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

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                                  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

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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

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                                             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-

-------
                                                                   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-

-------
                                8.   REFERENCES

Aldred,  J.E.    1978.   Report  of  the  Consultative  Council   on  Congenital
Abnormalities   In  the  Yarrom  District.    Minister   of   Health,  Melbourne,
Victoria, Aust.  (Cited 1n U.S.  EPA,  1985)

Allen.  O.R.,   D.A  Barsottl,  L.K.   lambrecht  and  J.P.  Van  Miller.    1979.
Reproductive  effects  of   halogenated  aromatic  hydrocarbons  on  nonhuman
primates.  Ann. NY Acad.  Sc1.   320:  419-425.  (died  1n U.S. EPA,  1985)

Axelson, 0. and L. Sundell.   1974.   Herbicide exposure, mortality,  and  tumor
Incidence.  An ep1dem1olog1cal  Investigation  on  Swedish railroad workers.
Work Environ.  Health.  11: 21-28.  (Cited  1n U.S.  EPA, 1985)

Axelson, 0.,  C.  EdUng,  H. Kllng,  K.  Anderson,  C. Hogstedt 'and  L. Sundell.
1979.   Updating  of the  mortality  among pesticide exposed railroad workers.
Lakartlgnlngen.  76: 3505-3506.  (Cited 1n U.S.  EPA.1985)

Axelson, 0.,  L.  Sundell, K.  Anderson,  C.  EdUng, C.  Hogstedt and  H.  Kllng.
1980.   Herbicide  exposure  and  tumor  mortality:   An updated  epldemlologlc
Investigation  on  Swedish railroad  workers.  Scand. J. Work Environ.  Health.
6: 73-79.   (Cited  1n U.S. EPA, 1985)

Berry,  O.L.,  P.K. Zacharlah,  M.O.  Namkung and  M.R.   Juchau.   1976.   Trans-
placental  Induction  of  carclnogen-hydroxylatlng  systems  with 2,3,7,8-tetra-
chlorod1benzo-p-d1ox1n.   Toxlcol.  Appl. Pharmacol.   36(3): 569-584.   {Cited
1n U.S.  EPA,  1985)
                                     -28-

-------
Blsantl,  L.,  F.  Bonettl and  F.  Caramaschl,  et al.   1980.   Experiences  from
tfie accident  of  Seveso.   Acta.  Morphol. Acad. Sd. Hung.   28(1-2):  139-157.
(CHed 1n U.S. EPA, 1985)

Bonaccorsl, A.,  R. FanelH  and  G.  Tognonl.   1978.   In  the Wake of  Seveso.
Amblo.  7(5): 234-239.  (Cited 1n U.S. EPA, 1985)

Boobls,  A.R.   and   O.W.  Nebert.   1976.   Induction   and  Inhibition  of  the
formation  of  benzo(a)pyrene metabolites  that  covalently   bind  to  ONA  by
Inbred mice.  J.  Pharmacol.  18(2):  210.  (Abstr.)  (Cited 1n U.S.  EPA,  1985)

Bronzettl,  6.,  E. Zelger,   I.  Lee,  K.   Suzuki  and  H.V.  Mailing.   1983.
Mutagen1c1ty  study  of TCDD and ashes  from urban Incinerator "Jn. vitro"  and
"lH vivo" using yeast 07 strain.  Chemosphere.  12: 549-553.   (CHed  1n  U.S.
EPA, 1985)

Cantonl,  L.,  M.   R1zzard1n1, 6.  Belvedere,  R.  Canfonl,  R.  FanelH  and  M.
Salmona.   1981.   Induction  of  mixed-function oxldase  by chronic  treatment
with   2,3,7,8-tetrachlorod1benzo-p-d1ox1n   1n  female   rats.   Toxicology.
21(2): 159-167.  (Cited In  U.S.  EPA,  1985)

Cockerham, L.G.,  A.L.  Young  and C.E. Thalken.  1980.  Hlstopathologlcal  and
ultrastructural studies of  Hver  tissue from TCOO-exposed beach mice  (Pero-
myscus pollonotus). J. AD-A083  323/6 PC A04/MF A01.   p. 61.   (Cited  In  U.S.
EPA, 1985)
                                     -29-

-------
Collins, T.F.S.,  C.H.  Williams  and 6.C.  Gray.   1971.   Teratogenlc  studies
with  2,4,5-T  and  2,4-D  In  the hamster.   Bull.  Environ.  Contam.  Toxlcol.
6(6): 559-567.  (Cited  1n U.S.  EPA,  1985)

Cook,  R.R.    1981.   D1ox1n,  chloracne  and  soft  tissue  sarcoma.   Lancet.
618-619.  (Cited 1n U.S.  EPA,  1985)

Cook, R.R., J.C. Townsend,  M.G.  Ott and L.G. Sllversteln.   1980.   Mortality
experience  of   employees   exposed  to   2,3^7,8-tetrachlorodlbenzo-p-dloxln
(TCOD).  J.  Occup.  Med.  22: 530-532.   (Cited 1n  U.S.  EPA,  1985)

Courtney,  K.D.   1976.   Mouse  teratology  studies  with  chlorod1benzo-p-
dloxlns.  Bull.  Environ.  Contam. Toxlcol.   16(6): P674-681.   (Cited  1n  U.S.
EPA, 1985)
                                                              i
Courtney, K.O.   1977.   Prenatal  effects  of herbicides:  Evaluation by  the
prenatal development  Index.  Arch. Environ.  Contam: Toxlcol,   6(1):  33-46.
(Cited 1n U.S. EPA, 1985)

Courtney, K.D.  and  J.A.  Moore.  1971.   Teratology studies with  2,4,5-T  and
2,3,7,8-TCDD.  Toxlcol.  Appl.  Pharmacol.  20: 396-403.   (Cited  1n  U.S.  EPA,
1985)

Courtney, K.D.,  D.W. Gaylor,  H.D.  Hogan and  H.L.  Falk.   1970a.   Teratogenlc
evaluation of  pesticides: Large-scale  screening  study.   Teratology.  3:  199.
(Cited  1n U.S. EPA, 1985)
                                     -30-

-------
Courtney,  K.D..  D.W.   Gaylor,  M.D.  Hogan,  M.L.  Falk,  R.R.  Bates  and  I.
Mitchell.   19705.   Teratogenlc   evaluation   of   2,4,5-T.    Science.    168:
864-866.  (Cited 1n U.S. EPA, 1985)

Czelzel,  E.  and  0.   Klraly.   1976.   Chromosome  examinations  1n  workers
producing KloMnol and  Bvlnol  (Hung.)   In: The  Development  of  a  Pesticide as
a  Complex  Scientific  Task, L. Bankl,  Ed.   Budapest,  Medldna.  p.  239-598.
(Cited 1n IARC, 1982.)

DEC  (Department  of   Environmental  Conservation,  New  York  State).   1985.
Draft environmental  Impact statement  for  proposed policy on contaminants  In
fish.   Prepared by Department  of  Environmental  Conservation.  Division  of
F1sh and Wildlife, Bureau of Environmental  Protection.   Albany, New York.

Department of  Health,  New  Zealand.   1980.   Report to the Minister  of  Health
of an Investigation Into allegations of an association  between human congen-
ital defects  and  2,4,5-T spraying  In  and  around  teKuHL  New  Zealand  Med.
3.  p. 324-315.  (Cited 1n  U.S. EPA, 1985)

D1G1ovann1, J.,  O.L.  Berry, T.J.  Slaga, A.H.  Jones  and M.R.  Juchau.   1979.
Effects   of  pretreatment  with 2,3,7,8-tetrachlorod1benzo-p-d1ox1n  on   the
capacity of hepatic and extrahepatlc mouse tissues to convert  procardnogens
to mutagens  for Salmonella  typhlmurlum auxotrophs.   Toxlcol.  Appl.  Pharma-
col.  50(2): 229-239.   (Cited 1n U.S.  EPA,  1985)
                                     -31-

-------
Emerson, J.L., D.J. Thompson, C.G. Gerblg and V.B. Robinson.  1970.  Terato-
genlc study of 2,4,5-tr1chlorophenoxyacet1c add In the rat.  Toxlcol. Appl.
Pharmacol.   17: 317.   (CHed 1n  U.S.  EPA,  1985)

Emerson, J.L.,  D.J.  Thompson, R.J.  Streblng,  C.G. Gerblg  and  B.  Robinson.
1971.  Teratogenlc studies  of 2,4,5-T 1n  the  rat  and rabbit.  Food Cosmet.
Toxlcol.  9: 395-404.   (CUed 1n  U.S.  EPA,  1985)

Eriksson, M., L. Hardell, N.  O'Berg, T. Moller and 0.  Axelson.  1981.  Soft-
tissue sarcomas and exposure to  chemical  substances:  A case-referent  study.
Br. J. Ind. Med.   38:  27-33.  (Cited  1n U.S.  EPA, 1985)

Field, B.  and C.   Kerr.   1979.   Herbicide use  and Incidence of  neural-tube
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Federal  Register.   1984.   Environmental  Protection Agency.   Proposed  guide-
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Food  Drug  Cosmetic Law  Reports.  1981.   FDA  Advises Great  Lake States  to
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                                     -32-

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Gelger, L.E.  and R.A. Neal.   1981.   MutagenUUy testing of  2,3,7,8-tetra-
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Glavlnl,  E.,  M. Pratl  and C.  Vlsmara.   1982a.   Effects  of  2,3,7,8-tetra-
chlorodlbenzo-p-dloxln administered  to pregnant  rats during  the  prelmplanta-
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Glavlnl, £., M.  Pratl  and C.  Vlsmara.  1982b.   Rabbit  teratology  study  with
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Glavlnl,  E.,  M.  Pratl   and  C.   Vlsmara.   1983.   Embryotoxlc   effects  of
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mating.  Environ. Res.  31: 105-110.   (Cited 1n  U.S.  EPA,  19851

Gilbert,  P.,  G.  Sa1nt-Ruf,  F.  Poncelet  and  M.  Herder.   1980.   Genetic
effects of  chlorinated anilines and azobenzenes on Salmonella  typhlmurlum.
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changes   In   mixed   function   oxygenases,  and   hlstopathologlcal   changes.
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                                     -33-

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Goldstein, J.A., P. L1nko and  H.  Bergman.   1982.   Induction of porphyrla In
the rat  by chronic  versus  acute  exposure  to  2,3,7,8-tetrachlorod1benzo-p-
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Green,  S. and  F.S.  Moreland.   1975.   Cytogenetlc  evaluation  of  several
dloxlns 1n the  rat.   Toxlcol. Appl. Pharmacol.   33:  161.   (Abstr.)   (CHed
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Green,  S.,  F.  Moreland  and  C.  Sheu.   1977.  .Cytogenlc effect  of 2,3,7,8-
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Grelg, 3.B.   1972.   Effect  of 2,3,7,8-tetrachlorod1benzo-l,4-dloxln on  drug
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Gurtoo, H.L.  1980.  Genetic expression of aflatoxln. Bl metabolism:  Effects
of  3-methylcholanthrene  and  2,3,7,8-tetrachlorod1benzo-p-d1ox1n  on   the
metabolism of  aflatoxln  Bl  and  aflatoxln  B2 by  various  Inbred  strains of
mice.  Mol. Pharmacol.   18(2): 296-303.   (CHed 1n U.S.  EPA, 1985)

Hanlfy,  J.A.,  P.  Metcalf,  C.L.  Nobbs and   R.J.  Worsley.   1981.    Aerial
spraying  of  2,4,5-T  and  human  birth malformations: An  epldemlologlcal
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                                     -34-

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'  Harden,  L.   1977.  Soft-tissue  sarcomas  and exposure to  phenoxy  adds:   A
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  Hardell,  L.,  M.  Eriksson,  P.  Lenner  and   E.  Lundgren.   1981.   Malignant
  lymphoma  and exposure  to  chemicals,  especially organic solvents, chlorophe-
  nols   and phenoxy  acids:   A  case-control   study.   Br.   J.  Cancer.   43:
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                                                      •
  Hay,  A.   1978.   Vietnam's  dloxln problem.  Nature.  271: 597-598.  (Cited In
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  Hay,  A.   1982.   Toxicology  of  dloxlns.   In.:   The Chemical  Scythe Lessons of
  2,4,5-T  and  01ox1n.  Plenum  Press,  NY.  p. 41-47.

  HlnsdUl, R.O.,  D.L.   Couch  and  R.S.  Spelrs.   1980.   Immunosuppresslon  1n
  mice   Induced by  dloxln  (TCOD)  1n  feed.    J.   Environ.   Pathol.  Toxlcol.
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                                       -35-

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Holden, C.   1979.   Agent Orange  furor  continues  to  build.   Science.   205:
770-772.  (Cited 1n U.S.  EPA,  1985)

Honchar,  P.A.  and  W.E.  Halpern.   1981.   2,4,5-T,  tMchlorophenol and  soft
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Hussaln,  S.,  L. Ehrenberg,  G.  Lofroth  and  T. Gejvall.   1972.   Mutagenlc
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IARC (International Agency for Research on  Cancer).   1977.  Monographs.   15:
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Khera, K.S. and W.P. McKlnley.  1972.   Pre- and postnatal  studies  on  2,4,5-T
and  2,4-0 and  their  derivatives 1n  rats.  Toxlcol.  Appl.  Pharmacol.   22:
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Khera,  K.S.  and  J.A.  Ruddlck.   1973.    Polychlorod1benzo-p-d1ox1ns:   Peri-
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                                     -36-

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Khera,  K.S.,   B.L.  Huston  and  W.P.  McKlnley.   1971.   Pre- and postnatal
studies on  2,4,5-T,  2,4-D,  and derivatives  In  VMstar  rats.  Toxlcol. Appl.
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Klmbrough,  R.D.,  H.  Falk, P.  Stehr,  C. Portler and  G.  Fries.  1983.   Risk
assessment  document   on   2,3,7,8-tetrachlorodlbenzodloxln  (TCOD)  levels  In
soil.   Center  for Environmental  Health,  Centers  for  Disease Control,   Na-
tional Institute of Environmental  Health Sciences, USOA,  Beltsvllle, MD.

King, M.E.  and  A.R.  Roesler.   1974.   Subacute Intubation study  on rats  with
the   compound   2,3,7,8-tetrachlorod1ox1n.    U.S.   Department  of  Commerce.
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Kodba, R.J.,  P.A.  Keeler,  C.N.  Park  and  P.J.  Gehrlng.   1976.  2,3,7,8-
Tetrachlorod1benzo-p-d1ox1n   results  of  a  13-week  oral  toxtelty  study  1n
rats.  Toxlcol. Appl. Pharmacol.   35:  553-574.   {Cited  1n U.S.  EPA, 1985)
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Kodba, R.J.,  D.G. Keyes, J.E. Beyer,  et  al.   1978.   Results of a two-year
chronic  toxldty  and oncogenldty  study  of  2,3,7,8-tetrachlorodlbenzo-p-
dloxln  In  rats.   Toxlcol. Appl.  Pharmacol.   46{2):  279-303.   (Cited  In  U.S.
EPA, 1985)

Kodba, R.J.,  D.G. Keyes, J.E.  Beyer,  R.M. Carr.eon  and  P.J.  Gehrlng.  1979.
Long-term  toxlcologlc  studies  of 2,3,7,8-tetrachlorod1benzo-p-d1ox1n  (TCDD)
In  laboratory  animals.   Ann. NY  Acad.  Sc1.    320:  397-404.   (Cited  In  U.S.
EPA, 1985)
                                     -37-

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HcCann.  1978.   Unpublished study.   (Cited  1n  U.S.  EPA.  1985)

McQueen, E.G.,  A.M.O. Veale, W.S.  Alexander  and M.N. Bates.  1977.   2,4,5-T
and  human  birth  defects.    Report  of  the Division  of Public  Health,  New
Zealand Dept.  of Health.   (Cited 1n U.S.  EPA, 1985)

Moore, J.A., 8.N. Gupta, J.G.  Z1nkl and J.G. Vos.   1973.   Postnatal  effects
of  maternal  exposure  to  2,3,7,8-tetrachlorod1benzo-p-d1ox1n  (TCDO).    En-
viron.  Health  Perspect.  5:  81-85.   (Cited 1n U.S. EPA, 1985)

Moses,  M.  and  I.J.  Sellkoff.   1981.   Soft  tissue sarcomas,  phenoxy herbi-
cides,  and chlorinated  phenols.   Lancet.   1(8234): 1370.   (Cited 1n  U.S.
EPA, 1984a)

Mottura,  A.,  G.  Ze1,  F.  Nuzzo, et  al.   1981.   Evaluation»of results  of
chromosome analyses on  lymphocytes  of TCDO exposed subjects after  the Seveso
accident (Abstract).  Mutat.  Res.  80:  238-239.  (Cited 1n IARC. 1982)

Murray. F.J.. F.A.  Smith.  K.D.  NUschke. C.G. Humlston. R.J.  Koclba and B.A.
Schwetz.   1979.   Three-generation  reproduction study of rats  given 2,3,7,8-
tetrachlorod1benzo-p-d1ox1n  (TCDD)  1n  the  diet.   Toxlcol. Appl.  Pharmacol.
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NAS  (National Academy of Sciences).   1977.   Drinking Water and  Health:   Part
II.  NAS,  Washington, DC.  (Cited 1n U.S. EPA, 1985)
                                     -38-

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Nebert, 0.,  S.  Thorglersson and  J.  Felton.   1976.   Genetic differences  1n
mutagenesls,  carclnogenesls,  and  drug  toxldty.   in:  lr±  vitro  metabolic
activation 1n mutagenesls  testing.   F.  de Serros, J. Folets, J.  Bend  and  R.
Phllpot,  Ed.   Elsevler/North  Holland   Blomedlcal   Press,   Amsterdam.    p.
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Nelson, C.J., J.F. Holson, H.G. Green and  D.W.  Gaylor.   1979.   Retrospective
study  of  the  relationship between  agricultural  use  of  2,4,5-T and  cleft
palate occurrence 1n Arkansas.   Teratology.  19: 377-384.

Neubert,  D.  and  I.  Olllmann.   1972.   Embryotoxlc  effects  In  mice  treated
with   2,4,5-tr1chlorophenoxyacet1c   add   and   2,3,7,8-tetrachlorodlbenzo-p-
dloxln.  Arch. Pharmacol.  272(3):  243-264.  (Cited  1n U.S. EPA,  1985)

Nlsbet, I.C.T. and H.B.  Paxton.  1982.  Statistical  aspects  of  three-genera-
tion  studies  of the reproductive  toxldty of  TCOO  and 2,4,5-T.  Am.  Stat.
36(3):  290-298.  (Cited  1n U.S. EPA, 1984a)

Nolan,  R.J.,  F.A.  Smith and  J.G.   Hefner.   1979.    Elimination  and  tissue
distribution  of  2,3,7,8-tetrachlorod1benzo-p-d1ox1n  (TCOO) 1n female  guinea
pigs  following  a  single oral  dose.  Toxlcol.  Appl.  Pharmacol.  48:  A162.
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                                     -39-

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•  NTP (National Toxicology  Program).   1980.   Bloassay of 2,3.7,8-tetrachloro-
  d1benzo-p-d1ox1n for possible cardnogenlclty (Gavage study).  DHHS Publica-
  tion No. (NIH) 82-1765.  Cardnogenesls Testing Program. NCI, NIH, Bethesda.
  HO.  and National Toxicology Program, Research Triangle Park, NC.  (Cited In
  U.S. EPA,  1985)

  Olson,   J.R.,  T.A.  Gaslewlcz  and  R.A.  Neal.   1980.   Tissue  distribution,
  execretlon  and  metabolism of 2,3,7,8-tetrachlorod1benzo-p-d1ox1n  (TCDO)  1n
  the Golden  Syrian hamster.  Toxlcol.  Appl.  Pharmacol.  56: 78-85.  (CHed In
  U.S. EPA,  1984a)

  Piper,   W.N.,  R.Q.  Rose  and  P.J.   Gehrlng.   1973.   Excretion   and  tissue
  distribution   of  2,3,7,8-tetrachlorod1benzo-p-d1ox1n In  the rat.  Environ.
  Health  Perspect.  5:241-244.   (CHed  In U.S.  EPA, 1985)
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  dermal   and  Intestinal   absorption  of  TCDD.   Food  Cosmet.  Toxlcol.   18(5):
  477-481.  (CHed In  U.S. EPA,  1985)

  Reddy,   T.V.,  T. Benjamin,  P.H.  Grantham,   E.K.  Welsburger and  S.S.   Thor-
  gelrsson.   1980.  Mutagenlclty  of urine  from rats  after  administration of
  2,4-d1am1no-an1sole:  the effect of mlcrosomal enzyme Inducers.  Mutat. Res.
  79(4):  307-317.   (CHed 1n U.S.  EPA,  1985)

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  Toxlcol. Environ. Health.   6(1):  27-43.   (CHed  In U.S.  EPA, 1985)
                                       -40-

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•  R11h1make,  V.,  S.  Asp, A.M. Seppalalnen and  S.  Herberg.   1980.  Symptomato-
  logy,  Morbidity and Mortality Experience of  Chlorinated  Phenoxy Add Herbi-
  cide  (2,4-0  and  2,4,5-T)  Sprayers  1n  Finland:  A  Clinical  and  Ep1dem1o-
  loglcal  Study.   Institute of Occupational  Health, Helsinki, Finland.  (Cited
  1n  U.S.  EPA,  1985}

  Rogers,   A.M.,   M.E.  Anderson  and   K.C.   Back.    1982.   Mutagenldty  of
  2,3,7,8-tetrachlorod1benzo-p-d1ox1n  and  perfluoro-n-decanolc add  1n L5178Y
  mouse  lymphoma  cells.  Mutat. Res.  105: 445-449

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  Cosmet.   Toxlcol.   9(5):  671-676.  (Cited 1n  U.S. EPA, 1985)

  Rose,  O.Q.,  J.C.  Ramsey,  T.H.  Wentzler,  R.A.  Hummel   and  P.J.  GehMng.
  1976.   The fate of  2,3,7,8-tetrachlorod1benzo-p-d1ox1n  following single and
  repeated oral doses to the  rat.  Toxlcol.  Appl. Pharmacol.  36(2): 209-226.
  {Cited  1n U.S.  EPA.  1985)

  ScarpelH,  D.6.,  M.S. Rao,  V.  Subbarao, M.  Beversluls,  D.P. Gurka and P.P.
  Hollenberg.   1980.   Activation of nltrosamlnes  to mutagens by  postmltochon-
  drlal  fraction  of  hamster  pancreas.   Cancer Res.  40(1):  67-74.  (Cited 1n
  U.S.  EPA, 1985)

  Seller,   3.P.   1973.   A  survey  on  the  mutagenldty of  various pesticides.
  Exper1ent1a.  29: 622-623.   (Cited 1n  U.S.  EPA,  1984a)
                                       -41-

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Smith,  F.A.,  B.A.  Schwetz  and  K.O.  NHschke.   1976.   Teratogenlclty  of
2,3,7,8~tetrachlorod1benzo-p-d1ox1n  1n CF-1  mice.  Toxlcol.  Appl.  Pharma-
col.  38{3): 517-523.   (Cited In U.S.  EPA,  1985)

Sparschu, G.L.,  Jr.,  F.L. Dunn,  Or.,  V.K. Rowe, Jr.   19713.   Study of the
teratogenlcHy  of  2,3,7,8-tetrachlorod1benzo-p-d1ox1n   1n  the  rat.   Food
Cosmet. Toxlcol.  9:  405-412.  (Cited  1n  U.S.  EPA, 1985)

Sparschu, 6.L.,  F.L.  Dunn,  R.W.  Llsowe  and  V.K. Rowe.   1971b.   Effects of
high  levels of  2,4,5-tr1chlorophenoxyacet1c add on fetal development 1n the
rat.  Food Cosmet. Toxlcol.  9(4): 527-530.  (CUed  1n U.S.  EPA,  1985)

Tenchlnl, M.L., C. CMmaudo,  G.  S1mon1,  L. DeCarll, R.  G1org1 and F. Nuzzo.
1979.  Approaches  to  the evaluation of  genetic  damage  after  a major hazard
1n  chemical  Industry:    Preliminary  cytogenetlc  findings OB  TCDD-exposed
subjects  after  the Seveso  accident.   .In:  Genetic  Damage  In  Han  Caused by
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Thless,  A.M.  and R.  Frentzel-Beyme.   1977.   Mortality  Study  of  Persons
Exposed  to  D1ox1n Following  on Accident  Which  Occurred 1n the  BASF  on 13
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1977.  (Cited 1n U.S. EPA, 1984a)
                                     -42-

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Thlgpen, J.E., R.E.  Faith,  E.E.  McConnell  and J.A. Moore.   1975.   Increased
susceptibility to  bacterial  Infection  as. a  sequela  of exposure to  2,3,7,8-
tetrachlorod1benzo-p-d1ox1n  on   the  Immune  response  of  young  mice.   Drug
Chem. Toxlcol.  2(1,2): 77-98.   (Cited  1n U.S.  EPA, 1985)

Thomas, R.F.   1980.   Internal  memo to  P.  Cohn,  Office of  Toxic  substances,
U.S. EPA,  Washington, DC.  (Cited In U.S. EPA,  1985)

Thompson,  D.J., J.L. Emerson and 6.L. Sparschu.  1971.  Study  of  the effects
of  2,4,5-tr1chlorophenoxyacet1c  add   (2,4,5-T)   on   rat  and  rabbit  fetal
development.  Teratology.  4: 243.   (Abstr.)   (Cited  1n U.S. EPA,  1985)

Toth,  K.,   J.  Sugar,  S.  Somfal-Relle  and  J.  Bence.   1978.   Carcinogenic
bloassay of the herbicide,  2,4,5-trlchlorophenoxyethanol  (TCPE) with differ-
ent  2,3,7,8-tetrachlorod1benzo-p-d1ox1n  (dloxln)   content   In  Swiss  mice.
Prog. Blochem. Pharmacol.  14:  82-93.   (Cited 1n  U.S.  EPA,  1985)
                                                    •
Toth,  K.,  S.  Somfal-Relle,  J.  Sugar  and  J.  Bence.    1979.   Carc1nogen1c1ty
testing of  herbicide 2,4,5-trlchlorophenoxyethanol containing dloxln and  of
pure dloxln  1n Swiss mice.  Nature  (Lend).   278(5704): 548-549.   (Cited  In
U.S. EPA,  1985)

Townsend,   J.C.,  K.M.  Bodner,  P.P.  Van Peenen,  R.D.  Olsen  and  R.R.  Cook.
1982.   Survey of  reproductive  events  of  wives  of  employees  exposed  to
chlorinated dloxlns.   Am.  J.  Ep1dem1ol.  115(5): 695-713.  (Cited  1n  U.S.
EPA. 1985)
                                     -43-

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Uotlla, P., Parkkl, M.G.  and  A.  AHIo.  1978.  Quantitative and  qualitative
changes 1n  the  metabolism of -benzo(a)pyrene  In  rat tissues after  Intragas-
trlc  administration  of  TCOD.  Toxlcol.  Appl. Pharmacol.   46(3):  671-683.
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U.S. EPA.   1979.   Report  of  Assessment of a Field  Investigation  of  Six-year
Spontaneous Abortion  Rates  In Three  Oregon  Areas  In  Relation  to  Forest
2,4,5-T Spray  Practice.   OTS/EPA.   (Cited 1n  U.S.  EPA,  1985}

U.S.  EPA.   1980.   Guidelines and  Methodology Used  1n  the  Preparation  of
Health  Effects   Assessment  Chapters  of  the  Consent  Decree  Water  Quality
Criteria.   Federal Register.   45:79347-79357.

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minations  Based on  Chronic   ToxUHy  Data.   Prepared by  the  Environmental
Criteria and Assessment Office, Cincinnati,  OH, OHEA  for the Office  of Solid
Waste and.Emergency Response,  Washington, DC.

U.S. EPA.   1984a.  Health Assessment Document  for  Polychlorlnated D1benzo-p-
D1ox1ns.  Environmental  Criteria  and Assessment Office, Cincinnati, OH.
EPA 600/8-84-OHA.  NTIS PB 84-220268.

U.S. EPA.   1984b.  Ambient Water  Quality Criteria  for 2,3,7,8-tetrachlorodl-
benzo-p-d1ox1n.    Environmental  Criteria and Assessment  Office,  Cincinnati,
OH.  EPA 440/5-84-007.  (Cited 1n U.S.  EPA, 1985)
                                     -44-

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U.S.  EPA.   1985.   Drinking Water Criteria  Document  for  2,3,7,8-Tetrachloro-
d1benzo-£-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.  Ol1e  and  0.  Hutzlnger.   1983.   Uptake and  selective
retention  1n  rats  of  orally administered  chlorinated  dloxlns and  dlbenzo-
furans from fly  ash and  fly ash extract.   Chemosphere.   12(4/5):  537-544
(Cited 1n U.5. EPA, 1984a)

Van  MUler,  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-p-
dloxln.  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-p-
dloxln.  Chemosphere.  6(9): 537-544.   (CUed In U.S% EPA, 1985)

Vos,  J.6.,  J.A. Moore and  J.G. Zlnkl.  1973.   Effect of  2,3.7,8-tetrachloro-
d1benzo-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:   Dloxln:  Toxlcologlcal  and  Chemical Aspects.   SO  Medical  and
Scientific Books, NY.  p.  163-175.   (Cited In U.S.  EPA,  1985)
                                     -45-

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Z1nkl, J.G.,  J.G.  Vos, J.A.  Moore and  B.N.  Gupta.   1973.  Hematologlc  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)
                                     -46-

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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.
                                     -48-
           U.S.  Environmental Protectton Agency
           Region V, Library
           230  South Dearborn Street
           Chicago,  JUinols  60604

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