United States
Environmental Protection
1=1 m m Agency
EPA/690/R-03/001F
Final
8-01-2003
Provisional Peer Reviewed Toxicity Values for
o,p '-DDT
(CASRN 789-02-6)
Derivation of a Carcinogenicity Assessment
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
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NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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8-1-2003
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
o,p'~DDT (CASRN 789-02-6)
Derivation of a Carcinogenicity Assessment
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions or the EPA Headquarters Superfund Program
sometimes request that a frequently used PPRTV be reassessed. Once an IRIS value for a
specific chemical becomes available for Agency review, the analogous PPRTV for that same
chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a
PPRTV cannot be derived based on inadequate data.
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8-1-2003
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
IRIS (U.S. EPA, 2001) does not list o,p '-DDT \o,p '-dichlorodiphenyltrichlorocthanc; 2-
(2-chlorophenyl)-2-(4-chlorophenyl)-l,l,l-trichloroethane] and no oral slope factor is listed in
the HE AST (U.S. EPA, 1997) or in the Drinking Water Standards or Health Advisories List
(U.S. EPA, 2000). The CARA lists (U.S. EPA, 1991, 1994) include two health effects
assessment documents (U.S. EPA, 1984, 1988) and a carcinogenicity assessment document for
DDT and related compounds (U.S. EPA, 1986). None of these documents contained specific
information regarding carcinogenicity of o,p '-DDT, although all discussed carcinogenicity assays
testing technical grade DDT, which contains o,p '-DDT as a minor nearly inactive component
(<22%). A NIOSH Special Occupational Hazard Review (NIOSH, 1978), an Environmental
Health Criteria document (WHO, 1979), and IARC (1974, 1991) monographs on DDT and
related compounds contain no information regarding carcinogenicity of o,p '-DDT. IARC (1991)
assigned "DDT" to Group 2B, possibly carcinogenic to humans, based on inadequate evidence in
humans and sufficient evidence in animals. It is not clear whether IARC intended that evaluation
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8-1-2003
to apply to o,p '-DDT, since most of the available cancer studies involved p,p '-DDT or technical
grade DDT. The ATSDR Toxicological Profile for DDT and related compounds (ATSDR,
2000) discusses a few studies regarding cancer epidemiology and the weak estrogenic properties
of o,p '-DDT. The NTP status report (NTP, 2001) does not list o,p '-DDT. Literature searches
were conducted from 1998 to January 2001 for studies relevant to the derivation of an oral slope
factor for o,p '-DDT. The databases searched were TOXLINE, MEDLINE, CANCERLIT,
RTECS, GENETOX, HSDB, CCRIS, TSCATS, EMIC/EMICBACK, and DART/ETICBACK.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
Reviews by U.S. EPA (1988), WHO (1979), and IARC (1974, 1991) listed no data
regarding carcinogenicity of o,p '-DDT, aside from studies on technical grade DDT of which o,p
DDT is a minor nearly inactive component (<22 %). The ATSDR toxicological profile for DDT
and related compounds (ATSDR, 2000) cited several epidemiological studies, none of which
reported an association between o,p '-DDT exposure and cancer (Wasserman et al., 1976;
Sturgeon et al., 1998; Dorgan et al., 1999). In these epidemiological studies o,p'-DDT was
identified in the serum of participants. No additional studies regarding carcinogenicity of o,p
DDT in humans were located in the literature search.
Animal Studies
No studies were located regarding chronic oral exposure of animals to o,p '-DDT.
Other Studies
o,p '-DDT treatment induced chromosomal breakage in cultured cells of the rat kangaroo
Palmer et al. (1972). No additional genotoxicity studies for o,p -DDT were located in the
literature search.
Weak estrogenic activity of o,p -DDT has been demonstrated in acute injection studies in
rats (Bitman et al., 1968; Bitman and Cecil, 1970). In vitro assays have shown that o,p '-DDT
binds weakly to the estrogen receptor (Kelce et al., 1995; Danzo, 1997; Shelby et al., 1996) and
that it is a weak activator of the estrogen receptor gene (Gaido et al., 1997; Sohoni and Sumpter,
1998). o,p -DDT does not activate the androgen receptor gene, but inhibits testosterone binding
to its receptor (Danzo, 1997; Kelce et al., 1995; Maness et al., 1998). These results indicate that
o,p '-DDT is a weak antiandrogen that has weak estrogenic activity and provide limited evidence
for its carcinogenic potential.
The MCF-7 human breast cancer cell line has been used to evaluate the transforming
potential of o,p '-DDT. o,p '-DDT significantly increased the phosphorylation of c-Neu, a
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8-1-2003
tyrosine kinase that is also activated as a result of estrogen binding to the estrogen receptor (Enan
and Matsumura, 1998). However, the activity of o,p '-DDT in these assays was independent of
the estrogen receptor. In another study, o,p '-DDT significantly increased foci formation in MCF-
7 cells, although less effectively than estradiol (Hatakeyama and Matsumura, 1999). Induction of
foci was associated with the activity of the c-Neu tyrosine kinase. The authors suggest that the
apparent causal relationship between c-Neu tyrosine kinase and foci formation may provide a
mechanism for the induction of breast cancer by organochlorine compounds such as o,p T)DT. In
support of this hypothesis, they cite a study by Berger et al. (1988), which found a high
correlation of Neu activation with an increased incidence of breast cancer.
FEASIBILITY OF DERIVING A PROVISIONAL
ORAL SLOPE FACTOR FOR o,p'~DDT
A provisional oral slope factor for o,p '-DDT cannot be derived due to the lack of suitable
data.
REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). 2000. Toxicological Profile for
4,4'-DDT, 4,4'-DDE, 4,4'-DDD. Update. U.S. Department of Health and Human Services,
Public Health Service, Atlanta, GA.
Berger, M.S., G.W. Locher, S. Saurer et al. 1988. Correlation of c-erbB-2 gene amplification
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biphenyls. J. Agric. Food Chem. 18:1108-1112.
Bitman, J., H.C. Cecil, S.J. Harris and G.F. Fries. 1968. Estrogenic activity of o,p'-DDT in the
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Dorgan, J., J. Brock, N. Rothman et al. 1999. Serum organochlorine pesticides and PCBs and
breast cancer risk: Results from a prospective analysis (USA). Cancer Causes Control. 10: 1-11.
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Enan, E. and F. Matsumura. 1998. Activation of c-Neu tyrosine kinase by o,p'-DDT and P-HCH
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1296-1300.
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Sohoni, P. and J. Sumpter. 1998. Several environmental oestrogens are also anti-androgens. J.
Endocrinol. 158: 327-339.
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U.S. EPA. 1988. Updated Health Effects Assessment for DDT. Prepared by the Office of
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478-484.
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WHO (World Health Organization). 1979. DDT and its Derivatives. Environ. Health Criteria
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