Document jNzvMo6Dxkeo7ZqM45KDRpZ99
EPA-540/1-86-044
e.2
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_____________________________________________________________________________
____
rr
HEALTH EFFECTS ASSESSMENT
',,*7
FOR 2,3,7,8-TETRACHLORODIBENZO-p-DIOXIN
D O not remove. TWs document ,,wvM.iri be retained in the EPA
i
U.S. Environmental l^rotectfon Agency Region V, Library
230 South Dearboril Street
Chicago, Illinois 6 0 6 '
EPA/540/1-86-044 September 1984
HEALTH EFFECTS ASSESSMENT FOR 2,3,7,8-TETRACHL0R0DIBENZ0--DI0XIN
J
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 it 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
PREFACE
This report summarizes and evaluates Information relevant to a prelimi nary Interim assessment of adverse health effects associated with 2,3,7,8tetrachlorod1benzo-j)-d1ox1n (2,3,7,8-TCOO). 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 toxicologic 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 Toxicologic 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 Polychlorinated 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 2.3,7,8Tetrachlorod1benzo-p-d1ox1n. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-072.
U.S. EPA. 1985. 0r1nk1ng Water Criteria Document on 2,3,7,8Tetrachlorod1benzo--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 (l.e., protective) estimates. Never theless, the Interim values presented reflect the relative degree of hazard associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for sys temic toxicants (toxicants for which cancer 1s not the endpoint of concern). The first, the AIS or acceptable Intake subchronic, 1s an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs during a limited time Interval (1.e., for an Interval that does not constitute a significant portion of the lifespan). 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. Subchronic 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 lifespan (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 noncarcinogens 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 carcinogenicity, 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-j*s have been computed based on oral and Inhalation data 1f available.
1v
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-TCDO has been shown to be carcinogenic In many Independent rodent bioassays with oral exposure resulting In Increases In Incidence of a variety of tumor types. Results of in vitro mutagenicity 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-TCDO, a carcinogenic potency for oral exposure to humans {q-j*) of 1.56x10s (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 wasthe 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
*
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE....... .........................
1
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS ..........
2
2.1. O R A L ...................................................... 2.2. INHALATION................................................
2 3
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS .....................
4
3.1. SUBCHRONIC................................................ 4
3.1.1. Oral............................................. 3.1.2. Inhalation.......................................
4 4
3.2. CHRONIC.................................................... 7
3.2.1. Oral............................................. 3.2.2. Inhalation.......................................
7 7
3.3. TERATOGENICITY ANOOTHER REPRODUCTIVE EFFECTS..............
7
3.3.1. Oral.............................................. 7
3.3.2. Inhalation........................
14
3.4. TOXICANT INTERACTIONS............................. > . . . . 15
4. CARCINOGENICITY.................................................. 16
4.1. HUMAN D A T A ..............
16
4.1.1. Oral............................................. 4.1.2. Inhalation.......................................
16 16
4.2. BIOASSAYS.................................................. 16
4.2.1. Oral.............................................. 16 4.2.2. Inhalation....................................... 23
4.3. OTHER RELEVANT DATA........................................ 4.4. HEIGHT OF E V I D E N C E .......................................
23 23
5. REGULATORY STANDARDS AND CRITERIA ............................... 26
v 11
TABLE OF CONTENTS (coni.)
Page
6. RISK
ASSESSMENT......................................... 27
6.1.
6.2. 6.3.
ACCEPTABLE INTAKE SUBCHRONIC(AIS) ........................
ACCEPTABLE INTAKE CHRONIC (AIC)........................... CARCINOGENIC POTENCY (q^*) ...............................
27
27 27
6.3.1. Oral.............................................. 27
7. REFERENCES...............................................
28
APPENOIX A: Summary Table for 2,3,7,8-TCDO ........................... 47
APPENDIX B: Cancer Data Sheet for the Derivation of q-j*. . ........... 47
i
v111
LIST OF TABLES
No. Title
Page
3-1 Effects of Subchronic Exposure to 2,3,7,8-TCDD............... 5
3-2 Effects of Chronic Oral Exposure to 2,3,7,8-TCDD............. 8
3-3 Studies on the Potential Teratogenic Effects of
2,3,7,8-TCD0-Contam1nated 2,4,5-T ...........................
9
3-4 Studies on the Potential Teratogenic and Reproductive Effects of 2,3,7,8-TCDD ..................................... 12
4-1 Carcinogenicity Bioassays of 2,3,7,8-TCDD Administration by the Oral R o u t e ........................................... 17
4-2 The Results of Mutagenicity Assays 1n Salmonella typhlmurlum..........................
24
l
lx
AOI AIC AIS BCF bw CAS CS e d 50 GI LOAEL LOEL MED NOAEL PCDD PPb ppm PPt TWA
LIST OF ABBREVIATIONS
Acceptable dally Intake Acceptable Intake chronic Acceptable Intake subchronic 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 Polychlorinated d1benzo--d1ox1n Parts per billion Parts per million Parts per trillion Time-weighted average
/
X
1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of 2,3,7,8-TCDD (CAS No. 1746-01-6) are given as follows {U.S. EPA, 1984a):
Chemical class:
Molecular weight:
Vapor pressure at 25C:
Water solubility (at unspecified temperature):
Octanol/water partition coefficient:
BCF:
Half-Hves In A1r :
Water: Soil:
halogenated d1benzo-p-d1ox1ns - 321.98
1.7x10"* (estimated)
0.2 g/l 1.4x10'* to 1.9x10"' (estimated) 5000
unknown 1-2 years 10-12 years
No estimates of the half-Hfe of 2,3,7,8-TCDD 1n the atmosphere are available. Based on the available Information, photodegradation and wet and dry deposition of particle-bound 2,3,7,8-TCDD are probably the most signifi cant fate-determining processes for atmospheric 2,3,7,8-TCDD (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-TCDD on soil (U.S. EPA, 1984a).
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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:com oil (2:25 or 1:9) were -70-86% absorbed (Rose* 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 1n 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
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differences 1n concentrations of PCDOs 1n the U v e r between fly ash and extract-fed rats were greater with the more highly chlorinated PCODs than with 2,3,7,8-TCDD. 2.2. INHALATION
Pertinent data regarding to the absorption of 2,3,7,8-TCDD from the respiratory tract could not be located 1n the available literature.
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. SUBCHRONIC 3.1.1. Oral. The subchronic oral toxicity of 2,3,7,8-TCDD 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 teratogenic and reproductive effects of dietary 2,3,7,8-TCDD (0, 0.001, 0.01 or 0.1 vg/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^a and Flb generations. The F^b and F2 rats were mated at -130 days of age, producing the F2 and F3 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 gestational Index, decreased fetal weight, Increased Hver-to-body-we1ght ratios and an Ihcreased 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 toxoid, and cell-mediated Immunity was measured by the delayed-type hypersensitivity to Mycobacterium 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 subchronic Inhalation toxicity of 2,3,7,8-TCDD were located 1n the available literature.
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TABLE 3-1 Effects of Subchronic Oral Exposure to 2,3,7,8-TCDD3
Species
Dose yg/kg/day
Duration of Exposure
Effect Level
Endpoints
Reference
Rat Rat Rat Rat Rat Rat Rat Rat
Rat
Mouse Mouse Mouse Mouse
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
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
NOAEL LOAEL NOAEL LOAEL NOAEL NOAEL LOAEL LOAEL
L0AELb
LOAEL NOAEL LOAEL LOAEL
Decreased body weight
Decreased body weight
Toxic hepatitis
Toxic hepatitis
Decreased body weight
Decreased body weight
Thrombocytopenia
Decreased body weight and thymus weight
Decreased body weight, decreased fertility, decreased fetal sur vival
Toxic hepatitis
Porphyria
Porphyria
Decreased thymus weight and graft-versus-host response
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
Murray et al., 1979
NTP, 1980 Goldstein et al., 1978 Goldstein et al., 1978 Vos et al., 1973
TABLE 3-1 (cont.)
Species
Oose yg/kg/day
Duration of Exposure
Effect Level
Endpoints
Reference
House House House
Guinea pig
Guinea pig
0.14 0.21 1.3
4 weeks 4 weeks 5 weeks
0.0011
8 weeks
0.0057
8 weeks
LOAEL
Decreased resistance to Sal monella
LOAEL
Increased endotoxlc (E. coll) susceptibility
LOAEL
Decreased tetanus response, antigenic RBC response, sensiti zation to DNFB, resistance to Salmonella Infection, resistance to Listeria Infection
NOAEL
Decreased body weight, thymus weight and tuberculin hypersen sitivity
LOAEL
Decreased body weight, thymus weight and tuberculin hypersen. sltlvlty
Thigpen et al., 1975 Vos et al., 1978 Hlnsd111 et al., 1980
Vos et al., 1973 Vos et al., 1973
aSource: U.S EPA, 1984b
^Reported as NOAEL by Hurray et al. 1979; considered a LOAEL by Nlsbet and Paxton (1982) during a rvaluation of the data.
RBC = red blood cells; DNFB = 2,4-dlnltro, 1-fluorobenzene
3.2. CHRONIC 3.2.1. Oral. The chronic oral toxicity of 2,3,7,8-TCDD 1s summarized In Table 3-2. In rats, NOAELs for U v er toxicity were noted at 0.001 (Koclba et al., 1978, 1979), 0.0014 (Goldstein et al., 1982; NTP, 1980) mg/kg/day. These levels resulted 1n evidence of U v e r toxicity In mice (NTP, 1980; Toth et al., 1978, 1979). In rats, levels of 2,3,7,8-TCDD 1n the ranges of 0.007-0.71 mg/kg/day were regarded as LOAELs (Goldstein et al., 1982; King and Roesler, 1974; Koclba 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-TC00/kg bw/week (TWA * 0.0, 0.001, 0.1 or 1.0 yg 2,3,7,8TCDD/kg bw/day) to male Swiss mice by gavage for 104 weeks. Dermatitis and amyloidosis of the kidney, spleen and U v e r were observed at all dose levels. This study, therefore, establishes a L0AEL of 0.001 yg/kg bw/day. 3.2.2. Inhalation. No data pertinent to the chronic Inhalation toxicity of 2,3,7,8-TCDD 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 teratogenicity of 2,3,7,8-TCD0-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).
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TABLE 3-2 Effects of Chronic Oral Exposure to 2,3,7,8-TCDD*
Species
Dose (yg/kg/day)
Rat Rat Rat
Rat
Rat
Rat Rat Rat Rat House House
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)
Effect Level
Endpoints
16
NOAEL
elevated porphyrin levels
16
LOAEL
elevated porphyrin levels
28
LOAEL
fatty changes In liver,
decreased body weight
104
NOAEL
degenerative and necrotic
changes In the liver
104
LOAEL
degenerative and necrotic
Changes In the liver
104
NOAEL
toxic hepatitis
104
LOAEL
toxic hepatitis
45
LOAEL
porphyria
45
LOEL
hepatic enzyme Induction
104
LOAEL
toxic hepatitis
104
LOAEL
dermatitis and amyloidosis
`Source: U.S, EPA, 1984b
Reference
Goldstein et al., 1982 Goldstein et al., 1982 King and Roesler, 1974 Koclba et al., 1978, 1979 Koclba et al., 1978, 1979 NTP, 1980 NTP, 1980 Cantonl et al., 1981 Cantonl et al., 1981 NTP, 1980 Toth et al., 1978, 1979
TABLE 3-3 Studies on the Potential Teratogenic Effects of 2,3,7,8-TCDD-Contaalnated 2,4,5-T*
Species/ Route/
Strain
Vehicle
Fora of 2.4.5-T
Nice/ rape-seed NNR1 oil
acid
TCDO level
<0.02 ppa (Saaple A)
rape-seed oil
acid
0.05 0.0? ppm
(Sample B)
rape-seed oil
add
NR (Saaple C)
rape-seed oil
butyl ester NR
Nice/ NR NHRI
acid
0.05*0.02 ppa
Nice/ CD-I
corn oil: acetone
(9:1)
add
<0.05 ppa
Dally Dose
Treat ment Days
8, 15, 30. 45, 60,90
and 120
mq/kq
6-15
30, 60 and 90 ag/kg
6-15
90 ag/kg
6-15
12 and 17 ag/kg
6-15
20, 35, 60,
90 and 130 ag/kg
6-15
115 ag/kg
10-15
Obser vation
Day
Haternal Response
fetal Response
Reference
18
18 18 18
NR . w-18
No toxic effects; decreased aaternal weight at doses of 90 ag/kg and
greater
Significant Increases In the Incidence of cleft palates at doses above 30 ag/kg (see text for
additional details). Sig nificantly decreased (p<0.005) fetal weight
at all dose levels.
No toxic effects; decreased aaternal weight at 90 ag/kg
Increases In the Incidence of cleft palate at 60 and 90 ag/kg; significant (p<0.005) at all dose levels.
No toxic effects but decreased aaternal weight
Increase In the Incidence
of cleft palate; significant (p<0.005) decrease In fetal weight.
No toxic effects
Significant decrease In fetal weight but no effect on mortality; Increase In the frequency of cleft
palate similar to that seen
with acid (see text).
Toxic effects
observed at 90 and 130 ag/kg
Increases In the percent age of resorptions and/or dead fetuses at 90 and 130 ag/kg; Increases In the Incidence of cleft palate and retardation of skeletal development at 35 ag/kg and above.
No significant
effect on weight gain or liver-tobody weight ratios
No effect on fetal mortal ity or fetal weight, but
an Increase In the inci dence of cleft palate.
Neubert and Dlllaan, 1972
Roll. 1971 Courtney, 1977
Species/ Route/
Strain
Vehicle
form of 2,4,5-T
Mice/
honey:water acid
C57B1/6 (1:1)
TCOD Level
30 ppm
Nice/ AKR
honey:water acid (1:1)
Rats/ Sprague-
Dawley (groups
of 25 rats)
gavage/ hydroxy-
propyl methylcellulose
acid
30 ppm 0.5 ppm
Rats/ Ulstar
gavage/ aqueous gelatin or corn oil
acid
<0.5 mg/kg
gavage/ aqueous gelatin or
corn oil
butyl ester <0.5 mg/kg
TABLE 3-3 (coni.)
Dally Dose
Treat ment Days
46.4 and 113 6-14 mg/kg
113 mg/kg
6-15
1. 3. D. 12. or 24 mg/kg/ day
6-15
25, 50. 100, -15 or 150 mg/kg/ day
50 or 150 mg/kg/day
6-15
Observatlon
Day
Maternal Response
fetal Response
Reference
18 NR
Significant (p<0.01) Increases In the Incidence of cleft palate In the htghdose group and cystic kidney In both dose groups; Increased fetal mortality also observed In the hlghdose group.
Courtney et. at., 1970a.b
19 Increase In llver- Significant (p<0.05)
Courtney et.
to-body-wetght
Increases In the Incidence
al., 1970a,b
ratio.
of cleft palate and fetal
mortality
20
No effect on body A slight but statistically
Emerson et
weight and no
significant (p<0.05)
al. 1970, 1971
observable signs decrease In Implantations
N.B. This
of toxicity.
and litter size In lowest
appears to be
dose group only; no frank
a full publi
teratogenic effects based
cation of the
on a detailed examination
abstract su m -
of the control and 24 mg/
Mary by
kg dose group; the only
Thompson et
effect noted was an In
al.. 1971
crease In the Incidence of
Sth partially ossified
sternebrae.
22
Some maternal
At 100 or 150 mg/kg.
Khera and
mortality and
decreased fetal weight.
HcKtnley,
decreased body
Increased fetal mortality
1972;
weight gain at 150 and an Increase of skel
Khera et al.,
mg/kg; no signs of etal anomalies; no signi
1971
toxicity at 100
ficant effect at the two
mg/kg or below.
lower dose levels.
22 NR
No significant effect on fetal morality, fetal
weight, or the Incidence of anomalies.
Khera and McKinley, 1972; Khera et al., 1971
7
TABLE 3-3 (cont.)
Species/ Route/
Strain
Vehicle
form of 2..5-T
Rats/ Holtzman
gavage/ 1:1 solu
tion of
honey and water
acid
TCDD Level
30 ppm
Rats/ CD
gavage/
acid
15X sucrose
solution
0.5 ppm
i
^ Rats/ gavage/
acid
1 Sprague- methocel-
Dawley lulose
0.5 ppm
gavage/ methocellulose
acid
0.5 ppm
Syrian ham sters/ Heso-
crlcetus euratus
gavage/ acetone, corn oil, and carboxymethyl
cellulose In ratio of 1:5.8:10
acid
<0.1-4.5 ppm
Source: U.S. EPA, 19BS NS = Not specified; NR not reported
Dally Dose
Treatment
Days
4.6, 10.0 and 46.4 mg/kg/day
10-15
10.0, 21.5, 46.4 and
00.0 mg/kg/ day
6-15
50 mg/kg
6-15
100 mg/kg
6-10
20, 40, 80 and 100
mg/kg
6-10
Obser vation
Day 20
20
NS
NS
14 w-
Maternal Response
fetal Response
NR 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.
Reduced maternal weight gain at the 2 higher dose levels (p<0.05)
and Increased ltver-to-bodywelght ratio at the highest dose
level (p<0.05)
Increase In the Incidence of kidney anomalies but
no Increase In cleft palate.
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.
Increased mor
tality and decreased body weight gain.
Increase In the Incidence
of delayed ossification and poorly ossified or
malallgned sternebrae (p<0.05)
NS Dose-related Increases In fetal mortality, gastro intestinal hemorrhages, and fetal abnormalities
Reference Courtney et al., 1910a,b
Courtney and Moore 1911
Sparschu et al.. 1911a
Sparschu et al., 1911a
Collins et al.. 1911
TABIE 3 4 Studies on the Potential Teratogenic and Reproductive Effects of 2,3,7,8-TCDDa
t
Specles/Straln Vehicle
Compound
Dally Dose
Treataent Days
Observation Day
Haternal Response
Fetal Response
Reference
Nouse/C57Bl/6 Nouse/AKR
House/CD-I House/DBA/2J House/C57Bl/6J House/C5781/6
House/CD-1
DHSO or honey:water 11:1)
DHSO
acetone: corn oil (1:9)
DHSO or corn oil
2.4.5-T containing 30 ppm TCDO
2,3.7,8-TCDD
21.5, 46.4, 113.0 ag/kg
0.5. 1. 3 vg/kg
6-14 or 9-17
. 6-15
2,3,7,8-TCDD 1, 3 ng/kg
10-13 or 10
2,3.7,8-TCDD
25, 50, 100, 200, 400 ug/kg
7-16
19b 17b or 18 18b 18d
House/CF-1 House/NHRI
corn oil: acetone (98:2)
rape-seed oil
Rat/CD
DHSO
Rat/SpragueDawley
corn oil/ acetone
2,3.7,8-TCDD 2,3,7,8-TCDD
0.001. 0.01, 0.1, 1.0, 3.0 vg/kg
0.3, 3.0, 4.5, 9.0 |ig/kg
6-15
6-15 f
18b 18
2,3,7,8-TCDD
0, 0.5, 2.0 tig/kg
2,3,7,8-TCDD
0, 0.03, 0.125, 0.5, 2.0, and
8.0 ug/kg
6-15, 9 and 10, or 13 and 14
6-15
20b 20b
Increased llver-tobody-welght ratio
Increased llver-tobody-welght ratio
Fetal death, cleft palate, cystic kidney
Cleft palate, kidney anoma!1esc
Courtney et al., 1970a,b
Courtney and Hoore, 1971
None reported
Cleft palate, kidney anomallesc
Hoore et al., 1973
Increased llver-tobody-welght ratio
None reported No effect observed
None reported
Cleft palate, hydronephrotlc kidneys, hydro cephalus, open eyes, edeaa, petechlae
Cleft palate, dilated renal pelvis
Fetocldal at the high dose; cleft palate at doses at or above 4.5 vg/kg
Kidney aalforaatlons at both dose levels
Courtney, 1976
Smith et al., 1976 Neubert and Dlllaan, 1972
Courtney and Hoore, 1971
Vaginal heaorrhage at 2.0 and 8.0 v9/kg
Intestinal hemorrhage at 0.125 and 0.5 ug/kg; fetal death at
higher doses; subcutaneous
edema
Sparschu et al.. 1971b
TA B U 3 4 (conl.)
T
Specles/Straln Vehicle
Compound
Dally Dose
Treatment Oays
Observation Day
Maternal Response
fetal Response
Reference
Rat/Ulstar
corn oil/ anlsole
Rat/SpragueOawley
corn oil/ acetone
(9:1)
Rat/SpragueDawley
diet
Rabbit/ New Zealand
Honkey/rhesus
corn oil/ acetone (9:1)
diet
Honkey/rhesus diet
2.3,7.8-TCDD
2,3,1,8-TCDD
2,3,7,8-TCOD
2,3,7.8-TCDD 2,3,7,8-TCOD 2,3,7,8-TCOD
0.0, 0.125, 0.25, 1, 2. 4, a, 16 wg/kg
0.1. 0.5, 2.0 |ig/kg
0.001, 0.01 and 0.1 ng/kge
0.0, 0.1, 0.25, 0.5 and 1 wg/kg 8.6 pg/kg/day
55.7 pg/kg/day
6-15
1-3
throughout gestation
6-15
T months prior to and during gestation 7 months prior to and during gestation
22 Maternal toxicity observed at or
above 1 wg/kg
21 Decrease In body
weight gain In the htgh-dose group
post-parturi tion
Low fertility at
0.01 and 0.1 wg/kg; decreased body weight at 0.01 and 0.1 vg/kg; dilated renal pelvis
28 Maternal toxicity at doses of 0.25 wg/kg and above
at term
6/8 conceived; nor mal serum estradiol
and progesterone
at term
3/8 conceived; de creased serum estra
diol and progester one
Increased fetal death observed at or above 1 wg/kg;
subcutaneous edema
and hemorrhages In
the 0.25 wg/kg groups
Khera and Ruddlck. 1973
Decreased fetal
weight In the 0.5
and 2 wg/kg group; cystic kidneys and dilated renal pel vis occurred in the
2 wg/kg group
Glavlnl et al., 1982a
Low survival at 0.01 and 0.1 wg/kg; decreased body
weight at 0.01 slight dilated renal pelvis at
0.001 wg/kg
Murray et al., 1979
Increases In extra Glavlnl et al., ribs and total soft 1982b
tissue anomalies
3/8 normal births
Allen et al., 1979
1/8 normal births
Allen et al., 1979
aSource: U.S. fPA, 1905 bflrst day of gestation designated day 0. cKldney anomalies were not specifically defined.
1rsl day of gestation designated day 1. eIhe high dose level (0.1 w9/kg/day) was discontinued due to very low fertility In adults. DHSO * dimethyl sulfoxide
. Neubert and Dlllmann (1972) reported an EDgQ 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 yg 2,3,7,8-TCDD/kg bw/day for the production of teratogenic effects 1n CF--1 mice. Rats are less sensitive to the teratogenic 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 McKinley, 1972). The teratogenic and reproductive effects of low doses of 2,3,7,8-TCDD have been Investigated In a 3-generat1on reproduction study using 16 male and 32 female Sprague-Dawley rats/generatlon (Murray et al., 1979). The authors concluded that doses of 0.01 or 0.1 yg 2,3,7,8-TCDD/kg bw/day resulted 1n decreased fertility, decreased litter size and decreased fetal survival, and that 0.001 yg 2,3,7,8-TCD0/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 yg 2,3,7,8-TCDD/kg bw/day signifi cantly reduced the gestational Index and fetal weights, and Increased the Hver-to-body-we1ght ratios and the Incidence of dilated renal pelvis. 3.3.2. Inhalation.. Pertinent data regarding the teratogenicity 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 2,3,7,8TCDD 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; Regg1an1, 1980). The .Individuals 1n 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.*. 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 potentiation 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-j (Gurtoo, 1980); nltrosamlnes (ScarpelH et al., 1980), N-2-fluor1nylacetam1de (DIGIovannl et al., 1979), 3,4-d1am1n1so1e (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 (Grelg, 1972).
-15-
4. CARCINOGENICITY 4.1. HUMAN DATA 4.1.1. Oral. Pertinent data regarding the oral carcinogenicity of 2.3.7.8- TCOD 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-TCDD 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; Hardell 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-TCDD unequi vocally with Induction of tumors 1n humans. 4.2. BIOASSAYS 4.2.1. Oral. The available data on the carcinogenicity of orally admin istered 2,3,7,8-TCDD 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 thehard palate In both sexes of rats (Koclba et al., 1978), and follicular-cell adenomas of the thyroid 1n male rats and female mice (NTP, 1980). The studies of Tothet al. (1979) and Van Miller et al. (l977a,b) are of limited value for risk assessment
-16-
TABLE 4-1 Carcinogenicity Btoassays of 2,3,7,8-TCDD Administration by the Oral Route9
Exposure Species/ Sex
Route
Strain
Gavage
rats/ Osborne-
Mendel
M
Dose or
Exposure
0.0 |ig/kg/week
0.01 vg/kg/week
0.0S |ig/kg/week
0.5 ng/kg/week
Gavage
rats/ Osborne-
Mendel
E
0.0 |ig/kg/week 0.01 vO/kg/week
0.05 vg/kg/week
0.5 vQ/kg/week
Duration of
Treatment
Duration of
Study
Vehicle
Tumor Type
Tumor
P
Incidence Value
Reference
104 weeks
104 weeks
104 weeks
104 weeks
104 weeks
104 weeks
104 weeks
104 weeks
105 weeks
107 weeks
107 weeks
107 weeks
105 weeks
107 weeks
107
weeks
107 weeks
corn oilacetone (9:1)
corn oilacetone (9:1)
corn oilacetone (9:1)
corn oilacetone (9:1)
corn oilacetone (9:1)
corn oilacetone (9:1)
corn oilacetone (9:1)
corn oilacetone (9:1)
follicular-cell adenomas of the thyroid, carcinoma of the thyroid
follicular-cell adenomas of the thyroid. carcinoma of the thyroid
follicular-cell adenomas of the thyroid. carcinoma of the thyroid
folllcular-cell adenomas of the thyroid. carcinoma of the thyroid
neoplastic nodules of the liver, hepatocellular carcinoma of the liver
neoplastic nodules of the liver. hepatocellular carcinoma of the liver
neoplastic nodules of the liver. hepatocellular carcinoma of the liver
neoplastic nodules of the liver, hepatocellular carcinoma of the liver
1/69 0/69 5/48 0/48 6/50 2/50 0/50 1/50 5/75 0/75
0.006 0.042 0.021 0.001 <0.001
NTP, 1980 NTP, 1980
1/49 0/49
NS
3/50 0/50
NS
12/49 3/49
0.006
TABLE 4-1 (cont.)
Exposure Species/ Sex
Route
Strain
Gavage Ice/ B8C3F i
H
Dose or
Exposure
0.0 |ig/kg/week
0.01 vg/kg/week
0.0S ug/kg/week
O.S |ig/kg/week
Gavage Ice/ B6C3F]
F 0.0 |!g/kg/week 0.04 |ig/kg/ueek
0.2 vg/kg/week
-
Oral
rat/ SpragueOawley
N
2.0 vg/kg/week 0.0 ppb 0.001 ppb
Duration of
Treatment
DuratIon of
Study
Vehicle
Tuaor Type
Tumor
P
Incidence Value
Reference
104 weeks
104 weeks
104 weeks
104 weeks
104 weeks
104 weeks
104 weeks
104 weeks
78 weeks
78 weeks
10S weeks
107 weeks
107 weeks
107 weeks
10S weeks
107 weeks
107 weeks
107 weeks
9S weeks
95 weeks
corn oilacetone (9:1)
corn otlacetone (9:1)
corn oilacetone (9:1)
corn oilacetone (9:1)
corn oilacetone (9:1)
corn oilacetone (9:1)
corn otlacetone (9:1)
corn oilacetone (9:1)
In diet
hepatocellular carctnoaa
hepatocellular carctnona
hepatocellular carcInoM
hepatocellular carctnoaa
hepatocellular carcinoma follicular-cell adenomas of the thyroid hepatocellular carctnoaa, follicular-cell adenomas of the thyroid hepatocellular carcinoma, follicular-cell adenomas of the thyroid hepatocellular carcinoma, follicular-cell adenomas of the thyroid all tumors'*
In diet
all tumors'*
8/73 0.002 NTP, 1980
9/49 NS
8/49 NS
17/S0 0.002
1/73 0/89
0.008 0.018
NIP, 1980
2/50 3/50
NS NS
2/48 1/47
NS NS
8/47 5/48
0.014 0.009
0/10 NR 0/10 NR
Van Hiller et al.. 1977a,b
TABLE 4-1 (coni.)
Exposure Species/ Sex
Route
Strain
Oral (cont.)
Oral
rat/
SpragueDawley
H
Dose or
Exposure
0.005 ppb
0.05 ppb
0.5 ppb
1.0 ppb
5.0 ppb
0.0 |ig/kg/day
0.001 ug/kg/day
N 0.01 ug/kg/day
0.1 ug/kg/day
Duration of
Treatment
Ouratlon of
Study
Vehicle
78 weeks
95 weeks
In diet
78 weeks
78 weeks
78 weeks
78 weeks
105 weeks
95 weeks
95 weeks
95 weeks
95 weeks
105 weeks
In diet In diet In diet In diet In diet
105 weeks
105 weeks
105 weeks
t
In diet
105 weeks
In diet -
105 weeks
105 weeks
In diet
Tumor Type
Tumor
P
Incidence Value
Reference
all tumorsb all tumorsb
5/10 NR 3/10 NR
Van Miller
et al.. 1977a,b
all tumorsb
4/10 NR
all tumorsb
4/10 NR
all tumorsb
7/10 NR
squamous celi carcinoma of th hard palate. squamous celi carcinoma of th tongue. adenoma of th adrenai cortex
squamous celi carcinoma of th hard palate, squamous celi carcinoma of th tongue, adenoma of th adrenai cortex
squamous celi carcinoma of th 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
0/85 0/85 0/85
NS NS NS
Koclba et al.. 1978
0/50 1/50 0/50
NS NS NS
0/50 1/50 2/50
NS NS NS
4/50 3/50 5/50
<0.05 <0.05 <0.05
TABLI 4-1 (cont.)
Exposure Species/ Sex
Route
Strain
Oral
rat/ Sprague-
Oawley
F
f
Gavage
Ice/ Swlss/H/
Rtop
n
'
Dose or Exposure 0.0 g/kg/day
0.001 pg/kg/day
0.01 yg/kg/day
0.1 |ig/kg/day
0.0 eg/kg/week 0.001 ng/kg/week 0.1 ng/kg/week 1.0 vg/kg/ueek
Duration of
Treataent
Duration of
Study
Vehicle
Tuaor Type
Tuaor
P
Incidence Value
Reference
10S weeks
105 weeks
105 weeks
105 weeks
365 days
365 days 365 days 365 days
105 weeks
105 weeks
105 weeks
105 weeks
588 days 649 days 633 days 424 days
In diet
In diet
In diet
In diet
sunflower oil
hepatocellular carctnoaa. squaaous cell carctnoaa of the tongue. squaaous cell carctnoaa of the lung
hepatocellular cardnoaa. squaaous cell carctnoaa of the tongue. squaaous cell carctnoaa of the lung
hepatocellular carctnoaa. squaaous cell carctnoaa of the tongue. squaaous cell carctnoaa of the lung
hepatocellular carctnoaa. squaaous cell carctnoaa of the tongue, squaaous cell carctnoaa of the lung
Itver tuaorsc
0/86 0/86 0/86 0/50 0/50 0/50 2/50 1/50 0/50 11/49 4/49 1/49 1/38
NS NS NS NS NS NS NS NS NS <0.05 <0.05 <0.05 NS
sunflower oil
sunflower oil
sunflower oil
liver tuaorsc liver tuaorsc liver tuaorsc
13/44 NS 21/44 <0.01 13/43 NS
Koclba et al.. 1918
Toth et al.. 1919
TABLE 4-1 (coni.)
Exposure Species/ Sex
Route
Strain
Dose or
Exposure
Duration of
Treatment
Duration of
Study
Vehicle
Oral
Ice/
h
Peromvscus and
Dollonotus f
0.001? pg/kg/day 0.0 vQ/kg/day
NA NA
NA contami nated soil
NA contami nated sol)
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)
Tumor Type liver
Tumor Incidence
0/15
liver
0/TS
P Value
Reference
NS Cockerham et al., I960
NS
I
purposes because of the relatively short exposure times and small group sizes or both. The study 1n beach mice (Peromvscus 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 Koclba et al. (1978) and NTP (1980) Involved sufficiently long dosing schedules and large enough groups to be used for quantitative risk assessment.
Koclba et al. (1978) fed diets resulting 1n doses of 0.0, 0.001, 0.01 or 0.1 tig 2,3,7,8-TCD0/kg bw/day to groups of 50 male and 50 female SpragueDawley 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 hepatocellulir 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 carcinogenicity 1n B6C3F^ mice and Osborne-Mendel 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 vg 2,3,7,8-TCDD/kg bw/week, and female mice received 0, 0.04, 0.2 or 2.0 tig 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 neoplastic nodules were noted 1n the high dose-males, and Increased Incidences of hepatocellular carcinomas and adenomas, fibrosarcoma, histiocytic lymphoma, thyroid follicular-cell
-22-
adenoma and cortical adenoma or carcinoma were observed 1n high-dose females. A statistically significant Increase In the Incidence of follicu 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 fibromas, adrenal cortical adenomas, and hepatocellular carcinomas and neoplastic nodules. 4.2.2. Inhalation. Pertinent data regarding the Inhalation carcinogeni city of 2,3,7,8-TCDD could not be located 1n the available literature. 4.3. OTHER RELEVANT DATA
With few exceptions, 2,3,7,8-TCDD has not proven mutagenic 1n Salmonella tvph1mur1um. 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 hostmediated assays (Bronzettl et al., 1983). 2,3,7,8-TCDO has been shown to Increase the frequency of reverse mutations 1n E.`coll; Sd~4 (Hussain 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 Wlstar rats. Conflicting results have been obtained from 1n vivo. In vitro and epidemiological 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 carcinogenicity to humans to be "Inadequate," the evidence for carcinogenicity to animals to be "sufficient"
-23-
The Results of Mutagenicity Assays In Salwonclla typhlwurluw3
Strains of Salaonella TvohlMirlua
Type of Assay S-9 TA98 TA1530 TA1S3S TA1537 TA1538 TA1S32 TA1950 TA197S TA1978 646 TA100 TA1531 TA1534
References
Spot test
/- NT
NT
0
00
0
NT NT NT NT NT NT NT McCann, 1978
Plate Incor f/- NT
NT
0
00
0
NT NT NT NT NT NT NT McCann, 1978
poration
Plate Incor NR NT NT poration
0
NT 0
NT NT NT NT NT NT NT NT Nebert et al.. 1976
Plate lncor- /- 0
0
0
00
0
0
0
000
NT NT Gilbert et
poratlonb
al., 1980
fluctuation * / - 0
0
0
0
0
0
0
0
00 0
NT NT Gilbert et
al., 1980
Spot test
- NT 0
NT NT NT
*-
NT
NT
NT 0
NT
QR
QR Seller, 1973
Plate Incor
0
NT
0
0
0
NT NT NT NT NT 0
NT NT Geiger and
poration
Neal. 1981
Plate Incor - NT NT NT 0 poration
NT NT NT NT NT NT NT NT NT Geiger and Neal, 1981
Suspension assay
- NT 0
NT NT NT
NT NT NT NT NT NT NT Hussain et al.. 1972
^Source: U.S. IPA. 19B4a bThe assay was perforieed 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 carcinogenicity 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 82 - 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 commerlcal fish exported to the United States. This limit 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"4 yg 2,3,7,8-TCDD/kg bw/day, based on a 13-week rat feeding study (Koclba et al., 1976). This ADI was proposed before convincing evidence for the carcinogenicity of 2,3,7,8-TCDD had been obtained. The U.S. EPA Is considering criteria of 1.3xl0"7, 1.3xl0"8 or 1.3x10"* 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).
Kimbrough 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 bioassays have clearly demonstrated the car
cinogenicity 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
J
of
Koclba
et
al. (1978) and the NCI bioassay (NTP, 1980). The highest q^* obtained
[1.56x10s (mg/kg bw/day)-1] was based on a reviewof the Koclba et al.
(1978) study (U.S. EPA, 1984b). This q^* was derived from the dose-
response data for tumors of the Uver, lung, hard palate and/or nasal
turbinates 1n female rats. The data used 1n the derivation of this q^*
are presented In Appendix B.
-27-
8. REFERENCES
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U.S. EPA. 1985. Drinking Water Criteria Document for 2,3,7,8-Tetrachlorod1benzo--d1ox1n. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Drinking Water, Washington, DC. (Final draft)
Van der Berg, M., K. O U e and 0. Hutzlnger. 1983. Uptake and selective retention 1n rats of orally administered chlorinated dioxins and dlbenzofurans from fly ash and fly ash extract. Chemosphere. 12(4/5): 537-544 (Cited 1n U.S. EPA, 1984a)
Van Miller, J.P., J.J. Lallch and J.R. Allen. 1977a. Increased Incidence of neoplasms In rats exposed to low levels of 2,3,7,8-tetrachlorod1benzo-pdloxln. Chemosphere. 6(10): 625-632. (Cited 1n U.S. EPA, 1985)
Van Miller, J.P., J.J. Lallch and J.R. Allen. 1977b. Increased Incidence of neoplasms In rats exposed to low levels of 2,3,7,8-tetrachlorod1benzo-pdloxln. Chemosphere. 6(9): 537-544. (Cited In U.S* EPA, 1985)
Vos, J.G., J.A. Moore and J.G. Zlnkl. 1973. Effect of 2,3,7,8-tetrachlorod1benzo-p-d1ox1n on the Immune system of laboratory animals. Environ. Health Perspect. 5: 149-162. (Cited 1n U.S. EPA, 1985)
Vos, J.G., J.G. Kreeftenberg and L. Kater. 1978. Immune Suppression by TCDD. Ijn: Dioxin: Toxicological and Chemical Aspects. SO Medical and Scientific Books, NY. p. 163-175. (Cited In U.S. EPA, 1985)
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Z1nkl, J.G., J.G. Vos, J.A. Moore and B.N. Gupta. 1973. Hematologic and clinical chemistry effects of 2,3,7,8-tetrachlorod1benzo-p-d1ox1n 1n labora tory animals. Environ. Health Perspect. 5: 111-118. (Cited In U.S. EPA, 1985)
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APPENDIX A Summary Table for 2,3,7,8-TCDD
Carcinogenic Potency
Species
Experimental Dose/Exposure
Effect
Inhalation Oral
rat
Ixl0~`-lxl0"4 mg/kg bw/day
tumors of the liver, lung, hard palate,
and/or nasal tur binates
ND = Not derived
Unit Risk or qi*
ND
1.56x10* (mg/kg/day)'1
Reference
Koclba et al., 1978; U.S.EPA, 1983b
r
APPENDIX B Data Used as a Basis for the q-|*a
Species, strain, sex =
Rats, Sprague-Dawley, female
Body weight (measured) a
0.370 kg
Length of exposure =
720 days
Length of experiment
720 days
Lifespan
720 days
Tumor slte/type (one or more)
squamous cell carcinomas of the lung, nasal turbinate and hard palate; neoplastic nodules and hepatocellular carcinomas of the Uv e r
Dose (mq/kq/dav)
0.0
0.001x10" 0.1x10"
0.1x10"
Incidence (No. responders/No. tested)
16/86
8/50
27/50 34/47b
aSource: A reanalysis 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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