PB-243 009
ESTIMATING LIMITING RISK LEVELS FROM ORALLY INGESTED
DDT AND DIELDRIN USING AN UP-DATED VERSION OF THE
MANTEL-BRYAN PROCEDURE
GEORGE WASHINGTON UNIVERSITY
PREPARED FOR:
ENVIRONMENTAL PROTECTION AGENCY
9 APRIL 1974
DISTRIBUTED BY:
Nations! Technical Information Service
U. S. DEPARTMENT OF COMMERCE
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TECHNICAL REPORT DATA
(Please read futtruclions on the reverse before completing)
1. REPORT NO.
EPA560/5-75-003
2.
3. R
4. TITLE AND SUBTITLE Estimating Limiting Risk Levels
From Orally Ingested DDT and Dieldrin Using
Up-dated Version of The Mantel-Bryan Procedure
5. REPORT DATE
April 9, 1974
6. PERFORMING ORGANIZATION CODE
243
7. AUTHOR(S)
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Nathan Mantel
Research Professor of Biostatistics
George Washington University
7979 Old Georgetown Rd., Bethesda, MD
10. PROGRAM ELEMENT NO.
2LA328
11. CONTRACT/GRANT NO.
20014
P4-01-02962
12. SPONSORING AGENCY NAME AND ADDRESS
Office of Toxic Substances (WH-557)
Environmental Protection Agency
401 M St., SW
Washington, DC 20460
13. TYPE OF REPORT AND PERIOD COVERED
FINAL
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
Mathematical extrapolations of the upper limits on risk of cancer
at various low levels of exposure to dieldrin and DDT are presented.
The statistical model used is that described by Mantel, ejt al. ,
Cancer Research, 3j5, 865-872, 1975, the so-called "updated"~llantel-
Bryan procedure. The data upon which the extrapolations are based
are derived from the studies by Tomatis, e_t al. , International'
Journal of Cancer, 10, 489-506, 1972 for DDT and by Walker, ejt al.
Food and Cosmetics Toxicology,, 11, 415-432, 1972 for dieldrin.
Several alternative methods of treating the data are presented, and
pesticide levels associated with various levels of risk are estimated
Certain precautions which must be observed in applying the "updated"
Mantel-Bryan technique are discussed.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
I).IDENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Group
Dieldrin
DDT
Mantel/Bryan
Carcinogens
Risk Estimates
Statistical Extrapolation
8. DISTRIBUTION STATEMENT
Unlimited Distribution
19. SECURITY CLASS (ThisReport!
Unclassified
20. SECURITY CLASS (This page)
Unclassified
EPA Form 2220-1 (9-73)
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ESTIMATING LIMITING RISK LEVELS FROM ORALLY INGESTED
DDT AND DIELDRIN USING AN UP-DATED
VERSION OF THE MANTEL-BRYAN
PROCEDURE
-------
ESTIMATING LIMITING RISK LEVELS FROM ORALLY INGESTED DDT AND DIELDRIN
USING AN UP-DATED VERSION OF THE MANTEL-BRYAN PROCEDURE
by
Nathan Mantel
Research Professor of Biostatistics
George Washington University
7979 Old Georgetown Road
Bethesda, Maryland 20014
prepared for the
Office of Toxic Substances
Environmental Protection Agency
Washington, D.C. 20460
Project Officer
Michael J. Prival
Contract No. P4-01-02962
April 9, 1974
..' 3<
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NOTICE
This report has been reviewed by the Office of
Toxic Substances, EPA, and approved for publication.
Approval does not signify that the contents neces-
sarily reflect the views and policies of the
Environmental Protection Agency, nor does mention
of trade names or commercial products constitute
endorsement or recommendation for use.
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I will give below a description of the up-dated Mantel-Bryan
procedure and the rationale for such up-dating. Let me begin
however, with a description of the data to which the Mantel-Bryan
method was applied.
DATA EVALUATED
DDT
The basic DDT data came from a report by Tomatis, Torusov, Day,
and Charles appearing in the International Journal £f Cancer (The.
Effect of Long-Term Exposure to DDT on CF-1 Mice, Vol. 10, A89-506,
1972). In this work 6-to 7-week old CF-1 mice received dietary DDT at
levels up to 250 ppm for their remaining life span. One-third of the
females in each group were mated when 9 to 10 weeks old, and their
offspring were given similar dietary levels of DDT. Only sufficient
first generation offspring were added to the treatment group as
approximately to double the total— there would thus be something on
the order of 120 mice of a sex on a treatment level, and the authors
report in many instances only combined results for both parents and
t
offspring. (Results are also given for a positive control group re-
ceiving urethane in their drinking water.) Except for a few mice
with tumors killed early for transplantation tests and two mice per
> •
sex-generation-DDT level-group killed for study of DDT levels in their
tissues, mice were Kept until natural death or killed when moribund.
At experiment termination all survivors were killed and autopsied, the
parent generation having been carried to 140 weeks of age, the offspring
to 130 weeks. The data reported include: number of survivors at the end
5<
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-2-
of each ten-week period; the total number of tumors and of tumor-bearing
animals; the total number of tumors at a specific site. For liver tumors,
lung tumors and lymphomas data are given separately for three time
periods of tumor occurrence: between 0 and 69 weeks of age; between
70 and 94 weeks; from age 100 weeks on. Data are not given on the ,
instances where mice fell into more than one of these tumor groups, and
the total of such tumors frequently exceeds the total number of mice
under study.
I note that the total number of tumor-bearing animals is likely
unsuitable for analysis since many non-malignant tumors are included
in any case this is such a broad catch-all category that upwards of
80% of control animals developed some kind of tumor. The main tumor of
interest seems to be those of the liver which the authors report to be
metastatic and dose-dependent in frequency. (Transplantation of such tumors
was unsuccessful in 2 cases with young adult recipients, successful in 1 of
2 newborn recipients.) For these reasons, I have made a "safe"* dose analysis
using liver tumor data. In this analysis, I have alternatively included
or excluded tumors arising from 100 weeks on, with the exclusion giving
less weight to the late-appearing tumors and minimizing any spontaneous tumor
effects. I have made a similar analysis relative to lung tumors, but indicate
the "safe" doses resulting as not reliable. The cause of unreliability is
that at high dose levels of DDT liver tumors arise so early that the mice do
not have a chance to develop lung tumors.
*The word "safe" as used in this report is not necessarily meant to imply
complete absence of hazard or risk. The "safe" dosages obtained are
ones for which, by the procedures used and under the assumptions made,
the true risk does not exceed some pre-specified low level.
6<
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-3-
This competitive effect from liver tumors is largely responsible for
the failure of the authors to detect any dose-progressiveness in their
occurrence.
The consequent data going into my analysis are shown in table 1.
I have additionally examined a report by Tarja'n and Kemeny in Food
and Cosmetics Toxicology (Multigeneration Studies on DDT in Mice, vol. 7,
215-222, 1969) on the effects of dietary DDT. The multigeneration study
in BALB/c mice was unsuitable for ''safety" analysis for a variety of
reasons. For one thing, DDT was fed for only 6 months, and at only
comparatively low levels, about 3 pptn. (But the data do seem suggestive
of tumorigenic and leukemogenic effects at this time- and dose-restricted
treatment. The authors attribute this to the generational method of their
study which could have permitted fetal exposure to DDT.) Nextly, while
the authors do give separate data on tumors by sex, they do not give a
corresponding sex breakdown on the number of animals examined. The real
curiosity about the data, however, is that no data on tumors arising
during the course of the study are provided-^—what the investigators
report are their findings on an examination of surviving animals 26 months
after the study began,'at which time the fifth-generation mice were
typically 4-6 months younger than the first generation mice. The data
to me seem to show about the same tumor rates for all generations (which
might indirectly indicate higher rates for the later generations since
they are younger) so I am surprised to see the authors claiming almost
logarithmic increase in tumor incidence with tumor generation. The number
of animals with tumors does increase with generation, but so do the number
i
of mice examined so that incidence rates remain stable, in which case the
authors' remarks on fetal exposure become less meaningful.
7<
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Dieldrin ^ ' •'<"-•• • :
These data came from a report by Walker, Thorpe, and Stevenson
appearing in Fpod and Cosmetics Toxicology (The Toxicology of Dieldrin
(HEOD). 1. Long-Term Oral Toxicity Studies in Mice, vol. 11, 415-432,
1972). Here in various experiments and subexperiments CF-1 mice received
dietary dieldrin at levels ranging as high as 20 ppm, for variously
104, 128, or 132 weeks, ADAB being used as a positive control treatment.
Treatment was initiated in the week following the period in which the
mice as 3-week-old weanings were housed together so as to accustom them
to the change from the breeding to the experimental unit. In the first1
study, experiment 1, dose levels used varied by 10-fold increments;
experiment 2.1, of study 2, directed to elucidating dose response
relationships involved 2-fold dose increments of dieldrin, the diet t
being sterilized by use of-ethylene oxide; in experiment 2.2, a
single dose level of dieldrin was used, interest focussing on the
influence of radiation-sterilization of'diet and use of litter.
For the present analysis I have ignored manipulations of sterilization
in experiment 2.2 and of litter^ combining all control groups into
one, and all dieldrin<-treated groups into one". •» ;;:
The report gives the percentage of animals with tumors of.
various sites but does not permit identification*of instances of
mice with tumors of several-rsltes. v •Here^l' have chosen liver tumor
data as the basis for "safety"''aiValysis^ making alternate determinations
according to whether all liver tumors (a-tb) or only those showing areas
of papilliform or adenoid ^growth' (b)r are- considered. '1 do not use
the data from two additional experiments "reported,: one directed: to
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getting at the combined effect of dieldrin and DDT, the other to the
effect of changing the duration of dleidrin treatment.
I note that the data published in this report were incomplete in
that they represent percentages of animals with tumors, not actual numbers as
I would have needed. In table 2, I give my best efforts reconstruction
of the actual data, which reconstruction I used in my analysis. An uncer-
tainty results from situations like that in which 20% of 288 mice are
/
shown to have liver tumors — I took this as 58 tumorous mice, but 57
or 59 are alternative values which would have rounded off at 20%. My
analysis is probably not critically dependent on which of these
alternative values I used. I note th°.t in experiment 2.1, liver tumor
frequency at the two highest dose levels was reduced suggesting that
lethal toxicity of treatment had interfered with tumor appearance. Such
lethality is further indicated by the reduced numbers of animals shown
as at risk which are less here (and also elsewhere in the table) than
those the authors describe in their text as being allocated to each
group. I would judge that the authors reasonably reduced the numbers of
animals considered at risk so as to allow for mortality occurring
before any tumors were likely to occur. But they nowhere make clear
just how they did this. It may be that the reduction in tumor
incidence at high dose levels would not have occurred if the author
used a more effective method of reducing the numbers considered
at risk. For example, at 20 ppm, the report shows that nearly 50% of
female mice died within 3 months (all were dead within a year), yet
the number of "such mice for which tumor incidence was calculated is
21, or 70% of the original number. While the authors accept that their
9<
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data demonstrate the induction of liver lesions, it seems to me that
they are concerned with the failure to induce other lesions like
sarcomas, which ADAB(but tested at 600 ppm) seems to induce. They in-
dicate that their results support the idea that the mouse may be
Unsatisfactory for testing compounds which induce hepatic microsomal
enzymes.
THE UP-DATED MANTEL-BRYAN "SAFETY" PROCEDURE
In the original publication by Mantel and Bryan in the Journal
of the National Cancer Institute ("Safety" Testing of Carcinogens, vol.27,
455-470, 1961) two particular qualifications are noted. One point is
that the procedure is overconservative in the handling of spontaneous
tumor rates, a minor point when control tumor rates are low. In more
recent long-term testing of carcinogens the occurrence of high spontaneous
rates, say on the order of 40% is not uncommon, and overconservatism
by the original Mantel-Bryan procedure can become extreme.
An up-dating of the procedure to remove this conservatism has been
prepared by a cooperative effort of investigators at several institutions
and will in the near future be prepared for publication and it is this
up-dated method that I applied to the instant data. The method formally
takes care of spontaneous responses by formulating a model, jnplicitly
suggested in the Mantel-Bryan paper, that the response at a dose level
reflects the independent addition of probabilities—observed proportion *»
Induced proportion + spontaneous proportion - product of induced and
spontaneous proportions.
The up-dated procedure further incorporates a second modifi-
cation, the need for which Mantel and Bryan indicate in an appendix
ii.'i superior to the method of "justifiable" combined results described
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7 ; .
in the text— that modification was suggested in part by Cornfield.
The "justifiable" combined results approach has a kind of bending-over-
backward aspect in that it permits treating any outcome observed at a :
higher dose as though it had in fact occurred at a lower dose-—this sometimes
could result in a higher estimate of the "safe" level by the Mantel-Bryan
method since that method could be used only for the outcome at a single dose
level. What this second modification does is to permit the simultaneous
handling of data at several dose levels so that the outcome at a higher
dosage is not artificially treated as an outcome at a lower dosage. In
applying the method a principle suggested by Mantel and Patwary at the 32d
session of the International Statistical Institute (Interval Estimation of
Single Parametric Functions, Tokyo, Japan, 1960) is employed. A maximum
likelihood estimate is made of all the parameters of the system, that is
the spontaneous tumor rate or rates, and of the "safe" dose, or equivalently,
the intercept for the induced tumor rate since the probit slope is conser-
vatively fixed at unity, or some other prespecified value. (The Intercept
parameter is the normal deviate corresponding to the induced rate at unit
dose, I.e. log dose equal to zero.) The next step is to find an alternate
"safe" dose or intercept value such that when a conditionally maximum
likelihood estimate of the remaining unspecified parameters is made, the fit
is just significantly worsened. A consequenqe here however, is that use
,'••', •'••'' 1 ' '< !'
of exact binomial probabilities as Mantel and Bryan espouse is no longer
i •• ' .• -1
feasible, and the up-dated Mantel-Bryan procedure instead relies on use of
':, f'
-2 loglikelihood ratio taken as following an asymptotic chi-square
" ' . t
distribution for setting limits. Of interest, it is not essential under the
modifications incorporating the handling both of spontaneous response and
•« • . i
multiple dose levels that control data be available. If the data available
over several non-zero dose levels suggest that there is spontaneous response
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8 .•,£-'/ ;
this will be automatically weighed into the analysis.
There is one basic way' in which both standard" and' up-dated; Mantel^
Bryan procedures remain the same relative to the use"of data at several
dose levels. Suppose we have determined the "safe" level using all the
data up to a certain dose level, and then add the'data for the next ,
higher dose level, calculating a new "safe" level. If the new "safe"
level is higher we accept 'it, otherwise not.The logic here is that the
assumed probit slope of unity is conservatively shallow, the true slope
in the observable region somewhat steeper. A decrease in the "safe" •
level can accordingly be explained away-—but an increase is accepted
because this means that the added information relative to safety has
outweighed the tendency for use of higher dose level data to" reduce the
calculated "safe" dose. ' . • - ; t"
this rule for using higher "safe" levels when they arise, discard-
ing lower ones must be used with judgement, the rule should not be" used
where the increase has occurred because the response at higher doses has
flattened out or turned down—it should be reserved: for the case where
the increase in "safe" dose has occurred despite a rapidly rising response
rate with dose. As I noted above, and will refer "to again below, the
case of DDT elicited lung tumors is one whe're responses may turn down
at high levels because of earlier-appearing liver tumors. For the
liver tumors elicited by high dosesi of 'dleldr in '"intone "experiment ;
there also was a reduction,"'but this perhaps could have been "avoided by
reducing further the number of mice considered as at'risk.
In general the "safe" dose procedure"has to be used with care and '
with thoughtful interpretation.5" it"'mayF'be7" for1 example", if'an
extended time study is conducted with late-appearirtg tumors getting
full weight that an agent may appear tumorigenic by virtue of its life-
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prolonging qualities. This is the reverse of the situation where tumor-
igenicity is masked by early lethal toxicity. It is thus important
to check whether higher tumor frequencies in treated animals might not
be due to increased longevity, whether only a chance increase or one
actually attributable to treatment. This is an added reason for not
giving great emphasis to late-appearing tumors the other reasons
are that they magnify the spontaneous-response problem and that anyway
they are less important.
Up-dating of the Mantel-Bryan procedure is characterized by a
novel feature—it permits handling independent sets of data. If an
agent has been tested independently on two or even more occasions,
how do you get the "safe" dose? If you calculate a "safe" dose for
each separate test, which do you use or how do you use them? If you
calculate one "safe" dose for males and one for females using data
i
obtained at the same occasion, how use or combine them? It would
seem improper to use the higher of the separate "safe" doses, because
this may be too high for the other sex—also biases could result
if we permitted repeated testing, then selecting the highest
individual "safe" dose. Yet if individually calculated "safe"
doses are about equal, somehow the appropriate pooled "safe" dose
should be higher than either one alone because of the reduced
l
statistical variability and increased Information available.
Our new feature accomplishes this kind of thing. If we want
to come out with a single number for the I'safe" dose albeit we
have data from several experiments, we should postulate that a
single common '"safe" dose exists, then proceed to estimate it,
> 1 »,
then finally putting a statistical lower limit on that estimate.
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10
This we do by fitting a joint model to all the data under which the
intercept parameter is common to the various data sets but each
data set has its own spontaneous response parameter — the slope
parameter remains fixed for all the data sets at its specified *•
conservatively low value.
In application to the DDT and dieldrin data described above,
the combined "safe" dose was consistently higher than the (geometric)
average of the separate "safe" doses, and substantially higher than
either "safe" dose when the individual "safe" doses were about equal.
As between sexes, note that the model postulates males and females
to differ only in their spontaneous tumor rates but to be identical
in their "safe" dose values if this premise is unacceptable, then
*
separate "safe" doses would be required and in practice the lower of
the two would have to be used. An incidental consequence of the
added feature is that it can permit combining results, but with
caution, from several test species if we are willing to commit
ourselves to a particular way of scaling dosages, e.g. mg/m^
milligrams of agent per square meter of surface area of the test
i
animal.
RESULTS OF ANALYSIS
Tables 3 and 4 give certain summary analyses of the DDT and diel-
drin tumorigenicity data. These summary analyses are premised on use
of a unit probit slope, an assurance level of 99% and a "safety"
level of 10~* as initially illustrated by Mautel and Bryan. Results
of additional computations and manipulations will be given in a
supplementary report rather than in an appendix to the present one,*
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so that it can be self-contained.
"Safe" levels shown in Tables 3 and 4 are expressed in parts per
trillion (parts per lO^ or ppt), These can be converted to "10 or 10"
"safe" levels by multiplying respectively by either 2.59 or 7.23.
Use of a higher probit slope of 1.5 would likely result in "safe"
levels upwards of 20 times greater, the respective multipilication
factors for 10~7 or 10~6 risk then being 1.88 and 3.74. I would
recommend against, use of such a steeper slope as being inadequately
Q
conservative. With a slope of 1, 'the 10 risk dose level is
l/1930th the 1% risk dose level. If we should have used the one-hit
_Q ' .
model for extrapolation our apparent 10- ° risk dose would represent
' • I ;'"•.-
a risk of 1/193,000. With a change in slope to 1.5, the 10"8 risk
dose level is l/l$5th the 1% risk dose so that the true risk if the
one-hit model obtained would be 1/15,500. (For a slope of 2 the
fraction and one-hit model risk would be 1/44 and 1/4400 respec-
tively. Note that use of a slope somewhere between 1.5 and 2 gives
1 i
results on the order of the standard practice of using 1% of the
' ••, ) *
apparent no risk dose.) Another modification which could lead to
% ' .. » •
an increase in the"saf"e," dose would be that of -reducing the
assurance level, say from 99% to 95%.
Inspection of Table 3 shows that the combined data "safe" dose
1 '
of DDT relative to' liver tumors ranges from 5Q6-2390 ppt depending
< * ; '' ' • ' ! *'
on whether all tumors or only tumors within 99 weeks are considered
<.
. ' •* ' . •
and on whether the risks for all mice or only for those surviving
70 weeks are considered. As illustration of how the procedure
combines independent data I show in Table 3 the separate results
for male and female mice. The combined "safe" level is much closer
|J . i '
to the higher female values of 670-3270 ppt than they are to those
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12
1
lor male mice, 50-420 ppt. The lower "safe" level values for male mice
do not necessarly presage greater vulnerability of males'to DDT;—'—It,
could also reflect that in some way the data for male mice are less
informative. A possible way for such reduced information to come, about
is through a high spontaneous rate, a situation true for males but not
for females, as then the effect of treatment cannot be measured as
precisely. Calculated estimates of the spontaneous rates associated with
each set of data analyzed are also shown as a matter of interest—these
should be given limited credence since they are based on use of all, the
cUta and with the acceptance of a unit probit slope. Inclusion of the •• -
data at the dose level of 250 ppm would have resulted in overestimates
of the spontaneous rates as the responses at that dose level were higher
than the unit slope would have called for. In support of this, in 11 of
12 instances related to liver tumors the highest "safe" dose, level of
DDT resulted with the analysis of data up to 50 ppm; the dose level at .-.„..,
which this maximum occurred is designated in Table 3 as the '-highest.'. ,
influential dose", signifying that incorporation of data at the next
higher dose level would have resulted in a reduction in the calculated
"safe";,dose. , , ...... ,
In the lower half of Table 3 I show the "safe" levels for lung tumors, TV
combined "safe" levels range from 1820 - 19,100 ppt and I show them in
parentheses in order to convey that they cannot be reliably accepted.
This is due to the fact that at high DDT levels many mice-getwearly
liver tumors and so fail to display lung tumors the fact that the
highest influential dose is the highest dose employed reflects this ,in
part. An interesting feature In the lung tumor analysis, however,.is
that it shows the combined "safe" dose to be higher, sometime much,, so,
than the separate sex "safe" doses where the separate "safe" levels
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differ only moderately.
The dieldrin "safe" levelg in Table A relate only, to, the combined
analysis, individual aqalysep by sex and/or experiment being reserved
. ' '*,''•, i
for the supplemental record,, • These "safe" levels are 11 ppt relative
to all tumors, 87 ppt re.lat:J.ve to }.iver tumors showing areas of
papilliform or adenoid growth. In both cases the "safe" dose occurred
. ','"•" , -
at an intermediate value for the highest influential dose, 1.25 ppm
*' • i i
and 5 ppm respectively, notwithstanding the reversal at high .dose
levels in experiment 2.1, Th,e shajp increase in response at .10 ppm in the
other two experiments apparently more than compensated for the reversal.
Recall, also, that the authors apparently dropped early deaths from
the number of mice at r:f.sk and so avoided extre'me reductions in response
rates at high dose levels. As a poiqt of interest I include' two sets
of estimated spontaneous tumor rat;e^ in Table 4? one based on all the
I'*-'.
available data, the other based only pn data at dose levels up to and
, > . , •
i
including the highest influential dqse. ' , .
* • - * *' t ' *
Let me now come to question of hpw the "safe" dose values can be
i' V , ' .' :l '' \ ' ' •'•.','. \ • :• v • .
' f '..-'' ,'.".••
used. First, note th,3t th^y are in this case expressed in parts per
"';••' :•'''' ', i '"* '••<'"" • ^" "
trillion of diet, Tfie dietary 4-nJ;a^e of a mammal is, to an approximations,
proportional to its surface area. Th,us no further adjustment need be
1 • '' ' •:'}'.'-•
made if we extrapolate tQ another species,, as to nan.- There could be some
point, if we wished, tp use an 4d.d.itipnal safety factor (as distinct
from an extrapolation factor) to ppyey the possibility that even after
species size adjustment.man is pfi}4 more sensitive than mouse. (There
is a curiosity about use of one-hit !!safety'' determination methods. By
its underlying logic the absolute s$fe dope in man should be the same
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14
as for mouse with no further adjustment permitted for species size. In
fact the absolute daily "safe" dose would be lower for a man ,
than for a mouse because of his greater longevity lifetime "safe" doses
would remain the same.)
Daily food and water intakes of a mammal are, in many cases,
approximately equal. Thus the dietary "safe" levels can be interpreted
as drinking water "safe" levels if drinking water is anticipated to be
the source of human exposure to DDT or dieldrin. But a "safe" level in
water actually drunk, which is limited in quantity, should not be loosely
interpreted as a permitted level in water available for drinking, as in
water supply systems,which is a much larger quantity. Much less should
it be interpreted as a permitted level in water supply sources which
vastly exceed the amount of water actually drunk. The adverse effects
of permitting in all fresh water bodies in the United States chemical levels
seemingly safe for humans is not immediately predictable. One likely
consequence could be extreme harm for fish and other animals inhabiting
the water since their total exposure at a given water concentration
would be much higher than for man or other animals which consume only
limited amounts of water each day.
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Table 1. Data from Tomatis, et al., on t|u, occurrence of liver and of lung tumors in CF-1 mice receiving vatving levels
of dietary DDT, parent and first noneration offspring combined. Results are shown separately for all mice
and for those surviving to the 70th week of age.
All Mice
DDT Dietary
Dose Level
pom
- o
2
10
50
250
0
2
10
50
: 250
A
Number at .
Risk
125
126
111
135
1 117
117
110
126
109
T.05
With Liver Tumors
1
Within 99
Weeks
7
22
25
31
72
0
1
1
3
43
At Any
Time
With Lune Tumors
Within 99
Weeks
Male Data Only
24 18
57 34
50 33
66 36
81 35
Female Data Only
4.
4
11
13
60
12
11
23
' 21
,20
At Any
Time
42
70
58
64
42
35
30
50
40
30
A
Mice surviving to week 70 only
Number at
Risk
94
104
85
110 '
72
94
'Jl
107
-' 85
76
With Liver Tumors
1
Within 99
Weeks
7
20
25
30
60
0
1
1
2
39
•
At Any
Time
24
55
50
65
69
4
4
11
12
56
•
With Lune Tumors •
Within
99 | At Any
Weeks
16
27
25
34
29
8
10
21
18 -
18
•
Time
40
63
50
62
36
31
29 - '
48
-37
28 i
1
1
:
j
1
-------
Table 2. Reconstructed data frota Walker et a.1. on the occurrence of liver tumors in CF-1 nice receiving varying Bevels
of dietary dieldrin. Results are shown separately for three exper liticn.cs.
Dieldrin
Dietary Dose
Level, ppm
0
0.1
1
: 1.25
• 2.5
5
10
20
£
7(-
0
0.1
1
1.25
2.5
Experiment 1
Number at
Risk
,/ '
288 [
124 i'
111
__ • .
__ '• ' :
~»—
176 r
• '•'' .
297
90
87
___
___
S «-T— —
10 i 148
20
-^—
Liver Tumors
Total
58
32
34
__
- _
165
;
39
I 25
.! 32
!\
— — -
^ _-«~»
? 136
„ —-*-»*•
:1
i
With
Papilli-
form and
Adenoid
Growth
Experiment 2.1
Number at
Risk
Male Data Only
12
5
9
.
100
- —
Fema
0
4
5
__«.
81
*^""^^
i
78
—
—
30
30
30
11
17
le Data Only
78
' '
' *
30
28
30
17
21
; i
:
Liver Tumors
Total
9
—
6
13 .
26
5
12
8
—
5
12
.5 ,18 : rj f
•'• •; 9
8
With
Papillifonn
and Adenoid
Growth
0
2
1
3
1
9
0
— —
0
1
.5. ' •
•• >. • 2 ;
3
Experiment 2.2
Number at
Risk
77
—
—
:
-. '•
56
"• '
74
-
— — ;
'; ; ; ..• . ••
is. ^ 65
Liver Tumors .
Total
25
,— —
— —
—
• . — —
— —
45
•"•• ^
' . : -
12
• .•
• ' ,'
~
". ' T • ' •
' / '
36
r.
With
Papilli-
fonn and
Adenoid
Growth
i
i
2 ' i
— — ]
•™— • ;
• '
•
.
13
( ^"^^
:;• ;; ' >• ,
;-, I \ >
';. ,;0.::.;': '
• ' ' r ~7" '. - '
•r ;'.'; !
' -* ;• " ' : *
1 ' '~ - [ '
•i— — .
12
••
- '. J
«
-------
Table 3. "Safety" analysis of. the data from Tomatis et al. shown in Table 1. A combined analysis is shown tor males
and females as well as separate sex analyses. Analyses use a slope of unity, an assurance level of 99%,
and a "safety" level of 10~8. . •
Data Analyzed
Liver Tumors
All Mice
Tumors Within 99 Weeks
All Tumors
70 Week Survivors Only
Tumors Within 99 Weeks
All Tumors
"-Lung Tumors
..All Mice
Tumors Within 99 Weeks
All Tumors
70 Week Survivors Only
Tumors Within 99 Weeks
-All Tumors
'
^
*
Combined Sex Analysis
DDT
"Safe"
Dose
ppt '
2390
697
'2130
506
(4540)
:i9,100)
(1820)
(5080)
figures
.ndicate
Highest
Influential
Dose
PPt
50
50
50
-50
-
V 250
250
. •
250
250
.n parenthesi
I in the tex
Estimated Spontaneous
Response Using All
Data %
Males
14.3
34.7
17.5
44.4
23".7
45.0
,
24.5
54.0
is represent
, because c
Females
0
2.4
0
2.3
13.5
32.6
12.8
38.2
"safe" dc
f the higt
Separate Sex Analyses
Males
DDT
"Safe"
Dose
ppt
420
191
271
50
(2920)
(11,600)
(966)
(2690)
se estima
frequenc
Highest
Influen-
tial
Dose
ppm .
50
250
50
50
, 250
250
250
250
:ea which
f of early
Estimated
Spontane-
ous
Rate %
10.3
31.7
10.6
33.2
23.6
45.0
23.5
54.0
ire cons id
liver tun
Females
DDT
"Safe"
Dose
PPt
3270
891
3110
670
(3590)
(7400)
(1800)
(2650)
•red unre
ors.
Highest
Influential
Dose
ppm
50
50
50
50
.250
250
250
250
Liable, as .
Estimated
Spontane-
ous
Rate %
•
0
2.7
0
2.9
•
13.6
32.6.
13.4
38.2
^
-------
Table 4. "Safety" analysis of the data from Walker et al.shown in
table 2. Only the combined analysis for both sexes, all
three experiments, is shown. Analysis uses a slope of unity,
assurance level of 99%, and a "safety" level of 10"^.
All Liver Tumors With Papilliform
Tumors and Adenoid Growth
Dieldrin "Safe" Dose, ppt 11 87
Highest Influential Dose, ppm 1.25 5
Estimated Spontaneous Rates, %
Using All Data
Expt. 1, Males 20.3 4.4
Females 15.6 0.3
Expt. 2.1, Males 9.6 0
Females 6.9 0
Expt 2.2, Males 32.6 2.0
Females 13.3 0
Up To Influential Dose Only
Expt. 1, Males 20.7 4.2
Females 16.7 0.9
Expt. 2.1, Males 10.5 0
Females 9.0 0
Expt. 2.2, Males 32.5* 2.6*
Females 16.2* 0*
*Represents tumor rates among controls. There were no actual test groups
in this experiment below the highest influential dose.
-------
ESTIMATING LIMITING RISK LEVELS FROM ORALLY INGESTED
DDT AND DIELDRIN USING AN UP-DATED VERSION
OF THE MANTEL-BRYAN PROCEPURE
(SUPPLEMENTARY REPORT)
23<
-------
ESTIMATING LIMITING RISK LEVELS FROM ORALLY INGESTED DOT AND DIELDRIN
USING AN UP-DATED VERSION OF THE MANTEL-BRYAN PROCEDURE
Nathan Mantel
Research Professor of Biostatisties
George Washington University
7979 Old Georgetown Road
Bethesda, Maryland 200T4
prepared for the
Office of Toxic Substances
Environmental Protection Agency
Washington,.D.C. 20460
Project Officer
Michael J. Prival
Contract # P5-01-2598-J
December 27,, 1974
-------
NOTICE
This report has been reviewed by the Office of
Toxic Substances, EPA, and approved for publication.
Approval does not signify that the contents neces-
sarily reflect the views and policies of the
Environmental Protection Agency, nor does mention
of trade names or commercial products constitute
endorsement or recommendation for use.
25<
-------
the risk level, specifically 10"8, 10~7, 10~6, 10~5. For each of the
The accompanying tables show the results of application of the "safe"*
dose determination procedure with varying specification of the assurance
level (95% or 99%) and varying specification of the postulated shallow
slope (1.0 or 1.5 normal deviates per 10-fold dose increase). Yet another
variation, but one readily obtainable, was that of alternative limitations
on
two agents overall "safe" levels were determined using all available data
and separate "safe" levels were determined for certain data subsets.
Relative to DDT there were only two data subsets, male or female. But
for dieldrin there were eleven such data subsets—two for sexes, three for
^-,
experiments, six for each sex in each experiment.
Other variants in the analyses made have been indicated in the
initial report. For DDT the variants included whether data for all
animals or only for 70-week survivors should be considered, and whether
all tumors or only those occurring within 99 weeks should be considered.
In the present report relative to DDT, I am showing "safe" level deter-
minations only for liver tumors, since I do not consider the lung tumor
determinations to be reliable, for reasons indicated in my initial report—at
increasing dose levels lung tumor rates fail to increase because of the
earlier occurrence of liver tumors. The added variant relative to
dieldrin was only that of alternatively considering all liver tumors
or only those liver tumors displaying areas of papilliform or adenoid
growth.
*The word '-'safe" as used in this report is not necessarily meant 1.0 imply
complete absence of hazard or risk. The "safe" dosages obtained are
ones for which, by the procedures used and under the assumptions riiac.;;,
the true risk does not exceed some pre-specified low level.
-------
-2-
The several variant analyses of the DDT liver tumor data are given
in tables 1A, IB, 1C, and ID, the tables varying in the postulated
assurance levels and slopes. The column headings in the tables indicate
-./hether results relate to combined data or to sex-specific data, whether
all tumors or only early tumors are considered, and whether data for all
animals or only for 70-week survivors are considered. Tables 2A, 2B, 2C,
and 2D relate similarly to the dieldrin data on all liver tumors, the
column headings indicating to which subset of the data the results shown
relate. This pattern is repeated in tables 3A, 3B, 3C, and 3D which
related to the dieldrin data on liver tumors showing papilliform and
adenoid growth.
Specifically what is shown in the various tables is this. All the
non-zero dose levels, in parts per million (ppm) in the experiment or
experiments are arranged in ascending order at the left end of the
table. The row entry in a column represents the computed upper limit on
the intercept parameter (see initial report) using data obtaining for
dose levels at or below the dose level shown for that row—the entry,
however, relates to the analysis indicated by the column heading. Where
no entry would be appropriate because of unavailability of data a dash
is used. The dash is also used to indicate instances where the entry
should be the same as at a preceding lower dose level, since no new data
have been introduced which could influence the analysis. In each column,
the lowest of the upper limits on the intercept parameter has been
routinely (but see discussion below) underlined. Those lowest upper
limits on the intercept parameter are decoded into "safe" level estimates.
expressed in parts per trillion (ppt) which are shown in the lower portion
-------
—3—
of each table, for the alternative limitations on the risk level as
\
designated in the left most column of the table. No attempt is made in
this report to give estimates of the spontaneous tumor rate for each
experiment, though such estimates are available if desired. My reason
for this is the multiplicity of such estimates which can be made. A
different estimate can be made for each analysis into which a data set
i3 entered, for each different progressively increasing dose level,
and for each of the two specified slope values.
DISCUSSION OF DDT RESULTS. TABLES 1A. IB. 1C. ID.
Table 1A duplicates in large part the liver tumor results given in
table three of the Initial report. Overall "safe" doses at the 10~8 risk
level range from 500-2390ppt depending on which of the four alternative sets
of data is considered. The overall "safe" doses are heavily weighted
toward the higher female "safe" doses which range between 670-3270 ppt, while
the lower male "safe" levels range between 50-420 ppt. (Note that in
only 1 of 12 instances does the "safe" dose shown result from the
inclusion of data at the highest dose level of 250 ppm.) As the limiting
—8 —5
risk level is increased in stages from 10 to 10 , the "safe" level can
l.e seen to increase by a factor of approximately 3 for each 10-foid
Increase in risk.
The altered assurance level of 95% used in Table IB produces no
great changes from the results of Table 1A—typically the "safe" levels
of Table IB are about 30% larger than those of Table 1A. Much more
profound effects on the "spfa" dose are evidenced in Table 1C in which
the slope parameter has been increased from 1 to 1.5. "Safe" doses are
i-.ow 20 to 100 times greater than those of Table 1A at the 10~? risk level.
28<
-------
—3—
of each table, for the alternative limitations on the risk level as
\
designated in the left most column of the table. No attempt is made in
this report to give estimates of the spontaneous tumor rate for each
experiment, though such estimates are available if desired. My reason
for this is the multiplicity of such estimates which can be made. A
different estimate can be made for each analysis into which a data set
is entered, for each different progressively increasing dose level,
and for each of the two specified slope values.
DISCUSSION OF DDT RESULTS. TABLES 1A. IB, 1C. ID.
Table 1A duplicates in large part the liver tumor results given in
table thre€ of the initial report. Overall "safe" doses at the 10"8 risk
level range from 500-2390ppt depending on which of the four alternatiye sets
of data is considered. The overall "safe" doses are heavily weighted
toward the higher female "safe" doses which range between 670-3270 ppt, while
the lower male "safe" levels range between 50-420 ppt. (Note that in
only 1 of 12 instances does the "safe" dose shown result from the
inclusion of data at the highest dose level of 250 ppm.) As the limiting
—8 —5
risk level is increased in stages from 10 to 10 , the "safe" level can
le seen to increase by a factor of approximately 3 for each 10-foid
increase in risk.
The altered assurance level of 95% used in Table IB produces no
great changes from the results of Table 1A—typically the "safe" levels
of Table IB are about 30% larger than those of Table 1A. Much wore
t""found effects on the "s?fa" dose are evidenced in Table 1C ir. which
the slope parameter has been increased from 1 to 1.5. "Safe" clones are
iv.iv 20 to 100 times greater than those of Table 1A at the 10" risk level.
-------
-4-
At higher risk levels the multiplicative factor is somewhat reduced since
at the slope of 1.5, each 10-fold increase in the animal risk level results
in only about a 2-fold increase in the "safe" dose. (In these analyses
with a slope of 1.5 there are 2 added instances in which the "safe" dose
results from inclusion of the data at 250 ppm, but these are marginal cases,
and, in fact, disappear in the Table ID analyses in which the assurance
level is changed to 95%.) When the assurance level is altered to 95%
using the 1.5 slope, the effect, as shown in Table ID, is even more moderate
than before, the "safe" dose level being increased by only about 20%, or
even less.
DISCUSSION OF DIELDR1N RESULTS. ALL LiVER TUMORS. TABLES 2A, 2B, 2C. 2D.
The overall "safe" dose at the 10~8 risk level shown in Table 2A is
11 ppt with only a moderate difference between 13 ppt for males, 6 ppt
for females. The range of the variously determined "safe" levels is from
2-16 ppt. In only one instance is the "safe" level associated with the
inclusion of data at the highest of several dose levels employed. This
instance relates to the data of experiment 2.1 which, as described in
my first report, show a questionable inversion at the two highest dose
levels. Since in experiment 2.2 only a single non-zero dose level was
employed, any "safe" levels calculated specifically for that experiment
must employ data at the highest dose level therein. And as the overall
calculated "safe" dose results from data at dose levels of 1.25 ppm. or less,
there can be no ambiguous effects due to data inversion.
As in the case of the DDT data analysis (Table 1A), each 10-fold
increase in the risk level results in about a 3-fold increase in the "safe"
level. Table 2B, shows, as before, that change in the assurance level to
95% produces only a moderate increase in the "safe" level, again about 30%.
-------
-5-
Changing of the slope parameter, Table 2C, again produces dramatic Increases
in the "safe" dose, in one instance by a factor in excess of 100. The in-
crease in the "safe" dose per 10-fold increase in the risk level is again
about 2 at the higher slope of 1.5. A particular effect of use of the
higher slope is that it has allowed the data inversions of experiment 2,1
to dominate certain analyses. Thus, all "safe" dose determinations for
experiment 2.1 and the overall female "safe" dose are based on the use
of all data including that at the highest dose level of 20 ppm. An
anomalous consequence is that the overall "safe" dose of 580 ppt is lower
than that of either 590 ppt for males or 620 ppt for females. The
anomaly disappears, however, if we discount the high "safe" level for females
as attributable in part to the data inversion at the highest dose levels of
experiment 2.1. With such discounting the overall female "safe" dose would
be reduced to 450 ppt. The same kind of pattern occurs in Table 2D in
which the assurance level has been altered to 95%, the effect of the change
in assurance level being only to increase the "safe" levels by a moderate
10-20%.
DISCUSSION OF D1ELDR1N RESULTS. LIVER TUMORS SHOWING AREAS OF PAPILLIFORM
AND ADENOID GROWTH. TABLES 3A. 3B. 3C. 3D.
The results of these analyses parallel those for all liver tumors
obtained with dietary dieldrin, but at somewhat increased "safe" levels.
This at the 10 risk level with slope of one the overall "safe" dose
is raised from 11 to 87 ppt, while that for males is raised from 13
to 78 ppt, and that for females from 6 to 57 ppt. There is again a
pattern of moderately increased "safe" doses as the assurance level is
changed to 95%, of sharply increased "safe" doses as the slope is in-
creased to 1.5 and of 2 or 3-fold increases in the "safe" dose with
10-fold increases in the risk level. Again the data Inversions of
30<
-------
-6-
experiment 2.1 give rise co some instances of estimated "safe" doses
which should perhaps be discounted, but these are not so pronounced as
in the preceding analyses.
GENERAL DISCUSSION AND SOME INTERPRETATIONS
From the foregoing the pattern of effect of altered assurance
levels, slope parameters, or risk levels seems somewhat evident and I
will not dwell on these here. A particularly interesting point however,
to which I specifically alluded in my first report, was the large
difference between males and females in their "safe" DDT doses, with the
combined "safe" dose somewhat closer to the higher of the two. I suggested
that this could reflect a difference in the relative amounts of information
available for the two sexes, rather than any true difference in their
«
susceptibilities to DDT.
I give next a simple hypothetical example which brings out my point.
It consists of five experiments in whicli the control spontaneous rate,
based on 50 animals, increases progressively from 0 to 50%, while the
apparent induced rate (measured by (Pt - PC)/(I - PC)) remains constant
at 10% . The following table shows the "safe" doses for the separate
experiments and the combined "safe" dose as determined by the method
I have used, employing an assurance level of 99%, .a slope of unity, and a
limiting risk level of 10~8.
-------
-.7-
i
Experiment Controls
1 0/50
2 10/50
3 20/50
4 30/50
5 40/50
Treated
lOOppm
5/50
14/50
23/50
32/50
41/50
"Safe"
Dose, ppt
1380
700
400
220
90
Combined - ; 1700
What is curious about this result is that the highest "safe" dose
attaches to the first experiment which is the one exhibiting the most
clear evidence for a carcinogenic effect. Yet only a low "safe" dose
attends the results for experiment 5 which displays questionable evidence
of carcinogenicity. The explanation is that in the first experiment, though
the data suggest a carcinogenic effect to exist, the upper limit on that
effect is probably limited to something under about 20%, say as due to a
zero control rate and a 20% treated rate. The upper limit on the tumor
induction rate for experiment 5 is considerably higher—the data, for
example, are not too inconsistent with true rates of 70% for controls,
90% for treated, for an induction rate of 67%. The high spontaneous rate
in experiment 5 led to such an imprecise estimate of the induced rate that
the data in it are consistent with the possibility either of a zero ,,
induction rate and of a rather high induction rate. Interestingly, the
combined "safe" dose is higher than the individual experiment "safe" doses-
in fact the data for the last few experiments, while not so informative
In themselves, did add to the total information available and so did serve
to raise the "safe" dose estimate.
-------
-8-
The lesson here is the need to avoid un in formative experiments in
establishing "safe" doses. If one's interest is in obscuring carcinogenic
<*
effects, an experiment which is less informative because of the obscuring
effect of a high spontaneous rate can be ideal but by the Mantel-Bryan
approach such uninformative experiments will be penalized by the assignment
of a low "safe" dose. In a mixture of experiments, some highly informative
others with only minimal information, the up-dated Mantel-Bryan procedure
will be much more influenced by the high "safe" doses of the informative
experiment than by the low ones of the uninformative experiment. (However
if a low "safe" dose arises in a relatively informative experiment, it
will be given high weight. This could signify a situation in which there
is a true difference in "safe" doses in the several experiments.) To
the extent that high spontaneous rates lead to less clear indications of
induced tumor rates, certain kinds of experiments would be best avoided.
These include experiments with animal strains with high spontaneous rates.
Also it would be better not to count tumors which occur very late in
animal life (though we can be free to observe- them if we wish). Such tumors
are, in principle, less important; they give rise to higher spontaneous rates,
hence less information about induced rates and so to reduced "safe" doses;
they could lead to misinterpreting a life-prolonging effect as a tumor-
inducing effect.
An added point of interest I wish to make is the improper high "safe"
dose estimates which could result when data at excessively high dose levels
are included. I deliberately permitted these to be shown routinely as they
occurred in the foregoing analyses so that I might point them put. If tumor
33<
-------
-9-
rates go down at high doses because of early lethal toxicity, these reduced
rates should not be given full faith and credit. Apparently the investigators
in the dieldrin study did make some allowance for early toxicity by excluding
from animals considered at risk those dying early—but their adjustment did
not seem to have been fully adequate. Note that in dieldrin experiment 2.2
there was only a single non-zero dose level. Suppose that in such an
experiment we knew only the final outcome and had no clue as to whether an
observed low tumor rate were due to competing lethal toxicity or whether it
resulted from the test agent being only weakly carcinogenic. Any "safe"
dose we might calculate would then be necessarily suspect. The remedy here
is that our experiment should involve a series of dose levels in order to
permit differentiating between true and only apparent low tumor rates.
Let me note that the feature of the up-dated Mantel-Bryan procedure which
allows combining the data of several experiments also permits making up-dated
estimates of "safe" doses as the results of new experiments are added to the
old.
34<
-------
Tnblo 1. Influence of va.yliis HIP Hipp-, i'.u- nHHc.nini-p Icvpl, mil lli« rink Irvi'l on tin- "milYly" nnnlyHln of the ilntn from Tomnttn Pt nl., HVM .
tiiMir d:it;i inily, illrMry HOT.
DUT DOSE DATA FOK Al.l, MICK DATA FOK 7(1 WliliK SURVIVORS
!'!!oi>?r " tumors vll'hln 70 wfcku only nil llvrr iiimini ' luimirs wlihln <>') wi'rkH only oil liver tumors
2
10
50
250
10-;
W?
io"u
io°-
2
10
50
2 SO
10-8
10-'
10"*
2
!.0
SO
iO
10-8
10"?
10~5
2
10
50
250
ID*8
10-'
10"*
10-5
both ilexes
combined
-1.719
-2.473
-2.990
-2.587
. l
2390
6180
17.300
53,100
-1.874
-2.606
-3.108
-2.636
3130
8110
22.600
it. TOO
-1.870
-2.967
-3.862
-3.635
68,100
128,000
255,000
539,000
-2.024
-3.124
-3.985
-3.688
82,300
155,000
308, QUO
651,000
nuil en onljj females
. only
-1.059
-1.470
-2.235
-2.131
-1.965
-2.663
-3.127
-2.734
"safe" doses, p
420
1090
.1010
9330
IB upf
-1.163
-1.560
-2.350
-2.200
"81
550
1420
3950
12,200
-1.209
- 1 . UH5
-1.222
-3.260
27,000
50, '100
101,000
214,000
-1. 113
-2.104
-3.348
-3.135
30,900
58.300
116,000
245,000
3270
8470
2 3, .7 00
72,800
er limits on
-2.143
-2.774
-3.265
-2.795
fe'* doses, p
4500
11,600
32.500
100,000
It
-2.116
-1.200
-3.970
-3.762
80,400
152,000
301,000
636,000
ID l
-2.293
-3.405
-4.115
-3.830
"s«f
100,000
189,000
376,000
794,000
both SOXUH] ninliin nnly
' cnmblnril
-1.449
-2.000
-2.455
-2.286
it. DDT, corr
700
1800
5030
15,500
Intercept p
-1.597
-2.101
-2.544
-2.337
it DDT, corr
850
2210
6180
19,000
iipprr 1 Imll
-1.599
-2.49')
-3.110
-3.348
31,000
58,100 .
116,000
245,000
ipper limits
-1.747
-2.608
-3.433
-3.407
;" doses (pp
35,300
66,500
132,000
279,000
-0.400
-0.914
-1.671
-1.894
espondlng t<
190
490
1380
4260
aramcter, a]
-0.499
-1.007
-1.790
-1.986
espondlng to
240
610
' 1710
5260
< tin Inlrrrr
-0.550
-1.450
-2.711
-LA"?
21,400
40,400
80,200
170,000
on Inlorcop
-0.650
-1.578
-2.842
-3.207
t). DDT cotro
24,900
47,000
93,200
197,000
femnlvH
nnly
-1.790
-2.116
-2.562
-2.328
minimum, ut
890
2310
6440
19,800
ope • 1.0,
-1.978
-2.250
-2.668
-2.387
ninimum, utt
1140
2940
8220
23.300
)l irir-imrUT
-1.940
-2.M2
-3.427
-3.346
34,900
65,9111)
111,000
276,000
parameter.
-2.129
-2.734
-3.553
-3.415
^ponding' to
42,400
79,900
158,000
335,000
liotll HUXUH
-1.689
-2.381
-2.941
-2.387
tnnli
-------
NOT REPRODUCIBLE
Table }. Inflnvn r »;irjlnx llu- ulnix-. tin- nnimriiiirv l.-vrl, HIM) Ito rink li'vi'l >m ito "iwtMy" iwiilinlit nf Ito ilolo (ran Vnlkvr I>1 nil '}£?*'
dntit hir nil llv.T UuurH, dlrlnry illHilrlii • • OO
OltUattt
DOSC, py
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Mm
0.1
1.0
1.11
1.3
1
10
10
10-8
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w*
10-3
S.I
1.0
1.11
I.I
10
to
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10-7
10-6
10-'
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1.0
1.11
1.1
10
to
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10
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0.108
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11
29
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0.101
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0.701
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160
1010
1160
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1220
7410
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190
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610
1160
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270
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110
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490
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610
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