Evaluation of the Potential Carcinogenicity of DDT (50-29-3)

UNITED STATES        '                 EPA/600/8-9171QT
ENVIRONMENTAL PROTECTION               JUNE 1988
AGENCY                               FINAL
	;	
RESEARCH  AND
DEVELOPMENT
EVALUATION OF THE POTENTIAL CARCINOGENICITY OF

DDT

(50-29-3*
IN SUPPORT OF REPORTABLE QUANTITY 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.
                                     it

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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 CNLM]), RTSCS
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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.
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ABSTRACT
DDT 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 for DDT is estimated to be 5.58 (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, DDT 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
1.1.1 SINGLE-GENERATION STUDIES 1-1
-1.1,2 MULTIGENERATION STUDIES 1-2
1.1.3 CONCLUSION ...... 1-3
1.2 HUMAN STUDIES, . 1-4
1.3 WEIGHT-OF-EVIDENCE ASSESSMENT . 1-5

2.0 POTENCY ........ 2-1

3.0 HAZARD RANKING 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
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1.0 WEIGHT OF EVIDENCE
1.1 ANIMAL STUDIES

A number of investigators have studied the effect of DDT in comprehensive
bioassay experiments. Single and multiple generation studies have been made.
-These will be discussed.

1.1.1 Single-Generation Studies

CF-1 mice were fed 0 and 100 ppm DDT continuously in the feed for their
lifetime (110 weeks), Thorpe and Walker (1973). Survivals were good in this
experiment and no overt toxicity from DDT was observed at 100 ppm; however,
liver .enlargement was observed as early as 50 weeks. Both benign and malignant
liver tumors were increased significantly, but the total tumor-bearing CF-1
mice did not differ among controls and treated groups. Walker et al. (1973)'
found similar results, but most liver tumors were benign. In another study,
CF-1 mice were fed 0 or 250 ppm DDT for 15 or 30 weeks and then observed for
65, 95, or 120 weeks before sacrificing (Tomatis and Turusov, 1975; Tomatis et
al, 1974). Increased time of exposure to 250 ppm DDT was proportional to the
increased total dose of DDT, which in turn appeared to be functionally linked
to increased benign liver tumors in both males and females. The appearance of
benign liver tumors was observed earlier than in other studies using this
strain. These liver tumors increased in size with longer exposure to DDT.
Thus, the latency period for benign liver tumors in CF-1 mice from DDT exposure
was shortened with increased exposure. Further, cessation of exposure after 15
or 30 weeks did not causer tumor regression in the liver; instead, the
DDT-induced benign liver tumors continued to grow,

Cabral et al. (1982a) fed HRC Portion rats (Wistar-derived) with 0, 125, 250,
or 500 ppm DDT for essentially the natural lifetime of this strain of rat. The
total number of tumor-bearing rats did not vary with dosage. The female rats
1-1
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responded with a slight increase in benign tumors, which were neither invasive
locally nor disseminated to other organs. The male rats did not respond. The
tumor response in female rats was weak compared to the response in nice.

Results similar to those of the Cabral et al. (1982a) study were found in
(C57BL/6 x C3H/Anf) Fl and (C57BL/6 x AKR) Fl mice (Innes et al., 1969). No
increase in tumors were observed, however, in a highly sensitive newborn mouse
bioassay following a single subcutaneous injection of 15,000 mg/kg DDT (Gargus
et al., 1969), or after chronic exposure of male and female B6C3F1 nice to
diets containing 22 or 44 ppm, and 87 or 175 ppm DDT, respectively, for 78
weeks. Liver tumors were produced in Wistar rats fed diets containing 500 ppm
DDT (Rossi et al., 1977) while no increase in tumors was observed in rats fed
diets containing 200 ppm DDT (Deichmann et al,, 1967; Radomski et al., 1965) or
in a study in which male rats were maintained on diets containing 210 or 420
ppm DDT for 78 weeks (NCI, 1978), Also in limited studies in hamsters (Agthe
et al., 1970), dogs (Lehman 1952, 1965) and monkeys (Durham et al., 1963) no
treatment related increases in tumor incidence were observed.

Syrian Golden hamsters were fed DDT at levels of 0, 125, and 500 ppm (Cabral et
al., 1982b). Male hamsters did not exhibit liver tumors, but mice and rats did
exhibit liver tumors at comparable levels of DDT. The number of tumor-bearing
.animals in male Porton-Wistar rats did not vary with dosage of DDT.

1.1.2 Multigetieration Studies

One of the first studies of DDT was a multigeneration study in which BALB/c
mice were fed DDT continuously for their lifetimes (Tarjan and Kemeny, 1969).
Five generations were each fed 3 ppm DDT, and each mouse was examined for
tumors after a lifetime of ingesting DDT. This study did not produce a
significant liver response: 3 benign hepatomas/683 mice, as compared to 0/406
in control BALB/c mice. Only lung tumors (41,3% of the observed tumors) and
leukemia (30.2% of the observed tumors) are considered significant; the
remaining tumors appeared not to be dose related or in excess of those same
tumors occurring in control nice.
1-2
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A six-generation study In CF-1 mice has been reported In which DDT was
incorporated in the diet at 0, 2, 10, 50, and 250 ppm (Turusov et al. , 1973;
Tomatis et al., 1972) Table 2-1 shows the benign liver tumor results (although
the authors refer to the benign tumors as "hepatomas"). Historical control
incidence for hepatomas in CF-1 mouse livers have been found to be 20 percent
in males and 13 percent in females. The liver response appears to be an
increase in an already-present event in untreated CF-1 controls. There was no
trend in tumor response from generation to generation. DDT also produced
increases in lung tumors in a 5-generation study in strain A mice (Shabad et
al., 1973). A two-generation study of BALB/c mice was performed in which 0,
2, 20, and 250 ppm DDT was incorporated into the diet (Terracini.et al.,1973).
Mice were fed DDT continuously for their lifetimes. The results indicated only
benign tumors.

1.1.3 Conclusion

Nine dietary,feeding studies have been conducted on DDT in mice. These
carcinogenicity bioassays were done in the U.S.S.R., Italy, England, the United
States, India, and Hungary on a total of 4,333 mice of various strains. Only
one of these studies (NCI, 1978) indicated no excess tumors due to DDT
exposure, while six other studies indicated excess liver tumors (and, in two
studies, lung tumors) in the mouse. In the one study that did not indicate an
excess of tumors due to DDT exposure, mice were dosed for a relatively short
period of 78 weeks.

Both benign tumors (hepatocellular adenomas) and malignant tumors
(hepatocellular carcinomas) were observed in the six positive liver tumor
studies. Benign and malignant lung tumors were observed in the two
multigeneration studies. Generally, the mouse tumors were not life-threatening
since dosed mice lived as long as control mice and as long as expected for the
various strains tested.
1-3
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The most common response to DDT in mice occurred in the Liver. Heterogeneous
cellular responses in mouse liver were observed, indicating various stages of
stimulated growth and tumorigenieity, as well as certain necrotic conditions,
seen especially at higher DDT dose levels. The livers first showed reversible
focal hyperplasia. With continued DDT exposure, some of these foci are known
to be able to convert to nodules. The nodules resulting from DDT varied in
size and cellular organization, but were most often composed of solid cords of
closely packed cells one to two cells thick. These cells differed little from
normal hepatocyte. The larger nodules compressed the surrounding parenchyma.
More malignant states were observed in the mouse"livers and were classified as
hepatocellular carcinomas. These DDT-induced lesions were morphologically
organized in wide trabeculae that formed papillary, glandular, and sometimes
whorl patterns. Occasionally, anaplastic regions were observed arranged in
rosettes. Necrotic or hemorrhagic areas were observed along with cystic areas.
Invasiveness was limited locally in the liver and lung, and dissemination
followed by metastasis was not observed in any of the studies.

These studies indicate either that DDT is acting in the mouse liver and lung as
a complete carcinogen (that is, as both an initiator and a promoter) or that
laboratory mice are already inherently initiated and are thus uniquely
sensitive to a compound such as DDT, which has well-documented promotion
potential (Peraino et al., 1975; Scribner et al., 1983; Hilpert et al., 1983;
Ito et al., 1983; and discussions and references in Pltot and Sirica, 1980), In
either case, however, DDT by itself causes liver and lung tumors in mice, a
finding which indicates that there is a potential for the same reaction in
humans,

A complete review of the literature on the carcinogenicity of DDT may be found
in U.S. EPA, 1985,

1.2 HUMAN STUDIES

There have been two studies of humans occupationally exposed to DDT, In the
first, Ortelee (1958) examined 40 employees of DDT manufacturing and formula-
1-4
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tlon plants. Of these 40 employees, 23 were exposed for <4 years and 17 were
exposed for 5-8 years. The estimated exposures range from 10-40 lag/kg/day, as
indicated from urinary DDA levels. No neoplastlc lesions were reported. In a
more recent retrospective cohort study, Ditraglia et al. (1981) reviewed tHe
mortality records of 354 employees of a DDT manufacturing plant who had worked
for at least 6 months prior to December 31, 1964. As of December 31, 1976,
there was no statistically significant increase in any neoplastic disease among
the exposed workers. It was noted, however, that the exposed population was
-young and that only a few deaths had occurred. The authors suggested that more
Information will be available with further observation of this cohort study and
the accumulation of more information on causes of death.

The effects of DDT on humans have been reviewed previously (IARG, 1974; WHO,
1979; U.S. EPA, 1980). It was the consensus of these reviews, which included
several prospective and case-control studies, that the data were based on
studies too limited and/or too short for any conclusions to be made as to
carcinogenesis.

1.3 WEIGHT-OF-EVIDENCE ASSESSMENT

Administration of DDT in the diet to rats and nice has resulted in the
development of liver tumors. Increased Incidences of leukemia also have been
reported in a study in which mice were maintained for 5 generations on diets
containing DDT. In rats, liver tumors were observed in some studies but not in
others. Negative results also have been reported in a single study using
hamsters. The reports regarding rats and mice provide sufficient evidence that
DDT is an animal carcinogen. No increased risk of cancer was observed in
studies of workers exposed to DDT. However, these studies are considered
inadequate since the length of observation time from the first exposure to DDT
was short. Thus, using the EPA Guidelines for Carcinogen Risk Assessment (U.S.
EFA, 1986a) for evaluating the overall weight of evidence to humans, DDT is
most appropriately classified as a Croup B2 chemical. The appendix contains
summaries of the significant human and/or animal studies cited In this review.
1-5
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2.0 POTENCY
The potency factor (F) for DDT is estimated to be 5.58 (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 DDT.

The U.S. EPA (1986c) used a geometric mean of similar potencies from several
studies of DDT, DDE, ODD, and dicofol to estimate the potency of DDT for risk
assessment purposes. For this ranking of carcinogens, however, it is
considered important that all substances be ranked by the same methodology as
nuch 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: DDT
REFERENCE:
EXPOSURE ROUTE:
SPECIES:
STRAIN:
SEX:
VEHICLE OR PHYSICAL STATE:
BODY UEIGHT:8
DURATION OF TREATMENT:
DURATION OF STUDY:
LIFESPAN OF ANIMAL:
TARGET ORGAN:
TUMOR TYPE:
EXPERIMENTAL DOSES/EXPOSURE:
TRANSFORMED DOSES :b
(mg/kg/day)
TUMOR INCIDENCE:
ANIMAL POTENCY:
(mg/kg/day)'1
HUMAN POTENCY:0
(mg/kg/dsy)"1
Turusov et al., 1973
oral
mice
CF-1
H
diet
0.03 kg
910 days
910 days
910 days
liver
hepatoma
0.0 ppm 2 ppm 10 ppm 50 ppm 250 ppm
0.0 0.26 1.3 6.5 32.5
97/328 179/354 181/362 214/383 301/350
0.42
5.58
b To derUe the transformed dose from the experimental dose data: experimental dose (ppm) x 0.13 (fraction of species body weight consumed as
food per day) x duration of treatment (days)/ duration of study (days).
c Human potency = animal potency x (70 kg/0.03 kg) f
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3,0 HAZARD RANKING
Based on the weight-of-evidence Group B2 for DDT, and the potency factor (F) of
5.58 (ng/kg/day}-l, DDT receives a hazard ranking of "MEDIUM."
3-1
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4.0 REFERENCES
Agthe, C,, H, Garcia, P. Shubik, L, Tooatis, and E. Wenyon, 1970. Study of the
Potential Carcinogenieity of DDT in Syrian Golden Hamsters. Proc. Soc. Exp.
Med., NY. 134: 113. (Cited in IARC, 1973),

Cabral, J.R.P., R. K. Hall, L. Rossi, S, A. Bronczyk, and K. P. Shubik, 1982a.
Effects of Long-Term Intake of DDT on Rats. Tumori 68:11-17.

Cabral, J.R.P., R. K. Hall, L. Rossi, S. A. Bronczyk, and K. P. Shubik, 1982b.
Lack of Carcinogenieity of DDT in Hamsters. Tumori 68:5-10.

Deichmann, W.B.,. M. Keplinger, F. Sala and E. Glass, 1967. Synergism Among
Oral Carcinogens. IV. Simultaneous Feeding of Four Tumorigens to Rats.
Toxicol. Appl. Pharmacol. 11: 88.

Ditraglia, D., D.P. Broan, T. Namekata, and N. Iverson, 1981. Mortality Study
of Workers Employed at Organochlorine Pesticide Manufacturing Plants, Scand,
J. Work Environ. Health. Supp. 4: 140-146.

Durham, W.F., Ortega, P. and W.J. Hayes, Jr., 1963. The Effect of Various
Dietary Levels of DDT on Liver Function, Cell Morphology and DDT Storage in the
Rhesus Monkey. Arch. Int. Pharmacodyn. 141: 111. (Cited in IARC, 1973).

Gargus, J.L., D.E. Paynter and W.H. Reese, 1969. Utilization of Newborn Mice
in the Bioassay of Chemical Carcinogens. Toxicol. Appl, Pharmacol. 15(3);
552-559.

Hilpert, D., W. Romen, Hans-Gunter Neumann, 1983. The Role of Partial
Hepatectomy and of Promoters in the Formation of Tumors in Non-Target Tissues
of Trans-4-Acetlyaminostilbene in Rats. Carcinogenesis 4(12):1519-1525,
4-1
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International Agency for Research on Cancer (IARC), 1974. DDT and Associated
Substances. In: Some Organochlorine Pesticides. IARC Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Han, Lyon, France: WHO.
IARC, Vol. 5, pp. 83-124.

Innes, J.R.M., B.M. Ulland, M.G. Valerio et al., 1969. Bioassay of Pesticides
and Industrial Chemicals for Tumorigenicity in Mice. A Preliminary Note, J,
Nat. Cancer Inst. 42: 1101.

Ito, N., H. Tsuda, R. Hasegawa, and K. Imaida, 1983. Comparison of the
Promoting Effects of Various Agents in Induction-of Preneoplastic Lesions in
Rat Liver. Environ. Health Perspect. 50:131-138,

Lehman, A.J., 1952. Chemicals in Foods - A Report to the Association of Food
and Drug Officials on Current Developments. II. Pesticides III. Subacute and
Chronic Toxicity. Quarterly Bull, Assoc. F and D. Officials of U.S. 16: 47.
(Cited in IARC, 1973).

Lehman, A.J., Ed., 1965. DDT fa Mixture of 1,1,l-Trichloro-2,2-Bis-
(p-Chlorophenyl)Ethane and l,l,l-Trichloro-2-(o-Chlorophenyl)-2-
(p-Chlorophenyl)Ethane. In: Summaries of Pesticide Toxicity, Food and Drug
Administration, U.S. DHSW, Washington, D.C., U.S. Government Printing Office.
p. 17. (Cited in IARC, 1973).

NCI (National Cancer Institute), 1978. Bioassay of DDT, TDE and p,p'-DDE for
Possible Carcinogenieity. Publication No. NCI-CG-TR-131. U.S. DHEW, PHS, NIH,
NCI p. 117.

Ortelee, M.F., 1958. Study of Men with Prolonged Intensive Occupational
Exposure to DDT. Arch. Industr. Health. 18: 433,

Peraino, C., R.J.M. Fry, E, Staffeldt, andJ. P. Christopher, 1975. Compara-
tive Enhancing Effects of Phenobarbltal, Amobarbital, Diphenylhydantoin, and
DDT of 2-Acetylaminofluorene-Induced Hepatic Tumorigenesis in the Rat. Cancer
Research 35:2884-2890.
4-2
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Pitot, H. C. and A. E, Sirica, 1980. The Stages of Initiation and Promotion in
Hepatocarcinogenesis. Biochim. Biophys. Acta 605:191-215.

Radomski, J.L., W.B. Deichmann, W.E. MacDonald and E.M. Glass, 1965. Synergistn
Among Oral Carcinogens. I. Results of Simultaneous Feeding of Four Tumorigens
to Rats, Toxicol. Appl. Fharmacol. 7: 652.

Rossi, L. , M. Ravera, G, Repetti and L. Santi, 1977. Long-Terra Administration
of DDT or Phenobarbital-NA in Wistar Rats. Int. J. Cancer. 19(15): 179-185.

Scribner, J. D,, B. Woodworth, G. Koponen, and E. H. Holmes, 1983. Use of
2-Acetamidophenanthrene and 2-Acetamidofluorene in Investigations of Mechanisms
of Hepatocarcinogensis, Environ. Health Perspect. 49:81-86.

Shabad, L.M., T.S. Kolesnichenko and T.V. Nikonova, 1973. Transplacental and
Combined Long-Term Effect of DDT in Five Generations of A-Strain Mice. Int. J,
Cancer. 11(3): 688-693.

TarJan. R. and 1. Kemeny, 1969. Multigeneration Studies on DDT in Mice. Food
Cosmet. Toxicol. 7: 215.

Terracini, B.,, M.C. Testa, J.R. Cabral and N. Day, 19-73. The Effects of
Long-Tern Feeding of DDT to BALB/c Mice. Int. J. Cancer. 11: 747.

Thorpe, E. and A.I.T. Walker, 1973. The Toxicology of Dieldrin (HEOD). II.,
Comparative Long-Term Oral Toxicity Studies in Mice with Dieldrin, DDT,
Phenobarbitone, Beta-BHC and Gamma-BHC. Fd. Cosmet. Toxicol. 11: 433.

Toaatls, L,, V, Turusov, N. Day and R.T. Charles, 1972. The Effect of Long-
Term Exposure to DDT on CF-1 Mice. Int. J. Cancer. 10: 489.

Tonatis, L., V. Turusov, M. Boiocchi, and E. Gati, 1974. Liver Tumors in CF-1
Mice Exposed for Limited Periods to Technical DDT. Z. Krebsforsch. 82:25-35.
4-3
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Tomatls, L. and V. Turusov, 1975. Studies on the Carcinogenlcity of DDT. GANN
17:219-241.

Turusov, V.S., N.E. Day. L. Tomatls, E. Gatl and R.T. Charles, 1973. Tumors In
CF-1 Mice Exposed for Six Consecutive Generations to DDT. J. Nat. Cancer Inst.
51: 983.

U.S. EPA, 1980. Ambient Water Quality Criteria for DDT. EPA 440/5-80-038.
Washington, D.C. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, Ohio, for
the Office of Drinking Water Regulations and Standards, NTIS PB-110904/AS.

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

U.S. EPA (Environmental Protection Agency), 1986b. Methodology for Evaluating
Potential Carclnogeniclty 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 Protection Agency), 1986c. The Assessment of the
Carclnogeniclty of Dlcofol (Kelthane), DDT, DDE and DDD (ID1) , IPA-600/6-86-
001, February 1986. Office of Health and Environmental Assessment, NTIS
U.S. EPA (Environmental Protection Agency), 1988. Technical Background
Document to Support Rulemaking Pursuant to CERCLA Section 102, Volume 3, Draft,
Appendix A, April 26, 1988.

Walker, A.I.T., E. Thorpe and D.I. Stevenson, 1973, The Toxicology of Dleldrln
(HEOD) , I. Long -Term Oral Toziclty Studies in Mice. Fd. Cosine t, Toxlcol. 11:
415.
4-4
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World Health Organization (WHO), 1979. Environmental Health Criteria No, 9:
DDT and Its Derivatives. ISBN 924-154069-9.
4-5
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APPENDIX
SUMMARY OF SIGNIFICANT HUMAN AND/OR ANIMAL STUDIES
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Table A. Animal

Agent: DDT

Reference: Innes et al., 1969
Exposure
Route
initially
g.
followed
by o
initially
9,
followed
by o
initially
9.
followed
by o
initially
9,
followed
by o

Strengths
Weaknesses
Species/
Strain
mouse/
(C57BL/
6 x C3H/
Anf )F1
mouse/
(C57BL/
6 x C3H/
Anf )F1
mouse/
(C57BL/
6 x AKR)
F1
mouse/
(C57BL/
6 x AKR)
F1

of Study:
of Study:
Overall Adequacy:
Dose
or
Sex Exposure
M 46.4 mg/kg
initial dose
F followed by
140 ppm
H 0.0 mg
F
H 46.4 mg/kg
initial dose
F followed by
140 ppm
N 0.0 mg
f

Animals were exposed
Duration Duration
of of
Treatment Study
14 days 562 days
initial dose
followed by
18 months
NA 562 days
14 days 562 days
initial dose
followed by
18 months
NA 562 days
QUALITY OF
from days 7 to 20 of life by
The group size was small; for the treated animals.
Adequate

Purity Vehicle or
of Physical Target
Compound State Organ
NR 0.5X gelatin liver
for initial
dose followed
by incorporation
into diet
NA NA liver
NR 0.5X gelatin liver
for initial
dose followed
by incorporation
into diet
NA NA liver
EVIDENCE
gavage, followed by incorporation of
only one dose level was used.

Tumor
Tumor Type Incidence
hepatoma 11/17
4/11
hepatoma 8/73
0/83
hepatoma 7/18
1/13
hepatoma 5/89
1/75

the compound into the diet.

NA = Not applicable; NR = Not reported
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Table A. Animal

Agent: DDT

Reference: NCI, 1978
Exposure
Route
o
o
o
o
o
o
o
o
Dose
Species/ or
Strain Sex Exposure
rat/ M 0.0 ppm
Osborne-
Mendel
rat/ H 321 ppm8
Osborne-
Mendel
rat/ M 642 ppm8
Osborne-
Hendel
rat/ F 0.0 ppm
Osborne-
Hendel
rat/ f 210 ppm8
Osborne-
Mendel
rat/ f 420 ppm8
Osborne-
Mendel
mouse/ M 0.0 ppm
B6C3F1
mouse/ M 22 ppm8
B6C3F1
Duration Duration Purity Vehicle or
of of of Physical Target
Treatment Study Compound State Organ Tumor Type
NA 111 uks NA NA all organs all tumors
78 uks 110 uks technical diet all organs all tumors
grade
78 uks 110 uks technical diet all organs all tumors
grade
NA 111 uks NA NA all organs all tumors
78 uks 110 uks technical diet all organs all tumors
grade
78 uks 110 uks technical diet all organs all tumors
grade
NA 91 uks NA NA all organs all tumors
78 uks 91 uks technical diet all organs all tumors
grade
Tumor
Incidence
(P value)
(NA)
(NS)
(NS)
(NA)
(NS)
(NS)
(NA)
(NS)
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Table A. Animal

Agent: DDT

Reference: NCI, 1978 (cont.)
Exposure
Route
o

Dose
Species/ or
Strain Sex Exposure
mouse/ N 44 ppm*
B6C3F1
mouse/ F 0.0 ppn
B6C3F,
mouse/ F 87 ppm*
B6C3F,
mouse/ f 175 ppma
B6C3F1
Duration
of
Treatment
78 uks

78 uks

Duration
of
Study
91 uks

91 uks

Purity
of
Compound
technical
grade
NA

technical
grade
technical
grade
Vehicle or
Physical Target
State Organ Tumor Type
diet all organs all tumors

NA all organs all tumors

diet all organs all tumors

Tumor
Incidence
(P value)
(NS)

(NA)

(NS)

Strengths of Study:

Weaknesses of Study:

Overall Adequacy:
QUALITY OF EVIDENCE

Both rats and mice were administered the compound by a natural route for an appreciable portion of their lifespan. An
extensive histologic examination was conducted on all major organs.

The dose was changed several times during the study. There uas high mortality in all groups of male mice.

Adequate
• The concentration is expressed as the time-weighted average concentration over the treatment period.
NA = Not applicable; NS = Not significant
-------
Table A. Animal

Agent: DDT

Reference: Rossi et al., 1977
Exposure
Route
o
0
o
o
Species/
Strain Sex
rat/ H
Ulster
rat/ F
Ulster
rat/ M
Ulster
rat/ f
Ulster
Dose
or
Exposure
0.0 ppm
0.0 ppm
500 ppm
500 ppm
Duration Duration
of of
Treatment Study
HA H5 weeks
NA 145 weeks
145 weeks 145 weeks
145 weeks 145 weeks
Purity
of
Compound
NA
NA
technical
grade
technical
grade
Vehicle or
Physical
State
NA
NA
diet
diet
Target
Organ
I iver
1 iver
I iver
I iver
Tumor
Tumor Type Incidence
NR 0/36
NR 0/35
NR 9/37
NR 15/35
Strengths of Study:

Ueaknesses of Study:

Overall Adequacy:
QUALITY OF EVIDENCE

Lymphatic system, lung, mammary tissue, uterus, testes, ovaries, thyroid, adrenals, and skin were among other tissues
examined for a tumorigenie effect.

Only one dose level was evaluated.

Adequate
NA = Not applicable; NR = Not reported
-------
Table A. Animal

Agent: DDT

Reference: Tarjan and Kemeny, 1969
Exposure Species/
Route Strain Sex
o mouse/ H,F
BALB/c
o mouse/ M,F
BALB/c
o mouse/ M,F
BALB/c
o mouse/ M,F
BALB/c
o mouse/ M,F
BALB/c
o mouse/ M,F
BALB/c
o mouse/ H,F
BALB/c
o mouse/ M,F
BALB/c
o mouse/ H,F
BALB/c
o mouse/ H,F
BALB/C
Dose Duration
or of
Exposure Treatment
0.0 ppm HA
0.0 ppm NA
0.0 ppm NA
0.0 ppm NA
0.0 ppn NA
2.8-3.0 ppm lifespan8
2.8-3.0 ppm lifespan8
2.8-3.0 ppm lifespan8
2.8-3.0 ppm lifespan8
2.8-3.0 ppm lifespan8
Duration Purity Vehicle or
of of Physical
Study Compound State
lifespan NA NA

lifespan NA NA

lifespan NRb NA
-------
Table A. Animal

Agent: DDT

Reference: Tarjan and Kemeny, 1969 (cont.)

Exposure
Route

Species/
Strain Sex
Oose
or
Exposure
Duration
of
Treatment
Duration
of
Study
Pur i ty
of
Compound
Vehicle or
Physical
State

Target
Organ

Tumor
Tumor Type Incidence
QUALITY OF EVIDENCE

Strengths of Study: Animals were exposed from completion for a maximum of 26 months. A "wide range" of organs was examined histologically.

Weaknesses of Study: Only one dose level was studied. All animals were examined for tumors 26 months after the first animal was started on
treatment. The maximum exposure was for 6 months in the Fj generation.

Overall Adequacy: Adequate

" The aninals were exposed in utero from the time of conception.
b The nelting point of the crystalline DDT was 108°-109°C.
NA - Not applicable; MR = Not reported
-------
Table A. Animal

Agent: DDT

Reference: Terracini et al., 1973
Dose
Exposure Species/ or
Route Strain Sex Exposure
o mouse/ N 0.0 ppm
BALB/c
o mouse/ H 2 ppn
BALB/c
o mouse/ N 20 ppn
BALB/c
o mouse/ H 250 ppn
BALB/c
o mouse/ F 0.0 ppn
BALB/c
o mouse/ f 0.0 ppn
BALB/c
o mouse/ F 2 ppm
BALB/c
o mouse/ F 2 ppm
BALB/c
o mouse/ F 20 ppn
BALB/c
o mouse/ F 20 ppm
BALB/c
o mouse/ F 250 ppm
BALB/c
Duration
of
Treatment
HA

lifespan

Mfespan

lifespan

I ifespan

lifespan

I i fespan

Durat ion
of
Study
I ifespan8

lifespan8

I Ifespan8

I ifespan8

Ufespanb

1 i f espanc

lifespan6
1
Ufespanc

Ufespanb

I ifespanc

I i fespan

Purity Vehicle or
of Physical Target
Compound State Organ
NA NA liver

technical diet liver
grade
technical diet liver
grade
technical diet liver
grade
NA NA liver

NA NA liver

technical diet liver
grade
technical diet liver
grade
technical diet liver
grade
technical diet liver
grade
technical diet liver
grade
Tumor
Tumor Type Incidence
all tumors 2/107

all tumors 3/112

all tumors 1/106

all tumors 15/106

all tumors 0/62

all tumors 0/69

all tumors 0/63

all tumors 0/72

all tumors 1/61

all tumors 0/67

all tumors 28/63

-------
Table A. Animal

Agent: DDT

Reference: Terracini et al., 1973 (cont.)

Exposure
Route
o

Species/
Strain Sex
mouse/ F
BALB/c
Dose
or
Exposure
250 ppni

Duration
of
Treatment
lifespan

Duration
of
Study
I ifespanc

Puri ty
of
Compound
technical
grade
Vehicle or
Physical
State
diet

Target
Organ
liver

Tumor
Tumor Type Incidence
all tumors 43/58

QUALITY OF EVIDEHCE

Strengths of Study: Animals uere exposed from 4-5 weeks of age for 2 generations. A complete autopsy was performed on all animals.

Overall Adequacy: Adequate
8 The animals from the parental and first generation were combined.
b The parental group started on the diet at 4-5 weeks of age.
c The first generation obtained from matings of animals initially exposed to DDT at 4-5 weeks of age.
NA » Not applicable
-------
Table A. Animal

Agent: DDT

Reference: Thorpe and Walker, 1973
Exposure
Route
o
o
o
0

Strengths
Weaknesses
Dose Duration Duration Purity Vehicle or
Species/ or of of of Physical Target
Strain Sex Exposure Treatment Study Compound State Organ
mouse/ H 0.0 ppn NA 110 weeks NA NA liver
CF-1
mouse/ F 0.0 ppn NA 110 weeks NA NA liver
CF-1
mouse/ N 100 ppm 110 weeks 110 weeks >99.SX diet liver
CF-1
nouse/ F 100 ppm 110 weeks 110 weeks >99.5X diet liver
CF-1
QUALITY OF EVI DEUCE
of Study: Cross and histologic pathology was performed on all major internal organs.
of Study: Only one exposure group was used.
Tumor
Incidence
Tumor Type (P value)
all tumors 11/45
all tumors 10/44
(p<0.001)
all tumors 23/30
(p<0.001)
all tumors 26/30

Overall Adequacy: Limited
' Two distinct types of tumors were observed: one. nodular and benign, and the second, papilliform.
NA = Not applicable
-------
Table A. Animal

Agent: DDT

Reference: Tomatis et al., 1972
Exposure Species/
Route Strain
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1
Sex
N
F
M
F
M
F
N
F
N
F
N
F
H
F
N
F
N
F
M
F
Dose
or
Exposure
0.0 ppm
2 ppm
10 ppm
50 ppm
250 ppm
0.0 ppm
2 ppm
10 ppm
50 ppm
250 ppm
Duration
of
Treatment
NA
lifespan8
lifespan8
lifespan8
lifespan0
NA
lifespanb
lifespan6
lifespan6
I i f espan
Duration
of
Study
1 if espan8
I if espan
I if espan
I i f espan
li f espan
I i f espan
lifespan
I if espan
I if espan
lifespan
Purity
of
Compound
NA
technical
grade
technical
grade
technical
grade
technical
grade
NA
technical
grade
technical
grade
technical
grade
technical
grade
Vehicle or
Physical
State
NA
diet
diet
diet
diet
NA
diet
diet
diet
diet
Target
Organ
I iver
1 iver
liver
liver
liver
liver
liver
liver
liver
I iver
Tumor Type
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
hepatoma
Tumor
Incidence
12/55
2/56
25/58
3/56
28/53
2/59
24/53
7/55
38/50
3/149
13/58
2/55
32/66
1/49
24/51
9/65
43/74
6/49
44/53
29/41
-------
Table A. Animal

Agent: DDT

Reference: Tomatis et al., 1972 (cont.)

Exposure
Route

Species/
Strain Sex
Dose
or
Exposure
Duration
of
Treatment
Duration
of
Study
Purity
of
Compound
Vehicle or
Physical
State

Target
Organ

Tumor
Tumor Type Incidence
QUALITY OF EVIDENCE

Strengths of Study: Animals Mere exposed for 2 generations; all major internal organs were examined for tumors.

Overall Adequacy: Adequate

a Animals were exposed from 6 weeks of age.
b The Ff generation Mas exposed IQ utero from conception.
MA « Not applicable
-------
Table A. Animal

Agent: DDT

'Reference: Turusov et al., 1973
Exposure
Route
o
o
o
o
o

Species/
Strain
mouse/
CF-1
mouse/
CF-1
mouse/
CF-1
mouse/
CF-1
mouse/
CF-1

Strengths of Study:
Overall
Adequacy:
Dose Duration
or of
Sex Exposure Treatment
H 0.0 ppm HA
F
N 2 ppm lifespan
F
M 10 ppm lifespan
F
N 50 ppm lifespan
F
N 250 ppm lifespan
F

The animals were exposed for six
Adequate
Duration Purity Vehicle or
of of Physical Target
Study Compound State Organ Tumor Type
lifespan NA NA liver hepatoma
lifespan technical diet liver hepatoma
grade
lifespan technical diet liver hepatoma
grade
lifespan technical diet liver hepatoma
grade
lifespan technical diet liver hepatoma
grade
QUALITY OF EVIDENCE
continuous generations; all major organs were examined for tumors.

Tumor
Incidence
(P value)8
97/328
16/340
179/354 (p<0.001)
12/339 (p=0.28N)
181/362
-------
Table A. Animal

Agent: DDT

Reference: Walker et al., 1972
Exposure Species/
Route Strain
o mouse/
CF-1
o mouse/
CF-1
o mouse/
CF-1

Strengths of Study:
Weaknesses of Study:
Overall Adequacy:
Dose Duration Duration Purity Vehicle or
or of of of Physical Target
Sex Exposure Treatment Study Compound State8 Organ Tumor Type
H 0.0 ppm NA 112 weeks NA diet liver all tumors
F
M 50 ppm 112 weeks 112 weeks >99.5X diet liver all tumors
F
H 100 ppm 112 weeks 112 weeks >99.5X diet liver all tumors
F
QUALITY OF EVIDENCE
Gross and histologic examination was performed on all major internal organs.
The majority of liver tumors were benign.
Adequate
Tumor
Incidence
(P value)
6/47
8/47
12/32
15/30
17/32
24/32

8 The diets were sterilized by ethylene oxide prior to mixing with the test compound.
b Two distinct types of tumors were observed: nodular and papilliform. The latter type was seen only in control animals.
NA - Not applicable
-------
(Plea?
TECHNICAL REPORT DATA
1. RiPORT NO.
EPA/600/8-91/101
2.
4, TITLE AND SUBTITLE
Evaluation of the Potential Carcinogenicity of
DDT (50-29-3)
3.
PB93-185254
5. REPORT DATE

Jimp IQAfl
6. PERFORMING ORGANIZATION CODE
7. AUTHQR(S)
8. PERFORMING ORGANIZATION REPORT MO
Syracuse Research Corporation
Environmental Monitoring & Servires, Tnr.
MIZATION NAME
OHEA-C-Q73-n7E;
*OGRAM 6LEMENT NO.
9, PERFORMING ORGANIZATION NAME AND ADDRESS
Syracuse Research Corporation, Syracuse, NY
Environmental Monitoring & Services, Inc. (now ABB
Environmental Services, Inc.), Washington, DC
10. PROGRAM
1 I. 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
t3. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/021
15. SUPPLEMENTARY NOTES
is. ABSTRACT
DDT 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 DDT is estimated to be 5.58 (mg/kg/day)'1, 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, DDT is assigned a
"MEDIUM" hazard ranking for the purposes of RQ adjustment.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
c, COSATi Field.Croup
18. DISTRiaUTION STATEMENT

Release to Public
19, SECURITY CLASS iTIiis Report)

Unclassified
21 NO, OF PAGES
33
20. SECURITY CLASS (Tliii pulp'.'
• Unclassified
22.
f PA Farm 2230-1 (fUv. 4-77) f»*cvious SDITION is O»»OLBTK
-------