Evaluation of the Potential Carcinogenicity of DDE (72-55-9)


UNITED STATES
ENVIRONMENTAL PROTECTION               JUNE 1988
*GEKCY       	FINAL
RESEARCH  AND
DEVELOPMENT
EVALUATION OF THE POTENTIAL CARCINOGENICITY OF

DDE

(72-55-9)




IN SUPPORT OF REPORTABLE dUANTITY ADJUSTMENTS

PURSUANT TO CERCLA SECTION 102
PREPARED  FOR

OFFICE OF EMERGENCY AND REMEDIAL RESPONSE

OFFICE OF SOLID WASTE AND EMERGENCY RESPONSE
PREPARED  BY
CARCINOGEN ASSESSMENT GROUP
OFFICE  OF HEALTH AND
ENVIRONMENTAL ASSESSMENT
WASHINGTON,  D.C.   20460

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                                  DISCLAIMER
This document has been reviewed in accordance with U.S.  Environmental
Protection Agency policy and approved for publication.   Mention of trade names
or commercial products does not constitute endorsement  or recommendation for
use.
                                      ii

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', .• PREFACE

This report summarizes and evaluates information on the potential
• carcinogenicity of a substance designated as hazardous.under Section 101 (14)
of the Comprehensive Environmental Response, Compensation and Liability Act of
1980•(CERCLA!. Pertinent epidemiologic and toxicologic data were obtained
through on-line searches and from hard-copy sources. On-line searches were
extended as far back as the data bases would allow. Retrieval of historical
data was accomplished through searches of hard-copy sources and bibliographies
of relevant publications. Every attempt has been made to rely upon primary
publications as opposed to data summaries or abstracts contained in secondary
sources such as monographs, surveys, review articles, criteria documents, etc.
The on-line data bases that were searched included CHEMLINE (National Library
of Medicine [NLM]>, RTECS CNLM), Toxicology Data Bank {NLM), TOXLINE
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effort to produce this document. Environmental Monitoring & Services, Inc.,
under EPA Contract No. 68-03-3182, has been involved in an extensive review of
all the Syracuse documents. In some cases, this review involved updating the
information provided but it was primarily a quality assurance effort. The
present document is a result of this effort.
IV
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ABSTRACT
DDE Is a probable human carcinogen, classified, as weight-of-evidence Group B2
under the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a).
Evidence on potential carcinogenicity from animal studies is "Sufficient," and
the evidence from human studies is "Inadequate."

The potency factor (F) for DDE is estimated to be 3.82 (mg/kg/day)"^, placing
it in potency group 2 according to the CAG's methodology for evaluating
potential carcinogens (U.S. EPA, 1986b).

Combining the weight-of-evidence group and the potency group, DDE is assigned a.
"MEDIUM." hazard ranking for the purposes of RQ adjustment.
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TABLE OF CONTENTS

' ' Page

1.0 WEIGHT OF EVIDENCE 1-1
1.1 ANIMAL STUDIES . 1-1
1.2 HUMAN STUDIES. 1-2
1.3 tfEIGHT-OF-EVIDENCE ASSESSMENT ... 1-2

2.0 POTENCY . 2-1

3.0 HAZARD HANKING 3-1

4,0 REFERENCES . 4-1

APPENDIX: SUMMARY OF SIGNIFICANT HUMAN AND/OR ANIMAL STUDIES
TABLES
Table 2-1. DERIVATION OF POTENCY FACTOR (F) 2-2
vl
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1.0 WEIGHT OF EVIDENCE
1.1 ANIMAL STUDIES

In a study conducted by the NCI (1978), B6C3F1 mice were fed 148 ppm and 261
ppni l,l-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) for 78 weeks, with 15
additional weeks of observation before termination. Thus for the 93 week study
the'transformed doses were 16.3 rag/kg/day and 28.7 mg/kg/day. DDE in the
females caused a DDE-dependent loss in weight as early as 10 weeks; the male
weights were unaffected. The mortality curve (increased deaths before
termination of the experiment) in the female mice was also affected by DDE
(P<0.001). The control male mortality was 15/20 (75%) at 70 weeks.
Hepatocellular carcinomas were observed in mice of both sexes, with the
strongest response occurring in the females. The incidence of carcinoma in the
control, low-, and high-dose animals, respectively were as follows: females,
0/19, 19/47 and 34/48; males, 0/19, 7/41, and 17/47.

In a parallel NCI study (1978), male Osborne-Mendel rats were fed 437 ppm and
839 ppm and females were fed 242 and 462 ppm DDE for 78 weeks, and observed for
an additional 15 weeks. None of the rats responded with tumors within the
2-year study period. The rats exhibited liver involvement in the form of
centrilobular necrosis and fatty metamorphosis.

In a study by Tomatis (1974), CF-1 mice were fed 250 ppm DDE for 130 weeks.
The female mice treated with DDE showed increased hepatomas (authors'
terminology) (54/55 vs 1/90 in controls) as well as early appearance of
hepatomas. Male CF-1 mice responded similarly (39/53 vs 33/98 in controls) and
died earlier with hepatomas. The hepatomas were largest in size and occurred
with the greatest multiplicity (hepatomas/mouse) in DDE-treated mice as
compared with control mice.

Residue data from autopsies performed on the CF-1 mice showed that DDE was
retained in the liver to a degree second only to its rate of retention in body
fat. DDE residues occurred in normal livers at about the same levels as in
1-1
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tumorous livers, thereby indicating that the residual presence of DDE is not,
in and of itself, a sufficient cause of carcinogenesis in mice.

DDE was also tested for carcinogenicity in the hamster (Rossi et al. , 1983) .
At doses of 500 ppm and 1000 ppm, DDE in the diet of hamsters caused a
significant increase in the incidence (P <0.05) of hepatomas in males (7/30 and
8/39) and in females (4/39 and 6/39) . The incidence of tumors in controls was
"0/31 (males) and 0/42 (females). These hamster liver tumors had a latency
period of more than 76 weeks. (DDT did not produce tumors in hamsters at the
same dose levels.)

1.2 HUMAN STUDIES

Pertinent data regarding the carcinogenic effects of human exposure to DDE were
not located in the available literature.

1.3 WEIGHT- OF-EVIDENCE ASSESSMENT

DDE has been shown to produce liver tumors in mice in two independent studies
and liver tumors in hamsters in an additional study. The value of the NCI study
was limited by the poor survival in the control male mice. Fifteen of the 20
control mice died by week 70, This limited survival could have curtailed the
development of late-developing hepatomas in the controls. In all these studies,
the compound was administered by incc - - - '- — : — ''~~ •*'-*- T- •* "••'""•'lar
study using rats, no statistically s: — , /, > • . of any
|As_ tiait\dtj,, te-A mtn-4 , ,
tumors was observed in the treated ai
carcinogenic effects of DDE in human; p I- 2s r
Carcinogen Risk Assessment (U.S. EPA weight
of evidence to humans, DDE is most a 42
chemical. Appendix A contains summa ni animal
studies cited in this review.
Despite the quantitatively greater i / Tomatis
study, relative to the NCI study, ar - ' e in the
NCI study, the latter was chosen for potency *>„. ., .me NCI used 2
1-2
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treated groups, compared to 1 used by Tomatis. Furthermore, the historical
hepatocellular carcinoma rate in untreated female B6C3F1 mice was S7/1683, as
of 12/5/88 (NTP, personal communication). The Incidences of hepatocellular
malignancies in both groups of treated female mice therefore appeared to exceed
background levels. The appendix contains summaries of the significant human
and/or animal studies cited in this review.
1-3
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2.0 POTENCY
The potency factor (F) for DDE is estimated to be 3.82 (mg/kg/day)"^, placing
it in potency group 2 under the CAG's methodology for evaluating potential
carcinogens (U.S. EPA, 1986b), Table 2-1 contains data from the selected study
used to derive the potency factor (F) for DDE.

The U.S. EFA (1986c) used a geometric mean of similar potencies from general
studies of DDT, DDE, ODD, and dicofol to estimate the potency of DDE for risk
assessment purposes. For this ranking of carcinogens, however, it is
considered important that all substances be ranked by the same methodology as
much as possible. Therefore, the study judged most appropriate for each
substance individually has been used in ranking these substances.
2-1
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Table 2-1. Derivation of Potency Factor(F)
Agent: DDE
REFERENCE:

EXPOSURE ROUTE:

SPECIES:

STRAIN:

SEX:

VEHICLE OR PHYSICAL STATE:

BODY WEIGHT:8

DURATION OF TREATMENT:

DURATION OF STUDY:

LIFESPAN OF ANIMAL:8

TARGET ORGAN:

TUMOR TYPE:

EXPERIMENTAL DOSES/EXPOSURE:

TRANSFORMED DOSES:b
(ing/kg/day)

TUMOR INCIDENCE:
ANIMAL POTENCY:
(nig/kg/day)

HUMAN POTENCY:0
(mg/kg/day)
1
1
NCI. 1978

oral

mice

B6C3F1

diet

0.03 kg

546 days
V
644 days

730 days

liver

hepatocellular carcinoma

0.0 ppm 148 ppm

0.0 16.3
0/19

0.198

3.82
19/47
261 ppm

28.7

34/48
the transformed dose from the experimental dose data: experimental dose (ppm) x an empirically-derived food factor corresponding to
8 Estimated
** Jo dcr ive _ __
the fraction ofbody'yeight that is consumed each day as food (0.13 in mice) x (duration of treatment/duration of study).
c Human potency = animal potency x (70 kg/0.03 kg)
1/3
x (730 days/644 days)3 to adjust for the short study duration.
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3.0 HAZARD RANKING
Based on the weight-of-evidence Group B2 for DDE, and Che potency factor (F) of
3.82 (ng/kg/day)"1, DDE receives a hazard ranking of "MEDIUM."
3-1
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4.0 REFERENCES
NCI (National Cancer Institute), 1978. Bioassays of DDT, TDE, and p,p'-DDE for
Possible Carcinogenlcity. Publ. No, NCI-CG-TR-131. U.S. DH1¥, PHS, NIH,
p. 117.

Rossi, L,, 0. Barbieri, M. Sanguineti, C. Marina, R.P. Jose, P. Bruzzl and L.
Santl, 1983. Carcinogenlcity Study with Technical-Grade Dichlorodlphenyltri-
chloroethane and l,l-Dichloro-2,2-Bis(p-Chlorophenyl)Ethylene in Hamsters.
Cancer Ees, 43(2): 776-781.

Tomatls, L., V. Turusov, R.T. Charles and M. BoloccM, 1974. The Effect of
Long-Term Exposure to i,l-Dichloro-2,2-Bls(p-Chlorophenyl)Ethylene (p.p'-DDE),
to 1,l-Dichloro-2»2-Bls(p-Chlorophenyl)Ethane (p,p'-DDD) and to the Two
Chemicals Combined, on CF-1 Mice. J. Natl. Cancer Inst. 52: 883-891.

U.S. EPA (Environmental Protection Agency), 1986a. Guidelines for Carcinogen
Risk Assessment, 51 FR 33992-34003, September 24, 1986.

U.S. EPA (Environmental Protection Agency), 1986b. Methodology for Evaluating
Potential Carclnogenicity in Support of Reportable Quantity Adjustments
Pursuant to CERCLA Section 102, OHEA-C-073, December 1986. Available from
CERCLA Docket 102RQ-273C. The public docket for RQ rulemaking is located in
room M2427, U.S. Environmental Protection Agency, 401 M Street, SW, Washington,
DC 20460. It Is available for inspection Monday through Friday excluding
Federal holidays, between the hours of 9:00 a.m. and 4:00 p.m.

U.S. EPA (Environmental frotection Agency), 1986c. The Assessment of the
Carcinogenlcity of Dlcofol (Kelthane), DDT, DDE, and DDD (TDE), EPA-600/6-86-
001, February 1986,- AJT) S

U.S. EPA (Environmental frotection Agency), 1988. Technical Background
Document to Support Rulemaking Pursuant to CERCLA Section 102, Volume 3, Draft,
Appendix A, April 26, 1988.
4-1
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APPENDIX
SUMMARY OF SIGNIFICANT HUMAN AND/OR ANIMAL STUDIES
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Table A. Animal

Agent: DDE

Reference: NCI. 1978
Dose Duration Duration Purity Vehicle or
Exposure Species/ or of of of Physical Target
Route Strain Sex Exposure Treatment Study Compound State Organ
Tumor Type
Tumor
Incidence
(P value)
oral
oral
oral
oral
oral
oral
oral
oral
rat/
Osborne-
Hendel

rat/
Osborne-
Hendel

rat/
Osborne-
Mendel

rat/
Osborne-
Hendel

mouse/
B6C3F1

mouse/
B6C3M
H 0.0 ppm NA 111 uks NA
NA
any organ any tumor
H 437 ppma 78 uks 111 uks 95X diet any organ any tumor
H 839 ppma 78 uks 111 uks 95% diet any organ any tumor
F 0.0 ppm NA 111 uks NA
H 0.0 ppm NA
NA
92 uks
H 148 ppma 78 uks 92 uks
NA
95%D
NA
any organ any tumor
F 242 ppma 78 uks 111 uks 95Xb diet any organ any tumor
F 462 ppma 78 uks 111 uks 95Xb diet any organ any tumor
NS
NS
NA
NS
NS
liver hepatocellularc 0/19
carcinoma
diet liver hepatocellular 7/41
carcinoma
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Table A. Animal

Agent: DDE

Reference: NCI, 1978 (cont.)
Dose
Exposure Species/ or
Route Strain Sex Exposure
oral mouse/ H 261 ppma
B6C3F1
oral mouse/ F 0.0 ppm
B6C3F1
oral mouse/ F 148 ppm8
B6C3F1
oral mouse/ F 261 ppm°
^t> B6C3F1
UD
Duration Duration
of of
Treatment Study
78 uks 92 uks

NA 92 uks

78 uks 92 uks

Puri ty
of
Compound
95Xb

95Xb

Vehicle or
Physical Target
State Organ
diet I iver

NA liver

diet liver

Tumor Type
hepatocel lular
care inoma
hepatocel lular
carcinoma
hepatocel lular
carcinoma
hepatocel lular
carcinoma

Tumor
Incidence
(P value)
17>47
(P<0.001)
0/19

19/47
(P<0.001)
34/48
(P<0.001)

QUALITY OF EVIDENCE
Strength of Study:
Extensive histopathological examinations uere performed. Tuo levels of exposure uere used. A significant dose-response
uas observed in the female mice as uell as the male mice.
Weaknesses of Study: The survival of both control and high dose male mice uas belou historical values. Survival in control female mice uas
also belou historical values.

Overall Adequacy: Adequate for female mice, but poor survival in the control male mice (15 of 20 control mice died by ueek 70) limited
evaluation in the male mouse.
8 The exposure is expressed as the time-ueighted average exposure calculated for the treatment period.
b Gas liquid chromatography uas used to confirm that the compound uas p,p'-DDE.
c The pathologist made no differentiation among the liver tumors. All uere designated hepatocellular carcinomas. No adenomas uere reported.
NA = Not applicable; NS = Not significant
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Table A. Animal

Agent: DDE

Reference: Rossi et al., 1983
Exposure
Route
o
o
o
o
0
o
0
o
Dose
Species/ or
Strain Sex Exposure
hamster/ H 500 ppm
Syrian
Golden
hamster/ F 500 ppm
Syrian
Golden
hamster/ H 1000 ppm
Syrian
Golden
hamster/ F 1000 ppm
Syrian
Golden
hamster/ H 0 ppm
Syrian (control)
Golden
hamster/ F 0 ppm
Syrian (control)
Golden
hamster/ H 1000 ppm
Syrian DDT
Golden
hamster/ F 1000 ppm
Syrian DDT
Golden
Duration Duration Purity Vehicle or
of of of Physical
Treatment Study Compound State
120 weeks 120 weeks 99% olive oil/
diet
120 weeks 120 weeks 99% olive oil/
diet
120 weeks 120 weeks 99% olive oil/
diet
120 weeks 120 weeks 99% olive oil/
diet
120 weeks 120 weeks NA olive oil/
diet
120 weeks 120 weeks NA olive oil/
diet
120 weeks 120 weeks technical olive oil/
grade diet
120 weeks 120 weeks technical olive oil/
grade diet
Target
Organ
I i ver
adrenal
I iver
adrenal
1 iver
adrenal
I iver
adrenal
I iver
adrenal
I iver
adrenal
I iver
adrenal
I iver
adrenal
Tumor Type
neoplast ic
nodules
adenoma
neoplast ic
nodules
adenoma
neoplastic
nodules
adenoma
neoplast ic
nodules
adenoma
neoplast ic
nodules
adenoma
neoplast ic
nodules
adenoma
neoplast ic
nodules
adenoma
neoplast ic
nodules
adenoma
Tumor
Incidence
(P value)
V/30
I
5/30
4/39
7/39
8/39a
17/39
6/39b
8/39
0/31
8/31
0/42
2/42
0/35C
U/35
0/36C
10/36
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Table A. Animal

Agent: DDE

Reference: Rossi et al., 1983 (cont.)

Exposure
Route

Species/
Strain Sex
Dose
or
Exposure
Durat ion
of
Treatment
Duration
of
Study
Puri ty
of
Compound
Vehicle or
Physical
State

Target
Organ
Tumor
Incidence
Tumor Type (P value)
QUALITY Of EVIDENCE
Strengths of Study:

Overall Adequacy:

Comments:
Histological studies were carried out on a variety of tissues and organs. Animals were treated from 8-128 weeks of age.
Two levels of exposure were used.

Adequate

DDT was also tested in this study. The authors concluded that DDE, a metabolite of DDT, plays a major role in DDT
careinogenesis. •
a Five additional animals showed hyperplastic foci of the liver.
Three additional animals showed hyperplastic foci of the liver.
NA = Not applicable
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Table A. Animal

Agent: DDE

Reference: Tomatis et al., 1974
Exposure
Route
o
o
o
0
Species/
Strain Sex
mouse/ H
CF-1
mouse/ H
CF-1
mouse/ F
CF-1
mouse/ F
CF-1
Dose
or
Exposure
0.0 ppm
250 ppm
0.0 ppm
250 ppm
Durat ion
of
Treatment
NA
123 ueeks
NA
123 ueeks
Durat ion
of
Study
123 ueeks
123 ueeks
123 ueeks
123 ueeks
Purity
of
Compound
NA
NR
NA
NR
Vehicle or
Physical Target
State Organ
NA liver
diet liver
NA liver
diet I iver
Tumor
Incidence
Tumor Type (P value)
hepatoma 33/d8
hepatoma 39/53
hepatoma 1/90
hepatoma 54/55
QUALITY OF EVIDENCE

Strengths of Study: Animals were treated from 7 ueeks old until 130 ueeks old. The incidence of lymphomas. lung tumors, and osteomas uere
also enumerated.

Weaknesses of Study: Only one level of exposure uas used.

Overall Adequacy: Adequate

NA = Not applicable; NR = Not reported
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(Pteasf
TECHNICAL REPORT DATA
completr
1. REPORT NO.
EPA/600/8-91/100
2.
3,
PB93-185247
«. TITLE AND SUBTITLE
Evaluation of the Potential Carcinogenicity of
DDE (72-55-9)
5. REPORT DATE

.Innp 1QRS
6. PERFORMING ORGANIZATION CODE
7. AUTHORISi
8- PERFORMING ORGANIZATION REPORT NO
Syracuse Research Corporation
Environmental Monitoring & Services,
Jrui,
OHEA-C-Q73-D74
9, PERFORMING ORGANIZATION NAME AND ADDRESS
Syracuse Research Corporation, Syracuse, NY
Environmental Monitoring & Services, Inc. (now ABB
Environmental Services, Inc.), Washington, DC
10, PROGRAM ELEMENT NO.
1 1. CONTRACT/GRANT NO.
68-03-3112
68-03-3182
12. SPONSORING AGENCY NAME AND ADDRESS
Office of Health and Environmental Assessment
Carcinogen Assessment Group (RD-689)
U.S. Environmental Protection Agency
Washington, DC 20460
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
. EPA/600/021
. SUPPLEMENTARY NOTES
IB. ASSTBACT
DDE is a probable human carcinogen, classified as weight-of-evidence Group B2
under the EPA Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a). Evidence on
potential carcinogenicity from animal studies is "Sufficient," and the evidence from human
studies is "Inadequate."
The potency factor (F) for DDE is estimated to be 3.82 (mg/kg/day)'1, placing it in
potency group 2 according to the CAG's methodology for evaluating potential carcinoqens
(U.S. EPA, 1986b).
Combining the weight-of-evidence group and the potency group, DDE is assigned a
"MEDIUM" hazard ranking for the purposes of RQ adjustment.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b,IDENTIFIERS/OPEN ENDED TERMS
COS ATI Field, Group
18. DISTRIBUTION STATEMENT

Release to Public
19. SECURITY CLASS (Tins Rtpmij

Unclassified .
21 NO OP
19
20, SECURITY CLASS iTIns paw;
• Unclassified
22-
EPA-Farm 2220-1 <«•». 4-77)
PREVIOUS EDITION IS OBSOLETE
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