutrition
Foundation, 1983) about the validity of
mouse liver tumors 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 the mouse-liver-only tumor
response, when other conditions for a
classification of "sufficient" evidence in
animal studies are met, should be
considered as "sufficient" evidence of
carcinogenicity with the understanding
that this classification could be changed
to "limited" if warranted when a
number of factors such as the following
are observed: The occurrence 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
predominately benign, showing no
evidence of metastases or invasion; 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.
Positive carcinogenic responses in one
species/strain/sex are 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 and 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, andjhe valid ascertainment of
the causes of morbidity and death.
The strength of the epidemiologies
evidence for carcinogenicity depends on
the magnitude, specificity, and
statistical significance of the response
and increases rapidly with the number
of adequate studies which show the
same results on populations exposed to
the same agent under different
conditions.
It should be recognized that
epidemiologic studies are inherently
capable of detecting only comparatively
large increases in the relative risk oi
cancer. Negative results from such
studies cannot prove the absence of
carcinogenic action; however, negative
results from a well-designed and
conducted epidemiologic study that
contains usable exposure data can serve
to define upper limits of risk which are
useful if animal evidence indicates that
the agent is potentially carcinogenic.
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 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 bFa weight-oi-evidence .
judgment. Judgments about the weight ot
evidence involve considerations of the
quality and adequacy of the data and
the kinds of responses induced by a
suspect carcinogen. There are three
major steps to characterizing the weight
of evidence for carcinogenicity: (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 a final indication of the overall
weight of evidence for human
carcinogenicity, and (3) evaluation of all
supportive information to determine if
the overall weight of evidence should be
modified.
A system for stratifying the weight of
evidence is recommended, and EPA has
developed a scheme (see the Appendix).
The EPA scheme is modeled after the
classification system developed by the
International Agency for Research on
Cancer (IARC. 1982). In the IARC
classification method, the evidence tha.
• an agent produces cancer in humans is
divided into three categories: Sufficient.
limited, and inadequate. A similar
characterization of evidence is prdVided
for animal data.
The EPA classification system is. in
general, an adaptation of the IARC
approach for classifying the weight if
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46297
uai
i
evidence for human data and animal
data. The EPA classification system for
e characterization of the overall
tight of evidence for carcinogenicity
animal, human, and other supportive
•irita) includes: Group A—Carcinogenic
to Humans: Group B—Probably
Cardnogenic to Humans; C—Possibly
Carcinogenic to Humans; Group 0—Not
Classifiable as to Human
Carcinogenicity: and Group E—No
Evidence of Carcinogenicity for
Humans.
In addition, the following
modifications of the IARC approach
nave been made for classifying human
r short-term evidence). (4) A "no
>»vide>ir.»iv" category is also added. This
•;purational category would include
substances for which there is no
increased incidence of neoplasms in at
It^st two well-designed and well-
conducted animal studies of adequate
powgr and dose in different species.
i). Guidance For Quantitative
\ssessment
The qualitative evidence for
genesis should be discussed for
irposes of guiding the dose-response
•:.;essmem. The guidance should be
in terms of the appropriateness
i-,d
«:
and limitation of specific studies as well
as phannacokinetic 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. The appropriateness of
quantifying the risks from agents in
Group C, specifically those agents that
are at the boundary of Groups C and D.
would be judged on a case-by-case
basis. Agents that are judged to be in
Groups D and E would generally 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. Uncertainties
in the evidence as well as factors that
may affect the relevance of the chronic
animal study to humans should be
discussed. The conclusion should
present both the weight-of-evidence
rankng and a description that brings out
the more subtle aspects of the evidence
that .may not be evident from the
ranking-alone;
ITI. Dose-Response Assessment.
Exposure Assessment, and Risk
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
oncertainities 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
document (U.S. EPA. 1S84): however.
section III.B. of these Guidelines
includes a brief description of the
specific type of exposure information
that is necessary for use in carcinogenic
risk assessment. Finally, in section II1.C.
there is a description of the type of
information and its interpretation
necessary for accurately characterizing
risk and the dnyree to which it can be
known.
It should be emphasized that
calculation of quantitative estimates of
cancer risk does not require that an
agent be a human carcinogen. 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
likelihood that the agent is a human
carcinogen. Appropriately qualified
quantitative estimates of risk, together
with estimates of their uncertainty, are
-useful in cost-benefit analyses, in setting
regulatory priorities, and for evaluating
residual risks associated with the
application of regulatory controls.
It should be emphasized in every
quantitative risk estimation that the
results are uncertain. The 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 differnces
in uptake, metabolism, and organ
distribution of carcinogens, as well as
species and strain differences in target
site susceptibilty. 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.
c\
A. Dose-Response Assessment
1. Selection of Data
As indicated in section II.D. guidance
needs to be given by the individuals
doing the qualitative assessment
(lexicologists, pathoiogists.
pharmacologists, etc.) to the statisticans
doing the quantitative assessment as lo
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.
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If available, estimates based upon
human epidemiologic data are preferred.
If adequate exposure data exist in a well-
designed and conducted negative
epidemiologic study, an upper-bound
estimate of risk should be used in
preference to higher risks estimated
from animal data. In the absence of
human data, 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. The tumor incidence data are
. separated according to organ site and
tumor type. All biologically and
statistically acceptable data sets are
presented. The range of the risk
estimates is identified with due regard
to biological relevance (particularly in
the case of animal studies) and
appropriateness of route of exposure.
Because it is possible that human
sensitivity is as high as the most
sensitive responding animal species, in
;he 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, uncertainties about the dose
delivered to the target organs from
different exposure media should be
explicitly considered, and the
assumptions should be carefully stated.
Where two or more significantly
elevated tumor sites or types^re
jbserved 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; if the
'.umor sites or types are occurring
dependently, this procedure is the same
as summing the risks from the several
dnds of statistically significant tumors.
The pooled estimates will generally be
jsed in preference to risk estimates
Dased on single sites or types.
Benign tumors should generally be
:ombined with malignant tumors for risk
estimates unless the benign tumors are
Tot considered to have the potential to
progress to the associated malignancies
of the same morphologic type. However,
the contribution of the benign tumors to
the total risk should be indicated.
2. Choice of Mathematical Extrapolation
Model
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.
However, different extrapolation models
may fit the observed data reasonably
well but may lead to large differences in
the projected risk at low doses.
No single mathematical procedure is
recognized as the most appropriate for
low-dose extrapolation in
carcinogenesis. When relevant
biological evidence on mechanism of
action exists, the models or procedures
employed should be consistent wj,th the
evidence. However, when data and
information are limited, as is the usual
case given the high degree of
uncertainty associated with the
selection of a low-dose extrapolation
model, specific guidance on model
selection is necessary to provide a
desirable degree of consistency in risk
assessments. The choice of low-dose
extrapolation models should be
consistent with current understanding of
the mechanisms of carcinogenesis and
-not solely on goodnesa-of-frt to the
observed tumor data. Although
mechanisms of the carcinogenesis
process are largely unknown, at least
some elements of the process have been
elucidated, e.g., linearity of tumor
initiation. In further support of a linear
model, it has been shown that, if a
carcinogenic agent acts by accelerating
the same stages of the carcinogenic
process that lead to the background
occurrence of cancer, the added effect of
the carcinogen at low dose is virtually
linear. Thus, a model that is linear at
low dose is plausible.
The linearized multistage model
procedure for low-dose extrapolation
(U.S. EPA, 1980) is therefore
recommended in most cases unless there
is evidence on carcinogenesis
mechanisms or other biological evidence
that indicates the greater-suitability of
an alternative extrapolation model, or
there is statistical or biological evidence
that excludes the use of the linearized
multistage model.
It should be emphasized thai the
linearized multistage model leads to a
plausible upper limit to the risk which is
consistent with some mechanisms of
carcinogenesis. However, such an
estimate does not necessarily give a
realistic prediction of the risk. In certain
cases, the linearized multistage model
cannot be used successfully 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 the
procedure to achieve low-dose linearity.
When phannacokinetic or metabolism
data are available, or when other
substantial evidence on the mechanistic
aspects of the carcinogenesis process
exists, a different low-dose
extrapolation model might be
considered more appropriate on
biological grounds. When a different
model is chosen, the risk assessment
should clearly discuss the nature and
strength of the evidence that lead to the
choice. In most cases, considerable
uncertainty will remain concerning
response at low doses; therefore, an
upper-limit risk estimate using the
linearized multistage model 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 mz 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 extrapolation of
body weight to the 0.67 power is
considered to be appropriate.
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 Proposed
Guidelines for Exposure Assessment
(U.S. EPA, 1984) for specific details, it is
important that the cancer risk assessor
and the decision-maker have an
appreciation of the impact of the
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Federal Register / Vol. 49. No. 227 / Friday. November 23, 1984 / Notices 46299
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 data on hand and
the level of sophistication required (e.g.,
preliminary assessment using crude data
and worst case assumptions versus a
final assessment using extensive
monitoring data). 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
data are generated from monitoring
information, modeling results, and/or
reasoned estimates. An appropriate
treatment of exposure should consider
the potential for exposure via ingestion,
inhalation, and dermal penetration from -
relevant sources of exposures. Where
feasible, an attempt should be made to
assess the dose to the target organ,
either through experimental evidence or
reasonable assumptions and modeling.
Special problems arise when the
human exposure situation of concern
suggests exposure regimens, e.g., route
and dosing schedule, which 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 the
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 coresponding 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 1II.C.) in order to provide the
decision-maker with a clear
understanding of the impact of this
uncertainty on any final quantitative
risk estimate.
C. 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/m 3 in air.
b. The 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—
Risk may be characterized either in
terms of the excess individual lifetime
risks or the excess number of cancers
produced per year in the exposed -
population or both.
/respective 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 from the various assumptions
and uncertainties upon which they -ere
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 "possible human
carcinogen" (Group C) should be
designated as:
2X10-«(C]
This bracketed designation of the
qualitative 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 inclutia
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.
FV. Appendix—EPA Classification
System for Evidence of Carcinogenicity
From Human Studies and From Animal
Studies (Adapted From IARC)
A. Assessment of Evidence for
Carcinogenicity From Studies in
Humans
Evidence of Carcinogenicity from
human studies comes from three main
sources:
1. Case reports of individual cancer
patients who were exposed to the
agent(s).
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 which
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 degrees 01 evidence k>r
Carcinogenicity* from studies in humans
are categorized as:
1. Sufficient evidence of
'For purpose of public health protection.
agents associated with life-threatening
benign (umors in humans are included in the
evaluation.
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Federal Register / VoL 49. No. 227 / Friday, November 23. 1984 / Notices
:arcinogenicity, which indicates that
here is a causal relationship between
he agent and human cancer.
2. Limited evidence of carcinogenicity,
•vhich indicates that a causal
nterpretation is credible, but that
ilternative explanations, such as
;hance, bias, or confounding, could not
adequately be excluded.
3. Inadequate'evidence, which
indicates that one of two conditions
prevailed: (a) There were few pertinent
Jata, or (b) the available studies, while
showing evidence of association, did not
exclude chance, bias, or confounding.
4. 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.
5. No data, which indicates that data
are not available.
B. Assessment of Evidence for
Carcinogenicity From Studies in
Experimental Animals
These assessments are classified into
five groups:
1. Sufficient evidence* of
carcinogenicity, which indicates that
there is an increased incidence of
malignant tumors or combined
malignant and benign tumors §: (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 tumor, or 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 carcinogenicity.
which means that 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
+ Under specific circumstances, such as
the production of neoplasms that occur with
high spontaneous background incidence, the
evidence may be decreased to "limited" if
warranted (e.g.. there are widely diverging
scientific views regarding the validity of the
mouse liver tumor as an indicator of potential
human carcinogenicity when this is the only
response ooserved. even in replicated
experiments in the absence of short-term or
other evidence).
5 Benign and malignant tumors will be
combined unless the benign tumors are not
considered to have the potential to progress
;o ;he associated malignancies of the same
morphologic type.
survival, too few animals, or inadequate
reporting; or (c] an increase in the
incidence of benign turmors 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 evidence, which indicates that
there is no increased incidence of
neoplasms in at least two well-designed
and well-conducted animal studies in
different species.
5. No data, which indicates that data
are not available.
The categories "sufficient evidence"
and "limited evidence" refer only to the
strength of the experimental evidence
that these agents(s) are carcinogenic
and not to the power of their
carcinogenic action.
C. Categorization of Overall Evidence
Group A—Human Carcinogen
This category is used only when there
is sufficient evidence from
epidemiologic studies to support a
causal association between exposure to
the agent(s) and cancer.
Group B—Probable Human Carcinogen
This category includes agents for
which the evidence of human
carcinogenicity from epidemiologic
studies ranges from almost "sufficient"
to "inadequate." To reflect this range,
the category is divided into higher
(Group Bl) and lower (Group BZ)
degrees of evidence. Usually, category
Bl is reserved for agents for which there
is at least limited evidence of
carcinogenicity to humans from
epidemiologic studies. In the absence of
adequate data in humans, it is
reasonable, for practical purposes, to
regard agents for which there is
sufficient evidence of carcinogenicity in
animals as if they presented a
carcinogenic risk to humans. Therefore,
agents for which there is inadequate
evidence from human studies and
sufficient evidence form animal studies
would usually result in a classification
ofBZ.
In some cases, the known chemical or
physical properties of an agent and the
results from short-term tests allow its
transfer from Group B2 to Bl.
Group C—Possible Human Carcinogen
This category is used for agents with
limited evidence of carcinogenicity in
animals in the absence of human data. It
includes a wide variety of evidence: (a)
Definitive malignant tumor response in a
single well-conducted experiment, fb)
marginal tumor response 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) marginal
responses in a tissue known to have a
high and variable background rate.
In some cases, the known physical or
cehmical properties of an agent and
results from short-term tests allow a
transfer from Group C to B2 or from
Group D to C.
Group D—Not Classified
This category is used for-agent(s) with
inadequate animal evidence of
carcinogenicity.
Group E—No Evidence of
Carcinogenicity for Humans
This category is used for agent(s) that
' show no evidence for carcinogenicity in
at least two adequate animal tests in
different species or in both
epidemiologic and animal studies.
V. References
Albert, R.EM Train, R.E.. and Anderson. E.
1977. Rationale developed by the
Environmental Protection Agency for the
assessment of carcinogenic risks. ]. Nad.
Cancer Inst. 58:1537-1541.
Feron, V.J., Grice, H.C., Griesemer, R.. Peto
R.. Agthe, C, Althoff, J.. Arnold. D.L.. ^
BlumenthaL H., Cabral, J.RJ>.. Delia Porta.
G., Ito. N., Kimmejle, G., Kroes, R., Mohr.
U., Napalkov, N.P., Odashima. S., Page.
N.P., Schramm, T.. Steinhoff, D., Sugar, J..
Tomatis, L., Uehleke. H., and Vouk, V. 1980.
Basic requirements for long-term assays for
carcinogenicity. In: Long-term and short-
term screening assays for carcinogens: a
critical appraisal. 1ARC Monographs.
Supplement 2. Lyon. France: International
Agency for Research on-Cancer, pp 21-83.
Interagency Regulatory Liaison Group (IRLG).
1979. Scientific basis for identification of
potential carcinogens and estimation of
risks. J. Nad. 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
(1ARC). 1982. IARC Monographs on the
Evaluation of the Carcinogenic Risk of
Chemicals to Humans. Supplement 4. Lyon.
France: International Agency for ReseHrch
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 analysis of data from
retrospective studies of disease. J. Natl.
Cancer Inst. 22:719-748.
National Center for loxicoiogicai Research
(NCTR). 1981. Guidelines for statistical
tests for carcinogenicity in chronic
bioassays. NCTR Biometry Technical
Report 81-001. Available from: National
Center for Toxicological Research.
National Research Council (NRC',. 1983. Risk
assessment in the Federal government:
-------
Federal Register / Vol. 49, No. 227 / Friday. November 23. 1984 / Notices
46301
managing the process. Washington, D.C.:
National Academy Press.
National Toxicology Program. 1984. Report of
the Ad Hoc Panel on Chemical'
Carcinogenesis Testing and Evaluation of
the National Toxicology Program. Board of
Scientific Counselors. Available from: U.S.
Government Printing Office, Washington,
D.C. 1984-421-132:4726.
Nutrition Foundation. 1983. The relevance of
mouse liver hepatoma 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). 1984. Chemical carcinogens:
review of the science and its associated
principles. Federal Register 49:21595-21661.
Peto, R.. Pike, M., Day, N.. Gray, R., Lee, P..
Parish, S., Peto,}.. Richard. S., and
Wahrendorf. ]. 1980. Guidelines for simple.
sensitive, significant tests for carcinogenic
effects in long-term animal experiments. In:
Monographs on the long-term and short-
term screening assays for carcinogens: a
critical appraisal. IARC Monographs.
Supplement 2. Lyon. France: International
Agency for Research on Cancer, pp. 311-
428.
Tomatis, L. 1977. The value of long-term
testing for the implementation of primary
prevention. In: Origins of human cancer.
Hiatt H.H., Watson. J.D., and Winstein.
J.A., eds. Cold Spring Harbor Laboratory.
pp. 1339-1357.
U.S. Environmental Protection Agency (U.S.
EPA). 1976. Interim procedures and
guidelines for health risk economic impact
assessments of suspected carcinogens.
Federal Register 41:21402-21405.
U.S. Environmental Protection Agency [U.S.
EPA). 1980. Water quality criterial
documents; availability. Federal Register
45:79318-79379.
U.S. Environmental Protection Agency (U.S.
EPA). 1983a. Good laboratory practices
standards—toxicology testing. Federal
Register 48:53922.
U.S. Environmental Projection Agency (U.S.
EPA). 1983b. Hazard evaluations: humans
and domestic animals. Subdivision F.
Available from: NTIS, Springfield. VA. PB
83-153916.
U.S. Environmental Protection Agency (U.S.
EPA). 1983c. Health effects test guidelines.
Available from: NTIS Springfield. VA. PB
83-232984.
U.S. Environmental Protection Agency (U.S.
EPA). 1984. Proposed guidelines for
exposure assessment.
U.S. Food and Drug Administration (U.S.
FDA). 1982. Toxicological prir.-iplc^ for the
safety assessment of direct food additives
•and color additives used in food. Available
from: Bureau of Foods. U.S. Food and Drug
Administration.
Ward. J.M., Griesemer, R.A., and Weisburger,
E.K. 1979a. The mouse liver tumor as an
endpoint in carcinogenesis tests. Toxicol.
Appl. Pharmacol. 51:389-397.
Ward, J.M. Goodman. D.G., Squire. R.A.-Chu,
K.C., and Linhart. M.S. 1979b. Neoplastic
and nonneoplastic lesions in aging (C57BL/
6N x C3H/HeN)F, (B6C3F,) mice. J. Nail.
Cancer Inst. 63:849-854.
IFR Doc. 84-30724 Filed 11-21-84: 8:45 am]
BILLING CODE 65SO-50-M
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£ife Systems, Jnc.
PART 2 - EXPOSURE ASSESSMENT
A3-3
-------
Friday
November 23, 1d84
Part VIII
Environmental
Protection Agency
Proposed Guidelines for Exposure
Assessment; Request for Comments
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46304
Federal Register / Vol. 49. No. 227 / Friday. November 23. 1984 / Notices
ENVIRONMENTAL PROTECTION
AGENCY
IFRL-2706-5]
Proposed Guidelines for Exposure
Assessment
AGENCY: Environmental Protection
Agency (EPA).
ACTION: Proposed Guidelines for
Exposure Assessment and Request for
Comments.
SUMMARY: The U.S. Environmental
Protection Agency is proposing
Guidelines for Exposure Assessment
(Guidelines). These Guidelines are
proposed for use within the policy and
procedural framework provided by the
various statutes which EPA administers
to guide Agency analysis of exposure
data. We solicit public comment and
will take public comment into account in
revising these Guidelines. These
Guidelines will be reviewed by the
Science Advisory Board in meetings
now tentatively scheduled for April
1985.
These proposed Guidelines were
developed as part of a broad guidelines
development program under the
auspices of the Office of Health and
Environmental Assessment (OHEA),
located in the Agency's Office of
Research and Development. Consonant
with the role of OHEA's Exposure
Assessment Group (EAG) as the
Agency's senior health committee for
exposure assessment, the Guidelines
were developed by an Agency-wide
working group chaired by the Director of
EAG.
DATE: Comments must be postmarked
by January 22.1985.
ADDRESSES: Comments may be mailed
or delivered to: Dr. James W. Falco,
Exposure Assessment Group (RD-689),
Office of Health and Environmental
Assessment, U.S. Environmental
Protection Agency, 401 M Street S.W..
Washington, DC 20460.
FOR FURTHER INFORMATION CONTACT:
Dr. James W. Falco, Telephone: 202-475-
8909.
SUPPLEMENTARY INFORMATION:
Preliminary drafts of these Guidelines
were sent out for review to 15 scientists
and engineers in the field of exposure
assessment within government,
universities in the United States and
abroad, and the private sector.
Comments received from these reviews,
generally favorable, were taken into
account in developing the Guidelines
proposed here.
In addition, as a result of the reviews.
four areas requiring further research
were identified as follows:
(1) Development of Mathematical
Model Selection Criteria.
A large number of mathematical
models are used to estimate a wide
variety of parameters needed for
estimating exposures. Guidance in the
form of selection criteria are needed to
ensure that the most appropriate
mathematical model is used for each
exposure parameter estimate.
(2) Development of Guidance for
Analysis of Metabolism Data.
Guidance is needed to provide
appropriate consideration of metabolism
data in the calculation of whole body
dose and in the extrapolation of whole
organism dose from one species to
another.
(3) Definition of the Relationship
Between Exposure Assessment and
Epidemiology.
Guidance is needed to ensure that
pertinent parameters of exposure are
measured in prospective epidemiologic
studies. Methods providing the best
estimates of exposure for retrospective
and historical epidemiologic studies
must be defined.
(4) Development of Methods to Relate
Exposures Measured by Personal
Monitoring to Source Contributions.
Guidance is needed to establish
methods to relate exposures as
measured by personal monitoring to
controllable sources and to discriminate
among possible sources and between
background and anthropogenic sources.
It is the Agency's intent to revise the
Guidelines periodically to incorporate
the results obtained in the four research
areas defined above as they become
available.
In addition to the publication of the
Guidelines, the Agency also will provide
technical support documents that
contain detailed technical information
needed to implement the Guidelines.
Two of these technical reports entitled
"Development of Statistical Distribution
or Ranges of Standard Factors Used in
Exposure Assessments" and
"Methodology for Characterization of
Uncertainty in Exposure Assessments"
are currently available. Technical
reports for the four new guideline areas
described above will be available at the
time of publication of the corresponding
guideline section. These technical
support documents will be revised
periodically to reflect improvements in
exposure assessment methods and new
information or experience.
Support documents used in the
preparation of these Guidelines as well
as comments received 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.
Dated: November 9.1984.
William D. Ruckelshaus.
Administrator.
Contents
I. Introduction
II. General Guidelines and Principles
A. Exposure and Dose
B. Decision Path to Determine Scope of the
Assessment
C. Uncertainty
III. Organization and Contents of an
Exposure Assessment
A. Overview
B. Detailed Explanation of Outline
1. Executive Summary
2. Introduction
3. General Information
4. Sources
5. Exposure Pathways and Environmental
Fate
6. Monitored or Estimated Concentration
Levels
7. Exposed Populations
8. integrated Exposure Analysis
9. References
10. Appendexes
I. Introduction
These Guidelines provide the Agency
with a general approach and framework
for carrying out human or nonhuman
exposure assessments for specified
pollutants. The Guidelines have-been—
developed to assist future assessment
activities and encourage improvement in
those EPA programs that require, or
could benefit from the use of exposure
assessments. The Guidelines are
procedural. They should be followed to
the extent possible in instances where
exposure assessment is a required
element in the regulatory process or
where exposure assessments are carried
out on a discretionary basis by EPA
management to support regulatory or
programmatic decisions.
This document, by laying out a set of
questions to be considered in carrying
out an exposure assessment, should help
avoid inadvertent mistakes of omission.
EPA recognizes that gaps in data will be
common, but the Guidelines will
nevertheless serve to assist in
organizing the data that are available,
including any new data developed as
part of the exposure assessment. It is
understood that exposure assessments
may be performed at many different
levels of detail depending on the scope
of the assessment.
These. Guidelines should also promote
consistency among various exposure
assessment activities that are carried
out by the Agency. Consistency with
respect to common physical, chemical,
and'biological parameters, with rsspect
to assumptions about typical exposure
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Federal Register / VoL 49, No. 227 / Friday, November 23, 1984 / Notices
46305
situations, and with respect to the
characterization of uncertainty of
estimates, will enhance the
comparability of results and enable the
Agency to improve the state-of-the-art of
exposure assessment over time through
the sharing of common data and
experiences.
It is recognized that the main
objective of an exposure assessment is
to provide reliable data and/or
estimates for a risk assessment Since a
risk assessment requires the coupling of
exposure information and toxicity or
effects information, the exposure
assessment process should be
coordinated with the toxicity/effects
assessment. This document provides a
common approach to format, which
should simplify the process of reading
and evaluating exposure assessments
and thereby increase their utility in
assessing risk.
. As the Agency performs more
exposure assessments, the Guidelines
will be revised to reflect the benefit of
experience.
II. General Guidelines and Principles
A. Exposure and Dose •
Exposure has been denned by
Committee E-47, Biological Effects and
Environmental Fate, of the American
Society for Testing and Materials.Tas the
contact with a chemical or physical
agent The magnitude of the exposure is
determined by measuring or estimating
the amount of an agent available at the
exchange boundaries, i.e., lungs, gut
skin, during some specified time.
Exposure assessment is the
determination or estimation (qualitative
or quantitative] of the magnitude,
frequency, duration, and route of
exposure. Exposure assessments may
consider past present and future .
exposures with varying techniques for
each phase, i.e., modeling of future
exposures, measurements of existing
exposure, and biological accumulation
for past exposures. Exposure
assessments are generally combined
with environmental and health effects
data in performing risk assessments.
In considering the exposure of a
subject to a hazardous agent there are
several related processes. The contact
between the subject of concern and the
ai^ent may lead to the intake of some of
the agent. If absorption occurs, this
constitutes an uptake (or an absorbed
dose) which then may lead to health
effects. When biological tissue or fluid
measurements indicate the presence of a
chemical, exposures can be estimated
from these data. Presence of a chemical
in such biological samples is the most
direct indication that an exposure has
occurred The route of exposure
generally impacts the overall exposure
and should be considered in performing
risk assessments.
B. Decision Path to Determine Scope of
the Assessment
The first step in preparing an
exposure assessment should be the
circumscription of the problem at hand
to minimize effort by use of a narrowing
process. A decision logic path that
describes this process is shown in
Figure 1. As illustrated in Figure 1, the
preliminary assessment and the in-depth
assessment are two major phases in this
logic path.
The preliminary assessment phase
should commence by considering what
risk is under study and what law might
regulate the exposure to the agent
Within this framework, a preliminary
data base should be compiled from
readily available scientific data and
exposure information based on
manufacturer, processor, and user
practices. Next the most likely areas of
exposure (manufacuring, processing,
consumer, distribution, disposal,
ambient water and food, etc.) should be
identified. Since a complete data search
has not been conducted, well-identified.
assumptions and order of magnitude
estimates are used to further narrow the
exposure areas of concern.
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Data from this preliminary exposure
assessment can then be coupled with
toxicity information to perform a
preliminary risk analysis. As a result of
this analysis, a decision will be made
that either an in-depth exposure
assessment is necessary or that there is
no need for further exposure
information. The organization and
contents of an in-depth exposure
assessment are given in the following
section.
•In assembling the information base for
either a preliminary assessment or a
more detailed assessment, its adequacy
should be ascertained by addressing the
following considerations:
—Availability of information in every
area needed for an adequate
assessment;
—Quantitative and qualitative nature of
the data;
—Reliability of information;
—Limitations on the ability to assess
exposure.
C. Uncertainty
Exposure assessments are based on
monitoring data, simulation model
estimates, and assumptions about
parameters used in approximating
actual exposure conditions. Both data
and assumptions contain varying
degrees of uncertainty which influence
the accuracy of exposure assessments.
An evaluation of these uncertainties is
important when the assessment is the
basis for regulatory action.
The uncertainty analyses performed
will vary depending on the scope of the
assessment the quantity and quality of
monitoring data collected, and the type
and complexity of mathematical models
used. A discussion of the types of
analysis used for quantifying
uncertainties in exposures is presented
in the next section.
III. Organization and Contents of an
Exposure Assessment
A. Overview
A suggested outline for an exposure
assessment document is given in Exhibit
1. The five major topics to be addressed
within most exposure assessments are
as follows: Source(s); Exposure
Pathways; Monitored or Estimated
Concentration Levels and Duration;
Exposed Population(s); and Integrated
Exposure Analysis. These five topics are
appropriate for exposure assessments in
general, whether the assessments are of
global, national, regional, local, site-
specific, workplacerrelated. or other
scope. The topics are appropriate for
exposure assessments on new or
existing chemicals and radionuclides.
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46306
Federal Register / Vol. 49. No. 227 / Friday. November 23. 1984 / Notices
They are also applicable to both single
media and multimedia assessments.
Since exposure assessments are
performed at different levels of detail,
the extent to which any assessment
contains items listed in Exhibit 1
depends upon its scope. The outline is a
guide to organize the data whenever
they are available.
B. Detailed Explanation of Outline
1. Executive Summary
The "Executive Summary" should be
written so that it can stand on its own
as a miniature report. Its main focus
should be on a succinct description of
the procedures used, assumptions
employed, and summary tables or charts
of the results. A brief discussion of the
uncertainties associated with the results
should be included.
2. Introduction (Purpose and Scope)
This section should state the intended
purpose of the exposure assessment and
identify the agent being investigated, the
types of sources and exposure routes
included, and the populations of
concern.
Exhibit 1.—Suggested Outline for an
Exposure Assessment
1. EXECUTIVE SUMMARY
2.. INTRODUCTION
a. Purpose
b. Scope —,-
3. GENERAL INFORMATION
a. Identity
(1) Molecular formula and structure. CAS
number. TSL number
(2) Description of technical grades,
contaminants, additives
(3) Other identifying characteristics
b. Chemical and Physical Properties
4. SOURCES
a. Characterization of Production and
Distribution
(1) Production and processing
(2) Distribution in commerce
b. Uses
c. Disposal
d. Summary of Environmental Releases
5. EXPOSURE PATHWAYS AND
ENVIRONMENTAL FATE
a. Transport and Transformation
b. Identification of Principal Pathways of
Exposure
c. Predicting Environmental Distribution
6. MONITORED OR ESTIMATED
CONCENTRATION LEVELS
a. Summary of Monitoring Data
b. Estimation of Environmental
Concentrations
c. Comparison of Concentration Estimates
with Monitoring Data
7. EXPOSED POPULATIONS
a. Human Populations (Size. Location, and
Habits)
(1) Population size and characteristics
(2) Population location
(3) Population habits
b. Nonhuman Populations (where
appropriate)
(1) Population size and Characteristics
(2) Population location
(3) Population habits
8. INTEGRATED EXPOSURE ANALYSIS
a. Calculation of Exposure
(1) Identification and characterization of
the exposed populations and critical
elements of the ecosystem
(2) Pathways of exposure
b. Human Dosimetry and Monitoring
c. Development of Exposure Scenarios and
Profiles
d. Evaluation of Uncertainty
9. REFERENCES
10. APPENDICES
3. General Information
' a. Identity. (1) Molecular formula and
structure, synonyms, Chemical Abstract
Service number, Toxic Substance List
number.
(2) Description of technical grades,
contaminants, additives.
(3) Other identifying characteristics.
b. Chemical and Physical Properties.
This subsection should provide a
summary description of the chemical
and physical properties of the agent.
Particular attention should be paid to
the features that would affect its
behavior in the environment. Examples
of factors to be included are molecular
weight, density, boiling point, melting
point vapor pressure, solubility, pK..
partition coefficients, and half-lives.
4. Sources
The points at which a hazardous
substance is believed to enter the
environment should be described, along
with any known rates of entry. Points of
entry may be indoors as well as
outdoors, and environments include
indoor settings such as offices as well as
outdoor environments. A detailed
exposure assessment should include a
study of sources, production, uses,
destruction/disposal, and environmental
release of a substance. The studies
should include a description of human
activities with respect to the substance
and the environmental releases resulting
from those activities. It should account
for the controlled mass flow of the
substance from creation to destruction
and provide estimates of environmental
releases at each step in this flow.
Seasonal variations in environmental
releases should also be examined. All
sources of the substances should be
accounted for with the sum of the uses,
destruction, and the environmental
releases. The environmental releases
can be described in terms of geographic
and temporal distribution and the
receiving environmental media, with-the
form identified at the various release
points.
a. Characterization of Production and
Distribution. All sources of the
substance's release to the environment.
consistent with the scope of the '
assessment, should be included, such as
production, extraction, processing,
imports, stockpiles, transportation.
accidental/incidental production as a
side reaction, and natural sources. The
sources should be located, and activities
involving exposure to the substance
should be identified.
b. Uses. The substance should be
traced from its sources through various
uses (with further follow-up on the
products made to determine the
presence of the original material as an
impurtiy], exports, stockpile increases,
etc.
c. Disposal. This subsection should
contain an evaluation of disposal sites
and destruction processes, such as
incineration of industrial chemical
wastes, incineration of the substance as
part of an end-use item in municipal
waste, landfilling of wastes, biological
destruction in a secondary wastewater
treatment plant, or destruction in the
process of using the end product.
Hazardous contaminants of the
substance may be included, and
products containing the substance as a
contaminant may be followed from
production through destruction/
disposal.
d. Summary of Environmental
Releases. Estimates should be made of
the quantities of the substances released
to the various environmental media.
Sources of release to the environment
include production, use, distribution/
transport, natural sources, disposal, and
contamination of other products.
Environmental releases should be
presented at a reasonable level of detail.
Extremely detailed exposure estimates
would attempt to specify the following
information for each significant
emission source: Location, amount of the
substances being released as a function
of time to each environmental medium,
physical characteristics of the emission
source, and the physical and chemical
form of the substance being released.
Evaluation of the uncertainties
associated,with the emission estimates
should be given. A detailed discussion
of procedures for estimating uncertainty
is presented in section S.d.
5. Exposure Pathways and
Environmental Fate
The exposure pathways section
should address how a hazardous agent
moves from the source to the exposed
population or subject. For a less detailed
assessment broad generalizations on'
environmental pathways and fate may
be made. In the absence of data, e.g., for
new substances, fate estimates may
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Federal Register / Vol. 49. No. 227 / Friday. November 23. 1984 / Notices
46307
have to be predicted by analogy with
data from other substances. Fate
estimates may alscrbe made by using
models and/or monitoring data and
laboratory-derived process rate
coefficients. At any level of detail,
certain pathways may be judged
insignficiant and not pursued further.
For more detailed assessments
involving environmental fate, the
sources analysis described previously
should provide the amount and rate of
emissions to the environment, and
possibly the locations and form of the
emissions. The environmental pathways
and fate analysis follows the substance
from its point of initial environmental
release, through the environment, to its
ultimate fate. It may result in an
estimation of the geographic and
temporal distribution of concentrations
of the substance in the various
contaminated environmental media.
a. Transport and transformation. The
substance, once released to the
environment, may be transported (e.g.,
convected downstream in water or on
suspended sediment, through the
atmosphere, etc.) or physically
transformed (e.g., volatilized, melted,
absorbed/ desorbed, etc.]; may undergo
chemical transformation such as
photoysis, hydrolysis, oxidation.
reduction; may undergo
biotransformation such as
biodegradation; or may accumulate in
one or more media. Thus, the
environmental behavior of a substance
should be evaluated before exposures
are assessed. Factors that should be
addressed include:
• How does the agent behave in air,
water, soil, and biological media? Does
it bioaccumulate or biodegrade? Is it
absorbed or taken up by plants?
* What are -the principal mechanisms
• for change or removal in each of the
environmental media.
• Does the agent react with other
compounds in the environment?
• Is there intermedia transfer? What
are the mechanisms for intermedia
transfer? What are the rates of the
intermedia transfer or reaction
mechanisms?
• How long might the agent remain in
each environmental medium? How does
its concentration change with time in
each medium?
• What are the products into which
the agent might degrade or change in the
environment? Are any of these
degradation products ecologically or
biologically harmful? What is the
environmental-behavior of the harmful
products?
• Is a steady-state concentration
distribution in the environment or in
specific segments of the environment,
achieved? If not can the nonsteady-
state distribution be described?
• What is the resultant distribution in
the environment—for different media.
different types or forms of the agent, for
different geographical areas, at different
times or seasons?
b. Identification of Principal
Pathways of Exposure. The principal
pathway analysis should evaluate the
sources, locations, and types of
environmental releases, together with
environmental behavioral factors, to
determine the significant routes of
human and environmental exposure to
the substance. Thus, by listing the
important characteristics of the
environmental release .(entering media,
emission rates, etc.) and the agent's
behavior (intermedia transfer,
persistence, etc.) after release to each of
the entering media, it should be possible
to follow the movement of the agent
from its initial release to its subsequent
fate in the environment. At any point in
the environment, human or
environmental exposure may occur.
Pathways that result in major
concentrations of the agent and high
potential for human or environmental
contact are the principal exposure
pathways.
c. Predicting Environmental
Distribution. Models may be used to
predict environmental distributions of
chemicals. Many modeling estimates of
environmental distribution of chemicals
are based in part on monitoring data. In
predicting environmental distributions
of chemicals, available monitgring data
should be considered.
In this section an estimation is made,
using appropriate models, of
representative concentrations of the
agent in different environmental media,
and its time-dependence in specific
geographical locations (e.g., river basins,
streams, etc.).
6. Monitored or Estimated Concentration
Levels
a. Summary of Monitoring Data.
Monitoring data are used to identify
releases (source terms) and, in the
exposure pathways and fate
assessments, to quantitatively estimate
both release rates and environmental
concentrations. Some examples of uses
of monitoring data are: Sampling of
stacks of discharge pipes for emissions
to the environment; testing of products
for chemical or radionuclide content:
testing of products for chemical or
radioactive releases; sampling of
appropriate points within a
manufacturing plant to determine
releases from industrial processes or
practices; and sampling of solid waste
for chemical or radionuclide content.
These data should be characterized as
to accuracy, precision, and
representativeness. If actual
environmental monitoring data are
unavailable, concentrations can be
estimated by various means, including
the use of fate models (see previous
section) or. in the case of new
chemicals, by analogy with p-.isting
chemicals.
The analysis of monitoring data '
should be considered a complement to
environmental pathway and fats
analysis for the following reasons: For
most pollutants, particularly organic and
new chemicals, monitoring data are
limited; analysis of monitoring data does
not often yield relationships between
environmental releases and
environmental concentration
distribution in media or geographic
locations that have not been monitored;
analysis of monitoring data does not
provide information on how and where
biota influence the environmental
distribution of a pollutant: and
monitored concentrations may not be
traceable to individual sources that EPA
can regulate. Monitoring data are,
however, a direct source of information
for exposure analysis and, furthermore,
they can be used to calibrate or -
extrapolatejnodels or calculations to
assess environmental distribution.
b. Estimation of Environmental
Concentrations. Concentrations of
agents should be estimated for all
environmental media that might
contribute to significant exposures.
Generally, the environmental
concentrations are'estimated from
monitoring data, mathematical models.
or a combination of the two.
The concentrations must be estimated
and presented in a format consistent
with available dose-response
information. In some cases an estimate
of annual average concentration will be
sufficient, while in other cases the
temporal distribution of concentrations
may be required. Future environmental
concentrations resulting from current or
past releases may also be projected. In
some cases, both the temporal and
geographic distributions of the
concentration may be assessed.
Moreover, if the agent has natural
sources, the contribution of these to
environmental concentrations may be
relevant. These "background"
concentrations may be particularly
important when the results of tests of
toxic effects show a threshold or
distinctly nonlinear dose-response.
The uncertainties associated with the
estimated concentrations should be
evaluated by an analysis of the
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46308
Federal Register / Vol. 49. No. 227 / Friday. November 23. 1984 / Notices
uncertainties of the model parameters
and input variables. When the estimates
of the environmental concentrations are
based on mathematical models..the
model results should be compared to
available monitoring data, and any
significant discrepancies should be
discussed. Reliable, analytically-
determined values should be given
precedence over estimated values
whenever significant discrepancies are
found.
7. Exposed Populations
Populations selected for study may be
done a priori, but frequently the
populations will be identified as a result
of the sources and fate studies. From an
analysis of the distribution of the agent,
populations convected and
subpopulations (i.e., collections of
subjects) at potentially high explosure
can be identified, which will then form
the basis for the populations studied.
Subpopulations of high sensitivity, such
as pregnant women, infants, chronically
ill, etc., may be studied separately.
In many cases, exposed populations
can be described only generally. In some
cases, however, more specific
information may be available on matters
• such as the following:
a. Human Populations. (1) Population
size and characteristics (e.g.. trends,
sex/age distribution)
(2) Population location
(3) Population habits—transportation
habits, eating habits, recreational habits,
workplace habits, product use habits,
etc.
b. Nonhuman Populations (where
appropriate). (I) Population size and
characteristics (e.g., species, trends)
(2) Population location
(3) Population habits
Census and other survey data may be
used to identify and describe the
population exposed to various
contaminated environmental media.
Depending on the characteristics of
available toxicological data, it may be
appropriate to describe the exposed
population by other characteristics such
as species, race-age-sex distribution,
and health status.
8. Integrated Exposure Analysis
The integrated exposure analysis
combines the estimation of
environmental concentrations (sources
and fate information] with the
description of the exposed population to
yield exposure profiles. Data should be
provided on the size of the exposed
populations; duration, frequency, and
intensity of exposure: and routes of
exposure. Exposures should be related
to sourc es.
For more detailed assessments, the
estimated environmental concentrations
should be considered in conjunction
with the geographic distribution of the -
human and environmental populations.
The behavioral and biological
characteristics of the exposed
populations should be considered and
the exposures of populations to various
concentration profiles should be
estimated.The results can be presented
in tabular or graphic form, and an
estimate of the uncertainty associated
with them should be provided.
a. Calculations of Exposure. The
calculation of exposure involves two
major aspects:
(1) Identification of the Exposed
Population and Critical Elements of the*
Ecosystem.
The estimate of environmental <
concentrations also should give the
geograhical areas and environmental
media contaminated. The stated purpose
of the assessment should have
prescribed the human and
environmental subjects for which
exposures are to be calculated. If the
subjects are not listed, the contaminated
geographical areas and environmental
media can be evaluated to determine
subject populations. The degree of detail
to be used in defining the exposed
population distribution depends on the
concentration gradient over geographic
areas.
(2) Identification of pathways of
exposure.
(a) Identification and description of
the routes by which the substances
travel from production site, through
uses, through environmental releases/
sources, through transport and fate
processes, to the target population.
(b) Quantitative estimates of the
amounts of the chemical following each
exposure pathway. Such estimates allow
the various pathways to be put in the
perspective of relative importance.
From the geogrpahic and tempral
distribution of environmental
concentrations, the exposed population,
the behavioral characteristics, and the
critical elements of the ecosystem,
exposure distributions can be estimated.
The results of exposure calculation
should be presented in a format that is
consistent with the requirements of the
dose-response functions which may
later be used in a risk assessment. For
example, when health risks caused by
exposure over extended durations are
considered, average daily exposure over
the duration of exposure usually is
calculated. When lifetime risks are
considered, average daily exposure .over
a lifetime usually is calculated. In
contrast when health risks caused by
exposures over short durations are
considered, exposure rates are
calculated over short time intervals to
ensure that peak risks are defined.
Many exposure assessments are based
on the average exposure occurring over
the exposure period. The range of
possible exposures is usually divided
into intervals, and the exposures within
each interval are counted. The reuslts
can be presented in a tabular form or as
a histogram.
The population residing in a specific
geographic area may be exposed to a
substance from several exposure routes.
For each exposure route, exposure of
individuals in these populations may be
determined by summing the contribution
of all sources to the exposure route.
When exposures involve more than one
exposure route, the relative amounts of
a substance absorbed is usually route
dependent. Consequently, total
absorbed dose estimates must account
for these differences. Because EPA
regulates sources of releases, the
contribution to exposures from each
type of source being considered should
be displayed. Exposure estimates should
be presented for each significant
exposure route (i.e., those routes
consistent with the regulatory purpose),
and the results should be^ tabulated in
such a way that total externally applied
and-absorbed dose can be determined.
b. Human Dosimetry and Monitoring.
Biological monitoring of human body
fluids and tissues for substances or their
metabolites can be used to estimate
current or past exposure to chemicals.
When analytical methods are available,
chemicals that have been absorbed into
the body can be measured in body
tissue and fluid. Such measurements can
be used to estimate exposure. However.
the substances to which humans are
exposed are highly variable in the
degree to which they leave in the body
reliable indicators of exposure.
Furthermore, although a compound may
be relatively easy to detect in body
tissue, for some compounds, attributing
body burdens to specific environmental
releases may be difficult because of
limited ability to obtain environmental
monitoring data.
c. Development of Exposure Scenarios
and Profiles. Depending on the scope of
the exposure assessment, the total
exposure may be fractionated into one
or more "exposure scenarios" to
facilitate quantification. As an example.
Table 1 lists seven very broad scenarios:
Occupational, Consumer.
Transportation. Disposal, Food, Drinking
Water, and Ambient. For each of the
scenarios, the major topics necessary to
quantify exposure include sources,
pathways, monitoring, and population
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Federal Register / Vol. 49. No. 227 / Friday, November 23. 1984 /Notices
46309
characteristics. Investigation of only one
scenario may be necessary for the scope
of some assessments. For example, a
pesticide application exposure
assessment may consider the
occupational scenario which would
address the exposure to applicators and
populations in the vicinity of the site. An
exposure assessment around a
hazardous waste site may focus on the
disposal scenario. The exposure
• assessment also may consider other
scenarios. The more extensive and
comprehensive the scope, the more
scenarios are usually involved.
TABLE 1. EXPOSURE ASSESSMENT NEEDS FOR VARIOUS EXPOSURE SCENARIOS
Exposure scenario
Source needs
Fata needs
Population characteristics needs
Monitoring needs
Occupations! (chemical production)..
Consumer (direct use ol chemical or
inaovenam use).
Transportation/storage/spills
Disposal (include incineration, land-
fill).
Site/plant locations irvplant/on-site
materials balance.
Consumption rates, iflsti (button pat-
t3cn amounts in products.
Patterns ol distribution and transpor-
tation? models for spills.
Materials balance around disposal
mottled, officNMny, rtthimii-i to en*
Ptty steal and
models.
chemical properties
Workers, families, peculation around
sites/plants.
Physical and chemical properties,
snetl life release rates, models.
Physical and chemical properties,
enwonmentaj fate models.
Fate within disposal process; envi-
ronmental fata ol releases;
Consumers....
Drinking water....
Ambient..
Food chain, rrarfr aging, inriflvea .-]
Groundwater. surface water, dbtrfeu-
don system.
Releases to environment air, land.
Food cnajii models, late during
preparation or processing of food.
Leach lataa from pipes, ctdonnation
processes, fate in water models.
Environmental fate models
Storage, transportation workers.
general population in area.
Workers at site of disposal, general
population around site.
General population, nonhuman pop-
ulation.
General population
General population, nonhuman pop-
ulation. A,
In-ptam/on-site releases, ambient
levels surrounding site/plants.
human monitoring.
Levels in products releases.
Releases, ambient levels.
Releases, levels at various points
wrtrun process, ambient levels.
Levels in food, feedstuff; food chain
sampling. • .
Levels in drinking water, groundwat-
er. surface water, treatment
plants.
Ambient Air. water, soil, etc.; human
monitoring.
It will usually be advantageous in
performing an exposure assessment to
identify exposure scenarios, quantify the
exposure in each scenario, and then
integrate the scenarios to estimate total
exposure. In this "integrated exposure
analysis," summation of independent
exposures from different scenarios
(keeping exposure routes separate) often
will result in a breakout of exposure by
subpopulations. since the individual
scenarios usually treat exposure by
subpopulation. Therefore, the
integration of the scenarios, or
integrated exposure analysis, will often
result in an exposure profile.
For each exposed subpopulation,
exposure profiles should include the size
of the group, the make-up of the group
(age, sex, etc.), the source of the agent,
the exposure pathways, the frequency
and the intensity of exposure by each
route (dermal, inhalation, etc.), duration
of exposure, and the form of the agent
when exposure occurs. Assumptions
and uncertainties associated with each
scenario and profile should be clearly
discussed.
d. Evaluation of Uncertainty. (1)
Introduction. Often an exposure
assessment progresses through several
stages of refinement. The purpose of
these Guidelines is to present methods
appropriate for characterization of
uncertainty for assessments at various
stages of refinement, from assessments
based upon limited initial data to those
based upon extensive data.
The appropriate method for
characterizing uncertainty for an
exposure assessment depends upon the
underlying parameters being estimated.
the type and-extent of data available,
and the estimation procedures utilized.
The uncertainty of interest is always
with regard to the population
characteristic being estimated. For
example, when the population
distribution of exposures is being
estimated, characterization of
uncertainty addresses the possible
differences between the estimated
distribution of exposure and the true
population distribution of exposure.
An exposure assessment quantifies
contact of a substance with affected
population members (human or
nonhuman subjects). The measure of
contact (e.g., environmental level of
absorbed dose) depends upon what is
needed to predict risk. An integrated
exposure assessment quantifies this
contact via all routes of exposure
(inhalation, ingestion, and dermal) and
all exposure pathways (e.g.,
occupational exposure, exposure from
consumption of manufactured goods,
etc.). The exposed population generally
is partitioned into subpopulations such
that the likely exposure of all members
of a subpopulation is attributable to the
same sources. The exposure for each
member of a subpopulation is then the
sum of exposures over a fixed set of
sources and pathways. The measured or
estimated exposures for members of a
sub'population are ideally used to
estimate the subpopulation distribution
of exposure or characteristics thereof.
However, a lack of sufficient
information sometimes precludes
estimation of the subpopulation
distributions of exposure and only
summary measures of this distribution,
such as the mean, minimum, maximum,
etc.. are estimated. In each case
characterization of uncertainty for the
exposure assessment primarily
addresses limitations of the data and the
estimation procedures. The proportions
of the population members in the
individual subpopulations are usually
estimated and can be used (by
combining estimated distributions for
the subpopulations) to estimate the
distribution of exposure for the total
population. Uncertainty concerning the
sizes of the subpopulations should be
"~arfdres"sed~b5rdiscussing limitations of
the data and estimation methods as well
as by tabulating confidence interval
estimates for the population sizes
whenever possible.
(2) Assessments Based Upon Limited
Initial Data. The initial exposure
assessment for a substance may be
based upon limited data for exposure
and/or input variables for an exposure
prediction model (i.e., an equation that
expresses exposure as a function of one
or more input variables). These data
might be either extant data'or data
produced by an initial small-scale study.
The initial limited data frequently are
insufficient to permit estimation of the
entire distribution of exposure. Instead.
summary measures of this distribution,
such as the mean, minimum, and
maximum, are usually estimated.
If the assessment is based upon
' measured exposures, the methods used
to characterize uncertainty depend
mainly upon whether or not the data
result from a probability sample for
which the probability of inclusion is
known for each sample member.
Characterization of uncertainty for an
assessment based upon a probability
sample of exposures is discussed later
in section 8. d. (5). If the measured
exposures are not based upon a
probability sample, acknowledgement
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46310 Federal Register / Vol 4a No. 227 / Friday. November 23. 1384 / Notices
that no strictly valid statistical
inferences can be made beyond the
units actually in the sample is one
aspect of the characterization of
uncertainty. If'inference procedures are
implemented, the assumptions upon
which these inferences are based (e.g.,
treatment of the sample as if it was a
simple random sample, or assumption of
an underlying model) should be
explicitly stated and justified. The data
collection methods and inherent
limitations of the data should also be
discussed.
An initial exposure assessment also
may be based upon limited data, such as
estimated ranges, for input variables for
an exposure prediction model.- The
exposure prediction mode! would be •
derived from a postulated exposure
scenario that describes the pathways
from sources to contact with population
members. If the data were only
sufficient to support estimates of the
ranges of the input variables, the
exposure assessment might be limited to
a sensitivity analysis. The purpose of
the sensitivity analysis would be to
identify influential model input
variables and develop bounds on the
distribution of exposure. A sensitivity
analysis would estimate the range-of
exposures that would result as
individual model input variables were
varied from their minimum to their
maximum possible values with the other
input variables held at fixed values, &£.,
their midranges. The overall minimum
and maximum possible exposures
usually would be estimated also. For an
exposure assessment of this type, the
uncertainty would be characterized by
describing the limitations of the data
used to estimate plausible ranges of
model input variables and by discussing
justification for the model. Justification
of the model should include a
description of the exposure scenario,
choice of model input variables, and the
functional form of the model Sensitivity
to the model formulation also can be
investigated by replicating the
sensitivity analysis for plausible
alternative models.
If the maximum possible exposure
estimated by the sensitivity analysis
presented no significant health risk,
there might be no need to refine the
assessment. If both the minimum and
maximum exposures presented a
potentially significant health risk, it
would be known that the exposure
scenario represented a significant health
problem without refining the
assessment When the minimum
exposure estimate does not present a
potentially significant health risk and
maximum dose, then greater importance
is placed
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Federal Register / Vol. 49. No. 227 / Friday. November 23. 1984 / Notices
^6311
distribution. Alternatively, the sample
survey data can be used to compute
joint confidence interval estimates for
percehtiles of the input variable
distribution, which can then be used to
generate confidence interval estimates
for percentiles of the exposure
distribution. In either case, the interval
estimates for percentiles of the exposure
distribution are a useful quantitative
characterization of uncertainty.
Characterization of uncertainty for the
exposure assessment would contain a
thorough discussion of limitations of the
data and justification for the model.used
to compute expected exposures. The
design of the sample survey used to
produce the data base should also be
discussed. If a probability sample were
not used, the lack of a probability
sample would be an additional source of
uncertainty. Any assumptions used in
computing the confidence interval
estimates, such as independence of
model input variables, should be
explicitly stated and justified.
Sensitivity to model formulation can be
investigated by estimating the
distribution of exposure for plausible
alternative models and comparing the
estimated percentiles, if sample survey
data have been collected for the input
variables of the alternative models.
Appropriate available data for exposure
should be used to validate the predicted
distribution of exposure. If specific
probability distributions have been
presumed for any model input variables,
the data for these variables should be
used to test for goodness of fit for these
distributions.
(5) Assessment Based Upon Data for
Exposure. A major reduction in the
uncertainty associated with an exposure
assessment can be achieved by directly
measuring the exposure for a sufficiently
large sample of members of the affected
population. This reduction in
uncertainty is achieved by eliminating
the use of a model to predict exposure.
The measured exposure levels can be
used to directly estimate the population
distribution of exposure and confidence
interval estimates for percentiles of the
exposure distribution. Direct confidence
interval estimates also can be computed
for other characteristics of the exposure •
distribution, such as the mean exposure.
These confidence interval estimates
are then the primary characterization of
uncertainty for the exposure
assessment. Limitations of the data and
design of the sample survey used to
collect the data also should be
discussed. If the sample was not a
probability sample, this would again be
an additional source of uncertainty.
(6) Summary. A summary of the
primary methods recommended for
characterizing uncertainty in exposure
assessments is presented in Table 2.
Virtually all exposure assessments.
except those based upon measured
exposure levels for a probability sample
of population members, rely upon a
model to predict exposure. The model
may be any mathematical function,
simple ox complex, that expresses an
individual's exposure as a function of
one or more input variables. Whenever
a model that has not been validated is
used as the basis for an exposure
assessment, the uncertainty associated
with the exposure assessment may be
substantial. The primary
characterization of uncertainty is at
least partly qualitative in this case, i.e..
it includes a description of the
assumptions inherent in the model and
their justification. Plausible alternative
models should be discussed. Sensitivity
of the exposure assessment to model
formulation can be investigated by
replicating the assessment for plausible
alternative models.
TABLE Z—SUMMARY OF PRIMARY METHODS-FOR CHARACTERIZING UNCERTAINTY FOR EXPOSURE ASSESSMENTS
Type and extern of date
Population characteristic being estimated
Primary methods lor characterizing uncertainty
Qualitative method*
Quantitative methods
Measured exposures lor a large sample at
population uieinboia.
Measured exposures lor a small sample of
population members.
Measured model input variables lor a large
sample of population members.
Estimated distnputions of model input varia-
Umitad data for model input variables..
Distribution or exposure....
Summary parameters) of the exposure distri-
bution, e.g., mean or a percentae.
Disbibulion of exposure....
1. Limitations of the survey design and meas-
urement techniques.
1. Limitations of the survey design and meas-
urement tecnrnquea. /
1. Limitations of the survey design and
urement techniques.
2. Validity of the exposure model
Distribution of exposure...
1. Validity of the exposure model
2. Limitations of the data or other basis lor
the input variable distributions.
&nd
sure distribution.
1. Limitations of the data
2. Validity of the exposure model..
1. Confidence interval estimates lor percent-
des of the exposure distribution.
2. Goodness of fit lor exposure models, if any
have been postulated.
1. Confidence interval estimates lor the sum-
mary parameter(s).
2. Goodness of fit for exposure models, if any
have been postulated.
1. Confidence interval estimates for percent-
lies of the exposure distribution.
2. Goodness of fit for input variable distribu-
tion functions, it any have been postulated.
3. Estimated distribution of exposure based
upon alternative models.
1. Confidence interval estimates for percent-
iles of the exposure distribution.
2. Goodness of fit for input variable distribu-
tions, if input variable data are available.
3. Estimated distribution of exposure based
upon alternative models.
If input variable data are very limited, e.g.,
some extant data collected lor other pur-
poses, quantitative characterization of un-
certainty may not be possible.
When an exposure assessment is
based upon directly measured exposure
'.evels for a probability sample of
population members, uncertainly can be
greatly reduced and described
quantitatively. In this case, the primary
sources of uncertainty are measurement
errors and sampling errors. The effects
of these sources of error are measured
quantitatively by confidence interval
estimates of psrcentiles of the exposure
distribution. Moreover, the sampling
errors can be limited by taking a large
sample.
Whenever the latter is not feasible, it
is sometimes possible to obtain at least
some data for exposure and model input
variables. These data should be used to
assess goodness of fit of the model and/
or presumed distributions of input
variables. This substantially reduces the
amount of quantitative uncertainty for
estimation of the distribution of
exposure and is strongly recommended.
It is recognized, however, that it may not
be feasible to collect such data.
9. References
The references should contain a
listing of all reports, documents, articles.
memoranda, contacts, etc. that have
been cited in the report.
10. Appendices
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46312 Federal Register / Vol. 49, No. 227 / Friday. November 23. 1964 / Notices
The appendices may contain such
items as memoranda and letters that are
not readily accessible, other tables of
monitoring data, detailed lists of
emission sources, detailed tables of
exposures, process flow diagrams,
mathematical model formulations, or
any other item that may be needed to
describe or document the exposure
assessment.
(FR Doc. 84-30723 Filed 11-21-84:8:45 am)
BILLING CODE «S60-«0-M
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£ifc Systems, Jnc.
PART 3 - MUTAGENICITY RISK ASSESSMENT
A3-4
-------
Friday
November 23, 1984
Part IX
Environmental
Protection Agency
Proposed Guidelines for Mutagenicity
Risk Assessment; Request for Comments
-------
46314
Federal Register / Vol. 49. No. 227 / Friday. November 23, 1984 / Notices
ENVIRONMENTAL PROTECTION
AGENCY
[FRL-2706-6]
Proposed Guidelines for Mutagenicity
Risk Assessment
AGENCY: Environmental Protection
Agency (EPA).
ACTION: Proposed Guidelines for
Mutagenicity Risk Assessment and
Request for Comments.
SUMMARY: The U.S. Environmental
Protection Agency is proposing
Guidelines for Mutagenicity Risk
Assessment (Guidelines). These
Guidelines are proposed for use within
the policy and procedural framework
provided by the various statutes that
EPA administers to guide Agency
analysis of mutagenicity data. We solicit
public comment and will take public
comment into account in revising these
Guidelines. These Guidelines will be
reviewed by the Science Advisory Board
in meetings now tentatively scheduled
for April 1985.
These proposed Guidelines were
developed as part of a broad guidelines
development program under the
auspices of the Office of Health and
Environmental Assessment (OHEA),
located in the Agency's Office of
Research and Development. Consonant
with the role-of OHEA's Reproductive
Effects Assessment Group (REAG) as
the Agency's senior health committee
for mutagenicity assessment, the
Guidelines were developed by an
Agency-wide working group chaired by
the REAG.
DATES: Comments must be postmarked
by January 22,1985.
ADDRESSES: Comments may be mailed
or delivered to: Dr. David Jacobson-
Kram, Reproductive Effects Assessment
Group (RD-689). Office of Health and
Environmental Assessment U.S.
Environmental Protection Agency, 401 M
Street SW., Washington, DC 20460.
FOR FURTHER INFORMATION CONTACT
Dr. David Jacobson-Kram, Telephone:
202-382-7338.
SUPPLEMENTARY INFORMATION: Public
comments received as a result of the
proposed guidelines for Mutagenicity
Risk Assessment, which was published
in the Federal Register [45(221):74984-
74988) on November 13. 1980. have been
addressed. The guidelines published
here reflect the suggestions that were
provided during that initial comment
period. A new draft of these Guidelines,
taking into account the earlier public
comments, was recently sent for review
to approximately 14 scientists in the
field of chemical mutagenesis within
government, universities in the United
States, and the private sector.
Comments received from these reviews,
generally favorable, were also taken
into account in developing the
Guidelines proposed here.
References and supporting documents
used in the preparation of these
Guidelines as well as comments
received are available for inspection
and copying at the Public Information
Reference Unit (202-382-5926), EPA
Headquarters Library, 401 M Street, SW,
Washington, DC, between the hours of
8:00 a.m. and 4:30 p.m.
Dated- November 9,1984.
William D. Ruckelshaus,
Administrator.
Contents
I. Introduction
II Comments Received From the Federal
Register Publication of the Proposed 1980
Guidelines and Agency Responses to
These Comments
A. Comments on the Introduction
B. Concepts Relating to Heritable Genetic
Risk
C. Testing Systems
D. Weights-Evidence Approach
E. Quantitative Assessement of Results
III. Proposed Guidelines
A. Introduction
1. Concepts Relating to Heritable
Mutagenic Risk
2. Test Systems
B. Qualitative Assessment (Hazard
Identification)
1. Mutagenic Activity
2. Chemical Interactions in the
Mammalian Gonad
3. Weight-of-Evidence Determination
C. Quantitative Assessment
1. Dose-Response
2. Exposure Assessment
3. Risk Characterization
IV. References
I. Introduction
On November 13,1980, the U.S.
Environmental Protection Agency (EPA)
published purposed guidelines for
Mutagenicity Risk Assessment (1} and
solicited comments on those guidelines.
The proposed guidelines of 1980
described the procedures that the
Agency would follow to evaluate the
genetic risks associated with the
exposure of humans to chemical
mutagens. These procedures
incorporated a weight-of-evidence
approach that considered the quality
and adequacy of all the available data «•
on a chemical substance in order to
make qualitative, and. where possible,
quantitative evaluations of mutagenic
potential. The Agency stated that '
mutagenicity risk assessments prepared
pursuant to the proposed guidelines
would be utilized within the
requirements and constraints of the
applicable statutes that the Agency
administers to arrive at regulatory
decisions concerning mutagenicity.
The current proposed Guidelines
address the comments received in
response to the Agency's proposed
mutagenicity risk assessment guidelines
and provide the basis for the Agency's
risk assessments for mutagenicity.
These Guidelines, which adopt the
general approach set forth in the 1980
proposal, reflect additional changes
made in response to the comments and
to new scientific information generated
since the time of the proposal.
The current proposed Guidelines
reflect changes made in response to the
public comments to the proposed
guidelines of 1980. These changes dealt
primarily with the section addressing
the weight-of-evidence approach. This
section has been expanded to define
"sufficient," "suggestive," and "limited"
evidence for potential human germ-cell
mutagenicity and to include two
categories of evidence, "sufficient" and
"suggestive" for chemical interaction
with the gonads. Also, in the
quantitative assessment section, the
dominant skeletal and dominant
cataract tests have been added to the
list of systems for possible use in
estimating the magnitude of genetic '
risks. Other minor changes have been
made in the text for clarification.
A draft of the current proposed
Guidelines was submitted for review to
individuals from industry, educational
institutions, enivornmental groups, and
other government agencies. These
reviews were useful in revising the
Guidelines.
The Agency has not attempted to
provide in the current proposed
Guidelines a detailed discussion of the
mechanisms of mutagenicity or of the
various test systems that are currently
in use to detect mutagenic potential.
Background information on mutagenicity
•end mutagenic test systems is available
in "Identifying and Estimating the
Genetic Impact of Chemical
Environmental Mutagens," National
Academy of Sciences (NAS) Committee
on Chemical Environmental Mutagens
(2), as well as in other recent
publications^, 4).
For the information of the reviewer,
Chapter II discusses the comments that
were received in response to tne
proposed guidelines of 1980 and the
Agency's responses to those comments.
The current proposed Guidelines for
Mutagenicity Risk Assessment, for
which comments are currently invited.
are described in Chapter III. The Agencj
anticipates that as methods for
mutagenicity risk assessment are
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Federal Register / Vol. 49. No. 227 / Friday. November 23. 1984 / Notices
46315
refined, and more information becomes
available in the area of mutagenicity.
•visions to these Guidelines may be
sirable or necessary.
- II. Comments Received From the Federal
Register Publication of the Proposed
isau Guidelines and Agency Responses
to These Comments
As stated in the Introduction, the
current Guidelines are being proposed to
encourage further public comment. For
the information of the reviewer, a
summary of the public comments
received in response to the proposed
guidelines of 1980 and the Agency
responds to those comments are
presented here.
A totul of 34 comments were received.
17 from manufacturers of regulated
products, eight from associations, four
from individuals, three from educational
institutions, and one each from a private
consulting laboratory and a government
agency. Many responses noted that the
proposed guidelines of 1080 were timely
and appropriate and praised the Agency
fur initiating procedures for scientific
evaluation of mutagenicity data. Other
commenters felt that the proposed
guidelines were "premature." Various
reasons were given for this position: (1)
The mechanisms by which mutations
occur are not understood: (2) the data
lases for many mutagenicity tests are
Timited, and hence the tests have not
been validated: (3) the Agency should
wait until the EPA Gene-Tox Program is
completed: and (4) epidemiologic studies
have failed to document chemically-
induced mutations in humans.
It is the opinion of the Agency that
there is a need for mutagenicity
guidelines because various statutes
administered by the Agency provide the
authority to regulate chemicals on the
basis of mutagenicity. The purpose of
the current proposed Guidelines is to
promote Agency-wide consistency in the
evaluation of mutagenicity data. In
response to the specific concerns
enumerated above relating to the issue
of prematurity, the Agency has
concluded that the comments do not
provide an adequate basis for delaying
the development of mutagenicity
guidelines. Specifically, with regard to
the first comment that the mechanisms
by which mutations occur are not
understood, the Agency does not believe
that a full understanding of all aspects
of these mechanisms is necessary to
evaluate the mutagenic potential of
chemicals in the environment.
Additionally, the comment ignores the
«tensive body of data on specific
emical DNA adducts. repair
processes, and mutational expression
that enable description of the mutational
process in specific physiochemical terms
(2).
With regard to the second comment,
the Agency agrees that the data bases
for many mutagenicity tests are limited:
however, the Agency does not agree that
the validity of a test is a function of the
•ize of the data base. Validity is the
extent to which a test measures the
particular biological end point of
interest and should not be confused with
sensitivity, the proportion of known
mutagens that are positive in a system.
or specificity, the proportion of
nonmutagens that are negative. Hence, a
mutagenesis assay ia validated when Its
ability to detect a heritable genetic
change is demonstrated.
In response to the third comment, the
Agency does not believe it is necessary
to wait for completion of the Gene-Tox
Program before issuing guidelines for
evaluating mutagenicity data. The
Agency acknowledges that future
scientific developments can be expected
to affect the methods for the evaluation
of mutagenicity data. Such
developments may stem from phase II of
the Gene-Tox Program (which focuses
on test applications) as well as from
other collaborative activities in basic
and applied research. However, the
Agency believes that the current
Guidelines, as written, can
accommodate new information.
With respect to the fourth comment
the Agency does not agree that the
failure to identify a chemical as a
known human mutagen is justification
for not proposing guideline* to evaluate
mutagenicity data. Despite the difficulty
in translating changes in mutation rate
to alterations in disease frequency, the
NAS Committee on Chemical
Environmental Mutagens has concluded
that the aet effect of an increase in
mutation rate is harmful because almost
all mutants with any detectable effect
are deleterious (2).
A. Comments on the Introduction
Many commenters on the proposed
guidelines of 1980 were critical of the
statement, "Since the prospect of curing
most heritable diseases caused by
mutagens in the near future is unlikely.
minimizing exposure to mutagens is
among the best available means to
protect against further deterioration of
the human gene pool." At the present
time there is no direct evidence in
humans that heritable diseases are
being caused by chemical mutagens, and
there is no evidence of deterioration of
the gene pool. This sentence has been
deleted.
Several commenters objected to the
statement, "Mutations are largely
recognized as being deleterious." and
pointed out-that many mutations are
silent or have no effect. In the current
proposed Guidelines, this sentence has
been changed to read. "It is generally
recognized that most mutations that are
phenotypically expressed are in some
ways deleterious to the organism
carrying them."
Gne commenter requested an
explanation of how mulageninity
guidelines would be administered and
requested a statement indicating
requirements for genetic toxicology
testing in premarket manufacturing
notices. The Agency believes that the
language in the current proposed
Guidelines clearly states that they will
be used to assess risks associated with
human exposure to chemical mutugens.
Requirements for genetic toxicology
testing are the responsibility of the
appropriate Agency office.
B. Concepts Relating to Heritable
Genetic Risk
One commenter objected to the
definition of a mutagen because it was
not limited to stable and heritable
alternations in the ONA. The Agency
agrees that the ultimate end point of
concern for the purpose of the current
proposed Guidelines is heritable and
stable-mutation. For gene mutations,
heritability is an obvious and necessary
component, since all tests used to detect
gene mutations actually detect mutant
cells or organisms that are descendants
of the treated cells. The same is not
always true for certain cytogenetic end
points, such as chromatid breaks, etc..
which may be 'detected in the same cell
generation in which they occur. Since
these latter end points provide
information relevant to heritable
mutation, they will be considered in any
mutagenicity assessment. As a result.
the Agency feels that the general
definition of a mutagen as used in these
Guidelines is appropriate.
C. Testing Systems
One commenter felt that most
cytogenetic end points that are routinely
evaluated (e.g.. chromosome breaks,
micronuclei) are not transmitted, and
therefore, are not germane to the issue
of heritable mutation. The Agency
disagrees. Although it is clear that cells
that carry such aberrations generally do
not reproduce, other related aberrations
(i.e., balanced translocations.
inversions, small duplications, and
deficiencies) are compatible with cell
survival in germ cells and can be
transmitted. Additionally, there is no
evidence indicating that the non-
transmissible aberrations occur by
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Federal Register / Vol. 49. No. 227 / Friday. November 23, 1984 / Notices
mechanisms different from transmissible
aberrations.
- Several commenters requested that
the Agency establish minimal criteria by
which assays are to be judged for use in
risk assessment determinations. The
Agency believes that to list a specific set
of criteria that must be met for each
assay before the Agency evaluates data
would be overly restrictive and
inappropriate. Data generated in any
system that measures or correlates with
a true genetic end point may provide -
some useful information. The Agency
believes that the general protocols and
criteria for data evaluation established
by the expert committees of the Phase-I
Gene-Tox Program as well as other
sources provide sufficient guidance for
those planning to conduct mutagenicity
tests.
D. Weight-of-Evidence Approach
Several commentes suggested that the
weight-of-evidence section required
clarification of the phrase, "positive
response in any two different point
mutation test systems," because this
phrase may be subject to various
interpretations. The Agency agrees that
the section as proposed may have been
subject to misinterpretation. Therefore,
the current proposed Guidelines define
sufficient evidence of potential human
mutagenicity to include positive
responses in any two different gene
mutation test systems (one of which
utilized mammalian cells) or positive
responses in two different somatic
cytogenetic tests (one of which utilizes
mammalian cells), coupled with
sufficient evidence of germ-cell
interaction in both caes. Alternatively,
the combination of a positive finding in
one mammalian gene mutation assay
and one mammalian cytogenetics test
and sufficient evidence of germ-cell
interaction also provides sufficient
evidence of potential human
mutagenicity. The demostration of
heritable effects induced in mammalian
germ cells is by itself sufficient evidence
for mutagenicity.
Many commenters objected to the
criterion that considers a chemical
mutagen a potential human germ-cell
mutagen if there is "evidence for the
presence of the test substance and/or its
matabolites in mammalian gonadal
organs." First, they pointed out that the
presence of a chemical in the testis or
ovary does not necessarily mean it has
reacted with germ-cell DNA. Such
studies are generally performed with
radiolabeled chemicals, and it is
possible that metabolism of the
compound could result in incorporation
of the radiolabel into normal cellular
macromolecules. The Agency recognizes-
the shortcomings in the various criteria
used to determine whether a mutagen
interacts with germ-cell DNA. As a
result, in the current Guidelines, two
categories of such evidence have been
adopted. Sufficient evidence that a
mutagen interacts in the mammalian
gonad will be the demonstration that an
agent interacts with germ-cell DNA or
other chromatin constituents, or that it
induces such end points as unscheduled
DNA synthesis, sister chromatid
exchange (SCE), or chromosomal
aberrations in germinal cells. Suggestive
evidence will include advese gonadal
effects following acute, subchronic, or
chronic toxicity testing or adverse
reproductive effects, such as decreased
fertilization index, reduced sperm count.
or abnormal sperm morphology.
One commenter suggested that the
Agency develop a scale of weighting
tests which would place more emphasis
on test systems more relevant to human
beings. The Agency .has explored the
possibility of developing such a scale
and has concluded that the assignment
of fixed values for each test system
could be overly simplistic and might not
allow for the consideration of such
variables as dose range, route of
exposure, and magnitude of respone.
The Agency believes that the scheme in
the current proposed Guidelines, which_
generally gives greater weight to
mammalian rather than submammalian
assays and to germ cell rather than
somatic cell data, is currently the most
appropriate way to evaluate the
information from a variety of systems.
E. Quantitative Assessment of Results
Several commenters expressed the
opinion that it is'not possible to
quantitatively express the risk of genetic
disease from exposure to a chemical,
and therefore no attempt should be
made to do so. The Agency does not
suggest that it is necessarily possible to
generate a numerical estimate of the
genetic risk that will result from
exposure to any particular chemical. It
is well-recognized and documented that
the mutational component of certain
categories of human genetic disease is
not known. However, mutagenicity data
have been used to generate semi-
quantitative estimates of the impact of
ionizing radiation on genetic disease(5,
6). The current proposed Guidelines
state the Agency's commitment to utilize
existing relevant mutagenicity data to
give some estimate of potential human
mutagenicity. All such estimates will
include a careful delineation of the
assumptions and uncertainties
associated with the assessment.
Many commenters objected to the use
of "linear or nonthreshold models" for
low-dose extrapolation on point
mutation rates. The Agency
acknowledges that linearity and the
presence or absence of a threshold are
separate issues. The Agency will strive
to use the most appropriate
extrapolation model for risk analysis
and will be guided by the available data
in this selection. However, it is
anticipated that for whole-animal germ-
cell assays, few dose points will be
available to define a dose-response
function. In these situations there is a
theoretical basis for a linear,
nonthreshold extrapolation provided
that no major germ-cell killing (and thus
possible cell selection) has occurred(2,
7).
One commenter suggested (hat for
quantitative risk it is more appropriate
to rely on tests for structural
chromosomal aberrations than on gene
mutations, particularly since many
diseases can be more readily associated
with an identifiable chromosome
abnormality. The Agency agrees that
associations between diseases and
specific chromosomal changes can be
estimated. This concept is well
documented and has been discussed at
length in the NAS report(2). However,
similar estimates can be made for gene
mutations, and such techniques have
been used for some time for effects of
ionizing radiation(5, 5). Because the
spectrum of mutational effects induced
by different chemicals is known to be
variable, the Agency believes that it is
necessary to perform estimates on all
end points.
/One commenter objected to the
. omission of the dominant skeletal and
cataract mutation systems for
quantitative risk assessment. The
Agency recognizes that these dominant
mutation systems do have relevance in
the preparation of quantitative risk
assessment along with specific-locus
test systems. The current proposed
Guidelines have been modified to
include both types of tests.
III. Proposed Guidelines
A. Introduction
This section describes the procedures
that the U.S. Environmental Protection
Agency will follow in evaluating the
potential genetic risk associated with
human exposure to existing industrial
chemicals and to pesticides*. The central
purpose of the health risk assessment is
to provide a judgment concerning the
weight of evidence that an agent is a
potential human mutagen with respect
to transmitted genetic changes, and, if
so, how great an impact it is likely to
have on public health. Regulatory
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Federal -Register / Vol. 49. No. 227 / Friday, November 23, 1984 / Notices
46317
decision making involves two
components: Risk assessment and risk
anagement Risk assessment estimates
c potential adverse health
consequences of exposure to toxic
chemicals; risk management combines
the risk assessment with the directives
of the enabling 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
chemnicals. The issue of risk
management will not be dealt with in
these Guidelines.
Risk assessment is comprised of the
following components: Hazard
identification, dose-response
assessment, exposure assessment, and
risk characterize tion(5). Hazard
identification is the qualitative risk
assessment, dealing with the inherent
toxicity of a chemical substance. The
qualitative mutagem'city assessment
answers the question of how likely an
agent is to be a human mutagen. The
three remaining components comprise
quantitative risk assessment, which
provides a numerical estimate of the
public health consequences of exposure
to an agent. The quantiative
mutagenicity risk assessment deals with
the question of how much mutational
damage is likely to be produced by
exposure to a given agent under
particular exposure scenarios.
In a dose-response assessment, the
relationship between the dose of a
chemical and the probability of
induction of an adverse effect is defined.
The component generally entails an
extrapolation from the high goses
administered to experimental animals or
noted in some epidemiologic studies to
the low exposure levels expected from
human contact with the chemical in the
environment.
The exposure assessment identifies
popu'atioris exposed to toxic chemicals,
describes their composition and size,
and presents thu types, magnitudes,
frequencies, and durations of exposure
to the r.hemcials. This component is
developed independently of the other
components of the mutagenicity
assessment and is addressed in separate
Agency guidelines(S).
In risk characterization, the outputs of
the exposure assessment and the dose-
response assessment are combined to
estimate quantitatively the mutation
risk, which is expressed as either
es'mated increase of generic disease per
generation or per lifetime, or the
fractional increase in the assumed
background mutation rate of humans. In
each step of the assessment, the
strengths and weaknesses of the major
H.ssumptions need to be presented, and
the nature and magnitude of
uncertainties need to be characterized.
The procedures set forth in these
Guidelines will ensure consistency in
the Agency's scientific risk assessments
for mutagenci effects. The necessity for.
a consistent approach to the evaulation
of mutagenic risk from chemical
substances arises from the authority
conferred upon the Agency by a number
of statutes to regulate potential
mutagens. As appropriate, these
Guidelines will apply to statutes
administered by the Agency, including
the Federal Insecticide. Fungicide, and
Rodenticide Act; the Toxic Substances
Control Act; the Clean Air Act; the
Federal Water Pollution Control Act; the
Safe Drinking Water Act; the Resource
Conservation and Recovery Act; and the
Comprehensive Environmental
"Response, Compensation, and Liability
Act. Because each statute is
administered by separate offices, a
consistent Agency-wide approach for
performing risk assessments is
desirable:
The mutagenciry risk assessments
prepared pursuant to these Guidelines
will be utilized within the requirements
and constraints of the applicable
statutes to arrive at regulatory decisions
concerning mutagenicity. The standards
of the applicable statutes and
regulations may dictate that additional
considerations (e.g., the economic and
social benefits associated with use of
the chemical substance) will come into
play in reaching appropriate regulatory
decisions.
The Agency is concerned with the risk
associated with both germ-cell
mutations and somatic cell mutations.
Mutations carried in germ cells are
inherited by future generations and may
contribute to genetic disease, whereas
mutations occurring in somatic cells
may be implicated in the etiology of
several disease states, including cancer.
These Guidelines, however, are only
concerned with genetic damage as it
relates to germ-cell mutations. The use
of mutagenicity test results in the
assessment of carcinogenic risk is
described in the .proposed Guidelines for
Carcinogen Risk Assessment (JO).
As a result of the progress in the
control of infectious diseases, increases
in average human life span, and better
procedures for identifying genetic
disorders, a considerable heritable
genetic disease burden has been
recognized in the human population. It is
estimated that at least 10% of all human
disease is related to specific genetic
states, such as abnormal composition,
arrangement, or dosage of genes and
chromosomes(2 8,11). Such genetic
diseases can lead to structural or
functional health impairments. These
conditions may be expressed in utero: at
the time of birth; or during infancy,
childhood, adolescence, or adult life:
they may be chronic or acute in nature.
As a result, they often have a severe
impact upon the affected individuals
and their families in terms of physical
and mental suffering and economic
losses, and upon society in general,
which often becomes responsible for
institutional care of severely affected •
individuals. Some examples of genetic
conditions are Down's and Klinefelter's
syndromes, cystic fibrosis, hemophilia.
sickle cell anemia, and achondroplastic
dwarfism. Other commonly recognized
conditions that are likely to have a
genetic component include
hypercholesterolemia. hypertension,
pyloric stenosis, glaucoma, allergies.
several types of cancer, and mental
retardation. These disorders are only a
few of the thousands that are at least
partially genetically determined^).
Estimation of the fraction of human
genetic disease that results from new
mutation is difficult, although in certain
specific cases insights are available(i3).
It is clear that recurring mutation is
important in determining the incidence
of certain genetic conditions, such as
some chromosomal aberration
syndromes (e.g.,-Down's) and rare
dominant and X-linked recessive
diseases (e.g., achondroplasia and
hemophilia A). For other single-factor
conditions (e.g., sickle-cell anemia and
color blindness) and certain
multifactorial conditions (e.g., pyloric
stenosis), the contribution of new
mutations to disease frequency is
probably very small. However, it is
generally recognized that most
mutations that are phenotypically
expressed are in some ways deleterious
to the organism receiving them. Adverse
effects may be manifested at the .
biochemical, cellular, or physiological
levels of organization. Although
mutations are the building blocks for
further evolutionary change of species, it
is believed that increases in the
mutation rate above the spontaneous
level could lead to an accumulation of
deleterious mutations in the human
population and. to a varying extent, an
increased frequency of expressed
genetic disease.
Life in our technological society
results in exposure to many natural and
synthetic chemicals. Some have been
shown to have mutagenic activity in
mammalian and submammalian test
systems, and thus may have the
potential to increase genetic damage in
the human population. Chemicals
exhibiting mutagenic activity in various
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46318 Federal Register / Vol. 49. No. 227 / Friday, November 23. 1984 / Notices
test systems have been found
distributed among foods, tobacco, drugs,
food additives, cosmetics, industrial
compounds, pesticides, and consumer
products. As our knowledge of genetics
and disease etiology increases, and
techniques for detecting mutations in
.human beings improve, we may become
aware of chemically-induced human
genetic effects. The extent to which
exposure to natural and synthetic
environmental agents may have
increased the amount of genetic damage
in the present human population and
contributed to the mutational "load"
that will be transmitted to future
generations is unknown at this time.
However, for the reasons cited above, it
seems prudent to limit exposures to
potential human mutagens.
1. Concepts Relating to Heritable
Mutagenic Risk
For the purposes of these Guidelines,
a muta'gen is considered a chemical
substance or mixture of substances that
can induce alterations in the DNA of
either somatic or germinal cells. The
mutagenicity of physical agents (e.g.,
radiations] is not addressed here. There
are several mutagenic end points of
concern to the Agency. These include
point mutations (i.e., submicroscopic
changes in the base sequence of DNA)
and structural or numerical chromosome
aberrations. Structural aberrations
include deficiencies, duplications,
inversions, and translocations, whereas
numerical aberrations are gains or
losses of whole chromosomes (e.g.,
trisomy, monosomy) or sets of
chromosomes (haploidy, polyploidy).
It is conceivable that only one or a
few molecules of an active compound
may be sufficient to cause certain types
of heritable changes in DNA. Mutagenic
effects may also come about through
mechanisms other than chemical
alterations of DNA. Among these are
interference with normal DNA
synthesis, or induction of DNA
misrepair, DNA methylation, abnormal
nuclear division processes, or lesions in
non-DNA targets (e.g., protamine,
tubulin).
The best evidence that an agent
induces heritable mutations in human
beings would be epidemiologic data
indicating a strong association between
chemical exposure and a heritable
response. Such data do not exist at this
time because any specific mutation is a
rare event, and only a small fraction of
the estimated thousands of human genes
and conditions are currently useful as
markers in estimating mutation rates.
Human genetic variability, small
numbers of offspring per individual, and
long generation times further
complicates such studies. In addition,
only dominant mutations, some sex-
linked recessive mutations, and certain
chromosome aberrations can be
detected in the first generation after
their occurrence. Conditions caused by
autosomal recessive mutations (which
appear to occur more frequently than
dominants) or by interaction of multiple
factors may go unrecognized for many
generations. Therefore, in the absence of
human germ-cell data, it is appropriate
to rely on data from experimental
animal systems.
Despite species differences in
metabolism, DNA repair, and other
physiological processes affecting
chemical mutagenesis, the virtual
universality of DNA as the genetic
material and of the genetic code
provides a rationale for using various
nonhuman test systems to predict the
intrinsic mutagenicity of test chemicals.
Additional support for the use of
nonhuman systems is provided by the
observation that chemicals causing
genetic effects in one species or test
system frequently cause similar effects
in other species or systems. There also
exists evidence thai chemicals can
induce genetic damage in somatic cells
of exposed humans. For example, high
doses of mutagenic chemotherapeutic
agents have been shown to cause
chromosomal abnormalities^), sister
chromatid exchange'^), and, quite
probably, point mutations in human
lymphocytes exposed in vivo(15). While
these results are not in germ cells, they
do indicate that it is possible to induce
mutagenic events in human cells in vivo.
Furthermore, a wide variety of different
types of mutations have been observed
in humans including numerical
chromosome aberrations, translocations.
base-pair substitutions, and frameshift
mutations. Although the cause of these
mutations is uncertain, it is clear from
these observations that the human germ-
cell DNA is subject to the same types of
mutational events that are observed in
other species and test systems.
Certain test systems offer notable
advantages: Cost; anatomical,
histological, and/or metabolic
similarities to humans; suitability for
handling large numbers of test
organisms; a large data base; and a
basis for characterizing genetic
events(iO).
2. Test Systems
Many test systems are currently
available that can contribute
information about the mutagenic
potential of a test compound with
respect to various genetic end points.
These tests have recently been
evaluated through the EPA Gene-Tox
Programs and the results of Phase I have
been published(4). The Agency's Office
of Pesticides and Toxic Substances has
published various testing guidelines for,
the detection of mutagenic effects(m
17].
Test systems for detecting point
mutations include those in bacteria. •
eukaryotic microorganisms, higher
plants, insects, mammalian somatic cells
in culture, and germinal cells of intact
mammals (e.g., the mouse specific-locus
test). Positive results in a mouse
germinal gene-mutation test argue
strongly that a chemical is a potential
human mutagen because such tests
demonstrate that the mutations occur in
mammalian germinal cells and are
transmitted to the next genera ton.
However, because large numbers of
offspring must usually be generated, it is
not expected that many chemicals will
be tested using these systems. To obtain
data on a large number of
environmental chemicals, it will be
necessary to rely on other tests to
identify and characterize hazards from
gene mutations.
Test systems for detecting structural
chromosome aberrations have been
developed in a variety of organisms
including higher plants, insects, fish.
birds, and several mammalian species. •
Many of these assays can be performed
in vitro or in vivo, and in either germ or
somatic cells. Procedures available for
detecting structural chromosome
aberrations in mammalian germ cells
include measurement of heritable
translocations or dominant lethality, as
well as direct cytogenetic analyses of
germ cells and early embryos in rodents.
Some chemicals may cause numerical
chromosome changes (i.e., aneuploidy)
as their sole mutagenic effect. These
agents may not be detected as mutagens
if evaluated only in tests for DNA
damage, gene mutations, or chromosome
breakage and rearrangement. Therefore.
it is important to consider tests for
changes in chromosome number in the
total assessment of mutagenic hazards.
Although tests for the detection of
variation in the chromosome number are
still at an early stage of development,
systems exist in such diverse organisms
as fungi, Drosophila, mammalian cells in
culture, and intact mammals (e.g.. mouse
X-chromosome loss assay).
Mondisjunction and chromosome lagging
are recognized sources of numerical
aberrations. Aneuploidy can also arise
from chromosome breakage and reunion
followed by segregation's). The
mechanmisms by which nondisjunction
occurs are not well understood.
However, proteins (e.g., spindle •
apparatus), rather than DNA. may be
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Federal Register / Vol. 49. No. 227 / Friday. November 23. 1984 / Notices 46319
the target molecules for at least some
mechanisms of induced nondisiunction.
Other end points that provide
information bearing on the mutagenicity
of a chemical can be detected by a
variety of test systems. Such tests
measure DNA damage in eukaryotic or
prokaryotic cells, unscheduled DNA
synthesis in mammalian somatic and
germ cells, mitotic recombination and
gene conversion in yeast, and .sister-
chroma tid exchange in mammalian
somatic and germ cells. Results in these
assays are useful because the induction
of these end points often correlates
positively with the potential of a
chemical to induce mutations.
In general, for all three end points (i.e..
point mutations and numerical and
structural aberrations) the Agency will
place greater weight on tests conducted
in germ cells than in somatic cells, on .
tests performed in vivo rather than in
vitro, in eukaryotes rather than
prokaryotes. and in mammalian species
rather than in submammalian species.
Formal numerical weighting systems
have been developed(7S); however, the
Agency has concluded that these do not
readily accommodate such variables as
dose range, route of exposure, and
magnitude of response.
The Agency anticipates that from time
to time data from chemically-exposed
human beings will be available (e.g..
cytogenetic markers in peripheral
'lymphocytes). When posssible, the
Agency will use such data in
conjunction with other studies for the
purpose of performing risk assessments.
The test systems mentioned
previously are not the only ones that
will provide evidence of mutagenicity or
related DNA effects. These systems are
enumerated merely to demonstrate the
breadth of the available techniques for
characterizing mutagenic hazards, and
to indicate the types of data that the
Agency will consider in its evaluation of
mutagenic potential of a chemical agent.
Most systems possess certain
limitations that must be taken into
account. The selection and performance
of appropriate tests for evaluating the
risks associated with human exposure to
any suspected mutagen will depend on
sound scientific judgment and
experience, and may necessitate
consultation with geneticists familiar
with the sensitivity and experimental
design of the test system in question. In
view oi the rapid advances in test '
methodology, the Agency expects that
both the number and quality of the tools
for assessing genetic risk to human
beings will increase with time. The
Agency will closely monitor
developments in mutagenicity
evaluation and will refine its risk
assessment scheme as better test
systems become available.
B. Qualitative Assessment (Hazard
Iden tification)
The assessment of potential human
germ-cell mutagenic risk is a multistep
process. The first step is an analysis of
the evidence bearing on a chemical's
ability to induce mutagenic events,
while the second step involves an
analysis of its ability to produce these
events in the mammalian gonad. All
relevant information is then integrated
into a weight-of-evidence scheme which
presents the strength of the information
bearing on the chemical's potential
ability to produce mutations in human
germ cells. For chemicals demonstrating
this potential, one may decide to
proceed with an evaluation of the
quantitative consequences of mutation
' following expected human exposure.
For hazard identification, it is clearly
desirable to have data from mammalian
germ-cell tests, such as the mouse
specific-locus test for point mutations
and the heritable translocation or germ-
cell cytogenetic tests for structural
chromosome aberrations. It is
recognized, however, that in most
instances such data will not be
available, and alternative means of .
evaluation will be required. In such
• cases the Agency will evaluate the
evidence bearing on the agent's
mutagenic activity and the agent's
ability to reach and interact with or
affect the mammalian gonadal target.
When evidence exists that an agent
possesses both these attributes, it is
reasonable to deduce that the agent is a
potential human germ-cell mutagen.
1. Mutagenic Activity
In evaluating chemicals for mutagenic
activity, a number of factors will be
considered: (1) Genetic end points (e.g.,
gene mutations, structural or numerical
chromosomal aberrations) detected by
the test systems, (2) sensitivity and
predictive value of the test systems for
various classes of chemical compounds,
(3) number of different test systems used
for detecting each genetic end point, (4)
consistency of the results obtained in
different test systems and different
species, (5) aspects of the dose-response
relationship, and (6) whether the tests
are conducted in accordance with
appropriate test protocols agreed upon
by experts in the field.
The array of mutagenicity tests
available will be reviewed within the
following qualitative perspective:
greater weight will be attributed to tests
conducted in germ cells than in somatic
ceils, to studies in mammalian ceils than
in submammalian cells, and to studies in
eukaryotic cells than in prokaryotic
cells.
2. Chemical Interactions in the
Mammalian Gonad
Evidence for chemical interaction in
the mammalian gonad spans a range of
different types of findings. Each
chemical under consideration needs to
be extensively reviewed since tiiis type
of evidence may be part of testing
exclusive of mutagenicity per se (e;g..
reproduction, metabolism, and
mechanistic investigations). Although i!
is not possible to classify clearly each
type of information that may be
available on a chemical, two possible
groups are illustrated.
Sufficient evidence of chemical
interaction is given by the
demonstration that an agent interacts
with germ-cell DNA or other chroma tin
constituents, or that it induces such end
points as unscheduled DNA synthesis.
sister-chromatid exchange, or
chromosomal aberrations in germinal
cells. Positive results in a mammalian
germ-cell mutation study also
demonstrate the action of the chemical
in the gonadal target cells.
b. Suggestive evidence will include
the finding of adverse gonadal effects
following acute, subchronic, or chronic
toxicity testing, or findings of adverse
• reproductive effects, which are
consistent with interaction with germ
cells.
3. Weight-of-Evidence Determination
The evidence for a chemical's ability
to produce mutations and to interact
with the germinal target are integrated
into a Weight-of-evidence judgment thai
the agent may pose a hazard as a
potential human germ-cell mutagen. All
information bearing on the subject.
whether indicative of potential concern
or not, must be evaluated. Whatever
evidence may exist from humans must
also be factored into the assessment.
Information available will vary
greatly from chemical to chemical
because there are many mutageniciiy
test systems, and there has been no
systematic attempt to develop
information on all chemicals of concern.
The responses noted for different tests
may also vary from chemical to
chemical since often one does not find
consistent positive or negative results
across all tests. Chemicals may show
positive effects for some end points in
some test systems, but negative
responses in others. Each review must
take into account the limitations in the
testing and in the types of response;;
that mav exist.
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46320
Federal Register / Vol. 49. No. 227 / Friday. November 23, 1984 / Notices
To provide guidance as to the
categorization of the weight of evidence,
a classification scheme is presented to
illustrate, in a simplified sense, the
strength of the information bearing on
the potential for human germ-cell
mutagenicity (Table 1). It is not possible
to illustrate all potential combinations of
evidence, and considerable judgment
must be exercised in reaching
conclusions. The factors illustrated in
Table 1 and discussed previously in
sections 1, 2, and 3 must all be
considered in making an assessment of
mutagenicity. In addition, certain
responses in tests that do not measure
well-defined mutagenic end points (e.g..
SCE induction in mammalian germ cells)
or germ-cell tests in higher eukaryotes
(e.g., Drosophila tests) may provide a
basis for raising the weight of evidence .
from one category to another:
Sufficient evidence for potential
human germ-cell mutagenicity would
include cases in which positive
responses are demonstrated in a
mammalian germ-cell test. Also, in
general, sufficient evidence exists when
there is confirmed mutagenic activity in
nher test systems (positive responses in
it least two different test systems, at
•oast one of which is in mammalian
•,eiis), and there is sufficient evidence
tor germ-cell interaction as defined
nbove.
Suggestive evidence encompasses a
weight-of-evidence category between
sufficient and limited that includes
cases in which there is some evidence
for mutagenic activity and for
interaction with germ cells.
Limited evidence for potential human
germ-cell mutagenicity exists when
evidence is available only for
mutagenicity tests (other than
mammalian germ cells) or only for
chemical interactions rathe gonad.
Table 1.—Classification of Weight of
Evidence for Potential Human Germ-Call
Mutagenicity •
1. Sufficient evidence exists when positive .
responses are demonstrated in:
a. at least one in vivo mammalian germ-cell
mutation test, or
b. al least two point mutation tests (at least
one in mammalian cells) plus sufficient
evidence that the chemical interacts with
mammalian germ cells, or
c. least two structural chromosome
• Takes into consideration the extent
quality, and consistency of responses bearing
on an agent's ability to product mutagenic
events and to interact with the mammalian
gonadal target Nonmutagenic test responses
(e.g.. SCE in germ ceila) may help to etevate
evidence of mutagenicity from one category
to Another.
2. Suggestive evidence exists in those cases
in which there are positive data for both
mutagenic activity and evidence for chemical
interactions in the gonad, but the evidence is
less than sufficient. This category is
potentially large and heterogeneous in nature
and ranges from almost sufficient to
essentially limited.
3. Limited evidence denotes a situation in
which the evidence is limited to information
on mutagenic activity or to evidence of
chemical reactivity in the target
aberration tests (at least one in mammalian
cells) plus sufficient evidence that the
chemical interacts with mammalian germ
cells, or
d. one gene mutation assay in mammalian
ceils and one structural chromosome
aberration test in mammalian cells and
sufficient evidence for chemical interaction
with mammalian germ cells.
Designation of evidence as limited does
not preclude the use of such information
to set priorities for further testing or to
support a case for potential
carcinogenicity.
Although definitive proof of
nonmutagenicity is not possible, it
seems appropriate that a chemical could
be classified operationally as not a
human germ-cell mutagen, if it gives
negative responses in those test systems
that together fulfill the criteria (i.e., all
relevant end points) for sufficient
evidence1 of a potential human germ-cell
mutagen, providing that all assays have
been properly performed. Test systems
used to define a negative should be
capable of detecting weak responses
(adequate statistical power) and should
be appropriate for the chemical or class
of chemicals under investigation.
Negative evidence of chemical
interaction in the gonad hi the presence
of evidence of mutagenic activity may
still signal some concern in regard to
somatic effects(JO). Other combinations
of relevant information will most likely
require case-by-case evaluation. It may
also be possible to operationally define
a chemical as not being a human germ-
cell mutagen based on negative results
from other assays which provide
information about mutagenicrty and/or
interaction with germ-cell chromatm.
C. Quantitative Assessment
The preceding section addressed
primarily the processes of hazard
identification, i.e., the determination of
whether a substance is a potential germ-
cell mutaaen. Often, no further data will
be available, and judgments will need to
be based on mainly qualitative criteria.
For quantitative risk assessment further
information is required, namely,
determination of the heritable effect per
unit of exposure (dose-response) and the
relationship between mutation rate and
disease incidence. Dose-response
information is combined with
anticipated levels and patterns of
human exposure in order to derive a
quantitative assessment (risk
characterization).
I. Dose-Response
Two approaches to obtaining dose-
response data are available. One
approach requires experimental uai« on
germinal mutations induced in intact
mammals. Several test systems may
provide such information, e.g., the
mouse heritable translocation, dominant
skeletal, dominant cataract, and
specific-locus tests. Although the
dominant skeletal and cataract assays
have the advantage of measuring
dominant mutations, the heritability of
observed effects has not been clearly
demonstrated. The experimental data on
induced mutation frequency are usually
obtained at exposure levels much higher
than those that will be experienced by
human beings. An assessment of human
risk is obtained by extrapolating the
induced mutation frequency or the
observed phenotypic effect downward
to the approximate level of anticipated
human exposure.
The Agency will strive to use the most
appropriate extrapolation models for
risk analysis and will be guided by the
available data and mechanistic
considerations in this selection.
However, it is anticipated that for tests
involving germ cells of whole mammals.
few dose points will be available to
define dose-response functions. In these
situations certain theoretical
considerations will apply(20). For point
mutations, linear extrapolations with no
threshold may be used as a conservative
approximation, provided the results
allow one to rule out major germ-cell
selection. For structural chromosome
rearrangements such as heritable
translocations, linear extrapolation of
the experimental data is thought to
overestimate the risks at low levels of
exposure and use of a multiple-hit model
is more appropriate.
The second experimental approach for
quantitative assessment of genetic risk
uses molecular dosimetry data from
intact mammals in conjunction with
mutagenicity and dosimetry data from
other validated test systems(^). The
intact mammal is used primarily for
relating the exposure level for a giver.
route 01 administration of a chemical to
germ-ceil dose, i.e.. the level of mutagen-
DNA interactions. This information is
then used in conjunction with results
obtained from mutagenicity test systems
in which the relationship between the
induction of mutations and chemical
interactions with DNA can be derived.
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Federal Register / Vol. 49. No. 227 / Friday, November 23. 1984 / Notices 46321
Using mutagen-DNA interactions as the
common denominator, a relationship
San be constructed between mammalian
xposure and the induced mutation
frequency. The amount of DNA binding
induced by a particular chemical agent
may often be determined at levels of
anticipated human exposure. This
approach is still experimental and its
application involves many unknowns,
such as possible differences between
mammalian'germ cells and cells of the
reference system with regard to types of
genetic damage induced and magnitude
of repair.
For some mutagenic events, DNA may
not necessarily be the critical target.
interaction of chemicals with other
macromolecules, such as tubulin, which
is involved in the separation of
chromosomes during nuclear division.
can lead to chromosomal'
nondisjunction. At present, general
approaches are not available for dose-
response assessments for these types of
mutations. Ongoing research should
provide the means to make future
assessments on chemicals causing
aneuploidy.
1. Exposure Assessment
Tlie exposure assessment identifies
populations exposed to toxic chemicals,
Describes their composition and size,
'and presents the types, magnitudes,
frequencies, and durations of exposure
to the chemicals. This component is
developed independently of the other
components of the mutagenicity
assessment(d).
3. Risk Characterization
In performing mutagenicity risk
assessments, it is important to consider
each genetic end point individually. For
example, although certain chemical
substances that interact with DNA may
cause both point and chromosomal
mutations, it is expected that the ratio of
these events may differ for individual
chemicals and between doses for a
given chemical. Furthermore,
transmissible chromosomal aberrations
appear to be inducible with higher
frequencies in meiotic and postmeiotic
germ-cell stages, which have a brief life
span, than in spermatogonial stem ceils,
which can accumulate genetic damage
throughout the reproductive life of an
individual. For these reasons, when data
are available; the Agency, to the best
extent possible, will assess risks
associated with all genetic end points.
Any risk assessment should clearly
delineate the strengths and weaknesses
of the data, the assumptions.made, the
uncertainties in the methodology, and
the rationale used in reaching the
conclusions, e.g., similar or different
routes of exposure and metabolic
differences between humans and test
animals. When possible, quantitative
risk assessments should be expressed in
terms of the estimated increase of
genetic disease per generation or per
lifetime, or the fractional increase in the
assumed background spontaneous
mutation rate of humans(5). Examples of
quantitative risk estimates have been
published (6, 22); these examples may be
of use in performing quantitative risk
assessments for mutagens.
IV. References
(1) U.S. Environmental Protection Agency.
1980. Mutagenicity risk assessment: proposed
guidelines. Federal Register 45 (221): 74984-
74988.
(2) Committee on Chemical Environmental
Mutagens. 1982. Identifying and estimating
the genetic impact of chemical environmental
mutagens. Washington. DC: National
Academy Press.
(3) Committee 1 Final Report. 1983.
Screening strategy for chemicals that are
potential germ-cell mutagens in mammals.
Mutat. Res. 114:117-177.
[4] A complete reference of ail Gene-Tox
publications is available-from the TSCA
Industry Assistance Office (TS-794), Office of
Toxic Substances, U.S. Environmental
Protection Agency, Washington, DC 20460.
(5) Committee on the Biological Effects of
Ionizing Radiation. 1980. The effects on
populations of exposure to low levels of
ionizing radiation. National Academy of
Sciences. Washington, DC: National
Academy Press.
(6) United Nations Scientific Committee on
the Effects of Atomic Radiation. 1977.
Sources and effects of ionizing radiation.
Report of the General Assembly, 32nd
Session. Supplement No. 40(A/32/40), United
Nations, New York.
(71 Ehling. U.H., D. Averback, P.A. Cerutti,
J. Friedman, H. Greim. A.C. Kolbye, and M.L.
Mendelsohn. 1983. Review of the evidence for
the presence or absence of thresholds in the
induction of genetic effects by genotoxic
chemicals. Mutat. Res. 123:281-341.
(8) Committee on the Institutional Means
for the Assessment of Risks to Public Health.
1983. Risk assessment in the Federal
government: managing the process.
Commission on Life Sciences, National
Research Council. Washington. DC: Nalionu.l
Academy. Press.
(9} U.S. Environmental Protection Agency.
1984. Proposed guidelines for exposure
assessment. Office of Health and
Environmental Assessment.
(10] U.S. Environmental Protection Agency.
1984. Proposed guidelines for carcinogen risk
assessment. Office of Health and
Environmental Assessment.
(11} Flamm, W.G. 1977. DHEW Report on
approaches to determining the mutagenic
properties of chemicals: risk to future
generations. ]. Environ. Pathol. Toxicol.
1:301-352.
(12) McKusick, V.A. 1973. Mendelian
inheritance in man: catalogs of autosomal
dominant, autosomal recessive and x-linked
phenotypes. Baltimore, MD: Johns Hopkins
University Press.
(73) Crow, J.F., and C. Denniston. 1981. The
mutation component of genetic damage.
Science 212:888-893.
(14) Musilova, ]., K. Michalova, and J.
Urban. 1979. Sister chromatic! exchanges and
chromosomal breakage in patient treated
with cytostatics. Mutat. Res. 67:289-294.
(15) Strauss, G.H.. and R.J. Albertini. 1970.
Enumeration of 8-thioguanine-resistant
peripheral blood lymphocytes in man as it
potential test for somatic cell mutations
arising in vivo. Mutat. Res. 61:353-379.
(16] U.S. Environmental Protection Agency.
1983. Health effects test guidelines. Office of
Toxic Substances. EPA 560/6/82-001.
Available from: NTIS. Springfield, VA.
Enuirnnmpntal Protection Agency.
November 24; 1982. Pesticides registration;
'proposed data requirements. Federal Register
47: 53192-53203.
(18) Parker, D.R., and J.H. Williamson. 1974.
Some radiation effects on segregation in
Drosophila. Genetics 78:163-171.
(19] Russell, L.B., C.S. Aaron, F. de Serres.
W.M. Generoso, K.L. Kannan, M. Shelby, J.
Springer, and P. Voytek. Evaluation of
existing mutagenicity bioassays for purposes
of genetic risk assessment. Mutat. Res. in
press.
(20) Ehrenberg L, E. Moustacchi, and S.
Osterman-Golkar. 1983. Dosimetry of
genotoxic agents and dose-response
relationships of their effects. Mutat. Res.
123:121-179.
(21) Lee. W.R. 1979. Dosimetry cf chemical
mutagens in eukaryote germcells. In: A.
Hollaender and F.J. de Serres, eds. Chemical
mutagens: principles and methods for their
detection. Vol. 5. New York: Plenum Press.
pp. 177-202.
(22} Ehling. U.H., and A. Neuhauser. 1979.
Procarbazine-induced specific-locus
mutations in male mice. Mutat. Res. 59:245-
256.
(FR Doc. 84-30722 Filed 11-21-84: 8:45 am|
3ILUNG CODE 6560- SO-M
-------
£ife Systems, Jnc.
PART 4 - HEALTH ASSESSMENT OF SUSPECT
DEVELOPMENTAL TOXICANTS
A3-5
-------
Friday
November 23, 1984
Part X
•
Environmental
Protection Agency
/ ~
Proposed Guidelines for the Health
Assessment of Suspect Developmental
Toxicants and Request for Comments
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46324
Federal Register / Vol. 49. No. 227 / Friday. November 23. 1984 / Notices
ENVIRONMENTAL PROTECTION
AGENCY
IFRU-2706-7]
Proposed Guidelines for the Healfi
Assessment of Suspect
Developmental Toxicants
AGENCY: Environmental Protection
Agency (EPA).
ACTION: Proposed Guidelines for the
Health Assessment of Suspect
Developmental Toxicants and Request
for Comments.
SUMMARY: The U.S. Environmental
Protection Agency is proposing
Guidelines for the Health Assessment of
Suspect Developmental Toxicants
(Guidelines). These Guidelines are
proposed for use within the policy and
procedural framework provided by the
various statutes that EPA administers to
guide Agency analysis of developmental
toxicity data. We solicit public comment
and will take public comment into
account in revising these Guidelines.
The Guidelines will be reviewed by the
Science Advisory Board in meetings
now tentatively scheduled for April
1985.
These proposed Guidelines we're
developed as part of a broad guidelines
development program under the
auspices of the Office of Health and
Environmental Assessment (OHEA),
located inthe Agency's Office of
Research and Development. Consonant
with the role of OHEA's Reproductive
Effects Assessment Group (REAG) as
the Agency's senior health committee
for developmental toxicity assessment,
the Guidelines were developed by an
Agency-wide working group chaired by
the.REAG.
DATE: Comments must be postmarked
by January 22,1985.
ADDRESSES: Comments may be mailed
or delivered to: Dr. Carole A. Kimmel,
Reproductive Effects Assessment Group
(RD-689), Office of Health and
Environmental Assessment, U.S.
Environmental Protection Agency, 401 M
Street, SW.. Washington. DC 20460.
FOR FURTHER INFORMATION CONTACT:
Dr. Carole A. Kimmel, telephone: 202-
382-7331.
SUPPLEMENTARY INFORMATION: A
preliminary draft of the Guidelines was
sent for review to approximately 20
scientists in the field of developmental
toxicology within government,
universities in the United States, and the
private sector. Comments received from
these reviewers, generally favorable,
were taken into account in developing
the Guidelines proposed here.
References and supporting documents
used in the preparation of these
Guidelines as well as comments
received are available for inspection
and copying at the Public Information
Reference Unit (202-382-5926), EPA
Headquarters Library, 401 M Street,
SW., Washington, DC. between the
hours of 8:00 a.m. and 4:30 p.m.
Dated: November 9.1984.
William D. Ruckelshaus,
Administrator.
Contents
L Introduction
II.. Definitions and Terminology
III. Qualitative Assessment (Hazard
Identification of Developmental
Toxicants)
A. Conventional Developmental
Toxicology Protocols: End Points and
Their Interpretation
1. End Points of Maternal Toxicity
2. End Points of Developmental Toxicity
3. Overall Evaluation of Maternal and
Developmental Toxicity
B. Functional Teratology
C. Short-Term Testing in Developmental
Toxicity
1. In Vivo Mammalian Teratology Screen
2. In Vitro- Teratology Screens
3. Application
D. Pharmacokinetica
E. Human Studies
F. Comparisons of Molecular Structure
G. Weight-of-Evidence Determination
IV. Quantitative Assessment
A. Dose-Response Assessment
B. Exposure Assessment
C. Risk Characterization
V. References
I. Introduction
These. Guidelines describe the
procedures that the U.S. Environmental
Protection Agency will follow in
evaluating potential developmental
toxicity associated with human
exposure to environmental toxicants. In
the past, the Agency has sponsored
conferences and issued publications
which addressed issues related to such
evaluations^, 2, 3). These publications
provided some of the scientific basis for
these risk assessment Guidelines, and
testing guidelines have provided
protocols designed to determine the
potential of a test substance to induce
structural and/or other abnormalities in
the developing conceptus. The Agency's
authority to regulate substances that
have the potential to interfere adversely
with human development is derived
from a number of statutes which are
implemented through multiple offices
within the Agency. Because many'
different offices evaluate developmental
toxicity, there is a need for intra-agency
consistency in the approach to assess
these types of effects. The procedures
described here will promote consistency
in the Agency's assessment of
developmental toxic effects.
Approximately 50% of human
conceptuses fail to reach term(3, 4);
approximately 3% of newborn children
are found to have one or more
significant congenital malformations at
birth, and, by the end of the first
postnatal year, about 3% more are found
to have serious developmental defects
(5, 8). It is estimated that 20% of human
congenital malformations are caused by
mutations, 10% are attributable to
known environmental factors, and the
remainder result from unknown causes
(7).
Numerous agents have been shown to
be developmental toxicants in animal
test systems(fl). Several of them have
also been shown to be the cause of
adverse developmental effects in
humans, including alcohol, aminopterin.
busulfan, chlorobiphenyls,
diethylstilbestrol, isotretinoin, organic
mercury, thalidomide, and valproic acid
(9,10,11,12). Exposure to agents
affecting development generally results
in multiple manifestations
(malformation, functional impairment,
altered growth, and/or lethality).
Therefore, assessment efforts should
encompass a wide array of adverse
developmental end points such as
spontaneous abortions, stillbirths,
malformations, and other adverse
functional physical changes that occur
postnatally.
The developmental toxicity
assessments prepared pursuant to these
Guidelines will be utilized within the
requirements and constraints of the
applicable statutes to arrive at
regulatory decisions concerning
developmental toxicity. These
Guidelines provide a general format for
analyzing and organizing the available
data for conducting risk assessments.
The Guidelines do not change any
statutory or regulatory prescribed
standards for the type of data necessary
for regulatory action. Moreover, risk
assessment is just one component of the
regulatory process and defines the
adverse health consequences of
exposure to a .toxic agent. The other
component, risk management, combines
risk assessment with the directives of
the enabling regulatory legislation
together with socio-economic, technical,
political, and other considerations to
reach a decision as to whether or how
much to control future exposure to the
suspected toxic agent. The issue of risk
management will not be addressed in
these Guidelines.
The National Research Council(.73)
has defined risk assessment as being
comprised of some or all of the following
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Federal Register / Vol 49, No. 227 / Friday. November 23. 1984 / Notices
46325
components: hazard identification, dose-
uuonse assessment, exposure
^•ssment and risk characterization. In
general, the process of assessing the risk
'of human developmental toxicity may
be adapted to this format However, due
to. special considerations in assessing
developmental toxicity, which will be
-discussed later in these Guidelines, it is
not always appropriate to follow the
exact standards as defined for each
component.
Hazard identification is the
qualitative risk assessment in which all
available experimental animal and
human data are used to determine if an
agent is likely to cause developmental
toxicity. In considering developmental
toxicity, these Guidelines will address
not only malformations, but also fetal
wastage, growth alteration, and
functional abnormalities that may result
from developmental exposure to
environmental agents.
The dose-response assessment
defines the relationship of the dose of an
agent and the occurrence of
developmental toxic effects. According
to the National Research Council(J3),
this component would usually include
the results of an extrapolation from high
doses administered to experimental
jimals or noted in epidemiologic
_to_thfi-law_fixposute. levels
tpected for human contact with.the
agent in the environment However,
since at present there is no
mathematical extrapolation model that
is generally accepted for developmental
toxicity, the Agency, for the most part,
continues to use safety factors and
margins of safety, which will be
discussed in these Guidelines.
The exposure assessment identifies
populations exposed to the agents,
describes their composition and size,
and presents the types, magnitudes, .
frequencies, and durations of exposure
to the agent
In risk characterization, the exposure
assessment and the dose-response
assessment are combined to estimate
some measure of the risk of
developmental toxicity. As part of risk
characterization, a summary of the
strengths and weaknesses in each
component of the assessment are
presented along with major
assumptions, scientific judgments, and.
to the extent possible, estimates of the
uncertainties.
II. Definitions and Terminology
The Agency recognizes that there are
^fferences in the use of terms in the
feld of developmental toxicology. For
the purposes of these Guidelines the
following definitions and terminology
will be iisnd.
Developmental Toxicology—The field
dealing with the induction of adverse
effects on the developing organism
occurring up to the time of puberty. The
manifestations of developmental
toxicity include: (1) Death of the
developing organism, (2) structural
abnormality (teratogenicity), (3) altered
growth, and (4) functional deficiency.
Embryotoxicity and Fetotoxicity— _
Any toxic effect on the conceptus as a
result of prenatal exposure; the
distinguishing feature between the terms
is the period during which the insult
occurred. The terms, as used here,
include malformation, altered growth,
and in utero death.
Altered Growth—A significant
alteration in fetal or neonatal organ or
body weight Body weight may or may
not be accompanied by a change in
crown-rump length and/or hi skeletal
ossification. Altered growth can be
induced at any stage of development
may be reversible, or may result in a
permanent change.
Functional Teratology—The field
dealing with the causes, mechanisms,
and manifestations of alterations or
delays in functional competence of the
organism or organ system following
exposure to an agent during critical
periods of development either pre- or
.postnatally.
Malformations and Variations—A
malfunction is usually defined as a
permanent structural deviation which
generally is incompatible with or
severely detrimental to normal postnatal
survival or development A variation is
usually defined as a divergence beyond
the usual range of structural constitution
but which may not have as severe an
effect on survival or health as a
malformation. Distinguishing between
variations and malformations is difficult
since there exists a continuum of
responses from the normal to the
extreme deviant. There is no generally
accepted classification of malformations
and variations. Other terminology that is
often used but no better defined.
includes anomalies, deformations, and
aberrations.
III. Qualitative Assessment (Hazard
Identification of Developmental
Toxicants)
Developmental toxicity studies
provide a number of end points that are
useful for evaluating the potential of an
agent to produce adverse outcomes of
pregnancy. The four types of effects on
the conceptus that may be produced by
in utero exposure to toxicants include
death, structural abnormality, altered
growth, and functional deficits. Of these,
the first three effects are measured in
the conventional developmental toxicity
(teratogenicity) protocol (discussed
below), while functional deficits are
seldom evaluated in routine
assessments of environmental agents.
This section will discuss the format and
analysis of conventional studies as well
as the use of data from other types of
studies, including functional studies.
short-term tests, and pharmacokinetic.i.
A. Conventional Developmental
Toxicology Protocols: End Points and
Their Interpretation
The most commonly used protocol for
assessing developmental toxicity
involves the administration of a test
substance to pregnant animals (usually
mice, rats, or rabbits) during the period
of major organogenesis, evaluation of
maternal responses throughout
pregnancy, and examination of the dam
and the uterine contents just prior to
term(£ 3,14,15). Other protocols may
use exposure periods of one to a few
days to investigate periods of particular
sensitivity for induction of anomalies in
specific organs or organ systems(76).
Fetuses alive at maternal sacrifice are
thoroughly evaluated for alterations in
morphological development Because
the relationship of maternal and fetal
toxicity is important in assessing the
developmental toxicity of an agent,
dose-response data are important.
Ideally, study designs should include a
high dose, which produces some
maternal toxicity (i.e., a level that
produces marginal but significantly
reduced body weight or weight gain
during pregnancy up to a level that
produces no more than 10% maternal
mortality), a low dose, which
demonstrates a no observed effect level
(NOEL) for maternal and/or fetal
effects, and at least one intermediate
dose level. Test animals should be
selected based on considerations of
species, strain, age, weight and health
status, and should be randomized to
dose groups in order to reduce bias and
provide a basis for performing valid
statistical tests. Replication of the study
is desirable and strengthens the
confidence of data interpretation.
The next two sections discuss
individual end points of maternal and
developmental toxicity, respectively, as
measured in the conventional
developmental toxicity study. The third
section deals with the integrated
evaluation of all data including the
relative effects of exposure on maternal
animals and their offspring.
1. End Points of Maternal Toxicity
A number of end points that may be
observed as indicators of maternal
toxicity are listed in Table 1. Maternal
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mortality is an obvious end point of
maternal toxicity; however, a number of
other end points can be observed which
may give an indication of the subtle
effects of the agent For example, in
well-conducted studies the end point,
percent pregnant, indicates the general
fertility rate- of the animal stock used
and is an important indicator of toxic
effects if treatment begins prior to
implantation.
Table 1.—-End Points of Maternal Toxicity
Mortality
Percent Pregnant (includes all litters with
implants)
Body Weight
Treatment days (at least first, middle, and
last'treatment days) Sacrifice day
Body Weight Change
Throughout Gestation
During treatment (including increments of
time within treatment period)
Post-treatment to sacrifice
Corrected maternal (body weight change
throughout gestation minus gravid
uterine weight or litter weight at
sacrifice)
Organ Weights (in cases of suspected specific
organ toxicity)
Absolute
Relative to body weight
Food and Water Consumption (where
relevant)
Clinical Signs (on days of treatment and at
sacrifice) _
Daily welglit changes during treatment
Types and incidence of clinical signs
Body weight and the change in body
weight are viewed collectively as
indicators of maternal toxicity for most
species, although these end points may
not be as useful in rabbits, because
body weight changes in rabbits are not
goocMndicators of pregnancy status.
Body weight changes may provide more
information than a daily body weight
measured during treatment or during
gestation. Changes in weight during
treatment could occur that would not be
reflected in the overall weight change
throughout gestation, because of
compensatory weight gain that may
occur following treatment but before
sacrifice. For this reason, changes in
weight during treatment can be
examined as another indicator of
maternal toxicity.
Changes in maternal body weight
corrected for gravid uterine weight at
sacrifice may indicate whether the effect
is primarily maternal or fetai. For
example, there may be a signficant
reduction in weight gain throughout
gestation and in gravid uterine weight,
but no change in corrected maternal
weight gain which would indicate
primarily an intrauterine effect.
Conversely, a change in corrected
weight gain and no change in gravid
uterine weight suggests primarily
maternal toxicity and little or no
intrauterine effect. An alternate estimate
of maternal weight change during
gestation can be obtained by subtracting
the sum of the weights of the fetuses.
However, this weight does not include
the uterine tissue, placental tissue, or
the amniotic fluid.
Changes in other end points should
also be determined. For example,
changes in relative and absolute organ
weights may be signs of maternal effect
when an agent is suspected of causing
specific organ toxicity. Food and water
consumption data are useful, especially
if the agent is administered in the diet or
drinking water. The amount ingested
(total and relative to body weight) and
the dose of the agent (relative to body
weight) can then be calculated, and
changes in food and water consumption
with treatment can be evaluated along
with changes in body weight and body
weight gain. Consumatory data are also
useful when an agent is suspected of
affecting appetite, water intake, or
excretory function. Clinical signs of
toxicity may also be used as indicators
of maternal toxicity. Daily body weight
changes during treatment along with
clinical observations may be useful in
describing the profile of maternal
toxicity.
2. End Points of Developmental Toxicity
Because the maternal animal and not
the conceptus is the individual treated
during gestation, statistical analysis of
the data should consider both the
individual fetus and the litter. Table 2
indicates the way in which fetal and
litter end points can be expressed.
Table 2.—End Points of Developmental
Toxicity
All litters
No. implantation sites/dam
No. corpora lutea (CL)/dam*
Percent Preimplantation. loss •
No. and percent live fetuses/litter
No. and percent resbrptions/litter
No. and percent litters with resorptions
No. and percent late fetal deaths/litter
No. and percent nonlive (late fetal deaths +
resorptions) implants/litter
No. and percent litters with nonlife implants
No. and percent affected (nonlive +
malformedl implants/litter
No. and percent with affected implants
No. and percent litters with total resorptions
Litters with live fetuses
No. and percent litters with live fetuses
No. and percent live fetuses/litter
No. males/litter
No. females/litter
No. ratio/litter
Mean (x) fetal body weight/litter
Mean (x) male body weight/litter
Mean (x) female body weight/litter
No. and percent externally malformed
fetuses/litter
No. and percent viscerally malformed
fetuses/litter
No. and percent skeletally malformed
fqtuse.s/litter
No. and percent malformed fetuses/litter
No. and percent litters with malformed
fetuses
No. and percent malformed males/litter
No. and percent malformed females/litter
No. and percent fetuses with variations/litter
No. and percent litters having fetuses with
variations
Types and incidence of individual
malformations
Types and incidence of individual variations
Individual fetuses and their malformations
and variations (grouped according to litter
and dose)
• Only when treatment begins prior to
implantation. May be difficult in mice.
When treatment begins prior to
implantation, an increase in
preimplatation loss could indicate an •
adverse effect either on the developing
blastocyst or on the process of
implantation itself. Further studies
would be necessary to determine the
cause and extent of this type of effect.
The number of live fetuses per litter,
based on all litters, includes any litters
that have no live implants. On the other
hand, total nonlive implants
(postimplantation loss), is a combination
of the end points, resorptions, and late
fetal deaths. An increased incidence per
litter for any of the end points indicating
postimplantation loss would be
considered a significant toxic effect to
the conceptus. The number of litters
showing an increased incidence for
these end points is less useful than
incidence per litter, because a litter is
counted whether it has one or all
resorbed, dead, or nonlive implants.
A statistically significant increase in
postimplantation loss following
exposure to an agent is a severe form of
developmental toxicity, but there is
considerable interlitter variability in the
incidence of postimplantation loss(17). If
a statistically significant increase is
found after exposure to an agent, the
data may be compared not only with
concurrent controls, but also with recent
historical control data. If a given study
control group exhibits an unusually high •
or low incidence of postimplantation
loss compared to historical controls,
then scientific judgment would have to
be used to determine the adequacy of
the studies for risk assessment purposes.
The end point for affected implants
(i.e., the combination of nonlive and
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46327
malformed conceptuses) given an
'ication of the total intrauterine
ponse to an agent and sometimes
reflects a better dose-response
relationship than each taken
individually. This is especially true at
ihe high end of the dose-response curve
in cases where most implants die in
uiero. In such cases, the malformation
rate may appear to decrease because
only unaffected fetuses have-survived to
term. If the incidence of prenatal death
or malformation is unchanged, then the
incidence of affected implants will not
provide any additional information.
The number of live fetuses per litter.
based on those litters that have one or
more live fetuses, may be unchanged
even though the incidence of nonlive in
all litters is increased. This could occur
either by an increase in the number of
litters with no live fetuses or by an
increase in the number of implants per
litter. A decrease in the number of live
fetuses per litter should be accompanied
by an increase in the incidence of
nonlive implants per litter, unless the
implant numbers differ among dose
groups.
The sex ratio per litter, as well as the
body weights of males and females, can
be examined to determine whether or
|0t one sex is preferentially affected by
e agent. However, this is an unusual
occurrence.
- A change in fetal body weight is a
.sensitive indicator of developmental
toxicity. in part because it is a
continuous variable. In some cases, fetal
weight reduction may be the only
indicator of developmental toxicity: if
so. there is always a question remaining
as to whether weight reduction is a
permanent or transitory effect. When
fetal weight reduction is the only
indicator of developmental toxicity, data
from the two-generation reproduction
studyfJ) may be useful for evaluating
these parameters. Ideally, follow-up '
studies to evaluate postnatal viability,
an.'wth. and survi%ral through weaning
should be conducted. There are other
factors tlint should be considered in the
uvalu.-ition of fetal weight changes. For
axainple. in polytocous animals, fetal
weighl is usually inversely correlated
with litter size, and the upper end of the
dose-response curve may be confounded
by smaller litters and increased fetal
'.-.eight. Additionally, ihe average body
weight of male fetuses is greater than
rhat of female fetuses in the more
commonly used laboratory animals.
Live fetuses should be examined for
••xternal, visceral, and skelatal
'malformations. If only a portion of the
litter is examined, then it is preferable
ih;it (hose to be examined be selected
»n * random basis from each litter. The
incidence of individual types of
malformations and variations gives an
indication of the types of developmental
deviations produced by a particular
agent. A listing of individual
malformations and variations by fetus
gives an indication of the pattern of
developmental deviations. The
incidence of external, visceral, and
skeletal malformations gives an
indication of which systems may be
specifically affected A significant
increase in the incidence of particular
malformations or of the total number of
fetuses malformed per treated litter as
compared with controls indicates a
teratogenic effect. If variations are
significantly increased in a dose-related
manner, these should also be evaluated
as a possible indication of
developmental toxicity. The Interagency
Regulatory Liaison Group noted that
dose-related increases in spontaneously
occurring defects are as relevant as
dose-related increases in any other
developmental toxicity end points(W).
The number and percentage of litters
with malformed fetuses are more
reliable indicators of developmental.
toxicity than the number of litters with
resorptions, since malformations do not
occur frequently in controls. The data on
the incidence of individual types of
malformations and variations should be
examined for significant changes which
may be masked if the data on all
malformations and variations are
pooled. This information can also be
used for comparison with historical
control data. Appropriate historical
control data are helpful in interpretation
of major malformations, especially those
that normally occur at a low incidence
when seen in an individual study
apparently unrelated to dose.
3. Overall Evaluation of Maternal and
Developmental Toxicity
As discussed previously, individual
end points are evaluated hi
developmental toxicity studies, but an '
integrated evaluation must be done
considering all maternal and
developmental end points in order to
interpret the data fully. The overall
interpretation usually consists of the
evaluation of maternal toxicity and the
dose levels at which it occurs, then the
evaluation of developmental toxicity
and the levels ai which these end points
occur. In general, an agent that produces
changes in any of the four major classes
of developmental toxicity at a dose that
is minimally toxic or not toxic to the
maternal animal is considered to have
selective developmental effects.
However, when effects are produced at
maternally toxic doses by agents to
which adult human exposure may occur
at toxic levels (e.g., smoking, alcohol,
solvents], these developmental effects
should no be ignored.
Approaches for ranking agents for
their selective developmental toxicity
are being developed; Schardein(S) has
reviewed several of these. Of current
interest are approaches that develop
ratios relating an adult toxic dose tu a
developmental toxic dose(19, 20, 21).
Ratios near unity indicate that
developmental toxicity occurs only at
doses producing maternal toxicity; as
the ratio increases, there is a greater
likelihood of developmental effects
occurring without maternal
manifestations. Although further
exploration and validation are
necessary, such approaches may
ultimately help in identifying those
agents that pose the greatest threat and
should be given priority for further
testing^).
B. Functional teratology
Developmental effects, which are
inducible by exogenous agents, are not
limited to death, structural
abnormalities, and altered growth.
Rather, it has been demonstrated in a
number of instances that subtle
alterations in the functional competence
of an organ or a variety of organ
systems may result from exposure
during critical developmental periods
that may occur between conception and
puberty. Often, these functional defects
are observed at dose levels below those
at which gross malformations are
evident(23). Much of the early work in
this field was related to behavioral
evaluations, and the term "behavioral
teratology" became prominent in the
mid 1970s. Less work has been done on
other functional systems, but sufficient
data have accumulated to indicate that
the cardiopulmonary, immune,
endocrine, digestive, urinary, and
reproductive systems are subject to
alterations hi functional competence.
Hence the term "functional teratology"
has been applied to this general area.-
The variety of systems and end points
that may be evaluated is too extensive
to discuss here(24). (25). At present no
standard testing procedures are
routinely used, and this has led to
apparent discrepancies in the outcome
of certain studies. Some attempts to
standardize and evaluate procedures
are being made(26). The determination
of functional competence often involves
highly specialized training and
equipment and is not generally practical
for routine test procedures. Therefore.
these approaches may have their
greatest application in determining the
nature of a suspected alteration in term
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Federal Register / Vol. 49. No. 227 / Friday. November 23, 1984 / Notices
of its biological significance and dose-
response relationship.
The means for appropriate
interpretation of data from functional
teratology studies is not always clear
due to the lack of knowledge about the
toxicological significance of specific
functional alterations. However, several
general concepts have arisen from the
research to date which may be useful in
designing studies and evaluating data.
• 1. Several aspects of study design are
similar to those used in standard
developmental toxicity studies (e.g., a
dose-response approach with the
highest dose producing minimal overt
maternal or fetal toxicity, number of
litters large enough for adequate
statistical power, randomization of
animals to dose groups, litter generally
considered the statistical unit, etc.).
2. Replication of a study strengthens
the confidence of data interpretation.
3. Use of a pharmacological challenge
may aid in evaluating function and
"unmasking" effects not otherwise
detectable, particularly in the case of
organ systems that are endowed with a
reasonable degree of functional reserve
capacity.
4. Choice oHunctional tests with a
moderate degree of background
variability may be more useful in
detecting effects of agent exposure than
tests based on functional systems with
low variability that may be impossible
to disrupt without being life-threatening.
Butcher et al.(27) have discussed this
with relation to behavioral end points.
/ 5. A battery of functional tests is often
necessary to evaluate fully the
functional competence of any given
system; these tests may need to be
conducted at several ages to account for •
maturational changes.
6. Critical periods for.the disruption of
functional competence may include both
the prenatal period to the time of
puberty, and the effect is likely to vary
depending on the time of exposure.
Although interpretation of functional
data may be difficult at present, there
are at least two days in which the data
from these studies may be useful for risk
assessment purposes. First, these
studies can be used to indicate whether
or not an agent has the potential'to
cause functional alterations, and
whether these effects occur at doses
lower than those that produce other
forms of toxicity. Second, if the agent in
question is already in the environment,
the functional data may be used for
focusing on organ systems to evaluate in
exposed human populations.
C. Short-Term Testing in Development'
Toxicity • : •
The need for developmental toxicity
screens has arisen from the large
number of agents in or entering the
environment and the increased interest
in reducing the number of animals used
in and the expense of testing. Currently,
two approaches are being considered for
their applicability in the overall testing
process: an in vivo mammalian screen
and a variety of in vitro systems.
Neither approach is seen at this time as
replacing current in vivo developmental
toxicity testing. Rather, they are being
considered for their usefulness in
assigning priorities for further, more
extensive testing..
1. In Vivo Mammalian Teratology
Screen
An in vivo approach developed by
Chemoff and Kavlock(2fl) uses the
pregnant mouse and it designed to
reduce the resources required for
precliminary indication of
developmental toxicity. This approach is
based on the hypothesis that a prenatal
insult, which results in altered
development, will be manifested
postnatally as reduced viability and/or
impaired growth. In general, the test
substance is administered over the
period of major organogenesis at a
single dose level that will elicit some
degree of maternal toxicity. After birth,
the pups are counted and weighed on
days 1 and 3. End points that are
considered in the evaluation include:
general maternal toxicity (including
survival and weight gain), litter size,
viability and weight of the offspring, and
gross malformations. Basic priority
categories for further testing have also
been suggested: (1) Agents that induce
perinatal death should receive highest
priority, (2) agents inducing perinatal
weight changes should be ranked lower -
in priority, and (3) agents inducing no
effect should receive the lowest
priority(2a). The major goal of this test is
to predict the potential for
developmental toxicity of an agent in
the species utilized. It does not increase
the ability to extrapolate risk to other
species, including humans. Additional
studies to evaluate the validity of this
approach as a screen for developmental
toxicity are currently being carried out.
and a system for giving a numerical
ranking to the results has been-
suggested to prioritize agents for further
testing(29, 30).
2. In Vitro Teratology Screens
Test systems that fall under the
general heading of "in vitro" include any
system that employs a test subject other
than the intact pregnant mammal. These
systems have long been used to assess
events associated with normal and
abnormal development, but only
recently have they been considered for
their potential as screens in testing (31.
32, 33). Many of these systems are now
being evaluated for their ability to
predict the developmental toxicity of
various agents. This validation process
requires certain considerations in study
design, including defined end points for
toxicity and an understanding of the
system's ability to handle various test
agents(32, 34). A list of agents for use in
these validation studies has been
developed(35).
3. Application
When the validity of a screening
system is established, it may be used to
set priorities for further, more
comprehensive in vivo testing. In many
cases, a battery of two or more
screening systems may be needed,
employing tests with end points that
collectively represent several
embryologic processes. In addition,
many of these systems can be applied in
an attempt to answer specific questions
of a dose-response, target-organ, or
mechanistic nature. In vitro approaches
may aid in establishing the effective
dose that reaches the target tissue.
Either the in vivo or in vitro short-term
approaches may be useful in addressing
structure-activity relationships and the
synergistic-antagonistic potential of
chemical interactions. Thus, pertinent
information can be derived from these
approaches and may be useful in the
assessment of potential risk.
D. Pharmacokinetics
Extrapolation of data between species
can be aided considerably by the
availability of data on the
pharmacokinetics of a particular agent
in the species tested and, if possible, in
humans. Information on half-lives,
placental metabolism and transfer, and
concentrations of the parent compound
and metabolites in the maternal animal
and conceptus may be useful in
predicting risk for developmental
toxicity. Such data may also be helpful
in defining the dose-response curve,
developing a more accurate comparison
of species sensitivity including that of
humans (36. 37], determining dosimetry
at target sites, and comparing
pharmacokinetic profiles for various
dosing regimens or routes of exposure.
Pharmacokinetic studies in
developmental toxicology are most
useful once a developmental toxic effect
has been produced in a give species
with a particular agent. Pharmacokinetic
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Federal Register / Vol. 49. No. 227 / Friday. November 23, 1984 / Notices 46329
data for risk assessment in
developmental toxicology ideally should
be derived from pregnant females at the
stage when developmental insults occur.
Often the only data available are from
males, nonpregnant females, or from
pregnant females at a time unrelated to
the event of interest (e.g.,
pharmacokinetic analyses done during
the fetal period when malformations
were induced early in organogenesis).
The correlation of pharmacokinetic and
developmental toxicity data may be
useful in determining the contribution of
specific pharmacokinetic parameters to
the effects observed (38).
E. Human Studies
Because of the ethical considerations
involved, little human testing has been
or is likely to be done. Therefore, dose-
effect developmental toxicity data from
humans are generally not available.
Human epidemiologic'studies may
provide the best information for
assessing human risk and would reduce
the problems in species-to-species
:':Xtrapolation. However, interpretation
of epidemiologic data must account for
-omounding factors, such as maternal
•.ae, parity, multiple exposures to
-nvironmental agents, difficulty in .
-staining accurate estimates of
exposure levels in the environment,
insufficient data on background
incidence of certain developmental end
points, etc. When human data are
available, they can be used with other
supporting animal data to assess human
risk.
F. Comparisons of Molecular Structure ~
Comparisons of the chemical or
physical properties of an agent with
those of known developmental toxicants
may provide some indication of a
potential for developmental toxicity.
Such information may be useful in
priority-setting of Agents for testing or -
for further evaluation when only
minimal data are available.
C. Weight-of-Evidence Determination
Information available from studies
discussed previously, whether indicative
of potential concern or not, must be
evaluated and factored into the
assessment. The types of data may vary
from chemical to chemical, and certain
types of data may be more relevant than
other types of data in performing
developmental toxicity assessments.
Therefore, all data pertinent to
developmental toxicity-should be
examined in the determination of a
chemical's.potential to cause
developmental toxicity in humans.
Whatever evidence may exist from
humans must also be factored into the
assessment.
IV. Quantitative Assessment
Risk assessment involves the
description of the nature and often the
magnitude of potential human risk.
including a description of any attendant
uncertainty. In the final phase of the risk
assessment, the outputs of the
qualitative evaluation, the dose-
response, and the exposure data are
combined to give qualitative and/or
quantitative estimates of the
developmental toxicity risk. As part of
the risk assessment a summary of the
strengths and weaknesses of the hazard
identification, dose-response
assessment, exposure assessment, and
the risk characterization are presented.
Major assumptions, scientific judgments,
and, to the extent possible, estimates of
the uncertainties in the assessment are
also presented.
A. Dose-Response Assessment
Because human dose-effect data
usually are not available, other methods
have been used in developmental
toxicology for estimating exposure
levels that are unlikely to produce
adverse effects in humans. The dose-
response assessment-js-usually based^.
upon the evaluation of tests performed
in laboratory animals. Two approaches
frequently employed involve the use of
safety factors and margins of safety,
which in some respects are conceptually
similar. However, they are computed
differently and are often used in
different regulatory situations. The
choice of approach is dependent upon
many factors, including the statute
involved, the situation being addressed,
the data base used, and the needs of the
decision-maker.
The safety factor approach is intended
to derive a calculated exposure level
that is unlikely to cause any
developmental toxic responses in
humans. The size of the safety factor
will vary from agent to agent and will
require the exercise of scientific
judgment(d, 39), taking into account
interspecies differences, the nature and
extent of human exposure, the slope of
the dose-response curve, and the .
severity of the developmental effects
observed at exposure levels below
maternal toxicity in the test species. The
safety factor selected is then divided
into the NOEL obtained from the most
appropriate and/or sensitive
mammalian species examined to obtain
an acceptable exposure level. Currently,
there is no one laboratory animal
species that can be considered most
appropriate for predicting risk to
humans(S). Each agent should be
considered on a case-by-case basis.
The margin of safety approach derives
a ratio of the NOEL from the most
.sensitive species to the estimated
human exposure'level from all potential
sources(40). The adequacy of the margin
of safety is then considered, based upon
the weight of evidence, including quality
of data, number of species affected,
dose-response relationships, and. other
factors such as benefits of the agent.
As discussed earlier, the preferred
study design for a developmental
toxicity study includes a minimum of
three doses: a high dose that produces
minimal maternal toxicity, at least one
intermediate dose, and a low dose that
demonstrates a NOEL. Nevertheless,
there may be circumstances in that there
is a need to perform a risk assessment
based on the results of a study in which
a NOEL could not be identified, but.
rather, in which the lowest dose
administered caused some marginally
significant effect(s). This lowest dose
could be identified as the lowest
observed effect level (LOEL). In
circumstances where a LOEL can be
identified, it may be appropriate to
apply an additional safety factor. The
magnitude of this additional factor is
dependent upon scientific-judgment. In .
some instances, additional studies may
be needed to strengthen the confidence
in this additional safety factor.
B. Exposure Assessment
The results of the dose-response
assessment are combined with an
estimate of human exposure in order to
obtain a quantitative estimate of risk.
The proposed Guidelines for Exposure
assessment are being developed
separately and will not be discussed in
any detail here. In general, the exposure
assessment describes the magnitude,
duration, schedule, and route of
exposure. This information is developed
from monitoring data and from
estimates based on modeling of
environmental exposures. Unique
considerations relevant to
developmental toxicity are duration and
period of exposure as related to stage of
gestation (i.e., critical periods), and the
fact that a single exposure may be
sufficient to produce adverse
developmental effects (i.e., chronic
exposure is not necessary for
developmental toxicity to be
manifested).
C. Risk Characterization
There are numerous uncertainties
associated with the toxicological and
exposure components of risk assessment
that in the past have often not been
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46330
Federal Register / Vol 49. No. 227./ Friday, November 23. 1984 / Notices
readily apparent or consistently
presented. The presentation of any
qualitative or quantitative risk
assessment for developmental toxicity
should be accompanied by statements
concerning the quality of the data.
resolving power of the studies, number
of end points examined, selection of
doses, replication of the data, the
number of species examined,
pharmacokinetic considerations, and
any other factors that affect the quality
and precision of the assessment The
presentation of any numerical estimate
should be sufficiently qualified as to the .
assumptions used and the accuracy of
the estimates.
In the assessment of developmental
toxicity,-statistical considerations
require special attention. For example,
the power of a study (i.e., the ability to
demonstrate an effect), is limited by the
sample size used in the study, the
background incidence of the end point
observed, and the variability in the
incidence of the end point As an
example, Nelson and Holson(47) have
shown that the number of litters needed
to detect a 5 or 10 percent change was
dramatically lower for fetal weight (a
continuous variable with low
variability) than for resorptions (a
binomial response with high variability).
With the current recommendation in
testing protocol being 20 rodents per
dose group(7. 3], it is possible to detect
an increased incidence of malformations •
in the range of 5 to 12 times above
control levels, an increase of 3 to 6 times
the in utero death rate, and a decrease
of 0.15 to 0.25 times the fetal weight
Thus, even within the same study, the
ability to detect a change in fetal weight
is much greater than for the other end
points measured. Consequently, for
statistical reasons only, changes in fetal
weight are often observable at doses
below those producing other signs of
developmental toxicity.
At present, there is no mathematical
model that is generally used for
estimating developmental toxicity
responses below the applied dose range.
This is due primarily to the lack of
understanding of the biological
mechanisms underlying developmental
toxicity, intra/interspecies differences in
the types of developmental events, the
influence of maternal effects on the
dose-responss curve, and whether or not
a threshold exists below which no effect
will be produced by an agent. The
assumption of a threshold is based
largely on the biological rationale that
the embryo is known to have some
capacity for reoair of the damage or
insult(42), and that most developmental
deviations are probably multifactorial in
narure(43). However, the existence of a
no effect level cannot be proven
statistically.
Discussions of risk extrapolation
procedures have noted that further work
is needed to improve mathematical tools
for developing estimates of potential
human developmental risk( J9, 44).
Gaylor(45) has suggested an approach
for controlling risk that combines the
use of mathematical models for low-
dose estimation of risk with the
application of a safety factor based on a
preselected level of allowable risk. This
approach is similar to approaches
proposed for carcinogenesis, but does
not preclude the possibility of a
threshold, and may provide a more
quantitative approach to controlling
risk. For the present the Agency will
continue to use safety factors and
margins of safety as described above,
where applicable. However, more
appropriate models will be sought and
applied if considered acceptable.
These Guidelines summarize the
procedures that the U.S. Environmental
Protection Agency will follow in
evaluating the potential for agents to
cause developmental toxicity. These
Guidelines will be reviewed and
updated as advances are made in the
field, since it is evident that our ability
tO PvaliiafajapH prpriirt
developmental toxicity is imprecise.
Further studies that delineate the
mechanisms of developmental toxicity -
and pathogenesis, provide comparative
pharmacokinetic data, and elucidate the
. functional modalities that may be
altered by exposure to toxic agents will
aid in the interpretation of data and
interspecies extrapolation. These types
of studies, along with further evaluation
of the relationship between maternal
and fetal toxicity and the concept of a
threshold in developmental toxicity, will
provide for the development of
improved mathematical models to more
precisely assess risk.
V. References
(1) U.S. Environmental Protection Agency.
1982. Health effects test guidelines. Chapter
II. Specific organ/tissue toxicity-
teratogenicity. Office of Toxic Substances.
Available from: NT1S. Springfield VA. PB82-
232984.
[2] U.S. Environmental Protection Agency.
1980. Assessment of risks to human
reproduction and to development of the
human concepms from exposure to
environmental substances, pp. 99-116.
Available from: NTIS, Springfield. VA. DE82-
007897.
(3) U.S. Environmental Protection Agency.
1982. Pesticides registration: proposed data
requirements. Federal Register 47:53192-
53203.
(4) Hertig, A.T. 1967. The overall problem
in man. hr K. Benirschke, ed. Comparative
aspects of reproductive failure. New York,
NY: Springer-Verlag, pp. 11-41.
(3) McKeown, T.. and R.C. Record. 1903.
Malformations in a population observed fur
five years after birth. In: G.E.W.
Wolstenholme and C.M. O'Conner, eds.. Ciba
Foundation symposium on congenital
malformations. Boston, MA: Little Brown, pp
2-18.
(6) Mellin. G.W.. and M. Katzenstein. 1964.
Increased incidence of malformations-
change. J. Am. Med. Asaoc. 187:570-573.
(7) Wilson, J.G. 1977. Erabryotoxicity of
drugs in man. In: J.G. Wilson and F.C. Fraser.
eds. Handbook of teratology. New York. NY:
Plenum Press, pp. 309-355.
(8) Shepard. T.H. 1980. Catalog of
teratogenic agents. Third Edition. Baltimore.
MD: Johns Hopkins University Press.
(9) Schardein. J.L. 1983. Teratogenic risk
assessment In: H. Kalter, ed. Issues and
reviews in teratology. Vol. 1. New York. NY:
Plenum Press, pp. 181-214.
(10] Shepard. T.R 1984. Teratogens: an
update. Hosp. Pract, Jan., pp. 191-200.
(11} Brown, N.A., and S. Fabro. 1983. The
value of animal teratogenicity testing for
predicting human risk. Clin. Obstet. Gynecol.
26:487-477.
(12) Kimmel, C.A., J.F. Holson. C.J. Hogue.
and GX. Carlo. 1984. Reliability of
experimental studies for predicting hazards
to human development. NCTR Technical
Report for Experiment No. 6015. NCTR.
Jefferson, Arkansas.
• (13) Committee on the Institutional Means
jor. the Assessment oLRisks to Pubjic Health.
1983. Risk assessment in the Federal
government: managing the process.
Commission on Life Sciences, National
Research Council. Washington. DC: National
Academy Press, pp. 17-83.
(14) Food and Drug Administration. 1966.
Guidelines for reproduction and teratology of
drugs. Bureau of Drugs.
(IS) Food and Drug Administration. 1970.
Advisory Committee on Protocols for Safety
Evaluations. Panel on Reproduction Report
on Reproduction Studies in the Safety
Evaluation of Food Additives and Pesticide
Residues. Toxicol. Appl. Pharmacol. 16:264-
296.
(18) Symposium on effects of radiation and
other deleterious agents on embryonic
development 1954. J. Cell. Comp. Physiol. 43
(suppl. 1).
(77) Woo. D.C., and R.M. Hoar. 1979.
Reproductive performance and spontaneous
malformations in control Charles River rats.
A joint study for MART A. Teratology 19:54A.
(;a)1nteragency Regulatory Liaison Group
1981. Report of the Developmental Toxicity
'End Points Workgroup. Workshop on
Reproductive Toxicity Risk Assessment.
Rockville, MD, September 21-23.
(19) Johnson, E.M. 1901. Screening for
teratogenic hazards: nature of the problem.
Annu. Rev. Pharmacol. Toxicol. 21:417-429.
(20) Johnson. E.M., and B.E.G. Gabel. 1983.
An artificial embryo for detection of
abnormal developmental biology. Fund. Appl.
Toxicol. 3:243-249.
(21) Fabro. S.. G. Schull. and N.A. Brown.
1982. The relative teratogenic index and
teratogenic potency: proposed components of
-------
Federal Register / Vol. 49. No. 227 / Friday. November 23. 1984 / Notices
46331
developmental toxicity risk assessment.
Teratogenesis Carcinog. Mutagen. 2:61-76.
(22) Johnson. E.M. 1984. A prioritizalion
and biological decision tree for
developmental toxicity safety evaluations. J.
Am. Coll. Toxicol. 3:141-147.
(23) Rodier. P.M. 1978. Behavioral
teratology. In: J.G. Wilson and F.C. Fraser,
eds.. Handbook of teratology. Vol. 4. New
York, NY: Plenum Press, pp. 397-428.
(24) Buelke-Sam. J., and C.A. Kimmel. 1979.
Development and standardization of
screening methods for behavioral teratology.
Teratology 20:17-29.
(25) Kavlock. R.J., and C.T. Grabowski, eds.
1983. Abnormal functional development of
the heart lungs, and kidneys: approaches to
functional teratology. Prog. Clin. Biol. Res.,
Vol. 140. New York, NY: Alan R. Liss, Inc.
(26) Kimmel. C.A.. J. Buelke-Sam. J. Adams.
L.W. Reiter, T.J. Sobotka. and H.A. Tilson.
1982. Design considerations in the evaluation
of standardized methods in a behavioral
teratology study. Teratology 25:S4A.
(27) Butcher, R.E., V. Woolen, and C.V.
Vorhees. 1980. Standards in behavorial
teratology testing: test variability and
sensitivity. Teratogenesis Carcinog. Mutagen.
1:49-61.
(28) Chernoff. N., and R.J. Kavlock. 1982.
An in vivo teratology screen utilizing
- pregnant mice.}. Toxicol. Environ. Health
10:541-550.
(29) Brown. J.M. 1984. Validation of an in
vivo screen for the determination of embryo/
fetal toxicity in mice. SRI International. EPA
contract no. 68-01-5079.
(30) Schuler R.. B. Hardin. R. Niemeyer. G.
Booth, K. Hazelden. V. Piccirillo, and K.
Smith. 1984. Results of testing fifteen glycol
ethers in a short-term, in vivo reproductive
toxicity assay. Environ. Health. Perspect. in
press. «
(31) Wilson. J.G. 1978. Survey of in vitro
systems: their potential use in teratogenicity
screening. In: J.G. Wilson and F.C. Fraser,
eds. Handbook of teratology. Vol. 4. New
York, NY: Plenum Press, pp. 135-153.
(32) Kimmel. G.L., K. Smith. D.M. Kochhar.
and RM. Pratt. 1982. Overview of in vitro
teratogenicity testing: aspects of validation
and application to screening. Teratogenesis
Carcinog. Mutagen. 2:221-229.
(33) Brown. N.A., and S.E. Fabro. 1982. The
in vitro approach to teratogenicity testing. In:
K. Snell, ed. Developmental toxicology.
London. EnglanduCroom-Helm, pp. 31-57.
(34) Kimmel, G.L. 1984. In vitro tests in
screening teratogens: considerations to aid
the validation process. In: M. Morris, ed.
Prevention of physical and mental congenital
defects. Part A. New York. NY: Alan R. Liss.
Inc., in press.
(35) Smith, M.R., G.L. Kimmel. D.M.
Kochhar, T.H. Shepard. S.P. Spielberg, and
J.G. Wilson. 1983. A selection of candidate
compounds for in vitro teratogenesis test
validation. Teratogenesia Carcinog. Mutagen.
3:461-480.
(36) Wilson. J.G., W.J. Scott E.J. Ritter, and
R. Fradkin. 1975. Comparative distribution
and embryotoxicity of hydroxyurea in
pregnant rats and rhesus monkeys.
Teratology 11:169-178.
(37) Wilson. J.G., E.J. Ritter. W.J. Scott and
R. Fradkin. 1977. Comparative distribution
and embryotoxicity of acerylsalicylic acid in '
pregnant rats and rhesus monkeys. Toxicol.
Appl. Pharmacol. 41:67-78.
(38) Kimmel. C.A.. and J.F. Young. 1983.
Correlating pharmacokinetics and teratogenic
end points. Fund. Appl. Toxicol. 3:250-255.
(39) Hogan. M.D., and D.G. Hoel. 1982.
Extrapolation to man. In: A.W. Hayes, ed.
Principles and methods of toxicology. New
York. NY: Raven Press, pp. 711-731.
(40) Chitlik, L.D.. Q.Q. Bui, G.J. Burin, and
S.C. Dapson. 1984. Standard evaluation
procedures for teratology studies (Draft).
Toxicology Branch. Hazard Evaluation
Division. Office of Pesticide Programs. U.S.
Enironmental Protection Agency.
(41) Nelson, C.J., and J.F. Holson. 1978.
Statistical analysis of teratogenic data:
problems and advancements.}. Environ.
Pathol. Toxicol. 2:187-199.
(42) Wilson, J.G. 1973. Environment and
birth defects. New York, NY: Academic Press,
pp. 30-32.
(43) Fraser. F.C. 1977. Relation of animal
studies to the problem in man. In: J.G. Wilson
and F.C. Fraser. eds. Handbook of teratology.
Vol. 1. New York, NY: Plenum Press, pp. 75-
96.
(44) Environmental Health Criteria 30.1984.
Principles for evaluating health risks to
progeny associated with exposure to
chemicals during pregnancy, pp. 111-114.
World Health Organization, Geneva.
Switzerland.
(45) Gaylor. D.W. 1983. The use of safety
factors for controlling risk.}. Toxicol.
Environ. Health 11:329-336.
[FR Doc. M-30721 Filed 11-21-34: 8:4! °m| ^
BIUJNQ CODE M8O-SO-*
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£tfe Systems, Jnc.
PART 5 - HEALTH RISK ASSESSMENT
CHEMICAL MIXTURES
A3-6
-------
Wednesday
January 9, 1985
Part III
Environmental
Protection Agency
Proposed Guidelines for the Health Risk
Assessment of Chemical Mixtures and
Request for Comments; Notice
-------
1170
Federal Register / Vol. 50, No. 8 / Wednesday, January 9, 1985 / Notices
ENVIRONMENTAL PROTECTION
AGENCY
[FRL-2742-8]
Proposed Guidelines for the Health
Risk Assessment of Chemical Mixtures
AGENCY: Environmental Protection
Agency (EPA.
ACTION: Proposed guidelines for the
Health Risk Assessment of Chemical
Mixtures and request for comments.
SUMMARY: The U.S. Environmental
Protection Agency is proposing
Guideline? for the Health Risk
Assessment of Chemical Mixtures
(Guidelines). These Guidelines are
proposed for use within the policy and
procedural framework provided by the
various statutes that EPA administers to
guide Agency analysis of health effects
data. We solicit public comment and
will take public comment into account in
revising these Guidelines. These
Guidelines will be reviewed by the
Science Advisory Board in meetings
now tentatively scheduled for April
1985.
These proposed Guidelines were
developed as part of a board guidelines
development program under the
auspices of the Office of Health and
Environmental Assessment (OHEA),
located in the Agency's Office of
Research and Development. Consonant
with the role of OHEA's Environmental
Criteria and Assessment Office in
Cincinnati (ECAO-Cin) as the Agency's
senior health committee for health risk
assessment of chemical mixtures, the
Guidelines were developed by an
Agency-wide working group chaired by
the Director of ECAO-Cin.
DATE: Comments must be postmarked
by March 11.1985.
ADDRESS: Comments may be mailed or
delivered to: Dr. Jerry Stara,
Environmental Criteria and Assessment
Office. U.S. Environmental Protection
Agency. 26 West St. Clair. Cincinnati,
OH 45268.
FOR FURTHER INFORMATION CONTACT:
Dr. Richard Hertzber. Telephone: 513-
684-7531.
SUPPLEMENTARY INFORMATION:
Preliminary drafts of these Guidelines
were sent for review to approximately
20 scientists in the fields of toxicology.
pharmacokinetics and statistics within
the Agency and a later draft was sent
for external review to 12 scientists
within government, academia and the
private sector. Comments received from
these reviewers, generally favorable.
were considered in developing the
Guidelines proposed here.
References and supporting documents
used in the preparation of these
guidelines as well as comments received
are available for inspection and copying
at the Public Information Reference Unit
(202-382-5926), EPA Headquarters
Library, 401 M Street, SW., Washington,
DC, between the hours of 8:00 a.m. and
4:30 p.m.
Dated January 2.1985.
William 0. Ruckelshaus,
Administrator.
Contents
I. Introduction
II. Proposed approach
A. Data Available on similar mixtures
B. Data Available only on Mixture
Components
1. Systemic Toxicants
2. Carcinogens
3. Interactions
4. Uncertainties
a. Health Effects
b. Exposure Uncertainties
c. Uncertainties Regarding
Composition of the Mixture
III. Assumptions and Limitations
IV. Mathematical Models and the
Measurement of Joint Action
A. Dose Addition
B. Response Addition
• C Interactions
V. References
I. Introduction
The primary purpose of this document
is to generate a consistent Agency
approach for evaluating data on the
chronic and subchronic effects of
chemical mixtures. It is a procedural
guide which emphasizes broad
underlying principles of the various
science disciplines (toxicology,
pharmacology, statistics) necessary for
assessing health risk from chemical
mixture exposure. Approaches to be
used with respect to the analysis and
evaluation of the various data are also
discussed.
It is not the intent of these Guidelines
to regulate any social or economic
aspects concerning risk of injury to
human health or the environment
caused by exposure to a chemical
agents(s). All such action is addressed
in specific statutes and federal
legislation and is independent of these
Guidelines.
While some potential environmental
hazards involve significant exposure to
only a single compound, most instances
of environmental contamination involve
concurrent or sequential exposures to a
variety of compounds that my induce
similar or dissimilar effects over
exposure periods ranging from short-
term to lifetime. In some instances, the
mixtures are highly complex consisting
of scores of compounds that are
generated simultaneously as by-
products from a single source or process
(e.g., coke oven emissions and diesel
exhaust). In other cases, complex
mixtures of related compounds are
produced as commercial products (e.g..
PCBs, gasoline and pesticide
formulations) and eventually released to
the environment. Another class of
mixtures consists of compounds, oftn-
unrelated chemically or commercially,
which are placed in the same area for
disposal or storage, eventually come
into contact with each other, and are
released as a mixture to the
environment. The quality and quantity
of pertinent information available for
risk assessment varies considerably for
different mixtures. Occasionally, the
chemical compositions of a mixture is
well characterized, levels of exposure to
the population are known, and detailed
toxicologic data on the mixture are
available. Most frequently, not all
components of the mixture are known,
exposure data are uncertain, and
toxicologic data on the known
> components of the mixture are limited.
Nonetheless, the Agency may be
required to take action because of the
number of individual at potential risk or
because of the known toxicologic effects
of these compounds that have been
identified in the mixture.
Guidelines for single compound risk
assessments have been developed for
subchronic and chronic exposures to
both systemic toxicants and
carcinogens. In the current document,
these approaches are extended to
provide compatible guidelines for
assessing the effects of multiple toxicant
or multiple carcinogen exposures.
The ability to predict how specific
mixtures of toxicants will interact must
be based on an understanding of the
mechanisms of such interactions. Most
reviews and texts that discuss toxicant
interactions make some attempt to
discuss the biological or chemical bases
of the interactions (e.g., Klaassen and
Doull, 1980; Levine, 1973: Goldstein et
aL, 1974; NRC. 1980a; Veldstra. 1956;
Withey, 1981). Although different
authors use somewhat different
classification schemes for discussing the
ways in which toxicants interact, it
generally is recognized that toxicant
interactions may occur during any of the
toxicologic processes that take place
with a single compounds-absorption.
distribution, metabolism, excretion, and
activity at the receptor site(s). In
addition, compounds may interact
chemically, causing a change in the
biological effect or they may interact by
causing different effects at different
receptor sites.
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Federal Register / VoL 50. No. 6 / Wednesday. January 9. 1985 / Notices
1171
Because of the uncertainties inherent
in any approach to predicting the
magnitude and nature of toxicant
interactions, any assessment of health
risk from chemical mixture must include
a thorough discussion of all
assumptions. No single approach is
recommended in these Guidelines.
Instead, guidance.is given for modifying
a few simple approaches involving risk
addition or dose addition. The
mathematical details are presented in
Section IV.
III. Proposed Approach
No single approach can be
recommended to risk assessments for
multiple chemical exposures.
Nonetheless, general guidelines can be
recommended depending on the type of
mixture, the known toxic effects of the
components in the mixture, the
availability of toxicity data on the
mixture or similar mixtures, the known
or anticipated interactions among
components in the mixture, and the
quality of the exposure data. Given the
complexity of this issue and the relative
paucity of empirical data from which
sound generalizations can be
constructed, emphasis must be placed
on flexibility, judgment, and a clear
articulation of the •assumption and
limitations in any risk assessment that is
developed. The proposed approach is
summarized in Table I and detailed
below.
A. Data Available on Similar Mixtures
For predicting the effects of
subchronic or chronic exposure to •
mixtures, the preferred approach. is to
use subchronic or chronic health effects
data on the mixture of concern and '
adopt the same procedures as those
used for single compounds, either
systemic toxicants or carcinogens. Such
data are most likely to be available on
highly complex mixtures, such as coke
oven emission or diesel exhaust, which
are generated in large quantities and
associated with or suspected of having
adverse health effects. Even if such data
are available, attention should be given
to the persistence of the mixture in the
environment as well as the variability of
composition of the mixture over time or
from different sources of emissions. If
the components in the mixture are
known to partition into different
environmental compartments or to
degrade or transform at 'different rates
in the environment, then those factors
must also be taken into account, or the
confidence in and applicability of the
risk assessment is diminished.
TABLE 1.— OUTLINE or THE RISK ASSESSMENT
APPROACH FOR CHEMICAL MIXTURES
1. MeaMi eftecti MumiegUf> it
on *» cMmical
a, * yes. proceed O Step 5.
6. n no. uiULUUd 03 Stop 2
2. Aasec* Om (Moty of tie masum on wMtfi bee«i
effects data ant svatebie to the nurture of concern. «*ti
emphasis on any difference* in components, proportions
d components, and environmental partitioning.
I. » euMcientt* samtm. proceed Ml Step S.
ta. II not sufficiently writer or If no tucfi dsta exist,
picceed e Stop 3.
a Oeme acpraprieM none* of *Li.eyfel
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1172
Federal Register / Vol. 50. No. 6 / Wednesday, January 9. 1985 / Notices
assessments, the exposure levels may be
expressed in a variety of ways such as
Acceptable Daily Intakes (ADIs), levels
associated with various Margins Of
Safety (MOS), or Ambient Air
Standards. For the purpose of this
discussion, the term "Acceptable Level"
(AL) will be used to indicate any of the
criteria, standards, or advisories derived
by the Agency. For such estimates, the
"hazard index" (HI) of a mixture based
on the assumption of dose additivity
may be defined as:
HI = Ei/AL,+E2/AL,+...-f Ei/Al, (II-l)
where:
£,= exposure level to the i"1 toxicant, and
AL,= maximum acceptable level for the itt
toxicant
Since the inverse of the acceptable level
can be used as an estimate of toxic
potency, Equation U-I can be interpreted
as a normalized weighted-average dose,
with each component dose scaled by its
potency. As this index approaches unity,
concern for the potential hazard of the
mixture increases. If HI>1, the concern
for the potential hazard is the same as if
an acceptable level were exceeded for
an individual compound, i.e., if EjAL,
exceeded 1. If the variabilities of the
acceptable levels are known, or if the
acceptable levels are given as ranges
{e.g., associated with different margins
of safety^ then HI should be presented
with estimates of variation or as a
range.
The hazard index is not a
mathematical prediction of incidence of
effects or severity. Statistical properties
of this index and its dependence on the
shape of the dose-response curves for
the components are not yet known.
Much additional research is required to
determine the accuracy of the hazard
index as a numerical prediction of toxic
severity. The hazard index is only a
numerical indicator of the transition
between acceptable and unacceptable
exposure levels and should not be
overinterpreted.
As discussed in Section IV, the
assumption of additivity is most
properly applied to compounds that
induce the same effect by the same
mechanism. Consequently, the
application of Equation II-l to a mixture
of compounds that does not interact and
is not expected to induce the same types
of effects could overestimate hazard.
Thus, if the application of Equation II-l
results in an index near to or greater
than unity, it may be desirable to
segregate the compounds in the mixture
by critical effect and derive separate
indices for each effect. Conversely, if the
dissimilar effects influence one another
(e.g., liver failure diminishing the
function of another organ), then simple
dose addition could underestimate the..
total hazard; this is discussed more fully
in Section HI.
The Agency has developed methods
for estimating dose-response curves for
single chemicals, e.g. carcinogens (U.S.
EPA, 1984). In attempting to assess the
response to mixtures using dose-
response curves for the components of
the mixture, dose-additive or response-
additive assumptions can be used, with
preference given to the most biologically
plausible assumption.
2. Carcinogens
. For carcinogens, whenever linearity of
the dose-response curve can be assumed
(usually restricted to low doses], the
increase in incremental risk P, caused
by exposure d, is related to carcinogenic
potency B, as:
P = d B. (II-2)
For multiple compounds, this equation
may be generalized to:
P = 2 d, B,. (H-3)
This equation assumes independence of
action by the several carcinogens and is
equivalent to the assumption of dose
addition- as well as to response addition
with completely negative correlation of
tolerance (see Section FV). Analogous to
the procedure used in Equation II-l for
systemic toxicants, an index could be
developed by dividing exposure levels
(E) by doses (DR) associated with
varying levels of risk:
HI = E./DR, + E,/DR, + ... = E,/DR,
(II-l)
It should be emphasized that because of
the uncertainties in estimating dose
response relationships for single
compounds and the additional
uncertainties in combining the
individual estimate to assess response
from exposure to mixtures, response
rates and hazard indices may have merit
in comparing risks but should not be
regarded as measures of absolute risk.
3. Interactions
None of the above equations
incorporates any form of synergistic or
antagonistic interaction. Some types of
information, however, may be available
that suggest that two or more
components in the mixture may interact.
Such information must be assessed in
terms of both its relevance to subchronic
or chronic hazard and its suitability for
quantitatively altering the risk
assessment.
For example, if chronic or subchronic
toxicity or carcinogenicity studies have
been conducted that permit a
quantitative estimation of interaction for
two chemicals, then it may be desirable
to consider using equations detailed in
Section IV, or modifications of these
equations, to treat the two compounds
as a single toxicant with greater or
lesser potency than would be predicted
from additivity. Other compounds in the
mixture, on which no such interaction
data are available, could then be treated
in an additive manner. Before such a
procedure is adopted, however, a
discussion should be presented of the
likelihood that other compounds in the
mixture may interfere with the
interaction of the two toxicants on
which quantitative interaction data are
available. If the weight of evidence
suggests that interference is likely, then
an attempt to quantitatively alter the
risk assessment may not be justified. In
such cases, the discussion of the risk
assessment may only indicate the likely
nature of interactions, either synergistic
or antagonistic, but not attempt to
quantify the magnitude of this
interaction.
Other types of available information.
such as those relating to mechanisms of
toxicant interaction, or quantitative
estimates of interaction between two
chemicals derived from acute studies,
are even less likely to be of quantitative
use in the assessment of long-term
health risks. Usually it will be
appropriate only to discuss these types
of information. Indicate the relevance of
the information to subchronic or chronic
exposure, and, as above, indicate, if
possible, the nature of any pgtential
interaction, without attempting to
quantify the magnitude of the
interaction.
4. Uncertainties
In addition to uncertainties on the
nature and magnitude of toxicant
interactions in the mixture, data may be
inadequate to assess exposure to human
populations or the potential health
effects of one or more components of the
mixture. In such a case, the less studied
chemicals must not be assumed to be
harmless. Instead the uncertainty is
increased. Confidence in the risk
assessment is reduced because the
contribution of these components to the
toxicity of the mixture and.
consequently, the toxicity of the mixture
itself are not known.
a. Health Effects. In some cases, when
health effects data are incomplete, it
may be possible to argue by analogy or
quantitative structure-activity
relationships that the compounds on
which no health effects data are
available are not likely to significantly
affect the toxicity of the mixture. If a
risk assessment is conducted based on
such an argument, the limitations of the
• approach must be clearly articulated.
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Federal Register / Vol. 50, No. 8 / Wednesday, January. 9, 1985 / Notices
1173
Since a methodology has not been
adopted for estimating an acceptable
level (e.g., ADI) or carcinogenic potency
for single compounds based either on
quantitative structure-activity
relationships or on the results of short-
term screening tests, such methods are
not presently recommended as the sole
basis of a risk assessment on chemical
mixtures.
b. Exposure Uncertainties. If levels of
exposure to certain compounds known
to be in the mixture are not available.
but information on health effects and -
environmental persistence and transport
suggest that these compounds are not
likely to be significant in affecting the
toxicity of the mixture, then a risk
assessment can be conducted based on
the remaining compounds in the
mixture, with appropriate caveats. If.
such an argument cannot be supported,
no final risk assessment can be
performed until adequate monitoring
data are available. As an interim
procedure, a risk assessment may be
conducted for those components in the
mixture for which adequate exposure
and health effects data are available. If
the results of the interim risk
assessment suggest that a hazard
already exists, resources might be better
expended on remedial action as part of
the a risk management decision rather
than on further assessment. Concern is
not reduced if the interim risk
assessment does not suggest a hazard
because not all components in the
mixture have been considered.
c. Uncertainties Regarding
Composition of the Mixture. As a worst
case scenario, information may be
lacking not only on health effects and
levels of exposure, but also on the
identity of some components in the
mixture. Analogous to the procedure
described in the previous paragraph, an
interim risk assessment can be
' conducted on the components of the
mixture for which adequate health
effects and exposure information are
available. If a hazard is indicated, then
the resulting partial assessment should
be carefully'qualified to avoid over
interpretation of the accuracy of the
assessment. If no hazard is indicated,
the risk assessment should not be
quantified until better health effects and
monitoring data are available.
III. Assumptions and Limitations
Most of the data available on toxicant
interactions are derived from acute
toxicity studies using experimental
animals in which mixtures of two
compounds were tested, often in only a
single combination. Major areas of
uncertainty with such data involve the
appropriateness of interaction data from
an acute toxicity study to quantitatively
alter a risk assessment for subchronic or
chronic exposure, the appropriateness of
interaction data on two component
mixtures to quantitatively alter a risk
assessment on a mixture of several
compounds, and the predictability of
interaction data on experimental
animals to quantitatively assess
interactions in humans.
The use of interaction data from acute
toxicity studies to assess the potential
interactions on chronic exposure would
be highly questionable unless the
mechanism(s) of the interaction on acute
exposure were known to apply to low
dose chronic exposure. However, most
known biological mechanisms for
toxicant interactions involve some form
of competition between the chemicals or
phenomena involving saturation of a
receptor site or metabolic pathway. As
the doses of the toxicants are decreased,
it is likely that these mechanisms either
no longer will exert a significant effect
or will be decreased to an extent which
cannot be measured or approximated.
The use of information from two
component mixtures to assess the
interactions in a mixture containing
more than two compounds also is
questionable from a mechanistic
perspectives-For example.'if two
compounds are known to interact, either
synergistically or antagonistically,
because of the effects of one compound
on the metabolism or excretion of the
other, the addition of a third compound
which either chemically alters or affects
the absorption of one of the first two
compounds could substantially alter the
degree of the toxicologic interaction.
Usually, detailed studies quantifying
toxicant interactions are not available
on multicomponent mixtures,'and the
few studies that are available on such
mixtures (e.g., Gullino et al., 1956) do not
provide sufficient information to assess
the effects of interactive interference.
Concerns with the use of interaction
data on experimental mammals to
assess interactions in humans is based
on the increasing appreciation for
systematic differences among species in
their response to individual chemicals. If
systematic differences in interspecies
sensitivity exist among species, then it
seems reasonable to suggest that the
magnitude of toxicant interactions
among species also may vary in a
systematic manner. Consequently, even
if excellent chronic data are available
on the magnitude of toxicant
interactions in a species of experimental
mammal, there is uncertainty that the
magnitude of the interaction will be the
same in humans. Again, data are not
available to properly assess the
significance of this uncertainty.
Last, it should be emphasized that
none of the models for toxicant
interaction can predict the magnitude of
toxicant interactions in the absence of
extensive data. If sufficient data are
available to estimate interactive
coefficients as described in S^c-tinn IV.
then the magnitude of the toxicant
interactions for various proportions of
the same components can be predicted.
The availability of an interaction ratio
(observed response divided by predicted
response) is useful only in assessing the
magnitude of the toxicant interaction for
the specific proportions of the mixture
which were used to generate the
interaction ratio.
The basic assumption in the
recommended approach is the risk
assessments on chemical mixtures are
best conducted using toxicologic data on
the mixture of concern or a reasonably
similar mixture. While such risk
assessments do not formally consider
toxicologic interactions as part of a
mathematic model, it is assumed that
responses in experimental mammals or
human populations noted after exposure
to the chemical mixture can be used to
conduct risk assessments on human
populations. In bioassays of chemical
""mixtures using'experimental mammals,
the same limitations inherent in species-
to-species extrapolation for single
compounds apply to mixtures. When
using health effects data on chemical
mixtures from studies on exposed
human populations, the limitations of
epidemiologic studies in the risk
assessment of single compounds also
apply to mixtures. Additional limitations
may be involved when using health
effects data on chemical mixtures if the
components in the mixture are not
constant or if the components partition
in the environment.
If sufficient data are not available on
the effects of the chemical mixture of
concern or a reasonably similar mixture,
the proposed approach is to assume
additivity. Dose additivity is based on
the assumption that the components in
the mixture have the same mode of
action and elicit the same effects. This
assumption will not hold true in most
cases, at least for mixtures of systemic
toxicants. For systemic toxicants,
however, most single compound risk
assessments will result in the derivation
of acceptable levels, which, as currently
defined, cannot be adapted to the
different forms of response additivity as
described in Section IV.
Additivity models can be modified to
incorporate quantitative data on
toxicant interactions from subchronic or
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174
Federal Register / Vol. 50, No. 6 / Wednesday. January 9. ISfoS / Notices
hronic studies using the models given
i Section IV or modifications of these
lodels. If this approach is taken,
owever, it will be under the assumption
.iat other components in the mixture do
.ot interfere with the measured
nteraction. In practice, such subchronic
•r chronic interactions data seldom will
>e available, and most risk assessments,
n the absence of health effects data on
he mixture of concern, will be based on
in assumption additivity.
Dose-additive and response-additive
'.ssumptions can lead to substantial
•rrors in risk estimates if synergistic or
mtagonistic interactions occur.
\lthough dose additivity has been
;hown to predict the acute toxicities of
nany mixtures of similar and dissimilar
:ompounds (e.g., Pozzani et al., 1959;
Smyth et al.. 1969,1970; Murphy, 1980).
)ome marked exceptions have been
loted. For example, Smyth et al. (1970)
ested the interaction of 53 pairs of
ndustrial chemicals based on acute
ethality in rats. For most pairs of
:ompounds, the ratio of the predicted
LDso to observed LD5o did not vary by
more than a factor of 2. The greatest
variation was seen with an equivolume
mixture of morpholine and toluene, in
which the observed LDso was about five
times less than the LDso predicted by
dose addition. In a study by Hammond .
et al. (1979), the relative risk of lung
cancer attributable to smoking was 11,
while the relative risk associated, with
asbestos exposure was 5. The relative
risk of lung cancer from both smoking
and asbestos exposure was 53,
indicating a substantial synergistic
effect. Consequently, in some cases,
additivity assumptions may
substantially underestimate risk. In
other cases, risk may be overestimated.
While this is certainly an unsatisfactory
limitation, it is a limitation associated
more with the nature and quality of the
available data on toxicant interaction
than with the proposed approach itself.
IV. Mathematical Models and the
Measurement of Joint Action
The simplest mathematical models for
joint action assume no interaction in
any mathematical sense. They describe
either dose addition or response
addition and are motivated by data on
acute lethal effects of mixtures of two
compounds.
A. Dose Addition
Dose addition assumes that the
toxicants in a mixture behave as if they
were dilutions or concentrations of each
other, thus the slopes of the dose-
response curves for the individual
compounds are identical, and the
response elicited by the mixture can be
predicted by summing the individual
doses after adjusting for differences in
potency; this is defined as the ratio of
equitoxic doses. Probit transformation
typically makes this ratio constant at all
doses when parallel straight lines are
obtained. Although this assumption can
be applied to any model (e.g., the one-hit
model in NRG, 1980b), it has been most
often used in toxicology with the log-
dose probit-response model, which will
be used to illustrate the assumption of
dose additivity. Suppose that two
toxicants show the following log-dose
probit-response equations:
Y, =03+3 log Z, (IV-l)
where Y, is the probit response associated
with a dose of Z, (i =1,2).
The potency, p, of toxicant-2 with
respect to toxicant-1 is defined by the
quantity Zi/Z-j when Yi=Y2 (that is
what is meant by equitoxic doses). In
this example, the potency, p, is
approximately 2. Dose addition assumes
that the response, Y, to any mixture of
these two toxicants can be predicted by:
Y=0.3 + 3log(Zi+pZj) (IV-3)
Thus, since p is defined as Zi/Zj,
Equation IV-3 essentially converts Za
into an equivalent dose of Zi by
adjusting for the difference in potency.
A more generalized tonn of this
equation for any member of toxicants is:
Y=a,+blog(f, + 2f,p,)+blogZ (IV-4)
where ai is the y-intercept of the dose-
response equation for toxicant-1, b is the
slope of the dose-response lines for the
toxicants, f, is the proportion of the i"1
toxicant in the mixture, pt is the potency
of the i'Moxicant with respect to
toxicant-1 (Zi/Z,), and Z is the sum of
the individual doses in the mixture. A
more detailed discussion of the
derivation of the equations for dose
addition is presented by Finney (1971).
B. Response Addition
The other form of additivity is
referred to as response addition. As
detailed by Bliss (1939), this type of joint
action assumes that the two toxicants
act on different receptor systems and
that the correlation of individual
tolerances may range from completely
negative (r= —1) to completely positive
(r= +1) correlation. Response addition
assumes that the response to a raven
concentration of a mixture of toxicants
is completely determined by the
responses to the components and the
correlation coefficient. Taking P as the
proportion of organisms responding to a
mixture of two toxicants which evoke
individual responses of Pi and Pt. then
p=p, if r=l and P,>P, (IV-S)
P=Piifr=landP,
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Federal Register / Vol. 50, No. 6 / Wednesday. January 9. 1985 / Notices
1175
also been proposed, along with
appropriate statistical tests for the
assumption of additivity (Korn and Liu,
1983; Wahrendorf et al. 1981).
In the epidemiologic literature,
measurements of the extent of toxicant
interactions (S) can be expressed as the
ratio of observed relative risk to relative
risk predicted by some form of
additivity assumption. Analogous to the
ratio of interaction in classical
toxicology studies, S=l indicates no
interaction, S<1 indicates synergism,
S<1 indicates antagonism. Several
models for both additive and
multiplicative risks have been proposed
(e.g., Hogan et al., 1978; NRG, 1980b;
Walter. 1976). For instance, Rothman
(1976) has discussed the use of the
following measurement of toxicant
interaction based on the assumption of
risk additivity:
where R10 is the relative risk from
compound-1 in the absence of
compound-2, Roi is the relative risk from
compound-2 in the absence of
compound-1. and Rn is the relative risk
from. exposure to both compounds. A
multiplicative risk model adapted from
Walter and Holford (1978, Eq. 4) can be
stated as:
S=Rl,/(R,0Roi) (IV-12) _
As discussed by both Walter and
Holford (1978) and Rothman (1976), the
risk-additive model is generally applied
So agents causing diseases while the
multiplicative model is more appropriate
to agents that prevent disease'. The
relative merits of these and other „
indices have been the subject of /
considerable discussion in the
epidemiologic literature (Hogan et al.,
1978; Kupper and Hogan, 1978; Rothman;
1978; Rothman et al., 1980; Walter and
Holford, 1978) which has not yet been
resolved.
Both the additive and multiplicative
models assume statistical independence
in that the risk associated with exposure
to both compounds in combination can
be predicted by the risks associated
with separate exposure to the individual
compounds. As illustrated by
Siemiatycki and Thomas (1981) for
multistage carcinogenesis, the better
fitting statistical model will depend not
only upon actual biological interactions
but clso upon the stages of the disease
process which the compounds affect.
Consequently, there is no a priori basis
for selecting either type of model in a
risk assessment. As discussed by Stara
et al. (1983), the concepts of multistage
carcinogenesis and the effects of
promoters and cocarcinogens on risk are
extremely complex issues. Although risk
models for promoters have been
proposed (e.g., Burns et al., 1983) no
single approach can be recommended at
this time.
V. References
ACGIH (American Conference of
Governmental Industrial Hygienists). 1983.
TLVs: threshold limit values for chemical
substances and physical agents in the work
environment with intended changes for 1983-
1984. Cincinnati. OH. p. SB.
Alstott, R.L., M.E. Tarrant, and R.B. Forney.
1973. The acute toxicities of 1-
methylxanthine, ethanol. and 1-
methylxanthine/ethanol combinations in the
mouse. ToxicoL Appl. Pharmacol. 24:393-404.
Bliss, C.L 1939. The toxicity of poisons
applied jointly. Ann. Appl. Biol. 28:585-615;
Burns, P.. R. Albert, E. Altschuler. and E.
Morris. 1983. Approach to risk assessment for
genotoxic carcinogens based on data from
the mouse skin initiation-promotion model.
Environ. Health Perspect 50:309-320.
Durkin, P.R. 1979. Spent chlorination liquor
and chlorophenolics: a study in detoxication
and joint action using Daphnia magna. Ph. D.
Thesis. Syracuse, NY: State University of
New York College of Environmental Science
and Forestry, p. 145.
Durkin, P.R. 1981. An approach to the
analysis of toxicant interactions in the
aquatic environment. Proc. 4th Ann. Symp.
Aquatic Toxicology. American Society for
Testing and Materials, p. 388-401.
Finney, D.J. 1942. The analysis of toxicity
tests on mixtures of poisons. Ann. Appl. Biol.
29:82-94
Finney, D.J. 1971. Probit analysis. 3rd ed
Cambridge, Great Britain: Cambridge
University Press. 333 p..
Goldstein, A., L. Aronow, and S.M.
Kalman. 1974. Principles of drug action: the
basis of pharmacology, 2nd ed. New York,
NY: John Wiley and Sons. Inc., 854 p.
Gullino. P.. M. Winitz, S.M Birnbaum. J.
Cornfield. M.C Otey, and J.P. Greenstein.
1956. Studies on the metabolism of amino
acids and related compounds in vivo. I.
Toxicity of essential amino acids,
individually and in mixtures, and the
protective effect of L-arginine. Arch. Biochem.
Biophys. 64:319-332.
Hammond. E.G.. I.V. Selikoff. and H.
Seidman. 1979. Asbestos exposure, cigarette
smoking and death rates. Ann. NY Acad. Sci.
330:473-490.
Hewlett P.S. 1969. Measurement of the
potencies of drug mixtures. Biometrics.
25:477-487.
Hogan M.D., L Kupper, B. Most, and J.
Haseman. 1978. Alternative approaches to
Rothman's approach for assessing synergism
(or antagonism) in cohort studies. Am. J.
Epidemiol. 108(l):80-fl7.
Klaassen. CD., and I. Doull. 1980.
Evaluation of safety: Toxicologic evaluation.
In: ]. Doull. C.D. Klaassen. and M.O. Amdur.
eds. Toxicology: The basic science of
poisons. New York. NY: Macmillan
Publishing Co.. Inc., P. 11-27
Korn. E.L. and P-Y. Liu. 1983. interactive
effects of mixtures of stimuli in life table
analysis. Biometrika 70:103-110
Kupper. L. and MJ). Hogan. 1978.
Interaction in epidemiologic studies; Am. ].
Epidemiol. 108(6):447-453.
Levine, R.E. 1973. Pharmacology: drug
actions and reactions. Boston, MA: Little.
Brown and Company, 412 p.
Murphy, S.D. 1980. Assessment of the
potential for toxic interactions among
environmental pollutants. In: C.L Galli. S.D.
Murphy, and R. Paoletti. eds. The nrinriples
and methods in modern toxicology,
Amsterdam. The Netherlands: Elsevier/North
Holland Biomedical Press.
NRG (National Research Council). 1980a.
Drinking water and health. Vol. 3.
Washington, DC: National Academy Press, p.
27-28.
NRC (National Rescrach Council). 1980b.
Principles of toxicological interactions
associated with multiple chemical exposures.
Washington. DC: National Academy Press, p.
204.
OSHA (Occupational Safety and Health
Administration). 1983. General Industry
Standards. Subpart 2. Toxic and Hazardous
Substances. Code of Federal Regulations.
40:1910.1000(d)(2)(i). Chapter XVII—
Occupational Safety and Health
Administration, p. 667.
Plackett. R.L and P.S. Hewlett.. 1948.
Statistical aspects of the independent joint
action of poisions. Ann. Appl. Biol. 35:347-
358.
Pozzani, U.C.. C.S. Weil, and C.P.
Carpenter. 1959. The toxicological basis of
threshold values: 5. The experimental
inhalation of vapor mixtures by rats.' with
notes upon the relationship between single
dose inhalation and single dose oral data.
Am. Ind. Hyg. Assoc. J. 20:364J69.
Rothman. K. 1978. The estimation of
synergy or antagonism. Am.). Epidemiol.
103(5):506-511.
Rothman. K. 1978. Estimation versus •
detection in the assessment of synergy. Am. J.
Epidemiol. 108(1):9-11.
Rothman. K., S. Greenland, and A Walter.
1980. Concepts of interaction. Am. ].
Epidemiol. 112(4):467-470.
Siemiatycki. J.. and D.C. Thomas. 1981.
Biological models and statistical interactions:
An example from multistage carinogenesis.
Int. J. Epidemiol. 10(4):383-387,
Smyth. H.F.. C.S. Weil. J.S. West, and C.P.
Carpenter. 1969. An exploration of joint toxic
action: I. Twenty-seven industrial chemicals
intubated in rats in all possible pairs.
Toxicol. Appl. Pharmacol. 14:340-347.
Smyth. H.F., C.S. Weil. J.S. West, and C.P.
Carpenter. 1970. An exploration of joint toxic •
action: II. Equitoxic versus equivolume
mixtures. Toxicol. Appl. Pharmacol. 17:498-
503.
Stara, J.F., D. Mukerjee. R. McGaughy, P.
Durkin. and M.L. Dourson. 1983. The current
use of studies on promoters and
cocarcinogens in quantitative risk
assessment. Environ. Health Perspect. 50:359-
368.
U.S. EPA. 1984. Proposed guidelines for
carcinogen risk assessment. Office of Health
and Environmental Assessment. Carcinogen
Assessment Group. Draft.
Veldstra. H. 1956. Synergism and
potentiation with special reference to the
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1176 Federal Register / Vol. 50. No. 6 / Wednesday, January 9. 1985 / Notices
combination of structural analogues.
Pharmacol. Rev. 8339-387.
Wahrendorf.}.. R. Zentgrof. and C.C.
Brown. 1981. Optimal designs for the analysis
of interactive effects of two carcinogens or
other toxicants. Biometrics. 37:45-54.
Walter, S.D. 1978. The estimation and
interpretation of attributable risk in health
research. Biometrics. 32:829-849.
Walter, S.D.. land T.R. Holford. 1978.
Additive, multipicative, and other models for
disease risks. Am. J. Epidemiol. 108:341-346.
Withey, J.R. 1981. Toxicodynamics and
biotransformation. In: International
Workshop on the Assessment of
Multichemical Contamination. Milan. Italy.
(Draft copy courtesy of J.R. Withey)
WHO (World Health Organization). 1981.
Health effects of combined exposures in the
work environment. WHO Tech. Rept. Series
No. 662.
[FR Doc. 85-589 Filed 1-6-85; 8:45 am]
BtLum cooe asto so n
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£ifc Systems, fac.
APPENDIX 4
TEST PROTOCOL CRITERIA FOR ANIMAL ASSAYS
Several test systems have been devised to determine the potential for
development of various toxicologic endpoints following exposure to various
chemical substances. These assays share in common certain fundamental
features with respect to design and conduct. These are discussed below:
1. Dose
In acute studies, a single administration of the test substance at four or
five varying dose levels should be sufficient for determining ranges of
mortality and toxic effects. Doses are selected to provide data sufficient to
estimate the LD (the dose at which 50% of the test organisms die) and to
produce a dose-response curve.
For subchronic and chronic studies, at least three dose levels should be used
in addition to a concurrent control group. The highest dose level should
elicit some signs of toxicity without causing excessive lethality. The lowest
dose level should not produce toxicity. To obtain maximum information on the
dose-response characteristics of the test chemical, at least one intermediate
dose is generally used.
2. Route of Exposure and Duration of Treatment
The most common routes of compound administration for chronic and subchronic
testing are inhalation, oral and dermal. Corresponding routes, in addition to
ocular exposure, are employed in acute toxicity studies.
/'
In subchronic testing, oral and inhalation studies are accomplished in three
months. In most inhalation studies, comparable results will be obtained from
either the 5- or 7-day/week exposure. The inhalation exposure schedule is
usually .5 days/week, 6 hours/day. For repeated dermal route studies, a
maximum of 21 applications to rabbits on a 5-day/week basis is considered to
be practical and of sufficient duration.
In chronic toxicity testing, the oral route of administration is usually pre-
ferred if the test substance is known to be absorbed from the gastrointestinal
tract. If the test substance is administered in the drinking water or mixed
in the diet, exposure is continuous. If the test substance is administered by
gavage or capsule, the animals are dosed seven days per week. For cutaneous
exposure, dosing schedules should be selected to simulate human exposure. For
inhalation exposures, the choice of intermittent or continuous dosing depends
on che objectives of the ocudy and on the expected human exposure conditions.
Long-term inhalation studies are patterned on expected occupational exposures
of 6 to 8 hours/day for 5 days/week or possible environmental exposures of 22
to 24 hours/day for 7 days/week.
A4-1
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tifc Systems, JHC.
3. Selection of Species
The selection of species should take into account, whenever possible, whether
the test species' metabolism of the chemical, or its analogues, is similar to
that of humans.
Historically, it has generally been recommended that chronic and subchronic
testing be performed with two mammalian species, one a rodent and the other a
nonrodent. The rat has normally been the rodent of choice. Dogs are the
species of choice for the nonrodents. The strains of test species used should
be well characterized, commonly used, disease resistant, and free from
interfering congenital defects. In special circumstances with a small number
of chemicals, other species have been shown to be more sensitive than either
the rat or the dog. However, the use of additional species would often not
appreciably affect the determination of a safe exposure level for man.
4. Number of Animals
The number of animals to be employed in chronic tests varies depending on the
goals and needs of the investigation. A sufficient number of animals should
be used so that reliable statistical analysis can be performed to evaluate the
test results. At the end of the study, enough animals should be alive in each
group for a thorough clinical and morphological examination. With respect to
species tested, a minimum of 50 rodents/sex/dose level and 8 dogs/sex/dose
level should be utilized in chronic toxicity tests. At least 20 rats/sex/dose
level and 4 dogs/sex/dose, level are considered to be sufficient for subchronic
testing. For repeated skin application studies, 20 r-abbits/sex/dose are
usually required.
5 . Age of Animals
The age at which animals are/started on a test is an important consideration
in toxicity testing. In routine subchronic testing it is generally
recommended that rodents be started on treatment as young as practically
possible. The earliest practical age to start rodents on test is 5 to 8
weeks. For nonrodents, especially the dog, starting the exposure at 4 to 10
months is preferable to using older animals.
In chronic testing, exposure of rodents and dogs should be no later than six
weeks and four months of age, respectively.
A4-2
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£ife Systems, Jnc.
APPENDIX 5
DEFINITION OF TOXICOLOGIC ENDPOINTS
A wide range of chemicals have been reported to produce adverse health effects,
The effects manifested have been characterized as toxicologic endpoints which
include primarily neurotoxicity, behavioral toxicity, hepatotoxicity, renal
toxicity, blood toxicity, teratogenicity, reproductive toxicity, mutagenicity,
or carcinogenicity. These endpoints can be characterized as follows:
• Neurotoxicity refers to effects of toxic substances on various
.structures comprising the nervous system. The effects exerted may
involve direct damage to structures including axons of peripheral
neurons, myelin, synaptic junctions, etc. Manifestations of neuro-
toxicity include acute toxic effects such as muscular twitching,
weakness, convulsions, and respiratory paralysis. Delayed neuro-
toxicity may result from direct action of the toxic substance
through axon degeneration followed by demyelination of tracts in the
spinal cord or peripheral nerves with resultant paralysis.
• Behavioral toxicity refers to changes in adaptive behavioral
capacity that result from the effect of toxic substances on the
neural system. Changes may occur in behavioral functions such as
acquisition of skills, learning, short- and long-term memory,
decision-making, and psychomotor functioning.
• Hepatotoxicity is the elicitation of adverse effects in the -.
morphology and/or function of the liver. Some common endpoints of
chemical injury include the following:
• Accumulation of abnormal.amounts of hepatic lipid, especially
triglycerides
Inhibition of protein synthesis
Lipid peroxidation of hepatic microsomes
Necrosis
Cholestasis
Cirrhosis
Carcinogenesis
Renal toxicity is the elicitation of adverse effects in the
morphology and/or functions of the kidney. Some manifestations of
renal toxicity include depression of creatinine clearance and phos-
phate reabsorption.to severe tubular degeneration.
Blood toxicity refers to chemical-induced alteration in components
of the blood by influencing their production, rate of peripheral
destruction or distribution.
Teratology may be defined as the study of permanent structural or
functional abnormalities arising during embryogenesis and that are
generally incompatible with, or severely detrimental to, normal
post-natal survival or development.
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Reproductive toxlcity refers to detrimental effects on reproduction
and on the offspring following parental exposure. Manifestations of
reproductive toxicity include impaired fertility, fetal death and
birth or developmental defects.
Mutagenicity is the capacity to cause heritable changes in the
genetic make-up of a cell. Manifestation of mutagenic effects
include point mutations, numerical aberrations, and structural aberr
rations.
Carcinogenicity refers to the ability of a chemical to significantly
increase the incidence of malignant lesions in animals or humans, to
induce rarely occurring tumors, or significantly decrease the
latency period for tumor development relative to an appropriate
background or control group.
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