2,3,7,8-TETR ACHLORO -
DIBENZO-p-DIOXIN
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Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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ATSDR/TP-88/23
TOXICOLOGICAL PROFILE FOR
2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN
Date Published June 1989
Prepared by:
Syracuse Research Corporation
under Contract No. 68-C8-0004
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. 1857-B026-A1
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DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund)
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the 100
most significant hazardous substances was published in the Federal
Regiscer on April 17, 1987.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans."
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
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Foreword
Each toxicological -profile begins with a public health statement.
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
James 0. Mason, M.D., Dr. P.M.
Assistant Surgeon General
Administrator, ATSDR
iv
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CONTENTS
FOREWORD
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS DIOXIN? 1
1.2 HOW MIGHT I BE EXPOSED TO 2,3,7 ,8-TCDD? 1
1.3 HOW DOES 2,3,7,8-TCDD GET INTO MY BODY? 2
1.4 HOW CAN 2,3,7,8-TCDD AFFECT MY HEALTH? 3
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE
BEEN EXPOSED TO 2,3,7,8-TCDD? 3
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN
HARMFUL HEALTH EFFECTS? 4
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH? 7
2. HEALTH EFFECTS SUMMARY 9
2.1 INTRODUCTION '.'.'.'.'. 9
2.2 LEVELS OF SIGNIFICANT EXPOSURE '. .'. 10
2.2.1 Key Studies and Graphical Presentations 10
2.2.1.1 Inhalation 11
2.2.1.2 Oral 11
2.2.1.3 Dermal 18
2.2.2 Biological Monitoring as a Measure of Exposure
and Effects 20
2.2.3 Environmental Levels as Indicators of Exposure
and Effects 22
2.2.3.1 Levels found in the environment 22
2.2.3.2 Human exposure potential 22
2.3 ADEQUACY OF DATABASE 23
2.3.1 Introduction 23
2.3.2 Health Effect End Points 24
2.3.2.1 Introduction and graphic summary 24
2.3.2.2 Descriptions of highlights of graphs .... 27
2.3.2.3 Summary of relevant ongoing research .... 28
2.3.3 Other Information Needed for Human
Health Assessment 28
2.3.3.1 Pharmacokinetics and mechanisms
of action 28
2.3.3.2 Monitoring human biological samples 31
2.3.3.3 Environmental considerations 31
3. CHEMICAL AND PHYSICAL INFORMATION 35
3.1 CHEMICAL IDENTITY 35
3.2 PHYSICAL AND CHEMICAL PROPERTIES 35
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Contents
4. TOXICOLOGICAL DATA 3
4.1 OVERVIEW ' ' ' . 3.
4.2 TOXICOKINETICS 43
4.2.1 'Abs'orption 43
4.2.1.1 Inhalation 43
4.2.1.2 Oral 43
4.2.1.3 Dermal 44
4.2.2 Distribution 44
4.2.2.1 Inhalation 44
4.2.2.2 Oral 44
4.2.2.3 Dermal 45
4.2.3 Metabolism 46
4.2.4 Excretion 46
4.2.4.1 Human 46
4.2.4.2 Animal 47
4.3 TOXICITY 48
4.3.1 Lethality and Decreased Longevity 48
4 3.1.1 Inhalation 48
-3.1.2 Oral 48
4.3.1.3 Dermal 49
4.3.2 Systemic/Target Organ Toxicity 49
4.3.2.1 Chloracne 49
4.3.2.2 Wasting syndrome 51
4.3.2.3 Hepatic effects 52
4.3.2.4 Immunotoxicity 54
4.3.3 Developmental Toxicity 5'
4.3.3.1 Inhalation 5
4.3.3.2 Oral 56
4.3.3.3 Dermal 57
4.3.3.4 General discussion 57
4.3.4 Reproductivity Toxicity 58
4.3.4.1 Inhalation 58
4.3.4.2 Oral 58
4.3.4.3 Dermal 59
4.3.4.4 General discussion 59
4.3.5 Genotoxicity 60
4.3.5.1 Human 60
4.3.5.2 Nonhuman 61
4.3.5.3 General discussion 61
4.3.6 Carcinogenic ity 61
4.3.6.1 Inhalation 61
4.3.6.2 Oral 64
4.3.6.3 Dermal 64
4.3.6.4 General discussion 68
4.4 INTERACTIONS WITH OTHER CHEMICALS 68
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL 69
5.1 OVERVIEW 69
5.2 PRODUCTION 69
5.3 IMPORT 69
5.4 USE 69
5.5 DISPOSAL/STABILIZATION 6
vi
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Contents
6. ENVIRONMENTAL FATE 71
6.1 OVERVIEW 71
6.2 RELEASES TO THE ENVIRONMENT 71
6.2.1 Production and Use of Certain Herbicides and
Chlorophenols and Bleaching Process in
Pulp and Paper Industry 71
6.2.2 Photochemical Reactions 72
6.2.3 Thermal Reactions 72
6.2.4 Improper Disposal of Chlorinated Chemical Wastes . 73
6.3 ENVIRONMENTAL FATE 73
7. POTENTIAL FOR HUMAN EXPOSURE 75
7.1 OVERVIEW 75
7.2. LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 76
7.2.1 Air 76
7.2.2 Water 77
7.2.3 Soil 77
7.2.4 Other 78
7.3 OCCUPATIONAL EXPOSURES 83
7.4 POPULATIONS AT HIGH RISK 83
8. ANALYTICAL METHODS 85
8.1 ENVIRONMENTAL MEDIA 86
8.1.1 Air, Water, Soil, and Food 86
8.2 BIOMEDICAL SAMPLES 86
8.2.1 Fluids/Exudates and Tissues 86
9. REGULATORY AND ADVISORY STATUS 93
9.1 INTERNATIONAL 93
9.2 NATIONAL 93
9.2.1 Regulations 93
9.2.2 Advisory Guidance 93
9.2.2.1 Air 93
9.2.2.2 Water 93
9.2.2.3 Food 94
9.2.3 Data Analysis 94
9.2.3.1 Reference doses (RfDs) 94
9.2.3.2 Carcinogenic potency, q * 94
9.2.3.3 Carcinogenic potency, methods used by
other agencies 95
9.3 STATE 95
10. REFERENCES 97
11. GLOSSARY 125
APPENDIX: PEER REVIEW 129
vii
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LIST OF FIGURES
1.1 Health effects from ingesting 2,3,7,8-TCDD 5
1.2 Health effects from skin contact with 2,3,7,8-TCDD 6
2.1 Effects of 2,3,7,8-TCDD--oral exposure .. 12
2.2 Effects of 2,3,7,8-TCDD--dermal exposure 13
2.3 Levels of significant exposure for 2,3,7,8-TCDD--oral 14
2.4 Levels of significant exposure for 2 , 3,7,8-TCDD--dermal 15
2.5 Availability of information on health effects of
2,3,7,8-TCDD (human data) 25
2.6 Availability of information on health effects of
2,3,7,8-TCDD (animal data) 26
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LIST OF TABLES
2.1 Research in progress on 2,3,7,8-TCDD 29
3.1 Chemical identity of 2,3,7.8-TCDD 36
3.2 Physical properties of 2,3,7,8-TCDD 37
4.1 Recommended TEFs for CDDs and CDFs 42
4.2 Genotoxicity of 2,3,7,8-TCDD in vitro 62
4.3 Genotoxicity of 2, 3, 7, 8-TCDD in vivo 63
4.4 Summary of the oral carcinogenicity bioassay of
Kociba et al. (1978a,b) 65
4.5 Other oral studies supporting the conclusion that
2,3,7,8-TCDD is an animal carcinogen 66
7.1 Levels of 2,3,7,8-TCDD in soil from different locations 79
8.1 Analytical methods for environmental samples 87
8.2 Analytical methods for biomedical samples 90
XL
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS DIOXIN?
The chlorinated dibenzo-p-dioxins are a class of compounds that are
loosely referred to as dloxins. There are 75 possible dioxins. The one
with four chlorine atoms at positions 2, 3, 7 and 8 of the dibenzo-p-
dioxin chemical structure is called 2,3,7,8-tetrachlorodibenzo-p-dioxin
(2,3,7,8-TCDD). It is a colorless solid with no known odor. 2,3,7.8-TCDD
does not occur naturally nor is it intentionally manufactured by any
industry, except as a reference standard. It can be inadvertently
produced in very small amounts as an impurity during the manufacture of
certain herbicides and germicides and has been detected in products of
incineration of municipal and industrial wastes. At the present time,
2,3,7,8-TCDD is not used for any purpose other than scientific research.
1.2 HOW MIGHT I BE EXPOSED TO 2,3,7.8-TCDD?
The main environmental sources of 2,3,7,8-TCDD are:
Use of herbicides containing 2,4,5-trichlorophenoxy acids (2,4,5-T)
Production and use of 2,4,5-trichlorophenol in wood preservatives
Production and use of hexachlorophene as a germicide
Pulp and paper manufacturing plants
Incineration of municipal and certain industrial wastes
Small amounts formed during the burning of wood in the presence of
chlorine
Accidental transformer/capacitor fires involving chlorinated
benzenes and biphenyls
Exhaust from automobiles powered with leaded gasoline
Improper disposal of certain chlorinated chemical wastes
Although 2,4,5-T, 2,4,5-trichlorophenol and hexachlorophene are no
longer produced commercially (except for certain medical purposes),
disposal sites of past production wastes are still sources of present
exposure. 2,3,7,8-TCDD has been found in at least 28 of 1,177 hazardous
waste sites on the National Priorities List (NPL). Very low levels of
2,3,7,8-TCDD have been detected in ambient air. Detection of 2,3,7,8-
TCDD in drinking water has not been reported. 2,3,7,8-TCDD has not been
detected in most rural soils examined, but it can be present at trace
levels in urban soils. The highest concentration of 2,3,7,8-TCDD was
detected in a waste-oil-contaminated soil In Missouri that contained a
2,3,7,8-TCDD level more than one million times higher than soils from
normal urban areas. 2,3,7,8-TCDD was detected in fish obtained from the
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2 Section 1
contaminated sections of Lake Ontario, Saginaw Bay, the Michigan rivers
and several watersheds including those from Maine, Wisconsin, and
Minnesota. In human milk, minute amounts of 2,3,7,8-TCDD have been
detected in the United States and in several European countries.
Consumer sources are:
Skin contact with surfaces such as soil or vegetation contaminated
by the chemical
Skin contact and inhalation of wood dusts from use of
pentachlorophenol-treated woods
Inhalation of air near improperly maintained dump sites or
municipal incinerators
Consumption of fish and cow's milk from contaminated areas
Consumption of breast milk containing 2,3,7,8-TCDD by babies
Minute exposure from the use of paper towels, napkins, coffee
filters, computer papers, and other contaminated paper products
Workers at risk of contacting 2,3,7,8-TCDD are:
Workers who have been involved in the production or use of
trichlorophenol and salts, hexachlorophene, and 2,4,5-T or other
herbicides containing this chemical. The production of 2,4,5-T and
2,4,5-trichlorophenol, however, has been discontinued in the United
States.
Workers in the pump and paper industry
Workers at certain municipal and industrial incinerators
Workers involved in the high-temperature/pressure treatment of
woods with pentachlorophenol
Workers at certain hazardous waste sites
Workers involved in the cleanup of certain accidental
capacitor/transformer fires and in the salvaging of transformers
Workers who have been involved in spraying of phenoxy herbicides
such as Agent Orange
1.3 HOW DOES 2,3,7,8-TCDD GET INTO MY BOOT?
Absorption through skin from contaminated soils and other materials
Ingestion of 2,3,7,8-TCDD through the consumption of contaminated
fish, cow's milk, foodstuffs, and, in the case of small children,
soil
Breathing contaminated ambient air. This may contribute very small
amounts Co total body intake; however, particulates such as fly ash
from municipal and industrial incineration may constitute a major
source of exposure.
Intake of 2,3,7,8-TCDD from the consumption of drinking water
should be negligible
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Public Health Statement 3
According to one. estimate of ambient exposure, breathing air
constitutes 2%, drinking water less than 0.01%, and consuming foods
98% of the total human exposure to 2,3,7,8-TCDD. No estimate of
relative intake of 2,3,7,8-TCDD due to skin absorption is
available.
1.4 HOW CAN 2,3.7,8-TCDD AFFECT MY HEALTH?
In humans, 2,3,7,8-TCDD causes chloracne, a severe skin lesion chat
usually occurs on the head and upper body. Unlike common acne,
chloracne is more disfiguring and often lasts for years after the
initial exposure.
There is suggestive evidence that 2,3,7,8-TCDD causes liver damage
in humans, as indicated by an increase in levels of certain enzymes
in the blood, although these effects might also have resulted from
the concomitant exposure to the chemicals contaminated with
2,3,7,8-TCDD or to the solvents in which these chemicals are
usually dissolved. Animal studies have demonstrated severe liver
damage in some species.
There is suggestive evidence that 2,3,7,8-TCDD causes loss of
appetite, weight loss, and digestive disorders in humans, although
these effects might also have resulted from the concomitant
exposure to the chemicals contaminated with 2,3,7,8-TCDD or to the
solvents in which these chemicals are usually dissolved. Animal
exposure to 2,3,7,8-TCDD results in severe loss of body weight
prior to death.
Although not demonstrated in humans, in animal studies 2,3,7,8-TCDD
produced toxicity to the immune system. This toxicity can result in
greater susceptibility to infection.
Although not demonstrated in humans, in some animal species
exposure to 2,3,7,8-TCDD resulted in adverse reproductive effects
including spontaneous abortions. The monkey is very sensitive to
this toxic property of 2,3,7,8-TCDD.
Although not demonstrated in humans, in some animal species
exposure to 2,3,7,8-TCDD during pregnancy resulted in malformations
in the offspring. Low levels of 2,3,7,8-TCDD have been detected in
human milk, but the effects on infants and children are unknown.
The human evidence for 2,3,7,8-TCDD alone is inadequate to
demonstrate or reflect a carcinogenic hazard, although certain
herbicide mixtures containing 2,3,7,8-TCDD as an impurity provide
limited evidence of causing cancer in exposed humans. Based on the
positive evidence in animal studies, 2,3,7,8-TCDD is probably
carcinogenic in humans.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE
BEEN EXPOSED TO 2,3,7.8-TCDDT
There is no common medical test available to demonstrate
convincingly that you have been exposed to 2,3,7,8-TCDD. It is believed
that a blood test to detect certain enzymes indicating liver damage may
be helpful in determining whether exposure has occurred. These tests do
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4 Section 1
not indicate with certainty that you have been exposed to 2,3,7,8-TCDD.
since other chemicals, as well as drinking alcohol, can cause similar
results. When tests for these enzymes have been performed, changes in
these enzymes were demonstrated only in some of the people suspected of
2,3,7,8-TCDD exposure.
Other tests are available that are not commonly conducted by a
physician but appear to more adequately indicate that you have been
exposed to 2,3,7,8-TCDD. One test consists of removing a small piece of
body fat by a simple surgical procedure; the fat is then analyzed for
the presence of 2,3,7,8-TCDD. In another recently developed test, blood
serum is obtained and analyzed for the presence of 2,3,7,8-TCDD. The
initial study appears to indicate that the method is sensitive enough to
detect extremely low levels of 2,3,7,8-TCDD. If the levels of 2,3,7,8-
TCDD are higher than the determined background range for people in the
United States, the test indicates that you have probably been exposed to
more 2,3,7,8-TCDD than the average population, or exposure has occurred
more recently than that of the comparison group. In addition, detection
of 2,3,7,8-TCDD in mother's milk would also indicate exposure; the level
of 2,3,7,8-TCDD in the milk may provide some indication of whether
exposure was to background levels or if additional exposure had
occurred. This method has not been-used widely to evaluate human
exposure.
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS7
The graphs on the following pages show the relationship between
exposure to 2,3,7,8-TCDD and known health effects. In the first set of
graphs labeled "Health effects from ingesting 2,3,7,8-TCDD" (Fig. 1.1),
exposure is measured in milligrams of 2,3,7,8-TCDD per kilogram of body
weight (mg/kg) In the second set of graphs (Fig. 1.2), the same
relationship is represented for the known "Health effects from skin
contact with products containing 2,3,7,8-TCDD." Exposures are again
measured in milligrams of 2,3,7,8-TCDD per kilogram of body weight
(mg/kg). In all graphs, effects in animals are shown on the left side
and effects in humans on the right side.
The levels marked on Fig. 1.1, which are dose estimates associated
with minimal risk for health effects other than cancer, in humans, are
based on information from animal studies; therefore, some uncertainty
still exists. For cancer, the U.S. Environmental Protection Agency (EPA)
has estimated that lifetime exposure to 1 nanogram of 2,3,7,8-TCDD per
kilogram per day would result in 1,560 or 1,560,000 additional cases of
cancer in a population of 10,000 or 10,000,000 people, respectively. It
should be noted that these risk values are plausible upper-limit
estimates. Actual risk levels are unlikely to be higher and may be
lower. (One nanogram is one-billionth of a gram.) EPA is in the process
of reviewing its risk assessment of 2,3,7,8-TCDD.
There was not enough information to prepare a graph for exposure by
breathing.
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Public Health Statement 5
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
DOSE
(mg/Kg/day}
DEATH.
0001
oL
T
DEVELOPMENTAL <
EFFECTS
00005
0.0001
«
0.00008
0.00004
0.00002
0 000008
0.000006
0.000004
0.000002
0 000001.
EFFECTS
IN
HUMANS
EFFECTS
IN
ANIMALS
DOSE
(mg/Kg/day)
DEATH
0.00001
0.000005
REPRODUCTIVE I
TOXICITYAND RJ
CHLORACNE |
r 0000001
0.0000008
LIVER DAMAGE ^
0.0000006
0.0000004
MINIMAL RISK
FOR EFFECTS
OTHER THAN
.CANCER
0 0000002
00000001
1
T
0.00000005
0 00000001
T
0 000000005
0000000001.
EFFECTS
IN
HUMANS
MINIMAL RISK
FOR EFFECTS
OTHER THAN
.CANCER
Fig. 1.1. Health effects from ingesting W.8-TCDD.
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Secclon 1
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
DEATH.
DOSE
(mg/kg/day)
1.0
0.8
0.6
0.4
0.2
EFFECTS
IN
HUMANS
QUANTITATIVE
DATA WERE
NOT AVAILABLE
EFFECTS EFFECTS
IN DOSE IN
ANIMALS (mg/kg/day) HUMANS
0
0.
0.
0
CHLORACNE
0.
QUANTITATIVE
DATA WERE
NOT AVAILABLE
01
308
)06
304
)02
Fig. 1.2. Health effects from skin contact with 24,7,8-TCDD.
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Public Health Scacemenc /
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH?
Both the EPA and the International Agency for Research on Cancer
(IARC) have concluded that 2,3,7,8-TCDD causes cancer in animals and
probably causes cancer in humans.
The EPA calculated health advisories (HAs) for 2,3,7,8-TCDD in
drinking water, that is, estimates of levels below which adverse health
effects are not expected to occur. The 1-day HA Is 1 part of 2,3,7,8-
TCDD per trillion parts of waste (1 ppt) for a child; the 10-day HA is
0.1 ppt for a child. The longer-term HA is 0.01 ppt for a child and
0.035 ppt for an adult; the lifetime HA is also 0.035 ppt for adults.
These are very small amounts. The EPA also calculated the amount of
2,3,7,8-TCDD in ambient water (lakes and rivers) that would be
associated with increases in one additional incidence of cancer over
background cancer incidence in a population of 1,000,000 to be 0.013
parts per quadrillion, an extremely small amount. This calculated
measurement takes into account that 2,3,7,8-TCDD concentrates in fish;
hence, exposure may occur through both the drinking of water and the
eating of fish. With regard to advisories based on EPA's cancer risk
estimate for 2,3,7,8-TCDD, it should be noted that the Agency is in the
process of revising this risk estimate.
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2. HEALTH EFFECTS SUMMARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to 2,3,7,8-TCDD. The purpose of this section is to
present levels of significant exposure for 2,3,7,8-TCDD based on key
toxicological studies, epidemiological investigations, and environmental
exposure data. The information presented in this section is critically
evaluated and discussed in Sect. 4, Toxicological Data, and Sect. 7,
Potential for Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of 2,3,7,8-TCDD and (2) a
summarized depiction of significant exposure levels associated with
various adverse health effects. This section also includes information
on the levels of 2,3,7,8-TCDD that have been monitored in human fluids
and tissues and information about levels of 2,3,7,8-TCDD found in
environmental media and their association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt clinical findings in exposed
persons or with the identification of persons with the potential to
develop such disease may be interested in levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health officials
and project managers concerned with response actions at Superfund sites
may want information on levels of exposure associated with more subtle
effects in humans or animals (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse -Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels, MRL) are of interest
to health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies on exposure to 2,3,7,8-TCDD in the scientific literature and
displays these data in three-dimensional graphs consistent with the
format in Sect. 2.2. The purpose of this section is to suggest where
there might be insufficient information to establish levels of
significant human exposure. These areas will be considered by the Agency
for Toxic Substances and Disease Registry (ATSDR), EPA, and the National
Toxicology Program (NTP) of the U.S. Public Health Service in order to
develop a research agenda for 2,3,7,8-TCDD.
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10 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of
exposure-- inhalation, ingestion, and dermal--and then by toxicological
end points that are categorized into six general areas lethality,
systemic/target organ toxicity, developmental toxicity, reproductive
toxicity, genetic toxicity, and carcinogenicity. The data are discussed
in terms of three exposure periods--acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type is
a "thermometer" graph. It provides a graphical summary of the human and
animal toxicological end points (and levels of exposure) for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing NOAELs and
LOAELs reflect the actual doses (levels of exposure) used in the key
studies. No adjustments for exposure duration or intermittent exposure
protocol were made.
Adjustments reflecting the uncertainty of extrapolating animal data
to humans, intraspecies variations, and differences between experimental
versus actual human exposure conditions were considered when estimates
of levels posing minimal risk to human health were made for noncancer
end points. These minimal risk levels were derived for the most
sensitive noncancer end point for each exposure duration by applying
uncertainty factors. These levels are shown on the graphs as a broken
line starting from the actual dose (level of exposure) and ending with a
concave-curved line at its terminus. Although methods have been
established to derive these minimal risk levels (Barnes et.al. 1987),
shortcomings exist in the techniques that reduce the confidence in the
projected estimates. Also shown on the graphs under the cancer end point
are risks (10*^ to 10'7) estimated by EPA. In addition, the actual dose
(level of exposure) associated with tumor incidence is plotted.
2.2.1 Key Studies and Graphical Presentations
It is difficult to assess the risk to humans from exposure to
2,3,7,8-TCDD. There are many species differences in toxicity; the monkey
and guinea pig are apparently the most sensitive and the hamster is the
least sensitive. It is not known how sensitive humans are to 2,3,7,8-
TCDD. In addition, 2,3,7,8-TCDD strongly adsorbs to materials such as
soil, which may significantly affect the bioavailability and toxicity of
this compound. Animal studies have generally been conducted with
2,3,7,8-TCDD administered in oily vehicles from which the compound is
readily bioavailable. There are insufficient data available to consider
the effect of bioavailability on the toxicity studies used to define the
risk from exposure to 2,3,7,8-TCDD. Both bioavailability and species
differences in sensitivity should be considered when evaluating the
remainder of the data presented.
-------
Health Effaces Summary 11
Oral and dermal'NOAELs and LOAELs are presented on "thermometer"
graphs in Figs. 2.1 and 2.2, respectively. Although some qualitative
data are available for humans, quantitative data were insufficient to
graphically present inhalation effects.
Levels of significant exposure are depicted in Figs. 2.3 and 2 4
for the oral and dermal routes. There were insufficient human and animal
inhalation data for graphical representation. The intermediate minimal
risk level for oral exposure was calculated by EPA (1985a) from a
three-generation reproductive toxicity study in the rat. with effects
observed in the fetuses. Since the effects were attributed to in utero
fetal exposure, which chronologically represents an exposure of
relatively short duration, as well as to the chronic exposure of the
dams, the same minimal risk level for chronic exposure was calculated
from these data.
2.2.1.1 Inhalation
No studies are available on the inhalation toxicity of
2,3,7,8-TCDD. Exposure through inhalation, however, may also have
occurred in the population exposed to chemicals contaminated with TCDD
in accidental releases or in the workplace (especially herbicide
spraying).
2.2.1.2 Oral
Lethality and decreased longevity. There have been no reports of
death in humans as a result of oral exposure to 2,3,7,8-TCDD.
2,3,7,8-TCDD is highly toxic to all laboratory animals tested, even
though there is a large difference in species sensitivity. LDso values
range from 0.6 MgAg in male guinea pigs (Schwetz et al. 1973) to 5,500
AigAg in hamsters (Henck et al. 1981). These values are plotted in
Figs. 2.1 and 2.3 for the lethality of acute oral exposure. Death
usually occurs 13 to 18 days after a single exposure. Extended exposure
in a 90-day feeding study in guinea pigs resulted in an estimated 50%
mortality after consumption of a total of 0.8 /*g of 2,3, 7,8-TCDDAg
(0.008 /JgAg/day) (DeCaprio et al. 1986), whereas deaths did not occur
at 0.0006 MgAg/day (NOAEL) . Five of eight female monkeys that ingested
approximately 0.01 /*g of 2,3,7,8-TCDDAg/day for 9 months died (Allen et
al. 1977). These FELs in guinea pigs and monkeys and the NOAEL in guinea
pigs are shown in Figs. 2.1 and 2.3.
Target organ/systemic toxicity. Four major toxic effects
characteristic of 2,3,7,8-TCDD are chloracne, the wasting syndrome,
hepatotoxicity, and immunotoxicity. The latter three effects have been
clearly demonstrated only in laboratory animals. Chloracne,
immunotoxicity, hyperpigmentation, hyperkeratosis, hirsutism of the
skin, possible hepatotoxicity, hypertriglyceridemia and
hypercholesterolemia, aching muscles, loss of appetite, weight loss,
digestive disorders, headaches, neuropathy, insomnia, sensory changes,
and loss of libido have been observed in humans exposed to chemicals
contaminated with 2,3,7,8-TCDD. These reported effects may have been the
result of 2,3,7,8-TCDD exposure, or exposure to the chemicals of which
2,3,7,8-TCDD is a contaminant or to the solvents in which these
-------
12 Section 2
ANIMALS
(n»*g/<»y)
HUMANS
10000
1.000
100
01
001
0001
00001 «
HAMSTER L0» SINGLE DOSE
MOUSE. MONKEY CHLORACNE SINGLE OOSE
- MOUSE. DEVELOPMENTAL TOXRrTV 10 DAYS. CONTINUOUS
GUINEA PIG. LO» SINGLE DOSE
O MOUSE. DEVELOPMENTAL TOXKfTY 10 DAYS. CONTINUOUS
RAT. DEVELOPMENTAL TOX1CI7Y <0 OAYS. CONTINUOUS
- GUINEA PK). UVERTOXICITY. SINGLE OOSE
GUINEA PtO. IMMUNOTOXICrrV I WEEKS. INTERMITTENT
O RAT. DEVELOPMENTAL TCUOCfTV. 10 DAYS, CONTINUOUS
- MONKEY. DEATH. 9 MONTHS. CONTIM
KEY CHLORACNE. 7 MONTHS. CONTINUOUS
"*««TWUOUS
--------- ..... ------ . - .....
GUINEA PKX DEATH. 90 DAYS. CONTINUOUS
GUINEA PKLIMMUNOTOXICITV. 8 WEEKS. INTERMTITENT
GUINEA PW. WASTING SYNDROME UVERTOXICITY. 90 DAYS. CONTINUOUS
MONKEY. REPRODUCTIVE TOJOCITY 7 MONTHS CONTINUOUS
RAT. REPRODUCTIVE TOXICITY 3 GENERATIONS. RAT. UVER TOXICITY 2 YEARS. CONTINUOUS
GUINEA PIG. WASTING SYNDROME. UVER TOXICITY 90 OAYS CONTINUOUS
GUINEA PKJ. DEATH. 90 OAYS. CONTINUOUS
LOAEL
O NOAEL
QUANTITATIVE DATA
WERE NOT
AVAILABLE
Fig. 2.1. Effects of 23,7,8-TCDDoral exposure.
-------
ANIMALS
(Wjfcg/day)
1000 r-
100
10
I i-
RABBIT LD,o. SINGLE OO6E
MCXJSE. DERMAL LESIONS 4 WEEKS INTERMITTENT
LOAEL
Health Effects Summary 13
HUMANS
QUANTITATIVE DATA
WERE NOT AVAILABLE
Fig. 2.2. Effects of 2,3,7,8-TCDDdermal exposure.
-------
14 Section 2
10000
1000
100
10
1
01
001
0001
00001
000001
0 000001
0 0000001
0 00000001
0000000001
0 0000000001
o 00000000001
0 000000000001
0 0000000000001 I-
ACUTE INTERMEDIATE CHRONIC
(SI4 DAYS) (15-364 DAYS) (2365 DAYS)
DEVELOP- TARGET DECREASED REPRO- TARGET TARGET
LETHALITY MENTAL ORGAN LONGEVITY DUCTION ORGAN ORGAN CANCER
s
k. m (SKIN)
g
r
r
g (LIVER)
k
g (BODY WEIGHT
I LIVER)
O r (LIVER)
10-*-,
10-5-
io-7-l
ESTIMATED
UPPER-
BOUND
HUMAN
CANCER
RISK
LEVELS
MINIMAL RISK LEVEL
FOR EFFECTS OTHER
THAN CANCER
g GUINEA PIG
k MONKEY
m MOUSE
r RAT
S HAMSTER
ILOAEL AND NOAEL
IN SAME SPECIES
LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
MINIMAL RISK LEVEL FOR
CHRONIC EXTRAPOLATED
FROM INTERMEDIATE
EXPOSURE
Fig. L3. Leveb of significant exposure for 23,7,8-TCDDoraL
-------
Healch Effects Summary 15
ACUTE
(< 14 DAYS)
LETHALITY
INTERMEDIATE
(15-364 DAYS)
TARGET ORGAN
CHRONIC
(2 365 DAYS)
(ng/kg/day)
10.000 r
1000
100
10
QUANTITATIVE
DATA WERE
NOT AVAILABLE
m (SKIN)
1 L-
LOAEL m MOUSE
h RABBIT
Fig. 2.4. LeTda of significant exposure for
-------
16 Section 2
compounds are normally dissolved. Because some herbicides and some
industrial chemicals contain 2,3,7,8-TCDD as a contaminant, the primary
route of exposure is most likely to be dermal, although some oral and
inhalation exposure probably also occurs.
Since chloroacne, the only lesion definitively identified in humans
as resulting from 2,3,7,8-TCDD exposure, can only be detected in a few
species, the investigation of this effect has been limited. In hairless
mice, chloracne was produced after a single dose of 2,3,7,8-TCDD at
70 MgAg (Greig 1984) , whereas a single dose of 70 MgAg (McConnell et
al. 1978), or a dose of -0.01 MgAg/day in a 9-month feeding study in
monkeys (Allen et al. 1977), produced similar lesions on the face. These
data are indicated in Figs. 2.1 and 2.3.
The wasting syndrome is characterized by extreme loss of body
weight. In acute studies, this syndrome is associated with lethal doses.
A dose-response relationship for the wasting syndrome has been defined
in a 90-day study in guinea pigs (DeCaprio et al. 1986). Female Hartley
guinea pigs were maintained on diets providing average 2,3,7,8-TCDD
doses of 0, 0.12, 0.68, 4.86, and 31 ng/kg/day. The high dose
represented a FEL; a 40% decrease in body weight and death occurred. The
4.86-ng/kg (0.005 MgAg) dose represented a LOAEL, with a 13% decrease
in body weight and no mortality. The 0.68 ng/kg (0.0007 MgAg) is a
NOAEL. The LOAEL and NOAEL for intermediate exposure are indicated in
Figs. 2.1 and 2.3.
2,3,7,8-TCDD is hepatotoxic in all species tested; however, the
severity of the lesions depends on the species studied. Although liver
damage is not as severe in the guinea pig, the most sensitive species
tested with regard to lethality, liver changes such as focal necrosis
and hypertrophy have been observed at very low doses by Turner and
Collins (1983). In this study, a small group of male and female guinea
pigs was given a single dose of 2,3,7,8-TCDD at 0.1, 0.5, 2.5. 12.5, or
20 MgAg. Effects on the liver occurred in all groups. The low dose was
considered a LOAEL (see Figs. 2.1 and 2.3), but a NOAEL was not
available. A minimal risk for effects of acute oral exposure (see Fig.
2.3) was calculated from this LOAEL, since it was the most sensitive end
point in acute studies. Similar liver damage was observed in guinea pigs
in the 90-day feeding study by DeCaprio et al. (1986). The NOAEL was
0.68 ngAg and the LOAEL was 4.86 ngAg, the same as the NOAEL and LOAEL
for the wasting syndrome (see Figs. 2.1 and 2.3). There are no chronic
studies in guinea pigs; however, in chronic studies in rats, Kociba et
al. (1978a,b) and NTP (1982a) reported "toxic hepatitis" and
degenerative changes at the lowest dietary exposure that provided a dose
of 0.001 Mg of 2,3,7,8-TCDDAg/day in these 2-year studies. Again, only
a LOAEL, which is plotted in Figs. 2.1 and 2.3, is available for this
end point after chronic exposure.
The guinea pig also appears to be the most sensitive species to the
immunotoxic effects of 2,3,7.8-TCDD. Vos et al. (1973) observed a
decrease in thymus weight, total lymphocyte number, and total leukocyte
number in groups of 10 guinea pigs given 2,3,7,8-TCDD weekly for 8 weeks
at doses of 0, 0.008, 0.04, or 0.2 MgAg- The high dose was a FEL and
also produced other toxic effects including loss of body weight. A LOAEL
of 0.04 MgAg and a NOAEL of 0.008 MgAg were defined. At the LOAEL,
-------
Health Effects Summary 17
body weight was comparable to controls. The LOAEL and NOAEL for
immunotoxicity are plotted on Fig. 2.1, but not on Fig. 2.3, because
liver toxicity and wasting syndrome are more sensitive end points of
intermediate oral exposure in guinea pigs. Immunotoxicity is not limited
to guinea pigs; Thigpen et al. (1975) reported that mice given 4 weekly
exposures to 2,3,7,8-TCDD at doses as low as 1 MgAg were more sensitive
to Salmonella-induced death. This dose caused no gross signs of toxicity
in animals not exposed to Salmonella.
Developmental toxicity. There have been no well-substantiated
reports of developmental toxicity in humans as a result of oral exposure
to 2,3,7,8-TCDD.
2,3,7,8-TCDD produces anomalies in the fetus, including cleft
palate and hydronephrotic kidneys in mice and internal organ hemorrhage
in the rat. FELs in rats were reported to be 0.125 pgAg/day after
administration of the compound on days 6 through 15 of gestation
(Sparschu et al. 1971a,b), whereas the next lower dose tested, 0.03
MgAg, was a NOAEL (see Figs. 2.1 and 2.3). Doses of 1 MgAg caused
fetal death. Although developmental effects are also observed in mice,
this species appears less sensitive, with FELs of -1 ^gAg/day (when
administered during organogenesis) and a NOAEL of -0.3 MgAg (Neubert
and Dillman 1972) (see Figs. 2.1 and 2.3).
Reproductive toxicity. There have been no well-substantiated
reports of reproductive toxicity in humans as a result of oral exposure
alone to 2,3,7,8-TCDD.
In studies with monkeys maintained on a diet for 7 months, which
provided 2,3,7,8-TCDD at levels of 0.0015 and 0.01 ^gAg/day, there were
spontaneous abortions in two-thirds of the monkeys at both dose levels
(Allen et al. 1979, Schantz et al. 1979). The 0.0015-Aig/kg/day level is
indicated on Figs. 2.1 and 2.3. This study, which reported severe frank
effects, indicates that monkeys may be the most sensitive species with
regard to the reproductive toxicity of 2,3,7,8-TCDD. This study,
however, only provided FELs, and additional data were not available for
determining a NOAEL or the actual relationship between species
sensitivity.
Murray et al. (1979) conducted a three-generation reproductive
toxicity study in rats. 2,3.7,8-TCDD was administered in the diet at
levels that provided doses of 0.001, 0.01, and 0.1 /ig/kg/day. The high
dose resulted In decreased fetal survival. Murray et al. (1979)
concluded that the 0.01-dose represented a LOAEL (with effects observed
on litter size and fetal and neonatal survival) and that the 0.001-dose
was considered to be a NOAEL. Nisbet and Paxton (1982) reevaluated the
above data, using different statistical methods, and concluded that the
lowest dose tested produced dilated renal pelvises, decreased fetal
weight, and changes in the gestational index, which indicated that
0.001 jigAg was « LOAEL. As discussed in Sect. 4.3.4.2. EPA (1988b)
criticized the approach used by Nisbet and Paxton (1982) and concluded
that 0.01 pgAg/day was che lowest effect level in the study by Murray
et al. (1979) that could be supported by the data, although further
analysis of this study and the studies in monkeys (Allen et al. 1979;
Schantz et al. 1979) may provide support for a LOAEL of 0.001 j*g/kg/aay.
As a dose level of 0.0015 MgAg/day was associated with abortions in
-------
18 Section 2
monkeys (Allen et al." 1979), It is prudent to consider 0.001 MgAg/<*ay
as the LOAEL (see Figs. 2.1 and 2.3) from which to derive a minimal ris.
level for subchronic and chronic oral exposure (see Fig 2.3).
*
Genotoxicity. There have been no reports of genotoxicity in humans
as a result of oral exposure to 2,3,7,8-TCDD.
2,3,7,8-TCDD has produced mostly negative responses in tests for
genotoxicity; however, there are a few positive responses, which may
suggest that 2,3,7,8-TCDD is genotoxic (see Sect. 4.3.5 on
genotoxicity). Some of the inconsistencies observed may be related to
experimental difficulties in testing 2,3,7,8-TCDD, such as the very low
solubility of this compound and the high toxicity in vivo (which limits
the quantity that can be tested), rather than to inherent biological
inactivity.
Carcinogenicity. There have been no reports of increased cancer
incidence in humans as a result of oral exposure to 2,3,7,8-TCDD.
2,3,7,8-TCDD has been demonstrated to be an animal carcinogen in
both rats and mice in an NTP (1982a) bioassay, and in rats in a 2-year
bioassay by Kociba et al. (1978a,b). EPA (198Sa) used female rat data
from the Kociba et al. (1978a.b) study to derive a q.*. In this
derivation, the total incidences for tumors of the liver, lung, hard
palate, or nasal turbinates, as reported by Kociba et al. (1978a,b),
were combined. These data, along with a similar set of data derived for
EPA by Squire on the reevaluation of the histologic section from the
Kociba et al. (1978a,b) study, were used by EPA (1985a) to derive a q^
The tumor incidences reported by Kociba et al. (1978a,b) for doses of
0, 0.001, 0.01, and 0.1 /*gAg/d«y were 9/85, 3/48, 18/48, and 34/40,
respectively, whereas the respective values reported by Squire were
16/85, 8/48, 27/48, and 34/40. The q * thus calculated was 1.56 x 105
(jig/kg/day)"1. The dose of 0.01 pgAg/day, which is associated with
increased tumor incidence in the Squire reevaluation, is indicated on
Fig. 2.3. For cancer, EPA has estimated that for a population of 10,000
people exposed to 0.6 pgAg/day. the cancer risk is not likely to exceed
1/10,000, and similarly, that for a lesser exposure of 0.0006 pgAg/day
to 10,000,000 people, the expected cancer risk would not exceed
1/10,000,000 (Fig. 2.3). EPA is in the process of reviewing its risk
assessment of 2,3,7,8-TCDD (EPA 1988a).
2.2.1.3 Dermal
Lethality and decreased longevity. There have been no reports of
death in humans as a result of dermal exposure to 2,3,7,8-TCDD.
Schwetz et al. (1973) reported a dermal U>50 value of 275 /igAg in
rabbits. As in oral studies, there was a protracted length of time
between application and death. No other data were available. The U>50-is
plotted on Figs. 2.2 and 2.4.
Target organ/systemic tozicity. Chloracne ; the only
substantiated effect in humans produced by certa-.i compounds
contaminated with 2,3,7,8-TCDD. As reviewed by Taylor (1979) and Suskind
(1985), these persistent, deforming face and uoper body lesions have
been recognized for many years as resulting from exposure to certain
halogenated aromatic compounds, and it is believed that 2,3,7,8-TCDD is
-------
Health Effects Summary 19
the most effective compound in producing this lesion. There is no
information on determined levels of exposure to 2,3,7,8-TCDD needed to
produce chloracne in humans. By extrapolating dose-effect data obtained
from the ingestion of contaminated rice oil containing polychlorinated
biphenyls and polychlorinated dibenzofurans to dose-effect data for
2,3,7,8-TCDD, and taking into consideration the minimum toxic dose for
production of chloracne in nonhuman primates, Stevens (1981) estimated a
minimum toxic dose for 2,3,7,8-TCDD of 0.1 /igAg for humans.
In addition, there are data that suggest that 2,3,7,8-TCDD is
hepatotoxic in humans. In populations exposed to herbicides and other
industrial chemicals contaminated with 2,3,7,8-TCDD, there have been
reports of increased serum levels of liver enzymes and the development
of porphyria cutanea tarda (EPA 198Sa). In all studies, however,
exposure may have been to chemicals that also could cause liver damage,
and as pointed out by Jones and Che1sky (1986), the diagnosis of
porphyria cutanea tarda in some of the studies may be questionable. It
is thus difficult to assert that the presumed exposure to 2,3,7,8-TCDD
resulted in liver injury, and even if 2,3,7,8-TCDD induced liver damage,
there are no human data available that could provide dose-response
information. Similarly, data suggest that 2,3,7,8-TCDD might affect the
immune system in humans (Hoffman et al. 1986), but the same limitation
discussed with regard to hepatotoxicity applies to immunetoxicity.
The only dermal animal data that provide quantitative information
on chloracne are provided by the study of Puhvel et al. (1982), in which
hairless mice given 0.1 pg of 2,3,7,8-TCDD per application three times
per week for 4 weeks developed dermal lesions that resembled some
features of chloracne in humans. Assuming that a mouse weighs 0.03 kg,
the dose is 1.4 /jgAg- This study, however, only used one dose which was
a PEL; hence, it does not provide the necessary information for defining
a dose-response relationship. The dose is plotted on Figs. 2.2 and 2.4
for intermediate target organ toxicity of dermal exposure.
Developmental toxicity. Studies of human populations exposed to
herbicides and other industrial chemicals contaminated with 2,3,7,8-TCDD
have suggested that 2,3,7,8-TCDD produces a variety of developmental
effects (Hanify et al. 1981, McQueen et al. 1977, Nelson et al. 1979,
Smith et al. 1982). After reviewing these studies, EPA (1985a, 1988b)
indicated that the data were not inconsistent with 2,3,7,8-TCDD
adversely affecting development, but as a result of the limitations of
the data, these studies could not prove an association with 2,3,7,8-TCDD
exposure and the observed effect. The major limitations in these human
studies were the concomitant exposure to other potentially toxic
chemicals, the lack of any specific quantitative data on the extent of
exposure of individuals within the study group, and the lack of
statistical power of the studies.
No animal studies were available on the developmental toxicity of
2,3,7,8-TCDD following dermal exposure.
Reproductive toxicity. EPA (1985a, 1988b) has reviewed human
reproductive toxicity studies of groups exposed to herbicides and other
industrial chemicals contaminated with 2,3,7,8-TCDD (Aldred 1978;
Bisanti et al. 1980; Bonaccorsi et al. 1978; Department of Health, New
Zealand 1980; EPA 1979a; Field and Kerr 1979; McQueen et al. 1977;
-------
20 Seccion 2
Nelson et al. 1979; Reggiani 1980; Smith et al. 1982; Thomas 1980).
These studies did not provide a scientifically valid indication that
2,3,7,8-TCDD adversely affects either male or female reproductive
performance, or that exposure to 2,3,7,8-TCDD is without effect. The
limitations of the studies are similar to those discussed in the section
above.
No animal studies were available on the reproductive toxicity of
2,3,7,8-TCDD following dermal exposure.
Carcinogenicity. EPA (1985b, 1988b) and Hiremath et al. (1986)
reviewed several epidemiology studies of humans exposed to herbicides
contaminated with 2,3,7,8-TCDD. A series of studies (Eriksson et al.
1979, 1981; Hardell and Eriksson 1988; Hardell and Sandstrom 1979;
Hardell et al. 1980, 1981; Lynge 1985; Merlo and Puntoni 1986; Puntoni
et al. 1986) reported an association between exposure and soft tissue
sarcomas (of various sites) and lymphomas. Although many of these
studies had confounding factors, the problems with these studies were
not sufficient to explain the highly significant risks of soft tissue
sarcoma in the exposed workers (EPA 1988b). EPA (1988b) also reviewed a
number of studies (Balarajan and Acheson 1984; Cantor 1982; Cook et al.
1986; Fett et al. 1984; Kang et al. 1987; Kogan and Clapp 1985; Milham
1982; Smith et al. 1984; Woods et al. 1987; Zack and Suskind 1980) that
were considered to be consistent with or tended to support the findings
of soft tissue sarcoma in groups thought to be exposed to chemicals
contaminated with 2,3,7,8-TCDD. A number of studies found no association
between risk of soft tissue sarcoma and exposure to herbicides
contaminated with 2,3-,7,8-TCDD (Axelson et al. 1980; Fingerhut et al.
1984; Greenwald et al. 1984; Lathrop et al. 1984; Ott et al. 1980;
Rlihimaki et al. 1982; Thiess et al. 1982; Wiklund and Holm 1986;
Uiklund et al. 1987; Wolfe et al. 1984, 1985). EPA (1988b) concluded
that the epidemiological data appear to provide limited evidence that
exposure to phenoxyacetic acid herbicides and/or chlorophenols is
causally related to the risks of soft tissue sarcoma, but none of the
data are sufficient to implicate 2,3,7,8-TCDD alone.
There are some data from experimental animal studies regarding the
dermal carcinogenicity of 2,3,7,8-TCDD. In Swiss mice, females, but not
males, developed skin tumors following dermal application of
2,3,7,8-TCDD at 0.01 pg per application three times per week
(NTP 1982b). There has also been mixed evidence that 2,3,7,8-TCDD is a
tumor promoter. Poland et al. (1982) observed tumor-promoting activity
in hairless mice, but not in mice heterozygous for the hairless trait.
Similarly, Berry et al. (1978), Slaga and Nesnows (1985), and NTP
(1982b) have not been able to demonstrate promoting activity in CD-I,
Sencar, or Swiss-Webster mice.
2.2.2 Biological Monitoring as a Measure of Exposure and Effects
Biological monitoring of body fluids provides qualitative
indications of exposure. With commonly available analytical techniques,
2,3,7,8-TCDD is not detected in body fluids, such as blood or urine,
although a recent method with parts-per-quadrillion sensitivity has
detected 2,3,7,8-TCDD in human serum (Patterson et al. 1987b).
Biomonitoring of adipose tissue provides qualitative and quantitative
-------
Health Effects Summary 21
information on exposure, but the techniques are not commonly available.
Adipose tissue has been shown to be one of the primary storage sites for
2,3,7,8-TCDD, and tissue samples have been analyzed, although mixed
results have been obtained. As reported by Nygren et al. (1986), Young
et al. (1983) failed to detect elevated levels of 2,3,7,8-TCDD in the
adipose tissues of Vietnam veterans exposed to Agent Orange, whereas
Gross et al. (1984) detected increased levels in veterans who had been
exposed to high levels of Agent Orange. As reported by Nygren et al.
(1986), higher levels of 2,3,7,8-TCDD in adipose tissue have also been
reported in individuals exposed during a transformer fire accident in
Binghamton, New York, or the accident in Seveso, Italy. In another
study, 39 exposed individuals in Missouri had median adipose 2,3,7,8-
TCDD levels of 17 ppt, with a range of 2.8 to 750 ppt, whereas the
unexposed control group had a median level of 6.4 and a range of 1.4 to
20 ppt (Patterson et al. 1986). Although six of the subjects in the
exposed group had levels >5 times higher than the highest control, there
was also extensive overlap between the groups.
EPA (1988c) estimated an upper limit value for the average
2,3,7,8-TCDD concentration in adipose tissue to be 6.72 ppt in the U.S.
population. From this adipose tissue burden and pharmacokinetic
considerations, it was estimated that the upper-bound 2,3,7,8-TCDD daily
intake ranges from 0.04 to 0.51 pgAg- However, the level of 2,3,7,8-
TCDD in the adipose tissue of certain individuals with no known history
of exposure to 2,3,7,8-TCDD generally are in the range of 5 to 18 ppt.
This would suggest a ubiquitous exposure to 2,3,7,8-TCDD, which makes it
difficult to assess the contribution to body burden from any particular
small additional exposure. A similar lack of correlation between
estimated exposure to 2,3,7,8-TCDD and sera levels of 2,3,7,8-TCDD was
reported in a preliminary study in the MMWR (1987), in which Vietnam
veterans with military histories indicating exposure to herbicides
containing 2,3,7,8-TCDD were compared to non-Vietnam veterans with
presumably no unusual exposure to 2,3,7,8-TCDD. In these preliminary
results, at least, there was no difference in the range of 2,3,7,8-TCDD
levels (1 to 9 ppt of both groups based on lipid weight) or the median
2,3,7,8-TCDD level (3.9 ppt for the presumably exposed group and 3.8 ppt
for'the nonexposed group). This lack of correlation may in part be
attributed to the difficulty of identifying persons exposed to 2,3,7,8-
TCDD, since inclusion of nonexposed individuals in the exposed
population will tend to make the two groups appear similar.
There are also no clear tests for the effects of exposure to
2,3,7,8-TCDD. Chloracne is the only effect that is clearly associated
with exposure to chemicals contaminated with 2,3,7,8-TCDD; however,
chloracne is also caused by other halogenated aromatic compounds. The
development of chloracne in an individual who may have been exposed to
2,3,7,8-TCDD would provide supportive evidence that exposure to this
chemical had occurred. The development of chloracne, however, does not
indicate the extent of exposure. Other signs of toxicity observed in
animal studies (i.e., liver damage, effects on lipid metabolism, and
types of circulating lipids) have not been demonstrated in humans and
are not useful in determining that exposure to 2,3,7,8-TCDD has
occurred.
-------
22 Section 2
2.2.3 Environmental Levels as Indicators of Exposure and Effects
2.2.3.1 Levels found in the environment
2,3,7,8-TCDD has been monitored in the areas of extensive herbicide
use and areas contaminated with 2,3,7,8-TCDD through industrial
accidents; however, epidemiologic studies of inhabitants of these areas
have lacked adequate exposure data that would permit the demonstration
of a clear association between exposure and effects. The biological
half-life of 2,3,7,8-TCDD in humans, calculated to be 5 years by Poiger
and Schlatter (1986) and 7 years by the CDC (1987), would indicate that
repeated exposure to low levels of 2,3,7,8-TCDD could substantially
elevate the body burden of this compound to a level equivalent to the
level obtained after a single exposure to a high level. Given the long
half-life of 2,3,7,8-TCDD, the total exposure history of an individual
has to be taken into account; hence, the environmental levels during a
single particular exposure scenario may be misleading with regard to
either effects observed or levels of body burden. The difficulties of
estimating safe environmental levels have been discussed by Kimbrough et
al. (1984), who concluded that levels >1 ppb of 2.3,7.8-TCDD are of
concern in residential soil.
2.2.3.2 Human exposure potential
The human exposure pathways to 2,3,7,8-TCDD have changed since the
late 1970s. Because 2,3,7,8-TCDD was a contaminant in herbicide
preparations containing 2,4,5-T, the manufacture, use, and disposal of
these herbicides were the primary sources of exposure to 2,3,7,8-TCDD.
In 1979, EPA (1979) completely banned the use of 2,4,5-T. With the
stoppage of production of 2,4,5-T and other pesticide preparations
containing the contaminant 2,3,7,8-TCDD, both occupational and general
population exposure to 2,3,7,8-TCDD due to manufacture and use of the
herbicides ceased to exist. Presently, the important sources of
2,3,7,8-TCDD exposures to the general population are contaminated soil,
dumpsites, and municipal incinerators. With the change of sources, the
exposure pathways have also changed over the years (i.e., dermal and
inhalation exposure from the manufacture and use of 2,4,5-T to ingestion
of foods obtained from contaminated sites). Thus it is not possible to
state precisely which route of exposure to 2,3,7,8-TCDD is most relevant
to the human population. As with many human exposure scenarios, it is
anticipated that all routes of exposure occur, although there are few
data available to quantify the relative contribution of each route. An
environmental partitioning model has been used to estimate the levels of
2,3,7,8-TCDD in different environmental media (Travis and Hattemer-Frey
1987). From the estimated concentration levels, the average daily human
intake of 2,3,7,8-TCDD was predicted to be 98% from ingestion of food,
2% from air, and <0.01% from ingestion of drinking water. EPA (1988)
estimated the human exposure potential to 2,3,7,8-TCDD from a variety of
exposure scenarios resulting from contaminated soils, various land
disposal situations, and municipal waste incinerators. The highest
exposure was attributed to the food chain, i.e., from ingestion of
contaminated fish, beef, dairy products, and other foods. Ingestion of
contaminated soil, especially by children with pica tendencies; dermal
-------
Health Effects Summary 23
contact with contaminated soil, dust, and sediment; and inhalation of
contaminated dust and vapor further contribute to human exposure.
Based on data on dermal and oral absorption in animals, it is
anticipated that 2,3,7,8-TCDD adsorbed to soil will not be as
bioavailable as the 2,3,7,8-TCDD used in experimental studies and
administered in oily vehicles. In the studies available, oral absorption
of 2,3,7,8-TCDD adsorbed to soil was still substantial but only 50% of
that from corn oil (absorption of SO to 80%) (Lucier et al. 1986,
McConnell et al. 1984, Umbreit et al. 1986a). Bioavailability also
varies with the type of soil, as demonstrated by Umbriet et al. (1986b)
for New Jersey and Missouri soils, where bioavailability from New Jersey
soils was less than that from Missouri soils. The limited studies
available may not be representative of the variation in bioavailability,
since Poiger and Schlatter (1980) demonstrated that strong binding
vehicles, such as activated carbon, can apparently reduce
bioavailability to zero, and Philippi et al. (1981) and Huetter and
Philippi (1982) demonstrated that the strength of adsorption increases
with contact time in soil. Hence, factors such as soil type and contact
time may affect the bioavailability of 2,3,7,8-TCDD.
It is likely that many of the same physical properties that result
in strong binding to soil, such as extremely low water solubility and
planar configuration, also result in very high bioconcentration factors.
Because of the high lipophilicity and long half-life of 2,3,7,8-TCDD,
exposure through ingestion of fatty tissues of fish that inhabit
contaminated areas is anticipated to be significant. In addition, as a
result of the lipophilic nature of milk, secretion of milk can provide a
relatively efficient mechanism for decreasing the body burden of
2,3,7,8-TCDD in females. As discussed by Rappe et al. (1985), this
elimination of 2,3,7,8-TCDD through mother's milk can result in exposure
of the infant. Since both milk and the fatty tissues of fish are
essentially providing an oily vehicle, it seems likely that these
sources would provide 2,3,7,8-TCDD in a form that is readily
bioavailable.
2.3 ADEQUACY OF DATABASE
2.3.1 Introduct ion
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of
significant human exposure for the substance and the
associated acute, subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and
chronic health effects.
-------
24 Section 2
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans."
This section'identifies gaps in current knowledge relevant to
developing levels of significant exposure for 2,3,7,8-TCDD. Such gaps
are identified for certain health effects end points (lethality,
system/target organ toxicity, developmental toxicity, reproductive
toxicity, and carcinogenicity) reviewed in Sect. 2.2 of this profile in
developing levels of significant exposure for 2,3,7,8-TCDD, and for
other areas such as human biological monitoring and mechanisms of
toxicity. The present section briefly summarizes the availability of
existing human and animal data, identifies data gaps, and summarizes
research in progress that may fill such gaps.
Specific research programs for obtaining data needed to develop
levels of significant exposure for 2,3,7,8-TCDD will be developed by
ATSDR, NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs. 2.5 and 2.6, respectively.
The bars of full height indicate that there are data to meet at
least one of the following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no-effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or "probable human carcinogen" by both EPA
and International Agency for Research on Cancer (IARC)
(qualitative), and the data are sufficient to derive a cancer
potency factor (quantitative).
3. For animal carcinogenicity, a substance causes a statistically
signficant number of tumors in at least one species, and the data
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause this
health effect via this exposure route.
Bars of half height indicate that "some" information for the end
point exists but does not meet any of these criteria.
The absence of a column indicates that no information exists for
that end point and route.
Although adequacy of data is indicated in Fig. 2.5 for dermal
exposure only, the route of exposure in the available studies is not
clearly defined. Because of the nature of exposures to 2,3,7,8-TCDD,
both inhalation and oral exposure are likely to occur along with dermal
exposure; in some instances, exposure from these other routes will
contribute substantially to the body burden.
-------
HUMAN DATA
V SUFFICENT
^INFORMATION'
SOME
INFORMATION
NO
INFORMATION
INHALATION
DERMAL
LETHALITY
ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOQENICITV
/ TOXICITV TOXICITV
SYSTEMIC TOXICITY
3-
o
n
to
'Although data for human exposure were discussed lor the dermal route, inhalation and oral exposure also contribute to the total environmental exposure of
humans to 2.3,7,8 TCDD
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
hig. 2.5. Availability of information on health effects of 2,3,7,8-1 ( 1)1) (human data).
-------
LETHALITY
ANIMAL DATA
ro
§
SUFFICIENT *»
INFORMATION*
V SOME
/INFORMATION
J
NO
INFORMATION
ORAL
INHALATION
DERMAL
ACUTE INTERMEDIATE
CHRONIC DEVELOPMENTAL REPRODUCTIVE CAHCINOOENICITY
/ TOXICITY TOXICITY
SYSTEMIC TOXICITY
'Sufficient information exists to meet at least one ot the criteria for cancer or noncancer end points.
Fig. 2.6. Availability of information on health effects of 2,3,7,8-TCDD (animal data).
-------
Health Effects Summary 27
2.3.2.2 Descriptions of highlights of graphs
Human. Figure 2.5 indicates that there are very little human data
on the toxicological effects of exposure to 2.3,7,8-TCDD. The data
obtained from human studies are considered to be from dermal exposures,
since most humans were exposed in contaminated areas considerably after
the application or initial release of the chemicals containing
2,3,7,8-TCDD. This long-term exposure would occur through contact of the
skin with soil and other articles contaminated with 2,3,7,8-TCDD.
Inhalation and oral exposures were also likely to occur through
inhalation of contaminated dust and ingestion of contaminated food and
dust. From reports of human exposure (acute accidental exposure as well
as repeated exposure), there is a clear indication that chemicals
containing 2,3,7,8-TCDD cause chloracne and there is some indication
that chemicals containing 2.3,7,8-TCDD are hepatotoxic; however, data
are insufficient to determine the levels of exposure required for
induction of these effects. Schecter et al. (1987) reported a calculated
effect level of 9.7 Mg for the body burden of 2,3,7,8-TCDD that resulted
in chloracne in some industrial workers; however, verification of this
value is not available. By extrapolating dose-effect data obtained from
the ingestion of contaminated rice oil containing polychlorinated
biphenyls and polychlorinated dibenzofurans to dose-effect data for
2,3,7,8-TCDD and taking into consideration the minimum toxic dose for
the production of chloracne in nonhuman primates, Stevens (1981)
estimated a minimum toxic dose for 2,3,7,8-TCDD of 0.1 MgAg f°r humans.
The epidemiologic data on the effects of 2,3.7,8-TCDD on fetal
development, human reproduction, immuno function, and the development of
cancer are not adequate to either prove or disprove an association.
There are no additional data on the toxicity of 2,3,7,8-TCDD
following inhalation exposure or oral exposure.
Animal. Figure 2.6 indicates that there are considerably more data
on the toxicological effects of 2,3,7,8-TCDD in animals than in humans,
although the data are primarily limited to oral studies. For animal
data, it should be recognized that "adequate" may only apply to the
specific species tested, since large species differences are observed
with 2,3,7,8-TCDD. As a result of these large differences in species
sensitivity (4 orders of magnitude for LD50 values), .complete
information on a specific end point will be difficult to obtain. For the
complete understanding of a toxicological end point, the most sensitive
species must be determined and adequately tested, or it must be clearly
demonstrated which animal species is most representative of humans. The
lack of adequate data on species sensitivity is a significant gap in the
toxicological data on 2,3,7,8-TCDD.
Although dermal exposure is a potentially significant route of
human exposure, the only animal data available for this route are a
single determination of a lethal dose in rabbits (Schwetz et al. 1973)
and a few studies of the effects of 2,3,7,8-TCDD in the two-stage
tumorigenesis assay (EPA 1985a) of the mouse. Both of these types of
studies provide only limited data on the dermal toxicity of
2,3,7,8-TCDD.
-------
28 Section 2
2.3.2.3 Summary of relevant ongoing research
A review of Federal Research in Progress will show that
investigations of the toxicological properties of 2,3,7,8-TCDD are very
active. This ongoing research is summarized in Table 2.1. Also, a very
important area of ongoing research is reviewed by Young and Kang (1985)
and Hanson (1987). This area consists of 15 ongoing epidemiology studies
that are being conducted for the U.S. government and coordinated by the
White House Agent Orange Working Group. Subject areas include mortality
and morbidity, with particular concern for carcinogenic effects,
including the development of soft tissue sarcomas, and anatomical birth
defects. A number of these studies are concerned with veterans exposed
to the herbicide Agent Orange in Vietnam.
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Pharmacokinetics and mechanisms of action
Mechanisms of action. The mechanism of 2,3,7,8-TCDD toxicity is
under extensive investigation. As reviewed by Roberts et al. (1985), it
has been proposed that 2,3,7,8-TCDD functions by a receptor-mediated
mechanism. There is evidence that this mechanism is associated with many
of the toxicological end points of 2,3,7,8-TCDD, as indicated by the
segregation of the toxic properties of 2,3,7,8-TCDD with the Ah locus,
which is near the locus for the 2,3,7,8-TCDD receptor. Some toxicologic
end points, however, do not segregate with the Ah locus. It has been
shown in tissue cultures with human lymphoblastoid cells that there is a
large genetic variation in aryl hydrocarbon hydroxylase inducibility
(Nagayama et al. 1985), and the susceptibility of these cells to the
toxicity of 2,3,7,8-TCDD parallels the induction of this monooxygenase
system. In addition, the levels of the receptors in a particular species
do not necessarily correspond to species sensitivity. Thus, although a
receptor-mediated mechanism is well established, the complete
integration of this mechanism with the toxic action of 2,3,7,8-TCDD has
not been fully characterized.
Other studies on the mechanisms of action of 2,3,7,8-TCDD are also
being followed; for example, Rozman et al. (1985) have described results
of a study which indicates that the thyroid hormone thyroxine (T4) has
the ability to modulate the toxicity of 2,3,7,8-TCDD. Male Sprague-
Dawley rats were divided into groups of normal rats, thyroidectomized
rats, and thyroidectomized rats that received T4 replacement therapy.
Following administration of 2,3,7,8-TCDD, mean time to death and percent
mortality at 90 days were similar between the normal rats and the
thyroidectomized rats that received T& (35 days and 89%, and 37 days and
80%, respectively). Thyroidectomized rats that did not receive T4
survived longer (mean time to death of 63 days) and had lower mortality
at 90 days (44%). It was also demonstrated that the 2,3,7,8-TCDD
treatment resulted in a decrease in serum T4 levels in both normal and
thyroidectomized T4-supplemented rats. The modulation of the lethal
effects of 2,3,7,8-TCDD was considered by the authors to be related to
thyroid hormone modulation of energy metabolism. The participation of
this mechanism in the development of 2,3,7,8-TCDD toxicity needs further
study.
-------
Table 2.1. Research In progress OB 2^,7,8-TCDD
Principal
investigator
Ami. S.D.
Ausl. J.B.
Bowman. R
Dubold. G J.
Fujimolo. J.M
Gasicwicz, T.A.
Gasiewicz, T A
Title
Toxic and anorectic effects of TCDD (rats, mice)
Fat tissue analysis for 2.3,7.8-telrachlorodibenzo-/>-dioxin (TCOD)
Kinetic*, reproductive, unmunofunclion, behavioral toxicily
studies (monkeys)
Oploacouslic detection of carcinogens
Effects of 2.3.7.8-lctrachlorodibcnzodioxin on hcpatobiliary
function in animals
Molecular toxicology of TCOD (rats, mice, guinea pigs, hamsters)
Chlorinated dibenzo-p-dioxms mechanisms of toxicity
Performing
organization0
Michigan Stale University
VA Medical Center, San Antonio
University of Wisconsin Primate
Research Center
Brown University
VA Medical Center. Milwaukee
University of Rochester
University of Rochester
Sponsoring
organization"
NIEHS
VA
EPA
NIEHS
VA
NIEHS
NIEHS
(rats, mice, guinea pigs)
Gtertby. J F Dioxin-cpithelial cell interactionsMechanism and assay
Giesy, J.P. Effects of toxic chemicals on aquatic systems
Gustafsson, J. Structure and function of the TCDD receptor (rats)
Guslafsson, J Binding and metabolism of toxic agents in the prostate (rats)
Holsapple, H.P Immunotoxicology by chlorinated dibenzo-p-dioxins (mice)
Kurth. M.J. Immunoassays for pyrrolizidme alkaloids and metabolites (rodents)
Miller. E.C Biochemical studies in chemical carcmogenesis
Ncben. D W Pharmacogenelics
Nelson. K Receptor interaction and liver tumor promotion
Olson, J.R Mechanism(s) for loxicily of chlorinated dibenzodioxins
Peterson. R E Environmental pollutants and toxicology of the liver (rats, monkeys)
(rodents, humans)
Piper. W N Toxicant deregulation of endocrine heme biosynthesis
(rats, hamsters, guinea pig)
N.Y Slate Department of Health
Michigan Slate University
Caroline Institute
Caroline Institute
Virginia Commonwealth University
University of California, Davis
University of Wisconsin
NICHD
NIEHS
SUNY at Buffalo
University of Wisconsin
NIEHS & NYSDH
USDA
NIEHS
NCI
NIEHS
NIEHS
NCI
NICHD
NIEHS
NIEHS
NIEHS
ID
to
A
O
n
(a
to
University of Nebraska Medical Center NIEHS
ro
vO
-------
Table 2.1 (coBliBoed)
Principal
investigator
Rice. R.H.
Russell. D.H.
Safe. S.H.
Safe. S.H.
Safe. S.H.
Shiremao, R B
Shivcnck, K.T.
Shiverick. KT
Silkworth, J.B
Whitlock, J.P.. Jr
Title
Keratinocyte envelopes physiology and toxic mechanisms
(rau, rabbits, humans)
Mechanism(i) of TCDD toxicity (rats)
Mechanisms of dioxin toxicity (mice. rau. guinea pigs, avian)
Environmental toxicology of balogenated aromatic compounds
TCDD effects of receptor modulators/antagonists
(mice, hamsters, guinea pigs)
Mechanisms of the transfer of sterols and glyccrides into cells
TCDD efTccU on steroid hormone synthesis in pregnancy (rau)
Steroid and xcnobiolic metabolism in the placenta (rats)
PCB unmunotoxicily (mice)
Carcinogen-metabolizing enzymes action in variant cells (mice)
Performing
organization"
Harvard University
University of Arizona
Texas AAM University
Texas AAM University
Texas AAM University
University of Florida
University of Florida
University of Florida
N.Y. Slate Department of Health
Stanford University
Sponsoring
organization"
NIAMSD
NIEHS
NIEHS
USDA
NIEHS
USDA
NIEHS
NICHD
NIEHS, A NYSDH
NCI
"NCI - National Cancer Institute.
NIAMSD - National Institute of Arthritis and Musculoskeletal and Skin Diseases
NICHD - National Institute of Child Health and Human Development.
NIEHS - National Institute of Environmental Health Sciences
NYSDH - New York State Department of Health
USDA United Slates Department of Agriculture.
VA Veterans Administration.
CO
It
n
it
i-.
s
is»
-------
Health Effects Summary 31
In addition, mechanisms for individual end points, such as the
wasting syndrome and the development of cleft palate, have also been
investigated. Although a number of mechanisms have been proposed for
such end points, there has yet to be a definitive understanding of the
underlining biochemical processes that result in the observed effects of
2,3,7,8-TCDD. Further investigation of these processes is necessary not
only to understand how 2,3,7,8-TCDD induces certain toxic end points,
but also how the different target organ responses relate to each other.
Target organ/pharmacokinetic profiles. There are few data to
indicate that target organs (such as liver and thyroid) contain
relatively higher levels of 2,3,7,8-TCDD than other, nontarget tissues.
In general, 2,3,7,8-TCDD appears to distribute to organs in proportion
to lipid content (Ryan et al. 1985b) rather than in regard to the
sensitivity of the organ to the toxic effect of 2,3,7,8-TCDD. Roberts et
al. (1985), however, reported that the distribution of the 2,3,7,8-TCDD
receptor may be a better indicator of target organ than the distribution
of 2,3,7,8-TCDD itself. Further work is needed to clarify this issue.
Further research is also needed to determine the association
between a species' capability to metabolize 2,3,7,8-TCDD and the
sensitivity of that species to 2,3,7,8-TCDD-induced toxicity. Although
there are data suggesting that the ability to metabolize 2,3,7,8-TCDD is
important in determining species sensitivity to this chemical, the data
are not complete and a mechanism has not been proven.
Ongoing research. There are a relatively large number of studies
reported in Federal Research in Progress that are involved with the
toxicokinetics and the mechanisms of action of 2,3,7,8-TCDD. The list of
projects is too extensive for inclusion in this profile.
2.3.3.2 Monitoring human biological samples
Adequate analytical methods are available to investigate 2,3,7,8-
TCDD levels in biological materials that are lipophilic and thus
concentrate 2,3,7,8-TCDD. Biological fluids with high lipid content for
which 2,3,7,8-TCDD quantification methods in the low ppt range are
available are cow's milk and human breast milk (Sect. 7.2.4). Young
(1984) reported that the methodology is not available for detecting
2,3,7,8-TCDD in blood or tissues with low lipid content, although a
recent method reported the detection of 2,3,7,8-TCDD in parts-per-
quadrillion levels in human serum (Patterson et al. 1987b). The
development of more sensitive analytical methods is necessary for
environmental analysis, and the resulting technology will be used in
monitoring biological samples. At present, the ability to monitor
2,3,7,8-TCDD in human tissues appears to exceed the ability to interpret
the toxicological significance of the observed results.
2.3.3.3 Environmental considerations
Analytical methods. Concentrations of 2,3,7,8-TCDD in ambient air
and drinking water are generally so low that the existing analytical
methodologies cannot measure the levels in these two media.
-------
32 Section 2
Bioavailability. .The dependence of 2,3,7,8-TCDD bioavailability r
the matrix to which it is bound has been suggested by several
investigators. In guinea pigs, the bioavailability of 2,3,7,8-TCDD from
a contaminated soil in Newark, New Jersey, was reported to be 0.5% of
the administered dose, whereas a different soil from Newark showed a
bioavailability of 21.3% (Umbrtet et al. 1986). From the studies of
McConnell et al. (1984), Umbriet et al. (1986) estimated a
bioavailability of about 85% in guinea pigs for soils from the Times
Beach area of Missouri. Similarly, the uptake of 2,3,7,8-TCDD from fly
ash to freshwater fish was found to depend on the carbon content of the
fly ash (Kuehl et al. 1985). The bioavailability of 2.3.7.8-TCDD in male
Wistar rats was at least 10 times lower when the administered dose was
in the form of fly ash particle compared with dosage in oily vehicles
(Van den Berg et al. 1987). With oral dosage of contaminated Missouri
soil, Lucier et al. (1986) observed a dependence of bioavailability in
rats on its concentration in soil, the bioavailability being higher at
higher dosage. The dermal bioavailability in rats, however, was
approximately 1% of the administered dosage following 24 hours of
contact with skin, and the uptake was not influenced either by the
concentration of 2,3,7,8-TCDD in soil or the presence of oily vehicles
(Shu et al. 1987). The insufficient data that exist today indicate that
2,3,7,8-TCDD can bind strongly in soils with high organic carbon
content, thus decreasing its bioavailability. The available data also
indicate that bioavailability from soil may depend on its residence time
in soil (Shu et al. 1987). As it remains in soil, the fraction of the
irreversibly sorbed part increases and thus renders it less
bioavailable. Certain other factors (e.g., the concentration of
2,3,7,8-TCDD in a medium, difference in species, presence of co-
contaminants in the dosage medium, lipid content of diet, and
interaction of 2,3,7,8-TCDD with host site) may alter the
bioavailability. Although fragmentary data on the dependence of
bioavailability on different parameters are available, no systematic
study has been made that attempts to explain the dependence of
bioavailability on the several possible parameters.
Environmental fate and transport. Some progress on the fate and
transport of 2,3,7,8-TCDD in environmental media has been made in recent
years. Substantial gaps still exist in quantitative data regarding its
biodegradability, photolysis, and volatility from environmental media.
Interactions with other common co-contaminants. There are no data
to indicate that 2,3,7,8-TCDD will interact chemically with other
contaminants under environmental conditions. The presence of 2,3,7,8-
TCDD in both biological systems and the environment, and the lack of any
reactive groups, would support the conclusion that 2,3,7,8-TCDD will not
easily react with other compounds.
Ongoing research. Present research efforts are focused primarily
on analytical methodology to develop more monitoring data. The objective
of most of this research is to develop new analytical methods that will
unequivocally identify and quantify very small amounts of 2,3,7,8-TCDD
in various environmental media with a faster turnover time. An example
of such an ongoing research is the investigation now being performed b**
Robens and Zabik (n.d.). Substantial research is in progress to
determine the concentration of 2,3,7,8-TCDD in serum and human milk
-------
Health Effects Summary 33
samples. Groups of investigators in the Centers for Disease Control,
research organizations in Sweden, and at Rutgers University, the State
University of New York at Binghamton, and the Canadian Food Research
Division are involved in such efforts (Ryan 1987).
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35
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
The chemical identity of 2,3,7,8-tetrachlorodibenzo-p-dioxin, to
be referred to as 2,3,7,8-TCDD throughout this document, is given in
Table 3.1.
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Selected physical and chemical properties of 2,3,7,8-TCDD are shown
in Table 3.2. 2,3,7,8-TCDD is stable toward heat, acids, and alkalies,
but begins to decompose at 500"C. The decomposition is virtually
complete within 21 s at 800°C. 2,3,7,8-TCDD is susceptible to photo-
degradation in the presence of ultraviolet light, particularly in the
presence of a hydrogen-donating solvent. Gamma radiation degrades
2,3,7,8-TCDD in organic solvents (EPA 198Sa).
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36 Section 3
Table 3.1. Chemical identity of 2,3,7,8-TCDD
Chemical name
Trade name
Chemical formula
Wiswesser line notation
Chemical structure
Identification Nos.
CAS Registry No.
NIOSH RTECS No.
EPA Hazardous Waste No.
OHM-TADS No.
DOT/UN/NA/IMCO Shipping No.
STCC No.
Hazardous Substances Data Bank No.
National Cancer Institute No.
2,3,7,8-tetrachlorodibenzo[b,e]( 1,4)-dioxin;
2,3,7,8-tetrachlorodibenzo-p-dioxin; dioxin; TCDBD;
2,3,7,8-TCDD; 2,3,7.8-tetrachlorodibenzodioxm;
2,3,7,8-tctrachlorodibenzo-l,4-dioxm (EPA 1985)
None. (The compound is not produced commercially.)
(EPA 1985b)
C,2H4CU02
TC666 BO IOJ EG FG LG MG or
TC666 BO IOJ DG EG LG MG (HSDB 1987)
Cl
1746-01-6 (SANSS 1987)
HP3500000 (SANSS 1987)
Not assigned (HSDB 1987)
8300192 (SANSS 1987)
Not assigned (HSDB 1987
Not assigned (HSDB 1987)
4151 (HSDB 1987)
NCI-C03714 (SANSS 1987)
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Chemical and Physical Information 37
Table 3.2. Physical properties of 2,3,7,8-TCDD
Property
Value
References
Molecular weight
Color
Physical state
Odor
Melting point
Boiling point
Autoigmtion temperature
Solubility
Water (ng/L)
321.97
Colorless
Solid at room temperature
Unknown
305 °C
412.2°C (estimated)
NAfl
7.91 (20-22°C), 19.3 (22°C)
Organic solvents (mg/L) o-Dichlorobenzene, 1400; chlorobenzene, 720;
benzene, 570; chloroform, 370;
methanol, 10; acetone, 110
Density (g/mL)
Partition coefficients
Vapor pressure (mm Hg)
Henry's Law constant
Flash point
Refractive index
Flammability limits
Conversion factors
Vapor
1.827 (estimated)
Log 1^:6.15-7.28
Log K^: 6.0-7.39
1.52 X 10-'(25°C)
1.4 X 10~9 (estimated at 25°C)
8.1 X 10~s atm-mj/mol (25°C) (estimated
from water solubility and vapor pressure)
6.4 X 10~* atm-m3/mole (estimated)
Unknown
Unknown
Unknown
1 ppb = 13.384 Mg/m3 at 20°C
EPA 1985a
EPA 1985a
Schroy et al. 1985, 1986
Schroy et al. 1985
Adams and Blame 1986,
Marple et al. 1986a
Schroy et al. 1985
Schroy et al. 1985
EPA 1985a.
Schroy et al. 1985,
Jackson et al. 1986,
Marple et al. 1986b
Schroy et al. 1986
Palansky et al. 1986
Podoll et al. 1986
"Not available.
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39
4. TOXICOLOGICAL DATA
4.1 OVERVIEW
Human and animal data indicate that 2,3,7,8-TCDD can be absorbed
following ingestion, and although bioavailability is affected by binding
to soils, the extent of absorption is only decreased by -50%. In
addition, animal data indicate that 2,3,7,8-TCDD may be absorbed well
through the skin depending on such variables as the dose or the material
to which 2,3,7,8-TCDD is adsorbed. Following absorption, 2,3,7,8-TCDD is
distributed to tissues in proportion to the lipid content. 2,3,7,8-TCDD
can cross the placenta with subsequent exposure of the fetus, and the
newborn can be exposed following redistribution of 2,3,7,8-TCDD during
lactation. Metabolism of 2,3,7,8-TCDD is currently thought to result
primarily in detoxification and relatively rapid removal of the
metabolites through excretion in the bile and urine. Unmetabolized
2,3,7,8-TCDD is also excreted through direct intestinal elimination in
feces as well as through lactation. There are species and strain
differences in both metabolism and elimination rates, with elimination
half-lives varying from 11 days in the hamster, which is relatively
resistant to 2,3,7,8-TCDD toxicity, to >1 year in the monkey, which is
sensitive to the toxicity of 2,3,7,8-TCDD. There is, however, no clear
correlation between toxicity and the elimination half-life for 2,3,7,8-
TCDD.
Although humans have been exposed to 2,3,7,8-TCDD as a contaminant
of herbicides and industrial chemicals, there have been no reported
deaths from acute exposure. Lethal oral doses of 2,3,7,8-TCDD vary from
0.6 to 5,000 pg/kg for guinea pigs and hamsters, respectively, with
other species tested having LD50 values between these two extremes.
Subchronic LD50 values for cumulative (total) exposure during a 90-day
oral study with guinea pigs were essentially the same' as those observed
after acute exposure. A 9-month feeding study of a small number of
monkeys indicated that a dose of 2 to 3 MgAg resulted in death. The
acute dermal LD50 value for 2,3,7,8-TCDD in rabbits has been reported to
be 275 MgAg: however, no other species have been tested, and rabbits
are only intermediate in sensitivity to 2,3,7,8-TCDD in oral toxicity
studies. Inhalation experiments have not been conducted.
The only effect clearly demonstrated to be produced in humans
following 2,3,7,8-TCDD exposure is chloracne. This lesion is a systemic
toxic effect and not solely a dermal effect. Although animal models are
available to study chloracne, there are limitations in investigating
this toxicological end point. The lesions produced in animals are
different from the lesions in humans, and the expression of this lesion
may be limited to monkeys, specific strains of mice, and rabbits
(observed only on the ears after dermal application).
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40 Section 4
In animals, the toxic effect of 2,3,7,8-TCDD exposure most often
observed is the wasting syndrome, in which the animals progressively
lose body weight prior to death, although no one organ is altered to
such an extent that it can be associated with the overt signs of
toxicity. Although this syndrome is observed in all species of chorduca
tested, it occurs predominantly only at doses that are lethal or near
lethal. The wasting syndrome has not been confirmed in humans, although
loss of weight has been included in the list of effects associated with
acute exposure to chemicals contaminated with 2,3,7,8-TCDD.
Immunotoxicity has also been observed in a variety of animal
species and may be one of the most-sensitive effects of 2,3,7,8-TCDD.
Immunotoxicity, however, has not been directly related to 2,3,7,8-TCDD
exposure in humans.
Hepatotoxicity has been observed in a variety of animal species,
and there is suggestive evidence that this effect also occurs in humans.
The human data are not completely clear, however, since mixed exposure
to other potentially hepatotoxic chemicals occurred. In addition,
species variations in induction of hepatotoxic effects indicate that the
two most sensitive species, guinea pigs and monkeys, develop relatively
less severe hepatic lesions than many other species.
Other organ systems are also affected by 2,3,7,8-TCDD. There is
suggestive evidence in humans that the nervous system may be affected;
in animals, there are data on effects on the digestive system and the
kidney. These additional organ systems have not been investigated as
extensively as those described later. Also, they do not appear to be
prime indicators of 2,3,7,8-TCDD toxicity or provide any special insight
into extrapolating effects observed in animals to those in man.
Many of the toxic end points discussed have been observed to have
extensive species and strain differences in sensitivity. These
differences may be related to the receptor-mediated mechanism of
toxicity proposed for 2,3,7,8-TCDD. This mechanism follows the scheme of
2,3,7,8-TCDD binding to a soluble cytoplasmic receptor protein, which
subsequently migrates into the nucleus of the cell as a receptor-
2,3,7,8-TCDD complex. Once in the nucleus, it is proposed that both
transcription and translation of DNA may be affected. The receptor
protein is known genetically to segregate with the Ah locus, and many of
the strain differences in toxicity observed in mice are explained by
this segregation. The receptor protein is known to be widely dispersed
in different organ systems and in different species, although
quantitative levels differ. These quantitative differences may help
explain some of the species differences in sensitivity. The receptor
mechanism cannot explain all the species and strain differences in
2,3,7,8-TCDD toxicity, because some toxic responses segregate with the
Ah receptor while others do not.
The evidence from studies of human populations exposed to
herbicides and other industrial chemicals known to be contaminated with
2,3,7,8-TCDD is inadequate to demonstrate that 2,3,7,8-TCDD is a human
developmental toxicant. The data from studies in laboratory mice and
rats, however, clearly demonstrate in these species that 2,3,7,8-TCDD
induces a variety of developmental abnormalities.
-------
Toxicologies! Data 41
The data from human populations exposed to herbicides and other
industrial chemicals contaminated with 2,3,7,8-TCDD are not adequate to
determine if 2,3,7,8-TCDD adversely affects reproductive health in
humans. Animal studies clearly demonstrate that 2,3,7,8-TCDD is
fetotoxic in several species, causing several effects including
spontaneous abortions. There is additional evidence that 2,3,7,8-TCDD
affects male hormone levels and the function of male reproductive
organs.
Although 2,3,7,8-TCDD has not consistently produced positive
results in genotoxicity assays, there are positive results in diverse
bioassay systems which may suggest that 2,3,7,8-TCDD is a genotoxic
agent; however, the large numbers of negative results in assays usually
predictive of genotoxic agents suggest that 2,3,7,8-TCDD is not a
genotoxic agent.
The human evidence that 2,3,7,8-TCDD is a carcinogen is
conflicting, with both positive associations and nonassociations
observed for the induction of cancer in cohorts exposed to herbicides
and other chlorinated chemicals known to be contaminated with 2,3,7,8-
TCDD. As a result, the human data only provide inadequate evidence that
2,3,7,8-TCDD is a human carcinogen. The animal data, however, provide
clear evidence that 2,3,7,8-TCDD is carcinogenic in animals.
Exposure to 2,3,7,8-TCDD in the environment is never to 2,3,7,8-
TCDD alone but to materials such as incinerator fly ash or industrial
wastes, which contain 2,3,7,8-TCDD along with many other congeners of
PCDDs, as well as other potentially toxic materials. The EPA has
recognized the public and toxicological concerns resulting from exposure
to these compounds, as well as the gaps in available information with
which to evaluate the human health potential from exposure (EPA 1987).
In response to this problem, the EPA Chlorinated dibenzo-p-
dioxins/Chlorinated dibenzofurans Technical Panel of the Risk Assessment
Forum has developed and recommended an interim method for assisting in
estimating the risk from exposure to these chemical mixtures that can be
used until the data gaps are filled. This procedure generates the
"2,3,7,8-TCDD equivalence factors" (TEFs) of complex mixtures of
chlorinated dibenzo-p-dioxins and dibenzofurans based on congener- and
isomer-specific data. The TEFs presented in Table 4.1 are relative
values and are a means of relating toxicity data for other chlorinated
dibenzo-p-dioxins and dibenzofurans to an equivalent level of 2,3,7,8-
TCDD. The TEF for 2,3,7,8-TCDD is defined as unity, whereas all other
TEFs are unity or less, thus reflecting the lower toxic potency of most
PCDD congeners. These relative values were developed using a tiered
approach to the evaluation of existing data. Definitive data on the
human carcinogenicity of a congener of 2,3,7,8-TCDD are the most
appropriate data for establishing the TEF. If this human data were not
available, animal carcinogenicity data would be used, followed by the
data on reproductive toxicity. Estimated exposure levels resulting in
reproductive and carcinogenic effects are very similar for 2,3,7,8-TCDD.
Finally, if none of the above data are available, the TEFs are
determined by the weight of evidence from in vitro tests with
particular weight placed on data from tests evaluating receptor binding
interactions and induction of oxidative enzymes. The TEFs thus generated
can be used, assuming additivity of the toxic response, for estimating
-------
42 Section
Table 4.1. Recommended TEFs" for CDDs* and CDFsc
Compound
CDDs
EPA current
CDDs recommended values
MonoCDDs
DiCDDs
TriCDDs
2,3.7,8-TCDD
Other TCDDs
2,3.7,8-PeCDDs'
Other PeCDDs
2J,7,8-HxCDDs'
Other HxCDDs
2,3,7,8-HpCDDs'
Other HpCDDs
OCDD
0
0
0
I
0.01
0.5
0.005
0.04
0.0004
0.001
0.00001
0
Compound
CDFs
EPA current
CDFs recommended values
MonoCDFs
DiCDFs
TriCDFs
2,3.7,8-TCDFs
Other TCDFs
2,3,7,8-PeCDFs*
Other PeCDFs
2,3,7,8-HxCDFs*
Other HxCDFs
2,3,7,8-HpCDFs'
Other HpCDFs
OCDF
NR
NR
NR
0.1
0.001
0.1
0001
0.01
0.0001
0.001
0.00001
0
TEFs = Toxicity equivalence factors.
*CDDs = Chlorinated dibenzo-p-dioxins.
cCDFs = Chlorinated dibenzofurans.
rfNR = Not reported.
'Any isomer that contains chlorine in the 2,3,7,8 positions.
Source: EPA 1987a.
-------
ToxLcoLogical Data 43
the toxicity relative-to 2,3,7,8-TCDD of a mixture containing a known
distribution of congeners of 2,3,7,8-TCDD.
4.2 TOXICOKINETICS
4.2.1 Absorpt ion
4.2.1.1 Inhalation
Pertinent data regarding the absorption of 2,3.7,8-TCDD by humans
or animals following inhalation exposure were not found in the available
literature.
4.2.1.2 Oral
Human. The absorption data available are from an elimination study
of 2,3,7,8-TCDD in which a male volunteer ingested 3H-2,3,7,8-TCDD in
corn oil at a dose of 1.14 ng/kg (Poiger and Schlatter 1986).
Measurements of cumulative elimination in the feces and urine, as well
as a determination of sequestering in fat via biopsy samples, indicated
that >87% of the dose was absorbed. Following absorption, the half-life
for elimination was calculated to be 2,120 days. CDC (1987) determined a
half-life of 2,595 days by measuring the decrease in serum levels of
2,3,7,8-TCDD in Vietnam veterans.
Animal. Studies reviewed in EPA (1985a) show that 2,3,7,8-TCDD is
generally well absorbed (50 to 80%) when administered to rats, guinea
pigs, or hamsters in a lipophilic vehicle by gavage (Nolan et al. 1979,
Olson et al. 1980, Piper et ai. 1973). There appeared to be no change in
absorption rates with repeated dosing, but there was some decrease in
absorption at higher dose levels. Absorption of 2,3,7,8-TCDD when
administered in the diet was also between 50 and 60% (Fries and Marrow
1975).
The vehicle in which 2,3,7,8-TCDD is administered has substantial
effects on its gastrointestinal absorption. As described in EPA (1985a),
Poiger and Schlatter (1980) observed a decrease in the absorption of
2,3,7,8-TCDD when administered in a soil suspension compared with a
solution in 50% ethanol, whereas no absorption occurred when the
compound was administered as a suspension of activated carbon. Since
2,3,7,8-TCDD in the environment is likely to be adsorbed to soil,
McConnell et al. (1984) and Lucier et al. (1986) compared the absorption
of 2,3,7,8-TCDD from contaminated soil with that from 2,3,7,8-TCDD
administered in corn oil. As indicated by biological effects and the
amount of 2,3,7,8-TCDD in the liver, the absorption was -50% less from
soil than from com oil. Umbreit et al. (1986a) showed that 2,3,7,8-
TCDD-contaminated soil was less toxic than an equivalent amount of
2,3,7,8-TCDD, suggesting that binding to soil had an influence on
bioavailability. Van den Berg et al. (1983, 1985, 1987) have studied the
bioavailability of polychlorinated dibenzodioxins and dibenzofurans from
fly ash and determined that bioavailability was lowest on fly ash (0.4%
for 2,3,7,8-TCDD) as compared to extracts of the same fly ash
administered in an oily vehicle (45% for 2,3,7,8-TCDD). Other effects on
the observed bioavailability, species (rats, hamsters, and guinea pigs),
and specific congener may have resulted from differences in metabolism
-------
44 Section 4
or distribution, since 2,3,7,8-TCDD bioavailability was measured by
retention of the compounds in the liver. These data indicate that
substantial absorption occurs from contaminated soil; however, soil type
and duration of contact, as suggested from the data that demonstrated
decreased extraction efficiency with increasing contact time between
soil and 2,3,7,8-TCDD (Huetter and Philippi 1982, Philippi et al. 1981),
may substantially affect the absorption of 2,3,7,8-TCDD from soils
obtained from different contaminated sites. Bioavailability appears to
be low from fly ash; however, studies have been very limited, and
factors such as source of the fly ash, moisture content, or the co-
ingestion of lipophilic material may affect bioavailability.
4.2.1.3 Dermal
Human. Pertinent data regarding the absorption of 2,3,7,8-TCDD
following dermal exposure in humans were not found in the available
literature.
Animal. Data regarding dermal absorption in animals are limited.
2,3,7,8-TCDD is absorbed well through the skin, although as with oral
absorption the vehicle can substantially affect absorption. As discussed
in EPA (1985a), it was estimated that 40% of the dose was absorbed by
rats when the compound was applied in methanol, whereas application in
vaseline or polyethylene glycol resulted in 1.4 and 9.3% absorption,
respectively (Poiger and Schlatter 1980). Applying 2,3,7,8-TCDD as a
paste in soil or activated carbon resulted in poorer absorption than
observed in oral studies, with absorption of <2% and nondetectable,
respectively.
4.2.2 Distribution
4.2.2.1 Inhalation
Pertinent data regarding the distribution of 2,3,7,8-TCDD following
inhalation exposure of humans and animals were not found in the
available literature.
4.2.2.2 Oral
Human. Poiger and Schlatter (1986) estimated that -90% of the body
burden of 2,3,7,8-TCDD was sequestered in the fat after a volunteer
ingested 3H-2,3,7,8-TCDD in corn oil at a dose of 1.14 ng/kg. During
this study, which lasted 135 days, elevated radioactivity was detected
in the blood only during the initial 2 days following treatment. The
data would be consistent with the high bioconcentration potential of
2,3,7,8-TCDD in humans, as calculated by Geyer et al. (1986) from daily
intake assumptions, levels in human adipose tissue, and pharmacokinetic
models. Adipose tissue has been examined to determine if levels of
2,3,7,8-TCDD in this reservoir correlated with exposure. Adipose tissues
of Vietnam veterans exposed to Agent Orange and humans occupationally
exposed to potential sources of 2,3,7,8-TCDD were reported to have up to
10 times the level of 2,3,7,8-TCDD in unexfosed control subjects
(Schecter et al. 1985, Gross et al. 1984); however, another study by
Weerasinghe et al. (1986) failed to detect any difference between a
group of veterans and unexposed subjects. Although a clear correlation
-------
Toxicologies! Data 45
with exposure was not demonstrated, it was apparent that adipose tissue
is a depot for 2,3,7,8-TCDD, and detectable levels were observed in
subjects with no known exposure. Ryan et al. (1985b) further examined
the distribution of 2,3,7,8-TCDD in two humans at autopsy. They
determined on a weight basis that 2,3,7,8-TCDD distributed in descending
order to fat (-6 ppt) and liver (-2 ppt), with levels in muscle and
kidney below detection; however, 2,3,7,8-TCDD levels compared on a per
lipid basis were similar between tissues. These data should be
interpreted with caution, since only two subjects were examined and one
of the subjects was suffering from fatty liver syndrome; therefore, the
data cannot be generalized to the entire population.
Animal. EPA (1985a) reviewed a number of early studies that
described the distribution of 2,3,7,8-TCDD in rats, mice, and guinea
pigs. In rats and mice, the liver contained the greatest amount of
2,3,7,8-TCDD, followed by the fat; however, in guinea pigs this was
reversed. Similar patterns were observed after intraperitoneal
administration. In studies of congenic mice which differ only at the
Ah locus, the distribution patterns were similar to those previously
described, except that relatively higher levels of 2,3,7,8-TCDD were
reported in the livers of the responsive mice compared with the
nonresponsive strain (Gasiewicz et al. 1983a,b; Birnbaum 1986). Thus, it
appears that there is little potential for strain difference in the
distribution pattern of 2,3,7,8-TCDD. Lakshmanan et al. (1986) reported
that the tissue distribution of 2,3,7,8-TCDD is mediated through
transport in the lymph system in the rat, with initial high levels of
2,3,7,8-TCDD in the lymph decreasing rapidly with progressive
accumulation in the fat during the first 24 h. The half-life for
redistribution of 2,3,7,8-TCDD out of adipose tissue and liver was 7.6
and 5.3 weeks, respectively.
2,3,7,8-TCDD crosses the placenta and accumulates in the mouse
fetus after gavage administration (Weber and Birnbaum 1985). In this
study, -0.5% of the dose was detected in the fetus. Similar results were
reported by Krowke (1986) in mice treated with 2,3,7,8-TCDD by
subcutaneous injection. Fecal distribution was not uniform, with 75% of
the 2,3,7,8-TCDD located in the fetal liver. In addition to in utero
exposure of the fetuses, Nau et al. (1986) reported that postnatal
exposure of the young occurred via the milk after a single
administration of 2,3,7,8-TCDD to pregnant mice between gestation days
14 and 17. Again, the fetal and pup liver was the predominant storage
site.
4.2.2.3 Dermal
Human. Studies of humans exposed to herbicides or other industrial
compounds known to be contaminated with 2,3,7,8-TCDD were discussed in
Sect. 4.2.2.2 (oral distribution) for easier comparison with the only
available human experimental data. Routes of exposure in these studies
are not clearly defined; the most likely route is probably dermal,
although oral and inhalation exposure are also likely to occur.
Animal. No studies are available.
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46 Section 4
4.2.3 Metabolism
Pertinent data regarding the metabolism of 2,3,7,8-TCDD following
inhalation or dermal exposure of humans or animals, or following oral
exposure of humans, were not found in the available literature. However,
data regarding the metabolism of 2,3,7,8-TCDD following oral exposure of
animals are available.
2,3,7,8-TCDD is relatively slow to metabolize, but once metabolites
are formed they are rapidly excreted through the urine and bile as
glucuronide and sulfate conjugates (Olson et al. 1980, 1983, as reviewed
in EPA 198Sa). Recently, however, Olson (1986) reported that up to 28%
of the radioactivity in the tissues of guinea pigs treated with labeled
2,3,7.8-TCDD was associated with metabolites, indicating that under the
conditions used, the metabolites of 2,3,7,8-TCDD were not eliminated as
rapidly as previously believed. Sawahata et al. (1982) identified 1-
hydroxy-2,3.7.8-tetrachlorodibenzo-p-dioxin and 8-hydroxy-2,3,7-
trichlorodibenzo-p-dioxin formed by insulation of 2,3,7,8-TCDD with
isolated rat hepatocytes, and Poiger et al. (1982) identified 2-
hydroxy-l,3,7,8-tetrachlorodibenzo-p-dioxin in dogs as major metabolites
of 2,3,7,8-TCDD. Other hydroxylated products were identified as minor
metabolites. Mason and Safe (1986a,b) synthezised some of these
metabolites and demonstrated that they had considerably less biological
activity than 2,3,7,8-TCDD, which supports the observation by Weber et
al. (1982) and Poiger et al. (1982) that metabolites extracted from the
bile of dogs treated with 2,3,7,8-TCDD were less toxic to rats and
guinea pigs, respectively, than equivalent amounts of 2,3,7,8-TCDD.
Species and strain differences in the metabolism of 2,3,7,8-TCDD
have been investigated to determine if differences in metabolism could
account for the large observed difference in toxicity. Gasiewicz et al.
(1983b) reported that qualitative evaluations of the elution profiles of
the urinary and biliary metabolites of 2,3,7,8-TCDD were similar for
responsive and nonresponsive strains of mice. In dogs (in vivo) and rats
(in vitro), pretreatment with 2,3,7,8-TCDD resulted in a 100 and 320%
increase, respectively, in the rate of metabolism of a subsequent dose
of 2,3,7,8-TCDD, whereas in guinea pigs (in vitro), pretreatment with
2,3,7,8-TCDD had no effect on the rate of metabolism of a subsequent
dose of 2,3,7,8-TCDD (Olson and Wroblewski 1985, Poiger and Schlatter
1985, Wroblewski and Olson 1985). These data suggest that some of the
differences in the toxicity of 2,3,7,8-TCDD may be related to the rate
of metabolism as well as qualitative and quantitative differences in the
metabolites formed.
4.2.4 Excretion
Pertinent data regarding the excretion of 2,3,7,8-TCDD following
inhalation or dermal exposure of humans or animals were not found in the
available literature. However, data regarding the excretion of 2,3,7,8-
TCDD following oral exposure of humans and animals are available.
4.2.4.1 Human
Poiger and Schlatter (1986) studied the elimination profile of
2,3,7,8-TCDD from a volunteer who ingested a single 1.14-ng/kg dose of
the tritiated chemical. Urinary levels of radioactivity were never above
-------
lexicological Data 47
background levels during the 135 days the individual was studied. Fecal
elimination was initially rapid, with 11% of the dose eliminated in the
first 3 days (speculated to be nonabsorbed material), whereas during
days 7 to 125, only-3.5% of the dose was eliminated. From these data, a
half-life of 2,120 days in the body was calculated assuming first-order
kinetics.
CDC (1987) has also estimated the half-life for elimination of
2,3,7,8-TCDD. From participants in the Air Force Ranch Hand study, blood
samples were obtained in 1982 from 50 subjects selected as having high
exposure to 2,3,7,8-TCDD. Serum obtained from this blood was used to
determine 2,3,7,8-TCDD on a lipid-weight basis. Similar determinations
were made in 1987. The final test population consisted of 36 subjects
that had 2.3,7,8-TCDD levels of greater than 10 ppt (considered the
background level) at both testing times. The decrease in serum 2,3,7,8-
TCDD levels during the interval time was used to calculate the half-
life. The median half-life calculated was 7.1 years. For 31 of the
individuals, the range of half-life values was between 2.9 and 26.9
years, while the calculated half-life for 1 individual was 743 years.
Values could not be calculated for 4 individuals because the 1987
2,3,7,8-TCDD level was greater than the 1982 value. The variation in
half-life calculations were likely the result of random variation in the
measurements of serum 2,3,7,8-TCDD levels. Considering the difference in
experimental design, the values determined by CDC (1987) are very
similar to those previously reported by Poiger and Schlatter (1986).
4.2.4.2 Animal
In laboratory animals, 2,3,7,8-TCDD and its metabolites are
eliminated predominantly in the feces and in the urine in an apparent
first-order process. There appear to be no major differences whether the
material was administered by the oral or intraperitoneal routes (EPA
1985a). Although metabolites were observed in the bile, unmetabolized
2,3,7,8-TCDD detected in the feces probably was derived from direct
intestinal elimination, as demonstrated by Olson (1986) in guinea pigs.
Nau et al. (1986) reported that elimination of 2,3,7,8-TCDD through
lactation is significant in mice. EPA (1985a) reported that between 91
and 99% of the excreted 2,3,7,8-TCDD-derived radioactivity was found in
the feces of rats and guinea pigs; 54 and 72% was detected in the feces
of mice, with greater fecal excretion in the responsive C57B1/6J strain;
and 59% was observed in the feces of hamsters. Half-lives for
elimination also varied with species and strain as follows (in
decreasing order): guinea pigs (22 to 30 days); rats (17 to 31 days);
mice (11 to 24 days, 11 days in responsive mice and 24 days in
nonresponsive strains); and hamsters (10 to 15 days). Olson (1986)
reported even longer half-lives of >90 days in guinea pigs. Although
there are no adequate excretion data from monkeys, there are indications
that 2,3,7,8-TCDD is very persistent in this species, with a possible
half-life of >1 year (EPA 1985a).
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48 Section 4
4.3 TOXICITY
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Inhalation
Pertinent data regarding lethality and decreased longevity
following inhalation exposure of humans or animals to 2,3,7,8-TCDD were
not found in the available literature.
4.3.1.2 Oral
Human. No studies are available.
Animal. Results of extensive investigations of the acute lethality
of 2,3,7,8-TCDD indicate that this chemical is toxic at very low levels
in all species tested. Species differences in lethality cover 4 orders
of magnitude in dose level. LDso values, after gavage administration in
lipophilic solvents, were reported to range from 0.6 to 2.1 MgAg in
Hartley guinea pigs (Schwetz et al. 1973), 20 to 60 MgAg in rats, 100
to 600 MgAg in mice, and 1,000 to 5,000 MgAg in hamsters (EPA 1985a,
McConnell 1985). Rhesus monkeys have also been studied, but the lowest
dose tested, 70 MgAg. was lethal (McConnell et al. 1978). Reproductive
toxicity studies indicate that female rhesus monkeys are very sensitive
to the lethal effects of 2,3,7,8-TCDD. Eight of 16 pregnant monkeys died
after treatment with a total dose of 1.0 MgAg over a 9-day period
during gestation (McNulty 1985); toxic effects, as indicated by
abortion, were observed at a total 2,3,7,8-TCDD dose of 0.2 MgAg-
Following acute administration, death is generally observed only after
an extended period of time that ranges from 5 to 40 days; this lag time
appears to be, to some extent, independent of dose after a threshold is
reached.
Other factors besides species differences affect the acute toxicity
of 2,3,7,8-TCDD. These variables include the strain of animal tested,
with responsive C57BL/6J mice demonstrated to be twice as sensitive to
2,3,7,8-TCDD-induced lethality as DBA/2J nonresponsive strains
(Gasiewicz et al. 1983a,b), and differences in lethal dose (ranging from
165 to 320 /*gAg) reported for four strains of rats (Walden and Schiller
1985). Strain differences have not been investigated in other species
but would be anticipated to occur. Also, the vehicle substantially
affects the acute lethality of 2,3,7,8-TCDD, probably by altering the
bioavailability of the compound. However, as discussed by Kaminsky et
al. (1985) and illustrated by Umbreit el al. (1985, 1986a,b), the
influence of matrix on bioavailability is complex, with factors such as
the properties of the matrix as well as duration of contact with the
matrix substantially altering the bioavailability. The complexity of
this issue is further illustrated by the protective effect of orally
administered activated charcoal on the lethality of subcutaneously or
intraperitoneally administered 2,3.7,8-TCDD (Manara et al. 1984),
suggesting that some of the effects are the result of processes other
than bioavailability.
The lethal effects of subchronic exposure to 2,3,7,8-TCDD have
been studied by DeCaprio et al. (1986) in Hartley guinea pigs. Guinea
pigs were maintained on diets containing 2, 10, 76, or 430 ppt of
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lexicological Data 49
2,3,7,8-TCDD for 90 days. At 76 and 430 ppt, mortalities of 10 and 70%,
respectively, were observed, and an LD50 value of 0.8 pgAg for the
total consumption of 2,3,7,8-TCDD was calculated. This value is similar
to that observed -in the previously described study of the acute exposure
of male guinea pigs to 2,3,7,8-TCDD. Exposures of 0.61 ngAg/day
resulted in no deaths. In rhesus monkeys, however, Allen et al. (1977)
observed deaths in 5 of 8 animals maintained for 9 months on a diet that
contained 500 ppt of 2,3,7,8-TCDD. From food intake, the total dose
ingested was calculated to be 2 to 3 pgAg or 0.0093 to 0.014 MgAg/d*y.
4.3.1.3 Dermal
Human. No documented death has resulted from the acute systemic
toxicity of 2,3,7,8-TCDD following accidental exposure of humans.
Animal. There is only one study available regarding the lethality
of 2,3,7,8-TCDD by the dermal route. Schwetz et al. (1973) determined
that the acute LD50 of 2,3,7,8-TCDD in acetone was 275 /*gAg (range, 142
to 531 pgAg) in New Zealand white rabbits. As was observed after oral
administration, the time to death was protracted, with deaths observed
between 12 and 22 days after treatment.
4.3.2 Systemic/Target Organ Tozicity
4.3.2.1 Chloracne
Inhalation. Pertinent studies regarding the development of
chloracne by humans or animals following inhalation exposure were not
found in che available literature.
Oral, human. No studies are available.
Oral, animal. Greig (1984) observed typical skin lesions in male
and female hairless A2G-hr/+ mice 4 weeks after a single gavage
administration of 2,3,7,8-TCDD at 75 /igAg- The females appeared to be
more severely affected than the males. McConnell et al. (1978) observed
acne form eruptions in rhesus monkeys given a single dose of 2,3,7,8-TCDD
at 70 MgAg- This dose was severely toxic, resulting in many gross
effects and ultimately death. Longer-term exposure of monkeys to
2,3,7,8-TCDD in the diet at 500 ppt (0.0094 to 0.014 pgAg/day) f°r
9 months also produced lesions that resembled chloracne (Allen et al.
1977). This dose was not a threshold for the formation of chloracne,
since the lesions were severe and associated with other dermal effects
such as subcutaneous edema and loss of facial hair. In addition, this
level of 2,3,7,8-TCDD resulted in the deaths of 5 of 8 animals tested.
Dermal, human. Since the turn of the century, chloracne has been
observed in humans after a few days from the time of accidental exposure
to a variety of chlorinated aromatic compounds. The prevalence of these
lesions has been reviewed by Taylor (1979) and Suskind (1985). 2,3,7,8-
TCDD is known to be one of the most potent compounds in producing
chloracne; however, sufficient data on exposure are not available to
define the doses necessary to produce this lesion. The lesions usually
appear on the face and upper trunk area. These lesions can be very
disfiguring and can be persistent, lasting many years after exposure.
Mild cases of chloracne generally result in no permanent disfigurement
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50 Section 4
(Moses and Prioleau 1985). After the Seveso accident, children appeared
to develop chloracne more frequently than adults, but this may have beer.
related to greater exposure to contaminated soils during play rather
than to a greater sensitivity in the young (Suskind 1985, Taylor 1979).
Other signs of toxicity have been reported in case studies of small
groups of people exposed to 2,3,7,8-TCDD. These signs include aching
muscles, loss of appetite, weight loss, digestive disorders, easy
fatigability, insomnia, loss of libido, headache, neuropathy, sleep
disturbance, sensory changes, and uncharacteristic bouts of anger (Bauer
et al. 1961, Kimmig and Schulz 1957, Oliver 1975, Poland et al. 1971,
Schulz 1957). Many of these symptoms are commonly observed with acute
exposure to chemicals, and since exposure to 2,3,7,8-TCDD is a mixed
exposure, with 2,3,7,8-TCDD being only a minor component (on a
percentage basis), it is difficult to state with certainty that these
symptoms are produced from 2,3,7,8-TCDD. The other chemicals that
provide concomitant exposure include not only the chlorinated compound
of which 2,3,7,8-TCDD is a contaminant, but, in many cases (such as with
herbicide use), petroleum solvents and other "inert ingredients" used in
the formulation of the final product. Epidemiologic studies have failed
to demonstrate an association between 2,3,7,8-TCDD exposure and any of
the above effects; however, the epidemiclogic studies have many
limitations and may not have had the statistical power to detect any
effects that did not occur in a large segment of the exposed population.
Dermal, animal. Puhvel et al. (1982) applied 0.1 /ig of 2,3,7,8-
TCDD to the skin of hairless Skh:HR-l mice 3 times/week for 4 weeks. Th
mice developed skin lesions which appeared on histologic examination to
resemble chloracne. Changes in the skin included hyperkeratinization,
hyperplasia, absences of sebaceous glands, and buildup of keratin into
dermal cysts. 2,3,7,8-TCDD was the most effective agent of the seven
tested in inducing this dermal response, with the next most effective
compound, 3,4,3',4'-tetrachlorobiphenyl, inducing a response at 200 pg
per application. The use of a single dose in this study precludes the
determination of a threshold dose.
Toth et al. (1979) administered 2,3,7,8-TCDD to Swiss mice by
gavage for 1 year at doses of 0, 0.007, 0.7, or 7.0 pgAg/veek.
Amyloidosis was observed in the kidney, spleen, and liver, along with
dermatitis, in all treatment groups. The dermatitis had some
similarities to chloracne, although it is not clear if the etiology is
the same. If this dermatitis is similar to chloracne, then the LOAEL in
mice would be 0.007 ^g/kg/week.
General discussion. Chloracne is a persistent deformative skin
lesion that can be induced by single or multiple exposure to 2,3,7,8-
TCDD in humans. Chloracne is the first toxic effect usually observed in
humans exposed to chemicals contaminated with 2,3,7,8-TCDD and appears
to be a sensitive toxicological end point. It is believed that humans
can develop chloracne following exposure to 2,3.7,8-TCDD by any route.
but data are not available regarding the dose necessary to induce
chloracne in humans.
Moses and Prioleau (1985) studied humans who had recovered from
chloracne and determined that histologic examination of the skin was
incapable of providing any indication of past exposure to 2,3,7,8-TCDD.
r
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lexicological Data 51
Only a few experimental animals develop chloracne upon exposure to
compounds that produce this lesion in humans; the limitation of
appropriate animal models has resulted in a poor understanding of this
lesion and little information on dose-response relationships. In vitro
studies by Greenlee et al. (1984) using human epidermal cultures
suggested that 2,3,7,8-TCDD may affect the receptors for epidermal
growth factors, which ultimately results in the typical dermal lesions
associated with 2,3,7,8-TCDD exposure.
4.3.2.2 Wasting syndrome
Inhalation. Pertinent data regarding wasting syndrome in humans or
animals following inhalation exposure to 2,3,7,8-TCDD were not found in
the available literature.
Oral, human. No studies are available.
Oral, animal. The wasting syndrome has been observed in all
species tested after administration of acute lethal doses of 2,3,7,8-
TCDD (EPA 1985a). As described in the above review, body weight will
decrease (or the rate of gain will be severely limited) after
administration of 2,3,7,8-TCDD, possibly in a biphasic pattern, until
death occurs 15 to 30 days after exposure. These changes in body weight
may be observed within 24 hours of administration of 2,3,7,8-TCDD
(Peterson et al. 1984). Studies with pair-fed rats suggest that the
wasting syndrome results from 2,3,7,8-TCDD-induced appetite suppression
rather than malabsorption or altered food energy utilization (Kellin et
al, 1985; Potter et al. 1986; Rozman 1984; Seefeld et al. 1984a.b;
Seefeld and Peterson 1984). Recently, however, Lu et al. (1986)
demonstrated that total parenteral nutrition only partially protected
Hartley guinea pigs from loss of weight. Treated guinea pigs maintained
relatively stable body weight until a few days prior to death,
demonstrating that decreased food consumption accounts for most of the
observed loss in body weight but that other mechanisms must account for
the final decrease in weight and ultimate death. Additional studies in
cold-adapted Sprague-Dawley rats, which maintain high levels of food
intake after treatment with 2,3,7,8-TCDD, support the observation that
decreased food consumption only partially accounts for the wasting
syndrome, since the cold-adapted rats lost weight twice as fast as rats
treated at normal temperatures (Rozman and Greim 1986).
Rhesus monkeys and Hartley guinea pigs also lose body weight after
prolonged exposure to diets containing 2,3,7,8-TCDD (Allen et al. 1977,
DeCaprio et al. 1986). Weight loss was -20% in female monkeys ingesting
2,3.7,8-TCDD at -0.01 ng/kg/day (the only dose level studied) for 9
months. Only eight monkeys were tested and five died at this dose.
Guinea pigs (10 males and 10 females) maintained for 90 days on diets
that provided doses of 2,3,7,8-TCDD of 0.0049 MgAg/day *»* a 15%
decrease in body weight, whereas guinea pigs given doses of 0.026
MgAg/day had a 40% decrease in body weight. All guinea pigs in the
high-dose group died or were killed (when moribund) before the end of
the study. No effects were observed at the 0.00061-MgAg/day level. It
appears that even in long-term studies, the severe loss of body weight,
characteristic of exposure to 2,3,7,8-TCDD, Is associated with dose
levels that are lethal to the animal.
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52 Section 4
Dermal, human. As discussed In the previous section on chloracne ,
case reports have indicated that weight loss was observed in some
individuals following acute exposure to 2 , 3 , 7 ,8-TCDD. The data are
insufficient to conclude that this reported weight loss was the result
of 2,3,7,8-TCDD exposure or that it is similar to the wasting syndrome
reported in laboratory animals. Epidemiologic studies have not detected
a condition similar to the wasting syndrome in populations with
potential exposure to 2,3,7,8-TCDD.
Dermal, animal. Pertinent data regarding the wasting syndrome in
animals exposed dermally to 2,3,7,8-TCDD were not found in the available
literature.
General discussion. The wasting syndrome is a characteristic sign
of 2,3,7,8-TCDD toxicity in experimental animals. This syndrome is
observed in both acute and longer-term studies and is most commonly
associated with lethal doses. The wasting syndrome has not been observed
in humans.
Since the mechanism is not clearly understood, it remains to be
determined whether the severe body weight loss associated with 2,3,7,8-
TCDD toxicity is the cause of the subsequent death of the animal or an
effect that can be segregated from lethality. Mechanisms have been
proposed by Aust (1984) that suggest that the effect of 2,3,7,8-TCDD on
the thyroid results in activation of thyrotropin-releasing hormone,
which has an anorectic action, and, in conjunction with 2, 3, 7,8-TCDD-
induced vitamin A depletion, results in loss of body weight. Regardless
of the mechanism or length of exposure, the wasting syndrome appears tc
be an indicator of impending death rather than an early sign of
toxicity. No reports of abnormal weight change as a result of 2,3,7,8-
TCDD exposure in humans were found.
4.3.2.3 Hepatic effects
Inhalation. Pertinent data regarding hepatotoxicity in humans or
animals exposed by inhalation to 2,3,7,8-TCDD were not found in the
available literature.
Oral, human. No studies are available.
Oral, animal. The acute administration of 2,3,7,8-TCDD to rats and
mice results in toxic effects in the liver, whereas no severe changes in
the liver are observed upon acute administration of 2,3,7,8-TCDD to
guinea pigs and monkeys (EPA 198Sa) . Lesions in rodents consist of
necrosis, proliferative changes, cellular membrane alterations, bile
duct proliferation, altered lipid metabolism, and excess amounts of
porphyrin. These liver effects have generally been observed following a
single exposure at relatively high doses of 5 to 200
Turner and Collins (1983), however, did observe morphologic changes
in a small number of guinea pigs (groups of one male and four to six
females, strain not reported) given a single gavage dose of 2,3,7,8-TCDD
at 0.1, 0.5, 2.5, 12.5, or 20 Mg/kg- Changes including hypertrophy,
steatosis, focal necrosis, and hyalin-like bodies were reported in all
guinea pigs, although no indication of an association between dose and
increased severity or incidence was reported. Deaths were reported for
doses >0.5 and 12.5 jig/kg in males and females, respectively. In a
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Toxicological Data S3
90-day feeding study with Hartley guinea pigs, similar mild liver
changes were observed in animals maintained on diets that provided doses
of 0.0049 /JgAg/day; liver changes were not observed at the next lower
dose of 0.00061 A*gAg/day (DeCaprio et al. 1986). Although chronic
studies are not available in guinea pigs, studies reviewed by EPA
(1985a) in rats (Kociba et al. 1979, NTP 1982a) and mice (NTP 1982a)
indicated that doses of -0.001 MgAg/day were LOAELs for liver effects
due to chronic oral exposure to 2,3,7,8-TCDD.
Dermal, human. Studies of the hepatotoxic effects of 2,3,7,8-TCDD
on humans have been conducted on populations exposed to herbicides and
other industrial chemicals contaminated with 2,3,7,8-TCDD. In these
studies, it is considered that the predominant route of exposure is
dermal, although some exposure by the oral and inhalation routes would
also be expected. In addition, all individuals studied were exposed to
multiple chemicals, which may have contributed to or been the cause of
the effects observed.
Reports reviewed by EPA (1985a), May (1973), Holden (1979), Bogen
(1979), and Holmstedt (1980) have reported "liver dysfunction" as one of
the symptoms in workers and Vietnam veterans exposed to the herbicide
2,4,5-T contaminated with 2,3,7,8-TCDD. Since these were essentially
case reports, no firm association between exposure and effect could be
made. A more complete clinical study of the levels of serum liver enzyme
was conducted in children ages 6 to 10 who were potentially exposed to
2,3,7,8-TCDD in the Seveso accident (Mocarelli et al. 1986). The
children were examined yearly for 6 years following the accident. During
the initial 2 years, elevated serum levels of gamma-glutamyltransferase
(GGT) and alanine aminotransferase (ALT) were observed in both boys and
girls who resided in the most highly contaminated area. The increase was
slight, with a total incidence of 4.3% compared to 3.6% in the control
group. Values returned to normal after 2 years. Ideo et al. (1982)
reported elevated urinary D-glucaric acid in the urine of children in
the Seveso area -2.5 years after the accident. They also noted that
there was a strong correlation between glucaric acid levels and the
activity of hepatic microsomal enzymes. However, no liver effects, as
indicated by serum enzyme levels, were observed by Falk et al. (1984) in
a pilot epidemiologic study of 122 persons exposed in Missouri to
chemicals contaminated with 2,3,7,8-TCDD.
Liver involvement, as indicated by porphyria cutanea tarda, has
also been reported to be associated with 2,3,7,8-TCDD exposure. The
major studies have been reviewed by Jones and Chelsky (1986), who
reported that in all cases the porphyria cutanea tarda may not have been
definitively diagnosed or that the other chemicals to which subjects
were exposed may have been the causative agents. The pilot epidemiology
study by Falk et al. (1984) of the Missouri accident failed to detect
porphyria cutanea tarda in a population with known exposure. The results
of Falk et al. (1984) may be confounded by misidentifying exposed
individuals. Patterson et al. (in press) explained the wide variation in
2,3,7,8-TCDD levels in adipose tissues from 16 Missouri residents who
reported exposure to 2,3,7,8-TCDD in a questionnaire by determining
through independent sources that exposure at the site in question was
unlikely in the individuals in whom measured adipose tissue levels of
2,3,7,8-TCDD were low.
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54 Section 4
Dermal, animal. No studies are available.
General discussion. Hepatotoxic effects have been investigated iu
human populations exposed to chemicals contaminated with 2,3,7,8-TCDD
because of the known hepatotoxicity of 2,3,7,8-TCDD in rodents. Results
of these studies have generally been inconsistent with regard to the
detection of altered liver serum enzymes or porphyria cutanea tarda.
These inconsistencies may be related to the populations studied, the
level of contamination, or the bioavailability of the 2,3,7,8-TCDD under
the specific conditions of the contaminated site. These confounding
factors, along with the ubiquitous nature of and causative agents for
slight changes in liver function, have made confirmation of 2,3,7,8-
TCDD- induced adverse effects on the liver in humans impossible. In rats
and mice, 2,3,7,8-TCDD clearly produces adverse effects on the liver;
however, there are no studies available that investigated the dose-
response relationship. Thus, it is not known if initial changes in the
liver are a first toxic manifestation of 2,3,7,8-TCDD exposure or an
effect observed only after other toxic effects in other organ systems
have been manifested.
Although Turner and Collins (1983) reported mild liver effects in
guinea pigs (a species generally resistant to 2,3,7,8-TCDD-induced liver
damage) at doses as low as 0.1 pgAg, the lack of association between
increasing dose and increasing severity of effect in this study makes it
difficult to determine a threshold dose. Observing similar liver changes
in a subchronic study in guinea pigs and in chronic studies in rats and
mice, however, supports the observation of the acute study that
hepatotoxicity is a sensitive indicator of 2,3,7,8-TCDD toxicity.
Additionally, induction of hepatic microsomal enzymes has often
been associated with exposure of laboratory animals to 2,3,7,8-TCDD.
Early studies by Buu-Hoi et al. (1972) suggested that the toxicity of
2,3,7,8-TCDD was related to altered enzyme function. Later studies,
however, have demonstrated that 2,3,7,8-TCDD toxicity appears in many
cases to segregate with induction of enzyme activity rather than be the
cause of the toxic response. This has been demonstrated for DT-
diaphorase (Beatty and Neal 1976) and for mixed function oxidase (Greig
1979, Kociba and Schwetz 1982, Poland et al. 1979). In addition, the
toxicity of structurally related chlorinated dibenzo-p-dioxins
correlates well with the relative ability of these compounds to induce
enzyme activity (Poland and Glover 1973).
4.3.2.4 Immunotoxic ity
Inhalation. Pertinent data regarding immunotoxic effects of
2,3,7,8-TCDD following inhalation exposure of humans or animals were not
found in the available literature.
Oral, human. No studies are available.
Oral, animal. 2.3,7,8-TCDD has been extensively investigated for
immunotoxicity in mice, rats, and guinea pigs, and as indicated in the
reviews by EPA (1985a, 1988b) and Knutsen (1984), this is a sensitive
end point of toxicity. Most studies were conducted with weekly exposures
for durations of between 4 and 8 weeks, and minimum effective doses
ranged from 1 pg/kg/week for mice to 5 pg/kg/week for rats, and
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lexicological Data 55
0.04 /jgAg/week guinea pigs. As the study by Vos et al. (1973)
indicates, the Hartley guinea pig may be the most sensitive species,
with a LOAEL of 0.04 /igAg/day and a NOAEL of 0.008 pg/kg/week. In
addition to species differences, strain differences in sensitivity to
the immunotoxic effects of 2,3,7,8-TCDD have been observed in mice, with
immunotoxic sensitivity segregating with the Ah locus. Segregation of
immunotoxicity has also been demonstrated in fetal thymus organ cultures
in vitro (Dencker et al. 1985). Thymus cultures from C57B1/6 mice, which
are Ah responsive, were very sensitive to the toxicity of 2,3,7,8-TCDD
(EC5Q of 10"10 Af) compared with no observed effects on thymus cultures
from the nonresponsive DBA/2J mouse at 3 x 10"8 M, the highest
concentration tested. Effects of 2,3,7,8-TCDD on the immune system
included decreases in thymus weight, sensitization to antigens
(bacterial antigens, skin grafts, and tumor cell development), serum
immunoglobins, and B but not T lymphocytes. Thigpen et al. (1975)
demonstrated that C57BL/6JFh mice that received as little as 1 pg/kg of
2,3,7,8-TCDD once a week for 4 weeks were more susceptible to death from
subsequent bacterial infection. This dose of 2,3,7,8-TCDD did not result
in any gross signs of toxicity, suggesting that host susceptibility was
an early effect of 2,3,7,8-TCDD exposure. Immunotoxic effects have also
been reported in pups of Fischer rats and B6C3F1 mice following in utero
exposure and postnatal exposure through lactation (Luster et al. 1982).
The effective doses on a maternal weight basis were approximately the
same as those that produced effects in adults. The study by Greenlee et
al. (1985), using thymic epithelium cell cultures, provides evidence
that 2,3,7,8-TCDD acts directly on the epithelium cells by inhibiting
the maturation of the thyaocytes. Longer-term studies of the effect of
2,3,7,8-TCDD on the immune system are not available.
Dermal, human. There is little information on the immunotoxic
effects of 2,3,7,8-TCDD in humans exposed to herbicides or other
chemicals contaminated with 2,3,7,8-TCDD. In a pilot epidemiologic study
of 82 high-risk and 40 low-risk subjects from areas in Missouri where
2,3,7,8-TCDD exposure occurred, Stehr et al. (1986) failed to detect any
signs of immunotoxicity. In a study of 154 exposed and 155 unexposed
persons in Gray Summit, Missouri, Hoffman et al. (1986) reported that
the exposed group had an increased frequency of anergy (11.8% vs 1.1%)
and relative anergy (35.3% vs 11.8%). The exposed group also had non-
statistically significant increased frequencies of abnormal T-cell
subset test results (10.4% vs 6.8%), a T4/T8 ratio of <1.0 (8.1% vs
6.4%), and an abnormality in the functional T-cell test results (12.6%
vs 8.5%). Although the effects have not resulted in an excess of
clinical illness in the exposed group, these data suggest that exposure
to 2,3,7,8-TCDD may be associated with depressed cell-mediated immunity.
In a recent, more comprehensive review of these data, Knutsen et al.
(1987) indicated that confounding factors in the study design may have
affected the results. The readers of the immunologic test results were
inconsistent with regard to recall antigens, and psychological stress
may also have affected the results. It was concluded that further
studies were necessary to confirm any effect of 2,3,7,8-TCDD on the
Immune system. Retesting of the subjects who were reported to be anergic
or relatively anergic in the Hoffman et al. (1986) study revealed that
none of the subjects were anergic and only one exposed and one
nonexposed subjects were relatively anergic (Evans et al. 1988).
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56 Section 6
Dermal, animal. No studies are available.
General discussion. There are abundant animal data that indicate
that immunetoxicity may be one of the most sensitive toxicologic end
points for 2,3,7,8-TCDD. There have been very limited investigations of
this end point in humans; thus, the importance of 2,3,7,8-TCDD-induced
immunotoxicity in humans cannot be evaluated. The time of onset, the
duration of the altered immune response, and the fact that evaluation of
altered immune response is a specialized analysis not routinely
performed in clinical settings will make the assessment of this end
point in humans difficult.
The animal data show that 2,3,7,8-TCDD produces immunologic effects
in a number of species, and most of the studies have been concerned with
the investigation of alterations induced in the immune system. There are
less data available regarding dose-response relationships and species
and strain differences in sensitivity; these data would be of assistance
in evaluating response with regard to human health. Also, no data are
available on the immunotoxicity of 2,3,7,8-TCDD in monkeys, a species
that appears to be very sensitive to other toxic effects of 2,3,7,8-
TCDD.
4.3.3 Developmental Toxicity
4.3.3.1 Inhalation
Pertinent data regarding the developmental toxicity of 2,3,7,8-TCDD
following inhalation exposure of humans or animals were not found in th
available literature.
4.3.3.2 Oral
Human. No studies are available.
Animal. 2,3,7,8-TCDD has been extensively studied for
developmental toxicity, and these studies, reviewed in EPA (1985a,
1988b), indicate that 2,3,7,8-TCDD is teratogenic in mice and rats after
gavage administration. In mice, the most commonly observed developmental
effects were hydronephrotic kidney and cleft palate (Courtney 1976,
Moore et al. 1973, Neubert and Dillmann 1972, Smith et al. 1976). Both
of these anomalies have been observed at doses as low as 1 jig/kg
(Courtney 1976, Smith et al. 1976), with the kidney effects observed
after only a single exposure on day 10 of gestation. In rats, gavage
administration of 2,3,7,8-TCDD during organogenesis at doses of -0.12S
to 0.25 pg/kg produced hemorrhage of internal organs and subcutaneous
edema (Sparschu et al. 1971a,b; Khera and Ruddick 1973). No effects were
observed at 0.3 and 0.03 pgAg. respectively, in NMRI mice and Sprague-
Dawley rats. These teratogenic effects have been confirmed by a number
of studies in which 2.3,7,8-TCDD was administered subcutaneously
(studies summarized in EPA 1985b).
It has been demonstrated that both genetic susceptibility and
concomitant exposure to other compounds affect the developmental
toxicity of 2,3,7,8-TCDD. Poland and Glover (1980) and Dencker and Pratt-
(1981) demonstrated genetic differences in the susceptibility of mice;
only responsive C57B1/6J mice developed the characteristic cleft palate
-------
Toxicological Data 57
and hydronephrotic kidneys after treatment. This indicates that
developmental toxicity, in addition to many other toxicological end
points of 2,3,7,8-TCDD, segregates with the Ah locus. Additionally, it
was demonstrated th'at simultaneous exposure to 2,3,7,8-TCDD and specific
polychlorinated biphenyls (Birnbaum et al. 1985), or to the hormones
hydrocortisone (Birnbaum et al. 1986) or thyroxine and triiodothyroxine
(Lamb et al. 1986), increases the sensitivity of mice to the
developmental effects of 2,3,7,8-TCDD. An additive effect was observed
by Weber et al. (1985) for simultaneous exposure to 2,3,7,8-TCDD and
2,3,7,8-tetrachlorodibenzofurans (TCDF).
4.3.3.3 Dermal
Human. The EPA (1985a, 1988b) evaluated several epidemiology
studies of human populations exposed to herbicides contaminated with
2,3,7,8-TCDD. It is assumed that the exposure in these studies was
predominantly dermal; however, some oral and inhalation exposure was
also likely. The studies reviewed were predominantly geographic
correlation studies that reported elevated incidence of birth defects,
including cleft palate, cleft lip, neural-tube defects, heart
abnormalities, hypospadias and epispadias, talipes, and cystic kidney
disease, as well as increases in stillbirths (EPA 1979a, Field and Kerr
1979, Hanify et al. 1981). Similar studies reviewed failed to
demonstrate a correlation between birth defects and possible exposure to
2,3,7,8-TCDD (Aldred 1978; Bisanti et al. 1980; Bonaccorsi et al. 1978;
Department of Health, New Zealand 1980; McQueen et al. 1977; Nelson et
al. 1979; Reggiani 1980; Smith et al. 1982; Thomas 1980). In addition, a
case control study of the offspring of Vietnam veterans potentially
exposed to 2,3,7,8-TCDD in Agent Orange detected increases in birth
defects that included spina bifida, cleft palate, and certain congenital
tumors (Erickson et al. 1984). When all types of defects were combined,
there was no elevated risk, and authors noted that the seemingly higher
risk for individual birth defects may have resulted from chance or other
unidentified risk factors. In a similar study, Townsend et al. (1982)
investigated the pregnancy outcome of wives of employees of Dow Chemical
Company who were potentially exposed to 2,3,7,8-TCDD. When compared with
a control population, there was no statistical difference in pregnancy
outcome or several types of malformations. As a result of the inherent
uncertainty in interpreting geographic correlation studies, the
concomitant exposure to other potentially active compounds, and the
review of similar studies that failed to demonstrate any association, it
was concluded that these investigations could neither prove nor disprove
the hypothesis that 2,3,7,8-TCDD was a teratogen in humans.
Animal. No studies are available.
4.3.3.4 General discussion
The lack of a clearly defined exposed population, with adequate
quantitative data on levels and duration of exposure, and the
confounding presence of exposure to other chemicals that may in
themselves be developmental toxicants, have made results of epidemiology
data difficult to evaluate and inadequate for determining whether
2,3,7,8-TCDD induces developmental defects in humans. As with many
developmental toxicants, the animal data indicated that the time of
-------
58 Section 4
exposure was critical for Che induction of effects, with treatment on
days 8 or 11 producing maximal effects and treatment after 13 days being
ineffective in mice (Neubert et al. 1973).
r
4.3.4 Reproductive Tozicity
4.3.4.1 Inhalation
Pertinent data regarding the reproductive toxicity of 2,3,7,8-TCDD
in humans or animals following inhalation exposure were not found in the
available literature.
4.3.4.2 Oral
Human. No studies are available.
Animal. The fetotoxicity of 2,3,7,8-TCDD has been demonstrated
following short-term exposure in utero (rats and mice) as well as in a
multigeneration study (rats). Fetal death and vaginal bleeding have been
observed in developmental toxicity studies [reviewed by EPA (1985a,
1988b)] at doses of between 2 and 9 jig/kg/day. The three-generation
study of Murray et al. (1979) reported that dietary administration of
2,3,7,8-TCDD at 0.01 and 0.1 /igAg/day resulted in adverse effects on
litter size, fetal survival, and neonatal survival in Sprague-Dawley
rats. The 0.1-/ig/kg/day dose also resulted in a significant decrease in
fertility. Murray et al. (1979) considered the low dose of 0.001
/*gAg/day to be without substantial effects, since the only effect
observed was an increase in dilated renal pelvises in the Fl generation
This effect was not observed at statistically significant levels in any
other generation. The absence of effects at this lower dose level has
been questioned by Nisbet and Paxton (1982), who reevaluated the data
statistically and concluded that gestational index, decreased fetal
weight, and the incidence of dilated renal pelvis were all increased at
both the 0.01- and 0.001-pg/kg/day doses. The analysis by Nisbet and
Paxton (1982) indicates that reproductive performance and the fetus are
very sensitive to the toxic properties of 2,3,7,8-TCDD.
In this reevaluation, Nisbet and Paxton (1982) applied a
statistical approach that included pooling of data across all
generations. However, since litters from different generations (as from
subsequent mating within a generation) are not the same, they have
different histories of exposure and each is tied to the effect of the
agent on its parental generation. Therefore, EPA (1988b) considered such
an approach of pooling of data across all generations to be biologically
inappropriate. According to EPA (1988b), the 0.01 pgAg/day dose in the
study by Murray et al. (1979) is the lowest effect level that can be
supported by the data. Further analysis of this study and of studies in
monkeys (Allen et al. 1979, Schantz et al. 1979), which indicate that
doses of 0.0015 /ig/kg/day result in abortions, may provide support for a
lower effect level of 0.001 pg/kg/day. Therefore, the 0.001 pgAg/day
dose, rather than the 0.01 pgAg/day dose, appears to be the LOAEL.
The monkey, however, appears more sensitive to the toxicity of
2.3,7,8-TCDD than either rats or mice. McNulty (1984, 1985) described
the common occurrence of abortion in rhesus monkeys treated with a to to.
of 1 MgAg of 2,3,7,8-TCDD over days 20 to 40 of gestation; the lowest
-------
lexicological Data 59
total dose tested, 0.2 /*g/kg, produced abortion in 1 of 4 test monkeys.
In fetuses examined, there was either only minimal indication (palatal
abnormalities) or no indication of developmental toxicity. In an earlier
feeding study, groups of eight monkeys were maintained on diets
containing 50 or 500 ppt (the total dose ingested was 1.8 and 11.7 ^g,
respectively) of 2,3,7,8-TCDD for 7 months prior to pregnancy and during
pregnancy (Allen et al. 1979, Schantz et al. 1979). In both groups,
two-thirds of the pregnancies ended in abortion.
As reported in EPA (1985a), chronic exposure of rats to 2,3,7,8-
TCDD in the diet results in a decrease in the weight of male
reproductive organs. It was suggested by Moore et al. (1985) that this
effect on the reproductive organs might be the result of decreases in
the plasma concentrations of androgens, which may account for the
reduced male Uistar rat reproductive performance following 2,3,7,8-TCDD
exposure that had been earlier observed by Khera and Ruddick (1973).
Levels of circulating androgens in 2,3,7,8-TCDD-treated male rats were
studied by Moore et al. (1985) and shown to be depressed as a result of
treatment. It was speculated that these depressed hormone levels may
participate in the reproductive dysfunction in males. Circulating
estradiol levels in pregnant females, however, appear not to be affected
by 2,3,7,8-TCDD exposure, although 2,3,7,8-TCDD does affect some
estrogen-metabolizing pathways when studied in vitro (Shiverick and
Muther 1983).
4.3.4.3 Dermal
Human. Epidemiology studies have been performed on groups of
individuals exposed to herbicides or industrial chemicals contaminated
with 2,3,7,8-TCDD. Although the dermal route is considered to be the
predominant route of exposure in these studies, some exposure by other
routes would also occur. These studies, which include those reviewed by
EPA (1985a, 1988b) and Friedman (1984) (Aldred 1978; Bisanti et al.
1980; Bonaccorsi et al. 1978; Department of Health, New Zealand 1980;
EPA 1979a; Field and Kerr 1979; Hanify et al. 1981; McQueen et al 1977;
Nelson et al. 1979; Reggiani 1980; Smith et al. 1982; Thomas 1980;
Tognoni and Bonaccorsi 1982; Townsend et al. 1982) and that of Forsberg
and Nordstrom (1985), were conducted in groups of male herbicide
application workers, chemical plant employees, and soldiers exposed to
Agent Orange in Vietnam, and to both males and females exposed through
major industrial accidents or inappropriate disposal, which permitted
the escape of large amounts of chemical from production plants. Studies
of these groups have not clearly demonstrated that 2,3,7,8-TCDD produced
any adverse effects on reproductive performance, although as a result of
the limitations of the study, particularly with regard to the extent of
exposure, it is not possible to interpret the results as indicative of
the absence of reproductive toxicity for 2,3,7,8-TCDD in humans.
Animal. No studies are available.
4.3.4.4 General discussion
The evidence that 2,3,7,8-TCDD is a reproductive toxicant in humans
is limited by the lack of exposure data and the concomitant exposure to
other chemicals that may have been biologically active. The greatest
-------
60 Section 4
exposure to 2,3,7,8-TCDD occurred in male herbicide sprayers, soldiers,
and chemical plane workers, whereas the studies conducted have been
concerned mostly with fetotoxicity and spontaneous abortion. Although
the possibility of premating exposure in males resulting in fetotoxicity
and abortion is of concern, this end point is difficult to assess,
particularly when the exposure is temporally removed from the time of
conception. In addition, there is a lack of data on the functioning of
male reproductive organs during the time of potential exposure to
2,3,7,8-TCDD. There are no equivalent female populations studied that
have had extended periods of high exposure to chemicals contaminated
with 2,3,7,8-TCDD and only limited populations [females in the vicinity
of Seveso (Bisanti et al. 1980, Bonaccorsi et al. 1978, Reggiani 1980)
in the period immediately after the accident] from which to assess
effects on reproduction in females exposed while pregnant.
Given the above limitations, the present epidemiology studies are
only consistent with observations in animals that 2,3,7,8-TCDD elicits
adverse effects on reproduction; they do not provide sufficient evidence
to prove that this chemical is a reproductive toxicant. Animal studies
indicate that 2,3,7,8-TCDD is a powerful reproductive toxicant; however,
differences in species sensitivity have been observed. The available
data indicate that the monkey may be the most sensitive species, but
tests in this species have been limited to rhesus monkeys, with only a
few animals studied at any dose level, which provides insufficient data
to fully evaluate the range and extent of potential toxic effects in
this species. In addition, the sensitivity of humans compared to
monkeys, rats, or mice can only be speculated.
4.3.5 Genotozic1ty
4.3.5.1 Human
Although there have been no studies of human populations exposed to
2,3,7,8-TCDD alone, there are a number of studies on human populations
exposed to chemicals contaminated with 2,3,7,8-TCDD, as reviewed in EPA
(1985a). Czeizel and Kiraly (1976) reported that there was an increase
in chromosomal aberrations of peripheral lymphocytes from workers in an
East European 2,4,5-trichlorophenoxyethanol plant. Studies of soldiers
(spouses and children of soldiers) exposed to Agent Orange (Mulcahy
1980) and of individuals involved in the Seveso accident (DiLernia et
al. 1982, Kaye et al. 1985, Mottura et al. 1981, Reggiani 1980, Tenchini
et al. 1983) have, however, failed to detect chromosomal aberrations.
Some of the individuals in these studies had skin eruptions consistent
with exposure to 2,3,7,8-TCDD. The only chromosomal effect in the latter
studies was a decrease in satellite association (SA), which is evidence
of functional ribosomal genes, in 2,3,7,8-TCDD-exposed subjects
(DiLernia et al. 1982). The authors noted that similar decreases
observed after x-irradiation exposure may possibly represent damage to
the nucleolar organizing regions. All human data on chromosomal
aberrations were confounded by mixed exposure to other potentially
active compounds and the inability to determine quantitatively the
extent of exposure to 2,3,7,8-TCDD.
-------
Toxicologies! Data 61
4.3.5.2 Nonhuman
A recent review by Girl (1986) of the mutagenic and genotoxic
effect of 2.3,7,8-TCDD concluded that there is evidence for the
genotoxic activity of 2,3,7,8-TCDD, but additional testing would be
required to demonstrate this activity with certainty. The results of
nonhuman genotoxicity studies are summarized in Tables 4.2 and 4.3. The
early positive results of Hussain et al. (1972) and Seller (1973) are
likely artifacts resulting from extensive cell death and possibly from
impurities in the test material. In vitro cytogenic tests in yeast in
both the standard plate test and the intrasanguineous host-mediated
assay (using CD-I mice) have produced positive results (Bronzetti et al.
1983). In in vivo cytogenetic assays, Loprieno et al. (1982) observed
that the positive responses depended on sampling time, with negative
results obtained 24 h posttreatment and positive results 96 h posttreat-
ment. Although the toxic properties of 2,3,7,8-TCDD usually segregate
with the Ah locus, Meyne et al. (1985) observed negative responses in
vivo after administration of 2,3,7,8-TCDD at hepatotoxic levels to both
responsive, C57B1/6J, and nonresponsive, DBA/2J, mice when sampled at 24
h. There are also limited supportive data for the mutagenicity of
2,3,7,8-TCDD from the observation in vivo of the low-level binding of
2,3,7,8-TCDD to liver macromolecules (Poland and Glover 1979).
4.3.5.3 General discussion
The nonhuman genotoxicity data on 2,3,7,8-TCDD are conflicting;
negative results were reported in many of the assay systems, and when
positive results were observed, the response was generally weak. These
conflicting data may result from technical difficulties in testing
2,3,7,8-TCDD rather than from a lack of biological activity. Testing
difficulties arise from the extreme insolubility of this compound and
the high toxicity observed in some test systems, which would be
anticipated to result in a very narrow window for effective genotoxic
doses. As a result of the largely negative data from nonhuman
genotoxicity assays, some investigators, as discussed by Paustenbach et
al. (1986), have concluded that 2,3,7,8-TCDD is not a genotoxic agent.
Sufficient data are not available to precisely define the toxicological
mechanism of 2,3,7,8-TCDD and resolve these differences of opinion.
Human studies are primarily limited by the lack of data on the
extent of exposure. The only indication of exposure in these studies was
the development of gross skin lesions, which does not provide a good
estimate of either the extent of exposure or the duration. In addition,
the time after exposure that the cells were examined may not have been
optimal for observing cytogenetic effects. Because of the limitations of
the studies in humans, these data cannot be used to demonstrate that
2,3,7,8-TCDD does not pose a genotoxic hazard.
4.3.6 Carcinogenicity
4.3.6.1 Inhalation
Pertinent data regarding the carcinogenicity of 2,3,7,8-TCDD
following inhalation exposure of humans or animals were not found in the
available literature.
-------
Table 4.2. Genoloxicily of 2,3,7,8-TCDD in vitro
End point Species (test system)
Gene mutation Salmonella lyphimurium
(reverse mutation)
S. lyphimurium
(reverse mutation)
Escherichia coli
Results
with activation/without activation
-/-
Not tested/ +
Not tested/ +
References
McCann 1978,
Gilbert et al. 1980.
Geigerand Ncal 1981,
Mortelmans et al. 1984
Hussain et al. 1972,
Seiler 1973
Hussain et al. 1972
'ection 4
Cytogenetic
(reverse mutation)
Saccharomyces cerevisiae
(reversion)
LSI78Y mouse lymphoma
cells (forward mutation)
5. cerevisiae
(gene conversion)
Not tested/+, and
not tested/ -
Bronzelliet al 1983
Rogers et al. 1982
Bronzettiet al. 1983
Cell transformation
S. cerevisiae
(host mediated)
Chinese hamster cells
(sister chromatid exchange)
Baby hamster kidney cells
BHK
C3H/ 10 TI/2 cells
+ /NA"
Not tested/ -
Not tested/ +
Not tested/ -
Bronzelliet al. 1983
Toth et al. 1984
Hay 1982
Abernathy et al 1985
"Not available.
-------
lexicological Data 63
Table 4.3. Geootoxicity of 2,3,7,8-TCDD in vivo
End point
Species (test system) Results
References
Gene mutation Drosophila (sex-linked
recessive lethal)
Cytogenetic Drosophila (sister
chromatid exchange)
Drosophila
(structural aberration)
Rat
(sister chromatid exchange)
Rats marrow cells
(structural aberration)
Rats - marrow cells
(structural aberration)
Mouse - marrow cells
(structural aberration)
Mouse - marrow cells
(sister chromatid exchange)
Mouse - marrow cells
(structural aberration)
Mouse - marrow cells
(micronucleus)
Zimmenng et al. 1985
Zeiger 1983
Zeiger 1983
Lundgren et al. 1986
Green and Moreland 197S
Green et al. 1977
Loprienoet al. 1982
Meyne et al. 198S
Meyne et al. 1985
Meyne et al. 1985
-------
64 Section 4
4.3.6.2 Oral
Human. No studies are available.
Animal. A number of bioassays have been conducted, and all have
demonstrated that 2,3,7,8-TCDD is carcinogenic in animals via the oral
route. The NTP (1982a) and Kociba et al. (1978a,b) studies are key
bioassays of 2,3,7,8-TCDD. Although both studies used sufficient numbers
of animals and exposure durations, the study by Kociba et al. (1978a,b)
is relevant to human exposure scenarios because the compound was
administered daily in the diet rather than biweekly by gavage as in the
NTP (1982a) study. Furthermore, the study by Kociba et al. (1978a,b) has
proven to be the most sensitive indicator of the carcinogenic potency of
2,3,7.8-TCDD. The details of the Kociba et al. (1978a,b) study are
summarized in Table 4.4. Other oral studies which support the conclusion
that 2,3,7,8-TCDD is an animal carcinogen are presented in Table 4.5.
4.3.6.3 Dermal
Human. Although there are no known cohorts that have been exposed
solely to 2,3,7,8-TCDD, a number of cohorts that have been exposed to
herbicides or industrial chemicals contaminated with 2,3,7,8-TCDD have
been studied. The predominant exposure route for these cohorts was
probably dermal, although some inhalation and oral exposure was also
likely. In addition, 2,3,7,8-TCDD was only a minor contaminant of these
compounds, and any effects observed may have been either caused or
potentiated by the contaminated compound itself.
EPA (1985b, 1988b) and Hiremath et al. (1986) reviewed several
epidemiology studies of humans exposed to herbicides contaminated with
2,3,7,8-TCDD. The studies by Axelson et al. (1980) and Theiss and
Frentzel-Beyme (1977) found an association between exposure and stomach
cancer. A series of other studies (Eriksson et al. 1979, 1981- Hardell
and Sandstrom 1979; Hardell et al. 1980, 1981; Lynge 1985; Puntoni et
al. 1986; Merlo and Puntoni 1986) reported an association between
exposure and soft-tissue sarcomas (of various sites) and lymphomas. EPA
(1988b) discussed criticisms of the studies by Hardell and Sandstrom
(1979) and Eriksson et al. (1979, 1981). These criticisms include recall
bias, unreliability of the exposure data, information bias, observation
bias, and confounding factors. EPA concluded that the problems with
these studies were not sufficient to explain the highly significant
risks of soft-tissue sarcoma in the exposed workers. In addition,
Hardell and Eriksson (1988) conducted a case-referent study in which
they controlled for recall and observation bias and found a three-fold
increased risk for soft-tissue sarcoma for exposure to phenoxyacetic
acids.
EPA (1988b) also reviewed several studies (Balarajan and Acheson
1984, Cantor 1982, Cook et al. 1986, Fett et al. 1984, Kang et al. 1987
Kogan and Clapp 1985, Milham 1982, Smith et al. 1984, Woods et al. 1987,
Zack and Suskind 1980) that were consistent with or tended to support
the findings of soft-tissue sarcoma in groups thought to be exposed to
chemicals contaminated with 2,3,7,8-TCDD. In most of these studies,
however, exposure to 2,3,7,8-TCDD sufficient to produce a significant
change in risk estimates could only be assumed. Also, some of the
-------
Toxicologies! Data 65
Table 4.4 Summary of the oral carcinogenicity bioassay of
Kociba et al. (1978a,b)
Animal Sex
Dose tested
(Mg/kg/day)
Tumor type
Incidence
Sprague- M Control Squamous cell carcinoma of 0/85
Dawley the tongue, adenoma of the
cats adrenal cortex, and squamous
cell carcinoma of the hard
palate
0.001 Squamous cell carcinoma of I/50
the tongue
0.01 Squamous cell carcinoma of 1/50
the tongue
Adenoma of the adrenal 2/50
cortex
0.1 Squamous cell carcinoma of 3/50
the tongue
Adenoma of the adrenal 5/50
cortex
Squamous cell carcinoma of 4/50
the hard palate
F Control Hepatocellular carcinoma 1/86
0.001 Hepatocellular carcinoma 0/50
0.01 Hepatocellular carcinoma 2/50
Squamous cell carcinoma of 1/50
the hard palate
0.1 Hepatocellular carcinoma 11 /49
Squamous cell carcinoma of 4/49
the hard palate
Squamous cell carcinoma of 7/49
the lung
-------
o\
Table
Method of
exposure
Diet
Gavage
(0
ft
o
n
t
0
4.5. Other oral studies supporting the conclusion that 2,3,7,8-TCDD is an animal carcinogen 3
*»
Animal
Sprague-
Dawley
rats
Osborne-
Mendel rats
Osborne-
Mendel rats
B6C3F1 mice
B6C3FI mice
Swiss mice
Sex/
number
M/IO
M/50
F/50
M/50
F/50
M/44
Doses tested
0.01,0.005,
0.05,0.5, 1.0,
or 5 ppb
0.01,0.05, or
0.5 /ig/kg/week
0.01,005, or
0 5 /ig/kg/week
0.01,0.05, or
0.5 Mg/kg/week
0.01,0.05. or
0.5 Mg/kg/week
0.007, 0.7. or
7.0 jig/kg/week
Tumor type
Increase in total tumor
incidence
Follicular-cell adenomas and
carcinomas of the thyroid
Neoplaslic nodules and hepato-
cellular carcinomas of the
liver
Hepatocellular carcinomas
Hepatocellular carcinoma and
follicular-cell adenomas of
the thyroid
Hepatomas and hepatocellular
carcinomas
References
Van Miller
et al. I977a,b
NTP I982a
NTP I982a
NTP I982a
NTP I982a
Tolh et al
1979
-------
lexicological Data 67
investigators reported that their results did not support the studies by
Hardell and Sandstrom (1979) and Eriksson et al. (1979, 1981).
Nevertheless, risks of soft-tissue sarcoma, although not statistically
significant, wer.e detected in the studies. A number of studies found no
association between risk of soft-tissue sarcoma and exposure to
herbicides contaminated with 2,3,7,8-TCDD (Axelson et al. 1980;
Fingerhut et al. 1984; Greenwald et al. 1984; Lathrop et al. 1984; Ott
et al. 1980; Riihimaki et al. 1982; Thiess et al. 1982; Wiklund and Holm
1986; Wiklund et al. 1987; Wolfe et al. 1984, 1985). However, some of
these studies suffer from problems that include low power to detect a
significant risk, selection and survivorship bias, and insufficient
latency periods (EPA 1988b).
EPA (1988b) concluded that the epidemiological data provide limited
evidence that exposure to phenoxyacetic acid herbicides and/or
chlorophenols is causally related to the risks of soft-tissue sarcoma,
but none of the data are sufficient to implicate 2,3,7,8-TCDD alone.
Animal. There is only limited evidence that 2,3,7,8-TCDD produces
tumors in laboratory animals following dermal exposure. NTP (1982b)
administered 2,3,7,8-TCDD alone to Swiss mice. Female mice, but not male
mice, had an increased incidence of fibrosarcomas in the integumentary
system.
As reviewed by EPA (1985a, 1988a), there is conflicting evidence
that 2,3,7,8-TCDD acts as a tumor promoter when applied to the skin.
Berry et al. (1978) failed to detect any tumor-promoting activity by
2,3,7,8-TCDD in CD-I mice skin initiated with dimethyIbenzanthracene
(DMBA), and Slaga and Nesnow (1985) reported that unpublished data
indicated that 2,3,7,8-TCDD either had no promoting activity or very
weak promoting activity in Sencar mice skin. NTP (1982b) also examined
the ability of 2,3,7,8-TCDD to act as a tumor promoter in Swiss Webster
mice, and animals treated with 2,3,7,8-TCDD alone had similar tumor
incidences to animals treated first with DMBA followed by treatment with
2,3,7,8-TCDD. NTP (1982b) concluded, however, that "in the DMBA-TCDD
experiment, failure to have included groups skin painted with only DMBA
precludes interpretation of these results." Poland et al. (1982),
however, not only demonstrated promotion, but also that genetic
differences in CD-I mice affect the ability of 2,3,7,8-TCDD to act as a
promoter. In HRS/J mice homozygous for the hairless trait, promotion
with 2,3,7,8-TCDD after initiation with DMBA produced as many skin
tumors (both incidence and multiplicity) as promotion with the known
promotor TPA, whereas in mice heterozygous for the hairless trait (and
wild type), skin tumors could only be promoted by TPA but not 2,3,7,8-
TCDD. Even in the homozygous mice, 2,3,7,8-TCDD did not produce the
commonly observed hyperplasia associated with promoters such as TPA,
suggesting that 2,3,7,8-TCDD has a different mechanism of action. Other
studies indicated that pretreatment with 2,3,7,8-TCDD could block the
subsequent DNA binding of known carcinogens and also prevent tumor
initiation (Berry et al. 1979, Cohen et al. 1979). Although not a dermal
study, Pitot et al. (1980) also demonstrated promotion by administering
a single intragascric dose of the hepatocarcinogen diethylnitrosamine
(DEN) followed by repeated subcutaneous injections of 2,3,7,8-TCDD. No
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68 Section 4
hepatic tumors were observed in animals given DEN or 2,3,7,8-TCDD alone,
but the combined treatment resulted in the development of hepatocellulai
carcinomas.
4.3.6.4 General discussion
The evidence from human epidemiology studies that 2.3,7,8-TCDD is
carcinogenic is difficult to assess because (1) exposure to 2,3,7,8-TCDD
is poorly documented and (2) exposure occurred to other potentially
active materials. The strongest evidence is from the induction of soft-
tissue sarcomas at various sites, and it has been questioned whether
combining tumor data from various sites is appropriate. EPA (1985b)
regards the human evidence for soft-tissue sarcomas and lymphomas as
"limited" (i.e., some evidence) from exposure to phenoxyacetic acid
herbicides and/or chlorophenols which have 2,3,7,8-TCDD impurities.
Thus, for 2,3,7,8-TCDD alone, the evidence is considered inadequate.
With regard to the observed increase in stomach cancer, the two groups
of workers studied were relatively small, and similar increases in
stomach tumors have not been reported in other more extensive studies.
The animal data, however, clearly indicate that 2,3,7,8-TCDD is
carcinogenic, although there is some disagreement in the scientific and
international regulatory community as to whether 2,3,7,8-TCDD acts as a
complete carcinogen or as a carcinogen promotor (Shu et al. 1987). The.
rationale for describing 2,3,7,8-TCDD as a promotor is based on the poor
response of 2,3,7,8-TCDD in many short-term mutagenicity assays, the
lack of strong evidence for binding to DNA, and positive results in in
vivo promotion assays using the classic skin-painting technique (as
described above) and the study of Pitot et al. (1980) using the two-
stage model in rat liver. The classic feeding study bioassays, however,
would support the view that 2,3,7,8-TCDD is a complete carcinogen.
4.4 INTERACTIONS WITH OTHER CHEMICALS
There are few data on the interactions of 2,3,7,8-TCDD with other
chemicals. As discussed in EPA (198Sa), 2,3,7,8-TCDD is a strong inducer
of microsomal enzymes; hence, prior exposure to 2,3,7,8-TCDD will alter
the race of metabolism and toxicity of many compounds that are either
detoxified or activated by this enzyme system. The observed inhibition
by 2,3,7,8-TCDD of the tumorigenic response of known tumorigens in the
mouse skin bioassay (Berry et al. 1979, Cohen et al. 1979) may be an
example of 2,3,7,8-TCDD-induced enzyme changes altering the metabolic
fate and toxicity of another compound.
The only other interactions that have been observed are the
additive effect of 2,3,7,8-TCDD and similar polychlorinated
dibenzofurans and polychlorinated biphenyls on the induction of cleft
palate in mice (Weber et al. 1985, Birnbaum et al. 1985) and the
increased sensitivity of mice to 2,3,7,8-TCDD-induced cleft palate with
the co-administration of the hormones thyroxine and triiodothyroxine
(Lamb et al. 1986). With regard to environmental exposure, the relevance
of interactions of 2,3,7,8-TCDD and the high levels of hormones used in
the latter study is unclear.
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69
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL
5.1 OVERVIEW
2,3,7,8-TCDD is neither commercially manufactured nor imported into
the United States. It was produced inadvertently in small amounts as an
impurity during the manufacture of compounds for which 2,4,5-
trichlorophenol was a synthetic intermediate. At the present time, its
only use is in chemical research. Several field-tested and untested
methods are available for the disposal/stabilization of 2,3,7,8-TCDD-
containing wastes. Some of the promising methods are incineration at
high temperature, oxidative destruction with the aid of a catalyst,
biodegradation by a fungus, photochemical destruction in the presence of
a hydrogen-donating substrate, and stabilization (in case of soils)
through the in situ addition of cementitious and asphaltic materials or
burial under a protective layer.
5.2 PRODUCTION
2,3,7,8-TCDD is synthesized on a laboratory scale primarily by two
processes: (1) condensation of dichlorocatechol with substituted
dichlorobenzer.es and (2) halogenation of dibenzo-p-dioxin or its
dichloro-substituted derivative (EPA 1985b). 2,3,7,8-TCDD is not
commercially manufactured in the United States but is produced as an
undesirable product during the manufacture of compounds for which
2,4,5-trichlorophenol is a synthetic intermediate (see Sect. 6.2 on
Releases to the Environment).
5.3 IMPORT
2,3,7,8-TCDD is not imported into the United States (EPA 1985b).
5.4 USE
2,3,7,8-TCDD has been tested for flame-proofing polyesters and as a
control against insects and wood-destroying fungi in Germany; however,
it has probably never been commercially produced or used for these
purposes. At present it is only used as a research chemical (HSDB 1987).
5.5 DISPOSAL/STABILIZATION
For the destruction of wastes and residues containing 2,3,7,8-TCDD,
incineration at a minimum temperature of 800 to 1,200'C and a contact
time of >30 s was found to be satisfactory. Polychlorophenols containing
2,3,7,8-TCDD as an impurity have been destroyed by dispersing or
dissolving the material in water, or a nonnucleophilic organic solvent,
and oxidizing with ruthenium tetraoxide catalyst at -70°C (HSDB 1987).
Satisfactory field-tested methods for the disposal of 2,3,7,8-TCDD-
containing soils were not available until recently. The following
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70 Section 5
methods have either shown promise or are presently used for the
disposal/stabilization of 2,3,7,8-TCDD: (1) stabilization through the L.
situ addition of cementitious and asphaltic materials; (2) degradation
with Phanerochaete chrysosporium, a white rot fungus; (3) a mobile
incineration system for the thermal destruction of 2,3,7,8-TCDD; and (4)
ultraviolet photolysis in the presence of alkali polyethylene glycolate
reagents (des Rosiers 1986). A method (similar to method 4) for
photochemical destruction of 2,3,7,8-TCDD in the presence of olive oil
(a hydrogen donor) was used with soil from the area of the Seveso
accident. A recent report discusses the disposal/stabilization of
2,3,7,8-TCDD by a mobile poly(ethylene)glycol-potassium hydroxide
destruction unit (Rogers et al. 1987). Other methods for the
stabilization of contaminated soil that are cost effective and produce
minimal dusting have been proposed (Hungerford 1988). In these proposed
methods, stabilization is achieved either by placing a protective layer
consisting of compacted soil with vegetation cover, asphalt, or concrete
over the contaminated soil or by inversion of the soil horizon to
effectively bury the contaminated surfacial material.
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71
6. ENVIRONMENTAL FATE
6.1 OVERVIEW
The important sources of 2,3,7,8-TCDD in the environment are
production and use of certain herbicides and chlorophenols, incineration
of municipal and industrial wastes, and improper disposal of chemical
wastes produced during the manufacture of 2,4,5-trichlorophenol, 2,4.5-
T, and related herbicides, hexachlorophene, and chlorinated benzenes.
The bleaching process in the pulp and paper industry, and exhaust from
vehicles not equipped with catalytic converters are also important
sources of 2,3,7,8-TCDD. The fate of 2,3,7,8-TCDD in the environment is
not clearly understood. It appears that particulate-bound 2,3,7,8-TCDD
in the air may undergo photolysis and may be removed by wet and dry
deposition. The half-life of atmospheric 2,3,7,8-TCDD is such that
2,3,7,8-TCDD can be transported long distances in the air, although this
transport will be of shorter distances compared with the transport of
higher chlorinated dibenzodioxins having longer half-lives. The ultimate
sink of airborne 2,3,7,8-TCDD is sediments of surface waters. The two
processes that are likely to remove 2,3,7,8-TCDD from water and soils
are vaporization and photolysis. The estimated half-life of 2,3,7,8-TCCD
in surface water is >1 year, and the ultimate sink of aquatic 2,3,7,8-
TCDD is sediments. The bioconcentration factor of 2,3,7,8-TCDD in
rainbow trout (Sal/no gairdneri) is 39,000. 2,3,7,8-TCDD is immobile in
most soils, but horizontal movement of soil-bound 2,3,7,8-TCDD may occur
in runoff water during flooding. As observed in Seveso, Italy, minimal
vertical movement may occur in soils containing low organic matter. The
estimated half-life of 2,3,7,8-TCDD is 1 to 3 years on soil surfaces and
10 to 12 years in the interior of soils. Although not accumulated, the
level of 2,3,7,8-TCDD absorbed in parts of plants underground is of the
same order of magnitude as in soil, but the aerial parts of plants
contain 50% lower concentrations.
6.2 RELEASES TO THE ENVIRONMENT
Although the following paragraphs discuss the sources of 2,3,7,8-
TCDD in the environment, the sources responsible for its background
levels are not clear.
6.2.1 Production and Use of Certain Herbicides and Chlorophenols and
Bleaching Process in Pulp and Paper Industry
The phenoxy herbicide 2,4,5-T produced prior to 1960 contained up
to 100 pg/g 2,3,7,8-TCDD. The level of 2,3,7,8-TCDD in commercial
2,4,5-T was reduced in recent years to <0.1 Mg/g. and most commercial
2,4,5-T available before its banning contained <0.02 pg/g 2,3,7,8-TCDD.
Agent Orange, a 1:1 mixture of butyl esters of 2,4,5-T and 2,4-D
produced before 1970, contained 0.02 to 54 pg/g 2,3,7,8-TCDD.
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72 Section 6
Hexachlorophene, a germicide manufactured from trichlorophenol,
contained 0.2 to 0.5 ng/g 2,3,7,8-TCDD. 2,4,6-Trichloro-, 2,3,4.6-
tetrachloro-, and pentachlorophenol were found to contain <0.1 A»g/g
other tetra isomers but no 2,3,7,8-TCDD. 2,3,7,8-TCDD was detected at a
concentration <1 ng/g (2,3,7,8-TCDD detection limit of 0.03 ng/g) in all
samples of sodium pentachlorophenate, 2,3,4,5-tetrachlorophenol, and
hexachlorophene. It has been speculated that catalytic dechlorination of
higher chlorinated dibenzodioxins in metal containers during pressure
treatment of wood may be an additional source of 2,3,7,8-TCDD in
pentachlorophenol and sodium pentachlorophenate-treated woods.
Therefore, pentachlorophenol-treated woods might well be one of the main
sources in the contribution of human body burden for 2,3,7,8-TCDD. A
sample of 2,4,5-trichlorophenol manufactured in 1969, on the other hand,
contained up to 6.2 pg/g 2,3,7,8-TCDD. Similarly, diphenyl ether
herbicides were found to contain other tetrachloro isomers but no
2,3,7,8-TCDD (EPA 1985b, Firestone et al. 1972, Hagenmaier 1986, HSDB
1987, Rappe 1984, Weeren and Asshauer 1985). From the analysis of
sediments of a western Lake Ontario site, Czuczwa and Hites (1986)
concluded that the likely source of tetrachlorodibenzo-p-dioxins was a
pentachlorophenol production facility. The analytical method used,
however, could not distinguish 2,3,7,8-TCDD from other tetra isomers.
Sludge from seven pulp and paper mills showed a 2,3,7,8-TCDD
concentration range from not detectable (1 pg/g) to >400 pg/g (Kuehl et
al. 1987). The bleaching process used in this industry is the most
likely causative factor for the production of 2,3,7,8-TCDD and other
higher chlorinated dibenzodioxins.
6.2.2 Photochemical Reactions
The photochemical reaction of phenoxy herbicides has been found to
produce polychlorinated dibenzo-p-dioxins through photodechlorination
and subsequent condensation reactions; however, this process does not
produce 2,3,7,8-TCDD (Rappe 1984). Lower substituted dibenzo-p-dioxins
are also formed during photodechlorination of higher chlorine-
substituted dibenzo-p-dioxins. Trace amounts of 2,3,7,8-TCDD were
observed from the photodechlorination of both 1,2,3,6,7,8-hexa- and
1,2,3,7,8,9-hexachlorodibenzo-p-dioxin (Buser 1979).
6.2.3 Thermal Reactions
Small amounts of 2,3,7,8-TCDD have been detected in the flue gases
from municipal incinerators. From the experimentally determined
concentrations in flue gases of five municipal incinerators, the maximum
average concentration of 2,3,7,8-TCDD in ambient air at ground level was
estimated as 38 fg/g. Incineration of industrial wastes containing
2,4,5-T salts and esters, polychlorinated benzenes, and chlorophenoxy
ethers also produced 2,3,7,8-TCDD (Barnes 1983, Rappe 1984). Upon
analysis of sediments from Saginaw Bay, Saginaw River, and the Great
Lakes, Czuczwa and Hites (1984, 1986) concluded that the source of
tetrachlorodibenzo-p-dioxins was incineration, although the analytical
method used was unable to separate 2,3,7,8-TCDD from other tetra
isomers. Combustion of coal did not produce 2,3,7,8-TCDD at a detectio-
limit of 1.2 ng/kg (HSDB 1987), but burning of woods did produce 0.65
pg/kg 2,3,7,8-TCDD (EPA 1985b). Exhausts from automobiles powered with
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Environmental Face 73
leaded gasoline were reported to contain <0.05 to 0.3 ng 2,3,7,8-
TCDD/24.8 km, but no 2,3,7,8-TCDD was detected in exhausts of
automobiles powered with unleaded gasoline (Harklund et al. 1987). It
was speculated that dichloroethane used as a scavenger was the source of
2,3,7,8-TCDD in exhaust from leaded gasoline. In automobiles powered
with unleaded gasoline and equipped with a catalytic converter, the
absence of dichloroethane may prevent formation of 2,3,7,8-TCDD and the
catalytic converter may additionally destroy any 2,3,7,8-TCDD that may
be formed. Therefore, with the replacement of older automobiles, this
source of 2,3,7,8-TCDD should be on the decline. Accidental fires
involving capacitors or transformers containing chlorobenzene will also
release 2,3,7,8-TCDD to the environment. An example of such a
contamination is the transformer fire in the State Office Building in
Binghamton, New York.
6.2.4 Improper Disposal of Chlorinated Chemical Wastes
Improper disposal of certain chemical wastes produced during the
manufacture of 2,4,5-trichlorophenol, 2,4,5-T, and related herbicides,
hexachlorophene, and chlorinated benzenes, may be a source of 2,3,7,8-
TCDD in the environment. Examples of such improper disposal leading to
the contamination of the environment are the Love Canal, Niagara Falls,
New York, sites where 2,3,7,8-TCDD up to a level of 672 pg/kg was
detected. Similarly, several sites in the state of Missouri were
contaminated with up to 1,750 MgAg 2,3,7,8-TCDD (Tiernan et al. 1985).
6.3 ENVIRONMENTAL FATE
The fate of 2,3,7,8-TCDD in air, water, and soil is not understood
with certainty. Although some experimental efforts have been directed in
recent years to elucidate its fate in different media, a substantial
data gap exists in this area. In air, 2,3,7,8-TCDD is likely to be
present partly in the gas phase and predominantly in the particle-sorbed
phase. The two important processes that may remove 2,3,7,8-TCDD from the
atmosphere are photochemical degradation and wet deposition. The
photodegradation of gas phase 2,3,7,8-TCDD with an estimated half-life
of a few hours is expected to be much faster than particle-sorbed
chlorinated dibenzodioxins. Even an estimate of the atmospheric half-
life of 2,3,7,8-TCDD is not available. On the basis of photochemical
experiments with 2,3,7,8-TCDD coated on silica gel, the half-life of
atmospheric particulate 2,3,7,8-TCDD may be a few days. The lifetime of
atmospheric 2,3,7,8-TCDD is such that it can be transported long
distances in the air, although this transport will be of shorter
distances compared with the transport of higher chlorinated
dibenzodioxins. The ultimate environmental sink of airborne particulate
2,3,7,8-TCDD is likely to be sediments of surface waters (Choudhry and
Hutzinger 1982, Czuczva and Kites 1986, Eitzer and Hites 1986, Miller et
al. 1987, Podoll et al. 1986).
The biodegradation of 2,3,7,8-TCDD in water is probably slow. The
two processes that may be important for the removal of 2,3,7,8-TCDD are
volatility and photodegradation. Although the photolysis of 2,3,7,8-TCDD
in hydrogen-donating solvents is a fast process, a suspension of
2,3,7,8-TCDD in distilled water showed no appreciable photodegradation.
In natural waters, the presence of small amounts of hydrogen-donating
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74 Section 6
substrate or the presence of photosensitizers may account for its
observed photodegradation; however, the photochemical degradabllity of
2,3,7.8-TCDD in water, as provided by model ecosystem studies (Matsumura
et al. 1983, Tsushimoto et al. 1982), has not provided definite evidence
through mass balance that the observed loss of 2,3,7,8-TCDD attributed
to photolysis was not due to its sorption on sediment and biota. The
estimated half-lives for dissolved 2,3,7,8-TCDD in sunlight may range
from 118 hours in winter to 21 hours in clear near-surface water under
clear skies. The photodegradation is usually a dechlorination process
leading to the formation of tri- and dichlorinated dibenzo-p-dioxins. In
sediment-containing lake water, the estimated half-life of 2,3,7,8-TCDD
is >1.S years. In lake water alone, the estimated half-life is >1 year.
The ultimate sink of aquatic 2,3,7,8-TCDD is the sediment. Recent flow-
through experiments with fathead minnows (Pimephales promelas) have
shown that the bioconcentration factor for 2,3,7,8-TCDD in this species
is 7,900 to 9,300 on a wet-weight basis (Adams et al. 1986, EPA 1985b,
Podoll et al 1986). Recently, the steady-state bioconcentration factor
for 2,3,7,8-TCDD in rainbow trout (Salmo gairdneri) as extrapolated from
experimental data has been estimated to be 39,000 (Mehrle et al. 1988).
The lower values reported by earlier authors may be due to nonattainment
of steady-state concentration in fish tissues.
2,3,7,8-TCDD is expected to be immobile in most soils by irrigation
and rainfalls. A downward movement of 10 cm in 12 years was observed
with soil from Eglin Air Force Base. Although 2,3,7,8-TCDD usually does
not leach through soil, leaching is possible in some instances from
soils of very low organic carbon content as a result of 2,3,7,8-TCDD
solvation with organic solvent or biotic mixing by earthworms or other
soil invertebrates. A white rot fungus (Phanerochaete chrysosporium") has
been shown to degrade 2,3,7,8-TCDD. This biodegradation does not occur
significantly in natural soils, probably because of the lack of this or
other degrading microorganisms. Both volatilization and photoreaction
may remove some 2,3,7,8-TCDD from soil surfaces. The photoreaction on
soil surfaces can be greatly enhanced by the presence of hydrogen-
donating substrates (e.g., olive oil or arachis oil) in soil. The
photoreaction will be insignificant beyond the surface soil layers. The
environmental half-life of 2,3,7,8-TCDD is highly dependent upon soil
characteristics, the mode of contamination, and climatological
conditions. The estimated half-life of 2,3,7,8-TCDD on soil surfaces is
1 to 3 years, but the half-life in the interior of soil may be 10 to 12
years (Bumpus et al. 1985, EPA 1985b, Freeman and Schroy 1986, HSDB
1987, Miller et al, 1987).
2,3,7,8-TCDD present on leaves of plants as a result of spraying
herbicides will photolyze with a half-life of a few hours. The chemical
is absorbed by higher plants and is probably translocated, but it is not
accumulated. The absorption by underground parts may be at the same
level as soil, but the aerial part contains -50% lower concentrations
(Choudhry and Hutzinger 1982. Sacchi et al. 1986). Consumption of foods
derived from contaminated areas (e.g., near municipal incinerators),
could represent a significant dietary source. However, Insensee and
Jones (1971) and Wipf and Schmid (1983) observed no significant plant
uptake in mature oats and soybeans, and edible parts of roots vegetable
contained much less 2,3,7,8-TCDD than the surrounding soil.
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75
7. POTENTIAL FOR HUMAN EXPOSURE
7.1 OVERVIEW
The human exposure pathways to 2.3,7,8-TCDD have changed since the
late 1970s. Because 2,3,7,8-TCDD was a contaminant in herbicide
preparations containing 2,4,5-T, the manufacture, use, and disposal of
these herbicides were the primary sources of exposure to 2,3,7,8-TCDD.
In 1979, EPA (1979) completely banned the use of 2,4,5-T. With the
stoppage of production of 2,4,5-T and other pesticide preparations
containing the contaminant 2,3,7,8-TCDD, both occupational and general
population exposure to 2,3,7,8-TCDD due to manufacture and use of the
herbicides ceased to exist. Presently, the important sources of
2,3,7,8-TCDD exposures to the general population are contaminated soil,
dump sites, and municipal incinerators. 2,3,7,8-TCDD has been found in
at least 28 of 1,177 sites on the National Priorities List (View 1989).
With the change of sources, the exposure pathways have also changed over
the years (i.e., dermal and inhalation exposure from the manufacture and
use of 2,4,5-T to ingestion of foods obtained from contaminated sites).
There is a paucity of data on the level of 2.3.7.8-TCDD in ambient
air due to sampling and analytical difficulties associated with
quantification of very low levels of 2,3,7,8-TCDD. The ambient level of
2,3,7,8-TCDD in urban areas in West Germany and Sweden ranged from
<0.001-0.08 pg/m3. Although ambient air samples from several locations
in the United States have been collected for the quantification of
2,3,7,8-TCDD levels, results from these studies are not yet available.
The concentration of total tetrachlorodibenzo-p-dioxin (not
2,3,7,8-TCDD alone) in ambient air in Bloomington, Indiana, was 18 to
92 fg/m3 (femtograms per cubic meter). Assuming that the 2,3,7,8-TCDD
isomer constitutes 5% of the total tetra isomers, the concentration of
2,3,7,8-TCDD in Bloomington air would be 0.9 to 4.6 fg/m3. The
concentration of 2,3,7,8-TCDD in the air around the stack of a municipal
incinerator has been estimated as 38 fg/m3. The accidental transformer
fire in Binghamton, New York, produced a much higher level of 2,3,7,8-
TCDD- -at 0.23 to 0.47 pg/m3. The concentration of 2,3,7,8-TCDD in the
air surrounding a field after the application of Silvex containing
15 ppm 2,3,7,8-TCDD was 0.62 pg/m3. Other than certain industrial
effluents and leachates from chemical dump sites, no 2,3,7,8-TCDD has
ever been reported in drinking water. The concentrations of 2,3,7,8-TCDD
in most uncontaminated soils are below the detection limits of
analytical methods. In urban soils, the level of 2,3,7,8-TCDD is in the
range <0.0002 to 0.011 ng/g. Much higher levels have been detected in
soils contaminated by certain hazardous wastes, waste oils, and spillage
of 2,4,5-trichlorophenol. A soil from Shenandoah Stables in Missouri
contaminated by waste oil containing 2,3,7,8-TCDD had up to 1,750 ng/g
of 2,3,7,8-TCDD. Fish samples collected from lakes and a selected
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76 Section 7
Michigan river contained undetectable levels to 67 pg/g 2.3 . 7,8-TCDD. N
2,3,7,8-TCDD was detected in rice, soybeans, and crawfish in thfc United
States, or in Canadian chicken and pork samples. 2,3,7,8-TCDD at a
concentration range of 0.021-0.049 ng/kg has been detected in three of
six samples of cow's milk from Switzerland. Although several other PCDDs
and PCDFs have been detected in some foods in Japan, no 2,3,7,8-TCDD has
been found in these samples at sub-ppt detection limits. Since fat is
the chief contributor to the body burden of 2,3,7,8-TCDD in humans, it
has been analyzed by many investigators. Levels of 2,3,7,8-TCDD in
adipose tissue of exposed and control persons in Missouri have been
determined. The level of 2,3,7,8-TCDD in adipose tissue in certain
segments of the general population in the United States and Canada
ranges from undetectable to 20 pg/g, with a mean value of 5 to 7 pg/g.
Values as high as 99 pg/g were detected in an individual heavily exposed
during the spraying operation in South Vietnam. 2,3,7,8-TCDD has been
detected in human milk in the United States at 0.29 pg/g; in members of
the general population in Sweden at trace to 2.3 pg/g, with a mean value
of 0.6 pg/g; and in Germany at 1.3 to 3.3 pg/g, with a mean value of
I-9 Pg/g- 2,3,7,8-TCDD was also found in human milk in other European
countries. Although there are no data regarding exposure levels, workers
at sites of improper chemical waste disposal and the general population
residing near these sites may be susceptible to higher exposure to
2,3,7,8-TCDD. Breast-fed babies nursed by mothers residing near
improperly operated municipal incinerators may also be at higher risk.
The estimated daily human exposure to 2,3,7,8-TCDD, expressed as
picograms per kilogram of body weight (pgAg) , is 0.02 through
inhalation, 0.5 to 5 through the consumption of milk, and 20 through th
consumption of fish. The daily exposure of a 5-kg baby resulting from
the consumption of 850 mL of breast milk is 20 to 200 pg/kg. From the
estimated body burden and the half-life of 2,3,7,8-TCDD in the human
body, the daily human intake of 2,3,7,8-TCDD has been estimated as
0.05 ng in one study and in the range of 0.003-0.036 ng in another.
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
7.2.1 Air
Due to sampling and analytical difficulties associated with
quantification of very low concentrations of 2,3,7,8-TCDD, very few data
are available for the levels of this compound in ambient air. The
concentration of total tetrachlorodibenzo-p-dioxin isomers in both vapor
and particulate phase in the ambient air in Bloomington. Indiana, was
approximately 18 to 92 fg/m3. The analytical method used could not
unequivocally identify 2,3,7,8-TCDD from other tetra isomers. Using the
measured concentration in flue gases from five municipal incinerators
and an air dispersion model, the maximum ambient concentration of
2,3,7,8-TCDD in the area around the stacks was estimated as 38 fg/m3.
Since municipal incinerators are one of the prime sources of atmospheric
2,3,7,8-TCDD, there are a vast number of publications concerning the
level of these compounds in the fly ashes of the incinerators; however,
most of the publications failed to distinguish 2,3,7,8-TCDD from its
isomers. The levels of 2,3,7,8-TCDD in the flue gas of European
incinerators are 0.05 to 1.3 ng/m3; in U.S. incinerators, the levels ai
a maximum of 3.5 ng/m3 (under normalized conditions of the emitted
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Potent Lai for Human Exposure 77
gases) (Barnes 1983, Eitzer and Hites 1986, EPA 1985b, Marklund et al.
1986, Nottrodt and Ballschmiter 1986). The measured concentrations of
2,3,7,8-TCDD in four locations in Hamburg, West Germany, were in the
range of 0.02-0.08 pg/m3 (Rappe and Kjeller 1987). The locations
consisted of an urban site, a traffic tunnel, a site downwind from a
municipal incinerator, and a site in the vicinity of a dump site and a
metal refinery. The levels of 2,3,7,8-TCDD in urban air in Sweden ranged
from 0.001-0.009 pg/m3 (Rappe and Kjeller 1987). Although ambient air
samples from several locations in the United States have been collected
for quantifying the levels of PCDDs and PCDFs, the results are not yet
available.
Accidents involving certain transformer/capacitor fires can release
larger amounts of 2,3,7,8-TCDD in the air. The concentration of
2,3,7,8-TCDD in the air of the State Office Building in Binghamton, New
York, following an accidental fire, was 0.23 to 0.47 pg/m3. Following an
accidental locomotive fire in Sweden, the concentration of 2,3,7,8-TCDD
was 50 pg/m3. The concentration of 2,3,7,8-TCDD in the air surrounding a
field after the application of Silvex containing 15 ppm 2,3,7,8-TCDD was
0.62 pg/m3, but the concentration dropped to a level of 0.18 pg/m3 on
the second day (EPA 1985b, Rappe et al. 1985, Smith et al. 1986).
7.2.2 Water
No report is available on the detection of 2,3,7,8-TCDD in drinking
water, using methods with detection limits in the pico-per-liter range;
however, 2,3,7,8-TCDD has been detected in aqueous industrial effluents,
sediments, and leachates from hazardous waste sites. The concentrations
of tetrachlorinated dibenzo-p-dioxins, including 2,3,7,8-TCDD, in
effluents from a trichlorophenol manufacturing facility ranged from none
detected (detection limit, 10 to 30 pg/g) to 100 pg/g. The discharged
wastewater effluent from Dow into the Tittabawassee River, in Michigan,
has been reported to be approximately 15 pg/L. The leachate samples from
a waste disposal site in Jacksonville, Arkansas, had a mean 2,3,7,8-TCDD
level of 14 ng/L. The sump pump water from residences and leachates from
the Love Canal area in New York contained 2,3,7,8-TCDD ranging from none
detected to 1,560 ng/L. The concentrations of 2,3,7,8-TCDD in sediments
from storm sewers, residential sump water, and surface water around the
same site were none detected (detection limit, 10 to 100 pg/g) to 9,570
ng/g (EPA 1985b, Lamparski et al. 1986, Tieman et aL. 1985). The
concentration of 2,3,7,8-TCDD in the sludge of seven pulp and paper mill
wastewaters in the U.S. had concentration levels ranging from none
detectable (<1.0 pg/g) to 414 pg/g (Kuehl et al. 1987).
7.2.3 Soil
Concentrations of 2,3,7,8-TCDD in most soils with no obvious source
of contamination are below the detection limits of current analytical
methods. In urban soils, the level of 2,3,7,8-TCDD is in the range of
<0.0002 to 0.009 ng/g. In a national dioxin study, EPA sampled soils
from 138 rural and 221 urban sites not associated with sources of
2,3,7,8-TCDD. Only 17 of the rural and urban soils had detectable levels
of 2,3,7,8-TCDD at a concentration range of 0.2-11.2 pg/g (TMN 1987).
2,3,7,8-TCDD has been detected in samples that originated from certain
industrial sites, waste disposal sites, and sites involved in accidental
-------
78 Section 7
spillage of chemicals containing 2,3,7,8-TCDD. The levels of 2,3 7 8-
TCDD in soils from different locations are given in Table 7.1.'it is
apparent from Table 7.1 that the accidental or improper disposal of
still-bottom residue -from the manufacture of 2,4,5-trichlorophenol
(2,4,5-TCP) may produce one of the highest levels of 2,3,7,8-TCDD in
soils.
7.2.4 Other
There are limited data that 2,3,7,8-TCDD does not bioaccumulate in
crop plants (Anonymous 1985). Crops grown in soil contaminated with
2,3,7,8-TCDD (up to 752 ppt) after the Seveso accident contained only a
few parts per trillion of 2,3,7,8-TCDD in the aboveground portions. The
roots of these plants, however, contained higher levels of 2,3,7,8-TCDD
than the surrounding soil, suggesting that a similar study using root
crops would demonstrate the contamination of the edible portion of the
plant. This could represent a significant source of dietary intake in
some areas. However, Wipf and Schmid (1983) reported that edible
portions of root vegetables contained much less 2,3,7,8-TCDD than the
surrounding soil.
Since aquatic organisms bioconcentrate 2,3,7,8-TCDD, a few
investigators analyzed fish-eating birds as an indicator of possible
pollution in the suspected water bodies. A herring gull sample from Lake
Huron contained 75 pg/g 2,3,7,8-TCDD. Similarly, herring gull eggs
collected from the Great Lakes contained 12 to 101 pg/g 2,3,7,8-TCDD.
Samples from Lake Ontario and Saginaw Bay had the maximum levels of
2,3,7,8-TCDD (Stalling et al. 1986); those from Lake Michigan and Lake
Superior had the minimum levels of contamination (Buser and Rappe 1984).
Fish samples from the Great Lakes and selected Michigan rivers were
shown to contain between undetectable amounts (detection limit 2 pg/g)
and 67 pg/g 2,3,7,8-TCDD (Fehringer et al. 1985, Niemann 1986, Ryan et
al. 1984). Yellow perch samples from Woods Pond, Massachusetts, were
found to contain 26 pg/g 2,3,7,8-TCDD (Buser and Rappe 1984). Fish
obtained from the Androscoggin River in Maine, the Wisconsin River in
Wisconsin, and Rainy River in Minnesota, all of which received
discharges from pulp and paper mills, contained 29, 125 and 185 pg/g of
2,3,7,8-TCDD, respectively (Kuehl et al. 1987). Fish collected from
about 400 selected and random sites by EPA contained 2,3,7,8-TCDD at
levels ranging from none detected «0.2 pg/g) to 85 pg/g (TMN 1987). No
2,3,7,8-TCDD was found in rice, soybean, and crawfish samples from
Arkansas and Louisiana at a detection limit of 10 pg/g, or in Canadian
chicken and pork samples at a detection limit of 2 to 4 pg/g (Ryan et
al. 1985a, Firestone et al. 1985). As a result of the present day
bleaching processes used in the pulp and paper industry, trace amounts
of 2,3,7,8-TCDD have been detected in paper products. Preliminary
results indicate that 2,3,7,8-TCDD is present at 3 to 4 pg/g in certain
samples of paper towels and 13 to 39 pg/g in samples of communication
papers, such as stationery, computer papers, and envelopes (TMN 1987).
A model to estimate 2,3,7,8-TCDD intake by humans from inhalation
of air and ingestlon of drinking water and food predicted that the food
chain accounts for 98% of the dally human intake of 2,3,7,8-TCDD (Travi
and Hattemer-Frey 1987). Connect and Webster (1987) also concluded that
food could be the predominant source of 2,3,7,8-TCDD Intake by far,
-------
Table 7.1. Levels of 2,3,7,8-TCDD in soil from different locations
Site
Sample history
TCDD concentration**
(ng/g)
Love Canal, N.Y.
Jacksonville, Ariz.
Midland, Mich.
St. Louis, Mo.
Shenandoah Stables, Mo.
Soils outside the dump site
Waste disposal site
Inside DOW facility
Urban sample of no obvious
source of contamination
Contaminated by waste oil
ND (0.001 -0020)
ND-29
0.01 -52
0.12
101-33,000
Timberlme Stables, Mo
Bliss Farm, Mo.
Bubbling Springs Ranch, Mo.
Minker Resident, Mo.
Times Beach, Mo
Urban areas, Umled Slates
New Jersey
New Jersey
Lansing, Mich
Gaylord. Miss
Detroit, Mich
Contaminated by waste oil
Contaminated by waste oil
Contaminated by waste oil
Contaminated by waste oil
Contaminated by waste oil
Urban samples of no obvious
source of contamination
Spillage of 2,4,5-TCP
still bottom
Scrap yard where used reactor
vessels were collected
Urban sample
Urban sample
Urban sample
30-42
382f
76-95
50'
44-317
<0.0002-0 009
26.000f
1,100'
ND(00007) 0003
ND(00002)
00021 00036
References
EPA I985b
tPA I985b
Neslncket al 1986
EPA I985b
Tiernan et al 1985,
Kimbrough el al
1977
Tiernan et al 1985
Tiernan et al 1985
Tiernan el al 1985
Tiernan el al 1985
Tiernan et al 1985
Nestnck et al 1986
Jackson el al 1986
Jackson et al 1986
Nolrick cl al 1986
Neslnck el al 1986
Neslnck el jl 1986
O
rt
n
»-.
Di
I
o
in
c
-------
CO
o
Table 7.1 (continued)
Site
Chicago. III.
Akron, Ohio
Nashville, Tenn.
Pittsburgh, Pa.
Philadelphia, Pa.
Brooklyn, N.Y.
Arlington. Va.
Sample history
Urban sample
Urban sample
Urban sample
Urban sample
Urban sample
Urban sample
Urban sample
TCDD concentration"-*
(ng/g)
0.0042-0.0094
0.0063
0.0008
0.0026
0.0009
0.0026
ND(0.0003)
References
Nestnck et al. 1986
Nestrick et al. 1986
Nestrick et al. 1986
Nestrick et al. 1986
Nestrick et al. 1986
Nestrick et al. 1986
Nestrick et al. 1986
"ND = not detected.
^Values within parentheses are detection limits.
'Only one sample was analyzed.
Co
n
o
rt
-------
Potential for Human Exposure 81
compared with inhalation intake. Actual data on measured levels of
2,3,7,8-TCDD in food, however, are limited. Fat specimens fron three of
seven steers that were confined to a fenced pasture sprayed with 2,4,5-T
herbicide contained 3-4 ngAg 2,3,7,8-TCDD (Korcher et al. 1978). This
result indicates that beef obtained from cattle grazing in contaminated
pastures (for example, those near municipal incinerators) may contribute
to 2,3,7,8-TCDD ingestion from contaminated food. Six samples of cow's
milk from various locations in Switzerland were analyzed for PCDDs.
Although sub-ppt (ng/kg) levels of 2,3,7,8-TCDD-substituted hepta-CDDs
were found in all samples, only three contained 2,3,7,8-TCDD at a
0.021-0.049 ngAg range (detection limit <0.013 ngAg) (Rappe et al.
1987). The daily intake of PCDDs by residents of Japan through
consumption of food has been estimated by several investigators (Ogaki
et al. 1987, Ono et al. 1987, Takizawa and Muto 1987). None of these
investigators, however, reported the detection of 2,3,7,8-TCDD in any
food.
Since adipose tissue appears to be the chief contributor to the
body burden of 2,3,7,8-TCDD, many investigators analyzed fat tissue from
both exposed and control populations. That fat has the highest burden is
confirmed by the tissue analysis of a woman who died 7 months after the
accident in Seveso, Italy. The following levels of 2.3,7,8-TCDD (pg/g)
were found in different organs: fat, 1,840; pancreas, 1,040; liver, 150;
thyroid, 85; brain, 60; lung, 60; kidney, 40; and blood, 6. The levels
of 2,3,7,8-TCDD in adipose tissue in certain segments of the general
population of the United States and Canada ranged from undetectable to
20 pg/g, with a mean value of 5 to 7 pg/g. In a U.S. National Human
Adipose Tissue Survey (Stanley et al. 1986), 2,3,7,8-TCDD was detected
with a frequency of 76%. In Europe, the range of 2,3,7,8-TCDD
concentration in the adipose tissue in segments of the general
population is not detectable to 9 pg/g, with a mean value of 3 pg/g.
Instances of higher levels in adipose tissue have been reported in
individuals exposed to this chemical either during spraying herbicides
containing 2,4,5-T or during accidental capacitor or transformer fires.
For example, the adipose tissue of a few exposed individuals in the
State Office Building fire in Binghamton, New York, had 2,3,7,8-TCDD
concentrations in the range 11.6 to 28.3 pg/g. with a mean value of
17.4 pg/g. The adipose tissue of a few heavily exposed individuals
involved in spraying operations in Vietnam had 2,3,7,8-TCDD levels
ranging from undetectable (detection limit, 3 pg/g) to 99 pg/g, with a
mean value of 37 pg/g; however, no difference in the level of 2,3,7,8-
TCDD was found in lightly exposed, possibly exposed, and other Vietnam
veterans who sought medical help compared with the control population
group (EPA 1986a; Graham et al. 1986; Gross et al. 1984; Nygren et al.
1986; Patterson et al. 1987c; Schecter et al. 1985, 1986; Stanley et al.
1986; Weerasinghe et al. 1986; Young 1984). The median concentrations of
2,3,7,8-TCDD (concentration range in parentheses) in control and exposed
populations in Missouri have been reported to be 6.4 pg/g (1.4 to
20.2 pg/g) and 17 pg/g (2.8 to 750 pg/g), respectively (Patterson et al.
1986). The levels of 2,3,7,8-TCDD in human serum have been reported by
researchers from Centers for Disease Control (Patterson et al. 1987b,
Patterson et al.). On a lipid-adjusted basis, the levels of 2,3,7,8-TCDD
in human serum of certain members of the general population was reported
to range from 4 pg/g to 7.6 pg/g. Determination of 2,3,7,8-TCDD levels
-------
82 Section 7
in blood may be used as an indicator of body burden. The advantage of
this method is that it requires a noninvasive technique for withdrawing
sample specimens.
Human breast milk has also been analyzed for 2,3,7,8-TCDD. It has
been reported that human breast milk is the largest contributor to the
body intake of 2,3,7,8-TCDD in breast-fed babies (Rappe et al. 1986,
Schecter and Gasiewicz 1987). The following levels (the detection limits
are given in parentheses) of 2,3,7,8-TCDD have been determined in human
breast milk from different countries: United States, none detected (0.1
to 6.0 pg/g) in mothers from 2,4,5-T-exposed areas and in control areas;
none detected (<0.2 pg/g) and 0.29 pg/g in two mothers' milk collected
in 1986 from fiihghamton, New York; Canada, 0.17 pg/g in a single pooled
sample of 200 mothers' milk collected in 1980-81; Seveso, Italy, 2.3 to
28.0 pg/g from mothers near accident area; South Vietnam, none detected
(0.5 pg/g) to 40 to 50 pg/g from mothers in sprayed areas; Sweden, trace
to 2.3 pg/g, with a mean of 0.6 pg/g; and Germany, 1.3 to 3.3 pg/g, with
a mean of 1.9 pg/g. 2,3,7,8-TCDD was also detected in human milk
obtained from Denmark, the Netherlands, and Yugoslavia (EPA 1985b, Heath
et al. 1986, Jensen 1987, Nygren et al. 1986, Patterson et al. 1986,
Rappe et al. 1986, Schecter et al. 1987, Young 1984). There is a large
unexplainable difference in the values of 2,3,7,8-TCDD concentrations in
milk from South Vietnamese mothers analyzed by two groups of
investigators (Schecter et al. 1987, Young 1984).
According to a statement by CDC (1986), "Contamination of breast
milk with trace amounts of a variety of chlorinated compounds should not
discourage women from breastfeeding except under unusual circumstances
which have to be evaluated on an individual basis. . . .Substitutes useo
for human milk are not entirely free of these compounds and may have
high metal levels. . . .Avoiding breastfeeding would deprive the infant
of immunological protection and psychological benefits for the infant
and mother."
Other human tissues, obtained from the autopsy of two subjects in
Canada, were analyzed for 2,3,7,8-TCDD with the following results:
liver, none detected to 2.5 pg/g; muscle, none detected; and kidney,
none detected. The detection limit in these determinations were in the
range of 1 to 4 pg/g (Ryan et al. 1985b). No 2,3,7,8-TCDD was detected
in the blood of exposed workers following the accident in Binghamton,
New York, at a detection limit of 1 to 2 pg/g (Schecter et al. 1985).
Serum 2,3,7,8-TCDD levels in veterans who were heavily exposed to Agent
Orange in Vietnam during 1967-1968 have been reported by the Centers for
Disease Control to range between none detected (0.0013 pg/g) and
25 Pg/g, with a median value of 3.8 pg/g. The same study reported serum
2,3,7,8-TCDD levels in a group of non-Vietnam veterans to range between
none detected (0.0013 pg/g) and 12 pg/g, with a median value of
3-9 Pg/g- Serum levels in a group occupationally exposed to 2,3,7,8-TCDD
prior to 1970, however, have been reported to be 30-fold higher in the
same study (MMWR, 1987). Using an environmental partitioning model to
estimate the concentration levels of 2,3,7,8-TCDD in various
environmental media, Travis and Hattemer-Frey (1987) estimated the
following average daily intake (with the per cent of the total intake in
parenthesis): air, 0.001 ng (2%); water, 6.5 x 10'6 ng (<0.01%); and
food, 0.046 ng (98%). It is likely that the secondary source of
-------
Potential for Human Exposure 83
2,3,7,8-TCDD in foods is atmospheric emissions. EPA (1988c) estimated
the human exposure to 2,3,7,8-TCDD from a variety of exposure scenarios
resulting from contaminated soils, various land disposal situations, and
municipal waste incineration. The highest exposure was attributed to the
food chain, i.e., ingestion of contaminated fish, beef, dairy products,
and other foods. Ingestion of contaminated soil, especially by children
with pica tendencies; dermal contact with contaminated soil, dust, and
sediment; and inhalation of contaminated dust and vapor further
contribute to human exposure. EPA (1988c) estimated an upper limit value
for the average 2,3,7,8-TCDD concentration in adipose tissue to be 6.72
ppt in the U.S. population. From this adipose tissue burden and
pharmacokinetic considerations, it was estimated that the upper bound
2,3,7,8-TCDD daily intake ranges from 0.04 to 0.51 pg/kg. These
estimates apply to ambient exposure and not to exposure scenarios
related to accidents.
7.3 OCCUPATIONAL EXPOSURES
Occupational exposures to 2,3.7,8-TCDD occured in the past during
the production and use of hexachlorophene, trichlorophenol, and
herbicides containing 2,4,5-T. The potential for heaviest exposure is
likely to occur during the step that is used to purify 2,4,5-
trichlorophenol from its contaminants, since these products contain much
higher levels of 2,3,7,8-TCDD than the purified products. Detection of
the highest level of 2,3,7,8-TCDD (1.1 jig/wipe) in wipe samples taken
from different trichlorophenol production and purification areas of a
production facility also confirms this (Ott et al. 1987). Few data on
the occupational exposure to 2,3,7,8-TCDD during the manufacture of
these chemicals are available (Rappe 1984). The indirect evidence of
occupational exposure to 2,3,7,8-TCDD is the significantly higher
adipose tissue levels of the compound in heavily exposed Vietnam
veterans and in certain workers at the State Office Building in
Binghamton, New York, following the transformer fire. The adipose
tissues of nine workers from a former trichlorophenol manufacturer in
Missouri showed a mean 2,3,7,8-TCDD level of 246 pg/g compared with a
mean value of 8.7 pg/g for nonexposed workers at the same site. The
lipid-adjusted mean 2,3,7,8-TCDD level in serum of the same exposed
workers was 363 pg/g- compared with a value of 47.1 pg/g for nonexposed
workers (Patterson et al. in press).
7.4 POPULATIONS AT HIGH RISK
From the monitoring data discussed in Sects. 7.2 and 7.3, it is
possible to predict the segments of the general population and of
occupational groups that may be exposed to higher levels of 2,3,7,8-
TCDD. Among the occupational groups, workers involved in the production
or use of trichlorophenol or its salts, hexachlorophene, and 2,4,5-T or
other herbicides containing 2,4,5-T have the potential for exposure to
higher levels of 2,3,7,8-TCDD than the general population. 2,4,5-T and
2,4,5-trichlorophenol and its salts, however, are no longer manufactured
in the United States (SRI 1987). Workers in the wood treatment industry
have the potential for 2,3.7,8-TCDD exposure due to the possibility of
2,3,7,8-TCDD formation as a result of catalytic dechlorination of higher
chlorinated dibenzodioxins during pressure treatment of wood with
-------
84 Section 7
pentachlorophenol or sodium pentachlorophenate (Hagenmaier and Brunner
1987). Workers in pulp and paper mills also have the potential for
exposure to 2,3,7,8-TCDD due to the occurrence of 2,3,7,8-TCDD in
bleached Kraft paper-making processes (Amendela 1987, Clement et al.
1987, Kuehl et al. 1987). Since both flue gases and ashes from municipal
and industrial incinerators contain 2,3,7,8-TCDD, workers in this
profession are likely to be at higher risk of exposure to 2,3,7,8-TCDD.
Populations residing near municipal incinerators may also be subjected
to exposure. Workers at sites of improper chemical waste disposal (from
trichlorophenol, hexachlorophene, 2,4,5-T, and associated industries)
and the general population residing near those sites are potentially
exposed to 2,3,7,8-TCDD. Breast-fed babies nursed by mothers residing
near improperly operated municipal incinerators or other sources of
exposure are expected to receive 2,3,7,8-TCDD through the milk.
Studies in humans have not demonstrated that there is a sensitive
subpopulation. Animal studies, however, suggest that the fetus and
newborn infants may represent such a sensitive population. As discussed
in Sects. 4.3.3 and 4.3.4 on developmental and reproductive toxicity,
2,3,7,8-TCDD is a demonstrated teratogen in rats and mice and also
results in spontaneous abortions and fetal death in monkeys. Since these
effects occur at low doses, and in the case of teratologic effects at
doses that do not appear to adversely affect the mother, it is likely
that, at certain stages of fetal development, the fetus represents a
sensitive subgroup. Animal data also demonstrate that toxic levels of
2,3,7,8-TCDD can be ingested during nursing and that lactation is a
major route for elimination of 2,3,7,8-TCDD.
-------
85
8. ANALYTICAL METHODS
Several methods are available for the analysis of 2,3.7,8-TCDD in
different media. Some of the more recent methods are given in Tables 8 1
and 8.2. The statement of work for organic analysis in the EPA Contract
Laboratory Program does not list any method for 2,3,7,8-TCDD analysis
(EPA 1987b). The methods listed in these tables are not exhaustive but
are illustrative of a few recent methods. Methodologies for collecting
samples before their analysis are important, since the concentrations of
2,3,7,8-TCDD in most samples are low. This is particularly important for
stack samples that exist both in the vapor and particulate phase. The
details of stack-sampling methods are available in Velzy (1986) Ozvacic
(1986), and Brenner (1986).
The accuracy of analysis has increased in recent years with the
availability of stable isotope-labeled (37C1 and 13C) 2,3,7,8-TCDD for
use as an internal standard in mass spectral analysis. With a
combination of one of several methods available for sample cleanup,
high-performance gas chromatography (GC) (HRGC), and high-resolution
mass spectrometry (MS) (HRMS), unequivocal identification and
quantification of 2,3,7,8-TCDD can be performed at very low levels.
Although negative chemical ionization MS (NCI/MS) shows a higher
sensitivity to all other polychlorinated dibenzo-p-dioxins than electron
impact MS (EI/MS), it has a lower sensitivity for 2,3,7,8-TCDD (Buser et
al. 1985). The analysis of fly ash samples poses a special challenge
because of poor solvent extraction recovery and the difficulty in the
resolution of 2,3,7,8-TCDD from a large number of congeners present in
these samples. Best results were obtained by using digestion with excess
dilute HC1, followed by freeze-drying of the residue and hot extraction
with toluene. The HC1 treatment opens the pore structure of fly ash to
permit access to the solvent, and freeze-drying removes water to improve
material transfer from the hydrophilic surface of the fly ash to the
solvent (Stieglitz et al. 1986). Emphasis has been placed on the
analysis of adipose tissue and mother's milk, because these two tissues
may be indicators of the human body burden for 2,3,7,8-TCDD. The
analysis of fish is also important since some bottom feeders (e.g.,
channel catfish and carp) and those fish that feed upon bottom feeders
may be indicators of 2,3,7,8-TCDD-polluted water (Ryan et al. 1984a.
Jensen 1987).
Besides the commonly used analytical methods, other newly developed
but yet generally untested methods are available for the analysis of
2,3,7,8-TCDD. Some of these methods are GC with a polymeric liquid
crystal capillary column (Natkwadi and Karasek 1986), GC with matrix
isolation Fourier transform infrared spectrometry (Wurrey et al. 1986).
and HRGC with microwave- induced plasma detection (Mohamad et al. 1986)!
More detailed descriptions of the analytical methods for 2,3,7,8-TCDD
-------
86 Section 8
can be found in Buser et al. (1985), Tieman et al. (1985), Rappe
(1984), and EPA (1985b).
8.1 ENVIRONMENTAL MEDIA
8.1.1 Air. Water. Soil, and Food
See Table 8.1.
8.2 BIOMEDICAL SAMPLES
8.2.1 Fluids/Ezudates and Tissues
See Table 8.2.
-------
Table 8.1. Analytical method* for emlromntiilal samples
Sample matrix
Ambient room air
following accidental
transformer fire
Sample preparation
Vapor phase sample collected
by silica gel, paniculate
sample collected on glass fiber
Analytical method"
HRGC/HRMS
Detection limn
0003 pg/m1
Accuracy0
131 ± 27% al
J- 10 pg/m1
References
Smith el al 1986
Ambient outdoor air
Stack emission
Fly ash from
municipal incinerator
Water
filler, solvent extracted, and
precleaned by alumina and carbon
Vapor and paniculate collected
on polyurethane foam and glass
fiber, precleaned by Floruit
and modified silica
Vapor and particle collected on
polyurethane and glass fiber,
precleaned by silica and alumina
Vapor and panicle collected on
XAD-2 and glass fiber by modified
EPA method S; solvent extracted
and precleaned by silica, alumina,
and Biobead
Solvent extraction, HPLC separa-
tion on normal-phase and reverse-
phase column
Solvent extraction, precleaning
by two adsorbent columns, and
further fractionalion on reverse-
and normal-phase HPLC
Solvent extraction, precleaned on
silica and alumina
Sample passed through glass fiber
filler and adsorbent cartridge,
solvent extracted and precleaned
by acid alumina, graphatued
carbon and alumina
HRGC/NICI/MS
HRGC/NIEC/MS-SIM
HRGC/MS
GC/MS or HROC/FID
GC/LRMS
HRGC/LRMS
GC/MS
01-0 2 pg/m1 (method
detection limit loo high
for TCDD determination)
NR (TCDD not separated
from other telra isomers)
NR
NR (TCDD not separated
from other telra isomers)
40 pg
NR
NA Oehme el al 1986
NA Eiucr and Hues 1986
NR Hagenmaier el al 1986
NR Tong el al 1984,
Tong and Karasek 1986
NR Lamparski and
Ncstnck 1980
NR Buttr and Rappe 1980
88% at O'Kccrcci al 1986
6 5 pg/L
b
K-.
V!
s-
o
Q.
in
-------
TaMe 8.1 (coBtiaoed)
Sample matrix
Waslcwatcr
Sod
Fiib
Sample preparation
Analytical method"
Detection limit
Sample spiked with an internal
standard is solvent extracted, extract
cleaned by column chromatography
Solvent extraction. KOH wash, pie-
cleaned in alumina, revened-
phase HPLC. and carbon
Solvent extraction. KOH wash, pre-
cleaned in chemicaUy treated
silica, basic alumina
Homogenized fillet digested with
ethanobc KOH and solvent
extracted; extract cleaned by
silica gel-supported HjSO4 column
and HPLC
Homogenized Fillet solvent
extracted, partitioned with con-
centrated H,SO«, cleaned
by Florisil
Homogenate digested with concen-
trated HCI and solvent extracted.
extract cleaned by silica gel-
supported H,SO,. chemically
treated silica and alumina, and
reverse-phase HPLC
Digested with alkali, solvent
extracted, washed with concen-
trated H]SO,. and cleaned up
by ute exclusion chromatography.
normal- and reverse-phase HPLC
HRGC/LRMS or HRMS 0 2 mg/l
(EPA method 613)
HRGC/LRMS
HRGC/LRMS
HRGC/MS
HKGC/HRMS
HRGC/MS/MS
HRGC/EC
3ng/g
NR
5-IOpg/g
2-10 pg/g
<«Pg
I2pg/g
Accuracy"
92 4% at
2 5 mg/l
NR
NR
References
EPA 1982
Donnelly el al. 1986
Freeman et al 1986
oo
CO
o
00
NR Fehrmger el al 1985
NR Ryan el al 1984
NR Clement el al 1986
105% at Niemann 1986
I8-4J
-------
Sample main*
Fish and herring gull
Sample preparation
Solvent extracted, cleaned up by
potoitium ulicale-silica gel.
Table 8.1 (condone
Analytical method"
HRGC/LRMS
d)
Detection limn
l-8pg/g
Accuracy'
NR
References
Stalling el al 1983.
Rappc 1984
Fun, egg. or sediment
Chicken and pork
carbon, and HjSO,-silica gel cesium
silicate and alumina
Added HCI and solvent extracted.
extract cleaned by gel permeation,
tnsodium phosphate, H]SO,,
alumina and carbon columns
Fat and liver solvent extracted,
partitioned with concentrated
HjSO4. cleaned by Flonsil and
reverse-phase HPLC
HRGC/EC/LRMS
HRGC/MS/MS
NR
2-4pg/g
72% Lawrence el al 1985
NR Ryan el al I985a
"HRGC - High-resolution gas chromalography, HRMS - high-resolution mass apcclromelry. NICI/MS - negative ion chemical lomzalion mass speclromelry,
NIEC/MS - negative ion electron impact mass spectrometry. SIM - selective ion monitoring. MS - mass ipectrometry. GC - gas chromatography. FID - flame
lomzation detector; LRMS - low-resolution mass speclrometry. EC - electron capture detector; NR - not reported. NA - not applicable
I
O
to
3:
n
-------
Table 8.2. Aoalyl
«hoda for Mosaedical samples
Sample niftlru
Adipose tissue
Sample preparation
Detection limit
Analytical method" (pg/g)
Accuracy/
% Recovery"
References
Sapomficalion with hoi alkali, solvcbt
eitraclion, cleaned with concentrated
HjSO,. alumina
Extraction with potassium oxalate and
mixture of solvents, cleaned by gel
Acidic digestion, solvent extraction
multiple cleanups with adsorbents and
chemically modified adsorbents.
normal- and reverse-phase HPLC
Tissue solvent extracted and subjected
to eight different preparations
Cleaned through potassium silicate/
silica gel. carbon. H^./silica
and alumina
Washed with concentrated H,SO4 and
passed through silica, chemically
treated silica, alumina, reverse- and
normal-phase HPLC
Digested in concentrated HCI and
cleaned up by silica/H]SO,. alumina.
carbon/celite
Saponified with alkali, solvent
extracted, and cleaned up by alumina.
charcoal/silica
Saponified with alkali, solvent
extracted, washed with concentrated
H,SO4. and chromalographed on silica
acid and alumina
Washed with H,SO, and chromalographed
on Florisil
Washed with H,SO4, chromatographcd on
alumina, charcoal/celite, alumina
HRGC/HRMSand 0 1-0.6. 05-6
LRGC/HRMS
HRGC/LRMS
LRGC/LRMS
HRGC/LRMS
HRGC/LRMS
HRGC/LRMS
HRGC/LRMS
HRGC/HRMS
HRGC/CIMS
HRGC/HRMS
5 (fat basis)
05
-------
Table 8.2 (i
Sample matrix
Adipose luiue
Sample preparation
Paued through ulica/potaMium silicate,
Analytical method"
HRGC/NICI/MS
Detection limit
(Pg/g)
Accuracy/
% Recovery"
90%
References
Blood, liver, kidney
and muscle
Serum
ilka/carbon, potassium silicate/
H]SO,/«lKa and alumina
Automated extraction and enrichment HRGC/MS or <2
apparatus consisting of solvent ex- HRGC/HRMS
traction, cleanup by carbon and
silicate/silica gel
Homogenized sample solvent extracted. HRGC/MS/MS 1-4
cleaned up with HjSO,, chromatography.
or Ftonsil
Solvent extraction, concentrated Isoiopic I 25 X 10'
sulfuric acid wash and cleanup by dilution with
carbon and silicate/silica gel. followed HRGC/HRMS
by silicate/H,SO./silica gel and
alumina columns
>8S% at 24 pg/g
(internal standard)
NR
69% at I 2 pg/g
(external standard)
Lapeza et al 1986.
Patterson et al I987a
Ryan el al I985b.c
Patterson el al I987b
"HRGC High-resolution gas chromatography. LRGC low-resolution gas chromalography. NICI/MS negative :or. chemicai lunnaiion mass
spectrometry. HRMS high-rssoluticn mass spectrumeiry, MS mass speclrometry. LRMS low-resolution mass spcctromelry. CIMS chemical
lomzation mats speciromelry; NR - not reported
n
to
3:
n
3-
o
CL
bi
-------
93
9. REGULATORY AND ADVISORY STATUS
9.1 INTERNATIONAL
No World Health Organization standards were found. The World Health
Organization advisory developed by IARC is presented below.
9.2 NATIONAL
9.2.1 Regulat ions
The reportable quantity (RQ) for 2,3,7,8-TCDD is 1 Ib, which places
2,3,7,8-TCDD in category X (EPA 1985c). EPA (1985d) has listed under
RCRA wastes containing dioxins as acute hazardous wastes, defined as
"wastes that are so hazardous that they may, either through acute or
chronic exposure, cause or significantly contribute to an increase in
serious irreversible, or incapacitating reversible illness regardless of
how they are managed." In addition, EPA (1986b) has prohibited,
effective November 8, 1986, further land disposal of certain dioxin-
containing hazardous wastes.
9.2.2 Advisory Guidance
9.2.2.1 Air
No health advisories (HAs) for levels of 2,3,7,8-TCDD in air were
encountered.
9.2.2.2 Water
AGENCY ADVISORY
EPA Drinking water advisories:
1-day HA--1.0 x 10'6 mg/L (child)
10-day HA--1.0 x 10'7 mg/L (child)
Long-term HA--1.0 x 10'8 mg/L (child)
Long-term HA--3.5 x 10'8 mg/L (adult)
Drinking water equivalent level--3.5 x 10'8 mg/L
10'4 to 10'7 excess cancer risk--2.2 x 10'8 to 2.2 x 10'11
mg/L (EPA 1986c)
EPA Ambient water quality criteria
10'4 to 10'7 excess cancer risk--1.3 x 10'9 to 1.3 x 10'1Z mg/L
(EPA 1984)
-------
94 Section 9
9.2.2.3 Food
AGENCY ADVISORY
FDA Levels in fish: No serious health concerns--<25 ppt (EPA 1985b)
NIOSH 2.3,7.8-TCDD is regarded as a potential occupational carcinogen,
and occupational exposure to 2,3,7,8-TCDD should be controlled
to the fullest extent feasible (NIOSH 1984).
9.2.3 Data Analysis
9.2.3.1 Reference doses (RfDs)
EPA (1985a) calculated a chronic oral RfD for 2,3,7,8-TCDD based on
the data from a three-generation study in rats by Murray et al. (1979),
as reanalyzed by Nisbet and Paxton (1982). In this study, rats were
exposed to diets containing 2,3,7,8-TCDD at levels that provided doses
of 0.001, 0.01, and 0.1 ^g/kg/day. The highest dose resulted in
decreased fetal survival; the middle dose resulted in effects on litter
size and fetal and neonatal survival. The lowest dose resulted in
dilated renal pelvises, decreased fetal weight, and changes in the
gestational index. Therefore, the dose of 0.001 ;*gAg/day is a LOAEL,
and the RfD was calculated as follows:
RfD - (0.001 j*gAg/day)/(100)(10) - 0.000001 MgAg/day ,
where: 0.001 /igAg/day - LOAEL,
100 - uncertainty factor for inter- and intraspecies
extrapolation,
10 - uncertainty factor for use of a LOAEL.
9.2.3.2 Carcinogenic potency, q *
EPA (1985b) has classified 2,3,7,8-TCDD in Group B2 when 2,3,7,8-
TCDD is considered alone, and in Group Bl when 2,3,7,8-TCDD is
considered in association with phenoxyherbicides and/or chlorophenols.
Group B2 indicates chat although evidence in humans is. inadequate, there
are sufficient animal carcinogenicity data to consider 2,3,7,8-TCDD a
probable human carcinogen. Group Bl indicates that there are not only
sufficient animal data but also limited human data to support the
consideration that 2,3,7,8-TCDD, in conjunction with phenoxyherbicides
and/or chlorophenols, is a human carcinogen. IARC (1982) has classified
2,3,7,8-TCDD in Group 2B, which is analogous to the EPA classification
of Group B2. NIOSH (1984) recommended that 2,3,7,8-TCDD be considered a
potential occupational carcinogen and that exposure be limited to the
fullest extent feasible.
EPA (198Sa) developed a quantitative unit cancer risk estimate
based on the study by Kociba et al. (1978a,b) and a reexamination of the
histologic evidence from that study conducted by Squire for the EPA. The
calculations were based on the increased incidence of tumors of the
lungs, liver, hard palate, and nasal turbinates in female rats
maintained on diets containing 2,3,7,8-TCDD for 2 years. The two
-------
Regulatory and Advisory Status 95
different pathologic examinations produced differences in tumor
incidence and, hence, slightly different q^* values. The final value
derived, 1.56 x 105 (mgAg/day) "1, was an average based on separate
calculations of the q.* values. EPA is in the process of considering a
revision in the risk estimate for 2,3,7,8-TCDD (EPA 1988a) .
9.2.3.3 Carcinogenic potency, methods used by other agencies
Both the Centers for Disease Control (CDC) (Kimbrough et al. 1984)
and the Food and Drug Administration (FDA 1983) have calculated a
virtual safe dose for 2,3,7,8-TCDD, which corresponds to an excess
cancer risk of 10'^. The FDA calculations were based on the Kociba et
al. (1978a,b) study, whereas the CDC calculations were based on the
Squire evaluation of the Kociba et al. (1978a,b) study. Thus, human
intake values that correspond to an estimated 10'6 risk derived by EPA,
CDC, and FDA, respectively, are 6.4, 27.6, and 57.2 fgAg/day. EPA is in
the process of considering a revision in the risk estimate for 2,3,7,8-
TCDD (EPA 1988a).
9.3 STATE
Regulations and advisory guidance from the states were not
available.
-------
97
10. REFERENCES
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-------
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-------
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-------
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125
11. GLOSSARY
Acute Exposure--Exposure Co a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Bioconcentration Factor (BCF)--The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.
Carcinogen--A chemical capable of inducing cancer.
Ceiling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously. .
Chronic Exposure--Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.
Developmental Toxicity--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnataliy
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxlcity and Fetotoxicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
Frank Effect Level (FEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
EPA Health Advisory--An estimate of acceptable drinking water levels for
a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH)--The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-impairing symptoms or irreversible
health effects.
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126 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Imnunologic Tozi'city--The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro--Isolated from the living organism and artificially maintained,
as in a test tube.
In vivo--Occurring within the living organism.
Key Study--An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentration(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(SO) (LCso)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(SQ) (LDSO)--The dose of a chemical which has been calculated
to cause death in 50% of a defined experimental animal population.
Lovest-Observed-Adverse-Effect Level (LOAEL)--The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
Lovest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
Malformations--Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level--An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen--A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
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Glossary 127
Neurotoxicity--The occurrence of adverse effects on the nervous system
following exposure to a chemical.
No-Observed-Adverse-Effect Level (NOAEL)--That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
No-Observed-Effect Level (NOEL)--That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL)--An allowable exposure level in
workplace air averaged over an 8-h shift.
q.*--The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The q.* can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for
food, and pg/m3 for air).
Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ)--The quantity of a hazardous substance that is
considered reportable under CERCLA. Reportable quantities are: (1) 1 Ib
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24-h period.
Reproductive Toxicity--The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical. The
toxicity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this systea.
Short-Tern Exposure Limit (STEL)--The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
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128 Section 11
Target Organ Toxlclty--This term covers a broad range of adverse effect'
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
Teratogen--A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV)--A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA)--An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF)--A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population,
(2) the uncertainty in extrapolating animal data to the case of humans.
(3) the uncertainty in extrapolating from data obtained in a study that
is of less than lifetime exposure, and (4) the uncertainty in using
LOAEL data rather than NOAEL data. Usually each of these factors is set
equal to 10.
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129
APPENDIX: PEER REVIEW
A peer review panel was assembled for 2,3,7,8 tetrachlorodibenzo-
p-dioxin (TCDD). The panel consisted of the following members:
Dr. Herbert Cornish, University of Michigan; Dr. Shane Que Hee,
University of Cincinnati Medical Center; and Dr. James Olson, State
University of New York at Buffalo, School of Medicine. These experts
collectively have knowledge of 2,3,7,8-TCDD's physical and chemical
properties, toxicokinetics, key health end points, mechanisms of action,
human and animal exposure, and quantification of risk to humans. All
reviewers were selected in conformity with the conditions for peer
review specified in the Superfund Amendments and Reauthorization Act of
1986, Section 110.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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