GUIDANCE FOR ASSESSING CHEMICAL CONTAMINANT DATA
FOR USE IN FISH ADVISORIES
VOLUME II: RISK ASSESSMENT AND FISH CONSUMPTION LIMITS
June 15, 1994
Contract # 68-C3-0374
Prepared for:
Work Assignment Manager
Jeffrey Bigler
Office of Science and Technology
Office of Water
U.S. Environmental Protection Agency
Washington, DC
-------
-------
EXECUTIVE SUMMARY
EXECUTIVE SUMMARY
State, local, and federal agencies currently use various methods to estimate
risks to human health from the consumption of chemically-contaminated, non-
commercial fish. A 1988 survey, funded by the U.S. Environmental Protection
Agency (EPA) and conducted by the American Fisheries Society, identified the
need for standardizing the approaches to evaluating risks and developing fish
consumption advisories that are comparable across different jurisdictions (RTI,
1990). Four key components were identified as critical to the development of
a consistent risk-based approach: standardized practices for sampling and
analyzing fish, standardized risk assessment methods, standard procedures for
making risk management decisions, and standardized approaches to risk
communication (RTI, 1990).
To address concerns raised by the survey respondents, EPA is developing a
series of four documents designed to provide guidance to state, local, regional,
and tribal environmental health officials responsible for issuing fish advisories.
The documents are meant to provide guidance only and do not constitute a
regulatory requirement. The documents are:
Guidance for Assessing Chemical Contaminant Data for Use in Fish Advisories
Volume 1: Fish Sampling and Analysis
Volume 2: Risk Assessment and Fish Consumption Limits
Volume 3: Risk Management
Volume 4: Risk Communication
Volume 1 was released in September, 1993. Volumes 3 and 4 are scheduled
for release, in early-1995 and late-1994, respectively. It is essential that all four
documents be used together, since no single volume addresses all of the topics
involved in the development of risk-based fish consumption advisories.
The objective of Volume 2: Risk Assessment and Fish Consumption Limits is
to provide guidance on the development of risk-based meal consumption limits
for 23 high-priority chemical fish contaminants (target analytes). The target
analytes addressed in this guidance series (See Table 1-1) were selected as
particularly significant fish contaminants by EPA's Office of Water, based on
their occurrence in fish, their potential for bioaccumulation, and their toxicity
to humans. The criteria for their selection are discussed in Volume 1 of this
series. In addition to a presentation of consumption limits, Volume 2 contains
a discussion of risk assessment methods used to derive the consumption limits.
ES-1
-------
EXECUTIVE SUMMARY
as well as a discussion of methods to modify these limits to reflect local
conditions. Additional sources of information are listed for those seeking a
more detailed discussion of risk assessment methods.
Earlier drafts of Volume 2 have been reviewed by experts at the federal, state,
tribal, and local levels. Their input was used to revise the document to make
it more useful and informative to public health professionals. For example,
Volume 2 contains many refinements of the previous guidance Assessing
Human Health Risks from Chemically Contaminated Fish and Shellfish: A
Guidance Manual (U.S. EPA, 1989a), including the addition of consumption
limit tables and detailed toxicity data on the target analytes.
Part I of this document contains the information needed to use and modify the
consumption limit tables provided for the 23 target analytes. The tables list a
number of alternative consumption limits for each target analyte, based upon
different meal sizes, contaminant levels, risk levels, and toxicity endpoints.
Specific consumption limits have been developed, and are presented separately,
for young children and adults in the general population. In addition,
consumption limits specifically targeted to women of reproductive age have
been developed for methylmercury. Information is also provided on methods
for calculating consumption limits for multiple species diets and for multiple
contaminant exposures.
Part II contains an overview of the current EPA risk assessment methodology
used to derive the recommended meal consumption limits. This includes a
discussion of the four main steps of the risk assessment: hazard identification,
dose-response evaluation, exposure assessment, and risk characterization.
Detail has been added on the toxicity of the target analytes, including new
information on developmental toxicity. EPA risk values (chronic Reference
Doses and cancer potency factors) from sources such as EPA's Integrated Risk
Information System (IRIS) and the Office of Pesticide Programs are provided,
with a discussion of supporting dose-response data.
The information in this document may be used in conjunction with
contamination data from local sampling programs and fish consumption surveys
(or from consumption data provided in Volume 3), to select or calculate risk-
based consumption limits for contaminated non-commercial fish. The
consumption limits may be used with other types of information (e.g., cultural
and dietary characteristics of the populations of concern, social and economic
impacts, and health issues, including benefits of fish consumption and
accessibility of other food sources) to establish health advisories. The decision-
making process for the development of advisories will be discussed in the risk
management document in this series (Volume 3).
ES-2
-------
EXECUTIVE SUMMARY
In keeping with current EPA recommendations, discussions of uncertainty and
assumptions are included in each section of the document. Although
information was sought from a variety of sources to provide the best available
data regarding the development of fish advisories, limited data exist for some
critical parameters (e.g., toxicological properties of certain chemicals, and
susceptibilities of specific population subgroups such as the elderly, children,
and pregnant or nursing women). Although substantial toxicological
information is available for all target analytes discussed in this document,
readers are cautioned to always consider the methods and values presented in
the context of the uncertainty inherent in the application of science to policies
for safeguarding the general public from environmental hazards.
EPA welcomes your suggestions and comments. A major goal of this series is
to provide a clear and usable summary of critical information necessary to make
informed decisions regarding the development of fish consumption advisories.
These documents are being prepared in binder form so that individual sections
may be revised and replaced as significant new information becomes available.
We encourage comments, and hope this document will be a useful adjunct to
the resources used by states, local governments, and tribal bodies to make
decisions regarding the development of fish advisories.
ES-3
-------
-------
TABLE OF CONTENTS
TABLE OF CONTENTS
Page
Figure vi
List of Tables . . vii
Acknowledgements viii
Glossary xii
Part I , . 1
1. Introduction 1-1
1.1. Overview and Objectives 1-1
1.2. Sources 1-6
2. Development and Use of Risk-based Consumption Limits ...... 2-1
2.1. Overview and Section Organization 2-1
2.2. Equations Used to Develop Risk-Based Consumption Limits 2-2
2.2.1. Calculation of Consumption Limits for
Carcinogenic Effects . 2-2
2.2.1.1. Calculation of Daily Consumption Limits 2-3
2.2.1.2. Calculation of Meal Consumption Limits 2-3
2.2.1.3. Input Parameters 2-4
2.2.2. Calculation of Consumption Limits
for Noncarcinogenic Effects 2-6
2.2.2.1. Calculation of Daily Consumption Limits 2-6
2.2.2.2. Calculation of Meals Per Month 2-7
2.2.2.3. Input Parameters 2-7
2.2.3. Calculation of Consumption Limits for
Developmental Effects 2-7
2.3. Default Values and Alternative Values
For Calculating Consumption Limits 2-8
2.3.1. Maximum Acceptable Risk Level (RL) 2-9
2.3.2. Chronic Reference Doses and
Cancer Potencies (RfDs and q^s) ... 2-10
-------
TABLE OF CONTENTS
2.3.3. Consumer Body Weight 2-10
2.3.3.1. Derivation of Multipliers for
Body Weight Adjustment 2-13
2.3.4. Meal Size 2-17
2.3.5. Meal Frequency 2-21
2.4. Modification of Consumption Limits for Multiple Species,
Single Contaminant Exposure 2-26
2.4.1. Carcinogenic Effects 2-26
2.4.2. Noncarcinogenic Effects 2-27
2.5. Modification of Consumption Limits for
Multiple Contaminant Exposures 2-30
2.5.1. Carcinogenic Effects 2-31
2.5.2. Noncarcinogenic Effects 2-32
2.5.3. Species-Specific Consumption Limits in a
Multiple Species Diet 2-34
2.6. Choice of Consumption Limits 2-35
3. Risk-based Consumption Limit Tables 3-1
3.1. Overview and Section Organization 3-1
3.2. Consumption Limit Tables 3-4
PART II 1
4. Risk Assessment Methods 4-1
4.1. Introduction 4-1
4.1.1. Other Information Sources 4-4
4.2. Hazard Identification . . . 4-4
4.2.1. Approach for Fish Contaminants 4-6
4.2.1.1. Toxicological Data 4-6
4.2.1.2. Contaminant Data 4-7
" 4.2.1.3. Sources of Exposure 4-8
4.2.2. Assumptions and Uncertainty Analysis 4-9
4.3. Dose-Response Assessment 4-11
4.3.1. Acute Exposure Toxicity 4-13
4.3.2. Chronic Exposure Toxicity 4-15
4.3.3. Carcinogenicity 4-16
4.3.4. Mutagenicity/Genotoxicity 4-17
-------
TABLE OF CONTENTS
4.3.5. Developmental Toxicity 4-18
4.3.6. Multiple Chemical Exposure: Interactive
Effects 4-19
4-3.7. Assumptions and Uncertainties 4-20
4.4. Exposure Assessment . 4-24
4.4.1. Chemical Occurrences jn Fish 4-25
4.4.1.1. Distribution in Fish Tissues 4-26
4.4.1.2. Fish Contaminants 4-17
4.4.2. Geographic Distribution of Contaminated
Fish 4-29
4.4.3. Individual Exposure Assessment ......... 4-29
4.4.3.1. Exposure Variables 4-31
4.4.3.2. Averaging Periods Versus Exposure
Durations, 4-34
4.4.3.3. Parameters Used in Determining
Individual Consumption Patterns .... 4-36
4.4.3.4. Multiple Chemical Exposures
4.4.4. Population Exposure Assessment 4-37
4.4.5. Uncertainty arid Assumptions 4-37
4.4.5.1. Chemical Concentrations in Fish 4-38
4.4.5.2. Body Weight . 4-38
4.4.5.3. Consumption Rate 4-38
4.4.5.4 Multiple Species and Multiple
Contaminants 4-40
4.4.7.6. Other Sources of Exposure 4-41
4.5. Risk Characterization 4-41
4.5.1. Carcinogenic Toxicity 4-42
4.5.2. Noncarcinogenic Toxicity 4-43
4.5.3. Subpopulation Considerations .4-43
4.5.4. Multiple Species and Multiple
Contaminant Considerations 4-44
4.5.5. Incorporating Considerations of Uncertainty in
Consumption Limits 4-44
5. Toxicity Data for Target Analytes and Methodology
for Risk Value Calculation 5-1
5.1. Introduction 5-1
in
-------
TABLE OF CONTENTS
5.2. Categories of Information Provided in Section 5.6
for Target Analytes 5-2
5.2.1. Pharmacoklnetics . . 5-4
5.2.2. Acute Toxicity 5-4
5.2.3. Chronic Toxicity 5-5
5.2.4. Developmental Toxicity 5-5
5.2.5. Mutagenicity 5-6
5.2.6. Carcinbgenicity 5-6
5.2.7. Special Susceptibilities 5-7
5.2.8. Interactive Effects 5-8
5.2.9. Data Gaps 5-8
5.2.10. Summary of EPA Risk Values 5-8
5.2.11. Major Sources 5-8
5.2.12. Statement Regarding Uncertainty 5-9
5.3. Methods for Calculating Developmental Toxicity Exposure
Limits 5-10
5.3.1. Definitions 5-12
5.3.2. Special Issues in the Evaluation of
- Developmental Toxins 5-13
5.3.3. Methods for Estimating Exposure Limits .... 5-15
5.3.3.1. Identify the Most Appropriate NOAEL
or LOAEL 5-15
5.3.3.2. Apply Relevant Uncertainty -
and Modifying Factors 5-17
5.3.3.3 Sources of Additional Information on
Developmental Toxicity. . 5-25
5.4. Methods for Calculating Alternative Values
for Systemic Chronic Effects 5-26
5.4.1. Identify the Most Appropriate NOAEL
or LOAEL 5-26
5.4.2. Apply Relevant Uncertainty
and Modifying Factors 5-27
5.5. Toxicity Characteristics of Groups of Analytes 5-28
5.5.1. Organochlorine Pesticides 5-29
5.5.2. Organophosphate Pesticides 5-31
5.6. Toxicity Data for Target Analytes 5-33
5.6.1. Chlordane 5-36
5.6.2. DDT, DDE, ODD 5-42
IV
-------
TABLE OF CONTENTS
5.6.3. Dicofol 5-49
5.6.4. Dieldrin 5-52
5.6.5. Endosulfan 1,11 5-59
5.6.6. Endrin 5-64
5.6.7. Heptachlor Epoxide 5-68
5.6.8. Hexachlorobenzene 5-72
5.6.9. Lindane . . . . 5-77
5.6.10. Mirex . 5-83
5.6.11. Toxaphene . .' . 5-88
5.6.12. Carbophenothiion 5-94
5.6.13. Chlorpyrifos 5-97
5.6.14. Diazinon 5-100
5.6.15. Disulfoton 5-103
5.6.16. Ethion . 5-106
5.6.17. Terbufos . . 5-108
5.6.18. Oxyfluorfen .5-112
5.6.19. PCBs 5-114
5.6.20. Dioxin 5-123
5.6.21. Cadmium 5-124
5.6.22. Methylmercury 5-131
5.6.23. Selenium 5-140
6. Literature Cited 6-1
Appendices
A. Mutagenicity and Genotoxicity A-1
B. Additional Sources of Information B-1
-------
LIST OF FIGURES
FIGURE
4-1 National Academy of Science Risk Assessment Paradigm 4-2
VI
-------
LIST OF TABLES
LIST OF TABLES
1-1 Target Analytes Examined in This Document . 1-4
2-1 Input Parameters for Carcinogenic Risk Equations 2-5
2-2 Risk Values Used in Risk-Based Consumption Tables in Section 3 . 2-12.
2-3 Average Body Weights and Associated Multipliers 2-14
2-4 Alternative Meal Sizes and Associated Multipliers 2-19
3-1 Tables Contained in Section 31 • 3-5
4-1 Mean Body Weights of Children and Adults 4-32
5-1 Health and Toxicological Data Reviewed for Target Analytes ..... 5-3
5-2 Uncertainty Factors and Modifying Factors for Estimating
Exposure Limits for Developmental Effects 5-18
5-3 Target Analytes and Chemical Categories 5-35
1 Table 3-1 contains a list of the risk-based intake limit tables in Section
3.
VII
-------
-------
ACKNOWLEDGEMENTS
ACKNOWLEDGEMENTS
This report was prepared by the U.S. Environmental Protection Agency,
Office of Water, Fish Contaminant Section. The EPA Work Assignment
Manager for this document was Jeffrey Bigler who provided overall
project coordination as well as technical assistance and guidance. EPA
was supported in the developmen t of this document by Abt Associates
under the direction of Project Manager Kathleen Cunningham.
Preparation of this guidance document was facilitated by the substantial
efforts of the numerous Workgroup members and reviewers (listed
below). These individuals, representing EPA Headquarters, EPA Regions,
State and Federal agencies, and Native American groups provided
technical information, reviews and recommendations throughout the
preparation of this document. Participation in the review process does
not imply concurrence by these individuals with all concepts and
methods described in this document.
FISH CONTAMINANT WORKGROUP AND OTHER REVIEWERS
EPA Headquarters
Charles Abernathy
Kenneth Bailey
Jeffrey Bigler
Denis Borum
Robert Cantilli
James Cogliano
Julie Du
Rick Hoffmann
Skip Houseknecht
Frank Gostomski
Bruce Mintz
Amal Mahfouz
Edward Ohanian
Betsy Southerland
Margaret Stasikowski
Yogi Patel
EPA/Office of Water
EPA/Office of Water
EPA/Oft ice of Water (Workgroup Chair)
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
EPA/Office of Water
VIII
-------
ACKNOWLEDGEMENTS
William Farland
Gregory Kew
Carole Kimmel
Gary Kimmel
Jackie Moya
Lorenz Rhomberg
Reto Engler
George Ghali
Michael Metzger
Esther Rinde
Steve Shaible
Richard Whiting
Other EPA Office Staff
Eletha Brady-Roberts
John Cicmanec
Michael Dourson
Susan Velazquez
Chon Shoaf
Jerry Stober
Charles Kanetsky
Milton Clark
Philip Crocker
Other Federal Agency Staff
Michael Bolger
Gregory Cramer
EPA/Office
EPA/Office
EPA/Office
EPA/Office
EPA/Office
EPA/Office
EPA/Office
EPA/Office
EPA/Office
EPA/Office
EPA/Office
EPA/Office
of Research
of Research
of Research
of Research
of Research
of Research
of Pesticide
of Pesticide
of Pesticide
of Pesticide
of Pesticide
of Pesticide
and Development
and Development
and Development
and Development
and Development
and Development
Programs
Programs
Programs
Programs
Programs
Programs
EPA/Office of Research and Development,
Cincinnati, OH
EPA/Office of Research and Development,
Cincinnati, OH
EPA/Office of Research and Development,
Cincinnati, OH
EAP/Office of Research and Development,
Cincinnati, OH
EPA/Environmental Criteria and Assessment
Office, RTP,NC
EPA/Environmental Research Laboratory,
Athens, GA
EPA/Region 3
EPA/Region 5
EPA/Region 7
U.S. Food and Drug Administration
U.S. Food and Drug Administration
IX
-------
ACKNOWLEDGEMENTS
Gunnar Lauenstein
Thomas Siewicki
Janice Cox
State Agency Staff
Anna Fan
Gerald Pollock
Richard Green
Joseph Sekerke
Tom Long
Dierdre Murphy
Jack Schwartz
John Hesse
Pamela Shubat
Gale Carlson
Alan Stern
Robert Tucker
Tony Forti
Luanne Williams
Martin Schock
Kandiah Sivarajah
Robert Marino
Kim Blindauer
Alan Anthony
Peter Sherertz
Ram Tripathi
Denise Laflamme
Jim Amrhein
Henry Anderson
National Oceanic and Atmospheric
Administration
National Oceanic and Atmospheric
Administration
Tennessee Valley Authority
California
California
Delaware
Florida
Illinois
Maryland
Massachusetts
Michigan
Minnesota
Missouri
New Jersey
New Jersey
New York
North Carolina
North Dakota
Pennsylvania
South Carolina
Utah
Virginia
Virginia
Virginia
Washington
Wisconsin
Wisconsin
-------
ACKNOWLEDGEMENTS
Native American Tribes
Neil Kmaicik
Ann Watanabe
John Banks
Clemon Fay
Great Lakes Indian Fish and Wildlife
Commission
Columbia River Inter-Tribal Fish Commission
Penobscot Nation
Penobscot Nation
XI
-------
GLOSSARY & ABBREVIATIONS
GLOSSARY & ABBREVIATIONS
acute exposure
ARL
ATSDR
BW
m,j
carcinogen
exposure at a relatively high level over a short period
of time (minutes to a few days)
{This is defined In IRIS as 24 hours or less; however,
sources consulted utilized exposure periods of up to a
few days. Consequently, the more encompassing
definition is appropriate in reading this document.)
acceptable risk level. The maximum level of individual
lifetime carcinogenic risk, usually calculated using a
cancer potency value, which is considered
"acceptable" by risk managers. See Section 4 for more
detail.
Agency for Toxic Substances and Disease Registry,
U.S. Dept. of Health and Human Services, Public
Health Service
body weight of an individual consumer (kg)
concentration of contaminant m in the edible portion of
fish (mg/kg)
concentration of contaminant m in the edible portion of
fish species / (mg/kg)
Total concentration of chemical m in an individual's
fish diet,
an agent capable of inducing a carcinogenic response
XII
-------
GLOSSARY & ABBREVIATIONS
cancer potency
(often used interchangeably with slope factor) the
slope of the dose-response curve in the low-dose
region used with exposure to calculate the estimated
lifetime cancer risk. Often expressed as risk per one
milligram of exposure to the toxic chemical per
kilogram body weight per day (mg/kg-d).
multiple exposures occurring over an extended period
of time, or a significant fraction of the lifetime
central nervous system
condition or variable that may be a factor in producing
the same response as the agent under study.
mean daily consumption rate of fish (kg/day)
consumption rate of fish species / (kg/day)
limit on the amount of fish that can be consumed per
day (kg/day)
limit on the number of fish meals that can be
consumed per month (meals/mo)
limit on the number of fish meals that can be
consumed per day (meals/day)
the first adverse effect, or its known precursor, that
occurs as the dose rate increases
d day, as in mg/kg/d
developmental toxicity study of adverse effects on the developing organism
resulting from exposure prior to conception, during
prenatal development, or postnatally up to the time of
sexual maturation.
chronic exposure
CNS
confounder
CR
CRj
CR,im
CR
mm
CR
md
critical effect
XIII
-------
GLOSSARY & ABBREVIATIONS
dose-response
relationship
-m
-me
~mn
endpoint
EPA
exposure limits
FDA
FRAC
HI
Hlmix
HSDB
relationship between the amount of an agent and
changes in aspects of the biological system apparently
in response to that agent
exposure to contaminant m from ingesting fish (mg/kg-
day)
exposure to a given contaminant in a given species of
fish associated with a given risk of cancer (mg/kg-day)
exposure to contaminant m from ingesting fish species
/ {mg/kg-day)
maximum acceptable exposure (dose) of a
noncarcinogen from a specific contaminant in a
specific fish species (rng/kg-day)
response measure in a toxicity study
United States Environmental Protection Agency
a daily limit on exposure based upon health and
toxicity data, which the reader may calculate, using
the study data provided in this or other sources
{mg/kg-day)
United States Food and Drug Administration
fraction of a given fish species in an individual's diet
(unitless)
hazard index, or ratio of the estimated exposure dose
to the RfD for the chemical (unitless)
hazard index of a chemical mixture (unitless)
Hazardous Subsitances Data Bank, developed by EPA,
available on line through TOXNET
XIV
-------
GLOSSARY & ABBREVIATIONS
incidence
consumption limits
IRIS
latency period
LEL
LOAEL
kg
mg
mg/kg-day
modifying factor
number of new cases of a disease within a specified
time
a daily fish consumption limit, based upon health and
toxicity data. They are provided in Chapter 3 of this
document. They may also be calculated by the reader
using guidance in Chapters 2,4, and 5.
Integrated Risk Information System, a data base
maintained by EPA, available on line through TOXNET
and by subscription through NTIS
time between induction of a health effect and its
manifestation
same as LOAEL (per IRIS), see below
lowest exposure level at which there are statistically or
biologically significant increases in frequency of
severity of adverse effects between the exposed
population and its appropriate control group.
kilogram, one thousand grams, equivalent to 2.205
pounds (avoiirdupois)
milligrams, one one thousandth (10~3) of a gram
milligrams exposure per kilogram body weight of the
exposed individual per day
a factor used in operationally deriving the RfD from
experimentai data. It addresses concerns regarding
differences in absorption, tolerance to a chemical, or
lack of a sensitive endpoint. See Table 5-2
xv
-------
GLOSSARY & ABBREVIATIONS
MRL
MS
mutagenic
NOAEL
NOEL
NTIS
NTP
OPP
oz
PJ
PNS
R
avg
Minimal Risk Level, from ATSDR. An estimate of daily
exposure that is likely to be without an appreciable risk
of deleterious effects (noncancerous) over a specified
duration of exposure: acute - 1 to 13 days;
intermediate -14 to 365 days; chronic - over 365 days
meal size (kg/meal)
capable of inducing changes in genetic material (e.g.
DNA)
exposure level at which there are no statistically or
biologically significant increases in the frequency or
severity of adverse effects between the exposed
population and its control ,
the same as NOAEL with the exception of the word
adverse. NOEL specifies the absence of any effect
National Technical Information Service
National Toxicology Program
Office of Pesticide Programs at U.S. EPA
ounces
proportion of a given species in the diet (unitless)
peripheral nervous system
cancer slope factor, lifetime cancer risk per mg/kg-day
incremental risk above background associated with
contaminant at given dose (lifetime"1)
mean individual risk in the exposed population
(risk/person-lifetime)
XVI
-------
GLOSSARY & ABBREVIATIONS
Reference Dose (RfD) estimate (with uncertainty spanning perhaps an order
of magnitude) of a daily exposure to the human
population (including sensitive subgroups) that is likely
to be without an appreciable risk of deleterious effects
during a lifetime. Units are mg/kg-day.
RfD
risk
RL
Rmix
SF
m
SIZ
slope factor
teratogenic
threshold
reference dose of a chemical mixture (mg/kg-day)
the probability of injury, disease, or death under
specific circumstances.
maximum acceptable risk level (unitless)
individual cancer risk from the chemical mixture
cancer slope factor, usually the upper 95 percent
confidence limit on the linear term (q.,) in the multi-
stage model
slope Factor of a chemical mixture
size of the exposed population (number of persons)
see SF above
the screening level concentration for a single
contaminant in a given fish species (mg/kg)
screening values of a given noncarcinogenic
contaminant in a given species of fish (mg/kg)
capable of causing physical defects in the developing
embryo or fetus
dose or exposure below which a significant adverse
effect is not expected
XVII
-------
GLOSSARY & ABBREVIATIONS
uncertainty factors
weight of evidence
one of several, generally 10-fold factors, used in
operationally deriving the RfD from experimental data.
They are intended to account for (1) the variation in
sensitivity among the members of the human
population (intraspecies variability); (2) the uncertainty
in extrapolating animal data to humans; (3) the
uncertainty in extrapolating from data obtained in a
study that is of less-than-lifetime exposure to chronic
exposure toxicity; (4) the uncertainty in using LOAEL
data rather than NOAEL data; and (5) uncertainty
generated by data gaps. See also Table 5-2 in Chapter
5.
for carcinogens this is a classifications assigned to a
chemical by EPA, based on the types of data available
regarding carcinogenicity. On a scale of A to E, the
classifications reflect the extent to which the available
biomedical data support the hypothesis that a
substance causes cancer in humans. See EPA (1986a)
for additional information.
XVIII
-------
-------
PART/
PART I.
This document is divided into two parts so that readers wishing to use it as a
reference source may refer directly to sections containing relevant material
without having to refer to background material in other sections. Part I of this
document is designed to provide readers with an overview of the critical
information used in the calculation of risk-based consumption limits, options for
modifying the limits to meet specific local needs, and actual consumption limit
tables for the 23 target analytes. Part II of this document contains more
detailed information on specific aspects of the risk assessment methodology
used to calculate the fish consumption limits and a brief discussion of the
toxicity of each of the target analytes.
-------
PARTI
-------
1. INTRODUCTION
SECTION 1
INTRODUCTION
1.1 Overview and Objectives
Toxic chemicals from point sources such as industrial or municipal outflow
pipes, and non-point sources such as agricultural runoff and atmospheric
deposition have contaminated surface waters and their sediments across the
United States. In some areas contamination arises from one or a few related
chemicals. For example, in the Hudson River in New York, attention has
focused on high levels of a group of related chemicals called polychlorinated
biphenyls, or PCBs. In other areas a complex mixture of chemicals is present.
For example, over 900 different synthetic organic compounds have been found
in Puget Sound in Washington State, while nearly 1,000 chemical contaminants
have reportedly been found in the Great Lakes.
Many pollutants concentrate in fish tissues by accumulating in fatty tissues or
selectively binding to fish muscle tissue (the fillet). Even extremely low
concentrations of bioaccumulative pollutants in water or bottom sediments may
result in fish tissue concentrations high enough to pose health risks to fish
consumers. Lipophilic contaminants, particularly certain organic compounds,
tend to accumulate in the fatty tissues of fish. Consequently, fish species with
a higher fat content, such as carp, bluefish, some species of salmon, and
catfish, may pose greater risks from some contaminants than leaner fish such
as bass, sunfish, and yellow perch. Although exposure to some contaminants
may be reduced by removing the fat, skin, and viscera before eating, other
contaminants, such as methylmercury, accumulate in the fillet, and therefore
cannot be removed by trimming. In addition, some fish are consumed whole,
or used whole in the preparation of fish stock for soups and other foods. Under
these conditions the entire burden of bioaccumulative contaminants contained
in the fish would be ingested (U.S. EPA, 1991b).
In addition to the risks borne by the general population due to consumption of
contaminated fish, populations eating higher-than-average quantities of fish are
at greater risk of having higher body burdens of contaminants. Those at
greatest risk include sport and subsistence fishers.1 Within these populations,
1 Subsistence fishers are considered in this document to be people who
rely on non-commercial fish as a major source of protein.
1-1
-------
1. INTRODUCTION
pregnant women and children may be at greater risk of incurring adverse
effects than other members of the populations, due to their proportionally
higher consumption rates and/or increased susceptibility to adverse effects.
Fish contaminants vary widely in chemical structure and toxic properties.
Potential adverse health effects include cancer, chronic systemic effects, and
developmental and reproductive effects. The severity of effects varies with the
exposure level and characteristics of the individual, and may range from
relatively mild disease states to premature death. Recently, attention has
focused on the developmental effects of chemical contaminants because
studies conducted over the last two decades have identified many
environmental pollutants as causing developmental abnormalities and other
adverse reproductive outcomes. For example, in developing a protocol for
uniform sport fish consumption advisories across the Great Lakes, the Great
Lakes Sport Fish Advisory Task Force used developmental and reproductive
toxicity endpoints in calculating their recommended consumption limits.
State, local, and federal agencies and tribal bodies currently use a range of
methods to estimate risks to human health from consumption of chemically-
contaminated fish. Results of a 1988 survey of such methods, funded by the
U.S. Environmental Protection Agency (EPA)2 and conducted by the American
Fisheries Society, identified the need for standardizing the approaches to
assessing risks and for developing advisories for contaminated fish. Four key
components were identified as critical to the development of a consistent risk-
based approach to developing fish consumption advisories: standard practices
for sampling and analyzing fish, standardized risk assessment methods,
standard procedures for making risk management decisions, and standardized
approaches to risk communication.
To address concerns raised by the survey, EPA is developing a series of four
documents designed to provide guidance to state, local, regional, and tribal
environmental health officials who are responsible for issuing fish advisories for
non-commercial fish.3 The documents are meant to provide guidance only and
do not constitute a regulatory requirement. The documents are: Guidance for
Assessing Chemical Contamination Data for Use in Fish Advisories, Volume 1:
Fish Sampling and Analysis (released 1993), Volume 2: Risk Assessment and
Fish Consumption Limits, Volume 3: Risk Management, and Volume 4: Risk
2 Throughout this document the abbreviation EPA will be used to represent
the U.S. Environmental Protection Agency.
3 "Fish" specifically refers to non-commercial, sport- and subsistence-
caught fresh water and estuaririe fish, unless otherwise noted.
1-2
-------
1. INTRODUCTION
Communication. EPA recommends that the four volumes be used together,
since no one volume provides all the necessary information to make decisions
regarding the issuance of fish consumption advisories.
Some information provided in this document is repeated in more than one
section. This was done so that readers wishing to use this document as a
reference source may refer directly to sections containing relevant material
without having to refer to background material in other sections. For example,
the consumption limit tables should be used with an understanding of the
uncertainties and assumptions involved in their development; a brief summary
of uncertainties and assumptions is provided in Part I and greater detail is
provided in Part II.
Volume 2 provides guidance on risk-based consumption limits for the 23 high-
priority chemical fish contaminants identified in Volume 1 (See Table 1-1 ).4
It represents a refinement of the 1989 EPA publication entitled Assessing
Human Health Risks from Chemically Contaminated Fish and Shellfish: A
Guidance Manual (U.S. EPA, 1989a). The new volume is divided into two
parts. Part I of this new volume contains a description of the methods used to
calculate consumption limits and ways to modify the limits for specific
purposes (e.g., to take multiple contaminants into account). It also contains
consumption limit tables {expressed as maximum allowable meals over a given
period of time) which were calculated using default values for meal size,
consumer body weight, maximum allowable risk level, cancer potencies, and/or
chronic reference doses. The tables were developed for two fish-consuming
populations: young children, and adults.5 In addition, consumption limits are
provided for methylmercury for women of reproductive age. The information
contained in the consumption limit tables may be used directly or modified to
better approximate local conditions, as discussed in Section 2.
4 The target analytes listed in Table 1-1 were selected as particularly
significant fish contaminants by EPA's Office of Water, based upon their
occurrence in fish, their potential for bioaccumulation, and their toxicity. The
criteria for their selection is discussed in Volume 1, Section 4 of this series.
5 In future revisions of this document, additional health intake limit tables
based on developmental health endpoints will be provided for women of
reproductive age and children.
1-3
-------
1. INTRODUCTION
Table 1-1. Target Analytes Examined in This Document3
Cadmium
Carbophenothion
Chlordane
Chlorpyrifos
DDT, ODD, DDE
Diazinon
Dicofol
Dieldrin
Dioxin (2,3,7,8-TCDD)
Disulfoton
Endosulfan 1,11
Endrin.
Ethion
Heptachlor Epoxide
Hexachlorobenzene
Lindane
Methylmercury
Mirex
Oxyfluorfen
RGBs
Selenium
Terbufos
Toxaphene
Source: Volume 1 of this series (U.S. EPA 1993a)
a
This list may not include all chemical fish contaminants which pose human
health risks. In the future, chemicals may be added or deleted from the list as
new occurrence data, toxicity data, and environmental fate data become
available. See Volume 1 for information on how the target analytes were
selected.
1-4
-------
1. INTRODUCTION
Part II contains more detailed technical information including an overview of
EPA risk assessment methods used to derive the consumption limit tables,6
and a discussion of the adverse health effects associated with each of the 23
target analytes. The critical studies and toxicity values (cancer potencies and
Reference Doses) used in developing the consumption limit tables and a
discussion of uncertainty and assumptions are also provided in Part II.
Risk values for chronic and cancer health effects used in the consumption limit
tables and discussed in Section 5 were obtained from the Integrated Risk
Information System (IRIS) and other EPA sources.7 Reference Doses (RfDs)
based specifically upon developmental effects have not yet been developed by
EPA for most of the target analytes. Because this is an area of interest to
many readers, a summary of dose-response data on developmental effects is
provided in Section 5 for each target analyte, along with methods for deriving
developmental exposure limits. Other recently published toxicity data are also
provided. These data provide readers with an opportunity to develop
consumption limits as they deem necessary, in addition to the limits offeced in
Section 3 of this document.8
This document does not provide guidance on the evaluation of the overall risk
associated with multimedia exposure to chemical contaminants found in fish
(e.g., exposure due to other food sources, air, water, and soil). Rather, the
focus of this document is exclusively on the risk due to consumption of non-
commercial fish from estuarine and fresh water sources. For example, risk from
eating co/77/77erc/a//y-caught fish is not included in this guidance. EPA
recommends that a comprehensive risk assessment be considered for all
confirmed fish contaminants, including an evaluation of all significant exposure
pathways.
Risk assessment and risk management of contaminated fish are complex
processes due to the many considerations involved in setting fish advisories,
6 That is, the four-step risk assessment process: hazard assessment, dose-
response evaluation, exposure assessment, and risk characterization.
7 EPA risk values refer to cancer potency values (q^s) for carcinogenic
toxicity and Reference Doses (RfDs) for non-carcinogenic toxicity. These are
defined in the Glossary and in Section 4. The values for each of the target
analytes is provided in Table 2-2.
o
0 Data are not provided on dioxin because it is currently undergoing EPA
review. Information on dioxin will be provided in future revisions to this
document.
1-5
-------
1. INTRODUCTION
including both the health risks and benefits of fish consumption, the roles of
state and federal agencies, and the potential impact of advisories on economic
and societal factors. These topics will be discussed in Volume 3 (Risk
Management), currently under development.
Additional information on risk assessment methods and issues specifically
related to fish risk assessment may be obtained from the documents listed in
Appendix B. These documents and scientific papers cover a range of topics,
from general risk assessment methods, to chemical-specific lexicological data,
to identification of chemical contaminant pathways.
1.2 Sources
Information from a wide range of government and academic sources was used
in the development of this document. Current approaches developed by states,
regional groups such as the Great Lakes Sport Fish Advisory Task Force, and
federal agencies including EPA and the U.S. Food and Drug Administration
(FDA) were reviewed. Section 6 contains a complete listing of sources cited.
In addition, EPA assembled an Expert Review Group consisting of officials from
several EPA offices, FDA, regional groups, and the following states: California,
Florida, Michigan, Delaware, Illinois, Minnesota, Missouri, North Dakota, New
Jersey, and Wisconsin, to review earlier drafts of this document. A list of the
experts and their affiliations is provided in the acknowledgements section at the
beginning of this document. The Expert Review Group contributed significant
technical information and guidance in the development of this document.
Written recommendations made by the experts were incorporated into the final
document. Some members were also consulted further on specific issues
related to their expertise. In a second round of reviews, this document was
circulated to all states, several Native American tribes, and various federal
agencies for comment and additional modifications were made. Participation
in the review process does not imply concurrence by these individuals with all
concepts and methods described in this document.
l»
1-6
-------
2. DEVELOPMENT AND USE OF FtlSK-BASED CONSUMPTION LIMITS
SECTION 2
DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
2.1. Overview and Section Organization
This section describes the derivation and use of the risk-based consumption
limit tables provided in Section 3. Tables were developed for each of the 23
target analytes listed in Table 1-1 and described in further detail in Volume 1
of this series. This section covers:
• Equations used to calculate the consumption limit tables,
• Default values used in developing the consumption limit tables, and
• Modifications to the consumption limit calculations involving different
input values, multiple species consumption, and/or multiple contaminant
exposure.
Methods for deriving consumption limits for pollutants with carcinogenic and/or
noncarcinogenic effects are shown.1 Methods for calculating consumption
limits for multiple contaminants causing the same health effects are also
discussed below. Species-specific consumption limits are calculated in
kilograms per day and converted to allowable fish meals per 10-day period or
month. This approach is taken because consumers tend to think of fish
consumption in terms of meals rather than in terms of grams or ounces.
Developing fish consumption limits also requires making assumptions about the
edible portions of fish because most contaminants are not evenly distributed
throughout the fish. The portion of the fish typically eaten may vary by fish
species and/or the dietary habits of fisheir populations. Most fishers in the U.S.
consume fish fillets. Therefore, it is recommended that contaminant
concentrations be measured using skin-on fillets for scaled fish* and skinless
fillets for fish that do not have scales (See Volume 1 of this series for further
discussion). However, for populations that ingest whole fish, consumption
values corresponding to whole fish contaminant concentrations are more
1 When available data indicate that a target analyte is associated with both
carcinogenic and noncarcinogenic health effects, consumption limits based on
both types of effects are calculated.
2-1
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
appropriate. Fish consumption patterns are discussed in more detail in Volume
3 of this series.
People may be exposed to one or more fish contaminants through sources or
pathways other than non-commercial fish. These include ingestion of
contaminated commercially-caught fish, other contaminated food or
contaminated water, inhalation of the contaminant, or dermal contact with
contaminated material. Caution should be used in setting health safety
standards that do not take these other sources into account (See Section 4 for
further discussion). Methods for quantifying exposure via sources other than
non-commercial fish are not discussed in this series, though Appendix B
provides a list of references and government agencies which may be of
assistance in quantifying these other sources of exposure.
2.2. Equations Used to Develop Risk-Based Consumption limits
Two equations are required to derive meal consumption limits for either
carcinogenic or noncarcinogenic effects. The first equation (Eq. 2.1 for
carcinogenic effects or Eq. 2.3 for noncarcinogenic effects) is used to calculate
daily consumption limits in units of milligrams of edible fish per kilogram
consumer body weight per day (mg/kg-d); the second (Eq. 2.2) is used to
convert daily consumption limits to meal consumption limits over a specified
period of time.
2.2.1. Calculation of Consumption Limits for Carcinogenic Effects
To calculate consumption limits for carcinogenic effects it is necessary to
specify an "acceptable" lifetime risk level (ARL).2 This document provides
consumption limits which were calculated using a range of risk levels from one
in ten thousand (10~4) to one in one million (10~°). Equations 2.1 and 2.2 were
used to calculate risk-based consumption limits for the 12 target analytes with
cancer potency values, based on an assumed 70-year exposure.3 No
subpopulations were identified as being particularly susceptible to the
carcinogenic effects of the target analytes. However, readers may wish to
calculate consumption limits for specific cohorts (e.g., children, individuals
n
The appropriate risk level is determined by risk managers; see Volume 3
for further discussion.
o
A 70 year lifetime is used in keeping with the default value provided in
EPA's Exposure Factors Handbook (EPA, 1990a). This is a normative value;
individuals may actually be exposed for greater or lesser period of time,
depending on their lifespan, consumption habits, and residence location.
2-2
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
exposed to other carcinogens) based on their interpretation of the toxicological
literature and local conditions.
2.2.1.1. Calculation of Daily Consumption Limits
Equation 2. 1 calculates allowable daily consumption of contaminated fish based
on a contaminant's carcinogenicity, expressed in terms of kilograms of fish per
day:
—L ' BW Equation 2.1
where:
CR,jm = Maximum allowable fish consumption rate (kg/day),
ARL = Maximum acceptable individual lifetime risk level (unitless),
BW '=• Consumer body weight (kg),
q1 * = Cancer potency, usually the upper 95 percent confidence limit on
the linear term in the multistage model used by EPA ((mg/kg-d)" ),
(see Section 4 for a discussion of this value), and
\
C = Measured concentration of contaminant m in a given species of
fish (mg/kg).
The calculated daily consumption limit (CRHm) represents the amount of fish (in
kilograms) expected to generate a risk no greater than the maximum acceptable
risk level (ARL) used, based on a lifetime of daily consumption at that
consumption limit.
2.2.1.2. Calculation of Meal Consumption Limits
Consumption limits may be more conveniently expressed as the allowable
number of fish meals that may be consumed over a given time period. The
meal consumption limit is determined in part by the size of the meal consumed.
Four meal sizes were used to develop the consumption limit tables for
carcinogens in Section 3: 0.114 kg (4 oz), 0.227 kg (8 oz), 0.341 kg (12 oz),
and 0.454 kg (16 oz). Note that while all calculations are in units of kilograms,
meal sizes are converted to ounces in the tables in Section 3 for ease of risk
communication to U.S. consumers. The conversion rate from ounces to
kilograms is approximately 1 oz to 0.028 kg, or 1 kg to 35.2 oz. Equation 2.2
2-3
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
can be used to convert the number of allowable kilograms per day (calculated
using Equation 2.1) to the number of allowable meals per month:
CRl]m - dylmnth
MS
Equation 2.2
where:
CR
mm
Maximum allowable fish consumption rate (meals/mo),
CRUrn = Maximum allowable fish consumption rate (kg/6), and
MS = . Meal size (kg fish/meal).
Equation 2.2 can also be modified to calculate meals per day (CRmd); this was
done to calculate the 10-day consumption limit tables for non-carcinogens in
Section 3. Note that this approach does not expressly limit the amount of fish
that may be consumed in a given day during the specified time period, so care
must be taken to inform consumers of the dangers of eating large amounts of
contaminated fish in one sitting when certain acute or developmental toxics
may be of concern. For example, consuming the monthly limit in one day could
result in exposures for non-carcinogens that are 30 times the RfD (See Section
4.3 for further discussion).
Other consumption rates, such as meals per week, could also be calculated
using this equation by substituting, for example, days/week for days/month.
In using Equation 2.2 in the table calculations in Section 3, one month was
expressed as 365.25 days/12 months.
All meal consumption limits in the tables in Section 3 have been rounded down
to the nearest whole number, with the exception of the six meals/year
consumption limits, which are expressed as 0.5 meals/month. Meal
consumption limits are rounded down to make them more protective; rounding
up would potentially cause them to exceed maximum acceptable risk levels
(ARLs) for carcinogens and/or chronic systemic Reference Doses associated
with fish contaminants.
2.2.1.3. Input Parameters
Calculating risk-based consumption limits for carcinogenic effects requires
developing appropriate values for the parameters in the equations. The default
values used to calculate the consumption limits listed in Section 3 are shown
in Table 2-1; a range of values are provided for Cm. Development and
modification of these values are discussed in Section 2.3.
2-4
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Table 2-1. Input Parameters for Risk Equations
Equation Parameter3
Maximum acceptable risk level (ARL)
Consumer body weight (BW)
Average fish meal size (MS)
Cancer potency (q-i*)b
Reference Dose (RfD)
Measured contaminant concentration in
edible fish tissue (Cm)c
Values
10'4 (unitless)
10~5 (unitless)
10"6 (unitless)
70 kg (general adults
14.5 kg (young children)
3 oz (0.085 kg) (children only)
4oz (0.114kg)
8 oz (0.227 kg)
1 2 oz (0.341 kg)
1 6 oz (0.454 kg)
in rate per(mg/kg-d); See Table 2-2
in mg/kg-day; See Table 2-2
in img/kg; varies with local conditions
a Choice of the appropriate acceptable risk level, consumer body weight, and
average fish meal size are considered to be risk management decisions. This
document provides a range of values; the risk management decision-making
process is discussed in Volume 3. Selection or calculation of the appropriate
cancer potency and RfD values may be considered lexicological, medical, or risk
management decisions. For information regarding these values see Sections 4
and 5 of this document and Volume 3.
b Most of the q., *s and RfDs were obtained from EPA's Integrated Risk
Information System (IRIS, 1993). The RfDs not listed in IRIS were obtained from
EPA's Office of Pesticide Programs or the HEAST tables. The q., *s and RfDs
used are listed in Table 2-2 and discussed in Section 5.
c Values for contaminant concentrations must be taken from local sampling and
analysis programs as described in Volume 1.
2-5
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
2.2.2. Calculation of Consumption Limits for Noncarcinogenic Effects
Noncarcinogenic health effects caused by consumption of contaminated fish
include acute exposure toxicity, chronic exposure health effects (i.e., liver,
kidney, neurological, muscular, ocular, reproductive system, respiratory,
circulatory system, or other organ toxicities), and adverse developmental
effects. Risk-based consumption limit tables for chronic exposure health
effects were developed for adults and young children.4 Section 5 contains a
summary of the overall toxicity of the target analytes. In future revisions of
this document, additional consumption limit tables for women of reproductive
age and children based on developmental health endpoints will be provided.
The equations provided in this section may be used by readers to calculate
additional or alternative consumption limits, based on their interpretation of
toxicological and other literature.
2.2:2.1. Calculation of Daily Consumption Limits
Equation 2.3 is used to calculate the allowable daily consumption (CR|im) of
contaminated fish, based on a contaminant's noncarcinogenic health effects,
and expressed in terms of kilograms of fish per day:
RfD - BW
Equation 2.3
where:
n = Maximum allowable fish consumption rate (kg/day),
RfD = Reference Dose (mg/kg-d),
BW = Consumer body weight (kg), and,
m
Measured concentration of contaminant m in a given species of
fish (mg/kg).
CRnrn represents the maximum lifetime daily consumption rate (in kilograms of
Consumption limit tables for women of reproductive age and children were
also calculated based on developmental effects of methylmercury.
2-6
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
fish) that would not be expected to cause adverse noncarcinogenic health
effects. Most RfDs are based on chronic exposure studies (or subchronic
studies used with an additional uncertainty factor). Because the contaminant
concentrations required to produce chronic health effects are generally lower
than those causing acute health effects, the use of chronic RfDs in developing
consumption limits is expected to also protect consumers against acute health
effects. They are designed to protect the most sensitive individuals. This may,
however, not be the case for developmental toxics (See Section 2.2.3 below).
2.2.2.2. Calculation of Meals Per Month
Equation 2.2, shown above in Section 2.2.1.2, is used to convert daily
consumption limits, in kilograms, to meal consumption limits over given time
periods, as a function of meal size. Five meal sizes were used to develop the
consumption limit tables for noncarcinogenic effects: 3 oz (children only), 4 oz,
8 oz, 12 oz (adults only), and 16 oz (adults only). Monthly and short term (10-
day) consumption limits were derived. Monthly consumption limits pertain to
seasonal and subsistence fish consumers, while 10-day consumption limits
apply to short-term recreational fishers. Note that both sets of tables use the
same chronic systemic RfDs; the difference is in the averaging periods (i.e., 10
days versus one month) used in Equation 2.2.5
2.2.2.3. Input Parameters
For noncarcinogenic effects, calculating risk-based consumption limits requires
developing appropriate values for similar parameters to those required for
carcinogenic effects. These are listed in Table 2-1.
2.2.3. Calculation of Consumption Limits for Developmental Effects.
This guidance document considers three groups of fishers in deriving risk-based
consumption limits: general adults, women of reproductive age, and young
children. Both women of reproductive age and young children are known to be
at risk from developmental toxics.6 It is well-documented that women
5 As noted earlier, this approach does not expressly limit the amount offish
that may be consumed in a given day during the specified time period, so care
must be taken to inform consumers of the dangers of eating large amounts of
contaminated fish in one sitting when certain acute or developmental toxins are
of concern.
6 There is currently very limited information on the potential developmental
impact resulting from exposure of men to developmental toxins. However,
2-7
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
exposed to developmental toxic (e.g., methylmercury) may pass on sufficient
levels of the contaminants in utero or through breast-feeding to induce pre- or
post-natal developmental damage in their offspring. Information on
developmental toxicity has only recently become available for many chemical
contaminants. Consequently, the IRIS database, the source of most of the
chronic RfDs used to calculated consumption limits, does not contain detailed
developmental toxicity data for all target analytes. Consumption limits
specifically designed to address developmental health effects in women of
reproductive age and children have been calculated for methylmercury (See
Section 3). In addition, the RfD used for PCBs is considered protective against
developmental toxicity, based on the data available on Aroclor 1016 (See the
discussion of PCBs in Section 5). New data are being reviewed by EPA and will
be incorporated in future versions of this document.
Readers are referred to Sections 4 and 5 which contain discussions of
developmental toxicity. Developmental study data, sources of additional
toxicity data, and a methodology for calculating exposure limits are provided
in Section 5 so that readers may evaluate available information and make
informed decisions regarding developmental toxicity and consumption limits.
Exposure limits for developmental and other health endpoints may be calculated
by readers, as deemed necessary, using methods described in Section 5.
2.3. Default Values and Alternative Values For Calculating Consumption Limits
The consumption limit tables provided in Section 3 are based on default values
for consumer body weights and average meal sizes. These values may not be
valid for some recreational and subsistence fisher populations. Readers are
encouraged to modify these variables, if necessary, to better fit local conditions
relating to consumer body weight, risk level, of concern, meal size, new
toxicological data, and/or the presence of multiple contaminants. This section
describes the default input values shown in Table 2-1 and provides additional
input values and multipliers for use in modifying and/or recalculating the
consumption limit tables.
Seven variables are involved in calculating the values in the consumption limit
tables (See Equations 2.1 to 2.3):
• Maximum acceptable risk level (ARL),
* Cancer potency (q^),
• Chronic Reference Dose (RfD),
• Consumer body weight (BW),
some information on this is provided in Sections 4 and 5.
2-8
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
• Fish meal size (MS),
• Contaminant concentration in edible fish tissue (Cm), and
• Maximum allowable consumption rate (CR|jm).
Blank table templates are provided at the end of this section for use in
developing new consumption limit tables based on changes in input parameters.
2.3.1. Maximum Acceptable Risk Level i[ARL)
The consumption limit tables shown in Section 3 for target analytes with
carcinogenic effects were calculated for maximum individual acceptable risk
levels (ARLs) of 10~4 to 10"6. Note that the variable ARL appears in the
numerator of Equation 2.1, the equation for calculating the daily consumption
limit for carcinogens. Since ARL appears in multiples of 10, one may derive
new meal consumption limits from the existing tables by multiplying or dividing
the existing meal consumption limits by factors of 10, as appropriate. Equally,
changing the ARL by a factor of 10 would cause the same meal consumption
limits to be valid for chemical concentrations 10 times higher or 10 times lower
than those associated with the original ARL. For example:
• To go from an ARL of 10~4 to an ARL of 10~3, shift the meal
consumption limit values for the ARL of 10"4 to chemical concentrations
1O times greater than the original (e.g., if the original meal consumption
limit is 12 8-oz meals per month at a contaminant concentration of 0.6
mg/kg for an ARL of 10"4, then the new meal consumption limit for an
ARL of 10~3 would be 12 8-oz meals per month at a contaminant
concentration of 6 mg/kg. This increases the estimated individual
lifetime risk by a factor of 10.
• To go from an ARL of 10'6 tov an ARL of 10~7, shift the meal
consumption values for the ARL of 10"6 to chemical concentrations 10
times /owerthan the original (e.g., if the original meal consumption limit
is 12 8-oz meals per month at a contaminant concentration of 0.006
mg/kg for an ARL of 10"6, then the new meal consumption limit for an
ARL of 10~7 would be 12 8-oz meals per month at a contaminant
concentration of O. OOO6 mg/kg. This decreases the estimated individual
lifetime risk by a factor of 10.
EXAMPLE: Modified Risk Level (ARL)
The consumption limit table for general adults for the non-carcinogenic effects
of chlordane was taken from Section 3 and modified to include consumption
limits for risk levels of 10~3 (one in 1000) and 10~7 (one in 10,000,000) for an
2-9
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
8-oz meal size (shown in bold). Consumption limits for other meal sizes have
been deleted for clarity. Table 3-1 Oa is shown below.
2.3.2. Chronic Reference Doses and Cancer Potencies (RfDs and q1 *s)
Table 2-2 contains the risk values used in the development of the consumption
limit tables shown in Section 3. All of the q.,*s and RfDs were obtained from
EPA data bases, primarily from IRIS (1993). Preference was given to IRIS
values because they represent consensus within EPA. When IRIS values were
not available, RfDs from other EPA sources were used (See Section 5).
EPA evaluates dose-response data as they become available. Because
toxicological data is continually being generated, there may be data not yet
incorporated into the risk values. This is especially relevant for developmental
toxicity, neurotoxicity, and immunotoxicity, which are the subject of much
current research. To address this, a summary discussion of the toxicity data
has been provided in Section 5 for each target analyte; the summaries include
a discussion of acute, chronic, developmental, carcinogenic,and genetic
toxicity, and special susceptibilities. The summaries cbntain a brief synopsis
of the toxicity data current through 1993, based on a review of summary
documents and data bases. Readers are urged to review this information for
those target analytes of interest in their geographic areas. A method for
estimating acceptable exposure levels from the new data is provided in Section
5; the methods follow the basic dose-response approach recommended by EPA
for calculation of RfDs (discussed in Sections 4 and 5). This information is
provided to enable readers to use new dose-response data to develop
consumption limits if they feel the data warrant such an approach. This may
be particularly useful when there are concerns regarding the exposure of
pregnant and lactating women and children to developmental contaminants.
2.3.3. Consumer Body Weight (BW)
The consumption limit tables in Section 3 are based on non-commercial fish
consumers of two body weights: 70 kg (156 pounds) and 14.5 kg (32
pounds). Seventy kg corresponds to the average body weight of male and
female adults in the U.S. (EPA, 1990a). The 14.5 kg body weight corresponds
to that of a young child of three to four years (EPA, 1990a). As Equation 2.3
shows, consumption limits are linearly related to body weight. That is, the
higher the body weight assumed for the population, the higher the consumption
limits. EPA's Exposure Factors Handbook (EPA, 1990a) provides additional
specific body weight information which can be used to adjust the body weight
component of Equation 2.3. The values can also be used as to develop a set
of multipliers to directly adjust consumption limits for body weight variations
(See below).
2-10
(\
-------
W
"c
"o
o
C
LI
.c
1
i
0
"c
ffi
D)
0
C
•D
is
O
•2
c
.2
Q.
E
U
CO
c
o
O
s
E
o
5
ctt
0
1
TO
ffi
_Q
CO
TJ
1
D) D
CD ^>^
S - E E
^ te o> ™ S
S ffi o TO MJ
0 O ° ^ ^
O
CO
u_
ffi >> i.
5 •«-* *"* £
•S . . -^ .2 •-
"^ C D) O
•g .0 'ffi Q. C
ffi D.T3 C "
.c o o co <5
O Q- CD O Q
I
0
E
.
ffi
a
to
§
E
**•*'
As
E
3
.0
E
3
CO
o
O
TJ
CD
CO
m
|
V)
ir
1
CD
.Nl
CO
•3
ffi
2
c
^o
o
•E
a)
o
c
o
o
'E
a
sz
O
CO
CM
co
^.
TJ
C
CO
O!
c
"5
CO
CO
c
-Q
c
1
_J
cc
E
CO
DJ
O
CL
CO
'co
>.
•3
c
<
o
^
T
o
'L
„.
t
o
rt
0
£
:*
C
_E
2
3
Z
2
Z)
S
•z.
S
z
CO
0
c
c
c
d
V
CM
Z
5
Z
3
5
Z
S
z
CO
0
o
o
o
d
O>
Z
5
Z
2
z
s
z
3
co
0
o
o
o
d
N
Z
s
Z
5
Z
S
z
3
o
o
c
o
eo
z
5
Z
2
Z
Z
Z
CM
O
O
C
0
*-
Z
^
Z
"5.
Z
S
z
3
o
o
c
d
-
CM
s
Z
2
Z
S
Z
3
CO
o
o
o
d
in
d
o>
s
Z
2
z
S
z
3
co
o
o
o
o
in
d
f-
2
Z
2
z
2
z
3
o
c
0
UJ
O
Z
TO
-5
Z
2
z
S
z
3
CM
O
O
d
UJ
Z
Z
'-
s
Z
5
Z
Z)
S
z
3
o
o
d
UJ
Z
Z
"-
CM
"£.
Z
S
z
3
co
o
c
o
UJ
Z
O
Z
in
d
a>
2
Z
S
z
3
CO
c
c
o
UJ
Z
O
Z
in
d
^
2
Z
S
Z
3
o
6
UJ
z
O
Z
o
z
TO
s
z
s
z
3
CM
C
d
UJ
Z
O
z
D
Z
•*"
2
z
S
z
3
0
d
UJ
Z
O
z
z
o
z
*-
CM
2
z
3
co
0
d
UJ
Z
O
•z
Z
o
z
in
d
o>
i
Z
3
co
c
o
UJ
Z
O
z
z
o
z
in
d
"*•
2
z
3
^_
o
UJ
Z
O
z
z
o
z
z
o
z
CO
2
Z
3
CM
O
UJ
Z
z
z
o
z
z
o
z
^~
5
Zj
z
3
^.
d
UJ
Z
O
z
z
o
z
z
z
T<~
CM
CO
0
UJ
3
Z
z
o
z
0
tn
d
0)
CO
o
UJ
Z
z
z
o
z
z
z
d
N.
*-
UJ
z
z
z
o
z
D
Z
UJ
o
z
»
CM
UJ
z
z
z
o
z
z
o
z
HI
o
z
"-
-3-
UJ
0
z
z
o
z
z
o
z
UJ
o
z
'•
CO
UJ
z
z
UJ
z
o
z
z
o
z
UJ
o
z
d
CO
UJ
z
z
uu
z
z
z
o
z
UJ
o
z
U)
d
o
1
UJ
z
z
HI
z
o
z
z
o
z
UJ
o
z
UJ
o
z
o
A
i?
•£
o
£
i^"
^_ c
— - o
-g o
ffi ® 2
S w £
* w
ffi "~ ^
*•* .* ^rf 2J
Q. Jrt *- m
5 <8 - c
(A (D Q. ff) C
J2.o Q-Q.E-o °~
O C^" Q)(D"O--
JJ -o 3 ^ c— i"®^
.y52o*s>o^7
(0-j:: flj«2^fflffl
S — N ^QjftQ>C"^
° " ^1 |1 ll5
cZO'n'5'o=o5
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Table 2-2. Risk Values Used in Risk-Based Consumption Limit Tables in Section 3
Chronic RfD q1*
Target Analyte (mg/kg-day)a (per mg/kg-day)a
Cadmium
Carbophenothion
Chlordane
Chlorpyrifos
DDT, ODD, DDE
Diazinon
Dicofol
Dieldrin
Dioxin (2,3,7,8-TCDD)
Disulfoton
Endosulfan
Endrin
Ethion
Heptachlor epoxide
Hexachlorobenzene
Lindane
Methylmercury (Chronic Systemic)6
Methyimercury (Developmental)*
Mirex
Oxyfluorfen
PCBs
Selenium
Terbufos
Toxaphene
1 x 1CT3
1.3x10"4b
6x 10'5
3x 10'3
5x 10"4
9 x 1CT5b
.1 x 10"3b
5x 10'5
—
4x10"5
5 x icr5
3x 10'4
5x 10'4
1.3x 10'5
8x 10'4
3x 10'4
3x 10'4
6x 10'5g
2x10'4
3x 10"3
2x10'5h
5x 10'3
5x10'5b
2.5x 1CT4b
—
—
1.3
. —
0.34
0.4b'c
16
1.56 x 10+5
—
__
—
9.1
1.6
1.3d
__
—
1.86
0.13
7.7d
—
__
1.1
All risk values cited are from the Integrated Risk Information System (IRIS, 1993) unless noted. All
risk numbers provided in this table are subject to change as new toxicological data and methodology
become available.
b Developed by EPA Office of Pesticide Programs.
° The q., * for dicofol and ODD, DDT and/or DDE combined is 0.34 per mg/kg-d (IRIS, 1993)
Developed by EPA and listed in the Health Effects Assessment Summary Tables (HEAST, 1992)
* Used in calculations for the general adult population
Used in calculations for women of reproductive age and children.
j> Source: EPA (1993a). Developed by EPA's Office of Water. See Section 5 on methylmercury.
h The RfD for PCBs is based on Arpclor 1254 (IRIS, 1993); the q,* for PCBs is based on Aroclor
1260 (IRIS, 1993).
2-12
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Table 2-3 provides a range of average body weights (based on age and sex) for
the U.S., and their associated multipliers. Values shown in bold represent
those used in the calculation of the consumption limit tables in Section 3. A
multiplier is provided for each age group which represents the number by which
the meal consumption limits in the general adult population tables may be
multiplied in order to calculate new meal consumption limits using an alternative
body weight.
2.3.3.1. Derivation of Multipliers for Body Weight Adjustment
Body weight multipliers represent the ratio of the alternative body weight to the
standard 70 kg body weight. Body weight multipliers were calculated as
shown:
Multiplier = Aftemate Consumer Body Weight
General Adult Body Weight
EXAMPLE: Calculating Multiplier for Body Weight
To calculate the multiplier for a 9 to 12 year old with an average body weight
of 36 kg (See Table 2.3), the equation is:
Multiplier = - = 0.51 (unitless)
70 kg
where 0.51 represents the ratio between the child body weight (36 kg) and the
general adult body weight (70 kg). In this document, a body weight of 70 kg
was used for all adults, including women of reproductive age, to calculate the
consumption limits shown in Section 3. {Readers may wish to modify some or
all of these consumption limits using alternative body weight values, based on
the health endpoint of concern. For example, in cases where certain
developmental toxics are of concern, exposure of women of childbearing age
could be assessed separately. As described in Section 4, a body weight value
of 64 kg (143 pounds) can be used to represent the body weight for women
of reproductive age, based on the arithmetic mean of the average weights of
women of three age groups (18-25, 26-35, and 36-45) given in the Exposure
Factors Handbook (EPA, 1990a; see Table 2-3). A more protective body
weight value would be to use the lower 95th percentile body weight of women
age 18 to 25 years (Blindauer, 1994). Readers are encouraged to use local
information when available to determine appropriate body weights for
calculating exposure limits.
2-13
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Table 2-3. Average Body Weights
Age
Group
(yrs)b
< 3
3 to 6
0 to 6
6 to 9
9 to 12
12 to 15
15 to 18
18 to 25
25 to 35
35 to 45
45 to 55
55 to 65
65 to 75
18 to 45
18 to 75
Average Male
Body Weight
(kg)
11.9
17.6
14.8
25.3
35.7
50.5
64.9
73.7
78.7
80.8
81.0
78.8
74.8
-
78.1
Average Female
Body Weight
(kg)
11.2
17.1
14.2
24.6
36.2
50.7
57.4
60.6
64.2
67.1
67.9
67.9
66.6
64
65.4
and Associated Multipliers
Average Body
Weight for Males and
Females Combined
(kg)
11.6
17.4
14.5
25.0
36.0
50.6
61.2
67.2
71.5
74.0
74.5
73.4
70.7
-
71.8 (70)c
Multiplier3
0.17
0.25
0.21
0.36
0.51
0.72
0.87
0.96
1.0
1.1
1.1
1.0
1.0
0.91
1.0
a The multiplier is multiplied by the consumption limits associated with 70 kg
general adult fish consumers to obtain new consumption limits using the
alternative body weight (See text). The multiplier represents the alternate body
weight divided by the general adult body weight.
b Numbers in bold represent the default values used to calculate the consumption
limit tables.
0 Per recommendations in the Exposure Factors Handbook, the body weight
value of 71.8 kg for the general population was rounded to one significant digit,
or 70 kg (EPA, 1990a).
(I
2-14
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
To derive modified consumption limits using alternate values for body weight,
multiply the existing consumption limits (in meals per month) found in the
tables for the general 70 kg fisher population by the multiplier associated with
the new body weight:
New CRmm = CRmm • Multiplier BW
where:
CRmm = Maximum allowable fish consumption rate (meals/mo),
CRmm.70 kg BW = Maximum allowable fish consumption rate of a 70-kg
fish consumer Imeals/mo),
BW = Consumer body weight (kg), and
MultiplierBW = Body weight multiplier (unitless).
If the resultant meal frequency value is not a whole number, round down to the
nearest whole number.7
EXAMPLE: Modified Body Weight
To modify Table 3-9 (which shows the monthly consumption limits for chronic
systemic health effects in general adults from exposure to chlordane) to
represent consumption limits for 9 to 1 2-year olds weighing an average of 36
kg, multiply each value in the consumption limit table by 0.51:
New CRmm = CRmn.n • 0.51
mm n""70-*jr BW
Table 3-9 has been modified to represent consumption limits for 36-kg
consumers, shown below as Table 3-9a. For example, while general adults
7 Rounding up would make the advisory less protective. It is also
important to note that rounding down the modified CRlim could lead to
unnecessarily conservative meal consumption limits, since the original CR|im
values for general adults have already been rounded down once. Readers may
wish to derive more accurate estimates by recalculating meal consumption
limits using Equations 2.1 to 2.3 instead of using a multiplier (See Section
2.3.4).
2-15
-------
Table 3-9a. Monthly Consumption for Chronic Systemic Health Endpoints
Chemical Name: Chlordape
Population: Children
Body Weight: 36
Reference Dose: 6E-05 mg/kg-d
Detection Limit 1 E-03 mq/kq
Risk-Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
>2
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
8
7
6
5
2
1
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
8
UNLIM
UNLIM
UNLIM
7
5
4
4
3
3
2
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
6
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
7
4
3
2
2
2
1
1
1
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
JNLIM = Unlimited consumption; more than 4 meals per week (17/month).
vIONE = No consumption; less than six meals per year.
).5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
tote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
AH values were rounded down to the nearest whole meal size.
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
may be able to safely eat nine 8-oz fish meals contaminated with 0.06 mg
chlordane/kg fish per month, 9 to 12-year olds would only be able to safely eat
four meals per month at this contaminant level (9 • 0.51 = 4.59, rounded
down to 4) to achieve the same daily contaminant exposure in mg/kg-day.
Scaling to a different body weight may cause the contaminant concentrations
of concern to change substantially. Note, for example, that Table 3-9a only
includes meal consumption limits of eight meals per month and below, since all
meal frequencies listed in the original table were effectively halved to derive the
new meal frequencies for 36-kg consumers. Section 2.3.5 describes the
methods used to add meal frequency values to concentration ranges that fall
under unlimited ("UNLIM") or no ("NONE") consumption in the original table for
the 70-kg consumer, but no longer do in the modified table.8
2.3.4. Meal Size
Meal size is defined as the amount of fish (in kilograms) consumed at one
sitting. Four average meal sizes were used for developing consumption limits
for the general adult population. Three were used for children under four. Note
that while children tend to eat smaller portions than adults, they may consume
significantly more fish per unit of body weight. Women of reproductive age
(considered separately for methylmercury consumption limits) were assumed
to eat the same amount of fish per meal as other adults.
EPA has identified a value of eight ounces (227 grams) of cooked fish fillet per
70 kilogram consumer body weight as an average meal size for the general
adult non-commercial fish consuming population and for women of reproductive
age.9 This meal size, however, does not represent higher end exposures,
where persons consume more than average in a given meal. These larger meal
sizes are particularly important to consider in cases where acute or
developmental effects from fish contamination are of concern. Therefore, the
consumption limit tables in Section 3 provide meal limits based on a range of
8 For the purposes of this document, unlimited safe fish consumption
(represented by "UNLIM" in the tables) has been defined as an intake limit of
more than 17 fish meals per month, or four fish meals per week for the
monthly tables, and more than one meal per day for the 10-day tables. The
definition of no safe fish consumption (represented by "NONE" in the tables)
is a health intake limit of less than one meal in two months for the monthly
tables, and less than one meal per 10 days for the 10-day table. These
definitions do not represent EPA recommendations.
9 See Section 4.4.2.3 for rationale and references.
2-17
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
meal sizes from 4 oz to 1.6 oz. For children younger than four years, the EPA
has estimated the average fish meal size to be 3 ounces (85 grams) of cooked
fish fillet. Meal sizes of 3, 4, and 8 ounces are used in Section 3 for children
under four. Discussion of the development of these values is found in Section
4.
Readers may wish to develop fish consumption limits using other meal sizes,
obtained from data on local fish consumption patterns and/or other fish
consumption surveys as appropriate (See Volume 3 of this series). Table 2-4
provides other meal sizes and their associated multipliers. To obtain modified
consumption limits using alternate values for meal size, multiply the existing
consumption limits found in the tables for the 8-oz meal size by the multiplier
associated with the new meal size:
= CRmmaozus • MultiplierMS
where variables are as defined above. If the resultant meal frequency value is
not a whole number, round down to the nearest whole number (See Footnote
8).
EXAMPLE: Modified Meal Size
To modify Table 3-9 to develop values for a 24-oz meal size, multiply the
consumption limits for 8-oz meals in the table by 1/3, or 0.33:
New
-.- = CRm-
nan mmg_oz ^g
0.33
Table 3-9 has been modified to represent consumption limits for general adults
consuming 24 oz (1 1/2 Ib or 0.680 kg) fish meals, shown below as Table 3-
9b. This shows that, for example, while a 70-kg adult could consume nine 8-
oz fish meals contaminated with 0.06 mg chlordane/kg fish, he or she could
only consume three 24-oz meals per month (9 • 1/3 = 3).
Scaling to a different meal size may cause the concentrations of concern to
change substantially. Note, for example, that Table 3-9b only includes values
for meal consumption limits of four meals per month and below for 24 oz
meals, since all meal frequencies listed in the original table (Table 3-9) were
divided by 3 to derive the new meal frequencies. Section 2.3.5 describes the
2-18
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Table 2-4.
Meal Size
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
24
32
Alternative Meal Sizes and Associated Multipliers
(oz)a Multiplier11
8
4
2.67
2.0
1.6
1.33
1.14
1.0
0.89
0.80
0.73
0.67
0.62
0.57
0.53
0.5
0.33
0.25
a Bolded values are those used in the consumption limit tables in Section 3.
b The multiplier is multiplied by the consumption limits associated with eight
ounce meals to obtain new consumption limits using the alternative meal size.
2-19
-------
Table 3-9b. Monthly Consumption for Chronic Systemic Health Endpoints
Chemical Name: Chlordane
Population: General
Body Weight: 70 kg
Reference Dose: 6E-05 mg/kg-d
Detection Limit 1 E— 03 mq/kq
Risk-Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
>2
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
16
14
12
11
5
3
2
2
1
1
1
1
1
0.5
NONE
8
UNLIM
UNLIM
UNLIM
14
11
9
8
7
6
5
2
1
1
1
0.5
0.5
0.5
0.5
0.5 -
NONE
NONE
12
UNLIM
UNLIM
12
9
7
6
5
4
4
3
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
16
UNLIM
14
9
7
5
4
4
3
3
2
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
24
UNLIM
UNLIM
UNLIM
4
3
3
2
2
2
1
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
UNLIM = Unlimited consumption; more than 4 meals per week (1 7/month).
NONE = No consumption; less than six meals per year.
3.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
Mote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
Meal sizes of 4. 8. 12. and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kq.
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
methods used to add meal frequency values to concentration ranges that fall
under unlimited ("UNLIM") or no ("NONE") consumption in the original table for
the 8-oz meal size, but no longer do in the modified table.
In addition, if specific meal consumption limits are desired for consumers ages
four to adult, modifications can be made for both body weight and meal size
using the following equation:
NewCRmm = CRmm • MultiplierBW • MultiplierMS
where the parameters are as defined above.
EXAMPLE: Modified Body Weight and Meal Size
To modify Table 3-9 for a 3-oz meal size for 3 to 6 year olds with an average
body weight of 1 7.4 kg, multiply the values for the 8-oz meal size by 0.25 (the
body weight multiplier; see Table 2-3) and 2.67 (the meal size multiplier; see
Table 2-4):
New CR = CR- 0.25 -2.B7
In this example, the new consumption limits are equivalent to 2/3 of the old
consumption limits. Table 3-9 has been modified to represent consumption
limits for 1 7.4-kg children consuming 3-oz (0.085 kg) fish meals, shown below
as Table 3-9c. For clarity, only the meal frequencies for a 3-oz meal size have
been calculated. This shows that, for example, while a 70-kg adult could
consume nine 8-oz fish meals contaminated with 0.06 mg chlordane/kg fish,
a 1 7.4 kg child could only consume six 3-oz meals per month at the same
contamination level (9 • 0.25 • 2.67 = 6). Again, as noted above, readers will
need to use the methods described in Section 2.3.5 to add meal frequency
values to concentration ranges that fall under unlimited ("UNLIM") or no
("NONE") consumption in the original table for general adults, but no longer do
in the modified table.
2.3.5. Meal Frequency (CRlim)
Readers may wish to add meal frequency values to the consumption limit tables
if 1 ) other modifications to the tables shift the concentrations of concern so
that some values need to be added (See above), 2) multiple modifications to
the tables are required, justifying recalculation of the tables, and/or, 3) different
definitions for unlimited and no consumption are desired for other reasons.
2-21
-------
Table 3-9c. Monthly Consumption for Chronic Systemic Health Endpoints
Chemical Name:
Population:
Body Weight:
Reference Dose:
Detection Limit
Chlordane
Children
17.4kg
6E-05 mg/kg-d
1E-03 mg/kg
Risk-Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
Meal Size
2
3
<0.04
UNLIM
0.04
9
0.05
0.06
0.07
5
0.08
0.09
0.1
3
0.2
0.3
0.5
0.4
0.5
0.5
0.5
•0.5
NONE
A meal size of 3 02 corresponds to 0.085 kg.
JNLIM = Unlimited consumption; more.than 4 meals per week (17/month).
MONE = No consumption; less than six meals per year.
3.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Monthly limits are based on the total dose allowable over a one-month period (based on
tie RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
tote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
All values were rounded down to the nearest whole meal size.
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Recalculating meal frequencies requires the use of Equations 2.1 to 2.3 (See
Section 2.2). These equations are provided here for convenience.
Equation 2.1 is used to calculate daily consumption limits (in kg fish/day) for
carcinogens:
ARL ' BW *+•*><,
- Equation 2.1
*
where:
CR|jm = Maximum allowable fish consumption rate (kg/day),
ARL = Maximum acceptable risk level (unitless),
BW = Consumer body weight (kg),
q1 * = Cancer potency, usually the upper 95 percent confidence limit on
the linear term in the multistage model used by EPA ((mg/kg-d)"1),
and
Cm = Measured concentration of contaminant m in a given species of
fish (mg/kg).
Equation 2.3 is used to calculate daily consumption limits (in kg fish/day) for
noncarcinogens:
BW Equation 2.3
Cm
where:
CRHm = Maximum allowable fish consumption rate (kg/day),
RfD = Reference Dose (mg/kg-d),
BW = Consumer body weight (kg), and,
Cm = Measured concentration of contaminant m in a given species of
fish (mg/kg).
2-23
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Daily consumption rates (in kg fish/day) calculated in Equations 2.1 and 2.3 are
then converted to meals per month using Equation 2.2:
mm
= C/?lim • dylmnth
MS
Equation 2.2
where parameters are defined as above. The resultant meal consumption limits
calculated are then placed at the point in the table where the meal size (and risk
level, if a carcinogen) and the chemical concentration used in the equations
intersect (See Section 3 for illustration).
EXAMPLE: Calculating Meal Consumption limits
The monthly meal consumption limits shown in Table 3-9 include a limit for a
contaminant concentration of 0.07 mg chlordane/kg fish and a meal size of 4
oz (0.114 kg), based on a chronic systemic RfD of 6 x 10~5 mg/kg-d, and a
consumer body weight of 70 kg. Using these values for the parameters in
Equation 2.3 yields a maximum daily consumption rate of 0.060 kg fish/day:
With a meal size of 0.114 kg (4 oz), a consumption rate of 0.060 kg fish/day,
and a time period of one month (expressed as 365.25 days/12 months),
Equation 2.2 yields a meal consumption limit of 16 meals per month, as shown
in Table 3-9, below:
CR
'-'"FTim
0.060 kgld
365"25
12
0.114 kg}meal
= 16 mealslmo
All meal consumption limit modifications may be done in this manner by
substituting the appropriate values into Equations 2.1 to 2.3. Note that while
meal sizes are given in ounces in the tables in Section 3, they need to be
calculated in kilograms in Equations 2.1 to 2.3. The conversion rate from
ounces to kilograms is approximately 1 oz to 0.028 kg, or 1 kg to 35.2 oz.
2-24
-------
Table 3-9. Monthly Consumption for Chronic Systemic Health Endpoints
Chemical Name: Chlordane
Population: General
Body Weight: 70 kg
Reference Dose: 6E-05mg/kg«d
Detection Limit 1 E-03 mg/kg
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
>2
Meai Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
16
14
12
11
5
3
2
2
1
1
1
1
1
0.5
NONE
8
UNLIM
UNLIM
UNLIM
14
11
9
8
7
6
5
2
1
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
12
UNLIM
UNLIM
12
9
7
6
5
4
4
3
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
16 .
UNLIM
14
9
7
5
4
4
3
3
2
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE - No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
All values were rounded down to the nearest whole meal size.
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
2.4. Modification of Consumption limits for Multiple Species, Single Contaminant
Exposure
Equations 2.1 and 2.3 may be modified to calculate consumption limits for
exposure to a single contaminant through consumption of several fish species.
This section describes the modifications required to do so.
Individuals often eat several species of fish in their diets. Equations 2.1 and
2.3, however, are based on contaminant concentrations in single species of
fish. Where multiple species of contaminated fish are consumed by a single
individual, such limits may not be sufficiently protective. If several fish species
are contaminated with the same chemical, then doses from each of these
species must first be summed across all species eaten, in proportion to the
amount which is eaten. This is described by Equation 2.4:
Equation 2.4
where:
Cmj
I
= Total concentration of chemical m in an individual's fish diet,
= Concentration of chemical m in species/ (mg/kg), and,
= Proportion of species/ in the diet (unitless).
Note that this equation requires that the risk assessor know or be able to
estimate the proportion of each fish species in the exposed individual's diet.
Equation 2.4 yields the weighted average contaminant concentration across all
fish species consumed (Ctm), which then may be used in modified versions of
Equations 2.1 to 2.3 to calculate overall and species-specific risk-based
consumption limits (See below).
2.4.1. Carcinogenic Effects
The equation to calculate an overall daily consumption limit based on exposure
to a single carcinogen in a multiple species diet is very similar to Equation 2.1.
However, in place of Cm, which indicates the average chemical concentration
in one species, Equation 2.5 uses the equation for Ctm, the weighted average
chemical concentration across all of the species consumed:
2-26
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
ARL • BW
. Equation 2.5
where:
CR|im = Maximum allowable fish consumption rate (kg/day),
ARL = Maximum acceptable lifetime risk level (unitless),
BW = consumer body weight (kg),
Cmj = Concentration of chemical m in species/ (mg/kg),
Pj = Proportion of a given species in the diet (unitless), and,
Q! = Cancer potency, usually the upper 95 percent confidence limit on
the linear term in the multistage model used by EPA ((mg/kg-d)"1).
The daily consumption limit for each species is then calculated as:
CRj = Cflllm • Pj Equation 2.6
where:
CRj = Consumption rate of fish species/ (kg/day),
CRHm = Maximum allowable fish consumption rate (kg/day), and
Pj = Proportion of a given species in the diet (unitless).
Meal consumption limits may then be calculated for each species as before,
using Equation 2.2 (See Section 2.2), with CRj substituted for CRnm in the
equation. Note that Equation 2.6 may be used before or after Equation 2.2,
with the same results.
2.4.2. Noncarcinogenic Effects
For noncarcinogenic effects, the equation to calculate consumption limits based
on exposure to a single noncarcinogenic chemical in a multiple species diet is
similar to Equation 2.3 for a single species. However, in place of Cm, which
indicates the chemical concentration in one species, Equation 2.7 uses the
equation for Ctm, the weighted average chemical concentration across all of the
species consumed:
2-27
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
CR. = MD ' BW
lim " Equation 2.7
where the parameters are as defined above. The consumption limit for each
species Is then calculated using Equation 2.6. Meal consumption limits for
each species may then be calculated as before, using Equation 2.2.
EXAMPLE: Consumption Limits for Multiple Species, Single Contaminant
Exposure
The combined results from a sampling and analysis program and a local fish
consumption survey determine that local fishers eat a diet of 30 percent catfish
contaminated with 0.006 mg/kg chlordane, and 70 percent trout contaminated
with 0.008 mg/kg chlordane. The RfD for chlordane reported in IRIS is
0.00006 mg/kg-d (IRIS, 1993). Since chlordane causes both chronic and
carcinogenic effects, consumption limits must be calculated for both health
endpoints. The q.,* for chlordane reported in IRIS is 1.3 per mg/kg-d (IRIS,
1993). The average body weight of a general adult is estimated to be 70 kg.
Carcinogenic Effects: Using a risk level of 10~5 and the values specified
above, Equation 2.5 yields a daily consumption rate of 0.073 mg/kg, based on
carcinogenic endpoints:
CR = IP"5 • 70 kg
'Sm
(0.006 mglkg - 0.3 + 0.008 mglkg - 0.7) • 1.3 per mglkg-d
= 0.073
Equation 2.2 is used as before to calculate a meal consumption limit, based on
a meal size of 8 oz (0.227 kg):
0.073 kgfd • 365'25 d/mo
Equation 2.2 yields a meal consumption limit of nine 8-oz meals per month, or
three 8-oz meals per 10 days, based on chlordane's carcinogenicity. Equation
2.6 indicates that two 8-oz catfish meals and six 8-oz trout meals per month
may be consumed without increased risk of developing cancer:
2-28
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
CRcatHsh = 9 meals!mo • 0.3 = 2.7 .* 2 meals/mo
trout = 9 mealslmo • 0.7 = 6.3 * 6 mealslmo
Note that in both cases the meal consumption limits were rounded down. This
is a conservative approach. One might also round up the number of meals of
the species with the lower contaminant concentration, and round down the
number of meals of the species with the higher contaminant concentration, so
that the total number of fish meals per month equals that found in Equation
2.5. In this case, since catfish were less contaminated than trout, the
consumption limit would be three 8-oz catfish meals and six 8-oz trout meals
per month. This approach is based upon the proportion of each type of fish
eaten. If the actual proportion differs from that used in the equation, the
resulting risks may be higher or lower than the targeted risk level (e.g., 10 ~5).
Noncarcinogenic Effects: Equation 2.7 is used to calculate the daily
consumption limit based on chlordane's chronic health effects, using the RfD
rather than the c^ *.
CRm = _ 6 x 10-5 mglkg-d - 70 kg - = Q570
"m 0.006 mglkg - 0.3 + 0.008 mglkg • 0.7
As with carcinogenic effects. Equation 2.2 is used to convert the daily
consumption limit of 0.570 kg fish to a rneal consumption limit:
0.570 kgld
CRmm = - — - = 76.4 = 76
mm 0.227 kg
This analysis indicates that 0.57 kg/d is equivalent to 76 8-oz fish meals per
month, or over two 8-oz fish meals per day under this mixed-species diet. This
is categorized as unlimited consumption ("UNLIM") in the consumption limit
tables in Section 3. Thus, based on the above results, risk managers might
choose to issue a consumption advisory for general adults of two (or three) 8-
oz catfish meals and six 8-oz trout meals per month based on chlordane's
carcinogenic effects, the more sensitive of the two health endpoints, or elect
to base their advisories on non-carcinogenic effects. In addition, they may also
review the toxicity data and develop exposure limits based on their
interpretation of the toxicity data.
2-29
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
2.5. Modification of Consumption Limits for Multiple Contaminant Exposures
Equations 2.5 and 2.7 discussed in Section 2.4 can be further modified to
develop consumption limits for multiple chemical exposures across single or
multiple species. Section 5 and Volume 3 provide additional information on
exposure to multiple chemical contaminants.
Individuals who ingest chemically contaminated fish may be exposed to a
number of different chemicals simultaneously. This could occur when: 1) a
single fish species is contaminated with several different chemicals, 2) an
individual consumes a mixture of species in his or her diet, each contaminated
with a different chemical, or, 3) some combination of the above circumstances
occurs.
Possible toxic interactions in mixtures of chemicals are usually placed in one of
three categories:
• Antagonistic, where the chemical mixture exhibits less toxicity than the
chemicals considered individually,
• Synergistic, where the chemical mixture is more toxic than the sum of
the individual toxicities of the chemicals in the mixture, and
• Additive, where the toxicity of the chemical mixture is equal to the sum
of the toxicities of the individual chemicals in the mixture.
Using available data is especially important in cases where mixtures exhibit
synergistic interactions, thereby increasing toxicity. Very little data are
available on the toxic interactions between multiple chemicals, however, and
no quantitative data on interactions between any of the target analytes
considered in this document were located. Some qualitative information is
provided in Section 5.
In cases where all of the chemicals in a mixture induce the same health effect
by similar modes of action (e.g., cholinesterase inhibition), contaminants may
be assumed to contribute additively to risk (EPA, 1986d), unless specific data
indicate otherwise. Chemicals in a particular class (e.g., organochlorine or
organophosphate pesticides) usually have similar mechanisms of toxicity and
produce similar effects. Effects of chemicals and chemical groups are
discussed in more detail in Section 5. For mixtures of chemicals that cause
similar endpoints, consumption limits are derived by summing the contaminants
from all fish species consumed, as discussed below.
2-30
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Some chemical mixtures may contain chemicals that cause dissimilar health
effects. Methods currently do not exist for combining dissimilar health effects
to characterize overall health concerns from chemical mixtures. Instead, the
risks from these contaminants need to be characterized and presented
separately. It is important to review the overall toxicity of a contaminant in
evaluating combined risks because most contaminants are capable of causing
multiple effects in numerous organ systems at elevated exposures.
2.5.1. Carcinogenic Effects
Cancer evaluations and q., *s for most carcinogens are based on animal studies,
which are not generally assumed to predict the site of cancer in humans.
Consequently, carcinogenic effects are not usually categorized by the cancer
site observed in animal studies. Rather, carcinogenic effects are generally
assumed to be additive, unless data derived from human studies show them to
be otherwise. Carcinogenic effects for the 12 carcinogens considered in this
guidance series are assumed to be additive.
Equation 2.8 can be used to calculate daily consumption limits for chemical
mixtures of carcinogens in single or multiple fish species. It is similar to
Equation 2.1, with the summation of all species and all chemicals substituted
for Cm in the denominator:
CR = ARL ' BW
lim - '» x Equation 2.8
" m
m=i \j=i /
where:
CR|im = Maximum allowable fish consumption rate (kg/day),
ARL = Maximum acceptable lifetime risk level (unitless),
BW = Consumer body weight (kg),
Cmj- = Concentration of chemical m in species/ (mg/kg),
PJ = Proportion of a given species in the diet (unitless), and,
q., * = Cancer potency, usually the upper 95 percent confidence limit on
the linear term in the multistage model used by EPA ((mg/kg-d)"1),
2-31
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Meal consumption limits for mixtures of carcinogens are then calculated using
Equation 2.2, as above. When only one fish species is involved. Equation 2.8
may be simplified to Equation 2.9, shown below:
ARL - BW
X
YC
f-^i m
m=1
Equation 2.9
m
where the variables are as defined above.
2.5.2. Noncarcinogenic Effects
Equation 2.10, used to calculate daily consumption limits for noncarcinogenic
chemical mixtures in single or multiple fish species, is similar to Equation 2.3,
with the summation of all species and all chemicals assumed to act additively
substituted for
numerator:
Cm in the denominator, and their respective RfDs in the
x
£
m=1
BW
Equation 2.10
where the parameters are defined as above. Meal consumption limits are then
calculated using Equation 2.2, as above. Again, when only one fish species is
involved. Equation 2.10 can be simplified to Equation 2.11, shown below:
m
BW
Equation 2.11
where the variables are as defined above. Note that Equations 2.10 and 2.11
may not be used for contaminants causing dissimilar health effects.
EXAMPLE: Consumption Limits for Single Species, Multiple Contaminant Exposure
A single fish species is contaminated with 0.04 mg chlordane/kg and 0.01 mg
heptachlor epoxide/kg. A maximum acceptable risk level of 10~5 and a general
adult body weight of 70 kg are used. Because chlordane and heptachlor
epoxide cause both carcinogenic and chronic systemic health effects, both
health endpoints must be considered in establishing consumption limits for
these chemicals.
2-32
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Carcinogenic:
The q1 * for chlordane reported in IRIS is 1 .3 per mg/kg-d (IRIS, 1 993). The q1 *
for heptachlor epoxide reported in IRIS is 9.1 per mg/kg-d (IRIS, 1993).
Equation 2.9 is used to calculate daily consumption limits based on the
combined carcinogenic effects of both contaminants:
CR,m = - 10 '70 - = 0.005 kgfd
"m (0.04 -1.3) +(0.01 -9.1) y
A daily consumption limit of 0.005 kg fish per day is calculated. Using
Equation 2.2, this daily consumption limit is converted to a meal consumption
limit of one 4-oz meal per month (or six 8-oz meals per year).
Noncarcinogenic:
Chlordane and heptachlor10 are both organochlorine pesticides and cause
many similar noncarcinogenic effects. Adverse liver effects formed the basis
of the RfDs for both chemicals (IRIS, 1993). A combined daily consumption
limit based on an RfD of 6 x 10~5 mg/kg-d for chlordane and 1 .3 x 10~5 mg/kg-
d for heptachlor was calculated using Equation 2.1 1 :
mglkg-d 1.3 xlO"5 mglkg-d .
Equation 2.1 1 yields a daily consumption rate of 0.2 kg fish per day, at the
contaminant concentrations described above. Using Equation 2.2, a meal
consumption limit of 26 meals per month is calculated. This meal frequency
falls under unlimited consumption ("UNLIM") in the consumption limit tables in
Section 3.
Therefore, based on the carcinogenic and chronic systemic consumption limits
calculated for combined heptachlor epoxide and chlordane contamination, a risk
manager may choose to advise 1 ) limiting fish consumption to six 8-oz meals
10 Heptachlor epoxide is a metabolite of heptachlor, a pesticide. When
heptachlor is released into~the environment, it quickly breaks down into
heptachlor epoxide. Therefore, the toxicity values used in this document are
for heptachlor epoxide, not heptachlor (See Chapter 5).
2-33
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
per year, based on the combined carcinogenic effects, or 2) unlimited
consumption, based on non-carcinogenic effects.11
2.5.3. Species-Specific Consumption Limits in a Multiple Species Diet
To calculate the risk-based consumption limits for each species in a multiple
species diet the following equation is used for both carcinogenic and non-
carcinogenic toxicity:
CR, = CR{im ' Pj Equation 2.6
where the variables are as defined above. CRjjm is calculated using Equations
2.8 or 2.10, for carcinogenic and non-carcinogenic toxicity respectively. As
with the consumption limits for single chemicals, these consumption limits are
only valid if the assumed mix of species in the diet is correct, and if the
contaminant concentrations in each species are accurate.
EXAMPLE: Consumption Limits for Multiple Contaminant, Multiple Species Exposure
Chlorpyrifos and carbophenothion both cause cholinesterase inhibition, so are
considered together when developing meal consumption limits. The RfD for
Chlorpyrifos reported in IRIS is 0.003 mg/kg-d (IRIS, 1993), while the RfD for
carbophenothion is 0.00013 mg/kg-d (IRIS, 1993).
A local fish consumption survey reveals that adult fishers consume trout and
catfish at a ratio of 70:30, respectively. A sampling and analysis program
reports Chlorpyrifos and carbophenothion contamination in both species. Trout
are contaminated with 4.0 mg/kg chlorpyrifos/kg fillet and 0.3 mg
carbophenothion/kg fillet. Catfish are contaminated with 6.0 mg
chlorpyrifos/kg fillet and 0.8 mg carbophenothion/kg fillet. Given a general
adult body weight of 70 kg, a risk-based consumption limit of 0.065 kg fish per
day is calculated using Equation 2.10:
°-003 °-00013 ^70=0.065*07
kO - 0.7) + (6.0 • 0.3) (0.3 • 0.7) + (0.8 • 0.3)
11 In addition, risk assessors or risk managers may also elect to use a third
health endpoint (e.g., developmental toxicity), based on their review of the
toxicological data.
2-34
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
Using Equation 2.2, a meal consumption limit of eight 8-oz meals per month is
derived. Note that if chlorpyrifos and carlbophenothion did not cause the same
health endpoint, then separate meal consumption limits would have to be
calculated for each as described in Section 2.4.2, with the more protective
meal consumption limit usually serving as the basis for a fish consumption
advisory (See Section 2.5.4).
Equation 2.6 is used to determine meal consumption limits for trout and catfish,
based on a diet of 70 percent trout and 30 percent catfish:
= 8 B-oz meals/mo • 0.7 = 5.6 » 5 8-oz mealslmo
CRcatfjsh = 8 8-oz meals/mo • 0.3 = 2.4 * 2 8-oz mealslmo
According to Equation 2.6, a general adult may safely consume five 8-oz meals
of trout per month and two 8-oz meals of catfish per month. Again, as
mentioned in Section 2.4.2, rounding down both species-specific consumption
limits is a conservative approach. One might also round up the number of
meals of the species with the lower contaminant concentration, and round
down the number of meals of the species with the higher contaminant
concentration, so that the total number of fish meals per month equals that
found in Equation 2.10. In this case, since trout were less contaminated than
catfish, the species-specific consumption limit would be six 8-oz trout meals
and two 8-oz catfish meals per month.
2.6. Choice of Consumption Limits
Where chemicals found in a given species cause dissimilar health effects, dose
addition is not often justified scientifically; if dose addition is used in these
cases, it must be supported by biological plausibility (EPA, 1986d). Thus, in
most cases where chemicals cause different effects, readers are advised to use
the consumption limits for the contaminant that results in the most protective
fish consumption advisory for the population of concern. This approach may
result in different advisories for each subpopulation of concern, since different
subpopulations may have varying health effects of concern. It is important to
compare the consumption limits calculated for all chemicals found in a given
species and choose the most appropriate consumption limits for each consumer
population. This selection may be considered a risk management decision or
a medical/toxicological decision.
If, for example, local sampling and analysis programs and fish consumption
surveys determine that consumers are exposed to all four of the contaminants
2-35
-------
2. DEVELOPMENT AND USE OF RISK-BASED CONSUMPTION LIMITS
discussed in the above examples (chlordane, heptachlor epoxide, chlorpyrifos
and carbophenothion), then risk assessors could consider a number of separate
fish consumption limits for the chemical mixture:
• A consumption limit could be based on the combined carcinogenic
effects of chlordane and heptachlor epoxide, as described in the first
example above,
• A consumption limit could be based on chronic liver damage caused by
exposure to the chlordane and heptachlor, as shown in the first example
above,
• A consumption limit could be developed for the chronic health effect
(cholinesterase inhibition) caused by exposure to both chlorpyrifos and
carbophenothion, as shown in the second example above, and
• Consumption limits could be based on new study data reviewed by
readers (e.g., xenoestrogenic effects of organochlorines, or
developmental effects), using the equations provided in this
document.12
Readers might then base fish consumption advisories for this particular
chemical mixture on the most appropriate of the consumption limits for each
population of concern. Decisions regarding selection and implementation of
consumption limits will be discussed in Volume 3 of this series.
Most fish contaminants have the potential to cause multiple adverse health
effects, given sufficiently-high exposure levels. Readers are advised to examine
the chemical profiles in Section 5 to determine the most appropriate health
endpoints on which to base fish consumption limits. Many of the chronic RfDs
for organophosphates, for example, are currently based on cholinesterase
inhibition as the critical health endpoint of concern. However, the EPA's
Scientific Advisory Board recently raised concerns about using cholinesterase
inhibition as a critical endpoint in the absence of clinical symptoms (EPA,
1993q; see Section 5 for further discussion). For those who wish to calculate
alternative exposure limits for these or other fish contaminants for use in
developing alternative consumption limits, Section 5 provides a summary of
current EPA methods for doing so and sources of additional guidance.
12 Intake limits based on developmental or other effects can be calculated
using the same equations as are used for chronic health endpoints throughout
Section 2.
2-36
<|
-------
i auie — . ivionmiy ^/onsumption
Chemical Name:
Population:
Body Weight:
Reference Dose:
Detection Limit
ror unronic oysTemic neaim tnc
jpoints
7
kg
mg/kg-d
mq/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kg)
.
r
1
Meal Size
(02)
-------
IS
£
S
TJ
TO
t«
O Q
g
N
55
•g
o
o
fa
&2'§
i
-------
3. RISK-BASED CONSUMPTION LIMIT TABLES
SECTION 3
RISK-BASED CONSUMPTION LIMIT TABLES
3.1. Overview and Section Organization
This section provides consumption limit tables for chronic and carcinogenic
health endpoints for the general adult population, and chronic health endpoints
for young children for each of the 23 chemical analytes listed in Section 1. In
addition, consumption limit tables based on developmental effects associated
with exposure to methylmercury are included for women of reproductive age
and children. The consumption limits in these tables were calculated using
Equations 2.1 to 2.3 and the default values for each of the variables described
in Sections 2.2 and 2.3.
Variables involved in calculating the consumption limits include fish meal size,
consumer body weight, contaminant concentration, and maximum acceptable
risk level (for carcinogenic health endpoints).1 Default values for these
variables are listed in Section 2 and described further in Section 4.
Current EPA risk values (cancer potency factors and RfDs) were also used in
the consumption limit calculations, as described in Section 2.2 and Section 5.
Because there are new toxicity data for some target analytes not reflected in
the current RfDs, readers are encouraged to review Section 5.6, which contains
a summary of toxicity data for the target analytes. Methods for using this
information to generate additional consumption limits are discussed in Section
5.3 and 5.4.
Most target analytes are known to cause multiple effects at elevated exposure
levels, according to the results of animal studies. However, because the levels
of fish contaminants typically ingested by non-commercial fish consumers are
lower than those used in animal studies, consumers may experience only one
or a few of the known chronic effects, and/or only the more susceptible
1 Three maximum acceptable risk levels are offered as options in the
consumption limit tables. Selection of the most appropriate risk level is a risk
management decision to be made at the state, local or tribal level and is
discussed in Volume 3.
3-1
-------
3. RISK-BASED CONSUMPTION LIMIT TABLES
members of the population may develop the health endpoints of concern. For
example, analytes which cause developmental toxicity pose risk to children and
women who are having or are expecting to have children (See Section 5 for
discussion). Readers are advised to consider these data in reviewing the
consumption limit tables and the toxicity discussions in Section 5.
Alternatively, some effects are of concern to all exposed individuals. For
example, women of reproductive age do not necessarily develop cancer or
chronic exposure health effects at different rates than others in the general
population. Consequently, the consumption limit tables for carcinogenic and
chronic exposure toxicity for the general population are also applicable to this
subgroup.
Monthly consumption limits were developed for carcinogenic health endpoints,
while ten-day and monthly consumption limit tables were derived for chronic
exposure health endpoints. Both the 10-day and the monthly consumption limit
tables are based on the same chronic reference doses because there are not
currently reference doses for acute health endpoints available from the EPA
RfD/RfC Workgroup (See Section 5). Ten-day consumption limits for chronic
exposure health endpoints apply to short-term recreational and subsistence
fishers, while monthly consumption limits pertain to both seasonal (e.g., three-
month) and year-round non-commercial fish consumers.
Ten-day consumption limit tables for chronic health endpoints were developed
for both adults and children, while monthly consumption limit tables were
developed for general adults only. Monthly consumption limit tables were not
calculated for children because, for example, the lower limit of allowable
consumption (i.e., six meals per year) represents sixty times the RfD, based on
the methodology used in this document (See Section 4 for discussion). This
was not considered appropriate. If it is anticipated that children's exposure will
occur over an extended period of time, readers may use the ten-day limits for
longer periods by adding time increments as appropriate. Alternatively, readers
may wish to calculate consumption limits for children based on developmental
toxicity data discussed in Chapter 5 for some of the target analytes. Chapter
5 also contains a description of a methodology which can be used to derive
risk-based consumption limits for developmental and other toxicities.
Each consumption table lists, by chemical and fisher population, the maximum
fish meals per unit time that may be safely eaten by the population of concern.
Limits are given for a range of fish meal sizes, population members (adults and
children), and contaminant levels. In addition, for carcinogens, limits are
f\
Note that women of reproductive age are defined as a separate
population only for health intake limits based on developmental health effects.
3-2
-------
3. RISK-BASED CONSUMPTION LIMIT TABLES
provided for a range of maximum acceptable risk levels. Readers may use
these tables by: 1) determining the chemical concentration found in local
sampling and analysis programs, 2) determining the meal size (and risk level,
for carcinogens) they wish to use, 3) locating the point where the parameters
intersect, and, 4) reading the value for maximum safe number of meals per
month that may be eaten for each contaminant, based on its reference dose
and/or cancer potency value. All consumption limits have been rounded down
to the nearest integer, with the exception of the limits of six meals per year,
which are expressed as 0.5 meals per month in the tables.
Some of the contaminant concentrations in the tables are below current
laboratory detection limits. Because of improvements in technology, however,
chemical detection limits regularly decrease. The concentrations which are
currently below the detection limits are provided so that risk managers may use
them once detection is possible. Current detection limits are listed at the top
of each of the consumption tables.
For the purposes of this document, unlimited safe fish consumption
(represented by "UNLIM" in the tables) has been defined as a consumption limit
of more than 17 fish meals per month (four fish meals per week) for the
monthly consumption limit tables, and more than one meal per day for the 10-
day tables.3 The definition of no safe fish consumption used in this document
(represented by "NONE" in the tables) is a consumption limit of less than one
meal in two months for the monthly tables, and less than one meal per 10 days
for the 10-day tables.4 These definitions do not represent EPA
recommendations. Rather, it is the responsibility of risk managers to define
"unlimited" and "no" fish consumption, based on a variety of considerations,
including adverse health effects and the consumption patterns of the
populations of interest. Note that the chemical concentrations listed are only
those that fall in between these two parameters, and that they are not listed
in a linear fashion. Directions for calculating other meal frequencies not found
in the tables are given in Section 2.
3 i.e., in the case of the monthly consumption limits, where risk
calculations indicate that more than 17 meals per month may be eaten without
incurring undue risk of cancer or developing adverse chronic health effects, risk
managers may choose to not advise restricting consumption of non-commercial
fish.
4 i.e., under the definition of no consumption for the monthly tables, where
risk calculations indicate that six fish meals per year may not be safely eaten,
risk managers may choose to advise zero consumption of contaminated non-
commercial fish.
3-3
-------
3. RISK-BASED CONSUMPTION LIMIT TABLES
Specific guidance regarding the use of these limits in a fish advisory program
will be provided in Volume 3: Risk Management. Readers are encouraged to
review this and the other documents in the series regarding selection of
consumption limits for their fish advisory programs. Fish advisories involve
many factors that are not represented in these tables, including societal,
economic, nutritional, and cultural impacts. These factors are discussed in
Volume 3.
3.2. Consumption Limit Tables
Table 3-1 provides a directory of the consumption limits given in Section 3.
Readers using the tables as a basis for fish consumption advisories should note
that the values given in the tables are valid only for single contaminants in
single species diets. Section 2 describes the use of the tables to calculate
consumption limits for multiple contaminants and multiple species diets.
3-4
-------
TO
C
O
+5
O
0)
CO
c
TJ
CD
C
>+-•
O
O
CO
•^
CO
1 —
T
CD
2
<5
Q
E
ZJ
Z
_CD
f-
**—
0
n
o
""5
o
o
75
o
"E
JC
O
8V
^— fZ.
TJ.Q
o
* JS 0
c "5 g
CL "?5
° «j
0
o>
TO
-H- <
•1
O TO *•>,
C C -p
Q) "C ^
E 5 o
O J2 •«;
s£ 32
lc
c ^
l_ -^ ™
CD (0 ;Jj
III
DL "^
0)
TO
H— ^^
O O) >
c .E «
CD >= Q
E m 1
o .a o
5 2 T~
6
c _
75 .° £
0> "0$ Q
Jfi
CL "•"
«
•2 '""""
CO O
Q c
>» c
-•= o
O-^—
++
l&
"c
ns
as
•§•*
O
O
TO
TO
TO
CM
1
TO
T™
CM
co"
in"
|| Cadmium
TO
CO
TO
IO
1
TO
CM
t—
CD"
in
c
o
Carbofenot
T—
1
TO
O
T
TO
0)
TO
00
1
TO
T-;
CO
IO
|| Chlordane
^
i—
\
TO
.,
TO
T
TO
CM
T
TO
TO
CD
IO
en
U Chlorpyrifo!
00
T
TO
N
T
TO
(O
T
TO
IO
T—
1
TO
CM
CO
in
ill
Q
Q
b"
Q
Q
Q
CM
1
TO
O
CM
1
TO
O
T
TO
*
co"
in"
1 Diazinon
in
CM
1
TO
CM
1
TO
TO
CM
1
TO
,
CM
CM
1
TO
TO
CD
m
"o
o
b
en
CM
1
TO
CO
CM
1
TO
CM
1
TO
CO
CM
1
TO
*
CD
in
Dieldrin
o
TO
1
TO
O
CM
co"
10"
c
'x
o
b
TO
TO
1
TO
CM
TO
1
TO
TO
1
TO
IO
T—
CO
IO
I Disulfoton
(O
TO
1
TO
IO
TO
1
TO
TO
1
TO
iq
CD
IO
=.
|| Endosulfan
o>
TO
1
TO
CO
TO
1
TO
TO
1
TO
CO
CD
in
c
~
c
LU
CM
1
TO
f
5
1
TO
O
1
TO
CD
CD
10"
C
.O
m
(O
1
TO
IO
1
TO
^
1
TO
TO
1
TO
^
CD
IO
CD
"x
O
Q.
LU
|| Heptachlor
C)
10
1
TO
O)
1
TO
CC)
1
TO
N.
1
TO
CC|
CO
IO
OJi
c;
CO
m
.0
CO
CO
O
Q.
h-
1
TO
TO
1
TO
CM
N-
1
TO
TO
CM
CD
m
|| Selenium
^^
^^
1
TO
(O
1*-
1
TO
IO
1
TO
T—
(O
IO
||Terbufos
oo
1
TO
O
00
1
TO
cn
1
TO
CO
1
TO
T—
T—
CO
in
iToxaphene
m
CM
l_
o
o
2
c
0
TJ
CD
CO
o
. w
co —
0) CO
— CQ
To O
** O.
CD ,_
Wn
o
TJ
c 'o 9
*""" "S3 ^J
»o ®
IK C
« o c
LJ t- CD
S 'S~ ®
C3 o
TJ m
C r-J >
CO g CO
0) CM -C
h ~<-r- co
o-i- -t:
0) ~~ ^—
^ 2 "CD
o"^ "«> "%
_. f~\ r*.
® O ••- C
<» TJ ^ £1
TJ fj) .O £
Q CO C »
Hi CO o CD
O- CD o O
LU CO r C
>» co ® -ir
-Q CO ;=- ~
TJ Q .C
CD Q. .-K 5
T '*- •— n
° "x ^> £
S •&* -2 "o w
TJ ;s .0 •>< ^
1 Illl
£ n c g ^
w "2 2 E S
-Q 2 o §• S
!|§!!
O CD "O TJ -rj
*= J«i CD CD m
U CO CO CO 4S
CD 1± CO CO JS
CO i CD CD jjj
cs ^3 -a « CO
-------
Table 3-2. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Cadmium
Population: General
Body Weight: 70 kg
Reference Dose: 0.001 mg/kg-d
Detection Limit: 0.005 mq/kq
Risk-Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.2
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
>10
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
8
7
6
6
3
2
1
1
1
NONE
8
UNLIM
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
12
UNLIM
10
6
5
4
3
2
2
2
2
1
NONE
NONE
NONE
NONE
NONE
16
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
MONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Mote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period (based on the
3(0). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
AH values were rounded down to the nearest whole meal size.
-------
Table 3-3. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Cadmium
Population: General
Body Weight: 70kg
Reference Dose: 0.001 mg/kg-d
Detection Limit 0.005 mq/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kcj)
<0.3
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5.
6
7
8
9
10
20
30
40
>40
Meal Size
(oz)
4 8 12
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
0.5
0.5
0.5
NONE
UNLIM
UNLIM
UNLIM
UNLIM
15
13
11
10
9
4
3
2
1
1
1
1
1
0.5
NONE
NONE
NONE
NONE
UNLIM
UNLIM
15
12
10
8
7
6
6
3
2
1
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
16
UNLIM
15
11
9
7
6
5
5
4
2
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (1 7/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-4. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Cadmium
Population: Children
Body Weight: 14.5kg
Reference Dose: 0.001 mg/kg-d
Detection Limits: 0.005 ma/kq
Risk-Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kg)
<0.06
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
>3
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
8
5
4
3
2
2
2
1
1
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
6
4
3
2
2
1
1
1
1
NONE
NONE
NONE
8
UNLIM
10
9
7
7
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0,227 kg.
JNLIM = Unlimited consumption; more than 1 meal/day.
VJONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
^Jote that some values may be below detection limits.
^ote nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period
Dased on the RfD). When this dose is delivered in less than 10 days (e.g.,
In a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size
-------
Table 3-5. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Carbophenothion
Population: General '
Body Weight: 70kg
Reference Dose: 1 E - 04 mg/kg - d
Detection Limit: 1 E-03 mq/kg_
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
fmg/kg)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
>1
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
10
8
6
5
5
4
4
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
8
6
5
4
3
3
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
10
6
5
4
3
2
2
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-6. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Carbophenothion
Population: General
Body Weight: 70 kg
Reference Dose: 1 E- 04 mg/kg - d
Detection Limit: 1 E-03 ma/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mci/ka)
<0.04
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
>4
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
13
8
6
4
4
3
3
2
2
1
0.5
0.5 .
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
17
15
13
12
6
4
3
2
2
1
1
1
1
0.5
NONE
NONE
NONE
12
UNLIM
UNLIM
16
13
11
10
9
8
4
2
2
1
1
1
1
0.5
0.5
NONE
NONE
NONE
NONE
16
UNLIM
15
12
10
8
7
6
6
3
2
1
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
JNLIM = Unlimited consumption; more than 4 meals per week (17/month).
^JONE = No consumption; less than six meals per year.
).5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
slote that some values may be below detection limits.
vlote nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size
-------
Table 3—7. 10— Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Carbophenothion
Population: Children
Body Weight: 14.5kg
Reference Dose: 1E-04mg/kg-d
Detection Limits: 1 E-03 mq/kq
Risk- Based Consumption Limit (meals per 1 0 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.008
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
>0.4
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
7
5
4
3
3
2
2
2
1
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
8
5
4
3
2
2
2
1
1
NONE
NONE
NONE
NONE
8
UNLIM
10
9
8
4
2
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten -day limits are based on the total dose allowable over a 1 0-day period
based on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—8. 10— Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: fChlordane
Population: General
Body Weight: . 70kg
Reference Dose: 6E-05 mg/kg-d
Detection Limit: 1 E-03 mq/kq
Risk- Based Consumption Limit (meals per 1 0 days)
Chemical Concentration
Found in Sampling and
Analysis Program
fmq/kq}
<0.009
0.009
0.01
0,02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
>0.7
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
7
6
5
4
4
3
1
1
NONE
NONE
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
6
4
3
2
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
10
9
4
3
2
1
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Mote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period (based on the
RfD). When this dose is delivered in less than 1 0 clays (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—9. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Chlordane
Population: General
Body Weight 70kg
Reference Dose: 6E-05mg/kg-d
Detection Limit 1E-03 ma/kg
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/ka)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
>2
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
16
14
12
11
5
3
2
2
1
1
1
1
1
0.5
NONE
8 12
UNLIM
UNLIM
UNLIM
14
11
9
8
7
6
5
2
1
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
UNLIM
UNLIM
12
9
7
6
5
4
4
3
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
16
UNLIM
14
9
7
5
4
4
3
3
2
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
s
3
5
IT
cy
tt
Chi mica] Na
Population:
BodyWUght:
Cnnctr Po
D«t«
'i
O)
c £ ,
3«g:
II-
li
5!
fH
•
,.2
ozOw'S'S'o — "OE
-------
Table 3-11 . 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Chlordane
Population: Children
Body Weight: 14.5kg
Reference Dose: 6E-05 mg/kg-d
Detection Limits: 1 E-03 mg/ka
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kq)
<0.004
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
>0.2
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
5
3
2
2
1
1
1
1
1
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
> NONE
NONE
NONE
8
UNLIM
9
7
6
5
4
4
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 10 clays.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period
based on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-12. 1 0-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Chlorpyrifos
Population: General
Body Weight: 70 kg
Reference Dose: 3E-03 mg/kg-d
Detection Limit: 3E-03 mg/kg
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kd)
<0.5
0.5
0.6
0.7
0.8
0.9 '
1
2
3
4
5
6
7
8
9
10
20
30
>30
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
NONE
NONE
NONE
8 I 12
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
4
3
2
1
1
1
1
1
NONE
NONE
NONE
NONE
UNLIM
UNLIM
10
8
7
6
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
9
7
6
5
5
4
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
AH values were rounded down to the nearest whole meal size.
-------
Table 3—13. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Chlorpyrifos
Population: General
Body Weight 70
Reference Dose: 3E-03 mg/kg— d
Detection Limit: 3E-03 mg/kg
Risk- Based Consumption Limit (rneals per month)
Chemical Concentration
Found in Sampling and
Analysis Program •
(mg/kq)
<0.8
0.8
0.9
1
2
3
4
5
6
7
8
9
10
20
30
40
50
>50
Meal Size
(kg)
4,8
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
14
11
9
8
7
6
5
2
1
1
1
NONE
UNLIM
UNLIM
UNLIM
UNLIM
14
9
7
5
4
4
3
3
2
1
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
NONE
NONE
NONE
NONE
NONE
16
UNLIM
17
15
14
7
4
3
2
2
2
1 .
1
1
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (1 7/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest wholes meal size.
-------
Table 3-14. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Chlorpyrifos
Population: Children
Body Weight: 14.5kg
Reference Dose: 3E-03 mg/kg-d
Detection Limits: 3E-03 mq/kq
Risk— Based Consum
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.2
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
>10
ption Limit (meals per 1 0 days)
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
10
8
7
6
5
5
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
9
7
6
5
4
4
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
8
UNLIM
9
6
4
3
3
2
2
2
1
NONE
- NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
JNUM = Unlimited consumption; more than 1 meal/day.
^JONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
vlote that some values may be below detection limits.
vlote nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period
Dased on the RfD). When this dose is delivered in less than 1 0 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-15. 10-Day Consumption Limits for Chronic Systemic Health Ertdpoints
Chemical Name: DDT/DDE/DDD
Population: General
Body Weight: 70kg
Reference Dose: 5E-04 mg/kg-d
Detection Limit: 1 E-04 mg/kg
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kg)
<0.08
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5 '
6
>6
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLM
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE .
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
10
5
3
2
2
1
1
1
1
1
NONE
NONE
NONE
JSJONE
NONE
NONE
16
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0. 1 14, 0.227, 0.341 , and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-16. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: DDT/DDE/DDD
Fisher Population: General
Fisher Body Weight: 70kg
Reference Dose: 5E-04mg/kg-d
Detection Limit: 1 E-04 mq/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
>10
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
15
13
11 .
10
9
4
3
2
1
1
1
1
1
0.5
NONE
8
UNLIM
UNLIM
15
11
9
7
6
5
5
4
2
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
12
UNLIM
15
10
7
6
5
4
3
3
3
1
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
16
UNLIM
11
7
5
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
JNLIM = Unlimited consumption; more than 4 meals per week (17/month).
MONE = No consumption; less than six meals per year.
3.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
vlote that some values may be below detection limits.
vjote nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
m
c
'5
Q.
TJ
c
LU
ID
O
'c
0)
O)
g
e
s.
ss
E
c
'a.
1
8
>,
^
o
*«.
co
0)
j§
TJ
D>
§ la
QH ^
H S ••- •*
8. <5 a>o o
1- c Je 1 I
Q » 0 HI 111
a O N. co -^-
hemical Name:
opulation:
ody Weight
ancer Potency Factor .
etection Limits:
u a. m u Q
s per month]
•o
?
£
.t;
I
Q.
i
fi
TJ
0)
1
^
m
ir
"N
Q
&
CO
•5
0>
i
Chemical Concentration
0
I
o
1
o
V
o
3
D
1
b
r-
D
1
5
z
UNLIM
S
^
D
UNLIM
UNLIM
UNLIM
UNLIM
?
_i
z
2
3
ZJ
D
-I
D
S
2
3
0.0008
V
r^
i
Z
s
2j
3
2
_J
z
3
2
Zi
rj
i
z
2
_i
z
?
_l
z
2
z
3
ZJ
D
ZJ
Z>
2
Z
3
i
3
O
m
2
_i
ID
S
3
2
n
z>
s
rs
Z)
i
z
3
S
_l
3
?
_j
Z
2
Z
z
3
Zi
13
2
Z
3
D
O
O
(O
s
_J
3
1
3
en
5
Z
1
z
D
CO
?
_l
z
S
Z
2
D
=i
^3
S
•z.
3
N
O
O
O
n
•s.
_l
z
D
2
Z
D
Tf
S
Z
2
_i
D
(O
•5
_l
3
2
Z
CO
Zi
D
2
z
1-
o
0
o
CM
i
Z
s
z
CO
S
_i
3
S
_1
z
u
1-
•^
Zi
U
2
_i
3
CD
Z
Z)
2
z
CD
o
0
0
Tr-
N.
•s.
z
CM
2
_1
3
S
_1
Z
CO
•s
ZJ
U
s
_l
3
Z
Z)
2
z
10
_1
z
Z)
2
_1
13
0
o
in
o"
(D
2
z
U)
o"
en
2
Zi
Z
-
co
•s.
z
CM
_1
Z
3
2
z
CM
0
o
HJ
o
CO
s
— i
3
LU
0
•f
2
Zi
Z
m
o
CO
S
•z.
•r~
co
•s.
•z.
13
S
o
HI
z
CM
S
— ;
D
til
0
co
2
Zi
Z
HI
Z
z
*
2
z
10
o
en
S
Z
3
(0
o
O
Ul
O
-
Ul
0
CM
^
Zi
Z
D
Ul
O
co
S
z
!
111
Z
Z
•"
D
Z
M
.S
J
^
•3
CM
O
UJ
Z
HI
O
CO
HI
Z
HI
O
1-
HI
Z
z
in
o"
(0
Z
z
*-
•f
0
uj
z
H!
O
CM
HI
Z
HI
O
CO
HI
O
D
•»
D
in
o
en
(O
o
HI
Z
HI
O
HI
O
HI
O
CM
u
o
z
Z
Z
CO
Z
Z
Z
Z
(O
co
0
H
O
Z
HI
O
HI
O
HI
O
*-
HI
D
Z
Z
z
CM
§
Z
z
in
••-
H
O
HI
\
in
o
HI
O
HI
Z
in
o"
HI
3
Z
D
\
\
CM
CM
UJ
o
z
HI
o
HI
Z
HI
O
HI
Z
HI
Z
Ul
|
z
z
o
Z
z
TC
UJ
o
HI
O
Ul
O
HI
O
HI
O
HI
D
HI
\
Z
z
HI
z
z
z
•z.
d
to
u
c
H
C
Ul
o
HI
C
Ul
0
HI
D
HI
Z
D
Z
HI
Z
D
Z
z
HI
Z
CO
A
ri)
J£
t
in
2t S
II .1
T-"S "> "
5 £ c ,5
co C- o m
° -g '•§ -S
£ [ I to "H S
CM * - § »
°-s.ig ii s
- -S §. ^ « a £
5 S s S c • 1 1
° E n.g>T2-g| £
3 c o S g | -B » |
g 11 S-S-f J5 s S
sssSSi-sss
eal sizes of 4, 8, 1 2, and 1 6 oz. cori
MLIM = Unlimited consumption; me
ONE = No consumption; less than
5 meals per month represents six rr
eferences for cancer potency factor
structions for modifying the variable
ote that some values may be below
ote nonlinear scale of concentration
I values were rounded down to the
ARL = Acceptable Risk Level
Sr>Zoir.£zz<.
-------
Table 3-18. 1 0-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: DDT/DDE/DDD
Population: Children
Body Weight: 14.5kg
Reference Dose: 5E-04
Detection Limits: 1 E-04 mq/kq
Risk— Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.03
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
>1
Meal Size
(oz)
3 48
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
8
4
2
2
1
1
1
1
. NONE
NONE
NONE
UNLIM
UNLIM
UNLIM
UNLIM
10
9
7
7
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
JNLIM = Unlimited consumption; more than 1 meal/day.
^JONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Mote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
Tep-day limits are based on the total dose allowable over a 1 0-day period
aased on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—19. 1 0— Day Consumption Limits? for Chronic Systemic Health Endpornts
Chemical Name: Diazinon
Population: General
Body Weight: 70 kg
Reference Dose: 9E-05 mg/kg-d
Detection Limit: 5E-02 mg/kg
Risk- Based Consumption Limit (meals per 1 0 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kg)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
>1
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLiM
UNLIM
9
7
6
6
5
2
1
1
1
NONEE
NONE
NONE
NONE
NONE
NONE
8 12
UNLIM
UNLIM
9
6
5
4
3
3
3
2
1 .
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
UNLIM
9
6
4
3
3
2
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
6
4
3
2
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day."
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose alloy/able over a 10-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole mealsize.
-------
Table 3—20. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Diazinon
Population: General
Body Weight: 70kg
Reference Dose: 9E-05mg/kg-d
Detection Limit: 5E-02 ma/kg
Risk-Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.03
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
>3
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
.16
. 8
5
4
3
2
2
2
1
1
0.5
0.5
NONE
8 12
UNLIM
UNLIM
UNLIM
16
14
12
10
9
8
4
2
2
1
1
1
1
0.5
0.5
NONE
NONE
NONE
UNLIM
UNLIM
14
11
9
8
7
6
5
2
1
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
NONE,
16
UNLIM
14
10
8
7
6
5
4
4
2
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
AH values were rounded down to the nearest whole meal size.
-------
Table 3—21 . 10— Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Diazinon
Population: Children
Body Weight: 14.5kg
Reference Dose: 9E-05 mg/kg-d
Detection Limits: 5E-02 rng/kg
Risk- Based Consumption Limit (meals per 1 0 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
< 0.006
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
>0.3
Meal Size
(oz)
3 | 4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE
NONE
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
5
3
2
2
1
1
1
1
1
NONE
NONE
NONE
8
UNLIM
9
8
7
6
5
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten -day limits are based on the total dose allowable over a 1 0-day period
based on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-22. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Dicofol
Population: General
Body Weight: 70 kg
Reference Dose: 1E-03mg/kg-d
Detection Limit: 3E-03 mq/kq
Risk-Based Consumption Limit (meals per 10 davs)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.2
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
>10
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
8
7
6
6
3
2
1
1
1
, NONE
NONE
NONE
NONE
NONE
8
UNLIM
UNLIM
10 *
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
10
6
5
4
3
2
2
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
JNLIM = Unlimited consumption; more than 1 meal per day.
MONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Mote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—23. Monthly Consumption Limits for Chronic Systemic Health Endpofnts
Chemical Name: Dicofol
Population: General
Body Weight: 70 kg
Reference Dose: 1 E-03 mg/kg-d
Detection Limit: 3E-03 mg/kg
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.3
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
20
30
40
>40
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
0.5
0.5
0.5
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
15
13
11
10
9
4
3
2
1
1
1
1
1
0.5
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
15
12
10
8
7
6
6
3
2
1
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
16
UNLIM
15
11
9
7
^ 6
5
5
4
2
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2,3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
S
I
2
S
E"
,0.
i
i
0
i
o
o
g
1
5
J-
\
g
8
s
)
1
CO
Q
§
T3
1
;? o
N
,1 51
**• o oo o
111^
Chamlcal Nama:
Population:
Body Weight
Cancer Potency Factor."
Detactton limit
2
1
m
«
ai
j=
-3
c
_c
'c
&
"8
1
i
,c
S
fft
I
,£
1 Chemical Concentration
CO
CM
CO
Tf
i
£
1:
s.
5:
o^t^toco CM-^I
cco------^"!
T niiiiiii8
o SSS
Ojr^2;O5^"Wc\jT-(;
<£;~iZZ4ZZZrfZ2?Z
5» S ^ "S ^ ^ "5J ^ ^
«• ^Mc«£^ m u
UJUJUIIUUJUJLUUJ1UUJ
Z ZZ eZZZZZ^t^c
LU 111 UJ UJ H
•* w oi *- g 00000
ZZZZ^TO0
lOZZZZZZiZZZ
til UJ LU til
«> * « CM ^ % § § § §
5555
D D D 3
UJUJUJUJLULULUlil
c3Oooo5555
J J J
^Tnincj-r-^. ---
.OJttjiocM — Q ^ .j 3
iiiii^ en ID 10 CM
D D D D 3
• CO CO
OOO^-CM^fCOCO
u
o
UJ
UJ
o
111
^.
^.
UJ
^
III
2;
in
o
UJ
J
UJ
O
in
O
UJ 1
(.
UJ I
O (
^ *
UJ I
n (
UJ LJ
^ 2
Z2
UJ U
z z
UJ U
Z 2
I I
UJ U
II II
O C
IT) P
« *•-
> o
: >> .
J O O)
0 C .*
D-S •*
te o in
S*5t 3
fill §
28^.;| ui'-s
i CO II iN. _
^1^^S..£S<2 E
ilii^I-l-1 i
S^S^-^^cSc i
igissalilsi
^Illliill
• The cancer status for dicofol is und
dicofol appears with DDT, DDD, and/
Meal sizes of 4, 8, 1 2, and 1 6 oz. corr
UNLIM = Unlimited consumption; mo
NONE = No consumption; less than
0.5 meals per month represents six m
References for cancer potency factor
Instructions for modifying the variable
Note that some values may be below
Note nonlinear scale of concentration
All values were rounded down to the
* ARL = Acceptable Risk Level
-------
Table 3-25. 10- Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Dicofol
Population: Children
Body Weight: 14.5kg
Reference Dose: 1E-03mg/kg-d
Detection Limits: 3E-03 mq/kq
— Risk- Based Consumption Limit (meals per 10 days)
.. Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.06
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
>3
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
8
5
4
3
2
2
2
1
1
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
6
4
3
2
2
1
1
1
1
NONE
NONE
NONE
8
UNLIM
10
9
7
7
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period
based on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—26. 10- Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Dieldrin
Population: General
Body Weight: 70 kg
Reference Dose: 5E-05 mg/kg-d
Detection Limit: 1 E-04 mq/kq
Risk-Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
< 0.008
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
>0.6
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
8 12
UNLIM
UNLIM
UNLIM
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE
NONE
NONE
NONE1
NONE
UNLIM
UNLIM
UNLIM
10
5
3
2
2
1
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg,
UNLJM = Unlimited consumption; more than 1 meal per day.
References for RfDs are found in Part II, Section 5.
References for estimated threshold values are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Mote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—27. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Dieldrin
Population: General
Body Weight: 70kg
Reference Dose: 5E-05mg/kg-d
Detection Limit: 1 E-04 mq/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
>1
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
15
12
11
10
9
4
3
2
1
1
1
1
1
0.5
NONE
8
UNLIM
UNLIM
15
11
9
7
6
5
5
4
2
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
12
UNLIM
15
10
7
6
5
4
3
3
3
1
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
16
UNLIM
11
7
5
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
1
I
1
I
1
§
S
3
S
I
1
[
I
i
?
n
e
1
•D
V- *g
lltll
ihemleal Name:
opulaflon:
-ody Weight
toncer Potency Factor.
election Umtt
u a. CD u a
•S
I
•S
1
I
"S
1
1
,0
1
•k
Chemical Concentration
CO
CO
1
I
ft.
£
CO
c
1
£
cc
-J
cc
c
c
I
c
1
o
^
o
r
o
»
o
j>
o
°
2
1
h
o
D
i
5
2
S
Z
S
s
Z
_J
5
_J
D
D
3
J
D
«»
D
3
D
-1
D
0.00002
V
2
2
Z.
s
2
S
s
Z
5
_J
Z
z
n
Zi
2
•y
3
— i
D
M
3
3
N
5
Z
S
z
O)
s
2
E
Z
£
^
Z
ZI
s
z
2
1
3
S
-J
3
Tt
5
2
•s.
Z.
CO
s
2
5
Z
en
*r
Zi
2
S
2
3
3
1
3
•s.
_j
3
3
CO
S
2
S
2
-
S
13
5
Z
^
Zi
z
Zi
•u-
1
3
_J
S
3
3
CM
•s.
z.
s
2
CO
s
z
s
Z
3
in
^r
Zi
Z
S
Z
~
§
3
S
— i
3
3
O
O
3
••-
2
5
Z
-
S
Z
3
S
Z
3
CM
*7
Z
1
2
3
in
Zi
3
S
— i
3
CM
O
o
O
3
U
O
t-
s
z
in
d
O)
5
Z
3
'-
*
2
CM
Zi
3
_i
=
3
3
UJ
Z
z
*
5
z
in
d
CO
s
Z
in
d
en
Zi
3
•*~
Zi
13
— i
3
1
3
3
C
CO
s
z
UJ
Z
Tf
S
Z
in
d
>••
2
Zi
Z
•*~
^.
S
— i
3
co
o
o
o
o
C
CM
5
Z
— )
D
CO
s
Z
3
in
d
in
Zi
3
•*•"
^_
— i
~>
3
O
O
C
••-
n
0
2
2
3
2
Z
CM
Zi
3
d
in
-J
3
CM
O
0
o
z
in
d
'*'
UJ
0
d
en
2
••-
;
z
CM
_J
3
O
Z
z
ID
•a-
UJ
D
d
CO
2
2
in
d
en
2
3
CO
o
o
o
z
z
ID
co
UU
0
Z
111
O
2
"*
Z
Z
in
d
r-
i
*
§
o
c
2
CM
11
C
2
UU
0
co
O
in
d
in
i
'~
o
o
C
9
'r~
UU
UJ
0
~
2
Z
Z
CM
Z
in
ri
in
CM
o
o
\
o
u
z
it
z
in
d
Z
z
z
-
2
Z
UU
z
2
CM
S
o
Z
2
UJ
T'
U
C
UJ
0
u>
d
2
2
Z
in
d
Z
z
UJ
z
z
•r"
(0
O
o
C
Z.
o
UJ
o
til
0
111
D
111
D
\
Z
Z.
in
d
Z
z.
UJ
z
z
CO
O
o
C
Z
UJ
c
11
z
UJ
D
HI
0
z
2
2
in
d
Z
z
11
2
o
C
2
UJ
c
0
o
UJ
3
2
2
Z
LU
D
Z
z
UJ
2
in
CM
o
C
UJ
z.
Ill
LL
C
111
z
UJ
3
Z
Z
Z
LU
D
Z
z
u
z
HI
CM
d
A
1- -
11 .J
,_--§. in o
II Is- .- (D
co C- o ro
CM" 1 W "i S
CM * _r 3 w
d
-------
Table 3—29. 1 0— Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Dieldrin
Population: Children
Body Weight: 14.5kg
Reference Dose: 5E-Q5 mg/kg-d
Detection Limits: 1 E— 04 mg/kg
Risk- Based Consumption Limit (meals per 1 0 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.003
0.003
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
o.oa
0.09
0.1
>0.1
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
8
4
2
2
1
1
1
1
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
10
9
' 7
7
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
8
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period
based on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Dlo
70kg
2E+05 per mg/kg-d
7E-07 mo/k
lation:
Weight:
er Potency
mlt:
Che
Pop
Bod
Det
!i
J
11,
III
"
a
it .
°£
5J
ra
CM
c
— o
- 0>
3!
-------
Table 3-31 . 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Disulfoton
Population: General
Body Weight: 70kg
Reference Dose: 4E— 05 mg/kg-d
Detection Limit: N/A
Risk- Based Consumption Limit (meals per 1 0 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.006
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4 .
>0.4
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
8
6
4
4
3
3
2
2
1
NONE
NONE
NONE
8 12
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
6
4
3
2
2
1
1
1
1 "
NONE
NONE
NONE
NONE
UNLIM
UNLIM
UNLIM
10
9
8
4
2
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
10
8
7
6
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 02. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 10 days.
N/A = not available
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-32. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Disulfoton
Population: General
Body Weight: 70kg
Reference Dose: 4E-05 mg/kg-d
Detection Limit: N/A
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kcrt
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
>1
Meal Size
(tart
0.114
UNLIM
UNLIM
UNLIM
UNLIM
14
12
10
9
8
7
3
2
1
1
1
1
0.5
0.5
0.5 .
NONE
0.227
UNLIM
UNLIM
12
9
7
6
5
4
4
3
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
0.341
UNLIM
12
8
6
4
4
3
3
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
0.454
UNLIM
9
6
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
JNLIM = Unlimited consumption; more than 4 meals per week (17/month).
MONE = No consumption; less than six meals per year.
M/A = not available
X5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
slote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-33. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Disulfoton
Population: Children
Body Weight: 14.5kg
Reference Dose: 4E - 05 mg/kg - d
Detection Limits: N/A
Risk- Based Consum
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/ka)
<0.003
0.003
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
>0.1
ption Limit (meals per 1 0 days)
Meal Size
(oz)
3 I 4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
8
7
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
UNLIM
UNLIM
UNLIM
10
8
7
6
5
5
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
8
UNLIM
8
6
5
4
3
3
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 rneal/day.
NONE = No consumption; less than one meal per 10 days.
N/A = not available
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period
based on the RfD). When this dose is delivered in less than 1 0 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-34. 1 0-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Endosulfan
Population: General
Body Weight: 70 kg
Reference Dose: 5E-05 mg/kg-d
Detection Limit: 0.005-0.07 ma/ka
Risk-Based Consumption Limit (meals oer 10 davsV
Chemical Concentration
Found in Sampling and
Analysis Program
fma/kcrt
<0.008
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
>0.6
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNUM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
10
5
3
2
2
1
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
JNLIM = Unlimited consumption; more than 1 meal per day.
slONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Nlote that some values may be below detection limits.
vjote nonlinear scale of concentration values.
"en-day limits are based on the total dose allowable over a 1 0-day period (based on the
3fD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
hat the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size
-------
Table 3-35. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Endosulfan
Population: General
Body Weight: 70kg
Reference Dose: 5E-05 mg/kg-d
Detection Limit: 0.005-0.07 mg/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kg)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
>1
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
15
13
. 11
10
9
4
3
2
1
1
1
1
1
0.5
NONE
8 12
UNLIM
UNLIM
15
11
9
7
6
5
5 -
4
2
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
UNLIM
15
10
7
6
5
4
3
3
3
1
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
16
UNLIM
11
7
5
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (1 7/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-36. 10— Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Endosulfan
Population: Children
Body Weight: 14.5kg
Reference Dose: 5E-05 mg/kg-d
Detection Limit: 0.005-0.07 mq/kci
Risk— Based Consum
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kg)
<0.003
0.003
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
>0.1
ption Limit (meals per 1 0 days)
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
8
4
2
2
1
1
1
1
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
10
9
7
7
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
8
UNLIM
10
7
6
5
4 .
3
3
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNUM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Mote that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period
based on the RfD). When this dose is delivered in less than 1 0 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—37. 10^Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Endrin
Population: General
Body Weight: 70 kg
Reference Dose: 3E-04 mg/kg-d
Detection Limit: 1E-03mq/kg
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.05
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
<3
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
4
3
2
1
1
1
1
1
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
8
7
6
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
9
. 7
6
5
5
4
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-38. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Endrin
Population: General
Body Weight: 70kg
Reference Dose: 3E-04 mg/kg-d
Detection Limit: 1 E-03 mq/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.08
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
>10
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
14
11
9
8
7
6
5
2
1
1
1
0.5
0.5
0.5
0.5
0.5
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
14
9
7
5
4
4
3
3
2
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1 .
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
17
15
14
7
4
3
2
2
2
1
1
1
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14; 0.227, 0.341, and 0.454 kg.
JNLIM = Unlimited consumption; more than 4 meals per week (1 7/month).
>4ONE = No consumption; less than six meals per year.
).5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
tote that some values may be below detection limits.
tote nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—39. 10— Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Endrin
Population: Children
Body Weight: 1 4.5 kg
Reference Dose: 3E-04 mg/kg-d
Detection Limits: 1E-03mg/kg
_ Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
>1.0
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
10
8
7
6
5
5
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
9
7
6
5
4
4
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
8
UNLIM
9
6
4
3
3
2
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 nneal/day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period
based on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-40. 1 0-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Ethion
Population: General
Body Weight: 70kg
Reference Dose: 5E-04 mg/kg-d
Detection Limit: 2E-02 mq/kq
Risk— Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.08
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
>6
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
8 12
UNLIM
UNLIM
UNLIM
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
UNLIM
UNLIM
UNLIM
10
5
3
2
2
1
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
AH values were rounded down to the nearest whole meal size.
-------
Table 3-41 . Monthly Consumption Limits tor Chronic Systemic Health Endpoints
Chemical Name: Ethion
Population: General
Body Weight: 70kg
Reference Dose: 5E— 04mg/kg-d
Detection Limit: 2E-02 mq/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.2
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
>10
Meal Size
(oz)
4
UNLJM
UNLIM
UNLIM
UNLIM
UNLIM
15
13
11
10
9
4
3
2
1
1
1
1
1
0.5
NONE
8
UNLIM
UNLIM
15
11
9
7
6
5
5
4
2
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
12
UNLIM
15
10
7
6
5
4
3
3
3
1
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
16
UNLIM
11
7
5
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (1 7/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—42. 10— Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Ethion
Population: Children
Body Weight: 14.5kg
Reference Dose: 5E-04 mg/kg-d
Detection Limits: 2E-02 mg/kq
Risk— Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/ka)
<0.03
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
>1
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
8
4
2
2
1
1
1
1
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
10
9
7
7
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
8
UNLIM
10
7
6
5
4
3
3
3
. 1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 02. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten— day limits are based on the total dose allowable over a 1 0-day period
based on the RfD). When this dose is delivered in less than 1 0 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
AH values were rounded down to the nearest whole meal size.
-------
Table 3—43. 1 0— Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Heptachlor Epoxide
Population: General
Body Weight: 70 kg
Reference Dose: 1E-05mg/kg-d •
Detection Limit: 1 E— 03 mg/kg
Risk-Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kg)
< 0.002
0.002
0.003
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
>0.1
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
10
8
6
5
5
4
4
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
8
6
5
4
3
3
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
10
6
5
4
3
2
2
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-44. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Heptachlor Epoxide
Population: General
Body Weight 70kg
Reference Dose: 1E-05mg/kg-d
Detection Limit: 1E-03mq/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kcrt
<0.004
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
>0.4
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
12
8
6
4
4
3
3
2
2
1
0.5
0.5
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
17
15
13
12
6
4
3
2
2
1
1
1
1
0.5
NONE
NONE
NONE
12
UNLIM
UNLIM
16
13
11
10
9
8
4
2
2
1
1
1
1
0.5
0.5
NONE
NONE
NONE
NONE
16
UNLIM
15
12
10
8
7
6
6
3
2
1
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 02. correspond to 0. 1 14, 0.227, 0.341 , and 0.454 kg.
JNUM = Unlimited consumption; more than 4 meals per week (17/month).
^ONE = No consumption; less than six meals per year.
X5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
vJote that some values may be below detection limits.
vlote nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
AH values were rounded down to the nearest whole meal size.
-------
'o
•o
c
LU
X
0
'c
CD
D)
o
£.
3*~
£
1
"Z
_o
a.
CO
c
o
O
f-^"
o
S
10
1
co
CD
CB
•a
CD |
•^ D)
X vx
o ^-
LU E 5
O CD 3
r- Q. c
g S O CO
hemical Name:
opulation:
ody Weight
ancer Potency Factor
etection Limit:
O D- m O Q
|
o
CD
Q
•3
CD
1
C
o
I
c
5
•a
CD
|
V
CO
IT*
"N
5
co
15
S
S
Chemical Concentration
CO
CM
oo
•*
1
0.
1
c
£
a;
cc
_j
_,
DC
Analysis Program
i
o
o
1
o
o
T
o
f
0
o
*"
o
1
o
^~
«
i
o
n
0
**"
O
(mg/kg)
S
z
^3
s
z
ZJ
5
Z
D
s
Z
S
Zi
3
2
_J
13
5
z
S
Zi
Z
5
Zi
ZJ
5
Z
^)
S
Z
S
Zi
z
ZJ
S
o
o
o
d
V
CM
S
Zi
Z
5
z
^
5
Zi
13
5
i
Z
5
Zi
ZJ
2
Zi
Z
5
z
5
Z
31
S
Z
p
S
ZJ
z
ZJ
S
o
d
00
5
Z
S
z
^z
5
ZJ
3
5
^^
_l
z
£
S
Zi
Z
S
Zi
ZJ
5
Z
ZJ
S
•z.
ZJ
S
Zi
z
113
S
o
d
(0
5
Z3
Z
5
Z
oo
5
Zi
3
5
i
z
ZJ
CM
S
Zi
Z
5
Zi
13
5
Z
ZJ
S
•z.
_
2
Zi
z
3
S
o
o
o
d
IO
S
Z
S
•z.
CO
S
Zi
3
5
z
0
2
Zi
•z.
5
Zi
ZJ
S
•z.
ZJ
5
Z
Zi
•z.
ZJ
0
o
o
o
CM
5
Zi
Z
5
Z
oo
S
Zi
3
5
i
Z
ZJ
IO
S
Zi
Z
2
Zi
ZJ
o
5
•z.
ZJ
Zi
Z
ZJ
CM
0
o
o
o
T-
00
5
•z.
ZJ
»~
£
5
i
•z.
ZJ
CM
S
I]
z
ZJ
5
^
ZJ
IO
5
•z.
ZJ
Zi
•z.
ZJ
S
o
o
o
IO
d
oo
5
•z.
1-
T-
5
Z
ZJ
—
'-
2
Zi
ZJ
CO
5
Z
ZJ
•s.
Zi
z
ZJ
§
o
o
o
IO
d
to
5
•z.
IO
d
00
5
_i
Z
ZJ
•^
CM
2
ZJ
z
ZJ
CM
5
ZJ
Zi
•z.
ZJ
§
o
o
o
in
d
IO
•s.
•z.
ZJ
IO
d
ID
5
z
ZJ
T-
0
2
Zi
ZJ
CM
5
Z
ZJ
Zi
Z
ZJ
0
o
LU
0
Z
CM
5
z
ZJ
IU
o
z
CO
5
z
ZJ
IO
d
IO
2
Z3
z
ZJ
*-
o
Zi
z
ZJ
CM
0
o
LU
§
Z
-
CM
LU
O
Z
T-
t
LU
O
Z
w
5
Z3
ZJ
IO
d
10
Zi
Z
HD
S
o
LU
0
z
IO
d
oo
LU
z
o
z
•r-
^
LU
O
z
^™
N.
LU
O
Z
m
Zi
Z
ZJ
8
o
Q
LU
0
IO
d
CO
LU
Q
z
d
co
LU
o
z
'*"
CM
IU
p
z
CM
•i
z
•3
8
o
LU
0
z
IO
d
IO
LU
o
z
d
(0
LU
o
z
'*"
o
LU
o
z
CM
Zi
z
ZJ
0
o
LU
0
z
LU
o
z
CM
LU
O
z
UJ
o
z
co
LU
o
z
IO
d
IO
LU
o
z
•*-
o
CM
0
o
IU
o
z
LU
o
z
1-
LU
o
z
LU
o
z
*-
LU
o
z
IU
o
CM
LU
o
z
IO
d
IO
S
o
LU
0
z
LU
o
z
IO
d
LU
z
o
z
LU
o
z
*-
LU
o
z
LU
i
T-
LU
o
z
LU
o
z
co
8
o
LU
o
z
UJ
o
z
IO
d
LU
z
o
z
UJ
o
z
IO
d
LU
o
z
LU
\
•^
LU
o
z
LU
o
z
CM
§
o
LU
O
Z
LU
O
Z
IO
d
LU
z
O
Z
LU
O
Z
IO
d
LU
O
z
UJ
1
T-
LU
O
Z
LU
o
Z
CM
-:
LU
O
z
LU
O
Z
UJ
O
z
LU
O
Z
LU
O
Z
IU
2
O
Z
LU
O
z
LU
0
IO
ci
LU
O
z
LU
i§
Z
1-
CM
Q
LU
O
Z
IU
o
z
LU
o
z
LU
O
z
LU
O
Z
IU
2
O
z
LU
O
z
IU
0
LU
g
Z
LU
0
Z
LU
o
Z
IO
d
Q
UJ
O
z
LU
O
Z
LU
O
Z
LU
O
Z
LU
O
Z
LU
2
O
z
LU
O
z
UJ
O
Z
UJ
§
z
LU
0
Z
UJ
O
z
UJ
C§
Z
d
0)
^
S
^ *^> °?
0 £ CM
i° i
CO C ~
,r g. m o
ra C. o <®
d -^ '"^ .£
CM i W "c .ti
CM f _- 3 CO
o Q) * "™" *2 "c5
^ ^ * ? £ . ®
°" E S. S ^ 2 J j|
^^"J9^*c 5
li iisf i| 1
1 i ci.!-82|.i.c
Nrtt^ tn •*- at & ^ Q
leal sizes of 4, 8, 1 2, and 1 6 o
NLIM = Unlimited consumptic
ONE = No consumption; less
,5 meals per month represent!
eferences for cancer potency
istructions for modifying the v<
ote that some values may be
ote nonlinear scale of concen
II values were rounded down 1
ARL = Acceptable Risk Level
SZJZoCCiZZ<*
-------
Table 3-46. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Heptachlor Epoxide
Population: Children
Body Weight: 14.5kg
Reference Dose: 1 E— 05 mg/kg— d
Detection Limit: 1E-03mq/kq
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/ka)
<0.0008
0.0008
0.0009
0.001
0.002
0.003
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
>0.04
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
7
5
4
3
3
2
2
2
1
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
8
5
4
3
2
2
2
1
1
NONE
NONE
NONE
NONE
8
UNLIM
10
9
8
4
2
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period
based on the RfD). When this dose is delivered in less than 1 0 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-47. 1 0-Day Consumption Limits -for Chronic Systemic Health Endpoints
Chemical Name: Hexachlorobenzene
Population: General
Body Weight: 70 kg
Reference Dose: 8E-04mg/kg-d
Detection Limit: 1 E— 04 mq/kq
Risk- Based Consumption Limit (meals per 1 0 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.2
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
>9
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
9
8
7
6
5
4
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
8 I 12 I 16
UNLIM
UNLIM
8
6
4
4
3
3
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
UNLIM
8
5
4
3
2
2
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
UNLIM
6
4
3
2
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten -day limits are based on the total dose allowable over a 10-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-48. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Hexachlorobenzene
Population: General
Body Weight: 70kg
Reference Dose: 8E-04 mg/kg-d
Detection Limit: 1 E-04 mq/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.3
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
20
>20
Meal Size
(oz)
4 8 12 16
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
16
14
7
4
3
2
2
2
1
1
1
0.5
NONE
UNLIM
UNLIM
UNLIM
15
12
10
9
8
7
3
2
1
1
1
1
0.5
0.5
0.5
NONE
NONE
UNLIM
16
1,2
9
8
7
6
5
4
2
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
NONE
UNLIM
12
9
7
6
5
4
4
3
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
LJNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE = No consumption; less than six meals per year.
D.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Mote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
I
0)
•£
o
a.
•o
ui
o>
o
'c
CO
en
O
a
0
&
£
E
Zi
§
TO.
1
c
o
>.
I
o>
f
co
CD
n
o
Hexachlorobenzene
General
70kg
2E+OOpermg/kg-d
1E-04 mg/kg
hemical Name:
opulation:
ody Weight
ancer Potency Factor
etection Limit
O Q_ CO O Q
o
a:
-••. ,
fi
,0
• a
CO
§
<:
Chemical Concentration
to
oo
TT
Found in Sarnpling and
EC
<
_i
tr
<
_j
or
<
o:
<
1
a>
1
•o
\
O
in
1
O
,
o
0
1O
o
Tt
o
NO
1
o
7
o
»
1
o
0
o
*
0
"5
=*
G
UNLIM |
UNLIM
5
z
UNLIM
5
z
D
5
_j
Z>
UNUM
2
z
D
UNLIM
UNLIM i
5
_J
z
3
UNLIM
CM
0
O
o
C)
V
*r
t—
2
n
3
2
z
5
Zi
z
3
2
Z
2
_J
z>
2
z
3
5
Z
z>
i
z
s
n
z
2
_i
Z>
1
Z
D
CM
O
§
O
f-
1
z
z»
5
Z
o>
S
Z
2
_J
z
3
•*
2
Z
Z)
i
z
5
ri
z
5
_i
z
3
i
z
D
TT
O
1-
S
Z
Z)
5
z
(O
2
Z
s
_1
z
=>
o>
2
z
D
i
Z
2
D
Z)
5
_i
Z
3
1
Z
Z)
CO
o
§
o
to
1
z
z>
5
Z
•*
2
Z
s
Zi
z
Z)
N.
s
z
Z)
i
z
•*
s
—1
z
Z)
i
z
Z)
CO
o
o
o
0
CM
S
Z
Z)
2
_1
D
co
2
Z
2
Z
z>
w
2
Z
z>
i
z
-
2
_l
z
Z)
i
z
z>
o
0
0
-
•*
s
_l
n
-
5
Z
5
z
D
01
2
Z
1
Z
to
2
_i
Z
Z)
i
z
Z)
CM
8
0
in
o"
i^.
S
_i
D
to
o
o>
2
z
V-
1
z
CM
2
_i
Z
D
1
Z
z>
TC
§
o
Ul
3
^~
S
Ij
13
V)
Q
CO
5
z
U)
o
O)
1
z
-
2
_i
Z
Z)
i
z
Zl
o
til
o
CO
5
_i
ZJ
Ol
o
f
2
z
u>
o
r^
i
z
-
*
1
z
Z)
o
[11
z
CM
2
_l
D
UJ
O
co
2
_i
Z
D
in
0
to
i
z
-
T-
i
Z
Z)
o
o
111
D
-
til
D
S
_j
Z
=>
111
z
CM
2
z
in
C)
to
1
z
•3
CM
O
O
U
D
in
o"
I'-
ll!
D
o
o
111
3
•*
u
O
CM
1
Z
^3
s
O
111
i
z:
ui
5
z
•*
HI
z
o
z:
o
CD
111
Z
ci
a>
u;
d
Z
il
z
Zl
CO
o
o
111
Z
111
z
CO
111
D
111
Z
n-
111
Z
o"
1^
Ul
O
•*
S
o
Ul
O
111
O
CM
111
O
Ul
O
CO
ill
Z
o
in
111
O
-
o
HI
O
n
Z
HI
O
Ul
O
Ul
z
Ul
z
CM
Ul
o
in
o
to
CM
o
u
Z
Ul
1
o
111
O
Ul
O
d
Ul
Z
Ui
z
-
Ul
O
Ul
Z
CM
1-
O
Ul
o
[11
z
Ul
o
Ul
O
Ul
O
o"
Ul
D
111
Z
in
c!
Ul
O
Ul
z
-
to
0
111
Z
HI
Z
111
o
m
o
Ul
O
ui
Z
111
o
111
z
in
o
Ul
O
111
Z
-
op
o
HI
Z
HI
Z
Ul
o
Ul
o
Ul
o
Ul
z
Ul
D
Ul
0
to
o
Ul
O
Ul
z
-
*-
Ul
o
HI
z
Ul
o
111
o
Ul
o
111
z
Ul
o
Ul
z
111
o
Ul
o
Ul
z
"0.
0
CM
Ul
z
HI
z
111
o
Ul
o
111
o
111
z
111
o
Ul
0
Ul
z
Ul
o
Ul
z
Ul
o
CM
A
CD
je
•»
in
5 - "-
°£ CM
O £! f
§i °
-•£ iri*
ZL r* .— (D
SJZ- §«
°" •£ ? ~
J5 I !•? 8-
CM * _- 3 ">
d S ^ ^-2 "3
- °- c fe co o>
*-S 1. £ «s E
-g^gCJBf «
siih*l i
•OCKJfOg.Wtgm--
c <8 ID Q.-y £ o a> g
IHIHIII
eal sizes of 4, 8, 1 2, and 1 6 oz. cor
NLIM .= Unlimited consumption; me
ONE = No consumption; less than
5 meals per month represents six rt
eferences for cancer potency factor
structions for modifying the variable
ote that some values may be below
ote nonlinear scale of concentratior
I values were rounded down to the
ARL = Acceptable Risk Level
5ZJZo(r.EZZ<*
-------
Table 3-50. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Hexachlorobenzene
Population: Children
Body Weight: 14.5kg
Reference Dose: 8E— 04mg/kg-d
Detection Limit: 1 E-04 mig/kg
Risk-Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kcrt
<0.05
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
>2
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
6
4
3
2
2
1
1
1
1
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
5
3
2
2
1
1
1
1
1
NONE
NONE
8
UNLIM
10
8
7
6
5
5
2
1
1
1
NONE
NONE
NONE
NONE
NONE
" NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
JNLIM = Unlimited consumption; more than 1 meal/day.
vlONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
vlote that some values may be below detection limits.
Njote nonlinear scale of concentration values.
Ten -day limits are based on the total dose allowable over a 1 0-day period
aased on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-51 . 1 0-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Lindane
Population: General
Body Weight 70kg
Reference Dose: 3E-04 mg/kg-d
Detection Limit 1 E-04 ma/kg
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/ka)
<0.05
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1 *
2
3
>3
Meal Size
(oz)
4 ! 8
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
NONE
NONE
NONE
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
4
3
2
1
1
1
1
1
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
8
7
6
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
9
7
6
5
5
4
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3). ,
All values were rounded down to the nearest whole meal size.
-------
Table 3-52. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Lindane
Population: General
Body Weight 70kg
Reference Dose: 3E-04 mg/kg-d
Detection Limit: 1 E- 04 mq/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.08
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
>10
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
14
11
9
8.
7
6
5
2
1
1
1
0.5
0.5
0.5
0.5
0.5
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
14
9
7
5
4
4
3
3
2
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
17
15
14
7
4
3
2
2
2
1
1
1
0.5
NONE
NONE
NONE
• NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
JNUM = Unlimited consumption; more than 4 meals per week (17/month).
MONE = No consumption; less than six meals per year.
X5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
vjote that some values may be below detection limits.
vlote nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
j»
c
'6
Q.
£
i
ID
O
'5-
D)
i
§
<3
3.
£
e
LJ
c
B.
3
10
8
j>.
|
CO
ID
CO
|
jx:
CO
if
5
8
CO
1
5
Chemical Concentration
(O
CM
oo
Tf
Found in Sampling and
EC
£
_i
5
S!
<
Analysis Program
?
o
o
t
1
o
r-
1
o
T-
?
o
*
1
o
o
^—
1
o
*
o
I
o
o
^
1
o
"5
=¥
a
UNLIM I
UNLIM
UNLIM
UNUM
UNLIM
5
^
D
UNLIM
_i
z
s
z
_i
Z)
1
Zj
D
UNLIM
0.0004
V
O)
1
z
o
1
z
o
CM
2
Zi
z
2
3J
Z)
18.05002
Zi
z
5
z
_i
Z)
->
_1
Z)
5
z
TT
o
o
o
o
CO
S
_i
•z.
ZJ
5
Z
Z)
00
5
Zi
Z
2
3j
Z»
CM
Zi
z
Z)
5
Z
_l
z
Z)
•«s
—1
z
Z)
5
z
(O
o
o
o
o
•*
5
Z
z»
2
z
z>
(O
5
Zi
3
2
23
a
CD
n
z
Z)
5
•z.
t^
*—
i
_i
z
D
1
Z
§
a
O
CO
2
_I
•z.
D
2
Z
D
•*
1
Z
2
Z)
r<-
Zi
Z)
2
•z.
1-
5
Zi
Z
D
2
_j
3
5
0
o
-
2
_j
D
2
_i
D
CM
1
Z
1
Z)
CO
^
Zi
Z)
2
D
r^
5
Zi
Z
2
_i
D
CM
O
o
o
•*>.
o
O)
2
_l
z
-
CM
2
•z.
Z)
-
•^
z
2
Z)
co
2
Zi
•z.
•s.
_i
Z
D
s
o
in
C3
CD
2
_i
•z.
ID
C9
OO
2
Z
Z)
-
CM
2
D
CM
"5
Zi
Z)
2
_i
Z
z>
S
o
UJ
z
Tf
2
Zi
Z
u>
o
CD
2
Z
u>
d
O)
2
Z>
•*~
r-.
2
Zi
Z
D
§
o
UJ
!
CO
•s.
Zi
Z
UJ
O
•»
2
Z
a
in
d
(^
2
D
•*"
•a-
2
Z3
Z
D
0
o
UJ
0
-
•s.
_i
Z
UJ
O
•z.
CM
2
Z
UJ
O
CO
•s.
D
«?
o
N.
•s.
Zi
Z
Z)
S
o
UJ
z
10
o
O)
UJ
O
-
UJ
3
•^-
S
D
z
z
CO
2
Zi
Z
3
i
o
UJ
!
U)
o
(D
UJ
O
10
o
00
UJ
o
»-
0
CM
•s.
ZJ
z
o
CO
o
o
UJ
g
Z
UJ
z
o
z
•«•
UJ
z
o
z
10
d
u>
UJ
Z
o
z
u>
c>
o»
O
Z
"*"
Is-
a>
o
o
UJ
•z.
UJ
z
CO
UJ
o
z
UJ
•z.
•9
UJ
1
in
d
3
**
TI-
o
it
O
UJ
•z.
•r-
UJ
O
UJ
z
CM
UJ
O
O
CO
|
10
d
t^
CM
o
UJ
O
UJ
Z
10
d
UJ
O
til
O
UJ
O
O
Z
3
Z
CO
TI-
CS
Ul
•z.
Ul
z
10
d
UJ
O
Ul
O
in
o
JJ
0
3
Z
•z.
z
CM
(O
o
UJ
o
UJ
•z.
Ul
o
Ul
o
UJ
O
in
d
UJ
\
3
d
Z
Z
Z
-
00
o
UJ
O
Ul
z
UJ
0
UJ
1
Ul
o
UJ
•^
0
Ul
•z.
3
d
Z
z
z
-
'-
UJ
a
Ul
z
UJ
1
til
\
Ul
o
UJ
z
Ul
|
O
UJ
O
z
z
z
z
10
d
CM
NONE i
UJ
z
z
NONE
u.
z
Ul
a
UJ
y
O
UJ
•z.
3
Ul
0
3
3
UJ
z
z
CM
A
£
S
d£- ^
0 £ CM
DC r-
£ ° o
0 E . £
s's- » s
S3Z. g»
° -g "•§ •£ :
IS I c) — -Sw-j:;
C g CD Q-Zocc.Ezz<*
-------
Table 3-54. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Lindane
Population: Children
Body Weight: 14.5kg
Reference Dose: 3E-04 mg/kg-d
Detection Limits: 1 E-04 mq/kq
Risk-Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
>1.0
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
10
8
7
6
5
5
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
9
7
6
5
4
4
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
8
UNLIM
9
6
4"
3
3
2
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
JNUM = Unlimited consumption; more than 1 meal/day.
MONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
vJote that some values may be below detection limits.
Mote nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period
Dased on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-55. 1 0-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Methylmercury
Population: General
Body Weight: 70kg
Reference Dose: 3E-04 mg/kg— d
Detection Limit: 1 E-02 mg/kg
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.05
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
<1
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
4
3
2
1
1
1
1
1
NONE
NONE
12
UNLIM
UNLIM
UNLIM
8
7
6
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
16
UNLIM
9
7
6
5
5
4
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNUM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten -day limits are based on the total dose allowable over a 10-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
A dose- response variable of 3 x 1 0~4 mg/kg -d may be appropriate for adult males (See
Section 5.6).
-------
Table 3-56. 10-Day Consumption Limits for Developmental Health Endpoints
Chemical Name: Methylmercury
Population: Women of Child -Bearing Age
Body Weight: 70 kg
Interim Dose-Response Variable: 6E-05mg/kg-d
Detection Limit: 1E-02ma/ka
Risk- Based Consumption Limit (meals per 1 0 davs)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kcO
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
>0.4
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
7
6
5
4
4
3
1
1
NONE
NONE
8
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
6
4
3
2
2
1
1
1
1
NONE
NONE
NONE
NONE
16
UNLIM
10
9
4
3
2
1
1
1
1
1
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
LJNLIM = Unlimited consumption; more than 1 meal per day.
MONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
^ote that some values may be below detection limits.
vlote nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period (based on the
3fD). When this dose is delivered in less than 1 0 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-57. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Methylmercury
Population: General
Body Weight: 70kg
Reference Dose: 3E-04mg/kg--d
Detection Limit: 1 E-02 ma/ka
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.08
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
>10
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
14
11
9
8
7
6
5
2
1
1
1
0.5
0.5
0.5
0.5
0.5
NONE
8 12
UNLIM
UNLIM
UNLIM
UNLIM
14
9
7
5
4
4
3
3
2
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
17
15
14
7
4
3
2
2
2
1
1
1
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (1 7/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
All values were rounded down to the nearest whole meal size.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
A dose- response variable of 3 x 1 0~4 mg/kg-d may be appropriate for adult males (See
Section 5.6).
-------
Table 3-58. Monthly Consumption Limits for Developmental Health Endpoints
Chemical Name: Methylmercury
Population: Women of Child -Bearing Age
Body Weight: 70kg
Interim Dose-Response Variable: 6E-05mg/kg-d
Detection Limit: 1 E-02 ma/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
fma/ka)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
>2
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
16
14
12
11
5
3
2
2
1
1
1
1
1
0.5
NONE
8
UNLIM
UNLIM
UNLIM
14
11
9
8
7
6
5
2
1
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
12
UNLIM
UNLIM
12
9
7
6
5
4
4
3
1
1
0.5
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
16
UNLIM
14
9
7
5
4
4
3
3
2
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.114, 0.227, 0.341, and 0.454 kg.
LJNUM = Unlimited consumption; more than 4 meals per week (1 7/month).
MONE = No consumption; less than six meals per year.
D.5 meals per month represents six meals per year.
References for the interim dose-response variable are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Monthly limits are based on the total dose allowable over a one- month period
When this dose is delivered in less than one month (e.g., in a few large meals),
lote that the daily dose exceeds the interim dose-response variable (see Section 4.3).
Mote that some values may be below detection limits.
Note nonlinear scale of concentration values.
All values were rounded down to the nearest whole meal size.
-------
Table 3-59. 1 0-Day Consumption Limits for Developmental Health Endpoints
Chemical Name: Methylmercury
Population: Children
Body Weight: 14.5kg
Interim Dose-Response Variable: 6E— 05 mg/kg-d
Detection Limit: 1E-02mg/ka
Risk- Based Consumption Limit (rneals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/ka)
<0.004
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
1 0.08
0.09
0.1
>0.1
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
5
3
2
2
1
1
1
1
1
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
NONE
NONE
8
UNLIM
9
7
6
5
4
4
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 10 clays.
References for the dose- response variable are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period
When this dose is delivered in less than 10 days (e.g., in a single meal),
note that the daily dose exceeds the dose-response variable (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-60. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Mirex
Population: General
Body Weight: 70kg
Reference Dose: 2E-04mg/kg-d
Detection Limit: 1 E-03 mq/kq
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.03
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
>2
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
6
4
3
2
2
1
1
1
1
NONE
NONE
8 12
UNLIM
UNLIM
UNLIM
UNLIM
10
8
7
6
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
UNLIM
UNLIM
10
8
6
5
5
4
4
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-61 . Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Mirex
Population: General
Body Weight: 70 kg
Reference Dose: 2E-04mg/kg-d
Detection Limit: 1 E-03 ma/kq
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
,(mg/kg)
<0.06
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
>7
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
12
9
7
6
5
4
4 .
3
1
1
0.5
0.5
0.5
0.5
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
17
15
13
12
6
4
3
2
2
1
1
1
1
0.5
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
15
13
11
10
9
4
3
2
1
1
1
1
1
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
g-d
Mtrsx
General
70kg
2E+00 per
E-03
actor.
11
lf£
1111
UJ
CM
C
O
8*
i o s-e-s | § s
^Z n-j » gj S
ii *" ?* rt •*-' ^~ (/)
» II -5 g -B ^ o
-------
Table 3-63. 1 0-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Mirex
Population: Children
Body Weight: 14.5kg
Reference Dose: 2E-04mg/kg-d
Detection Limit: 1 E-03 mq/kq
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
>0.6
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
8
6
5
4
4
3
3
1
1
NONE
NONE
NONE
NONE
4
UNLIM
UNLIM
8
6
5
4
3
3
2
2
1
NONE
NONE
NONE
NONE
NONE
8
UNLIM
6
4
3
2
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 rneal/day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period
based on the RfD). When this dose is delivered in less than 1 0 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
AH values were rounded down to the nearest whole meal size.
-------
Table 3-64. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Oxyfluorfen
Population: General
Body Weight: 70kg
Reference Dose: 3E-03mg/kg-d
Detection Limit: N/A
Risk- Based Consumption Limit (meals per 10 davs)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kcrt
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
20
30
>30
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
4
3
2
1
1
1
1
1
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
10
8
7
6
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
9
7
6
5
5
4
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
JNUM = Unlimited consumption; more than 1 meal per day.
sIONE = No consumption; less than one meal per 1 0 days.
sl/A = not available
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
tote that some values may be below detection limits.
slote nonlinear scale of concentration values.
"en-day limits are based on the total dose allowable over a 10-day period (based on the
tfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-65. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Oxyfluorfen
Population: General
Body Weight: 70kg
Reference Dose: 3E-03mg/kg-d
Detection Limit: N/A
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kq)
<0.8
0.8
0.9
1
2
3
4
5
6
7
8
9
10
20
30
40
50
60
70
80
90
100
>100
Meal Size
(oz)
4 8 12 16
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
14
' 11
9
8
7
6
5
2
1
1
1
0.5
0.5
0.5
0.5
0.5
NONE
UNLIM
UNLIM
UNLIM
UNLIM
14
9
7
5
4
4
3
3
2
. 1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
UNLIM
17
15
14
7
4
3
2
2
2
1
1
1
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.114, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (1 7/month).
NONE = No consumption; less than six meals per year.
N/A = not available
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Chamlcal Name: Oxyflurofen
Population: General
Body Weight 70kg
Cancer Potency Factor: 1 E-01 per mg/kg-d
Detection Umit N/A
Risk-Based Conaumptlon Limit (meals per month) I
Meal Size (oz
CO
CM
CO
rr
f
o
i£°
f
1
o
ir—
tr o
< "
"
^
,
R?i;
< r
3
Chemical Concentration
Found In Sampling and
Analysts Program
(ma/ka)
_
z z :
•>*;•
z z :
Zi CM e
Z **"
22:
z z ;
55:
z z ;
52
Z Z T
3 Z)
22:
Zi Zi _
z z ;
D D :
22:
Z Z 2
3 Z) I
£22
3 3 Z
2 S 2
_i_i I
z> z> z
*£ >c£ «
ziziz
D zi z
j-l-CC
Roc
o o o
V 3 :
Z Z.
zz
O (O
52
z Z
£2
:z
io>
>2
j _i
^ ^
3 O
E2
* 21
33
•
}
= ?
j _i
) =>
; 5
iZJ
) Z>
m
o
o
3
z
Z
*»•
2
Z
5
Z
•-
2
_i
7"
D
2
Z
*r
5
_j
3
•?
_i
D
O
3
z
z
CM
2
Z
2
Z
CO
5
7*
D
2
^
0
i^
;p
Zi
3
!3
D
CM
O
3
O
cn
Z
-
W
2
Z
-
2
_j
•^
n
2
z
co
2
D
^
Zi
Z)
TI-
CS
3
0
CO
z
u>
o
co
2
Z
-
CM
2
D
CM
2
D
Z3
D
CO
o
3
tu
o
^
z
in
o
CO
2
Z
IT
O)
2
2
3
Zi
D
m
o
3
Z
co
2
Z
u.
2
•
Z
-
2
Z
LU
Z
2
CM
2
Z
Z)
UJ
z
2
co
2
V
O
O
O
1^
^J
3
CM
n
0
u>
o
cn
UJ
Z
2
-
CM
UJ
Z
z
~
2
—1
2
D
LLJ
0
^~
CO
^
Zi
Z)
•*
n
Z
u
o
CO
11
C
in
00
II
Z
-
UJ
0
*~
CM
Zi
Z)
CO
o
z
z
•2.
t
UJ
2
Z
IT
o"
CO
UJ
Z
in
o'
o>
UJ
O
**"
00
n
^,
4.
Z.
CO
UJ
z
2
UJ
z
2
t
U
z
ir
C3
r-
UJ
D
Z
TJ-
^
Z
-
UJ
z
2
UJ
z
2
CM
UJ
**
UJ
2
Z
CO
UJ
o
*~
n
f-
CM
^.
Z
Z
in
o
u
2
UJ
z
z
-
Ul
3
UJ
z
2:
UJ
j
**"
UJ
CO
4.
4~
•2.
at
o
l
2
U
Z
z
in
Ul
z:
z
U]
z
z
Ul
j
**
Ul
CM
CO
O
^,
Z.
u
C
Ul
C
u
C
o
Ul
2
Z
Ul
!
z
10
0
UJ
z
UJ
on
^.
Z
Z
u
C
Ul
z
z
u
n
z
UJ
z
z
UJ
z
z
u
z
in
d
Ul
o
UJ
u
o
£
^.
•2.
u
C
UJ
2
2
u
C
UJ
2
2
UJ
2
Z
III
Z
Ul
z
z
UJ
0
UJ
u
in
o
3
0
C
UJ
C
z
UJ
2
2
Ul
^
2
Ul
£
2
Ul
2
Z
1
Z
Ul
3
2
Ul
j
Ul
u
Ul
2:
5
3
A
d>
Is- •*
if c
§| .1
5^ cS
co C. o ro
°1 s^ *
MS CO C .M
CM f _- 3 «
C3
-------
Table 3-67. 1 0-Day Consumption Limits for Chronic Systemic Health Endpornts
Chemical Name: Oxyfluorfen
Population: Children
Body Weight 14.5kg
Reference Dose: 3E-03 mg/kg-d
Detection Limit: N/A
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.2
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
10
>10
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
10
8
7
6
5
5
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
9
7
6
5
4
4
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
8
UNLIM
9
6
4
3
3
2
2
2
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 1 0 days.
N/A = not available
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten -day limits are based on the total dose allowable over a 10-day period
based on the RfD). When this dose is delivered in less than 1 0 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-68. 1 0-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: - PCBs (Aroclor 1254)
Population: General
Body Weight: 70 kg
Reference Dose: 2E-05 mg/kg-d
Detection Limit: 1E-03ma/kq
Risk- Based Consumption Limit ('meals per 10 davs)
Chemical Concentration
Found in Sampling and
Analysis Program
(rria/kcrt
<0.003
0.003
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
6
4
3
2
2
1
1
1
1
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
10
8
7
6
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
10
8
6
5
5
4
4
2
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
JNLIM = Unlimited consumption; more than 1 meal per day.
MONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Nlote that some values may be below detection limits.
slote nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period (based on the
RfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—69. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: PCBs (Aroclor 1 254)
Population: General
Body Weight: 70kg
Reference Dose: 2E-05mg/kg--d
Detection Limit: 1E-03mg/kg
Risk-Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
<0.006
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
12
9
7
6
5
4
4
3
1
1
0.5
0.5
0.5
0.5
8
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
6
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
17
15
13
12
6
4
3
2
2
1
1
1
1
0.5
NONE
NONE
NONE
NONE
NONE
16
UNLIM
15
13
11
10
9
4
3
2
1
1
1
1
1
0.5
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5. .
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
1
?
1
1
g
si
e
1
?
|
c
S*
g
g
U
g
c
3
CO
— TJ
CM ff
1 N
1 oil
O i o UJ UJ
0. O |>- CO -r-
g
1
LU
I i?*
5 S ® •§
llflj
j± o o 5 "S
o a. m o o
f
O
Q)
a
_
i
Q.
i
cS
T3
ffi
S
£
A,
f9
2
r N
5
03
"5
2
1
1
vc
•H
~
&
°
CO
CM
co
•»*•
1
M
I"
KJ
CO
£
S
U.
CC
OC
|
r
_i
D)
g
a.
tn
o
i
o
*
1
o
f
o
o
*•
o
r
o
^
o
S^ -°?
° £ CM
1° §
"I "^
S^ N. c- CO
c. § «>
o •* tS •—
(C S "> 13 S
•\i 3 03 c .t:
o" co • ~ S- "5
^» °" * c3 £ "
cjlilfj! j
|l1il|| jl
||||||||1
5-ll.lliiiil
•DgCfO-g^BO-tJ^
(8 g •<= §<»cffl
«(JJyjCCO([(WJ ^Q
™-"lo£2^co™oQ
•s^o"5^^!™™"
«-jj>zS'g|2=*<
liilllllls
2zjzda:£zz<*
-------
Table 3-71 . 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: PCBs (Aroclor 1 254)
Population: Children
Body Weight: 14.5kg
Reference Dose: 2E-05mg/kg-d
Detection Limit: 1 E— 03 mg/kg
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kg)
<0.002
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
>0.06
Meal Size
(oz)
3
UNLIM
8
6
5
4
4
3
3
1
1
NONE
NONE
NONE
NONE
4
UNLIM
6
5
4
3
3
2
2
1
NONE
NONE
NONE
NONE
NONE
8
UNLIM
3
2
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period
based on the RfD). When this dose is delivered in less than 1 0 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-72 1 0- Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Selenium
Population: General
Body Weight: 70 kg
Reference Dose: 5E-03 mg/kg-d
Detection Limit: 2E-02 ma/ka
Risk-Based Consumption Limit (meals per 1 0 davs)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kcri
<0.8
0.8
0.9
1
2
3
4
5
6
7
8
9
10
20
30
40
50
60
>60
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
10
5
3
2
2
1
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
JNLIM = Unlimited consumption; more than 1 meal per day.
vlONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
xlote that some values may be below detection limits.
vJote nonlinear scale of concentration values.
fen-day limits are based on the total dose allowable over a 10-day period. (based on the
=lfD). When this dose is delivered in less than 10 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3—73. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Selenium
Population: General
Body Weight: 70 kg
Reference Dose: 5E-03 mg/kg-d
Detection Limit: 2E-02 mg/kg
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<2
2
3
4
5
6
7
8
9
10
20
30
40
50
60
70
80
90
100
>100
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
15
13
11
10
9
4
3
2
1
1
1
1
1
0.5
NONE
8 12
UNLIM
UNLIM
15
11
9
7
6
5
5
4
2
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
UNLIM
15
10
7
6
5
4
3
3
3
1
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
16
UNLIM
11
7
5
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-74. 10-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name:
Population:
Body Weight:
Reference Dose:
[Detection Limits:
Selenium
Children
14.5kg
5E-03mg/kg-d
Risk- Based Consumption Limit (meals per 1 0 davs)
| Chemical Concentration
Found in Sampling and
Analysis Program
I (ma/ka)
<0.2
0.2
0.3
0.4
0.5
0.6
0.7
0.8
P-9
1
i 2
3
4
| 5
6
7
8
9
10
>10
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
8
4
2
2
1
1
1
1
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
7
7
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
8
UNLIM
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
IUNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 10 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period
based on the RfD). When this dose is delivered in less than 1 0 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
I AH values were rounded down to the nearest whole meal size
-------
Table 3-75. 1 0-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Terbufos
Population: General
Body Weight: 70kg
Reference Dose: 5E-05 mg/kg— d
Detection Limit: N/A
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/ka)
< 0.008
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
>0.6
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
12 | 16
UNLIM
UNLIM
UNLIM
10
5
3
2
2
1
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.114, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 1 meal per day.
NONE = No consumption; less than one meal per 10 days.
N/A = not available
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period (based on the
RfD). When this dose is delivered in less than 1 0 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3). *
All values were rounded down to the nearest whole meal size.
-------
Table 3-76. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Terbufos
Population: General
Body Weight: 70kg
Reference Dose: 5E-05 mg/kg-d
Detection Limit: N/A .
Risk— Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kg)
<0.02
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
>1
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
15
13
11
10
9
4
3
2
1
1
1
1
1
0.5
NONE
8 12 16
UNLIM
UNLIM
15
11
9
7
6
5
5
4
2
1
1
0.5
0.5
0.5
0.5
0.5
NONE
NONE
UNLIM
15
10
7
6
5
4
3
3
3
1
1
0.5
0.5
0.5
NONE
NONE
NONE
NONE
NONE
UNLIM
11
7
5
4
3
3
2
2
2
4
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE = No consumption; less than six meals per year.
N/A = not available
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one-month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
AH values were rounded down to the nearest whole meal size.
-------
Table 3-77. 10- Day Consumption Limits for Chronic Systemic Hearth Encfpoints
Chemical Name: Terbufos
Population: Children
Body Weight: 14.5kg
Reference Dose: 5E-05 mg/kg-d
Detection Limits: N/A
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mq/kg)
< 0.003
0.003
0.004
0.005
0.006
0.007
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
>0.1
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
9
8
4
2
2
1
1
1
1
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
10
9
7
7
6
3
2
1
1
1
NONE
NONE
NONE
NONE
NONE
8
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 meal/day.
NONE = No consumption; less than one meal per 10 days.
N/A = not available
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten -day limits are based on the total dose allowable over a 10-day period
based on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-78. 1 0-Day Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Toxaphene
Population: General
Body Weight: 70kg
Reference Dose: 3E-04 mg/kg-d
Detection Limit: 3E-03 mq/kci
Risk-Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(ma/kcrt
<0.04
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
>3
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
9
8
7
3
2
1
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
10
8
7
6
5
5
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
9
7
6
5
4
4
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 12, and 16 oz. correspond to 0.1 14, 0.227, 0.341, and 0.454 kg.
JNLIM = Unlimited consumption; more than 1 meal per day.
vJONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
nstructions for modifying the variables in this table are found in Section 2.3.
Mote that some values may be below detection limits.
slote nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 1 0-day period (based on the
=lfD). When this dose is delivered in less than 1 0 days (e.g., in a single meal), note
that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
Table 3-79. Monthly Consumption Limits for Chronic Systemic Health Endpoints
Chemical Name: Toxaphene
Population: General
Body Weight: 70kg
Reference Dose: 3E-04mg/kg-d
Detection Limit: 3E-03 ma/kg
Risk- Based Consumption Limit (meals per month)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.07
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
2
3
4
5
6
7
8
9
>9
Meal Size
(oz)
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
15
11
9
7
6
5
5
4
2
1
1
. 0.5
0.5
0.5
0.5
0.5
NONE
8
UNLIM
UNLIM
UNUM
UNLIM
UNLIM
11
7 '
5
4
3
3
2
2
2
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
12
UNLIM
UNLIM
UNLIM
,17
15
7
5
3
3
2
2
1
1
1
0.5
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
16
UNLIM
16
14
13
11
5
3
2
2
1
1
1
1
1
0.5
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 4, 8, 1 2, and 1 6 oz. correspond to 0.1 14, 0.227, 0.341 , and 0.454 kg.
UNLIM = Unlimited consumption; more than 4 meals per week (17/month).
NONE = No consumption; less than six meals per year.
0.5 meals per month represents six meals per year.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Monthly limits are based on the total dose allowable over a one- month period (based on
the RfD). When this dose is delivered in less than one month (e.g., in a few large meals),
note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
1
1
G
1
1
1
5
I
1
3
X
f
w
1
•O
1
D)
, »!
•1 "3 on
|S£??
.2 a. m u Q
^
1
a
e>
.£
a±
c
0
i
8
•a
CD
1
.IS
i
N
«fi
S
(0
•*
Chemical Concentration
CD
i™
N
T—
CO
•*r
1
?
5.
CO
£
1
cc
t
1
D
^
|
5
z
5
Z
2
|
2
Z
2
Z
•;
Z
D
5=
_l
U
s
_l
D
•«7
Ii
D
5
3
D
5
•j
D
•0-
3
O
V
o
2
z
5
z
TJ-
5
Z
5
Z
1
_l
z
?
—1
z
D
5
_i
Z
Zi
2
3
5
rs
13
1
D
•a-
3
f-
5
Z
5
Z
a>
2
Z
5
Z
rf
?
_J
Z
Z)
5
_i
Z
••7
n
z
Z)
2
:j
3
2
D
3
3
in
2
Z
2
z
1^
5
Z
5
Z
o
?
_j
Z
3
s
_1
Z)
n
^
r>
5
3
3
•?
D
o
D
D
•<«•
5
Z
2
z
to
5
Z
S
Z
CO
•?
«i
Z
3
s
_J
13
0
1
a
•p
D
3
O
3
CM
s
Z
•c
Z
CM
5
Z
5
Z
M-
?:
Z
a
s
_j
13
co
1
5=
3
\i
D
•^
O
^—
S
Z
-
pf
s
z
CM
•p
J
Z
13
2
_J
=3
rf
1
D
•?
^
•a-
o
0
o
in
o
N.
2
Z
in
o
5
Z
'-
Tl-
2
_l
Z
3
CM
1
D
•^
D
8
o
in
o
10
5
Z
to
c5
S
Z
*-
0
2
_i
•^
12
CM
2
_l
3
•^
~1
D
co
3
O
O
II
C
Z
•*
5
Z
to
o
5
Z
u>
o
CO
S
_j
Z
Z3
•'-
(O
i
3
3
O
II
^.
Z
CM
s
z
11
I
:>
z
D
T
5
_i
Z
a
in
o
co
i
=3
CM
O
O
||
^
Z
"-
IU
z
z
'
o
CM
2
_l
2
D
Z
r
rf
2
—
D
•*
o
o
Z
Z
u>
o
h-
1L
O
Z
j:
o
O)
z
Z
'I~
•*
Z
2
CM
2
D
(O
o
o
Z
Z
10
o
in
u.
C
Z
Kl
O
s.
3
•^
0
Z
Z
CM
2
1
Z
a
CO
o
o
z
Z
.<£
^
•*
111
\
w
o
to
z
z
1O
o"
co
Z
z
0
o
Z
z
*•:
c*
CM
LU
|
LU
„••
O
CM
Z
Z
Z
z
•*
z
z
10
CM
o
Z
Z
<•:
,-•
^~
LL
a
ai
^
•^
z
z
z
z
CM
2£
5
LU
2
o
2*
•*
o
Z
Z
^
^
0
LU
2
Z
LU
^"
0
Z
z
z
z
z
z
LU
2;
o
z
(0
o
^
z
*£
^
0
LU
Z
Z
LU
s
o
o"
I
Z
0
z
z
LU
z
z
CO
o
Z
Z
o
s
LU
o
LU
a
LU
^
o"
Z
Z
z
U)
C3
2
D
LU
2
Q
2
"2.
2
LU
^
^
LU
LU
Z
z
LU
^
LU
Z
z
z
LU
o
•^
•£_
D
LU
•^
o
2
in
0
CM
"2.
Z
LU
^
LU
LU
Z
Z
LU
^
LU
Z
z
III
n
Z
LU
>»•
m
2t S
11 .1
T-"S "> ^
ZZ r*» — 0)
2C i- 5 co
o -* '•« .E
ic 8 8-0 a
c\i a? CO c N
CM * _- 3 W
d S ^ - -2 To
- °- 0 ^0) <"
-•§ 1 £ « « E
-g^^co'E o
3 e « S ^ -o •- °
o|S-S.|4Sc f
2|§S.I|-1||
slll!-|iil
eal sizes of 4, 8, 1 2, and 1 6 oz. corr
vILJM = Unlimited consumption; me
ONE = No consumption; less than
5 meals per month represents six rr
sferences for cancer potency factor
structions for modifying the variable
ote that some values may be below
ote nonlinear scale of concentration
I values were rounded down to the
ARL = Acceptable Risk Level
5 ID Z o" CC c Z Z < *
-------
Table 3-81 . 1 0-Day Consumption Limits for Chronic Systemic Health tndpomts
Chemical Name: Toxaphene
Population: Children
Body Weight: 14.5kg
Reference Dose: 3E-04 mg/kg-d
Detection Limits: 3E-03ma/ka
Risk- Based Consumption Limit (meals per 10 days)
Chemical Concentration
Found in Sampling and
Analysis Program
(mg/kg)
<0.005
0.008
0.009
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
>0.8
Meal Size
(oz)
3
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
8
7
6
5
4
4
2
1
1
NONE
NONE
NONE
NONE
NONE
4
UNLIM
UNLIM
UNLIM
UNLIM
UNLIM
10
7
6
5
4
3
3
3
1
1
NONE
NONE
NONE
NONE
NONE
NONE
8
UNLIM
UNLIM
UNLIM
UNLIM
7
5
3
3
2
2
1
1
1
NONE
NONE
NONE
NONE
NONE
NONE
NONE
NONE
Meal sizes of 3, 4, and 8 oz. correspond to 0.085, 0.1 14, and 0.227 kg.
UNLIM = Unlimited consumption; more than 1 nneal/day.
NONE = No consumption; less than one meal per 1 0 days.
References for RfDs are found in Part II, Section 5.
Instructions for modifying the variables in this table are found in Section 2.3.
Note that some values may be below detection limits.
Note nonlinear scale of concentration values.
Ten-day limits are based on the total dose allowable over a 10-day period
based on the RfD). When this dose is delivered in less than 10 days (e.g.,
in a single meal), note that the daily dose exceeds the RfD (see Section 4.3).
All values were rounded down to the nearest whole meal size.
-------
-------
PART II
PART II.
This section of the guidance document provides an overview of the basic EPA
methodology used to carry out a risk assessment for contaminated non-
commercial fish consumption. Section 4 focuses on those aspects relevant to
evaluating risk and setting guidelines for fish, and provides more detail on the
methods used to calculate consumption limits. Section 5 contains summaries
of toxicological data for the 23 target analytes and methods for estimating
exposure limits for developmental and chronic exposure effects. Section 6 lists
the references used in this document. Appendix A provides further information
on genotoxicity and mutagenicity, while Appendix B provides a list of additional
sources of information.
-------
PART II
-------
4. RISK ASSESSMENT METHODS
SECTION 4
RISK ASSESSMENT METHODS
4.1 Introduction
The presentation of risk assessment methods in Section 4 follows the format
of the risk assessment process recommended by EPA for cancer and non-
cancer toxicity:
• Hazard identification,
• Dose-response assessment,
• Exposure assessment, and
• Risk characterization (EPA, 1986a, c; IRIS, 1993).
EPA methods follow the outline developed in the National Academy of Sciences
(NAS) report entitled Risk Assessment in the Federal Government: Managing
the Process (NAS, 1983; see Figure 4-1). According to NAS,
"risk assessment can be divided into four major steps: hazard
identification, dose-response assessment, exposure assessment,
and risk characterization. A risk assessment might stop with the
first step, hazard identification, if no adverse effect is found or if
an agency elects to take regulatory action without further
analysis, for reasons of policy or statutory mandate." {NAS, 1983)
Readers may wish to consult the new NAS document, entitled Science and
Judgement in Risk Assessment, which provides an update and expansion of the
1983 work (NAS, 1994).
Hazard identification is the first step in the risk assessment process. It consists
of a review of biological, chemical, and exposure information bearing on the
potential for an agent to pose a specific hazard (Preuss and Erlich, 1986).
Hazard identification involves gathering and evaluating data on the types of
health effects which are associated with chemicals of concern under specific
exposure conditions (e.g., chronic, acute, airborne, or foodborne; EPA,
1985).1
1 Some groups within EPA which conduct primarily chemical-specific
evaluations do not incorporate considerations of occurrence or exposure into
their hazard identification process.
4-1
-------
4. RISK ASSESSMENT METHODS
RESEARCH
RISK ASSESSMENT
RISK MANAGEMENT
Laboratory and field
observations of adverse
health effects and ex-
posures to particular
agents
Hazard Identification
(Does the agent cause
the adverse effect?)
Information on
extrapolation methods
for high to low dose
and animal to human
Dose-Response Assessment
(What is the relationship
between dose and inci-
dence in humans?). •
Field measurements,
estimated exposures,
characterization of
populations
Exposure Assessment
(What exposures are
currently experienced
or anticipated under
different conditions?)
Risk Characterization
(What is the estimated
incidence of the ad-
verse effect in a
given population?)
Development of
regulatory options
Evaluation of public
health, economic,
social, political
consequences of
regulatory options
Agency decisions
and actions
Figure 4-1. Elements of Risk Assessment and Risk Management (NAS, 1983}
4-2
-------
4. RISK ASSESSMENT METHODS
Section 4.2 provides an overview and summary of the hazard identification
process and specific information on hazard identification for non-commercial
fish chemical contaminants. It does not provide detailed guidance on hazard
identification since EPA's Office of Water has already completed the hazard
identification step with respect to fish contaminants. This work was
undertaken to identify the fish contamination target analytes of concern, as
described in Volume 1: Fish Sampling and Analysis (EPA, 1993a) in this
guidance series. This process included an evaluation of information regarding
toxicity, occurrence, persistence, and other factors. The methods for selecting
the highest priority chemicals as target analytes are described in Volume 1 and
summarized briefly in Section 4.2.1. of this document.
The second step in the risk assessment process is the evaluation of the dose-
response dynamics for chemicals of concern (See Section 4.3). The dose-
response dynamic expresses the relationship between exposure and health
effects. To evaluate this relationship, the results of human and animal studies
are reviewed; the dose-response evaluation may focus on specific types of
effects (e.g., developmental, carcinogenic) or be designed to encompass all
adverse effects which could occur under any plausible scenario.
The third step in the risk assessment process is exposure assessment (See
Section 4.4). Individual exposure assessments use data on chemical residues
in fish and human consumption patterns to estimate exposure for hypothetical
individuals. Population exposure assessments consider the distributions of
exposure in a population. Exposure assessments are then combined with dose-
response data to determine risk.
The final step in risk assessment is risk characterization (See Section 4.5),
which provides an estimate of the overall individual or population risks. Risk
characterization can be used by risk managers to prioritize resource allocation
and identify specific at-risk populations; it is also used to establish regulations
or guidelines, and to estimate individual or population risk. In this document,
risk characterization involves developing the risk-based consumption limits
provided in Section 3. When risk characterization is used to estimate individual
or population risk, it serves to provide the risk manager with necessary
information regarding the probable nature and distribution of health risks
associated with various contaminants and contaminant levels. This aspect of
risk characterization is discussed in more detail in Volume 3 of this series. An
overview of the methods which would be used when chemical concentrations
exceed screening values is also provided in Volume 1 (EPA, 1993a).
The importance of describing and, when possible, quantifying the uncertainties
and assumptions inherent in risk assessment has been long recognized, though
not consistently practiced (Habicht, 1992). Uncertainty analysis is particularly
4-3
-------
4. RISK ASSESSMENT METHODS
critical in risk characterization and must be performed throughout the risk
assessment process in order to adequately characterize assumptions in this last
step of the process. Consequently, a description of various sources of
uncertainty and a discussion of assumptions is provided for each of the four
activities which comprise risk assessment.
4.1.1. Other Information Sources
This document contains only an overview of risk assessment as it applies to
fish advisories. For readers who wish to obtain more detail, EPA has issued
several guidelines for conducting specific portions of the risk assessment
process, which address the following areas:
• Exposure assessment (EPA, 1992a),
• Carcinogenicity risk assessment (EPA, 1986a),
• Mutagenicity risk assessment (EPA, 1986c),
• Developmental toxicity risk assessment (EPA, 1991 a),
• Assessment of female and male reproductive risk (EPA, 1988a;
1988b),
• Health risk assessment of chemical mixtures (EPA, 1986d), and
• Exposure factors (EPA, 1990a).
These guidelines were developed by EPA to ensure consistency and quality
among Agency risk assessments. EPA's Risk Assessment Forum is in the
process of developing quantitative guidelines on dose-response assessment of
systemic toxicants. One approach used to estimate Reference Doses for
chronic exposure toxicity is presented in the Background Documents for the
Integrated Risk Information System (IRIS). It is also found in many EPA
publications and has been summarized in recent papers which discuss risk
assessment within EPA (s.f., Barnes and Dourson, 1988; Abernathy and
Roberts, 1994). Relevant sections of each of the above guidelines were
consulted in developing this section, along with other resources cited
throughout the section. Additional references are listed in Section 6 and
Appendix B.
4.2. Hazard Identification
Hazard identification assesses the likelihood that exposure to specific chemicals
under defined exposure conditions will pose a threat to human health. Hazard
identification is often used effectively to determine whether a chemical or
groups of chemicals occurring in specific exposure situation require action. It
has been narrowly defined for some applications to provide only chemical
specific hazard data (NAS, 1983). However, in the new NAS document,
Science and Judgement in Risk Assessment, the use of an iterative approach
4-4
-------
4. RISK ASSESSMENT METHODS
to evaluating risk is emphasized which entails the use of relatively inexpensive
screening techniques to determine when to proceed to more in-depth
evaluations (NAS, 1994). This is analogous, Sn practice, to what is already
frequently done at the state and local level. The early stages of risk
assessment often include consideration of the existence or likelihood of
exposure in order to determine whether further work on a chemical should be
pursued. At the state, local and tribal levels, administrators and risk managers
concurrently evaluate both the hazard and the occurrence of chemicals to
assess whether sufficient risk exists to justify an investment of time and
resources in further action. Their needs for information to guide further action
are, therefore, different from that of a federal agency, which may evaluate
hazards independently of exposure considerations.
A preliminary risk evaluation typically precedes an in-depth risk assessment
because most states, localities, and tribal bodies do not have the resources to
conduct detailed risk analyses in the absence of information indicating that
health risks may occur. As a result of this practical need for information,
hazard identification is discussed in this section in a manner designed to enable
readers to make preliminary decisions regarding further action on fish
advisories. This approach is similar to the screening methodology used for the
identification of the 23 target analytes addressed in this guidance series and is
discussed in Volume 1: Sampling and Analysis in this series (EPA, 1993a).
Although hazard identification is essentially a screening process, it may entail
a complex evaluation of the exposure scenarios and toxicological and biological
properties of contaminants (e.g., bioavailability, degradation, existence of
breakdown products and metabolites). Hazard identification ranges in scope
from the use of existing summary data (e.g., IRIS, or ATSDR Toxicological
Profiles) to a detailed evaluation of each aspect of exposure and risk; the depth
of analysis is usually determined by time and resource availability. For example,
an evaluation of a contaminant's toxicological properties may include an
analysis of all health endpoints likely to occur in the exposure scenarios of
concern. Recent EPA guidance (Habicht, 1992) describes hazard identification
as:
"a qualitative description based on factors such as the kind and
quality of data on humans or laboratory animals, the availability of
ancillary information (e.g., structure-activity analysis, genetic
toxicity, pharmacokinetics) from other studies, and the weight-of-
evidence from all of these data sources. "
Under some circumstances extensive data collection may be undertaken. For
example, to evaluate carcinogenic risk, EPA has recommended the following
information be reviewed in a hazard identification: physical-chemical properties.
4-5
-------
4. RISK ASSESSMENT METHODS
routes and patterns of exposure, structure-activity relationships, metabolic and
pharmacokinetic properties, lexicological effects (including subchronic and
chronic effects, interactions with other chemicals, pathophysiological reactions,
and time-to-response analysis), short-term tests (including mutagenicity and
DNA damage assessment), long-term animal studies, human studies, and
weight-of-evidence (EPA, 1986a). At the state, local, and tribal level, this type
of in-depth analysis is rarely carried out for each health endpoint of a chemical
hazard, due to the time and resources required. Alternatively, data bases, such
as IRIS and the Hazardous Substances Data Bank (HSDB) which summarize
health endpoints and associated risk values, are inexpensively, readily available,
and often consulted in the development of a hazard profile.
4.2.1. Approach for Fish Contaminants
The hazard identification step in risk assessment of chemically-contaminated
fish has been refined by EPA through careful review of the chemical
characteristics considered to be critical parameters in determining human health
risk. These parameters are:
High persistence in the aquatic environment.
High bioaccumulation potential,
Known sources of contaminant in areas of interest,
High potential toxicity to humans, and
High concentrations of contaminants in previous samples of fish
or shellfish from areas of interest (EPA, 1989a).
These characteristics are described in detail in Volume 1: Fish Sampling and
Analysis in this series. Additional information on persistence and
bioaccumulation potential may be obtained from EPA documents such as the
Technical Support Document for Water Quality-Based Toxics Control from the
Office of Water (EPA, 1991b), which contains a brief description of the
bioaccumulation characteristics considered for the development of reference
ambient concentrations (RAC). Readers may also wish to consult the open
literature (s.f., Lyman et al., 1982, Callahan et al., 1979).
4.2.1.1. Toxicological Data
The toxicity of a chemical to humans can be evaluated based on its acute
(short-term) exposure toxicity and/or chronic (long-term) exposure toxicity. The
chronic toxicity of a chemical is usually of primary concern for environmental
toxics; however, the varied consumption patterns of fish consumers
complicate the analysis of fish contaminants. Section 4.3 contains a discussion
of this issue. There are a number of data bases which contain risk values for
various types of chronic toxicity (e.g., carcinogenicity, liver toxicity, and
4-6
-------
4. RISK ASSESSMENT METHODS
neurotoxicity). IRIS is a widely-accepted data source due to the extensive
review conducted on the risk values contained in the data base. EPA's Health
Effects Assessment Summary Tables (HEEAST) are also a frequently-used risk
data base (HEAST, 1992). Other relevant data bases include HSDB, the
National Cancer Institute's Chemical Carcinogenesis Research Information
System (CCRIS), EPA's GENE-TOX, and the National Institute of Occupational
Safety and Health's (NIOSH) Registry of Toxic Effects of Chemical Substances
(RTECS). All of the above data bases except HEAST are available through
TOXNET.2 ATSDR's Toxicity Profiles also provide toxicity data summaries,
4.2.1.2. Contaminant Data
Information on the prevalence and measured concentrations of fish
contamination has been generated through numerous sampling and analysis
programs. EPA has provided a summary of preliminary screening results on the
prevalence of selected bioaccumulative pollutants in fish in Volume 1 of the
National Study of Chemical Res/dues in Fish (EPA 1992b). In addition,
substantial guidance is provided on planning a sampling strategy and
conducting fish contaminant analyses in Volume 1 of this series (EPA, 1993a).
Likely sources of contaminants are often known to state, regional, and tribal
officials or can be identified through a review of data on manufacturing, toxic
releases, or complaints regarding contamination of food, soil, air, or water.
Recommended sources and lists for obtaining data regarding probable
contaminants include:
• EPA recommended target arialytes (see Table 1-1),
• Chemical releases reported in EPA's Toxics Release Inventory
(TRI) data base,
• The Manufacturers' Index,
• EPA priority pollutants,
• State inventories of manufacturers and operations,
• Chemicals identified in industrial and POTW effluents as non-
biodegradable,
• Known spills and contaminants (as reported under CERCLA to the
Office of Emergency and Remedial Response),
• EPA source inventory for contaminated sediments,
• ATSDR's HAZDAT database.
TOXNET is managed by the U.S. Department of Health and Human
Services' National Library of Medicine (Bethesda, MD). For more information,
call (800) 848-8990 (for CompuServe), (800) 336-0437 (for Telenet), (800)
336-0149 (for TYMNET), or (301) 496-6531 for technical assistance.
4-7
-------
4. RISK ASSESSMENT METHODS
• Listing of Superfund (NPL) sites, and
• Common-use chemicals based on practices in the state or region
(e.g., agriculture or fuels).
This information can be used to develop descriptions of local water bodies
incorporating geographic and source-specific data. The geographic distribution
of potential contaminants can be used to guide the selection of monitoring sites
for sampling and analysis of potentially contaminated fish.
Volume 2 of the National Study of Chemical Residues in Fish (EPA, 1992b)
provides an example of how information on the first three characteristics of
chemical contaminants listed above (high persistence in the aquatic
environment, high bioaccumulation potential, and high concentrations of
contaminants in previous samples of fish or shellfish from areas of interest) can
be summarized to form the basis for a hazard evaluation. The document
provides a summary of the results of the National Bioaccumulation Study,
correlates contaminant prevalence with sources of pollutants, and provides a
brief description of the chemical and toxicological properties of 37 chemicals
and chemical groups (EPA, 1992b).
4.2.1.3. Sources of Exposure
Hazard identification may also include a comprehensive evaluation of all sources
of exposure, including those which augment the primary exposure of concern,
to obtain an estimate of total exposure. For fish contaminants, a
comprehensive exposure evaluation would involve an evaluation of exposures
from other sources such as air, water, soil, the workplace, or other foods,
including commercially-caught fish. In some cases, in fact, other routes of
exposure may contribute more to overall contaminant body burden than does
contaminated non-commercial fish. It is beyond the scope of this guidance
document to provide direction on evaluating exposures occurring via other
media; however, readers are encouraged to include an assessment of other
sources of exposures in their hazard evaluations.
If exposure from non-commercial fish consumption were added to already
elevated exposure levels arising from other sources, it could produce an overall
exposure associated with adverse health effects. Under such circumstances,
a more stringent fish consumption limit (or some other risk management option)
may be needed. Readers may wish to determine whether such an evaluation
is warranted through consideration of the likelihood that exposures are
occurring via non-fish routes, and the availability of data and resources to carry
out a comprehensive exposure evaluation.
4-8
-------
4. RISK ASSESSMENT METHODS
EPA's Office of Water, in conjunction with the Interagency Relative Source
Contribution Policy Workgroup, is currently developing guidance on the use of
a "Relative Source Contribution" (RSC) approach. According to the preliminary
information available on this approach:
The RSC concept could be used in fish advisory activities. The
amount of exposure from fish consumed is determined along with
the estimated exposure from all other relevant sources (e.g.,
drinking water, food, air, and soil) for the chemical of concern. By
comparing the overall exposure with the Reference Dose, it can
then be determined whether the amount of total exposure to the
chemical may result in an adverse effect and warnings can be
issued regarding the safety of consuming such fish (Borum,
1994).
The CERCLA office at EPA, which offers assistance on multimedia assessments
of hazardous waste sites, may also be consulted for information on methods
to estimate background levels of various contaminants. They have developed
guidance documents which may be useful to those readers who plan to
conduct comprehensive exposure assessments. See Appendix B for a listing
of sources of additional information.
4.2.2. Assumptions and Uncertainty Analysis
Hazard identification, as described in this guidance, is a screening process used
to select the chemicals and exposure scenarios of greatest concern. As a
screening process, it uses simplifications and assumptions in each step of the
process. Because each aspect of hazard is not examined in its entirety, the
process generates some uncertainty.
Uncertainty is introduced by the variability in persistence and bioaccumulation
potential of chemicals which may occur in untested media. The behavior of
chemicals in all types of media cannot be anticipated. For example, interactions
of the target analytes in sediments containing multiple chemical contaminants
may cause chemicals to change their forms as well as their bioaccumulation
and persistence characteristics. For example, binding of the target analyte to
organic matter may cause it to become more or less persistent or available for
bioaccumulation, or decomposition may occur, producing metabolites which
have significantly different properties than those of the original target analyte.
These chemical and biological interactions are more likely to occur in a complex
system (e.g., a hazardous waste site), with relatively unstable chemicals, and
with metals having multiple valence states.
4-9
-------
4. RISK ASSESSMENT METHODS
The persistence of a chemical in the aquatic environment and its
bioaccumulative potential are based on its physical and biochemical properties.
Although the critical information is available for many chemicals of concern, it
is not available for all chemicals. For example, chemicals which have been
recently introduced into the environment may not be well-characterized in terms
of their persistence and bioaccumulation potential. Consequently, there is the
potential for under- or overestimating the risk they pose to human health.
Estimation of chemical toxicity can be a source of significant uncertainty in the
hazard identification process. A toxicity evaluation incorporates data on a
variety of health endpoints and usually requires that human toxicity estimates
be derived from studies in experimental animals. There are often insufficient
data in the toxicological literature to fully characterize the toxicity of a
chemical. Some types of toxicity are well-described in the toxicological and
risk literature. Others, such as developmental toxicity, neurotoxicity, and
immunotoxicity, have only recently become subjects of intensive research.3
Consequently, there are limited data for most chemicals on these types of
effects. Uncertainties associated with toxicity and health risk values (e.g., q1 *s
and RfDs) are discussed in Section 4.3.
The two remaining characteristics of hazard identification (known sources of
contaminants in areas of interest and high concentrations of contaminants in
previous samples of fish or shellfish) are excellent indicators of potential hazard.
A major uncertainty associated with these characteristics arises from the
potential for omitting areas not known to be contaminated from sampling
programs. During an era of limited resources, it is a commpn, but not
necessarily valid, assumption that known contaminated areas should be the
focus of evaluation and action. Given an array of known contaminated sites,
attempts to identify additional contamination may appear unnecessary.
However, it is recommended that readers conduct a detailed review of potential
contamination sources for all waterbodies before determining whether or not
adequate hazard identifications have been conducted.
Because the goal of the risk assessment process is protection of human health,
it is typically designed to provide the maximum protection against
i//7cterestimating risk. Therefore, the hazard identification step in the risk
assessment process may result in the inclusion of chemicals or exposure
situations which, later in the process, are found not to pose significant health
risks. This type of approach is taken because the consequences of
3 Although studies of developmental toxicity date from the 19th century,
there has been a dramatic increase in both epidemiological and toxicological
studies in recent years.
4-10
-------
4. RISK ASSESSMENT METHODS
underestimating risk, or excluding a chemical which poses a public health
hazard, are potentially more serious than the risks of overestimating risk at this
early stage of evaluation.
The hazard identification process forms the basis for decisions regarding those
chemicals and exposure scenarios which warrant further analysis. It entails the
collection and evaluation of information regarding toxicity, bioaccumulation
potential, persistence, and prevalence. Although there is uncertainty associated
with this aspect of the assessment, quantitative evaluation of the uncertainty
can best be conducted in later steps in the risk assessment process. Because
each aspect of hazard identification is carried out in more detail in the risk
assessment steps which follow, the uncertainties and assumptions can be
better refined and quantified during subsequent steps. The information
generated on toxicity and exposure in this process also serves as the basis for
the subsequent dose-response evaluation and exposure assessment steps in the
risk assessment.
4.3. Dose-Response Assessment
This section briefly outlines the current EPA methodology for carrying out a
dose-response assessment. Additional information on dose-response
evaluations can be obtained from the references cited in Section 6, and in
Appendix B.
A dose-response relationship expresses the correlation between exposure and
health effects. To evaluate this relationship, the results of human and animal
studies with controlled and quantified exposures are reviewed. This evaluation
may focus on specific types of health effects, or be designed to encompass all
adverse effects which could occur under any plausible exposure scenario.
Dose-response evaluations result in the derivation of toxicity values such as
cancer potencies and Reference Doses.
Actual fish consumption patterns may not correspond well to the typical
periods of exposure which are studied in toxicity tests (i.e., acute or chronic
exposure). Many fish consumers ingest intermittent doses of varying sizes and
may consume fish over a short period of time (e.g., a vacation) or on a regular
basis over a lifetime. The potentially large, intermittent dose (bolus dose) has
not been evaluated in most toxicity studies. Chronic exposure studies
commonly use daily dosing and acute studies may use one or a few very large
doses over a very short time period (e.g., two to three days). Short-term
dosing is frequently used in developmental toxicity studies (discussed in
Section 5); two of the 23 target analytes have RfDs based on developmental
toxicity (methylmercury and PCBs).
4-11
-------
4. RISK ASSESSMENT METHODS
Fish consumption patterns are discussed in more detail in Volume 3; however,
it is important to be aware that there is not information available on the impact
of bolus dosing when developing fish advisories. The methods used to
calculate fish consumption limits allow the daily RfD to be aggregated over a
period of time (e.g., ten days or one month) into one or more meals. Thus the
consumption averaged over the ten days or one month corresponds to an
average daily dose indicated by the RfD. However, the actual dose which may
be consumed in one day can be ten times (in the case of a ten-day advisory)
or thirty to sixty times (in the case of a 30-day advisory) the daily RfD.
A bolus dose may not be a problem for many individuals; however, it is a
concern for those who are particularly susceptible to toxics. For example, a
relatively large single dose may be problematic for those with decreased ability
to detoxify chemicals (e.g., children and the elderly) and those with special
susceptibilities (e.g., persons taking certain medications, children, and pregnant
or lactating women). Potential adverse effects in some subgroups are noted for
many of the target analytes in Section 5. For example, organochlorines may
interact with some commonly prescribed Pharmaceuticals; consequently,
individuals using specific drugs may find the efficacy altered by large doses of
contaminants which interact with their drug-metabolizing systems. Infants
have an immature immune system and may be less able to detoxify certain
chemicals. Children have rapidly developing organ systems which may be more
susceptible to disruption. A recent NAS report. Pesticides in the Diets of
Infants and Children (NAS, 1993), concluded that children age zero to eighteen
years are substantially different from adults in the relative immaturity of their
biochemical and physiological functions and structural features. These
differences can alter responses to pesticides, especially during windows of
vulnerability, leading to permanent alteration of the function of organ systems.
The authors, who included pediatricians, toxicologists, epidemiologists and
other health specialists, concluded that:
"[ilnfants and children may exhibit unique susceptibility to the
toxic effects of pesticides because they are undergoing rapid
tissue growth and development, but empirical evidence to support
this is mixed"
and
"[tlraditional approaches to toxicological risk assessment may not
always adequately protect infants and children" (NAS, 1993).
Although the focus of the NAS report was on pesticides (many of the target
analytes are currently or were formerly used as pesticides) much of the analysis
is relevant to other chemical exposures as well. Readers may wish to refer to
4-12
-------
4. RISK ASSESSMENT METHODS
the NAS report for a more complete discussion of various related topics of
interest including neurotoxicity in children, various dosimetry scaling methods,
and consumption patterns.
A dose-response evaluation has already been carried out by EPA for the 23
target analytes addressed in this guidance series. These evaluations resulted
in the calculation of risk values: either cancer potency factors (q^s).
Reference Doses (RfDs), or both. The risk values used in this work and cited
in the toxicological discussions in Section 5 were obtained primarily from EPA's
IRIS data base. All data searches were carried out in 1993 or early 1994. For
chemicals lacking IRIS risk values, values were obtained from EPA's Office of
Pesticide Programs (OPP) or EPA's Health Effects Assessment Summary Tables
(HEAST, 1992).
A comprehensive dose-response evaluation requires an extensive review of both
the primary literature, including journal articles and proceedings, and the
secondary literature, such as books, government documents, and summary
articles. It is typically very time-consuming and requires data evaluation by
toxicologists, epidemiologists and other health professionals. Because risk
values are available for the target analytes, it is not recommended that readers
undertake further detailed dose-response evaluations for these chemicals.
However, new data is continually being generated which may require
evaluation. In addition, chemicals which are not included in the target analyte
list may require analysis. It is strongly suggested that an evaluation begin with
a review of current government documents on a chemical. In many cases,
EPA, FDA, or the Agency for Toxic Substances and Disease Registry (ATSDR)
conduct detailed dose-response evaluations when a chemical is identified as an
environmental pollutant or when new data become available. This may save
readers hundreds of hours of research by providing data and risk values.
4.3.1. Acute Exposure Toxicity
Acute exposures are those which occur over brief periods of time, e.g., a few
hours or days. They do not necessarily result in an acute (immediate) response,
and so the exposure and response periods must be considered separately. The
pesticide paraquat is an example of a chemical which usually causes no
immediate response to acute exposure but often results in fatal outcomes after
several days or weeks.
i
Acute exposures have traditionally been considered primarily in the realm of
occupational health or poisoning incidents, rather than environmental health,
because the brief, low-level-exposure associated with most environmental
exposures do not usually result in overt symptoms. The exceptions to this
have been individuals with allergies or chemical sensitivities. However, there
4-13
-------
4. RISK ASSESSMENT METHODS
has been a very limited analysis of most environmental pollutants with regard
to both the nature and the critical dose for acute non-lethal effects. Acute
exposures are of concern for fish contaminants, due to the ability of fish to
bioaccumulate chemical contaminants to fairly high levels, and the relatively
large and frequent meals (i.e., bolus doses) which may be consumed by sport
and subsistence fishers and their families.
The goal of an acute exposure dose-response evaluation is to identify a
threshold exposure level below which it is safe to assume no adverse health
effects will occur. There are no widely-used methods within EPA for setting
such exposure levels. Prenatal acute exposures are discussed in Section 5 as
a special case because there are substantial animal data on short-term prenatal
exposure for many target analytes. Additional guidance on acute exposure risk
assessment methods may be provided in future revisions to this document.
EPA welcomes comments and recommendations on this and other
methodologies.
Most toxicological information currently available on acute exposure is in the
form of LD50s from animal studies. These studies identify the (usually single)
dose which was lethal to 50 percent of the study animals via a specific
exposure route. The data are used primarily to give a qualitative sense of the
acute toxicity of a chemical. The information is generally used for purposes of
planning industrial and application processes, transportation, handling, disposal,
and responses to accidental exposures. The data are also used for regulatory
purposes and to select the less-toxic alternatives among a group of chemical
options. LD50s may also be used to evaluate ecological toxicity.
LD50s are not easily adaptable to an evaluation of the human response to acute
exposures. Because they are focused on the level at which 50 percent of
animals die, they do not provide information on other types of toxic responses,
including those which led to death. Fatal toxic responses may be substantially
different from the responses observed at lower, but still acutely toxic, doses.
The LD50 also does not provide information on the exposure threshold for
lethality, which is always lower (and may be much lower) than the exposure
level required to kill 50 percent of the study subjects. For these reasons, the
LD50s have very limited utility in identifying a threshold for effects of acute
exposure. LD5Os may, however, provide comparative information regarding
differences in sensitivity between various age groups or sexes which can be
used to qualitatively evaluate toxicity.
Human and veterinary poisoning centers (e.g., Poison Control Centers) are
primary sources of data on acute exposure effects and thresholds. The
poisoning data are limited, however, in many of the same ways in which LD50
data are limited. The severe responses which often lead to the reporting of an
4-14
-------
4. RISK ASSESSMENT METHODS
incident do not indicate the level at which more moderate responses may
occur. In addition, the dose is often not known or is estimated imprecisely.
The poisoned individual may have predisposing medical conditions, or have
been exposed concurrently to other chemicals (including medicines) which
affect the nature of their responses.
EPA's Health Advisories also provide some acute exposure information and
guidance regarding one- and ten-day exposure limits for children with an
assumed 10-kg body weight (available from the EPA's Office of Water). The
Toxicological Profiles developed by ATSDR also contain some information on
acute effects. Additional information may be obtained from HSDB. A
qualitative summary of acute effects and estimated human lethal doses are
provided for most target analytes in Section 5.
4.3.2. Chronic Exposure Toxicity
Chronic exposure toxicity refers to effects resulting from multiple exposures
occurring over a significant period of time (IRIS, 1993). For humans, this
usually means exposures over months or years. For animals in studies used to
evaluate human chronic toxicity, the temporal definition of chronic exposure
depends on the species, but is usually defined as a significant portion of the
animal's life. Chronic studies are reviewed in order to determine critical effects
for specific chemicals. The critical effect is the first adverse effect, or its
known precursor, that occurs as the dose rate increases (IRIS, 1993).
Subchronic exposures in toxicity studies (usually three months to one year) may
also be used to evaluate chronic toxicity.
To protect against chronic toxicity resulting from exposure to contaminants,
EPA has developed Reference Doses (RfDs). The RfD is defined as "an
estimate (with uncertainty perhaps spanning an order of magnitude) of a daily
exposure to the human population (including sensitive subgroups) that is likely
to be without an appreciable risk of deleterious effects during a lifetime." (EPA,
1987). The use of IRIS RfDs is recommended for evaluation of chronic
exposure toxicity of the target analytes. These are listed in Table 2-2 in
Section 2, and again in Section 5. Additional chronic exposure toxicity data for
the target analytes are presented in Section 5, with a brief description of how
estimated exposure limits could be calculated based on chronic toxicity. Note
that the RfDs listed in IRIS are subject to change as new methodologies and
toxicological data become available. Readers are advised to consult the IRIS
data base to ensure that they are using the most up-to-date toxicity values.
RfDs calculated for chronic non-carcinogenic effects reflect the assumption that
for non-carcinogens and non-mutagens, a threshold exists below which
exposure does not cause adverse health effects. This approach is taken for
4-15
-------
4. RISK ASSESSMENT METHODS
non-carcinogens because it is assumed that for these types of effects there are
homeostatic, compensating, and adaptive mechanisms which must be
overcome before a toxic endpoint is manifested (IRIS, 1993).4 It is
recommended that concern be directed to the most sensitive individuals in a
population, with the goal of keeping exposures below calculated RfDs for them
{IRIS, 1993). RfDs are generally expressed in terms of milligrams of
contaminant per kilogram consumer body weight per day (mg/kg-d).
Methods used to calculate RfDs are described in the IRIS Background Document
1A, Reference Dose (RfD): Description and Use in Health Risk Assessments
(IRIS, 1993) and in two recent publications on EPA risk assessment methods
(Dourson et al., 1992; Abernathy and Roberts, 1994). The methods are also
described briefly in Section 5.3.
4.3.3. Carcinogenicity
EPA has developed guidelines, published in the Federal Register, for conducting
cancer risk assessments (EPA, 1986a).5 EPA (and many other risk assessors)
takes a probabilistic approach to estimating carcinogenic risks. Cancer risk is
assumed to be proportional to cumulative exposure, and at low exposure levels
may be very small or even zero. EPA assumes that carcinogens do not have
"safe" thresholds for exposure; i.e., any exposure to a carcinogen may pose
some cancer risk. Carcinogenic risk is usually expressed as a cancer potency
(q., ) value with units of risk per mg/kg-day exposure. Risk may also be
estimated for specific media. When risks in air and water are provided, these
are referred to as unit risks because they are expressed as risk per one unit of
concentration of the contaminant in air or water.
The cancer potency value is derived from dose-response data obtained in an
epidemiological study or a chronic animal bioassay. Because relatively high
doses are used in most human and animal toxicity studies, the data are usually
extrapolated to the low doses expected to be encountered by the general
population. The dose-response data from one or more studies are fit to
standard cancer risk extrapolation models which usually incorporate an upper-
Some chemicals such as lead, however, appear to show non-threshold
non-carcinogenic effects.
5 Subsequently, new information on a variety of issues related to cancer
risk assessment has become available (e.g., mechanisms of carcinogenesis,
weight-of-evidence classification, study design and interpretation, and dose-
response assessment. EPA is currently reevaluating its cancer risk assessment
methodology.
4-16
-------
4. RISK ASSESSMENT METHODS
bound estimate of risk (often the 95 percent upper bound). This provides a
margin of safety to account for uncertainty in extrapolating from high to low
doses and variations in the animal bioassay data (IRIS, 1993). The model most
often used to calculate the cancer potency is the linearized multistage model
(LMS). Cancer potency is estimated as the 95 percent upper confidence limit
of the slope of the dose-response curve in the low-dose region. This method
provides an upper estimate of risk; the actual risk may be significantly lower,
and may be as low as zero. It is important to recognize that the use of this
model results in risk estimates that are protective, but not predictive of cancer
incidence (Velazquez, 1994).
Cancer potencies may be calculated for both oral and inhalation exposure.
There are four major steps in calculating cancer potencies:
• Identify the most appropriate dose-response data,
• Modify dose data for interspecies differences,
• Develop an equation describing the dose-response relationship,
and
• Calculate an upper confidence bound on the data.
These are described in more detail in EPA (1986a), and in texts on risk
assessment. Cancer potency values are provided for those target analytes
which EPA has determined have sufficient data to warrant development of a
value. The values are listed in Table 2-2 and discussed in Section 5; they
were used to calculate the consumption limits in Section 3.
As discussed under chronic toxicity above, children may have special
susceptibilities to some chemicals and some types of effects. Exposure to a
carcinogen early in life may generate greater risk than exposure later in life.
This is due to a variety of factors including the rapid growth and development
ongoing in children and the proportionally-greater consumption by children of
some foods. The experimental literature on this subject is not conclusive and
readers may wish to review the NAS report to obtain additional information
(NAS, 1993).
4.3.4. Mutagenicity/Genotoxicity
Mutagenicity and genotoxicity data are not generally used to develop risk
estimates by themselves, although they are frequently used in conjunction with
other information to evaluate other toxicity endpoints (e.g., cancer). There is
a wide variety of assays designed to assess the mutagenicity of chemicals;
however, there is a limited amount of mutagenicity dose-response data which
can be used in quantitative risk assessment. The majority of data involve in
vitro test systems, which can provide only qualitative evidence of mutagenicity.
4-17
-------
4. RISK ASSESSMENT METHODS
The evaluation of weight-of-evidence (WOE) for carcinogenicity, carried out by
EPA for all chemicals having a cancer classification, includes an evaluation of
mutagenicity data. Information on genetic toxicity also needs to be considered
when developing risk values for developmental and reproductive system
effects. Mutagenicity data are summarized in the chemical discussions of
target analytes in Section 5. Readers are urged to consider this information in
reviewing the toxicity of target analytes. Because information is less readily
available on genetic toxicity and mutagenicity than on other types of risk
assessment, and because this type of toxicity is relevant to evaluating
developmental toxicity, a brief summary of the current EPA guidelines on these
types of toxicity have been included in Appendix A.
4.3.5. Developmental Toxicity
Developmental toxicity has been a recognized medical concern, research
subject, and impetus for restricting exposures of pregnant women to
developmental contaminants for several decades. However, it is not as well-
studied as other health effects such as cancer, and significant gaps in our
understanding of causality and appropriate protective measures remain.
Developmental toxicity incorporates a wide range of effects involving all organ
systems in the body. Prenatal and lactational exposure involve indirect
exposure of the developing fetus; the effective dose may vary with the period
of exposure and the specific chemical. In the last two decades, researchers
have determined that the hypothetical maternal barrier, in the past thought to
provide protection for the fetus during the prenatal period, does not effectively
exist. In fact, prenatal exposure may be especially risky due to the rapid cell
replication and differentiation which occurs in the fetus prior to birth. These
same processes also occur at elevated rates in children and adolescents,
causing them to be more susceptible to some chemical-induced toxicity than
adults. Chemical exposures which cause alterations in the cell replication and
developmental processes can lead to serious birth defects, miscarriage,
stillbirth, developmental delays, and a variety of other adverse effects. A large
number of toxic chemicals which have been tested in recent years have
demonstrated developmental toxicity in animal test systems. Consequently,
the exposure of pregnant women to toxic chemicals has become an area of
considerable concern.
Many developmental effects may have environmental causes; however it is
difficult to establish a causal link in epidemiological studies due to confounders
which arise from the variability in human exposure. It has been estimated that
20 percent of the developmental defects observed in children are due to genetic
causes, 10 percent to known factors, and 70 percent to unknown factors (EPA,
4-18
-------
4. RISK ASSESSMENT METHODS
1991 a); some portion of the 70 percent may be attributable to environmental
exposures.
«
Section 5 provides a brief overview of definitions, some issues related to
developmental toxicity risk assessment:, an outline of methods currently
recommended by EPA for conducting dose-response evaluation, and examples
of calculations used to identify risk-based maximum exposure limits. This is
followed by a summary of toxicological data for the 23 target analytes which
readers are encouraged to consult to evaluate potential developmental risks and
identify appropriate exposure limits for populations of concern.
4.3.6. Multiple Chemical Exposures: Interactive Effects
Most humans are simultaneously exposed to a number of environmental
contaminants. Risk evaluations, however, typically proceed on a chemical-by-
chemical basis. Similarly, the development of risk-based exposure guidelines
typically focuses on the effects of exposure to chemicals individually rather
than as a group. In many cases, the individual exposures and/or risks are then
summed to estimate risks or safe exposure levels for a group of chemicals.
EPA provides guidance on mixtures in risk assessments in Guidelines for the
Health Risk Assessment of Chemical Mixtures (EPA, 1986d). The guidelines
advise the use of the additive approach when data are available only on
individual mixture components. Section 2 provides a method for calculating
exposure limits for multiple chemical occurrence in single or multiple species.
The approach is recommended for use when chemicals have the same health
endpoints and mechanisms of action. It does not address chemicals with
dissimilar actions.
The 1986 Guidelines also address circumstances when data are available on
antagonistic or synergistic interactions. They state that "information must be
assessed in terms of both its relevance to subchronic or chronic hazard and its
suitability for quantitatively altering the risk assessment". These two criteria
are essential for selection of interactive data applicable to quantitative risk
assessment. However, the criteria preclude the use of most interactive data
in risk assessments of long-term exposures, because many interactive studies
focus on short-term exposure. An additional complication is introduced to this
type of analysis for mixtures containing more than two chemicals. For those
groups, it is necessary to ascertain whether the presence of additional
chemicals in the mixture will alter any known interactions between any two
chemicals having interactive data (EPA, 1986d).
The type of information which is often available (acute effects interactions and
mechanisms of action) is not readily applicable to the quantitative assessment
4-19
-------
4. RISK ASSESSMENT METHODS
of chronic health risks of multiple chemical exposures (EPA, 1986d). The
guidelines recommend that this type of information be discussed in relation to
its relevance to long-term health risks and interactive effects, without making
quantitative alterations in the risk assessment. Much of the interactive
information included in the specific chemical discussions contained in Section
5 was obtained from the ATSDR Toxicological Profiles for various chemicals.
Readers are encouraged to consult these ATSDR documents if they require
interactive data.
The information obtained from ATSDR, and/or which may be implied from the
toxicological nature of many of the target analytes, is related to the chemical's
interaction with basic processes, such as metabolism. When these functions
are altered (e.g., by the induction of microsomal enzymes), the metabolism of
other endogenous or exogenous chemicals may be altered. This is particularly
problematic for individuals using pharmaceutical drugs to address medical
conditions. As the DDT discussion in Section 5 notes, alteration in metabolism
of medications may require adjustment of dosages. This is not a hypothetical
problem; exposure to various chemicals has reportedly resulted in altered
response to medications. Information regarding these types of effects are
discussed in Section 5 for the target analytes.
EPA has recently developed a data base to disseminate available information on
interactive effects of chemical mixtures. This data base, called MIXTOX,
contains summaries of information from primary studies in the open literature
on binary mixtures of environmental chemicals and pharmaceutical chemicals.
Data provided include the duration of the study, animal species, dose ranges,
site, effects, and interactions. Available MIXTOX information on the target
analytes is presented in Section 5. The majority of data obtained through
MIXTOX consisted of the results of acute studies. Many studies indicated
additive effects. Other types of interactions (e.g., inhibition, synergism) were
usually not provided. The relevance of this information to specific water bodies
will depend upon the chemical mixtures which are known to occur, based upon
fish sampling results. In the absence of quantitative information on interactive
effects, these guidelines suggest the use of an additive approach to evaluation
of chemical mixtures for carcinogens and for noncarcinogens which are
associated with the same adverse health endpoints. The equation used in this
approach is presented and discussed in Section 2.
4.3.7. Assumptions and Uncertainties
Numerous assumptions are required to develop risk values from dose-response
data. Uncertainties arise from the assumptions, from the nature of the dose-
response data, and from our imperfect understanding of human and animal
physiology and toxicology. Depending on the quality of the studies, there may
4-20
-------
4. RISK ASSESSMENT METHODS
also be uncertainty regarding the nature and magnitude of the effects observed
in toxicological and epidemiological studies. However, evaluation of study
quality is a complex process and involves such diverse topics as animal housing
conditions and pathological evaluations. Often there is not sufficient
information provided in study summaries (either in a journal article or report) to
fully evaluate the quality of the study and the assumption must be made that
good laboratory practices and scientific methods were followed.
Major assumptions which are used in the evaluation of dose-response data are
discussed at length in the EPA risk assessment guidance documents on specific
toxicities (e.g., for carcinogenicity, numerous assumptions are discussed
including: the selection of the dose-response model, use of benign tumors in
estimating response, use of the upper bound estimate of the slope, and use of
surface area instead of body weight to adjust dose; EPA, 1986 a,c,e). Many
of these assumptions are in this document in sections dealing with specific
types of toxicity.
A critical assumption underlying all animal-human extrapolations is that there
is a relationship between toxicity in test animals and the toxicity anticipated in
humans. There can be significant differences in metabolism and other
physiological aspects of study animals and the human population (e.g.,
absorption, metabolism, and excretion). Although many of these aspects are
well-characterized, the relationship between interspecies differences and the
toxicity of specific chemicals is usually not known. There is also uncertainty
regarding the appropriateness of the test species for evaluation of a chemical's
effects on humans. Generally, the species of animal which most closely
resembles humans in response to the toxicity of a particular chemical is used
in the risk assessment. When such information is not available (as is often the
case) the species of animal which is most sensitive to a particular effect is used
in the evaluation of that effect for a chemical. Although the existence of a
relationship between animal and human toxicity is acknowledged by most
scientists, there is not universal consensus on the nature of the relationship for
many chemicals and endpoints (e.g., male rat kidney toxicity associated with
alpha-2u-globulin may not be applicable to humans).
A second critical assumption is the existence of a threshold for most non-
carcinogens and no threshold for carcinogens. The threshold issue is under
evaluation for many chemicals and endpoints (e.g., epigenetic (non-genetic)
carcinogens, developmental effects). Issues of this type will be resolved as
more information becomes available on the basic mechanisms of toxicity and
actions of specific chemicals. Future revisions of this document will provide
additional guidance as it becomes available.
4-21
-------
4. RISK ASSESSMENT METHODS
Additional uncertainty regarding dose rate and the duration of exposure are
generated by the use of test animals. Many animal studies are conducted for
the lifetime of the animals; however, the human lifetime is significantly longer
than the two-year study period of the usual experimental subjects (e.g., dogs
or rodents), which may impact bioaccumulation and toxicity. When human
studies are used as the basis for risk estimates, they are usually of
occupationally-exposed individuals, who were exposed intermittently during
adulthood over two to three decades, rather than continuously exposed over
a lifetime. Often they are not followed into old age, when many effects
become clinically detectable. In addition, human exposures are often
confounded by concurrent exposure to other chemicals. Consequently, the use
of human studies also introduces numerous uncertainties to the toxicity
evaluation process.
Various assumptions are made in most risk assessments regarding the use of
numeric adjustments for extrapolation of study results from animals or human
studies to the general population. The extrapolation models which are used to
estimate individual or population risks from animal or human studies introduce
"margins of safety" to account for some aspects of uncertainty- These models
are designed to provide an upper bound on cancer risk values and a
conservative Reference Dose (RfD) for non-carcinogens. Uncertainties arise
from the application of uncertainty and modifying factors in the calculation of
RfDs. These factors are based upon the best available scientific information
and are designed to provide a safe margin between observed toxicity and
potential toxicity in a sensitive human. The RfD is considered to be an estimate
with uncertainty spanning approximately perhaps one order of magnitude. EPA
considers the RfD to be a reference point to be used in estimating whether
adverse effects will occur (IRIS, 1993). The IRIS Background Documentation
has provided additional insight into the uncertainty inherent in RfDs:
"Usually doses less than the RfD are not likely to be associated
with adverse health risks, and are, therefore, less likely to be of
regulatory concern. As the frequency and/or magnitude of
exposures exceeding the RfD increase, the probability of adverse
effects in a human population increases. However, it should not
be categorically concluded that all doses below the RfD are
"acceptable" (or will be risk-free) and that all doses in excess of
the RfD are "unacceptable" (or will result in adverse effects)"
(IRIS, 1993).
For carcinogens, the upper 95 percent confidence bound on the linear
component of the linearized multistage model is often used in estimating a
cancer potency to introduce a safety margin. It is assumed that this provides
a plausible upper bound estimate of potency in the human population.
4-22
-------
4. RISK ASSESSMENT METHODS
Many numerical assumptions related to anatomy and physiology are used in
calculating risk values (e.g., average adult body weight of 70 kg, animal dietary
consumption estimates). The application of these assumptions depends on the
type of data which is being used. These assumptions are typically based on a
substantial amount of information on average or mean values. However,
individual variations within the human population generate uncertainty related
to the application of the assumptions.
Uncertainty is significantly related to the amount and quality of toxicological
and epidemiological data which is available. There is a greater degree of
certainty for chemicals having human epidemiological studies which encompass
a variety of population subgroups over a dose range. However, this type of
data is not usually available. Uncertainty related to the data base is often
endpoint-specific. For example, there may be a substantial amount of data
regarding carcinogenic effects but little information on developmental toxicity.
This is the case for many of the target analytes discussed in Section 5.
Selection criteria for studies are listed for chronic toxicity, carcinogenicity,
developmental toxicity, and mutagenicity in this section. Where the most
appropriate types of data are not available (based on these selection criteria)
there is usually greater uncertainty regarding the risk values and risk estimates
which are calculated. Many of the criteria address the quality of the studies
used to estimate dose-response parameters. Weight-of-evidence guidelines,
also discussed in this section for specific toxicity types, provide useful insight
into the adequacy of the data supporting a risk value.
Bioassays conducted on single cell lines generate greater uncertainty than
animal studies due to their isolation from normal physiological processes.
However/ some types of effects can be most efficiently studied using these
tests. Various types of mutagenicity and cellular level assays provide insight
into the potential for genetic damage and damage to specific types of cell
systems. This data is very difficult to interpret in the context of human risk
because the relationship between study results and human effects has not been
well-characterized. This type of study is most often used to support other
study results (e.g., positive mutagenicity studies support animal studies
indicating carcinogenicity).
Certain chemicals have such limited data for one or more toxic effects that
toxicity reference values cannot be determined. Some of these chemicals are
poorly characterized for all known/suspected toxicity endpoints. For other
chemicals, data may be well-characterized for certain toxic effects, .but
inadequate for others. For instance, the carcinogenicity of organochlorines has
been well-characterized in animals and humans, but other toxic endpoints,
including systemic effects and reproductive effects, have not been extensively
4-23
-------
4. RISK ASSESSMENT METHODS
investigated. Limitations for the 23 contaminants in this assessment are
described in detail in Section 5.
EPA does not recommend specific factors for modifying toxicity data in cases
where these data are so limited that a dose-response relationship cannot be
determined. However, as the above examples show, lack of toxicity reference
values for a given chemical does not necessarily mean that the chemical causes
no effect. Therefore, readers will need to evaluate if the lack of specific kinds
of toxicity data affect the adequacy of protection afforded by the consumption
limit. For example, if the chemical is a suspected developmental toxin, but
quantitative developmental toxicity data are lacking, readers may determine
that a consumption limit based on other health endpoints is not sufficiently
protective of women of reproductive age and children.
In summary, uncertainty may be generated by many components of a dose-
response evaluation. Some of these are dealt with quantitatively through the
application of uncertainty factors, modifying factors, or the use of an upper
bound estimate. Others may be referred to qualitatively, through a discussion
of data gaps or inferential information (e.g., studies that appear to show greater
susceptibility at certain ages). The goal of providing the qualitative information
on uncertainty is to give the risk assessor and decision makers sufficient
information on the context and support for risk values and estimates so that
they can make well-informed decisions.
4.4. Exposure Assessment
This section is meant to provide readers with a brief overview of EPA exposure
assessment methodology. Readers wishing to do exposure assessments are
advised to read the more detailed documents listed in Appendix B.
Exposure assessment of contaminants in fish involves six components:
• Chemical occurrence in fish,
• Geographic distribution of contaminated fish,
• Individual exposure assessment,
• Population exposure assessment,
• Multiple species exposure, and
• Multiple chemical exposure.
Each of these components is discussed below.
4-24
-------
4. RISK ASSESSMENT METHODS
4.4.1. Chemical Occurrences in Fish
Contaminant concentrations vary among different fish tissues, fish species, fish
sizes, and contaminants present in ecosystems. Chemical contaminants are not
distributed uniformly in fish tissues; some toxics bind primarily to lipids and
others to proteins. Fatty and/or larger fish often contain higher organic
contaminant concentrations than leaner, smaller fish. Knowing how
contaminants differentially concentrate iri fish enables risk managers to advise
fish consumers on alternative fishing and cooking practices to minimize
exposure.
Many readers will have information on the geographic distribution of
contaminants in fish from their sampling and analysis programs. Others may
need to identify areas of likely contamination. This topic is discussed in
Guidance for Assessing Chemical Contamination Data for Use in Fish
Advisories,, Volume 1: Fish Sampling and Analysis (EPA, 1993a). This section
only briefly reviews likely patterns of chemical distribution based on chemical
properties and other factors. Such geographic information is important in
population exposure assessment and for risk communication; readers are
encouraged to develop maps showing areas of fish contamination which,
combined with demographic information, help target exposed fisher populations
for additional outreach efforts.
Volume 1 of this series provides comprehensive guidance on cost-effective,
scientifically-sound methods for use in fish contaminant monitoring programs
designed to protect public health. It is designed to promote consistency in the
data states use to determine the need for fish consumption advisories. By
standardizing protocols across regions, risk managers can avoid significant
differences in advisories when actual concentrations of contaminants in fish are
very similar.
Volume 1 suggests that screening values be compared to annual sampling and
analysis data to determine where problems may exist. The document also
discusses sampling design and field procedures for collecting and analyzing fish
tissue samples for pollutant contamination. It discusses specific cost-effective
analytical methods and QA/QC procedures and identifies certified reference
materials and federal agencies that conduct interlaboratory comparison
programs. Procedures for data reporting and analysis that are consistent with
the development of the National Fish Tissue Data Repository are also included.
Information on contaminant distributions in different types of fish and fish
tissues and across geographical areas is required for a number of reasons.
Differential concentrations of contaminants in fish tissues and across fish
species affect fish consumer exposures due to differences in individual
4-25
-------
4. RISK ASSESSMENT METHODS
consumption practices. The geographic origins and modes of transport of
chemical contaminants determine the extent and location of these chemicals
in fish. Identifying areas of high contamination enables readers to choose initial
screening sites and focus limited resources on fisher populations most at risk
from consuming contaminated fish.
4.4.1.1. Distribution in Fish Tissues6
Chemical contaminants are not distributed uniformly in fish. Fatty tissues, for
example, will concentrate organic chemicals more readily than muscle tissue.
Muscle tissue and viscera will preferentially concentrate other contaminants-
Some contaminants, such as methylrriercury, are distributed throughout fish
tissue. Contaminant distribution information has important implications for
consumers. Depending on how fish are prepared and what parts are eaten,
consumers may have greatly differing exposure levels to chemicals. In general,
contaminant concentrations differ between:
• Fatty tissues, muscle tissue, and internal organs,
• Different species of fish,
• Larger and smaller fish within species, and
• The type of contaminant present in the fish.
Lipophilic chemicals accumulate mainly in fatty tissues, including the belly,
lateral line, subcutaneous, and dorsal fat, and the dark muscle, gills, brain, and
internal organs (Harrison and Klaverkamp, 1990, Kuehl et al., 1987, Kleeman
et al., 1986a, Kleeman et al, 1986b, Branson et al., 1985). Some heavy
metals, such as cadmium, concentrate more in the liver and kidneys. Muscle
tissue often contains lower organic contaminant concentrations than fatty
tissues (Anderson and Amrhein, 1993).
Most people remove the internal organs before cooking fish and trim off fat
before eating, thus decreasing exposure to lipophilic and other contaminants.
Removing the fat, however, will not decrease exposure to other contaminants,
such as methylmercury, that are also concentrated in muscle and other protein-
rich tissues (Minnesota Department of Health, 1992). Certain subpopulations
eat more of the fish than just the fillet, and use whole fish for making soups.
As a result, these subpopulations consume much more of the fish's body
burden of contaminants and are at a higher risk of experiencing negative health
effects. Readers are encouraged to, whenever possible, take preparation
6 This section is an overview; states should consult primary research
studies for more information.
4-26
-------
4. RISK ASSESSMENT METHODS
methods of local fisher populations into account when assessing exposure
levels (See Volume 3 of this series).
Different fish species in the same water body may contain very different levels
of contaminants. Due to bioaccumulation, higher trophic level species are more
likely to have higher contaminant concentrations. For some contaminants, the
contaminant concentrations in the tissues of the top predators can exceed
ambient water or sediment levels by many orders of magnitude. Where a fish
feeds in the water body may also determine its relative bioaccumulation
potential. Bottom feeders, for example, such as carp or flounder, are exposed
to more sediments than are fish that feed in the water column, and have a
tendency to accumulate more of the dense, hydrophobic contaminants, such
as chlordane or PCBs, that are adsorbed to the sediment particles.
In addition, fish species vary widely in their fat content. Fish which are low in
fat, such as bass, sunfish, crappies, yellow perch, and walleyes, are less likely
to accumulate lipophilic toxics than fattier fish such as bluefish, some salmon,
catfish, and carp. Aquatic organisms also differ in their abilities to metabolize
and excrete contaminants. For example, one study found fish more able to
metabolize benzo[a]pyrene than shrimp, amphipod crustaceans, and clams,
respectively (EPA, 1993a). Since specific enzymes are required to metabolize
different chemicals, it is likely that the ability to break down and excrete
contaminants also differs among fish species. Because of this differential
accumulation of contaminants, individuals eating different species of fish may
have very different exposure levels.
Within species, larger fish generally contain higher concentrations of
bioaccumulative contaminants, especially of more persistent chemicals (such
as methylmercury, DDT, PCBs, and toxaphene; EPA, 1993a) because they are
usually older than smaller fish of the same species, and have had more time to
bioaccumulate chemicals from their food. In addition, larger predatory fish are
more able to catch larger prey, which themselves have had a longer time to
bioaccumulate chemicals (Minnesota Department of Health, 1992). Older fish
also concentrate more contaminants in their muscle tissues, which are fattier
than muscle tissue in younger fish, particularly along the dorsal area and lateral
lines (Klee/nan et al., 1986a). Taking these observations into account, readers
may choose to issue size-specific consumption limits and/or explain this
correlation in public education efforts.
/ . .
4.4.1.2. Fish Contaminants
Due to contaminant-specific chemical and pharmacokinetic properties, the
target analytes discussed in this volume preferentially concentrate in different
4-27
-------
4. RISK ASSESSMENT METHODS
tissues in fish. Some data" are described below; data on individual target
analytes are discussed in more detail in Section 5.
Heavy Metals Methylmercury, unlike many other bioaccumulative fish
contaminants, is found not only in fatty tissues, but also binds strongly to
proteins, and thus concentrates in muscle tissues of fish (Minnesota
Department of Health, 1992). Methylmercury also concentrates in the liver and
kidneys, though at generally lower rates (Harrison and Klayerkamp, 1990,
Marcovecchio et al., 1988). Thus, methylmercury concentrations in edible fish
tissues are not effectively decreased through trimming. Cadmium largely
concentrates in the liver, followed by the kidneys and gills, and not as much in
the muscle tissue (Harrison and Klaverkamp, 1990, Marcovecchio et al., 1988,
Jaffar et al., 1988, Norey et al., 1990) This indicates that cadmium
concentrations could be decreased by trimming and gutting fish before
consuming. Selenium was shown to concentrate in both the liver and muscle
tissues at similar rates (Harrison and Klaverkamp, 1990).
Organochlorines Organochlorine pesticides and PCBs have a high affinity to
concentrate in fatty tissues (Ryan et al., n.d., Kleeman et al., 1986a, Branson
et al., 1985, EPA, 1993a). One study positively correlated PCB and mirex
levels with fat levels across ten freshwater fish species (Ryan et al., n.d.).
These compounds are neither readily metabolized nor excreted, and thus tend
to bioaccumulate through the food web (EPA, 1993a). As fish species store
fat differently, so will they concentrate organochlorines differently.
PCB levels have been studied in several species and tissues of fish. Higher
chlorinated biphenyls have been found to bioaccumulate more readily than/
lower chlorinated biphenyls (Bruggeman et al., 1984, EPA, 1993a).
Unfortunately, some of these higher chlorinated biphenyls tend to be the more
potent toxics as well (Williams et al., 1992).
Other Contaminants The other chemicals examined in this exposure
assessment (organophosphate pesticides and oxyfluorfen) have also been found
to bioaccumulate in fish, but no information was found as to how they
differentially accumulate in fish tissues. Organophosphates have some
chemical characteristics which are similar to organochlorines, though they differ
in lipophilicity, metabolism, mode of action, and persistence (EPA, 1993a; see
Section 5).
Readers may wish to use this chemical-specific information on distribution in
fish tissues to assess whether a local population may be unreasonably exposed
to a given contaminant, due to particular eating habits such as eating only one
species of fish, eating specific parts of the fish, or eating only fatty fish
species.
4-28
-------
4. RISK ASSESSMENT METHODS
4.4.2. Geographic Distribution of Contaminated Fish
The extent of contamination of fish is an important element in determining the
need for further action. These data are also useful in performing population
exposure assessments and risk characterization. Two types of information are
particularly useful: the locations where contaminated fish have been found,
and the sources of potential contamination. The first type of information is
provided by fish sampling and analysis programs. When such data are absent,
several available sources can help locate sites of possible contamination by the
target analytes. Section 4.2.1.2 contains a list of sources of information on
potential fish contaminants. Volume 3 discusses methods for mapping both
population demographics and the distribution of pollutants.
4.4.3. Individual Exposure Assessment
Individual exposure assessments provide descriptions of the overall, media-
specific, or site-specific exposure of an individual. These may be normative
or high (e.g., highly exposed individual) estimates, or be based on actual
measurement data.
Individual exposure assessments use essentially the same equation as is used
with fish contaminants to calculate fish consumption limits, though they solve
for different variables:7
C -CR Eq^tion 4.1
Em =
m BW
where:
Em = Individual exposure to contaminant m from ingesting fish (mg/kg-
day),
Cm = Concentration of contaminant m in the edible portion of fish
(mg/kg),
CR = Mean daily consumption rate of fish (kg/day), and,
BW = Body weight of an individual consumer (kg).
7 Exposure is defined in the U.S. EPA Guidelines for Exposure
Assessment (1992a) as the "contact of [the] chemical with [the] outer
boundary of a person, e.g, skin, nose, mouth."
4-29
-------
4. RISK ASSESSMENT METHODS
Individual exposure assessments use data on known chemical residues in fish
(Cm) and on human consumption patterns (CR/BW) to estimate exposure (Em)
for hypothetical individuals within given populations (See Equation 4.1).
Conversely, the consumption limits described in Section 2 and provided in
Section 3 use the data on known chemical residues in fish (Cm) combined with
dose-response data (q^s and RfDs, which correspond to maximum "safe"
exposure) to estimate maximum safe human consumption rates (CR|im/BW; see
Equations 2.1 and 2.3). This document uses this equation only to calculate
fish consumption limits. Volume 3 of this series provides additional information
on estimating individual and population exposures for purposes of generating
risk estimates used in risk management decision-making. Individual exposure
assessment is discussed in this volume for informational purposes only; it is not
used directly in calculating fish consumption limit tables. Increased detail is
provided where information is shared between individual exposure assessments
and consumption limit calculations.
Depending on the geographic region and/or contaminant involved, contaminant
concentrations in fish (Cm) are determined by public health officials, natural
resource agencies, environmental protection agencies, FDA, EPA, and/or
agricultural departments through state, local and tribal sampling and analysis
programs. The consumption rate (CR) represents the amount of fish an
individual in a given population eats in a day, and may be estimated through
fish consumption surveys. Finally, the daily dose is divided by consumer body
weight (BW) to arrive at individual exposure.
By using information on the number of individuals in each exposure category,
risk managers may aggregate exposures determined in individual assessments
to derive population exposure assessments. Population exposure assessments
can allow readers to focus limited resources on those contaminants or areas
that may pose the highest risks to a large number of persons or to particular
subpopulations of interest (e.g., subsistence fishers).8
o
As mentioned before, the consumption limits described in this document
assume that no other exposure to any of the 23 target analytes occurs.
However, a potentially significant source of contaminant exposure is the
consumption of commercially-caughtfreshwater and marine fish. Consumption
limits for non-commercial fish may not be sufficiently protective of consumers
of both commercial and non-commercial fish. It is recommended therefore,
that, whenever possible, readers take other significant sources of exposure into
account when doing exposure assessments and/or developing consumption
limits.
4-30
-------
4. RISK ASSESSMENT METHODS
4.4.3.1. Exposure Variables
Equation 4.1 (See Section 4.4.2.1) uses three parameters to calculate individual
exposure (Em) to non-commercial fish contaminants: consumption rate (CR),
consumer body weight (BW), and contaminant concentration (Cm). Equations
2.1, 2.2, and 2.3 in Section 2 also use body weight and contaminant
concentration, and also use meal size (MS) in developing consumption limits
(See Section 2). With the exception of Cm, which is found in sampling and
analysis programs, these parameters are discussed below.
Body Weight Both consumption limit and exposure assessment calculations
require specific body weights (usually in kilograms) for individuals in order to
derive the contaminant daily dose in milligrams contaminant per kilogram
consumer body weight per day (mg/kg-d). The Exposure Factors Handbook
(EPA, 1990a) recommends values for average weights for children and adults,
based on the second National Health and Nutrition Examination Survey
(NHANES II). Conducted from February 1976 to February 1980, NHANES II
surveyed approximately 28,000 non-institutionalized U.S. civilians aged six
months to 74 years. The survey oversampled population groups thought to be
at risk from malnutrition (low-income individuals, preschool children, and the
elderly). Adjusted sampling weights were then calculated for age, sex, and
race categories to reflect body weight values for the estimated civilian, non-
institutionalized U.S. population. Although EPA recommends these values for
typical Americans, they may not adequately represent some subpopulations
(e.g., Asian-Americans, who are generally smaller than the average U.S.
citizen). Whenever more accurate data on average body weights of local fisher
populations are available, readers are encouraged to use these data in place of
the default values.
Table 4-1 lists recommended body weight values for general adults, women of
childbearing age (women from 18 to 45 years of age), and children. These
values are derived from data in the Exposure Factors Handbook (EPA, 1990a);
the values listed for general adults are used directly, while the value for women
of reproductive age represents an arithmetic average of three age groups (18-
25, 26-35, and 36-45), and the value for children is an arithmetic average of
two groups (children <3 and children from 3 to <6). A more protective body
weight value for women of reproductive age would be to use the lower 95th
percentile body weight of women age 18 to 25 years (Blindauer, 1994). In this
document, however, a body weight of 70 kg was used for all adults, including
women of reproductive age, to calculate the consumption limits shown in
Section 3.
4-31
-------
4. RISK ASSESSMENT METHODS
Table 4-1. Mean Body Weights of Children and Adults
Age Group
Mean Body Weight (kg)
Males Females
Adults 78 65
Women of - 64
Males and
Females
(Averaged)
70
Reproductive Age
Children <6
14.8
14.2
14.5
Source: Adapted from EPA, 1990a.
Readers are encouraged to use values that average together male and
nonpregnant female body weights when assessing exposure to the general
adult population. Where consumption rates are known to differ significantly
between men and women, however, readers may wish to make gender-specific
exposure assessments and use unaveraged gender-specific body weight
estimates. In cases where certain developmental toxins are of concern, readers
are encouraged to make separate exposure assessments for children and
women of childbearing age.
Meal Size Meal size is a critical parameter in expressing fish consumption
limits, though is not used directly in calculating exposure (which is expressed
in mg/kg-d). Limits expressed in terms of meal per given time period is a more
understandable measure than consumption limits expressed in kilograms per
day. Meal size estimates can also be used to calculate peak acute exposures
to fish contaminants (although that information is not used in this document).
Several values for average meal size have been determined through both non-
commercial and commercial fish consumption surveys, though these values
may not be comparable across studies. For instance, some surveys report meal
sizes on a basis of whole, raw fish, while others refer to cooked fillets. Still
others do not specify whether the value is based on cooked or raw fish. The
average meal size most often cited is 227 grams, or eight ounces (Minnesota
Department of Health, 1992, Missouri Department of Health, 1992, Anderson
and Amrhein, 1993, EPA, 1993a). This meal size corresponds to the value
used in the Michigan Anglers Survey; in this survey, individuals were asked to
estimate their average meal size compared to a picture showing a eight ounce
(227 gram) fish meal (West et al., 1989). The same meal size also represents
the high-end range used by Dourson and Clark (1990), which is based on the
value used in the EPA Region V Risk Assessment for Dioxin Contaminants
4-32
-------
4. RISK ASSESSMENT METHODS
(1988c). A discussion of fish consumption surveys is provided in Volume 3 of
this series.
EPA has developed meal size estimates for both general adults and children
under four. The general adult population includes all adult men and women.
Children eat smaller portions than adults, although they may consume
significantly more fish per unit body weight. Women of reproductive age were
assumed to eat proportionally (per kg body weight) the same amount of fish per
meal as other adults.
EPA suggests using a default value of 8 oz (227 grams) of cooked fish fillet per
70 kilogram consumer body weight as an average meal size for both the
general adult population and for women of reproductive age for use in exposure
assessments and fish advisories if population-specific data are not available.
This meal size, however, is not likely to represent higher end exposures, where
persons consume more than the average amount in a given meal. These larger
meal sizes are important to consider in cases where acute and/or developmental
effects from fish contamination are of concern.
Meal size can also differ for other subpopulations and must be scaled
accordingly. Children and adolescents, for example, often consume more fish
per kilogram body weight than adults. A national food consumption survey
conducted by the United States Department of Agriculture (USDA) was used
to scale the adult meal size value to child meal size values (USDA, 1983). The
USDA survey evaluated consumption patterns of approximately thirty-eight
thousand U.S. citizens over three-day periods from 1977 to 1978, and is the
largest consumption survey of its kind that includes fish. The survey results
included meal size data for ten age groups. Although respondents included
both fishers and non-fishers, relative differences reported between the age
groups were used to approximate differences in average meal size between
different age categories within fisher populations in the current assessment.
For children younger than four years old, EPA suggests using a default meal
size of 3 oz (85 grams), if population-specific data are not available. For older
children, modifications in consumption limits can be made to tailor limits to
their body weights and consumption patterns. The methodology to do so is
discussed in Section 2.
Consumption Rate Although it is necessary to estimate the overall average
consumption rate in order to characterize risk, this information is not necessary
to provide risk-based consumption limits as in Section 3. Consumption rate
information is primarily used to make risk management decisions regarding the
allocation of resources and implementation of various public health protection
strategies related to consumption of contaminated fish. Consequently, fish
consumption patterns and methods for evaluating the resulting risks are
4-33
-------
4. RISK ASSESSMENT METHODS
presented in Volume 3 of this series (Risk Management). Volume 3 will contain
a review of fish consumption rates for various population subgroups including
the average national consumer, sport fishers, and subsistence fishers.
However, due to the significant variability in fish consumption among
individuals, readers are urged to conduct their own surveys to determine actual
consumption levels when accurate risk estimates are required.
4.4.3.2. Averaging Periods Versus Exposure Durations
The exposure duration is the time period over which an individual is exposed
to one or more contaminants. In the case of an individual fisher, the exposure
duration is equivalent to the time interval over which he or she catches and
consumes fish. However, fish consumption is frequently not constant over the
time period of interest for examining certain health endpoints (e.g., lifetime for
chronic effects), particularly for short-term or seasonal recreational fishers. For
short-term or seasonal fishers, periods of consumption must be averaged with
periods during which no consumption occurs, in order to correspond with the
time periods over which chronic health effects are likely to develop. For
example, the method usually employed to obtain a lifetime average daily dose
is to divide the cumulative dose over an individual's lifetime by the number of
days in an average lifetime. For developmental and subchronic effects, the
time period over which dose is averaged is much shorter. Consequently, the
time periods of concern chosen for use in exposure assessments are called
averaging periods.
A ten-day averaging period was chosen for the short-term consumption limit
tables for several reasons. Ten days is one of the averaging periods used by
the EPA Office of Water in developing Health Advisories for drinking water. It
is also relevant to the short time period often considered critical for exposure
to developmental toxins (i.e., there may be a brief window of time during which
adverse effects can be induced by toxins). This time period also corresponds
to a typical vacation period. Although some fish consumption advisories use
three weeks as an exposure period to describe recreational fish consumption
(Missouri Department of Health, 1992, Minnesota Department of Health,
1992), no evidence was found to support it as a more accurate period than ten
4-34
-------
4. RISK ASSESSMENT METHODS
days.9 Ten-day meal consumption limit tables have been developed for
chronic systemic toxins and for the developmental toxicity of methylmercury,
as shown in Section 3.10
For pollutants with carcinogenic properties, EPA currently assumes that there
is no threshold below which the risk is zero; i.e., for any non-zero exposure,
there may be some increase in cancer risk. There is no current methodology
for evaluating the difference in cancer risks between consuming a large amount
of the carcinogenic contaminant over a short period of time and consuming the
same amount over the course of one's lifetime. Therefore, EPA's current
cancer risk assessment guidelines recommend prorating exposure over the
lifetime of the exposed individual (U.S. EPA, 1986a). To provide usable and
easily understood consumption guidance, the unit of one month was used as
the basis for expressing meal consumption limits in Section 3. The limits for
carcinogens are based on the assumption that consumption over a lifetime, at
the monthly rate provided, would yield a lifetime cancer risk no greater than the
acceptable risk listed in each column (i.e., one in ten thousand, one hundred
thousand and one million).
The likelihood of occurrence of non-carcinogenic effects associated with
chronic exposure is evaluated through the use of RfDs (as discussed in Section
4.3). Exposure below the RfD is assumed by EPA to be safe over a lifetime of
exposure. Consequently, the relevant averaging period for both carcinogenic
and non-carcinogenic chronic exposure is a lifetime.
As with the carcinogens, the unit of one month was used in Section 3 as the
basis for expressing meal consumption limits based on chronic systemic health
effects. The limits for non-carcinogens are based on the assumption that
consumption over a lifetime, at the monthly rate provided, would not generate
a health risk. Although consideration was given to inclusion of an acute
exposure period (e.g;, one day), insufficient information on one-day
consumption and acute effects is available to evaluate acute exposure for many
9 Vacationers may identify better with two-week periods than with ten-day
periods (Shubat, 1993a). For this reason, readers intending to develop
advisories based on ten-day fish consumption should consider expressing
consumption limits in terms of two-week vacations instead of ten-day periods.
10 However, those fishers who catch and freeze large quantities of fish to
eat later might be considered seasonal or subsistence fishers, depending on the
extent of their catch and subsequent consumption.
4-35
-------
4. RISK ASSESSMENT METHODS
of the fish contaminants at this time.11 It is anticipated that subsequent
revisions of this document will more fully characterize acute exposure (See
Section 4.3 for a brief discussion).
Consumption of large, intermittent fish rneals (bolus doses) do not correspond
well to dosing patterns typically evaluated in toxicity studies. This is
problematic for the application of an RfD based on chronic exposure studies to
this fish consumption scenario. See Section 4.3 for further discussion.
4.4.3.3. Multiple Species Exposures
Local information on the consumption of multiple species and fish
contamination levels can be used to assess exposure and establish consumption
limits for consumers with multiple-species diets. Equation 4.1 can be modified,
as follows, to consider consumption of multiple species:
where:
E -
mj
Equation 4.2
Cm, =
CRj
Individual exposure to contaminant m from ingesting fish species
/ (mg/kg-day).
Concentration of contaminant m in the edible portion of fish
species / (mg/kg).
Consumption rate of fish species/ (kg/day).
Proportion of a given fish species in an individual's diet (unitless),
and,
BW = Consumer body weight (kg).
Regional or local angler surveys that estimate catch data and measure fish
consumption can provide data on the mix of species eaten by particular
populations. One study, the Columbia River Survey (Honstead et al., 1971),
is described in Rupp et al. (1979). This survey calculated the total number of
each species of river fish eaten by residents in the area. Although the
11
Chlorpyrifos and mercury are notable exceptions.
4-36
-------
4. RISK ASSESSMENT METHODS
information is a composite of fishers and non-fishers, the data could be used
to estimate the mix of species that an average individual in the area would eat.
The Columbia River Survey also includes data on the mix of species consumed
by each of ten individuals who ate the most fish during the year, which might
be used to estimate exposure for high-risk individuals. Readers may wish to
incorporate similar information from local surveys into multiple-species exposure
assessments and/or consumption limits.
4.4.3.4. Multiple Chemical Exposures
Fish can be contaminated with more than one chemical, and individuals can
consume multiple species of fish that contain different contaminants. In these
cases, exposure across species needs to be calculated separately for each
chemical; these exposures can then be combined in a variety of ways to
estimate risks of different health endpoints. Section 2 provides methods for
calculating consumption limits for individuals exposed to multiple contaminants.
Readers also may adapt these calculations (s.f.. Equation 4.2) to estimate
individual exposure to multiple fish contaminants.
4.4.4. Population Exposure Assessments
Population exposure assessments are not directly used in developing risk-based
consumption limits. Rather, they are primarily used in risk management (e.g.,
to prioritize resource allocation) and to identify particular subpopulations of
interest (e.g., in areas where subsistence fishing is common). Consequently,
methods for carrying out and utilizing population exposure assessments are
discussed in Volume 3 of this guidance series.
4.4.5. Uncertainty and Assumptions
Readers must evaluate if the exposure assumptions made in deriving risk-based
limits provide adequate protection to sensitive or highly exposed
subpopulations. Some of the assumptions associated with the exposure
parameters can lead to an underestimate of total risk (and therefore an
overestimate of allowable consumption). For example, the calculation of
exposure to a given chemical may ignore background sources of that chemical.
For chemicals that exhibit health effects based on a threshold level, the
combination of background contaminant and fish consumption exposure may
exceed the threshold. The use of average fish contaminant concentrations to
estimate exposure is another assumption that could underestimate risk if an
individual regularly consumes fish from a contaminant hot spot.
Exposure assumptions may not always be sufficiently conservative. However,
these assumptions may be balanced by overly conservative assumptions in
4-37
-------
4. RISK ASSESSMENT METHODS
other aspects of the assessment. Readers need to judge if the overall margin
of safety afforded by the use of uncertainty factors and conservative
assumptions provides satisfactory protection to fish consumers.
4.4.5.1. Chemical Concentrations in Fish
Accurate determination of the chemical concentrations in fish is an important
area of uncertainty which is discussed in detail in Volume 1 in this series.
4.4.5.2. Body Weight
The estimates used for body weight use several assumptions that affect the
accuracy of the exposure assessment. First, the figures for body weight are
taken from data in the late 1970s. Body weights can vary dramatically over
time, and therefore the values may be an over or under-estimate of current
body weights. In addition, average body weights were not distinguished for
various ethnic populations. For example, Southeast Asian-American
subsistence fishers may have slighter body frames and weight than the general
adult population. Compared, to other assumptions, however, body weight
values are associated with relatively low variability and uncertainty. In addition,
the consumption limit tables take differences in body weight into account by
scaling meal size to body weight (e.g., 8-oz meal per 70-kg body weight).
4.4.5.3. Consumption Rate and Averaging Period
The two most sensitive variables involved in calculating individual exposure
often are consumption rate and averaging period. Non-commercial fish
consumers differ immensely in their consumption habits. Some may consume
fish for one week during a year or for several weekends each year (e.g., as
recreational fishers). Others may consume fish for much longer periods during
a year or may rely on fish year-round as a major part of their diet. Within these
groups, some individuals are more susceptible to contaminants, including
women of reproductive age, children, and persons with pre-existing health
problems:
Short-term recreational and seasonal fishers are assumed to be exposed to
contaminated fish for only part of the year. Recreational vacation fishers are
those who eat fish only a short time during the year. Seasonal fishers are often
those who live near a lake or river, fish regularly throughout a season (e.g.,
summer fishing, winter ice fishing), eat their catch throughout the season, but
do not rely on fish as a major dietary staple during the rest of the year. Sport
fishers have been shown to have higher fish consumption rates than the
general U.S. population (EPA, 1989a); the potential for large exposures over
4-38
-------
4. RISK ASSESSMENT METHODS
short time periods make them especially susceptible to acute, developmental,
and subchronic health risks as compared to non-fishers.
Subsistence fishers eat fish as a major staple in their diets for a greater
percentage of the year than do recreational fishers. In addition, subsistence
fishers may prepare fish differently than other groups; they may use the whole
fish in soups, or consume more highly contaminated tissues, such as the liver,
brains, and subcutaneous fat. Both their longer exposure durations and
consumption habits make many subsistence fishers more likely to be affected
by cancer and adverse chronic systemic, developmental, and reproductive
health effects resulting from fish contaminant exposure than those who do not
fish or fish for shorter periods of time. Some populations may subsist on non-
commercial fish year-round, including Native Americans and certain recent
immigrants accustomed to self-sufficiency and fishing (particularly Asian-
Americans), and economically disadvantaged populations, who may be
particularly at risk since much of their fishing might be expected to occur in
more urbanized areas with higher levels of water pollution.
Any estimates of typical fish consumption patterns in a population include
certain assumptions. West et al., (1989) described variations in fish
consumption in communities in Michigan by ethnicity, income and length of
residence. In general, African Americans and Native Americans ate more fish
than Caucasians; older individuals ate more fish than younger individuals;
individuals with lower incomes tended to consume greater quantities of fish
than individuals with higher incomes; longer-term residents of the communities
West studied tended to consume more fish than other individuals. To the
extent that members of the target population have characteristics associated
with higher-than-average consumption, the recommended consumption values
may underestimate their consumption. Unless surveyed specifically, subsistence
fishers may be under-represented by available surveys. Surveys associated
with the issuance of fishing licenses are traditional mechanisms used in
surveying fish consumption behavior; however, subsistence fishers may not
apply for fishing permits or licenses.12
In addition, fish consumption limits that are based on single species for single
chemicals do not account for exposures from multiple chemicals contaminating
a single species, or for multiple species diets. Consumption limits that focus
on a single water body do not account for the possibility that consumption can
occur from a variety of water bodies. Single species consumption limits also
12 Native Americans on reservations do not need fishing permits, and often
times other individuals may not know that they need to have a license or find
them too expensive to buy.
4-39
-------
4. RISK ASSESSMENT METHODS
do not address related species that may be contaminated but were not
sampled. Such consumption limits could seriously underprotect persons who
eat a variety of fish species from a number of waterbodies. Readers need to
decide if consumption limits have a wide enough margin of safety to protect
such consumers.
Other methodological assumptions may also lead to increased uncertainty- The
calculation of consumption limits that express allowable dose as a number of
meals over a given time period may neglect potential acute effects if
consumption occurs over a very short time period. For example, a meal limit
of two meals per month conceivably could be interpreted by consumers to
mean that two meals on one day in a given month is allowable; this behavior
could lead to short-term acute effect:;. This could be avoided by always
expressing the consumption in terms of the time interval in which one meal
may be consumed, e.g., one meal per two weeks, rather than two meals per
month.
The use of averaging periods treats large, short-term doses as lexicologically
equivalent to smaller, long-term exposures when comparing exposure to the
toxicity reference value. This assumption may underestimate the potential
toxicity to humans if the toxicity depends on a mechanism sensitive to large,
intermittent doses. (This may occur more often with acute and developmental
effects than with other effects).
The averaging periods of 10 days and one month used in this document are
based primarily on the types of health data currently available and the risk
assessment methods recommended by EPA. Consequently, there is no acute
exposure methodology recommended (which could correspond to bolus doses;
see Section 4.3) in this document. In subsequent editions, this type of
information may be included.
4.4.5.4. Multiple Species and Multiple Contaminants
As discussed above, individuals often eat more than one species of non-
commercial fish in their diet. If consumption limits or exposure assessments
consider only a single-species diet, exposure from contaminated fish could be
underestimated if other species have higher concentrations than the species
under consideration. On the other hand, an exposure assessment may be
overprotective if an individual's diet is a mix between contaminated and
uncontaminated species. Use of local information to the extent possible to
characterize mixed diets can avoid some of this uncertainty.
An individual may consume a given species that is contaminated with multiple
chemicals, or may consume several species, each with different contaminants,
4-40
-------
4. RISK ASSESSMENT METHODS
or both. In these circumstances, exposure assessments that examine
contaminants individually in individual species will underestimate exposure.
This situation may be avoided by using the equation in Section 4.4.2.4 for
multiple species exposures and characterizing exposure to all known
contaminants for a given individual. These exposure values can be used in
methods described in Section 2 to set consumption limits based on multiple
species and multiple contaminants.
4.4.5.5. Other Sources of Exposure
The methods described in this guidance consider exposure only from non-
commercial fish consumption. This approach may lead to an underestimate of
exposure, and consequently an underestimate of risk for some contaminants.
For individuals exposed to fish contaminants through other contaminant sources
(e.g., other foods, inhalation, dermal contact, or drinking water), additional
background exposure may cause them to experience negative health effects
and/or increased cancer incidence, even if they abide by the consumption rates
recommended in fish consumption advisories. Readers are encouraged to use ,
available information on other sources of exposure whenever possible in setting
consumption limits, or set the limits such that the allowable consumption
accounts for only a fraction of the total allowable daily dose. These
approaches would allow a margin of safety to guard against the potential for
background exposure leading to an exceedence of contaminant thresholds
and/or maximum acceptable risk levels.
4.5. Risk Characterization
In general, the risk characterization step of the risk assessment process
combines the information for hazard identification, dose-response assessment
and exposure assessment in a comprehensive way that allows the evaluation
of the nature and extent of risk (Barnes and Dourson, 1988). Risk
characterization can be used by risk managers to prioritize resource allocation
and identify specific at-risk populations; it is also used to establish regulations
or guidelines, and to estimate individual or population risk. In this document,
risk characterization has been used to develop the risk-based consumption
limits provided in Section 3. The methods involved in developing consumption
limits are described in detail in Section 2 and will not be repeated here. When
risk characterization is used to estimate individual or population risk, it serves
to provide the risk manager with necessary information regarding the probable
nature and distribution of health risks associated with various contaminants and
contaminant levels. This latter aspect of risk characterization is discussed
briefly here and is discussed in more detail in Volume 3 of this series. An
overview of the methods which would be used when chemical concentrations
exceed screening values is provided in Volume 1 (EPA, 1993a).
4-41
-------
4. RISK ASSESSMENT METHODS
Risk characterization in general has two components: presentation of numerical
risk estimates, and presentation of the framework in which risk managers can
judge estimates of risk (EPA, 1986a). A characterization of risk, therefore,
needs to include not only numerical characterizations of risk, but also a
discussion of strengths and weaknesses of hazard identification, dose-response
assessment and exposure and risk estimates; major assumptions and
judgments should be made explicit, and uncertainties elucidated (EPA, 1986a).
Numerical presentations of risk can include either estimates of individual risk or
risks across a population. For example, for cancer risks, numerical estimates
can be expressed as the additional lifetime risk of cancer for an individual, or
the additional number of cases that could occur over the exposed population
during a given time period. Numerical risk estimates can also be expressed as
the dose corresponding to a given level of concern (EPA, 1986a). These values
can be used to estimate the environmental concentration or contact rate below
which unacceptable health risks are not expected to occur. For the
determination of fish advisories, the environmental concentration takes the form
of screening levels (i.e., contaminant concentrations in fish, as discussed in
Volume 1) and the contact rate takes the form of risk-based consumption limits
for specified populations.
4.5.1. Carcinogenic Toxicity
In this guidance series, screening values are defined as the concentrations of
target analytes in fish tissue that are of potential public health concern and that
are used as standards against which levels of contamination can be compared.
For carcinogens, EPA recommends basing screening values on chemical-specific
cancer potency factors. Screening values are used to establish the
concentration in fish that can trigger further investigation and/or consideration
of fish advisories for the water bodies and species where such concentrations
occur. The method for calculating screening values is given in Volume 1 of this
series.
When presenting a risk characterization, it should be noted that use of most
cancer potency values indicates that the cancer estimates are upper bound
estimates or risk; the lower bound estimate of cancer risk may include zero.
Other uncertainties and assumptions also need to be discussed. The influence
of uncertainties of toxicity reference values and exposure assessment values
on the risk assessment are described in detail in Sections 4.3 and 4.4.
4.5.2. Noncarcinogenic Toxicity
For chronic systemic toxicants, the RfD is used as a reference point in
assessing risk. The RfD is calculated such that there is little probability of an
4-42
-------
4. RISK ASSESSMENT METHODS
adverse health effect occurring due to chronic exposure to chemical
concentrations below the RfD. Exceedence of the RfD implies there may be
some risk of the adverse health effect occurring; however, the magnitude of
risk and severity of the effect are not quantified by this approach.
Estimation of the incidence of noncarcinogenic health effects in the exposed
population would require knowledge of the shape of the dose-response function
above the RfD. Though methods have been developed for characterizing risk
above the RfD (Farland and Dourson, 1992), these methods have not yet been
widely applied. Until these methods are better developed and applied to a
wider range of chemicals, alternative methods of characterizing noncancer
population risks must be chosen. One way these risks often are expressed is
to indicate the number of persons in the exposed population whose exposure
exceeds the RfD. This numerical expression provides a quantitative way to
gauge the extent of possible risk within the population, though it does not
provide information on severity of the risk. Additional material, such as
information on the health effect upon which the RfD is based and on the
uncertainty factors applied to develop the RfD, can assist risk managers in
putting the population risk estimates into perspective.
An alternative approach is to express the dose as the magnitude by which the
NOAEL exceeds the estimated dose (termed the margin of exposure, or the
MOE). Where the MOE is greater than the product of the uncertainty and
modifying factors (used in calculating an RfD from a NOAEL), then concern is
considered to be low (Barnes and Dourson, 1988).
4.5.3. Subpopulation Considerations
Certain subpopulations (women of childbearing age, children, and individuals
with preexisting health conditions) may be of special concern when performing
risk assessment and developing risk-based consumption limits. Not all risks to
these populations are quantifiable; the toxicity literature may contain data that
suggest an effect could occur from exposure to a chemical for particular
sensitive subpopulations, but may not contain sufficient information to identify
a NOAEL or develop dose-response functions (See chemical-specific information
in Section 5).13 For example, DDT is thought to cause effects in two
sensitive populations for which no quantitative dose-response data exist. Based
on nnimal studies, DDT may cause cardiac sensitization leading to ventricular
fibrillation and death (Hayes, 1982). However, there are insufficient data to
relate this quantitatively to human populations that have cardiac disorders or
other stresses that could make them especially susceptible to these effects.
13 RfDs are intended to protect sensitive populations.
4-43
-------
4. RISK ASSESSMENT METHODS
DDT may also cause disturbances in the normal reproductive system of females
(Hayes, 1982), although again, no quantitative dose-response data exist for
these effects. Another example is that certain chemicals (such as
organophosphate pesticides) are metabolized more slowly in certain individuals
with specific enzyme deficiencies than in the general population (Hayes, 1982).
The dose-response data for these effects are not available. In all these cases,
the probability or the magnitude of the response that may result from a given
dose cannot be adequately quantified.
Information on these subpopulation effects of DDT and other chemicals that
may result in risk to certain sensitive populations are described in Section 5.
Readers can use this information in several ways. Sections 5.3 and 5.4 briefly
discuss methods for applying modifying factors to the toxicity reference values
in cases where there is insufficient data to quantify risks. Readers may also
choose to consider these effects qualitatively when developing consumption
limits and/or making risk assessments. In addition, consumption advisories can
contain a discussion of suspected effects of a given chemical for particular
subpopulations, so that individuals with such conditions can make informed
decisions regarding their consumption of fish. Finally, readers may wish to
apply an additional safety factor to the meal advice aimed at such populations
to provide some measure of additional protection.
4.5.4. Multiple Species and Multiple Contaminant Considerations
Readers are encouraged to take multiple species consumption and/or multiple
contaminant exposures into account when developing consumption limits
and/or assessing risk. Methods for doing so are described in Section 2, Section
4.4.2, and Section 5.
4.5.5. Incorporating Considerations of Uncertainty in Consumption Limits
Previous sections have discussed the many uncertainties associated with the
estimates of exposure and toxicity data assessments that form the basis of the
risk assessment and the derivation of risk-based consumption limits. Readers
may wish to estimate the direction the uncertainties are likely to have on the
risk estimates (i.e., do these uncertainties tend to exaggerate or diminish
potential risk?). The assumptions made in the risk assessments to account for
uncertainties need to be clearly outlined (e.g., Section 5 contains a description
of the nature of the uncertainties associated with each uncertainty factor
applied in deriving an RfD). The use of the 95 percent upper confidence limit
for the slope of the dose-response function at low doses for carcinogens is an
example of a conservative assumption imbedded in the most cancer potency
values. Likewise, exposure assessments frequently include conservative
assumptions where data on actual exposure are absent, such as the assumption
4-44
-------
4. RISK ASSESSMENT METHODS
that no dose modification occurs when the cooking and preparation methods
of target populations are unknown. Where possible, readers are encouraged to
attempt to quantify the magnitude of the effect of such assumptions on the
numerical risk estimates.
4-45
-------
-------
5. TARGET AWALYTES
SECTION 5.
TOXICITY DATA FOR TARGET ANALYTES AND METHODOLOGY
FOR RISK VALUE CALCULATION
5.1. Introduction
This section contains toxicological and human health risk data for the target
analytes listed in Table 1 -1. This section also contains a discussion of methods
which can be used,to calculate exposure limits1 based upon study data
presented in this document or other sources. These can be used to calculate
fish consumption limits analogous to those provided in Section 3. Section 5.2
contains a description of the categories of information provided for each target
analyte, 5.3 contains the methods for calculating exposure limits for
developmental toxics, 5.4 contains the methods for calculating exposure limits
for chronic exposure toxicity, 5.5 contains chemical class information for
organochlorineand organophosphate pesticides, and 5.6 contains toxicological
information on the individual target analytes.
Toxicity data were collected for the target analytes from a variety of sources.
Information on acute, chronic, carcinogenic, mutagenic, and developmental
toxicity, as well as interactive effects are included. The major sources used
were IRIS, HSDB, ATSDR Toxicological Profiles, the Office of Pesticide
Programs (OPP) tox one-liners, and recent toxicological reviews. The EPA risk
values discussed in this section were used along with exposure data (e.g., meal
size and fish contaminant concentration) to calculate the fish consumption
limits provided in Section 3. Primary literature searches and reviews were not
conducted for the development of this section, due to time and resource
constraints. Data on developmental and other types of systemic non-
carcinogenic effects (e.g., neurotoxicity, immunotoxicity, nephrotoxicity) were
reviewed and summarized.
EPA evaluates dose-response data for chemicals of environmental concern on
an ongoing basis. However, new toxicological data is continually being
generated. Consequently, there may be recent information which is not yet
1 An exposure limit is a daily limit on exposure (in mg/kg-day) based upon
health and toxicity data, which the reader may calculate, using the study data
provided in this or other sources.
iiGaiui aiiu LU^IOIiy udLd, VVIIIUII LI
provided in this or other sources.
5-1
-------
5. TARGET ANALYTES
incorporated into EPA risk values. This may be particularly relevant for
developmental toxicity, which is the subject of much current research. The
toxicological summaries found in Section 5.6 provide the reader with
information which they may elect to use to calculate alternative health-based
risk values and fish consumption limits. The methods for carrying this out are
included in Sections 5.3 and 5.4.
Risk values are provided in Section 5.6, accompanied by a discussion of a
number of toxicity studies for each target analyte, which yield various dose-
response results. These give some indication of the variability in the types
of effects and doses at which various effects were observed. Although EPA
has developed guidelines for study selection (discussed in Section 5.3.3), it is
clear that for many chemicals a number of study results could, potentially, be
used to estimate exposure limits. The reader is urged to review the information
presented, particularly the studies of chemicals of interest in their areas, so that
they may choose the optimal health endpoints from among those discussed in
this document (e.g., carcinogenic toxicity, chronic exposure toxicity) or
develop their own risk values, based upon their review of the information.
5.2. Categories of information Provided in Section 5.6 for Target Analytes
Specific types of information were sought for all target analytes to address
health and risk concerns for carcinogenic, developmental, and chronic exposure
noncarcinogenic effects. These include pharmacokinetics, acute and chronic
toxicity, developmental toxicity, mutagenicity, carcinogenicity, special
susceptibilities, interactive effects, and critical data gaps. The categories of
information provided for each target analyte in Section 5.6 are listed in Table
5-1. Although the same types of information were sought for all analytes, the
information presented for the contaminants varies, depending on the types of
data available. Many of the analytes listed have been recognized as
environmental contaminants for a number of years and have a fairly
comprehensive toxicological data base. Others have been introduced to the
environment relatively recently; consequently, only limited information is
available on these chemicals.
When a substantial amount of information was available on a contaminant, the
information included in the discussions focused on areas relevant to the
toxicities under evaluation. For example, a significant amount of
pharmacokinetic data is available for some chemicals in the ATSDR
2 Only a brief discussion is provided for dioxin because it is currently
undergoing extensive review within EPA.
5-2
-------
5. TARGET ANALYTES
Category
Table 5-1. Health and Toxicological Data Reviewed for Target Analytes
Specific Information
Background
Pharmacokinetics
Acute toxicity
Chronic toxicity
Developmental toxicity
Mutagenicity
Carcinogenicity
Special susceptibilities
Interactive effects
Critical data gaps
Summary of EPA risk values
Chemical structure/group
Use and occurrence
Target tissues
Absorption
Deposition-bioaccumulation potential/half-
life/body burden
Metabolism
Excretion
Susceptible subgroups
Quantitation
Susceptible subgroups
Organ systems
Animal studies-quantitation
Human studies-quantitation
Other studies-quantitation
Data base quality
Susceptible subgroups
Current risk values
Organ systems
Animal studies-quantitation
Human studies-quantitation
Other studies-quantitation
Data base quality
Susceptible subgroups
Current risk values
Type
Quantitation
Source
Data base quality
Organ systems
Animal studies-quantitation
Human studies-quantitation
Other studies-quantitation
Data base quality
Outstanding issues
Subgroups of concern
Qualitative
Quantitative
MIXTOX results
Description
5-3
-------
5. TARGET ANALYTES
Toxicological Profiles. In this document, most information was briefly
synopsized; however, detailed information on human milk bioconcentration was
included for developmental toxics where lactational exposure is of concern. In
addition, when the toxicological data indicated that a particular type of
information, not reported, was required for full exploration of relevant toxic
effects, additional information was provided (e.g., the interaction of DDT with
pharmaceutical efficacy arising from DDT-induced increases in levels of
microsomal enzymes).
The information collected is categorized by the temporal nature of the exposure
(e.g., acute, chronic). These groupings are most applicable to the standard risk
assessment methods that were employed to calculate risk values. The
temporal groupings and methods of evaluating dose-response data are briefly
discussed in Section 4, with a description of uncertainties and assumptions
associated with dose-response evaluation.
5.2.1. Pharmacokinetics
A brief summary of the pharmacokinetic data is presented for many chemicals.
The information, obtained primarily from ATSDR toxicological profiles, was
included if it had a bearing on the development of fish consumption limits or
would be useful to the reader in evaluating the toxicological characteristics of
a chemical. For more detailed information on pharmacokinetics the reader is
referred to the ATSDR profiles and the primary literature.
For most chemicals there was not sufficient quantitative information, such as
absorption, uptake, distribution, metabolism, excretion, and metabolite toxicity,
in the data reviewed to recommend modifications in exposure to yield an
altered internal dose. Some chemicals contained in the IRIS data base have risk
values which have incorporated pharmacokinetic considerations. If additional
information relevant to quantitative risk assessment becomes available, it may
be included in future versions of the guidance document.
5.2.2. Acute Toxicity
Very little acute exposure toxicity data were located which could have a
quantitative bearing on the development of fish consumption limits. A
qualitative description of acute effects is included. The minimum estimated
lethal dose to humans and a brief discussion of the acute effects are included
if the data were available. In addition, the Minimum Risk Levels (MRLs)
developed by ATSDR are included when available. They provide estimates of
the levels of exposure for a chemical (e.g., toxaphene) at which minimum risk
is expected to occur (ATSDR, 1990b). In addition, Section 5.5 contains a
discussion of general class information for two major categories of chemicals,
5-4
-------
5. TARGET ANALYTES
the organochlorinesand organophosphates, which comprise 15 of the 23 target
analytes.
5.2.3. Chronic Toxicity
Under the chronic exposure heading, significant effects associated with long
term exposure are listed. Data relevant to calculating an RfD are discussed, as
well as relationships between chronic effects and pharmacokinetic data or other
effects. The chronic exposure data for each analyte includes a description of
an RfD listed in IRIS or obtained from other sources and the critical study
serving as the basis for that RfD, including the species tested, duration of the
study, and critical effect noted. Information is provided on any unusual aspects
of the study or RfD (e.g., if the study is old or has very few subjects, or if the
confidence in the RfD is listed as "low").
Data are also provided on effects observed in recent dose-response studies or
which were not the subject of the IRIS RfD critical study. This was done to
provide a more comprehensive picture of the overall toxicological nature of the
chemicals than could be obtained from reviewing the RfD critical study alone.
For most analytes, the information is primarily a qualitative description of
effects. For some chemicals having significant new toxicological data, details
are provided on NOAELs, LOAELs, some study characteristics, and the usual
categories of uncertainty and modifying factors which should be considered for
significant studies. These are provided to give readers the option of developing
exposure limits as they deem necessary. Methods for doing so are discussed
in Section 5.4.
5.2.4. Developmental Toxicity
Developmental toxicity data were obtained for each target analyte (dioxin
information will be provided when EPA analysis is complete). Section 5.3
contains general information on developmental toxicity, including definitions,
methods for calculating exposure limits, and special issues related to
developmental toxicity. Chemical-specific toxicological information is presented
in Section 5.6 and relevant class information is provided in Section 5.5. The
data and methods information are provided to give readers the option of
developing exposure limits based on developmental effects, as they deem
necessary.
For many chemicals, information is provided on the tendency of the chemical
to accumulate in body tissue. Many of the target analytes bioaccumulate
and/or preferentially seek fat tissues. When such accumulation occurs,
exposure occurring prior to pregnancy can contribute to the overall maternal
body burden and result in exposure to the developing individual. Any body
5-5
-------
5. TARGET ANALYTES
burden may result in exposure, but lipid-seeking chemicals, such as
organochlorines, are often rapidly mobilized at the onset of pregnancy and may
result in elevated contaminant exposure to the developing fetus. As a result
of this, it may be necessary to reduce the exposure of females with
childbearing potential in order to reduce their overall body burden. Even if
exposure is reduced during pregnancy, but has occurred prior to pregnancy, the
pregnancy outcome may be affected, depending on the timing and extent of
prior exposure. This is noted for bioaccumulative analytes in the individual
toxicity discussions in Section 5.6.
5.2.5. Mutagenicity.
Although there were many reported mutagenicity bioassays for target analytes,
little in vivo mutagenicity dose-response data were located. As discussed in
Appendix A, in vivo studies are recommended by EPA for risk assessments of
suspected mutagens. A brief summary of the results of the mutagenicity
assays for the analytes is provided. There are numerous studies available for
some of the contaminants; consequently, all results could not be feasibly listed.
To provide a more concise overview of the results of greatest concern, the
nature of the positive studies is given. The direction of the majority of results
is also given (e.g., primarily positive, negative, or mixed).
5.2.6. Carcinogenicity
Cancer slope factors and descriptive data were obtained primarily from IRIS,
HEAST, and OPP. Preference was given to IRIS values; however, when IRIS
values were not available values developed by Agency program offices (e.g.,
OPP) are provided. The program office values have not necessarily undergone
the extensive interagency review which is required for inclusion in the IRIS data
base, although many have been reviewed by scientists within and outside of
EPA.
There are often insufficient studies to evaluate the carcinogenicity of a
chemical. EPA has recognized this and formalized the lack of data as
classification D: "not classifiable as to human carcinogenicity" in their cancer
weight of evidence scheme (EPA, 1986a). Many target analytes fall into this
category; for others, no data were found in the sources consulted regarding
their carcinogenicity. For chemicals with insufficient or no data on
carcinogenicity in the data bases consulted, the text under the
"Carcinogenicity" heading states that: "insufficient information is available to
determine the carcinogenic status of the chemical". This statement is used for
chemicals lacking a cancer slope factor unless an Agency-wide review has
determined that there is evidence that the chemical is not carcinogenic (i.e., an
E classification is provided in IRIS, 1993). For a complete description of the
5-6
-------
5. TARGET ANALYTES
weight of evidence classification scheme see EPA's Guidelines for Carcinogenic
Risk Assessment (1986a).
5.2.7. Special Susceptibilities
Toxicity data often indicate that some groups of individuals may be at greater
risk from exposure to chemicals or chemical groups. For example, a chemical
which causes a specific type of organ toxicity will usually pose a greater risk
to individuals who have diseases of that organ system (e.g., immunotoxicity
poses a greater risk to those with immunosuppression or with immature
immune systems). Persons with some genetic diseases (e.g., enzyme
disorders) nutritional deficiencies, and metabolic disorders may also be at
greater risk due to exposure to some chemicals. Qualitative data on special
susceptibilities is provided for many of the target analytes. In addition,
information is provided on susceptibilities of special concern for groups of
chemicals (e.g., organophosphates) in Section 5.5. However, there is not
quantitative data on subgroup susceptibilities for most chemicals which would
enable the risk assessor to modify risk values.
The RfDs are designed to take into account the most susceptible individuals
and RfDs often incorporate an uncertainty factor to account for variability
within the human species (See Table 5-2). The U.S. Public Health Service has
provided specific non-quantitative guidance regarding susceptible subgroups in
the ATSDR Toxicity Profiles; it is included in the target analyte discussions in
Section 5.6. In addition, there are some general caveats regarding special
susceptibilities that should be considered. Exposure to many types of toxics
pose higher risks to children due to their immaturity:
"embryos, fetuses, and neonates up to age 2 - 3 months may be
at increased risk of adverse effects...because their enzyme
detoxification systems are immature"
and
"Infants and children are especially susceptible to
immunosuppression because their immune systems do not reach
maturity until 10-12 years of age" (ATSDR, 1990b).
ATSDR has also cautioned that:
"the elderly with declining organ function and the youngest of the
population with immature and developing organs will generally be
more vulnerable to toxic substances than healthy adults" (ATSDR
1993a).
5-7
-------
5. TARGET ANALYTES
5.2.8. Interactive Effects
Data on interactive effects were located for many, but not all, of the target
analytes. Most data on interactive effects were obtained from ATSDR
Toxicological Profiles. Often the data indicate that certain classes of chemicals
may be of concern. For example, most organochlorines induce the mixed
function oxidase system. These chemicals may lead to unanticipated and
exaggerated or diminished effects arising from simultaneous exposure to other
chemicals which rely on the same metabolic system. In some cases this leads
to potentiation (increased toxicity) and in others it hastens the process of
detoxification.
The MIXTOX data base, developed by EPA, was also used to obtain information
on interactive effects (MIXTOX, 1992). The data base provides a very brief
summary of results of studies on combinations of chemicals. Most interactions
are reported as "potentiation", "inhibition" or "antagonism" (decreased
toxicity), "no apparent influence", or "additive." The interactions which differ
from additive or no apparent influence are reported because it is assumed in the
absence of contrary information, that the toxicity of mixtures of chemicals will
be additive for the same target tissue (See Section 4.3). The interactive
terminology used in MIXTOX is used in this document.
5.2.9. Data Gaps
Data gaps noted in IRIS files, OPP tox one-liners, RfD summaries, and the
ATSDR Toxicological Profiles are listed. In addition, data gaps that have been
identified from a review of the studies are listed, along with the reasons that
additional data are considered necessary. For example, if very limited study
data is available on developmental toxicity but developmental toxicity is
indicated in the data base, developmental studies are listed as a data gap.
5.2.10, Summary of EPA Risk Values
The EPA risk values (RfDs and cancer potencies) which were discussed in each
section and were used in the development of fish consumption limits are listed.
They are summarized in Table 2-2.
5.2.11. Major Sources
At the end of each target analyte file is a list of the major sources of
information consulted. Major sources are those which have been frequently
cited (i.e., more than once). Within the text of each target analyte file, all
information is provided with citations. -
5-8
-------
5. TARGET ANALYTES
The IRIS files were consulted in late 1993 for cancer potency values, chronic
exposure RfDs and additional study data. ATSDR ToxicologScal Profiles were
also consulted when available. The profiles have extensive toxicity,
pharmacokinetic, and epidemiological data reviews and provide estimated
Minimum Risk Levels (MRLs), which are analogous to RfDs in that they are
"estimates of levels posing minimal risk to humans" {ATSDR, 1992a). They are
based upon risk assessment methods similar to those used by EPA. The
ATSDR documents were particularly useful because they provide detailed
information and because many provide extensive discussions of developmental
effects as well as some MRLs for these effects. Some ATSDR profiles cited are
draft documents; however, the profiles have undergone extensive review within
and outside of the U.S. Public Health Service before they are released as the
draft bound copies which were cited in this work.
5.2.11. Statement Regarding Uncertainty
There are always significant uncertainties associated with estimating health
risks and safe exposure levels for human populations. While these are
discussed in Section 4, their importance warrants their mention in this section
also. The risk values provided for each chemical in this section are based upon
human or animal studies which evaluated either a small subset of the human
population, or an entirely different species. In either case, we can only
estimate the relevance of the study results to humans. Although a quantitative
methodology is used to extrapolate from various types of studies to the general
human population, there is considerable uncertainty in the estimated
relationship between study populations and the human population.
The use of uncertainty factors and upper bound cancer risk estimates provides
a margin of safety to account for some aspects of uncertainty in the
extrapolation. However, our knowledge of response variability in the human
population is very limited. The variations in response, which are engendered
by age, sex, genetic heterogeneity, and preexisting disease states, may be
considerable. Consequently, although current approaches to assessing risk
involve estimating the upper bound values for deriving exposure or risk and are
intended to be protective rather than predictive, the reader is urged to carefully
review the information provided in this section on data gaps and uncertainties.
It is important to describe the uncertainties and assumptions when
recommending fish consumption limits. With respect to toxicity, these include
both uncertainties associated with specific chemicals and uncertainties and
assumptions associated with the dose-response evaluation process (described
in Section 4). In some cases, a variety of dose-response data will enable the
reader to provide a quantitative estimation of the range of potential risk values
which could be used to calculate exposure and fish consumption limits. A
5-9
-------
5. TARGET ANALYTES
description of data gaps is may also be useful to the risk manager in
determining the best course of action. For chemicals having little data, only a
qualitative description may be possible.
5.3. Methods for Estimating Developmental Toxicity Exposure Limits
EPA has studied issues in developmental toxicity and risk assessment for
developmental toxics over the last two decades and has developed guidance
for evaluating developmental toxics and establishing health-based exposure
limits. The initial guidance for risk assessment of developmental toxics was
provided in 1986 (EPA, 1986e) and has been refined in the current Guidelines
for Developmental Toxicity Risk Assessment (EPA, 1991 a). The recommended
approach utilizes a NOAEL to calculate an RfD in a manner similar to that used
for the calculation of an RfD based upon chronic exposure toxicity. EPA is also
considering use of a benchmark dose approach for developmental toxics under
some circumstances; consequently, the guidelines may be amended in the
future (EPA, 1991 a). The methodology described in this guidance document
follows the current EPA recommendations. The reader is referred to this and
other sources cited throughout this section for further information on
developmental toxicity risk and risk assessment.
EPA is working to incorporate new data on developmental and other types of
toxicity into the RfDs. The reader can use the information provided on
individual target analytes (in Section 5.6) and the methodology discussed in this
section to calculate exposure limits based* upon their evaluation of the
toxicological literature. Section 5.6 contains text which identifies specific
developmental outcomes and the associated dose-response data (i.e., LOAELs
or NOAELs), which can be used to carry out the calculations. The reader may
also wish to conduct a data search to identify any recent data on the chemicals
of major interest in their areas.
Several chemicals are known to cause developmental toxicity in humans.
These include lead, PCBs, methylmercury and some Pharmaceuticals. These are
primarily known due to large-scale poisoning incidents which results in serious
effects in a large number of offspring. Human dose-response studies cannot
be carried out with planned dosing for developmental toxics. However,
developmental toxicity studies have been carried out on many environmental
contaminants in animals. Many of these have yielded positive results (EPA,
1991 a). It is difficult to specifically interpret the dose-response relationship
between effects in animal studies and anticipated observable effects in the
human population. Research has been conducted to evaluate the relationship
between known human developmental toxics and animal testing results; many
similarities in response were found. Alternatively, chemicals which caused
developmental effects in animals were studied for effects in humans. These
5-10
-------
5. TARGET ANALYTES
evaluations have yielded mixed results. It has been theorized that the lack of
concurrence in results may be due in part to the limited nature of the human
data and differences in route, timing and duration of exposure (EPA, 1992e).
Further analysis has indicated that:
"the minimally effective dose for the most sensitive animal species
was generally higher than that for humans usually within 10-fold
of the human effective dose, but sometimes was 100 times or
more higher" (EPA, 1991 a).
The Guidelines go on to state that:
"Thus, the experimental animal data were generally predictive of
adverse developmental effects in humans, but in some cases, the
administered dose or exposure level required to achieve these
adverse effects was much higher than the effective dose in
humans." (EPA, 1991 a)
A number of assumptions are made in approaching developmental toxicity risk
assessment in the absence of specific information. These assumptions include:
• adverse effects in experimental animals may pose a hazard to humans,
• the four manifestations of developmental toxicity (death, structural
abnormalities, growth alterations, and functional deficits) are all of
concern, rather than only malformations and death, which were the
primary effects considered in the past,
• the type of developmental effects seen in animals is NOT necessarily the
same as those produced in humans,
• the most appropriate species is used to estimate human risk when data
are available (e.g., pharmacokinetic). In the absence of such data, the
most sensitive species is used, and
• a threshold is assumed based on the capacity of the developing organism
to repair or compensate for some amount of damage (EPA, 1991 a).
Although it is assumed there is a threshold for developmental toxicity, EPA has
stated that:
"a threshold for a population of individuals may or may not exist
because of other endogenous or exogenous factors that may
increase the sensitivity of some individuals in the
population. "(EPA, 1991 a)
The Agency is currently sponsoring research to better characterize the dose-
response relationship for developmental toxicants. This includes an evaluation
5-11
-------
5. TARGET ANALYTES
of the threshold concept (EPA, 1991 a). The process of risk assessment, as
recommended in the 1991 EPA guidelines, generally follows the four step
process described in this document. However, hazard identification and dose-
response evaluation are combined in the developmental toxicity guidelines
because "the determination of hazard is often dependent on whether a dose-
response relationship is present" (EPA, 1991 a).
5.3.1. Definitions
There is no one consistent definition of developmental toxicity (EPA, 1986e).
Developmental toxicity may include the range of effects from early pregnancy
loss to cognitive disorders only detectable long after birth. The severity of
developmental effects ranges from minor alterations in enzyme levels with no
known associated pathology, to death. Developmental toxicity also
encompasses health endpoints having genetic and non-genetic bases. EPA's
1986 guidelines (EPA, 1986b) provide useful definitions which are used in this
document the purpose of classifying different types of developmental effects,
and for defining the scope of effects which are included under the overall
heading of developmental effects.
Developmental Toxicology: the study of adverse effects on the developing
organism that may result from exposure prior to conception (either parent),
during prenatal development, or postnatally to the time of sexual maturation.
Adverse developmental effects may be detected at any point in the lifespan of
the organism. The major manifestations of developmental toxicity include: 1.
death of the developing organism, 2. structural abnormality, 3. altered growth
(defined below), and 4. functional deficiency.
Functional Developmental Toxicology: the study of alterations or delays
in the physiological and/or biochemical functioning of the individual during
critical pre or postnatal development periods.
Embryotoxicity and Fetotoxicity: include any toxic effect on the conceptus as
a result of prenatal exposure. The distinguishing feature between the two terms
is the stage of development during which the injury occurred (the embryonic
stage lasts until approximately eight weeks post-conception followed by the
fetal stage). The terms include malformations and variations, altered growth,
and in utero death.
Altered Growth: includes an alteration in offspring organ or body weight or size.
These alterations may or may not be accompanied by a change in crown-rump
length and/or in skeletal ossification. Altered growth can be induced at any
stage of development, and may be reversible, or may result in a permanent
change.
5-12
-------
5. TARGET ANALYTES
Malformations: includes permanent structural changes that may adversely
affect survival, development, or function. The term teratogenicity is used to
describe only structural abnormalities.
Variations: includes divergences beyond the usual range of structural
constitution that may not adversely affect survival or health. Distinguishing
between variations and malformations is difficult because responses form a
continuum from normal to extremely deviant, (from EPA, 1986b and 1991 a).
Other terminology is often used (e.g., anomalies, deformations, and aberrations)
but definitions may vary.
For purposes of this guidance document, the definition of developmental
toxicology given above will be used to describe the range of effects considered
in this section. This provides a broad scope for evaluation of developmental
effects, including those resulting from both prenatal and preconception
exposures and effects which are observable pre- and postnatally. This section
does not include a discussion of reproductive system effects (i.e., damage to
the reproductive system), such as sterility, that result from exposure during
adulthood, and which may prevent conception from occurring, but which do
not effect the development of another individual. This type of toxicity is
included under the Chronic Toxicity heading.
Carcinogenic effects occurring prior to adulthood may be considered
developmental effects under some circumstances. These can be evaluated
using the methods described in the previous section on carcinogenicity (in
keeping with EPA recommendations in 1986e) and similarly, mutagenic effects
can be evaluated using criteria discussed in Guidelines for Mutagenicity Risk
Assessment (EPA, 1986c), as described in Appendix A.
5.3.2. Special Issues in the Evaluation of Developmental Toxics
Studies of developmental toxics which are most useful in quantitative risk
assessment include human epidemiological studies and animal toxicology
studies. Epidemiological studies have been conducted on very few chemicals.
Animal studies, which are more readily available, pose problems related to
interspecies extrapolation (See statements in Sections 4 and 5 regarding
uncertainty). The Guidelines for the Health Assessment of Suspect
Developmental Toxicants (EPA, 1991 a) provide guidance on evaluating various
types of developmental toxicity studies.
Some aspects of the evaluation of developmental toxicity studies differ from
the approaches and data that would be sought from most other types of
toxicity studies. One area of concern is the need to ascertain overall
5-13
-------
5. TARGET ANALYTES
reproductive performance, not only adverse effects on developing individuals.
Toxic exposure often results in developmental damage at a very early stage of
growth. This may prevent implantation or lead to very early fetal loss. Such
losses are usually only detectable in animal studies by comparing the number
of individuals per litter or the number of litters produced to the same outcomes
in control populations. Very early losses are often absorbed and are not
identifiable via other means. In human studies such losses are not usually
identified, although prospective studies have used the monitoring of pregnancy
markers, such as human chorionic gonadotropic (HCG) hormone, to identify
very early post-implantation pregnancy losses (See EPA's guidelines for further
discussion in 1991 a).
Another area of concern in developmental toxicity studies which is not usually
of significant interest in other types of toxicity studies is the importance of
weight changes. According to the federal guidelines "A change in offspring
body weight is a sensitive indicator of developmental toxicity..." (1986e). A
relatively small weight change is not generally considered important in
toxicological studies of adult subjects; however, this is considered an important
effect during development. For example, the human corollary to decreased
weight in animals may be low birth weight, although this cannot be directly
implied from animal studies. Low birth weight in infants is a significant and
often serious public health problem. Weight gain or loss may also be organ-
specific and may be indicative of organ toxicity. For example, decreased brain
weight may be indicative of retarded neuronal development.
An issue which is often raised in developmental toxicity studies is maternal
toxicity. Although some researchers have suggested that the presence of
maternal toxicity undermines the validity of results observed in offspring, some
level of maternal toxicity should be observed in this type of study at the high
end of the dose regimen (EPA, 1986e). The EPA health assessment guidelines
provide a description of appropriate endpoints of maternal toxicity. One reason
that identification of maternal toxicity is an important component of a
developmental toxicity study is that it can provide information on the likelihood
of developing individuals being more or less susceptible than adults to an agent.
Agents which produce developmental toxicity in offspring at doses which do
not cause maternal toxicity are of greatest concern because these dynamics
suggest that developing individuals are more sensitive or selectively affected
(EPA, 1986e). Those which produce effects in parent and offspring at the
same dose are also of concern; it should not be assumed that offspring toxicity
results from maternal toxicity because both may be sensitive to the given dose
level (EPA, 1986e).
5-14
-------
5. TARGET ANALYTES
5.3.3. Methods for Estimating Exposure Limits
This section was not designed to provide detailed guidance on conducting dose-
response evaluations. Rather, it provides an overview of an EPA method used
to calculate RfDs which can be used by the reader to estimate exposure limits
for developmental effects as they deem necessary. (The following section
discusses methods for calculating exposure limits for chronic exposure effects,
-which are similar to methods used for non-developmental RfDs.) The major
steps are identification of the most appropriate NOAEL or LOAEL, and
application of relevant uncertainty factors and modifying factors.3 This
discussion assumes a familiarity with basic concepts in epidemiology,
toxicology, and human biology. Guidance is also provided in the discussions
of individual target analytes (See Section 5.6) on selection of a sensitive health
endpoint or study, and use of uncertainty and modifying factors.
5.3.3.1. Identify the Most Appropriate NOAEL or LOAEL.
The approach discussed in this section utilizes "No Observable Adverse Effects
Levels" (NOAELs) and "Lowest Observable Adverse Effects Levels" (LOAELs)
in a manner analogous to that used for the development of chronic toxicity
RfDs.4 It is recommended that the reader review the 1991 guidance on
developmental toxicity risk assessment, which provides extensive specific
guidance on the evaluation and selection of various types .of developmental
toxicity studies (EPA, 1991 a). The 1991 guidelines provide a scheme for
categorization of health-related data, which includes descriptions of sufficient
evidence and insufficient evidence for dose-response evaluations. The
guidelines recommend that a dose-response evaluation not be conducted unless
3 Characterization of the data base is also an important step. However, it
is assumed in this document that an abbreviated approach will be taken to
estimating exposure limits. If the summary data provided in this work or taken
from other sources are used, it will not be possible to fully characterize and
categorize the data base. For a full discussion of this refer to EPA, 1991 a,
pages 63816-63817.
4 The EPA guidance on developmental toxicity (1991 a) also contains a
discussion of the use of a benchmark dose to evaluate toxicity. This approach
employs a different method of evaluation than that described under chronic
exposure later in Section 5. The benchmark approach utilizes the response rate
as a critical factor (e.g., the dose which is effective in 10 percent of the study
subjects). Such an approach requires more extensive information than was
available for most target analytes.
5-15
-------
5. TARGET ANALYTES
there is sufficient evidence. To evaluate developmental toxicity, data from
human studies may be used. However, for most chemicals human study data
are not available and toxicity studies in animals are used (EPA, 1987 and
1991 a). EPA's Office of Health Effects Assessment may also be consulted for
guidance on obtaining additional information and identifying existing data bases
on developmental toxics.
Exposure limits may be estimated using the NOAEL or LOAEL obtained from
toxicological studies of animals and humans or epidemiological studies of
humans. The NOAEL, usually expressed in mg dose per kg body weight of the
subject per day, is the highest dosage given to the animals over their lifetime
that results in no observable adverse effects (NOAEL). When a NOAEL is not
available, the lowest dose at which an adverse effect (LOAEL) was observed
is used. Often there are several NOAELS and LOAELs for a chemical; selection
of the most appropriate value is a judgement based upon the quality of the
studies, sensitivity of the health endpoint and test species and numerous other
factors. The following hierarchy may be useful in selecting a study from which
to use a NOAEL or LOAEL:
• a human study is preferable to an animal study. When a human study
is unavailable, an animal study is selected which uses a species most
relevant to humans, based on the most defensible biological rationale
(e.g., pharmacokinetic data),
• in the absence of a clearly most relevant species, using the most
sensitive species for the toxic effect of concern is preferable (e.g.,
exhibiting a toxic effect at the lowest dose);
• a study with the appropriate exposure route(s) is preferable, oral or
gavage is appropriate for oral exposure,
• a study with sufficient subjects to obtain statistical significance at
relatively low exposure levels is required,
• a recent study identifying adequately sensitive endpoints is preferred
(e.g., not mortality),
• an adequate control population is required, and
• in general, a NOAEL is preferable to a LOAEL. When a NOAEL is
unavailable, the LOAEL which generates the lowest exposure threshold
(after the application of Uncertainty and Modifying Factors) is usually
selected.
It is necessary to consider overall study quality and study design in selecting
the most appropriate study or studies. The reader should refer to the 1991
Guidelines for Developmental Toxicity Risk Assessment for further details (EPA,
1991a).
5-16
-------
5. TARGET ANALYTES
5.3.3.2. Apply Relevant Uncertainty and Modifying Factors.
Once a LOAEL or NOAEL is selected, the value obtained (in mg/kg-day) is
divided by factors to account for the various types of uncertainty inherent in
estimating a threshold for developmental effects. These factors, referred to be
EPA as uncertainty factors and modifying factors are summarized in Table 5-2.
It was adapted from a discussion of RfD development from Abernathy and
Roberts (1994). Many developmental toxicity studies utilize a brief dosing
period during gestation (although use of a study with a single dose is not
recommended). An uncertainty factor is usually not added for the short
duration of the study under these circumstances. This differs from the
calculation of exposure limits based on chronic exposure toxicity (discussed in
Section 5.3.3), when an uncertainty factor is typically applied for the use of a
less-than-lifetime study.
The total product of all of the uncertainty and modifying factors may range
widely depending on the types of studies available. If a chronic human
epidemiologic study is available, the uncertainty factor may be as small as 1.
However, uncertainty factors of 10,000 have been used (IRIS, 1993). While
the uncertainty factors address specific concerns, the modifying factors cover
a wider range of circumstances. A common modifying factor adjustment
results from differences in absorption rates between the study species and
humans, differences in tolerance to a chemical, or lack of a sensitive endpoint.
The default value for a modifying factor is 1. The uncertainty factor which
deals with data gaps is relatively new (Abernathy and Roberts, 1994). It has
been developed because the dose-response data often address a limited number
of effects and do not adequately address effects of major concern. In some
cases there are a number of studies, but the focus of analysis is narrow and
insufficiently sensitive. In other cases, there is not a sufficient number or
breadth of studies (See Dourson et al, (1992) for experimental support of this
data base factor). Other reasons for applying a modifying factor are discussed
in the specific developmental toxicity guidance (EPA, 1991 a); these include
data on pharmacokinetics or other considerations that may alter the level of
confidence in the data.
5-17
-------
5. TARGET ANALYTES
Table 5-2. Uncertainty Factors and Modifying Factors For Estimating
Exposure Limits For Developmental Effects
Uncertainty or
Modifying Factor
General Comments
Standard Value
Uncertainty Factor:
Human
(Intraspecies)
Uncertainty Factor:
Animal to Human
(Interspecies)
Uncertainty Factor:
Data Gaps
Uncertainty Factor:
LOAEL to NOAEL
Modifying Factor
Used to account for the 10
variability of response in
human populations.
Used to account for 10
differences in responses
between animal study
species and humans.
Used to account for the 3 to 10
inability of any study to
consider all toxic endpoints.
The intermediate factor of 3
(1/2 log unit) is often used
when there is a single data
gap exclusive of chronic
data (See IRIS
Documentation).
Employed when a LOAEL 3 to 10
instead of a NOAEL is used
as the basis for calculating
an exposure limit. For
"minimal" LOAELs, an
intermediate factor of three
may be used.
Has been used for 1 to 10
differences in absorption
rates, tolerance to a
chemical, or lack of sensitive
endpoint. The default value
is 1.
Source: Adapted from Abernathy and Roberts (1994). Their work also cites:
Barnes and Dourson, 1988; Abernathy et al, 1993; IRIS, Background
Documentation, 1993; and Jarabek et al, 1990.
5-18
-------
5. TARGET ANALYTES
The uncertainty and modifying factors are divided into the NOAEL or LOAEL to
obtain a Reference Dose (RfD) using the following equation:
RfD = NOAEL or LOAEL Equation 5.1
UF • MF
where:
RfD = the RfD or exposure limit for the target analyte,
NOAEL or LOAEL = the NOAEL from the selected study,
UF = the multiplicative product of uncertainty factors and,
MF = the modifying factor
If an exposure limit is calculated for developmental toxicity> the results, in
mg/kg-day, can be used in Equations 2.3 and 2.2 discussed in Section 2, to
calculate fish consumption limits. Examples of how this is carried out are
provided in Section 2.
As discussed above, it is necessary to have a full characterization of the
uncertainties and assumptions incorporated in fish consumption limits.
Assumptions and uncertainties associated with dose-response assessment are
discussed in Section 4.3.7 and 5.2.11. As a point of reference, EPA has
estimated that the RfDs which they develop have an uncertainty spanning
approximately one order of magnitude (EPA, 1987). A description of the
variability in dose-response results and their impact on fish consumption limits,
descriptions of the data gaps, study limitations, and assumptions are also
important in providing a context for fish consumption limits based upon
developmental toxicity, or other types of toxic effects. It may be useful to
review the description of uncertainties and assumptions associated with dose-
response evaluations provided in Section 4.3 to identify major sources of
uncertainty. In addition, the list of study characteristics provided in Section
5.3.3.1 may be useful for identifying data gaps and sources of uncertainty. If
this document is the only source consulted for dose-response data, it should be
noted that the literature review conducted for the development of values was
limited to secondary sources such as ATSDR Toxicological Profiles, IRIS, HDSB,
and standard toxicblogical texts (all are cited in the individual chemical
discussions). The inclusion of this type of information in the risk management
process following risk assessment will provide a better overall understanding
of the limitations and uncertainties inherent in the fish consumption limits.
5-19
-------
5. TARGET ANALYTES
The 1991 developmental toxicity risk assessment guidelines provide a scheme
for categorization of health-related data, including descriptions of sufficient and
insufficient evidence for dose-response evaluations. The guidelines recommend
that a dose-response evaluation not be conducted unless there is sufficient
evidence (EPA, 1987 and 1991a). The reader is referred to this source for
additional information on all aspects of risk assessment for developmental
toxicity.
EXAMPLE
The chemical group DDT, ODD, and DDE was chosen as an example of how an
estimated exposure limit for developmental effects can be developed for target
analytes. 11; was chosen because there is sufficient information from a recent
study with sensitive health endpoints to conduct such an analysis. In addition,
the current RfD is based upon a study which is over 40 years old.
It is advisable to conduct a thorough literature search to identify all relevant
studies. The summaries of dose-response and other toxicity data provided in
Section 5 provide an overview; however, it is advisable to seek additional data,
including any newly released information, whenever practical. A discussion of
an abbreviated approach to estimating an exposure limit, using the information
provided in this guide, is given below.
The developmental toxicity from the DDT5 section (5.6.2) is duplicated below
for the reader's convenience.
DDT causes embryotoxicity and fetotoxicity but not teratogenicity in
experimental animals (ATSDR, 1992c). Studies indicate that estrogen-like
effects on the developing reproductive system occur (A TSDR, 1992c)(this also
occurs with chronic exposure as discussed under chronic effects). Rabbits
exposed to 1 mg/kg-day early in gestation had decreased fetal brain, kidney and
body weights (A TSDR, 1992c). Prenatal exposure in mice at 1 mg/kg on three
intermittent days resulted in abnormal gonad development and decreased
fertility in offspring, which was especially evident in females (Hayes, 1982).
A three-generation rat reproduction study found increased offspring mortality
at all dose levels with a LOEL of 0.2 mg/kg-day. Three other reproduction
studies found no effects at much higher dose levels (IRIS, 1993). Effects on
the urogenital system were found with eight days prenatal exposure in mice.
5 The chemical group DDT, DDD, and DDE will be referred to as DDT
throughout this section.
5-20
-------
5. TARGET ANALYTES
Behavioral effects in mice exposed prenatally for seven days were noted at
17.5 mg/kg-day (HSDB, 1993).
Prenatal one day exposure of rabbits to DDT resulted in an abnormal
persistence of pre-implantation proteins in the yolk sac fluid. The results
suggest that DDT caused a cessation of growth and development before
implantation or during later uterine development. The authors suggest that
damage can be repaired but may result in offspring with prenatal growth
retardation in the absence of gross abnormalities (HSDB, 1993). Most dosages
tested for these effects have been relatively high. Postnatal exposure of rats
for 21 days at 21 mg/kg (only dose tested) resulted in adverse effects on
lactation and growth.
Biomagnification of DDT in human milk has been observed. In lactating women
with an intake of 5 x 10~4 mg/kg-day of DDT, the milk contained 0.08 ppm.
This was calculated to result in infant doses of O.0112 mg/kg-dayf which are
approximately 20 times the doses taken in by the mothers (HSDB, 1993). In
dogs placentalpassage of DDT to the fetus has been demonstrated. This was
confirmed in mice. Primary targets include the liver, adipose tissue and
intestine. Rabbit blastocysts (a very early stage of development) contained a
significant amount of DDT shortly after administration to the mother
(HSDB, 1993).
DDT is suspected of causing spontaneous abortion in humans and cattle
(Hayes, 1982). It is not known whether this is related to the reproductive
system toxicity of DDT (See Chronic Toxicity section) or developmental
toxicity. The average concentration of DDE in the blood of premature babies
(weighing less than 2500 grams) was significantly greater than those of higher
-birth weight infants (HSDB, 1993). The relationship between spontaneous
abortion, premature delivery and maternal exposure and body burden requires
clarification.
ATSDR reports a recent developmental study in mice found behavioral
abnormalities in offspring exposed prenatally at 0.5 mg/kg-day. Latent effects
were observed following cessation of exposure, and subsequent tissue
evaluation found structural/function alterations in the brain. Effects reported
include an abnormal increase in activity and probable altered learning ability.
The effects occurred at levels approximately 50-fold lower than those which
were noted in adults and did not cease when dosing was discontinued, or when
tissue levels had decreased. This information was used to support the
hypothesis of permanent structural changes in the brain. The results of this
study were used by ATSDR to calculate an acute exposure MRL of 5 x 10~4
mg/kg-day using standard uncertainty factors of 10 each for inter- and
intraspecies variability and the use of a LOEL rather than a NOEL (ATSDR,
5-21
-------
5. TARGET ANALYTES
1992c). This MRL is based upon a sensitive endpoint with structural and
functional toxicity correlations and should be considered for use as an exposure
limit for developmental effects of DDT, DDE, and ODD.
DDT accumulates in body tissue; consequently, exposure occurring prior to
pregnancy can contribute to the overall maternal body burden and result in
exposure to the developing individual. As a result of this it is necessary to
reduce exposure to children and females with childbearing potential to reduce
overall body burden. If exposure is reduced during pregnancy, but has occurred
prior to pregnancy, the pregnancy outcome may be affected, depending on the
timing and extent of prior exposure.
In addition to the data specifically discussing developmental toxicity, it is also
useful to review other relevant data. This includes chronic toxicity and
carcinogenicity, including especially reproductive system toxicity, and other
organ toxicities which are similar to, or affect the same system as that
observed in developmental toxicity studies. All other sections of the target
analyte file may also have a bearing on understanding and interpretation of the
results of developmental toxicity studies. They may support or refute the
results observed or point out potential data gaps (e.g., organ toxicities which
were observed in numerous studies of adult animals but which were not
evaluated in developmental toxicity studies).
It is especially necessary to review any discussions of reproductive system
toxicity in the "Chronic Toxicity" section of a target analyte discussion. This
may have a bearing on the interpretation of developmental toxicity study
results. For example, alteration in hormonal balances, structural changes in the
reproductive system, and other adverse effects may modify the ability to
maintain pregnancy. This could lead to a reduction in the number or size of
litters, or other impact on pregnancy outcome. These factors would need to
be considered when reviewing developmental toxicity studies which identify
effects such as increased fetal resorptions, fetal death, reduced litter size, and
related effects, because these effects could arise from damage to the mother,
rather than offspring.
There are numerous other effects on reproductive toxicity which may affect
interpretation of developmental toxicity study results. The reader may wish to
consult texts on this subject for further information. Some of these are listed
at the end of Section 5.3. A copy of the relevant reproductive system toxicity
discussion taken from the chronic toxicity section of the DDT profile (Section
5.6.2) is provided below.
DDT may cause reproductive system toxicity. It appears to bind to uterine
tissue and have estrogenic activity (Hayes, 1982). Metabolites of DDT bind to
5-22
-------
5. TARGET ANALYTES
the cytoplasmic receptor for estrogen which may result in inadvertent hormonal
response (agonist) or depression of normal hormonal balance (antagonist).
Either may result in reproductive abnormalities (HSDB, 1993). The animal
studies of the reproductive system have yielded mixed results. Chronic animal
studies have identified LOELs which range over orders of magnitude. Serious
adverse effects (decreased fertility and decreased litter size) have been
observed at 0.35 and 0.91 mg/kg-day respectively in subchronic animal
studies. Edema of the testes occurred at 2 mg/kg-day in a rat study. NOELs
are not available for these studies. Other studies have identified NOELs ranging
from 2.4 to 10 mg/kg-day with severe effects at 12 mg/kg-day (increased
maternal and offspring death) (ATSDR, 1992c). Significant reproductive
(function and lactation) abnormalities have also been observed at higher doses
(83 mg/kg-day in rats and at 33.2 mg/kg-day in mice). Function abnormalities
have also been observed in dogs (Hayes, 1982).
It may also be helpful to survey the available information on related chemicals
(e.g., structural relatives of DDT would include other organochlorine pesticides).
This may provide general information on effects which are common to all or
many members of a chemical group. Such findings lend support to conclusions
regarding toxicity. In addition, studies on related chemicals may have explored
effects which are anticipated (based on adult studies in the chemical of
concern) in developing individuals, but which have not been evaluated in
developmental studies on the chemical of concern. This provides useful
information for qualitatively evaluating potential toxicity and may point out
critical data gaps.
It is not feasible to duplicate the information on all organochlorines here for
purposes of discussing DDT; however, the reader may wish to review those
sections for their own information. The nervous system appears to be a
sensitive organ for developmental effects of organochlorines, based on a review
of the chronic and acute exposure toxicity of DDT's structural relatives. The
reader may wish to summarize the toxicity of structurally similar chemicals with
respect to the most relevant type of toxicity (e.g. a critical effect) for
establishing exposure limits. Only data regarding the nervous system is
summarized below for DDT since it appears to be the most sensitive indicator
of developmental toxicity in many of the organochlorines evaluated.
In summary, organochlorines are known to cause nervous system disorders in
acutely exposed humans, and central nervous system depression is a common
serious effect of organochlorine poisoning. Organochlorine exposure has
caused adverse nervous system effects in multiple species in numerous chronic
and developmental toxicity studies in animals. The association between DDT
exposure and nervous system effects in developing individuals is a plausible and
anticipated effect based upon the behavior of structurally similar chemicals.
5-23
-------
5. TARGET ANALYTES
Based on the information reviewed, prenatal exposure to DDT is associated
with adverse effects on multiple organ systems in multiple species. There are
limited human data, and they are not sufficiently quantified to use in calculating
an exposure limit. The study which identified behavioral abnormalities in
offspring exposed prenatally at 0.5 mg/kg-day appears to be the most sensitive
study available (See above). The results are supported by tissue evaluations
which found structural/functional alterations in the brain. The effects include
an abnormal increase in activity and probable altered learning ability. The
effects appeared permanent in nature. This information was used by ATSDR
to calculate an MRL of 5 x 10~4 mg/kg-day. Using the same approach as was
taken by ATSDR, with standard uncertainty factors of 10 each for inter- and
intraspecies variability and the use of a LOEL rather than a NOEL yields an
overall uncertainty divisor of 1000. This is divided into the LOAEL of 0.5
mg/kg-day to obtain an estimated exposure limit of 5 x 10~4 mg/kg-day.
Estimated Exposure Limit = °-5 mglkg-d = 5 x 10-4
where:
0.5 = the LOAEL from the selected study
1000 = the multiplicative product of the uncertainty factors for inter- and
intraspecies variability and the use of a LOAEL rather than a
NOAEL
A modifying factor equal to 1 was used in this example. The estimated
exposure limits developed by readers can be used in Equations 2.3 and 2.2
(discussed in Section 2), to calculate meal fish consumption limits. Examples
are provided in Section 2.
Although MRLs are not available to support an estimated exposure limit for
most chemicals, information is provided for each target analyte on studies with
sensitive developmental health endpoints6. The categories of uncertainty
factors and the need for a modifying factor are discussed. Readers are
encouraged to evaluate the data and utilize the factors they consider most
appropriate. Information on uncertainty and modifying factors is qualitative and
should be used in the context of the overall toxicity data for each target
analyte. The information provided on health endpoints with NOAELS and/or
6 In the absence of sensitive health endpoints, the lack of data is clearly
noted in the text.
5-24
-------
5. TARGET ANALYTES
LOAELS and regarding uncertainty and modifying factors should enable readers
to calculate and exposure limit as they deem necessary.
A discussion of uncertainty, assumptions, and data gaps should be a part of
information supporting an estimated exposure limit. This information can
include a summary of the various sources of uncertainty described in Sections
4 and 5 of this document, information included in the target analyte discussion,
and any other information the reader feels would be useful in characterizing
uncertainty. A copy of the "data gaps" section from the DDT discussion
follows.
IRIS notes the lack of a NOEL for reproductive effects and a relatively short
duration for the critical study on which the RfD is based. No intermediate or
chronic oral MRLs were calculated by A TSDR because of the lack of a NOEL
and the seriousness of the LOEL in significant studies (ATSDR, 1992c).
Information is not available for this document on the specific relationships
between various Pharmaceuticals and DDT/E/D body burdens or intakes.
Information on the relationship between pre- and postnatal exposure and
behavioral effects and maternal exposure and milk concentrations are also
needed.
An interagency group of researchers from NTP, ATSDR, and EPA have
identified the following data gaps, pharmacokinetic data, animal studies on
respiratory, cardiovascular, Gl, hematological, musculoskeletal and
dermal/ocular effects, the significance of subtle biochemical changes such as
the induction of microsomal enzymes in the liver and the decreases in biogenic
amines in the nervous system in humans, an epidemiological study in humans
of estrogen-sensitive cancers including endometrial, ovarian, uterine, and breast
cancer, reproductive system toxicity, developmental toxicity, a multiple assay
battery for immunotoxicity, subtle neurological effects in humans, and
mechanisms of neurotoxicity in the neonate (ATSDR, 1992c).
This discussion includes a list of the types of studies which are needed based
on an interagency review of the available data. Most major categories of
uncertainty are covered by this list of studies. The reader may wish to
elaborate on why certain studies are needed (e.g., pharmacokinetic studies to
generate better information on bioaccumulation, body burden, accumulation in
milk, etc).
5.3.3.3. Sources of Additional Information on Developmental Toxicity
The primary source the reader is referred to for additional information on
conducting risk assessment for developmental toxicity is: Guidelines for
5-25
-------
5. TARGET ANALYTES
Developmental Toxicity Risk Assessment (EPA, 1991 a). In addition, there are
165 citations listed in the Guidelines, which cover a broad spectrum of
literature on developmental toxicity and risk assessment. The reader may wish
to consult these sources for additional guidance on this topic.
5.4. Methods for Calculating Alternative Values for Systemic Chronic Effects.
EPA RfDs are provided for use in establishing exposure limits for chronic (non-
carcinogenic) effects. They have been used to calculate the fish consumption
limits provided in Section 3. If the reader wishes to calculate alternative
exposure limits based on the data which is provided in the toxicity discussions
which follow (e.g., if new data are indicated), or based upon data from other
sources, the EPA methodology shown below may be used. It is taken primarily
from the IRIS Background Document 1A, Reference Dose (RfD): Description
and Use in Health Risk Assessments (IRIS, 1993), Abernathy and Roberts
(1994), and Dourson et al. (1992). The method is very similar to the approach
used for developmental toxics, discussed in Section 5.3. The major difference
is that an uncertainty factor for the use of a less-than-lifetime study is not
generally applied for a developmental toxicity analysis; however, it is applied
for developing a chronic toxicity exposure limit when the selected LOAEL or
NOAEL is obtained from subchronic (e.g., three-month) studies are used. A
very brief overview of methods is provided below. The reader is urged to
consult additional sources cited in this section for more detailed information.
There are two major steps to calculating chronic exposure limits: identification
of the most appropriate NOAEL or LOAEL and the application of relevant
uncertainty and modifying factors (as with exposure limit estimating for
developmental toxicity).
5.4.1. Identify the Most Appropriate NOAEL or LOAEL.
The hierarchy for selection of a study described in section 5.3 is also
appropriate for use in identifying appropriate chronic toxicity studies. In
addition to the criteria listed, a chronic (lifetime) study is preferable to a
subchronic study (an acute study cannot be used to quantify risks associated
with chronic exposure). It is important that exposure occurs over a significant
portion of the experimental subject's life in order to parallel a lifetime exposure
of the human population. Issues related to the quality of the study should also
be considered in selecting the most appropriate studies. Additional information
on selection criteria can be reviewed in the IRIS documentation file (IRIS,
1993).
5-26
-------
5. TARGET ANALYTES
5.4.2. Apply Relevant Uncertainty and Modifying Factors.
The calculations for chronic systemic toxicity utilize the modifying and
uncertainty factors listed for developmental toxicity (See Table 5-2). In
addition, an uncertainty factor may be used when a chronic study is not
available and a subchronic (e.g., 90-day) study is used. This is generally a 10-
fold factor (Abernathy and Roberts, 1994, IRIS, 1993). The product of all
uncertainty/modifying factors may range widely depending on the toxicity data
base. If a chronic human epidemiologic study is available, the uncertainty
factor may be as small as 1. However, uncertainty factors of 10,000 may be
appropriate (U.S. EPA, 1990b; Bolger et al., 1990).
While uncertainty factors address specific concerns, the modifying factor
covers a wider range of circumstances. A common modifying factor
adjustment results from differences in absorption rates between the study
species and humans, differences in tolerance to a chemical, or lack of sensitive
endpoint. The default value for a modifying factor is 1, but may range up to
10 (See Table 5-2).
The uncertainty factor which deals with data gaps is relatively new (Abernathy
and Roberts, 1994). It has been developed because the dose-response data
often address a limited number of effects and may not adequately address
effects of major concern. In some cases there are a number of studies, but the
focus of analysis is narrow and not sufficiently sensitive. In other cases, there
is not a sufficient number or breadth of studies. Other reasons for applying a
modifying factor are discussed in the specific developmental toxicity guidance
(EPA, 1991 a); these include data on pharmacokineticis or other considerations
that may alter the level of confidence in the data. EPA has used the criteria
that the following studies be available for a high level of confidence in an RfD:
"two adequate mammalian chronic toxicity studies in different
species, one adequate mammalian 2-generation reproductive
toxicity study, and two adequate mammalian developmental
toxicity studies in different species" (Dourson et al, 1992 and
EPA, 1989c).
The same type of concern regarding the completeness of a data base is
reflected throughout the ATSDR Toxicological Profiles. For example, the
profiles do not provide an MRL for chemicals which have no NOAELs and only
LOAELs resulting in severe effects.
The uncertainty and modifying factors are divided into the NOAEL or LOAEL to
obtain an estimated exposure limit in mg/kg-day. This value is analogous to
EPA's Reference Dose (RfD). The equation is the same as that listed for
5-27
-------
5. TARGET ANALYTES
developmental toxicity (See Equation 5.1). If an alternative exposure limit is
calculated, the results, in mg/kg-day, can be used in Equation 2.3 and 2.2
which are discussed in Section 2, to calculate meal fish consumption limits.
As a point of reference, EPA has estimated that the RfDs they develop have an
uncertainty spanning approximately one order of magnitude (EPA, 1987). As
discussed previously, it is necessary to have a full characterization of the
uncertainties and assumptions which are incorporated in fish consumption
limits. A description of the variability in dose-response results and their impact
on fish consumption limits, descriptions of the data gaps, study limitations, and
assumptions are also important in providing a context for fish consumption
limits based upon developmental toxicity, or other types of toxic effects. It
may be useful to review the description of uncertainties and assumptions
associated with dose-response evaluations provided in Section 4.3.7 and
5.2.11.. If this document is the only source consulted for dose-response data,
it should be noted that the literature review conducted for the development of
these values was limited to secondary sources such as ATSDR Toxicological
Profiles, IRIS, HDSB, and standard lexicological texts (all are cited in the
individual chemical discussions). The list of study characteristics provided in
Section 5.3.3.1 may be useful for identifying data gaps and sources of
uncertainty. The inclusion of this type of information in the risk management
process which follows risk assessment, will provide a better overall
understanding of the limitations and uncertainties inherent in the fish
consumption limits.
EXAMPLE
The reader is referred to the example provided in Section 5.3.3 for guidance.
The difference between calculating chronic exposure limits and developmental
exposure limits is in the use of the uncertainty factor for a less-than-lifetime
study when evaluating chronic exposure toxicity. As with the example in
5.3.3, it is important to review all available information on a chemical and its
close structural analogs prior to making decisions regarding study selection and
the application of uncertainty and modifying factors.
5.5. Toxicity Characteristics of Groups of Analytes
Many chemicals on the list of target analytes (See Table 1-1) fall into two
groups: organochlorine pesticides and organophosphate pesticides. Chemicals
in these groups, while having many individual characteristics, have multiple
toxicity attributes in common with other members of the same group, due to
their structural similarity. Rather than listing all aspects of the toxicity of each
member under the individual chemical discussions, those characteristics
shared by members of the group are listed in this section.
5-28
-------
5. TARGET ANALYTES
The following information is of a qualitative nature and includes the spectrum
from acute high dose-responses to chronic exposure low dose-responses. This
range was included for a number of reasons. Individual responses to chemical
exposures will vary considerably. It is not anticipated that all people exposed
at the same dose will respond in the same manner. Those individuals who are
chemically sensitive may respond to chronic low doses as severely as less
sensitive individuals who are exposed to high doses. Secondly, the effects
elicited by organophosphate and organochlorine pesticides can be characterized
on a continuum for many organ systems (e.g., nervous system effects, liver
damage). Therefore, many effects are associated with both acute and chronic
exposure. Finally, there are very limited dose-response data establishing
specific human thresholds for effects to occur. The risk values (RfDs), derived
primarily from animal studies, do not predict the exposure level at which
response will occur, but rather incorporate uncertainty factors with the study
data to determine a level at which no one is anticipated to experience adverse
effects. Consequently, it is not possible, in most cases, to provide quantitative
data regarding the dose associated with a specific level of effect in a specific
organ system. Under most circumstances it is assumed that the very severe
effects such as convulsions, coma, and death are associated with acute high
level exposures to chemicals. The information provided below was obtained
from the following sources (See Literature Cited in Section 6 for full citation):
Recognition and Management of Pesticide Poisonings, USEPA (1982)
Casarett and Doull's Toxicology, Klaassen et al. (1986)
Pesticides and Human Health, Cunningham-Burns & Hallenbeck (1984)
Pesticides Studied in Man, Hayes (1982)
Handbook of Pesticide Toxicology, Hayes & Laws (1991)
In addition, the Hazardous Substances Data Bank (HSDB,1993) which was
consulted for specific information on target analytes, contains general clinical
effects information for organophosphate exposures and organochlorine
exposures which was used in the development of this section.
5.5.1. Organochlorine Pesticides
Organochlorine pesticides are readily absorbed via the digestive system. They
often accumulate in fatty tissue, including brain and adipose tissue, and may
also be found in human milk due to its high lipid content. The neurological
effects of organochlorine exposure are based upon interference with axonic
transmission of nerve impulses. This causes altered functioning of the nervous
system, primarily the brain.
The following symptoms are commonly associated with exposure to
organochlorines: behavioral changes, sensory and equilibrium disturbances,
5-29
-------
5. TARGET ANALYTES
involuntary muscle activity, depression of vital centers (particularly those
controlling respiration), myocardial irritability, tremor, twitching, nausea,
confusion, apprehension, excitability, dizziness, headache, disorientation,
weakness, paresthesias, convulsions, and unconsciousness (EPA, 1982,
HSDB,1993).
Organochlorines stimulate synthesis of hepatic drug-metabolizing microsomal
enzymes, primarily in the liver; however, they do so in different ways (Hayes
and Laws, 1991, p.739). Many organochlorines are associated with liver and
kidney toxicity. Organochlorine pesticides' induction of the hepatic microsomal
enzyme system causes alterations in the rate of metabolism of all other
endogenous or exogenous chemicals metabolized by this system. Metabolism
may detoxify or increase the toxicity of chemicals, depending on whether the
parent or metabolite is more toxic. For example, DDT is reported to promote
some tumorigenic agents and antagonize others as a result of the induction of
microsomal enzymes (ATSDR, 1992c). In addition, exposure to other
chemicals that induce the same enzymes may increase the toxicity of the
chemical under evaluation by enhancing its metabolism to its toxic
intermediate.
The induction of microsomal enzymes by organochlorines has serious
implications for the metabolism of some pharmaceutical drugs. Alterations in
response to drugs have been observed in both humans and in experimental
animals. For example, increased phenobarbital metabolism resulting from an
increased body burden of DDT (10 micrograms) led to a 25 percent decrease
in effectiveness of the drug in experimental animals (HSDB,1993). Concern
regarding interaction with drugs is indicated in discussions of especially
susceptible populations in the ATSDR Toxicological Profiles. For example, due
to the interactive effects of chlordane with other chemicals via microsomal
enzymes, ATSDR has cautioned that: "doses of therapeutic drugs and
hormones may require adjustment in patients exposed to chlordane" (ATSDR,
1990d). A similar caution is provided for DDT and its analogs: individuals who
use medications which involve the mixed function oxidase system (MFO
inhibitors) directly or for metabolic processes may be at risk for alteration of the
drugs efficacy and/or timing if they are exposed to DDT (ATSDR, 1992c).
For most chemicals, information was not available on the quantitative
relationships between various Pharmaceuticals and organochlorine body
burdens or intakes. When information was located on these types of
interactions, it was included in the chemical discussions. For more information
on this, the reader is referred to the ATSDR Toxicological Profiles and to the
open literature.
5-30
-------
5. TARGET ANALYTES
5.5.2. Organophosphate Pesticides
Organophosphates are efficiently absorbed via ingestion. Their toxicity depends
in part on the rate at which the chemicals are metabolized in the body. This
occurs principally by hydrolysis to nontoxic or minimally toxic byproducts. The
most studied and obvious effect of organophosphate poisoning is
cholinesterase inhibition. This results from phosphorylation of the
acetylcholinesterase enzyme at nerve endings. Loss of enzyme function allows
accumulation of acetylcholine (the neurotransmitter) at cholinergic
neuroeffector junctions causing muscarinic effects, and at skeletal myoneural
junctions, and in autonomic ganglia (nicotinic effects). Organophosphates
cause CNS disturbances through impairments of nerve impulse transmission in
the brain (EPA, 1982).
It is not clear what, if any, adverse effects are associated with exposure at
levels which produce only cholinesterase inhibition in the absence of any other
effects. This is currently under evaluation at EPA. In 1993 EPA's Scientific
Advisory Board (SAB) issued a report on cholinesterase inhibition and risk
assessment (EPA, 1993q). A key finding was:
"To date, analyses of studies of cholinesterase inhibition in plasma
and in red blood cells do not provide information useful for
evaluating potential hazards and risks in the nervous system. This
finding justifies a new science policy against the use of blood
cholinesterase inhibition data for risk assessment purposes."(EPA,
1993q)
Multiple adverse effects resulting from cholinesterase inhibition and other toxic
mechanisms have been associated with organophosphate exposure. The SAB
report states that:
"Clinical effects associated with exposure to cholinesterase
inhibitors can be used in risk assessment to define hazard and to
calculate benchmark doses and RfDs."(EPA, 1993q)
While the issue may be more clear for clinical effects, there has not, as yet,
been resolution of the questions as to whether cholinesterase inhibition alone
should be used as a critical endpoint. The 1993 report "does not provide a
simple yes or no answer to the issue of using RBC cholinesterase inhibition data
by itself (i.e., in the absence of clinical symptoms) for risk assessment."
Concern arises, in part, from the fact that blood enzyme inhibition may precede
and predict brain enzyme inhibition, which is of significant concern (EPA,
1993q). Additional information is required to clarify this issue.
5-31
-------
5. TARGET ANALYTES
The SAB report suggests that EPA continue research designed to evaluate the
correlation of clinical signs with blood cholinesterase inhibition, especially
correlations with respect to dose, time, and linearity (EPA, 1993q).
Cholinesterase inhibition has been used as the critical endpoint, on which RfD
calculations are based, for many organophosphates included in the IRIS data
base. The uncertainty surrounding the use of cholinesterase inhibition as an
effect is an example of a circumstance when the reader may wish to calculate
their own exposure limits. When the RfD for the target analytes is based on
cholinesterase inhibition, other chronic toxicity data are provided for analytes
having sufficient data. This enables the reader to calculate estimated exposure
limits (using Equation 5.1) and derive fish consumption limits (using Equations
2.2 and 2.3) based on other health endpoints if appropriate.
Effects commonly associated with organophosphate exposure include the
following: headache, dizziness, weakness, incoordination, muscle twitching,
tremor, nausea, abdominal cramps, diarrhea, sweating, blurred or dark vision,
confusion, tightness in the chest, wheezing, productive cough, pulmonary
edema, slow heartbeat, salivation, tearing, toxic psychosis with manic or
bizarre behavior, influenza-like illness with weakness, anorexia, malaise,
incontinence, unconsciousness, and convulsions (EPA, 1982, HSDB,1993).
In addition, some, but not all, organophosphates cause peripheral neuropathy
resulting from demyelination of the nerves. Specific effects include numbness,
tingling, pain, weakness, and paralysis in the arms and legs. These effects may
be delayed and may be reversible or irreversible (EPA, 1982).
Muscarinic effects in children exposed to organophosphates may differ from
those in adults. Those most commonly encountered with acute exposure
include: CNS depression, stupor, flaccidity, dyspnea, and coma. Seizures may
be more common in children than in adults (HSDB,1993).
Psychiatric symptoms which have been reported include defects in expressive
language and cognitive function, impaired memory, depression, anxiety or
irritability and psychosis. These are more common in individuals with other
clinical signs of organophosphate poisoning or with pre-existing psychological
conditions (HSDB,1993). Behavioral effects are a prominent concern based
upon the results of toxicity data reviewed for the target analytes. It appears
to be one of the most sensitive indicators of toxicity related to chronic
exposure. Behavioral effects, such as aggressiveness, irritability and
hyperactivity, occurred at low levels of exposure in animal studies. These
effects are particularly problematic because they are difficult to specifically
associate with organophosphate exposure in the human population, but could
have serious'consequences.
5-32
-------
5; TARGET ANALYTES
There is a recognized high-risk human population with respect to
organophosphate exposure. Approximately three percent of the human
population has an abnormally low plasma cholinesterase level resulting from
genetic causes. These people are particularly vulnerable to cholinesterase-
inhibiting pesticides. Others at greater risk include: persons with advanced liver
disease, malnutrition, chronic alcoholism, and dermatomyositis, because they
exhibit chronically low plasma cholinesterase activities. Red blood cell (RBC)
acetylcholinesterase is reduced in certain conditions such as hemolytic anemias;
people with these conditions are at greater risk than the general population
from exposure to organophosphates (EPA, 1982).
Compounds which are known to reduce plasma pseudocholinesterase activity
and thereby aggravate the effects of cholinesterase inhibitors are carbon
disulfide, benzalkonium salts, organic mercury compounds, ciguatoxins, and
solanines (EPA, 1982).
The Hazardous Substances Data Bank (HSDB,1993) contains a summary of
diseases and disorders which are of special concern for individuals exposed to
organophosphates. The following are listed as contraindications for work with
(and exposure to) these chemicals: "organic diseases of the CNS, mental
disorders and epilepsy, pronounced endocrine and vegetative disorders,
pulmonary tuberculosis, bronchial asthma, chronic respiratory diseases,
cardiovascular diseases and circulatory disorders, gastrointestinal diseases
(peptic ulcer), gastroenterocolitis, diseases of the liver and kidneys, and eye
diseases (chronic conjunctivitis and keratitis)" (HSDB,1993).
5.6. Toxicity Data for Target Analytes
This section contains a contaminant specific discussion of toxicity data and risk
values. The target analytes are listed with their section number in chemical
groupings in Table 5-3. This is the order in which they are presented in this
section. A summary of the cancer potency values and RfDs is provided in
Table 2-2.
Abbreviations Used
The abbreviations NOEL, NOAEL, LEL, LOEL, and LOAEL are used in this
document as they appear in the original sources. While they have specific
meanings (See the Glossary for abbreviations), NOEL-NOAEL and LEL-LOEL-
LOAEL are sometime used interchangeably. Since it was not possible to
determine the intent of the authors of the source documents, the terms were
used as they appeared in those documents.
5-33
-------
5. TARGET ANALYTES
The glossary contains a 'description of additional terms and abbreviations which
are found in this section
SCIENTIFIC NOTATION
Scientific notation is used where the values are less than 0.001 unless it would
introduce confusion to the text (e.g., when presenting a range, the same format
is used for both values in the range). In the summaries of risk values all non-
cancer risk values are presented in scientific notation to facilitate comparison
across health endpoints.
5-34
-------
5. TARGET ANALYTES
Table 5-3. Target Analytes and Chemical Categories
Chemical Category
Organochlorine pesticides
Organophosphate pesticides
Chlorophenoxy herbicides
Polychlorinated biphenyls (PCBs)
Dioxins
Metals
Target Analyte
Chlordane
DDT, ODD, DDE
Dicofol
Dieldrin
Endosulfan (1 and II)
Endrin
Heptachlor epoxide
Hexachlorobenzene
Lindane
Mirex
Toxaphene
Carbophenothion
Chlorpyrifos
Diazinon
Disulfoton
Ethion
Terbufos
Oxyfluorfen
Total Aroclors
2,3,7,8-Tetrachloro-
dibenzo-p-dioxin
Cadmium
Mercury
Selenium
Section Number
5.3.1
5.3.2
5.3.3
5.3.4
5.3.5
5.3.6
5.3.7
5.3.8
5.3.9
5.3.10
5.3.11
5.3.12
5.3.13
5.3.14
5.3.15
5.3.16
5.3.17
5.3.18
5.3.19
5.3.20
5.3.21
5.3.22
5.3.23
5-35
-------
5. CHLORDANE
ORGANOCHLORINE PESTICIDES
In addition to the discussions of individual target analytes, please refer to the
discussion of toxicity characteristics of the organochlorine chemical group in
Section 5.5.
5.6.1. Chlordane
Background
Chlordane is an organochlorine pesticide which is comprised of the sum of cis-
and trans-chlordane and trans-nonachlor and oxychlordane for purposes of
health advisory development (EPA, 1993a). It was used extensively until most
uses were banned in 1988. Due to its long half-life and ability to concentrate
in biological materials, it is still widely distributed in fish in the United States.
Pharmacokinetics
Chlordane bioaccumulates in biological materials (IRIS, 1993). It is highly
lipophilic and readily absorbed via all routes. Chlordane is metabolized via
oxidation which results in a number of metabolites, including oxychlordane,
which is very persistent in body fat. Reductive dehalogenation of chlordane
forms free radicals which are hypothesized to be significant in chlordane
toxicity (ATSDR, 1992d).
Human studies have found chlordane in pesticide applicators, residents of
homes treated for termites and those with no known exposures other than
background (e.g., food or airborne). Human milk fat contained a mean
chlordane residue of approximately 188 ppm. Oxychlordane residues were
detected in 68 percent of human milk samples in a low pesticide usage area
and in 100 percent of the 50 samples tested in Hawaii. It is anticipated that
all routes of exposure were involved in maternal exposure to chlordane. Fat
accumulation of chlordane appears to depend on the exposure duration
(ATSDR, 1992d).
Mechanisms of toxicity include: the binding of chlordane and its metabolites
irreversibly to cellular macromolecules, causing cell death or disrupting normal
cellular function; increasing tissue production of superoxide radicals which
accelerates lipid peroxidation and disrupt function of membranes; possible
suppression of hepatic mitochondrial energy metabolism, and alteration of
neurotransmitter levels in various regions of the brain, a reduction in bone
5-36
-------
5. CHLORDANE
marrow stem cells prenatally, and suppression of gap junction intercellular
communication (ATSDR, 1992d).
Acute Toxicity
Chlordane is moderately to highly toxic with an estimated lethal dose to
humans of 6 to 60 grams (IRIS, 1993). See the listing of usual effects
associated with organochlorine exposure in Section 5.5.
Chronic Toxicity
Chlordane has classic organochlorine toxicity as described in Section 5.5. The
principal systems affected by exposure are liver, nervous system, and immune
system. Other effects include neurological abnormalities including gran-mal
seizures and altered EEC results (ATSDR, 1992d).
Reduced fertility and survivability in mice and rats has occurred at 25 and 16
mg/kg respectively and may be associated with reduced binding of
progesterone in the endometrium or with altered metabolism and circulating
levels of steroid hormones. The studies were not designed to identify
thresholds or mechanisms for action (ATSDR, 1992d) and cannot be used to
derive dose-response data for estimation of an RfD.
Jaundice has been reported in humans living in homes treated with Chlordane
for termite control. Chemistry changes indicative of altered liver function were
observed in pesticide applicators in Japan exposed to chlordane (ATSDR,
1992d).
Multiple neurological effects have been reported in humans exposed both
acutely and chronically. According to ATSDR, neither animal or human studies
have evaluated subtle neurological or behavioral effects which may occur at
low levels. Consequently, it is not possible to assess the likelihood of human
effects at environmental exposure levels (ATSDR, 1992d).
IRIS provides an RfD of 6.0 x 10~5 based on a NOAEL of 0.055 mg/kg-day in
a study which found liver atrophy in female rats. The standard uncertainty
factors of 10 each for inter- and intraspecies variability were applied. An
additional safety factor of 10 was applied "to account for the lack of an
adequate reproduction study and adequate chronic study in a second
mammalian species, and the generally inadequate sensitive endpoints studies
in the existing studies, particularly since chlordane is known to bioaccumulate
over a chronic duration" (IRIS, 1993). Confidence in this RfD. is low for the
above stated reasons (IRIS, 1993).
5-37
-------
5. CHLORDANE
Developmental Toxicity
According to the IRIS file "there have been 11 case reports of CNS effects,
blood dyscrasias and neuroblastomas in children with pre/postnatal exposure
to chlordane and heptachlor" (IRIS, 1993). There was insufficient data to
calculate an exposure limit for developmental effects from this study.
ATSDR reports a number of developmental effects. Pre- and early postnatal
exposure in mice may have permanent effects on the immune system, including
a reduction in the number of stem cells which are required to form the mature
immune system. Effects were observed at 4 mg/kg-day. Neurological effects
include abnormal behavior and increased seizure thresholds in mice at 1 mg/kg-
day prenatal and postnatal (via lactation) exposure (no NOEL was identified).
Alterations in plasma corticosterone levels were observed which may result
from a change in the neuroendocrinological feedback mechanisms (ATSDR,
1992d).
There is insufficient information to develop a well-based estimated exposure
limit for developmental effects. According to ATSDR, neither animal or human
studies have evaluated subtle neurological or behavioral effects which may
occur at low levels. Consequently, it is not possible to assess the likelihood of
human effects at environmental exposure levels (ATSDR, 1992d). Neurological
and behavioral effects may be the most sensitive measures of chlordane
developmental toxicity. This appears to be the case for some other
organochlorine pesticides (See DDT and toxaphene). However, it is not
possible to estimate the threshold level because the LOEL caused multiple and
serious effects. If readers elect to calculate an exposure limit for
developmental effects, it should be considered a limited estimate due to the
lack of information on the threshold for effects. The standard uncertainty
factors used in this calculation would typically take into consideration inter- and
intraspecies variability, the use of a LOEL rather than a NOAEL, and the poor
quality of the data base.
Chlordane accumulates in body tissues; consequently, exposure occurring prior
to pregnancy can contribute to the overall maternal body burden and result in
exposure to the developing individual. As a result of this it is necessary to
reduce exposure to children and females with childbearing potential to reduce
overall body burden. If exposure is reduced during pregnancy, but has occurred
prior to pregnancy, the pregnancy outcome may be affected, depending on the
timing and extent of prior exposure.
Regarding cancer in children, see the discussion in the "carcinogenicity" section
below.
5-38
-------
5. CHLORDANE
Mutagenicity
Mutagenicity assays of chlordane have yielded mixed results with positive
results generally obtained in higher organism cell assays and negative results
in bacterial assays (IRIS, 1993).
Carcinogenicity
Chlordane is classified as a probable human carcinogen (B2) by EPA based on
oral studies in animals. The oral cancer potency factor of 1.3 per mg/kg-day
is the geometric mean of the cancer potencies calculated from four data sets
(IRIS, 1992). This value was used to develop fish consumption limits for
carcinogenic toxicity listed in Section 3.
Positive results have been obtained in four strains of mice of both sexes and in
male rats. In addition, numerous structurally related organochlorine pesticides
have been found to be carcinogenic.
Neuroblastoma and acute leukemia have also been associated with prenatal and
early childhood exposure to chlordane (ATSDR, 1993c - heptachlor epoxide
document).
Special Susceptibilities
Based on the results of animal studies showing prenatal exposure causes
damage to the. developing nervous and immune systems, fetuses and children
may be at greater risk than adults from chlordane exposure. According to
ATSDR:
"Given the generally greater sensitivity to toxics of incompletely
developed tissues, it seems possible that prenatal exposure of humans
to chlordane could result in compromised immunocompetence and subtle
neurological effects." {ATSDR, 1992d).
Due to the interactive effects of chlordane with other chemicals via microsomal
enzymes (See interactive effects below), ATSDR has cautioned that: "doses of
therapeutic drugs and hormones may require adjustment in patients exposed to
chlordane." The results of an acute aminal study suggest that protein-deficient
diets may also increase the toxic effects of chlordane (ATSDR, 1992d).
ATSDR has listed the following populations as unusually susceptible: those
with liver disease or impaired liver function, infants, especially those with a
hereditary predisposition to seizures, and the fetus regarding
imrnunosuppression. In addition, it has been hypothesized that a subpopulation
5-39
-------
5. CHLORDANE
may exist with a predisposition to blood dyscrasias resulting from chlordane
exposure. Identification of such a population is not now possible (ATSDR.
1990d).
Interactive Effects
Chlordane is a potent inducer of hepatic microsomal enzymes. (See a discussion
of organochlorine effects related to this induction in Section 5.5.) Chlordane
exposure has been associated with an increased rate of metabolism of
therapeutic drugs, hormones and many other endogenous and xenobiotic
compounds. Exposure to other chemicals which induce the same enzymes may
increase the toxicity of chlordane by enhancing its metabolism to its toxic
intermediate. The acute toxic effects of aldrin, endrin and methoxychlor with
chlordane were greater than the additive sum of the individual toxicities
(ATSDR, 1992d).
It has been suggested that increased dietary vitamins C or E or selenium may
be protective against free radical-induced toxicity (ATSDR, 1992d).
MIXTOX reported synergistic effects between chlordane and endrin in mice
exposed via gavage and both potentiation and inhibition with gamma-
hexachlorocyclohexane in rodents exposed via gavage. Synergism is reported
with toxaphene and malathion together with chlordane in mice exposed via
gavage (MIXTOX, 1992).
Critical Data Gaps
IRIS lists the following data gaps for chlordane: chronic dog feeding study, rat
reproduction study, rat teratology study, rabbit teratology study (IRIS, 1993).
It is clear from this list that the developmental effects of chlordane have not
been adequately evaluated.
According to ATSDR, neither animal or human studies have evaluated subtle
neurological or behavioral effects which may occur at low levels. These types
of studies are needed to assess the likelihood of human effects at
environmental exposure levels (ATSDR, 1992d).
ATSDR has declined to develop oral MRLs for acute, intermediate or chronic
duration oral exposure due to the lack of data on sensitive endpoints for these
durations. They note the need for a behavioral study because it appears to be
a sensitive endpoint. Other studies which are needed include a multigeneration
study which includes a measurement of reproductive system toxicity,
immunological effects, particularly with developmental exposures.
5-40
-------
5. CHLORDAfJE
pharmacokinetic studies, and studies to determine methods for reducing body
burden (ATSDR, 1992d).
Summary of EPA Risk Values
Chronic Toxicity 6 x 10~5 mg/k.g-day
Carcinogenicity 1.3 per mg/kg-day
Major Sources: IRIS (1993), HSDB, 1993, ATSDR (1992d)
5-41
-------
5. DDT, DDE, ODD
5.6.2. DDT, DDE, ODD
Background
DDT is an organochlorine pesticide which has not been marketed in the United
States since 1972, but which is ubiquitous due to its widespread use in
previous decades and its relatively long half-life. DDT's close structural
analogs, DDE and ODD, are metabolites of DDT and have also been formulated
as pesticides in the past (Hayes, 1982). DDT is very widely distributed; it has
been found in seals in Finland and reptiles in the Everglades (HSDB, 1993). The
NHANES II study (National Human Monitoring Program of the EPA) detected
DDE, a metabolite of DDT, is found in 99 percent of the 12 to 74 year old
study subjects (living in the Northeast, Midwest, and South). The median level
was 11.8 ppb in blood serum (HSDB, 1993).
Although some use of DDT continues throughout the tropics, it remains of
human health concern in the United States primarily due to its presence in
water, soil, and food (Hayes, 1982). Since individuals are typically exposed to
a mixture of DDE, DDT, and ODD and their degradation and metabolic products
(ATSDR, 1992c), the sum of the 4,4'- and 2,4'- isomers of DDT, DDE, and
ODD should be considered in the development of fish consumption limits for
this group of chemicals (EPA, 1993a).
Pharmacokinetics
DDT and its analogs are stored in fat, liver, kidney and brain tissue; trace
amounts can be found in all tissues (Hayes, 1982). DDE is stored more readily
than DDT (Hayes, 1982). DDT is eliminated through first-order reduction to
ODD, and to a lesser extent to DDE. The ODD is converted to more water-
soluble bis (p-chlorophenyl)-acetic acid, with a biological half-life of one year.
DDE is eliminated much more slowly, with a biological half-life of eight years.
Because elimination occurs slowly, ongoing exposure may lead to an increase
in the body burden over time.
Acute Toxicity
See the listing of usual effects associated with organochlorine exposure in
Section 5.5. The low effect dose for severe effects (acute pulmonary edema)
in infants has been reported to be 150 mg/kg. In adults, behavioral effects
were noted at 5 to 6 mg/kg and seizures at 16 mg/kg (HSDB, 1993).
Evidence from acute exposure studies of dogs indicate that DDT may sensitize
the myocardium to epinephrine. This was observed for both injected
epinephrine and epinephrine released by the adrenal glands during a seizure,
5-42
-------
5. DDT, DDE, ODD
and resulted in ventricular fibrillation (Hayes, 1982). DDT may concurrently act
on the CNS, in a manner similar to that of other halogenated hydrocarbons, to
increase the likelihood of fibrillation (Hayes, 1982). Chronic exposure to 10
mg/kg-day did not produce increased incidence of arrhythmias in rats or rabbits
(Hayes, 1982).
ODD is considered less toxic than DDT in animals. Symptoms develop more
slowly and have a longer duration with ODD than with DDT exposure. Lethargy
is more significant and convulsions are less common than with DDT exposure
(HSDB,1993).
Chronic Toxicity
Extensive research has been conducted on chronic and subchronic exposure
effects of DDT in animals and in humans working with DDT. These studies
have primarily focused on carcinogenic effects, which are discussed below.
Studies have also identified liver damage, and there is limited evidence that
DDT may cause leukocytosis and decreased hemoglobin level (Hayes, 1982).
Immunological effects have been associated with exposure to DDT. Exposure
to DDT at 2.63 mg/kg-day for 10 days resulted in immunological effects in
rabbits. With 31 days of exposure at 1 mg/kg-day in rats a decrease in the
number of mast cells were observed. A relatively recent eight week study in
rabbits found decreases in germinal centers of the spleen and atrophy of the
thymus (categorized as a serious effects by ATSDR) at 0.18 mg/kg-day. Other
effects were observed at higher doses. No studies were provided on
immunological effects following chronic exposure (ATSDR, 1992c).
DDT may have reproductive system toxicity. It appears to bind to uterine
tissue and have estrogenic activity (Hayes, 1982). Metabolites of DDT bind to
the cytoplasmic receptor for estrogen which may result in inadvertent hormonal
response (agonist) or depress normal hormonal balance (antagonist). Either
may result in reproductive abnormalities (HSDB,1993j. The animal studies of
the reproductive system have yielded mixed results. Chronic animal studies
have identified LOELs which range over orders of magnitude. Serious adverse
effects (decreased fertility and decreased litter size ) have been observed at
0.35 and 0.91 mg/kg-day respectively in subchronic animal studies. Edema of
the testes occurred at 2 mg/kg-day in a rat study. NOELs are not available for
these studies. Other studies have identified NOELs ranging from 2.4 to 10
mg/kg-day with severe effects at 12 mg/kg-day (increased maternal and
offspring death) (ATSDR, 1992c). Significant reproductive (function and
lactation) abnormalities have also been observed at higher doses (83 mg/kg-day
in rats and at 33.2 mg/kg-day in mice). Function abnormalities have also been
observed in dogs (Hayes, 1982).
5-43
-------
5. DDT, DDE, DDD
IRIS lists an oral RfD of 5 x 10"4 mg/kg-day, based on liver effects with a NOEL
of 0.05 mg/kg-day from a 27 week rat feeding study conducted in 1950.
Uncertainty factors of 10 each for inter- and intraspecies variability were used;
however, the usual factor of 10 for a less-than-lifetime study was not applied
"because of the corroborating chronic study in the data base" (IRIS, 1993).
The corroborating study was conducted in 1948.
More recent studies of the immunological and reproductive systems (noted
above) suggest a LOEL from subchronic studies in the range of 0.18 to 0.35.
There are numerous studies supporting the occurrence of both types of effects,
and both are serious in nature. An alternative estimated exposure limit could
be calculated using this more recent data. The most sensitive endpoint appears
to immunological effects observed in the rabbit study (noted above). This
study had a LOEL of 0.18 mg/kg-day. The standard uncertainty factors used
in this calculation would typically take into consideration inter- and intraspecies
variability, the use of a LOEL rather than a NOAEL; and the use of a less-than-
lifetime study.
Developmental Toxicity
DDT causes embryotoxicity and fetotoxicity but not teratogenicity in
experimental animals (ATSDR, 1992c). Studies indicate that estrogen-like
effects on the developing reproductive system occur (ATSDR, 1992c). This
also occurs with chronic exposure as discussed above under chronic effects.
Rabbits exposed to 1 mg/kg-day early in gestation had decreased fetal brain,
kidney and body weights (ATSDR, 1992c). Prenatal exposure in mice at 1
mg/kg on three intermittent days resulted in abnormal gonad development and
decreased fertility in offspring, which was especially evident in females (Hayes,
1982).
A three-generation rat reproduction study found increased offspring mortality
at all dose levels with a LOEL of 0.2 mg/kg-day. Three other reproduction
studies found no effects at much higher dose levels (IRIS, 1993). Effects on
the urogenital system were found with eight days prenatal exposure in mice.
Behavioral effects in mice exposed prenatally for seven days were noted at
17.5 mg/kg-day (HSDB,1993).
Prenatal, one day exposure of rabbits to DDT resulted in an abnormal
persistence of preimplantation proteins in the yolk sac fluid. The results
suggest that DDT caused a cessation of growth and development before
implantation or during later uterine development. The authors suggest that
damage can be repaired but may result in offspring with prenatal growth
retardation in the absence of gross abnormalities (HSDB,1993). Most dosages
tested for these effects have been relatively high. Postnatal exposure of rats
5-44
-------
5. DDT, DDE, ODD
for 21 days to 21 mg/kg {the only dose tested) resulted in adverse effects on
lactation and growth.
In dogs, placenta! passage of DDT to the fetus has been demonstrated. This
was confirmed in mice. Primary targets include the liver, adipose tissue and
intestine. Rabbit blastocysts (a very early stage of development) contained a
significant amount of DDT shortly after administration to the mother
(HSDB,1993).
Biomagnification in human milk has been observed. In lactating women with
an intake of 5 x 10"4 mg/kg-day of DDT, the milk contained 0.08 ppm. This
was calculated to result in infant doses of 0.0112 mg/kg-day, which is
approximately 20 times the dosage to the mothers (HSDB,1993).
DDT is suspected of causing spontaneous abortion in humans and cattle
(Hayes, 1982). It is not known whether this is related to the reproductive
system toxicity of DDT (See Chronic Toxicity section above) or developmental
toxicity. The average concentration of DDE in the blood of premature babies
(weighing less than 2500 grams) was significantly greater than those of higher
birth weight infants (HSDB,1993). The relationship between spontaneous
abortion, premature delivery and maternal exposure and body burden requires
clarification.
ATSDR reports that a recent developmental study in mice found behavioral
abnormalities in offspring exposed prenatally at 0.5 mg/kg-day. Latent effects
were observed following cessation of exposure, and subsequent tissue
evaluation found structural/function alterations in the brain. Effects reported
include an abnormal increase in activity and probable altered learning ability.
The effects occurred at levels approximately 50-fold lower than those which
were noted in adults and did not cease when dosing was discontinued, or when
tissue levels had decreased. This information was used to support the
hypothesis of permanent structural changes in the brain. The results of this
study were used by ATSDR to calculate an acute exposure MRL of 5 x 10~4
mg/kg-day using standard uncertainty factors of 10 each for inter- and
intraspecies variability and the use of a LOEL rather than a NOEL (ATSDR,
1992c). This MRL is based upon a sensitive endpoint with structural and
functional toxicity correlations and should be considered for use as an exposure
limit for developmental effects of DDT, DDE, and ODD. Readers may elect to
consider the ATSDR MRL for developmental toxicity. The MRL is the same
value as the current IRIS RfD (as listed in Chronic toxicity above).
DDT accumulates in body tissue; consequently, exposure occurring prior to
pregnancy can contribute to the overall maternal body burden and result in
exposure to the developing individual. As a result of this, it is necessary to
5-45
-------
5. DDT, DDE, ODD
reduce exposure to children and females with childbearing potential to reduce
overall body burden. If exposure is reduced during pregnancy, but has occurred
prior to pregnancy, the pregnancy outcome may be affected, depending on the
timing and extent of prior exposure.
Mutagenicity
"Genotoxicity studies in human systems strongly suggest that DDT may cause
chromosomal damage" (ATSDR, 1992c). This is supported by in vitro and in
vivo studies in animals (ATSDR, 1992c) and in some bacterial assays
(HSDB,1993). There are multiple positive assays including human
lymphocytes, human leukocytes, human fibroblasts, an oncogenic
transformation and unscheduled DNA synthesis in rats in multiple studies
(ATSDR 1992c; HSDB,1993).
Carcinogenicity
DDE, DDT, and DDD are all considered probable human carcinogens (B2) based
upon animal studies, with cancer potencies of 0.24, 0.34, and 0.34 per mg/kg-
day respectively (IRIS, 1993). Liver tumors were associated with each
chemical. It is noted in the IRIS file that 24 of the 25 carcinogenicity assays
of DDT have yielded positive results. The occupational studies of workers
exposed to DDT are of insufficient duration to assess carcinogenicity (IRIS,
1993). Elevated leukemia incidence, particularly chronic lymphocytic leukemia,
was noted in two studies of workers. Lung cancer has also been implicated in
one study. Bone marrow cells in experimental animals have also been affected
by exposure, including an increase in chromosomal fragments in the cells
(HSDB,1993).
It is recommended that the total concentration of the 2,4'- and 4,4'-isomer of
DDT and its metabolites, DDE and DDD be evaluated as a group using the
cancer potency of 0.34 per mg/kg-day (EPA, 1993a). In addition, the EPA
Carcinogenicity Assessment Group has recommended that this value be used
for combinations of dicofol with the above three compounds (EPA, 1993a).
Special Susceptibilities
Based on the information obtained from a recent developmental study which
found neurotoxicity and structural brain alterations at relatively low exposures
(approximately 50-fold less than in adults), children may be at greater risk from
DDT exposure than adults.
The results of the cardiac toxicity studies are not consistent; however, it is
safest to assume that exposure to DDT or its analogs may pose a risk for
5-46
-------
5. DDT, DDE, ODD
individuals with cardiac disease, at exposure levels which are estimated to be
safe for the general population {Hayes, 1982).
Individuals exposed to DDT may metabolize some drugs more rapidly than the
general population (HSDB,1993) (See also Section 5.5 on this topic). For
example, increased phenobarbital metabolism resulting from an increased body
burden of DDT (10 micrograms) led to a 25 percent decrease in effectiveness
of the drug in experimental animals. The toxicity of chloroform was enhanced
by the addition of DDT to the diet due to its capacity as a microsomal
stimulator (HSDB,1993). Alterations in the metabolism of drugs, xenobiotics
and steroid hormones may result from DDT exposure due to DDT's induction
of the hepatic mixed-function oxidase system at relatively low doses
(HSDB,1993). Individuals who use medications which involve the mixed
function oxidase system directly (MFO inhibitors) or through metabolic
processes may be at risk for alteration of the drugs efficacy and/or timing if
they are exposed to DDT. Information is not available for this document on the
specific relationships between various Pharmaceuticals and DDT/E/D body
burdens or intakes. This type of information merits further investigation.
ATSDR notes that persons with diseases of the nervous system of liver may be
particularly susceptible to the effects of DDT (ATSDR, 1992c). Based on
information discussed above regarding biomagnification in milk, nursing infants
may also be at greater risk due to their increased exposure.
Interactive Effects
As discussed under special susceptibilities above, DDT exposure may alter the
response to drugs, xenobiotics and endogenous steroid hormones. (See the
discussion of organochlorine effects related to induction of the mixed function
oxidase system in Section 5.5.) DDT is reported to promote some tumorigenic
agents and antagonize others. The actions may be related to the induction of
microsomal enzymes (ATSDR, 1992c).
Critical Data Gaps
IRIS notes the lack of a NOEL for reproductive effects and a relatively short
duration for the critical study on which the RfD is based. No intermediate or
chronic oral MRLs were calculated by ATSDR because of the lack of a NOEL
and the seriousness of the LOEL in significant studies (ATSDR, 1992c).
Information was not located for this document on the specific relationships
between various Pharmaceuticals and DDT/E/D body burdens or intakes.
Information on the relationship between pre- and postnatal exposure and
5-47
-------
5. DDT, DDE, ODD
behavioral effects and maternal exposure and milk concentrations are also
needed.
An interagency group of researchers from NTP, ATSDR, and EPA have
identified the following data gaps: pharmacokinetic data, animal studies on
respiratory, cardiovascular, G.I., hematological, musculoskeletal and
dermal/ocular effects, the significance of subtle biochemical changes such as
the induction of microsomal enzymes in the liver and the decreases in biogenic
amines in the nervous system in humans, an epidemiological study in humans
of estrogen-sensitive cancers including endometrial, ovarian, uterine, and breast
cancer, reproductive system toxicity, developmental toxicity, a multiple assay
battery for immunotoxicity, subtle neurological effects in humans, and
mechanisms of neurotoxicity in the neonate (ATSDR, 1993c).
Summary of EPA Risk Values .
These values should be used for the sum of the 4,4'- and 2,4'- isomers of DDT,
DDE, and ODD.
Chronic Toxicity 5x10"4
Carcinogenicity 0.34 per mg/kg-day
Major Sources: IRIS (1993), ATSDR (1992c), HSDB,1993, Hayes (1982)
5-48
-------
5. DICOFOL
5.6.3. Dicofol (Kelthane)
Background
,_s
Dicofol is an organochlorine pesticide which is structurally similar to DDT and
which is frequently contaminated with isomers of DDT, DDE, and DDD (EPA,
1993a). Dicofol is considered a DDT analog based upon its structure and
activity (Hayes and Laws, 1991). In the past, dicofol often contained nine to
15 percent DDT and its analogs. EPA has recently (1989) required that these
contaminants comprise less than 0.1 percent of dicofol (HSDB,1993).
Pharmacokinetics
Very little data were located regarding the pharmacokinetics of dicofol. Due to
its structural similarity to DDT, it may foe assumed to have some of the same
properties. Data regarding metabolites are not consistent. The mechanism of
action is hypothesized to be inhibition of the ATPase associated with oxidative
phosphorylation and cation transport in the plasma membranes (HSDB,1993).
Acute Toxicity
See the listing of usual effects associated with organochlorine exposure in
Section 5.5. The acute oral LD50s for dicofol from animal studies ranged from
640 to 1810 mg/kg (EPA, 1993g).
Chronic Toxicity
No IRIS file was located for this chemical (search 10/93). OPP lists an RfD of
0.001 mg/kg-day based upon a NOEL of 1 mg/kg-day in a two year rat feeding
study (no information was located on the critical effect). Uncertainty factors
totaling 1000 were applied (EPA, 1992d).
The liver is a target organ for dicofol both for systemic and carcinogenic
effects. Studies have also reported thyroid hypertrophy in rats at 25 mg/kg-
day. A NOEL of 0.9 mg/kg-day was identified in a recent study of liver
toxicity, based on gross and microscopic pathology and enzyme alterations, in
a one year dog study (EPA, 1993g). This study would yield an estimated
exposure limit within approximately one order of magnitude of the RfD listed
above.
i
Due to the limited information which was available for this review on the dose-
response dynamics for dicofol, it is recommended that the OPP value of 0.001
mg/kg-day be used for chronic systemic toxicity.
5-49
-------
5. DICOFOL
Developmental Toxicity
Two 3-generation reproductive studies in mice and rats both identified a NOEL
of 1.5 mg/kg-day with effects at 3.375 mg/kg-day noted as reduced litter size,
reduced body weight, and reduced offspring survival (EPA, 1993g). The
reviewed data did not contain information regarding underlying mechanisms of
fetal or neonatal toxicity. Additional uncertainty arises because of the limited
information available in the data base regarding the study outcomes. They are
gross measures of toxicity and do not provide any indication of the level of
exposure at which organ toxicity which led to death was occurring.
Consequently, an estimated exposure limit for developmental effects cannot be
estimated with precision. If these studies were used, the standard uncertainty
factors employed in the calculation would typically take into account
consideration of inter- and intraspecies variability. An additional modifying
factor for the limited information available in the data base could also be used.
As with the other organochlorines, it is anticipated that dicofol can accumulate
in body tissue; consequently, exposure occurring prior to pregnancy can
contribute to the overall maternal body burden and result in exposure to the
developing individual. As a result of this it is necessary to reduce exposure to
children and females with childbearing potential to reduce overall body burden.
If exposure is reduced during pregnancy, but has occurred prior to pregnancy,
the pregnancy outcome may be affected, depending on the timing and extent
of prior exposure.
Mutagenicity
Studies of dicofol in human lymphoid cells in vitro were positive with an
incidence of events 13 times that of controls. It induced sister chromatic
exchange with activation. Other mutagenicity studies in bacteria have yielded
negative results (HSDB,1993).
Carcinogenicity
Dicofol has been classified as a B2 and C carcinogen by offices within EPA.
OPP lists the potency value as 0.44 per mg/kg-day (EPA, 1992c). The EPA
Carcinogenicity Assessment Group (CAG) has recommended that 0.34 per
mg/kg-day be used for combinations of dicofol with DDT, DDE, and ODD (EPA,
1993a). The value of 0.44 per mg/kg-day was used to develop fish
consumption limits listed in Section 3 for carcinogenic effects.
5-50
-------
5. D1COFOL
Special Susceptibilities
Individuals taking medications which involve the mixed function oxidase system
may need to alter their dosages when exposure to dicofol is occurring at
significant levels. No specific information was available on the critical dosage
for interaction. See Section 5.5 for more information on this topic.
Individuals with liver disease and children exposed prenatally may also be at
risk based on the toxicity information which was reviewed.
Interactive Effects
As with other organochlorine pesticides, microsomal enzyme induction occurs
and may cause interactions with other chemicals. See a discussion of this in
Section 5.5. No additional data were located.
Critical Data Gaps
Information is lacking on neurotoxicity endpoints for chronic and developmental
toxicity. Based upon data available on other organochlorines, this type of
toxicity commonly occurs and may be a sensitive endpoint which could serve
as a useful basis for chronic or developmental toxicity exposure limits. The
reviewed data did not contain information regarding underlying mechanisms of
fetal lethality. A sensitive measure of developmental toxicity is necessary to
generate a protective exposure limit. Clarification is also needed regarding the
carcinogenic nature of dicofol.
Summary of EPA Risk Values
Chronic Toxicity 1.0 x 10~3 mg/kg-day
Carcinogenicity 0.44 per mg/kg-day for dicofol alone
0.34 per rng/kg-day in combination with DDT, DDE,
ODD (See text)
Major Sources: tox one-liners (EPA, 1993g), HSDB,1993
5-51
-------
5. DIELDRIN
5.6.4. Dieldrin
Background
Dieldrin is an organochlorine pesticide which was phased out between 1974
and 1987. It continues to be detected nationwide due to its relatively long
half-life. Dieldrin is also a product of aldrin metabolism (ATSDR, 1991 a).
Pharmacokinetics
Dieldrin is absorbed from the Gl tract and transported via the hepatic portal vein
and the lymphatic system. It is found shortly after exposure in the liver, blood,
stomach and duodenum. Dieldrin is lipophilic and is ultimately stored primarily
in fat and tissues with lipid components (e.g., brain) (ATSDR, 1991 a).
In human dosing studies at 0.0001 to 0.003 mg/kg-day over two years, the
time to achieve equilibrium was approximately 15 months. A dynamic
equilibrium was theorized with the average ratio of the concentration in adipose
tissue to blood of 156. Cessation of dosing led to decreases in blood levels
following first order kinetics with a half-life ranging from 141 to 592 days and
an average of 369 days (ATSDR, 1991 a).
The metabolism of dieldrin is described in detail in ATSDR, 1991 a. Sex and
species differences have been reported in the metabolism and tissue distribution
of dieldrin based upon chronic exposure studies and toxicokinetic studies in
animals. Males appear to metabolize and excrete dieldrin more rapidly than
females (ATSDR, 1991 a).
A correlation between exposure and dieldrin levels in human breast milk has
been established. Placental transfer of dieldrin has been observed in women,
with higher concentrations measured in fetal blood than in maternal blood
(ATSDR, 1991 a).
Acute Toxicity
See the listing of usual effects associated with organochlorine exposure in
Section 5.5. Effects noted in addition to those discussed in Section II include:
possible hematological effects in humans (pancytopenia and thrombocytopenia,
immunohemolytic anemia) (ATSDR, 1991 a). An estimated human lethal dose
is 65 mg/kg (HSDB,1993).
5-52
-------
5. DIELDRIN
Chronic Toxicity
IRIS provides an RfD of 5 x 10'5 mg/kg-day based upon a NOAEL of 0.005
mg/kg-day from a 1969 two year rat feeding study which found liver lesions.
Uncertainty factors of 10 each for inter- and intraspecies variability were
applied (IRIS, 1993). Liver toxicity has been observed in multiple animal studies
and in human acute exposure episodes. Adaptive changes (e.g., liver
enlargement) have been observed at 0.00035 mg/kg-day in a subchronic rat
study. ATSDR has calculated an MRL which is equal to the RfD listed in IRIS
(ATSDR, 1991 a).
Although the critical effect in the IRIS study was liver lesions, it was noted that
at the next highest dose (0.05 mg/kg-day) "all animals became irritable and
exhibited tremors and occasional convulsions" (IRIS, 1993). There was no
listing of additional neurobehavioral studies in the IRIS file. As an
organochlorine pesticide it is expected that dieldrin is a CNS toxicant. This is
supported by acute toxicity effects of dieldrin and the neurotoxicity studies
listed below.
Other effects associated with dieldrin exposure include: arterial degeneration
in rats with a chronic exposure to 0.016 mg/kg-day, hematological disorders
in experimental animals at 0.25 and 1 rng/kg-day, musculoskeletal pathology
at 0.015 mg/kg-day in a chronic rat study, kidney degeneration and other
changes at 0.125 mg/kg-day in chronic animal studies in multiple species,
hypertension in humans (exposure level unknown), and multiple deficits in
immune system function in multiple studies (ATSDR, 1991 a). Increased
susceptibility to tumor cells was observed in a subchronic mouse study (dose
not specified in material reviewed) (HSDB,1993).
Neurological effects of dieldrin have been observed in experimental animals and
in humans exposed acutely and chronically. Wheat mixed with aldrin and
lindane was consumed for six to 12 months by a small human population.
Effects were attributed to aldrin (converted to dieldrin via metabolism) because
the wheat had been mixed with lindane in previous years without adverse
effect. A variety of CNS disorders were observed and abnormal EEGs were
noted. Some symptoms (myoclonic jerks, memory loss, irritability) continued
for at least one year after cessation of exposure. A child is believed to have
developed mild mental retardation as a result of exposure. Quantitative
exposure information was not available in the data reviewed (ATSDR, 1991 a).
Neurotoxicity has been observed in humans with chronic inhalation and dermal
exposures (ATSDR, 1991 a). Chronic exposure by dieldrin of spraymen led to
idiopathic epilepsy which ceased when exposure was terminated (HSDB, 1993).
5-53
-------
5. DIELDRIN
Dermal and inhalation exposure were the likely routes of exposure. No
exposure quantitation was available.
A 1967 study of human exposure effects over 18 months at levels up to 0.003
mg/kg-day identified no effects on the CNS (as measured by EEC), peripheral
nerve activity, or muscle activity (ATSDR, 1991 a).
Animal studies have identified neurological effects including behavioral
disorders and learning deficits at doses of 0.1 to 0.25 mg/kg-day in subchronic
and chronic studies. Higher doses produced more dramatic effects (e.g.,
convulsions, tremors). Cerebral edema and degeneration were found with
chronic exposure of rats to 0.016 mg/kg-day (ATSDR, 1991 a). Neural lesions
(cerebral, cerebellar, brainstem and vascular) were observed in chronically
exposed rats at 0.004 mg/kg-day (HSDB,1993).
With the exception of the neurological study discussed directly above, the
information reviewed regarding neurotoxicity indicates that the IRIS RfD would
be protective against adverse effects, using standard assumptions for the
development of an exposure limit. Although the neurological rat study cited
above noted effects at 0.004 mg/kg-day, the human study of exposure over an
18 month period at 0.003 mg/kg-day found no effects on the CNS based upon
various sensitive measures. Taking the results of the human study under
consideration, it appears, based upon the information reviewed, that the IRIS
RfD provides adequate protection against neurological effects in the human
population.
Dieldrin causes reproductive system disorders in animals and one study
suggests that it may cause adverse effects in humans. In a study evaluating
the blood and placental levels of organochlorines associated with premature
labor or spontaneous abortions in women, positive results were obtained for
aldrin. Most exposed subjects had multiple chemical exposures; consequently,
interpretation of study results is difficult (ATSDR, 1991 a). See also notes
regarding estrogenic activity in the carcinogenicity section below.
Studies of reproductive effects in animals indicate that exposure to dieldrin may
cause a number of adverse effects. Dieldrin exposure causes changes in the
levels of serum luteinizing hormone (LH) in females and gonadotropin in males.
Dieldrin interferes with the binding of dihydrotestosterone to male sex hormone
receptors (HSDB, 1993). These three hormones are critical to normal
reproductive function. A mouse study found decreased fertility with exposure
to 1.3 mg/kg-day in females and 0.5 mg/kg-day in males. Another study found
no effects at much higher exposure levels. Adverse reproductive effects in
dogs exposed at a LEL of 0.15 mg/kg-day for 14 months prior to mating
included increased stillbirth rates, delayed estrus, reduced libido, and a lack of
5-54
-------
5. DIELDRIN
mammary function and development. Maternal behavior was studied in mice
exposed for four weeks prior to delivery until weaning at 1.95 mg/kg-day.
Exposed maternal animals violently shook the pups, ultimately killing them;
others neglected their litters {ATSDR, 1991 a).
Based on the information reviewed regarding reproductive toxicity, it appears
that the IRIS RfD would be protective against adverse effects, using standard
assumptions and uncertainty factors for calculating an estimated exposure limit.
Developmental Toxicity
IRIS provides limited information regarding the developmental toxicity of
dieldrin. A NOEL of 6 mg/kg-day was obtained from a mouse teratology study
with exposure occurring from the 7th to 16th day of gestation. Fetotoxicity
(decreased numbers of caudal ossification centers and an increased incidence
of extra ribs) was observed with an LEL of 6 mg/kg-day. This study was not
considered in development of the IRIS file because 41 percent of the maternal
fatalities occurred at the LEL dose (IRIS, 1993). An RfD based on
developmental effects is not provided in IRIS.
A variety of effects in multiple organ systems have been observed in
experimental animals exposed prenatally to dieldrin. Skeletal anomalies and
malformations (e.g., cleft palate, webbed foot, open eyes, extra ribs) were
identified at relatively large doses (LEL of 3 mg/kg-day) (ATSDR, 1991a).
Abnormalities of the CNS, eye and ear were noted with a TD Lo (similar to a
LOEL) of 30.6 mg/kg prenatal exposure, and craniofacial abnormalities were
observed at single prenatal dose of 15 mg/kg-day (HSDB,1993). Liver damage
has.been observed in experimental animals at dosages as low as 0.016 mg/kg-
day {ATSDR, 1991a).7 A multigeneration study in mice found histological
changes in liver, kidney, lungs and brain tissues in the 1st and 2nd generation
offspring at an LEL of 3 ppm (0.075 mg/kg-day) (HSDB,1993).
Multiple studies have reported increased postnatal mortality following prenatal
exposure to dieldrin. Studies in dogs, rats and mice have found LELs of 0.125
to 0.65 mg/kg-day associated with high mortality in offspring in the absence
of increased maternal mortality. Studies designed to evaluate the underlying
causes of mortality suggest that cardiac glycogen depletion, leading to cardiac
failure, may be causal (ATSDR, 1991 a).
7 Note that liver lesions are the basis for the chronic toxicity RfD derived
from a study of adult animals, as reported in IRIS (IRIS, 1993).
5-55
-------
5. DIELDRIN
Neural lesions in prenatally exposed rats were found at an LEL of 0.004 mg/kg-
day. Effects included cerebral edema, internal and external hydrocephalus and
focal neuronal degeneration. Postnatal exposure of rats from day five of
gestation to 70 days of age resulted in increased learning ability at 3.5 x 10~4
mg/kg-day (the only dose tested). ATSDR has cautioned that "interpretation
of the results is difficult because the significance of improved performance in
behavioral paradigms is unknown, and the study is limited because only one
dose of dieldrin was tested" (ATSDR, 1991 a). In a rat multigeneration study
a TD Lo of 0.014 mg/kg-day with behavioral effects was observed
(HSDB,1993).
Dieldrin is known to accumulate in human milk. In one study of 102 samples
in the U.S., 91.2 percent of the samples contained measurable levels of
dieldrin, with a mean concentration of 0.062 ppm lipid basis. Another U.S.
study found 80 percent of the 1436 samples were positive with a range of
0.16 to 0.44 ppm milk fat (HSDB,1993). This indicates that lactation may
provide a significant dietary source in infants with mothers who have been
exposed to dieldrin. As discussed above, studies in humans also determined
that dieldrin can pass through the placenta and is found in fetal blood.
Neurotoxicity appears to be a relatively sensitive endpoint for developmental
toxicity. The association of neurotoxic effects with dieldrin exposure is
supported by the observation of neurological effects in human populations
exposed to dieldrin. The study noted in the paragraph above which identified
neural lesions associated with prenatal exposure provided an LEL of 0.004
mg/kg-day provides the most sensitive developmental toxicity measure of those
reviewed. If the LEL from this study were used to calculate an estimated
exposure limit for developmental effects, the standard uncertainty factors
would typically take into consideration inter- and intraspecies variability, and
the use of a LEL rather than a NOAEL.
As with the other organochlorines, it is anticipated that dieldrin can accumulate
in body tissue; consequently, exposure occurring prior to pregnancy can
contribute to the overall maternal body burden and result in exposure to the
developing individual. As a result of this, it is necessary to reduce exposure to
children and females with childbearing potential to reduce overall body burden.
If exposure is reduced during pregnancy, but has occurred prior to pregnancy,
the pregnancy outcome may be affected, depending on the timing and extent
of prior exposure.
Mutagenicity
There is limited information on the mutagenicity of dieldrin. Positive in vivo
studies have found an increased incidence in the number of abnormal
5-56
-------
5. DIELDRIN
metaphases in dividing spermatocytes and in univalents. Dominant lethal
assays (in vivo) have yielded mixed results, in vitro assays have also yielded
mixed results. Positive results have been obtained in cultured human lung cells
and mouse bone marrow cells (both found increases in chromosome
aberrations), and sister chromatid exchange (SCE) assays.
Dieldrin may not act directly on DIMA; however, it may act by depressing
transfer RNA activity, increasing unscheduled DNA synthesis, and inhibiting
metabolic cooperation and gapjunctional intercellularcommunication, according
to mechanistic studies. The inhibition of gap junctional communication may be
responsible for carcinogenic activity through depressing the cells' ability to
control excess proliferation. This inhibition has been correlated with strains and
species in which dieldrin has been shown to be carcinogenic. This type of
activity is considered promotion, rather than initiation of tumors (ATSDR,
1991a).
Carcinogenicity
Dieldrin is classified as a probable human carcinogen (B2) by EPA based on oral
studies in animals. The oral cancer potency value is 16 per mg/kg-day. Liver
carcinoma was identified in the animal studies. The geometric mean of 13 data
sets (with a range of a factor of 8) were used to develop the cancer potency
(IRIS, 1992). This value was used to calculate fish consumption limits listed
in Section 3 for carcinogenic effects.
A variety of tumor types have been observed in animal studies including
pulmonary, lymphoid, thyroid, and adrenal (ATSDR, 1991 a). ATSDR has
concluded that dieldrin is probably a tumor promotor, based upon genotoxicity
and mechanistic studies which have been reviewed (ATSDR, 1991 a). Dieldrin
has recently been observed to have estrogenic effects on human breast cancer
estrogen-sensitive cells (Soto, et al, 1994). Xenoestrogens have been
hypothesized to have a role in human breast cancer (Davis, et al, 1993). In
addition to potential carcinogenic effects, dieldrin may also cause disruption of
the endocrine system due to its estrogenic activity (Soto, et al, 1994).
Special Susceptibilities
ATSDR has identified the following populations as unusually susceptible: very
young children with immature hepatic detoxification systems, persons with
impaired liver function, and persons with impaired immune function (ATSDR,
1991 a). Based upon the toxicity data reviewed above, individuals with the
following diseases or disorders may also be at increased risk: hypertension,
hematological disorders, musculoskeletal diseases, neurological diseases and
kidney disease.
5-57
-------
5. DIELDR1N
The data also indicate that prenatal exposure may generate risks to children at
relatively low levels of exposure. Postnatal exposure, especially via lactation,
may also be a significant concern.
See also a discussion of susceptibilities associated with pharmaceutical use in
Section 5.5.
Interactive Effects
See the discussion of organochlorine effects related to induction of the mixed
function oxidase system in Section 5.5. In cows, dieldrin exposure increased
the toxicity of diazinon; greater depression in blood cholinesterase activity
occurred, leading to severe clinical signs (HSDB,1993).
MIXTOX has reported inhibition between dieldrin and hexachlorobenzene in rats
exposed orally via food. Studies have also reported additive effects (MIXTOX,
1992).
Critical Data Gaps
A joint team of scientists from EPA, IMTP, and ATSDR have identified the
following study data gaps: animal carcinogenicity, genotoxicity in vivo and in
vitro, reproductive system toxicity, developmental toxicity, especially
mechanisms of postnatal mortality and teratogenesis, immunotoxicity,
neurotoxicity focusing on sensitive endpoints, and pharmacokinetics (ATSDR,
1991a).
Summary of EPA Risk Values
Chronic Toxicity 5x10"5 mg/kg-day
Carcinogenicity 16 per mg/kg-day
Major Sources: IRIS (1993), ATSDR (1991 a), HSDB (1993)
5-58
-------
5. ENDOSULFAN 1,11
5.6.5. Endosulfan 1,11
Background
Endosulfan is an organochlorine pesticide comprised of stereoisomers
designated I and II which have similar toxicities (EPA, 1993a).8 Endosulfan
has been found widely in food samples, including one of 10 fruit and fruit juice
samples for infants at a mean concentration of 0.01 ppb ( HSDB,1993).
Pharmacokinetics
Endosulfan is absorbed through the Gl tract and is distributed throughout the
body. Endosulfan is metabolized to lipophilic compounds and both the parent
and metabolites are found initially primarily in the kidney and liver and fatty
tissue, with distribution to other organs occurring over time. Endosulfan can
induce microsomal enzyme activity and is a non-specific inducer of drug
metabolism. In sheep approximately one percent of a single dose was
recovered in milk. Females may accumulate endosulfan more readily than
males according to animal studies. This may be causal in the higher toxicity
seen in females (See acute toxicity below) (ATSDR, 1993b).
Acute Toxicity
Endosulfan has a high acute toxicity to humans, with an estimated lethal dose
of 50 to 500 mg/kg. Multiple animal studies found females much more
sensitive to exposure than males (e.g., acute oral LD50 of 9.5 in females and
40.4 in males) (EPA, 1992c). See the listing of usual effects associated with
organochlorine exposure in Section 5.5. In addition to those listed in Section
5.5, bluing of the skin (IRIS, 1993), hematopoietic system damage and anemia,
possibly damage to red blood cell membranes, cardiac toxicity, and
immunotoxicity have been noted (ATSDR, 1993b).
Chronic Toxicity
IRIS previously provided an RfD of 5"5 mg/kg-day for endosulfan based upon
a LOAEL of 0.15 mg/kg-day from a two-generation rat reproduction study
which identified kidney toxicity. Uncertainty factors totaling 3000 were applied
(IRIS, 1992). The RfD was withdrawn in December, 1992 and a new RfD
summary is under development (IRIS, 1993). The Office of Pesticide Programs
has recently re-evaluated this chemical. The new value was not available on
8 Endosulfan I and II will be referred to collectively as endosulfan and
discussions will refer to both isomers unless specific note is made.
5-59
-------
5. ENDOSULFAN 1,11
IRIS when this document was prepared; however, it is anticipated that the hew
value will be listed in future versions of the document. Although the IRIS file
has been temporarily removed, the previous IRIS RfD can be used until a new
file entry is completed.
ATSDR developed intermediate exposure duration (14 - 365 days) and chronic
duration MRLs of 0.002 mg/kg-day for both intermediate and chronic
exposures. These MRLs are based upon immunotoxicity and hepatotoxicity
respectively (ATSDR, 1993b).
Other chronic effects of endosulfan noted in studies include: blood vessel
aneurysms at 0.65 mg/kg-day, neurological effects at 1.71 mg/kgrday, damage
to the hematopoietic system at 3.75 mg/kg-day, and elevated hemoglobin
levels at 0.1 mg/kg-day (EPA, 1993i). It appears that the old IRIS RfD would
be protective against the effects noted, based upon current risk assessment
methods.
Two National Cancer Institute studies have identified the following effects:
interstitial fibrosis or acute tubular necrosis of the kidney, atrophy of the testes,
polyarteritis, parathyroid hyperplasia, osteitis fibrosis of the bone, and
abscesses of the lung. The kidney effects led to most deaths (dosages were
not listed in the data base) (HSDB,1993). A number of additional studies have
also found damage to the male reproductive system associated with exposure
to endosulfan (e.g., testicular necrosis, aspermatogenesis, degeneration of
seminiferous tubule epithelium) {ATSDR, 1993b).9
A neurological study in rats exposed at 3 mg/kg-day for 30 days found
increased aggressive behavior at both doses along with a significant increase
in serotonin binding in the frontal cortical membranes that may have been due
to an increase in the affinity of the serotonin receptors (HSDB,1993). This
effect has negative implications for human behavior. AbnormaLincreases in
behavior in prenatally exposed animals has also been noted for other
organochlorinepesticides (See Section 5.5.1 on organochlorines); however, this
level of mechanistic detail has not been located for other organochlorines in the
reviews conducted for this document.
Developmental Toxicity
Multiple teratogenic effects Were associated with endosulfan exposure in a rat
developmental toxicity study including webbed forelimb, clubbed hind limbs,
hypoplastic aortic arch, edema and lordosis, increased incidence of small 4th
See also estrogenic activity discussed under carcinogenicity below.
5-60
-------
5. ENDOSULFAN 1,1)
and unossified 5th sternebrae, and decreased pup size and weight. An
increased incidence of misaligned vertebrae was observed at all dose levels
with a LEL of 0.66 mg/kg-day (EPA, 1993i).
Other developmental studies have yielded a variety of results which are often
inconsistent (e.g., two separate studies found unspecified effects at the lowest
dose tested of 5 mg/kg-day in one study and no effects at the highest dose
tested of 1.8 mg/kg-day in another study). A range-finding single-generation
reproductive study found increased liver weights at the lowest dose tested of
2.5 mg/kg-day. A two-generation reproductive study found increased pituitary
and uterine weights at 3.75 mg/kg-day and a NOEL of 0.75 mg/kg-day. Kidney
discoloration, which was originally attributed to hematopoietic damage at all
doses, has been reevaluated and is now considered by OPP to be part of the
elimination process rather than an adverse effect (EPA, 1993i). It is not clear
why significant differences in effects were noted in multiple recent rat studies
(i.e., the first and last studies discussed in this paragraph).
Postnatal exposure of rats for five weeks at 1 mg/kg-day resulted in aggressive
behavior and increased serotonin binding. This persisted after the dosing
stopped. The study authors concluded that the developing study subjects had
a greater sensitivity to endosulfan than adults (ATSDR, 1993b).
In the absence of more complete information, a conservative approach is
recommended for calculation of an estimated limit for developmental effects,
due to the severity of effects observed in the teratogenicity study with a LOEL
of .66 mg/kg-day (listed first above). If this study, which appears to be the
most sensitive, were used to calculate an estimated exposure limit, the
uncertainty factors used in this calculation would typically take into
consideration inter- and intraspecies variability, and the use of a LEL rather than
a NOEL.
As with the other organochlorines, it is anticipated that endrin can accumulate
in body tissue; consequently, exposure occurring prior to pregnancy can
contribute to the overall maternal body burden and result in exposure to the
developing individual. As a result, it is necessary to reduce exposure to
children and females with childbearing potential to reduce overall body burden.
If exposure is reduced during pregnancy, but has occurred prior to pregnancy,
the pregnancy outcome may be affected, depending on the timing and extent
of prior exposure.
Mutagenicity
Results of mutagenicity assays of endosulfan are mixed, with multiple positive
and negative studies (IRIS, 1993, HSDB,1993, ATSDR, 1993b). Endosulfan
5-61
-------
5. ENDOSULFAN 1,11
has resulted in an increase in the percentage of aberrant colonies and the
frequency of gene convertants and revertants in yeast and was genetically
effective without activation. Longer duration of exposure increased effects
(HSDB,1993). in vivo assays have found chromosomal aberrations and gene
mutations in mice (ATSDR, 1993b).
Carcinogenicity
Insufficient information is available to determine the carcinogenic status of
endosulfan I and II. The carcinogenic assays have yielded mixed results, with
carcinomas, sarcomas and lymphosarcomas identified at increased incidences
in some studies. ATSDR has concluded that the available animal study data
were negative or inconclusive (ATSDR, 1993b). Endosulfan has recently been
observed to haveestrogenic effects on human breast cancer estrogen-sensitive
cells (Soto, et al, 1994). Xenoestrogens have been hypothesized to have a role
in human breast cancer (Davis, et al, 1993). In addition to potential
carcinogenic effects, endosulfan may also cause disruption of the endocrine
system due to its estrogenic activity (Soto, et al, 1994).
Special Susceptibilities
As noted above, multiple animal studies found females much more sensitive to
endosulfan exposure than males, some by nearly one order of magnitude (EPA,
1992c). However, toxicity studies indicate that the male reproductive system
is a target organ for endosulfan toxicity (ATSDR, 1993b).
Animal neurobehavioral study results indicate that the developing test animals
had a greater sensitivity to endosulfan than adults based upon neurotransmitter
patterns and behavioral effects observed (ATSDR, 1993b). This may indicate
that children are at greater risk for neurotoxicity than adults. ATSDR has noted
that:
"There is evidence from animal studies indicating that unborn and
neonates may be more susceptible to the toxic effects of
endosulfan because hepatic detoxification systems are immature
and therefore unable to metabolize xenobiotic substances
efficiently." (ATSDR, 1993b)
Additional groups who may be at greater risk from endosulfan exposure include
those with: liver, kidney, immunological, or blood diseases, compromised
immune systems such as AIDS patients, infants, and elderly people,
hematologic disorders, seizure disorders, and those with low protein diets (See
below) (ATSDR, 1993b). See also a discussion of susceptibilities associated
with pharmaceutical use in Section 5.5.
5-62
-------
5. ENDOSULFAN 1,11
Interactive Effects
Human anecdotal information suggests that endosulfan may act synergistically
with alcohol (ATSDR, 1993b). In laboratory animals moderate protein
deprivation doubled the toxicity of endosulfan (Hayes and Laws, 1991).
Pentobarbital and endosulfan have demonstrated an interactive effect which is
probably related to microsomal enzyme activity. Endosulfan induces the mixed
function oxidase system (ATSDR, 1993b). Vitamin A inhibited the endosulfan-
induced activity of the mixed function oxidase system (ATSDR, 1993b). See
a discussion of organochlorine effects related to induction of the mixed function
oxidase system in Section 5.5.
Critical Data Gaps
The increased susceptibility of females to endosulfan should be studied to
determine the underlying cause, evaluate whether the effect occurs with
chronic exposure, and identify a numerical modsfier to adjust toxicity estimates
and exposure recommendations so that they provide adequate protection for
females.
Additional data is needed on the teratogenic and neurobehavioral effects during
development resulting from endosulfan exposure. Current data do not provide
a consistent picture nor do they explain underlying mechanisms of toxicity, and
thus somewhat compromise the determination of a exposure limit for
developmental effects.
A joint team of scientists from ATSDR, NTP, and EPA have identified the
following data gaps: acute oral exposure studies, mechanisms of anemia-
inducing effects, reproductive system toxicity and related performance,
developmental toxicity studies, mechanisms of immunotoxicity, sensitive
neurological function and histological studies for long-term exposures,
epidemiological studies, pharmacokinetics of intermediate and chronic duration
exposures, and studies evaluating mechanisms underlying the differences in
male and female toxicity. No ongoing studies were identified for endosulfan
(ATSDR, 1993b).
Summary of EPA Risk Values
Chronic Toxicity 5 x 10"5 mg/kg-day
Carcinogenicity Insufficient data to determine carcinogenic status
Major Sources: IRIS (1993), tox one-liners (EPA, 1993i), HSDB (1993), ATSDR,
(1993b)
5-63
-------
5. ENDRIN
5.6.6. Endrin
Background
Endrin is an organochlorine pesticide whose registration was canceled in 1984
(EPA, 1993a).
Pharmacokinetics
Endrin, like the other organochlorine pesticides, is lipophilic. It bioaccumulates
in fat and probably brain tissue and can cross the placenta. Endrin is
metabolized via oxidation of the methylene bridge. Metabolic products are
probably more toxic than endrin and the toxic entity has been hypothesized to
be 12-ketoendrin. In humans, this compound is excreted directly in urine and
feces (ATSDR, 1990c).
Acute Toxicity
Endrin has a high acute toxicity (IRIS, 1993). See the listing of usual effects
associated with organochlorine exposure in Section 5.5. Blood pressure
elevation has also been noted (IRIS, 1993), The primary target of endrin is the
central nervous system (ATSDR, 1990c).
Chronic Toxicity
IRIS provides an RfD of 2 x 10'4 mg/kg-day based on a NOAEL of 0.025
mg/kg-day from a 1969 chronic exposure dog study which identified
histological lesions in the liver and convulsions in study subjects exposed at the
LEL of 0.05 mg/kg-day. Uncertainty factors of 10 each for inter- and
intraspecies variability were applied (IRIS, 1993). ATSDR utilized the same
study and safety factors to calculate an MRL equal to the IRIS RfD (ATSDR,
1990c).
OPP tox one-liners list a 1959 two year dog feeding study with a LOAEL of
0.015 mg/kg-day based upon hypersensitivity in the neck and shoulder area.
Increased erythropoiesis was noted at 0.125 mg/kg-day (EPA, 1993m). The
LOAEL of 0.015 is within one order of magnitude of the LEL identified in the
critical IRIS study. The IRIS value was used to calculate fish consumption
limits for chronic exposure effects listed in Section 3.
Developmental Toxicity
No developmental effects were listed in the IRIS file for endrin (IRIS, 1993).
ATSDR listed a number of prenatal exposure studies which identified structural
5-64
-------
5. ENDRIN
abnormalities and neurotoxicity associated with endrin exposure. Structural
abnormalities have been observed in mice and hamsters exposed to endrin.
These include fused ribs and cleft palate at 5 mg/kg-day for three prenatal days
and webbed foot and open eye effects in hamster fetuses prenatally exposed
for one day. Meningeocephaloceles in hamsters were caused by a single
prenatal exposure "above" 1.5 mg/kg and fused ribs "above" 5 mg/kg in
hamsters. In mice, a single prenatal exposure to 2.5 mg/kg caused an increase
in open eyes. Exencephaly and fused ribs were seen with one exposure at 9
mg/kg endrin. A rat study reported no developmental effects with exposure to
0.45 mg/kg-day (it was not clear if behavioral effects were evaluated) (ATSDR,
1990c). The variation in effects is probably due in part to the different prenatal
periods during which exposure occurred (See ATSDR, 1990c). Reproductive
outcome was adversely affected in hamsters exposed to 1.5 mg/kg-day with
decreased survival of pups (16 percent mortality). The underlying cause was
not discussed (ATSDR, 1990c).
Nervous system effects are a significant concern with organochlorine exposure.
In hamsters, abnormally increased pup activity in hamsters was observed with
1.5 mg/kg prenatal exposures for nine days. The NOEL for these behavioral
effects was 0.075 mg/kg-day (ATSDR, 1990c). In rats increased activity was
seen with prenatal exposure to 0.3 mg/kg-day (ATSDR, 1990c). Abnormally
increased activity has been observed for other organochlorine pesticides (See
DDT) and has been associated with probable altered learning ability and
permanent structural changes to the brain.
Both structural skeletal changes and neurological abnormalities are significant
developmental effects associated with endrin. Decreased survival, while a
significant effect, is not usually a sensitive measure of toxicity. The behavioral
effects observed with a NOEL of 0.075 mg/kg-day (discussed above) are
recommended for estimation of an exposure limit for developmental toxicity due
to their greater sensitivity. The uncertainty factors used in this calculation
would typically take into consideration inter- and intraspecies variability.
As noted in the pharmacokinetics section above, endrin can accumulate in body
tissue; consequently, exposure occurring prior to pregnancy can contribute to
the overall maternal body burden and result in exposure to the developing
individual. As a result of this, it is necessary to reduce exposure to children
and females with childbearing potential to reduce overall body burden. If
exposure is reduced during pregnancy, but has occurred prior to pregnancy, the
pregnancy outcome may be affected, depending on the timing and extent of
prior exposure.
5-65
-------
5. ENDRIN
Mutagenicity
in vitro assays of endrin suggest that it is not genotoxic. There were no in vivo
assay results located (ATSDR, 1990c).
Carcinogenicity
Insufficient information is available to determine the carcinogenic status of
endrin. EPA has classified this as a Group D carcinogen (insufficient
information available). Some studies have yielded positive results and some
studies which reported negative results were considered to be inadequate (IRIS,
1993). Tumors have been noted in the adrenal glands, pituitary glands, liver,
mammary gland, uterus and thyroid in various studies and multiple species
(IRIS, 1993). Endrin is structurally related to a number of chemicals which are
carcinogenic in test animals including chlordane, aldrin, dieldrin, heptachlor, and
chlorendic acid (IRIS, 1993). Because endrin has been classified as a Group
D carcinogen, no cancer potency has been listed by EPA.
Special Susceptibilities
ATSDR has reported that children may be more sensitive to acute endrin
exposure than adults, based upon effects observed in children during a
poisoning incident. Children appeared more susceptible to neurotoxic effects
and have exhibited qonvulsions. This is supported by results observed in
experimental animals where young rats were more susceptible than adults
(ATSDR, 1990c).
In addition, the skeletal and behavioral abnormalities associated with endrin
exposure in experimental animals indicate that prenatal exposure may generate
special risks.
Based upon animal studies, females may be more susceptible than males to
endrin-induced toxicity (ATSDR, 1990c).
See also a discussion of susceptibilities associated with pharmaceutical use in
Section 5.5.
Interactive Effects
See a discussion of organochlorine effects related to induction of the mixed
function oxidase system in Section 5.5. Dietary pretreatment with endrin
potentiates the hepatotoxicity of carbon tetrachloride. MIXTOX has reported
5-66
-------
5. ENDR1N
synergism between endrin and chlordane in mice with gavage exposure
(MIXTOX, 1992).
Critical Data Gaps
A joint team of researchers from ATSDR, NTP, and EPA have identified the
following data gaps: human responses to acute, intermediate (14 to 365
days), and chronic exposures, subchronic reproductive tests in various species,
immunotoxicity studies of animals and humans, human dosimetry studies,
pharmacokinetic studies, and studies of interspecies differences in metabolism
and toxicity (ATSDR, 1990c).
Summary of EPA Risk Values
Chronic Toxicity
Carcinogenicity
3 x 10'4 mg/kg-day
insufficient data to determine
carcinogenic status.
Major Sources: IRIS (1993), ATSDR (1990c), tox one-liners (EPA, 1993m)
5-67
-------
5. HEPTACHLOR EPOXIDE
5.6.7. Heptachlor Epoxide
Background
Heptachlor epoxide is a breakdown product of the organochlorine pesticide
heptachlor and chlordane and is a contaminant of both products. It is more
toxic than either parent compound (ATSDR, 1993c). Although most uses of
heptachlor were suspended in 1978 and chlordane was removed from the
market in 1988 (EPA, 1993J), heptachlor epoxide continues to be a widespread
contaminant due to its relatively long half-life.
Pharmacokinetics
Based upon animal and limited human data, heptachlor epoxide is absorbed
through the Gl tract and is found primarily in the liver, bone marrow, brain, and
fat, although it is distributed widely to other tissues as well. It is stored
primarily in fat. Fetal brood levels were approximately four times those
measured in women. Levels in human milk range from zero to 0.46 ppm
(ATSDR, 1993c).
Heptachlor epoxide has a very long half-life, particularly in adipose tissue.
Human tissue levels have correlated well to age, with 97 percent of North
Texas residents tested (ages 41 to 60) having measurable levels. Based on the
Texas study, heptachlor epoxide tissue levels have not decreased appreciably
since the 1960s (ATSDR, 1993c).
Acute Toxicity
See the listing of usual effects associated with organochlorine exposure in
Section 5.5. The LD50s for heptachlor range from 40 to 162 mg/kg in rodents
(ATSDR, 1993c).
Chronic Toxicity
IRIS provides an RfD of 1.3 x 10"5 mg/kg-day based on a LEL of 0.0125 mg/kg-
day from a 60 week dog feeding study reported in 1958. The critical effect
was increased liver-to-body weight ratios in both males and females at the
lowest dose tested. Uncertainty factors of 10 each were applied for inter- and
intraspecies variability and the use of a LEL rather than a NOEL (IRIS, 1993).
No additional uncertainty factors were applied for the use of a less-than-lifetime
study. The principal study is of low quality and there is a low confidence in the
RfD (IRIS, 1993).
5-68
-------
5. HEPTACHLOR EPOXIDE
Animal studies have identified the following effects associated with heptachlor
(and subsequently heptachlor epoxide via metabolism) or heptachlor epoxide
directly: elevated bilirubin and white blood cell count, increased serum
creatinine phosphokinase levels suggestive of muscle damage, muscle spasms
secondary to CNS stimulation, adrenal gland pathology, and neurological
disorders (ATSDR, 1993c).
Significant changes in EEG patterns were found in female adult rats exposed
to 1 and 5 mg/kg-day for three generations (ATSDR, 1993c).
A study of reproductive system toxicity with males and females dosed at 0.25
mg/kg-day prior to and during gestation found a significantly decreased
pregnancy rate among exposed animals. Based on specific fertility tests it was
determined that males were most likely affected and that sperm were probably
killed (ATSDR, T993c). Another reproductive system toxicity study with doses
at and above 0.075 mg/kg-day resulted in the failure of animals to reproduce.
There were serious deficiencies in this study (ATSDR, 1993c).
Developmental Toxicity
A 1973 two-generation dog reproductive study identified a NOEL of 0.025
mg/kg-day with an LEL of 0.075 mg/kg-day with liver lesions in pups. Other
studies with higher LELs based upon a lethality endpoint are listed in the IRIS
file. They were not used in this evaluation due to insufficient information. The
IRIS file notes data gaps as rat and rabbit teratology studies (IRIS, 1993).
Exposure of adult rats to 6 mg/kg-day caused lens cataracts in 22 percent of
the adults, six to eight percent of the F1 generation offspring, and six percent
of the F2 generation offspring. A rat study with exposure to 0.25 mg/kg-day
occurring 60 days prior to mating and during gestation resulted in severely
reduced pup survival (15 percent) at 21 days postpartum (ATSDR, 1993c).
This is not a useful LOEL due to the severity of effects observed at the lowest
dose tested.
A human study conducted in Hawaii was not considered adequate due to many
study design deficiencies (ATSDR, 1993c). In another epidemiological studies
of women who had premature deliveries, significantly higher levels of
heptachlor epoxide and other organochlorine pesticides were detected in sera
(ATSDR, 1993c).
There is limited data on which to base an estimated exposure limit for
developmental effects. The NOEL in the two-generation study is not based
upon sensitive endpoints and is only a factor of 3 removed from the LEL. The
developmental toxicity data base is insufficient for heptachlor epoxide (per the
5-69
-------
5. HEPTACHLOR EPOXIDE
IRIS file). Consequently, the application of an uncertainty factor for the
insufficiency of the data base may be necessary. The dog study, with a NOEL
of .025 mg/kg-day, can be used to calculate an exposure limit for
developmental effects. The standard uncertainty factors used in this
calculation would typically take into consideration inter- and intraspecies
variability and a data base factor.
As noted in the pharmacokinetics section above, heptachlor can accumulate in
body tissue; consequently, exposure occurring prior to pregnancy can
contribute to the overall maternal body burden and result in exposure to the
developing individual. As a result of this it is necessary to reduce exposure to
children and females with childbearing potential to reduce overall body burden.
If exposure is reduced during pregnancy, but has occurred prior to pregnancy,
the pregnancy outcome may be affected, depending on the timing and extent
of prior exposure.
Mutagenicity
Mixed results have been obtained in mutagenicity assays of heptachlor epoxide.
Carcinogenicity
Heptachlor epoxide is classified as a probable human carcinogen (B2) by EPA
based on oral studies in animals. The oral cancer potency factor is 9.1 per
mg/kg-day. This value is based on the geometric mean of several studies
which identified liver carcinomas (IRIS, 1993). Six structurally related
compounds have produced tumors in mice and rats: chlordane, aldrin, dieldrin,
heptachlor and chlorendic acid (IRIS, 1993).
Statistically significant increases in adenomas and carcinomas of the thyroid
were found in female rats. Some researchers discounted the results due to the
low incidence and known variability in the control population (ATSDR, 1993c).
Heptachlor (and consequently heptachlor epoxide) exposure have been
associated with cerebral gliosarcoma in children exposed prenatally. Multiple
chromosomal abnormalities were also identified in the tumor cells. It was not
determined whether the effects were caused by environmental or familial
factors (ATSDR, 1993c).
Special Susceptibilities
Based on the toxicity data reviewed above, individuals with diseases or
disorders of the following systems may be at greater risk than the general
population: liver, hematopoietic, musculoskeletal, neurological, and adrenal
5-70
-------
5. HEPTACHLOR EPOXIDE
gland. ATSDR has noted that pre-adolescent children may be more susceptible
due to their greater rate of glutathionine turnover (ATSDR, 1993c). In addition,
children exposed prenatally may be at higher risk, based upon the results of
developmental toxicity studies.
See also a discussion of susceptibilities associated with pharmaceutical use in
Section 5.5.
Interactive Effects
r
See a discussion of organochlorine effects related to induction of the mixed
function oxidase system in Section 5.5.
Critical Data Gaps
The IRIS file notes data gaps as rat and rabbit teratology studies (IRIS, 1993).
The OPP notes the same data gaps (EPA, 1992c). A joint team of scientists
from EPA, NTP, and ATSDR have identified the following data gaps: a model
to describe the relationship between tissue and blood levels and exposure in
humans, chronic oral exposure effects in humans, epidemiological and in vivo
animal genotoxicity studies/ developmental and reproductive toxicity studies
and neurotoxicity and immunotoxicity studies in animals, and pharmacokinetic
studies (ATSDR, 1993c).
Summary of EPA Risk Values
Chronic Toxicity 1.3 x 10~5 mg/kg-day
Carcinogenicity 9.1 per mg/kg-day
Major Sources: IRIS (1993), ATSDR (1993c)
5-71
-------
5. HEXACHLOROBENZENE
5.6.8. Hexachlorobenzene
Background
Hexachlorobenzene is a byproduct of manufacturing and has been used as a
fungicide seed protectant in the past. It exists as a solid at ambient
temperatures, and in aquatic environments is found in higher quantities in
sediment than water due to its low solubility (ATSDR, 1990a).
Pharmacokinetics
Hexachlorobenzene is persistent in the body, accumulating preferentially in fat
and tissues with a high lipid content, due to its lipophilic nature. It is found in
human breast milk {ATSDR, 1990a), which may be a significant route of
exposure for young children.
Acute Exposure
Acute exposure studies in animals indicate a relatively low acute toxicity with
LD50s between 1700 and 4000 mg/kg (ATSDR, 1990a). Based on animal
studies the following systems are adversely affected following acute exposure:
liver, kidney, hematological, and dermal (ATSDR, 1990a). See also the
discussion of organochlorine pesticides in Section 5.5.
Chronic Toxicity
Hexachlorobenzene exposure of a large number of people in Turkey occurred
between 1955 and 1959 due to consumption of contaminated grain. No
precise exposure estimates are available for children or adults in this episode;
it is likely that exposures occurred over a continuum, with some individuals
consuming much higher levels than others. Researchers have estimated
relatively low exposure levels occurred over several years as a result of
consumption (50 to 200 mg/day). These exposure levels are approximately 0.7
to 2.9 mg/kg-day for a 70 kg individual. ATSDR has emphasized that the
exposure estimates are unverified (ATSDR, 1990a).
The following effects have been associated with hexachlorobenzene exposure
in individuals exposed chronically via contaminated bread (Turkey)10:
shortening of the digits due to osteoporosis, painless arthritis, decreased
uroporphyrin synthase levels, muscle weakness, rigidity and sensory shading,
thyroid enlargement, and histopathological changes in the liver often
10 Effects are also discussed under reproductive effects below.
5-72
-------
5. HEXACHLOROBENZENE
accompanied by skin lesions (ATSDR, 1990a). These effects were also
observed in numerous animal studies.
The hepatic system appears to be the most sensitive systemic endpoint for
hexachlorobenzene exposure, based upon animal studies, with a NOAEL of
0.08 mg/kg-day in a lifetime rat study. This has been converted by ATSDR to
an MRL of 8 x 10~4 mg/kg-day using uncertainty factors of 10 each for inter-
and intraspecies variability (ATSDR, 1990a). This value is also the IRIS RfD for
chronic systemic toxicity (IRIS, 1993). Numerous other studies identified
NOAELs in the same numerical range. The IRIS file notes that the sensitive
endpoint of porphyria, which is an effect which was noted in exposed human
populations, was not evaluated in the critical animal study (IRIS, 1993). It is
not possible, based on the current data, to determine whether the RfD will be
protective against that effect.
The oral RfD of 8 x 10'4 mg/kg-day developed by IRIS and ATSDR was used
to calculate the fish consumption limits listed in Section 3 for chronic exposure
toxicity. For a summary of the chronic systemic toxicity data the reader is
referred to the Toxicity Profile for Hexachlorobenzene (ATSDR, 1990a).
Developmental Toxicity
Lactational exposure to hexachlorobenzene is of significant concern, based on
the rapid transfer of the chemical through breast milk, and effects which have
been observed in children of exposed mothers. In a study of nursing infants,
the infants had blood levels of hexachlorobenzene two to five times that of
their mothers, as well as higher tissue levels. A study of monkeys found that
the concentration in milk was 17 times higher than that in maternal serum
(ATSDR, 1990a). Young children (under one year) of lactating mothers who
were exposed via contaminated bread had an extremely high mortality rate.
Skin lesions, weakness and convulsions were reported in these infants.
Although adults were also adversely affected, children appeared to be at higher
risk. The maternal exposure was roughly estimated to be 0.7 to 2.9 mg/kg-day
(ATSDR, 1990a).
Among slightly older children (average age of 7) exposure via food resulted in
the development of small or atrophied hands and fingers, short stature, pinched
faces, osteoporosis in the hands and other arthritic changes. Exposure was
estimated to be approximately 0.7 to 2.9 mg/kg-day (ATSDR, 1990a).
It is known that hexachlorobenzene can cross the human placenta; however,
no data were available on effects resulting from prenatal exposure in humans.
Very limited information is available on experimental animals. Cleft palate and
kidney abnormalitiesVere observed in one study in a single litter and fetus at
5-73
-------
5. HEXACHLOROBENZENE
100 mg/kg-day (ATSDR, 1990a). In another study, the survivability of
prenatally exposed rats was significantly reduced at 2 mg/kg-day (estimated
from ppm with conversion factor of 0.05 mg/kg per 1 ppm diet for rats). Death
was attributed to maternal body burden and cumulative lactational exposure
(ATSDR, 1990a). Alterations in immune function levels were reported in pre-
and postnatally exposed rats at 4 mg/kg (ATSDR, 1990a).
For purposes of quantitatively estimating an exposure limit, it is of concern that
prenatal and lactational exposure of humans at levels roughly estimated to be
0.7 to 2.9 mg/kg-day (maternal) induced serious structural changes in children
and increased mortality. Due to the poor quality of data supporting the
exposure estimates for the human exposure episode in Turkey, and, more
critically, the lack of a no effect level, it would be desirable to obtain a
developmental study with a more reliable exposure estimate. However, there
do not appear to be such studies currently available. Much higher exposure
levels were required to cause structural changes in an experimental animals and
the experimental results have not been duplicated. These data suggest that
humans may be more susceptible than the animals studied.
In the absence of better data, the human study data from Turkey can be used
to calculate an estimated exposure limit for developmental effects. The
standard uncertainty factors used in this calculation would typically take into
consideration intraspecies variability, the use of a LOAEL rather than a NOAEL,
and the overall inadequacy of the data base. An additional modifying factor
may be applied for the poor quality of the exposure data and the severity of the
effects noted at the LOAEL. Due to the incomplete nature of the data base and
the other inadequacies noted above, there would not be a high level of
confidence in exposure limits calculated from the current developmental toxicity
data base.
As noted above, hexachlorobenzene accumulates in body tissue; consequently,
exposure occurring prior to pregnancy can contribute to the overall maternal
body burden and result in exposure to the developing individual. As a result of
this, it is necessary to reduce exposure to children and women with
childbearing potential to reduce overall body burden. If exposure is reduced
during pregnancy, but has occurred prior to pregnancy, the pregnancy outcome
may be affected, depending on the timing and extent of prior exposure.
Mutagenicity
The results of mutagenicity studies on hexachlorobenzene are mixed (IRIS,
1993). Hexachlorobenzene was negative in dominant lethal studies (in vivo)
at doses from 60 to 221 mg/kg {ATSDR, 1990a).
5-74
-------
5. HEXACHLOROBENZENE
Carcinogenicity
Carcinogenic assays of hexachlorobenzene in animals have identified an
increased incidence of multiple tumor types including hepatomas,
hemangioendotheliomas, liver, and thyroid tumors in multiple species. EPA
developed a cancer potency of 1.6 mg/kg-day based on liver carcinoma in
female rats exposed via diet. In support of this value, cancer potencies were
calculated for 14 different data sets; the result were within one order of
magnitude. Hexachlorobenzene is classified as a probable human carcinogen
(B2) based on the results of animals studies (IRIS, 1993). The IRIS cancer
potency of 1.6 per mg/kg-day was used to calculate the fish consumption
limits listed in Section 3 for carcinogenic effects.
Human studies have not yet yielded useful results. Follow-up studies of
exposure victims in Turkey have not identified cancers in the 25 and 20 to 30
year exposure cohorts; however, ATSDR suggests that the enlarged thyroids
noted in members of these groups have not been sufficiently investigated
(ATSDR, 1990a). It should also be noted that most cancers have multiple
decade latency periods and often occur in the later part of life. Consequently,
it will not be possible to assess the carcinogenic impact of exposures in Turkey
for some time.
Special Susceptibilities
ATSDR has concluded that young children are susceptible to
hexachlorobenzene exposure based upon human poisoning episodes. Exposure
led to permanent debilitating effects. Both human and animal data suggest that
the risk of exposure to nursing infants may be greater than the risk to their
mothers (ATSDR, 1990a).
Based upon the toxicity data reviewed above individuals with liver disease may
be at greater risk that the general population.
See also a discussion of susceptibilities associated with pharmaceutical use in
Section 5.5.
Interactive Effects
Hexachlorobenzene induces microsomal enzymes. See Section 5.5 for a
discussion of associated effects. Pentachlorophenol increases the
porphyrinogeniceffects of hexachlorobenzene. Hexachlorobenzene potentiated
the thymic atrophy and body weight loss caused by 2,3,7,8-TCDD. A 50
percent food deprivation increased liver hypertrophy and microsomal enzyme
induction by hexachlorobenzene (ATSDR, 1990a).
5-75
-------
5. HEXACHLOROBENZENE
Critical Data Gaps
A joint team of scientists from EPA, NTP, and ATSDR have identified the study
following data gaps: human carcinogenicity, in vivo and in vitro genotoxicity,
animal reproductive toxicity, animal developmental toxicity, immunotoxicity
studies in humans, and pharmacokinetics (ATSDR, 1990a). Information is
needed to develop a model which can be used to estimate the relationship
between maternal intake, human milk concentration, and adverse effects in
infants.
Summary of EPA Risk Values
Chronic Toxicity 8x10"4 rng/kg-day
Carcinogenicity 1.6 per mg/kg-day
Major Sources: IRIS (1993), ATSDR (1990a)
5-76
-------
5. LINDANE
5.6.9. Lindane (gamma-hexachlorocyclohexane)
Background
Lindane is an organochlorine pesticide which is comprised of isomers of
hexachlorocyclohexane, with the gamma isomer Constituting the major {greater
than 99 percent) component. There appears to be some difference in toxicity
of the various hexachlorocyclohexane isomers (EPA, 1993a). The following
data assume that lindane can be defined as the gamma isomer.
Pharmacokinetics
Lindane is readily absorbed by the Gl tract following oral exposure. Distribution
is primarily to the adipose tissue but also to the brain, kidney, muscle, spleen,
adrenal glands, heart, lungs, blood and other organs. It is excreted primarily
through urine as chlorophenols. The epoxide metabolite may be responsible for
carcinogenic and mutagenic effects (ATSDR, 1992b).
Male exposure to lindane through the environment results in accumulation in
testes and semen in addition to the tissues listed above (ATSDR, 1992b). See
also a discussion of the accumulation of lindane by pregnant women under
developmental effects below.
Acute Toxicity
See the listing of usual effects associated with organochlorine exposure in
Section 5.5. The estimated human lethal dose is 125 mg/kg (HSDB,1993).
Occupational and accidental exposures in humans have resulted in headaches,
vertigo, abnormal EEC patterns, seizures, and convulsions. Death has occurred
primarily in children. ATSDR recommends an acute (14 days exposure or less)
exposure MRL of 0.003 mg/kg-day based on neurotoxic effects in rats (ATSDR,
1992b).
Chronic Toxicity
IRIS provides an RfD of 3 x 10~4 mg/kg-day based upon a NOAEL of 0.33
mg/kg-day from a subchronic rat study which found liver and kidney toxicity.
Uncertainty factors of 10 each for inter- and intraspecies variability and the use
of a less-than-lifetime study were applied (IRIS, 1993). A recently completed
two year study is under evaluation and may provide additional information
regarding toxicity (EPA, 1993k). Liver damage has been observed in animal
studies (EPA, 1993k). Immune system effects have been observed in humans
exposed via inhalation and in orally dosed animals. A five week study in rabbits
found immunosuppression at 1 mg/kg-day (ATSDR, 1992b).
5-77
-------
5. LINDANE
Most observed effects in humans exposed accidentally to lindane are
neurological. Behavioral effects have also been noted in many studies on
experimental animals, and at relatively high levels seizures were reported. More
subtle behavioral effects were noted at an LEL of 2.5 mg/kg-day with 40 days
of exposure in rats. No NOEL was reported (ATSDR, 1992b).
Two recent reproductive studies in rats found adverse effects on the male
reproductive system. In a seven week study, decreased sperm counts were
noted at 50 mg/kg-day and in a 180 day study, seminiferous tubular
degeneration was noted at 6 mg/kg-day with a NOEL of 3 mg/kg-day. An older
study had identified the same effects at 64.6 mg/kg-day in a three month
study. Experimental data indicate that the female reproductive system may
also be altered by lindane exposure. A study of rats found uterine, cervical,
and vaginal biochemical changes at 20 mg/kg-day in a 30 day study.
Antiestrogenic effects were found at 20 mg/kg-day in female rats in a 15 week
study with a NOEL of 5 mg/kg-day. This action was also found in two other
recent studies (ATSDR, 1992b). Based upon current risk assessment methods,
it appears that the current IRIS RfD for chronic effects is protective against
reproductive system toxicity. However, the effects in both the male and female
reproductive systems have been evaluated only in short-term studies.
Evaluation of these effects in a longer-term study, and identification of the
underlying mechanisms of toxicity, would provide information needed for a
more complete evaluation of toxicity and dose-response dynamics.
It is not clear whether the IRIS RfD is protective against neurotoxic effects
because the study of behavioral effects which resulted in an LEL of 2.5 mg/kg-
day was a short-term study and no NOEL was identified. Neurotoxic effects
have been reported widely in human poisoning incidents and among
occupationally exposed individuals. Consequently, it is of significant interest
for human toxicity. Additional information is needed to determine whether the
current RfD is protective against neurotoxic effects.
Developmental Toxicity
Two developmental toxicity studies in rats and rabbits both identified a NOEL
of 10 mg/kg (no effects were described for higher doses). A three-generation
rat study found no adverse reproductive effects at 5 mg/kg-day, the highest
dose tested (EPA, 1993k). A recent mouse study found increased resorptions
at 5 mg/kg-day. Studies in rats and mice have found increased incidence of
extra ribs at 5 to 20 mg/kg-day (ATSDR, 1992b). There are multiple studies
showing pre and post implantation fetotoxicity and skeletal abnormalities
resulting from prenatal exposure at higher doses (HSDB,1993).
5-78
-------
5. LINDANE
Lindane accumulates in the fatty tissue of pregnant (and non-pregnant) women
where it can be transferred to the fetus through the placenta and to infants
through breast milk. Human milk concentrations are approximately five to
seven time greater than maternal blood levels. Concentrations in maternal
blood are proportional to the length of time over which exposure occurred, with
older women having higher blood levels. During pregnancy the lindane
concentration in blood from fetal tissue, uterine muscle, placenta, and amniotic
fluid was higher than levels in maternal adipose tissue and blood serum levels
increased during delivery (ATSDR, 1992b). There is little information on the
effects of exposure during lactation. One study (dose unspecified) in rats
indicated that exposure during gestation and lactation did not cause
developmental effects; however, this is riot consistent with other studies which
found effects associated with gestational exposure.
Based upon what is known regarding the transfer of lindane into human milk,
nursing infants must be considered at some risk if their mothers have been
exposed to significant amounts of lindane (lindane is a lipid seeking chemical).
Additional information is needed to characterize the relationship between
maternal intake, body burden (blood or adipose levels), milk concentrations, and
adverse effects.
Multiple studies have reported that lindane exposure (as measured by body
tissue level of lindane) is associated with premature labor and spontaneous
abortions. The causal relationship has not been established for this action
(ATSDR, 1992b); however, the reproductive system effects discussed under
chronic toxicity (biochemical changes in uterine, cervical and vaginal tissues,
and antiestrogenic effects) may be involved.
Information was not located on developmental neurotoxicity, which may be an
expected effect of lindane based upon the toxicity of other organochlbrines.
Based on the limited data which is available, the most appropriate studies for
use in calculating an estimated exposure limit for developmental effects are the
rat and mouse studies which identified the development of extra ribs and fetal
resorptions respectively at an LEL of 5 mg/kg-day. Resorptions, which usually
arise from early fetal death, are typically the result of toxicity to the fetus.
Information on the nature of that toxicity was not available in the data reviewed
for this document. In this case, the resorptions could have arisen from
systemic toxicity, or there may have been hormonal effects which also
jeopardized maintenance of pregnancy, as indicated by the reproductive system
toxicity data (See chronic toxicity section above).
In estimating an exposure limit for lindane the uncertainty generated by the
potential for lactation exposure must also be considered. It may be advisable
to use an additional modifying factor to account for lack of critical information
5-79
-------
5. LINDANE
in the data base regarding the actual dose at which toxic effects occurred
(those more sensitive than lethality), the potential for premature labor and
spontaneous abortions, and the potential for increased exposure via lactation.
For purposes of calculating an exposure limit, if the rat and mouse LEL were
used, standard uncertainty factors would typically take into consideration inter-
and intraspecies variability and the use of a LEL rather than a NOEL. A
modifying factor may also be applied. (See also the interactive effects and
special susceptibilities sections below.)
As noted above, lindane accumulates in body tissue; consequently, exposure
occurring prior to pregnancy can contribute to the overall maternal body burden
and result in exposure to the developing individual. As a result of this, it is
necessary to reduce exposure to children and women with childbearing
potential to reduce overall body burden. If exposure is reduced during
pregnancy, but has occurred prior to pregnancy, the pregnancy outcome may
be affected, depending on the timing and extent of prior exposure.
Mutagenicity
In animals, ingestion of technical grade hexachlorocyclohexane induced
dominant lethal mutations in mice. Studies found that lindane binds to mouse
liver DNA at a low rate. Based on a review of genotoxicity studies, ATSDR
concluded that lindane "has some genotoxic potential, but the evidence for this
is not conclusive" (ATSDR, 1992b).
Carcinogenicity
Lindane has been classified as a probable/possible carcinogen (B2/C) based on
liver tumors in animals. The cancer potency is 1.3 per mg/kg-day (HEAST,
1992). In addition to tumors identified in experimental animals, human study
data indicate that this chemical may cause aplastic anemia (EPA, 1993a).
Lindane is currently under review by EPA. Lindane's related isomers, alpha and
beta hexachlorocyclohexane, are also clas>sified as probable human carcinogens
and have cancer potencies similar to that of lindane. The cancer potency
obtained from the HEAST tables was used to calculate the fish consumption
limits listed in Section 3 for carcinogenic effects.
Special Susceptibilities
ATSDR has recommended that pregnant and/or lactating women should not be
exposed to lindane. The potential for premature labor arid spontaneous
abortion is noted (ATSDR, 1992b). People with epilepsy, cerebrovascular
accidents, or head injuries who have lower thresholds for convulsions may be
at greater risk of lindane-induced CNS toxicity and seizures. Also, individuals
5-80
-------
5. LINDANE
with protein deficient diets, liver or kidney disease, or immunodeficiencies may
be at greater risk from lindane exposure than the general population (ATSDR,
1992b).
Children may also be at greater risk from lindane exposure due to the
immaturity of their immune and nervous systems. ATSDR has cautioned that:
"Infants and children are especially susceptible to
immunosuppression because their immune systems do not reach
maturity until 10 to 12 years of age" (ATSDR, 1990b).
See also a discussion of susceptibilities associated with pharmaceutical use in
Section 5.5.
Interactive Effects
See a discussion of organochlorine effects related to induction of the mixed
function oxidase system in Section 5.5.
High and low protein diets and Vitamin A and C deficiencies increased the
toxicity of lindane in experimental animals. Vitamin A supplements decreased
toxicity. Cadmium inhibited the metabolism of lindane. Combined cadmium
and lindane exposure caused significant embryotoxic and teratogenic effects
in rats at dosages which caused no effects when administered alone. Exposure
to the alpha, beta, and delta hexachlorocyclohexane isomers may reduce the
neurotoxic effects of lindane (ATSDR, 1992b).
MIXTOX has reported mixed results for studies of lindane and chlordane,
lindane and hexachlorobenzene, lindane and toxaphene, and lindane and mirex
interactions, including inhibition, no effect, and potentiation for these
combinations in rodents exposed via gavage (MIXTOX, 1992).
Critical Data Gaps
As discussed above, effects on both the male and female reproductive systems
have been evaluated in short-term studies. Evaluation of these effects in a
longer term study, and identification of the underlying mechanisms of toxicity
would provide information needed for a more complete evaluation of toxicity
and dose-response dynamics. Additional information is also needed, as noted
under developmental effects, on the potential for exposure via lactation and on
mechanisms and dose-response for premature labor and spontaneous abortion.
ATSDR has identified data gaps that include chronic duration oral studies, in
vivo genotoxicity tests, reproductive, developmental immunotoxicity,
5-81
-------
S. L1NDANE
neurotoxicity studies, human studies correlating exposure levels with body
burdens of lindane and with specific effects, and pharmacokinetic studies. A
large group of international studies recently submitted to ATSDR are currently
under review and six studies are ongoing in the United States (AtSDR, 1992b).
Summary of EPA Risk Values
Chronic Toxicity 3 x 10"4 mg/kg-day
Carcinogenicity 1.3 per mg/kg-day
Major Sources: IRIS (1993), ATSDR (1992b), HSDB (1993).
5-82
-------
5. MJREX
5.6.10. Mirex
Background
Mirex is a polymerizing agent and was used as an organochlorine pesticide and
fire retardant until 1975 (EPA, 1993a). Mirex has the potential to concentrate
many thousand-fold in food chains (Hayes and Laws, 1991).
Pharmacokinetics
Mirex is a lipophilic compound and is readily taken up in fat tissue. The highest
residues were found in fat and the liver,. Based on a study in cows, it is also
found in milk. At 0.01 and 1 ppm dietary exposure for 32 weeks, cows' milk
levels were 0.01 to 0.08 ppm (EPA, 1993o).
No clear data on half-life in humans was found; however, studies in primates
found that 90 percent of the original dose was retained in fat after 106 days.
The researchers predicted that mirex had an extremely long half-life in
monkeys. Based upon this, mirex would be expected to have a very long half-
life in humans.
Acute Toxicity
See the listing of usual effects associated with organochlorine exposure in
Section 5.5. Acute hepatic effects have been observed in experimental
animals. These may result from the following cytological effects: disaggregated
ribosomes, glycogen depletion, formation of liposomes, and proliferation of
smooth endoplasmic reticulum (EPA, 1993o).
Chronic Toxicity
IRIS lists a chronic exposure RfD of 2 x 10"4 mg/kg-day for mirex based upon
a NOAEL of 0.07 mg/kg-day from a chronic dietary rat study. The IRIS file
notes that the previous RfD was 2 x 10'6 mg/kg-day. The IRIS file states that
a dose related increase in hyperplasia of the parathyroid gland was observed in
males in the critical study at and above 0.007 mg/kg-day (IRIS, 1993). It is not
stated in the file why this value was not used as a LOAEL; although it is noted
that the effect was not observed in other studies. Additional effects noted in
the study were: nephropathy, renal medullary hyperplasia, multiple types of
liver damage, splenic fibrosis, and cystic follicles of the thyroid. The RfD is
based on the latter two effects. Uncertainty factors of 10 each were applied
for inter- and intraspecies variability and a factor of three was applied for lack
of a complete data base (multi-generational data on reproductive effects and
cardiovascular toxicity data). The IRIS file also indicates that effects on the
5-83
-------
5. MIREX
testis (testicular degeneration, hypocellularity and depressed spermatogenesis)
which were noted in other studies, may not have been detected in the critical
study because of age-related degenerative changes in the study animals (IRIS,
1993).
A subchronic study in rats identified an LEL of 0.01 mg/kg-day with liver
lesions and thyroid injury at the lowest dose tested. Another subchronic study
in rats noted similar effects with a NOEL of 0.01 in which only females were
tested. A 21 month rat feeding study identified a LEL of 0.01 mg/kg-day based
upon histological lesions in the liver and thyroid and altered enzyme levels (EPA,
1993o). These results are supported by 28 day feeding studies, which
identified LELs at a similar level to the studies listed above. Histopathology of
the liver was noted at 0.025 mg/kg-day in two rat studies. No NOELs were
identified (EPA, 1993o). Both structural and functional adverse effects on the
thyroid have been observed in experimental animals. The effects persisted for
more than one year after treatment ceased. Neurobehavioral effects have also
been associated with mirex exposure (Hayes and Laws, 1991).
Both the longer term and subchronic study which identified LELs of 0.01
mg/kg-day suggest that toxicity occurs at levels below those identified in the
NTP study, which is used as the basis for the IRIS RfD. The lower LELs can be
used to calculate an alternative estimated exposure limit. The standard
uncertainty factors used in this calculation would typically take into
consideration inter- and intraspecies variability, and the use of a LEL rather than
a NOAEL.
Developmental Toxicity
Numerous developmental toxicity studies have been conducted on mirex.
Effects associated with exposure include undescended testes (EPA, 1993o),
fetal cataracts, edema, ectopic gonads, hydrocephaly,abnormal kidney enzyme
levels,decreased brain and liver weights, scoliosis, runts, cleft palates, heart
defects (anatomical), effects on the fetal electrocardiogram, and decreased
fertility. Multiple studies have noted increased mortality and cataracts resulting
from both pre- and postnatal exposure (IRIS, 1993). Many of the deaths have
been due to congestive heart failure. Studies utilizing cross-fostering of litters
have found that both cataracts and reduced viability were less pronounced
when neonates did not receive their mothers' milk (mothers were dosed with
mirex during pregnancy) ( Hayes and Laws, 1991).
Mirex is lipophilic and has been found in human breast milk. A small study in
the Great Lakes region found levels from 0.1 to 0.6 ppm in human milk (Hayes
and Laws, 1991).
5-84
-------
5. MJREX
Many of the developmental studies noted significant effects at the lowest dose
tested (e.g., cardiac function abnormalities occurred at the LOEL of 0.25
mg/kg-day) (IRIS, 1993). Consequently, they do not provide a useful threshold
for effects. One study of cardiac effects in the fetus found a dose related
increase in first degree heart block; however, the levels which were tested
were quite high (5, 6, 7, and 10 mg/kg). A high rate of stillbirth and postnatal
mortality, first and second degree heart blocks, respiratory distress, and
cataracts were observed in a prenatal exposure study with an LEL of 1 mg/kg-
day (EPA, 1993o).
A single dose of 1.25 mg/kg to pregnant rats caused reduced viability and
growth, and a high incidence of cataracts in offspring. A developmental study
in rats identified an LEL of 0.25 mg/kg-day with an increase in stillborn pups
and decreased viability. A one-generation mouse study identified an LEL of
0.075 mg/kg in a single dose causing reduced litter size; no NOEL was
identified. A one-generation rat study identified an LEL of 0.125 mg/kg-day
with decreased litter size, histopathological changes in the liver and thyroid,
and cataracts (EPA, 1993o). Biochemical alterations include significant
decreases in plasma protein concentrations and colloid osmotic pressure in
fetuses (EPA, 1993o).
Mirex causes serious adverse effects in multiple organ systems in developing
animals. Frank teratogenic effects are observed at levels which are much
higher than those required to produce other effects. Teratogenic effects have
been observed at an LEL of 6.0 mg/kg with an increased incidence of visceral
anomalies and deciduomas. A teratogenic NOEL of 3.0 mg/kg was identified
(EPA, 1993o).
Due to the absence of a NOEL for many of the effects, there is considerable
uncertainty regarding the calculation of an exposure limit for developmental
effects. However, the seriousness of the effects argues for inclusion of a
developmental risk value to provide some guidance for exposure. Based on the
information reviewed, the most sensitive species appears to be the mouse, with
effects observed at 0.075 mg/kg in a single dose (LEL). Studies in other
species identified multiple effects at exposure levels equal to, or less than, a
factor of two-fold greater (0.125 and 0.25 mg/kg-day). If the mouse study
results are used to calculate an estimated exposure limit for developmental
effects, the standard uncertainty factors would typically take into consideration
inter- and intraspecies variability, and the use of an LEL rather than a NOAEL.
Due to the multiple and serious effects associated with mirex exposure during
development, and the potential for bioaccumulation and exposure through the
placenta and via breast milk, an additional modifying factor may be applied.
5-85
-------
5. MIREX
As noted above, mirex accumulates in body tissue; consequently, exposure
occurring prior to pregnancy can contribute to the overall maternal body burden
and result in exposure to the developing individual. As a result of this, it is
necessary to reduce exposure to children and women with childbearing
potential to reduce overall body burden. If exposure is reduced during
pregnancy, but has occurred prior to pregnancy, the pregnancy outcome may
be affected, depending on the timing and extent of prior exposure.
Mutagenicity
Most genotoxicity tests reported in the tox one-liners are bacterial assays and
are negative (EPA, 1993o). A dominant lethal mutagenicity tests in rats (in
vivo) found a decreased incidence of pregnancy at 6 mg/kg-day with a NOEL
of 3 mg/kg-day. Exposure took place over 10 days prior to mating. Additional
information is needed on the nature of the toxicity.
Carcinogenicity
Mirex has been classified as a probable human carcinogen (B2) based on liver
and adrenal tumors in experimental animals. The cancer potency is 1.8 per
mg/kg-day (HEAST, 1992). This chemical is currently under review by EPA.
Special Susceptibilities
Juveniles may be more susceptible than adults based upon the results of animal
studies. At 60 ppm (approximately 3 mg/kg-day) adult mice exposed for 15
days experienced only weight loss; this level was lethal for young mice (Hayes
and Laws, 1991).
Based upon a review of the toxicity data above, individuals with diseases or
disorders of the following organ systems may be at higher risk than the general
population: kidney, liver, spleen, thyroid, parathyroid, cardiovascular, and male
reproductive. Due to the developmental toxicity observed in experimental
animals, prenatal exposure and lactation exposure may pose a risk to children.
See also a discussion of susceptibilities associated with pharmaceutical use in
Section 5.5.
Interactive Effects
See a discussion of organochlorine effects related to induction of the mixed
function oxidase system in Section 5.5. No additional data were located.
5-86
-------
5. MIREX
MIXTOX reports mixed results for interactions between lindane and mirex and
for Aroclor 1254 and mirex. Other studies of Aroclor and mirex have not found
interactive results {MIXTOX, 1992).
Critical Data Gaps
Additional information is needed on the developmental effects of mirex to
identify a NOEL for sensitive developmental toxicity endpoints so that a well-
founded exposure limit for developmental effects can be determined. In a
related area, the mutagenicity data indicate a potential mutagenic effect based
upon in vivo studies. A better understanding of the relationship between the
results of these types of studies and mutagenic effects in the human population
is needed. The chronic exposure toxicity studies do not provide consistent
results. Additional clarification of the NOELs for sensitive endpoints in this area
is needed.
Summary of EPA Risk Values
Chronic Toxicity
Carcinogenicity
2x 10'4mg/kg-day
1.8 per mg/kg-day
Major Sources: IRIS (1993), tox one-liners (EPA, 1993o), Hayes and Laws
(1991)
5-87
-------
5. TOXAPHENE
5.6.11. Toxaphene
Background
Toxaphene is an organochlorine pesticide which is comprised of a mixture of
670 chlorinated camphenes. It was banned for most uses in 1982; however,
due to its relatively long half-life it persists in the environment. The soil half-life
is approximately one to 14 years (HSDB,1993).
Pharmacokinetics
Toxaphene is rapidly degraded via dechlorination, dehydrodechlorination, and
oxidation primarily through the action of the mixed function oxidase system and
other hepatic microsomal enzymes. Conjugation may occur but is not a major
route of metabolism. Each component of toxaphene has its own rate of
biotransformation, making the characterization of toxaphene pharmacokinetics
complex (ATSDR, 1990b).
Some adverse effects of toxaphene may result from repeated exposure, that do
not occur with a single exposure to a lesser dose. Exposures at 0.06 mg/kg-
day over five weeks caused adrenal hormone reductions whereas a single dose
of 16 mg/kg did not cause effects. This is significant when considering
potential risks arising from chronic exposure to toxaphene (ATSDR, 1990b).
Acute Toxicity
Acute high level exposures to toxaphene has resulted in death in adults and
children with an estimated minimum lethal dose of 2 to 7 grams which is
equivalent to 29 to 100 mg/kg for a male adult. Long-term damage to the
central nervous system and liver have also been observed. The kidney and
adrenal glands are also target organs (ATSDR, 1990b). A one day NOAEL of
10 mg/kg-day is available from a dog study which used death as the effect of
concern. A 14 day LOAEL of 5 mg/kg-day was identified in an eight day study
which was used as the basis for an MRL for acute exposure of 0.005 mg/kg-
day by ATSDR (ATSDR, 1990b). See the listing of usual effects associated
with organochlorine exposure in Section 5.5.
Chronic Toxicity
IRIS does not provide a discussion of chronic effects of exposure to toxaphene
or an RfD (IRIS, 1993). The EPA Office of Pesticide Programs provides an RfD
of 2.5 x 10"4 mg/kg-day , based on a two year dog feeding study with a NOEL
of 0.25 mg/kg-day. The effect noted was liver degeneration. Uncertainty
factors totalling 1000 were applied (EPA, 1992h, EPA, 1993b and p).
5-88
-------
5. TOXAPHENE
Chronic exposure to toxaphene may result in damage to the following systems:
liver, kidney, adrenal, immunological, and neurological. The use of the liver as
the endpoint of concern is supported by a recent subchronic oral rat study
which found NOAELs of 0.28 for males and 0.38 for females with liver and
kidney effects (ATSDR, 1990b).
Chronic exposure to toxaphene may cause hormonal alterations. A study found
increased levels of hepatic metabolism in vivo and in vitro of estradiol and
estrone and a decrease in their uterotropic action. Duration of exposure was
not specified in the source reviewed (HSDB,1993). See also notes regarding
estrogenic activity under the carcinogenicity section below.
Developmental Toxicity
Adverse developmental effects, including immunosuppressive and behavioral
effects, were noted in experimental animals at levels below those required to
induce maternal toxicity. Immunosuppression (reduction in macrophage levels,
cell-mediated immunity and humoral immunity) was observed in test animals
exposed during gestation and nursing with a LOAEL of 1.5 mg/kg-day.
Impairment of behavioral maturation (e.g., reflexes) occurred at 0.05 mg/kg-day
in a rat study with 47 days of exposure. Delayed ossification (bone
development) and alterations in kidney and liver enzymes suggestive of organ-
specific toxicity were observed at 15 mg/kg-day. Other adverse effects noted
in offspring of maternally exposed individuals included histological changes in
the liver, thyroid and kidney (ATSDR, 1990b).
Women exposed to toxaphene through entering a field that had recently been
sprayed exhibited a higher incidence of chromosomal aberrations in cultured
lymphocytes than was found in unexposed women. Dermal and inhalation
exposure were the probable routes of exposure; however, the exposure was
not quantified (ATSDR, 1990b). Animal study results suggest that toxaphene
does not interfere with fertility in experimental animals at the doses tested (up
to 25 mg/kg-day) (ATSDR, 1990b). However, chromosomal aberrations (as
observed in women) would lead to decreased fertility due to early fetal loss and
may result in heritable birth defects.
Toxaphene is known to be conveyed into milk rapidly after maternal exposure
to the chemical. The half-life of toxaphene has been estimated at nine days.
It has been found in the milk of cows at all doses tested (20 - 140 ppm). In
cows exposed to 20 to 140 ppm in food (mg/kg-day conversion not available)
for eight weeks, milk concentrations increased rapidly; they decreased rapidly
following cessation of exposure. Information was provided on the relationship
between feed and milk concentrations. The exposure range was from 20 ppm
feed with milk concentrations reaching 0.36 ppm to 140 ppm feed with a
5-89
-------
5. TOXAPHENE
maximum of 1.89 ppm in milk (ATSDR, 1990b). It may be advisable to use
this data to estimate the human dose to nursing infants.
Other aspects of developmental toxicity associated with toxaphene are based
on effects observed in adult individuals which are known to pose higher risks
to children. The ATSDR has cautioned that:
"embryos, fetuses, and neonates up to age 2-3 months may be
at increased risk of adverse effects...because their enzyme
detoxification systems are immature"
and
"Infants and children are especially susceptible to
immunosuppression because their immune systems do not reach
maturity until 10-12 years of age" (ATSDR, 1990b).
Immunosuppression was noted in multiple subchronic exposure animal studies.
ATSDR also noted that:
"animal studies suggest that detoxification of the toxaphene
mixture may be less efficient in the immature human than the
metabolism and detoxification of the single components such as
Toxicant A or B." (ATSDR, 1990b).
ATSDR provides an MRL for intermediate exposures (14 to 365 days) of 5 x
10~5 mg/kg-day based on an LEL of 0.05 mg/kg-day associated with impaired
behavioral development. Uncertainty factors of 10 each for inter- and
intraspecies variability and the use of an LEL were applied (ATSDR, 1990b).
This value can be used as the estimated exposure limit for developmental
effects for use developing fish consumption limits.
As noted above, toxaphene accumulates in body tissue; consequently,
exposure occurring prior to pregnancy can contribute to the overall maternal
body burden and result in exposure to the developing individual. As a result of
this, it is necessary to reduce exposure to children and women with
childbearing potential to reduce overall body burden. If exposure is reduced
during pregnancy, but has occurred prior to pregnancy, the pregnancy outcome
may be affected, depending on the timing and extent of prior exposure.
5-90
-------
5. TOXAPHENE
Mutagenicity
There are numerous positive mutagenicity assays of toxaphene: the Ames test,
sister chromatid exchange, chromosomal aberrations in toxaphene-exposed
humans, and forward mutation assays. The implications of this for human
germ cells is not known and one assay designed to assess the effects of
dominant lethal effects on implantations in mice yielded negative results.
Some data suggest that the polar fraction of toxaphene may be more
mutagenic than the nonpolar fraction (ATSDR, 1990b; HSDB,1993).
Changes in human genetic material have been noted in workers exposed to
toxaphene (HSDB, 1993).
Carcinogenicity
Toxaphene is classified as a probable human carcinogen (B2) by EPA based on
oral studies in animals. The cancer potency is 1.1 per mg/kg-day, based upon
liver tumors in experimental animals (IRIS, 1992). This value was used to
calculate fish consumption limits listed in Section 3 for carcinogenic effects.
No conclusive human epidemiological studies are available for toxaphene
(ATSDR, 1990b).
Toxaphene has recently been observed to have estrogenic effects on human
breast cancer estrogen-sensitive cells (Sato, et al, 1994). Xenoestrogens have
been hypothesized to have a role in human breast cancer (Davis, et al, 1993).
In addition to potential carcinogenic effects, toxaphene may also cause
disruption of the endocrine system due to its estrogenic activity (Soto, et al,
1994).
Special Susceptibilities
A protein deficient diet may increase the toxicity of toxaphene approximately
three-fold based on an LD50 study in rats (ATSDR, 1990b). Because this
information was obtained from an LD50 study it can not be used directly to
modify risk values. The Centers for Disease Control has specified that:
"This has important implications with regard to the possible increased
susceptibility of humans who ingest a protein-deficient diet and live in areas of
potential exposure to toxaphene." (ATSDR, 1990b)
If a population with protein deficient diets is the target group for fish
consumption limits, an additional modifying factor of 10 could used in
determining the appropriate exposure limit for developmental effects. A factor
of 10 rather than three (observed in animal studies) is recommended, because
5-91
-------
5.TOXAPHENE
it is unknown whether human populations exposed under the same conditions
will be more or less susceptible than the animals tested, and because the
results were obtained from an LD50 study, rather than a study with a more
sensitive toxic endpoint.
The nervous system is a primary target of toxaphene toxicity. Individuals with
latent or clinical neurological diseases, such as epilepsy or behavioral disorders,
may be at higher risk. In addition children may be especially susceptible to
toxaphene induced neurotoxicity based on early reports of acute ingestion
toxicity (ATSDR, 1990b).
As discussed above under "Developmental Toxicity" ATSDR has identified
pregnant women, fetuses, infants and children as populations at greater risk.
Other individuals who may be at higher risk are those with diseases of the
renal, nervous, cardiac, adrenal, and respiratory systems. Individuals using
certain medications are also at potential risk due to the induction of hepatic
microsomal enzymes by toxaphene (discussed further in the interactive effects
section below).
See also a discussion of susceptibilities associated with pharmaceutical use in
Section 5.5.
Interactive Effects
Metabolism of some drugs and alcohol may be affected by toxaphene's
induction of hepatic microsomal enzymes. This was observed in a man using
warfarin as an anticoagulant while he used toxaphene as an insecticide. The
effectiveness of the drug was reduced due to its increased metabolism arising
from toxaphene's induction of microsomal enzymes (ATSDR, 1990b).
See a discussion of organochlorine effects related to induction of the mixed
function oxidase system in Section 5.5.
Based on acute studies and anecdotal reports of acute exposure in humans,
exposure to chemicals which increase microsomal mixed-function oxidase
systems (e.g., lindane) are likely to reduce the acute toxicity of other chemicals
detoxified by the same system (e.g., toxaphene) because the system is
functioning at a higher than normal level. Toxaphene, in turn reduces the acute
toxicity of chemicals which require this system for detoxification (ATSDR,
1990b).
In experimental animals toxaphene antagonized the tumorigenic activity of
benzo(a)pyrene in the lung. It was theorized that this occurred because
5-92
-------
5. TOXAPHENE
toxaphene inhibited the biotransformation of B(a)P to a reactive metabolite or
by promoting its degradation to nonactive forms (ATSDR, 1990b).
MIXTOX has reported synergism between chlordane, toxaphene and malathion
in mice exposed via gavage and additive interactions between chlordane and
toxaphene. Antagonism was reported between toxaphene and diazinon in rats
exposed via gavage. Mixed results have been obtained between lindane and
toxaphene (MIXTOX, 1992).
Critical Data Gaps
The following data gaps have been identified by ATSDR, EPA, and the National
Toxicology Program: mammalian germ cell genotoxicity, studies which
investigate sensitive developmental toxicity endpoints including behavioral
effects, epidemiological and animal studies of immunotoxicity, long-term
neurotoxicity studies in animals using sensitive functional and neuropathological
tests and behavioral effects on prenatally exposed animals, epidemiological
studies evaluating multiple organ systems, and pharmacokinetic studies
(ATSDR, 1990b).
Summary of EPA Risk Values
Chronic Toxicity 2x10"4 mg/kg-day
Carcinogenicity 1.1 per mg/kg-day
Major Sources: IRIS (1993), ATSDR (1990b), HSDB (1993)
5-93
-------
5. CARBOPHENOTHION
ORGANOPHOSPHATE PESTICIDES
In addition to the discussions of individual target analytes, please refer to the
discussion of toxicity characteristics of the organochlorine chemical group in
Section 5.5.
5.6.12. Carbophenothion (trithion)
Background
Carbophenothion is an organophosphate insecticide which was widely used
until very recently when the registration was dropped by the registrant. No
IRIS file was located on this chemical (10/93 search).
Pharmacokinetics
Carbophenothion is metabolized to the oxon analog, and both parent and oxon
are metabolized to the sulfoxide and sulfone forms (Hayes and Laws, 1991).
The major metabolite of Carbophenothion is p-chlorobenzenesulfinic acid which
is probably derived from the -S-oxide and/or the oxon form of the parent
compound (HSDB, 1993). Excretion of Carbophenothion in experimental animals
is rapid; 75 percent of the dose in mice was excreted in 24 hours (Hayes and
Laws, 1991).
Acute Toxicity
See the listing of usual effects associated with organophosphate exposure in
Section 5.5. The acute oral LD50 in experimental animals ranged from 25 to
217 mg/kg (EPA, 1993d). HSDB lists this chemical as highly toxic with an
estimated fatal human oral dose of 8.5 mg/kg (HSDB, 1993).
Chronic Toxicity
As noted above, no IRIS file is available for Carbophenothion (search 10/93).
OPP lists a reference dose of 1.3 x 10"4 nng/kg-day based upon a two year dog
study which identified a LEL of 0.125 mg/kg-day with decreased plasma and
brain cholinesterase levels at the LEL. Uncertainty factors of 10 each were
used for intra and interspecies variability and the use of a LEL rather than a
NOEL (EPA, 1992h). Problems related to the use of cholinesterase inhibition
as a critical endpoint are discussed in Section 5.5.2.
A two year dietary study in rats identified a LEL of 4 mg/kg-day with reduction
of hemoglobin and increased adrenal weights (Hayes, 1982). A three month
5-94
-------
5. CARBOPHENOTHION
rat feeding study reported tremors and respiratory infection with an NOEL of
1.1 mg/kg-day. This data was obtained from the OPP tox one-liners and,
consequently, very little detail was provided. Due to the lack of information on
effects other than cholinesterase inhibition for this chemical, and the limited
information available to estimate an alternative risk value, it is recommended
that the OPP value be used.
•N
Developmental Toxicity
Data currently available regarding developmental toxicity is limited because
endpoints identified were gross measures of toxicity (death) and the underlying
causes of toxicity were not identified. The studies are not based on sensitive
measures of developmental toxicity.
A NOEL of 0.5 mg/kg-day is reported in a 1976 three-generation rat
reproduction study which identified decreased pup survival and pup weight at
the LEL of 1.5 mg/kg-day. An earlier similar study found a LEL (no NOEL) of
1 mg/kg-day with decreased pup survival and increased stillbirths at the LEL
(EPA, 1993d). The reviewed data did not contain any information regarding
underlying mechanisms of fetal or neonatal toxicity. Additional uncertainty
arises because the study outcomes are gross measures of toxicity and do not
provide any indication of the level of exposure at which the organ toxicity
which led to death was occurring.
If the 1976 study is used to calculate an estimated exposure limit for
developmental effects, the uncertainty factors used in this calculation would
typically take into consideration inter- and intraspecies variability, and the
inadequacy of the data base. Consideration should also be given to the
insensitivity of the toxicity measure. In cases where the available studies
provide information on only gross measures of toxieity (i.e., death), it may be
advisable to use the RfD for chronic toxicity and consider modifications for
application to pregnant women and children.
Mutagenicity
Carbophenothion yielded positive results in a sister chromatid exchange assay
in human lymphocytes (HSDB, 1993).
Carcinogen icity
Insufficient information is available to determine the carcinogenic status of
carbophenothion.
5-95
-------
5. CARBOPHENQTHION
Special Susceptibilities
No information was found specifically regarding carbophenothion. See also a
discussion of susceptibilities associated with organophosphate exposure in
Section 5.5.
Interactive Effects
MIXTOX reported additive interaction between carbophenothion and chlordane
gavage exposure in rats, with toxaphene antagonism in rats exposed via gavage
(MIXTOX, 1992).
Critical Data Gaps
There is very limited information on the chronic systemic toxicity of
carbophenothion other than cholinesterase inhibition. Based on the available
information, the reader may wish to calculate an alternative exposure limit.
However, additional studies are needed to identify toxic mechanisms and
sensitive endpoints. This is especially true for the developmental effects
because the endpoints in currently available studies are crude measures of
toxicity.
OPP lists the following data gaps: a chronic feeding study in rats and
developmental toxicity studies in two species (EPA, 1992d).
Summary of EPA Risk Values
Chronic Toxicity
Carcinogenicity
1.3x10"4 mg/kg-day (based upon cholinesterase inhibition)
Insufficient data to determine carcinogenic status
Major Sources: HSDB (1993), tox one-liners (EPA, 1993d)
5-96
-------
5. CHLORPYRJFOS
5.6.13. Chlorpyrifos
Background
Chlorpyrifos is an organophosphate insecticide which is applied throughout the
United States for various agricultural uses.
Pharmacokinetics
Chlorpyrifos accumulates in fat and has a longer half-life in fatty tissues than
in other tissues. It has been detected in cows' milk (HSDB,1993) and would
be expected to occur in human milk of exposed mothers. This is of concern
because organophosphates may have a higher toxicity for immature individuals
than adults (e.g., malathion was more toxic to juveniles in three species tested)
(EPA, 1992g). Chlorpyrifos is rapidly metabolized and excreted based upon
studies in animals (Hayes and Laws, 1991).
Acute Toxicity
See the listing of usual effects associated with organophosphate exposure in
Section 5.5.
Chronic Toxicity
IRIS provides an oral RfD of 0.003 mg/kg-day based on a NOAEL in a 20 day
study reported in 1972 which found cholinesterase inhibition in adult male
humans after nine days of exposure. There were four subjects per dosed
group. An uncertainty factor of 10 was used to calculate the RfD (IRIS, 1993).
There are limitations in the use of this study for a chronic toxicity RfD.
Although effects were observed at levels lower than the NOAEL, they were
discounted due to an inability to achieve statistical significance; however, it is
very difficult to achieve statistical significance with four subjects. No
uncertainty factor was applied for the acute nature of the study. Most
importantly, EPA is reviewing its methods for evaluating cholinesterase
inhibitors. Cholinesterase inhibition alone is not necessarily considered an
adverse effects, in the absence of other effects. Problems related to the use
of cholinesterase inhibition as a critical endpoint are discussed in Section 5.5.2.
The value listed on IRIS was confirmed in 1993 by an Office of Pesticide
Programs RfD Peer Review Committee (EPA, 1993e).
Other chronic exposure effects have been observed in study animals. In a
1991 two-generation rat study, adrenal lesions were reported at 1 and 5
5-97
-------
5. CHLORPYRIFOS
mg/kg-day. In a subchronic study at higher doses, the same effects were
observed along with increased brain and heart weight (EPA, 1992g).
There are significant uncertainties regarding an appropriate threshold for effects
of chlorpyrifos exposure. These include the very limited data on the recently
identified adrenal and cardiac effects of chlorpyrifos and the utility of a
cholinesterase endpoint. The IRIS value was used to calculate fish
consumption limits shown in Section 3 for chronic toxicity. Future
improvements in the data base may result in alteration in this recommended
value.
Developmental Toxicity
Chlorpyrifos is fetotoxic in numerous species. In a 1987 rat study, a
developmental toxicity NOEL of 2.5 mg/kg-day was determined; at the LOEL
of 15 mg/kg-day post-implantation losses were observed. In a 1991 rat study,
which was rated as "guideline" by OPP, a developmental NOEL of 1 mg/kg-day
was obtained, with increased pup mortality at 5 mg/kg-day. No data were
available for this document on underlying causes of mortality. Decreased fetal
length and increased skeletal variants were noted in mice with a fetotoxic NOEL
for the study of 10 mg/kg-day. In a 1987 study on rabbits, increased skeletal
variants and an increased incidence of unossified sternebra and xiphisternum
were observed at 81 mg/kg-day (EPA, 1992g).
A 1991 rat study yielded the most conservative NOEL at 1 mg/kg-day.
Unfortunately, the observed endpoint was mortality. An evaluation of the
underlying causes of mortality may yield a more sensitive endpoint. If this
study were used to estimate an exposure limit for developmental effects, the
standard uncertainty factors used in this calculation would typically take into
consideration inter- and intraspecies variability and data gaps, based upon the
inability of the current studies to identify critical information.
Currently available data regarding developmental toxicity is limited because
endpoints identified were gross measures of toxicity (death) and the underlying
causes of toxicity were not identified. The studies are not based on sensitive
measures of developmental toxicity. In cases such as this, where the available
studies provide information only on gross measures of toxicity (i.e., death), it
may be advisable to use the RfD for chronic toxicity and consider modifications
for application to pregnant women and children.
Mutagenicity
The results of mutagenicity assays of chlorpyrifos are mixed. Chlorpyrifos was
weakly positive with and without activation in gene conversion and
5-98
-------
5. CHLORPYRJFOS
recombination assays, and positive for direct damage to DNA in B. subtilis
(EPA, 1992g). in vivo assays of mouse liver DNA and RNA indicated that
chlorpyrifos caused more DNA and RNA alkylation than other organophosphates
(HSDB,1993). Its toxicity is probably related to formation of its oxon analog
(chlorpyrifosoxon) and subsequent enzyme inhibition of cholinesterase activity,
carboxylases and mitochondrial oxidative phosphorylases.
Carcanogenicity
Insufficient information is available to determine the carcinogenic status of
chlorpyrifos.
Special Susceptibilities
See a discussion of susceptibilities associated with organophosphate exposure
in Section 5.5.
Interactive Effects
No data were located.
Critical Data Gaps
IRIS lists the following data gap: chronic feeding/oncogenicity study in rats
(IRIS, 1993). Addition data is needed on the non-cholinesterase effects of
chronic exposure and on the toxicity which underlies early pup mortality in
developmental studies.
Summary of Risk Values
Chronic Toxicity 3 x 10"3 mg/kg-day
Carcinogenicity Insufficient data to determine carcinogenic status.
Major Sources: IRIS (1993), HSDB (1993), tox one-liners (EPA, 1992g)
5-99
-------
5. DIAZINON
5.6.14. Diazinon
Background
Diazinon is an organophosphorus insecticide which has been widely used since
its introduction in 1952.
Pharmacokinetics
Very little data were located. Metabolism appears to proceed by similar but
somewhat different paths in various mammalian species (HSDB, 1993). Human
milk may contain trace amounts of diazinon based upon the results of exposure
in cows (HSDB, 1993).
Acute Toxicity
Diazinon is highly toxic. The estimated adult oral fatal dose is approximately
25 grams (HSDB,1993). See the listing of usual effects associated with
organophosphate exposure in Section 5.5.
Chronic Toxicity
IRIS does not currently provide an oral RfD because it is under review within
the Agency (IRIS, 1993). OPP provides an RfD of 9 x 10~5 mg/kg-day based
upon cholinesterase inhibition observed in a 90 day rat feeding study with a
NOEL of .009 mg/kg/day and uncertainty factors totalling 100 (EPA, 1992d).
Problems related to the use of cholinesterase inhibition as a critical endpoint are
discussed in Section 5.2.2.
Very little dose-response data are available on chronic systemic toxicity, other
than cholinesterase effects. Hematocrit depression was observed in a rat
chronic feeding study at 50 mg/kg-day. Gastrointestinal disturbances were
noted at 5 mg/kg-day with a NOEL of 0.05 mg/kg-day in a chronic monkey
study (EPA, 1993f). If an alternative to cholinesterase inhibition is required, the
monkey study can be used with standard uncertainty factors which take into
consideration inter- and intraspecies variability.
Developmental Toxicity
The reproductive/teratogenic studies listed in the tox one-liners report no
adverse effects at the highest doses tested (EPA, 1993f).
HSDB reported multiple studies indicating diazinon is teratogenic. In a prenatal
exposure study (dose not specified) multiple doses of diazinon resulted in a
5-100
-------
5. DIAZiNON
higher incidence of urinary malformations, hydronephrosis and hydroureter.
Diazinon was teratogenic in rats administered a single dose on day 11 of
gestation. Decreased fetal body weight was the most sensitive indicator. No
dose was specified in the data base (HSDB, 1993). In chicks, diazinon exposure
led to abnormal vertebral column development including a tortuous and
shortened structure with abnormal vertebral bodies. In the neck region, the
vertebral bodies had fused neural arches and lacked most intervertebral joints.
More severe effects on other elements of the skeleton were observed at higher
doses (HSDB, 1993 and Hayes, 1982). The dose (1 mg/egg) is not easily
convertible to a mammalian dose.
Behavioral effects were observed in mice exposed prenatally at 0.18 and 9
mg/kg-day throughout gestation. The high dose group showed decreased
growth, several behavioral effects, and structural pathology of the forebrain.
The low dose group did not have brain pathology or growth abnormalities;
however, they showed small but measurable defects in behavior and a delay
in reaching maturity (Hayes, 1982). This study appears to provide a relatively
sensitive endpoint for evaluation of developmental effects associated with
exposure to diazinon. If the LOAEL of 0.18 mg/kg-day were used, the
uncertainty factors would typically take into consideration inter- and
intraspecies variability and the use of a LOAEL rather than a NOAEL. Based on
the available information, the current IRIS RfD would be protective against
developmental toxicity.
Mutagenicity
Most mutagenicity assays were negative; one positive sister chromatid
exchange assay was noted (EPA, 1993f)., A study on the effect of diazinon on
mitosis in human lymphocytes reported chromosomal aberrations in 74 percent
of the cells at 0.5 mg/ml (HSDB, 1993).
Carcinogenicity
Insufficient information is available to determine the carcinogenic status of
diazinon.
Special Susceptibilities
See a discussion of susceptibilities associated with organophosphate exposure
in Section 5.5.
5-1O1
-------
5. DIAZINON
Interactive Effects
MIXTOX has reported antagonistic effects between diazinon and toxaphene
with exposure in rats via gavage {MIXTOX, 1992).
Critical Data Gaps
OPP lists the following data gaps: reproduction study in rats, chronic feeding
oncogenicity study in rats and chronic feeding study in dogs (EPA, 1992d). A
multigeneration reproductive study which evaluated developmental effects at
low doses and defined a NOAEL would be useful in establishing an appropriate
RfD.
Summary of EPA Risk Values
Chronic Toxicity
9 x 10~5 mg/kg-day based upon cholinesterase
inhibition
Carcinogenicity insufficient information to determine carcinogenic
status
Major Sources: tox one-liners (EPA, 1993f), Hayes (1982), HSDB (1993)
5-102
-------
5. DISULFOTOAI
5.6.15. Disulfoton (disyston)
Background
Disulfoton is an organophosphate pesticide with high acute toxicity to all
mammals.
Pharmacokinetics
Metabolism of disulfoton involves sequential oxidation of the thioether sulfur
and/or oxidative desulfuration, in addition to hydrolytic cleavage. The major
metabolites are the sulfoxide acid sulfone analogs of the compound. These are
toxic metabolites which are degraded rapidly to water soluble non-toxic
metabolites. Their estimated half-life is 30 to 32 hours (EPA, 1993h).
Disulfoton is rapidly absorbed through the mucous membrane of the digestive
system and conveyed by the blood to body tissues. The kidneys are the main
route of elimination (HSDB, 1993).
Acute Toxicity
See the listing of usual effects associated with organophosphate exposure in
Section 5.5. The acute oral LD50 in animals ranges from 2 to 27.5 mg/kg
(EPA, 1993h). Disulfoton is very highly toxic to all mammals by all routes of
exposure (HSDB, 1993).
Chronic Toxicity
IRIS provides an RfD of 4.0 x 10'5 mg/kg-day based upon a LEL of 0.04 mg/kg-
day from a two year rat study that was associated with cholinesterase
inhibition and optic nerve degeneration (IRIS, 1993). The IRIS RfD was
calculated using a modifying factor of 10 to account for possible findings in the
additional recommended optic toxicity studies (EPA, 1992c).11 Although
there is some question regarding the use of cholinesterase inhibition as the
basis for establishing an RfD (problems related to the use of cholinesterase
inhibition as a critical endpoint are discussed in Section 5.5), optic effects also
serve as the basis for this RfD (EPA, 1992d).
Numerous other effects of disulfoton have been reported at doses within one
order of magnitude of the LEL identified in the critical study. Significant
11 Standard methods would typically utilize 10 each for inter and
intraspecies variability and for the use of a LEL rather than a NOEL. This plus
the modifying factor of 10 would yield an RfD of 4 x 10 "6 mg/kg/day.
5-103
-------
5. DISULFOTON
toxicity in multiple organ systems has been observed at 0.1 mg/kg-day (the
lowest dose tested) for the following systems: spleen, liver, pituitary, brain,
seminal vesicles, and kidneys (IRIS, 1993). In addition, at 0.65 mg/kg-day rats
exhibited atrophy of the pancreas, chronic inflammation and hyperplasia in the
stomach, and skeletal muscle atrophy (EPA, 1993h). Based upon the chronic
exposure information which was reviewed and standard assumptions regarding
the use of uncertainty factors, the IRIS RfD appears to be protective against the
effects listed above.
Developmental Toxicity
In a rat teratogenicity study, incomplete ossification of the parietals and
sternebrae were noted at 1 mg/kg-day with a NOEL of 0.3 mg/kg-day in rats.
In a 1966 three-generation reproduction study in rats, male offspring had
juvenile hypoplasia in the testes, females had mild nephropathy in the kidneys
and both had preliminary stages of liver damage at 0.5 mg/kg-day. No NOEL
was obtained and no data were provided on a number of critical parameters
including weight, growth rate, and number of stillborn animals. Insufficient
histologic data and incomplete necropsy reports were identified by EPA
reviewers (IRIS, 1993 and EPA, 1993h). Toxicity was incompletely
characterized in this study and additional studies are needed to provide an
adequately defined NOEL for developmental effects. Because multiple serious
effects were observed at the lowest dose tested, the multigeneration study
does not provide an optimal basis for calculation of an exposure limit for
developmental effects. However, it does indicate that adverse developmental
effects may occur with exposure to disulfoton and provides greater detail on
these effects than the other studies which are available.
A more recent two-generation rat study identified a NOEL of 0.04 mg/kg-day
with an LEL of 0.12 mg/kg-day based upon decreased litter sizes, pup survival
and pup weights at the LEL (EPA, 1993h). This study does not appear to
provide the same level of analysis of sensitive endpoints as the three-generation
study discussed above. However, it identifies a lower NOEL and LEL than the
two older studies. If this study is used to calculate an estimated exposure limit
for developmental effects, the uncertainty factors typically used in this
calculation would take into consideration inter- and intraspecies variability. A
modifying factor could be used for the lack of data on the level at which
toxicity occurred which led to death. Additional studies are needed to identify
the NOEL for sensitive measures of the testicular, liver and kidney toxicity
identified in the multigeneration study.
5-104
-------
5. DISULFOTON
Mutagenicity
Disulfoton was not mutagenic in most assays; however, it was positive for
unscheduled DNA synthesis without activation in human fibroblasts, in a
reverse mutation assay in salmonella (EPA, 1993h), and in other in vitro assays
(HSDB,1993).
Carcinogenicity
Insufficient information is available to determine the carcinogenic status of
disulfoton.
Special Susceptibilities
Based upon the organ toxicities observed in animal studies, individuals with
diseases or disorders of the following systems may be at greater risk from
exposure to disulfoton: pancreas, stomach, spleen, liver, pituitary, brain,
seminal vesicles, kidneys, musculoskeletal and ocular. In addition, children who
were exposed prenatally to disulfoton may be at risk, depending on the level of
exposure. Also see a discussion of susceptibilities associated with
organophosphate exposure in Section 5.5.
Interactive Effects
No data were located.
Critical Data Gaps
The IRIS file notes that additional rat reproduction studies and studies to
evaluate the ocular effects of disulfoton are needed (IRIS, 1993). HSDB notes
that because of data gaps, a full risk assessment cannot be completed. Major
relevant data gaps noted under the FIFRA heading in HSDB include chronic
toxicity, oncogenicity, and mutagenicity data, animal metabolism, subchronic
toxicity, and human dietary and non-dietary exposures (FIFRA, 1987, some
data gaps may have been filled, cited in HSDB,1993). As noted above,
additional studies are needed to identify the NOEL for sensitive measures of the
testicular, liver and kidney toxicity identified in the multigeneration study.
Summary of EPA Risk Values
Chronic Toxicity 4x10"5 mg/kg-day
Carcinogenicity Insufficient data to determine carcinogenic status
Major Sources: IRIS (1993), tox one-liners (EPA, 1993h), HSDB (1993)
5-105
-------
5. ETHION
5.6.16. Ethion
Background
Ethion is an organophosphate pesticide used primarily on citrus crops (EPA,
1993a).
Pharmacokinetics
No data were located.
Acute Toxicity
See the listing of usual effects associated with organophosphate exposure in
Section 5.5.
Chronic Toxicity
A 1970 study of 10 men (six test subjects) with a NOEL of 0.05 mg/kg-day
found plasma and brain cholinesterase inhibition (IRIS, 1993). IRIS provides an
RfD of 5 x 10~4 mg/kg-day based upon a subchronic study in dogs which found
a NOEL of 0.06 and 0.07 mg/kg-day for males and females respectively with
the same effects as the human study. Uncertainty factors of 10 each for
intraspecies sensitivity and for the effects observed at 0.71 mg/kg-day in the
dog study (IRIS, 1993). Problems related to the use of cholinesterase inhibition
as a critical endpoint are discussed in Section 5.5.2.
Developmental Toxicity
A developmental NOEL of 0.6 mg/kg-day was obtained in a rat study which
found delayed ossification at an LEL of 2.4 mg/kg-day (IRIS, 1993). A rabbit
study by the same laboratory also identified a LEL of 2.4 mg/kg-day with an
increased incidence of fused sternal centers and fetal resorptions at that dose
level. The NOEL was 0.6 mg/kg-day (EPA, 1993n). A three-generation rat
study was also listed in the tox one-liners; however information was only
provided on cholinesterase inhibition levels (EPA, 1993n).
The NOEL of 0.6 mg/kg-day from the rat and rabbit studies can be used to
calculate an estimated exposure limit for developmental effects. The
uncertainty factors would typically take into consideration inter- and
intraspecies variability. Teratogenic effects and fetal death often occur at
exposure levels considerably higher than levels associated with systemic
toxicity. Other organophosphates have shown this gradient of effects (See
5-106
-------
5. ETHION
diazinon) Consequently, there is concern that the studies available for
evaluation may not fully characterize the developmental toxicity of ethion.
In cases such as this, where the available studies provide information on only
gross measures of toxicity (i.e., death), it may be advisable to use the RfD for
chronic toxicity and consider modifications for application to pregnant women
and children.
Mutagenicity
The tox one-liners listed no positive study results.
Carcinogenicity
Insufficient information is available to determine the carcinogenic status of
ethion.
Special Susceptibilities
See a discussion of susceptibilities associated with organophosphate exposure
in Section 5.5.
Interactive Effects
Potentiation between ethion and malatlhion has been observed. In rats the
potentiation was approximately 2.9-fold. In dogs there was very slight, if any
potentiation (EPA, 1993n).
Critical Data Gaps
IRIS lists a chronic dog feeding study as a data gap (IRIS, 1993). A
multigeneration study and developmental study which evaluate neurobehavioral
toxicity are needed to clarify developmental effects.
Summary of EPA Risk Values
t
Chronic Toxicity 5 x 10~4 mg/kg-day
Carcinogenicity Insufficient data to determine carcinogenic status
Major Sources: IRIS (1993), tox one-liners (EPA, 1993n)
5-107
-------
5. TERBUFOS
5.6.17. Terbufos
Background
Terbufos is an organophosphorus insecticide.
Pharmacokinetics
No data were located.
Acute Toxicity
Terbufos has a high acute toxicity to humans. Animal studies yielded the
following results: an oral LD50 in rats of 1.3 to 1.6 mg/kg (surveillance index)
and an oral LD50 in mice of 1.3 - 6.6 mg/kg (EPA 1992f). See the listing of
usual effects associated with organophosphate exposure in Section 5.5.
Chronic Toxicity
Limited information is available on terbufos toxicity and the focus of most
toxicity evaluations is on its cholinesterase inhibition properties. IRIS does not
provide an RfD for terbufos. HEAST lists an RfD of 2.5 x 10"5 mg/kg-day
based on cholinesterase inhibition in a six month dietary dog study with a NOEL
of 0.0025 mg/kg-day. Uncertainty factors of 10 each for inter- and intraspecies
variation were used. No uncertainty factor was used for the subchronic nature
of the study. The HEAST table states that this value is under review (HEAST,
1992).
OPP has recently developed an RfD of 5 x 10~5 mg/kg-day based upon
cholinesterase inhibition. This is based upon a 28 day dog study with a NOEL
of 0.005 mg/kg-day and a one year dog study with a LOAEL of 0.015 mg/kg-
day. Uncertainty factors of 10 each for inter- and intraspecies variability were
applied (EPA, 1993p). Problems related to the use of cholinesterase inhibition
as a critical endpoint are discussed in Section 5.5.2.
i.
Quantitative chronic toxicity information on cholinesterase inhibition is available
which generally supports the OPP RfD. In rats, a 1974 lifetime oral study
found a LOEL of 0.0125 mg/kg-day (the lowest dose tested); a 1987 one year
oral study found a NOEL of 0.025 mg/kg-day. In dogs, a 1972 six month oral
study found a NOEL of 0.0025 mg/kg; 1986 one year study "found a LOEL of
0.015 mg/kg-day (the lowest dose tested); a 1987 28 day dog study identified
a NOEL of 0.00125 mg/kg-day (EPA7 1992f).
5-108
-------
5. TERBUFOS
Quantitative data on chronic effects which are not directly related to
cholinesterase inhibition are limited, due to the lack of "no effect levels" from
many studies, and the need for specific information on some effects. Chronic
exposure effects include: corneal cloudiness and opacity, eye rupture, alopecia,
disturbances in balance, and exopthalmia noted in multiple studies and multiple
species at 0.0125 mg/kg-day and above (EPA, 1992f). Increased liver weight
and increased liver extramedullary hernatopoiesis at 0.025 mg/kg-day and
above, and mesenteric and mandibular lymph node hyperplasia at 0.05 mg/kg-
day and above were noted in a subchronic (three month) rat study (animals
were not examined for this lesion at lower exposure levels) (EPA, 1992f).
Developmental Toxicity
Data currently available regarding developmental toxicity are limited because
the endpoints identified were gross measures of toxicity (death) and the
underlying causes of toxicity were not identified. The studies are not based on
sensitive measures of developmental toxicity. Results from two developmental
studies and one multigeneration study are available: a 1984 rat study found
NOEL of 0.1 mg/kg-day with increased fetal resorptions at 0.2 mg/kg-day; a
1988 rabbit study identified a NOEL of 0.25 mg/kg-day with fetal resorptions
at 0.5 mg/kg-day. A 1973 multigeneration reproductive study found a NOEL
of 0.0125 mg/kg-day in rats, based on an increase in the percentage of deaths
in offspring (EPA, 1992f).
The increase in deaths in offspring in the multigeneration study does not
provide insight into the causes of death. Fetal resorptions, noted in the
developmental studies, often result from gross abnormalities leading to early
fetal death or from direct fetotoxicity. A NOEL for adverse effects would be
a preferable endpoint, with exploration of the causes underlying fetal loss. A
multigeneration study which evaluated sensitive endpoints, including ocular
effects, and liver and lymph node toxicity which were observed at low doses
in adults animals (See the chronic exposure section above) would provide a
better basis for determining a safe developmental exposure level.
Based on the developmental data currently available, the multigeneration study
NOEL of 0.0125 appears to be the most sensitive study, (perhaps because
exposure occurred over a longer period of time than in the other developmental
toxicity studies). However, the developmental toxicity data base embodies
considerable uncertainty. Many chronic exposure effects were observed at
levels approximating the NOEL obtained from the multigeneration study.
Although these effects were not reported in the developmental toxicity studies,
it is not known whether effects observed in adult studies, such as liver and
lymph node toxicity, were evaluated in the developmental studies. Postnatal
5-109
-------
5. TERBUFOS
exposure would be expected to be at least as toxic to young individuals as to
adults.
If the multigeneration study is used calculate an exposure limit for
developmental effects, the standard uncertainty factors would typically take
into consideration intra- and interspecies variability and the inadequacy of the
data base. In cases such as this, where the available studies provide
information on only gross measures of toxicity (i.e., death), it may be advisable
to use the RfD for chronic toxicity and consider modifications for application to
pregnant women and children.
Mutagenicity
Terbufos was negative in most assays. It was positive in an in vivo dominant-
lethal assay in rats; at 0.4 mg/kg the numbers of viable implants were reduced
(EPA, 1992f).
Carcinogenicity
Insufficient information is available to determine the carcinogenic status of
terbufos.
All oncogenicity tests on terbufos have been considered negative by OPJ3 (EPA,
1992f). However, further exploration of mesenteric and mandibular lymph
node hyperplasia identified in a three month study (noted above) is warranted
because hyperplasia is often a precancerous condition. Evaluation of this
endpoint in a lifetime study is necessary to determine the ultimate course of the
hyperplasia.
Special Susceptibilities
See a discussion of susceptibilities associated with organophosphate exposure
in Section 5.5.
Interactive Effects
No data were located.
Critical Data Gaps
There are inconsistencies in the toxicity data base for terbufos based on a
comparison of acute study results and the results obtained in some chronic
feeding studies, developmental studies and the LD50s. Some longer term
studies reported no effects at exposure levels above the LD50s (EPA, 1992f).
5-110
-------
5. TERBUFOS
The animal and human studies available on terbufos do not provide a complete
and consistent basis for calculation of an alternative exposure limit. The
identification of mesenteric and mandibular lymph node hyperplasia is
problematic due to its potential oncogenic implications. A NOEL for these
effects was not identified and effects were not screened in low dose groups.
Other effects, which are not directly related to cholinesterase inhibition, were
also noted with terbufos exposure, including optic damage at 0.0125 mg/kg-
day in multiple species and studies. In addition, there is uncertainty regarding
a safe exposure level to prevent adverse developmental effects, as discussed
above. These results warrant further evaluation and may be considered, by
some, to justify an additional modifying factor to deal with data gaps and
uncertainties in the data base.
Summary of EPA Risk Values
Chronic Toxicity 2.5 x 10~5 mg/kg-day
Carcinogenicity Insufficient data to determine carcinogenic status
Major Sources: HSDB, 1993, tox one-liners (EPA, 1992f)
5-111
-------
5. OXYFLUORFEN
Chlorophenoxy Herbicides
5.6.18. Oxyfluorfen
Background
Oxyfluorfen is a recently introduced diphenyl ether pesticide in the
Chlorophenoxy class. Limited data were located on this chemical.
Pharmacokinetics
No data were located.
Acute Toxicity
The acute oral LD50 in rats is greater than 5000 mg/kg (Hayes and Laws,
1991).
Chronic Toxicity
IRIS provides an RfD of 3 x 10~3 mg/kg-day based upon a NOAEL of 0.3 mg/kg-
day from a 1977 twenty month mouse feeding study which identified
nonneoplastic lesions in the liver and increased absolute liver weight.
Uncertainty factors of 10 each for inter- and intraspecies sensitivity were
applied (IRIS, 1993).
Developmental Toxicity
A three-generation rat study provided a NOEL of 0.5 mg/kg-day and an LEL of
5 mg/kg-day. A rat teratology study identified a fetotoxic NOEL of 100 mg/kg-
day. A rabbit study found fused sternebrae at 30 mg/kg-day and a NOEL of 10
mg/kg-day (IRIS, 1993, EPA, 19931). A rabbit teratology study data gap is
noted in the IRIS file (IRIS, 1993). Nitrofen, a close structural relative of
Oxyfluorfen has been studied more extensively. Studies of nitrofen identified
multiple varied developmental abnormalities associated with prenatal exposure
(Hayes, et al., 1991).
The multigeneration study is the most sensitive study of those reviewed; this
may be due to the longer period of exposure and follow up than the prenatal
exposure studies. The standard uncertainty factors used in this calculation
would typically take into consideration inter- and intraspecies variability.
Additional information is needed on the nature of effects at the LEL.
5-112
-------
5. OXYFLUORFEN
Mutagenicity
Results of mutagenicity assays on oxyfluorfen are mixed (EPA, 19931).
Carcinogenicity
Oxyfluorfen has been classified as a possible human carcinogen (C) based upon
liver tumors identified in experimental animals. A cancer potency of 0.13 is
provided by OPP (EPA, 1992d).
Interactive Effects
No data were located.
Critical Data Gaps
The IRIS file notes a rabbit teratology study as a data gap.
Summary of EPA Risk Values
Chronic Toxicity 3 x 10"3 mg/kg-day
Carcinogenicity 0.13 per mg/kg-day
Major Sources: IRIS (1993), tox one-liners (EPA, 19931)
5-113
-------
5. PCBs
Polychlorinated Biphenyls
5.6.19. PCBs
Background
Polychlorinated biphenyls (PCBs) are a mixture of chlorinated biphenyl
chemicals which occur individually as 209 congeners, comprised of various
chlorine substitution patterns. Mixtures of PCBs were marketed under the trade
name Aroclor, with a numeric designation that indicated their chlorine content.
Although production and use were banned in 1979, the chemical group is
extremely persistent in the environment and bioaccumulates through the food
chain. There is evidence that the most potent, dioxin-like PCB congeners are
preferentially accumulated in higher organisms. Consequently, the aggregate
toxicity of a PCB mixture may increase as it moves up the food chain (EPA,
1993a). As a result of this, the composition of commercial PCB-mixtures may
differ significantly from that actually found in fish tissue. Often the mixtures
of interest are not those which have been used in studies of laboratory animals
to determine toxicity. The preferable studies, under these conditions, are those
which utilize human dose-response data from populations who have consumed
PCBs via fish. When reliable human data are lacking, animal data may need to
be used.
PCB exposure is associated with a wide array of adverse health effects in
human and experimental animals (as discussed below). Many effects have only
recently been investigated (e.g., hormonal effects), and the implications of
newer studies are not fully known. The health effects of PCBs are still under
active evaluation and currently there is not sufficient information on the specific
congeners to develop congener-specific quantitative estimates of health risk
(EPA, 1993a). Due to the lack of congener-specific information, the Office of
Water recommends, as an interim measure, that total PCB concentrations
reported as the sum of Aroclors. The first volume in this document series,
Sampling and Analysis, contains a detailed discussion of analysis of this group
of chemicals (EPA, 1993a).
Pharmacokinetics
PCBs are absorbed through the Gl tract and distributed throughout the body.
The highest concentrations are found in adipose tissue. According to ATSDR,
human milk may contain a large amount of PCBs due to their high fat content
(ATSDR, 1993d). A Canadian study found human milk concentrations more
than 10 times higher than whole blood concentrations. The PCB congener
composition of milk differs from the exposure composition of PCBs. Offspring
can be exposed to PCBs via milk and through transplacental transfer. PCBs
5-114
-------
5. PCBs
have also been measured in other body fluids including plasma, follicular fluid,
and sperm fluid. For a more extensive discussion of this topic see ATSDR
(1993d).
The retention of PCBs in fatty tissue is linked to metabolism, with higher
chlorinated PCBs persisting for longer periods of time. Pharmacokinetic
modeling of PCB disposition indicates that PCB movement in the body is a
dynamic process, with exchanges between various tissues that depend on
fluctuating exposure levels to specific congeners. The result is clearance of
congeners that are more easily metabolized and retention or those which resist
metabolism (ATSDR, 1993d). Studies of individual chlorobiphenyl congeners
indicate, in general, that PCBs are readily absorbed, with oral absorption
efficiency of 75 to greater than 90 percent in rats, mice and monkeys (IRIS,
1994). Indirect evidence of oral absorption in humans is available in studies of
PCB-contaminated fish (IRIS, 1994).
Studies indicate that the metabolism of PCBs by monkeys and rats is more
similar to humans than other species tested (IRIS, 1994). There are limited
data on the half-life of the various PCBs in humans. Under environmental
exposure conditions in China, half-lives ranged from four to 21 months and
from three to 12 months for two 5-chIorine PCBs. A detailed discussion of PCB
pharmacokinetics is available in the ATSDR Toxicological Profile for Selected
PCBs (ATSDR, 1993d).
PCBs induce mixed function oxidases and different congeners induce specific
forms (isozymes) of the cytochrome P-450 system. Many of the PCB
congeners also bind to the Ah receptor, which regulates the synthesis of a
variety of proteins. Although there has been much research into the
mechanisms of PCB toxicity, there has not been clear definition of the
mechanisms for most congeners. The congeners appear to act by a variety of
mechanisms (ATSDR, 1993d), and the resulting toxicity will vary depending on
the mixture of congeners to which an individual is exposed.
Acute Toxicity
The lethal doses observed in experimental animals do not indicate that PCBs
would be acutely toxic to humans (ATSDR, 1993d). Based upon study results
obtained for TCDD, it is suggested that exposure to TCDD-like PCBs may result
in delayed lethality. Immature animals appear to be more sensitive to acute
lethal effects of PCBs than adults {ATSDR, 1993d).
5-115
-------
5. PCBs
Chronic Toxicity
PCBs have a high chronic exposure toxicity. Dietary doses in animals of 0.1
to 1 mg/kg-day over many months may be lethal (ATSDR, 1993d). Based upon
human and animal studies, chronic oral exposure to PCBs affects numerous
organ systems including the cardiovascular, Gl, hematological, musculoskeletal,
hepatic, renal, dermal, immunological, neurological, and reproductive systems
(ATSDR, 1993d).
Information has been recently added to IRIS (1994) regarding toxicity of Aroclor
1254. A monkey study found ocular effects and distorted growth of finger and
toe nails at the lowest dose tested of 0.005 mg/kg-day. Significant reductions
in IgM and IgG in response to injected sheep red blood cells were also seen at
the lowest dose tested. On the basis of these effects a LOAEL of 0.005
mg/kg-day was established. Uncertainty factors of 10 for sensitive individuals,
3 for extrapolation from monkeys to humans and 3 for extrapolation from a
subchronic exposure to a chronic RfD, and 3 for use of a minimal LOAEL. This
yields an RfD of 2 x 10"5 mg/kg-day (IRIS, 1994). This new RfD is lower than
the RfD which is available for Aroclor 1016 (discussed below under
developmental toxicity) and is, consequently, protective against both chronic
systemic toxicity and developmental toxicity. Therefore, the RfD for Aroclor
1254 was used to calculate the consumption limits for non-carcinogenic effects
listed in Section 3.
ATSDR has determined that immunological effects are a sensitive endpoint for
chronic toxicity and developed a MRL of 2 x 10"5 mg/kg-day based on such
effects (ATSDR, 1993d). The studies used as the basis for the MRL are the
same as those listed above in the IRIS discussion. Uncertainty factors of 10
each for the use of a LOAEL and for human variability were used. A factor of
3 was used for extrapolation from animals to humans. Decreased IgG and IgM
levels were noted. Chronic toxicity in other organ systems (as listed above)
was noted at exposure levels higher than the LOAEL of 0.005 mg/kg-day
(ATSDR, 1993d).
Developmental Toxicity
All PCB mixtures tested have caused developmental effects in experimental
animals (ATSDR, 1993d). Several human studies have also suggested that PCB
exposure may cause adverse effects in children and to developing fetuses (EPA,
1993a). As with all epidemiological studies, there are difficulties in these
studies with confounding variables. Other problems with the studies include
exposure assessment, selection of exposed and control subjects, and the
comparability of exposed and control samples (ATSDR. 1993d).
5-116
-------
5. PCBs
The IRIS RfD for Aroclor 1016 is based upon developmental toxicity observed
in a 22 month monkey study (discussed below under longer-term
developmental studies), with a NOAEL of 0.007 mg/kg-day. The following
uncertainty factors were applied to calculate the RfD: 3 for sensitive
individuals (infants exposed transplacentally), 3 for interspecies extrapolation,
and 3 due to the limitations of the data base (male reproductive effects are not
directly addressed in studies and two-generation reproductive studies are not
available). This yields an RfD of 7 x 10~5 mg/kg-day (IRIS, 1994). Readers
may elect to use this value to develop alternative consumption limits which are
specifically designed for women of reproductive age. However, this approach
is not recommended because the developmental toxicity-based RfD was not
designed to be protective against the effects discussed under chronic toxicity
for Aroclor 1254. Consequently, if the sum of the Aroclors-approach is used
in developing fish advisories, the use of the value for Aroclor 1016 may not be
protective against adverse effects of ail Aroclors.
The following discussion of developmental toxicity contains study information
in the following order: human data, short-term, intermediate length, and
longer-term studies, and a summary.
A study was conducted of pregnancy outcomes in women who had consumed
PCB contaminated fish from Lake Michigan over an average of 16 years
(exposure both prior to and during pregnancy). Exposure quantification was not
precise; however, it has been estimated that the average exposure was 5x10"
mg/kg-day. Contaminated fish consumption correlated with maternal serum
PCB levels. Children whose mothers were exposed had significantly lower birth
weights, smaller head circumferences, shorter gestational ages, and poorer
neuromuscular maturity; at seven months the children had subnormal visual
recognition memory. The exposure estimates in this study were not precise
and varied widely; the recall ranged over a number of years with a mean
consumption duration (as noted above) of 16 years and the PCB concentrations
in different types of fish of 168 ppb to 3012 ppb. The study results were
confounded by exposure to other chemicals and the fact that the exposed
group, on average, drank more alcohol and caffeine, prior to and during
pregnancy, weighed more, and took more cold medications during pregnancy,
than the non-exposed group (review in Shubat, 1993a).
A pharmacokinetic approach to estimating safe exposure levels has been taken
by the Great Lakes Sport Fish Advisory Task Force using the Michigan study
data (Anderson and Amrhein, 1993). This approach utilized relationships
between milk PCB concentrations, fish intake and concentrations, and
developmental effects. Assumptions were made regarding body weight (60
kg), percentage of body fat (25 percent), and the biological half-life of PCBs in
humans (one year) (Anderson and Amrhein, 1993). The pharmacokinetic
5-117
-------
5. PCBs
approach has the potential for introducing more precision to the process of
estimating thresholds and evaluating dose-response relationships. However, it
relies on the use of many physiological variables, as well as dose and response
values. In the specific case of the Great Lakes approach, there is concern that
the assumptions which were made for the "average" women and "average"
body fat composition do not take into consideration the 49 percent of women
who have above-average values. Although this variability would introduce
minimal alterations at values near the average, there could be significant
deviation from predicted values at the 75th or 90th percentiles. The approach
also assumes that reproduction occurs at 25 years of age with the estimated
body burden based upon this assumption (Anderson and Amrhein, 1993).
Maternity over the age of 25 would entail greater exposure to the fetus due to
the higher maternal body burden associated with a longer accumulation period.
A study of the children of women with background body burdens of PCBs in
North Carolina was recently conducted which noted much more moderate
effects of PCB exposure, with no changes in birth weight or head
circumference. The authors reported that deficits observed through two years
of age were not detectable at ages three,, four, and five, based on intellectual
and motor function assays. Exposure was confounded by the presence of DDE
in blood and milk samples from the mothers. This study utilized body burdens,
rather than intake as measure of exposure (ATSDR, 1993d).
Studies of women who have spontaneously aborted, miscarried, or delivered
prematurely have found an association between these effects and
concentrations of PCBs in maternal blood (ATSDR, 1993d).
The results of animal studies generally support the occurrence of neurotoxic
effects following prenatal and neonatal childhood exposures to PCBs. Short-
term studies in animals exposed prenatally to PCBs have identified the following
effects: hydronephrosis in mice with a single dose of 244 mg/kg (Aroclor
1254); no effects in mice with 12 days of dosing up to 12.5 mg/kg-day
(Aroclor 1254); fetal weight reduction in rats with nine days of dosing at 5
mg/kg-day with reduced survival at 15 mg/kg-day and a NOEL of 2.5 mg/kg-
day (Aroclor 1254); impaired learning in rats at 4 mg/kg-day with 10 days of
dosing (Fenclor 42). Decreased survival was observed at higher doses. Based
on the results of short-term exposure assays, ATSDR concluded that
neurobehavioral endpoints may be the most sensitive for assessing
developmental effects.
Intermediate-length exposure studies (e.g., during the prenatal and lactational
periods) indicate neurological, thyroid, liver, growth, and hormonal
abnormalities in offspring. Reduced litter size was also observed. The lowest
NOAEL in this group of studies was observed in rats at 0.13 mg/kg-day, with
5-118
-------
5. PCBs
increased relative liver weight being the indicator of effects. This effect alone
may not indicate toxicity; however, other types of liver toxicity were observed
at higher doses. A LOAEL of 0.18 mg/kg-day was observed in mink which
found delayed growth and 89 percent neonatal death at this exposure level.
Mink and monkeys appear to be more sensitive species for PCB-induced
developmental toxicity than rodents (ATSDR, 1993d).
Longer-term developmental toxicity studies have been conducted on the
offspring of monkeys exposed over 12 to 22 month periods. Three different
studies have identified NOAELs in the range of 0.007 to 0.008 mg/kg-day. In
a study which found birth weight reduction at 0.03 mg/kg-day, a NOAEL of
0.007 mg/kg-day was established. In two studies which focused on
neurological abnormalities, exposure at 0.03 and 0.08 mg/kg-day was
associated with decreased performance in spatial learning and memory tasks.
The neurological effects NOAEL for both of these studies was 0.008 mg/kg-
day. Dose-related early abortions and low birth weight were associated with
prenatal exposures of 0.1 and 0.2 mg/kg-day, along with multiple gross and
microscopic organ system abnormalities. At 0.1 mg/kg-day prenatal exposure,
multiple studies in monkeys have identified PCB intoxication in offspring (acne,
swollen eyelids, loss of eyelashes, and hyperpigmentation of the skin) (ATSDR,
1993d).
In summary, the two sets of human studies carried out in Michigan and North
Carolina both indicate a strong association between PCB exposure and adverse
reproductive outcomes. However, there are serious deficits in the studies
regarding exposure quantification and confounding exposures to other
developmental toxics. The primary concern is with the quantification of
exposure. Although it is preferable to use dose-response data from human
studies, readers may wish to consider the results of the primate studies in
developing consumption limits for developmental effects, due to deficits in the
human studies. Primates are similar to humans in neurological development and
the primate studies focused on a sensitive indicator of developmental toxicity:
neurological effects. This was also the organ system of primary concern in
children in many human studies. The primate studies evaluated higher
cognitive functions rather than more basic neurological effects, such as reflex
actions. Effects on higher cognitive function appear to occur at lower levels of
exposure than effects on gross motor function or reflexes. The IRIS value for
Aroclor 1016 (provided above) is based on a primate toxicity study.
Exposure via lactation is a significant concern for neonates. Animal studies
indicate that lactational exposure may be more significant than prenatal
exposure. In monkeys, signs of PCB intoxication were observed in lactationally-
exposed offspring, but not in offspring exposed only prenatally {ATSDR,
1993d). Consequently, it is recommended that additional research be carried
5-119
-------
5. PCBs
out to establish a correlation between prenatal and lactational exposure in the
human population and the occurrence of neurological effects in children.
Mutagenicity
IRIS reports that the majority of rnutagenicity assays of PCBs have been
negative (IRIS, 1993 file for Aroclor 1260).
An increase in the percentage of chromosomal aberrations in peripheral
lymphocytes was reported in workers manufacturing PCBs for 10 to 25 years.
Increased sister-chromatid exchange was also reported. The study was
controlled for smoking and drinking; however, concurrent exposure to
formaldehyde and benzene occurred (ATSDR, 1993d).
ATSDR reports that most in vitro assays and in vivo animal assays yielded
negative results, although both positive and negative results were reported.
Positive study results include an increase in unscheduled DNA synthesis
(ATSDR, 1993d). See also Interactive Effects below.
Carcinogenicity
PCBs are classified by EPA as probable human carcinogens (Group B2). The
carcinogenic potency of the individual PCBs vary with their structure. A cancer
potency of 7.7 per mg/kg-day, derived from studies of Aroclor 1260, is listed
in IRIS, and was used to calculate fish consumption limits (IRIS, 1993). It is
suggested that this value be applied to the sum of the Aroclors (EPA, 1993a).
Human epidemiological studies of PCBs have not yielded conclusive results. As
with all epidemiological studies, it is very difficult to obtain clear unequivocal
results due to the long latency period required for cancer induction and the
multiple confounders arising from concurrent exposures, lifestyle differences,
and other factors.
A recent study of PCBs and pesticides in human breast lipids has found an
association between elevated levels of these chemicals and breast cancer
(Falck, et al, 1992).
Special Susceptibilities
ATSDR has indicated that embryos, fetuses, and neonates are unusually
susceptible to PCBs, due to their underdeveloped enzymatic systems which
may cause delayed elimination and, therefore, accumulation of PCBs in the
body. Breast-fed infants are at particular risk because a steroid secreted in
5-120
-------
5. PCBs
human milk, but not cows' milk, inhibits glucuronyl transferase activity, which
is critical to PCB metabolism and excretion (ATSDR, 1993d).
Other individuals at potentially greater risk include those with syndromes
associated with incompletely developed glucuronide conjugation mechanisms,
those with hepatic infections, compromised liver functions, or acute
intermittent porphyria (ATSDR, 1993d),,
Due to effects noted on the cardiovascular, Gl, hematological, musculoskeletal,
hepatic, renal, dermal, immunological, neurological, and reproductive systems,
individuals with diseases or disorders of these systems may be at greater risk.
In addition, PCBs cause induction of the mixed function oxidase system.
Individuals exposed to chemicals (including Pharmaceuticals) which rely on the
mixed function oxidase system for activation or detoxification may experience
altered effectiveness of the chemicals. This is discussed in Section 5.5 under
"Organochlorines."
Interactive Effects
PCBs induce microsomal enzymes. See Section 5.5 under "Organochlorines"
for potential interactions arising from this characteristic.
ATSDR reports that:
"it is well established that the addition of liver microsomal
preparations from PCB-treated animals to in vitro genotoxicity
assays potentiates the genotoxic activity of numerous carcinogens
by activation to reactive intermediates and proximate carcinogens"
(ATSDR, 1993d).
Mixtox reports potentiation between PCBS and Mirex in a rat dietary study.
Other studies of this combination have not found interactive results (MIXTOX).
Critical Data Gaps
A joint team of scientists from EPA, ATSDR, and NTP have identified the
following data gaps: human epidemiological studies; genotoxicity studies of
various mixtures of PCBs including cytogenetic analysis of human populations
exposed to PCBs; reproduction studies in humans and animals including fertility
studies in males of a sensitive species; developmental studies including
histological examination of developing neurological tissues in experimental
animals, neurodevelopmental studies designed to identify NOAELs, and
immunological studies in developing animals; irnmunotoxicity studies in humans
and animals; neurotoxicity studies in humans with high PCB body burdens and
5-121
-------
5. PCBs
in animals; chronic studies to determine the most sensitive animal target organ
and species; human studies on PCBs and hypertension and liver toxicity;
pharmacokinetic studies; and studies to elucidate the differing toxicities of the
various congeners comprising PCB mixtures (ATSDR, 1993d).
Summary of EPA Risk Values
Chronic Toxicity 7 x 10"5 rng/kg-day based upon Aroclor 1254
Carcinogenicity 7.7 per mg/kg-day based upon Aroclor 1260
Major Sources: IRIS for Aroclor 1254, 1260, and 1016 (1993 and 1994),
ATSDR (1993d), HSDB (1993)
5-122
-------
5. DIOXIN
Dioxins
5.6.20. Dioxin
Background
Dioxin is undergoing extensive review within EPA. Consequently, only a brief
summary, taken from the Sampling and Analysis Guidance, is provided below.
It is anticipated that EPA will provide the results of a detailed evaluation of
dioxin toxicity in the very near future.
Dioxin is a generic term which is used, in this case, to specify 2,3,7,8-
tetrachlorodibenzo-p-dioxin (TCDD). It is recommended that the seventeen
2,3,7,8- substituted tetra- through octa-chlorinated dibenzo-p-dioxins and
dibenzofurans be considered together as a simplifying and interim approach
until further guidance is available on this chemical. Alternatively, the reader
may consult guidance on the use of a toxicity equivalency approach to refine
the toxicity estimate and fish consumption limit calculations (Barnes and Bellin,
1989, U.S. EPA, 1991c).
Dioxin is extremely toxic to humans and animals and affects multiple organ
systems. Adverse effects observed in animal studies include teratogenicity,
fetotoxicity, reproductive dysfunction, carcinogenicity, and immunotoxicity
(EPA, 1993aj. Dioxin has the highest cancer potency in ianimals of the
chemicals evaluated by EPA. A cancer risk based health advisory can be
calculated using the existing cancer potency value of 1.56 x 10 + 5 per mg/kg-
day (EPA, 1993a).
Summary of Risk Values
Carcinogenicity 1.56 x 10 + 5 per mg/kg-day
Major Source: EPA (1993a)
5-123
-------
5. CADMIUM
Metals
5.6.21. Cadmium
Background
Cadmium is a heavy metal which is released through a wide variety of industrial
and agricultural activities. It accumulates in human and other biological tissue
and has been evaluated in both epidemiologies! and toxicological studies.
ATSDR has determined that exposure conditions of most concern are long-term
exposures to elevated levels in the diet (ATSDR, 1993a).
The FDA has estimated that cadmium exposure among smokers is
approximately 10 //g/day (0.01 mg/day). Passive exposure of non-smokers
may also be a source of exposure (U.S.FDA, 1993). This should be considered
in evaluating the total exposure and risks associated with cadmium.
Pharmacokinetics
Cadmium is not readily absorbed when exposure occurs via ingestion. Most
ingested cadmium passes through the Gl tract without being absorbed. Studies
in humans indicate that approximately 25 percent of cadmium consumed with
food was retained in health adults after three to five days; this value fell to six
percent after 20 days. Absorption may be much higher in iron deficient
individuals. Evaluations of the impact of cadmium complexation indicate that
cadmium absorption from food is not dependent upon chemical complexation.
However, some populations with high dietary cadmium intakes have elevated
blood cadmium levels, and this may be due to the particular forms of cadmium
in their food (ATSDR, 1993a).
Cadmium absorption studies in animals indicate that the proportion of an oral
dose which is absorbed is lower in animals than in humans. Absorption is
elevated during pregnancy, with whole-body retention in mice of 0.2 percent
in those that had undergone pregnancy and lactation and 0.08 percent in those
that had not. In rats absorption decreased dramatically over the early lifetime
ranging from 12 percent at two hours to 0.5 percent at six weeks after birth.
The placenta may act as a partial barrier to fetal exposure, with cord blood
concentrations being approximately half those of maternal blood. The human
data on placenta! concentrations are conflicting. Cadmium levels in human milk
is approximately five to 10 percent of those found in blood (ATSDR, 1993a).
Cadmium absorption appears to involve sequestering by metallothionein, and
plasma cadmium is found primarily bound to this protein. This binding appears
5-124
-------
5. CADMIUM
to protect the kidney from otherwise toxic effects of cadmium. It has been
suggested that kidney damage by cadmium occurs primarily due to unbound
cadmium (ATSDR, 1993a). Once cadmium is absorbed, it is eliminated slowly;
the biological half-life has been estimated at 10 to 30 years (U.S. FDA, 1993).
Body stores of iron, zinc and calcium may affect absorption and retention,
although the retention may not be in readily available tissues (e.g., intestinal
wall versus blood). The greatest concentrations of cadmium are typically found
in the liver and kidney. Cadmium is not directly metabolized, although the
cadmium ion binds to anionic groups in proteins, especially albumin and
metallothionein (ATSDR, 1993a).
Acute Toxicity
Effects of acute oral exposure to cadmium include Gl irritation, nausea,
vomiting, abdominal pain, cramps, salivation, and diarrhea. In humans lethal
doses caused massive fluid loss, edema and widespread organ destruction.
The ingested doses were 25 mg/kg and 1500 mg/kg (ATSDR, 1993a).
Chronic Toxicity
Kidney toxicity is a significant concern with cadmium exposure. Increased
death rates from renal disease have been observed in exposed human
populations in Belgium, England, and Japan (ATSDR, 1993a). There are also
extensive animal data indicating that the kidney is a target organ. IRIS contains
an RfD of 0.001 mg/kg-day in food based upon a NOAEL of 0.005 mg/kg-day
in multiple human studies of waterborne cadmium. The critical effect was
significant proteinuria (an indicator of kidney toxicity). To calculate the RfD,
it was assumed that 2.5 percent of cadmium in food was absorbed and
approximately five percent in water was absorbed. Using an uncertainty factor
of 10 to account for intrahuman variability in cadmium sensitivity, the RfD for
cadmium in food was calculated to be 0.001 mg/kg-day. The RfD was
calculated using a toxicokinetic model to determine the highest level of
cadmium in the human renal cortex not associated with significant proteinuria
(IRIS, 1993).
The FDA has calculated a tolerable daily intake of 55 /vg/person/day, which is
approximately equal to 0.78 //g/kg/day (7.8 x 10'4 mg/kg-day) in a 70 kg
person and 5.5 //g/kg/day (0.005 mg/kg-day) in a 10 kg child (their example
uses 2+ years of age). The FDA value is based upon a pharmaqokinetic
approach which utilized the critical body burden associated with kidney toxicity.
See FDA (1993) for more details.
5-125
-------
5. CADMIUM
ATSDR has also recently calculated a risk value for oral exposure based upon
kidney toxicity in humans. They developed a chronic MRL of 7 x 10~4 mg/kg-
day based upon a NOAEL of 0.0021 mg/kg-day in a large human cohort. The
critical endpoint was an elevation of urinary beta-(2)-microglobulin. A toxicity
threshold was estimated using a kinetic model of cadmium metabolism which
predicted that approximately five percent of non-smokers will reach or the dose
required to cause an effect at the NOAEL. To calculate the MRL, ATSDR used
an addition uncertainty factor of 3 to account for sensitive members of the
population. However, the critical study used a large population which included
the elderly, who are considered a sensitive subpopulation (ATSDR, 1993a).
The MRL developed by ATSDR is within one order of magnitude of the RfD
developed by IRIS.
Cadmium causes many other types of toxic effects in addition to
nephrotoxicity. In humans some studies have suggested an association
between neurotoxicity and cadmium exposure, at levels below those which
cause kidney toxicity (no additional details available). Cadmium exposure
reduces the Gl uptake of iron which may cause anemia if iron intakes are low.
Bone disorders including osteomalacia, osteoporosis and spontaneous bone
fracture have been observed in some chronically exposed individuals. Increased
calcium excretion associated with cadmium-induced renal damage may lead to
increased risk of osteoporosis, especially in post-menopausal women, many of
whom are already at risk of osteoporosis. Cardiovascular toxicity and elevated
blood pressure has been suggested in some human studies; however, the
results are conflicting (ATSDR. 1993a).
Animal studies indicate that cadmium causes a wide variety of alterations in the
function of the immune system. Some aspects of the systems were enhanced
and others were impaired (e.g., susceptibility to virally-induced leukemia). In
short-term studies serious effects occurred at levels as low as 1.9 mg/kg-day
and less serious effects (induction of anti-nuclear antibodies) at 0.57 mg/kg-day
in a ten week study in mice (ATSDR, 1993a). No longer term studies were
located for this work. An alternative exposure could be calculated for
immunological effects based upon the above study. The standard uncertainty
factors used in this calculation would typically take into consideration inter- and
intraspecies variability, use of a less than lifetime study, and the use of a
LOAEL rather than a NOAEL. Immunological effects require further
investigation to determine whether this is an effect which occurs in humans.
It appears to be a sensitive endpoint for chronic exposure toxicity.
Developmental Toxicity
Developmental toxicity has been associated with cadmium exposure both in
short and long term studies. In ten day prenatal dosing studies in rats at 18.4
5-126
-------
5. CADMIUM
mg/kg, malformations including split palate and dysplasia of the facial bones
were observed with a NOAEL of 6.1 mg/kg-day. A similar study in rats found
delayed ossification at 2 mg/kg-day. Other studies have found gross
abnormalities and reduced weight in the range of 2 to 20 mg/kg-day (ATSDR,
1993a). Oral cadmium exposure of young mice depresses their humoral
immune responses; the study did not find the same effect in adult mice
(ATSDR, 1993a).
More sensitive measures of effects for cadmium have identified effects at much
lower doses. ATSDR has determined that:
"the most sensitive indicator of development toxicity of cadmium
in animals appears to be neurobehavioral development, which was
impaired in offspring of female rats orally exposed to cadmium at
a dose of 0.04 mg/kg-day prior to and during gestation..."
(ATSDR, 1993a).
Reduced locomotor activity and impaired balance were noted at a LOEL of 0.04
mg/kg-day with 11 weeks of exposure occurring prior to and during gestation.
The effects were also observed at 0.7 mg/kg-day with exposure occurring only
during gestation. Neurobehavioral effects were observed in other
developmental studies and in chronic studies of effects in adult animals. Two
studies yielding similar results were conducted with maternal exposures of 4.3
to 17.2//g/ml of water (See numerous citations in Baranski,et al., 1983).
Studies of developmental toxicity in human populations have been conducted
on women exposed via inhalation in the workplace. Decreased birth weight has
been reported in two studies, one with statistically significant results and the
other lacking statistical significance. Inhalation studies in animals have found
structural and neurobehavioral abnormalities similar to those found in the oral
dosing studies (ATSDR, 1993a).
Based on the mutagenicity data results (discussed below), heritable defects
may result from exposure to cadmium. However, mutagenicity assays do not
provide dose-response data suitable for use for the calculation of a risk value.
Calcium deficiency has been shown to increase the fetotoxicity of cadmium,
and lindane exposure increased developmental toxicity in animal studies
(ATSDR, 1993a).
Based on the reviewed information, neurobehavioral effects appear to be a
critical endpoint for developmental effects as indicated by the LOEL of 0.04
mg/kg-day. The standard uncertainty factors used in the calculation of an
exposure limit would typically take into consideration inter- and intraspecies
variability, and the use of a LOEL rather than a NOAEL.
5-127
-------
5. CADMIUM
Estimating an exposure limit for cadmium based on developmental toxicity is
problematic because the average daily dose is approximately 0.03 mg/day
(ATSDR, 1993a) which is equivalent to 4 x 10"4 per mg/kg-day in a 70 kg
individual. The exposure for developmental effects which would be calculated
using the neurobehavioral LOEL noted above (approximately 4 x 10"5 mg/kg-
day) is one tenth of the average background consumption rate. Due to the
margin of safety introduced by these factors, the estimated exposure limit
should be viewed in the context of the overall exposure of population groups
from all sources, as well as the benefits of fish consumption. Balancing risks
and benefits is discussed in Volume 3 in this series, Risk Management.
Mutagenicity
Results of bacteria, yeast, and human lymphyocyte assays have been mixed.
Positive results were observed in chromosomal aberration studies on human
lymphocytes treated both in vitro and obtained from exposed workers. Mouse
and hamster germ cell studies indicate that cadmium may interfere with spindle
formation resulting in aneuploidy. Positive results have also been obtained in
Chinese hamster ovary and mouse lymphoma cell assays (IRIS, 1993).
Carcinogenicity.
No animal or human oral exposure studies suggest that cadmium is
carcinogenic via the oral exposure route. Animal studies conducted at relatively
low exposure levels (up to 4.4 mg/kg-day) have yielded negative results.
Studies have been conducted on population groups in high cadmium exposure
areas and organ-specific cancer rates have been examined (kidney, prostate,
and urinary tract). Most studies yielded negative results. A study in Canada
found that elevated rates of prostate cancer paralleled the elevated cadmium
exposure of the populations studied. ATSDR concluded that there was little
evidence of an association between cadmium exposure and increased cancer
risk in humans but that the statistical power of the studies to detect an effect
was not high. They determined that neither the human or animal studies
provided sufficient evidence to determine the carcinogenic status of cadmium
(ATSDR, 1993a).
Cadmium is classified as a probable human carcinogen (B1) by EPA based on
inhalation studies in humans. The airborne cancer potency is 1.8 x 10"3 per
//g/cubic meter (IRIS, 1993).
Special Susceptibilities
Populations with genetically-determined lower ability to induce metallothionein
are less able to sequester cadmium. Populations with depleted stores of dietary
5-128
-------
5. CADMIUM
components such as calcium and iron due to multiple pregnancies and/or
dietary deficiencies may have increased cadmium absorption from the Gl tract.
As stated above, increased calcium excretion associated with cadmium-induced
renal damage may lead to increased risk of osteoporosis, especially in post-
menopausal women. The relationship between cadmium toxicity and iron levels
is not well established; however, in some studies it appears that iron deficient
individuals may be at greater risk. Individuals with kidney disease, diabetes, and
age-related decreased kidney function may be at greater risk of cadmium-
induced kidney toxicity (ATSDR, 1993a).
Immunological effects may be of concern for children because it appears, based
upon animal studies, that young individuals may be at greater risk than adults.
In addition, the immune system is not fully developed in humans until
approximately 12 years of age. Immunological effects have also been observed
in multiple animal studies of adults. These pose special risks for individuals
with compromised immune systems (e.g., those with AIDS).
A variety of types of developmental effects have been associated with
cadmium exposure (See discussion above). These all pose special risks for
infants and children, as well as women having or planning to have children.
Interactive Effects
Dietary deficiencies of calcium, protein, zinc, copper, iron, and vitamin D may
cause increased susceptibility to adverse skeletal effects. Animal studies have
found an association between lindane and increase developmental toxicity and
between calcium deficiency and increased fetotoxicity. Ethanol increased liver
toxicity and garlic decreased kidney toxicity. Lead increased neurotoxicity and
selenium decreased the clastogenic effect of cadmium on bone marrow.
Exposure to chemicals that induce metallothionein (e.g., metals) reduced
toxicity with parenteral cadmium exposure (ATSDR, 1993a).
MIXTOX reports a number of interactive studies on cadmium and selenium
compounds. The studies have yielded mixed results with reports of inhibition,
potentiation, additive effects and no effects (MIXTOX, 1992).
Critical Data Gaps
A joint team of scientists from ATSDR, NTP, and EPA have identified the
following data gaps: immunotoxicity, neurotoxicity, and developmental toxicity
in human populations, quantitative data on acute and intermediate toxicity in
humans, and chronic exposure studies in humans using sensitive indicators of
kidney toxicity, animal and human studies of carcinogenic effects, human
5-129
-------
5. CADMIUM
genotoxicity, animal reproductive, immunotoxicity, and pharmacokinetic studies
{ATSDR, 1993a).
Summary of EPA Risk Values
Chronic Toxicity 1 x 10"3 mg/kg-day
Carcinogenicity Probable inhalation carcinogen (B1). Insufficient data
to determine carcinogenic status via oral exposure
route.
Major Sources: IRIS (1993), ATSDR (1993a), HSDB (1993), U.S. FDA (1993)
5-130
-------
5. METHYLMERCURY
5.6.22. Methylmercury12
Background
Mercury is widely distributed in the environment due to both natural and
industrial processes. Mercury is transformed through biological processes; in
fish it is found primarily in the form of methy|rnercury (EPA, 1993a). The data
regarding methylmercury toxicity are undergoing review within EPA. An IRIS
RfD is discussed below and was used to develop the consumption limits for the
general population. In addition, an interim dose-response value developed by
the Office of Water was used in this document to calculate the fish
consumption limits for women of reproductive age and for children (See
discussion under developmental toxicity below). Methylmercury has also been
the subject of evaluation by numerous states. Detailed analyses have been
conducted in some areas, which included evaluations of data regarding blood
and hair mercury levels, toxic effects, and biological half-life to estimate safe
consumption levels of contaminated fish (Shubat, 1991 and 1993a; Stern,
1993).
As discussed in previous sections, a total exposure assessment is beyond the
scope of this document. Readers may wish to consult other sources to obtain
information regarding background levels of methylmercury in the environment.
Additional information on dietary sources of mercury may be found in the FDA
Adult Total Diet Study, conducted from October 1977 through September
1978, which contains information on total mercury content (not restricted to
methymercury) in a number of foods (Podrebarac, 1984). Average airborne
exposure has been estimated for total mercury (elemental and methylmercury)
at 0.14 ug/day based upon an average ambient concentration of 7 ng/cubic
meter (Bennett, 1986); however, recent studies indicate that the levels may be
increasing (Slemr and Langer, 1992).
1 o
Methylmercury is an organic form of mercury which has similar
toxicological properties to other organic mercury forms. There are significant
differences in the toxicity of metallic, inorganic and organic mercury (ATSDR,
1992a). Based on a review of the toxicity of various forms of mercury, it is
assumed in this document that data on inorganic mercury and mercury in its
pure metallic form are less relevant to fish contamination than organic mercury,
and they are not used in evaluating health effects.
5-131
-------
5. METHYLMERCURY
Pharmacokinetics
Organic mercury compounds are rapidly and nearly completely absorbed (95
percent) following oral exposure (ATSDR, 1992a).13 The World Health
Organization (WHO) has similarly estimated an absorption of 90 to 100 percent
for methylmercury (WHO, 1990). Methylmercury is lipophilic, allowing it to
pass through lipid membranes of cells and facilitating its distribution to all
tissues, following absorption from the Gl tract. Methylmercury also binds
readily to proteins.14 The highest methylmercury levels in humans are
generally found in the kidney. Methylmercury and other organic mercury
compounds are transformed via the oxidation reduction cycle into an inorganic
form in most tissues, most significantly in the liver, kidney and brain. The
location of methylmercury in the brain shifts following exposure; this is
probably related to biotransformation (ATSDR, 1992a). Methylmercury causes
disruption of several enzyme systems, primarily sulfhydryl enzymes (HSDB,
1993). It also destroys microtubules which are critical to various physiological
and developmental functions (additional information is provided under
developmental toxicity below) (Clarkson, et al., 1987).
Methylmercury has been reported to occur in breast milk in women exposed to
methylmercury in fish and bread in Iraq. The concentration measured in breast
milk was approximately 5 percent of the methylmercury level in the blood of
the mother (WHO, 1976). In experimental animals, females eliminated
mercury more slowly than males, and young animals more slowly than adults.
Neonatal excretion is slowed by the immaturity of the transport system.
Methylmercury readily transverses the placental barrier. Often higher
concentrations are found in fetal organs than in maternal organs.
Methylmercury is secreted during lactation and is eliminated primarily via the
biliary system. The estimated half-life of organic mercury is 70 to 79 days.
(ATSDR, 1992a).
13 The ATSDR document cited in this work (ATSDR, 1992a) refers to
methylmercury under the broader heading of organic mercury. Consequently,
when cited information is taken from the ATSDR document, mercury is referred
to as "organic" mercury.
14 Methylmercury is found throughout fish tissue and a substantial portion
of the mercury in fish can be found in a trimmed fillet. Because of this,
methylmercury exposure is not significantly reduced by trimming fat and skin
from fish.
5-132
-------
5. METHYLMERCURY
Acute Toxicity
Acute high-level exposures to methylmercury may result in kidney damage and
failure, gastrointestinal damage, cardiovascular collapse, shock, and death. The
estimated lethal dose is 10 to 60 mg/kg (ATSDR, 1992a). An acute exposure
MRL calculated by ATSDR using a prenatal exposure study is discussed below
under developmental effects.
Chronic Toxicity
There have been numerous studies of human poisonings in various populations
around the globe exposed via contaminated grain and fish. Significant
population exposures to methylmercury have occurred in Minimata and Niigata,
Japan in the 1950s and in Iraq in 1971-1972. More recently, exposures in
New Zealand have been studied (WHO, 1976 and 1990; Stern, 1993).
Summaries of human and animal data are available (WHO, 1976 and 1990;
ATSDR, 1992a; Stern, 1993). The human exposure studies are often
complex, due in part to the difficulty in quantifying exposure and evaluating
neurological effects. In human poisoning incidents, exposure has resulted in
serious neurological effects in both adults and children (children are discussed
under developmental toxicity below). Readers is urged to review the data for
a comprehensive understanding of the toxicity of methylmercury.
The central nervous system (CNS) is a major target organ for methylmercury-
induced toxicity. Adverse effects in humans and experimental animals include
a wide variety of central and peripheral nervous system disorders including
neuronal degeneration, structural changes in the brain, motor incoordination,
blindness, tremor, weakness, and decreased performance on behavioral tests
(ATSDR, 1992a). Tilson and Sparber (1987) also provide detailed descriptions
and discussions, contributed by numerous specialists in neurobiology and
clinical neurology, of human, animal, and in vitro studies of developmental and
adult neurotoxicity due to methymercury exposure.
In addition to CNS effects, numerous other systems are affected by organic
mercury exposure. A study in rats found a persistent increase in systolic blood
pressure following three to four weeks of exposure at 0.4 mg/kg-day. At
higher exposure levels animal studies indicate that organic mercury may act on
the endocrine system. Results include altered hormone levels (decreased
testosterone and corticosterone levels), resulting in stress intolerance and
decreased sexual activity (ATSDR, 1992a). Reproductive system functional
abnormalities have been associated with methylmercury exposure. A
subchronic (20 week) study in monkeys studies found decreased sperm motility
and structural defects in the sperm with methylmercury exposure at 0.025
mg/kg/day. Numerous other animal studies have observed decreased fertility
5-133
-------
5. METHYLMERCURY
with organic mercury exposure. Organic mercury exposure caused increased
early abortions and stillbirths in pregnant monkeys and guinea pigs and
decreased litter size in many rodent studies (ATSDR, 1992a).
The kidneys are also a major target organ for methylmercury toxicity. Kidney
damage has been associated with methylmercury exposure in humans;
however, exposures were not well quantified. Multiple animal studies have also
noted kidney damage yielding sufficient information to estimate a kidney
toxicity-based exposure limit. However, kidney toxicity does not appear to be
as sensitive an endpoint as neurotoxicity based on currently available data.
Although the kidney studies are of short duration, one study was identified
which was of adequate duration {12 weeks) and used a sensitive endpoint
(ultrastructural changes in the kidney proximal tubules). This rat feeding study
identified a NOAEL of 0.08 mg/kg-day (ATSDR, 1992a). If the NOAEL from
this study were used to calculate an alternative estimated exposure limit,
standard uncertainty factors would typically take into consideration inter- and
intraspecies variability, and the use of a less-than-lifetime study.
IRIS provides an RfD of 3 x 10'4 mg/kg-day based upon a LOAEL of 0.003
mg/kg-day in environmentally-exposed humans reporting paresthesias. An
uncertainty factor of 10 was applied to adjust for the use of a LOAEL.
However, it was determined that no additional uncertainty factor was required
for intraspecies variability because a sensitive human population was used.
The LOAEL is based upon a review of several studies and utilizes an evaluation
of the levels of'methylmercury in the blood in relation to toxicity. The LOAEL
of 0.003 mg/kg-day is assumed to be equivalent to a mercury level of 200 ng
mercury/ml of blood (IRIS, 1993). The IRIS RfD was used to calculate the
consumption limits for the general adult population provided in Section 3.
ATSDR declined to estimate a chronic exposure MRL because in the study data
they reviewed "serious neurological effects were observed at the lowest doses
tested" (ATSDR, 1992a). This statement is based on their review of monkey
and cat studies with doses of 0.05 and 0.074 mg/kg-day respectively. These
studies found degeneration of the dorsal root ganglia, decreased fine motor
performance, diminished pain sensitivity, reflex impairment, and spatial visual
impairment associated with chronic exposure at the LOELs (ATSDR, 1992a).
These studies include evaluations of behavioral and complex sensory data,
which appear to be more sensitive endpoints for toxicity evaluation than those
serving as the basis for the IRIS value (ataxia and paresthesias), although they
are still considered too severe by ATSDR to form the basis for an MRL (ATSDR,
1992a). If the LOEL of 0.05 mg/kg-day from the monkey study were used to
calculate an alternative exposure limit, standard uncertainty factors would
typically take into consideration inter- and intraspecies variability and the use
5-134
-------
5. METHYL/WERCl/RY
of a LOEL. In addition, a modifying factor to account for the severity of effects
at the LOEL could be employed.
Developmental Toxicity
As discussed under chronic toxicity above, there have been numerous studies
of human poisonings in various populations around the globe via contaminated
grain and fish. Summaries of the human and animal data are available (WHO,
1976 and 1990; ATSDR, 1992a; Choi, 1989 (primarily a developmental
toxicity review); Burbacher et al, 1990 (primarily a developmental toxicity
review); Clarkson and Fitzgerald, 1991; Clarkson, 1990; Stern, 1993); readers
are urged to review the data for a comprehensive understanding of the toxicity
of methylmercury.
Prenatal and childhood exposure to methylmercury has caused severe nervous
system damage including retardation and a variety of nervous system disorders.
Central nervous system effects include mental retardation, inability to move,
paresthesias, seizures, blindness, neuromuscular weakness, and inability to
speak. Less severe effects including delayed development, subtle neurologic
abnormalities, irritability, and incoordination have also been reported. An
underlying mechanism for CNS disturbances has been hypothesized, based
upon anatomical evaluations of infants, to be the development of "abnormal
cytoarchitecture of the brain (e.g., incomplete or abnormal migration of neurons
to cerebellar and cerebral cortices and deranged cortical organization of
cerebrum)" (ATSDR, 1992a). A detailed description of the nature of the
structural and functional developmental changes seen in human populations is
provided in Tilson and Sparber (1987). Although some aspects of adult
methylmercury poisoning are reversible, most developmental effects of
exposure appear not to be reversible because they arise from permanent
structural changes in the brain.
Animal study results support the observations made in human studies.
Although they are limited in that interspecies extrapolation is required to use
animal studies as the basis for exposures limits for humans, they have the
advantage of having more precisely quantified exposures. In addition, some
animal studies have been carried out on sensitive neurological endpoints.
Animal studies may be consulted to support the human studies or to estimate
an independent exposure limit. A variety of CNS effects have been observed
in experimental animals, analogous to effects observed in children. In addition
to CNS effects, animal studies have found immunotoxicity, liver toxicity,
abnormal immune system function, incomplete ossification and calcification of
bones, and kidney damage associated with prenatal and lactational exposure
(ATSDR, 1992a).
5-135
-------
5. METHYLMERCURY
It has been hypothesized that the reason the developing nervous system is
particularly susceptible to methylmercury poisoning-is that microtubules are
destroyed by this form of mercury. This action causes inhibition of cell division
and cell migration, which are processes occurring primarily during development
and which are necessary to normal development (Clarkson, et al., 1987). This
is supported by autopsy data on prenatally-exposed children from Japan and
Iraq, who had significant disruption in cerebellar and cerebral cytoarchitecture
and a lack of regional specificity. This was in marked contrast to observations
of adults who had been exposed to methylmercury; considerable anatomic
selectivity in damage was seen with adult exposure (Chang, 1987). Reuhl has
suggested "that animals with longer gestational periods and more extended
"bursts" of neuronal development would be more likely than rodents to display
migratory disturbances, since neuronal commitment and migration in these
species occur over a longer period of time. He goes on to suggest that cats,
dogs, and non-human primates would be preferable to rodents as study
subjects for evaluating the developmental toxicity of methylmercury (Reuhl,
1987).
A critical question in evaluating the developmental toxicity of methylmercury
or other developmental toxics is the effect of the timing of exposure on
toxicity. It is difficult to determine the precise timing and duration of exposure
which is most damaging to developing individuals. Animal studies have shown
that exposure during early gestation results in embryo death with effects
resembling the embryocidal effects of ionizing radiation. Postnatal behavioral
effects (which also resemble the effects of ionizing radiation) are most
pronounced when fetuses are exposed late in gestation (Norton, 1987).
Readers may wish to consult Norton (1987) to obtain more specific
information.
EPA is currently conducting an extensive review of methylmercury toxicity. It
is anticipated that the IRIS value may change in the future. In the interim, the
Office of Water has recommended a dose-response value of 6 x 10"5 mg/kg-
day, which is listed in Volume 1 in this series (EPA, 1993a). The value is
based upon an evaluation of the human and animal toxicity data, and is derived
primarily from the human studies on exposed populations in Iraq. In Volume 1,
a discussion of the rationale for utilizing the lower value is presented. It is
based upon a concern that the fetus and possibly pregnant women are at
increased risk of adverse neurological effects from exposure to methylmercury.
Study findings suggest that fetal sensitivity may be five-fold greater than adult
sensitivity. Consequently, an additional uncertainty factor of 5 was applied to
5-136
-------
5. METHYL/MERCURY
the current IRIS RfD for methylmercury.15 This approach is an interim
measure until the reevaluation of the methylmercury RfD is complete (EPA,
1993a). The Office of Water value of 6 x 10~5 mg/kg-day was used in the
calculation of fish consumption limits listed in Section 3 for women of
reproductive age and children.
ATSDR provides an acute developmental MRL of 4 x 10"5 mg/kg-day based
upon a NOAEL of 0.004 mg/kg-day in rats from an acute exposure study (the
LOAEL was 0.008 mg/kg-day). A significant reduction in operant behavioral
performance was observed in four month old offspring (ATSDR, 1992a).
Longer term animal studies have not identified NOAELs as low as that found in
the acute study noted above. In a longer-term study of monkeys exposed pre-
and postnatally to methylmercury, a LOAEL of 0.01 mg/kg-day was identified
with impaired spatial visual function at and above the LOAEL. Dosing in this
study continued through four years of age (ATSDR, 1992a). This study yielded
the lowest LOAEL of the animal studies reviewed for this work and has a
relatively sensitive health endpoint. In addition, the study was carried out on
a species which is more similar to humans than the rodents used in most other
toxicity studies of methylmercury (See Reuhl's recommendation above (1987)).
Methylmercury accumulates in body tissue; consequently, exposure occurring
prior to pregnancy can contribute to the overall maternal body burden and result
in exposure to the developing individual. As a result of this, it is necessary to
reduce exposure to girls and women with childbearing potential, to reduce
overall body burden. If exposure is reduced during pregnancy, but has occurred
prior to pregnancy, the pregnancy outcome may be affected, depending on the
timing and extent of prior exposure.
Mutagenicity
Mutagenicity assays of methylmercury have yielded mixed results. Studies in
animals suggest species and often strain specificity in response. Data suggest
that mercury compounds may be clastogenic for mammalian germ cell lines but
less damaging to somatic cells. ATSDR concluded on the basis of in vitro and
animal studies that organic mercury compounds have some genotoxic potential
(ATSDR, 1992a).
The human data support consideration of the fetus as being more
sensitive than adults. Both structural data (Clarkson, 1987 and Chang, 1987
referred to above) and functional studies of mother-child pairs indicate a
greater fetal sensitivity (Clarkson, etal, 1987; Clarkson, et al, 1989; Clarkson,
1990; Clarkson and Fitzgerald, 1990; WHO, 1990).
5-137
-------
5. METHYLMERCURY
In a group of 23 humans exposed to methylmercury in fish, a correlation was
found between blood mercury levels and structural and numerical chromosome
aberrations in lymphocytes. Another study found a correlation between
consumption of contaminated seal meat and an increased incidence of sister
chromatid exchange. There were multiple confounders in these studies and
exposure was not quantified (ATSDR, 1992a).
There are not sufficient dose-response data on the mutagenicity of mercury to
calculate an exposure limit based upon mutagenicity. However, available
scientific data suggest that mercury miay be mutagenic. This should be
considered in determining appropriate consumption advisories for mercury
contaminated fish.
Carcinogenicity
Insufficient information is available to determine the carcinogenic status of oral
exposure to methylmercury.
Special Susceptibilities
Developing individuals are at significant risk from methylmercury exposure due
primarily to toxic effects on the developing nervous system. This is addressed
under developmental effects above. Additional risk may also result from the
apparently decreased ability of young individuals to eliminate mercury (See
pharmacokinetics above).
In addition, ATSDR has listed the following groups as particularly susceptible:
the elderly, people with impaired organ function (especially kidney, CNS, and
liver), the ill or malnourished (due to the absence of protective essential
minerals), and those who are exposed to other synergistic toxicants (ATSDR,
1992a).
Interactive Effects
Potassium dichromate and ethanol may increase the toxicity of mercury,
although these effects have been noted with metallic and inorganic mercury.
Atrazine increases the toxicity of methylmercury in experimental animals.
Vitamin D and E, thiol compounds, selenium, copper, and possibly zinc are
antagonistic to the toxic effects of mercury (ATSDR, 1992a). There is
insufficient information to recommend quantitative changes in risk estimations
based upon interactive effects.
5-138
-------
5. METHYLMERCURY
Critical Data Gaps
Additional data are needed regarding the exposure level at which humans
experience adverse neurological effects. Human and primate studies suggest
that neurotoxicity is a sensitive measure of methylmercury toxicity;
consequently, a well-founded NOAEL for this type of toxicity should be
obtained. Kidney toxicity is also a sensitive measure of toxicity; however, no
chronic exposure studies were available for this effect. A lifetime study using
sensitive endpoints and including various organ toxicities not fully explored in
other studies (e.g., reproductive system toxicity, blood pressure changes,
hormonal effects) is needed to more accurately estimate an exposure limit.
Although there are numerous developmental toxicity studies available, the dose-
response results are not consistent due, in part, to the variety of endpoints
which have been evaluated. Additional studies are needed to identify a NOAEL
based upon sensitive developmental toxicity endpoints.
Summary of EPA Risk Values
Developmental Toxicity 6 x 10~5 mg/kg-day for women of reproductive
age and children (EPA, Office of Water)
Chronic Toxicity 3 x 10~4 mg/kg-day for adults excluding
women of reproductive age (IRIS, 1993)
Carcinogenicity Insufficient data to determine carcinogenic
status
Major Sources: ATSDR (1992a), IRIS (1993), EPA (1993a), Stern (1993),
Shubat (1993a)
5-139
-------
5. SELENIUM
5.6.23. Selenium
Background
Selenium occurs naturally in many areas and is produced through industrial
processes. It is an essential nutrient with a Recommended Dietary Allowance
(RDA) of 55 //g/day (0.055 mg) for non-lactating women and 20 additional
//g/day during lactation. ATSDR has identified daily intake at non-toxic levels
of approximately 0.05 to 0.15 mg/day (ATSDR, 1989 and HSDB,1993). This
is approximately equivalent to 7 x 10~4 to 2 x 10'3 mg/kg-day in a 70 kg
individual. The RDA for adult males is 70 //g/day (NRC, 1989). Selenium plays
a critical role in the antioxidant enzyme glutationine peroxidase. Selenium
deficiency has been associated with muscle degeneration in humans. A serious
form of this, congestive cardiomyopathy (Keshan disease) has been studied in
areas of China with low naturally occurring levels of selenium. It has also been
shown to have a protective effect against chemically induced cancers in
laboratory animals (Robbins et al, 1989). Although selenium is an essential
nutrient, it is toxic at high exposure levels and is mutagenic in some test
systems (ATSDR, 1989).
Definitive information regarding the chemical forms of selenium which are
found in fish is not available (EPA, 1993a). Due to the lack of information on
chemical forms, the toxicity of a variety of selenium forms are included in the
discussion below. In some parts of the United States, particularly in western
states, soil concentrations lead to selenium levels in plants that can cause
human exposure at potentially toxic levels (ATSDR, 1989). This exposure
should be considered in evaluating the overall exposure to selenium and in
development of fish consumption advisories.
Pharmacokinetics
Selenium contained in food is generally associated with proteins as organic
selenium compounds. It is easily absorbed by the body and accumulates
primarily in the liver and kidneys. It accumulates to a lesser extent in the
blood, lungs, heart, testes and hair (ATSDR, 1989) Detailed information on
metabolism of selenium can be found in the Toxicological Profile for Selenium.
This document also contains an extensive discussion of the selenium
concentrations in human tissues and fluids correlated with specific health
effects (ATSDR, 1989).
Acute Toxicity
Signs of acute selenium poisoning include difficulty in walking, labored
breathing, cyanosis of the mucous membranes, congestion of the liver,
5-140
-------
5. SELENIUM
endocarditis and myocarditis, degeneration of the smooth musculature of the
Gl tract, gallbladder and bladder, and erosion of the long bones (IRIS, 1993).
Subacute selenosis (prolonged exposure at relatively high doses) causes
impaired vision, ataxia, disorientation and respiratory distress (IRIS, 1993).
Tachycardia has been reported in humans exposed to high doses; myocardial
disorders have also been associated with selenium deficiencies. Acute
exposure dog studies at high doses have found multiple alterations in blood
chemistry (ATSDR, 1989).
Chronic Toxicity
IRIS provides an RfD of 0.005 mg/kg-day for selenium and selenium
compounds based upon a NOAEL of 0.015 mg/kg-day from a 1989 human
epidemiological study which found clinical selenosis at the LOAEL of 0.023
mg/kg-day. The NOAEL was calculated from regression analysis of blood
selenium levels and selenium intake. An uncertainty factor of 3 rather than 10
was used for intraspecies variability (IRIS, 1993). Note that the NOAEL and
LOAEL for selenium in the 1989 human study are only slightly higher than the
average daily intake and the RDA (See above).
High levels of selenium exposure has caused the following effects: lowered
hemoglobin levels, mottled teeth, skin lesions, CNS abnormalities, fatigue,
anorexia, enlarged spleen, thickened and brittle nails, hair and nail loss,
decreased blood clotting ability, liver dysfunction, and muscle twitching (IRIS,
1993). Humans exposed to high dietary levels have reported Gl disturbances
(dose unspecified). Cows with high naturally occurring dietary exposures were
found to have ulcers in the upper Gl tract (ATSDR, 1989).
Lifetime exposure of mice to sodium selenate or sodium selenite at 0.31 mg/kg-
day caused amyloidosis of the lung, liver, kidney, and heart. Mice appear to be
more sensitive to selenium with regard to lung toxicity than rats. Rats may be
more sensitive to the cardiotoxic effects, with an LEL of 0.1 mg/kg-day in a
chronic study (the study had some deficits in study design) (ATSDR, 1989).
Hematological effects have been observed in multiple acute and chronic animal
studies. No human studies were located for this report or by ATSDR in their
literature review. Rats subchronically exposed to wheat containing selenium
at a dose of 0.68 mg/kg-day for six weeks had a reduction of blood
hemoglobin. At 0.75 mg/kg-day in a similar study red cell hemolysis was
observed (ATSDR, 1989).
Bone softening in livestock has been noted with an LEL of 0.2 mg/kg-day with
exposure over several months (less than 100 days). Adverse effects on the
liver have been observed in multiple animal studies with LELs of 0.8 mg/kg-day
5-141
-------
5. SELENIUM
and above. Kidney damage has also been noted with an LEL of 0.31 mg/kg-
day. Dermal effects have been observed at doses as low as 0.053 mg/kg-day
in humans with dietary exposure (ATSDR, 1989). This observation served as
a partial basis for the calculation of an MRL by ATSDR (See below).
Depression of the immune system was observed in rats exposed subchronically
to sodium selenite at 0.75 mg/kg-day. At lower doses (0.075 mg/kg-day and
0.28 mg/kg-day) mixed results were obtained, with a stimulation of some
components of the immune system and depression of others. No NOEL was
identified in the study (ATSDR, 1989).
Chronic exposure studies in animals have identified multiple adverse effects on
the reproductive ability of animals and on offspring viability. Effects include:
reduced rates of conception at 0.41 mg in pigs exposed from eight weeks of
age (other offspring effects are listed under developmental effects), abnormal
length estrus cycles in rats exposed subchronically to 0.34 mg/kg-day,
increased fetal resorption and decreased conception rate in livestock exposed
at a LEL of approximately 0.5 mg/kg-day, failure to breed in a three-generation
study of mice exposed at 0.42 mg/kg-day, no effects in a two-generation study
of mice at 0.21 mg/kg-day, and a 50 percent reduction in the number of young
successfully reared with maternal exposure to 0.35 mg/kg-day for one year.
Male fertility did not appear to be affected in the results reported, although the
testes are a storage site for selenium (ATSDR, 1989).
Neurological symptoms have been reported in human and animal studies. A
family exposed to approximately 0.26 mg/kg-day via drinking water reported
various symptoms of selenosis including listlessness and a lack of mental
alertness. Effects ceased when the water use was discontinued. More severe
effects have been observed in high-selenium areas of China. Peripheral
anesthesia and pain in the limbs were reported, although no associated
estimate of exposure was provided. Exaggerated tendon reflexes, convulsions,
paralysis and hemiplegia were estimated to occur at a minimum chronic
exposure of 0.053 and an average of 0.083 mg/kg-day. A NOAEL of 0.025
was estimated. This information was used by ATSDR to calculate a chronic
exposure MRL of 0.003 mg/kg-day (ATSDR, 1989).
Neurological effects identified in animal studies include: drowsiness, lethargy,
ataxia, paralysis, bilateral lesions in the spinal cord, impaired vision, aimless
wandering behavior, and neuronal degeneration of the cerebral and cerebellar
cortices. Many of these were observed at relatively high doses; however, the
neuronal degeneration was observed at a LEL of 0.6 mg/kg-day dosing with
sodium selenite mixed in food (ATSDR, 1989).
The IRIS RfD and ATSDR MRL are within one order of magnitude of each other.
The IRIS value was used to calculate fish consumption limits shown in Section
5-142
-------
5. SELENIUM
3 for chronic exposure toxicity. Please see the note at the end of the
developmental toxicity section for cautions regarding this use of these values.
Developmental Toxicity
Limited information is available on the developmental toxicity of selenium in
humans. One anecdotal report indicated that selenium exposure may be
associated with spontaneous abortion and skeletal abnormalities (ATSDR,
1989); however, the anecdotal nature of the report makes it inappropriate for
drawing conclusions regarding causality.
In animals selenium has caused growth retardation, decreased fertility,
embryotoxicity, fetotoxicity, and teratogenic effects. One researcher noted
that in a high selenium area teratogenic effects were not seen in humans, but
they were observed in chickens (IRIS, 1993).
A multigeneration study in mice dosed with selenate at 0.39 mg/kg-day
identified a significant increase in young deaths in the F1 generation, and
increased runts in the F1 through F3 generations. Because only one dose was
used, only a LOEL can be obtained from this study. A one-generation mouse
study found a NOEL of 0.39 mg/kg-day. An early five-generation study
identified a NOEL of 0.075 mg/kg-day and a LOEL of 0.125 mg/kg-day with a
5O percent reduction in the number of young reared at that dose. There are
multiple possible reasons for the reduction, including decreased fertility;
consequently it is not appropriate for use in calculating an exposure limit for
developmental effects. A recent study in primates identified no developmental
effects up to 0.3 mg/kg-day. However, the study utilized dosing over a portion
of the pregnancy, and unlike the multigenerational studies, it did not include
dosing prior to and during all of the pregnancy or dosing of the neonates (IRIS,
1993).
Multiple studies have determined that exposure of livestock (e.g., sheep, pigs,
cattle) to naturally seleniferous diets resulted in fetal malformations and
interference with normal fetal development. Malformations were'associated
with other manifestations of toxicity. The specific selenium compounds
associated with these effects have not been identified (ATSDR, 1989). At
0.41 mg pigs exposed from eight weeks of age had offspring with significantly
reduced birth weight and weaning weights (ATSDR, 1989).
ATSDR has reported studies on experimental animals that have yielded the
following results: prenatal exposure at 0.34 mg/kg-day caused reduced fetal
growth with a NOAEL of 0.17 mg/kg-day; mice exposed to 0.42 mg/kg-day for
three generations had an increased incidence in fetal deaths and a high
proportion of runts among survivors; macaques exposed prenatally at levels up
5-143
-------
5. SELENIUM
to 0.3 mg/kg-day exhibited no adverse effects. It was noted that exposure to
inorganic selenium compounds at levels that are not maternally toxic have not
produced teratogenic effects (ATSDR, 1989).16
Based on the reviewed information, the rnultigeneration mouse study cited in
IRIS with a LOEL of 0.39 mg/kg-day appears to be the most appropriate value
for calculating an estimated exposure limit for developmental effects because
there are no other appropriate studies which provide data on long term maternal
and offspring exposure effects. There is concern regarding the use of these
results because severe effects were seen at the LOEL and because severe
effects have been observed in other studies at approximately the same
exposure level. The standard uncertainty factors used to calculate an estimated
exposure limit would typically take into consideration inter- and intraspecies
variability and the use of a LOEL rather than a NOEL. A modifying factors for
the severity of effects at the LOEL could also be applied. The resulting value
is within one order of magnitude of an exposure limit which could be calculated
from the NOEL of 0.17 mg/kg-day for reduced fetal growth (as reported by
ATSDR). Due to the Jonger term nature of the dosing, the rnultigeneration
study cited in IRIS may be more appropriate.
NOTE: Decisions regarding thresholds for adverse effects of selenium are
complex because selenium is an essential nutrient. Consequently, the
application of uncertainty factors in the standard manner may not be
appropriate. Some exposure to selenium is necessary, as indicated by the RDA.
There appears to be a relatively small margin between the effective/necessary
dose and the toxic dose for this chemical. Additionally, the need for selenium
and the toxicity of selenium is expected to vary among individuals.
Consequently, it is necessary to evaluate the overall exposure to selenium in
order to evaluate potential risks and make well-informed decisions regarding
exposure limits. Decisions regarding the contribution to total selenium
exposure which can come from fish without generating toxicity will depend on
the cumulative exposures from other sources. This is expected to vary
considerably depending on the part of the country in which a person resides,
their dietary habits, and other factors.17 Readers should carefully review the
16 EPA's guidelines on developmental toxicity specify that dosing should
include doses which cause some level of maternal toxicity; therefore, this is not
cause for dismissing the study results.
17 If these factors were not a consideration for selenium exposure, an
additional modifying factor would be recommended when estimating exposure
limits for developmental effects due to the serious nature of effects observed
in multiple species at or near the LEL of .39.
5-144
-------
5. SELENIUM
toxicity data regarding selenium and determine the appropriate exposure limit
for developmental effects, based upon the exposures anticipated in their states
and their interpretation of the toxicological and epidemiological literature. See
also Abernathy, et al (1993) for additional guidance on this topic.
It will be necessary to obtain a NOEL from a multigeneration study and to
further explore the mechanisms of fetal and neonatal lethality associated with
selenium exposure to adequately determine the appropriate exposure limit for
developmental effects. A well designed human epidemiological study of
prenatally exposed individuals from high naturally occurring selenium areas is
needed to provide insight into human effects of selenium exposure.
Mutagenicity
There are many positive mutagenicity assays on selenium compounds including
unscheduled DNA synthesis, increased chromosomal aberrations in human
lymphocytes and in the bone marrow of rats, and an increase in sister
chromatid exchanges in human whole-blood cultures. There are also assays
with negative results (IRIS, 1993).
Inorganic selenium compounds appear to have genotoxic effects at relatively
high doses and antigenotoxic effects at lower doses. For example, a study of
mice exposed to mutagens and given doses of O.05 to 0.125 mg/kg-day of
selenium indicates that selenium may inhibit the mutagenic effects of chemical
agents (ATSDR, 1989). For a summary of study results see the Toxicological
Profile for Selenium (ATSDR, 1989).
Carcinogenicity
EPA has determined that there is insufficient data to assess the carcinogenic
potency of selenium. EPA has classified selenium sulfide as a probable human
carcinogen (B2), based on liver and lung tumors in oral exposure studies in
multiple species (IRIS, 1993).
Some human studies indicated that combined Vitamin E and selenium
deficiencies may lead to higher cancer risks {ATSDR, 1989).
Special Susceptibilities
ATSDR has listed the following groups as potentially having greater
susceptibility: pregnant women and their fetuses, persons exposed to high
fluoride levels in drinking water (evidence equivocal), those with vitamin E
deficiencies, and populations with elevated exposures arising from exposure via
food produced in high selenium areas (ATSDR, 1989).
5-145
-------
5. SELENIUM
Based on the occurrence of adverse effects reported in human and animal
studies, individuals with diseases or disorders of the following organ systems
may be at greater risk from selenium exposure than the general population:
hematopoietic, dermal, nervous, liver, kidney, cardiac and immune systems.
HSDB listed individuals with the following conditions as requiring additional
protection: chronic indigestion or a history of peptic ulceration, skin, lung,
kidney or liver disease, dermatitis, chronic bronchitis, skin allergy or respiratory
tract infection, jaundice, or albuminuria (HSDB, 1993). Their cautions are based
upon all routes of selenium exposure.
Interactive Effects
Selenium alters the toxicity of many chemicals. It reduces the toxicity of
mercury, cadmium, lead, silver and copper; some forms reduce arsenic
toxicity. Detailed information on specific interactions can be found in the
Toxico/ogicalProfile for Selenium (ATSDR, 1989). Selenium also interacts with
vitamins, sulfur-containing amino acids, xenobiotics, and essential and non-
essential elements. ATSDR notes that most interactions are beneficial (ATSDR,
1989).
Critical Data Gaps
ATSDR has reported the following data gaps: human epidemiological data for
all relevant effects, relationship between selenium dietary exposure levels and
cancer, mechanisms of genotoxicity, reproductive, developmental studies
regarding cataract formation, immunotoxicity, neurotoxicity, especially
behavioral and histopathological CNS effects, pharmacokinetic, and
bioaccumulation and bioavailability from environmental media (ATSDR, 1989).
A multigeneration study which utilizes sensitive endpoints for toxicity is needed
to develop a more adequately based exposure limit for developmental effects.
Summary of EPA Risk Values
Chronic Toxicity 5 x 10"3 rng/kg-day
Carcinogenicity Insufficient data to assess carcinogenicity.
Note that selenium sulfide is classified as a Group B2
carcinogen
Major Sources: IRIS (1993), ATSDR (1989), HSDB (1993)
5-146
-------
6. LITERATURE CITED
SECTION 6.
LITERATURE CITED1' 2
Abernathy, C.O. and W.C. Roberts. 1994. Risk Assessment in the
Environmental Protection Agency. Journal of Hazardous Materials in
press.
Abernathy, C.O., R. Cantilli, J.T. Du, O.A. Levander. 1993. Essentiality
Versus Toxicity: Some Considerations in the Risk Assessment of
Essential Trace Elements, J. Saxena, Ed. In Vol 8, Hazard Assessment
of Chemicals, Taylor and Francis, Washington, D.C.
Anderson, H.A. and J.F. Amrhein. 1993. Protocol for a uniform Great Lakes
sport fish consumption advisory. Prepared for the Great Lakes Advisory
Task Force. May.
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. Department
of Health and Human Services, Public Health Service. 1989.
Toxicological Profile for Selenium. Atlanta, Georgia.
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1990a. Toxicological Profile for Hexachlorobenzene. Atlanta, Georgia
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1990b. Toxicological Profile for Toxaphene. Atlanta, Georgia.
The addresses from which to obtain state documents are listed in
Appendix B, Sources of Additional Information.
2 Article titles were not usually available for citations obtained from HSDB;
consequently, page number were included for those citations (only).
6-1
-------
6. LITERATURE CITED
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1990c. Toxicological Profile for Endrin. Atlanta, Georgia.
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1991 a. Draft Toxicological Profile for Dieldrin. Atlanta, Georgia.
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1992a. Draft Toxicological Profile for Mercury. Atlanta, Georgia.
ATSDR (Agency for Toxic Substances Disease Registry). U.S. DHHS, PHS.
1992b. Draft Toxicological Profile for alpha, beta, gamma, and delta
Hexachlorocyclohexane. Atlanta, Georgia
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1992c. Draft Toxicological Profile forDDD, DDT, DDE. Atlanta, Georgia.
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1992d. Draft Toxicological Profile for Chlordane. Atlanta, Georgia.
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1993a. Toxicological Profile for Cadmium. Atlanta, Georgia.
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1993b. Toxicological Profile for Endosulfan. Atlanta, Georgia.
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1993c. Toxicological Profile for Heptachlor Epoxide. Atlanta, Georgia.
ATSDR (Agency for Toxic Substances and Disease Registry), U.S. DHHS, PHS.
1993d. Toxicological Profile for Selected PCBs. Atlanta, Georgia.
Baranski, B., I. Stetkiewicz, K., Sitarek, and W. Szymczak. 1983. Effects of
Oral, Subchronic Cadmium Administration on Fertility, Prenatal and
Postnatal Progeny Development in Rats. Archives of Toxicology, Vol.
54.
6-2
-------
6. LITERATURE CITED
Barnes, D.G., and J.S. Bellin. 1989. Interim Procedures for Estimating Risks
Associated with Exposure to Mixtures of Chlorinated Dibenzo-p-Dioxins
and Dibenzofurans (CDDs and CDFs). Risk Assessment Forum, U.S.
EPA, Washington, D.C.
Barnes, D.G. and M. Dourson. 1988. Reference Dose (RfD): Description and
Use in Health Risk Assessments. Regulatory Toxicology and
Pharmacology, Vol. 8.
Bennett, B.G. 1986. IARC Monograph Number 71, pages 115-128 (from
HSDB, 1993).
Blindauer, K.M. 1994. Comments on Volume 2 provided to EPA. April 20.
Utah Department of Health, Division of Community Health Services, Salt
Lake City, Utah.
Bolger, P.M., M.A. Adams, L.D. Sawyer, J.A. Burke, C.E. Coker, and R.J.
Scheuplein. 1990. Risk Assessment Methodology for Environmental
Contaminants in Fish and Shellfish. U.S. FDA, Center for Food Safety
and Applied Nutrition, Washington, DC.
Borum, D. 1994. Memo to Jeffrey Bigler, EPA Office of Water. Washington
D.C.: U.S. EPA, May.
Branson, Dean R., I.T. Takahashi, W.M. Parker, and G.E. Blau. 1985.
Bioconcentration Kinetics of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in
Rainbow Trout. Environmental Toxicology and Chemistryf Vol. 4.
Brown, M.P., M.B. Werner, R.J. Sloan, and K.W. Simpson. 1985.
Polychlorinated biphenyls in the Hudson River. Environmental Science
and Technology, Vol. 19.
Bruggeman, W.A., A. Opperhuizen, A. Wijbenga, and O. Hutzinger. 1984.
Bioaccumulation of Superlipophilic Chemicals in Fish. Toxicology and
Environmental Chemistry, Vol. 7.
6-3
-------
6. LITERATURE CITED
Burbacher, T.M., P.M. Rodier, and B. Weiss. 1990. Methylmercury
Developmental Neurotoxicity: A Comparison of Effects in Humans and
Animals, Neurotoxicology and Teratology, Vol.12.
Burr, J.L., J.F. Gilbert, R.M. Holliday, P.C. Elwood, A.M. Fehily, S. Rogers,
P.M. Sweetnam, and N.M. Deadman. 1989. Effects of Changes in Fat,
Fish, and Fibre Intakes on Death and Myocardial Reinfarction: Diet and
Reinfarction Trial (DART). The Lancet, September 30.
Callahan, M.Z., M.W. Slimak, N.W. Gable, I.P. May, C.F. Fowler, J.R. Freed,
P. Jennings, R.L. Durfee, F.C. Whitmore, B. Amestri, W.R. Mabey, B.R.
Holt, and C. Gould. 1979. Water-related environmental fate of 129
priority pollutants. Volumes I and II. EPA-440/4-79-029b. EPA,
Washington, D.C.
Klaassen, C.D., M.O. Amdur, and J. Doull, Eds. 1986. Casarett and Doull's
Toxicology: The Basic Science of Poisons. New York: Macmillan
Publishing.
Chang, L.W. 1987. Neuropathological Changes Associated with Exposure.
In: H.A. Tilson and S.B. Sparber Eds., Neurotoxicants and
Neurobiological Function, Effects of Organoheavy Metals. New York:
John Wiley & Sons.
Choi, B.H. 1989. The Effects of Methylmercury on the Developing Brain,
Progress in Neurobiology, Vol. 32.
Clarkson, W.T., Environmental Health Perspectives. Vol. 75, pages 59-64.
1987 (from HSDB, 1993).
Clarkson, W.T. and W.F. Fitzgerald. 1991. Mercury and Monomethylmercury;
Present and Future Concerns. EnvonmentalHealth Perspectives, Vol. 96.
Clarkson, W.T. 1990. Human Health Risks from Methylmercury in Fish,
Environmental Toxicology and Chemistry, Vol.9.
6-4
-------
6. LITERATURE CITED
Clarkson, W.T., D.O. Marsh, C. Cox, G.J. Myers, L. Amin-Zaki, and S. Al-
Tikriti. 1987. Fetal Methylmercury Poisoning: Relationship Between
Concentration in Single Strands of Maternal Hair and Child Effects,
Archives of Neurolology, Vol 44.
Clarkson, W.T., D.O. Marsh, C. Cox, G.J. Myers, L. Amin-Zaki, and S. Al-
Tikriti. 1989. Dose-response Analysis of Infants Prenatally Exposed to
Methyl Mercury: An Application of a Single Compartment Model to
Single-strand Hair Analysis, Environmental Research, Vol.49.
Columbia River Inter-Tribal Fish Commission. 1994.
Cunningham-Burns K.M., and W.H. Hallenbeck. 1986. Pesticides and Human
Health. New York: Springer-Verlag Press.
Davis, D.L., H.L. Bradlow, M. Wolff, T. Woodruff, D.G. Hoel, and H. Anton-
Culver, H. 1993. Medical Hypothesis: Xenoestrogens As Preventable
Causes of Breast Cancer. Environmental Health Perspectives, Vol. 101,
No. 5.
Dourson, M.L., and J.M. Clark. 1990. Fish Consumption Advisories: Toward
a Unified, Scientifically-credible Approach. Regulatory Toxicity and
Pharmacology, 12.
Dourson, M.L., L.A. Knauf, and J.C. Swartout. 1992. On Reference Dose
(RfD) and its Underlying Toxicity Data Base. Toxicology and Industrial
Health, Vol. 8, No.3.
Falck, F, A. Ricci, M.S. Wolff, J. Godbold, and P. Deckers. 1992. Pesticides
and polychlorinated biphenyl residues in human breast lipids and their
relation to breast cancer. Archives of Environmental Health, Vol. 47,
No. 2.
Farland, W. and M. Dourson. 1992. Chapter 7. Noncancer Health Endpoints:
Approaches to Quantitative Risk Assessment. In: C. Richard Cothern,
Ed., Comparative Environmental Risk Assessment. Ann Arbor, Ml:
Lewis Publishers.
6-5
-------
6. LITERATURE CITED
Habicht, H.F. Deputy Administrator, EPA. 1992. Memorandum: Guidance on
Risk Characterization for Risk Managers and Risk Assessors.
Harrison, S.E., and J.F. Klaverkamp. 1990. Metal Contamination in Liver and
Muscle of Northern Pike (Esox lucius) and White Sucker (Catostomus
commersoni) and in Sediments from Lakes Near the Smelter at Flin Flon,
Manitoba. Environmental Toxicology and Chemistry, Vol. 9.
Hayes, W.J. 1982. Pesticides Studied in Man. Baltimore, MD: Williams and
Wilkins.
Hayes, W.J., and E.R. Laws. 1991. Handbook of Pesticide Toxicologyf Vols.
1-3. San Diego: Academic Press Inc.
HSDB (Hazardous Substances Data Bank). All searches conducted on-line
through Toxnet in 1993 unless specifically noted. Developed by U.S.
EPA.
HEAST (Health Effects Summary Tables). 1992. U.S. EPA, Office of Research
and Development, Washington, D.C.
Honstead, J.F., T.M. Beetle, and J.K. Sotdat. 1971. A Statistical Study of the
Habits of Local Fishermen and Its Application to Evaluation of
Environmental Dose. Battelle Pacific Northwest Laboratories, Richland,
WA. [Cited in Rupp, E. et al., 1980.]
IRIS (Integrated Risk Information System). All searches conducted on-line
through Toxnet in 1993 unless specifically noted with another year.
Data base developed and maintained by U.S. EPA.
Jaffar, M. and M. Ashraf. 1988. Heavy Metal Contents in Some Selected
Local Freshwater Fish and Relevant Waters. Indian Journal of Marine
Science, Vol. 17, No. 3.
Jarabek, A.M., M.G. Menach, J.H. Overton, M.L. Dourson, and F.J. Miller.
1993. The Environmental Protection Agency's Inhalation RfD,
Methodology: Risk Assessment for Air Toxics, Toxicology and Industrial
Health, Vol. 6.
6-6
-------
6. LITERATURE CITED
Kleeman, James, J.R. Olson, S.S. Chen, and R.E. Peterson. 19S6a.
Metabolism and Disposition of 2,3,7,8-Tetrachlorodibenzo-p-dioxin in
Rainbow Trout. Toxicology and Applied Pharmacology, Vol. 83.
Kleeman, James, J.R. Olson, S.S. Chen, and R.E. Peterson. 1986b. 2,3,7,8-
Tetrachlorodibenzo-p-dioxin Metabolism and Disposition in Yellow Perch.
Toxicology and Applied Pharmacology, Vol. 83.
Kuehl, D.W., B.C. Butterworth, A. McBride, S. Kroner, and D. Bahnick. 1987.
Bioavailability of Polychlorinated Dibenzo-p-dioxins and Dibenzofurans
From Contaminate Wisconsin River Sediment to Carp. Chemosphere,
Vol. 16, No. 4.
Lyman, W.J., W.F. Reehl, and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. New York: McGraw-Hill Book Co. York.
Marcovecchio, J.E., V.J. Moreno, and A. Perez. 1988. The sole, Paralichthys
sp., as an Indicator Species for Heavy Metal Pollution in the Bahia Blanca
Estuary, Argentina. Science of the Total Environment, Vol. 75.
Minnesota Department of Health. 1992. Minnesota Fish Consumption
Advisory. Minneapolis, MN. May.
Missouri Department of Health. 1992. 1992 Fish Consumption Advisory.
Jefferson City, MO. May.
MIXTOX. 1992. Data base on toxicological interactions available on disc for
personal computers. Version 1.5 ECAO, EPA, Cincinnati, Ohio.
National Academy of Sciences (NAS). 1983. Committee on the Institutional
Means for Assessment of Risks to Public Health, Commission on Life
Sciences, National Research Council. Risk Assessment in the Federal
Government: Managing the Process. Washington, D.C.
6-7
-------
6. LITERATURE CITED
National Academy of Sciences (NAS). 1993. Pesticides in the Diets of Infants
and Children. Committee on Pesticides in the Diets of Infants and
Children, Board on Agriculture and Board on Environmental Studies and
Toxicology, Commission on Life Sciences. National Academy Press,
Washington, D.C.
National Research Council (NRC). 1989. Recommended Dietary Allowances.
10th Edition. Washington, D.C.: National Academy Press.
National Research Council (NRC). 1994. Science and Judgment in Risk
Assessment. Washington, D.C.: National Academy Press.
Norey, C.G., M.W. Brown, A. Cryer, and J. Kay. 1990. A Comparison of the
Accumulation, Tissue Distribution, and Secretion of Cadmium in Different
Species of Freshwater Fish. Comparative Biochemical Physiology, C.
Vol. 96C, No.1.
Norton, S. 1987. Unconditioned Behavioral Measures of Neurotoxicity. In:
Tilson, H.A. and S.B. Sparber, Eds., Neurotoxicants andNeurobiological
Function, Effects of Organoheavy Metals. NY: John Wiley & Sons.
Podrebarac, D.S., J. Assoc. Off. Anal. Chem. Vol. 67, pages 176-185, 1984
(from HSDB, 1993).
Preuss, P.W. and A.M. Erlich. 1986. The Environmental Protection Agency's
Risk Assessment Guidelines. Presented at the 79th Meeting of the Air
Pollution Control Association, June 23.
Reuhl, K.R.. 1987. Neuropathology of Organometallic Compounds. In: Tilson,
H.A. and S.B. Sparber Eds., Neurotoxicants and Neurobiological
Function, Effects of Organoheavy Metals. New York: John Wiley & Sons.
RTI (Research Triangle Institute). 1990. Current State Fish and Shellfish
Consumption Advisories and Bans. Research Triangle Park, N.C.
6-8
-------
6. LITERATURE CITED
Robbins, S.L., R.S. Cotran, Kumar, Vinay, Eds. 1989. Robbins Pathologic
Basis of Disease, 4th Edition. Philadelphia, PA: W.B. Saunders
Company.
Rupp, Elizabeth, F.L. Miller, and C.F. Baes III. 1979. Some Results of Recent
Surveys of Fish and Shellfish Consumption by Age and Region of U.S..
Residents. Health Physics, Vol. 39.
Shubat, P. 1991. Health Risk Assessment for the Consumption of Sport Fish
Contaminated with Mercury: Guidelines for the 1991-1992 Minnesota
Fish Consumption Advisory. Minnesota Department of Health,
Minneapolis.
Shubat, P. 1993a. Draft Health Risk Assessment for the Consumption of
Sport Fish Contaminated with Mercury, PCBs and TCDD. Minnesota
Department of Health, January.
Shubat, P., Minnesota Department of Health. 1993b. Conversation with Abt
Associates. August 25.
Slemr, F., and E. Langer. 1992. Increase in Global Atmospheric
Concentrations of Mercury Inferred from Measurements Over the Atlantic
Ocean, Nature, Vol. 355.
Soto, A.M., K.L. Chung, and C. Sonnenschein. 1994. The Pesticides
Endosulfan, Toxaphene, and Dieldrin Have Estrogenic Effects on Human
Estrogen-Sensitive Cells. EnvirironmentalHealth Perspectives, Vol. 102,
No. 4.
Stern, A.H. 1993. Re-evaluation of the Reference Dose for Methylmercury
and Assessment of Current Exposure Levels. Risk Analysis, Vol.13,
No.3.
Tilson, H.A. Tilson and S.B. Sparber, Eds. 1987. Neurotoxicants and
Neurobiological Function, Effects of Organoheavy Metals. New York:
John Wiley & Sons.
6-9
-------
6. LITERATURE CITED
U.S. Department of Agriculture. 1983. Food consumption: Households in the
United States, Seasons and Year 1977-78.
U.S. Department of AgricuIture/HNIS. 1989. Continuing Survey of Food
Intake by Individuals Data Set. (Released January, 1993.)
U.S. EPA. 1982. Recognition and Management of Pesicide Poisonings, 3rd
Ed., EPA-540/9-80-005, Washington, D.C.: U.S. Government Printing
Office, January.
U.S. EPA. 1985. Principles of Risk Assessment, A Nontechnical Review.
EPA3-85-000. Workshop on Risk Assessment, Easton, Maryland,
March.
U.S. EPA. 1986a. Guidelines for carcinogen risk assessment. U.S. EPA.
Federal Register, 51(185): 33992-34003.
U.S. EPA. 1986b. Guidelines for the health assessment of suspect
developmental toxicants. U.S. EPA, Washington, D.C., Federal Register,
51(185), 34028-34040.
U.S. EPA. 1986c. Guidelines for mutagenicity risk assessment. U.S. EPA.
Federal Register, 51(185): 34006-34012.
U.S. EPA. 1986d. Guidelines for the health risk assessment of chemical
mixtures. U.S. EPA, Washington, DC. Federal Register, 51(185):
34014-34025.
U.S. EPA. 1987. Integrated risk information system supportive
documentation: volume 1. Washington, D.C.: U.S. EPA, Office of
Research and Development, EPA/600/8-86/032a.
U.S. EPA. 1988a. Proposed guidelines for assessing female reproductive risk.
U.S. EPA. Federal Register, 53: 24834-24847. [Cited in U.S. EPA,
1992.]
6-10
-------
6. LITERATURE CITED
U.S. EPA. 1988b. Proposed guidelines for assessing male reproductive risk.
U.S. 'EPA. Federal Register, 53: 24850-24869. [Cited in U.S. EPA
1992.]
U.S. EPA. 1988c. Region V Risk Assessment for Dioxin Contaminants.
Chicago, Illinois.
U.S. EPA. 1989a. Assessing Human Health Risks From Chemically
Contaminated Fish and Shellfish: A Guidance Manual. Washington,
D.C.: U.S. EPA, Office of Water Regulations and Standards, EPA 503/8-
89-002.
U.S. EPA. 1989b. Risk Assessment Guidance For Superfund. Volume 1:
Human Health Evaluation Manual (Part A). EPA, Office of Emergency
and Remedial Response. EPA/540/1-89/002.
U.S. EPA. 1989c. Interim Methods for Development of Inhalation Reference
Doses. Office of Health and Environmental Assessment, Washington
D.C,
U.S. EPA. 1990a. Exposure Factors Handbook. Washington, D.C.: U.S. EPA,
Office of Health and Environmental Assessment, EPA 600/8-89/043.
U.S. EPA. 1990b. Risk assessment methodology for fish. U.S. EPA, Office
of Pesticide Programs.
U.S. EPA. 1991 a. Guidelines for developmental toxicity risk assessment.
U.S. EPA. Federal Register, 56: 63798-63826.
U.S. EPA. 1991b. Technical support document for water quality based toxics
control. Washington, D.C.: U.S. EPA, Office of Water, EPA 505/2-90-
001.
U.S. EPA. 1991c. National Bioaccumulation Study, Draft. Washington, D.C.:
Office of Water Regulations and Standards.
U.S. EPA. 1992a. Guidelines for exposure assessment. U.S. EPA,
Washington, DC. Federal Register, 57(104): 22888.
6-11
-------
6. LITERATURE CITED
U.S. EPA. 1992b National Study of Chemical Residues in Fish, Volumes I and
II. Washington, D.C.: EPA, Office of Science and Technology, EPA
823-R-92-008a.
U.S. EPA. 1992c. Consumption Surveys for Fish and Shellfish: A Review and
Analysis of Survey Methods. Washington, D.C.: Office of Water.
U.S. EPA. 1992d. Memorandum from Reto Engler (HED/OPP) to Chiefs,
Section Heads etc, entitled "List of Chemicals Evaluated for Carcinogenic
Potential" {also referred to as the Waxman Report) 2/27/92.
U.S. EPA. 1992e. Toxicology One-liners for Malathion. Washington, D.C.:
Office of Pesticide Programs.
U.S. EPA. 1992f. Toxicology One-liners for Terbufos. Washington, D.C.:
Office of Pesticide Programs.
U.S. EPA. 1992g. Toxicology One-liners for Chlorpyrifos. Washington, D.C.:
Office of Pesticide Programs.
U.S. EPA. 1992h. Office of Pesticide Programs RfD Tracking Report. January
27.
j
U.S. EPA. 1993a. Guidance for Assessing Chemical Contamination Data for
Use in Fish Advisories, Volume 1: Fish Sampling and Analysis.
Washington, D.C.: Office of Science and Technology.
U.S. EPA. 1993b. Toxicology One-Liners for Toxaphene. Washington, D.C.:
Office of Pesticide Programs.
U.S. EPA. 1993c. Drinking Water Regulations and Health Advisories.
Washington, D.C.: Office of Water, May.
U.S. EPA. 1993d. Toxicology One-liners for Carbophenothion. Washington,
D.C.: Office of Pesticide Programs.
6-12
-------
6. LITERATURE CITED
U.S. EPA. 1993e. Memo from G. Ghali to D. Edwards, OPP. RfD/Peer
Review Report of Chlorpyrifos. Washington, D.C.
U.S. EPA. 1993f. Toxicology One-liners 1*orDiazinon. Washington, D.C.: Office
of Pesticide Programs.
U.S. EPA. 1993g. Toxicology One-liners for Dicofol. Washington, D.C.: Office
of Pesticide Programs.
U.S. EPA. 1993h. Toxicology One-liners for Disulfoton. Washington, D.C.:
Office of Pesticide Programs.
U.S. EPA. 1993i. Toxicology One-liners for Endosulfan. Washington, D.C.:
Office of Pesticide Programs.
U.S. EPA. 1993J. Toxicology One-liners for Heptachlor/Heptachlor Epoxide.
Washington, D.C.: Office of Pesticide Programs.
U.S. EPA. 1993k. Toxicology One-liners for Lindane. Washington, D.C.:
Office of Pesticide Programs.
U.S. EPA. 19931. Toxicology One-liners for Oxyfluorfen. Washington, D.C.:
Office of Pesticide Programs.
U.S. EPA. 1993m. Toxicology One-liners for Endrin. Washington, D.C.: Office
of Pesticide Programs.
U.S. EPA. 1993n. Toxicology One-liners for Ethion. Washington, D.C.: Office
of Pesticide Programs.
U.S. EPA. 1993o. Toxicology One-liners for Mirex. Washington, D.C.: Office
of Pesticide Programs.
U.S. EPA. 1993p. Office of Pesticide Programs RfD Tracking Report. August
2O.
6-13
-------
6. LITERATURE CITED
U.S. EPA. 1993q. A SAB Report: Cholinesterase Inhibition and Risk
Assessment, Review of the Risk Assessment Forum's Draft Guidance on
the Use of Data on Cholinesterase Inhibition in Risk Assessment by the
SAB/SAP Joint Committee. Washington, D.C.
U.S. EPA. 1993r. Review of the Methodology for Developing Ambient Water
Quality Criteria for the Protection of Human Health. Prepared by the
Drinking Water Committee of the Science Advisory Board, Washington,
D.C.
U.S. EPA. 1994a. Memo from G. Ghali to R. Forrest, OPP. RfD/Peer
Review Report of Terbufos. Washington, D.C.
U.S. FDA. 1993. Guidance Document for Cadmium in Shellfish. Washington,
D.C.: Center for Food Safety and Applied Nutrition, U.S.FDA.
Velazzquez, Susan, EPA/Environmental Criteria and Assessment Office,
Cincinnati. 1994. Personal communication.
Watanabe, Ann, Columbia River Intertribal Commission. 1993. Conversation
with Abt Associates. October 15.
West, Patrick., et al. 1989. Michigan Sport Anglers Fish Consumption.
Natural Resource Sociology Research Lab Technical Report #2. Ann
Arbor, Ml: University of Michigan School of Natural Resources.
Williams, Lisa, J.P. Glesy, N. DeGalan, D.A. Verbrugge, D.E. Tillitt, G.T.
Ankley, and R.L. Welch. 1992. Prediction of Concentrations of 2,3,7,8-
tetrachlorbdibenzo-p-dioxin Equivalents from Total Concentrations of
Polychlorinated Biphenyls in Fish Fillets. Environmental Science and
Technology, Vol. 26, No. 6.
WHO (World Health Organization). 1976. Environmental Health Criteria 1:
Mercury. Geneva, Switzerland: WHO.
WHO. 1990. Environmental Health Criteria 101: Methylmercury. Geneva,
Switzerland: WHO.
6-14
-------
APPENDIX A
APPENDIX A
MUTAGENICITY AND GENOTOXICITY
EPA has developed and published Guidelines for Mutagenicity Risk Assessment
(EPA, 1986c). The information in this appendix was primarily taken from that
document. Quantitative assessment of mutagenicity requires two steps: 1)
determining the heritable effect per unit of exposure (dose-response) and the
relationship between mutation rate and disease incidence, and 2) combining
dose-response information with anticipated levels and patterns of human
exposure in order to derive a quantitative assessment of risk (EPA, 1986c).
Current EPA guidance on mutagenicity risk assessment specifies that:
"Dose-response assessments can presently only be performed
using data from in vivo, heritable mammalian germ-cell tests, until
such time as other approaches can be demonstrated to have
equivalent predictability." (EPA, 1986c).
The relationship between in vitro assay results and effects in mammalian
systems is not sufficiently characterized to be able to use in vitro assays as the
basis for developing a dose-response assessment.
An example of the type of study which could be used for mutagenicity risk
assessment is an assay that directly detects heritable health effects in the first
generation offspring. Human risk estimates are obtained by extrapolating the
induced mutation frequency or observed phenotypic effect downward to the
anticipated level of human exposure (EPA, 1986c). No one extrapolation model
has been identified as the most appropriate. The Agency notes that departures
from linearity at low exposure and exposure rates has been observed for at
least one chemical. According to EPA, "[t]he Agency will consider all relevant
models for gene and chromosomal mutations in performing low-dose
extrapolations and will choose the most appropriate model. This choice will be
consistent both with the experimental data available and with current
knowledge of relevant mutational mechanisms" (EPA, 1986c).
A-1
-------
APPENDIX A
The factors which should be considered in evaluating chemicals for mutagenic
activity include:
• Genetic endpoints,
• Sensitivity and predictive value of the test systems for various classes
of chemical compounds,
• Number of different test systems used for detecting each genetic
endpoint,
• Consistency of the results obtained in different test systems and
different species,
• Aspects of the dose-response relationship, and
• Whether the tests are conducted in accordance with appropriate test
protocols agreed upon by experts in the field (EPA, 1986c).
Although there are often no in vivo data available on a chemical, there are in
vitro assay results for most common chemicals. This data may be used
qualitatively to evaluate the mutagenicity of chemicals. They are often used
as supporting evidence in carcinogenicity, developmental toxicity and
reproductive toxicity evaluations.
Various types of test results may be obtained regarding mutagenicity. In
evaluating interactions in the mammalian gonad, two possible types of evidence
have been specified. Evidence for chemical interactions in the mammalian
gonad may be considered sufficient if it is demonstrated that "an agent
interacts with germ-cell DNA or other chromatin constituents, or that it induces
such endpoints as unscheduled DNA synthesis, sister-chromatid exchange, or
chromosomal aberrations in germinal cells" (EPA, 1986c). Suggestive
evidence of interaction in the mammalian gonad "includes effects such as
sperm abnormalities following acute, subchronic or chronic toxicity testing, or
finding of adverse reproductive effects such as decreased fertility, which are
consistent with the chemical's interaction with germ cells" (EPA, 1986c).
In practice, the outcomes of developmental and reproductivity toxicity testing
often do not indicate the type of toxicity which lead to effects such as
decreased fertility. The causes of decreased fertility range from mutagenicity
leading to early fetal death or failure to implant; to maternal, paternal, or fetal
toxicity. Positive significant mutagenicity studies along with fetal toxicity or
reduced fertility may be suggestive that mutagenic action was a causal action.
Developmental toxicity has been studied in most chemicals (other than frank
teratogens) only relatively recently. The use of the data from these studies
with other types of data such as mutagenic, pharmacokinetic and reproductive
system studies is developing; however, there is not currently clear guidance
on these types of evaluations.
A-2
-------
APPENDIX A
EPA has addressed the issue of weight-of-evidence for mutagenicity by
providing a classification scheme with categories presented in decreasing order
of strength of evidence:
1. Positive data derived from human germ-cell mutagenicity studies;
2. Valid positive results from studies on heritable mutational events in
mammalian germ cells;
3. Valid positive results from mammalian germ-cell chromosome aberrations
studies that do not include an intergenerational test;
4. Sufficient evidence for a chemical's interaction with mammalian germ
cells, together with valid positive mutagenicity test results from two
assay systems, at least one of which is mammalian (in vitro or in vivo).
The positive results from the two assays may be both for gene
mutations or both for chromosome aberrations; if one is for gene
mutations and the other for chromosome aberrations, both must be from
mammalian systems;
5. Suggestive evidence for a chemical's interaction with mammalian germ
cells, together with valid positive mutagenicity evidence from two assay
systems, as described under 4 above. Alternatively, positive
mutagenicity evidence of less strength than defined under 4 above,
when combined with sufficient evidence for a chemical's interaction with
mammalian germ cells;
6. Positive mutagenicity test results of less strength than defined under 4.,
combined with suggestive evidence for a chemical's interaction with
mammalian germ cells;
7. Although definitive proof of non-mutagenicity is not possible, a chemical
could be classified operationally as a non-mutagen for human germ cells,
if it gives valid negative test results for all end points of concern;
8. Inadequate evidence bearing on either mutagenicity or chemical
interaction with mammalian germ cells.
Certain responses in tests that do not measure direct mutagenicity endpoints
(e.g., sister chromatid exchange) may provide the basis for raising the weight
of evidence from one category to the next (EPA, 1986c).
EPA noted that it was not possible to illustrate all potential combinations of
evidence and suggests that judgment must be exercised in reaching
conclusions. In addition, the test results often do not provide a consistent
picture of the mutagenicity of a chemical. For example, most target analytes
discussed in Section 5 had both positive and negative mutagenicity data.
Although the use of mutagenicity data in risk assessment has been limited in
the past, a recent EPA Scientific Advisory Board (SAB) report, which addressed
the methodology for developing ambient water quality criteria, has
A-3
-------
APPENDIX A
recommended that it be used more extensively in cancer risk assessment in the
future (EPA, 1993r). The SAB report states that:
"Data on genetic activity of chemicals in short and long term tests
in vitro and even in vivo should be given greater weight in the
future. However, the incorporation of this information in risk
assessment should emphasize the relationships between specific
mutation sites, the resulting alterations in specific proteins, and
the development of cancer. The simple identification of the ability
of a given compound to produce mutations in various test
systems has limited utility in risk assessment, beyond the ability
of classifying compounds as putative mutagens or non-mutagens.
Studies that give insight into the normal and abnormal behavior of
human cells and tissues should be used to help bridge the gap
between studies in animals and effects in human beings" (EPA,
1993r).
As information becomes available on this topic, updates will be provided.
A-4
-------
APPENDIX B
APPENDIX B
SOURCES OF ADDITIONAL INFORMATION
The sources listed below were consulted in the development of this document
and may be useful to readers who wish to obtain more in-depth information on
specific topics. A listing of the state documents and addresses begins on paqe
B-9.
Anderson, H.A. and J.F. Amrhein, 1993. Protocol for a uniform Great Lakes
sport fish consumption advisory. Prepared for the Great Lakes Advisory
Task Force. May.
ATSDR (Agency for Toxic Substances Reduction), USDHHS, PHS. 1989. See
Toxicological Profiles for Various Chemicals. Obtain from ATSDR in
Atlanta, Georgia.
Baker, S.R., and C.F. Wilkinson, Eds., The Effects of Pesticides on Human
Health: Advances in Modern Environmental Toxicology Volume XVII.
Princeton, NJ: Princeton Scientific Publishing.
Barnes, D.G., and J.S. Bellin. 1989. Interim Procedures for Estimating Risks
Associated with Exposure to Mixtures of Chlorinated Dibenzo-p-Dioxins
and Dibenzofurans (CDDs and CDFs.) Risk Assessment Forum, U.S.
EPA, Washington, D.C.
Barnes, D.G., and M. Dourson. 1988. Reference dose (RfD): Description and
use in health risk assessments. Regulatory Toxicology and
Pharmacology, Vol. 8.
Bolger, P.M., M.A. Adams, L.D. Sawyer, J.A. Burke, C.E. Coker, and R.J.
Scheuplein. 1990. Risk assessment methodology for environmental
contaminants in fish and shellfish. Washington, D.C.: U.S. FDA, Center
for Food Safety and Applied Nutrition.
Crump, K.S. 1981. Statistical aspects of linear extrapolation. In: Richmond,
C. and E. Copenhaver, E., Eds., Proceedings of the 3rd Life Sciences
Symposium, Health Risk Analysis. Philadelphia, PA: Franklin Institute
Press.
B-1
-------
APPENDIX B
Dourson, M.L., and J.M. Clark. 1990. Fish Consumption Advisories: Toward
a Unified/ Scientifically Credible Approach. Regulatory Toxicology and
Pharmacology, Vol. 12.
Dourson, M.L., L.A. Knauf, J.C. Swartout. 1992. On Reference Dose (RfD)
and its Underlying Toxicity Data Base. Toxicology and Industrial Health,
Vol. 8, No.3.
Habicht, H.F. Deputy Administrator, EPA. 1992. Memorandum: Guidance on
Risk Characterization for Risk Managers and Risk Assessors.
Hayes, W.J., and E.R. Laws. 1991. Handbook of Pesticide Toxicologyf Vols.
1-3, San Diego: Academic Press Inc.
HEAST (Health Effects Assessment Summary Tables). 1992. Washington,
D.C.: ORD, U.S. EPA.
Hood, R.D., Ed. 1989. Developmental Toxicology: Risk Assessment and
Future. For: Reproductive and Developmental Toxicology Branch, OHEA,
USEPA. New York: Van Nostrand Reinhold.
Humphrey, H.E.B. 1988. Chemical contaminants in the Great Lakes: the
human health aspect. In: M.S. Evans, Ed., Toxic Contaminants and
Ecosystem Health: A Great Lakes Perspective. New York: John Wiley
and Sons, p. 153-165.
Hazardous Substances Data Base (HSDB). 1992. on-line from Toxnet.
I ARC (International Agency For Research on Cancer). 1986. Multiple volumes
on a variety of chemical contaminants. Obtain from World Health
Organization, IARC, Lyon, France.
IRIS (Integrated Risk Information System). 1993. Chemical-specific and
background document files are available. Obtain through Toxnet,
Developed by EPA.
Klaassen, C.D., M.O. Amdur, and J. Doull, Eds. 1986. Casarett and Doull's
Toxicology: The Basic Science of Poisons. New York: MacMillan
Publishing Company.
Kuehl, D.W., B.C. Butterworth, A. McBride, S. Kroner, and D. Bahnick. 1989.
Contamination offish by 2,3,7,8-tetrachlorodibenzo-p-dioxin: a survey
of fish from major watersheds in the United States. Chemosphere, 18:
1997-2014.
B-2
-------
APPENDIX B
National Academy of Sciences (NAS). 1983. Committee on the Institutional
Means for Assessment of Risks to Public Health, Commission on Life
Sciences, National Research Council, Risk Assessment in the Federal
Government: Managing the Process. Washington, D.C.
National Academy of Sciences (NAS). 1993. Committee on Pesticides in the
Diets of Infants and Children, Board on Agriculture and Board on
Environmental Studies and Toxicology, Commission on Life Sciences,
Washington, D.C.: National Academy Press.
Review of Environmental Contamination and Toxicology. 1988. USEPA,
Office of Drinking Water Health Advisories, (includes multiple
pesticides). Vol. 104, New York: Springer-Verlag.
RTI (Research Triangle Institute). 1993. Current State Fish and Shellfish
Consumption Advisories and Bans. Research Triangle Park, N.C.
Stern, A.M. 1993. Re-evaluation of the Reference Dose for Methylmercury
and Assessment of Current Exposure Levels. Risk Analysis, Vol. 13,
No.3.
TVA. 1992. Use of Risk Assessment Techniques to Evaluate TVA 's Fish
Tissue Contaminant Data, Tennessee Valley Authority Water Resources
Division (prepared by Janice P. Cox).
U.S. EPA. Memoranda titled "List of Chemicals Evaluated for Carcinogenic
Potential" issued regularly by the Office of Pesticide Programs.
U.S. EPA, Tox One liners for pesticides of interest. Obtain from Office of
Pesticide Programs, Washington, D.C.
U.S. EPA. 1986. Guidelines for carcinogen risk assessment. U.S. EPA.
Federal Register, 51(185): 33992-34003.
U.S. EPA. 1986. Guidelines for mutagenicity risk assessment. U.S. EPA.
Federal Register, 51(185): 34006-34012.
U.S. EPA. 1986. Guidelines for the health risk assessment of chemical
mixtures. U.S. EPA, Washington, DC. Federal Register, 51(185):
34014-34025.
B-3
-------
APPENDIX B
U.S. EPA. 1988. Proposed guidelines for assessing female reproductive risk.
U.S. EPA. Federal Register, 53: 24834-24847. [Cited in U.S. EPA,
1992.]
U.S. EPA. 1988. Proposed guidelines for assessing male reproductive risk.
U.S. EPA. Federal Register, 53: 24850-24869. [Cited in U.S. EPA,
1992.]
U.S. EPA. 1989. Interim Methods for Development of Inhalation Reference
Doses. Office of Health and Environmental Assessment, Washington,
D.C,
U.S. EPA. 1989. Workshop Report on EPA Guidelines for Carcinogen Risk
Assessment Risk Assessment Forum, Washington, D.C
U.S. EPA. 1989. Workshop Report on EPA Guidelines for Carcinogen Risk
Assessment: Use of Human Evidence, Risk Assessment Forum,
Washington, D.C
U.S. EPA. 1990. Exposure Factors Handbook. U.S. EPA, Office of Health and
Environmental Assessment, Washington, DC. EPA 600/8-89/043.
U.S. EPA. 1991. Guidelines for developmental toxicity risk assessment. U.S.
EPA. Federal Register, 56: 63798-63826. [Cited in U.S. EPA, 1992.]
U.S. EPA. 1991. Technical support document for water quality based toxics
control. U.S. EPA, Office of Water, Washington, DC. EPA 505/2-90-
001.
U.S. EPA, 1991. National Bioaccumulation Study, Draft. Office of Water
Regulations and Standards, Washington, D.C.
U.S. EPA. 1991. Risk assessment guidance for Superfund. Volume 1:. human
health evaluation manual supplemental guidance - "standard default
exposure factors". EPA, Office of Emergency and Remedial Response.
U.S. EPA. 1992. Guidelines for exposure assessment. U.S. EPA,
Washington, DC. Federal Register, 57(104): 22888.
U.S. EPA. 1992 National Study of Chemical Residues in Fish, Volumes I and
II, Washington, D.C.: EPA, Office of Science and Technology, EPA 823-
R-92-008a.
B-4
-------
APPENDIX B
U.S. EPA, 1993 Guidance for Assessing Chemical Contamination Data for Use
in Fish Advisories, Volume 1: Fish Sampling and Analysis. Washington,
D.C.: Office of Science and Technology.
U.S. EPA. 1993 (May). Drinking Water Regulations and Health Advisories.
Washington, D.C.: Office of Water.
U.S. EPA. Office of Pesticide Programs RfD Tracking Report - obtain the most
receint version. It is usually issued quarterly.
U.S.EPA. 1993. An Sab Report: Cholinesterase Inhibition and Risk
Assessment, Review of the Risk Assessment Forum's Draft Guidance on
the Use of Data on Cholinesterase Inhibition in Risk Assessment by the
SAB/SAP Joint Committee, Washington, D.C.
U.S. EPA. 1993. Review of the Methodology for Developing Ambient Water
Quality Criteria for the Protection of Human Health. Prepared by the
Drinking Water Committee of the Science Advisory Board, Washington,
D.C.
U.S. FDA. Guidance Documents for Chemicals in Fish and Shellfish. May be
obtained from the Center for Food Safety and Applied Nutrition, U.S.
DA, Washington, D.C.
STATE DOCUMENTS
The documents are listed in alphabetical order by state. The address, which
follows the first document listed for each state, is the location of the office(s)
which have participated in this project.
Monterey Bay Marine Environmental Health Survey: Health Evaluation,
California Environmental Protection Agency, Office of Environmental
Health Hazard Assessment, 1992
CA Environmental, Protection Agency
Office of Environmental Health Assessment
Pesticide and Environmental Toxicology Section
601 N. 7th Street, P. O. Box 942732
Sacramento, CA 94234-7320
B-5
-------
APPENDIX B
A Study of Chemical Contamination of Marine Fish From Southern California II.
Comprehensive Study, California Environmental Protection Agency,
Office of Environmental Health Hazard Assessment, 1991
California Sport Fishing Regulations, California (State of) Fish and Game
Commission, Department of Fish and Game, 1992
Exposure Guidelines for Mercury in Fish:: memorandum to Charles S. Mahan,
M.D. from Richard W. Freeman, Ph.D., Florida (State of) Department of
Health and Rehabilitative Services, 1993?
FL Dept. Health and Rehabilitative Services
Toxicology and Hazard Assessment
1317 Winewood Blvd.
Tallahassee, FL 32399-0700
Advisories on Mercury Concentrations in Large Mouth Bass (memorandum to
HRS District Administrators from Charles S. Mahan, M.D.), Florida (State
of) Department of Health and Rehabilitative Services, 1993
Guidelines for Issuing Advisories/Bans on the Consumption of Chemically
Contaminated Fish, Louisiana Department of Health and Hospitals, Office
of Public Health, Environmental Epidemiology Section, 1990 (updated
1991)
Louisiana Department of Health and Hospitals
Office of Public Health
New Orleans, Louisiana
70160
Summary of Revisions to the Michigan Sport Fish Consumption Advisory,
Michigan Department of Public Health, Division of Health Risk
Assessment, 1992
Ml Dept. of Public Health
Division of Health Risk Assessment
3423 N. Martin Luther King Blvd.
Lansing, Ml 48909
B-6
-------
APPENDIX B
Health Risk Assessment for the Consumption of Sport Fish Contaminated with
Mercury, PCBs and TCDD, Minnesota Department of Health (Pamela
Shubat), 1993
MN Dept. of Health
Div. of Environ. Health
Section of Health Risk Assessment
925 S.E. Delaware Street, P.O. Box 59040
Minneapolis, MN 55459-0040
PCB Reference Dose for Effects on Fetal Development: Development of a
reference dose based on human exposure data, Minnesota Department
of Health (Pamela Shubat), 1992
Fish Facts: Methylmercury in Fish, Minnesota Department of Health, 1991
Health Risk Assessment for the Consumption of Sport Fish Contaminated with
Mercury, PCBs and TCDD: Guidelines for the 1991-1992 Minnesota Fish
Consumption Advisory, Minnesota Department of Health (Pamela
Shubat), 1991
Criteria used to issue fish consumption advice: 1992 Minnesota Fish
Consumption Advisory, Minnesota Department of Health (Pamela
Shubat), 1992
Fish Facts: Contaminants in Lake Superior Fish, Minnesota Department of
Health, 1991
Fish Facts: Eating Minnesota Fish: Health risks and benefits, Minnesota
Department of Health, 1991
Which Fish Are Safe To Eat?, Minnesota Department of Health, 19??
Eating Minnesota Fish: A Guide to Your Health, Minnesota Department of
Health, 1991
Minnesota Fish Consumption Advisory, Minnesota Department of Health, 1992
Fish Tissue Criteria for Dioxin, Mississippi Department of Environmental
Quality, 1990
B-7
-------
APPENDIX B
Mississippi Bureau of Pollution Control
121 Fairmont Plaza
Pearl, Mississippi, 39208
Principles for Determining When and Where to Issue Health Advisories on
Chemical Contamination in Fish, Missouri Department of Conservation
Fish Contaminant Project, 1989
Missouri Department of Health
Bureau of Environmental Epidemiology
P.O. Box 570
1730E.EImSt.
Jefferson City, Mo. 65102
State Health Officials Issue New Advisories for Chlordane-Contaminated Fish
on Rivers, Lakes, Missouri Department of Health, 1991
Missouri Department of Health 1992 Fish Consumption Advisory, Missouri
Department of Health, 1992
A Study of Dioxin (2,3,7,8-Tetrachlorodibenzo-p-Dioxin) Contamination in
Select Finfish, Crustaceans and Sediments of New Jersey Waterways,
New Jersey Department of Environmental Protection, Office of Science
and Research (Thomas J. Belton, M.A.; Robert Hazen, Ph.D.; Bruce E.
Ruppell; Keith Lockwood; Robert Mueller, M.S.; Edward Stevenson;
JoAnn J. Post, M.A.), 1985
NJ DEPE
Division of Science & Research
CN 409
401 E. State St., 41E
Trenton, NJ 08625
Environmental Impact Statement for Policy on Contaminants in Fish (Final),
New York State Department of Environmental Conservation, 1985
New York State Department of Environmental Conservation
50 Wolf Rd.
Albany, N.Y.
12233
B-8
-------
APPENDIX B
The Procedure for North Dakpta's Public Health Advisory Regarding
Consumption of Fish Contaminated with Methylmercury, North Dakota
State Department of Health & Consolidated Laboratories, Environmental
Health Section (Martin R. Schock, Special Studies Coordinator; Francis
J. Schwindt, Chief), 1991
ND Dept. of Health and Consolidated Laboratories
Environmental Health Section
1200 Missouri Avenue
P.O. Box 5520
Bismarck, ND 58502-5520
•&U.S. GOVERNMENT PRINTING OFFICE: 1994 - 616-000/81487 B~9
-------
------- |