-------
(3.2%) groups. Lung carcinoma, which occurred In 116 of the 196 animals with
tumors, was the predominant type. Leukemia was found 1n 23 females and 21
males of the 196 animals that developed tumors. Tumors were also observed In
the liver, kidney, spleen, ovary and other organs. The authors emphasized
that the transplacental and translactatlonal exposure to DDT that occurred
during the experiment may have had an Important, but unquantlfled, effect upon
the results.
Under the auspices of IARC, Tomatls et al. (1972), Terradnl et al.
(1973a,b), Turusov et al. (1973) and Shabad et al. (1973) Investigated DDT
cardnogenlclty In mice. Several multlgeneratlon studies were conducted 1n
which mice were exposed continuously to DDT, Including transplacentally and
translactatlonally. Tomatls et al. (1972) found that mice of both sexes
exposed to 250 ppm DOT had a significantly higher Incidence of hepatomas.
When the mice exposed to lower doses of DDT (2-50 ppm) were allowed to age
past 60 weeks, the males, but not the females, had a significantly higher
Incidence of hepatomas. In another experiment, Tomatls et al. (1974) demon-
strated that hepatoma formation was dose-dependent and that exposure to DDT
early In life may result 1n tumor formation 1n the aging animal even after
removal of the source of DDT. Terrac1n1 et al. (1973a) found that the Inci-
dence of hepatomas was Increased 1n BALB/c mice exposed to DDT. In addition,
the mice exposed transplacentally and translactatlonally had an even higher
Incidence of liver tumors than the mice exposed after weaning only.
Walker et al. (1972) and Thorpe and Walker (1973) reported an Increased
Incidence of liver tumors 1n CF1 mice exposed to DDT 1n their food for 2
years. They divided the liver lesions Into two hlstologlcal types. Subse-
quent analysis by Reuber (1974, 1976) classified the lesions as hepatocellular
carcinomas and preneoplastlc lesions.
0026H -15- 05/10/88
-------
The NCI (1978) bloassay reported no carcinogenic effect from DDT exposure,
although the mortality of the female mice was significantly Increased In a
dose-related manner. The dose levels, however, were low 1n comparison with
other bloassays.
In rats exposed to 100-800 ppm DDT 1n the diet for 18 months, the dose-
related changes In the liver Included hypertrophy of centrolobular hepatic
cells, hyallnlzatlon of the cytoplasm and focal necrosis (FUzhugh and Nelson,
1947). More than half (111 of 192) of the rats died during the experiment.
Of the 81 that remained alive at the end of the treatment period, 4 had liver
carcinomas and 11 had preneoplastlc hepatic lesions. No liver pathology was
observed In the control animals (Fltzhugh and Nelson, 1947). Rossi et al.
(1977) reported an Increased Incidence of liver tumors In rats exposed to 500
ppm DDT In their diets. Other studies on the cardnogenlclty of DDT
administered to rats 1n doses ranging from 210-642 ppm (NCI, 1978; Welsburger
and Welsburger, 1968; Delchmann et al., 1967; Radomskl et al., 1965) reported
no Increased Incidence of liver tumors.
None of the bloassays 1n hamsters revealed an Increased Incidence of
tumors 1n DDT exposed animals (Agthe et al., 1970; Cabral and Shublk, 1977;
Gralllot et al., 1975), and Gralllot et al. (1975) reported a marked dose-
related decrease 1n the Incidence of lymphosarcoma In the DDT exposed hamsters
as compared with controls.
4.2.2. Inhalation. Pertinent data regarding the cardnogenlclty of Inhaled
DDT were not located 1n the available literature.
4.3. OTHER RELEVANT DATA
Additional qualitative evidence for the cardnogenlclty of DDT 1n animals
has been obtained from in vivo two-stage Initiation/promotion studies and from
genotoxldty studies. The welght-of-evldence from genotoxldty studies can be
summarized as follows. No Increase In the number of reverse mutants was
0026H -16- 11/10/88
-------
caused by DDT 1n Salmonella typhlmurlum (strains TA1535, TA1536, TA1537 and
TA1538) or EscheMchla coll (strains B/r try WP2, and WP2 try her), 1n the
presence or absence of rat liver mlcrosomes (Shlrasu et al., 1976; Marshall et
al., 1976). DDT caused no significant Increase In recombination mutants In
Bacillus subtlUs (Shlrasu et al., 1976), In recessive lethal mutants 1n
Neurospora crassa (Clark, 1974; Luers, 1953) or In reverse mutation frequency
In a host-mediated assay 1n Salmonella typh1mur1um In mice (Buselmaler et al.,
1972). Chromosomal aberrations have been reported 1n cultivated rat-kangaroo
cells (Palmer et al., 1972) and human lymphocytes (Lessa et al., 1976), but
not In rat cells (Legator et al., 1973). An Increase 1n dominant lethal
mutations was caused by DDT 1n DrosophUa melanogaster (Clark, 1974), the
Swiss mouse (Clark, 1974) and the rat (Palmer et al., 1972), but not 1n the
CF1 mouse (Wallace et al., 1976) or the ICR/Ha mouse (Epstein et al., 1972).
In the j_n vivo two-stage Initiation/promotion studies, DDT exhibited tumor
promotion activity In conjunction with a known number of Initiators, Including
2-acetylamlnofluorene (2-AAF), 2-acetam1tophenanthrene (AAP), and trans-4-
acetylamlnostllbene (trans-AAS). In all of the two-stage Initiation/promotion
studies, animals were treated with lifetime dietary exposure to DDT following
an Initial, brief exposure to a known tumor Initiator. Liver tumor Incidence
was significantly Increased 1n rats treated for 18 days with 0.02% 2-AAF then
followed by 0.05% DDT, when compared with those of the sham-control rats and
rats treated for 18 days with 0.02% 2-AAF (Peralno et al., 1975). In another
study using rats, DDT caused the acceleration of 2-AAP-1n1t1ated mammary
tumors and ear duct tumors In males, but was negative for liver tumor
promotion (Scrlbner and Mottet, 1981). Rats Initiated with trans-AAS were
found to have precancerous conditions 1n many tissues, Including the liver,
but only mammary tissue responded with tumors when promoted with exposures to
DDT 1n the diet (HUpert et al., 1983).
0026H -17- 11/15/88
-------
5. REGULATORY STANDARDS AND CRITERIA
The EPA banned all use of DDT, except for public health emergency, 1n 1972
(U.S. EPA, 1980a).
The WHO (1971) recommended a maximum Interim ADI In food of 0.005 mg/kg/bw
for DDT. The AC6IH (1986a) recommended a TLV-TWA of 1 mg/m3 based on
analogy with Undane, which was judged to be twice as toxic as DDT (ACGIH,
1986b). A STEL was not recommended. OSHA (1985) recommended an occupational
standard PEL of 1 mg/m3.
0026H -19- 11/15/88
-------
6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
DDT 1s known to be an animal carcinogen and data are sufficient for
computing a q,*. Therefore, 1t Is Inappropriate to calculate an RfD~Q or
RfD$I for DOT.
6.2. REFERENCE DOSE (RfD)
DDT 1s known to be an animal carcinogen and data are sufficient for
computing a q,*. Therefore, It Is Inappropriate to calculate an RfDQ or
RfDj for DDT.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. The Carcinogen Assessment Group has developed a quantitative
estimate of the carcinogenic potency of DDT (U.S. EPA, 1986a). The studies
selected for quantitative evaluation were Tarjan and Kemeny (1969), Turusov et
al. (1973), Terraclnl et al. (1973a), Thorpe and Walker (1973), Tomatls and
Turusov (1975), Cabral et al. (1982a) and Rossi et al. (1977). '
The data used for estimation of-a q,* from the Tarjan and Kemeny (1969)
study as shown 1n U.S. EPA (1986a) are presented In Table 6-1. Group sizes
were considered Inadequate for reliable evaluation 1n the F, and F~
generations. A potency estimate of 7.27 (mg/kg/day)"1 was calculated based
on the geometric mean of the potencies for generations F»-F5 for lung
cancers and leukemia.
The data used for estimation of a q,* from the Turusov et al. (1973)
study as shown 1n U.S. EPA (1986a) are presented 1n Table 6-2. A geometric
mean of the potencies across six generations for liver tumors of 0.80
(mg/kg/day)"1 for males and 0.42 (mg/kg/day)"1 for females was estimated.
0026H -20- 11/10/88
-------
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The data used for estimation of a q-j* from the Terradnl et al. (1973a)
study as shown 1n U.S. EPA (1986a) are presented 1n Table 6-3. A geometric
mean potency (q^*) of 0.082 (mg/kg/day)"1 for liver tumors was calculated
across sexes and two generations.
The data used for estimation of a q * from the Thorpe and Walker (1973)
study as presented 1n U.S. EPA (1986a) are shown 1n Table 6-4. The q *
values for the Incidence of malignant liver tumors In males and females were
calculated as 0.52 (mg/kg/day)"1 and 0.81 (mg/kg/dayJ"1, respectively.
The data used for estimation of a q * from the Tomatls and Turusov
(1975) study as presented 1n U.S. EPA (1986a) are shown 1n Table 6-5. The
q * values selected for benign liver tumors In males and females were 1.04
(mg/kg/day)"1 and 0.49 (mg/kg/day)"1, respectively, based on the 95-week
sacrifice, because this duration most nearly approximates the expected
lifetime of the mouse.
The data used for estimation of a q,* from the Cabral et al. (1982a)
study are shown 1n Table 6-6. A q,* of 0.084 (mg/kg/day)"1 was calculated
for liver tumors 1n female rats. The data used for q,* estimation from
Rossi et al. (1977) are also shown 1n Table 6-6. The q,* values for liver
tumors 1n male and female rats of 0.16 and 0.27 (mg/kg/dayJ"1, respectively,
were calculated.
Table 6-7 presents a summary of the calculated potency estimates. Of
these values, the q,* based on Tarj'an and Kem'eny (1969) was eliminated
based on the D1xon statistical criterion for rejecting outliers (p=0.01) and
the additional considerations that the study was from an unaudited laboratory
and that the feed was contaminated with DDT. A geometric average of the
values from the remaining six studies resulted In a final q * estimate for
DDT of 0.34 (mg/kg/day)"1: (0.80 x 0.42 x 0.082 x 0.52 x 0.81 x 1.04 x 0.49
x 0.084 X 0.16 x 0.27)1/10 = 0.34.
0026H -25- 11/10/88
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TABLE 6-3
Incidence of Benign Liver Tumors 1n BALB/c Mice Fed DDT During
a 2-Generat1on Experiment3»b
Incidence of Benlqn Liver Tumors by Generation0
Males
Dose Group
0 ppm
Trendd
2 ppm
20 ppm
250 ppm
qi*e
High dose q-j*
Parental + F-|
2/107
p<0
3/112
1/106
15/106
0.074
0.086
(1.9)
.001
(2.7)
(0.9)
(14.2)
Females
Parental
0/62
p<0
0/63
1/61
28/63
0.080
0.324
(0)
.001
(0)
(1.6)
(44.4)
0/69
p<0
0/73
0/67
43/58
0.094
0.718
h
(0)
.001
(0)
(0)
(74.1)
aSource: U.S. EPA, 1986a
^Number of animals with tumors/number of animals examined (percent).
Malignant tumors were not observed In liver.
cThe numbers In the groups of males were reduced by fighting, so the 2
generations of males were pooled. Each high-dose group shown 1s statistic-
ally different from Us control group (p<0.001). Other palrwlse tests were
not significant.
dBeneath the control Incidence Is the p value for positive trend In Inci-
dence over the dose levels.
eThe q-|*s were calculated using the human equivalent dose. The "high
dose q-|*" Is the result of using only the controls and the high-dose
groups In the calculations. The human equivalent doses are calculated by
multiplying the ppm values by 0.13 and then by the cube root of 0.030/70
(=0.0753949). For example, 250 ppm = 2.45 mg/kg/day for humans.
0026H
-26-
11/10/88
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TABLE 6-4
Incidence of Liver Tumors (Benign and Malignant) 1n CF-1 Mice
Fed DDT for a Single Generation3
Dose Group Incidence of Benign Incidence of Malignant
Liver Tumors'3 Liver Tumors'5
Males
Controls
100 ppm
Ql*
Females
Controls
100 ppm
q-,*
11/45
23/30
NO
10/44
26/30
ND
(24%)
(80%)
(23%)
(87%)
2/45
9/30
0.52
0/44
12/30
0.81
(4.4%)
(30%)
(0%)
(40%)
aSource: U.S. EPA, 1986a
bBen1gn Hver tumors 1n this study were referred to as "type a" and malig-
nant liver tumors as "type b."
ND = Not determined
0026H -27- 11/10/88
-------
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-------
TABLE 6-6
Incidence of Benign Liver Tumors 1n Rats Fed DDTa»b
Dose Group6
0 ppm
Trend'
125 ppm
250 ppm
500 ppm
qi*g
Cabral et
Males
1/38 (0)
NS
0.30 (0)
NS
1/30 (3.3)
NS
2/38 (5.3)
NS
NDh
al.. 1982ac
Females
0/38 (0)
p=0.003
2/30 (6.7)
NS
4/30 (13.3)
p=0.033
7/38 (18.4)
p=0.005
0.084
Rossi et
Males
0/35 (0)
NA
NA
NA
9/27 (33.3)
p<0.001
0.16
al.. 1977d
Females
0/32 (0)
NA
NA
NA
15/28 (53.6)
p<0.001
0.27
aSource: U.S. EPA, 1986a
^Number of animals with tumor/number of animals examined (percent).
cThese were Portion (Wlstar derived) rats.
dThese were Wlstar rats.
6The human equivalent doses are calculated by multiplying the ppm values
by 0.0085499, which Is 0.05 mg/kg/day (for rats) multiplied by the cube
root of 0.350/70 (=0.0753949). No adjustment for time was made because
rats were fed continuously for a lifetime.
^Beneath the control group Incidence 1s the p value for a positive trend
of Incidences as the dose Increases, when the p values 1s less than p=0.05,
otherwise NS (not significant). Beneath each dosed group Incidence Is the
p value for the comparison of the Incidence 1n the dosed group with Us
control group when 1t 1s less than p=0.05, otherwise NS.
9The q-j*s were calculated using the human equivalent dose. For example,
500 ppm = 4.275 mg/kg/day for humans.
nNot calculated due to lack of statistical Increase 1n hepatomas.
NS = Not significant; ND = not determined; NA = not applicable
0026H
-30-
Tl/10/88
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TABLE 6-7
Summary of Quantitative Potency Estimates for DOT*
Species
Mouse
Mouse
Mouse
Mouse
Mouse
Rat
Rat
Tumor Site
lung/leukemia
"liver
liver
liver
liver
liver
liver
qi* (mg/kg/dayr1
Males Females
7.27
(combined)
0.80 0.42
0.082
(combined)
0.52 0.81 -
1.04 0.49
0.084
0.16 0.27
Reference
Tarjan and
Kemeny, 1969
Turusov
et al.. 1973
Terradnl
et al., 1973a
Thorpe and
Walker, 1973
Tomatls and
Turusov, 1975
Cabral
et al., 1982a
Rossi et al. ,
1977
*Source: Adapted from U.S. EPA, 1986a
0026H
-31-
11/10/88
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6.3.2. Inhalation. Pertinent data regarding the carc1nogen1c1ty of Inhaled
DDT could not be located 1n the available literature.
0026H .32- 11/10/88
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986a.
Threshold Limit Values for Chemical Substances and Physical Agents 1n the
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Q026H -45- 11/10/88
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