EPA-540/1-86-044
Environmental Protection
Agency
Office of Emergency and
Remedial Response
Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
Superfund
c/EPA
HEALTH EFFECTS ASSESSMENT
FOR 2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN
Col.ect.on.
U.S.. Environmental ^hrotectton Agency
Region V, Library
230 South Dearborn StarJet
Chicago, Illinois 60604
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EPA/540/1-86-044
September 1984
HEALTH EFFECTS ASSESSMENT
FOR 2.3,7,8-TETRACHLORODIBENZO-E-DIOXIN
U.S. Environmental Protection Agency
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Cincinnati, OH 45268
U.S. Environmental Protection Agency
Office of Emergency and Remedial Response
Office of Solid Waste and Emergency Response
Washington, DC 20460
-------
DISCLAIMER
This report has been funded wholly or 1n part by the United States
Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse
Research Corporation. It has been subject to the Agency's peer and adminis-
trative review, and 1t has been approved for publication as an EPA document.
Mention of trade names or commercial products does not constitute endorse-
ment or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with 2,3,7,8-
tetrachlorod1benzo-p_-d1ox1n (2,3,7,8-TCDO). All estimates of acceptable
Intakes and carcinogenic potency presented 1n this document should be con-
sidered as preliminary and reflect limited resources allocated to this
project. Pertinent toxlcologlc and environmental data were located through
on-Hne literature searches of the Chemical Abstracts, TOXLINE, CANCERLINE
and the CHEMFATE/DATALOG data bases. The basic literature searched sup-
porting this document 1s current up to September, 1984. Secondary sources
of Information have also been relied upon 1n the preparation of this report
and represent large-scale health assessment efforts that entail extensive
peer and Agency review. The following Office of Health and Environmental
Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1983b. Review of Toxlcologlc Data In Support of Evalua-
tion for Carcinogenic Potential of 2,3,7,8-TCDD. Prepared by the
Carcinogen Assessment Group, OHEA for the Office of Solid Waste and
Emergency Response, Washington, DC.
U.S. EPA. 1984a. Health Assessment Document for PolychloMnated
D1benzo-p-D1ox1ns. Environmental Criteria and Assessment Office,
Cincinnati, OH. EPA 600/8-84-014A. NITS PB 84-220268.
U.S. EPA. 1984b. Ambient Water Quality Criteria for 2.3,7,8-
Tetrachlorod1benzo-p-d1ox1n. Environmental Criteria and Assessment
Office, Cincinnati, OH. EPA 440/5-80-072.
U.S. EPA! 1985. Drinking Water Criteria Document on 2,3,7,8-
Tetrachlorod1benzo-£-d1ox1n. Prepared by the -Environmental Cri-
teria and Assessment Office, Cincinnati, OH, OHEA for the Office of
Drinking Water, Washington, DC. (Final draft)
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates. Never-
theless, the Interim values presented reflect the relative degree of hazard
associated with exposure or risk to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for sys-
temic toxicants (toxicants for which cancer 1s not the endpolnt of concern).
The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval (I.e., for an Interval that
does not constitute a significant portion of the Hfespan). This type of
exposure estimate has not been extensively used or rigorously defined, as
previous risk assessment efforts have been primarily directed towards
exposures from toxicants 1n ambient air or water where .lifetime exposure Is
111
-------
assumed. Animal data used for AIS estimates generally Include exposures
with durations of 30-90 days. Subchronlc human data are rarely available.
Reported exposures are usually from chronic occupational exposure situations
or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, 1s similar 1n concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980) for a discussion of
this concept]. The AIC 1s route specific and estimates acceptable exposure
for a given route with the Implicit assumption that exposure by other routes
1s Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development 1s explained 1n U.S. EPA (1983).
For compounds for which there 1s sufficient evidence of carclnogenlcHy,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. Jor carcinogens, q-|*s have been computed based on oral
and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
2,3,7,8-TCDD has been shown to be carcinogenic In many Independent
rodent bloassays with oral exposure resulting In Increases In Incidence of a
variety of tumor types. Results of in vU.ro mutagenldty tests have been
mixed. Human exposure data suggest a link between 2,3,7,8-TCDD exposure and
Increased cancer Incidence, but are Inadequate for quantitative risk assess-
ment. Using data for tumor Incidence In female rats orally exposed to
2,3,7,8-TCOO, a carcinogenic potency for oral exposure to humans (q-j*) of
1.56x10* (mg/kg/day)"1 was estimated.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati. OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was ithe Project
Officer. The final documents 1n this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office *
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
ENVIRONMENTAL CHEMISTRY AND FATE ,
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . . ,
2.1.
2.2.
ORAL
INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1.
3.2.
3.3.
3.4.
SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
CHRONIC
3.2.1. Oral
3.2.2. Inhalation
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral
3.3.2. Inhalation
TOXICANT INTERACTIONS i . . .
CARCINOGENICITY
4.1.
4.2.
4.3.
4.4.
HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
OTHER RELEVANT DATA
HEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
Page
, , 1
. . 2
. . 2
. . 3
4
, . 4
, . 4
, . 4
, . 7
, . 7
, . 7
. 7
7
14
15
. 16
. 16
. 16
. 16
. 16
16
. 23
. 23
. 23
26
V11
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TABLE OF CONTENTS (cont.)
Page
6. RISK ASSESSMENT ......................... 27
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) ............ 27
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) .............. 27
6.3. CARCINOGENIC POTENCY {q} ................ 27
6.3.1. Oral ....................... 27
7. REFERENCES ....................... ..... 28
APPENDIX A: Summary Table for 2,3,7,8-TCOO .............. 47
APPENDIX B: Cancer Data Sheet for the Derivation of q^. . . ..... 47
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No.
3-1
3-2
3-3
3-4
4-1
4-2
LIST OF TABLES
Title
Effects of Subchronlc Exposure to 2,3,7,8-TCOD
Effects of Chronic Oral Exposure to 2,3,7,8-TCDD
Studies on the Potential Teratogenlc Effects of
2,3,7,8-TCDO-Contam1nated 2,4,5-T
Studies on the Potential Teratogenlc and Reproductive
Effects of 2,3,7,8-TCDD
Cardnogenlclty Bloassays of 2,3,7,8-TCOD Administration
by the Oral Route
The Results of MutagenlcHy Assays 1n
Page
5
8
9
12
17
Salmonella typhlmurlum 24
1x
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LIST OF ABBREVIATIONS
ADI
AIC
AIS
BCF
bw
CAS
CS
"50
GI
LOAEL
LOEL
MED
NOAEL
PCDD
ppb
ppm
ppt
TWA
Acceptable dally Intake
Acceptable Intake chronic
Acceptable Intake subchronlc
B1oconcentrat1on factor
Body weight
Chemical Abstract Service
Composite score
Effective dose for 50% of recipients
Gastrointestinal
Lowest-observed-adverse-effect level
Lowest-observed-effect level
Minimum effective dose
No-observed-adverse-effect level
PolychloMnated d1benzo-£-d1ox1n
Parts per billion
%
Parts per million
Parts per trillion
Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
2,3,7,8-TCDO (CAS No. 1746-01-6) are given as follows {U.S. EPA. 1984a):
Chemical class: halogenated d1benzo-p-d1ox1ns
Molecular weight: - 321.98
Vapor pressure at 25°C: 1.7xlO~« (estimated)
Water solubility (at
unspecified temperature): • 0.2 yg/l
Octanol/water partition 1.4xlO~« to 1.9xlO~7
coefficient: (estimated)
BCF: 5000
Half-lives In
A1r: unknown
Water: 1-2 years
Soil: 10-12 years .
i
No estimates of the half-life of 2,3,7,8-TCDO 1n the atmosphere are
available. Based on the available Information, photodegradatlon and wet and
•
dry deposition of particle-bound 2,3,7,8-TCDO are probably the most signifi-
cant fate-determining processes for atmospheric 2,3,7,8-TCDO (U.S. EPA,
1984a).
Based on the available data (U.S. EPA, 1984a), the possibility of verti-
cal movement of 2,3,7,8-TCDO 1n soil 1n negligible under most conditions.
Leaching of 2,3,7,8-TCDD from soil 1s possible under special conditions: for
example, from sandy soils, particularly after multiple 2,3,7,8-TCDD appli-
cation or accidental release of 2,3,7,8-TCDO on soil (U.S. EPA, 1984a).
-1-
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
The GI absorption of 2,3,7,8-TCDD 1s a function of both the dose admin-
istered and the vehicle used. Polger and Schlatter (1980) reported a linear
relationship between the dose of 2,3,7,8-TCDD and rat hepatic tissue levels
of 2,3,7,8-TCDD over the range of 0.06-1.4 yg/kg bw. The percentage of the
dose absorbed apparently decreased at doses higher than 1.4 yg/kg bw.
Rose et al. (1976) estimated that steady-state concentrations would be
reached within 13 weeks following gavage administration of 0.1-1.0 yg
2,3,7,8-TCDD/kg bw/day to rats for 5 days/week. Within the dosage range
tested, the rate constant defining the approach to steady state was Inde-
pendent of the dosage. Fries and Marrow (1975) found that 2,3,7,8-TCDD at 7
or 20 ppb 1n the diet fed to rats for 6 weeks was 50-60% absorbed. Single
or repeated (5 days/week for 7 weeks) doses given to rats by gavage In
acetone:corn oil (2:25 or 1:9) were -70-86% absorbed (Rose1 et al., 1976;
Piper et al., 1973). A similar extent of absorption was reported In
hamsters by Olson et al. (1980) who estimated absorption of a 650 yg/kg bw
dose In olive oil at 74%. In guinea pigs, absorption was estimated at 50%
[Nolan et al.. 1979 (detail of protocol not provided)]. The data for rats
suggest that a greater extent of absorption results from gavage rather than
from dietary treatment, Implying that adsorption to food particles may
Inhibit absorption. Adsorption on aqueous suspensions of soil has been
shown to markedly reduce GI absorption (Polger and Schlatter, 1980).
Replacing soil with activated charcoal nearly eliminated absorption from the
GI tract. Van der Berg et al. (1983) found lower hepatic levels of PCDD In
rats fed for 19 days with a diet containing PCDD-laden fly ash than 1n rats
fed an extract of fly ash containing PCDDs at comparable levels. The
-2-
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differences In concentrations of PCDOs 1n the liver between fly ash and
extract-fed rats were greater with the more highly chlorinated PCODs than
with 2,3,7,8-TCDO.
2.2. INHALATION
Pertinent data regarding to the absorption of 2,3,7.8-TCDD from the
respiratory tract could not be located In the available literature.
-3-
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. The subchronlc oral toxIcHy of 2,3,7,8-TCDO 1s summarized
1n Table 3-1. Two studies have Investigated the effects of very low doses
of 2,3,7,8-TCDO. Murray et al. (1979) Investigated the teratogenlc and
reproductive effects of dietary 2,3,7,8-TCDD (0, 0.001, 0.01 or 0.1 V9/kg
bw/day) In Sprague-Dawley rats. The FQ rats were maintained on the treat-
ment diets for 90 days and were then mated twice, producing the F, and
F,. generations. The F,. and F2 rats were mated at -130 days of age,
producing the F. and F» Utters, respectively. The authors reported a
NOAEL of 0.001 pg/kg bw/day for reduced fertility and fetal survival; how-
ever, Nlsbet and Paxton (1982) reanalyzed the data from this study using
different statistical techniques and concluded that a dose of 0.001 pg/kg
bw/day resulted In a significantly reduced gestatlonal Index, decreased
fetal weight, Increased I1ver-to-body-we1ght ratios and an Increased Inci-
dence of dilated renal pelvis.
Vos et al. (1973) measured the effect of eight-weekly gavage doses of
0.008, 0.04, 0.2 or 1.0 pg/kg bw/week (equivalent to 0.0011, 0.0057. 0.029
or 0.143 pg/kg bw/day) on Immune function 1n groups of 10 female Hartley
guinea pigs. Effects on humoral Immunity were measured by the response to a
subcutaneous Injection of tetanus toxold, and cell-mediated Immunity was
measured by the delayed-type hypersens1t1v1ty to Mycobacterlum tuberculosis.
The lowest dose that produced a reduction In Immune response was 0.0057
pg/kg bw/day, with a no-effect level of 0.0011 pg/kg bw/day.
3.1.2. Inhalation. No data on the subchronlc Inhalation toxldty of
2,3,7,8-TCDD were located 1n the available literature.
-4-
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TABLE 3-1
Effects of Subchronlc Oral Exposure to 2,3,7,8-TCDDa
Species
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Mouse
House
House
House
Dose
yg/kg/day
0.01
0.1
0.07
0.14
1.0
0.71
0.1
0.71
0.001
0.014
0.71
3.57
5.0
Duration
of Exposure
13 weeks
13 weeks
13 weeks
13 weeks
30 days
6 weeks
30 days
6 weeks
3 genera-
tions
13 weeks
4 weeks
4 weeks
4 weeks
Effect
Level
NOAEL
LOAEL
NOAEL
LOAEL
NOAEL
NOAEL
LOAEL
LOAEL
LOAEL0
LOAEL
NOAEL
LOAEL
LOAEL
Endpolnts
Decreased body weight
Decreased body weight
Toxic hepatitis
Toxic hepatitis
Decreased body weight
Decreased body weight
Thrombocytopenla
Decreased body weight and thymus
weight
Decreased body weight, decreased
fertility, decreased fetal sur-
vival
Toxic hepatitis
Porphyrla
Porphyrla
Decreased thymus weight and
Reference
Koclba et al., 1976
Koclba et al.. 1976
NTP, 1980
NTP. 1980
Harris et al.. 1973
Harris et al.. 1973
Zlnkl et al.. 1973
Vos et al.. 1973
Hurray et al., 1979
NTP. 1980
Goldstein et al.. 1978
Goldstein et al., 1978
Vos et al., 1973
graft-versus-host response
-------
TABLE 3-1 (cont.)
Species
Mouse
Mouse
Mouse
Guinea
pig
Guinea
pig
Dose
yg/kg/day
0.14
0.21
1.3
0.0011
0.0057
Duration
of Exposure
4 weeks
4 weeks
5 weeks
8 weeks
8 weeks
Effect
Level
LOAEL
LOAEL
LOAEL
NOAEL
LOAEL
Endpolnts Reference
Decreased resistance to Sal- Thlgpen et al., 1975
monella
Increased endotoxlc (E. coll) Vos et al.. 1978
susceptibility
Decreased tetanus response, Hlnsdtll et al., 1980
antlgenlc RBC response, sensltl-
zatlon to DNFB. resistance to
Salmonella Infection, resistance
to Llsterla Infection
Decreased body weight, thymus Vos et al., 1973
weight and tuberculin hyper sen-
sitivity
Decreased body weight, thymus Vos et al., 1973
weight and tuberculin hyper sen-
. sltlvlty
aSource: U.S EPA. 19845
bReported as NOAEL by Murray et al. 1979; considered a LOAEL by Nlsbet and Paxton (1982) during a
reevaluatlon of the data.
RBC = red blood cells; DNFB = 2,4-dlnltro, 1-fluorobenzene
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3.2. CHRONIC
3.2.1. Oral. The chronic oral toxldty of 2,3,7,8-TCDD 1s summarized In
Table 3-2. In rats, NOAELs for liver toxldty were noted at 0.001 (Kodba
et al., 1978, 1979), 0.0014 (Goldstein et al., 1982; NTP, 1980) mg/kg/day.
These levels resulted 1n evidence of liver toxldty In mice (NTP, 1980; Toth
et al., 1978, 1979). In rats, levels of 2,3,7,8-TCOO 1n the ranges of
0.007-0.71 mg/kg/day were regarded as LOAELs (Goldstein et al., 1982; King
and Roesler, 1974; Kodba et al., 1978, 1979; NTP, 1980; Cantonl et al.,
1981).
Toth et al. (1978, 1979) administered weekly doses of 0.0, 0.007, 0.7 or
7.0 yg 2,3,7,8-TCOO/kg bw/week (TWA * 0.0, 0.001, 0.1 or 1.0 vg 2,3,7,8-
TCDD/kg bw/day) to male Swiss mice by gavage for 104 weeks. Dermatitis and
amyloldosls of the kidney, spleen and liver were observed at all dose
levels. This study, therefore, establishes a LOAEL of 0.001 yg/kg bw/day.
3.2.2. Inhalation. No data pertinent to the chronic Inhalation toxldty
*
of 2,3,7,8-TCOO to experimental animals could be located 1n the available
literature. The effects of occupational and environmental exposure of
humans to 2,3,7,8-TCDD have been reported 1n a number of clinical case
studies and epidemiology studies (U.S. EPA, 1984a,b,c, 1985). The exposures
In these cases were probably predominantly by the Inhalation and dermal
routes. The major effects reported were chloracne, peripheral neuropathy,
fatigue, eye Irritation, headache, possibly Increased Incidences of birth
defects and possibly tumors. No dose-response Information was available
from any of these studies.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral.. The teratogenldty of 2,3,7,8-TCDO-contam1nated 2,4,5-T
has been studied by a number of Investigators (Table 3-3). Other Investi-
gators have studied the effects of purified 2,3,7,8-TCDD (Table 3-4).
-7-
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TABLE 3-2
Effects of Chronic Oral Exposure to 2,3,7,8-TCDD*
CO
Species
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Rat
House
House
Dose
(yg/kg/day)
0.0014
0.014
0.014
0.001
0.01
0.0014
0.007
0.71
0.0071
0.0014
0.001
Duration
of Exposure
(weeks)
16
16
28
104
104
104
104
45
45
104
104
Effect
Level
NOAEL
LOAEL
LOAEL
NOAEL
LOAEL
NOAEL
LOAEL
LOAEL
LOEL
LOAEL
LOAEL
Endpolnts
elevated porphyrin levels
elevated porphyrin levels
fatty changes In liver.
decreased body weight
degenerative and necrotlc
changes In the liver
degenerative and necrotlc
changes In the liver
toxic hepatitis
toxic hepatitis
porphyrla
hepatic enzyme Induction
toxic hepatitis
dermatitis and amyloldosls
Reference
Goldstein
Goldstein
et al.. 1982
et al.. 1982
King and Roesler,
1974
Koclba et
1979
Koclba et
1979
NTP, 1980
NTP, 1980
Canton! et
Cantonl et
NTP, 1980
Toth et al
1979
al.. 1978,
al., 1978,
al., 1981
al.. 1981
., 1978,
'Source: U.S. EPA, 1984b
-------
TABLE 3-3
Studies on the Potential Teratogentc Effects of 2,3.7,8-TCDD-ContaMlnated 2.4.S-T*
i
vO
I
Species/ Route/
Strain Vehicle
Nice/
NNRI
rape- seed
oil
rape-seed
oil
rape-seed
oil
rape-seed
oil
For* of TCDO
2.4. S-T Level
acid <0.0? pp*
(Sample A)
acid O.OSiO.02
pp*
(Sample B)
add NR
(Sample C)
butyl ester NR
Treat -
Daily *ent
Hose Days
8. IS. 30. 6-15
45, 60.90
and 120
Mg/kg
30. 60 and 6-15
90 Mg/kg
90 Mg/kg 6-H
12 and 17 6-15
Mg/kg
Obser- Maternal
vat Ion Response
Day
18 No toxic effects;
decreased Maternal
weight at doses of
90 Mg/kg and
greater
18 No toxic effects;
decreased maternal
weight at 90 Mg/kg
IB No toxic effects
but decreased
Maternal weight
18 No toxic effects
fetal Response
Significant Increases In
the Incidence of cleft
palates at doses above
30 Mg/kg (see text for
additional details). Sig-
nificantly decreased
(p<0.005) fetal weight
at all dose levels.
Increases In the Incidence
of cleft palate at 60 and
90 Mg/kg; significant
(p<0.005) at all dose
levels.
Increase In the Incidence
of cleft palate; significant
(p<0.005) decrease In fetal
weight.
Significant decrease In
fetal weight but no effect
Reference
Neubert and
DIllMan. 1972
Nice/ NR
NHftl
Nice/
CD-I
acid
0.05*0.02
PPM
20. 35. 60.
90 and 130
Mg/kg
6-1S
NR
Toxic effects
observed at 90
and 130 Mg/kg
corn oil:
acetone
(9:1)
acid
-------
TABLE 3-3 (cont.)
Species/
Strain
Mice/
CS7B1/6
Route/ for* of TCOD
Vehicle 2,4,5-T level
honey: water acid 30 ppm
(1:1)
Dally
Dose
46.4 and
Mg/kg
Treat -
•ent
Days
113 6-14
Obser- Maternal
vatton Response
Day
18 NR
Fetal Response
Significant |p<0.01)
Increases In the Incidence
of cleft palate In the high-
dose group and cysttc
kidney In both dose groups;
Increased fetal Mortality
also observed In the high-
dose group.
Reference
Courtney et.
al., 1970a,b
o
i
Mice/
AKR
Rats/
Sprague-
Davley
(groups
of 25
rats)
honey: water
(1:1)
gavage/
hydroxy-
propyl-
Methyl-
cellulose
acid
acid
30 PPM
0.5
113 Mg/kg
1. 3, 6. 12.
or 24 Mg/kg/
day
6-15
6-15
19
20
Rats/
Ulstar
gavage/
aqueous
gelatin or
corn oil
gavage/
aqueous
gelatin or
corn oil
acid
<0.5 Mg/kg
butyl ester <0.5 Mg/kg
25, 50. 100.
or 150 Mg/kg/
day
50 or 150
•g/kg/day
tf-15
22
6-15
22
Increase In llver-
to-body-uelght
ratio.
No effect on body
weight and no
observable signs
of toxlctty.
Some Maternal
Mortality and
decreased body
weight gain at 150
•g/kg; no signs of
toxlclty at 100
Mg/kg or below.
NR
Significant (p<0.05)
Increases In the Incidence
of cleft palate and fetal
Mortality
A slight but statistically
significant (p<0.05)
decrease In iMplantatlons
and Utter size In lowest
dose group only; no frank
teralogenlc effects based
on a detailed examination
of the control and 24 mq/
kg dose group; the only
effect noted was an In-
crease In the Incidence of
5th partially ossified
sternebrae.
At 100 or 150 Mg/kg.
decreased fetal weight.
Increased fetal Mortality
and an Increase of skel-
etal anomalies; no signi-
ficant effect at the two
lower dose levels.
No significant effect on
fetal Morality, fetal
weight, or the Incidence
of anomalies.
Courtney et.
al.. 1970a,b
EMerson et
al. 1970, 1971
N.B. This
appears to be
a full publi-
cation of the
abstract SUM-
Mary by
Thompson et
al.. 1971
Khera and
HcKtnley.
1972;
Khera et al..
1971
Khera and
McKlnley.
1972;
Khera et al..
1971
-------
1ABLE 3-3 (cont.)
Species/
Strain
Rats/
Holtzman
Rats/
CD
Route/ For* of TCDD
Vehicle 2.4.5-T Level
gav age/ add 30 ppm
1:1 solu-
tion of
honey and
water
gavage/ acid 0.5 ppn
15X sucrose
solution
Treat-
Dally >ent
Dose Days
4.6. 10.0 10-15
and 46.4
Mg/kg/day
10.0. 21.5. 6-15
46.4 and
80.0 Kg/kg/
day
Obser- Maternal
vat Ion Response
Day
20 NR
*•
20 Reduced Mternal
weight gain at the
2 higher dose
levels (p<0.05)
Fetal Response
Significant (p<0.01)
Increases In fetal Mor-
tality at the 2 higher
dose levels; dose-related
Increases In the percent
of abnormal fetuses per
litter; a high Incidence
of cystic kidneys In
treated groups.
Increase In the Incidence
of kidney anomalies but
no Increase In cleft
palate.
Reference
Courtney et
al.. 1970a.b
Courtney and
Moore 1971
Rats/ gavage/
Sprague- nethocel-
Dawley lulose
acid
0.5 ppM
50 Mg/kg
6-15
NS
and Increased
1 tver-to-body-
weight ratio at
the highest dose
level (p<0.05)
No effect on Mor-
tality or body
weight gain.
No significant effect on
fetal Mortality or fetal
weight; a significant
(p<0.05) Increase In the
Incidence of delayed
ossification.
'Source: U.S. EPA. 19B5
NS = Not specified; NR « not reported
Sparschu et
al.. 1971a
Syrian
ham-
sters/
Heso-
crlcetus
euratus
gavage/ acid
Methocel-
lulose
„
gavage/ acid
acetone.
corn oil,
and car-
boxymethyl
cellulose
In ratio
of 1:5.8:10
0.5 ppM 100 Mg/kg 6-10 NS
•
<0.1-4.5 20. 40. 80 6-10 14
ppM and 100
Mg/kg
Increased Mor-
tality and
decreased body
weight gain.
NS
•
Increase In the Incidence
of delayed ossification
and poorly ossified or
Malallgned sternebrae
(p<0.05)
Dose-related Increases In
fetal Mortality, gastro-
intestinal hemorrhages.
and fetal abnormal 1 ties
Sparschu et
al.. 1971a
Collins et
al.. 1971
-------
TABIE 3-4
Studies on the Potential TeratogenU and Reproductive Effects of 2.3.7.8-TCDDa
Species/Strain
Nouse/C57Bl/6
Nouse/AKR
House/CD-I
House/DBA/2J
Nouse/C57Bl/6J
Nouse/C57Bl/6
Nouse/CD-1
Nouse/CF-1
Nouse/NNRI
Rat/CD
Rat/Sprague-
Dawley
Vehicle
DNSO or
honey: water
(1:1)
DNSO
acetone:
corn oil
(1:9)
DNSO or
corn oil
corn oil:
acetone
(98:2)
rape -seed
oil
DNSO
corn oil/
acetone
Compound
2,4.5-T
containing
30 ppm TCDO
2,3.7.8-TCDD
2.3.7.8-TCDD
2.3.7.8-TCDD
2.3.7.8-TCOD
2.3.7.8-TCOD
2.3.7.B-TCDD
2.3.7.8-TCOD
Dally Dose
21.5. 46.4.
113.0 mg/kg
0.5, 1,
1, 3 tig/kg
25. 50. 100.
200. 400 ug/kg
0.001. 0.01.
0.1. 1.0.
3.0 yg/kg
0.3. 3.0. 4.5.
9.0 |ig/kg
0, 0.5,
2.0 ug/kg
0, 0.03.
0.125. 0.5.
2.0. and
8.0 tig/kg
Treatment
Days
6-14 or
9-17
. 6-15
10-13 or
10
7-16
6-15
'
6-15
ff
6-15.
9 and 10.
or 13 and
14
6-15
Observation
Day
19b
17b or 18
18°
18d
18°
18
20°
-
20b
Haternal Response
Increased llver-to-
body-welght ratio
Increased Itver-to-
body-welght ratio
None reported
Increased llver-to-
body -weight ratio
None reported
No effect observed
None reported
•
Vaginal hemorrhage
at 2.0 and
8.0 yg/kg
Fetal Response
Fetal death, cleft
palate, cystic
kidney
Cleft palate.
kidney anoma11esc
Cleft palate.
kidney anomallesc
Cleft palate.
hydronephrottc
kidneys, hydro-
cephalus, open
eyes, edema.
petechlae
Cleft palate.
dilated renal
pelvis
Fetocldal at the
high dose; cleft
palate at doses
at or above
4.5 yg/kg
Kidney malforma-
tions at both
dose levels
Intestinal
hemorrhage at
0.125 and
0.5 tig/kg;
fetal death at
higher doses;
subcutaneous
edema
Reference
Courtney et al..
1970a.b
Courtney and
Hoore. 1971
Noore et al.,
1973
Courtney, 1976
Smith et al..
1976
Neubert and
Dlllman. 1972
Courtney and
Noore, 1971
Sparschu et
al.. 19715
-------
TABLE 34 (cont.)
CJ
i
Species/Strain Vehicle
Rat/Ulstar corn oil/
antsole
ftat/Sprague- corn oil/
Dawley acetone
(9:1)
Rat/Sprague- diet
Day ley
Rabbit/ corn oil/
New Zealand acetone
(9:1)
Monkey/rhesus diet
-
Monkey/rhesus diet
Compound Dally Dose
2.3,7.8-TCOD 0.0. 0.125.
0.25. 1. 2. 4,
a. 16 wg/kg
2,3.7.8-TCDD 0.1. 0.5.
2.0 w9/kg
2.3.7.8-TCDD 0.001. 0.01
and 0.1
ng/kg*
2.3.7.B-TCDD 0.0. 0.1.
0.25. 0.5
and 1 |ig/kg
2.3.7.8-TCOO 8.6 pg/kg/day
2.3.1.B-TCOD 55.7 pg/kg/day
Treatment Observation
Days Day
6-15 22
1-3 21
throughout post-parturt-
gestatlon tlon
6-15 28
f Months at tern
prior to
and during
gestation
7 Months at tern
prior to +.
and during
gestation
Maternal Response
Maternal toxtclty
observed at or
above 1 tig/kg
Decrease In body .
weight gain In the
high-dose group
Low fertility at
0.01 and 0.1 ng/kg;
decreased body
weight at 0.01
and 0.1 wg/kg;
dilated renal
pelvis
Maternal toxlclty
at doses of 0.25
wg/kg and above
6/8 conceived; nor-
mal sertm estradlol
and progesterone
3/8 conceived; de-
creased serum estra-
dlol and progester-
one
Fetal Response
Increased fetal
death observed at
or above 1 wg/kg;
subcutaneous edema
and hemorrhages In
the 0.25 wg/kg
groups
Decreased fetal
weight In the 0.5
and 2 pg/kg group;
cystic kidneys and
dilated renal pel-
vis occurred In the
2 wg/kg group
Low survival at
0.01 and 0.1 w9/kg;
decreased body
weight at 0.01
slight dilated
renal pelvis at
0.001 wg/kg
Increases In extra
ribs and total soft
tissue anomalies
3/8 normal births
1/8 normal births
Reference
Khera and
Ruddlck. 1973
Glavlnl et al..
19824
Murray et al..
1979
Glavlnl et al..
1982b
Allen et al..
1979
Allen et al.,
1979
'Source: U.S. fPA. 1985
First day of gestation designated day 0.
cKldney anomalies were not specifically defined.
First day of gestation designated day 1.
elhe high dose level (0.1 vg/kg/day) was discontinued due to very low fertility In adults.
DHSO -- dimethyl sulfoxlde
-------
Neubert and Olllmann {1972} reported an ED5Q of 4.6 yg 2,3,7,8-TCDO/kg
bw for the production of cleft palate 1n mice. Smith et al. (1976) reported
a minimum effective oral dose of 1.0 wg 2,3,7,8-TCDD/kg bw/day for the
production of teratogenlc effects 1n CF-1 mice. Rats are less sensitive to
the teratogenlc effects of 2,3,7,8-TCDD; however, significant fetotoxlc
effects have been observed at doses of 1.0 yg/kg bw/day and higher
(G1av1n1 et al., 1982a, 1983; Khera and Ruddlck, 1973; Khera et al., 1971;
Khera and HcKlnley, 1972).
The teratogenlc and reproductive effects of low doses of 2,3,7,8-TCDD
have been Investigated In a 3-generatlon reproduction study using 16 male
and 32 female Sprague-Dawley rats/generation (Murray et al., 1979). The
authors concluded that doses of 0.01 or 0.1 vg 2,3,7,8-TCDD/kg bw/day
resulted 1n decreased fertility, decreased litter size and decreased fetal
survival, and that 0.001 v9 2,3,7,8-TCDO/kg bw/day was a NOEL. Nlsbet and
Paxton (1982) reanalyzed these data using different statistical methods;
they concluded that a dose of 0.001 vg 2.3,7,8-TCOD/kg bw/day signifi-
cantly reduced the gestatlonal Index and fetal wefghts, and Increased the
I1ver-to-body-we1ght ratios and the Incidence of dilated renal pelvis.
3.3.2. Inhalation.. Pertinent data regarding the teratogenlclty or other
reproductive effects of Inhalation exposure to 2,3,7,8-TCDD 1n experimental
•
animals could not be located In the available literature. Several Investi-
gators have studied the Incidence of birth defects In areas where 2,3,7,8-
TCDD has been accidentally released or 2,3,7,8-TCDD-contam1nated 2,4,5-T had
been sprayed (U.S. EPA, 1979; Hanlfy et al., 1981; Field and Kerr, 1979;
Nelson et al., 1979; Thomas, 1980; Department of Health, New Zealand, 1980;
McQueen et al., 1977; Aldred, 1978; Townsend et al., 1982; Bonaccorsl et
al., 1978; Blsantl et al., 1980; Regglanl, 1980). The -Individuals In these
-14-
-------
studies were probably exposed by a variety of routes (Inhalation, dermal,
oral). Even 1n those studies In which a positive correlation between expo-
sure and birth defects or abortions was found, 2,3,7,8-TCDD could not be
unequivocally Identified as the causative agent.
3.4. TOXICANT INTERACTIONS
2,3,7,8-TCDO 1s a potent enzyme Inducer and, as such, may Interact with
a wide range of xenoblotlcs. These Interactions can result In either
Inhibition or potentlatlon of the biological effects of the compounds that
are substrates for these enzymes. Thus. 2,3,7,8-TCDD pretreatment alters
the metabolism and reduces the carcinogenic potency of benzo[a]pyrene
(BoobIs and Nebert, 1976; Berry et al., 1976; Uotlla et al., 1978).
2,3,7,8-TCDD pretreatment has also been demonstrated to alter the metabolism
of aflatoxln B, (Gurtoo, 1980); nitrosamlnes (ScarpelH et al., 1980),
N-2-fluor1nylacetam1de (DIGIovannl et al., 1979). 3,4-d1am1n1sole (Reddy et
al., 1980) and 7,12-d1methylbenz[a]-anthracene (DIGIovannl et al., 1979).
Pretreatment with 2,3,7,8-TCDD also significantly alters the effects of the
anesthetics zoxazolamlne and hexabarbltone In rats (G/e1g, 1972).
-15-
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding the oral cardnogenlcHy of
2,3,7,8-TCOO 1n humans could not be located In the available literature.
4.1.2. Inhalation. Several Investigators have reported a possible link
between occupational or environmental exposure to 2.3.7,8-TCOO and the
development of tumors, mostly soft tissue sarcomas, lymphomas and stomach
carcinomas (Holden, 1979; Cook et al., 1980; Moses and Sellkoff, 1981;
Honchar and Halpern, 1981; Cook, 1981; Thless and Frentzel-Beyme, 1977;
Axelson and Sandell, 1974; Harden, 1977; Axelson et al., 1979; Harden and
Sandstrom, 1979; R11h1make et al., 1980; Axelson et al., 1980; Eriksson et
al., 1981; Hardell . et al., 1981). The routes of exposure were probably
mixed, but dermal and Inhalation exposure would be expected to be the most
common. Although the data are suggestive, the variety of compounds these
populations were exposed to (short follow-up periods, selfi-selectlon and
reliance on patients' recall to determine exposure and personal histories)
limit the ability of these studies to link exposure, to 2,3,7,8-TCDO unequi-
vocally with Induction of tumors 1n humans.
4.2. BIOASSAYS
4.2.1. Oral. The available data on the cardnogenlcHy of orally admin-
istered 2,3,7,8-TCDO are summarized 1n Table 4-1. Oral administration of
2,3,7,8-TCDD results 1n the Induction of hepatocellular carcinoma 1n both
sexes of mice and 1n female rats (Koclba et al., 1978; NTP, 1980; Toth et
al., 1979), squamous cell carcinomas of the hard palate In both sexes of
rats (Koclba et al., 1978), and folllcular-cell adenomas of the thyroid 1n
male rats and female mice (NTP, 1980). The studies of Toth et al. (1979)
and Van Miller et al. (l977a,b) are of limited value for risk assessment
-16-
-------
TABLE 4-1
Carclnogentclty Bloassays of 2.3,7.8-TCDD Administration by the Oral Route'
Dose
Exposure Species/ Sex or
Route Strain Exposure
Gavage rats/ N 0.0 pg/kg/week
Osborne-
Nendel
0.01 vg/kg/week
0.05 v9/kg/ueek
0.5 pg/kg/week
i
-J Gavage rats/ F 0.0 pg/kg/week
1 Osborne-
Nendel
0.01 vg/kg/week
0.05 v9/kg/week
.
0.5 vQ/kg/week
Duration
of
Treatment
104
weeks
104
weeks
104
weeks
104
weeks
104
weeks
104
weeks
104
weeks
104
weeks
Duration
of
Study
105
weeks
107
weeks
107
weeks
107
weeks
105
weeks
107
weeks
,
107
weeks
107
weeks
Vehicle
corn oil-
acetone
(9:1)
corn otl-
acetone
(9:1)
corn oil-
acetone
(9:1)
corn oil-
acetone
(9:1)
corn oil-
acetone
(9:1)
corn oil-
acetone
(9:1)
corn oil-
acetone
(9:1)
corn oil-
acetone
(9:1)
Tumor Type
folllcular-cell adenomas
of the thyroid,
carcinoma of the thyroid
folllcular-cell adenomas
of the thyroid.
carcinoma of the thyroid
folllcular-cell adenomas
of the thyroid.
carcinoma of the thyroid
folllcular-cell adenomas
of the thyroid.
carcinoma of the thyroid
neoplastlc nodules of
the liver.
hepatocellular carcinoma
of the liver
neoplastlc nodules of
the liver.
hepatocellular carcinoma
of the liver
neoplastlc nodules of
the liver.
hepatocellular carcinoma
of the liver
neoplastlc nodules of
the liver,
hepatocellular carcinoma
Tumor p
Incidence Value
1/69 .0.006
0/69
5/48 .0.042
0/48
6/50 .0.021
2/50
0/50 .0.001
1/50
5/75 <0.001
0/75
1/49 NS
0/49
3/50 NS
0/50
12/49 .0.006
3/49
Reference
NTP. 1980
NTP. 1980
of the liver
-------
TABLE 4-1 (cont.)
CO
i
Exposure Species/ Sex
Route Strain
Gavage mice/ N
B6C3F |
Gavage mice/ F
B6C3F)
-
Oral rat/ N
Sprague-
Oawley
Dose
or
Exposure
0.0 tig/kg/week
0.01 wg/kg/week
0.05 tig/kg/week
0.5 |ig/kg/week
0.0 |ig/kg/week
0.04 ng/kg/week
0.2 yg/kg/weefc
2.0 yg/kg/week
0.0 ppb
0.001 ppb
Duration
of
Treatment
104
weeks
104
weeks
104
weeks
104
weeks
104
weeks
104
weeks
104
weeks
104
weeks
78
weeks
78
weeks
Our at Ion
of
Study
10S
weeks
107
weeks
107
weeks
107
weeks
10S
weeks
107
weeks
107
weeks
107
weeks
95
weeks
95
weeks
Vehicle
corn oil-
acetone
(9:1)
corn oil-
acetone
(9:1)
corn oll-
acetone
corn oil-
acetone
(9:1)
corn oil-
acetone
(9:1)
corn oil-
acetone
(9:1)
corn otl-
acetone
(9:1)
corn oil-
acetone
(9:1)
In diet
In diet
Tumor Type
hepatocellular carcinoma
hepatocellular carcinoma
hepatocellular carcinoma
hepatocellular carcinoma
hepatocellular carcinoma.
foil Icular-cell adenomas
of the thyroid
hepatocellular carcinoma.
foil Icular-cell adenomas
of the thyroid
hepatocellular carcinoma.
foil tcular-cell adenomas
of the thyroid
hepatocellular carcinoma.
foil tcular-cell adenomas
of the thyroid
all tumors0
all tumors0
Tumor
Incidence
8/73
9/49
8/49
17/50
1/73
0/69
2/50
3/50
2/48
1/47
6/47
5/46
0/10
0/10
P
Value
.0.002
NS
NS
.0.002
.0.008
.0.016
NS
NS
NS
NS
.0.014
-0.009
NR
NR
Reference
NTP. 1980
NIP. 1980
Van Killer
et al..
1977a.b
-------
TABLE 4-1 (cont.)
Dose Duration
Exposure Species/ Sex or of
Route Strain Exposure Treatment
Oral O.OOS ppb 78
(cont.) weeks
O.OS ppb 78
weeks
0.5 ppb 78
weeks
1.0 ppb 78
weeks
S.O ppb 78
weeks
Oral rat/ N 0.0 tig/kg/day 105
, Sprague- • weeks
— • Dawley
\o
i
0.001 ug/kg/day 105
weeks
N 0.01 vg/kg/day 105
weeks
0.1 pg/kg/day 105
weeks
1
Duration
of
Study
95
weeks
95
weeks
95
weeks
95
weeks
95
weeks
10S
weeks
105
weeks
t
105
weeks
105
weeks
Vehicle
In diet
In diet
In diet
In diet
In diet
In diet
In diet
In diet
_
In diet
Tumor Type
all tiN»rsb
all tumors"
all tunorsb
all tumor sb
all tutor sb
squamous cell carcinoma
of the hard palate.
squamous cell carcinoma
of the tongue.
adenoma of the adrenal
cortex
squamous cell carcinoma
of the hard palate.
squamous cell carcinoma
of the tongue.
adenoma of the adrenal
cortex
squamous cell carcinoma
of the hard palate.
squamous cell carcinoma
of the tongue.
adenoma of the adrenal
cortex
squamous cell carcinoma
of the hard palate.
squamous cell carcinoma
of the tongue.
adenoma of the adrenal
cortex
Tumor
Incidence
5/10
3/10
4/10
4/10
7/10
0/85
0/8,5
0/85
0/50
I/SO
0/50
0/50
1/50
2/SO
4/50
3/50
5/50
P
Value
NR
NR
NR
NR
NR
NS
NS
NS
NS
NS
NS
NS
NS
NS
<0.05
<0.05
<0.05
Reference
Van Miller
et al..
1977a.b
Koclba et
al.. 1978
-------
TABU 4-1 (cont.)
i
r\>
O
Exposure Species/ Sex
Route Strain
Oral rat/ F
Sprague-
Oawley
F
Gavage Mice/ N
SwIss/H/
Rtop
•
Dose
or
E xposure
0.0 |ig/kg/day
0.001 tig/kg/day
0.01 yg/kg/day
0.1 |ig/kg/day
0.0 tig/kg/week
0.007 yg/kg/week
0.7 ng/kg/week
7.0 ug/kg/week
Duration
of
Treat went
10S
weeks
105
weeks
IDS
weeks
10S
weeks
365
days
365
days
365
days
365
days
Duration
of
Study
105
weeks
105
weeks
105
weeks
105
weeks
568
days
•
649
days
633
days
424
days
Vehicle
In diet
In diet
In diet
In diet
sunflower
oil
sunflower
oil
sunflower
oil
sunflower
oil
TiMor Type
nepatocellular carclnoM,
squamous cell carclnoaa
of the tongue.
squamous cell carcinoma
of the lung
hepatocellular carcinoma.
squamous celt carcinoma
of the tongue.
squamous cell carcinoma
of the lung
hepatocellular carclnona.
squanous cell carcinoma
of the tongue.
squamous cell carcinoma
of the lung
hepatocellular carcinoma.
squamous cell carcinoma
of the tongue.
squamous cell carcinoma
of the lung
liver tumor ic
liver tumors'
liver tumors'
liver tumors'
Tumor
Incidence
0/86
0/86
0/86
0/50
0/50
0/50
i
2/50
1/50
0/50
11/49
4/49
7/49
7/38
13/44
21/44
13/43
P
Value
NS
NS
NS
NS
NS
NS
NS
NS
NS
<0.05
<0.05
<0.05
NS
NS
<0.01
NS
Reference
Koctba et
al.. 1978
Toth et
al.. 1979
-------
TABLE 4-1 (conl.)
Exposure Species/
Route Strain
Oral alee/
Peromyscus
pollonotu*
Sex
H
and
t
Dose
or
Exposure
0.0012 pg/kg/day
0.0 tig/kg/day
Duration
of
Treatment
NA
NA
Duration
of Vehicle
Study
NA contami-
nated soil
NA contami-
nated soil
Tumor Type Tumor
Incidence
liver 0/15
liver 0/15
P
Value
NS
NS
Reference
Cocker ham
et al..
1180
'Source: U.S. EPA. 1985
bNo single target organ for cancer was outstanding.
cIncludes hepatomas and hepatocellular carcinomas.
NR . Not reported; NS . not significant
i
IV)
-------
purposes because of the relatively short exposure times and small group
sizes or both. The study 1n beach mice (Peromyscus pollontus) by Cockerham
et al. (1980) was reported 1n Insufficient detail (duration of treatment and
observation periods were not reported). Treatment was 1n soil as a vehicle,
a single low level was given, and negative results were obtained. The
studies by Kodba et al. (1978) and NTP (1980) Involved sufficiently long
dosing schedules and large enough groups to be used for quantitative risk
assessment.
Kodba et al. (1978) fed diets resulting 1n doses of 0.0, 0.001, 0.01 or
0.1 tig 2,3,7,8-TCDOVkg bw/day to groups of 50 male and 50 female Sprague-
Dawley rats for 2 years. The control group consisted of 86 males and 86
females. Tumor Incidences were significantly Increased 1n both sexes 1n the
high-dose group (p<0.05). The tumors observed were located 1n the hard
palate, tongue and adrenal cortex of males and 1n the liver, tongue and
lungs of females. The most common finding was hepatocellulaV carcinoma 1n
the females, with Incidences of 0/86, 0/50, 2/50 and 11/49 1n the control,
low-, mid- and high-dose groups, respectively.
The NTP, (1980) tested 2,3,7,8-TCDD for cardnogenldty 1n B6C3F1 mice
and Osborne-Hendel rats. Groups of 50 male and 50 female animals received
2,3,7,8-TCDD by gavage 1n corn o11:acetone (9:1), 2 days/week for 104
weeks. Male mice and male and female rats received 0, 0.01, 0.05 or 0.5
wg 2,3,7,8-TCDD/kg bw/week, and female mice received 0, 0.04, 0.2 or 2.0
yg 2,3,7,8-TCDD/kg bw/week. Control groups consisted of 75 vehicle
treated and 75 untreated animals. In mice, statistically significant
Increases 1n hepatocellular carcinomas and neoplastlc nodules were noted 1n
the high dose-males, and Increased Incidences of hepatocellular carcinomas
and adenomas, flbrosarcoma, hlstlocytlc lymphoma, thyroid folUcular-cell
-22-
-------
adenoma and cortical adenoma or carcinoma were observed 1n high-dose
females. A statistically significant Increase In the Incidence of folUcu-
lar cell adenomas occurred 1n all treated groups of male rats, but the Inci-
dence did not occur In a dose-related fashion. Among female rats, signifi-
cantly Increased Incidences of tumors occurred only 1n the high-dose group.
These tumor Incidences Include subcutaneous tissue flbromas, adrenal
cortical adenomas, and hepatocellular carcinomas and neoplastlc nodules.
4.2.2. Inhalation. Pertinent data regarding the Inhalation carclnogenl-
clty of 2,3,7,8-TCDD could not be located 1n the available literature.
4.3. OTHER RELEVANT DATA
HHh few exceptions, 2,3,7,8-TCDD has not proven mutagenlc 1n Salmonella
typh1rour1um. either with or without metabolic activation (Table 4-2). The
two positive tests with Salmonella were with TA1532, which Is particularly
sensitive to frame shift mutations. Positive results have been obtained In
i
yeast In both .In. vitro assays using a metabolic activating system and host-
mediated assays (Bronzettl et al., 1983). 2,3,7,8-TCDD has been shown to
Increase the frequency of reverse mutations 1n E. 'coll; Sd~* (Hussaln et
al., 1972). Hay (1982) reported positive results for transformation of baby
hamster kidney cells as did Rogers et al. (1982) for mouse lymphoma cells.
Khera and Ruddlck (1973) reported negative results 1n the dominant lethal
assay using VMstar rats. Conflicting results have been obtained from In.
vivo, in vitro and ep1dem1olog1cal Investigations of chromosomal aberrations
(IARC, 1977, 1982; Czelzel and Klraly, 1976; Hay, 1978; Tenchlnl et al.,
1979; Hottura et al., 1981; Green et al., 1977; Green and Moreland, 1975).
4.4. WEIGHT OF EVIDENCE
IARC (1982) considered the evidence for cardnogenlclty to humans to be
"Inadequate," the evidence for cardnogenlclty to an1ma>s to be "sufficient"
-23-
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TABLE 4-2
The Results of HuUgentctty Assays In Salnonella
Type of Assay
S-9
Spot test »/-
Plate Incor- »/-
poratlon
Plate Incor- NR
poratlon
Plate Incor- */-
poratlon''
Fluctuation t/-
Spot test
Plate tncor- »
poratlon
Plate Incor-
poration
Suspension
assay
TA98
NT
NT
NT
0
0
NT
0
NT
NT
TA1530
NT
NT
NT
0
0
0
NT
NT
0
TA1535
0
0
0
0
0
NT
0
NT
NT
TA1537
0
0
NT
0
0
NT
0
0
NT
TA1538
0
0
0
0
0
NT
0
NT
NT
Strains
TA1S32
0
0
NT
0
0
t
NT
NT
•
t
of Salmonella Typhlaurlua
TA19SO
NT
NT
NT
0
0
NT
NT
NT
NT
TA197S
NT
NT
NT
0
0
NT
NT
NT
NT
TA1978
NT
NT
NT
0
0
NT
NT
NT
NT
646
NT
NT
NT
0
0
0
NT
NT
NT
TA100
NT
NT
NT
0
0
NT
0
NT
NT
TA1S31
NT
NT
NT
NT
NT
QR
NT
NT
NT
TA1S34
NT
NT
NT
NT
NT
QR
NT
NT
NT
References
NcCann. 1978
NcCann. 1978
Nebert et
al.. 1976
Gilbert et
al., 1980
Gilbert et
al.. 1980
Seller. 1973
Gelger and
Neal. 1981
Gelger and
Neal, 1981
Hussaln et
al.. 1972
'Source: U.S. IPA. 19B4a
DThe assay was performed under both aerobic and anaerobic conditions.
NT = Not tested; NR « not reported; QR • questionable response; » - positive result; 0 - negative result
-------
and the evidence for activity 1n short-term tests to be "Inadequate."
Applying the criteria for evaluating the- overall weight of evidence for
carclnogenldty to humans proposed by the Carcinogen Assessment Group of the
U.S. EPA (Federal Register. 1984), 2,3,7,8-TCDO 1s most appropriately clas-
sified a Group B2 - Probable Human Carcinogen.
-25-
-------
5. REGULATORY STANDARDS AND CRITERIA
Canada established a limit of 20 ppt 2,3,7,8-TCDD (20 ng/kg fish) 1n the
Lake Ontario commeMcal fish exported to the United States. This 11 mH was
chosen to comply with an FDA determination that 2,3,7,8-TCDD levels <25 ppt
{25 ng/kg fish) 1n fish pose no serious health concern (Food Drug Cosmetic
Law Reports, 1981).
The National Academy of Sciences Committee on Drinking Water and Health
(NAS, 1977) proposed an ADI of 10"* wg 2,3,7,8-TCDD/kg bw/day, based on
a 13-week rat feeding study (Kodba et al., 1976). This ADI was proposed
before convincing evidence for the carc1nogen1c1ty of 2,3,7,8-TCDD had been
obtained. The U.S. EPA Is considering criteria of 1.3xlO"7, 1.3x10"* or
1.3xlO~* yg 2,3,7,8-TCDD/i (corresponding to excess cancer risks of
10~5, 10~* or 10~7) In ambient waters, based on an assumed dally con-
i
sumption of 6.5 g of contaminated fish and shellfish and 2 l of drinking
water (U.S. EPA, 1984b).
Klmbrough et al. (1983) recommended unofficially that contamination In
soil limited to 1 ppb 1n residential areas would result In Intake of
2,3,7,8-TCDD <126 pg/day, considered to be tolerable for a 70 kg human.
The New York State Dept. of Health has unofficially proposed 10 ppt In
fish as a celling level for safe human consumption (DEC, 1985).
-26-
-------
6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
2,3,7,8-TCDD has been demonstrated to be carcinogenic 1n laboratory ani-
mals and data are sufficient for estimation of carcinogenic potency. It Is
Inappropriate, therefore, to derive an AIS for this chemical.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
2,3,7,8-TCDD has been demonstrated to be carcinogenic 1n laboratory ani-
mals and data are sufficient for estimation of carcinogenic potency. It Is
Inappropriate, therefore, to derive an AIC for this chemical.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. A number of bloassays have clearly demonstrated the car-
c1nogen1c1ty of 2,3,7,8-TCDD In experimental animals (see Table 4-1). These
studies have recently been reviewed by the U.S. EPA (1984b). Human car-
cinogenic potency factors (q,*) were estimated from the study of Kodba et
• >
al. (1978) and the NCI bloassay (NTP, 1980). The highest q^ obtained
[1.56x10* (mg/kg bw/day)'1] was based on a review of the Kodba et al.
(1978) study (U.S. EPA, 1984b). This q^ was derived from the dose-
response data for tumors of the liver, lung, hard palate and/or nasal
turblnates 1n female rats. The data used 1n the derivation of this q *
are presented In Appendix B.
-27-
-------
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Z1nkl, J.G., J.G. Vos, J.A. Moore and B.N. Gupta. 1973. Hematologlc and
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APPENDIX A
Summary Table for 2,3,7,8-TCDD
Carcinogenic
Potency
Inhalation
Oral
Experimental
Species Dose/Exposure
rat Ixl0~«-lxl0~«
mg/kg bw/day
Effect
tumors of the liver,
lung, hard palate,
and/or nasal tur-
blnates
Unit Risk
or qi*
ND
1.56x10*
(rag/kg/day)'1
Reference
Koclba et al.,
1978; U.S. EPA,
1983b
ND = Not derived
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APPENDIX B
Data Used as a Basis for the q-|*a
Species, strain, sex =
Body weight (measured) =
Length of exposure =
Length of experiment =
Llfespan =
Tumor sHe/type (one or more)
Rats, Sprague-Dawley, female
0.370 kg
720 days
720 days
720 days
squamous cell carcinomas of the lung, nasal
turblnate and hard palate; neoplastlc
nodules and hepatocellular carcinomas of
the liver
Dose
(mq/kq/dav)
0.0
0.001xlO~»
0.1x10"'
O.lxlO"3
Incidence
(No. responders/No.
16/86
8/50
27/50
34/47b
tested)
aSource: A reanalysls of the Koclba et al. (1978) study by Dr. Robert
Squire of Johns Hopkins University (U.S. EPA, 1984a).
&Th1s dose-response point was dropped because of a poor fit to the linear-
ized multistage model.
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