Document Bv8kBm7RR4DLr8dZd6mKky0VX
x$f.4xfcdoesnotTpresent evidence
iiWn.--fiber :or 2 fiber'per' cc' standard. . Essentially',it arguesjthat risks from low level exposures . : ; to asbestos are indicated; by reports of mesotheliomas associated with briefwith non-occupational exposures, sodras "household* exposur s of persons living in the houses of asbestos workers/ but levels of such exposures are not stated. That "household" exposures have been substantial was indicated by Dr. Selikoff at a Conference on Environmental Cancer that I attended in Washington last week.
The NIOSH report mentions mesotheliomas in individuals with history of asbestos exposure for only one day. Such cases could, of course, be unrelated to asbestos, as indicated in the NIOSH statement (Page III-7) that approximately 15 per cent of mesotheliomas are not known to be related to exposure to asbestos.
An earlier NIOSH report (Gillam et al) has been cited as showing tumor response to low levels of asbestos. In referring to this, the 1976 NIOSH report (III-10) states: "In a study of a group of miners exposed to amphibole fibers in the cummingtonite-grunerite ore series, Gillam et al (1976) have demonstrated mortality from malignant respiratory disease three times that of the general population."
Referring to the same study, a 1975 OSHA report said: "Gillam et al (1975), studying the mortality and reviewing the chest x-rays of 439 underground metal miners exposed to an asbestiform mineral, found three times the risk of malignant respiratory disease than expected. The fiber concentrations averaged 0.24 fibers/ml." (Federal Register, Oct. 9, 1975 pages 47652-47665. Refer to page 47656).
I
-The claim by Gillam et al for an increased, incider, of. the cited miners has<not been born*out.-by am,,
':K- ^tudy byt McDofejKettal V(copy attacK$dj;i' ' S-'
doubt haveia^bopy/ of the above cited 1975 OS & On an enclosed^copy of it, I have marked paragrap ,, 111 <luantitate^exposures to asbesto*$in relation fence of asbestoses and/or cancer. 1should be not level of exposure: in 'the cited Britishffactory in
' 1933-1968:wats^iun^estimatedlevel?!hnd^tbat^-DO
offered' tha^ra2^fiber level haa^acSually bee
t976 NIOSHre^S^S-*7f II-Table 6)cites a study
,,on inhalation.exposures of rats to various prepara*
.and notes thatrftumors were found1*after-exposures
^day. A copy^ql^Wagner*s paper is attached. It
w itST the one-dayJ^exposure. was 7 hours exposure to
|taining 9.7 tol4.7 mg per cubic meter of the
Operations of asbestos.
.
-
In March 1976, NIEHS held a 3-day Conference on Extra polation of Data from Animals to Man. A report on that conference by its chairman is enclosed. I attended that conference and enclose copies of 3 papers that seem of particular pertinence.
The first is a paper by Rail (Director, NIEHS) which addresses the question of threshold levels for carcinogens.
The second
2 paper by Enterline ar.d Henderson "A .icdel
for Extrapolating to Low Levels of Asbestos Exposure."
The third is by Hardin Jones. He brings out the point that thresholds for carcinogens should be viewed not only in terms of yield of tumors but also latent period, i.e. that safe levels can be achieved by considering exposures with latent periods longer than the life span.
I understand that CONSAD Research Corp., contractor for inflationary impact study on proposed revision to asbestos standard, is also looking at technical feasibility and econc-ic implications of a 0.1 fiber per cc limit.
Trusting that these remarks may be of interest.
Very sincerely.
WES/elc Enclosures See addendum (page 3)
William E. Smith, V. D Director Health Research Inst.
150 2 s;
" Addendum
*: j.:, ;,?';
Page 3
* *#*?'
Cl
osed papers.from the NIEHS Conferee
^___xPf Data from Animals* to Man are offered'.
provide detail on' some current thinking
i. ''(/
'
^^bottom-line'a__t_t_i_t_u__d__e___t_h__a_t________ ,
' 'the.'. regulatory . agencies was /express
;gham/at, the^conference I covere /
` * the new^Asst'r Secretary.^;
cmal/jSafety and^Heai^fe^saidr acco
QP-5-^1V-"- : - -----
xeS'ignorant astowKether there is a safe level
for carcinogens. The lowest feasible level seems'
." ' .................
:'
^^Ckiwqila^. theme; the NIOSH document that you sent;W^:<: contain^j^statement on page VI-2' that the asbestos/standard
/VC "shoold^bepfsiet .at the lowest level detectable by available
- suiailytical'techniques, 2m approach consistent with HIOSH's
most recent recommendations for other carcinogens.*
This approach, or enactment of "zero" levels for carcinogens, would, of course, mean that investment of time and money to achieve any particular level would be precarious, since improvements in sensitiyity of analytical techniques could unpredictably change the picture.
Enclosed is an announcement of a seminar in Washington on 12-13 April on Federal Regulation of Environmental Carcinogens, Ine list of speakers may suggest someone that you could contact for conment or advice. Paul Kotin from Johns-Manville is scheduled to give the lead-off address.
Would it be agreeable for me to send a copy of this letter to Dr. Allan Harvey at R.T. Vanderbilt Co. ?
<5C<***''*'v V
Sensi^ye.
0*^ coKffo/Imfi
/fe predicted cjrft(/foh0^.
yelah^ rt'sl. Cax*
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f'O o, s,
0-2. //w?'
ond
25082172
i* K
bo equivalent to a 15 f/cc integrated exposure for factory workers--,'
%' II
' : "SB A* a first step is developing the model a simple linear se-response relationship was assumed resulting from one /ear's occupational exposure to
asbestos (8 hours a day, 5 days a week) and 40 cases were arbitrarily assigned to the lowest dose level (4 f/cc). Also, median time to tumor was assumed to beequal to the inverse cube root of dose with time.to himore for an exposure
level of'16 f/cc estimated at 39.1 years based on Table 1. A log normal dis
tribution was assumed for a single dose (one year's duration)witb a geometric
standard deviation of 1. 5. The results for four exposure levels are shown in Figure 1.
Based on a study of a factory population with a very high exposure of short duration (estimated at 30 f/cc for 3-11 months) for which we estimate the actual cumulative relative risk for respiratory cancer at the end of 28 years was 2.9, an expected animal number of respiratory cancer deaths was calculated. To do this it was necessary to estimate the number of cases caused by 5/8 year exposure at 30 f/cc under conditions set forth in Table 3. This was estimated as 215 cases with a median latent period of 31. 7 years. 81.3 of these cases would be observed in the first 28 years. Since the cumulative relative risk over a 28 year period corresponding to the 81.3 cases was known (2.9), expected case:
Presented at Conference on Problems of Extrapolating the Results of Laboratory Animal Data to Men and Extrapolating the Results from High Dose Level Experiments to Low Dose Level Exposure, Pinehurst, North Carolina, March 11, 1976.
25002173
r
___....,.i/w,jui a Known number of expected cases'-
peBiyear andaricnawp^nu
cases caused by asbestos-exposure per^ycarwyt&y
Igurerl), relative risks for each^year could- be
T^'Ta
fK nalrnlafinn frtA f/ ,, '' '
_ ........... ........................... ......... ..........
'asingle year of exposure is not of great interest. What we need to know is what might be observed as the result of continuous exposures at various levels. Table ^suggests the need for an additional par teter - a parameter we'll call tittrlndex.of Susceptability. Table 1 show tat rather than continuing to increase as dose increases the relative risk .m respiratory cancer starts to decline after 34 years of exposure. One explanation for this is that susceptability varies in a population and with continued^exposure the population.loses its ability to respond. One expression, > ' of this Is a function such that if one year's exposure at, for example, 15 f/cc causes 150 cases (estimated from Table 2) the 2nd yearfe exposure causes 150 x c cases, the 3rd year ISOxc2 cases, the 4th year 150 x cases, etc.*, where c is some constant < 1. To determine the value of c^data in Table 1 were first adjusted for an overstatement of the relative risk due to the use of corrected death certificates for observed deaths among insulation workers and the use of uncorrected death certificates to obtain expected deaths. The model was then fitted to these corrected data for various values of c. The best fit was obtained where c s .44 (the Susceptability Index). This fit is shown in Table 7. It is pretty good considering that the insulation workers data deal with fairly small numbers in some of the exposure categories.
Given a Susceptability Index, estimates can be made of the effects of continuous exposures of various durations and at various dose levels. Table 8 illustrates the effects of continuous exposure at 32 f/cc and Table 9 and 10 the predicted results for two study designs for various exposure levels. Relative risks are rounded so that a relative risk of 1.0,. for example, means less than a 5% increment in respiratory cancer. Also, distributions are discrete and somewhat more precise estimates could be obtained if continuous distributions were used.
25082174
Jand &-show^that thc5jifrcfcnccf due to the low Susceptabilxty
_-
V . -
I --mi I I
-
I'Cumulativerelktiveriska
psrould seem,
1th effects of exposure." and
can readily be translated Into cases caused by,exposure.
'} : X / .r - ;-sr',
Table 1
Lung Cancer Observed During 1967-72 by Tears'from Onset of. Exposure as of
January 1. 1967
-17. 800 Asbestos Insulation Workers
Years From Onset
<10 10-14 15-19 20-24 25-29* 30-34 35-39 40-44 45-49 50+
Expected Deaths
Lung Cancer Observed Deaths
Relative Risk
0.55
.0
1.97
5
2.5
5. 87
23
3.9
' 9.55
.34
3.&
10.70
56
5.2
8.20
60
7.3
4.68
29
6.2
4. 84
27
5.6
4.51
19
4.2
4.97
22
4.4
(Selikoff and Hammond. 1975)
25082175
in
titer
- ; -r V MrJt -
....
>
f
rr
144590
_Vtak*SiYM- Sasceptabilifcylndex = .44
Derived fromModel V
Table 3
Total Cases Caused by Exposure for One Year and Median Latent Period
Exposure Level (f/cc)
No. of Cases
Median Latent Period
4 40 62.1
6
. 80
49.3
16
160
39.1
32
320
31.1
G-- , '
Table 4
Observed and Expected Cases and Relative Risks
32 f/cc for One Year (1954)
Cumulative
Follo*r-up` Observed Expected RR in Period RR at end of
Period
Cases
Cases
Obs/Exp
Period
1955-59 1960-64
1965-69 1970-74 1975-79 1980-84 1985-89 1990-94
8 8 18 40 58 62 56 45
7.5 7.5 7. 5 7.5 7. 5 7. 5 7. 5 7.5
1.1 l.i 2. 4 5. 3 7. 7 8. 3 7. 5 6.0
1. 1 1.1 1. 5 2. 5 3. 5 . 4.3 4.8 4.9
25082176
*f l. s
\
....... Table 7
Relative Risk Predicted by Continuous Exposure Model at 15 f/cc Compared with Relative Risk Reported in Study of U. S. Insulation Workers
Years from Onset of Exposure
Predicted Relative Risk
Observed Relative Risk
(Adiusted)
410
1.0
0.0
>10-14
1.6
2.2
.15-19
2.8
3.4-
20-24
4. 3
3.1
25-29
5.4
4.5
30-34
5.7
6.4
35-39
5.4
5.4
40-44
4. 8
4.9
45-49 50+
4.1 3.4
3. 6 3. 8
25062177
`Follow-up
-5- am> i^xpccccauasesandRc Continuous Exposure at 32 f/cc'Starting in 1954
Observed Expected RR in Period.,: i-d-Obaf
Cumulative R
v: 'T v $592 %
S/Al
v* pm--
Observed and Expected Cases Caused by Continuous Exposure ' a First 20 Tears of Follow-up
Exposure Level (f/cc)
Observed Cases
(1955-74)
Expected Cases
(1955-74)
Cumulat End of
4
30 30
1.0
.8 16
32 30S
1.1
42 30 . 1.4
32 - "' "
98
30 .
3.3
Table 10
Observed and Expected Cases Caused by Continuous Exposure Second 20 Years of Follow-up
(Follow-up Starts 20 Years After First Year of Exposure)
Mean Exposure Level
(f/cc)
Observed Cases
(1975-94)
Expected Cases
(1975-94)
Cumulative RR End of 1994
4
39 30
1.3
8
69 30
2.3
16 161 30 5.4
32
371 30
12.4
25082178
t
laoic li
20 Year, 40 Year and 60 Year Cumulative Relative Risks Four Levels of Continuous Exposure
^Exposure Level ^ ff/cel
40 Year 1.2 1.7 3.4 7.8. ,
60 Year
1.4 .
2.1 = h- '
3.7
7.0
' A'.lt# &**?!*' 'yf' - <
---..............................-. -- - -
/:
^^RESWRATORY CANCER AT FOUR INTENSITY LEVELS
- FOR A UNEAR DOSE RESPONSE RELATIONSHIP
\< c ,,
,,\ * ; ** r.
m
frequency
BU (00 120
YEARS TO ONSET
160 180 2562l?9