United States
Environmental Protection
Agency
Office of Health and
Environmental Assessment
Washington DC 20460
Research and Development
EPA/600/S6-87/006 Aug. 1988
Project Summary
Carcinogenicity Assessment of
Aldrin and Dieldrin
Finis L. Cavender, Brion T. Cook, and Norbert P. Page
Evidence pertaining to the carcino-
genicity of aldrin/dieldrin is reviewed
and evaluated. The full report covers
studies completed before 1985. Case
reports and epidemiologic studies of
pesticide applicators and pesticide
manufacturing workers are reviewed,
but because of methodologic limita-
tions, these studies established neither
a positive nor a negative association
between cancer and aldrin/dieldrin
exposure. A number of independent
studies of laboratory animals, however,
demonstrated that aldrin/dieldrin
cause liver cancer in mice and rats.
Based on the accumulated evidence,
aldrin/dieldrin are classified as proba-
ble human carcinogens. Group B2.
using EPA's Guidelines for Carcinogen
Risk Assessment. The carcinogenic
potency of aldrin/dieldrin is estimated
by fitting mathematical models to the
laboratory animal data. These esti-
mates indicate that aldrin/dieldrin are
rather potent carcinogens, ranking in
the first (most potent) quartile of
potential carcinogens evaluated by
EPA's Carcinogen Assessment Group.
Separate mutagenicity assessments of
aldrin/dieldrin are attached as appen-
dices to the full report. The full report
also includes an extensive list of
references pertinent to the carcinogen-
icity of aldrin/dieldrin.
This Project Summary was devel-
oped by EPA's Office of Health and
Environmental Assessment, Washing-
ton, DC, to announce key findings of
the research project that is fully doc-
umented in a separate report of the
same title (see Project Report ordering
information at back).
Introduction
Aldrin and dieldrin were first synthe-
sized in the laboratory in 1948 with
commercial production in the United
States first reported in 1950. Aldrin and
dieldrin are organochlorine pesticides
extensively used in the 1960s and early
1970s for a large variety of pesticidal
uses. Most uses were banned in the
United States in 1974 under the Federal
Insecticide, Fungicide, and Rodenticide
Act. Uses were also restricted in many
other countries at about the same time.
The approved uses in the United States
now are mainly for termite control by
direct soil injection and for nonfood seed
and plant treatment. Production of aldrin
and dieldrin in the United States was also
discontinued along with the restrictions
of 1974, so that virtually all aldrin and
dieldrin now used in the United States
is imported. Exposure of humans has
been primarily from dermal and inhala-
tion exposure related to the application
of pesticides; however, due to the
persistence and bioaccumulation of
dieldrin, considerable exposure has
occurred through ingestion of contam-
inated water and food products. In
contrast, little human exposure from
environmental sources of aldrin occurs,
as it is readily converted to dieldrin by
direct expoxidation in the environment.
During the early 1970s, nearly all
humans sampled had measurable tissue
levels of dieldrin and, due to its stability
and persistence, dieldrin is still detected
in humans. However, the levels are
considerably low. Aldrin and dieldrin are
usually considered together, as they are
structurally related cyclodiene insecti-
cides, have similar uses, and because
aldrin is readily epoxidized to dieldrin in
the body or the environment.
The full report reviews the currently
available literature on the toxicity and
carcinogenicity of both aldrin and dieldrin
and conducts an assessment as to the
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potential carcinogenicity risk to humans.
The Carcinogen Assessment Group
(CAG) conducts a "weight-of-evidence"
evaluation that weighs data concerning
innate biological activity including
metabolism, toxic effects as related to
duration and levels of exposures, results
of mutagenicity and other short-term
tests, long-term animal bioassays, and,
where available, data derived from
epidemiologic studies. Since mutagenic-
ity is considered as one major mecha-
nism for cancer induction, those studies
are considered supportive of the in vivo
animal or human data.
Following a review of the data, those
data most appropriate for mathematical
extrapolation are selected for risk assess-
ment. Several mathematical .models, as
described in EPA's Guidelines for Car-
cinogen Risk Assessment are used. On
the basis of the "weight-of-evidence"
and risk extrapolation, the substance is
classified as a potential human carcin-
ogen according to the EPA Guidelines.
Discussion
Human Studies
Six case reports on aldrin toxicity
describe neurotoxicity, including convul-
sions and abnormal EEGs, as the main
toxic effects. Five case reports were
found for dieldrin. Like aldrin, effects of
the central nervous system, including
convulsions, were the main signs follow-
ing acute or prolonged exposure. In one
of the reports, however, immunohemo-
lytic anemia was the primary toxic effect.
Only two epidemiologic studies of
humans exposed to aldrin or dieldrin
were reported. One was a long-term
study of 233 industrial workers at
pesticide manufacturing and formulating
plants in the Netherlands. However, the
study focused mainly on clinical param-
eters and not cancer, and is considered
inadequate to determine the carcinogen-
icity of aldrin and dieldrin. The other
study included a retrospective mortality
analysis of 1,155 employess at a plant
that had produced aldrin, dieldrin, and
endrin for 30 years prior to the analysis.
There was a statistically significant (p
<0.01) increase in nonmalignant respi-
ratory disease (SMR=212, p<0.01).
While an SMR of 82 was found for all
malignant neoplasms, an SMR of 235
was found for cancer of the esophagus,
SMR=242 for cancer of the rectum,
SMR=225 for cancer of the liver, and
SMR=147 for cancer of the lymphatic and
hematopoietic system. However, none of
these was significnat. This study also has
serious limitations. No information was
presented on actual exposure levels, and
exposures to other chemicals were
known to occur. No attempts were made
to adjust for effects of other chemical
exposures, smoking, or alcohol con-
sumption. Since the number of workers
was small and vital status was unknown
for 10%, the power to detect an effect
was quite limited. Due to these meth-
odological limitations and the limited
data, it is difficult to draw either a
negative or positive association between
aldrin/dieldrin and carcinogenicity.
Hence, these studies are considered
inadequate epidemiologic evidence.
Animal Studies
Aldrin
Three adequately conducted long-term
carcinogenicity bioassays of aldrin have
been conducted with mice. The strains
used were C3HeB/Fe, C3H, and B6C3Fi.
In the study with B6C3Fi mice, aldrin was
fed at four doses of 3 to 8 ppm for 80
weeks with 10 to 13 weeks of additional
observation. A statistically significant (p
<0.001) increase in hepatocellular
carcinomas was observed in both the 4
and 8 ppm male groups but not in the
females. In the other two studies,
reported in 1962 and 1965, C3H and
CaHeB/Fe mice were fed aldrin at 10 ppm
for 24 months. In both, statistically
significant (p <0.001) increased inciden-
ces of hepatomas were diagnosed
although not broken down as to inciden-
ces in males or females. Reevaluation by
other pathologists diagnosed the lesions
as hepatocellular carcinomas with sta-
tistically significant (p <0.05) increases
in both male and female groups.
While it may be true that the CaH and
CaH/HeB/Fe strains have a large per-
centage of their gene pool in common,
we expect that B6C3Fi mice have approx-
imately half of the gene pool of the C3H
strain. Furthermore, the gene pool in
these mice changes from lab to lab and,
after many generations, in the same
laboratory. The fact that dieldrin, a
metabolite of aldrin, is carcinogenic in
the C57BL/6J, CBA/J, Swiss-Webster,
and CF-1 strains (highly different genet-
ically) as well as the C3 and B6C3F,
strains argues against the C3H strain's
unique genetic susceptibility to this
effect.
Seven carcinogenicity bioassays of
aldrin have been conducted with rats,
only one of which is considered adequate
in design and conduct. Five studies used
Osborne-Mendel rats, with one each
using Carworth and Holtzman strains.
Doses ranged from 0.5 to 150 ppm with
dietary exposure generally for at least 24
months. At 50 ppm and below, good
survival resulted. There was no evidence
of carcinogenicity in any of the studies.
However, a constant finding was liver
lesions comonly referred to as "chlori-
nated insecticide type lesions."
In the only adequate study, the
National Cancer Institute (NCI) bioassay
in Osborne-Mendel rats, there were
increased incidences of thyroid follicular
cell adenomas and carcinomas of the
thyroid in both males and females. These
incidences were significant in the low-
dose group but not the high-dose group
when compared to pooled controls but
not with matched controls. It should be
noted that there were only 10 animals
in the matched controls, which is not
usually enough to detect all but the
largest responses. Although NCI con-
cluded that the tumors were not asso-
ciated with treatment, our examination
using pooled controls indicates that there
was some positive response. Later
evaluations by other investigators indi-
cated that the thyroid follicular (in both
sexes) and adrenal cortex tumor in
female rats was suggestive evidence of
carcinogenicity for aldrin.
Another study with rats was consid-
ered inadequate because as few as 62%
of the treated animals in one dose group
(female high-dose group) and 75% of the
male controls were microscopically
examined. Reevaluation of the histopath-
ology indicated that the authors may
have under estimated and underreported
the incidence of malignant tumors by
approximately threefold. In all, there
were seven rat studies. Six of them were
considered inadequate. A well-designed
study on rats would be useful to answer
the specific question whether the car-
cinogenic potential of aldrin is limited to
mice or not.
Dieldrin
Twelve carcinogenicity bioassays of
dieldrin have been conducted with mice;
all but one were judged adequate in
design. Seven strains of mice were used:
CaHeB/Fe, C3H, CBA/J, Swiss-Webster,
CF,, B6C3F1( and C57BL/6J. In all
studies, either benign or malignant liver
tumors were observed. The authors of
six of these studies indicated that the
tumors were malignant (hepatocellular
carcinomas), whereas in five others the
tumors were diagnosed as hepatomas.
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In three of these five, a pathology
reevaluation was performed by other
pathologists who classified the lesions
as being malignant. In three studies, all
with CFi mice, many of the hepatocel-
lular carcinomas had metastasized to the
lung. In additon, in one study, a signif-
icant (p <0.05) reduction in latency
period was observed. In one of the
studies with CF1 mice, a slight but
significant (p <0.05) increase in the
incidence of pulmonary adenomas and
carcinomas, lymphoid tumors, and other
tumors was seen in female mice at 1
ppm. The doses used in the bioassays
ranged from 0.1 to 20 ppm with dietary
administration for 18 to 24 months.
Seven long-term carcinogenicity stud-
ies were conducted with rats, three of
which were considered adequate carcin-
ogenicity assays. The others suffered
mainly from too few animals, too high
mortality, too short a duration, and/or
inadequate pathology examination or
reporting. Four strains were used: Car-
worth, Osborne-Mendel, Holtzman, and
Fischer 344. Doses ranged from 0.1 to
285 ppm in the diet generally for 2 years
or more. Although liver pathology was
generally associated with exposure to the
chlorinated insecticides, there was no
firm evidence of a carcinogenic response
in any of the studies.
Conclusion
Aldrin
For aldrin, the finding of hepatocellular
carcinomas in male B6C3Fi mice and the
findings of the hepatomas in C3H and
C3HeB/Fe mice, which were later diag-
nosed as hepatocellular carcinomas, in
both males and females, constitute as a
first approximation/'sufficient" evidence
of carcinogenicity in animals, according
to criteria in the EPA's Guidelines for
Carcinogen Risk Assessment. However,
the Guidelines call for a careful analysis
of the nature of the mouse liver-tumor-
only response to ascertain whether there
is a sufficiently strong reason to down-
grade the evidence to "limited." This
downgrading was found not to be appro-
priate since the tumor increases were not
marginal in male B6C3Fi mice (which
have a high spontaneous incidence of
liver tumors), there was a dose-related
increase in the proportion of tumors that
were malignant, and the response
occurred in both males and females. In
addition, the response occurs in CaH and
CaHeB/Fe mouse strains with a low
spontaneous incidence of liver tumors.
which is a response not subject to the
downgrading factors.
One factor which would argue for a
"limited" classification is that the two
C3H strains are genetically closely related
and the B6C3Fi strain derives half of its
gene pool from these strains. However,
the fact that the epoxide metabolite,
dieldrin, produces liver tumors in seven
different mouse strains indicates
strongly that the carcinogenic effect of
aldrin is not limited to a restricted genetic
range of mice. Although in rats, one
adequate study with aldrin and three
adequate studies with dieldrin were
negative or equivocal, the multiplicity of
mouse strains responding is considered
to be enough for classification of "suf-
ficient" evidence in animals.
In the absence of adequate evidence
in humans, the sufficient animal evi-
dence amounts to an overall classifica-
tion of B2, or "probable" human carcin-
ogen for aldrin.
For aldrin, the carcinogenic potency,
obtained by averaging estimates from
most sensitive species tested (mice), is
17 per mg/kg/day. The potency using
the most sensitive sex and strain is 23
per mg/kg/day. These are plausible
upper bounds for the increased cancer
risk from aldrin, meaning that the true
risk is not likely to exceed these estimates
and may be lower. These estimates have
been calculated using the Agency's
preferred methodology in the absence of
specific physiologic, metabolic, or kinetic
information: the linearized multistage
model with doses scaled according to
relative body surface area. Other
assumptions about the dose-response
model or the interspecies dose adjust-
ment may result in lower estimates. The
molecular potency index for aldrin is 6.2
x 103 per mmol/kg/day. This places
aldrin in the first (most potent) quartile
of suspect carcinogens ranked by the
CAG.
Dieldrin
For dieldrin, the mouse liver tumor
response in seven mouse strains
(CaHeB/Fe, C3H, CBA/J, Swiss-Webster,
B6C3Fi, and C57BL/6J) along with the
appearance of pulmonary adenomas and
carcinomas and lymphoid tumors in one
strain (CFi) would justify the preliminary
classification of dieldrin as having
"sufficient" evidence in animals. Based
on the nature of the response there is
no reason to downgrade the classifica-
tion to "limited," since the carcinoma
response is unmistakably strong, it
occurs in both males and females, and
at both high and low doses. The occur-
rence in several strains implies that it
is not a genetically isolated finding. The
carcinogenicity studies in rats for dieldrin
were considered negative. However, the
ability of most studies to detect carcin-
ogenicity was compromised due to too
few animals, too high mortality, and too
short duration. Although liver pathology
was associated with exposure to the
chlorinated insecticides, there was no
firm evidence of a carcinogenic response.
In the absence of adequate evidence in
humans, the sufficient animal evidence
amounts to an overall classification of B2
or probable human carcinogen for
dieldrin.
For dieldrin, the carcinogenic potency,
obtained by averaging estimates from the
most sensitive species tested, is 16 per
mg/kg/day. The potency using the most
sensitive sex and strain, is 55 per mg/
kg/day. This estimate may, however, be
misleading because 100% of the exposed
animals developed cancer. The second
most sensitive estimate is 28 per mg/
kg/day. These are plausible upper
bounds for the increased cancer risk from
dieldrin, meaning that the true risk is not
likely to exceed these estimates and may
be lower. These estimates have been
calculated using the Agency's preferred
methodology in the absence of specific
physiologic, metabolic, or kinetic infor-
mation: the linearized multistage model
with doses scaled according to relative
body surface area. Other assumptions
about the dose-response model or the
interspecies dose adjustment may result
in lower estimates. The molecular poten-
cy index for dieldrin is 6.1 x 103 per
mmol/kg/day. This places dieldrin in the
first (most potent) quartile of suspect
carcinogens ranked by the CAG.
Although there is always uncertainty
in extrapolating potency from animals to
humans, our confidence in these animal
potency estimates is relatively high. This
confidence is based not only on the tight
clustering of aldrin and dieldrin potency
estimates, but on other factors as well.
The potency estimates for aldrin are
consistent with the potency estimates for
dieldrin, one of its metabolites. In
addition, aldrin's potency (and dieldrin's
as well) is based in part on studies of
mice with low-background tumor rates.
A study of female CaHeB/Fe mice, for
example, saw the tumor incidence
increase from 4% in controls to 85% in
the treated group. Potencies derived from
high-background strains are consistent
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with potencies from low-background
strains. Furthermore, potencies derived
from mouse liver tumors are consistent
with potencies derived from rat tumors
for two other related substances, chlor-
dane and heptachlor epoxide. Thus,
mouse liver tumors can provide a basis
for estimating cancer potency in humans,
recognizing the current issues asso-
ciated with use of this type of data and
attendant uncertainties in a risk estimate
based upon it.
This Project Summary was prepared by staff of Office of Health and
Environmental Assessment, Washington, DC 20460.
Dharm Singh is the EPA Project Officer fsee below).
The complete report, entitled "Carcinogenicity Assessment of Aldrin and
Dieldrin." (Order No. PB 88-139 951/AS; Cost: $19.95, subject to change)
will be available only from:
National Technical Information Service
5285 Port Royal Road
Springfield. VA 22161
Telephone: 703-487-4650
The EPA Project Officer can be contacted at:
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Washington. DC 20460
United States
Environmental Protection
Agency
Center for Environmental Research
Information
Cincinnati OH 45268
Official Business
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