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                                                              UKAM
of smoking behavior except the number of cigarettes smoked.
Correspondingly, Dean et al. found that the urban/rural risk
ratios did not change greatly when these factors were controlled
for (independently or together).  The data of Haenszel et al.
(1956) and Dean et al. (1977, 1978) thus provide strong evidence
against Doll and Peto's suggestion that these factors signifi-
cantly distort urban/rural ratios in cancer rates.
     Nevertheless, it would be desirable to calculate the likely
contribution of urban/rural differences in age at starting to
smoke on the urban/rural differential in lung cancer mortality.
However, to do so would necessitate combining data that are
not strictly comparable.  For a rough theoretical calculation,
we use the generalization of Peto  (1977) that the incidence
of lung cancer is proportional to the 4th power of the duration
of exposure to cigarette smoke.  Then, for two groups of men
who started smoking at ages 17 and 21, and whose smoking habits
were otherwise similar, the incidences of lung cancer at age
65 would be in the ratio (65-17)4/(65-21)4, or 1.416.  This
figure is consistent with data on U.S. Veterans, summarized
by Doll and Peto (1981:  Figure El).  Incorporating this ratio
into the calculation summarized in Table II-7, we obtain an
estimate of 1.48 for the urban/rural ratio that would be expected
on the basis of the observed differences in prevalence of smoking
in 1955, combined with an assumption that the mean age of starting
to smoke was 21 in rural areas and 17 in urban areas, in the
absence of urban/rural differences in other risk factors.
                              11-71

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Although this calculation involves a number of more or less
doubtful assumptions, it suggests that the hypothesized differ-
ence in mean age at starting would have to have been much greater
than 4 years to account for the observed urban/rural differences
in cancer frequency.  Although Table II-9 indicates a difference
of about 4 years between residents of two districts in one
county, Table II-8 does not indicate a systematic difference
of even 1 year between urban and rural areas.
     The most detailed and comprehensive attempt to control
for urban/rural differences in cigarette smoking habits is
that of Dean et al.  (1977, 1978), already referred to above.
The primary objective of the study was to "determine the changes
that had occurred in mortality from lung cancer and bronchitis
since 1963 and to see how far these were related to changes...
in the smoking habits of the population and in air pollution
levels."  Dean et al. compared data on a sample of 616 males
and 150 females who had died from lung cancer in Cleveland
County, England, between 1963 and 1972, with data on 2,666 living
males and 3,039 living females aged over 35 and interviewed
in 1973.  Data on the smoking habits and other characteristics
of the lung cancer victims were obtained from relatives and
from hospital records; data on the living samples were obtained
directly by interview.  In addition to a number of characteris-
tics of smoking habits,^ data were obtained on social class,
occupation, exposure to dust or fumes, location of residence,
and a number of other variables.  Data on air pollution were
                              11-72

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                                                              DRAFT
used to classify locations of residence as areas of high, medium,

or low pollution even within the areas classified as urban.  For

analysis, data were stratified by age and various combinations

of other variables, and age-adjusted relative risks were calculated

by maximum likelihood methods.

     The major conclusions of Dean et al. were:

    ...after standardizing for age and smoking habits,
    and after adjusting for differential population
    movements in the three pollution zones, male residents
    living at addresses within Stockton classified as
    having high smoke and sulphur dioxide pollution
    had over twice the relative risk of dying of lung
    cancer as had residents at other addresses.  An
    excess mortality, based on far smaller numbers of
    deaths, was also found for females.

         Secondly, ... only a small part of the marked
    excess lung cancer mortality rates [among residents
    of urban areas] would be explained by [smoking pat-
    terns] or because they tended to be of lower social
    class.

Dean et al. attempted to standardize for amount smoked, age

at starting smoking, type of cigarettes smoked (plain or filter),

and inhalation patterns.  They noted some anomalies  in relation

to age at starting smoking, which they believed may be due

to errors in estimating the age at starting smoking by relatives

of deceased lung cancer patients who supplied the information.

However, they added:

    ...it seems unlikely that, had age of starting to
    smoke been perfectly accurately assessed in the
    decedents, it could have explained the urban/rural
    mortality difference.

The third observation was that:

    ...between 1952/62 and 1963/72, the lung cancer
    rates of men aged over 55 who were reported never
    to have smoked increased significantly.   This dif-
                            11-73

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ference, about three-fold, could not plausibly be
attributed to changes in standards of diagnosis.
Equally, it could not be explained in terms of current
exposure to pollutants as there has been a downward
trend in levels of all the pollutants studied between
these two periods.  However this difference might
be explicable, at least in part, in terms of air
pollution if lifetime exposure to pollutants is
of importance, as due to the fact that some of the
sources of pollution in the area have existed only
for 50 years or less, older people in 1963/72 may
have had a greater life-time exposure than people
of similar age in 1952/62.

...we feel that, taking the facts together in combina-
tion it seems reasonable to conclude that air pollution
makes a significant contribution towards lung cancer
mortality.  This conclusion is consistent with the
results from Dean's study which showed that, after
standardising for age and smoking habits, male inhabi-
tants of Inner Belfast had 3.3 times the lung cancer
mortality, and 4.4 times the chronic bronchitis
mortality of inhabitants of truly rural areas of
Northern Ireland  (Wicken 1966) .

...smokers of filter cigarettes have a markedly
lower relative risk of lung cancer and chronic bron-
chitis mortality than smokers of plain cigarettes.
In view of the national switch towards smoking filter
cigarettes, and in view of the reductions in air
pollution that have followed the Cle'an Air Act of
1956, it was to be expected that, in due course,
overall mortality from both these causes would de-
crease if trends  in lung cancer mortality rates
are studied separately by age-group, the improvements
expected from the switch to filters and reduced
air pollution can be seen.  In 35-39 year old males,
for example, national lung cancer rates have dropped
38% between 1956-60 and 1971-75, and increases can
now only be seen  in men over 70.  Male bronchitis
rates show an even more marked improvement, with
a 30% reduction in overall death rate between 1968
and 1975 and rates declining at all ages except
in men 70 or over where they have levelled off  (Todd
et al. 1976).  Lee  (1977) has calculated, using
Peto's formula...  that even in the age groups at
which mortality rates are still rising, the rises
are markedly less than would have been expected
based only on knowledge of distribution of duration
of smoking habits, and ignoring the switch to filters
and the reduction in air pollution levels.  Of course,
if standards of diagnosis of lung cancer are still
                        11-74

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                                                              DRAFT
    improving ...then the benefits of the switch to
    filters and the reduction in air pollution are even
    greater than the data suggest.

     The major conclusions of the study by Dean et al. (1978)

are summarized in Table 11-10.  After standardizing for age,

smoking classification, and age at starting to smoke, urban/rural

ratios in lung cancer mortality were 1.50-2.02 for males and

1.46-1.77 for females.  Other analyses in the paper by Dean

et al. (1978) show that these urban/rural ratios were not strongly

affected by differences in the type of cigarette smoked (filter

or nonfilter) or by the depth of inhalation, and were not strongly

affected by differences in social class.  Moreover, there were

significant correlations of lung cancer frequency with measured

air pollution levels within the urban area.

     This study is of particular importance because it controlled

simultaneously for so many aspects of cigarette smoking behavior.

It has two major limitations.  First, although data were col-

lected on occupation and on occupational exposure to dusts

and fumes, these factors were not controlled for in the analysis.

Standardization for social class probably controlled indirectly

for some of the effects of occupational exposure, at least

within the urban areas, but a rigorous analysis would be needed

to establish this.  Second, the data on smoking habits and

other characteristics of decedents were collected primarily

from surviving relatives, and hence are subject to bias in

relation to those collected directly from the living controls.

The authors discussed this source of bias and presented evidence
                              11-75

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DRAFT
                                  TABLE 11-10

                 RELATIVE RISK OF MORTALITY  FROM LUNG CANCER,
                 STANDARDIZED FOR AGE,  SMOKING CLASSIFICATION,
                    AND AGE  AT STARTING TO SMOKE,  1963-1972
       Area                        Males               Females


       Eston                       2.02                  1.77

       Stockton                    1.50                  1.46

       Rural districts             1.00                  1.00


       SOURCE:   Dean et al.  (1978)


       that it  was not great.   In addition,  the bias is likely to

       have existed in both  urban and rural  areas,  so that the urban/

       rural ratios may not  have been seriously affected.

            One study of two geographic areas in Allegheny County,

       Pennsylvania, which were selected for study  on the  basis of

       substantially different lung cancer incidence rates in white

       males, found that the high risk area  had more men who smoked

       and that these men started smoking at an earlier age (Weinberg

       et al. 1982; see Table II-8).   The authors calculated that

       the combination of these factors accounted for almost of all

       of the difference observed between the two areas.  Their com-

       putations led to the  conclusions that 90% of male lung cancers

       in the "high" area were to be  attributed to  cigarette smoking.

       However, they used an unusually high  figure  for the risks of

       heavy smokers, which  may have  inflated this  estimate, and they

       did not  take interactions into account.   Moreover,  several
                                     11-76

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                                                              DRAFT
other factors, such as the proportion of industrial workers,
and at least one pollution measure—particulate dustfall—showed
equally large differences in the same direction as did the
cigarette smoking.  No correlation was shown with SO  measures.
                                                    X
No comparisons of smoking habits and lung cancer rates were
made in women.  The smoking data were gathered in a sample
survey and did not specifically apply to the men reported to
have developed lung cancer in the two areas.  As pointed out
earlier, the study areas were selected specifically on the
basis of an observed large difference in lung cancer rates,
so the results cannot be generalized to make inferences about
the contribution of smoking to urban/rural or other regional
differences in lung cancer rates.
     A related study was conducted in Denmark by Broch-Johnsen
(1982)  in which the author came to the conclusion that "the
risk of lung cancer [in Copenhagen]  is by 10-40% and 50-140%
higher than would be anticipated on account of smoking habits
in the youngest (1914-23) and oldest (1894-1903)  generations,
respectively."  While finding that smoking did not account
for the urban-rural differences, the author came to the conclu-
sion that "occupational factors are believed to have a greater
contribution to the urban factor than diffuse environmental
factors... after elimination of smoking".  This study is avail-
able in English only in abstract form, and a critical review
is not possible at this time.
                              11-77

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DRAFT
            Doll  and  Peto  (1981:   footnote  39) briefly  reported  unpub-
       lished  data  from  their earlier  study of mortality  in male British
       doctors (Doll  and Peto 1976).   Their results  are summarized
       in  Table 11-11 and  show  a much  smaller urban/rural  ratio  than
       other studies  that  have  controlled for smoking habits.  However,
       as  Doll and  Peto  pointed out, all the doctors had  been  educated
       in  big  cities  and may have  lived as  children  in  areas different
       from  those they inhabited in  1951.   The method of  standardization
       for smoking  was not stated.

                                  TABLE 11-11
                LUNG CANCER MORTALITY IN MALE BRITISH DOCTORS,
                      STANDARDIZED  FOR SMOKING AND  AGE,
                      STRATIFIED BY  LOCATION OF RESIDENCE
Location of
Residence in 1951
Conurbations
Large towns
(50,000-100,000)
Small towns (<50,000)
Rural areas
Expected
Deaths*
153.65
88.04
109.46
78.85
Observed
Deaths*
152
94
108
76
Ratio
0/E
0.99
1.07
0.99
0.96
       *Period  of  observation  unspecified
       SOURCE:   Doll  and  Peto  1981:   footnote  39
            In  each study in which  the  confounding  effects  of  smoking
       were  controlled, except for  that of  Doll  and Peto (1981),  urban
       residents were found to be  at  increased risk of  cancer  even
                                     11-78

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                                                             DRAFT
when differences in smoking habits were taken into account.

Summarizing these findings and pointing out the interaction

effects, Wilson et al. (1980) stated that most of the data

    ...agree that there may be a small increase in lung
    cancer among [urban]  nonsmokers due to air pollution;
    this is at most half the total incidence among non-
    smokers which is already small.  The increase of
    lung cancer among [urban] smokers due to air pollution
    is 4 times greater than the increase among nonsmokers
    and is statistically significant.

However, Wilson et al. (1980) did not present a statistical

analysis to support the last statement.

     The last point made by Wilson et al. (1980), about the

greater association with air pollution in smokers, is of par-

ticular importance.  The results of Haenszel et al.  (1962),

Dean (1966), Dean et al.  (1978)  and Cederlof et al.  (1975)

indicate that cigarette smoking and air pollution probably

interact synergistically.  A possible mechanism for this apparent

synergism was demonstrated by Cohen et al. (1979), who found

that smoking inhibits the action of cilia in long-term dust

clearance from the lungs.

     Interactions between smoking and air pollution would account

for some of the differences between men and women in patterns

of lung cancer.  If interactions of this nature did occur,

then we should expect that larger urban/rural differences would

be seen for males,  who smoke more than women and who generally

started smoking earlier.   This has been observed in several

studies (see Tables II-2, II-3,  II-4, II-5,  and 11-10).  Similarly,
                              11-79

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DRAFT
        if such interactions did occur, urban/rural differences for
        female smokers should be larger than those for female nonsmokers.
             The increase in the urban/rural difference among women
        smokers (relative to nonsmokers)  expected on the basis of an
        assumption of interaction, however, has not been consistently
        observed.   Haenszel and Taeuber (1964)  reasoned that this may
        be due to  the relatively small proportion of female smokers
        before the 1950's (this leads to large  sampling variation in
        estimated  risks and slopes of the smoking class gradient).
        They also  noted that the problem of small numbers of women
        smokers is compounded by the smaller "effective" exposures
        among women smokers relative to their male counterparts  (i.e.,
        women don't inhale as deeply as men and tend to smoke low-tar
        cigarettes and cigarettes with with less tobacco).   The other
        studies in which women's smoking habits were recorded (Dean
        1966, Dean et al. 1978, Hitosugi 1968,  and Cederlof et al. 1975)
        suffer from similar problems.  Of these studies, only the results
        of Cederlof et al. (1975) are consistent with an interaction
        effect among women.
             b. Occupational exposure
             Several investigators have also postulated that much of
        the urban  excess of lung cancer can be  accounted for by exposure
        to carcinogens in the work place.  In some situations, studies
        have provided support for this hypothesis.  For example, an
        excess of  lung cancer deaths was observed among white males
        in south central Los Angeles County during the years 1968-1972
                                      11-80

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                                                              DRAFT
 (Menck et al. 1974).  Lack of a clear basis for smoking or
occupational factors to explain the excess led the authors
to conclude that ambient air pollution was the causative factor.
A later case-control study was undertaken  (Pike et al. 1979)
and it was concluded that increased risks associated with occupa-
tion could account completely for the observed excess.
     However, Pike et al. (1979) in fact found associations
between lung cancer and both smoking and occupational categories;
on the basis of these associations, they calculated that the
differences in smoking habits and occupations between the areas
of Los Angeles County originally studied by Menck et al. (1974)
would account for a relative risk of 1.26.  This is smaller
than the relative risk of 1.40 originally observed by Menck
et al. (1974).  Hence, there is still a portion of this differ-
ence that is unexplained by smoking and occupation.  The sen-
sitivity of both studies was limited by the observation of
Pike et al. (1979) that most of the cases had migrated into
the area during the preceding 20-40 years.
     The data of Hammond and Garfinkel (1980)  also suggested
that occupational exposure may account for part of the urban
excess.  The excess of lung cancer deaths in urban and rural
areas in their study was reduced when occupational exposure
 (defined in the study questionnaire as exposure to dust, fumes,
gases, or X-rays)  was taken into account.  This reduction was
evident in almost every residence category.  This definition
of occupational exposure is not precise,  of course.  The study
                              11-81

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DRAFT
       population was composed  of  a larger  proportion of whites,  white-



       collar  workers,  and better  educated  individuals than the U.S.



       population as  a  whole, which could  lead  to an underestimate of



       the effects of both air  pollution and occupational exposure.



       When lung cancer mortality  versus location of residence is



       plotted separately for occupationally exposed and nonoccupation-



       ally exposed men, separate  effects  of both occupation and  residence



       are apparent (see Figure II-2).   Hammond and Garfinkel reported



       that these data  were corrected  for  cigarette smoking.



            Doll and  Peto (1981) provided  a quantitative interpretation



       of these data, noting that  after  standardizing for smoking,



       the mortality  from lung  cancer  was  only  14% greater in men



       who gave a history of exposure  to dust,  fumes or mists (including



       asbestos) than in men who did not.   Since only 38% of lung



       cancer  deaths  occurred  in men who gave a positive history  of



       occupational exposures,  Doll and  Peto calculated that the  total



       contribution of  these factors to  the production of lung cancer



       in the  ACS population appears to  have been 4.6%.  However,



       Doll and Peto  pointed out three ways in  which an estimate  of



       this kind could  be too low:  the  diluting effect of random



       errors, the possibility  that the  ACS population was biased



       by the  inclusion of proportionately few  blue-collar workers,



       and the possibility that undiscovered carcinogenic risks may



       occur in industries in which there are no recognized dust,



       mists,  or fumes.  Doll and  Peto proposed (on the basis of  admit-



       tedly subjective and "stop-gap" methods  of estimation) that
                                     11-82

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                                                                      DRAFT
                                FIGURE II-2

            RATIO OF OBSERVED/EXPECTED  LUNG CANCER DEATHS IN
        MEN BY RESIDENCE AND OCCUPATIONAL EXPOSURE,  1959-19653
   Ratio of
Observed/Expected
    Deaths

         1.4 	1
          1.3 —
          1.2 —
          1.1
          1.0
          0.9 —
          0.8 —
Occupationally
  Exposed
                          Rural
                          Areas
                                           Not Occupationally
                                               Exposed
        Smaller Non-
        Rural Places
Large City
   Areas
(1,000,000 +)
   aAdjusted for  age and  smoKing

   SOURCE:  Hammond and GarfinKel  (1980),  Goldsmith (1980)
                                   11-83

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the fraction of lung cancer deaths ascribable to occupational
hazards in the U.S. in 1978 was about 15% in males and 5% in
females.  At least in males, this fraction included some cases
also ascribed to cigarette smoking.  However, Doll and Peto
did not discuss possible interactions with air pollution, and
did not discuss or estimate the contribution of occupational
factors to the urban/rural ratio, except to quote the opinion
of Hammond and Garfinkel (p. 1247).
     The difficulty in separating occupational and air pollution
factors was also recognized by Greenberg (1979).  He attempted
to determine the relative importance of different risk factors
for male lung cancer.  He found that by adjusting air pollu-
tion indices to take into account wind direction and distance
from the air monitoring site, the relative contributions of air
pollution compared to occupation increased.  He later concluded,
however, that the high degree of intercorrelation between high-
risk lung cancer indicators  (smoking, air pollution, occupation,
etc.)  makes it infeasible to pull apart the separate contribu-
tions made by personal, occupational, and local environmental
risk factors.  Greenberg considered it likely that there are
interactions between air pollution, occupation, and smoking.
     In a case-control study of white male lung cancer patients
from Erie County, New York, from 1957 to 1965, Vena  (1982)
was able to study the effects of age, smoking, occupation,
and air pollution and their combinations.  Air pollution was
stratified into pollution zones by means of air sampling data
                              11-84

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                                                             DRAFT
for particulates collected from 1961 to 1963 and by an historical
review of point sources.  Exposure to air pollution was indexed
by the number of years of residence in a zone of high or medium
air pollution.  Occupational exposure was defined as the number
of years in a job category with potential exposure to respiratory
carcinogens or with documented elevations in risk for lung
cancer.  Smoking was defined in terms of years smoked, weighted
by four categories for amount smoked (less than 0.5 pack/day;
0.5-1 pack per day; 1-2 packs/day; and 2 or more packs per
day).  Data on age at starting, type of cigarettes and degree
of inhalation were not available.  Although misclassification
may have occurred and smoking may still be a confounding factor,
this study by Vena (1982) is among the most detailed available,
especially in that the simultaneous influences of smoking,
occupation, and smoking were assessed.
     When exposure to air pollution was defined as exposure
to high or medium pollution for 50 or more years, occupation
as exposure in high risk jobs for 20 or more years, and smoking
as exposure for 40 or more pack years, it was evident that
occupation and probably air pollution interact with cigarette
smoking to modify its effect.  Significant (p<0.05) age-adjusted
relative risks were observed for smoking (RR=3.30)  air pollution
and smoking (RR=4.73), occupation and smoking (RR=6.37), and
all three combined (RR=5.71).  When the data were stratified
by age to separate those born after the turn of the century
from those born before, the under 60 years of age category
                              11-85

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WFT
       showed significant  associations between cancer risk and each
       of  the three  individual  variables (smoking,  occupation and
       air pollution)  and  each  of  the  combinations  between variables.
       The over  60 years of  age category paralleled the associations
       observed  for  the overall, age-adjusted relative risks.
            When Vena  (1982)  adjusted  the relative  risks for age,
       occupation, and smoking, he observed a small (cind nonsignificant)
       unexplained lung cancer  risk for the medium  or high air pollution
       areas (compared to  the low  pollution areas)  of 1.03 for residence
       of  30 to  49 years and 1.26  for  residence of  more than 50 years.
       Vena (1982) cautiously interpreted this study as indicating
       that air  pollution  should not be dismissed as a. risk factor
       in  lung cancer  because of the apparent synergism of air pollution
       with smoking  and with the combination of smoking and occupation.
       He  concluded,  however, that his findings do  not support the
       hypothesis that air pollution alone significantly increases
       the risk  for  lung cancer.
            Other investigators have reported their belief that occupa-
       tion is not a  major factor  contributing to the urban excess.
       Doll (1978) stated  that  occupational hazards were "...unlikely
       to  be a major  factor  as  the known and suspected hazards...affect
       only a small  proportion  of  the  total urban population."  As
       mentioned earlier,  Blot  et  al.  (1977) made much the same point,
       noting that,  if the higher  cancer rates in petroleum counties
       were the  result of  occupational exposure, the relative risk
                                     11-86

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                                                            DRAFT
to these workers would have to be substantially higher than
the general population, but this has not generally been observed.
     c.  Migration
     Concerns have been raised that migration can have the
effect of increasing the apparent geographic variability because:
(1) it may produce areas in which the age distribution of the
population differs considerably from the U.S. average, and
(2) persons who migrate are likely to have a different health
status from that of those who remain behind.
     Mancuso  (1976) reported that much of the differences in
lung cancer mortality rates that he found in Ohio came about
as a result of the very high rates observed in migrants to
Ohio from the rural areas of the southeast United States.
Blot and Fraumeni  (1981) have recently reported that the lung
cancer mortality rates in the southeast now exceed those of
the northeast and Great Lakes states.  Mancuso interpreted
his findings to imply that a prior initiating exposure was
more likely to have occurred to the migrants (in contrast to
sedents)  and that later, promoting exposure then had a greater
effect on migrants than on life-long residents.
     The first problem can be avoided when enough data are
available to calculate age-specific and age-adjusted mortality
rates.  In the studies based on the mortality data for U.S. counties
compiled by the National Cancer Institute (e.g., Blot and Fraumeni
1976), appropriate standardization has already been performed.
                              11-87

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r-T
f" I
      The second problem,  the possibility of selective migration


 into or  out of an area,  might be corrected for if detailed


 statistics were available on duration of residence.  By studying


 only those individuals who have remained in an area for 20-30 years


 a more accurate assessment of environmental effects could be


 obtained.   In most studies of urban/rural differences, such


 data are generally not available.   It is possible that a small



 percentage of the urban/rural difference might be due to the


 migration of chronically ill persons to areas (generally urban)


 with better medical facilities, or migration of healthy individ-


 uals out of these urban  areas.  Migration between geographic


 areas, however, generally is expected to reduce the sensitivity


 of geographical studies  as the distinction between exposed


 and unexposed is gradually lost.  As such, the statistical


 power of such studies might be grossly overestimated if migration


 were not taken into account.  The  longer the latency period


 of disease, the larger this dampening effect of migration is


 likely to be.


      As  noted earlier, Polissar (1980)  has estimated that 40-50%


 of the relative excess risk is not reflected in the estimated


 risk for most cancers when rates are compared between exposed


 and unexposed counties and migration has taken place during



 a 30-year  latency period.  This finding is consistent with


 the results reported by, Haenszel et al. (1962), who found that


 the urban/rural gradient  for the standardized lung cancer mor-


 tality ratios (adjusted  for age and smoking) increased with
                               11-88

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                                                             DRAFT
the duration of residence.  The role of urban air pollution
in explaining this trend, however, is unclear because the SMR
for urban residents declined with duration of residence, possibly
reflecting improved survival patterns of the less exposed persons,
or the initiation—promotion phenomenon suggested by Mancuso.
     d.  Population density and other factors
     Demopoulos and Gutman  (1980) labeled a series of cities
as "clean" and "dirty," based on a qualitative characterization
of the nature of the local  industries but not on direct measures
of the nature or intensity of ambient air pollution.  They
concluded that when areas with comparable population densities
were compared, general air pollution (i.e., in "dirty" cities)
and workplace exposure (in regions of heavy industry) were
not associated with cancer risks.  This conclusion led them
to the speculation that much of the urban excess might be due
to higher population density.  However, their designations
of "clean" and "dirty" cities were not related to any measured
distinctions between areas of low and high air pollution.
Their presumption that heavy industries should be more likely
to be associated with cancer risks than light industries may
not be true.  Major carcinogenic hazards have been recognized
in a number of light and service industries.  Thus their char-
acterization of "clean" and "dirty" cities is unsatisfactory
even as a surrogate measure of either air pollution or of occupa-
tional exposure.  Among other problems with this study, no
                              11-89

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DRAFT
      attempt was made to standardize for smoking  or other risk factors,
      and the basis for selecting  the sample of  cities was unclear.
           Population density is strongly correlated with a number
      of other factors and may represent a proxy measure of air pollu-
      tion and a variety of other  variables.  In studying the relation-
      ships between population density,  vehicle  density (as an indi-
      cator of motor vehicle emissions), and total cancer mortality,
      Robertson (1980) concluded that vehicle density rather than
      some other correlate of population density is associated most
      strongly with cancer mortality. Vehicle density, of course,
      implies air pollution from burning fossil  fuels in mobile sources.
      Robertson found that the number of motor vehicles per square
      mile does not increase linearly with population density, but
      levels off in the more densely populated cities where puiDlic
      transportation is often more readily available.  He reported
      that cancer rates do not increase  linearly with city size but
      do appear to be linearly correlated with motor vehicle density.
      Robertson (1980) concluded that "motor vehicles appear to be
      a substantial part of the 'urban factor' in  cancer."  However,
      he failed to control for potential differences in several other
      important factors (such as smoking, occupation, and migration).
      Currently available data are insufficient  to estimate the rel-
      ative contributions of mobile sources and  stationary sources
      of air pollution.  It is likely that in some areas the largest
      source of conventional air pollutants is the automobile  (e.g.,
      Los Angeles) while in others, industrial sources are more
                                    11-90

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                                                              DRAM
portant  (e.g., Charleston, West Virginia).  In their recent
review, Wilson et al. (1980) came to much the same conclusion.
However, the relative contribution of mobile and stationary
sources to atmospheric concentrations of carcinogenic air pol-
lutants is not known.
     In studies where attempts have been made to control for
population density and other confounding factors, the correlation
between such variables as air pollution and population density
may seriously distort the estimated effects of air pollution.
There is some evidence that the onset of population-wide cigar-
ette smoking paralleled industrialization.  If that were the
case, regression analyses that attempt to estimate effects
of air pollution may be distorted by controlling for factors
that are correlated with air pollution.  Air pollution has
also been found to be inversely related to socioeconomic status
(SES) (Bozzo et al. 1979, Lave and Seskin 1977).  Since low
SES groups (who are usually heavier smokers) are exposed to
higher pollution levels than high SES groups, the true effects
of air pollution are likely to be underestimated by controlling
for effects of SES and/or smoking.

F.  Summary
     This chapter summarizes epidemiological studies of cancers
in the human population and their relation to air pollution
and other factors.  Section II.B introduces the four principal
types of epidemiological study and discusses issues that arise
in applying them to the cancer/air pollution problem.  Although
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there is evidence that air pollutants may affect cancers at
a number of anatomic sites, only lung cancers have been studied
in sufficient detail for critical analysis.  Air pollution
is a complex mixture of agents, and most available measurements
are of conventional pollutants which are unlikely to be carcino-
genic in themselves; furthermore, the use of a single component,
such as benzo[a]pyrene, as a surrogate measure of the carcinogenic
potential of polluted air may not be entirely satisfactory.
Significant exposure to some air pollutants occurs in indoor
environments, where monitoring data are scanty.  The long latent
periods for human cancers mean that current cancers should be
associated with exposures in past decades, when some pollutants
were present at higher levels and others at lower levels.
The most pervasive difficulty encountered in the conduct and
interpretation of epidemiological studies is the control of
confounding factors, especially cigarette smoking.  Other prob-
lems that arise include the interpretation of sex and racial
differences in patterns of cancer mortality, the insensitivity
of many studies, and the selection of appropriate comparison
populations.
     Section II.C summarizes source-specific or "neighborhood"
studies.  A number of studies have reported apparent elevations
in cancer rates in the vicinity of industrial facilities of
various types.  Some of these studies were of the large-scale
"ecologic" type, whose results are usually regarded as no more
than suggestive.  Most other studies in this category had sub-
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                                                              DRAFT
stantial limitations, including problems in identifying appro-
priate control populations, in controlling for smoking, occu-
pation, and demographic factors, and in verifying exposure.
The more persuasive evidence of this kind is the finding of
rare types of cancer characteristic of exposure to vinyl chloride
and asbestos near putative sources of these materials, and
the statistical association in several studies between lung
cancer rates and proximity to smelters and other facilities
handling arsenic compounds.
     Section II.D summarizes several studies that suggest.that
migrants from one country to another with higher (or lower)
air pollution levels continue to experience cancer rates charac-
teristic of their native countries.  However, the rigor of
the statistical comparisons of cancer rates is questionable,
and the differences were not related to specific data on exposure
to air pollution.
     Section II.E summarizes urban-rural and other geographical
studies.  Table II-l (Appendix A)  tabulates 44 epidemiological
studies of cancers of the lung and other sites in human popu-
lations.  In 25 of these studies,  a statistical association
was reported between cancer rates  and one or more (direct or
indirect)  measures of air pollution, and most of the rest reported
excess frequencies of cancer in urban areas relative to rural
areas.  Only five studies reported finding no association between
cancer rates and either  urban location or measures of air pol-
                              11-93

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lution.  However, all the studies were subject to various lim-



itations, which complicate their interpretation..



     The most pervasive and difficult problem in these studies



is control for the confounding effects of cigarette smoking.



Ten studies of lung cancer rates in nonsmokers have shown rather



consistent urban-rural differentials in males, but not in females.



However, all but one of these studies were limited by small



sample size, and none was controlled for occupational exposures.



In a number of studies, urban/rural differentials and statistical



associations between cancer rates and air pollution remained



significant after attempts were made to control for the effects



of smoking, using data on smoking habits in cancer victims



or population groups.  However, the completeness of the control



for smoking in these studies is disputed.  Some scientists



have argued that differences in aspects of smoking such as



age at starting to smoke and depth of inhalation cannot be



controlled for.  However, actual data on these aspects of smoking



do not confirm that they would contribute significantly to



urban/rural differentials.



     Only a few studies have been controlled for the effects



of occupational exposures.  One study that was so controlled



revealed significant urban/rural differentials in both occupation-



ally exposed and unexposed groups, after controlling for smoking.



Other studies have suggested interactions between effects of



occupation and air pollution.
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                                                             UKAH
         III.  EXPERIMENTAL EVIDENCE AND MONITORING DATA







A.  Introduction



     This chapter reviews and summarizes the evidence that



air contains substances capable of causing or contributing



to the incidence of cancer in humans.  Monitoring studies have



shown that air contains substances known on the basis of human



and animal studies to cause cancer.  In addition, extracts



of air pollution particulates have been shown to be both muta-



genic and carcinogenic in laboratory studies.



     Air pollutants arise from both anthropogenic and natural



sources, such as vegetation, weathering, and fires.  Air pollu-



tants of anthropogenic origin can be placed in three broad



categories:  vapor-phase organic chemicals, such as volatile



emissions from industrial processes; particulate organic matter,



which includes products of fossil fuel combustion and vehicle



emissions; and inorganic substances, such as compounds of the



metals lead, nickel, and arsenic, and the mineral asbestos.



The amount of vapor-phase organics emitted in the United States



has been estimated to be 1.9 x 10   g/yr, with particulate



organics being one-fiftieth to one-tenth of this amount (Hughes



et al. 1980, citing Duce 1978).  Estimates of the amount of



anthropogenic inorganic pollutants are difficult to make, because



of the wide variety of possible sources and the large contribu-



tion of natural sources to the levels found in ambient air.



Of the three categories of pollutants, however, the particulate
                              III-l

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OftAtf
     fraction of air pollution has been subjected to the most investi-
     gation and is of most concern for long-term human health effects.
     This concern stems from the known biological activity of many
     of the constituents of particulate matter, such as the polycylic
     aromatic hydrocarbons (PAHs), and because particulate matter
     occurs at high local concentrations around sources in populated
     areas.
          A sample of polluted air is a complex and dynamic mixture
     that can contain over 300 compounds.  It can consist of chemicals
     in the vapor or gaseous phase, relatively pure aerosols or
     particulates of specific substances, or heterogenous particular
     aggregates of many substances.  The relative distribution of
     chemicals between the vapor and particulate phases is highly
     dependent upon their source,  their vapor pressure and polarity,
     and the ambient air temperature.  Although particulate matter
     may be thought of as a collection of solid or liquid particles,
     vapor-phase organics may be adsorbed under a range of conditions
     into the particulate content  of polluted air, changing their
     chemical composition (Hughes  et al. 1980).  In addition, air
     pollutants, especially reactive species such as NOX and ozone,
     itself derived from precursor pollutants, can undergo photo-
     chemical or spontaneous reactions to produce new compounds that
     may have more or less biological activity than their precursors.
     All these factors complicate  the identification of the components
     of polluted air and their relation to the biological activity
     that is measured by in vivo or in vitro studies.
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                                                            DRAFT
     An additional consideration in reviewing the experimental



evidence associating air pollution and cancer is the difficulty



in determining the substances and the levels to which people are



actually exposed.  This difficulty stems, first, from problems



in sampling air for pollutants, and second, from the complicated



and largely uninvestigated processes through which inhaled



materials affect humans.  One of the problems in sampling is



that, although some monitoring stations can sample air contin-



uously over long periods of time, most samples are limited



in the period of time over which they are obtained and therefore



may not represent all the pollutants in an area that result



from changing weather conditions and pollution sources.  Also,



sampling is usually performed at roof level or close to a known



source of emissions; neither accurately reflects the air quality



at street level that most people experience.  Although advances



have been made in the design of personal sampling devices to



provide more accurate samples of the air that people breathe,



most of the studies of the biological activity of air pollution



and its chemical characterization have used samples that were



limited in both time and location and therefore may not be



representative of the actual toxicity and content of ambient



air.  In addition, determination of the effect of airborne



substances on human health must consider the physiological



processes that take place between the inhalation of a substance



and the ultimate site of its toxic effect.  The effect of an



inhaled carcinogen depends on its distribution in the lungs,
                              III-3

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its retention and absorption, possible metabolism by lung tissue,



its distribution via the circulation, and the concurrent presence



of irritating substances.  Some studies have investigated these



factors and are discussed below.





B.  Experimental Evidence



     Experimental evidence for the presence of carcinogens



in ambient air has been provided by both in vivo and in vitro



testing of extracts of airborne material.  This testing, however,



has been limited to particulate material.  Because of the volati-



lity, relatively low concentrations, and rapid degradation



of vapor-phase organic substances, no methods are currently



available for collecting of these chemicals from ambient air



and testing them in vivo or in vitro.  The carcinogenicity



of these substances can be assessed by testing them in pure



form at high concentrations, and this type of evidence is dis-



cussed in the section on monitoring data.  The basic approach



to determining the biological activity of airborne particulate



matter is to collect on filters the particulates that are sus-



pended in the air or released from an emission source, extract



this material with organic solvents, and apply the extract



to the test system.



     The composition of these extracts depends on the chemical



and physical nature of the original particulates—specifically,



whether they were homogeneous, aggregates, or contained adsorbed



organic chemicals—and on the ability of the fractionation and



extraction system to solubilize the chemicals that are present.
                              III-4

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                                                           DRAFT
Because of this approach and the dilute nature of air pollution,



the quantity of material available for testing is usually limited.



Researchers have worked around this problem by either making



extracts of more readily available material, such as soot and



tar that condense from combustion emissions, or by using a



small number of animals in assay systems that are sensitive



to carcinogens.  These systems include the painting of test



material on the skin of mice, injection into neonatal mice,



and instillation into the lungs of hamsters and rats.  Alterna-



tively, researchers have tested extracts in cell cultures that



are capable of detecting chemicals that cause mutations or



cell transformation although they do not directly measure car-



cinogenic activity.  Both phenonomena are considered predictors



of carcinogenic potential.





1.  In Vivo Tests of Extracts of Air Pollution for Carcinogenicity



     As mentioned above, the dilute nature of air pollution



limits the amount of material available for in vivo testing.



In the earliest studies, investigators prepared extracts of



soot, coal tar (a condensate resulting from the combustion



of coal under low oxygen conditions), and particulate matter



and applied them repeatedly to the skin of mice.  In a review



of these studies, Shabad (1960)  cited several investigations



in which skin tumors and adenomas of the lung were induced



by extracts of coal tar.  Also,  when dichloroethane extracts



of soot were painted on mice three times weekly, papillomas



(benign skin tumors) appeared after 10 weeks, metastasizing
                              III-5

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'RAFT
   in 37% of the animals to sites in the lungs and lymph nodes
   (Shabad 1960).  Shabad also reported that extracts made from
   airborne participates induced malignant tumors in 8% of the
   test animals when the same protocol was used.
        In another dermal application study, Hoffman (1964) applied
   to the skin of female mice an acetone solution that contained
   12.5% organic matter from an extract of polluted air that was
   measured as having 20 yg of organic material per m .  After
   9 months, 23 of the 30 mice had developed multiple papillomas,
   and 10 had carcinomas; after 3 more months of treatment, a
   total of 19 of the mice had malignant tumors.  Animals in a
   group that were being concurrently treated with a solution
   of a mixture of PAHs at a concentration equal to that of the
   air extract had 4 tumors, half of which were malignant.  Another
   group painted with an equivalent amount of BaP did not develop
   any tumors.
        Gasoline engine condensate (GEC) and diesel exhaust conden-
   sate  (DEC) were examined for carcinogenicity in a skin-painting
   study with female CFLP-mice (Misfeld 1980).  In addition to these
   materials, BaP and a mixture of 15 PAHs at the same proportions
   as found in GEC were tested.  Each material was tested at three
   concentrations in 80 mice per concentration.  GEC, DEC, BaP,
   and the PAH mixtures all gave positive responses with positive
   dose-response relationships.  The largest response given by
   GEC was 83% in the high concentration group.  DEC gave a high
   response of 13%.  It was calculated that GEC was 42 times as
                                 III-6

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                                                            DRAFT
potent as DEC, and the PAH mixture only accounted for 41% of
the GEC activity.  Calculations indicated that BaP contributed
9.6% and 16.7% of the activity found in GEC and DEC, respectively.
     Most recently, Nesnow et al. (1982) investigated the tumor-
initiating and tumor-promoting abilities of extracts of emissions
from automobiles with gasoline and diesel engines, from a coke
oven, from roofing tar, and from a residential furnace that
burned diesel fuel.  The animals used were Sencar mice, which
have been bred for their sensitivity to dermally applied carcino-
gens and are widely used in studies of the mechanism of carcino-
genesis.  The collected emissions were extracted with dichloro-
methane, which was removed by evaporation, and the resulting
material was applied as a solution in acetone in one or more
of four protocols in doses ranging from 100 to 10,000 yg/mouse.
Under the tumor initiation protocol, each dose was applied
once topically, followed after 1 week by twice weekly applica-
tions of the tumor promoter, tetradecanoylphorbol-13-acetate
(TPA).  To determine the ability of the extracts to act as
complete carcinogens, samples were administered weekly for
50 weeks.  Under the tumor promotion protocol, the mice were
treated with one dose of BaP and then weekly for 34 weeks with
the sample.  To test for cocarcinogenic activity, both the
test material and BaP were applied initially, followed by TPA
twice weekly.
     These studies indicated that BaP and extracts from emissions
of coke ovens, roofing tar, and one type of diesel-powered
                              III-7

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automobile were potent initiating agents.  The emissions from
the other diesel automobiles and the gasoline engine automobile
showed some initiating activity.  BaP, coke oven emissions,
and roofing tar emissions were also shown to be complete car-
cinogens.  None of the diesel emissions from the automobiles
or furnace gave positive results in the complete carcinogenesis
assay; the authors hypothesized that this result may have been
due to the cytotoxic effect of these extracts when applied
chronically.  BaP and coke oven and roofing tar emissions also
showed tumor-promoting ability; none of the diesel extracts
was tested in this protocol.  Because of the positive results
for BaP in all the protocols, the authors considered that the
activity of the emissions extracts may have been due to their
BaP content.  However, analysis of the samples for BaP and
comparison of these values to tumor-initiating ability indicated
that the BaP content did not account for all the activity of
the extracts.
     Depass et al. (1982) have also recently reported results
of their skin-painting study.  In this study, the initiating,
promoting, and complete carcinogenic activity of diesel exhaust
particulate  (DP) and dichloromethane extracts of diesel exhaust
particulates  (DCM) were examined using C3H strain mice.  The
study was to end with the death of all mice, but the reported
interim results covered 714 days of treatment with mice still
living in most groups.  The mice were treated with two concen-
trations of DP and four concentrations of DCM for the complete
                              III-8

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                                                             DRAFT
carcinogenesis study, one concentration of DP and two concen-
trations of DCM for the promotion study, and one concentration
of each for the initiation study.  Along with the specific
control groups, there was a total of 18 different groups consist-
ing of 40 mice each.
     In the study on complete carcinogenesis of DP and DCM,
only one tumor was found in a treated mouse.  This mouse was
in the high-dose DCM group.  Slight response was also seen
in the promotion study; one animal in each DCM dose group had
a squamous cell carcinoma, and a second low-dose DCM animal
had a papilloma.  Three mice in the DP and DCM groups had tumors
in the initiation study.  Tumors, however, were found in one
acetone-initiated control group mouse and two phorbol 12-myristate
13-acetate (PMA) initiated control group mice.  PMA was used
as a promoting agent for the promotion study.  The difference
in response between the studies of Depass et al. (1982)  and
Nesnow et al.  (1982) may have resulted from a difference in
the source of test substances, a difference in mouse strain
or sex, or a difference in treatment regimen.
     Extracts of polluted air have also been administered to
test animals by subcutaneous injection.  Hueper et al. (1962)
prepared benzene extracts of city air, concentrated them by
evaporation, and injected 1% (w/v) solutions into C3H or C57
mice monthly for periods of up to 2 years.  This treatment
induced local tumors in 2-18% of the animals, the latency period
being from 9 to 24 months.  These results were, however, dis-
                              III-9

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DRAFT
      torted by substantial mortality in the test group because of



      the toxicity of the extracts.  Epstein et al.  (1966) developed



      a more sensitive assay, giving neonatal mice one to three injec-



      tions of the test material during the 1st week of life and



      sacrificing the animals up to 1 year later.  Extracts of air



      particulates still caused mortality in the test group, but



      the survivors developed hepatomas, lymphomas, and solitary



      and multiple pulmonary adenomas at rates significantly greater



      than those for the control group.



           In a later study, Rigdon and Neal (1971) collected air



      pollutants in the vicinity of petrochemical plants, made benzene



      extracts, and injected these once into 30- to 50-day-old CFW



      mice.  They observed the animals for up to 1 year, noting when



      tumors appeared.  The treatment induced as much as a 60% inci-



      dence of local, nonmetastatic fibrosarcomas.  This rate was



      greater than that resulting from the injection of mice with



      an amount of BaP equal to that in the extracts.  This suggested



      to the authors that multiple carcinogens or cocarcinogens were



      present in the extracts.



           Asahina et al.  (1972) used Epstein's neonatal mouse assay



      to test 10 fractions of an extract of New York City air.,  Sig-



      nificant increases in the number of tumors, including pulmonary



      adenomas and lymphomas, were found for four of the fractions.



      More recently, Epstein-et al.  (1979) reported a dose-response



      relationship between total tumor incidence and the cumulative



      total dosage of the extracts injected into mice.  The extracts,
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                                                             DRAFT
which were found to contain PAHs, quinolines, and acridines,



induced solitary and multiple pulmonary adenomas and lymphomas



in both sexes and hepatocellular carcinomas in males.



     More recently, Pott et al.  (1980) collected airborne partic-



ulate matter from urban and rural locations, prepared organic



solvent extracts, and analyzed fractionated extracts for BaP



and other PAHs.  The extracts were then injected subcutaneously



and chronically into mice in a range of doses based on BaP



content.  Extracts with BaP contents of 0.37-1.1 yg induced



tumors at rates up to 30%, and a dose-response relationship



was seen with the fractions that predominantly contained PAHs.



Other fractions, containing primarily polar substances, had



some carcinogenic activity.



     A few investigations have been performed to test the capa-



city of fractions of polluted air to induce cancer in lung



tissue.  In these experiments, the test material was instilled



into the trachea of anesthetized animals from which it is easily



distributed into the lung.  Bogovski et al. (1970)  reported that



a benzene extract of oil shale soot containing 0.01% BaP induced



lung cancer in rats after this type of intratracheal instillation.



Mohr (1976) instilled a condensate of automobile exhaust into



the trachea of hamsters at 2-week intervals for 30 or 60 weeks.



The condensate, which contained a small amount of BaP (1.7 ug/ani-



mal), induced pulmonary adenomas in all the hamsters, a response



the author could not attribute to the BaP content alone.  In



a similar study, Kommineni and Coffin (1976) applied a gelatin
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DRAFT;
       suspension of air particulates, BaP, or participates and BaP



       to the trachea of hamsters once a week for 8 weeks.  All three



       groups showed progressive and severe inflammatory changes in



       the lungs; the third group, which was treated with the particu-



       lates and BaP, showed evidence of the formation of bronchial



       polyps.  In addition to these studies, researchers at the Health



       Effects Research Laboratory of the U.S. Environmental Protection



       Agency are completing studies of the effects of the long-term



       inhalation of diesel exhaust in mice and hamsters (Pepelko 1980).



            The studies of the biological activity of extracts of



       air pollution in animals do not provide data that are directly



       applicable to predicting health effects in humans.  Differences



       in the routes of exposure and the use of high concentrations



       limit the extent to which the results may be extrapolated to



       human exposures, while the toxic, noncarcinogenic, effects



       of the extracts limit the sensitivity of the tests to detect



       carcinogenesis.  In summary, however, they do indicate that



       ambient air, or materials released into air, contain compounds



       that by themselves or acting together have the ability to induce



       cancer in mammals.





       2.  In Vivo Studies of Irritant Effects of Particulates



            The ultimate effect of an inhaled carcinogen, which may



       be in the form of particles or adsorbed on particulate material,



       depends on several interrelated factors:  the distribution



       of the carcinogen in the lungs, its  retention and absorption,



       and the concurrent presence of respiratory irritants.









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                                                            DRAFT
     The size of a particle determines the extent to which



it penetrates the respiratory tract.  In nasal breathers, parti-



cles from 12.5 nm to 2.5 ym in diameter are capable of penetra-



tion of the alveolar region of the lungs.  Particles greater



than 2.5 ym in diameter are mostly removed in the nasal chambers,



and those less than 12.5 nm remain suspended in tidal air and



are exhaled (Kotin 1968, Shannon et al. 1974).  Studies have



also shown that retention of particulate matter in the lungs



is greatest at 1.0 ym in diameter and falls off sharply for



sizes greater than 2 ym or less than 0.25 ym  (Kotin and Falk



1963).  For mouth breathing the size of particles deposited



in the alveolar region of the respiratory tract can be up to



10 ym.  In addition, particles up to 15 ym may be deposited



in the tracheobronchial portion of the respiratory tract.



Clearance of very large particles in the alveolar region is



slower than for smaller particles (USEPA 1982).  Polluted urban



air contains particles in the range of 12.5 nm-2.5 ym; particles



of this size are also produced by the burning of solid fuels



and are present in the exhaust of gasoline and diesel engines.



Particle size may also influence the rate and extent of elution



of carcinogenic chemicals from the particles on which they



are adsorbed.   Falk and Kotin (1962) found that the lower size



limit for PAH release from particles in physiological conditions



in vitro was 100 nm in diameter.  Therefore, particles from



100 nm to 10 ym in diameter are probably of the greatest biolo-



gical significance, because they can readily penetrate and
                             111-13

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;FT
  be retained in the respiratory tract and adsorbed carcinogenic
  substances can be released.
       The role of the penetration and retention of particles
  in the lungs in inducing cancer has been investigated in a
  number of studies.  Inhaled ferric oxide (Fe2o3)  dust is an
  example of particulate material that, although not carcinogenic
  to laboratory animals by itself (Gilman 1962), enhances the
  effects of known carcinogens.  This observation was initially
  made by Saffiotti et al. (1968, 1972a,b) in studies in which
  ferric oxide particles and various carcinogens were concurrently
  instilled into the tracheas of hamsters.
       Feron et al. (1972) showed that the tumorigenic effect of
  diethylnitrosamine in the hamster respiratory tract was increased
  by a factor of 3 when instilled in hamsters with ferric oxide
  particles in solution.  This enhancing action of the ferric oxide
  particles has been attributed to their ability to increase the
  penetration and retention of carcinogenic substances that are
  bound to them.  This possibility was investigated by Sellakumar
  et al. (1973), who reported that adhesion of fine particles
  of BaP to equal-sized particles of ferric oxide was critical
  for tumor induction by intratracheal instillation.  Without
  the physical adhesion to the ferric oxide dust, much higher
  doses of BaP were needed to induce tumors in hamsters.
       Henry et al. (1975) confirmed these results and, by micro-
  scopic comparison of the lungs from the hamsters treated with
  ferric oxide particles coated with BaP to the lungs of those
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                                                           DRAFT
administered a mixture of the dust and the carcinogen, determined
that the particles of the mixture were removed from the lungs
more rapidly.  However, other studies have shown that the ability
of injections of the carcinogen diethylnitrosamine to induce
lung tumors in hamsters was increased by the tracheal instilla-
tion of ferric oxide particles  (Montesano et al. 1970, Nettesheim
et al. 1975).  These results suggest that the particles may
have a tumor-promoting effect in addition to enhancing carcinogen
penetration and retention.
     In addition to ferric oxide, other particulates have been
shown to enhance the action of carcinogens.  Studies have shown
this effect with BaP and particles of asbestos (Miller et al.
1965, Pylev and Shabad 1972), titanium oxide, aluminum oxide,
carbon (Stenback et al. 1976), and india ink (Pylev 1963).
The mechanism of these actions is unknown; Lakowicz and Hylden
(1978) demonstrated, however, that asbestos fibers increase
the lipid solubility of BaP, and hence could increase its cellular
uptake.
     Respiratory irritants present in polluted air also may
increase the carcinogenic effect of airborne substances by
changing the function and structure of the respiratory epithelium
and increasing their retention.   These irritants interfere
with ciliary activity and with the flow of the mucous stream.
Air pollutants that act as irritants to the lining of the respir-
atory tract include sulfur oxides, nitrogen oxides, ozone,
chlorine, ammonia, pollen, and allergens (Kotin 1968).  Laskin
                              111-15

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DRAFT
        et al.  (1970) demonstrated in rats that simultaneous inhalation
        of the  respiratory irritant sulfur dioxide and the carcinogen
        BaP resulted in the production of squamous cell carcinomas
        of the  lung.  Experiments performed by Richters et al. (1979)
        suggested that exposure to respiratory irritants also increased
        metastasis to the lung.  The authors injected melanoma cells,
        which readily metastasize to the lung, into mice that had been
        exposed for 10 weeks to an atmosphere containing nitrogen dioxide
        at 0.4  ppm.  At 10 and 21 days after infusion, the exposed
        animals showed significantly more melanoma nodules in the lungs
        than did the controls, which had breathed filtered air.

        3.  In Vivo Mutagenicity and Genotoxicity Testing
             The mutagenicity and genotoxicity of air pollutants, most
        notably diesel exhaust, have been studied in several animal
        models.  These in vivo tests are usually short term, and their
        use of  the whole animal is an obvious advantage over in vitro
        assay systems.  In addition, the test compound may be adminis-
        tered by appropriate routes.  These in vivo assays, however,
        usually are less sensitive and quantitative than in vitro assays
        where the cells come into direct contact with known amounts
        of test compound.
             In a series of genotoxicity studies on diesel and gasoline
        exhaust, as well as coke oven and roofing tar emission, several
        investigators used a variety of in vivo tests, which included
        the sex-linked recessive lethal test on Drosophila melanogaster,
        metaphase analysis, micronuclei assay, sperm morphology assay,


                                      111-16

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                                                            DRAFT
sister chromatid exchange assay, chromosomal abnormalities



assay, and a liver foci assay.



     Schuler and Niemer (1980) examined the effect of exposure



to Nissan diesel engine exhaust gases in producing sex-linked



recessive mutatations in Drosophila melanogaster.   The flies were



exposed to a five-fold dilution of exhaust gases for 8 hours.



The exposed male Oregon-R strain flies were mated with Muller-5



strain females.  Two broods of the F- generation and one F^



generation brood were examined for sex-linked recessive muta-



tion.  No mutagenic activity was observed.  The authors pointed



out that a more thorough assessment would necessitate testing



at higher exposure doses.



     Pereira et al. (1980a) examined the genotoxicity of diesel



engine exhaust in female Swiss mice using metaphase analysis



and a micronuclei assay.  The mice were exposed for 8 hours



per day, 5 days per week, for 1, 3, and .7 weeks.  The exhaust was



diluted 18-fold and contained a final particulate concentration



of 6-7 mg/m .   Bone marrow cells were used for the metaphase



analysis, which involved examination of cells in metaphase.



This assay can identify compounds capable of breaking chromosomes



and chromatids.  Only the animals exposed for 7 weeks were



examined, and no effects were observed.  The micronuclei assay



was done on animals at all three exposure periods.  Polychromatic



erythrocytes in bone marrow were examined.  This assay can



also detect chromosome breakage and disruption of the spindle



apparatus.  At all three exposure periods, no significant increases
                             111-17

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in micronuclei were found.  BaP was used as a positive control



in these studies and was given at a dose approximating that



expected in the diesel exhaust.  In both assays BaP was also



negative, suggesting that the sensitivity of these assays was



too low for the exposure conditions.



     Pereira et al. (1980b)  also conducted a micronuclei assay



using Chinese hamsters exposed to diesel exhaust for 8 hours



per day for 6 months.   In this study they found a significant



increase in the percentage of polychromatic erythrocytes with



micronuclei.  The difference found between the mouse and hamster



study was not explained.  In the same study with hamsters,



chromosomal abnormalities in bone marrow cells were also examined.



As in the mouse metaphase analysis, no increase in chromosomal



abnormalities was observed.



     In addition to the other two assays, Pereira et al.  (1980b)



conducted a sister chromatid exchange (SCE) bioassay with the



bone marrow from the exposed hamsters.  SCE are produced because



of DNA lesions induced by mutagens and may be related to recombi-



national or postreplicative repair of DNA damage.  In this



study there was no significant change in the frequency of SCE.



There was, however, a decrease in the mitotic index.  Guerrero



et al. (1980) examined SCE in lung cells of Syrian hamsters



treated by either intratracheal instillation of one dose of



diesel exhaust particles at 0-20 mg/animal or by inhalation



exposure to diesel exhaust with a 6 mg/m  particle concentration



8 hours a day for 3 months.   Twenty-four hours after the intratra-
                              111-18

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                                                            DRAFT
cheal instillation or following the 3-month inhalation exposure,



the animals were killed, and primary lung cell cultures were



established.  When the cultures had colonies of 50 cells or



more, SCE analysis was performed.  A positive dose-response



relationship was found for intratracheal doses between 0 and



20 mg/animal.  Animals exposed by inhalation to diesel exhaust



had no increase in SCE.  When the total amount of particles



that were expected to be inhaled by the latter group of animals



was calculated and compared to the amount administered by intra-



tracheal instillation, it was found to be below the levels



that gave positive responses by intracheal instillation.



     It has been shown that exposure of mice to known mutagens



and carcinogens leads to an increase in the frequency of abnormal



sperm.  Pereira et al. (1980c) exposed male strain A mice to



18-fold diluted Nissan diesel exhaust with 6 mg/m  particle



concentration for 31 or 39 weeks; these time periods represent



approximately six and eight complete spermatogenic cycles.



No detectable changes in sperm morphology were found at either



time period.  Pereira et al.  (1980b) also examined sperm shape



abnormality in Chinese hamsters exposed to diesel exhaust for



6 months.  In this study there was a significant increase in



abnormal sperm.  The authors caution that this result was obtained



from a small group and should be viewed as preliminary.



     Pereira et al.  (198-Od) also used a rat liver foci assay



to examine the genotoxicity of diesel exhaust.  This assay



is similar to the two-stage mouse skin model for carcinogenesis.
                             111-19

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DRAFT
      Rats  were  given  a partial  hepatectomy  to enhance  the  rate of



      cell  proliferation  and  then were exposed to diesel exhaust



      emissions  for  3  or  6 months.  During exposure the rats were



      fed a choline-devoid diet, inducing a  dietary deficiency that



      acts  as  a  promoter.  At 3  or  6 months  the  rats were sacrificed,



      and their  livers were histologically examined for foci of hepa-



      tocytes  containing  gamma glutamyl  transpeptidase.  Gamma glutamyl



      transpeptidase is used  as  a marker for  cancerous  hepatocytes.



      No  increase  in foci was detected after  3 or 6 months  of exposure.





      4.  In Vitro Tests  of Extracts of  Air  Pollution



           Extracts  of polluted  air and  of air emissions have been



      tested for mutagenic and genotoxic activity in a  wide range



      of  in vitro  systems.  These tests  are  performed more  quickly



      and inexpensively than  whole  animal studies and can utilize



      effectively  the  small amounts of test  material usually available



      in  air pollution extracts.  In addition, a large  number of



      fractions  of the extracts  that have been separated on the basis



      of  chemical  structure or particle  size, can be tested concur-



      rently,  allowing for the identification and isolation of the



      substances responsible  for the mutagenic or genotoxic activity.



      Direct extrapolation of the results of in  vitro tests to poten-



      tial  human health effects  is  not yet possible, although several



      studies  have been performed that have  established a high degree



      of  correlation between  mutagenic and carcinogenic activity



      for some classes of chemicals.
                                   111-20

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                                                            DRAFT
     Of the wide range of in vitro tests, those that have been



used in testing air pollutants can be placed in four groups.



Gene mutational assays utilize bacterial or mammalian cell



cultures to detect single or multiple base changes (mutations)



in genes.  Larger scale damage to the DNA, in the form of DNA



strand breaks and exchanges between chromosomes, is detected



in assays using cultured hamster embryo cells, liver cells,



hamster ovary cells, and mammalian (human) lymphocytes.  The



ability of chemicals or extracts to cause aberrations in chromo-



somes, such as breaks, deletions, and translocations, is tested



in both hamster cells and human leukocytes.  Transformation



assays measure the degree to which substances can alter normal



cultured cells to states in which they more closely resemble



cancer cells.



     Transformation of cells in culture is considered analogous



to transformation of cells in vivo.  These transformed cells



in culture may have morphological and biochemical traits similar



to cancer cells.  Most important, when a cell that has been



transformed in culture is implanted in a syngeneic host, it will



form a tumor.  A variety of cells has been used in transformation



assays, including cells from established cell lines and cells



freshly isolated.  There are actually two types of cell transfor-



mation assays.  In one assay, the test compound produces the



transformation while in the other assay, the test compound



enhances a virally induced transformation of the cell.  This



latter assay is considered more sensitive than the first one.
                             111-21

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Both these assays give results that correlate well with the
results of other tests for carcinogenesis and rnutagenesis.
     Several studies of these types have been conducted with
extracts of air pollution and emission particulate.  Freeman
et al. (1971) tested benzene extracts of the city air particu-
lates for their capacity to transform rat and hamster embryo
cells in culture.  Transformation was considered complete if
the cells treated with extracts formed tumors when transplanted
into neonatal mice.  The authors found that the extracts did
not transform rat embryo cells but did transform cells that
had previously been infected with Rauscher leukemia virus.
In these cultures of virus-infected cells, the extracts were
600 times more effective in inducing transformation than an
equal amount of pure BaP.  In addition to the results seen
in rat embryo cells, the extracts transformed both infected
and uninfected hamster cells.  The infected hamster cells were
as sensitive as the virus-infected rat cells; the uninfected
cells were one-tenth as sensitive as the virus-infected rat
cell cultures.
     In another study, Gordon et al. (1973) first removed the
PAHs by benzene extraction from particulates collected from
Los Angeles air.  The residue was further extracted with methanol,
and this fraction was tested for transforming ability in cell
cultures of Fischer rat. embryos or Swiss albino mouse embryos.
(The mouse cells, but not the rat cells, had been infected
with leukemia virus.)  Results were positive in both systems,
                              111-22

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                                                         DRAFT
indicating to the authors that non-PAH carcinogens were present
in the extract.
     Curren et al. (1981) investigated the transforming activity
of dichloromethane extracts of participates from several types
of diesel engines, a gasoline engine, and coke oven and roofing
tar emissions.  They used the BALB/c 3T3 cells in their assay
systems, which included or excluded the metabolic-activating
system from rat liver.  Several of the extracts showed signifi-
cant transforming activity, but no clear dose-response relation-
ships were found.  The metabolic-activating system reduced
the transforming activity of some extracts and did not greatly
increase the activity of any extract; this suggested that there
were direct-acting agents in the extracts.  The most potent
extracts came from coke oven emissions and the gasoline engine.
These were followed by extracts from a Nissan light diesel
engine exhaust and then roofing tar emission.  Essentially
no activity was found in extracts of exhaust from an Oldsmobile
light diesel engine and a heavy diesel engine.
     Using the same extract material, Castro et al. (1981)
were unable to show any transforming activity in their assay
system using Syrian hamster embryo cells.  However, when the
cells were first infected with simian adenovirus SA7,  several
extracts were capable of enhancing the viral transformation
of the cells.  Ranking the extracts according to the lowest
effective concentration shows that extract of roofing  tar emis-
sion >coke oven emission >cigarette smoke condensate >Nissan
                             111-23

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light diesel engine >a gasoline engine and a VW diesel engine.
Extract from the Oldsmobile light diesel engine and the heavy
diesel engine had little or no activity.
     Many other assays have been developed to identify carcino-
genic compounds using mammalian cell cultures.  Several of
these assays have been used to examine the genotoxic or mutagenic
activity of diesel engine particulate exhaust extracts and
extracts of particulates from other emission sources.  Mitchell
et al. (1981) used L51784 mouse lymphoma cells to examine the
mutagenicity of these extracts.  The assay was done with and
without a metabolic-activating system.  All extracts tested
gave positive results in the presence and absence of the meta-
bolic-activating system, indicating the presence of direct-
acting mutagens in the extracts.  Extract of the gasoline engine
exhaust emission was the most potent extract tested.  Castro et
al.  (1981) examined the same extracts for mutagenicity using
Chinese hamster ovary cells.  In this system, extracts of emis-
sions from the Nissan and Volkswagen diesel engines, the gasoline
engine, and coke oven were positive.  Unlike the results of
Mitchell et al.  (1981) with mouse lymphoma cells, extracts
of emissions from a heavy diesel engine, the Oldsmobile light
diesel engine, roofing tar, and cigarette smoke were not found
to be mutagenic.  Curren et al.  (1981) used mouse BALB/c 3T3
cells in a mutagenicity assay and found extracts of emissions
from roofing tar, the Nissan light diesel engine, the gasoline
engine, and coke oven to be mutagenic, and the heavy diesel
                              111-24

-------
                                                        DRAFT
engine and the Oldsmobile light diesel engine not to be muta-
genic.
     Using Syrian hamster embryo cells, Castro et al. (1981)
examined whether the extracts would cause DNA fragmentation.
This type of damage induced by chemical agents correlates fairly
well with their carcinogenic potential.  Only coke oven and
gasoline engine emission extracts caused detectable breakage
of the cellular DNA.
     Mitchell et al. (1981) examined whether these extracts
would increase sister chromatid exchanges (SCE)  in Chinese
hamster ovary cells.  Without metabolic activation, all extracts
tested showed some activity.  Coke oven emission and Nissan
light diesel engine exhaust extracts were the most active.
     Lockard et al. (1981)  examined whether extracts from air-
borne particulates would increase SCE in human lymphocytes
or V79 fibroblasts from Chinese hamster lungs.  They used extracts
from samples of airborne particulates, collected over a 5-month
period on the campus of the University of Kentucky in Lexington.
There was a linear dose-related increase of SCE in human lymphocytes
with 60-80 yg of extract necessary to induce a doubling in
the number of SCE.  Several extracts that were positive with
human lymphocytes failed to induce an increase of SCE in V79
cells, however, other extracts did cause an increase.  BaP
was used as a positive control and increased SCE in both cell
types.  The increase of SCE in human lymphocytes by BaP did
not occur in the presence of a metabolic activating system,
                             111-25

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DRAFT
    although, BaP generally needs to be metabolically activated
    to be effective.  The amount of BaP, 8 ug,  needled to induce
    a doubling of the SCE in these cells was much more than was
    likely to be in the extracts.  Therefore, the extracts must
    have contained active compounds other than BaP.
         The most widely used gene mutational assay in testing
    extracts of air pollution is the Ames assay (Ames et al.  1973,
    1974) , which measures the rate at which special, strains of
    the bacteria, Salmonella typhimurium, mutate or revert to a
    less specialized form.  The assay uses either the test material
    directly or the test material in combination with a biochemical
    preparation of liver or lung tissue that metabolizes the test
    material, thereby testing for the possibility of in vivo genera-
    tion of mutagens.  The correlation of positive results in the
    Ames assay with positive results in long-term carcinogenicity
    assays has been found to be Detween 30% and 90% depending on
    the class of chemical being tested  (McCann et al. 1975, Commoner
    et al. 1976).  A recent international study with 42 chemicals
    found the false positive rate, i.e., the rate at which a positive
    result was obtained for a noncarcinogen for bacterial assays,
    to be 5-10% (Bridges et al. 1981).
         Gene mutational assays have been used to test air pollu-
    tion from a number of sites and sources.  Using the Ames assay,
    investigators have detected mutagenic activity in extracts
    of particulates from residential and urban air (Talcott and
    Wey 1977, Pitts et al. 1977, Tokina et al.  1977, Commoner et al.
                                  111-26

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                                                           DRAFI
1978, Teranishi et al. 1978, Salamone et al. 1979, Moller and
Alfheim 1980, Lockard et al. 1981, Tokiwa et al. 1980, and
Walker et al. 1982), in fly-ash from coal-fired power plants
(Fisher et al. 1979), in particulates collected from air in
tunnels (Ohnishi et al.  1980), and in exhaust from gasoline-
and diesel-powered automo biles (Ohnishi et al. 1980, Wang et
al. 1981, Huisingh 1981, and Lewtas 1982).  One study (Tokiwa
et al. 1977) reported higher mutagenic activity in samples
taken from an industrial area than in samples from a residential
area.  In most of the studies, a linear dose-response relation-
ship was observed between the amount of material tested and
mutagenic activity (Tokiwa et al.   1976, Tokiwa et al. 1977,
Pitts et al. 1977, Teranishi et al. 1978, Commoner et al. 1978,
Salamone et al. 1979, Moller and Alfheim 1980, Ohnishi et al.
1980, Walker et al. 1982).
     Because the extracts of air pollution are composed of
a heterogenous mixture of substances, it is unlikely that the
mutagenic activity can be attributed to a single chemical or
class of chemicals.  Most of the tests, however, have indicated
that the airborne mutagens cause the same type of mutation.
Tokiwa et al (1977),  Teranishi et al. (1978), Salamone et al.
(1979), Moller and Alfheim (1980), Ohnishi et al. (1980), Claxton
(1980), and Walker et al. (1982) have reported the highest
activity of their samples were in the Salmonella strains most
sensitive to frameshift mutations.
                              111-27

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DRAFT
           BaP and other  PAHs  have been identified  in extracts of
      air pollutants by Talcott and Wei (1977),  Tokiwa et al.  (1977),
      Commoner et al.   (1978),  Dehnen et al.  (1978),  Salamone  et al.
      (1979),  Moller and  Alfheim (1980), Ohniski et al.,  (1980),  and
      Tokiwa et al.   (1980).   Several studies  have  indicated that
      PAHs require metabolic  activation by the liver  tissue preparation
      to have  a mutagenic effect (Wislocki et  al.  1976,,  Wood et al.
      1976).  Talcott and Wei  (1977)  found that 75% of the mutagenicity
      of their urban air  samples was due to an enzyme-activated frac-
      tion; this activity was  substantially reduced when an inhibitor
      of the PAH-metabolizing  enzymes was added to  the culture.
      Moller and Alfheim  (1980), Lockard et al.  1981, and Salamone
      et al. (1979), however,  found extracts from their  air pollutant
      sample usually gave similar results with and  without a metabolic-
      activating system.
           Pitts et al. (1980)  recently demonstrated that BaP deposited
      on a glass fiber filter  in the presence of ambient levels of
      ozone is transformed to strong mutagens in the Ames test.
      This suggests that  airborne BaP may not always require metabolic
      activation to exert a carcinogenic effect, but that is chemically
      activated in the atmosphere by ozone.  On the other hand, the
      finding indicates that  some mutagens found in the particulate
      extracts may be artifacts of the method of collection and,
      as indicated below, direct-acting mutagens are found in the
      extracts.
                                    111-28

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                                                           DRAFT
     Analyzing air samples from residential areas, Talcott
and Wei (1977), Holier and Alfheim (1980), Salamone et al. (1979),
and Tokiwa et al. (1977)  observed mutagenic activity that did
not require enzyme activation.  In later research, Wang et al.
(1978) found that the lead content of extracts of non-industrial
airborne particulates correlated well with mutagenic activity,
suggesting to the authors that the source of the mutagens was
vehicular emissions.  Further, they detected direct-acting
mutagens in extracts of automobile exhaust, although they did
not isolate the compound or compounds responsible.  Wang et al.
(1980) found that extracts from diesel exhaust particulates
were mutagenic and that the mutagenicity of the extract was
not dependent on metabolic activation by liver homogenate.
They actually showed that this activity was reduced by addition
of the homogenate.  The reduced activity was found not to be
from enzymatic activity but from nonspecific binding of the
mutagens to the protein in the homogenates instead of the DNA
of the bacteria.  They showed that glutathione, a natural con-
stituent of the body that can bind to electrophilic compounds,
reduced the mutagenicity of the extract, thus suggesting that
the mutagens are direct alkylating agents.  Claxton (1980)
also found that the majority of the mutagenic activity in extracts
of diesel exhaust was direct acting.   Mutagens in gasoline
engine exhaust extracts were partially direct acting, but meta-
bolic activation did increase the mutagenic activity of the
extracts.  Whether any of the direct-acting mutagenic activity
                             111-29

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DRAFT
     discussed  here  is  artificial  because  of  the method  of  collection



     is  not  known  this  makes  assessments of the extracts more  diffi-



     cult.



          In a  study designed to determine the size  of the  particles



     associated with airborne mutagens, Talcott and  Harger  (1979)



     detected the  highest  activity in  particles less than 2 urn in



     diameter and  found that  this  fraction contained alkylating



     agents. Fisher et al.  (1979)  and Tokiwa (1980)  also compared



     particle size and  mutagenic activity. Fisher et al.  (1979)



     found that fly-ash particles  of  3.2 urn diameter had the greatest



     mutagenic  activity, and  Tokiwa et al. (1980) found  the highest



     mutagenic  activity and PAH content  in particles with diameter



     of  0.3-1.0 urn.   Particles of  these  sizes readily penetrate



     lung  airways  (Kotin 1968).





     C.  Monitoring  Data



          A number of substances known to  cause cancer in humans



     or  laboratory animals have been  detected in ambient air.   These



     substances include PAHs, aza-heterocyclic compounds, vinyl



     chloride,  asbestos, metals, pesticides,  N-nitroso compounds,



     carbon tetrachloride, and many other  industrial chemicals.



          Table III-l (in  Appendix B)  is a compilation of suspected



     and known  carcinogens found in air  pollution.   This list  contains



     PAHS,  pesticides,  and inorganic  compounds



          The presence  in  air"of some  of the  suspected or known



     carcinogens listed in Table III-l has not been  established



     by  monitoring,  but is highly  probable.   These compounds are









                                  111-30

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                                                            DRAFT
used in industry or are industrial by-products; because of



their volatility or association with fume-producing processes,



they are likely to enter the air.  Alkylating agents such as



bis(chloromethyl)ether and chloromethyl methyl ether are potent



carcinogens in rodents (Laskin et al. 1971, Leong et al. 1971)



and humans (Albert et al.  1975, Lemen et al. 1976, Pasternack



et al. 1977,  Sakabe 1973).  The presence of these substances



in ambient air has not been determined, but the stability of



bis(chloromethyl)ether in moist air is at least 18 hours (Collier



1972), a period of time long enough for human exposure to occur.



     The presence of carcinogenic substances in the ambient air



strongly suggests that humans are exposed.  However, monitoring



data alone are generally inadequate to determine the extent



of exposure of individuals.  Given that the average person



inhales from 10 to 20 m /day of air, one can estimate the quan-



tity of the inhaled material to be in the microgram to milligram



range.



     Particulate air pollution is an important contributing



source of known and suspected carcinogens in the air.  In addi-



tion to the organic compounds, particulate air pollution contains



arsenic, beryllium, cadmium, chromium, lead, nickel, and asbestos.



As discussed in a review of particulate air pollution by USEPA



(1982), there is a multimodal distribution in the size of the



particulates.  Particles less than 0.1 urn are in the nuclei



(Aitken) mode and typically originate from combustion sources.



These particles are short-lived because of coagulation of the
                              111-31

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;£•*. £T
T..MS !
    particles  into particulates  with  the size  of  0.1-2.5  ym;  the



    newly formed  particles  are considered to be  in the  accumulation



    mode.   Particles  making up these  two modes are termed fine



    particles.  The final category is of particles greater than



    2.5  ym,  making up the coarse mode.   These  particles are usually



    derived  from  mechanical processes or wind  erosion and are not



    usually  formed to any great  extent from fine  particles.  Fine



    particles,  because of their  long  residence time and atmospheric



    formation,  can build up far  from  their source while coarse



    particles  normally occur only near strong  source emissions.



         As  a  general historical perspective,  total suspended parti-



    culate in  New York City in the early 1960s contained  10%  or



    less benzene-soluble organic material.  Control programs  put



    into effect between the early 1960s and mid  1970s produced



    a substantial reduction in total  suspended particulates.   With



    the  reduction of  particulates there was a  marked decrease in



    the  concentration of benzene-soluble organics and trace elements



    (USEPA 1982).



         A large  number of  gaseous air pollutants are suspected



    or known carcinogens.   The concentrations  of  these  compounds



    are  usually harder to measure than those associated with particu-



    lates because of the difficulty in collecting sufficient amounts



    to quantify.   Singh et  al.   (1982) has recently reported the



    results of a  3-year study on gaseous air pollutants.   They



    measured 44 different  organic chemicals in 10 cities  throughout



    the  United States.  In  general they found  a  number  of known
                                  111-32

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                                                             DRAFT
bacterial mutagens and suspected carcinogens.  Most of the
compounds measured were in the subparts per billion concentra-
tion, although concentrations of aromatic hydrocarbons and
formaldehyde averaged 5-20 ppb.  The concentrations of anthro-
pogenic compounds were generally one or two orders of magnitude
higher in urban air than in rural or clean remote air.  Diurnal
variations were observed and depended on source strength and
prevailing meteorology.  Afternoon mixing led to sufficient
dilution to produce minimum concentrations of several primary
pollutants.  Photochemical pollutants showed maximum concentra-
tions in the afternoon.

D.  Multimedia Exposure
     In addition to exposure to airborne carcinogens by inhala-
tion, studies of the environmental distribution of air pollutants
indicate that human exposure can also occur through routes other
than inhalation.  There is evidence that some substances released
into the air, if unaltered chemically, ultimately end up in soil
and water or on plants, including edible plants.
     Arsenic and lead have been studied for their environmental
distribution.  Lindau  (1977) found arsenic in drinking water
(0.08-3.0 yg/liter), soil (5-15 mg/kg), and vegetables and
grains (0.1 yg/g).  Levels measured in the vicinity of a copper
smelter were 500 yg/liter (water), 30 mg/kg  (soil), and 0.06
yg/g (barley).  Levels were considerably lower in samples taken
40 km from the plant.  Studies in 32 areas of the United States
showed a correlation between the amount of lead in rainfall


                              111-33

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RA.FT
    in a given locality and the amount of gasoline used  in  theit
    locality  (Lazrus et al. 1970).  Numerous other studies  have
    demonstrated an inverse relationship between the lead content
    of grasses and soil and their distance from highways  (NAS  1972a).
    Studies of crop plants indicated that, although the  lead content
    of exposed parts was proportional to air lead concentreitions,
    the levels of lead in the seeds and roots  (the edible portions)
    were unaffected (Motto et al. 1970).  After review of this
    and other studies, the Committee on Lead in the Human Environment
    of the National Academy of Sciences concluded that most of
    the lead content of plants, possibly as much as 90-99%,, origin-
    ates from atmospheric pollution.  They added, however,  that
    this estimate cannot be applied yet to crop plants,  or  to  the
    edible portions of crop plants  (NAS 1980).
         Kotin and Falk  (1963) demonstrated that BaP is  stable
    in the atmosphere, both in its crystalline form and  when it
    is adsorbed on soot.  Lunde and Bjorseth (1977) showed  that
    BaP can be transported long distances in the eiir.  In the  United
    States, BaP was found in higher concentrations in soil  around
    petroleum and chemical plants  (Menck et al. 1974); in the  Soviet
    Union, it was found in higher concentrations in soil around
    airfields, coke ovens, and oil refineries  (Shabad 1980).   Accord-
    ing to Shabad (1980), levels of BaP in water in the  Soviet
    Union are also higher in industrial areas.  Santodonato et
    al.  (1981) summarized multimedia human exposure to polycyclic
    aromatic hydrocarbons  (PAH), Table III-2.
                                  111-34

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                                                       DRAFT
                           TABLE III-2

                 ESTIMATED HUMAN EXPOSURE TO PAH
                   FROM VARIOUS  AMBIENT SOURCES
                             (yg/day)
Source
Air
Water
Food
BaP
0.0095-0.0435
0.0011
0.16-1.6
Carcinogenic
PAHa
0.038
0.0042
b
Total
PAH
0.207
0.0270
1.6-16
aTotal of BaP, BjF, and indeno[1,2,3-cd]pyrene

 No data available

SOURCE:  Sandodonato et al. 1981


     Atmospheric deposition of PAH onto food and into water

cannot be considered the only source of PAH exposure via these

routes since food preparation and local effluent sources may

add to PAH levels.


E.  Summary

     This chapter compiles and summarizes experimental evidence

and monitoring data.  A substantial number of studies has shown

that extracts of airborne materials from polluted air and mate-

rials emitted from motor vehicle engines and stationary sources

are frequently carcinogenic and mutagenic when tested in experi-

mental bioassay systems.  Results of in vivo tests have included

the induction of skin cancers, lymphomas, fibrosarcomas, liver

tumors and lung tumors in mice,  lung tumors in rats and hamsters,
                             111-35

-------
DRAFT
   and  chromosome  damage  and  sister  chromatid exchange  in hamsters.



   Respiratory  irritants  present  in  polluted air may  also enhance



   the  effects  of  other carcinogenic agents.  Results of in vitro



   tests  have included the  induction of point mutations in bacteria



   and  Drosophila  melanogaster, malignant  transformation of mammalian



   cells  in  culture,  and  sister chromatid  exchange  and  DNA fractiona-



   tion in cultured mammalian cells, including human  cells.  Positive



   results in these in vitro  tests are generally correlated with



   the  potential  for  carcinogenicity.



       Table III-l  (in Appendix  B)  lists  more than 50  chemicals



   that have been  detected  in ambient air  and that  are  known or



   suspected to be carcinogenic in humans  or in experimental anL-



   mals.  Where comparative data  are available, concentrations



   of  these  chemicals tend  to be  higher in urban areas  than in



   rural  areas, and higher  still  in  industrial emissions.  There



   is  evidence  of  significant multimedia exposure  to  several pol-



   lutants after  their release into  ambient air.
                                111-36

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                                                            DRAFT
                   IV.  QUANTITATIVE ESTIMATES

A.  Introduction
     Chapters II and III have reviewed the qualitative evidence
for an association between air pollution and cancer rates.
This chapter reviews and summarizes estimates of the possible
magnitude of this association—i.e., the number of cancers
that might be "attributable" to exposure to air pollution.
It should be emphasized that quantitative estimates of this
kind can be made (with caution, of course) even if the qualita-
tive evidence for the association is not regarded as fully
conclusive.  The "softer" the evidence that is used the wider
is the possible range of resulting estimates.  The question
addressed in this chapter is the following:  If air pollution
is a causative factor in human cancer, what estimates can be
made of the fraction of human cancers to which it contributes?
     It should be emphasized that the word "contributes" in
this question does not imply that air pollution would operate
independently as a single causative factor.  As emphasized
earlier, most cancers have multiple causes, and there is evidence
that air pollution may act in conjunction with other factors
to increase the risk of cancer.  Some reviewers have recognized
this by assigning a certain fraction of cancers to more than
one causative factor.  One way that has been used to develop
estimates of the fraction of cancers "attributable" to air
pollution is to "subtract out" the effects of other factors.
                              IV-1

-------
DRAFT
    This is almost certain to lead to underestimation of the contri-
    bution of  air  pollution,  by subtracting out the cancers attributa-
    ble to the joint action of these other factors with air pollution
    and attributing them solely to the other factors.

    B.   General Estimates
         Because of the limitations inherent in the epidemiologic
    studies,  estimates of what percentage of human cancers may
    be  attributable to air pollution have been the subject of dis-
    agreement.  Several participants in the recent. EPA rulemaking
    cited estimates by Higginson and Muir (1979,  1976)  and Wynder
    and Gori  (1977) that no more than one percent of total cancer
    deaths are attributable to air pollution.   The data on which
    these estimates are based were not fully described, but these
    estimates  appear to be "subtracted out" estimates,  since in
    both reviews the fractions of human cancer rates attributed
    to  various factors add up to 100%.  Hence, these authors impli-
    citly excluded multiple causation.
         The  most extensive recent review of data providing evidence
    for associations between  cancer and environmental factors is
    that of Doll and Peto (1981).  In the conclusion of their review
    (Table 20), they proposed 2% as the "best estimate" of the
    percentage of all cancer  deaths attributable to pollution of
    all kinds, with a "range  of acceptable estimates"  extending
    from less  than 1% to 5%.   Although the basis for these figures
    is  not completely clear,  they appear to have been based on
    the estimates of Pike et  al. (1975) and Cederlof et al. (1978),
                                  IV-2

-------
                                                            DRAFT
both of which were cited for the conclusion that urban air
pollution (as characterized by BaP) might have contributed
to about 10% of lung cancer in big cities, i.e., about 1% of
all cancers in the country as a whole.  The effects of industrial
emissions were regarded as negligible, and cigarette smoking
was considered sufficient to account for most, if not all,
of the patterns of variation in lung cancer rates, including
urban/rural differences.  A critique of this secondary review
paper is presented in Appendix E.
     Shy and Struba (1982) presented another review of the
scientific evidence on air pollution and cancer.  While citing
some of the epidemiologic and experimental evidence reviewed
in this report, they concluded that "firm conclusions about
air pollution and lung cancer are simply not warranted by the
current state of knowledge."  Although they did not make quanti-
tative estimates of the possible magnitude of the association,
they discussed attempts to estimate the risks from exposure
to BaP by linear extrapolation from data on occupationally
exposed workers, and concluded that such extrapolation "would
support an extremely low risk (0.1 to 0.01 of a two to threefold
excess)  for ambient air."  A risk of this magnitude would consti-
tute between 1% and almost 20% (between 0.01(2-1)  and 0.1(3-1))
of all lung cancers, and thus would fall within the range of
other estimates discussed in this chapter.  Further comments
on Shy and Struba1s review are presented in Appendix E.
                              IV-3

-------
DRAFT
    C.   Estimates Based on Analysis of Epidemiologies! Data

         A number of investigators have attempted to derive estimates

    of  the quantitative relationship between lung cancer rates

    and air pollution, using BaP and other substances as indices.

    Although we believe that BaP has become less and less useful

    as  an indicator of generalized air pollution over time, we

    report 12 published estimates:

         •  NAS (1972b) based on the data of Carnow and Meier (1973)

         •  Pike et al. (1975)  based on the data of Doll et al.
            (1965, 1972)

         •  Pike et al. (1975)  based on the data of Stocks (1957)

         •  Wilson et al.  (1980)  reviewing estimates of Pike et
            al. 1975

         •  Pike and Henderson (1981)

         •  Lave and Seskin (1977)

         •  Doll  (1978)

         •  Cederlof et al. (1978)

         •  Wilson et al.  (1980)  based on the data of Hammond et al.
            (1976)

         •  Wilson et al.  (1980)  based on a review of several of
            the above estimates

         •  CAG (1978)

         •  CAG (1982)

         We also present an independent estimate, based on analysis

    of data of Hammond and Garfinkel  (1980), as reassemoled by

    Goldsmith  (1980), and not based on BaP levels.   (The data cited

    by Hamrtond and Garfinkel on ambient levels of pollutants were

    based on observations made after the mortality from lung cancer
                                   IV-4

-------
                                                             DRAFT
had occurred.  These after-the-fact data are not used in our

independent computation.)

     An earlier review by the National Academy of Sciences'

Committee on Biologic Effects of Atmospheric Pollutants  (NAS

1972b) laid out the argument for using BaP as an air pollution

indicator:

        It appears, then, that there is an "urban factor"
    in the pathogenesis of lung cancer in roan.  The poly-
    cyclic organic molecule mentioned most prominently
    in this report has been benzota]pyrene.  It was felt
    that benzota]pyrene could be used as an indicator
    molecule of urban pollution, implying the presence
    of a number of other polycyclic organic materials of
    similar structure that may also have some carcinogenic
    activity.  The standard measure of benzol a]pyrene con-
    centration in the air is the number of micrograms per
    1,000 m  of air.  On the basis of epidemiologic data
    set against information regarding the benzo[a]pyrene
    content of the urban atmosphere, one can develop a
    working hypothesis that there is a causal relation
    between air pollution and the lung cancer death rate
    in which there is a 5% increase in death rate for
    each increment of urban air pollution.  In this study,
    an increment of pollution corresponded to 1 ng of
    benzo[a]pyrene per 1,000 m  of air.  On the basis
    of this assumed relation, a reduction in urban air
    pollution equivalent to 4 benzo[a]pyrene units (i.e.,
    from 6 tig/1,000 m  to 2 ng/1,000 m )  might be ex-
    pected to reduce the lung cancer death rate by 20%.
    These data, however, are not to be interpreted as in-
    dicating that benzol a]pyrene is the causative agent
    for lung tumors.  There is much to support the idea
    of synergism or cocarcinogenesis, especially with
    respect to cigarette smoking.  In addition, the car-
    cinogenic significance of other polycyclic organic
    molecules in urban air pollution should be determined.

                                    (NAS 1972b, p.  246)

     However, BaP seems to have become less useful, with time,

as a general indicator of air pollution.   A recent review of

problems associated with air pollution (Karolinska Institute

Symposium on Biological Tests in the Evaluation of Mutagenicity
                              IV-5

-------
HRMT
      and Carcinogenicity of Air Pollutants, 1982) ,  scheduled for

      publication in Environmental Health Perspectives (major authors,

      Lars Freiberg and Norton Nelson)  came to the conclusion:

          At the present time there is no way to quantitate
          how changes in air pollution levels may have reduced
          mortality from lung cancer because there has been
          a lack of a completely reliable indicator  of air
          pollution carcinogenicity.

      The Karolinska 1982 review repeated the conclusions of an earlier

      review (Cederlof 1978)

          combustion products of fossil fuels in ambient air,
          probably acting together with cigarette smoke,  have
          been responsible for cases of lung cancer  in large
          urban areas, the numbers produced being of the order
          of five-ten cases per 100,000 per year

      and indicated no basis for any revision in the conclusions

      drawn by NAS (1972b) in view of current data.   Five to 10 cases

      per 100,000 per year is about 6 to 15% of all  lung cancer cases.

           There is evidence that BaP levels have decreased in the

      United States (CEQ 1980) in the past 20 years, without a propor-

      tional decrease in all other air pollutants—thus currently

      making BaP a poor index of trends in air pollution levels.

      In 1958-59, the median level of BaP measured in urban air was
                  •3                  O
      about 6 ng/mj (range, 1-60 ng/m ), and that in rural air was

      about 0.4 ng/m3 (Sawicki et al. 1960).  By the mid-1960s the

      median level at urban sites was reduced to 3.2 ng/m , and by

      the mid-1970s it was reduced to below 1.0 ng/m'1 (Wilson et

      al. 1980, CEQ 1980, Shy and Struba 1982).  Although earlier

      measurements are not available for the United  States, Shy and

      Struba (1982) suggested that levels in the 1930s and 1940s
                                    IV-6

-------
                                                              DRAFT
would have been several-fold higher.  Wilson et al. (1980)
cited data compiled by Ludwig et al. (1971), which showed that
dustfall rates declined by a factor of about 2 in Pittsburgh,
Cincinnati, and Chicago between 1935 and 1958, and by the same
factor in New York City between 1945 and 1958.  Since much
of the dustfall in these urban areas was associated with incom-
plete combustion of fossil fuels in these periods, dustfall
rates may provide a surrogate measure of likely changes in
BaP levels.  However, there was no marked change in dustfall
rates between 1958 and 1966, a period in which the data cited
above suggest a substantial decrease in BaP levels.  Levels
of BaP in the United Kingdom in the mid-1970s were several
times higher than in the United States, probably in the range
of 3-5 ng/m3 (Lawther 1980, Wilson et al. 1980).
     One consequence of the changes in BaP levels since the
1950s (or earlier) is that differences between regions (e.g.,
between urban and rural areas) have been reduced (CEQ 1980),
so that associations between air pollution (as measured by
BaP)  and cancer rates are more difficult to demonstrate.   Compar-
ison of cancer rates with contemporaneous BaP levels is likely
to overestimate the strength of the relationship between them,
because cancer rates are actually influenced by exposures 20
or more years earlier, when BaP levels (and differentials)
were higher.  Also, as discussed in Section II.B.S.d., levels
of other carcinogenic components of ambient air have probably
increased, while those of polynuclear aromatic hydrocarbons
                              IV-7

-------
(of which BaP serves as an index) have decreased.  Hence, apply-
ing the relationship of cancer rates to BaP levels at some
time in the past will overstate the BaP effect per unit dose
and will underestimate the hazards posed by present-day ambient
air, and hence will underestimate the contribution of present-day
exposures to future cancer risks.
     Recognizing these difficulties, we have summarized in
Table IV-1 the estimates made by others of the dependence of
lung cancer rates on BaP levels.  Most of these estimates were
obtained by linear regression techniques (i.e., calculation
of the linear relationship between differentials in lung cancer
rates and differentials in BaP levels).  Hence, the dependence
of lung cancer rates on air pollution levels is expressed in
units of incremental lung cancer rate per ng/m  of BaP.
     The 13 estimates reviewed above are listed in the second
column of Table IV-1.  In comparing these estimates, it. should
be recognized that they fall into two categories that are not
strictly comparable.  The estimates by GAG (1978, 1982), Pike
et al.  (1975) based on data of Doll et al. (1965, 1972), Pike
and Henderson (1981), and Wilson et al.  (1980) based on delta
of Hammond et al.  (1976) , were based on  studies of workers
occupationally exposed to products of incomplete combustion.
In these studies BaP was used as an index of exposure to these
products.  The remaining estimates were  based primarily  (or
entirely) on studies of the general population exposed to ambient
air, and used BaP as an index of exposure to a wider mixture
                               IV-8

-------
                          DRAFT








































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IV-9

-------
DRAFT
        of materials.  The fact that the worker studies yield lower



        estimates of dose-response coefficients (0.1-0.8 x 10   )  than



        the population studies  (0.8-5.0 x 10"^) (p<0.01, Mann-Whitney



        test) suggests that products of incomplete combustion may be



        associated with only a part of the excess of lung cancers in



        urban areas, thus making BaP a poor indicator of total  air



        pollution.



             The principal limitation in quantifying the population



        studies is that they all relate cancer deaths observed  in the



        period 1959-1975 to BaP levels measured or estimated for  the



        period 1958-1969.  If levels of BaP and related products of



        incomplete combustion were higher in the 1930s and 1940s  (more



        coal-burning emissions, but fewer automobiles), these studies



        would overestimate the dose-response coefficient between lung



        cancer rates and BaP levels.  As an illustration of the likely



        magnitude of this effect, we present in the third column of



        Table IV-1 adjusted estimates of the dose-response coefficient,



        derived by assuming that the effective population exposure to



        polluted air for cancers developing in the 1960s and later was



        in the period 1935-45, and that levels of BciP at that period



        (using dustfall rates as a surrogate index of likely BaP  levels,



        as discussed above) were about twice those measured in  the early



        1960s.  For the estimates based on European studies  (Lave and



        Seskin 1977, Doll 1978~, Cederlof et al. 1978), the figures in



        the second column were based on a value of 3.5 ng/m  for  the



        urban-rural differential in BaP levels, which was appropriate
                                      IV-10

-------
                                                               DRAFT
for the mid-1970s.  We have adjusted these European figures
by a factor of 4 to account for the assumed reduction in BaP
levels since the period 1935-45.  Estimates based on studies
and occupationally exposed workers have not been adjusted.
     To place these estimates of dose-response relationships
in quantitative perspective, the last two columns in Table IV-1
present calculations of the number of lung cancer deaths that
could be attributed to air pollution characterized by 6.4 ng/m
of BaP.  This is approximately twice the average level of BaP
to which the U.S. population was exposed in the mid-1960s,
and hence is the average level of BaP to which we have assumed
the U.S. population was exposed in the period 1935-45.  The
figures in the last two columns of Table IV-1 are derived by
multiplying the "adjusted" dose-response coefficients in the
third column by 6.4 ng/m3.  These figures give estimates of
the number of lung cancer deaths in the 1960s (per 100,000,
expressed as a percentage of total U.S. lung cancer deaths in
1975; this percentage is an understatement of the percentage
of deaths in the 1960s related to BaP exposure)  attributable
to air pollution levels in prior decades.  The estimates based
on studies of the general population fall into the range between
2 and 8 deaths/year per 100,000 people, or between 5% and 20%
of the lung cancer rates in the mid-1970s.  The estimated median
from these population studies is 4.5 deaths/year per 100,000,
or about 11% of the almost 90,000 lung cancer deaths in the
United States in 1975.
                              IV-11

-------
DRAFT5
             These estimates of the contribution of BaP-indexed air
        pollution to lung cancer rates in the 1960s are not sensitive
        to changes in our assumption about BaP levels in the period
        1935-45.  If we had assumed a higher figure for average BaP
        levels in that period, our estimates of adjusted dose-response
        coefficients in the third column of Table IV-1 would have been
        lower, but the multiplier used to derive the estimates in the
        last two columns would have been correspondingly higher.
               Despite the relative stability of these estimates, they
        unfortunately cannot be used to generate reliable estimates
        of the future effects of present air pollution, or even to
        make firm estimates of the contribution of past air pollution
        to current cancer rates.  This is because BaP is not a stable
        index of the carcinogenicity of polluted air.  Although the
        general population exposure to BaP and to other products of
        incomplete combustion has decreased considerably since the
        1950s, it appears unlikely that the carcinogenicity of polluted
        air has decreased in direct proportion.  The fact that BaP
        levels relative to other air pollutants have changed with time
        implies that all the estimates in Table IV-1 are time-dependent,
        and unfortunately cannot be used to predict the future conse-
        quences of present-day air pollution using BaP levels as a
        surrogate for all air pollution.
             Despite these limitations, each of the studies listed
        in Table IV-1 is considered in more detail below.
                                      IV-12

-------
                                                               DRAFT
     Carnow and Meier (1973) estimated the risk of lung cancer

mortality by relating 1960 deaths to 1968 levels of BaP.  Wilson

et al. (1980) reduced this estimate (NAS 1972D) by half to

1.0 death/10^ persons per ng/m^ of BaP.  Wilson cited monitoring

data from 28 sites in 1959, which seemed to indicate that levels

of BaP had declined.  There are few data on levels of BaP before

1966, and it is not possible to establish whether or not Wilson

et al.'s correction was appropriate.  The more complete monitoring

data available from 1966 to 1977 indicate that levels from

1966 to 1969 were steady or slightly increasing (CEQ 1980)

and then declined.  Thus, we do not know whether or not Wilson

et al.'s correction of Carnow and Meier's estimate is the same

as the adjustment we have applied in Table IV-1 to allow for

likely reduction in BaP levels prior to 1959.  For this reason,

either of the two adjusted estimates may be appropriate.

     Pike et al. (1975), assuming a linear relationship between

exposure and carcinogenic response, extrapolated the results

of a study of gas workers by Doll et al. (1965, 1972) to the

general population:

    The carbonization workers were exposed to an estimated
    2,000 ng/nr BP 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/nr BP
    general air pollution.  This exposure caused an
    extra 160/10  lung cancer cases, so that we may
    estimate, assuming a proportional effect, that each
    ng/nr BP causes 0.4/10b (160/105 divided by 440)
    extra lung cancer cases per year.   A city with 50
    ng/m  BP air pollution might, therefore, have an
    extra 18/10  lung cancer cases per year.  These
    numbers are not negligible, although they are small
    when compared, say, to smoking a pack of cigarettes

    every da*'              (Pike et al. 1975, p. 231)
                            IV-13

-------
DRAFT
         Thus,  based  on the  experience of carbonization workers,  Pike

         et al.  (1975)  estimated the risk of lung cancer mortality as
                      C                 -3
         0.4 deaths/10   persons  per  ng/m° of BaP.

             Wilson  et al.  (1980)  reexamined this estimate by Pike

         et al.  (1975)  and  included  a doubling factor  to correct  for

         the fact that  the  gas workers were not exposed for all of their

         lives,  leading to  an estimate of 0.8 deaths/10  persons  per

         ng/m  BaP.   However, neither Pike et al. (1975)  nor Wilson

         et al.  (1980)  made  any  further adjustment for the fact that

         the gas workers were not all followed up to their deaths.

         Because the  incidence of human lung cancers increases in propor-

         tion to the  4th or  5th  power of age (or duration of exposure)

         the possibility exists  that Pike et al. (1975)  and Wilson et al.

         (1980)  have  underestimated  the full lifetime  cancer risks,

         probably by  a  factor of 3 or more.  For example, comparing

         exposures beginning at  birth, and continuing  for a lifetime

         with industrial exposures beginning at age 20 and assuming

         a  73-year life span, implies a ratio of (73/53)4=3.6).  Thus

         Pike et al.'s  original  estimate may be as low as one-sixth

         or one-seventh of  the appropriate estimates.   However, we have

         not amended  either  estimate to take account of this factor.

             Pike et al.  (1975)  also used the data of Stocks (1957)

         to obtain a  second  estimate.

             Second,  there  should be an increased lung cancer
             rate in  high PAH-polluted areas [25]; the effect
             is magnified in most studies when we consider the
             joint effect of urbanization and cigarette smoking.
             Table 2  presents data [26]  comparing rates in Liver-
             pool to  those  in rural  North Wales.  This study
                                     IV-14

-------
                                                                DRAFT
    by Stocks was done in an area of "stable" air pollu-
    tion.  A fair summary of these data  is that the
    urban effect produces an excess of 28/10  lung cancer
    deaths in nonsmokers and 100/10  such deaths in
    smokers, the latter figure being independent of
    the actual amount smoked.  We might  refer to this
    increase as a modified additive effect.  The differ-
    ence in BP levels in the air between the two areas
    was estimated to be 70 ng/nr (77 ng/nr compared
    to 7 ng/mj); thus, we may very crudely estimate
    the air pollution effect in the presence of cigarette
    smoking at 1.4/105 per ng/m  BP or 0.4/10  per ng/m
    BP in nonsmokers (Table 3).

                                          (at pp. 231-232)

Based on the prevalence of smoking in the United States in

the recent past (i.e., approximately one-third of all adults

are smokers), this estimate leads to a risk of lung cancer

mortality of 0.8 deaths/10  persons per  ng/m3 of BaP.  (If

based on earlier smoking habits, this estimate would be higher;

Wilson et al. (1980) listed this estimate as 1 death/105 persons,

possibly because it was based on past smoking habits.)  This

estimate may be low, if, as appears likely, the estimated average

difference in BaP levels between urban and rural areas is great.

     Pike and Henderson (1981) estimated the quantitative rela-

tionship between lung cancer risks and exposure to cigarette

smoke (data from various sources),  coke  oven emissions (data

from Lloyd 1971 and Redmond et al.  1972), and hot pitch fumes

(data from Hammond et al.  1976).  They calculated that exposure

to about 15 ng/m3 BaP could be equated to smoking 1 cigarette/day,

and hence estimated the "single cause lifetime risk" of lung

cancer to age 70 resulting from ambient  air exposure to 1 ng/m

BaP as 73x10  .   This corresponds to an  age-standardized lung

cancer rate of about 0.8x10   deaths/year per ng/m  BaP.
                              IV-15

-------
     Carnow (1978) suggested a number of factors that may have

led Pike et al. (1975) to an underestimation of risk.  Albhough

Pike et al.'s estimates of the risk of lung cancer mortality

may be low, it is likely that the ratio of 3.5 in risk between

smokers and nonsmokers (1.4/0.4 = 3.5) is reliable, although,

3.5 is lower than the usual estimates of the relative risks

of smokers.  The difference (3.5) was reported by Wilson et

al. (1980) to be statistically significant.  This difference,

plus some reasonable assumptions, permits estimation of the

average risk to the general population from data on males alone

(see Appendix D).  The general population excess is about 82%

of the male excess.

     Based on extensive regression analyses of lung cancer

mortality and air pollution levels, Lave and Seskin  (1977)

suggested that

    ... if the quality of air of all boroughs  (England)
    were improved to that of the borough with  the best
    air, the rate of death from lung cancer would fall
    by between 11 and 44 percent.

This corresponds to 4.4-17.6 deaths/10  persons at British

levels of pollution (assumed to be 3.5 ng/m  of BaP) or 1..3-

5.0 deaths/10  persons per ng/m  of BaP.

     Doll  (1978) estimated that the risk of lung cancer mortality

attributable to urban air pollution in Europe  was no more than

10 deaths per 10^ smokers and no more than 5 deaths per 10  non-

smokers.  Based on current U.S. smoking habits, this estimate

corresponds to 6.7 deaths/10  persons or 1.9 deaths/10"' persons

per ng/m  taking average levels of BaP to be 3.5 ng/m   in Europe.
                              IV-16

-------
                                                              DRAFT
Doll (1978), however, provided data to indicate that levels

of BaP ranged much higher than 3.5 ng/m  in highly urban areas

of Britain.   Doll (1978) also estimated the attributable risk

in smokers to be twice the risk in nonsmokers, which is lower

than the 3.5-fold ratio derived by Pike et al. (1975).  However,

it is not possible to ascertain whether the former is too high

or the latter is too low since the ratio cited by Doll (1978)

was a personal estimate of the author and not based on any

specific calculation or data.  No data were cited to support

Doll's estimates of attributable risk.

     Cederlof et al.  (1978), summarizing the conclusions of a

conference on air pollution and long-term health effects, stated:

    Combustion products of fossil fuels in ambient air,
    probably acting together with cigarette smoke, have
    been responsible for cases of lung cancer in large
    urban areas, the numbers produced being of the order
    of 5-10 cases per 100,000 males per year [European
    standard population].  The actual rate will vary
    from place to place and from time to time, depending
    on local conditions over the previous few decades.  (at p.9)

This estimate was a synthesis of material presented at a con-

ference, and the basis for it was not provided in detail.

Taking the risk to the general population as 82% of the risk

to males (see Appendix D) and average European levels of BaP

as 3.5 ng/m-*, this estimate corresponds to 1.2-2.4 deaths/10

persons per ng/m  BaP.

     The Carcinogen Assessment Group  (CAG 1978) of the Environ-

mental Protection Agency reviewed a number of epidemiological

and animal studies in an attempt to estimate the "excess lung

cancer incidence" resulting from lifetime exposure to polycyclic
                              IV-17

-------
DRAFT
      organic compounds.  For their overall estimate, CAG  (1978)

      took the geometric mean of the estimates derived from four

      epidemiologic studies.  (Using the geometric mean produces

      lower estimates than using the arithmetic mean.  If  risk is

      linearly related to exposure, the arithmetic mean is more appro-

      priate.)  This overall estimate was expressed as 0.28% excess

      lung cancer "incidence" (a slight misnomer since all the studies

      were mortality studies) per ng/m  of BaP.  As a percentage,

      this estimate is a ratio of the estimated excess lung cancer

      mortality rate to the background rate.  This would correspond

      to about 0.11 deaths/10  persons per ng/m3 BaP.

           By expressing the estimate in this way, CAG (1978) assumed

      that the effect of exposure to each ng/m  of BaP is  dependent

      on the background rate of lung cancer mortality in the exposed

      population.  This means that if the background rate  is high,

      the effect would be large, but if the background rate were

      low, there would be little or no effect.  It is reasonable
                                      /
      to expect that the magnitude of the effect attributable to

      BaP will vary as a function of the presence or absence of sub-

      stances  (such as cigarette smoke or other carcinogenic air

      pollutants) that interact with BaP in the induction  of cancer.

      However, it is not clear why this variation should otherwise

      depend on the background mortality rate of lung cancer.

           In 1982, CAG  (1982) updated one of the 1978 estimates.

      Reviewing the results of epidemiological studies of  workers

      exposed to coke oven emissions, they estimated that  the unit
                                    IV-18

-------
                                                                DRAFT
risk (for males) of dying from lung cancer as a result of a
                                                _c         3
working lifetime of exposure to BaP is 9.25 x 10   per ng/m
                                                      «. t:
of BaP.  This corresponds to a rate of about 0.14 x 10 3 deaths/year
per ng/mg  of BaP.  However, this estimate is not comparable with
some others in Table IV-1, because it was calculated exclusively
for exposure to products of incomplete combustion (as indexed
by BaP), whereas others were calculated for air pollution (as
indexed by BaP) with other pollutants assumed to be present
in proportion to the BaP values.  The latter type of calculation
includes the effect of compounds of air pollution other than
products of incomplete combustion (such as asbestos and synthetic
organic chemicals), whereas CAG's 1982 estimate does not.
CAG's 1978 estimate appears to have included and averaged esti-
mates of both types.
     Wilson et al.  (1980) derived an estimate of lung cancer
mortality of 0.2 x 10  per ng/m  BaP using the data of Hammond
et al.  (1976)  on a group of roofers and waterproofers working
with pitch and asphalt.  The estimate appears to be too low,
primarily because the comparison group was made up of other
members of the workers' own trade union, and this would tend
to underestimate the risk if other members of the trade union
were already at increased risk of lung cancer, as seems likely
from other occupational studies.
     The estimates made by Carnow and Meier (1973) ,  Pike et
al. (1975), Hammond et al. (1976), CAG (1978), and some animal
studies of benzo[ajpyrene, assembled by Wilson et al. (1980)
                              IV-19

-------
DRAFT
         indicated that the effect of BaP in the animal studies is much
         less than the "enhanced" effect attributable to BaP from occupa-
         tional or urban epidemiological studies.  The arithmetic mean
         of the estimates from the epidemiological studies led Wilson
         et al. (1980) to what they called a "best estimate," of 0.5
         deaths/10  persons per ng/m  of BaP.  There are several problems
         with this "best" estimate, not least of which was that sevesral
         of the separate estimates (Carnow and Meier 1973, Pike et al. 1975,
         and Hammond et al. 1976) appear to have entered Wilson's calcula-
         tions more than once.
              The estimates derived by CAG (1978) differ from those made
         by Wilson et al.  (1980)  (in their Table 5-4) from the same
         studies.  For example, Wilson et al. (1980) estimated the Carnow
         and Meier (1973) respcr.je coefficient as 1.0 death/10  persons
         per ng/m  of benzo[a]pyrene.  CAG (1978) reduced this estimate
         to less than one-tenth of the figure estimated by Wilson et
         al. (1980).  Also, as indicated earlier, the estimate of Pike
         et al. (1975) based on the data of Doll et al. (1965, 1972)
         was modified by Wilson et al. (1980) to 0.8 deaths/10  persons
         per ng/m  of BaP.  In the CAG (1978) analysis, this figure
         was given as 0.57 deaths/10  persons per ng/m  of BaP (160/10
         divided by 283 ng/m  of BaP) and then converted to a percentage
         by dividing by an anomalously high background rate of lung
         cancer mortality  (0.57/1Q5 divided by 200/105=0.285%).  This
         final CAG estimate is close to CAG's overall figure of 0.28%
         and converted to 0.12 deaths/10  persons by Wilson et al.  (1980)
                                       IV-20

-------
                                                               DRAFT
(0.28% x 40 deaths/105 persons = 0.11/105).  (Note that Wilson

et al. used a background rate of 40/10  persons, while CAG

used a background rate of 200/10  persons—a five-fold differ-

ence.  The age-adjusted mortality rate in the United States

for all respiratory cancers—i.e., lung cancer plus others—

was 45.9/105 persons in 1979.)

     The last estimate listed in Table IV-1 was developed for

this report and takes account of criticisms and suggestions

made concerning earlier estimates (Clement 1981, Karch and

Schneiderman 1981).   The detailed derivation of this estimate

is given in Appendix E.  The estimate follows from the lung

cancer mortality data of Hammond and Garfinkel  (1980)  as reas-

sembled by Goldsmith (1980), standardized for age and smoking,

stratified by occupational exposure and location of residence.

These data show significant effects of urban residence and

occupational exposure independently,  and.we calculate an attrib-

utable risk of 13% for occupationally exposed and 12% for non-

exposed categories.   It is likely that these figures are biased

downwards (possibly by factors between 1.4 and 3.3, as discussed
 Both Hammond and Garfinkel (1980)  and Goldsmith (1980) expressed
 the opinion that these data did not show a convincing effect
 attributable to air pollution.  However, neither set of authors
 analyzed the data in the way presented here (in Appendix E)
 to test the effect of urban residence.  Hammond and Garfinkel
 (1980) reported no statistical association between lung cancer
 rates in the 1960s and measures of air pollution that were made
 in 1968.  They apparently assumed that no change in pollution
 (relative or absolute) had taken place between the 1940s—when
 the cancer cases that appeared in the 1960s were initiated—
 and 1968 when their two air pollution measures were made.
                              IV-21

-------
DRAFT
        on p. E-8) because of selection bias in the study population.
        The population studied by Hammond and Garfinkel was more suburban,
        higher percentage white, lower percentage blue collar, more
        educated than the U.S. population as a whole.  However, no
        attempt is made to correct for this bias here.,

        D.  Summary
             This chapter summarizes attempts to estimate the possible
        magnitude of the association between lung cancer mortality
        rates and air pollution levels.  The index of air pollution
        most commonly used has been the average atmospheric concentration
        of benzo(a)pyrene (BaP).  Using this index, however, creates
        problems because average levels of BaP in the United States
        have declined considerably since 1966 and probably were still
        higher prior to 1966.  However, it is not clear that overall
        hazards posed by air pollution should have declined proportion-
        ately, because there is evidence that levels of other potential
        carcinogens have increased since 1940.  BaP is thus no longer
        a stable index of the carcinogenicity of polluted air, and
        estimates made for one time period cannot be applied directly
        to others.  Thus, the estimates based on study of lung cancers
        in the past cannot be used directly to predict future effects
        of current pollution.
             Recognizing this problem, Table IV-1 tabulates 13 estimates
        (but not based on 13 independent studies) of the quantitative
        relationship between lung cancer rates and air pollution levels
        as indexed by BaP concentrations.  Estimated slopes (regression
                                      IV-22

-------
                                                              DRAFT
coefficients) of this relationship range from 0.1-5.0 x 10
lung cancer deaths/year per ng/m  BaP.  Some of these figures
should probably be adjusted downwards by factors of 2 to 4 to
take account of the likely reduction in BaP levels since the
1930s and 1940s when most effective exposures took place.
The estimates derived from studies in the general population
(0.8-5.0 x 10~5) are significantly higher than those derived
from studies of workers exposed to products of incomplete combus-
tion (0.11-0.8 x 10~5).  This difference suggests that incomplete
combustion products are associated with only part of the excess
lung cancer rates observed in urban areas.  Most of the studies
were based on lung cancer mortality data from the 1960s, and
the results are consistent with the hypothesis that at that
time factors responsible for the urban excess in lung cancer
were associated with about 11% of lung cancers in the United
States.  In the one study in which both cigarette smoking and
potential industrial exposure could be accounted for, this
estimate was about 17%.  These quantitative estimates can be
derived without resolution of the issue whether the unexplained
urban excess of lung cancer can or cannot be attributed confi-
dently to air pollution, which depends on interpretation of
data summarized in Chapter II.
                              IV-23

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                                                             OR/5
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                               37

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                                                               DRAFT
                           APPENDIX A

                           TABLE II-l.

            Urban-Rural and Other Geographic Studies
                  of Cancer:  Code to Comments
a.   Limited information on types,  duration,  and intensity
     of exposure

b.   SmoKing habits not taKen into account in design or  analysis

c.   Occupational exposures not taKen into account in design
     or analysis

d.   No information on socioeconomic variables

e.   Dilution effect occurs due to migration

f.   Dilution effect occurs due to labelling  all residents
     of certain geographic areas as "exposed" or "not exposed"

g.   Cause of death as recorded on death certificate may be
     inaccurate

h.   SMR may be biased when numerators (counts of death)  are
     based on death certificates and denominators (population
     counts) on census data
                               A-l

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