United States
Environmental Protection
Agency
Office of Environmental Processes
and Effects Research
Washington DC 20460
EPA/600/9-86/004
January 1986 '/
Research and Development
«»EPA
Report of the
Research Planning
Workshop on
Bioavailability of
Dioxins
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EPA/600/9-86/004
January 1986
REPORT OF THE RESEARCH PLANNING WORKSHOP
ON BIOAVAILABILITY OF DIOXINS
RALEIGH, N.C.
SEPTEMBER 1984
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
WASHINGTON, DC 20460
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NOTICE
This document has been reviewed in accordance with
U.S. Environmental Protection Agency policy and
approved for publication. Mention of trade names
or commercial products does not constitute endorse-
ment or recommendation for use.
11
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FOREWORD
Research on the class of compounds called dioxins began several decades ago,
but the research activity increased substantially in the 1960s and 1970s, when the
complex problem of dioxin contamination received national and international
attention. Although considerable research has been done in this field, there are
certain gaps in scientific knowledge, related to understanding the bioavailability of
dioxins, that need to be identified to evaluate more accurately human and
environmental risks associated with these chemicals.
To accomplish this goal, the EPA Office of Research and Development sponsored
the Research Planning Workshop on the Bioavailability of Dioxins, September 9-12,
198*, that brought together scientists and managers in various aspects of dioxin work
from government agencies, academia, and industry. About ninety researchers focused
their attention during the four-day meeting on identifying the most obvious gaps in
knowledge and the consequent research needs.
This report is the outcome of the workshop; it addresses the current state of
knowledge on dioxins and defines the research needs perceived by top scientific
experts in this field. Because of the range and complexity of this scientific area, the
report is divided into three main parts to address different aspects of bioavailability:
environmental processes that determine bioavailability, the bioavailability to
ecosystems, and the bioavailability to humans. This document is primarily intended
for use by the Agency to plan future research programs. We also hope this document
will be useful to other research organizations in both the government and private
sectors.
Erich Bretthauer
Director
Office of Environmental
Processes and Effects
Research
m
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CONTENTS
Page
EXECUTIVE SUMMARY 1
INTRODUCTION 6
CHAPTER 1 - ENVIRONMENTAL PROCESSES IN BIOA VAIL ABILITY 8
1.1 Introduction 8
1.2 Physical and Chemical Properties 9
1.3 Transformation Processes 15
1.3.1 Photochemical Processes 15
1.3.2 Chemical Transformations 16
1.3.3 Biological Processes 16
1.3.* Surrogate Parameters for Combustion 17
1.* Transport Processes 17
1.4.1 Sorption/Desorption/Volatilization 18
1.4.2 Intermedia Transport 19
1.4.3 Advection/Diffusion/Dispersion 19
1.5 Modelling 20
1.6 Analytical Methodology for Analyses of TCDD in
Environmental and Human Samples 21
CHAPTER 2 - BIOAVAILABILITY IN ECOSYSTEMS 24
2.1 Introduction 24
2.2 Exchanges of Dioxin Among Ecosystem Components 26
2.2.1 Conceptual Model 26
2.2.2 Research Needs 26
2.3 Bioavailability: Aquatic Ecosystems 26
2.3.1 Introduction 26
2.3.2 Routes and Rates of Uptake, Metabolism, and Elimination 28
iv
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CONTENTS (continued)
Page
2.3.3 Effects of Dioxin and Ecosystem Processes 29
2.3.4 Biological Decontamination Processes 29
2.3.5 Biological Effects 29
2.3.6 Role of Food Chains in Human Exposure 30
2.3.7 Research Needs 31
2.* Bioavailability: Terrestrial Ecosystems 32
2.4.1 Introduction 32
2.4.2 Degradation of TCDD in Soil 32
2.4.3 Bioconcentration in Wildlife from Soil 32
2.4.4 Movement through Soil to Food Animals to Humans 33
2.4.5 Movement through Soil to Plants 34
2.4.6 Research Needs 34
CHAPTER 3 - BIOAVAILABILITY TO HUMANS 37
3.1 Introduction 37
3.2 Bioavailability of TCDD to Humans from Environmental
Matrices 38
3.2.1 General Properties of TCDD and Matrices 38
3.2.2 Research Needs 38
3.3 In Vivo Bioavailability 38
3.3.1 Mobilization and Redistribution 38
3.3.2 Research Needs 39
3.4 Host Factors Influencing Bioavailability 40
3.4.1 Dietary Factors 40
3.4.2 Genetic Differences 40
3.4.3 Age 40
3.4.4 Concomitant Exposures 40
3.4.5 Exposure History and Other Factors 40
3.4.6 Research Needs 41
3.5 Interspecies Differences Affecting Bioavailability 41
3.5.1 Dermal Route 41
3.5.1.1 Dermal Studies 4'
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CONTENTS (continued)
Page
3.5.1.2 Research Needs 42
3.5.2 Oral Route (Ingestion) 42
3.5.2.1 Oral Studies 42
3.5.2.2 Research Needs 42
3.5.3 Inhalation Route 43
3.5.3.1 Inhalation Studies 43
3.5.3.2 Research Needs 44
3.6 Pharmacokinetics and Structure-Activity Relationships 44
3.6.1 Pharmacokinetic Studies 44
3.6.2 Research Needs 44
3.7 Epidemiology 45
3.7.1 Epidemiological Studies 45
3.7.2 Research Needs 46
3.8 Need for Supply of TCDD 46
CHAPTER 4 - SUMMARY 49
4.1 Physical and Chemical Data 49
4.2 Field Studies 49
4.3 Modelling 49
4.4 Summary 50
APPENDIX - Participants 51
vi
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ACKNOWLEDGMENTS
The contributions of all workshop participants are gratefully acknowledged,
especially Rizwanul Haque of EPA who served as chairperson of the workshop. The
success of the workshop and this report were possible because of the assistance of the
co-chairpersons: Diane Courtney, Thomas Duke, and Walter Sanders, U.S.
Environmental Protection Agency; Michael Gallo, UMDNJ-Rutgers Medical School;
Mark Harwell, Cornell University; and Captain Terry Stoddart, U.S. Air Force.
The efforts of Dan Tisch, Workshop Coordinator, and Linda Cooper, Technical
Editor, Northrop Services, Incorporated, in coordinating the workshop and in producing
this report are also acknowledged. The final version of this report was integrated and
edited by Christine C. Harwell. We also thank Janice Wilson, Word Processing
Specialist, Northrop Services, Incorporated, and Roberta Sardo and Carin Rundle of
Cornell University for their efforts in producing this report.
PLANNING COMMITTEE
Rizwanul Haque - Chairman
Donald Barnes James Falco
Bruce Barrett Steve Jackson
Judy Bellin Harold Kibby
Erich Bretthauer Barry Korb
Michael Cook Robert Landers
Phil Cook Michael Mastracci
Michael Dellarco Charles Nauman
Paul desRosiers Ron Stanley
Robert Dixon Frode Ulvedal
Carl Enfield James Upham
vn
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EXECUTIVE SUMMARY
The goal of the Research Planning Workshop on Unavailability of Dioxins was to
evaluate the ongoing research on the bioavailability of chlorinated dioxins and related
chemicals, to identify research needs, and to develop a focused research plan.
Workshop participants were organized into three groups that addressed the topics:
environmental processes in bioavailability, bioavailability to ecosystems, and
bioavailability to humans.
Each group of participants at the workshop addressed specific areas regarding
bioavailability, within the broad range of dioxin research, and identified areas for
study in their final summary reports. However, the definition and concept of
bioavailability varied among the three groups. One group addressed dioxins in general,
while the other two groups focused discussions on 2,3,7,8-tetrachlorodibenzo-g-dioxin
(2,3,7,8-TCDD). Because the class of dioxins represents a large number of chemicals
and most attention to date has been focused on the isomer 2,3,7,8-TCDD, special
terminology is used in this document to address these chemicals: the term TCDD
refers to 2,3,7,8-TCDD; the term dioxins refers to other isomers.
Environmental Processes In Bioavailability
The group dealing with the environmental processes in the bioavailability of
TCDD evaluated the current state of the art in analytical methods, physical and
chemical properties, transport and transformation processes, and exposure modelling.
The group addressed the basic scientific understanding required for valid estimation of
exposure, bioavailability, and risk. The group identified major gaps in knowledge and
prioritized the research needs in these areas. In ranking the research objectives, the
group considered both short- and long-term needs.
Photochemical Processes
Available information indicates that photolysis offers the most promising
environmental process for degrading TCDD. Therefore, the highest research priority
was assigned to better characterization of the rates and extent of direct and indirect
photolysis in air, on surfaces, and in water.
Physical and Chemical Properties
The second research priority concerns the expansion of the data base covering
physical and chemical properties of TCDD and related compounds. The use of
structure-activity relationships, based on thermodynamic laws, to predict physical and
chemical properties offers a cost-effective alternative to numerous laboratory
determinations.
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Sorption/Desorption/Volatilization
To understand better the dynamics of TCDD movement in all environmental
media, extensive studies of sorption/desorption phenomena are needed. Specifically,
the effects of organic content of soils and sediments on the sorption/desorption of
TCDD from the saturated and unsaturated zones require further study, as do the
effects of particulates on TCDD in the atmosphere.
Chemical Transformations
The chemical transformations of TCDD have not been characterized. A
complete definition of the transformation processes will contribute greatly to the
understanding of transport as well as provide indications of specific chemical reactions
that may be employed to degrade TCDD. The ability of TCDD to undergo
oxidation/reduction, acid/base hydrolysis, nucleophilic displacement, and metal
chelation reactions needs to be determined.
Biological Processes
The use of biodegradation as a cost-effective procedure for TCDD degradation
must be ranked as a long-term, high-priority research need. Because the genes for
TCDD metabolism have been demonstrated in higher organisms, the employment of
recombinant DNA technology to construct a microorganism capable of TCDD
degradation may greatly benefit future cleanup operations and reduce the risk to the
environment and human populations.
Intermedia Transport
Although the rates of certain intermedia transfers can be predicted, appropriate
measurement techniques are not available to validate the predictions. The bulk
transport and intermedia transfer of TCDD require further characterization. The
movement of TCDD-contaminated particles appears to be a critical link in the
bioavailability of TCDD.
Modelling
Currently available mathematical exposure models are applicable to predict the
exposure concentrations of TCDD in the various environmental media, if and when the
various equilibrium and rate coefficients have been determined. However, research
will be required to apply and test the various media and multimedia models to
determine their degree of applicability, precision, and accuracy.
Surrogate Parameters for Combustion
The production of dioxins and furans from municipal incinerators is well
documented. Identification and measurement of these chemical species are costly. To
control effectively the combustion process so that the release of these compounds is
eliminated, new surrogate parameters for process control are needed.
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Need for Sufficient Supplies of TCOO for Research
An adequate supply of TCDD and laboratory standards for all possible isomers of
dioxins and furans is not readily available. These materials are required for quality
assurance and quality control and to facilitate investigations of dioxin and fur an
distribution in the environment. An appropriate toxicological evaluation of dioxins and
furans cannot be conducted without the appropriate laboratory standards.
Bioavailability In Ecosystems
To gain a better understanding of the pathways to humans and effects on the
ecosystem, the fate and transport of dioxin in the environment must be determined.
This determination includes addressing areas such as the bioavailability of dioxin to
biota, and how organisms influence the transport of dioxins within and across systems.
Also of interest are rates of exchange, such as the rate of dioxin uptake by plants from
soil, and the ultimate partitioning of the chemical.
To clarify such interactions, results of group discussion are presented in a
section on a conceptual framework for exchanges of dioxin among ecosystem
components, followed by sections on aquatic and terrestrial ecosystems with respect
to fate, transport, effects on biota (species and processes), and pathways to humans.
In these sections, three sets of topics were considered: 1) identification of
ecosystem processes that a.) are involved in routes, rates, and reservoirs of dioxins in
aquatic and terrestrial ecosystems; b.) are particularly susceptible to effects of dioxin
contamination; or c.) are involved in biological decontamination processes; 2)
identification of particular species and communities that are impacted or potentially
impacted by dioxins; and 3) identification of the role of food chains and webs in
human exposure and risk.
Research Needs
Data on the impact of dioxins at the ecosystem level are essentially nonexistent,
and relatively few data are available describing the effects of these chemicals on
single species. Therefore, many research needs were identified by group participants;
the following were considered the highest priority:
• Develop the capability to predict dioxin levels in tissues (particularly in
organisms that constitute human food chains) as a function of environmental
conditions; develop toxicity data for understanding the mechanisms of toxicity
and the factors responsible for differences in sensitivities among species.
• Measure the concentration of dioxins over time in organisms as a function of
dose in food, water, and other sources for model development. Use microcosms
for model verification.
• Conduct a full-scale ecological study at a highly contaminated site. Include
field studies of fate, chronic effects, and ecological processes, with supporting
laboratory studies.
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• Evaluate the chemical and biological characteristics of residue from
experimental incineration projects and incorporate results in risk assessment.
In addition to these research needs, there is a need to improve risk assessment
capability and to evaluate the uncertainties resulting from conflicting data,
unexpected indirect effects, and laboratory-to-field extrapolations.
Bioavailability To Humans
Risks may be inaccurately estimated in the absence of knowledge about factors
determining bioavailability, even when exposure is relatively well defined. Clearly,
matrix and route effects are likely to be significant. However, human responses and
risk are also influenced by exposure and by differences in the sensitivity of target sites
of action. To consider bioavailability adequately, exposure and toxic response must
also be examined.
The following research needs were identified to evaluate the bioavailability of
TCDD relative to human health.
Matrices
The bioavailability of TCDD from matrices of soil, fly ash, and respirable
particles should be determined using the same species and same toxicologic end points.
A range of concentrations should be utilized, because the bioavailability of TCDD may
differ at differing concentrations levels.
Host Factors; Deposition and Mobilization of TCDD
Because of the lack of knowledge of the critical target organ(s) in humans,
studies are needed to determine the appropriate animal species to use as models for
studying host factors, tissue distribution, and mobilization from body stores.
Additionally, the critical end points and other biochemical markers need to be
determined for both human and other animal models.
One of the sensitive end points in animals and possibly humans is the immune
system. The data that are available indicate further studies are needed of the effects
of TCDD on the immune system.
The body burden of TCDD in humans needs to be determined using adipose tissue
as the most important depot. Studies determining the residue of TCDD in other organs
might indicate possible target organs, as well as the mobilization, redistribution,
metabolic pathways, and secretion or excretion patterns in humans.
Pharmacokinetics and Structure-Activity Relationships
Because humans are often exposed to mixtures of compounds that would include
TCDD and similar chemicals, studies are needed to delineate the interactive effects c f
dioxin and furan isomers with TCDD, and to determine the additive, synergistic, or
antagonistic effects, as well as the pharmacodynamics of the mixtures and receptor
level modulations.
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Extrapolation of Animal Data to Humans
An animal model that best indicates TCOD toxicity in humans is still being
developed according to the criteria more fully discussed in Chapter 3. Because there
are so many manifestations of TCDD toxicity, it may be necessary to have more than
one model, depending on the end point.
Epidemiological Studies
Methods need to be developed to identify persons who have been exposed to
TCDD and related compounds as a basis for epidemiological studies. Additional
studies in humans should be done with cohorts not exposed to TCDD to establish the
baseline for the end points of toxicity. Rigorous epidemiological studies with sound
methods and proper execution are needed to determine the effects of TCDD in
humans. Until there are better epidemiological studies, the determination of TCDD
toxicity will not be known with any assurance, and the extrapolation of animal data to
humans cannot be done reliably.
Assay of TCDD
To perform many of the suggested studies, there is a need to develop and
validate assays of TCDD that are rapid and economical, either in vivo or in vitro, and
that can be used to determine the concentration of TCDD in various organs.
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INTRODUCTION
The class of chemicals polychlorinated dibenzo dioxins, commonly known as
dioxins, has attracted great attention and raised controversies during recent years. In
the United States, issues about dioxins surfaced during the 1960s, when 2,3,7,8-
tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) was found to be a contaminant in the
commonly used herbicide 2,4,5-T (2,^,5-trichlorophenoxy-acetic acid). The high
toxicity and persistence of 2,3,7,8-TCDD in the environment represent the primary
characteristics of dioxins that pose risks to human health and the environment.
Because the class dioxins represents a large number of chemicals and most attention
to date has been focused on the isomer 2,3,7,8-TCDD, special terminology is used in
this document to address these chemicals: the term TCDD refers to 2,3,7,8-TCDD;
the term dioxins refers to other isomers.
Since the 1960s, several incidents have focused attention on the contamination
problem: the human and environmental exposure to dioxins as a result of a chemical
plant accident in Seveso, Italy; the identification of dioxins at several hazardous waste
sites in the states of Missouri, New Jersey, New York, and Arkansas; and the
occurrence of dioxins in fish samples in the states of Michigan and Wisconsin. Dioxins
are also associated with combustion processes and are found in municipal incinerator
fly ash.
In spite of the release of dioxins to the environment and concomitant potential
exposure of humans, the pathways and persistence have not been fully investigated for
many environments. Additional study is required on dioxin accumulation and
partitioning in living systems, the toxicity associated with dioxins, the evaluation of
the human and environmental risks, and the development of control technologies
necessary to minimize such risks. This information is crucial to making appropriate
regulatory decisions about dioxins under the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA), the Toxic Substances Control Act (TSCA), the Resource
Conservation and Recovery Act (RCRA), and the Comprehensive Environmental
Response Compensation and Liability Act (CERCLA or Super!und).
Central to the complex issues of exposure and risk assessment is the evaluation
of the bioavailability of dioxins. The term bioavailability has not been clearly defined,
and the subject remains poorly understood. It involves the understanding of factors
related in the uptake, release, or bioaccumulation of dioxins by living organisms.
Recent findings at the National Institute of Environmental Health Sciences indicate
that TCDD was bioavailable to laboratory animals fed with contaminated soils from
Missouri. But a similar experiment done with New Jersey soil indicated that dioxin
was not detected in the bodies of laboratory animals. To understand the complex
issues of bioavailability, the environmental processes that can influence bioavailability
to ecosystems and humans must be characterized. Identification and quantification of
TCDD and other dioxins in environmental and biological matrices also require major
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attention. Most research data deal with TCDD; the toxic effects and environmental
risks associated with other dioxins also need to be evaluated.
Dioxin research currently funded by the U.S. Environmental Protection Agency
(EPA) addresses four main areas: 1) development of measurement methods and quality
assurance procedures for identifying and quantifying dioxins; 2) development and
evaluation of control technologies for containment and destruction of dioxins; 3) study
of the fate of dioxins in soils and investigation of the uptake of dioxins by plants and
animals; and 4) assessment of health and environmental risk associated with dioxins.
Because understanding the bioavailability of dioxins is essential to understanding
toxicity and risk, a workshop was held to obtain input in developing a focused research
plan. Scientists attending represented a broad range of expertise from research groups
in academia, industry, and government organizations. The goal of this workshop was
to evaluate the ongoing research on the bioavailability of chlorinated dioxins and
related chemicals, identify research needs, and develop a focused research plan.
Workshop participants were organized into three groups that addressed the topics: 1)
environmental processes in bioavailability; 2) bioavailability to ecosystems; and 3)
bioavailability to humans.
The Environmental Processes in Bioavailability Group focused on defining various
environmental processes controlling the bioavailability of TCDD in the biosphere.
Transformation processes and bioavailability assessments were also discussed in this
group. The Bioavailability to Ecosystems Group evaluated the factors relevant to the
bioavailability of dioxins in aquatic and terrestrial ecosystems, and the potential
impact of these chemicals on ecosystems. Ecosystem processes were identified,
particular species and communities that are potentially impacted by dioxins were
addressed, and the role of food chains and the food web in human exposure and risks
were discussed. The Bioavailability to Humans Group evaluated factors such as the
bioavailability of TCDD from environmental matrices, the host factors affecting
bioavailability, in vivo bioavailability, routes of exposure, toxic human effects,
inter species differences, and extrapolation from other animals to humans.
This report will be used by EPA in its research planning. We hope that this
report will be beneficial to other research organizations in planning their research.
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CHAPTER 1
ENVIRONMENTAL PROCESSES IN BIOAVAILABILITY
Co-chairpersons: Walter M. Sanders III and Capt. Terry Stoddart
1.1 Introduction
The presence of TCDD in the environment poses great concern because of its
known toxicity and persistence. Bioavailability of TCDD and other chlorinated
aromatic compounds in the environment depends on many factors that control their
concentration in the biosphere. Important factors include physical and chemical
properties, transport and transformation processes, and characteristics of the
environmental media.
One workshop group of scientists and engineers addressed the many complex
physical and chemical issues related to the bioavailability of TCDD. The group: 1)
evaluated available analytical methods, possible transport pathways, and
environmental transformation processes; 2) reviewed the current state of the
understanding of bioavailability of dioxins; 3) identified significant research needs; and
*) prioritized the efforts required to bring the state of the art up to an acceptable
scientific level to understand human and environmental exposure and risk assessment.
Also considered were the needs for significant supplies of TCDD for research and
standards/reference samples for quality assurance and quality control, the
applicability of available exposure modelling techniques specifically for TCDD, and
the need for surrogate parameters for combustion processes control. The consensus of
the group was that the fate of dioxin isomers and related chemicals, such as the
polychlorinated dibenzof urans and xanthenes, should be considered along with TCDD as
human and environmental toxicology dictates.
The seven highest priority research needs identified by the group are discussed in
order of importance, with a statement concerning the current state of the art and
research objectives. Three related items, analytical methods, modelling, and
surrogate parameters for combustion, were given equal priority, and are also identified
below.
Ranking Need
1 Photochemical Processes
2 Physical and Chemical Properties
3 Sorption/Desorption/Volatilization
* Chemical Transformations
8
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Ranking Need
5 Biological Processes (Longer-term)
6 Intermedia Transport
7 Advection/Diffusion/Dispersion Activities
o Analytical Methodology for Analysis of TCDD in
Environmental and Human Samples Modeling
o Modelling
o Surrogate Parameters for Combustion
These prioritized research needs have been grouped for discussion into five
categories: Physical and Chemical Properties, Transformation Processes, Transport
Processes, Modelling, and Analytical Methodology for Analysis.
In some cases, the research suggested by this working group related only to
TCDD, such as the measurement or validation of the physical and chemical properties
of TCDD. In other cases, the recommended research extends the current scientific
state of the art for characterizing environmental transport and transformation
processes and will be applicable to other hydrophobic organic chemicals. This would
include research efforts to characterize, identify, and measure the soil characteristics
(e.g., organic and moisture content, particle distribution, and temperature) that govern
the rates and extent of the various transport and degradation processes important to
TCDD and all other hydrophobic organic chemicals.
Results from the research outlined in this section will have major impacts on the
understanding and estimation of the bioavailability of TCDD to both humans and
ecosystem components. For example, if volatilization from sorbed surfaces at night is
a significant transport pathway, inhalation or dermal contact with vapor-phase TCDD
will be an exposure route that must be considered. Results from this research will also
apply directly to the modification of regulatory criteria and standards by providing
more accurate identifications of exposure pathways and rates. Likewise, results may
impact the treatment and control of TCDD-contaminated areas if direct vapor-phase
photolysis or biodegradation mediated by genetically engineered microorganisms could
be incorporated into significant in-place treatment processes.
1.2 Physical And Chemical Properties
The known physical and chemical properties for TCDD are summarized in Table
1.1, which includes literature values for measured and estimated properties and values
measured by Schroy and associates. Values not available from laboratory work or
literature were estimated. Comparable data for other dioxins, furans, and other very
low volatility chemicals are not available.
Research Needs
Reasonable estimates of physical and chemical properties of TCDD isomers,
other dioxins, and f urans in general are necessary to permit rational analysis of their
behaviorwithin the biosphere. The structure-activity relationship approach, based on
thermodynamic consideration, represents a cost-effective alternative for this purpose
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Table 1.1
PHYSICAL PROPERTY DATA SHEET*
CHEMICAL NAME
CHEMICAL FORMULA
MOLECULAR WEIGHT
2,3,7,8-Tetrachlorodibenzo-
p-dioxin
(Synonym 2,3,7,8-TCOD or Dioxin)
CAS//- 17*6-01 -6
321.97*
(IUPAC)
SPECIFIC HEAT,a/(°K-gmol)
gas @25°C
HEAT OF VAPORIZATION
@NBP, kj/gmol
@NBP, BTU/lb
@MP, kj/gmol
@MP, cal/g
@MP, BTU/lb
250.92*
71.81*
95.95*
85.00*
63.10*
113.57*
(SHA)
(RPS)
(RPS)
(MON)
(MON)
(MON)
CRITICAL CONSTANTS
P = Pressure, Pa
T = Temperature, K
Z = Compressibility
V = Volume, cm3
DENSITY, g/ml
Solid @ 25°C
Solid/Liquid @ MP
Liquid @ NBP
VAPOR PRESSURE
Pascals® 30.1°C
Pascals @ 5*.6°C
Pascals @ 62.QC
Pascals @ 71 .°C
2372.829*
93*.5 *
0.233*
763 *
1.827*
1.720*
1.021*
*.68 E-7
1.8* E-5
5.03 E-5
1.61 E-*
(RPS)
(RPS)
(RPS)
(RPS)
(BRM)
(RPS)
(RPS)
(MON)
(MON)
(MON)
(MON)
HEAT OF FUSION
@MP, kJ/gmol 38.91
OMP, cal/g 28.88
(3MP, BTU/lb 51.99
HEAT OF SUBLIMATION
@MP, k/gmol 123.91
(§MP, cal/g 91.98
@MP, BTU/lb 165.56
HEAT OF FORMATION
gas @25°C, k/gmol -205.*3*
FREE ENERGY OF FORMATION
gas @25°C, kJ/gmol -195.18*
(BRM)
(BRM)
(BRM)
(MON)
(MON)
(MON)
(SFT)
(SHA)
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Table 1.1 (cont.)
PHYSICAL PROPERTY DATA SHEET
ANTOINE CONSTANTS
Units log e, Pa & K
Temp. Range
A
B
C
T = 10 to 420°C
10 to 305°C
34.57083
14903.438
0.00
(MOM)
NORMAL BOILING POINT (NBP) @ 1 atm
Degrees C 421.4 *
Degrees K 684.52*
Degrees F 790.5 *
Degrees R 1250.1**
FREEZING POINT
305.0
303 to 420=>C
25.10*35*
9430.391*
0.00*
(MON)
(MON)
(MON)
(MON)
(MON)
(BRM)
SOLUBILITY IN (@ I atm)
T = °C milligrams/liter
Water
Agent Orange
o-Dichloro-
benzene
Chlorobenzene
Benzene
Chloroform
n-Octanol
22
25
25
25
25
25
25
0.00000791
5&0
1400
720
570
370
48
(ADB)
I-VA)
(ETD)
(ETD)
(ETD)
(ETD)
(ETD)
HEAT OF COMBUSTION
gas @25°C, kj/gmol
ENTROPHY @ 101.325kPa
gas (9250C, k3(OK-gmol)
-5000.3*
478.06*
SCHMIDT NUMBER (vapor in air @ dilute cone.)
Dimensionless
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Table 1.1 (cont.)
PHYSICAL PROPERTY DATA SHEET
ro
Methanol
Acetone
25
25
10
110
(ETD)
(ETD)
ACTIVITY COEFFICIENTS AT INFINITE DILUTION IN
Water
Agent Orange
o-Dichloro-
benzene
Chlorobenzene
Benzene
Chloroform
n-Octanol
Methanol
Acetone
T =
22
25
25
25
25
25
25
25
25
°C GAMMA
2.26 E12
2368
20*3
439*
6356
10854
4270
796000
39864
(CALC)
(CALC)
(CALC)
(CALC)
(CALC)
(CALC)
(CALC)
(CALC)
(CALC)
HENRY'S LAW CONSTANT FOR AIR/WATER SYSTEM
H, atm m3/gmol 4.88 E-5* (CALC)
Benzene
Chloroform
n-Octanol
Methanol
Acetone
25
25
25
25
25
1.3
2.25
8.8
1.6
8.25
E-8
E-8
E-8
E-6
E-8
(CALC)
(CALC)
(CALC)
(CALC)
(CALC)
ENVIRONMENTAL FACTORS
Oxygen Demand
ThOD, Ib O2/lb chemical 1.193 (CALC)
IMMEDIATELY DANGEROUS TO LIFE AND/OR HEALTH
ppm 0.001*
SAFETY
Acute Toxicity
oral (guinea pigs) LD LO, mg/kg 0.0006
(CDC)
(CAD)
Prepared by J.M. Schroy (1984). Physical properties without asterisks (*) are reported as measured values, but those with asterisks have
been reported as estimated by the author referenced or by a protocol in the referenced document. Those physical properties marked
with an asterisk and referenced as calculated were developed from other data on this sheet by Schroy. Values from laboratory work or
literature are referenced as in the Table 1.1 References. Values not available from laboratory work or the literature were estimated
using methods given by Reid et al. (1977), and are identified as RPS.
-------
References for Table 1.1
ADA
BRM
CAD
CALC
CDC
ETD
IUPAC
KEN
MON
RPS
SHA
SFT
Adams, W.3., and Elaine, K.M.. "A Water Solubility of 2,3,7,8-TCDD",
Monsanto Co., St. Louis, Missouri, Dioxin 85 - 5th International Symposium
on Chlorinated Dioxins and Related Compounds, Byreuth, FGR, September
16-19, 1985.
Boer, P.P., van Remoortere, P.P., and Muelder, W.W. (1972). The
preparation and structure of 2,3,7,8-tetrachloro-p-dioxin and 2,7-Dichloro-
p-dioxin. Journal of the American Chemical Society, 94(3).
Casarett, L.J., and Doull, J. (1980). Toxicology;
Poisons. 2nd Ed. Macmillan, New York.
The Basic Science of
Calculation based on other physical properties. Activity coefficient based
on water solubility. Theoretical oxygen demand based on molecular weight.
Partition coefficient for air/water based on activity coefficient.
Centers for Disease Control, U.S. Department of Health and Human
Services, personal communication. (1982)
Esposito, M.P., Teirnan, T.O., and Dryden, F.E. (1980). Dioxins. EPA-
600/2-80-197. U.S. Environmental Protection Agency, Office of Research
and Development, Washington, D.C.
International Union of Pure and Applied Chemistry. (1979). Atomic weights
of the elements 1977. In Pure and Applied Chemistry. 51:405-533.
Kenaga, E.E. (1980). Correlation of bioconcentration factors of chemicals
in aquatic and terrestrial organisms with their physical and chemical
properties. Environmental Science and Technology, 14(5), 553-556.
Cheng, S.C., Hileman, F.E., and Schroy, 5.M. (1984). Measurements of
vapor pressure at four temperature levels, and development of the heat of
sublimation from the correlation of the vapor pressure data using the
Clausius-Clapeyron equation; estimates of the heat of vaporization were
made using the measured heat of sublimation and the heat of fusion.
Monsanto Company, Physical Property Research, Dayton, OH and St. Louis,
MO.
Reid, R.C., Prausnitz, 3.M. and Sherwood, T.K. (1977). The Properties of
Gases and Liquids. 3rd Ed. McGraw-Hill, New York.
Shaub, W.M. (1982). Estimated thermodynamic functions for some
chlorinated benzenes, phenols, and dioxins. Thermochemica Acta, 58, 11-44.
Seaton, W.H., Freedman, E., and Treweek, D.N. (1974). CHETAH - The
ASTM Chemical Thermodynamic and Energy Release Evaluation Program.
ASTM DS 51. American Society for Testing and Materials.
13
-------
VA 3RB Associates. (1980). Review of Literature on Herbicides, Including
Phenoxy Herbicides and Associated Dioxins. Volume I. Analysis of
Literature. Veterans Administration, Department of Medicine, Washington,
D.C.
-------
because the agents of concern are primarily rigid-ring systems. This approach will
permit the estimation of Henry's Law Constant and distributive tendencies.
Estimation of partitioning behavior across organic liquid/water, air/water, and organic
liquid/air interfaces can then be made. This will aid estimates of mass transfer
processes such as sorption/desorption, volatilization, diffusion/dispersion, and
advection. These data are critical to understanding and ultimately controlling the
human and environmental impact of these low volatility materials.
1.3 Transformation Processes
Important transformation processes considered by the group included
photochemical processes, chemical transformations, biological processes, and
surrogate parameters for combustion.
1.3.1 Photochemical Processes
As the dominant transformation process for TCDD in the environment, photolysis
offers the most promise for degrading dioxins in air, on soil, and in water.
Experiments by workshop participants and others have demonstrated that sunlight
photolysis of TCDD in organic media, water, and on some surfaces may be rapid.
Other studies have indicated that the transport of TCDD occurs slowly but measurably
to the soil surface, where photolysis can occur either on the soil surface or in the
vapor phase above it. TCDD can be introduced into the atmosphere from incinerators
and other incomplete combustion processes and by volatilization from water. Sorption
onto airborne particulates and subsequent photolysis are also possible. All of these
degradation processes serve to reduce TCDD bioavailability in the environment.
Demonstrated degradation pathways for photolysis of TCDD involve both
reduction and ring cleavage, but other pathways are possible, especially in water and
air. Rate constants for sunlight photolysis in water and organic media are reasonably
well known. However, little or no data exist for photolysis of TCDD in the vapor
phase or for TCDD sorbed onto airborne particulates (e.g., fly ash, dust), or onto soil
particles.
Research Needs
The primary research needs in this area include:
• measurements of the rate constants, quantum yields, and pathways of vapor-
phase photolysis of TCDD in the solar range of light;
• similar measurements of TCDD sorbed onto airborne particulates, soil
surfaces, and environmental adsorbents; and
• determination of major pathways for photolysis in solution.
Secondary research needs include similar measurements on other chlorinated
dioxins and related compounds.
15
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1.3.2 Chemical Transformations
Little work has been done on characterizing the chemical degradation reactions
of dioxins or f urans. These chemicals are somewhat refractory to certain reactions, as
is the case with other highly halogenated aromatics. Few of these reactions have
been studied adequately, except the reduction involving alkaline glycol.
Highly charged metal ions are capable of splitting aromatic ethers when a
driving force is available through chelate ring formation. Thus, 1,2-
dimethoxyanthraquione is selectively demethylated at the 1-position by Sn(lV) chloride
to form the corresponding tin chelate. Such reactions suggest the possibility that tri-
and tetravalent metal ions can assist in splitting the ether bridges of dioxins to form
the very stable catecholate chelates of these metal ions. In addition, the loss of one
chlorine atom from TCDD results in a marked reduction of toxicity. Cleavage of the
oxygen linkages also produces a much less toxic product.
Research Needs
A study of chemical reactions of the dioxins, f urans, and related compounds will
provide information for exposure estimates and other methods of altering the toxicity
of these compounds. The types of reactions that should be studied include:
• dechlorination by alkaline-glycol treatment;
• oxidation and reduction by various reagents and catalysts, including metal
oxides;
• ether cleavage with various reagents, including highly charged metal ions;
• metal complexation and coordination; and
• other types of reactions that future research may indicate.
1.3.3 Biological Processes
Biological methods for TCDD degradation may offer significant economic
advantages over other technologies. Despite the evident persistence of TCDD in soil,
there are indications that it can be microbially detoxified. Because of its structure,
the initial step in the microbial transformation of TCDD requires either hydroxylation
by an oxygenase or a dechlorination reaction. Some microorganisms with a
monooxygenase system have been shown to degrade TCDD by incidental metablism to
a hydroxylated product. The rate of this transformation can be increased by
facilitating cellular uptake and by using a suitable substrate to induce the necessary
enzymes. The hydroxylated products formed are expected to be less toxic because
they can be biologically conjugated and eliminated; they are also more water soluble
and dispersible. Fungi and yeasts are known to have a broad range of monooxygenase
enzymes, including some that attack polycyclic aromatic hydrocarbons (PAHs).
Mammalian monooxygenases have been implicated in hydroxylation and dechlorination
of TCDD, and a mammalian monooxygenase gene has been transferred to and
16
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expressed in yeast. The possibility of reductive dehalogenation by microorganisms in
anaerobic environments also exists.
Research Needs
Microbiai degradation of TCOD in contaminated soil or sediment requires the
establishment of microorganisms that: can survive and thrive in the necessary
environments; uptake TCOO in low concentrations; and contain an oxygenase system
that can dechlorinate or hydroxylate TCDD. Research approaches to obtaining such
strains are to:
• screen and genetically modify bacteria, yeasts, and fungi that express
monooxygenases;
• construct bacterial systems through a continuous culture selection procedure;
and
• bioengineer yeasts or fungi for expression of suitable mammalian
monooxygenase activities.
Parallel studies are required to facilitate or genetically enhance the uptake of
TCDD. This may be accomplished by adding solvents or surfactants, or by using
surfactant-producing species.
1.3.4 Surrogate Parameters for Combustion
There exist today a large number and variety of facilities utilizing numerous
feedstocks and combustion processes that may emit TCDD in measurable
concentrations. Present methods of measuring TCDD in stack emissions from
combustion sources are extremely complex and prohibitively expensive. In addition,
the length of time for stack sample analysis prevents immediate feedback to the
system operator for controlling TCDD emissions. Present research in this area has
been confined to drawing limited correlations between TCDD emission levels and
regularly monitored combustion parameters.
Research Needs
A research effort is needed to determine if inexpensive measurements of real-
time combustion processes can be correlated with TCDD emissions and can be useful
in controlling TCDD emissions from combustion sources.
1.4 Transport Processes
The important transport processes considered by the group included
sorption/desorption/volatilization, intermedia transport, and advection/diffusion/
dispersion.
17
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1.4.1 Sorption/Desorption/ Volatilization
Considerable data are available to characterize the adsorption and partitioning
of organic chemicals, particularly pesticides, aromatic hydrocarbons, and PCBs, on
participate matter derived from soils and sediments. This has led to a number of
correlations for estimating adsorption by soils for chemicals whose adsorption has not
been measured. Organic matter content is considered to be the factor controlling the
extent of adsorption and has led to the use of the Koc (octanol/water coefficient)
concept for estimating adsorption.
Soil/water partition coefficients (Kj) of 10^ ml*g~l have been calculated for
TCDD, based on measured values for water solubility and estimated values for
octanol/water partition coefficients. Apparent TCDD partition coefficients ranging
from 10* to 10° have been estimated, utilizing leachate data from a few contaminated
soils from Missouri and New Jersey.
No information is available on partitioning behavior with respect to TCDD on
atmospheric participates. However, it has been postulated that the binding of TCDD
to fly ash during combustion is irreversible.
Considerable information has appeared in the literature on the application of
soil/water and air/water partition coefficients (Henry's Law Constant) to the transport
of organics to the surface of a soil column, where they will be subject to
volatilization. Currently, the estimated partition coefficients for TCDD must be
relied upon for determining the volatilization potential for dioxins.
Research Needs
The primary research needs in this area include:
• determining rates and extent of adsorption/desorption in soil and sediment
systems as a function of organic matter and mineral content, either to
validate or to reject the Koc concept for predicting partitioning;
• identifying the mechanisms influencing TCDD partitioning onto mineral
surfaces that are characteristic of soils having low organic matter content;
• determining adsorption/desorption on atmospheric particulates as a function
of organic matter, mineral, and water content;
• characterizing the vapor-phase desorption isotherms as a function of
participate (soil, sediment, or air) composition and water content; and
• identifying the factors that would alter the predicted compound behavior in
soil/sediment systems. Factors that should be investigated include: the
presence of strong acids and bases or high levels of dissolved organic matter
in interstitial waters; the presence of co-solvents; the movement cf
microparticulates, organic colloids, and colloidal clays; and the influence of
organic micelles (or emulsions).
18
-------
1.4.2 Intermedia Transport
Theoretical kinetic analyses of TCDD interphase transport have received limited
attention. Low volatility substances such as TCDD have enormous activity
coefficients in water. In volatilizing from water, TCDD probably forms a liquid film
(two-dimensional gas) on the water surface. Thus, its transport to the gas phase
probably depends directly on its thermodynamic activity. Transport between other
phases probably operates in more complex ways. No detailed analyses of these
transport systems are available. The lack of essential validated physical and chemical
data currently makes analyses of intermedia transport very difficult.
Research Needs
The mechanism for intermedia transport must be characterized to understand
and control the impact of any specific chemical on the environment. The rates of
transfer between media, the capacities of the media, and the mass transfer
coefficients need to be defined. In some cases, the kinetic measurements have not
been attempted because of the difficulty of monitoring the mechanism. Significant
environmental transport parameters in each medium, (e.g., participates, soils, and
sediments) must be characterized in terms of impact on the mechanisms of the
transport processes. Distribution of the specific chemicals on surfaces or on particles
of different sizes must also be examined. All these parameters must be characterized
for TCDD and all dioxins and furans.
1.4.3 Advection/Diffusion/Dispersion
Advection of a chemical in air, surface water, and interstitial water in
groundwater systems is the movement of the chemical with the bulk movement of the
air or water. In some environments, chemical phases also need to be considered,
including two-phase flow (water/organics), suspended participates, and colloids.
Although characterizing the advection of vapors and dissolved chemicals in water is
frequently difficult, predicting advection in a second phase presents a more serious
problem that remains unresolved in many instances.
The state of the art for estimating rates of diffusion and dispersion was ranked
at previous EPA workshops on exposure assessment as poor to fair, and current
estimations of diffusion and dispersion rates for TCDD isomers were ranked as poor.
In general, molecular diffusion rates are calculated using estimates of molecular
diffusivities. Procedures for estimating molecular diffusivities in the air are the most
accurate; procedures for estimating diff usivities in water and soils are less accurate.
In addition to estimation of diffusivities, other physical parameters must be
either measured or estimated to calculate diffusion rates in soils and sediments.
These parameters include void fraction of soils or sediment volumes and tortuosity of
the diffusion path.
Dispersion of chemicals in air and surface waters results from the turbulent
motion of the fluid. Dispersion rates in these media are functions of a variety of
physical parameters such as wind or water velocity, and temperature and density
19
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gradients. In addition to possible turbulent motion, dispersion may occur because of
the heterogenous characteristics of solid phases. Consequently, dispersion in soils and,
potentially, in sediments must take into account site-specific characteristics and scale
factors.
Research Needs
Calculations of the amount and rate of TCDD adverted into, through, and out of
each medium are required for both the vapor phase and TCDD sorbed to participates.
The need to improve abilities to characterize, measure, and predict advection in
saturated and unsaturated soils, sediments (interstitial waters), and estuarine waters
should receive the highest priority. Also, advection in two-phase flow must be
characterized for these systems.
The rates and extent of the diffusion and dispersion processes for TCDD must be
better characterized for saturated and unsaturated soils and sediment systems,
including the two-phase flow. This also includes the development of better techniques
for measuring the significant environmental factors that govern the process rates and
extent, such as void fraction and soil temperature.
1.5 Modelling
For the transport and transformation of individual chemicals in air, water, and
soil environments, many mathematical models are available to predict exposure
profiles necessary for bioavailability estimates. Models offer a method to organize
information on many different processes occurring simultaneously, and facilitate the
interpretation of laboratory and field observations and the determination of rate-
controlling steps. Models range from very simple, steady-state algorithms to very
complex, process-oriented dynamic codes. Simple models are easy to use but are
usually inappropriate for site-specific field situations. More comprehensive, complex
models, although possibly more realistic, may contain variables for which data are not
readily available or for which methods are inadequate or unavailable to measure
magnitudes in time and space. Examples of this problem include measuring the water
conductivity in soils and the spatial variability of dispersion coefficients in air and
soils. However, judicious selection and use of appropriate models can provide the most
reasonable approach for solving complex exposure problems.
Research Needs
With regard to the use of complex models, there is a continuing need to develop
more efficient numerical methods to solve coupled systems of nonlinear, partial
differential equations that are stable and present solutions with low levels of
numerical dispersion. To facilitate the development of realistic complex models, the
efforts of the laboratory scientists, field researchers, and modellers must be closely
coordinated. Without such coordination, inappropriate models may be developed and
applied to field conditions to predict exposure concentrations from contamination
episodes.
20
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In addition, it is necessary to determine the conditions under which single
chemical models can legitimately be used to predict the transport and transformation
of mixtures. It is tacitly assumed that for contaminants with low solubilities, and even
for most designated air pollutants, the concentrations in the transporting medium are
so low that they act independently of one another. This assumption is certainly not
true in a photochemical smog episode, and it remains an issue for which no clear
criteria exist to determine the set of chemical properties or concentrations for which
interactions are significant or negligible. Thus, models that address the issues of
mixtures and their interactions are needed, particularly for dioxins and furans. Also,
the application of models to the complexities of multiple-phase transport imposes an
additional level of difficulty in developing meaningful numerical solution techniques.
1.6 Analytical Methodology For Analyses Of
TCDO In Environmental And Human Samples
Analytical methodologies currently utilized by EPA for analyzing TCOD in
environmental and human samples involve:
1) fortification of the sample with an isotopically labeled TCDD;
2) extraction with an organic solvent when analyzing soil, sediment, and water; or
3) saponification with alkali followed by solvent extraction when analyzing
biologicals such as human tissue.
Interferences are removed by acid and base partitioning steps, followed by
chromatographic cleanup on alumina and charcoal columns or high performance liquid
chromatography. A portion of final concentrated extract is subject to isomer-specific
analysis by capillary gas chromatography and mass spectrometry, using selected ion
monitoring. The quantity of TCDD reported is corrected for recovery efficiency of
the labeled standard in each sample.
This analytical methodology has focused on TCDD; however, it has also been
extended for the quantitative determination of other dioxin isomers and
polychorinated dibenzofurans. Several matrices have been analyzed, and their
respective minimum detection limits (MDL) are listed in Table 1.2.
Rigorous quality assurance has been incorporated into the analytical
methodology. Samples are analyzed in well-defined sets that include blanks, spiked
matrices, duplicates, and blind samples. Some samples are exchanged and analyzed by
outside laboratory collaboration. A panel consisting of scientists outside of EPA has
been established to review analytical results before their release.
Research Needs
Sufficient supplies of TCDD are needed for research, as well as for standards and
reference samples for quality assurance and quality control.
21
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Table 1.2
Minimum Detection Limits (MDL) of Selected Matrices3
Matrix
Water
Human milk
Deer adipose muscle, liver, bone marrow
Human adipose, beef adipose, beef liver
Elk adipose
Pork adipose
Pottery clay
Dog adipose
Fish, herring gull tissue
Soil, sediment
Fly ash from coal-fired power plants
Fly ash and gas-phase effluents from municipal
incinerators
Chemical disposal sites
Chemical products and processes
Chemical destruction processes
MDL
0.008
0.1
0.4
0.5
1
h
h
1
1
1
1
1
10
20
20
Range
to
to
to
to
to
to
to
to
to
to
to
to
to
to
to
i.oi
5
5
10
5
7
7
10
10
10
10
300
800
800
800
a Prepared by A. Dupay and R. Harless.
b Based on 1000-g samples.
22
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Environmental Processes in Bioavailability Working Group
PARTICIPANTS
Jimmy Boyd
Peter Chapman
David Cleverly
Donald Crosby
Paul DesRosiers
Aubry Dupuy
Walter Farmer
Virgil Freed
Randy Freeman
Robert Harless
Takeru Higuchi
Greg Kew
Christopher Kouts
Douglas Kuehl
Bill Lamason
John Loper
Leland Marple
Arthur Martell
Danny McDaniel
Jay Means
Theodore Mill
Warren Piver
John Quenson
Michael Roulier
Walter Saunders
Jerry Schroy
Terry Stoddart
23
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CHAPTER 2
BIOAVAILABILITY IN ECOSYSTEMS
Co-chairpersons: Thomas Duke and Mark Harwell
2.1 bitroduction
Chlorinated hydrocarbons, including dioxins, are found in terrestrial and aquatic
ecosystems and are bioavailable to certain organisms. The bioavailability of these
chemicals should be considered in a holistic manner, because ecosystems typically
consist of dynamic assemblages of thousands of species existing within a complex and
heterogeneous chemical and physical environment, with which they interact.
Biological organisms control ecosystem processes of energy and material flow, and
they modify the chemical and physical environment. Alternatively, the environment
substantially affects the distribution, abundance, and diversity of these biota.
An important aspect of ecosystems is that they operate simultaneously on widely
differing spatial, temporal, and structural scales. The focus may be on individuals,
populations, and communities of species, or on integrative measures such as diversity,
productivity, respiration, and decomposition. For our purpose here, the term
ecosystem includes all of these aspects, and the term bioavailability means the
exchanges between the environment and the biota, and exchanges from biota to other
biota. In large part, this mutual interaction between the environment and biota
focuses on the interface between chemicals in an abiotic phase and between chemicals
within the biota. Exchange across this interface is the central element of
bioavailability. The concept of bioavailability here includes both the dynamic and
steady-state aspects.
Both the rates of exchange, such as the rate of dioxin uptake by plants from
soils, and the ultimate (steady-state) levels of dioxin accumulated in biota are of
interest, especially as represented by bioconcentration factors (e.g., the dioxin
concentration in plant tissue divided by the concentration in the soil).
The ecosystem considerations for dioxin have two distinct facets: the effects of
dioxin on the biota in the ecosystem, and the role of the ecosystem in mediating dioxin
exposure to humans. The human exposure pathways represent a special case of the
more general investigations of the fate and transport of dioxin within ecosystems.
Routes that take dioxin from an abiotic phase into biotic material ingested by humans
are worthy of careful attention; these are discussed in the following sections on
aquatic and terrestrial ecosystems.
Effects on ecosystems begin with effects on individuals. These effects can be
manifested as physiological responses, behavioral responses, or even death of
-------
individual organisms. But translating effects on individuals to effects on a population
is not a simple extrapolation. Effects on populations are influenced by the
interactions of the individuals within the population and with other species, and also by
the nature of the physicochemical environment. For example, compensatory
mechanisms may decrease adverse effects on populations; conversely, differential
sensitivity within life stages may result in greater effects on natural populations than
would be predicted from laboratory bioassays on individuals.
Community-level effects involve an increase in complexity, where indirect
effects may result when a population not directly exposed to dioxin in the biotic phase
becomes indirectly exposed through food-web interactions. Community composition
can be affected by indirect effects involving predator-prey interactions, changes in
competitive relationships, and induced susceptibility to disease or parasites, among the
many various possible interactions. In considering community compositional changes,
particular species or groups of species may be identified as being especially important,
whether for economic, aesthetic, or ecological reasons.
Finally, additional factors influence ecosystem process-level effects. For
example, if different species perform the same functional roles, whole species can be
lost or populations altered without changing ecosystem processes, because of such
functional redundancy. Conversely, if fundamental ecosystem processes are affected,
biological changes can be expected to occur in commmunity composition, which is
dependent on those processes. Thus, in some instances, biological responses to toxic
chemicals might be better understood by measuring ecosystem processes directly
rather than by monitoring species composition and diversity.
To predict effects of dioxin on ecosystems and on humans, the transport and fate
of dioxins in the environment must be understood. The bioavailability of dioxins to
biota, exchanges among biota, and influences of organisms on the movement of dioxins
within and across systems must be included. A conceptual model of exchanges of
dioxins among ecosystem components appears in the next section. Subsequent sections
address transport and fate in aquatic and terrestrial ecosystems, effects on biota
(species and processes), and pathways to humans.
In these sections, three sets of topics were considered: 1) identification of
ecosystem processes that are involved in routes, rates, and reservoirs of dioxins in
aquatic and terrestrial ecosystems, sensitive to effects of dioxin contamination, and
involved in biological decontamination processes; 2) identification of particular
species and communities that are potentially affected by dioxins; and 3) the role of
food chains and food webs in human exposure and risk.
Overlying all of these topics are issues of scale across time and space and issues
of uncertainty. Scale issues include determining the spatial and temporal extent of
exposure and effects, differentiating chronic versus acute exposures, and considering
whether there is sufficient time for potential compensatory mechanisms to operate.
Uncertainty follows from lack of information, spatial and temporal heterogeneity that
can obscure effects, differences among species in sensitivity to direct effectj,
propagation of indirect effects, and unexpected consequences.
25
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2.2 Exchanges Of Oioxin Among Ecosystem Components
2.2.1 Conceptual Model
The purpose of most ecosystem models is mathematically to describe complex
ecosystem interactions among biotic and abiotic components. Once an appropriate
model has been developed, it can be used to answer questions about higher-level
processes, such as chemical transfers through the ecosystem. Information on both
process rates and component concentrations is utilized. Mathematically, it becomes
more difficult to develop and verify a model which increases in complexity from
species to population to community level. At the ecosystem level, validation of
models is difficult or impracticable.
To obtain a. better understanding of the bioa vail ability of dioxins to both lower
and higher forms of life, and movement from one component to another, and to
identify areas of critical research needs, we have presented a food-web model
applicable to both aquatic and terrestrial ecosystems (Figure 2.1). The conceptual
model figuratively describes interactions and dioxin exchanges among abiotic and
biotic components. The dioxin pools in a number of biotic components are shown,
including the transfers among biotic compartments through feeding. Also shown is a
general abiotic pool of dioxins. The open arrows represent the exchanges of dioxin
among abiotic phases and each type of biota. Details can be added to this abiotic pool,
making the conceptual model applicable to different types of ecosystems.
The model is generic; from it, calculations can be made based upon assumptions
of the thermodynamics of tne toxicant. We recognize that equilibrium conditions do
not always exist in the environment; however, we believe this is a useful approach for
calculating initial estimates of dioxin concentrations for some components. In
general, the tendency for change is towards thermodynamic equilibrium. Thus, the
bioavailability of dioxins to organisms can be evaluated, and the hazard or risk of
compartmental concentrations can be assessed.
2.2.2 Research Needs
Research should be conducted to:
• measure concentrations of dioxins with time in organisms as a function of
dose in food, water, and other sources for model production;
• use microcosms to verify models; and
• conduct a full-scale ecological study at a highly contaminated site. This
should include field studies of fate, chronic effects, and ecological processes,
with supporting laboratory studies, and studies of the mechanisms of effects.
2.3 Bioavailability: Aquatic Ecosystems
2.3.1 Introduction
The distribution, transport, and fate of TCDD and other dioxins and furans in
aquatic ecosystems are governed by processes that are generally known from studies
26
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Dioxin Pool Food Web Model
Primary
Producer
Dioxin
Pool
Primary
Consumer
Dioxin
Pool
Macro-
invertebrate
Microbial
Decomposers
Dioxin J
Abiotic
Dioxin
Pool
Secondary
Consumer
Dioxin
Pool
Figure 2.1 Dioxin pool food-web model. Solid arrows indicate abiotic dioxin flux
by predation and feeding; open arrows indicate direct exchange between
the abiotic and biotic components. This concept can be expanded to
demonstrate dioxin pool exchange between two more foci webs of the
ecosystem.
27
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of other hydrophobia organochlorine compounds such as PCBs. All these compounds
share an affinity for the carbonaceous component of suspended and settled sediment
and for dissolved organic matter; these characteristics influence bioavailability. Less
can be inferred from these studies when we attempt to predict biological effects of
chlorinated dioxins and furans because of uncertainties that exist with regard to
uptake, metabolism, and the toxic model of action of these compounds. For example,
the selective bioconcentration of TCDD observed in fish exposed to mixtures of dioxin
isomers has not been predicted on the basis of dioxin isomers1 similar water
solubilities.
Our ultimate research goal is to develop methods for predicting the
bioavailability of dioxins and furans to aquatic organisms in different environmental
settings on the basis of the physical and chemical properties of isomers, routes of
exposure, water chemistry, sorbent interaction, and pharmacokinetics of uptake.
Estimates of the potential environmental impacts of dioxins will be improved and
strengthened if the dose received by organisms can be accurately predicted. From a
human health perspective, prediction of the amount of contaminant accumulated by
organisms can indicate whether unacceptable levels may be expected in animals
consumed by humans. Development of this capability will thus aid in designing water
quality criteria and in evaluating the environmental risks associated with existing
contamination and with future releases.
2.3.2 Routes and Rates of Uptake, Metabolism, and Elimination
The bioavailability and accumulation of a contaminant depends on its physical
and chemical form and the rates at which it is taken up, metabolized, and eliminated
by organisms. Physicochemical partitioning within the aquatic environment exerts a
major influence on bioavailability of dioxins because the rate at which a compound can
be taken up by an organism will vary widely, depending on the physical matrix with
which it is associated. By analogy with other organic compounds, dioxins dissolved in
water are expected to exhibit a high rate of uptake. Contaminants associated with
organic and inorganic particles, dissolved organic matter, or food appear to be less
readily incorporated. The rates of dioxin uptake from different source compartments
and the physical and biological factors that affect the rates of incorporation need to
be examined quantitatively so that the total incorporation by organisms can be
predicted.
Although dioxins, like many other organochlorine contaminants, do not appear to
be readily bio transformed, the rates and pathways of detoxification by aquatic
organisms need to be examined. Information on the pharmacodynamics of dioxin
distribution among tissues within an organism is needed to understand the metabolic
fate, the mechanisms of toxicity, and the accumulation in tissues that are consumed
by humans. Development of correlations between tissue distribution of dioxins and
molecular components of the tissue, such as lipid content, would be particularly
relevant.
Rates of elimination of TCDD appear to be very low, although other TCDIJ
isomers may be eliminated more rapidly. Because the body burden of dioxins
accumulated by organisms will be largely determined by their elimination rates, it is
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important to increase our knowledge about the rates and routes of elimination of
dioxins.
The rates and routes of uptake, metabolism, and elimination of dioxins, and thus
the body burden present at any time, will be affected by natural and human-induced
changes in the environment. The effect on these processes, of environmental
variables, such as temperature, salinity, water chemistry, and dissolved oxygen, as
well as the effects of nutritional status of the organism must be understood if a
predictive capability is to be achieved.
2.3.3 Effects of Dioxin on Ecosystem Processes
Toxic organics can alter ecosystem processes. Although there are no data
directly implicating dioxins in altered ecosystem processes, there are sufficient
toxicological data to warrant concern. From the known physical chemistry of dioxins,
it is expected that dioxin effects on ecosystem processes will be similar to effects of
other toxic organics for which data exist (e.g., PCBs and PAHs).
Productivity, both primary and secondary, is a fundamental process of
ecosystems. Dioxin contamination may pose a risk to the balance of productivity.
Should dioxins affect any functional group of organisms (e.g., phytoplankton, filter
feeders, or carnivores), there could be a shift in the energy flow patterns that might
be detrimental to the overall balance of the ecosystem.
At the ecosystem level, the processes most sensitive to dioxin toxicity would
likely be alterations of population behavior, fecundity, immunological resistance, and
other life-history characteristics. However, the classic approach to community
structure analysis is too coarse a measure. By the time parameters such as diversity
are affected, the system is usually heavily contaminated.
There are insufficient aquatic field data on effects of dioxins. A data base needs
to be developed from which the long-term consequences of dioxins in the environment
can be evaluated. Research should focus on the key ecosystem processes described
above.
2.3.4 Biological Decontamination Processes
Mechanisms to eliminate dioxins from ecosystems may have both biological and
physical components. Biologically, microorganisms have the potential to degrade
dioxins. Physically, photooxidation may be important in aquatic environments, but the
removal of dioxins from the biologically active zone by sediment accumulation
processes and burial is likely to be more important. Because dioxins are associated
with fine-grained sediments, the transport and long-term fate of dioxins will be
mediated by sediment transport processes. We also need to understand the dynamics
of sediment transport as a mechanism for remobilization.
2.3.5 Biological Effects
Toxic effects of dioxins and furans in actual aquatic ecosystems have been
studied in only a few instances. Factors complicating such studies include the virtual
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absence of useful exposure data, particularly for water concentrations, the presence of
complex mixtures of many organochlorine compounds, the nonspecific symptomology,
the slow mode of action, and the levels of accumulation.
Fish-eating birds can accumulate TCDO and related isomers. Reproductive
effects, including embryotoxicity and teratogenicity, are consistent with early
research on the chicken and the putative agent in chick edema disease,
hexachlorodibenzodioxin (1,2,3,7,8,9-HCDD). While previous studies on Lake Ontario
herring gulls are now artifactual, unpublished research on the Forster's tern on Lake
Michigan show continuing reproductive problems consistent with the known effects of
these compounds.
The available data describing TCDD toxicity to aquatic organisms are limited to
fish. Laboratory exposures of fish to TCDD that have been reported can only be used
for a gross estimate of toxic effects. No information exists on the toxicity of other
dioxin or furan isomers. In separate studies, northern pike (eyed eggs) and rainbow
trout (juveniles) were exposed for four days to a range of static TCDD concentrations
and held for depuration in noncontaminated well water. These studies indicate that
TCDD is a slow-acting toxicant. However, the mode of toxicity appears to be
different than for most other neutral lipophilic organic chemicals. It is not clear
whether short-term exposures can ultimately produce the same dose-response
relationships as continuous exposure to the same or lower levels over longer periods of
time. The mode of action of TCDD toxicity in aquatic organisms is unknown.
Traditional methods for assessing acute toxicity, such as the 96-hour LD5o> are
not useful in dioxin hazard evaluations. The available data are insufficient to gauge
the magnitude of variability in interspecies sensitivity, although this may be quite
large, as is the case for mammalian toxicity studies. At this time, a no-effect-
concentration cannot be determined. Growth and reproduction have not been
investigated for fish or invertebrates exposed to trace concentrations of TCDD for
sufficient periods of time to allow steady-state concentrations to be reached in
tissues. Bioassays performed with complex mixtures of dioxins, furans, and other
organochlorine compounds produce toxic effects that indicate additive and possible
synergistic interactions.
The toxicity of TCDD associated with suspended or settled sediments has not
been determined. Water TCDD concentrations resulting from partioning with
sediments may affect toxicity, especially if organism uptake is primarily via the gills.
The ingestion of contaminated sediments, particularly by bottom-feeding fish and
benthic organisms, presents a potentially important alternate route for uptake and
consequent toxic effects. Bioassay systems adequate for long-term, controlled
exposure of aquatic organisms to suspended and settled sediments are needed.
2.3.6 Role of Food Chains in Human Exposure
Aquatic organisms and fish-eating avians may accumulate dioxins and related
compounds to levels of concern relative to both toxic effects and risks to huma i
consumers of the organisms. However, a comprehensive understanding of dioxins that
would allow the prediction of body burdens from exposure data has not yet been
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achieved. Microcosm studies have provided estimates for bioconcentration factors
(BCFs) for aquatic piants and animals; however, measurement of steady-state BCFs
and those concentrations that may be achieved in nature have not been undertaken.
Relationships between sediment concentrations and fish tissue concentrations are open
to interpretation. Data suggest that fat or fat content of individual tissues may be an
important determinant of bioconcentration in aquatic species. In summarizing the
uncertainties related to body burdens in aquatic organisms, it appears that age, size,
species, feeding relationships, and fat content are key considerations from a biological
standpoint. Abiotic factors probably include: sediment transport and availability;
characteristics such as particle size, organic content, and general complexing ability
by organic compounds; and solvents as dissolution agents.
Sufficient information is available to establish the bioavailability and
bioconcentration of TCOD and related compounds in salmonids and other species in the
Great Lakes, in rivers and ditches that drain dumps, and in fields sprayed with 2,4,5-T.
Knowledge of dioxin kinetics is much more sketchy concerning estuarine and marine
species. Fish, snapping turtles, and fish-eating birds have been characterized in
individual situations, but there is little understanding of the potential for
biomagnification along food chains within a contaminated ecosystem. Because
biomagnification is associated with orders-of-magnitude increases across biotic media
boundaries, understanding the potential for biomagnification can be best determined
by placing special emphasis on birds and mammals feeding on aquatic organisms.
2.3.7 Research Needs
The key area to be addressed in future research is a better understanding of
factors controlling bioaccumulation. In addition to laboratory research on individual
aspects such as fat content and partition coefficients, full abiotic/biotic food-chain
research should be conducted to characterize contaminated areas. Areas differing in
the relative dominance of perceived factors affecting food-chain transfer of dioxins
and related compounds should be studied. To understand and develop a total human
exposure model and institute risk assessments, aquatic food-chain influences (e.g.,
fish, turtles, crayfish, and waterfowl) need to be integrated with terrestrial wildlife
concentrations, domestic food intake, and occupational/ambient exposures to
determine adequately the primary pathways to humans.
Research should be conducted to:
• develop the capability to predict dioxin levels in tissues (particularly in
organisms that constitute human food chains) as a function of environmental
conditions;
• develop data for understanding the mechanisms of toxicity and the factors
responsible for differential toxicity among species; and
• determine the nature and extent of disruption caused by dioxins in aquatic
communities and the mechanisms by which they are caused.
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2.4 Bioavailability: Terrestrial Ecosystems
2.4.1 Introduction
Few acute and chronic toxicity studies have been conducted to study TCDD
effects in the field. The few field studies conducted on wildlife that are reported in
the literature involve sampling trophic levels at contaminated sites and determining
TCDD concentrations. Very few laboratory studies have been conducted to study the
acute and chronic toxicity of TCDD to wildlife as well as effects on ecosystem
processes. The limited data that are available from controlled laboratory and field
studies show that TCDD bioaccumulates in terrestrial wildlife up to about 25-fold and
that bioconcentration among trophic levels does not occur to any significant extent.
In areas containing high concentrations of TCDD, studies are needed concerning TCDD
bioaccumulation, bioconcentration in trophic levels, and ecosystem process effects. In
isolated cases, some risk to humans could occur from food animals that have direct
access to contaminated soils. The risk is most significant when individuals consume
their own farm-raised products. Risk to the general public would be smaller because
of dilution through marketing channels and diversity of dietary sources.
The major routes of contamination in terrestrial ecosystems are likely to be the
movement of dioxins from soil to animals and from the atmosphere to plants. Liver
and adipose tissues are the most likely reservoirs for dioxins in animals, and those in
intimate soil contact harbor the highest dioxin concentrations. Assuming that
susceptibility will be largely a function of exposure, those animals ingesting or
inhabiting soil are the most likely to be affected by TCDD. This includes domestic
animals or wildlife that eat soil along with food or grooming, as well as burrowing
animals such as groundhogs, rodents, and rabbits. Soil-dwelling micro- and
macroinvertebrates are also likely to receive high exposures.
2.4.2 Degradation of TCDD in Soil
The major processes of TCDD removal from soil are photodegradation and
volatilization. It is generally agreed that microbial degradation of TCDD occurs to a
very limited extent. Preliminary results of microbial degradation studies underway in
Missouri indicate that microbial degradation occurs, but it is too early to draw firm
conclusions. Refer to Chapter 1 of this report, Environmental Processes in
Bioavailability, for additional information on this subject.
2.4.3 Bioconcentration in Wildlife from Soil
Whole-body and tissue concentrations of TCDD have been measured in a variety
of wildlife species under conditions of chronic field exposure. The highest
concentrations of TCDD are generally found in the liver and adipose tissues. Although
dioxin concentrations may be influenced by factors such as trophic level, fat content,
physiological state, and sex of the organism, the primary factor influencing uptake by
wildlife appears to be the degree of contact with contaminated soil. In earthworms,
which continually consume and contact soil, a direct linear correlation has been shown
between body burdens of TCDD and soil concentrations. Despite reported body
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burdens of TCDD in numerous organisms, no studies have definitively shown either
population or community effects.
Unlike aquatic animals, terrestrial animals do not concentrate TCDD to a
considerable extent. BCFs are generally around 25 or less. The highest BCF reported
is 42, found in earthworms in Seveso, Italy. Interestingly, absolute concentrations of
TCDD in aquatic animals have not exceeded those found in terrestrial animals despite
the high propensity for movement from the water column into aquatic animals. It
should be noted that BCFs for aquatic organisms usually describe the partitioning of
dioxins between water and organisms, whereas BCFs for terrestrial animals usually
describe the partitioning between soil and organisms that may not be in constant
contact with soil.
There may be potential human food-chain exposure from wild terrestrial birds,
such as wild turkey, pheasant, quail, and grouse, but no data exist to substantiate
whether TCDD and related compounds (e.g., furans) exist in these species. Turkeys
seem to be more sensitive to contaminants such as PCBs than the other species.
However, relative sensitivities among species may be important to humans because
wild birds may continue to accumulate concentrations of dioxins until consumed for
food.
2.4.4 Movement through Soil to Food Animals to Humans
The major route of potential TCDD exposure to farm animals is by direct
ingestion of soil. Intake of soil by grazing cattle and sheep is inversely related to the
amount of available forage and may range from 2 to 15% of dry matter intake. Cattle
may also consume soil at 2 to 4% of dry matter intake when confined to lots with no
vegetation. Pigs consume 2 to 3 times as much soil as cattle. Data are not available
for soil consumption by poultry with access to soil.
Monitoring data show a general correlation between herbicide application rates
and TCDD levels in cattle. It has been suggested that BCFs for TCDD from soil to
mammals range from 2 to 25. Field experience with the chemically related
polybrominated biphenyls suggests that this is a reasonable conclusion for nonlactating
ruminants such as cattle and sheep. This factor is slightly lower for lactating cattle
because of the secretion losses through milk. BCFs are several times higher in pigs
because of higher soil consumption. No BCFs are available for poultry.
TCDD is known to be highly toxic to domestic poultry, but essentially nothing is
known regarding the quantitative aspects of dioxin interaction with these birds,
particularly as related to potential metabolic pathways and residue retention by edible
tissues or secretion into eggs. However, because of the highly controlled environment
in which most commercial poultry is raised, soil contamination by dioxins is unlikely to
result in significant concentrations in commercial poultry. In barnyard poultry,
exposure at dioxin-contaminated sites is certainly possible, and limited studies suggest
that contamination of meat (and presumably eggs) would result. There are no data to
indicate what levels of dioxin residues in poultry meat or eggs would be expected from
a given dietary intake level.
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Given the nature of the presently known and likely to be discovered dioxin-
contaminated terrestrial sites, the major potential for human dietary exposure to
dioxin residues would probably occur through the consumption of meat or milk from
farm animals held on contaminated sites. A number of available studies clearly
indicate that exposure of farm animals, particularly cattle, to dietary dioxins will
result in residue retention by edible tissues and secretion into milk.
Studies with the higher chlorinated dioxins suggest that in livestock, a limited
degree of bioconcentration in tissues over dietary levels may occur. But, if
bioconcentration occurs with TCDD, it may be considerably less. The available data
on dioxin interactions with both lactating and beef cattle appear to be only marginally
definitive with respect to their value in predicting residue levels that would occur in
meat or milk as a result of specific levels of dietary exposure. Lactating cattle fed up
to 500 ppt dietary TCDD resulted in milk levels of approximately 100 ppt, although
24 ppt dietary TCDD to beef cattle gave up to 100 ppt in fat and 10 ppt in liver.
Studies have demonstrated that normal cooking processes do not generally reduce
dioxin levels present in raw meats.
2.4.5 Movement through Soil to Plants
TCDD can translocate through plants; however, uptake from soil is generally
very small, with an extremely small accumulation of dioxin into fruits and seeds. In
field studies, contamination of aboveground plant parts has often been attributed to
contaminated dust.
Dioxin binds to organic surfaces, including plant roots, and in the bound form is
unavailable for absorption and translocation. Concentrations in fleshy roots at the
root surface typically are similar to soil concentrations, with a sharp decrease toward
the root center.
Uptake from solution and translocation into aboveground plant tissues occurs at
rates that are easily measured and would be of concern under some conditions.
Concentrations in soybean and oat leaves have been shown to be five and ten times
(plant dry weight) the solution concentration after one day of exposure.
A possible contradiction between field studies and some laboratory uptake
studies probably results from imprecise descriptions of the root/soil solution interface.
In soil, dioxin is normally bound to particles and is therefore unavailable for uptake.
Even binding to exterior root surfaces makes dioxin unavailable for uptake. However,
when dioxin is in solution at the exterior root surface, uptake and translocation occur.
Therefore, conditions that change dioxin solubility in soil may facilitate plant uptake.
There is no evidence in the scientific literature of plants being affected by
dioxin, even at the highest levels of contamination studied. However, specific studies
to examine phytotoxicity have not been done.
2.4.6 Research Needs
Research should be conducted to:
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• evaluate the chemical and biological characteristics of residue from
experimental incineration projects and apply the results to risk assessment;
• identify the mechanisms by which TCOD in bound forms is released in the gut
and taken up by lactating and food animals; and
• determine the effects of soil organisms and plant roots on vertical transport
and bioavailability of TCDD.
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BIOAVAELABELITY IN ECOSYSTEMS WORKING GROUP
Brian Butterworth
Philip Cook
Robert Diaz
Tom Duke
George Fries
Mark Harwell
Robert Huggett
Wayne Ivie
Darcy Johnson
Kenneth Johnson
Steve Kennel
Tim Kubiak
PARTICIPANTS
Douglas Kuehl
Ray Lassiter
John McCarthy
James Craig McFarlane
Hap Pritchard
Thomas Sabourin
Richard Tucker
Barbara Walton
Armon Yanders
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CHAPTER 3
BIOAVADLABILITY TO HUMANS
Co-chairpersons: Diane Courtney and Michael Gallo
3.1 bitroduction
This work has focused on bioavariability to humans, which refers to those
characteristics of the toxicant (e.g., its form, route, matrix, and concentration) and
the host that determine the internal biologically active dose. Risks may be
inaccurately estimated in the absence of knowledge about factors determining
bioavailability, even when exposure is relatively well defined. Clearly, matrix and
route effects are likely to be significant. However, human responses and risk are also
influenced by exposure and by differences in the sensitivity of target sites of action.
To consider bioavailability adequately, exposure and toxic response must also be
examined.
TCOD was the main concern of this report. The biological effects of TCDD have
been more extensively studied than any other chlorinated dibenzodioxin or
dibenzofuran. However, because many isomers of dioxin are usually found at the same
sites, the possible influence of other isomers of dioxin on the bioavailability of the
TCDD isomer is well recognized, and workshop discussions could readily be applied to
these other dioxin isomers as well. Additionally, dibenzof uran isomers are often found
in the same sites as the dioxins, and the furans could easily influence the
bioavailability of TCDD and the other dioxin isomers. Because the furans and dioxins
have very similar toxic end points, it was recognized that the following discussion
would apply to tetrachloro-, pentachloro-, hexachloro-, and heptachloro- dioxin and
f uran isomers.
Bioavailability to humans, as the host organisms, has two aspects:
1) the uptake of chemicals from environmental matrices into the host and the
interactions with critical receptors and tissues within the host; and
2) the subsequent distribution, redistribution, or mobilization within the host.
Mobilization is a means of internal in vivo bioavailability that could be
beneficial (by promoting excretion) or detrimental (by increasing exposure to
critical organs).
These two aspects of bioavailability to humans served as the definition of
bioavailability for this workshop group. Additionally, it was recognized that
bioavailability could be an index of the potential for incorporation into humans.
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3.2 Bioavailability Of TCOO To Humans
From Environmental Matrices
3.2.1 General Properties of TCDD and Matrices
Physical and chemical properties of TCDD that should be considered include
partition coefficients, vapor pressure, lipid coefficients, and solubilities, which have
been discussed in Chapter 1.
Matrix types and characteristics that should be considered include soil, fly ash,
aerosols, and solutions. A recent finding is that the length of time the TCDD is bound
to soil may be critical for the subsequent extraction of TCDD from the soil, in that
the longer the time TCDD is bound to the soil, the harder it is to extract TCDD.
Various soil types result in distinctly different strengths of chemical binding with
TCDD. Bioavailability is primarily dependent on the binding of TCDD to different
matrices.
3.2.2 Research Needs
Matrices of various composition with known TCDD concentrations should be used
to determine the bioavailability of TCDD by using the same species and toxicologic
end points. Soil should be considered as a priority matrix because it is the most
common one to which humans are exposed. Contaminated fly ash or respirable
particles should be studied to determine their TCDD bioavailability to humans. A
range of concentrations should be utilized, because the bioavailability of TCDD may
differ at differing concentration levels.
3.3 In Vivo Bioavaiiability
3.3.1 Mobilization and Redistribution
In vivo bioavailability is a measure of the amount of TCDD that is at the target
organs, cells, or cellular constituents. In addition to the TCDD that is available from
environmental matrices, TCDD is also bioavailable from TCDD mobilization or
redistribution within the host in specific tissues, organs, or cells. After TCDD enters
the host from an environmental source, it is distributed to target organs or storage
depots. However, TCDD can be mobilized from depots and redistributed to target
organs or other depots, producing an in vivo bioavailability that should be recognized.
Although there are no data on the mobilization of TCDD in humans, knowledge of the
bioavailability of TCDD by mobilization has been documented in other animals. This
aspect of bioavailability is extremely important because any TCDD stored in the
human body in the adipose or other tissue is always a source that could be mobilized
under a number of conditions and has the potential to produce toxicity in the host.
The determination of the end points of toxicity and quantification of the degree of
toxicity will be dependent on the internal distribution of TCDD.
It is important to know how host factors such as possible pregnancy, age,
nutritional status, and prior exposure influence the in vivo bioavailability by
mobilization and redistribution of TCDD, with the possibility of altered end points or
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altered degree of toxicity. Moreover, several critical organs and cellular targets are
likely, so that all of the implications of redistribution are not known. Nevertheless, it
is important to enhance excretion, directly or by redistribution, to limit distribution or
redistribution to such sensitive tissues as fetuses and gonads, and to prevent secondary
exposure via breast milk.
3.3.2 Research Needs
There are very few data on animals or humans in which the concentration of
TCDD from an in vivo bioavailable source is known. Studies and techniques are needed
for the determination of TCDD from a primary exposure and from a secondary
exposure through mobilization and redistribution.
The determination of the TCDD body burden in humans is needed, with adipose
tissue being the most important tissue to be examined. This would permit a direct
comparison to the other halogenated hydrocarbons and dioxin and furan isomers that
would provide a background profile of the extent of contamination of these compounds
in the human population.
Additional studies should determine the residue of TCDD in other organs of
humans that might determine TCDD target organs as well as the possible mobilization
and redistribution of TCDD. This would also suggest the possible metabolic pathways
and/or secretion or excretion patterns in humans.
To perform many of the studies, there is a need to develop and validate assays
for TCDD that are rapid and economical, either in vivo or in vitro, and that can be
used to determine the concentration of the TCDD in the various organs of the body.
This would be necessary for studies to determine mobilization and redistribution of
TCDD.
Analytical chemical methods for the direct measurement of TCDD are available
for fat and for breast milk analyses (see Table 1.1 in Chapter 1). These methods
should be applicable to other organs, some of which can be assayed by biopsy. Biopsies
would permit the determination of TCDD in various organs which could be related to
the microscopic examination of the biopsy.
Toxicity end points could be used to estimate the bioavailability of TCDD, but
they lack specificity. It is well established that TCDD produces chloracne in humans
and some animals. Although this response is not specific for TCDD, the assay could be
a sensitive indicator of TCDD. Enzyme changes and alteration of porphyrin
metabolism could be explored as indicators of TCDD bioavailability, although they also
lack specificity. Extracts of various matrices could be assayed for TCDD
bioavailability by indirect in vitro methods, such as induction of rat hepatocyte aryl
hydrocarbon hydroxylase (AHH) activity, human lymphocyte AHH activity, and
porphyrin changes in human f ibroblasts, although there are no data on the alteration of
porphyrin metabolism in humans as seen in other animals. These indirect methods are
not specific for TCDD, and it should be recognized that other dioxins and furans can,
and do, affect these end points, confounding the results. Specificity might be obtained
by methods that are under development for estimating the concentration of TCDD
using radio!mmunoassay and monoclonal antibody techniques.
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3.4 Host Factors Influencing Bioavailability
Many host factors can modulate the bioavailability of TCDD with an increase or
decease of availability. Because there are many host factors, only some of the well
known factors will be addressed.
3.4.1 Dietary Factors
Dietary consumption patterns influence exposure and may also influence
bioavailability by affecting absorption and rate of retention in the gastrointestinal
tract. The nutritional status of the host in terms of deficiencies, malnutrition, and
specific diets (e.g., high or low fat) will influence bioavailability by increased or
decreased uptake. Body fat content will have a major effect on distribution and
mobilization.
3.4.2 Genetic Differences
It is well known that genetic differences can influence absorption,
biotransformation, receptor interaction, and excretion of many toxic agents in
numerous species. However, very little is known about these factors in humans.
Although few data are available, it is recognized that genetic differences could be a
major factor determining the variability of bioavailability in humans and subsequent
toxic manifestations. Studies should be undertaken with responsive and nonresponsive
mice to indicate a possible range of effects.
3.4.3 Age
Both behavioral and physiological characteristics related to age influence
bioavailability. Factors such as dermal penetrability and gastrointestinal absorption
change with age. Also, there is evidence from animal studies for oncogenetic
development of cellular receptors for TCDD.
3.4.4 Concomitant Exposures
TCDD is similar to other chlorinated hydrocarbons in its manifestation of
toxicity. Concurrent exposures to other chlorinated hydrocarbons as well as furans
and other dioxin isomers may influence the bioavailability of TCDD by competition,
inhibition, or enhancement. However, very few data are available on this topic
relating to humans.
3.4.5 Exposure History and Other Factors
Prior exposure to organic chemicals may enhance or reduce the uptake and
retention of TCDD, thus influencing the bioavailability.
Other host factors to be considered are behavior, lifestyle, and health and
disease states. Data are insufficient to warrant high priority consideration of theie
factors. However, information from occupational studies may assist in reevaluating
the importance of these factors.
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3.4.6 Research Needs
Adequate consideration of research needs in the area of host factors affecting
bioavailability is hampered by a lack of knowledge regarding critical target organs and
the best choice of an animal model for human toxicity. The appropriate animal
species to use as a model for studying host factors, tissue distribution, and
mobilization from body stores is needed because data show that the tissue distribution
of TCDD differs in monkeys and rodents (see discussion in Section 3.5). Many end
points of toxicity could be studied; however, the critical end point in TCDD toxicity is
not known. Some end points that should be considered are: elevation of blood lipids,
increased production of porphyrins, impaired immune response, peripheral
neuropathies, and dermal disorders such as chloracne. Other biochemical markers
need to be determined, especially those specific to TCDD; however, these would also
most likely be indicative of the other dioxins and f urans. Additionally, the extent to
which data on other dioxin and fur an isomers can be applied to TCDD should be
evaluated.
3.3 Ihterspecies Differences Affecting Bioavailability
Data derived directly from in vivo studies of TCDD bioavailability in humans
would obviously be most useful in addressing the issue of bioavailability. However, for
ethical and other reasons, it is likely that most of the data on bioavailability will, of
necessity, be derived from in vivo studies using laboratory animals as surrogate testing
species.
Therefore, it was deemed imperative that these anticipated animal studies on
bioavailability be planned, conducted, interpreted, and extrapolated to humans in a
scientifically appropriate manner that accommodates all the information on the
interspecies differences affecting bioavailability. These differences can be delineated
into two groups: the more general conceptual interspecies differences applicable to
many xenobiotics, and the more specific interspecies differences of particular
importance in evaluating the bioavailabiliity of TCDD and other halogenated dioxins
and f urans.
The interspecies differences affecting bioavailability by the three principal
routes of exposure (dermal, ingestion, and inhalation) would include, but are not
limited to, the following variables among humans and the various laboratory animal
species likely to be used in the in vivo studies of bioavailability.
3.5.1 Dermal Route
The dermal route of exposure to TCDD provides a direct mechanism for
absorption of the toxicant. This exposure can result from direct contact with
contaminated soil or through air transport of dust or fly ash.
3.5.1.1 Dermal Studies
Anatomical and physiological differences among humans and various laboratory
animal species would include factors such as the presence or absence of an
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integumentary hair coat, the thickness of the hair coat, the thickness of the epidermis
and dermis, the presence or absence of integumentary adnexai structures such as
sebaceous and sweat glands, the comparative aspects of the subcutaneous fat and
vasculature and lymphatics, the comparative ratios of skin surface area to body
weight, the comparative enzymatic capabilities of the dermis, and the comparative
potential for binding to plasma proteins after dermal absorption.
3.5.1.2 Research Needs
Evaluation of the suitability of various in vivo and in vitro models is needed for
predicting dermal absorption of TCDD. Dermal uptake of TCDD should be examined
in several species in vivo. Direct absorption from various matrices, such as soil and
fly ash, should be examined. Species that might be considered include pigs (neonatal
skin), rats, guinea pigs, and mice, including dermal uptake by both responsive and
nonresponsive strains of mice. Uptake by various species in vivo should be compared
to transport in at least one in vitro model using skin explants from the same species as
well as uptake in human skin culture. Species differences in uptake in vitro should be
compared with species differences in vivo to determine whether the in vitro model is
predictive of the in vivo data and to determine in which species dermal absorption
most closely resembles absorption by human skin.
3.5.2 Oral Route (Digestion)
In a second type of exposure, ingestion, bioavailability is a function of whether
TCDD intake is from eating contaminated foods or from exposure to TCDD-
contaminated soil or dust. If TCDD-contaminated food is consumed, bioavailability
becomes analogous to bioaccumulation.
3.5.2.1 Oral Studies
Comparative studies of bioavailability using various laboratory animal species as
surrogates for humans should consider the following variables: interspecies dietary
patterns (herbivorous, carnivorous, or omnivorous), anatomical differences such as the
presence or absence of cecum, comparative transit times via the gut, comparative
aspects of biliary salt production and pancreatic enzyme production, comparative
differences in pH within the gut, comparative aspects of enterohepatic circulation and
gut flora, and intestional vasculature and lymphatics.
3.5.2.2 Research Needs
In bioavailability studies of TCDD, feeding contaminated soils to various
laboratory animals has produced substantial differences in response. Thus, the
differences in bioavailability that have been identified warrant further studies. Some
of these further studies should use variations of the more conventional in vivo test
procedures that have been utilized in bioaccumulation studies with certain laboratory
species such a guinea pigs and rats.
Other types of studies that should be done, the results of which could lead to
generalizations that can be modeled, include in vitro gut sack and substituted
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gastrointestinal content studies as a means to estimate release of TCDD from
matrices. Gut sack studies allow the investigator to examine the role of different
areas of the intestinal tract in absorption and transport. This model is easily
adaptable to several animal species, including the human digestive tract from surgical
specimens. The human specimens would be necessary to extrapolate data from
animals to humans.
Substituted gastrointestinal content studies are currently carried out by the U.S.
Food and Drug Administration (FDA) and the U.S. Department of Agriculture to
determine the release of disiodgeable residue of pesticides and the release of active
ingredients from medications, particularly generic equivalents. This approach could be
coupled with high-resolution analytical techniques to estimate the effect of the
digestive process (time, pH, and volume) on dislodging TCDD from matrices.
The monitoring of the human diet by the FDA should be sufficient to estimate
the bioavailability of TCDD from diet. However, special situations may need direct
study, such as people on a high-fat diet, people growing gardens next to dump sites, or
children ingesting dirt.
3.5.3 tihalation Route
Municipal waste incinerators have been well characterized as being potentially
chronic, dispersive sources of low levels (parts per trillion) of chlorinated dioxin
isomers into the atmosphere. At some time following release from incinerator stacks,
those isomers not already adsorbed or absorbed to participates will become bound to
participates as the compounds reach sublimation. Therefore, human exposure can be
predicted to occur by inhaling TCDD-bound participates into the respiratory tract.
Bioavailability would then become a function of particle size, the chemical nature of
the participate, the distribution of TCDD in relation to particle size, the dynamics of
particle-size retention in the lungs, and the action of the lungs in dissolving, digesting,
or extracting TCDD from the particles.
3.5.3.1 Inhalation Studies
Inhalation of TCDD from environmental matrices should be studied in at least a
rodent model. One such study should determine the bioavailability of TCDD in rats
exposed to dusts generated from specific sites or matrices. The matrices should be
selected to represent extreme conditions of absorption, so that models can be built to
assess human risk without testing every contaminated site or matrix.
The dusts (participates) should be generated by a dust feeder that allows particle
sizing, such as the Wright Dust Feeder. The dust should be analyzed prior to animal
exposure. The analysis should include the compounds present, the type of matrix, and
the composition of the matrix. After nose-only exposure, the biochemical markers and
toxicity indicators should be determined. A major question to address is which
compounds are retained compared to compounds in the original sample. The nose-only
inhalation procedure eliminates the possibilities of dermal deposition and absorption,
as well as oral ingestion from grooming.
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3.5.3.2 Research Needs
In view of the predominant concern regarding exposure to particulates,
anatomical and physiological differences should be addressed. Anatomical differences
among humans and the various laboratory animal species should be examined in regard
to the upper respiratory tract, the bronchiolar tree, the alveoli, and the pulmonary
vasculature and lymphatics.
Physiological differences would include respiratory volume, respiratory rate,
participate sedimentation rates for the upper and lower respiratory tracts,
comparative aspects of clearance via mucociliary apparatus, retention time, and the
ultimate fate for particulates that do reach the alveoli.
When designing studies of bioavailability in laboratory animals, consideration of
these general issues should be supplemented by more specific issues of special
importance for the chlorinated dioxins and furans that are discussed in the following
two sections.
3.6 Pharmacokinetics And Structure-Activity Relationships
Absorption, distribution, and excretion of dioxins and furans have been studied in
a number of species. These compounds were found principally in the liver and fat of
all species examined. Differences among species in metabolism or distribution do not
appear to account for differences in species sensitivity.
3.6.1 Fharmaookinetic Studies
The most toxic isomer of dioxins and furans is substituted in all four lateral
2, 3, 7, and 8 positions; however, extensive in vitro and in vivo quantitative structure-
activity relationships have not been fully developed. This information could readily be
used to predict the toxic end points and human toxicity of isomers of this large class
of toxic environmental agents. The few structure-activity relationships of dioxin
isomers indicate that TCOD is the most toxic compound, with the other isomers being
less toxic. Estimating the toxicity of mixtures of these various dioxins and furans is
not possible, simply because too little is known about the toxicity of the individual
compounds or the possible interaction of the compounds.
3.6.2 Research Needs
The areas that should be studied include:
• the effects of structure on the biologic and toxic activities of dioxins and
furans;
• the development and validation of quantitative in vitro bioassays that can be
used to predict in vivo effects of dioxins and furans;
• a study of the in vivo interactive effects of dioxins and furans and the
determination of additive, synergistic, and antagonistic effects;
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• a study of dioxin and fur an isomers and the effects of structure on
pharmacokinetics in exposed animals;
• the role of interactive effects on the pharmacodynamics of mixtures; and
• the effects of receptor level modulation (e.g., by PCBs and PBBs) on the
toxicity of individual dioxins, f urans, and their mixtures.
3.7 Epidemiology
When reviewing the results of animals studies, it is easy to look at only one
compound, TCDD. However, when reviewing epidemiological data, it is extremely
difficult to deal with only one compound, because most exposure groups have been
exposed to a mixture of compounds or isomers. For this reason, we feel that the focus
of dioxin research must address a number of compounds, including dibenzodioxin,
dibenzofuran isomers, and halogenated hydrocarbons.
3.7.1 Epidemiological Studies
There have been a large number of animal studies on the adverse biological
effects of TCDD exposure such as hepatotoxicity, porphyria, dermal changes,
teratogenicity (e.g., cleft palate and hydronephorosis), and functional toxicity,
including modulation of immune response. Long-term effects of exposure are of
interest, especially as exposure may impact humans. Animal studies have shown
relatively long-term immunosuppression following perinatal exposure and increased
incidence of soft-tissue neoplastic disease. Despite the abundance of data from
animal studies, a great need remains for studies of the effects of TCDD exposure in
humans.
Regarding the carcinogenicity of TCDD, several epidemiological studies have
found a significant positive association between exposure to dioxin-contaminated
phenoxy acids and/or chlorophenols and soft-tissue sarcomas and non-Hodgkins
lymphomas. Additionally, in several small industrial cohorts exposed to TCDD-
contaminated chemicals, several cases of soft-tissue sarcoma have appeared where
none were expected because of the relative rarity of the disease. Also, chloracne was
either suspected or confirmed. These studies have several limitations that preclude
the estabishrnent of a causal relationship with TCDD exposure at this time, although
several other studies showing no effects suffer from limitations as well.
Epidemiological studies are needed to address the toxic manifestations of TCDD in
humans.
The results of immune function studies in humans following TCDD (or related
chemicals) exposure are ambiguous. Children exposed in the Seveso accident were
shown to have significantly elevated lymphoproliferative responses, but other
published studies have reported no effects. Unpublished studies have indicated
changes in lymphoproliferative responses (both enhancement and suppression) and
shifts in lymphocyte subpopulations. Studies of individuals exposed to PCBs have
shown that PCBs are immunomodulators in humans, causing suppression of delayed
hypersensitivity reactions, enhancement of lymphoproliferative responses, and
-------
increased incidence of infectious diseases. It is not known if these end points can
occur in humans exposed to TCDD.
3.7.2 Research Needs
Following is a list of research needs related to human health:
• Methods need to be developed to identify persons who have been exposed to
TCDD and related chemicals, and to identify more precisely the actual
compounds to which they were exposed. This will enable researchers to
evaluate more fully the human health effects of exposure.
• Because of the potential for interaction of the halogenated cyclic
hydrocarbons (additive, syngeristic, or antagonistic effects), studies are
needed to investigate the effects of multiple compounds. This includes
identifying human populations exposed to a mixture of compounds, describing
the effects of exposure in these populations, and performing laboratory
studies on the interaction of compounds.
• When possible, studies should be performed using in vitro exposure of human
tissues to dioxins (i.e., human tissues in culture) and the results of these
studies utilized to evaluate the studies of in vivo exposure of animals and to
facilitate extrapolation to humans.
• Additional epidemiological studies should be accomplished with cohorts not
exposed to TCDD or similar chemicals, to establish the baseline for humans
for the anticipated end points of toxicity. Although data from animal studies
are available in this area, data for human exposure are needed.
• Based on the sensitivity of the immune system (animal studies) to chemical
exposure and based on preliminary findings in human populations exposed to
TCDD about the importance of the immune system in resistance to neoplastic
and infectious disease, additional studies are needed to describe more fully
the effects of TCDD and related chemicals on the immune function in
humans. Establishing the proper measure of immune function may enable an
indication of low-level exposure in humans.
3.8 Need For Supply Of TCDD
To date, the toxicity of halogenated dioxins has been determined with studies
using only the single compound, TCDD. To evaluate and understand the problems with
the complex environmental matrices containing many halogenated dioxins and f urans,
mixtures of dioxins with and without f urans should be studied. This, in turn, requires
sufficient quantities of these compounds for toxicology studies.
EPA maintains a repository of purified, analytical-grade pesticides and industrial
chemicals for use by scientists throughout the world. This is a very successf Jl
program supplying small quantities of standards for chemical assays. In general,
commercial chemical companies do not make dioxins and f urans available to
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toxicologists because of a limited market. Supplies of these chemicals are needed in
sufficient quantities and purities for use by toxicologists.
By expanding current and proposed studies to include other dioxins and furans
with the study of TCDD, data will be generated that will be significantly more useful
to EPA by better focusing on the problems in dump sites and other areas of interest.
If the compounds are not available for a few years, answers to the critical questions
about dump sites could be delayed a decade or more because many of the studies would
have to be repeated to incorporate the other dioxins and furans. Thus, we recommend
that the EPA support production and supply these compounds to investigators studying
dioxins and furans.
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Donald Barnes
Oavid Bayliss
Judith Bellin
Diane Courtney
Sergio Fabro
Robert Faith
Marilyn Fingerhut
Michael Gallo
Joyce Goldstein
Maurene Hatch
Greg Kew
Renate Kimbrough
Richard Kociba
Bioavailability to Humans Working Grotj>
PARTICIPANTS
Barry Korb
David Marlow
James Melius
Patrick O'Keefe
Dhun Patel
Stephen Safe
John Schaum
Arnold Schecter
Barclay Shepard
Ellen Silbergeld
Frode Ulvedal
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CHAPTER*
SUMMARY
In order to understand the effects of transport and fate of dioxins and related
isomers through environmental media and, ultimately, bioavailability to humans, there
are four areas of research needing critical attention: physical and chemical data, field
studies, modelling, and human effects studies. Implicit in all of these is a need for
adequate supplies of and laboratory standards for all possible isomers and compounds
of dioxins and furans, to ensure quality assurance and quality control.
4.1 Physical and Chemical Data
The physical and chemical properties of TCDD isomers, other dioxins, and furans
need to be further investigated in order to analyze their behavior within environmental
media. This workshop has recommended the use of the structure-activity relationship
approach, based on thermodynamic consideration. An increased data base will further
enhance estimations of partitioning behavior across abiotic interfaces, which will aid
estimates of bulk transport and intermedia transfer processes. Understanding
intermedia transfer processes can aid in the investigations of methodologies for
degrading dioxins in the environment, through photolysis, chemical transformations, or
biological processes, ultimately, expansion of the information on physical and chemical
properties of dioxins and related isomers will assist the investigations of ecosystem-
level processes affecting and being affected by these chemicals and will add further
information to answer questions about bioavailability to humans and effects on human
tissues and organs.
4.2 Field Studies
In order to supplement and enhance the results of laboratory research on basic
questions of physical and chemical behavior of dioxins, output from field studies is
needed. Information can be used to verify and validate modelling and laboratory work,
as well as provide basic data on observed environmental effects. Particularly for the
issue of bioavailability in ecosystems, a full-scale field study needs to be conducted at
a highly contaminated site. This should include studies of transport and fate, chronic
effects, and ecological processes. Such a field study should be closely linked to
laboratory investigations.
4.3 Modelling
Further efforts need to be made to develop more accurate and applicable
mathematical models to predict exposure concentrations of dioxins in environmental
media. Concentrations of dioxins over time in organisms as a function of dose need to
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be measured for model development. The food-web conceptual model presented in
Chapter 2 can be a base upon which calculations can be made giving initial estimates
of dioxin concentrations for components. This generic model can be applicable to both
terrestrial and aquatic ecosystems, with more specific detail added as needed.
Development of ecosystem-level models should be one major goal of the full-scale
field study program.
4.5 Summary
Running as a common thread throughout this report is the need for further basic
research on the physical and chemical makeup of dioxins and related isomers,
compounds, and mixtures. But even more relevant to the end point of all
environmental regulations, effects on humans, is a need for a basic understanding of
how dioxins relate to the environmental media into which they are released. How they
affect and are affected by the physical and chemical processes with which they come
in contact as they are transported through the biosphere speaks to the ultimate
questions of control and degradation, of exposure, bioavailability, and risk. A focused
research plan would seek to understand these most basic processes and interactions,
from which base of information adequate assessment can be made of the levels of
regulation most practicable.
50
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APPENDIX
PARTICIPANTS
William Adams
Monsanto (NIB)
800 N. Lindbergh
St. Louis, MO 63167
Donald Barnes
U.S. Environmental Protection
Agency (TS-788)
401 M Street, SW
Washington, DC 20*60
David Bayliss
Carcinogen Assessment Group
U.S. Environmental Protection
Agency (RD-689)
401 M Street, SW
Washington, DC 20460
Judith Bellin
WH-562B, Room 5242
U.S. Environmental Protection
Agency
401 M Street, SW
Washington, DC 20460
3immy Boyd
J.M. Huber Corporation
P.O. Box 2831
Borger, TX 79008
Erich Bretthauer, Director
Off. Environ. Proc. & Effects Res.
U.S. Environmental Protection
Agency (RD-682)
401 M Street, SW
Washington, DC 20460
Brian Butterworth
Environmental Research
Laboratory
U.S. Environmental Protection
Agency
6201 Congdon Blvd.
Duluth, MN 55804
Peter Chapman
University of Minnesota
Dept. of Biochemistry
140Gortner Lab
1479 Gortner Avenue
St. Paul, MN 55108
Morris Chelsky
Diamond Shamrock Tower
717 N. Harwood
Dallas, TX 75201
David Cleverly
Off. of Air Quality Planning and
Standards
U.S Environmental Protection
Agency (MD-12)
Research Triangle Park, NC 27711
Michael Cook
WH-562
U.S. Environmental Protection
Agency
401 M Street, SW
Washington, DC 20460
Philip Cook
Environmental Research
Laboratory
U.S. Environmental Protection
Agency
6201 Congdon Blvd.
Duluth, MN 55804
51
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Diane Courtney
Health Effects Research Laboratory
U.S. Environmental Protection
Agency (MD-82)
Research Triangle Park, NC 27711
Russ Cristman
Dept. of Environ. Sciences &
Engrg. School of Public Health,
Duluth, MN 55804
University of North Carolina
Chapel Hill, NC 27514
Donald G. Crosby
Environmental Toxicology
Department
University of California-Davis
Davis, CA 95616
Ron Dagani
Chemical & Engineering News
1155 16th Street, NW
Washington, DC 20036
Michael Dellarco
OMSQA (RD-680)
U.S. Environmental Protection
Agency
401 M Street, SW
Washington, DC 20460
Paul DesRosiers
ORD-OEET
U.S. Environmental Protection
Agency (RD-681)
401 M Street, SW
Washington, DC 20460
Robert Diaz
Virginia Institute of Marine
Sciences
Glouster Point, VA 23062
Thomas Duke
Environmental Research
Laboratory
U.S. Environmental Protection
Agency
Sabine Island
Gulf Breeze, FL 32561
Aubry Dupuy
U.S. Environmental Protection
Agency
Building 1105
NSTL, MS 39529
Tom Evans
Off. of Waste Enforcement
U.S. Environmental Protection
Agency (WH-527)
401 M Street, SW
Washington, DC 20460
Sergio Fabro
Columbia Hospital for Women
2425 L St., NW
Washington, DC 20037
Robert Faith
Animal Care Operations
University of Houston
4800 Calhoun
Houston, TX 77004
Walter 3. Farmer
Dept. of Soil and Environ. Science
University of California-Riverside
Riverside, CA 92521
Marilyn Fingerhut
NIOSH
4676 Columbia Parkway
Cincinnati, OH 45226
Virgil Freed
Dept. of Agricultural Chemistry
Oregon State University
Corvallis, OR 97331
Randy A. Freeman
Monsanto
800 N. Lindbergh
St. Louis, MO 63137
George F. Fries
Pesticide Degradation Laboratory
Beltsville Agricultural Res. Center
Beltsville, MD 20705
52
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Michael Gallo
UMDN3
Rutgers Medical School
P.O. Box 101
Piscataway, NJ 08854
Bernard Goldstein
Assistant Administrator
Office of Research and Development
U.S. Environmental Protection
Agency
401 M Street, SW
Washington, DC 20460
Joyce Goldstein
NIEHS
P.O. Box 12233
Research Triangle Park, NC 27709
Rizwanul Haque
U.S. Environmental Protection
Agency
401 M Street, SW
Washington, DC 20460
Robert Harless
Environmental Monitoring Systems
Lab.
U.S. Environmental Protection
Agency (MD-67)
Research Triangle Park, NC 27711
Mark Harwell
Ecosystems Research Center
Corson Hall
Cornell University
Ithaca, NY 14853
Maurene C. Hatch
Division of Epidemiology
Columbia University
600 W. 168th St.
New York, NY 10032
Ralph Hazel
324 E. llth St.
Kansas City, MO 64106
Robert J. Huggett
Virginia Institute of Marine Science
Gloucester Point, VA 23062
Wayne Ivie
USDA, VTERL
P.O. Drawer GE
College Station, TX 77841
Darcy Johnson
Environmental Research
Laboratory
U.S. Environmental Protection
Agency
6201 Congdon Blvd.
Duluth, MN 55804
Kenneth L. Johnson
Environmental Research
Laboratory
U.S. Environmental Protection
Agency
6201 Congdon Blvd.
Duluth, MN 55804
Steve Kennel
Oak Ridge National Laboratory
P.O. Box Y, Biology Division
Building 9220
Oak Ridge, TN 37830
Greg Kew
Office of Health & Env. Assessment
U.S. Environmental Protection
Agency (RD-689)
401 M Street, SW
Washington, DC 20460
Renate Kimbrough
Centers for Disease Control
1600 Clifton Road
Atlanta, GA 30333
Richard J. Kociba
Dow Chemical Company
Midland, MI 48640
53
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Takeru Higuchi
2201 W. 21st St.
Lawrence, KS 660**
Christopher Kouts
U.S. Dept. of Energy
760* Jervis Street
Springfield, VA 22151
Tim Kubiak
U.S. Fish and Wildlife Service
University of Wisconsin-Green Bay
Green Bay,WI 5*302
Douglas Kuehl
U.S. Environmental Protection
Agency
ERL-Duluth
6201 Congdon Blvd.
Duluth, MN 5580*
Bill Lamason
Air Management Technology
Branch
OAQPS
U.S. Environmental Protection
Agency (MD-1*)
Research Triangle Park, NC 27711
Ray R. Lassiter
Environmental Systems Branch
Athens Environ. Res. Lab.
College Station Road
Athens, GA 30613
John C. Loper
Dept. of Microbiology and
Molecular Genetics (ML-52*)
College of Medicine
University of Cincinnati
Cincinnati, OH 45267
David Marlow
NIOSH
4676 Columbia Parkway
Cincinnati, OH 45226
Barry R. Korb
OSWER (WH562-A)
U.S. Environmental Protection
Agency
401 M Street, SW
Washington, DC 20*60
John McCarthy
Oak Ridge National Laboratory
P.O. Box X
Oak Ridge, TN 37831
Danny D. McDaniel
U.S. Environmental Protection
Agency
Building 1105
NSTL, MS 39529
James Craig McFarlane
Environmental Research
Laboratory
U.S. Environmental Protection
Agency
200 SW 35th St.
Corvallis, OR 97333
Jay Means
Chesapeake Biological Laboratories
P.O. Box 38
Solomons, MD 20688
James Melius
Robert A. Taft Laboratories
*676 Columbia Parkway
Cincinnati, OH *5226
Theodore Mill
PS 273
SRI
Menlo Park, CA 9*025
Ronald K. Mitchum, Dir., QA Div.
Environmental Monitoring Systems
Lab.
U.S. Environmental Protection
Agency
P.O. Box 15027
Las Vegas, NV 8911*
5*
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Leland Marple
Syntex Research
3401 Hillview Ave.
Palo Alto, CA
Arthur Martell
Dept. of Chemistry
Texas A & M University
College Station, TX 77843
3ay Murray
Syntex Research
3401 Hillview Ave.
Palo Alto, CA 94304
Patrick O'Keef e
NY State Department of Health
Center for Laboratories and
Research
Empire State Plaza
Albany, NY 12201
Dhun Patel
N3 Dept. of Environmental
Protection
Off. of Science and Research
190 W. State St.
Trenton, N3 08625
Dennis Paustenbach
Syntex Corporation-4A
3401 Hillview Ave.
Palo Alto, CA 94303
Warren Piver
MD-A2-05
NIEHS
P.O. Box 12233
Research Triangle Park, NC 27709
Hap Pritchard
Environmental Research
Laboratory
U.S. Environmental Protection
Agency
Sabine Island
Gulf Breeze, FL 32561
Charles Morgan
Off. of Waste Enforcement
U.S. Environmental Protection
Agency (WH-527)
401 M Street, SW
Washington, DC 20460
Michael Roulier
Municipal Environmental Research
Laboratory
26 West St. Clair Street
Cincinnati, OH 45268
Thomas Sabourin
Battelle Columbus Labs
505 King Ave.
Cincinnati, OH 43201
Stephen Safe
Texas A&M University
College of Veterinary Medicine
Dept. Vet Physiology &
Pharmacology
College Station, TX 77843
Walter M. Sanders III
Environmental Research
Laboratory
U.S. Environmental Protection
Agency
College Station Road
Athens, GA 30613
John Schaum
U.S. Environmental Protection
Agency (RD-689)
401 M Street, SW
Washington, DC 20460
Arnold Schecter
Upstate Medical Center
College of Medicine
Clinical Campus at Binghamton
Binghamton, NY 13901
55
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John F. Quenson
Pesticide Research Center
Michigan State University
East Lansing, MI 4882*
Gerald Rausa
Off. of Research and
Development/RSS
U.S. Environmental Protection
Agency
*01 M Street, SW
Washington, DC 20460
Barclay Shepard, VA Central Off.
Agent Orange Project Off. (IDA?)
Suite 308, Shoreham
810 Vermont Ave., NW
Washington, DC 20*20
Ellen Siibergeld
Environmental Defense Fund
1525 18th Street, NW
Washington, DC 20036
Ronald A. Stanley
4119 Military Road, NW
Washington, DC 20015
HQ AFESC/RDVW
Attn: Capt. Terry Stoddart
Tyndall AFB, FL 32*03
Richard E. Tucker
Dynamac Corporation
lll*ORockville Pike
Rockvilie, MD 20852
Frode Ulvedal
Office of Health Research
U.S. Environmental Protection
Agency
*01 M Street, SW
Washington, DC 20*60
Robert Schreiber
Dept. of Natural Resources
DEQ Administration
P.O. Box 1368
Jefferson City, MO 65102
Jerry Schroy
Monsanto
800 N. Lindbergh
St. Louis, MO 63167
Barbara T. Walton
Environmental Sciences Division
Oak Ridge National Laboratory
P.O. Box X
Oak Ridge, TN 37831
John E. Wilkinson
23*0 Taylor Way
Tacoma, WA 98*01
Armon Yanders
Environmental Trace Substances
Route 3
Columbia, MO 65203
Alvin Young
Office of Science & Technology
Policy
New Executive Office Bldg.
Room 5005
Washington, DC 20506
56
U.S.Government Print,ng O'fice: 1986 - 646-014/4O004
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