SEPA
United States	EPA/690/R-07/009F
Environmental Protection	Final
Agency	8-15-2007
Provisional Peer Reviewed Toxicity Values for
o,p '-Dichlorodiphenyldichloroethane (o,p '-DDD)
(CASRN 53-19-0)
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
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
i.v.
intravenous
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
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-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-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
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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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PROVISIONAL TOXICITY VALUES FOR
o,p'-DDD (CASRN 53-19-0)
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 new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. 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.
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.
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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
o,p -DDD [1,l-dichloro-2,2-bis(2,4 -dichlorophenyl)ethane, o,p -dichlorodiphenyl-
dichloroethane, o,p -TDE, or mitotane] was not listed on IRIS (U.S. EPA, 2007), the HEAST
(U.S. EPA, 1997), or the Drinking Water Standards and Health Advisories list (U.S. EPA, 2000).
The CARA list (U.S. EPA 1991, 1994) included a carcinogenicity assessment document for
DDT and related compounds (U.S. EPA, 1986), but this document contained no information
regarding the o,p 'isomer of DDD. OPP did not have an oral slope factor (OSF) for o,//-DDD,
The ATSDR Toxicological Profile for DDT and related compounds (ATSDR, 2000) included
little information relevant to carcinogenicity of o,//-DDD: one equivocal epidemiological study
and a few in vitro tests showed very weak estrogenic potential or no androgenic potential. The
NTP (2007) status report listed a 2-year carcinogenicity assay by intraperitoneal (i.p.) injection
and cited negative results for in vitro genotoxicity tests (mutagenicity in Salmonella,
chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells). An
Environmental Health Criteria document on DDT and related compounds (WHO, 1979)
contained no information related to carcinogenicity of o,p -DDD; the document did discuss its
therapeutic use, under the name mitotane, for chemical adrenalectomy in treatment of adrenal
cortical carcinoma or bilateral adrenal hyperplasia.
IARC (1991) also discussed use of o,p -DDD in treatment of adrenal cortical carcinoma,
but did not classify o,p -DDD with regard to carcinogenicity. IARC (1974, 1991) noted the
existence of a study in which testicular tumors developed in rats exposed to o,p -DDD in food
(Lacassagne and Hurst, 1965), but did not consider it further, probably because only three rats
were permitted to survive long enough for tumors to develop. IARC (1991) concluded from the
few available in vitro assays that there was no evidence that o,p -DDD induced genetic effects.
o,p -DDD did not induce mutation in Salmonella typhimurium or induce transformation in mouse
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embryos cells. An unspecified isomer of DDD did not induce unscheduled DNA synthesis in
primary hepatocyte cultures from rat, mouse, or Syrian hamster. Equivocal results were reported
for induction of chromosomal aberrations in cultured rodent cells. Potentially relevant
mechanistic data cited in IARC (1991) included the finding that o,p -DDD bound irreversibly in
the alveolar and bronchiolar areas of rabbit and mouse lung.
Literature searches were conducted from 1998 to June 2000 and 2000 to 2007 for studies
relevant to o,p -DDD. The databases searched were TOXLINE, MEDLINE, CANCERLIT,
RTECS, GENETOX, HSDB, CCRIS, TSCATS, EMIC/EMICBACK, and DART/ETICBACK.
This document has passed the STSC quality review and peer review evaluation indicating
that the quality is consistent with the SOPs and standards of the STSC and is suitable for use by
registered users of the PPRTV system.
REVIEW OF PERTINENT LITERATURE
Human Studies
Reviews by U.S. EPA (1986), WHO (1979), and IARC (1974, 1991) listed no data
regarding carcinogenicity of o,p -DDD to humans by any route of exposure. The ATSDR
toxicological profile for DDT and related compounds (ATSDR, 2000) cited one small
epidemiological study. In this study, Wassermann et al. (1976) calculated that the mean
concentration of o,/?'-DDD in cancerous breast tissue was higher than in noncancerous breast
tissue in the same small group of women (n=9); however, the difference was not statistically
different and the ranges of concentrations were nearly identical in the two kinds of tissue. The
literature search identified no new studies regarding carcinogenicity of o,p -DDD to humans
following oral exposure.
Several case reports described the use of o,p -DDD, as mitotane, in the treatment of
adrenocortical cancer (Baudin et al., 2001; Bergenstal et al., 1960; Decker et al., 1991; Hogan et
al., 1978; lino et al., 2000; Terzolo et al., 2000; Wooten and King, 1993). In general, patients
were given mitotane orally, delivering between 1 and 10 grams of o,p -DDD daily (14-143
mg/kg-day) in divided doses for up to 54 months. In all cases, patients were given steroid
replacement therapy to counteract side effects commonly associated with the suppression of
adrenal hormone production caused by o,p -DDD. The main side effects were gastrointestinal
(nausea, vomiting, diarrhea) and neurological (lethargy, somnolence, ataxia, confusion,
dysarthria, vertigo). These studies were not suitable for derivation of an RfD because of pre-
existing cancer and concurrent administration of other medications (steroid hormones and
chemotherapeutic agents).
Animal Studies
A 30-day study by Cueto and Brown (1958) identified an FEL of 4 mg/kg-day for o,p -
DDD in dogs based on adrenal necrosis leading to death. Cueto and Brown (1958) fractionated
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technical grade DDD and tested the fractions and isolates for adrenocorticolytic activity. They
fed 4 mg/kg-day of purified o,p -DDD in gelatin capsules to two male dogs for 30 days; one
control dog was left untreated for 100 days. The endpoints examined included general
appearance, periodic tests of adrenal activity, and after necropsy, examination of adrenal
histopathology. After four days of treatment, adrenal function, as measured by responses to an
injection of ACTH, was severely impaired; the expected increase in urinary excretion of 17-
hydroxycorticoids was abolished, and the expected decrease in eosinophil counts was reduced by
88%. Treatment with o,p -DDD caused massive necrosis and atrophy of the adrenals. Treated
dogs became anorexic and weak, leading to hair loss and death. The dose of 4 mg/kg-day was a
FEL in dogs because of adrenal necrosis leading to death. This study identified o,p -DDD as the
adrenocorticolytic fraction in technical grade DDD, but was not a suitable basis for derivation of
an RfD because the applied dose was a FEL.
Other subchronic studies in dogs supported the adrenocorticolytic action of o,p -DDD
administered as mitotane. In both healthy dogs and dogs with Cushing's disease
(hyperadrenocorticism), oral administration of o,p '-DDD at doses of 50 mg/kg-day or higher
caused a state of hypoadrenocorticism in some animals (den Hertog et al., 1999; Kirk and
Jensen, 1975; Schechter et al., 1973; Vilar and Tullner, 1959; Lorenz et al., 1973). Typically,
the adrenal cortex became necrotic and dogs developed weakness, in some cases with blindness,
anisocoria, and convulsions leading to death. Thus, 50 mg/kg-day was a FEL in dogs for severe
adrenal effects leading to death in some animals.
An incompletely described 5-week study by Hamid et al. (1974) reported adrenal atrophy
and a 12% reduction in the weight of adrenals, but no effect on plasma corticosteroid
concentration, in male Sprague-Dawley rats treated with 121 mg/kg-day of o,p -DDD, Reduced
body weight and impaired immune function (reduced organ weights of spleen and thymus,
reduced cellular immune responses to injected sheep red blood cells) also were reported. Gellert
and Heinrichs (1975) observed delayed onset of puberty and reduced adrenal weights relative to
body weights in female offspring of pregnant Sprague-Dawley rats gavaged with 29 mg/kg-day
of o,p'-DDD on gestational days 15-19. Fregly et al. (1968) found no significant effect on
adrenal weight (relative to body weight) or adrenal function but identified significant thyroid
effects (increased relative organ weight, hypothyroidism) in male Holtzman rats fed diets
containing 0.1 or 0.3% o,p -DDD (68 or 162 mg/kg-day) for six weeks. The results of these
studies suggested that the adrenals of rats were less sensitive to o,p -DDD than those of humans
or dogs.
Other Studies
In the study cited in the NTP (2007) status report, Weisburger (1977) administered 0,
125, or 250 mg/kg-day of o,p -DDD (vehicle not specified) by i.p. injection to groups of
Sprague-Dawley rats and Swiss mice (25 per gender per group) 3 days a week for 6 months and
monitored tumor development for 1 year following the last injection. Treatment with o,p -DDD
had no effect on survival of male and female rats, but apparently increased the tumor incidence
(primarily breast tumors in females and parathyroid tumors in males) 1.5- to 2-fold over controls
(tumor incidence and survival data were not reported for the doses individually). Tumor
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incidence in treated male mice was not significantly different from controls, possibly because of
significantly reduced survival. The tumor incidence in treated female mice was 1.5- to 2-fold
higher than controls and primarily involved the lung.
Lund et al. (1990) reported increased cell proliferation (increased thymidine
incorporation and mitotic number), in the lungs of female C57B1 mice that were injected once
intraperitoneally with 100 mg/kg of o,p'-DDD. In another experiment, groups of three mice
were gavaged with 0, 10 or 50 mg/kg of o,p -DDD in corn oil twice a week for 6 weeks; 3 days
after the last dose, mice were injected intravenously with 14C-o,p -DDD and sacrificed 24 hours
later. The amount of label covalently bound to lung protein (but not liver protein) was
significantly reduced in a dose-dependent manner. According to the authors, these results
demonstrated the specific bioactivation of o,p -DDD in the lung, which would result in localized
binding to cellular macromolecules.
Other studies have investigated the estrogenic or androgenic activities of DDT and
related compounds, since these properties might contribute to their carcinogenic potential. Using
an in vitro yeast reporter gene system, Gaido et al. (1997) found that o,p -DDD was very
ineffective with regard to activation of expression of the estrogen receptor gene. The calculated
effective concentration for 50% response (EC50) for op -DDD was 3.32 E-03, representing a
potency 15xl07 times less than estradiol. This experiment suggested that o,p -DDD was not
estrogenic. Using an in vitro human hepatoma cell reporter gene system, Maness et al. (1998)
found that o,p -DDD and related compounds did not stimulate expression of the human androgen
receptor (hAR) gene. However, the DDT isomers, including o,p -DDD, were able to inhibit
androgen-dependent expression of the hAR gene. The concentration of the most potent isomer,
p,p -DDE, required to inhibit androgen receptor activity by 50% was 1.86 (iinol; an inspection of
the dose-response curve indicated that the inhibitory concentration for 50% inhibition (IC50) for
o,p -DDD (not reported numerically) would be higher. These experiments suggested that o,p -
DDD has weak antiandrogenic activity.
No additional supporting information was located in the literature search.
The toxicity of o,p '-DDD has been associated with the biotransforming activity of
adrenocortical mitochondria (Cai et al., 1995a,b). o,p '-DDD undergoes P-hydroxylation, then
spontaneous dehydrohalogenation, leading to the formation of the reactive intermediate acyl
halide, which can convert to o,p '-dichlorodiphenylacetic acid or bind covalently to protein or
plasma membrane (but not DNA). In comparative in vitro studies of adrenal mitochondrial
extracts, Martz and Straw (1980) found the dog to have the highest production of o,p '-DDD
metabolites. Compared to the dog (set as 100%), the values were 41% in rabbit, 24% in human,
13%) in rat, and 5% in guinea pig. The covalent binding of o,p '-DDD to human adrenal
mitochondrial protein was confirmed by Jonsson and Lund (1994) using tumor-free tissue
derived from adrenalectomies.
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FEASIBILITY OF DERIVING A PROVISIONAL RfD FOR o,p'-DDD
The data were inadequate to derive a provisional RfD for o,p '-DDD. The available
clinical studies reported the use of dose levels, 14-143 mg/kg-day, that adversely affected the
adrenal cortex in humans (Bautin et al., 2001; Bergenstal et al., 1960; Decker et al., 1991; Hogan
et al., 1978; Terzolo et al., 2000; Wooten and King, 1993). Dogs and humans were similar in
that the adrenal cortex was the critical target of o,p '-DDD (Kirk and Jensen, 1975; Schechter et
al., 1973; Vilar and Tullner, 1959; Lorenz et al., 1973; den Hertog et al., 1999). However, the
lowest dose level reported in a subchronic dog study, 4 mg/kg-day, was a FEL because of severe
adrenal atrophy leading to death (Cueto and Brown, 1958). Rat studies (Hamid et al., 1974;
Fregly et al., 1968) reported more severe effects on the function of the thyroid or the immune
system than on the adrenals. These results suggested that the adrenal cortex is not the primary
target of o,p '-DDD in the rat, and that this species was not an appropriate model for o,p '-DDD
effects in humans. This is supported by mechanistic studies indicating that humans are less
sensitive than dogs, but more sensitive than rats to o,p '-DDD (Martz and Straw, 1980). Thus,
the database lacks a study that could serve as a suitable basis for derivation of an RfD for o,p '-
DDD. However, the data make clear that exposure to o,p '-DDD poses significant toxic risks to
the adrenal cortex.
FEASIBILITY OF DERIVING A PROVISIONAL RfC FOR o,p'-DDD
No inhalation toxicity data in humans or animals was identified, so no p-RfC could be
derived for o,p '-DDD.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR o,p'~DDD
Because the only available data were in rats and mice treated i.p., under the 2005
Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), this review classified o,p '-DDD
as having "Inadequate Information to Assess Carcinogenic Potential'.
FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR OR
INHALATION UNIT RISK FOR o,p -DDD
Neither a provisional oral slope factor nor a provisional inhalation unit risk could be
derived for o,p -DDD because of the lack of suitable human and animal oral or inhalation data.
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4,4'-DDT, 4,4'-DDE, 4,4'-DDD. Update. U.S. Public Health Service, Atlanta, GA.
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Baudin, E., G. Pellegriti, MBonnay, A. Penfornis, ALaPlanche, G. Vassal, M. Schlumberger.
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Bergenstal, D.M., R. Hertz, M.B. Lipsett and R.H. Moy. 1960. Chemotherapy of adrenocortical
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Cai, W., R.E. Counsell, T. Djanegara et al. 1995a. Metabolic activation and binding of mitotane
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Cai, W., R.Benitez, R.E. Counsell et al. 1995b. Bovine adrenal cortex transformations of
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Decker, R.A., P. Elson, T.F. Hogan et al. 1991. Eastern Cooperative Oncology Group study
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den Hertog, E., J.C.A. Braakman, E. Teske et al. 1999. Results of non-selective
adrenocorticolysis by o,p'-DDD in 129 dogs with pituitary-dependent hyperadrenocorticism.
Veter. Rec. 144: 12-17.
Fregly, M. J., I.W. Waters and J. A. Straw. 1968. Effect of isomers of DDD on thyroid and
adrenal function in rats. Can. J. Physiol. Pharmacol. 46: 59-66.
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Gellert, R.J. and W.L. Heinrichs. 1975. Effects of DDT homologs administered to female rats
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Hamid, J., A. Sayeed, and H. McFarlane. 1974. The effect of l-(o-chlorophenyl)-l-(p-
chlorophenyl)-2,2-dichloroethane (o,p'-DD) on the immune response in malnutrition. Brit. J.
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Hogan, T.F., D.L Citrin, B.M. Johnson et al. 1978. o,p -DDD (mitotane) therapy of adrenal
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2177-2181.
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IARC (International Agency for Research on Cancer). 1974. DDT and associated substances.
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lino, K., Y. Oki and H. Sasano. 2000. A case of adrenocortical carcinoma associated with
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Jonsson, C.-J. and B.-O. Lund. 1994. In vitro bioactivation of the environmental pollutant 3-
methylsulphonyl-2,2-bis(4-chlorophenyl)-l,l-dichloroethene in the human adrenal gland.
Toxicol. Lett. 71: 169-175.
Kirk, G. and H.E. Jensen. 1975. Toxic effects of o,p'-DDD in the normal dog. J. Am. Anim.
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Lund, B.-O., L. Busk, I. Brandt and B. Hellman. 1990. Effect of o,p'-DDD on the in vivo
incorporation of 3H-thymidine into DNA: Evidence for induced cell proliferation in the mouse
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Maness S., D. McDonnell and K. Gaido. 1998. Inhibition of androgen receptor-dependent
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Martz, F. and J.A. Straw. 1980. Metabolism and covalent binding of 1 -(o-chlorophenyl)- l (p-
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162: 629-639.
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Terzolo, M., A. Pia, A. Berruti et al. 2000. Low-dose monitored mitotane treatment achieves
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Vilar, O. and W.W. Tullner. 1959. Effects of o,p'-DDD on histology and 17-
hydroxy corticosteroid output of the dog adrenal cortex. Endocrinology. 65: 80-86.
Wassermann, M., D.P. Nogueira, L. Tomatis et al. 1976. Organochlorine compounds in
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Wooten, M.D. and D.K. King. 1993. Adrenal cortical carcinoma: Epidemiology and treatment
with mitotane and a review of the literature. Cancer. 72: 3145-3155.
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