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in cancer death rates with the direct effects of ,nna,ed air po,,utants The
studies by Winklestein et ,,.«74 and ^^ et ^m ^ ^
that tendency,. The major question which remains unanswered is what part of
the urban-rural gradient can be attributed to the air portion gradient to
which it corresponds.
6.7.2.2 Miarant^udies-studies on lung cancer rates ,„ migrant populations
(in the absence of portion monitoring data) tend to indicate that exposures
occurring ear,y in ,„. can lead to the ^^ Qf cancers ^ ^
the victims have Migrated to a different environment. !n this regard it
can be seen that the age-standardized lung cancer death rates among British
and Norwegian migrants to the United States are intermediate between those
in their original homeland and adopted country.«« other studies of cancer
mortality among migrants support the concept that these persons are affected
by^their former environments and length of exposure in that environment "",477-
It is suggested that differences in smoking habits are unlikely to
account for discrepancies in lung cancer rates among migrant and resident
populations.
6-7.2.3 Regression an.lys.s-On the assumption that populations exposed to
POM from the petroleum industry could be expected to have higher rates for
certain cancers than unexposed populations, Blot et .,.«5 conducted
of cancer mortality from ,950 to ,969 in 39 counties where the petroleum
industry is most heavily concentrated. They found that white male residents
of these counties had significantly higher rates for cancer of the ,ung, the
nasal cavity and sinuses, and the stomach compared with the residents of
counties with similar demographic features but without petro,eum-Process,ng
6-209
-------
plants. However, these correlations do not necessarily establish cause-and-
effect relationships. Ratios of age-adjusted mortality rates among white
males in the petroleum-industry counties to the rates in control counties
were: 1.15 for lung cancer (significant at 1 percent level); 1.48 for cancer of
nasal cavity and sinuses (significant at 1 percent level); 1.09 for stomach
cancer (significant at 1 percent level). The ratio for all sites combined was
1.06 (significant at the 1 percent level). White females in petroleum-industry
counties also had significantly elevated rates for lung cancer (though not for
cancer of the nasal cavity and skin, nor for all cancers combined), suggesting
the possibility that community exposure might be involved as well as occupational]
exposure. Data from Blot et al.435 are given in Table 6-48.
481
Using death certificate data from 1968 to 1969, Menck et al. found
elevated lung cancer mortality rates in white males living in certain heavily
industrialized areas of Los Angeles County. Populations at risk were deter-
mined from the 1970 Census data. Age-adjusted lung cancer mortality rates for
Caucasian males and females were calculated for 13 areas from Los Angeles
County death certificates. A direct method of age-adjustment using the U.S.
1970 Census population as a standard was carried out, and socioeconomic class
index based on average income and education level was assigned to each census
tract.
The age-adjusted lung cancer rates in 1968 and 1969 for male Caucasians
in the 13 study areas ranged from 43 to 75 per 100,000. In three contiguous
areas of south-central Los Angeles County, however, the mortality rate was 70
per 100,000 or greater. The excess of male lung cancers for these areas was
40 percent above the rate for the rest of Los Angeles County.
6-210
-------
TablS 6-*3- SSU2^;™U5IE? «9?TALITY RATES,
TO KKQ
Cancer site
• _
Buccal cavity and pharynx
Esophagus
Stomach
Colon
Rectum
Liver
Pancreas
Nasal cavity and sinuses
Larynx
Lung
Prostate
Testis
Kidney
Bladder
Melanoma and other skin
Brain
Thyroid and endocrine
Bone and connective tissue
Hodgkins's disease
Other lymphomas
Multiple myeloma
Leukemia
Rate
1.04
1.06
1.09a
1.02,
1.07b
1.06
1 .'48a
1.09
1.15a
0.98.
1.10b
1.05
1.02.
1.10b
0.94D
1.04
0.98
0.96
1.01
1.05
1.03
All sites combined
6-211
-------
The Inhabitants of the three areas of south-central Los Angeles County
are mainly lower and middle class, and the lung cancer rates for Los Angeles
County were 1.73 times higher in the lower than in the upper socioeconomic
classes. However, the excess for the three south-central areas remained when
deaths for the 13 study areas were examined for the lower socioeconomic
groupings.
Measurements of BaP and other PAH in the air and soil (made at four
sampling stations with and adjoining the three south-central areas) showed the
highest pollution levels at the center of the three study areas with increased
lung cancer mortality.
Neither smoking nor occupational history data were available in this
study, 'but the authors argue that neither smoking nor occupational exposure
could account for the excess. They suggest that synergistic action between
smoking and neighborhood air pollution, primarily of industrial origin,
provides the best explanation of the elevated lung cancer rates in south-
central Los Angeles County.
A follow-up study482 including additional mortality data from 1970 and
morbidity data from 1972 confirmed the findings of an elevated lung cancer
rate for south-central Los Angeles County. Age-adjusted lung cancer rates per
100,000 were 70.9, 70.2, and 69.2 for the three south-central areas compared
to an average rate of 55.8 for all 14 study areas in Los Angeles County.
Henderson et al.482 reported that the increased risk was present in different
social classes as well as in six of eight non-factory occupational categories.
Females did not have an elevated risk. Although current occupation was an
important factor in the lung cancer risk of Los Angeles County men, current
6-212
-------
occupation did not explain the excess male risk .in the south-central area.
The authors noted that detailed work histories might reveal an occupational
risk that could account for the observed increased cancer risk. It was sug-
gested that the excess lung cancer rate was not due to differences in smoking,
since cancers of other sites normally associated with smoking showed no excess
in the three south-central areas.
In a study of respiratory cancer in ten Polish cities, an apparent cor-
relation was found between cancer death rates and degree of pollution by rep-
resentative POM.483 Data on ambient levels of dust, tars, BaP, BeP, BghiPer,
and pyrene for the period 1966 to 1967 were compared with the age- and sex-
adjusted respiratory cancer death rates for the period 1962 to 1963 in the
same cities (Table 6-49). For the most part, it was shown that cities with
the highest death rates had the highest levels of POM pollution (correlation
coefficient, R = 0.66). No apparent relationship was seen between respiratory
cancer death rate and air pollution as measured by other indices (e.g., dust,
tar substances). Caution must be exercised, however, in the interpretation '
of cancer incidence data in the absence of historical information on ambient
levels of POM. The long latency period for tumor appearance (10 to 30 years)
often makes it impossible to establish levels of exposure at the time of the
initial carcinogenic event. Moreover, it cannot be stated with certainty
whether carcinogenesis in humans is determined by intensity or duration of
exposure, or a combination of both. In addition, a presumed lognormal distri-
bution of incubation periods for neoplastic disease may complicate the attempt
to correlate time of exposure with carcinogenic effect.484
Stocks has carried out many studies relating lung cancer mortality to air
pollution. In 1952,485 he reported that, in towns, lung cancer mortality
6-213
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increased in proportion to the number of inhabited dwellings (from a compara-
tive mortality ratio of 89 in towns with less than 20,000 occupied dwellings
to 162 in towns with over 200,000 occupied dwellings): Differences in smoking
habits could not account for the lung cancer excess in towns compared with
rural areas. Stocks put forward the hypothesis that the effects of tobacco
and atmospheric pollution are additive.
Stocks and Campbell472 compared the lung cancer rates among men with
different smoking habits in a rural area, a mixed urban-rural area, and a
highly urbanized area (Liverpool County borough) using data from a study of
environmental histories of persons with and without cancer carried out by the
British Cancer Campaign. The death rates were related to levels of BaP and
other POM and sulfur dioxide in the air in each area.
The rural death rate increased with increased number of cigarettes
.smoked per week. Liverpool rates.were higher than the rural rates in every
smoking category, but the urban-rural ratio decreased progressively from about
9 to 1 for nonsmokers to near unity for heavy cigarette smokers.
There was an "absolute urban excess" in each smoking group, suggesting
that an urban factor was added to the effects of smoking. Stocks and Campbell
estimated that about half the male lung cancer deaths in Liverpool were due to
smoking and about three-eighths were due to "a factor which is only slightly
present in the rural areas."
The level of air pollution increased with increasing urbanization. The
concentration of BaP in Liverpool was from 8 to 11 times that in rural areas,
and this ratio corresponded to the estimated mortality ratio among nonsmokers
in urban and rural areas.
6-215
-------
Stocks486'487 reported significant correlations between SMR's for lung
cancer and bronchitis and air pollution (undissolved deposit and smoke)
levels in 58 county boroughs (towns) in England and Wales when population
density was held constant. Stomach cancer was also positively correlated with
air pollution. Lung cancer gave a correlation of 0.500 with the amount of
deposit when the population density was held constant (p<.002). Lung cancer
gave a significant partial coefficient with smoke of 0.510 (p<.01). Bronchitis
gave a partial coefficient with amount of deposit of 0.579 in males and 0.511
in females.
In an expanded study,488 a high correlation was reported between smoke
density and lung cancer mortality (r = 0.873). Differences in mortality were
only partially explainable by social differences (housing indices based on
numbers of persons per room and the proportion of employed and retired males
in unskilled jobs). Bronchitis and pneumonia in males (r = 0.869 and r = 0.666,
respectively) and bronchitis in females (r = 0.751, significant at the 5 percent
level) were also strongly related to smoke. Analysis for the relative correla-
tion of four different POM indicated that BaP was the "substance of prime
importance" for lung cancer. The trace elements beryllium and molybdenum also
showed associations with lung cancer.
Stocks489 reported the results of three separate analyses:
(1) Lung cancer mortality showed "substantial and independent correla-
tions" with smoking and air pollution (measured by smoke, BaP, and three other
POM) in six European cities and two areas of Wales.
(2) Lung cancer mortality showed positive correlations with the per
capita consumption of cigarettes and solid fuel (but not with liquid fuel) in
6-216
-------
19 countries. Smoking appeared to account for ^ ^^^ of
deaths in the average country and coal consumption for about one-third.
(3) There was a large urban excess of lung cancer in English metropoli-
tan areas relative to surrounding regions after the effects of differences in
soc,a, and other factors were eliminated. This excess was attributed to air
pollution.
The analysis of ,ung cancer and mortality in relation to smoking and per
capita fuel consumption in 19 countries was repeated490 with more recant
mortality data. When lung cancer rates were adjusted for smoking differences
the adjusted rates were generally higher in countries with high coal
tlon than in countries with low coa, consumption. Smoking showed a greater
effect than air pollution from solid fuel burning on the lung cancer rate in
-n aged 35 to 44 (the correlation coefficients with lung cancer were 0 634
for smoking and 0.470 for solid fuel), but in men aged 55 to 64, air pollution
showed a greater effect even when snoMng was held constant Cthe correlation
coefficients were 0.599 for solid fuel and 0.380 for smoking).
Carnow and Meier491 reviewed the multiple regression analysis performed
by Stocks and Campbell4*9 on the age and sex-specific and adjusted lung cancer
death rates for ,9 countries. After taking account of the influence of the
covariate defined as per capita cigarette consumption, the analysis indicated
a substantial residual association between the age-sex adjusted lung cancer
death rate and per capita fuel consumption as an index of air pollution; the
average age-sex adjusted lung cancer death rates were estimated to increase
by a factor of about 20 percent per metric ton of solid fuel consumed per
capita per year. However, since fuel consumption may be a surrogate for
6-217
-------
numerous industrial, climatic, and other national characteristics, it would
be presumptuous to attribute all of this relationship to the effects of air
pollution.
In a similar regression analysis of age-sex-race specific and adjusted
lung cancer death rates for persons 35 years of age and older in the 48
contiguous United States, cigarette sales per person and average BaP con-
centrations in the ambient air were employed as the regressors. Population-
weighted averages of BaP concentrations in samples taken from 1967 to 1969 in
urban and non-urban strata throughout the country were used by the authors as
a convenient representation of general air pollution levels. The specific
BaP measure was used as an "alias" or surrogate variable to represent all
forms of general air pollution in the states. Thus, a unit of "air pollution-
was defined as a one-year average of 1 ug BaP/lOOOm3. It was found that the
lung cancer death rates for white males increased by a factor of 5 percent for
each such unit of pollution; the increase was 15 percent for non-white males,
6 percent for white females, and 1 percent for non-white females.
The authors felt that the foregoing effects could have been overestimates,
because 1967-69 levels of BaP were only about 40 percent of their general
levels in the more typical period of the early 1950's. It is questionable,
however, whether secular changes in BaP adequately reflect long-term changes
in overall air pollution levels. Then, if BaP is an inadequate surrogate for
!ong term changes, perhaps downward adjustment by a factor of 40 percent would
be an over-correction. This analysis by Carnow and Meier491 was included in
the National Academy of Science's report on Biologic Effects of Atmospheric
Pollutants: Particulate Polvcyclic Organic Matter.
179
6-218
-------
ive and prospective analy.es-Thls category of community
studies on POM includes both prospective and retrospective large scale
sampling designs. Prospective studies of lung cancer death rates were
carried out by Buell and Dunn492 in male veteran residents of California
and by Hammond and Horn493 in United States white male veterans. Retrospec-
tive studies were performed by Dean494 in Northern Ireland, Haenszel et al>7>
T"OO •
m the United States, and by Hitosugi495 near Osaka. The designs of
these studies permitted finer adjustment for the individually determined
background characteristics of age, sex, and smoking habits. In some of the
designs, individual and family histories permitted the evaluation of the
duration of urban or rural residence and other factors in conjunction with
the urban-rural exposures. The,characteristic high-to-low gradient in
urban versus rural residence was consistently confirmed in all of these
studies. When expressed per unit.of BaP as an index of pollution, male lung
cancer death rates increased by a factor of 4 to 5 percent per Mg/1000m3.
These agreed well with the gradients estimated by the cruder population
and regression studies previously cited.
Carnow and Meier's491 proposal.of a 1 Mg BaP/lOOOm3 "unit of pollution-
may have been more for analytical convenience than as an index of widespread
practical use. In addition to BaP concentrations, Hitosugi felt it necessary
to characterize air pollution levels in terms of measured rates of dust fall,
rates of sulfur dioxide accumulation, and suspended particulate concentrations
Carnow and Meier491 have also pointed out that long term trends in predominant
types of fuel might vitiate the validity of BaP as an index. Specifically,
data from Finland and New Orleans did not conform well with the BaP index/
primarily, it was believed, because of atypical fuel usage in those areas.'
6-219
-------
Even where the BaP index has seemed to perform well in past studies, the
habitual use of a single component as an index and its possible incorporation
into the language of regulations would seem to invite misinterpretation and
improper manipulation. A more prudent approach would involve a multiple
component index based on such measures as obtained in the study by
Hitosugi.495 It seems that Carnow and Meier would also prefer using a com-
posite index, since one of their strongest recommendations was to obtain more
precise measures of POM, particulates, and irritant gases in ambient air
sampling. They also strongly recommended better documentation of cigarette
smoking habits and obtaining a greater variety of samples from occupational
and residential strata.
Taking a different approach based on the risk of highly exposed workers,
Pike et al.434 calculated a small but non-negligible risk associated with air
pollution. Pike et al. used the level of exposure to BaP among British gas
workers showing an excess lung cancer rate in order to extrapolate to the
lung cancer rate attributable to BaP in general urban air pollution. They
explain the algorithm used in the extrapolation as follows: ^
" The carbonization workers were exposed to an estimated 2,000 ng/m
BaP for about 22 percent of the year (assuming a 40-hour working week,
2 weeks paid leave, 1 week sick leave); very roughly, the men were
exposed to the equivalent of 440 (2000 x 0.22) ng/m BaP general air
pollution. This exposure caused an extra 160/105 lung cancer cases,
so that we may estimate, assuming a proportional effect, that each
ng/m3 BaP causes 0.4/105 (160/105 * 440) extra lung cancer cases per
year..."
This calcuUtion yielded an excess rate of 18/100.000 lung cancer cases
per year for a city with 50 ng/m3 BaP air portion. The authors took this
calculation and Stocks comparable findings as support for the "notion of a
simple proportional relationship between increasing BaP concentration in the
6-220
-------
Qf
r
«r an, ^ rate of
excess ,ung cancer rate
U.S.) was eo.uiva,ent to the ,ate due to exposure to ,0 noV Bap ,„
WM1. occupationa, stud,es have p.ov,'^ stTOna evince that exposure
to high 1TOJ. of POM causes an jncreased Mi
and fo, non^io.nant respl>ato,y d1.M.a. the
t-n studies remain 1nconclu.1v.. flt
consensus that th. dWmnCM between ,ung
-as a,e due to 8ene,a, .1r po,lutl.on. ,„
1-n. cance, in the UnUe, states, „,„,„.<* has wr,tten that
ef ect ,. undoubted, n „ ..„„ not certal.n ^ n ^ ^ ^ ^ ^^
Ponutants in the .,r. . Goldsraitn and ^^^ ^ ^^ ^^ ^ ^
»t.«tur. on a,> ponton and lung cancer, conc,ude ^ ^ .^
not suppon the hypothesis that .p.llut1on ^ ^ ,. ^ urban factor „
they add that it is a,so not „...,„,. to reject the possibi,ity
Other reviews have conceded that *h,,e air p0llution My be a signif-
icant facto, in the etiology of ,ung cancer,
of r,.k vary t,emendously. « the Znternationa, Symposium on Genera, A1r
Ponution and Human HeaHh With Specia, Reference to Uong-Te™ Effects held in
Stockholm, March 8-n, ,977 severa, concisions Were reached concernin, carcin-
ogenic effects of PCM. participants at the Symposium agreed on the
conclusions: w
1; Lung cancer is more common in urban versus rural areas.
2- Cigarette smoking is the major cause of lung cancer, and
contributes to urban-rural differences.
6-221
-------
3. Differences in lifestyle (e.g., alcohol consumption,
nutrition) and occupation are not important causes of
the urban-rural difference.
4. Combustion products of fossil fuels, probably acting
together with cigarette smoke, can account for cases
of lung cancer in large urban areas. The number of
such cancers is in the order of 5 to 10 cases per 100,000
males per year.
5. Although well-documented urban-rural differences have
been described for cancers in other organs, it is, not
possible to evaluate the role of air pollution in deter-
mining such differences.
When evaluating the carcinogenic threat of POM to man no one has yet
considered the relevance of dietary sources or its impact on gradients of can-
cer for sites other than the respiratory tract. This may be especially impor-
tant in light of the fact that the absolute rate of digestive tract cancer in
both rural and urban populations can be considerably higher than the rate of
respiratory tract cancer.465'474'475 In addition, the oral administration of
POM to experimental mammals commonly produces lymphomas, leukemia, and tumors of
the lungs and endocrine tissues; thus the possibility is raised that the car-
cinogenic impact of POM in humans may be underestimated by considering only
inhalation as the primary route of exposure, and lung cancer as the.endpoint
of greatest concern.
6-222
-------
6.8 ECOLOGICAL EFFECTS
POM ,. ubiguitous ,„ the natural environment, ar^ng
(e.g., petrol spmaae, transport of combustion products) but
;ls; °:19r;9r ™
bactena, -499 aUhoggh SQme
anaerobe .acterta do not syntn^ze POM.=00
•col^lc., impact of POM ,„ our terrestM3l and
P> Seated by uncertainty OV6r th
6.8.1 Effects on Microorganisms and Algae
Pav^r and cow^ers^ have indicated tHat tne green a,ga> Scanedes»S
-tus, ,ay contain significant quantfties of POM wnicn vary ~
geograpMca, Ration where it tt grown (Table 6-50). From the
distribution of carcinogenic POM wMcn was datected_ these 1nwi1g(ttori
duo-ed that ..t of the POM present was due to Moaccu^ation fro™ envi
-ntal Ci.e., anthropogenic) sources as opposed to endogenous Nation
Effects of these POM on algal growth were not indicated.
Although it was reported that phenanthroquinone, a degradation product
of Phenantnrene, reduced the surviva, of various a,ga, species « concentra-
tions of 40 to BOO Mg/,iter,^ others demonstrated that POM at low ,eve,s
Qf
can enhance a,ga, growth. =«3 The
, and AnJdstiodesHs oranunii was enhanced by exposure to ,0 to
20 Mg/liter f,uoranthene; ,,,2-benzopery,ene; 3,4-benzofluoranthene; indeno-
C,2,3,cd)pyrene; 1 ,2-benzanthracene; BaP; and DBahA. Moreover, the degree
of growth enhancement appeared to correlate with carcinogenic potency
6-223
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Blowing.the demonstration that Chlorella vul^aris cou.d utiHze acetate
- the growth medium to biosynthesize BaP, an hypothesis was presented that
POM may act as an endogenous growth promoter ,„ plants.^ ^ Contant1on
is also supported by the observation that growth of higher pUnts (rye
radish^tobacco) is promoted by POM in the same fashion as the growth of
algae. However, in comparison to the POM accumulated in pUnts from
anthropogenic sources, the contribution by endogenous synthesis is ,ike,y
to be quite insignificant.501'504
In various microorganisms, POM may either promote or inhibit growth
Toxicity may be expressed more as a function of increasing concentration
rather than specific chemical structure. On the other hand, Hass and
^legate reported that a structure-activity correlation may exist for
the effects of polycyclic aromatic hydrocarbons on the growth of Escherichia
coll. At concentrations in the medium of lo'7 to lo'5 mo!ar, anthracene
Phenanthrene, chrysene, DBacA, and pentacene inhibited bacterial growth
The more angular configurations, 1,2-benzanthracene, DBahA, and BaP pro-
moted the growth of E, co,,. lt was concluded from these limited data that
growth promotion may require the presence of POM with an angular acene con-
formation, whereas inhibition might occur with both Hnear and angular acene
molecules.
Recent studies conducted with marine bacteria do not support the hypo-
thesis that the effect of POM on microorganisms might be structure-specific
Instead, Ca,der and Lader505 reported that aromatic hydrocarbons inhibited
the growth of Serratia marinoruba and Vibrio parahaemolvti^ ,„ . manner
which was dose-related and a function of water so,ub,my. Thusi a saturated
6-225
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solution of BaP would have the same impact on bacterial growth as a saturated
solution of naphthalene, even though their respective solubilities differ by
several orders of magnitude.. Consequently, when evaluating the effects of
POM on aquatic organisms it may be necessary to balance inherent toxicity on
a molar basis against water solubility. The significance of considering both
variables in the ranking of POM for toxicity to marine bacteria is depicted
in Table 6-51. Furthermore, one must recognize that under normal conditions
the low-to-medium molecular weight POM may contribute less to overall environ-
mental toxicity than the higher weight molecules because the former are more
readily lost by volatilization and degradation.
Poglazova and Meisel507 reported that a wide variety of bacterial types
can accumulate BaP without metabolizing it. Localization'of BaP occurs in
Hp1d granules and lipoprotein membranes, as would be expected based upon the
lipophilicity of most POM. Other investigators508 have reported that cultures
of Pseudomonas aeruginosa and E, coJl absorbed 90 percent of the BaP added to
the culture medium, 10-26 percent of which was metabolized. Whereas these
509
authors reported a growth-stimulating effect of BaP on bacteria, others
observed a BaP-induced disorganization of colony structure. The localization
of POM in bacterial membranes is the most likely explanation for observations
that BaP depressed the metabolism of lipids and inhibited the formation of the
electron transport system in Staphvlococcus aureus.510'511 Whereas BaP was
inhibitory to membrane formation and function, benzo[e]pyrene was not.
Several studies conducted with cultures of yeast have confirmed that
BaP readily'penetrates the cell, is partially metabolized, and becomes
6-226
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512-51'
localized in I1p1d components of the cell, including Uproprotein membranes.
As a result, qualitative and quantitative alterations in the formation of
11pids, especially phospholipids, have been observed when Saccharoses
cerevisiae was exposed to BaP or DBahA. On the other hand, weak- or non-
carcinogenic POM (e.g., pyrene, dibenz[a,c]anthracene) were reportedly without
effect.
It has also been suggested that once polycyclic aromatic hydrocarbons
are absorbed by microorganisms they can be transferred throughout the cell
population.by cell surface contact. Studies with various yeasts grown in the
presence of BaP demonstrated that greater than half of the hydrocarbon accum-
ulated by yeast cells could be transferred to recipient yeast cells .which
515
were grown in a normal medium.
Sludge microorganisms were adversely affected by a variety of carcino-
genic POM.516 An inhibition of oxygen uptake of varying degrees was obtained
with different sludge microorganisms exposed to: DBahA; 7-methyl-l,2-benz-
anthracene;'l,2,4,5-dibenzopyrene; MCA; 2-nttrofluorene; 2-fluoreneamine;
N-2-fluorenylacetamide; 7,9-dimethylbenz[c]acridine; 7,10-dimethylbenz[c]-
acridine; dibenz[a,h]acridine; dibenz[a,j]acridine.
6.8.2 Effects on Aquatic Organisms and Amphibians
The toxicity of POM has not been extensively studied in fish, amphibians,
or aquatic invertebrates. Nevertheless, it is known that marine fish and
J . 504,517-520 Furtner-
invertebrates can accumulate BaP from polluted waters. Further
more, freshwater and marine fish are capable of metabolizing a wide variety
of hydrocarbons.
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The induction of cytochrome P450-dependent MFO activity ,„ „.„ and
invertebrates is no* receiving considerab]e ^^ ^ ^ ^ ^
activation of carcinogenic POM.™ Investigators postdate that the capa.
city of aquatic organisms to absorb and metaboHze POM f. important ^
in deter^in, carcinogem.c r,sk for ^ speci.es_ ^ ^ a]so ^
fo, the t™,.f.r of POH and its activate, metabo,ites throu8h the food
.
Ue ana c^or^" shoKed that ' VnaphthaUne an, 3H.Bap were
up throuflh the „„,. Qf three ^^ ^^..^^^^ ^^ ^
. BaP Was metabo,iZed in the^ive, and, within a few hours> metaho-
1-t.. we. t™sfer,ed to the „„ „«„.,. and excreted predomjnant,y )n u-
,ne. The main product of BaP metabol1sn, was 7>a- flhokas and coworkers52, ^^^^ demnstrstea
that the oxidative metabo,ism of BaP by trout ,iver ,ed to the formation of
6-229
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reactive intermediates which became covalently bound by protein. Furthermore,
trout liver microsomal enzymes activated BaP, 2-aminofluorene, and 2-acetyl-
aminofluorene to compounds which were potent frameshift mutagens in the Ames
Salmonella assay system. In comparison to the Sprague-Dawley rat microsomes,
trout liver .1crosoa.es metabolized BaP 15 to 30 times faster when the quantity
of BaP metabolites produced in 15 minutes was expressed per nmole of cytochrome
P-450 or per unit of cytochrome c reductase.522 Hepatic levels of cytochrome
P-450 are higher than'in the rat, whereas cytochrome c reductase levels are
1oWer. However, the Vmax is higher than for the rat and the Km is lower when
BaP is used as a substrate.
Carcinogenicity testing of POM in lower organisms has been pursued for
many years. For the most part, compounds which are carcinogenic in mammals
also produce hyperplastic reactions or tumors in lower animals. Arffman and
Christensen523 summarized much of the early work performed with the newt, a
salamander. These studies showed that an early proliferation of the epidermis
accompanies the subcutaneous injection of tar, BaP, and MCA in the tail region
of the newt. They confirmed these results by showing that an epithelial
proliferation commonly occurred with the injection of BaP, MCA, or DBahA. The
highest incidence of epithelial reaction was obtained with DBahA.
Following the demonstration in the clawed toad, Xeno£us laevjs, that
implantation of MCA crystals induced lymphoid tumors, a similar study was
undertaken to confirm this result using BaP.524 The implantation of BaP
crystals (1.5 mg) in the abdominal cavity of adult Xenoeus laeyis laevls
produced lymphosarcomas in 11 of 13 animals within 86 to 288 days. Advanced
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tumors were found which affected the ,.ver
plantable to Immature recipient Xenopus.
POM are wide,y distributed ,„ the environment as evidanced by their
detection^ sediments, soi!s, air, surface waters, and p,ant and ani»a,
t-sues. The eco108ica, i^act of these chemicals, however,,is unc.rtain
Numerous studies show that despite their high Hpid soiubiHty, POM show
Uttl. tendency for bioaccunu,ation ,„ the fatty tissues of anira,s or „
This observation is not unexpected in Hght of convincing evidence to show
that POM are rap,d,y and extensively metabo,ized. since on,y ,„« ,eve,s of
P0« are detected in p,ants and ,ower organ,s.s,«5 transfer of pflM ^
the food chain does not see* me,y. The direct impact of POM on p,ants
ani.a,s, or the eco,ogica, ba!ance of nature is difficuH to eva,uate, since
data are avai^e which suggest that adverse effects «y occur
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6.9 SUMWRY AND CONCLUSIONS
6.9.1 Absorption, Distribution, and Excretion
In the environ«nt, exposure to POM occurs by direct inhalation of
ponuted air and -obacco smoke, by ingestion of contaminated food and water,
and by demal contact with soot, tars, and oils. Regardless of the route of
exposure, it can be demonstrated in laboratory animals that POM are readily
absorbed across all epithelia which are in contact with the external environ-
ment. The fact that POM are generally highly lipid-soluble neutral molecules
greatly facilitates their passage through the predominantly lipid-like cell
Kenbranes of animals, including man.
Under environmental conditions, POM reach the lungs by adsorption on
carrier particles. Moreover, the regional deposition and retention of
inhaled POM in the respiratory tract will be primarily determined by the
physical size of carrier particles and, to. a lesser extent, by their composi-
tion. Once deposited in the lungs, two processes begin to act on the
particulate material. First, depending on their si«, particles are cleared
from the respiratory tract by upward flow in the mucociliary tree or by
phagocytic action of pulmonary macrophages. Second, adsorbed POM is eluted
from the carrier particles and left free to react with the respiratory
tissues or traverse the epithelium to reach the systemic circulation. A
balance apparently exists between the.rate of particle clearance and the
degree of POM elution which ultimately establishes the degree of toxicant
exposure via the lungs. However, clearance of particles by mucus and
ciliary action does not necessarily remove them from the body, since most
trials cleared from the lungs are subsequently swallowed, thus allowing
for absorption via the gastrointestinal tract.
6-232
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Upon reaching the bloodstream, POM are rapidly distributed to most
internal body organs. Under experiments conditions with Moratory animals
the route of exposure has mtl. apparent influence on the tissue localiza- '
tion of POM. Extensive Ioc.11z.t1.,, in the fat and fatty tissues (e ,
breast, is observed, and suggests that these tissues may act as a chemical
trap, creating a situation for sustained release of the unchanged substance
In pregnant rats, it is apparent that BaP and DMBA, but probably not MCA
are capable of transplacental passage and localization in the fetus
Excretion of POM is rapid and occurs mainly via the feces; elimination
m the bile may account for a significant percentage of administered doses
The influence of route of administration on patterns of POM excretion is
not entirely clear. However, elimination of W from „„,„„ ^^
dung, liver, Mdney, urine, feces) of the hamster following intratracheal
insolation appeared to be biphasic. The slow phase of elimination from
the lung (involving less than l percent of the treatment dose) seemed
dependent on the administration of 3H-BaP together with an adsorbent it
1. not known to what extent bioexchange of the tritium label may have
accounted for retention of radioactivity. Although some investigators find
that retention of BaP in the lungs of experimental anima!s is dependent
upon the co-administration of particulates, others maintain that carrier
particles are more important in determining localization in the respiratory
tract.
6.9.2 Metabolism and Metabolic Activation
The relative lack of chemical reactivity for tumorigenic POM has in
the past been puzzling in light of their biological effects. . More recently
however, it has become recognized that these molecules are enzymatically
6-233
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activated by oxidative mechanisms to form reactive electrophiles. These
activated metabolites are capable of covalent interaction with cellular
constituents (RNA, DNA, proteins), and it is suggested that one of these
metabolites is the true ultimate carcinogenic form.
Metabolic reactions on the POM skeleton may take place at nearly any
position, although chemical theory predicts that certain locations will be
more reactive. The earliest theories designated a K-region having particu-
lar relevance to the biological activity of the molecule subsequent to
oxidative attack. More recently, a "bay region" hypothesis was formulated
which takes into account the ease of benzylic carbonium ion formation such
as would be formed from the epoxides of diol-epoxides on tetrahydrobenzo
rings in the "angular" region of a POM. These diol epoxides are postulated
as ultimate carcinogenic metabolites of POM, a contention which is supported
by circumstantial experimental data showing high mutagenicity/carcino-
genicity for such structures and specific alkylation products of genetic
material identical to that obtained with the parent compound under metabolic
activation conditions. Examples of a K-region and a bay region on the BaP
molecule can be depicted as follows:
Bay region *--v\ .
rlo-
K-region
POM is metabolized by the microsomal mixed-function oxidase system,
often designated aryl hydrocarbon hydroxylase. This enzyme system is
readily inducible and is found in most mammalian tissues, although predominantly
6-234
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m the liver. !„ conjunction with various P-450 type cytochro.es, this enzyme
complex is involved ,-n detoxification „, ^ ^^ ^ ^
the formation of reactive epoxide metabolites fading to carcinogenesis A
second microsoma, enzyme, epoxide hydrase, converts epoxide metaboMtes of POM
to vicina, g,ycols, a process which may a,so have critical instance to carcin
ogenesis.
Because of the importance of metabolic activation for the expression
of carcinogenic effects by POM, the chemical fate of many representative
compounds in mammalian cells has been extensively explored. By far the
».t widely studied of the POM has been BaP, one of the principal carcino-
genic products from the combustion of organic material. The metabolites of
BaP (and a!l POM) can be divided into a water-soluble and an organic solvent-
soluble fraction. Components of the latter fraction are primary ring-
hydroxyuted products, quinones, and ,*„. epoxide intermediates For BaP
there are at !east three dihydrodiols, three quinones, and two phenols
which can be detected as positiona! isomers. The K-region (4,5-) and non-
K-region (7,8-; 9,10-) epoxides are precursors of the corresponding diols
which are formed by the action of the epoxide nydrase enzyme. A subsequent
oxidative attack by the ary, hydrocarbon hydroxylase may convert the diols
to dio, epoxides, one of which (7,8-diol-9,10-epoxide) is an uHimate carcino-
genie form of BaP.
In the water-soluble fraction containing BaP metabolites are mainly
conjugates of hydroxylated products with glutathione, glucuronic acid, and
sulfate. This group of metabolites is tenatively regarded to be composed
of non-toxic excretion products.
6-235
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The general scheme of metabolism for unsubstituted POM closely parallels
that for BaP, although several other major environmental PAH and aza-arenes
have not been studied. It is also evident that K-region derivatives of POM
may be preferred targets for conjugation and excretion, whereas non-K-region
epoxides undergo further reductions and oxidative attack to form theologically
important molecules. For POM bearing alkyl substituents (e.g., DMBA, MCA), the
primary metabolites formed are hydroxymethyl derivatives. Nevertheless, epoxi-
dation reactions at K-region and non-K-region aromatic double bonds occur which
are catalyzed by aryl hydrocarbon hydroxylase. Removal of activated intermediatej
occurs by conjugation with glutathione or glucuronic acid, or by further metabo-
lism to tetrahydrotetrols.
Alternative explanations for the generation of reactive POM metabolites
exist, although supporting evidence for their toxicologic significance is not
as strong as for the diol epoxide (bay region) theory. One argument supports
the role of reactive radical cation intermediates of POM as the critical meta-
bolites capable for interaction with cellular constituents. Others have indicate
that a 6-oxy-BaP free radical or a hydroxymethyl derivative of POM may be bio-
logically important reactive metabolites.
The exact intracellular event by which a reactive POM metabolite initiates
a toxic or carcinogenic response is not known. However, it is a widely held
view that covalent binding of metabolites to DMA forms the molecular basis of
the carcinogenic and/or mutagenic consequence of exposure to certain POM. In
this regard it has been shown that carcinogenic POM in the presence of rat liverj
microsomes become bound to DNA and synthetic polynucleotides, and moreover that
the extent of binding is correlated with the known carcinogenic potency of the
compound and levels of microsomal enzyme activity. Covalent binding of reactivel
6-236
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POM metabolites also takes place with RNA and other cellular proteins, and these
processes cannot be excluded as potentially inportant Gators of toxic response
Various epoxide derivatives of POM have been tested for their ability to bind to
nucleic acids, and it appears that guanosine residues may be the preferred
targets for reactive arene oxides. Reactivity with nucleic acids and synthetic
polynucleotides-Cpoly G) varied with the position of the epoxide moiety; K-
region and non-K-region epoxides were capable of extensive covalent binding, it
was further shown that, for BaP, the binding to RNA occurring after in vivo
exposures may be due to the reaction of BaP 7,8-diol-9,10-epoxides with the 2-
amino group of guanosine. A DMBA dlol epoxide was also shown to be involved in
DNA binding in cultured mouse embryo cells. These studies have helped to strength-
en the concept that: (!) reaction with nucleic acids may be the molecular basis
by Which a POM exerts its oncologic effects, and (2) non-K-region diol epoxide
metabolites may be the ultimate reactive chemical forms of POM.
6.9.3 Toxicology
Not a great deal of attention has been paid to the noncarcinogenic effects
of exposure to POM. Nevertheless, it is known that tissues of the rapidly
proliferating type (e.g., intestinal epithelium, bone marrow, lymphoid organs,
testis) seem to be preferred targets for ROM-induced cytotoxicity. This action
is probably due to a specific attack on DNA of cells in the S phase of the
mitotic cycle.
Acute and chronic exposure to various carcinogenic POM has resulted in '
selective destruction of hematopoietic and lymphoid elements, ovotoxicity and
anti-spermatogenic effects, adrenal necrosis, and changes in the intestinal and
respiratory epithelia. For the most part, however, tissue damage occurs at dose
levels that would also be expected to induce carcinomas, and thus the threat of
6-237
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malignancy predominates in evaluating POM toxicity. For POM which are not
carcinogenic, very little seems to be known concerning their involvement in
toxic responses.
lwino.uppnui.1on by exposure to POM has been reported, although it is not
clear whether this effect may be involved in carcinogenesis. However, it appears
that the degree of immunosuppression (cell-mediated and humoral) by POM is
correlated with carcinogenic potency. On the other hand, a dissociation between
carcinogenic and immunosuppresive effects can be shown, whereby doses which are
insufficient to affect immunity can still induce tumors.
One of the most toxicologically significant processes, involved in the
response to POM absorption is the interaction with drug-metabolizing enzyme
systems. The induction of this enzyme activity in various body tissues by
substrate and non-substrate xenobiotics may be a critical determinant in the
generation of reactive POM metabolites at the target site for tumor induction.
Recent emphasis has been placed on determining the drug-metabolizing capacity of
humans as a measure of their potential to form activated POM metabolites.
Although it has not thus far been possible to definitely correlate enzyme activ-
ity in humans with susceptibility to carcinogenesis, it is known that wide
variations occur in human carcinogen-metabolizing capacity. Moreover, tissue-
specific enzyme inducibility may affect the response of different organs to
carcinogen action. Nevertheless, the obligatory coupling of metabolic activ-
ation with POM-induced neoplasia in animals indicates that the modulation of
drug-metabolizing enzymes in humans plays a central role in carcinogenesis.
6.9.4 Mutagenesis
The demonstration of mutagenic effect in bacterial and mammalian cells by
exposure to POM is generally equated with the capability to induce tumor formatil
6-238
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This assumption is based on the participation of a common electrophilic metabo-
lite in producing the carcinogenic/mutagenic event, and the common target site
in the cell (i.e., DNA or other components of the genome) for ^ ^^ ^ ^
produced.
In recent years, considerable research effort has been directed at deter-
mining the mutagenicity of various POM derivatives as a means of identifying
structural features associated with the biological effect produced. Working
with bacterial mutants which can be reverted to histidine independence by a
chemically-induced mutation, epoxides of carcinogenic POM were shown to possess
significant mutagenicity. In particular, it was found that a non-K-region 7,8-
diol-9,10-epoxide of BaP possesses the highest mutagenic activity of all its
possible oxidative metabolites.V
Further work with cultured mammalian cells established that carcinogenic
POM can produce forward mutations when a drug-metabolizing enzyme system is
available. Once again, a 7,8-diol-9,10-epoxide of BaP displayed the highest
mutagenicity among its various metabolites. This effect was seen in the absence
of drug-metabolizing enzymes, strongly suggesting that the diol epoxide deriva-
tive is an ultimate mutagenic agent. Additional Investigation* on the inter-
action of BaP derivatives with constituents of the same mammalian cells in which
mutations are induced revealed that a BaP 7,8-diol-9,10-epoxide was involved in
binding to DNA. The link between carcinogenicity and mutagenicity was strength-
ened by the demonstration that both neoplastic transformation and mutagenesis
could be induced by BaP or BaP 7,8-dihydrodiol (precursor of the 7,8-diol-9,10-
epoxide) in the same normal diploid hamster embryo cells.
Numerous attempts have been made to correlate exposure to POM with the
induction of chromosomal aberrations. Although variations in chromosome number
6-239
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and structure accompany POM-induced tumors in rodents, it is not clear whether
these changes are consistently observable. No evidence in the published liter-
ature has been found to indicate that POM may produce somatic mutations in the
absence of neoplastic transformation.
Mutations in germinal tissues induced by POM have been more easily demonstratj
in Drosophila than in mammals. The male dominant lethal assay in mice has
produced conflicting results, although it is known that BaP and MCA can induce
sperm abnormalities.
6.9.5 Carcinogenesis
Polycyclic aromatic hydrocarbons were the first compounds ever shown to be
associated with carcinogenesis. To this day, carcinogenic POM are still distin-
guished by severa! unique features: (1) several of the POM are among the potent
carcinogens known-to exist, producing tumors by single exposures to microgram
quantities; (2) they act both at the site of.application and at organs distant
to the site of absorption; and (3) their effects have been demonstrated in
nearly every tissue and species tested, regardless of the route of administrati on |
Mong the more co-on POM at least one, BaP, is ubiquitous in the environment
and produces tumors in animals which resemble human carcinomas. The demonstrat,o|
that organic extracts of particulate air pollutants are carcinogenic to animals
has raised concern over the involvement of POM in human cancer formation.
Ora! administration of POM to rodents can result in tumors of the forestomac
mammary gland, ovary, lung, liver, and lymphoid and hematopoietic tissues.
Exposure to POM by inhalation or intratracheal instillation can also be an
effective means of producing tumors of the respiratory tract using very small
doses of chemical. However, for both oral and intratracheal routes of admin,-
stration, BaP is less effective than other POM (..„.. DMBA, MCA, DBcgC) in
6-240
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producing carcinomas. On the other hand, BaP has a remarkable potency for the
induction of skin tutors in mice that cannot be matched by any other environ-
mental POM. Thus, caution must be exercised in considering the carcinogenicity
of POM as a class, or in using BaP as a representative example in evaluating
carcinogenic risk of POM.
The induction of skin cancer by POM is regarded to be a two-stage process
involving an irreversible initiation step and requiring the subsequent presence
Of a promoting agent for tumors to develop. Certain POM may act only as initiating
agents (e.g., DBacA, chrysene, benz[a]anthracene), or may supply both initiating
and promoting stimuli (e.g., BaP, DMBA, MCA, DBahA, DBcgC, DBahP, DBaiP) The
administration of a single subcarcinogenic dose of a POM (e.g., 100 nmoles of
BaP) followed by repeated application of a noncarcinogenic promoting agent
(e.g., croton oil) can cause the appearance of numerous skin tumors in mice.
The two-stage mechanism of carcinogenesis may also apply to nonepidermal tissues.
For the induction of respiratory tumors by POM, several species and modes
of carcinogen administration are employed. In studies conducted with the Syrian
golden hamster, intratracheal instillation of POM established that dose-related
increases in tumor yield are clearly evident, and the co-administration of
carrier particles such as Fe^ can markedly increase tumor incidence.
Several u, vitro procedures hold promise as useful screening tools for the
detection of environmental carcinogens, including POM. Morphological transform-
ation of cultured mammalian cells has proven to be a reliable indicator of
carcinogenicity by a chemical 1» vivo. Examination of DNA repair synthesis in
cultured human and animal cells exposed to a carcinogen is also predictive of in
vivo carcinogenicity for certain compounds. When combined with the results of
microbial mutagenicity tests, cell transformation assays are capable of accurately
distinguishing nearly all known carcinogens from noncarcinogens.
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An analysis'of dose-response relationships for POM-induced tumors in
animals raises several important points having relevance to environmental risk
assessment. A fundamental relationship which must be considered is the devia-
tion from linearity in dose-response curves, especially at low doses, and
whether this indicates the existence of a threshold level. It can be argued
that individual variability in thresholds for tumor induction resulting from
saturation of detoxification mechanisms may account for a convex curvature in
the dose-response curve in the low dose range. Once the dose exceeds threshold
levels, tumor yield should remain a linear function of dose, with the slope of
the dose-response curve being indicative of the animal's sensitivity to the
carcinogen. Thus, the extrapolation of the straight portion of the dose-response
curve for groups of animals is often regarded to provide a conservatively low
estimate of the average threshold for tumor induction, assuming the most likely
case of decreasing sensitivity with an increasing threshold. However, the use
of an average threshold as a parameter of safety wouTd not indicate the propor-
tion of individuals still at risk of tumorigenesis at extrapolated low dose
levels. Furthermore, the existence of a threshold for POM-induced carcino-
genesis has not been documented in either animals or man, and, in fact, it is
more likely that in diverse populations the effect of POM will be a continuous
function of dose. In support of this contention are data which indicate that,
in the two-stage model, tumor initiation with BaP is consistent with a linear
non-threshold pattern. Overt tumor induction, on the other hand, follows a dos<
response relationship consistent with a multi-hit promotion process. It is
conceivable'that in human populations, the multi-hit component of carc1nog.n..1.
may be supplied by environmental stimuli not necessarily linked or related to
POM exposure.
6-242
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The well-documented existence of cocarcinogenic and anticarcinogenic
agents dictates that only a muHifactorial analysis can provide a true assess-
ment of carcinogenic risk to humans for a particular POM. Although noncarcin-
ogenic POM were reported to antagonize the effects of carcinogenic POM's in
animals, others have shown that they have little influence on tumor incidence or
Yield. On the other hand, several noncarcinogenic POM found in cigarette smoke
(pyrene, fluoranthene, BeP) have potent cocarcinogenic acitivity. A significant
decrease in carcinogenicity can be achieved with antioxidant food additives, .
certain vitamins, and other naturally occurring components in the diet in the
experimental setting. The molecular basis of anticarcinogenesis cannot be fully
explained, but may be due, at least in part, to an effect on the production of
activated POM metabolites.
6.9.6 Reproduction and Teratology . ;
Little information is presently available to indicate whether POM present a
significant hazard to reproductive success. Furthermore, effects on the fetus
which may be due to maternal toxicity or experimental conditions (e.g., injec-
tion vehicle, stress) have not been adequately dissociated form true embryo-
toxicity or teratogenesis. In cases where teratogenic effects are clearly
evident (e.g., with DMBA), the required doses are far in excess of realistic
environmental exposures.
6.9.7 Human Studies
The presence of POM in the air, or as components of soot, tars, and oils,
have long been associated with an excess incidence of cancer in human populations.
However, it has never been possible to study a population having exposure to
POM in the absence of other potential carcinogens, cocarcinogens, tumor initi-
ators, or tumor promoters.
6-243
-------
Convincing evidence indicates an excess in lung cancer mortality among
workers exposed to large amounts of coal gas, tars, and coke oven emissions. In
such cases, cancer mortality can be correlated with both the type and duration
of exposure. Although occupational exposure to POM-containing substances is far
greater than would occur in most communities, our understanding of chemical
carcinogenesis would lead to the conclusion that the number of cancers produced
is directly proportional to the dose received. One must assume, therefore, that
the smaller amounts of'POM in ambient air contribute in some degree to the
observed incidence of lung cancer in most populations. It should be recognized,
however, that the influence of cigarette smoking may have an overriding impact
on the evaluation of the carcinogenic threat of POM in occupational or environ-
mental settings.
Nevertheless, an approximately two-fold excess of lung cancer occurs In
urban settings as compared to rural environments, which generally cannot be
accounted for by differences in cigarette smoking, age, or sex. Several invest-
igators have shown that the incidence of lung cancer is highest in cities where
POM pollutants are the most concentrated. Moreover, it is clear that among
groups which have migrated from one country to another, the influence of pollu-
tion exposure in their former residence is still expressed as a higher rate of
,ung cancer mortality while in their adopted country. This observation cannot
be explained on the basis of differences in cigarette smoking habits.
Sampling studies from different communities have attempted to separate the
various factors which may be contributing to lung cancer excesses in urban
settings. These studies have not provided the kind of definitive results which
have been achieved with homogeneous worker populations exposed to pollutants
which are well-defined both quantitatively and qualitatively. On the one hand,
6-244
-------
been conceded that POM in co.unit ai
air does
-pec t *" "
.. ,
unde.sti.tion of Hsks derived from data concerning BaP.
6.9.8 Ecological Effects
POH are found
these agents
, f,,h>
data
may thus
^ ^
»
cc
•" inS that POH are rapidly ^^ ^ '
, hiaher
6-245
-------
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