* UNITED STATUS ENVIRONMENTAL PROTECTION AGENCY
*
• VMSHIfJGTON DC 20460
OTFICE or
PLANNING AND MANAGEMENT
MEMORANDUM
SUBJECT: JCeponc Risk Assessment
/
FROM; Eli/abeth Anderson, Executive Diiector >/c//'7' ( /%-T/*' '
Interim Carcinogen Assessment Group //- '^ "' /
^ (..^
TO: "Ec|\vm Johnson, Deputy Assistant Administrator
Pesticides
The Carcinogen Assessment Group has completed the risk Assessment
for Kepone. I am herein transmitting the report of this analysis lo you,
Attachment
cc:
A. Aim
\V. Talley
VR.'Dreer
* F. Ilageman
P. Denney
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TUB CARCINOGEN ASSESSMENT GROUP
ANALYSIS OF ICE PONE
Participating Members
Elizabeth L,. Anderson
Robert Me Gaudily.
Lakshmi C. Misln a
Arnold M. Kuzmack
Mclvin Reuber
William Upholt
R. K.Albert, MD. Cliairman
Date
&
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Conclusion of The Keponc Risk Assessment
On the basis of animal tests summarized in this report, there is
significant evidence that Keponc is likely to be a human carcinogen.
The impact on the induction of cancer in humans by the continued
use of Keponc in ant and roach traps and pastes involves particularly
largo uncertainties chic to the lack of data upon which to base exposxire
extimates for the gcncial population. In the CAG's vicnv, the major
concern is probably tho iisk to children who accident}} inmost Ihe
Contents of traps and tubes of paste containing Kepone. Of the various
models of assessment, the "worst case" estimate oflifelime risk to
the individual child is one chance in 400 of de\eloping cancer due to
accidental exposure using the assumption of repeated episodes of
ingestion and a linear non-threshold model for cancernndur lion.
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MK'J A HO 1,1C CHARACTERISTICS
The tissue distribution of kcpone in animals has been measured by
several investigators (Kef. 1, 3, 4 & 7). These studies luuc shown
that the liver is the organ \\hcre the largest kcpone storage occurs,
and that it is also stored in brain, kidney and body fat. Accumulation
of kepone in these organs continues for longer than 150 da\s in mice
fed 40 ppm of kepone. Upon withdrawal of kepone from the diet, the
half-life-«is shorter than 20 days. Compared uilh mice, a close
structural analogue, kcpone is less fat soluble and the hvei /fat
storage ratio is larger lhan for mice. Kepone excretion is predomi-
nantly via the liver bile and fcces route.
in human studies of kepone factor}7 \vorkers in Ilopeuoll, \'a. , it has
been found that the ratio of fat to blood concentrations of kcpone is
only about 7/1*. Other chlotinated hydrocarbons are concentrated to a
much greater degree in the fat, for DDT the fat/blood jatio is close
to 300. The time it takes to equilibrate with blood after continuous
ingc&tion begins lias not been measured, but based on an analogy with
mice it may take as long as 2 years. After withdrawal of kcpone
exposure in people, the half-life in the blood is about 4 months.
Human liver levels have not been measured.
Several studies indicate that the effects of continued ingcstion are
cumulative. Good, et al, (Ref. 2) found that reproductive performance
in mice steadily declined over a 3-month feeding period at 5 ppm. In
his experiments mice on the kepone diet were bred and their progeny
were raised to maturity on the same diet. The second litters of the
progeny were smaller and less numerous than the first litters had
been. In the Allied study (Ref. 3) it was found that single closes which
"were 0. 1 times the L.D "30 had no effects on rats but 20 daily repetitions
"of this dose resulted in 50% mortality and marked growth ictardation.
Metabolites of kcpone have been looked for in liver and fat tissues
but not found. Mutagencsis studies of kepone have not been reported
(Ref. 6). -
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EXPERIMENTAL CARCINOGCNESIS STUDIES
Two carcinogenesis studies arc available (Ref. 3, 5): the chronic feeding
study in rats submitted in support of a tolerance petition for use of kepono
on bananas, and the 25-page sujnmary of an NCI feeding study on rats and
mice, dated Januaxy 1976.
A. NCI Rat and Mouse Studies
Technical grade kepone was administered for an 80 week period to four
groups of B6C3F1 mice and four groups of Osbomc-Mendel rats approxi-
mately 6 \veeks of age. The mice were killed alter 90 weeks and the rals
after 112 weeks. The four groups consist of males and females each fed
two doses. The dose levels were chosen on the basis of survival and
weight gam in a preliminary 6-week treatment panod. As the full scale
study progressed, it became apparent that the animals could not tolerate
the initial doses, and the feeding level was lowered Time-weighted avei -
age doses for the entire experiment were calculated and are given below,
along with Die initial doses:
a) Initial Dose
Species
Mice
Rats
b) Average Dose
Species
Mi ce
• Rats
DOSE LEVELS, (PPM)
Male
Low High
30
Female
High
~~M
60
Male
Low High
~~~
Female
8
The animals were housed in two rooms for this expcammcnt. Kepone was
the only compound under test in the room where iheas'ts were housed, \
whereas the mice were housed in a room \\here toxaRftene, chlordane, and
kepone weie concurrently under test. Initially the re we re 50 animals in
each of the Jour dosed groups. Controls consisted dfimatchcd controls and
of pooled controls. , ,
'The survival of the animals at the end of the experiraa-nt is given below,
v/here the conti ols for each dosage group are combiocd:
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TERMINAL SURVIVAL
Pose Group
Q-* Low High
a) Mice
1 Males G2/G8 (91%) 28/48 (58%) 25/49 (51%)
Females 43/50 (86%) 42/50 (84%) 41/49 (84%)
*
b) Rats
""Males 75/115(65%) 30/50(60%) 18/44 (41%)
Females 68/110 (62%) 27/49 (55%) 18/45 (-10%)
^Pooled and matched controls are grouped togcthei.
It can be seen that control mice survived the experiment in greater
numbers than control rats, and that survival decreased in all groups
as the dose increased
Qualitatively survival correlates well (negatively) "with aAerage dose, with
the notable exception of female mice, where the ratio of high to low ave-
rage dose is 2/1 but the percent survival is identical for the IMO groups.
In general rats tolerated the experiment less well than mice, fi om the
survival figures as well as the clinical signs of toxicit}'.
In lats some high dose ammals developed epistaxis and bleeding of the
eyes and four animals had died or had to be sacrificed dining the first 4 ~
months of the study. Females began developing generalised ticmors at
the fifth week in the high dose group and the 28th \veck foi the low dose
group. In all treatment groups adverse signs (rou^h hair coats,
dermatitis, anemia, tremors) occured at a moderate incidence during the
first year and^uith a gradually increasing frequency in the second year.
•Surviving animals at the termination of the experiment were generally
in very poor physical condition.
In mice, the -low level animals had the same appearance and behavior as
controls throughout the first-year, and a few low le«d males had palpable
nodules in the abdominal area during the second year. In the high level
animals, females developed generalized tremors dnnng the first week
of the study and these persisted until the end. Aboii20% of the high dose
male group were highly excitable during the secondyzai. Bloating or
"abdominal distenlion \\as noticed in high dose males,al week 45 and at
high dose females at week 68. . •' . .
•A significant increase was found in the incidence ofJbpnloccllular carcino-
mns in only high dose level rats of both sc\es and inmice of both sexes at
both dose levels of he pone (P<0. 01). The incidcncev(P<0. 05) in the high
dose groups were 7% and 22% for male and female io& (compaicd with
0% in controls for both sc.xcs) and 88% and 47% for rale and female mice
- 2 ~
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(compared with 16% for male pooled controls and 0% in females). The
incidence for the low dose groups of mice weie 01% for males and 52%
for females. The incidence for low dose rats was 20% for both males
and females. Extensive hyperplasia, fatty infiltration and degeneration
as well as occasional "neoplastic nodules" were also found in the hver
of mice and rats.
HEPATOCBIJ ULAR CARCINOMAS IN MA T E AND FEMALE RATS
'1' l NC; K'C \''(5m?
- Dose * Males Females
0 ppm 0/105 (0%)* 0/100 (0%K
low dose l/5'O (2%) 1/49(2%)
high dose 3/44 (7%) t 10/45 (22%)
* Pooled control groups
HEPATOCELLULAR CARCINOMAS IN MAI,K AMD FEMALE MICE
INGESTING KDPONE
1 • Dose Males Females
Pooled 8/49(16%): 0/40(0%)
• 0 ppm .
Matched 6/19 (32%) 0/10 (0%)
low dose 39/48(81%) 26/50(52%)
high dot,e 43/49 (88%) . 23/49 (47%)
*The NCI report states that the hepatocellular carcinoma incidence arm
control mice of this strain is usually betwcn 7 and 10% in males and about
l%>m females. The 16% in these males is theicfore not regarded as usual.
The information on time until the detection of the first grossly observable
tumors is summarized below.
TIME TO FIRST TUMOR, DAYS
Dose Group "
••- 0 - .Low
a) Mice *""
~Wles 87 70 62
Females - - 87 " 76
* "*
b) Rats
"""fifties - 112 ' ' 108
87.' 83
*
- 3 -
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As expected, the time is less for each high dose group than for the cor-
responding lov/ dose group. Ilouever the diffeience in time to first tumor
(high versus low dose groups) does not correlate well with changes in the
average dose le\el, since the male rats have only a four-day difference
in time to fiist tumor whereas the dose is three times higher in the high-
dose than the low-dose group. Male mice developed tumors sooner than
females, whereas female mice developed tumors sooner than males.
The overall incidence of tumors is not significant nhen benign and malig-
nant tumois are considered together. When malignant tumors are con-
sidered alone, theie arc more malignant tumors in treated as compared
to the contiol animals. Malignant tumors were present in the thyroid of
low dose male rats, and there-were tumors of the reproductive system in
females of both the low and high doses. There was no dilfcrence in be-
nign tumors because both control and treated animals developed adenomas
of the endoci me organs and because of the low number of control raib.
MALIGNANT TUMORS IN MALES INGESTING KEPONEg./
(NCI ]JAT STUDY)
No. Rats with No. Hats with
Li\er Carcinomas Other Malignant Tumors Total
0 ppm «. 0/10(0%) ' 0/10(0%) . 0/10(0%)
*
low dose 1/50 (2%) 7/50 (14%) 8/50 (16%)
high dose 3/44 (7%) . 5/44 (12%) 8/44 (18%)
MALIGNANT TUMORS IN FEMALES INGESTING KEPONE
' (NCI RAT STUDY!!?/
«
No. Rats with No. Rats with
7^ ,;, Liver Carcinomas Other Malignant Tumors **"• - Total
Oppro 0/10(0%) . 0/10(0%) 0/10(0%)
low dose , -1/49(2%) , . ,, 7/49(14%) " 8/49(16%)
high dose 10/45 (22%) . 9/45 (20%) 19/45 (42%)^
.«
oYData concc_rmng tumors other than the liver arezot available at
, this time for the remaining controls in the pooled groups.
The conclusion diawri from the NCI studies is that Kegnne is definitely
a carcinogen in mice and rats. There is nothing aboaftthc study (treat-
ment of annn.il.3, excess carcmogemcity in controls, jprc-mature death
due to other causes) that would cause any doubt aboulllic validity of the
study.
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NCI MOUSE STUDY
100 i, '
MALE MICE
RCCM N'PTCHEO LOW
CONTROL COXT^OL DOSE
FEMALE MICE
0s/-
25/50
52%
23/43
CONTROL
Comparison cf Incidence of Kepatoceilular Carcinoaa
'(Chlordecor.c) ,
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NCI RAT STUDY
100 -t
MALE RATS
FSiVIALg RATS
S SQ'
o
c:
<
o
c
o
o
c_
u
CO
u.
O
u
o
CZ.
ID
C.
SQ-\
»
I
70-
60-1 •
50-
.40-
30-
10-
0/105
3 I 2%
— l^ s \ 1
3™
\S^
I
i
0/100
~p%__
OL ^'^ ^g . CONTROL
1/49
27,
•^ \ \ t
1
LO'.'.' HIGH
D33H CCS£
Comparison of Incidence of HepacoQellular
(Chlordecor.e)
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B. Allied Chrome Ra< Study
In this study young albino rats of an unspecified strain ucro grouped into
12 groups (G male and G female) of 40 animals per group. They were fed
diets consisting of 0, 5, ?0, 25, 50 and 30 ppm oflepon^, v.lmh Allied
designated as compound 1189. At the end of 3 and 12 months, some
of the animals from each group were sacrificed and at 2-1 months the re-
maining animals were examined. The observations and measurements
were 1) food consumption, 2) animal weight, 3) organ \vcights, 4) hemo-
globin and hcmalocrit levels, 5) urinary sugar and protein levels,
G) histopathological examinations. In a separate two 3ear feeding study
rats were fed 1 ppm kcponc.
*
The animals receiving BO and 50 ppm developed muscular tremors by the
end of 2 and 3 weeks, respectively and had all died b) -1 and G months.
At 25 ppm mild tremors developed by 12 months. The number of animals
alive immediately prior to each sacrifice is shown belou.
NUMBER OF SURVIVORS (Males/Females)
a) Males
b)
Time
(months)
0
3 *
12
24
Females
Time
DOSE (ppm)
JD_
40
38
31
7
40
39
34
3
10
40
37
28
4
40
37
26
3
_50_
40
36
0
0
80
40
4
0
0
DOSE (ppm)
0
39
31
14
5
39
34
10
10
40
37
32
9
25
40
24
3
.,„ 5(J.
39
0
0
80 "
-10
5
0
0
- (months)
0
3
12
24
At the end of two years, the maximum number which could survive was
25 because of the planned sacrifices at 3 and 12 momlhs. Therefore the
percent survival at the six dose levels by the end of two years was,
TERMINAL SURVIVAL, Percent
Dose, ppm
0
~^T
5G
5
40
10
— ro-
se
25
12
12
50
— U
0
ao
— G
0
Males
Females
This is a smaller survival than observed in the NCIaiiulj at corresponding
doses (including contiols), so one would cxjxict fewer animals to live long
enough to develop cancer. . . .
- 7 -
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In fact whan the animals were examined after saci jfjcc only six of them
had gross liver lesions that were regaidcd important enough to subject
to special study and interpretation. The rcpoit regards the evidence
of carcmogcMiic it> as cqxu\ocal, since the opinions ol four pathologisls
differed in the interpretation of the slides, however, the consensus was
that the lotions were carcinomas. Furthermore, 1 1 should be noted that
carcinomas of the liver arc extremely rai c tumors in rats not treated v.'Jth
chemicals. Lack of time does not permit i e -examination of the lustologic
sections.
Dose
0 ppm
'5 ppm
10 ppm
25' ppm
Dose
0 ppm
' 5 ppm
10 ppm
25 ppm
LESIONS OF TIIE LIVER IN MALE RATS
IJyperplasia
plus
Hype
0/8
0/8
2/1
0/5
iplasia-B'
(0%)
(0%)
0 (20%)
(0%)
LESIONS OF
Carcinomas
0/8 (0%)
0/8 (0%)
0/10 (0%)
2/5 (40%)
THE LIVER IN
Carcinomas
0/8 (0%)
0/8 (0%) -
2/10 (20%)
2/5 (40%)
FHM.ALE RATS-5/
ITyperpIasia^r
0/18 (0%)
1/16 (6%)
1/15 (7%)
0/5 (0%)
Carcinomas
0/38 (0%)
0/16 (0%)
3/15 (20%)
1/5 (20%)
Hyperplasia
plus
Carcinomas
^ 0/18 (0%)
*,
1/16 (6%). ,v
4/15 (27%)
1/5 (20%)
a/Two male rats had hyperplasia of the liver aftei 85 weeks.'
- In other rats hyperplasia or carcinomas were present at
10-1 weeks.
b/Includes rat with hyperplasia of the hvoi only
- 8 -
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Malignant lurnoi s \\ere found predominantly in the liver in treated
animals. There \\eie in addition some othci malignant tumors such as
melanoma of the brain and leukemia, as \\ell as subcutaneous adenomas
and adenofjln omas (a thorough histopatho]ot';ical evaluation was not
attempted by Allied). Numbers of tumors .ne given in the tables (foi
animals that h\rd for G9 weeks, the time of appc.aiame of the first
tumor, 01 loncuM ). Two females ingesting 10 ppm kcpone with carci-
nomas of the h\ei also had "thrombosis of adienal veins."
NUMBER OF MALE RATS WITH TUMORS-/
»
No. Rats with No. Rats with
Dose Tumor sjy Malignant Tumors —
0 ppm 1/8(13%) 1/8(13%)
5 ppm 2/8 (25%)£/ 0/8(0%)
10 ppm 2/10 (20%) £/ 1/10(10%)
25 ppm 2/5 (40%) 2/5 (40%)
NUMBER OF FEMALE RATS WITH TUMORS-/
No. Rats with No. Rats with
Dose Tumors k/ Malignant Tumors £/
0 ppm 6/18(28%) ' 1/18(6%)
5 ppm 9/16 (50%) 1/16 (G%)
10 ppm 10/15(67%) 4/15(27%)
25 ppm 1/5 (20%) " ^ 1/5 (20%)
a/Based on individual animal diagnoses by Allied's pathologist.
]>/Some lats had more than one tumor. In such cases, the rat
is counted only once.
. £/Jn this column, rats which had bemgn tumors only have been
. excluded, to show whether there appears to be increased
incidence of malignancy (as \\ell as increased tuasor incidence
in the dcatod groups).
-------
The liver/hotly weight ratio increases in both groups \vilh dose level.
When linear regression of this ratio is clone with icspccl to dose, it is
found that the close at which the liver/body \\eight ratio is significantly
»(P . 05) hujhci than controls is 15 ppm for males and 5. 3 ppm for
females. Therefore liver enlargement occurs at a louer dose in
females than for males. These concentrations are virtually the same
at 2 years as at 3 months, indicating that no fin ther enlargement occurs
after the first lew months.
The kepone lexcl in fat increases with dose. At thiee months the fat
level ranges from 10 ppm in the 5 ppm dose gioup 1o 383 ppm in the 80
ppm dose group. This measurement was not done for animals on the diet
at longer times.
%
When regression of bod}r weight is done versus dose levels, it is found
that significant depression in growth rate occui s at a concentration of
5-10 ppm in females and 10-25 ppm in males.
Measurement of blood cells were done at 3 month inter \als. A tendency
toward depression of hematocrit was obseixed at 80 and 50 ppm at 3
months and depression of both hematocrit and hemoglobin occurred alter
15 months in the 25 ppm group.
The urinary excretion of sugar and protein were made at 3 month inter-
nals. Kepone dosing had no effect on sugar but did cause protein to be
excreted-m the urine. The effect got progressively larger and occurred
sooner as the dose increased. Kidney tissue was examined especially
to provide e\idcncc for this proteinurea. Females sho\\ed a trend toward
increasing incidence and severity of chronic 1 idncj lesions with increasing
dose. Renal disease in treated males was not as noticeable because un-
treated rats also had renal disease.
In the second study in which rats ingested 1 ppm Kupone, 2 of 1 0 (20%)
male rats and 2 of 13 (15%) female rats had malignant tum'ors, compared
to 0 of 17 female controls and 0 of 14 male controls. v
In summary, the Allied study does indicate that kepone is carcuiogenic
in rats, par lieular ly for liver, and could also be for tumors developing
in other organs, even though the overall mor lality w^s high. These
findings are similar to those of the NCI study.
« \ «
C. Comment
Carcinoma^ of the liver were induced by Kepone at hSgh and low dose
levels in mitu and at higher dose levels in rats Carcinomas of the
types icpoiled in this study have the morphologic c Ixau-actei istics of
milgnanl tumois. do invade and mctastasi/e to the lioigs and/or other
organs and giuw iollowmg transplantation to other aunmnls of the same
strain. 11 should be noted that the incidence ol lung snetaslases is not
- 10 -
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reliable unless, among other things, serial sections arc done, which
was not the case in these studies. JLikcwise, multiple sections are
necessary to demonstrate mvasiveness of carcinomas.
The development of carcinomas of the liver in treaiod rats is ex-
tremely impoi (ant. Carcinomas of the liver in rats arc preceded by
the development ol hyperplasia and hyperplastic nodules, i.e. benign
lesions. The in st hypcrlasia of the livei was noted in albino male
rats after 83 weeks and the first carcinomas at the end of 101 weeks.
If the ammalt. had survived for longer peiiods of tune, these lesions
would have continued to progress. Control rals did not develop car-
cinomas ol the liver in these studies. Fmthermore, carcinomas of the
liver are extremely rare in any strain of untreated rat.
D. Conclusions
Male and lemale BOC3F1 mice ingesting eithci the low or high dose
levels of kepone m the diet develop carcinomas of the liver. Carcino-
mas of the liver were foxmd in Osborne Mendel male and female rats
ingesting the highe: dose level of kepone. Albino male and female
rats ingesting high doses of kepone also had cai cinomas of the liver.
Such carcinomas of the liver not only have Ihc morphologic characteris-
tics of malignant tumors bui they also kill the host animal and are
capable of invading and metastasizing to the lungs and of growing on
transplantation 10 animals of the same strain. The overall incidence
of all malignant tumors was increased 111 both Osborne Mendel and
albino male and female rats.
\
The conclusion drawn from these studies is that kepone is definitely a
carcinogen in animals. There is nothing about the suuhcs (treatment
of animals, excessive carcinomas in controls, premature death due to
other causes) that would cause any doubt about the validity of these
studies. <
- 11 - '
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H1SK EXTRAPOLATION
A risk extrapolation has been performed for the possible eai cinogenic
effects of allowing existing slocks of Kc-ponc to be used up. Only a lincai
extrapolation was possible with the limited cxposxire (In la available, and
even that is parametric. Use of non-linear extrapolation mo 1 hods would
require estimates not only of average exposures but also of the distribu-
tion around the average, this is a particular problem in the picsent case,
where accidental mgoslion by children may be a significant poi tion of the
total human exposure.
Let N = the number of people exposed to Kcponc through use of the
existing stocks, y_ = the number of years necessary to u^e up the stocks
(•ourjcntly estimated at '1 and, in any case, small compaird to a human
lifetime), and p = the pi oportion of the Keponc stocks that vill eventually
be consumed by" humans via the various possible loutcs of exposure.
Total stocks are currently estimated at 537.-8 Ib (sub]cct to levision).
Then the average daily exposui e to Kepone, expressed as an equivalent
ppm in the diet, is
__ 537.8 Ib x 106 x p
2. 205 Tb/kg x N x 1. 5 kg/day x 3G5y days
= 4.455 x 105 p/Ny
To derive the slope of the dose-response curve, the NCI data for liver
tumors for male mice fed 20 ppm (the case that yields the highest
result) and the formulation niade by Dr. Todd Thorslund of OPP has
been used. (The lowest slope for mice derived from the NCI study is
Jower by a factor of 5. Values for rats are lower by factors of 9 to 77. )
Under the one-hit theoiy (he pi obability of a individual developing a tumor
due to an exposure to a dose x of a agent may be expressed as
H(x) = 1 - e~Bx
where "B" is a unknown parameter to be estimated from a bioassay where
the observed vaiiables aie the control and exposure incidence of tumors.
JvCt R be the incidence in »i exposure group and 0 the conliol incidence.
Under the usual assumption that whatever causes the tumor in the controls
is independent of the action of the agent, we have that
' ' R = O -I (1 - O) R(x) = O I (l-O)U - c ~B>V)
Solving for B, we have that
B = ( In(l-O) - In(l-R)] /x
In the case of Ki-ponc, estimates of O and R, when X is 23 ppm in the diet
of a mouse ovei its entire life span arc O = 0.10 and 11 - 0. 80 respectively
BO that
-------
B = [ln(l -O) ~ In(l-R)] /x = 0. 085
Since O and R are estimator! 13 as also estimated.
A question can be laised as to whether the appropriate measme of
increased risk is R(\) 01 (1-O)R(\). Since the difference is small in
this case, R(x) will be used for convenience.
Some may prefer to use an upper confidence limit for 13. This is not
done here because a best estimate of the risk is bem£ attempted and
because the estimate of B is alread}' based on the worst-case data
from the NCI stud}''. If a 95% confidence interval wheie chosen, the
results below Avould be about 50% higher,
Using tins as an estimate of the response for humans, \\e find the
lifetime risk of the a\erage exposed individual to be
U, 005 x 4. 455 x 10 5 p/Ny = 3. 79 x 10 4 p/N;>
If _N people are exposed, v,e obtain the number of cases cau^od per
year by multiplying this quantity by N/70 and the iiumbei of rases
in y_ years by multiplying b;> Ny/70. Thus, the total numbci of cases
pro]ccted as a result ofuising up the existing stocks of Kepone is
540 p
Obviously, an estimated of jp is needed to arrive at a final estimate.
For example, if it is estimated that 1-/10 of 1% of the total stocks would
ultimately -re a ch people (p - 0. 001), then about half a case of cancer
would be projected to result.
This calculation also assumes that the effect of exposure to Kepone would
be the same if the same dose \\ere taken in a single accidental ingestion
or spr&ad out ovei a period of several yeais. While tins assumption is
consistent with the one -hit thoc-ry, it may not be true in fact. Anatysis
.of the experimental record for various carcinogens is needed to develop
better methodologies for dealing with this situation.
Tins calculation does not take, into account the special circumstance that
exposure .of simll childi en to Kepone may be greater than exposure of
other age groups. 'I his could affect the results in two \\ays. First,
small children ma\ be moio or less susceptible than othri groups.
Se< on
-------
jcasonablc worst case. The following is illustrative and con easily be
varied to be moic or less conservative. It is also oriented lo the
"accessible" formulations Accidental cxposvncs from the "inaccessible"
ant traps would piesumablc be much less.
Assume that a child cats a 3-07, tube of ant paste every G months for
three years. Such paste contains 0.125% Kcponc. Assuming the child's
daily food consumption to be about 0. 75 kg, his average dietary exposure
to I^eponc would be about 0. 8 ppm for that period of lime. Using the
above methodology for calculating risk, his probability of conti acting
cancer as a result of exposure to Keponc would be about 0. 25%. This
means that 400 individuals \\ould have to be exposed to this high level
fpr there to be an exported one additional case of cancer.
Another approach \\ould be to estimate the numbers of UnIdron likely
to bo accidental]) exposed lo Kepone. Data in the Pesticide* Upisodc
Report System sho\\s an a\erage of 12. 5 cases per year in the home or
with children in vhich Kepone might ha\e been accidental!) ingested
foi those >ears for \\lmh substantial data is available. If on)\ 1% of
'the actual cases \\ere reported (probably a pessimistic assumption),
then there would be about 1200 such cases per year or about 3, 750 over
three years.
If these cases are assumed to involve an average of haK an ant trap, or
4 gm, then each child \\ould eat 5 mg of Kepone or about G. 7 ppm in his
diet for that da>.
Male mice exposed to tins dietary level for a lifetime \\oulcl be projected
to have an incremental cancer incidence of about 575* (Since the dose
is very close to the experimental doses, this resultnould not vary much,
whatever extrapolation method is used. ) Since the erposuios \\ould only
last for 1/70x305 of the individuals' lifetimes, the nuk to each individual
..would be approximately 0. 57/(70x3G5) = 2. 2 x 10 • Again, tins calcula-
tion neglects the lo-u competing risk early in life. YSlh these assump-
tions, there would be 3750 x 2. 2 x 10~^ = 0. 083 case*. Tins means,
roughly speaking, that there \\ould be a probability rffl/12 that one
case of cancer would lesult from this exposure.
•
Summary
Because of the lack of fn m exposure data, three diffxionl assumptions
weic made." Fust, the highest rir.lv to a single indivtlual horn the
worst reasonably pofc^ibJc exposure; was estimated ly> assuming that a
child-would cat six 3-o/, lubes of ant paste oxer 3 yens. 'Ihis would
result in a cancel ru.k of 1/100, exli apolalmg fiomilie animal data.
The numbci of ehildien exposed at this level, if any,is likely to be
vciy small.
•
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Second, using data from the Pesticide JJpisodc Reporting S\slem as a
slai ling point, it \sas <\<~,< \nncd that 3, 750 chikhcn might each cat about
half an ant trap containing Kcponc. This would result an c> pee led 0. 003
cases of cancer or a piobabihly of 1/12 of one case of cancer.
Finally, an attempt was made to estimate parametncall} the effects of
all routes of exposure, including vaporr/alioni spilling onto kitchen
surfaces, etc. in addition to accidental ingestion by childrc-n. Using a
linear no-threshold extrapolation, the resulting number of cases of
cancer would be-540 multiplied by the proportion of the Kcponc which
readies humans.
In addition to thr- uncertainties inherent in any extrapolation fiom
animals to humans and fi om high to low doses, additional uncertainties
Eire introduced in this ease because the exposuie is likely to be concen-
trated on children and is 111 ely to be the result of single accidental
ingeslions rather than conhnuous in the diet.
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Refer cncos
1. llubcr, J. J. "Same Physiological Effects of the Insecticide Kcpone
in the Laboratory Mouse", Toxicology and Applied Pharacology 7
51G-524 (1965) . ~
2. Good, F. E. , G. W. \Vare, D. F. Miller "Effects of Insecticides on
Reproduction in the L/aboratory House: I. Kepone", J. Economic
Entomology 58-751-757
3. United Fruit Company, EPA Pesticide Petition No. OCOH19, Section
C
4. Curley, A. "Koponn Meeting at State Health Dcpa? Imcnl, Jlichmond,
Va. September] 5, 1975" EPA memorandum SeptemlxM 10, 1973.
^
5. National Cancer Institute, "Report on CarcmogcnrMS Bioassay of
Technical Grade Chiordeconc (Kepone)" January 197G
6. Environmental Mulagen Information Center, Oak JJidgc Tenn.
(July 1976)
7. II. B. Matthews, National Institute of Environmental Health Sciences.
(July, 19 76)
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