EXTERNAL
A FT REVIEW DRAFT
JULY 1978
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CARCINOGEN ASSESSMENT GROUP'S
PRELIMINARY REPORT ON
POM EXPOSURES
NOTICE
This document is a preliminary draft. It has not been
formally released by EPA and should not at this stage be
construed to represent Agency policy. It is being
circulated for comment on its technical accuracy and
policy implications.
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U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Washington, D.C. 20460
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DRAFT
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CARCINOGEN ASSESSMENT GROUP'S
PRELIMINARY REPORT ON
POM EXPOSURES
This Document Is Being Released By FPA For External Review
Roy/[ (I Albert, H.D,
Chai rrnan
£<*£tij:j^atiji
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Tnis report Is dn asi.essiiie.it or tne carcinogenic impact
o^ ciroorne polycyciic organic C'jivi;,ounus. The polycyclic
hyorocarouns are a complex mixture OT compounds produced oy
combustion of oryanic niatter. Toe composition ot HOf-i
mixtures undouotealy varies consi uc-rau"! y depeiioing on the
source. The primary basis tor the assessment reported here
is an analysis of tour epi aeini al ogical stuaies which
exaiiiined the lung cancer experience in tnree occupational
circumstances involving Heavy exposure to HUM'S from various
sources and one urban-rural population study. In all cases
oenzo(a)pyrene was useu as trie indicacor of trie amount of
exposure. Also induced is an analysis of tr.ree animal
studies which deal with the lung cancer response to
benzol a)pyrene alone. Tnere are no animal stuaies wnich
deal with tne response to complex Mixtures of HUM as, for
example, coke oven, automobile, or fossil fuel power plant
emissions as the basis tor evaluating the relative
carcinogenic activity ot PUM's ana benzo(a)pyrene. However,
it is of interest tnat one of the aninal studies (Yanyshiva
et aj.) provided the oasis for the uenzo(a)pyrene standard
tor general air pollution whicn is useo. in the uSSR.
There is good consistency in the estimates ot excess
lung cancer from PUH exposure rrodi trie epl aemlol ogical
stuaies using a linear non-thresholu extrapolation model.
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Tne excess lung cancer incidence tor liretime exposure to
POM averaged u.^b* per nanogram/m3 witr. a range ot
U.3uWng/m3 to U.ko/ng/r.i-*. Tne estimates oaseu on
animal studies compared to the epidemic!ogical stuoies
ranged from a factor ot 3 higher lor the Yanysniva chronic
benzo(a)pyrene intubation study in rats to a tactor ot lu
lower in the chronic ueiizo( a) pyrene intubation stuoy in
hamsters (Feron) to a tactor ot lou lower in a cnronic
inhalation study to yenzo(d)pyrene ana Su^ in rats
(Laski n).
Using the epi aeini ol ogi cal data as a oasis tor the risk
estimate, HUH is estimated to cause about two hunareo. deaths
per year nationwide.
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Industrial Epidemiological Studies
The main problem in utilizing specific industrial exposures to
POMs to predict cancer response in the environment is that the spectrum of
the POMs to which workers are exposed may be very different froca that
encountered in the general environment. For example, the Ba? fraction of
POMs is much less in automobile exhaust than in coal combustion products.
Also, the fact that potential carcinogens other than POMs may be part of
the industrial exposures precludes an unconfounded assessment of the
effect of the POMs. However, there is rather close agreement in the
t
results of the three studies discussed immediately below regarding the
carcinogenic effect measured by the amount of the BaP indicator present.
This agreement tends to indicate that the estimates are reasonable.
Coke Ovens -- GAG 197R Report
In a recent revision of a GAG report on the risk to the U.S.
population due to coke oven emissions, it was estimated that the lifetime
3
probability of lung cancer due to a lifetime exposure of x ugm/m of BSO
in the in the inhaled air could be expressed as
_ .031521 + .00092975X
Q2() ~ 1 + .00092975X
A close approximation of the change in the background rate is thus
(.00092975 * .031521) x 100 = 2.95%/ugm BSO. Under the assumption that
1% of the BSO is BaP, this is a change of .295%/ngm BaP.
Gas Workers -- Doll (1972)
It was estimated that the British gas carbonization workers were
exposed to 2 ygm/m3 of BaP in their working environment for 22% of the
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year. If we make the additional assumption that the workers spent their
entire working lifetimes in this job, we estimate a lifetime average
exposure of
x = 2 x IQ3 x .22 x 45 T 70 = 283 ngm/m3 BaP.
This exposure was estimated to have produced an increase in the yearly
age-adjusted lung cancer rate of 1.6 x 10 . The age-adjusted lung cancer
rate in England and Wales during the study period was about 2.0 x 10
Thus the percentage increase in the lung cancer rate per pgm/m of BaP is
estimated to be (1.6 - 10~3) * (283 x 2.0 x 1Q~3) x 100 = .283%/ngm BaP.
Roofers Hammond et al. (1976)
The mortality experience of 5,939 roofers and waterproof ers
exposed to hot pitch fumes for at least nine years was studied over a two-
year interval. Estimates of exposure were obtained from breathing samples
of dust collected on masks worn during various job tasks. It was esti-
mated that the average worker inhaled 16.7 pgm BaP per seven-hour working
day.
The SMR for lung cancer in this sample was found to be 1.52 for
20 to 29 years of exposure and 1.61 for 30 to 39 years of exposure. The
3
lifetime air concentration x in ugm/m required to obtain the same life-
time exposure as that of workers, assuming a 240-day working year and a
breathing volume of 24 m per day, is
16.7 x 240
X ~
24 x 365 x 70
where £ = the number of years of on-the-job exposure and 70 is the average
lifetime.
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From these data we can obtain two points that can in turn be used
to estimate the increase in the lung cancer rate per change in -gm of 3aP
exposure. In the GAG (1978) report on risk due to arsenic exposures, it
was shown that, under a set ot simplifying assumptions, the slope of the
line through the origin of the relationship between the standard mortality
ratio minus one and the exposure is an estimate of the change in the rate
per change of unit exposure. Assuming the average of the exposure dura-
tions to be the midpoint of the exposure duration intervals, namely 25 and
35 years respectively, it follows that ,
o
y = SMR - 1 x = exposure ygm BaP/m
52 163.4
61 228.8
so that an estimate of the change in the rate per change of unit exposure is
79 QA9 = -00284, or a change of .284% per ngm BaP/m3.
Environmental Epidemiological Study
Carnow and Meier (1973)
In a very detailed study that took into account smoking
and other epidemiological factors, Carnow and Meier estimated that an
increase of 5% in the lung cancer rate could be expected for a change of
3
1 ngm/m of BaP in the atmosphere. This study has been criticized (in
our view somewhat unjustly) for the necessity of utilizing crude measures
of effect and exposure such as county-adjusted BaP levels and statewide
tobacco sales and lung cancer rates. Crudeness in data invalidates only a
negative result. A statistically highly significant result was found for
the association between lung cancer death rates and BaP measured which
was consistent for sex and race, and thus should be looked at with some
care.
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However, as noted by Carnow and Meier, the use of 1967-69 BaP
levels may not reflect at all accurately the lifetime average exposure of
those people who died in the 1959-61 period. For example, as discussed by
Pike et al. (1972), the BaP levels in downtown Los Angeles changed from
3 3
31 ngm/m in 1952-53 to 1.6 ngm/m in 1959 as a result of controls imposed
primarily on refuse burning. Making the rather tenuous assumption that
the Los Angeles situation is typical nationwide, we have a 19.4-fold drop
in exposure, which would change Carrow and Meier's estimate to an increase
of 5% T 19.4 = .258% in the lung cancer rate per increase of 1 ngm BaP in
the atmosphere.
Discussion of Results of Industrial and
Environmental Epidemiological Studies
Even though these studies were based on very different sources of
exposure to POMs and different methods were employed to obtain the esti-
mates, the end results are remarkably consistent. The geometric mean of
these four studies is
x - 4/(.284)(.283)(.295)(.258) = .2797
m
and an estimate of the standard deviation of the log x is
m
3.. - = .01236 .
log x
These values will be utilized in the exposure section to give a crude esti-
mate of the variability of the health hazard.
Animal Studies
The main problem in utilizing animal experiments to quantify the
carcinogenic effects of POMs is that no study of carcinogenic effect has
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been conducted based on what might be called a "typical" POM mixture. If
we utilize the studies employing BaP exposures we are still forced to make
an additional assumption specifying what percentage of the total carcino-
genic activity of a "typical" POM mixture is caused by BaP. As a result,
the findings in the animal studies are viewed as having only a very limited
use.
The geometric average of the estimates of carcinogenic potency
derived from the animal studies discussed in the next section will be
obtained. This average will then be compared to the geometric average
t
obtained from the human epidemiological studies to estimate a potency of
BaP relative to a POM mixture indexed by BaP. If this estimate appears to
be reasonable then we will say that the animal data is consistent with the
human data, thus giving us greater confidence in the epidemiological evi-
dence.
Intratracheal Intubation Studies
In order to utilize an intratracheal intubation animal study to
predict human risk it is necessary to equate the animal exposure usually
given in total lifetime mgs to the exposure level in air breathed by man.
We assume that an equivalent exposure between man and animal that results
in the same lifetime probability of tumor death is the daily average life-
time exposure on a mg-per-surface-area basis. If an animal is given a
total of x mg of a chemical during its lifetime and the air exposure to man
3
is u mg/m , then the equivalent dose is
x 24u
W 2/i x a x 365 W
a a m
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where W and W are the weights of man and animal respectively and I ±s
ma a
the lifespan in years of the animal. This equivalence is based on the
following assumptions:
(1) All the chemical breathed into the lungs is absorbed
3
(2) Man breathes in 24 m of air per day
(3) The breathing rate for all animals is proportional to their surface
area, which is taken to be proportional to the 2/3 power of their weight.
Solving for u we have that
xW2/3
m
u =
24 x 365 x i x w '
a a
Thus a dose-response relationship for an animal experiment based on x mg
can be converted to a human dose-response relationship by using the equiva-
lent human doses, u, instead of x in the estimate of the parameters of the
dose-response curve.
Feron et al. (1973)
A clear positive respiratory tract tumor dose-response relationship
was obtained in Syrian golden hamsters by repeated intratrachael instilla-
tion of a benzo(a) pyrene-ferric oxide mixture suspended in .9% NaCl solu-
tion. The lowest dose, 3.25 mg total per lifetime, induced a 10% response
in the experimental animals while none was observed in the controls.
The equivalent human air exposure in this case is
u (3.25)(70;2/3 - .0149
24 x 365 x 1.5 x (.15) '
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where: W = 70 kgm,
rn
m
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Wa=15C
1 =1.5 years, and
d.
x = 3.25 mg.
The estimated slope for humans from the one-hit curve is thus
3 = -ln[ln - .1] T .0149 = 7.071
3
where exposure is in mg/m in air. To express this rate as percentage
3
increase per ngm/m air exposure, we assume a .0315 probability of
t
respiratory trace cancer death in the absence of BaP, giving a value
[7.071xlO~6T .0315] x 102 = .0224% increase per change of r,gm/m3 of BaP.
Yanysheva and Antomonov (1976)
In this article little information was given about the experimen-
tal animal. We make the assumptions that the rats were W .400 kgm in
3.
weight, a common rat size, and their lifespan was equivalent to the longest
time noted to tumor appearance, 2. =2.25 years.
3.
A total of 5 malignant epithelial tumors of the lung were observed
in a group of 32 animals exposed to a total dose of .5 mg in 10 periods of
administration. The human- equivalent dose is thus estimated to be
u =
.5(70)
2/3
24 x 365 x 2.25 x (.4)
-4 3
-JTJ = 7.935 x 10 mg/m ,
the one-hit slope estimate is
3 = -ln[l - 5/32] / (7.935 x 10"4) = 2.1406 * 10~,
and the percentage change per ngm/m BaP is
(2.1406 x 102 T .0315) x 10~4 = .680%.
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Inhalation Study Laskins et al. (1970)
It is assumed that air exposures result in equivalent carcinogenic
responses for all species. Laskins, exposing rats to 10 rag/ra of BaP for
1 hour a day 5 times per week for their lifetimes and an additional SO
exposure, produced 5 tumors in 21 rats. An SO control group and a BaP-
exposed group in the absence of S0? did not show any tumors.
The equivalent lifetime average exposure to man that would result
in the estimated resoonse rate of 5/21 = .238 is
u = 10 x 5/7 x 1/24 = .2976 mg/m3.
Thus an estimate of the one-hit slope for man is
B = -ln[l - .238] * .2976 = .9133
and the percentage change in the rate per ngm/m of BaP is
[.9133 v .0315] * io"4 = .0029% .
Discussion of Animal Studies
The three estimates derived from the animal experiments varied 235-
fold. However, taking into account the differences in species utilized and
in exposure routes, differences of this magnitude are not really surprising.
The geometric mean of these estimates is
x = 3»(.0224)(.680)(.0029) = .03535 .
3-
Compared to the geometric mean of x = .2797 for the human epidemiological
experiments, we have an estimate of the relative potency
o = x /- = .03535 T .2797 = .1264 .
a x
m
10
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Thus 12.6% of the carcinogenic activity of the POMs is estimated to be
attributable to BaP. A value of this magnitude would not appear to be
grossly inconsistent with intuitive estimates. As a result the animal
data do not give any reason to doubt the results obtained from the epi-
demiological studies.
Risk to U.S. Population Exposed to PQMs
Energy and Environmental Analysis, Inc., estimates the exposure,
3
D, in units of 1,000 people * ngm/m for each state and the nation as a
whole (table E-2, Atmospheric POM: Sources and Population Exposure Esti-
mate, Draft).
Assuming that, in the absence of POM exposure, the lifetime
probability of death due to respiratory cancer is .0315 and the increase
in this rate is .2797% per ngm/m of BaP (the geometric mean of the epi-
demiological studies), an approximate estimate of the number of respira-
tory cancers caused per year by POMs is
ND = .0315 x .002797 x D x 1Q3 T 70.96 = .1242 x 10~2D
where D is the exposure in the given units and 70.96 is the average U.S.
lifespan.
For the entire nation, D is estimated to be 170,000 so that
N = 211 deaths/year due to POM exposure.
An estimate of the number of deaths per year in any individual
state is made by assuming that that state has the same proportion of
deaths as its exposure, D , is to the total U.S. exposure, D. Thus
D -
{I = _§. M= D 211 i 170,000 = 1.241 x 10 D .
s D D s s
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t"
DO IW i yw~.-. viv ui»
For example, the expected number of respiratory deaths in the state of
Washington due to POM exposure is estimated to be
N = 1.241 x 10~3 x 1,700 = 2.11 deaths per year.
Confidence Limits on Numberof Lung Cancer
Deaths per Year Due to POMs
If we are willing to accept the assumption that each of the epi-
demiological studies gives an unbiased estimate of the percentage increase
in the lung cancer rate per ngm/m of BaP and that each study is equally
valid, then it is possible to obtain approximate confidence limits for the
estimated total number of respiratory tumor deaths per year caused by the
POMs in the atmosphere.
The total number of respiratory tumor deaths per year may be writ-
ten in the form
ND = Ki3D
where K = (.0315 v 70.96) x 10 = .44391 is a constant derived from U.S.
health statistics; 3 is the change in the mortality rate per change of
3 3
ngm BaP/m exposure; and D is the exposure in units of 1,000 people x ngm/m
of atmospheric BaP.
Under the additional set of assumptions that:
(1) Our estimate of 6 is lognormally distributed so that
log 3 = log x = log (.2797) = -.553308
2 * 2
is normally distributed with mean log g and variance j ~ = (a.. )
= .15277 x 1Q~3
and
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(2) Our estimate of D is lognormally distributed so that
log D = log (170,000) = 5.23045
O 1 O
is normally distributed with mean log D and variance a = [~Tq7~] » where
the value of u is a "guesstimate" of the level of precision of our estimate
of D expressed in terms of being 95% confident that our estimate is between
[(1/u - 1) to u - 1] x 100% of the true value
The estimate of the total number of respiratory tumor deaths per
year is
«
ND (.44391)(.002797)(170,000) 211.07 .
Thus log ND = 2.32444 is normally distributed with mean log N and
2 , . 2
variance af" + o_
log 6 D
so that a 95% confidence interval for log ND given u is
log (211) ± 1.96/.153 x 10~3 + (\0
= log 211 ± /.588 10"3 + Iog2u .
For various values of u the upper and lower 95% confidence limit
A
of the estimate N = 211 is given below.
(u
- 1) x 100%
0%*
10%
25%
50%
100%
lower limit
199.6
188.9
167.6
140.1
105.3
upper limit
223.1
235.6
265.6
317.7
423.0
*Assumes no error in exposures.
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We note chat due to the highly consistent independent values
obtained from the epidemiological studies, most of the variability is due
to lack of precision in the exposure estimates. However it is felt that
the variability estimate associated with the epidemiological studies most
likely underestimates the true variability.
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REFERENCES
Carnow, B. W., and P. Meier. "Air Pollution and Pulmonary Cancer."
Arch. Environ. Health 27 (3):207-218, 1973.
Doll, R., M. P. Vessey, R. W. R. Beasley, A. R. Buckley, E. C. Fear,
R. E. W. Fisher, E. J. Gammon, W. Gunn, G. 0. Hughes, K. Lee,
and B. Norman-Smith. "Mortality of Gasworkers: Final Report
of a Prospective Study." Brit. J. Ind. Mrd. ^9:394-406, 1972.
Feron, V. J., D. De Jong, and P. Emmelot. "Dose-Response Correlation for
the Induction of Respiratory-Tract Tumours in Syrian Golden
Hamsters by Intratrachael Instillations of Benzo(a)pyrene."
Europ. J. Cancer. 9_:387-390, 1973.
Hammond, E. C., I. J. Selikoff, P. L. Lawther, and H. Seidman. "Inhala-
tion of Benzopyrene and Cancer in Man." Ann. N.Y. Acad. Sci.
271.: 116-124, 1976.
Laskin, S., M. Kuschner, and R. T. Drew. "Studies in Pulmonary Carcino-
genesis." In Inhalation Carcinogenesis, pp. 321-350. Edited by
M. G. Hanna, P. Nettesheim, and J. R. Gilbert. AEC Symposium
Series no. 18. Washington, D.C.: U.S. Atomic Energy Commission,
1970.
Pike, M. C., R. J. Gordon, B. E. Henderson, H. R. Mench, and J. SooHoo.
"Air Pollution." In Persons at High Risk of Cancer: An Approach
to Cancer Etiology and Control. Edited by J. F. Fraumeni, Jr.
New York: Academic Press, 1975.
U.S. Environmental Protection Agency. Carcinogen Assessment Group.
Preliminary Report on Population Risk to Ambient Coke Oven
Exposures. Washington, D.C., 1978.
Yanyshiva, N. Ya, and Yu G. Antomonov. "Predicting the Risk of Tumor
Occurrence under the Effect of Small Doses of Carcinogens."
Envir. Health Perspect. 13:95-99, 1976.
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