Environmental Sources of
                                                 Benzene Exposure:
                                      Source Contribution Factors
                      S. Drill
                      R. Thomas
                      July 1979
Contra:! Sponsor U.S. Environmental
          rrotection Agency


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                              ABSTRACT
     The National Interim Primary Drinking Water Regulations are
undergoing review.  As part of that effort, the health risks associ-
ated with selected organic drinking water contaminants for which
standards were not promulgated in the interim regulations are being
assessed.  This study is intended to assist the Office of Drinking
Water, U.S. Environmental Protection Agency,  in that effort by iden-
tifying the frequency of occurrence of benzene in the various envi-
ronmental media, characterizing the benzene levels in these media,
and determining the relative benzene contribution of each of these
sources to an individual16 total daily benzene uptake.
                                  ill

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                          ACKNOWLEDGEMENT

      The authors wish to thank Dr.  Charles L.  Trichilo for his
continuous support and encouragement during the preparation of this
document.

      This document was reviewed in  final draft form by Dr. Bernard
D. Goldstein, Institute of Environmental Medicine,  Mew York University
Medical Center.
                                iv

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                          EXECUTIVE SUMMARY
     The MITRE Corporation/Metrek Division has been assisting the
Criteria and Standards Division,  Office of Drinking Water, U.S. Envi-
ronmental Protection Agency in assessing the adequacy of the Interim
Primary Drinking Water Regulations.   Part of this effort has been the
identification of the frequency of occurrence of benzene in the vari-
ous environmental media, characterization of the benzene levels in
these media, and determination of the relative benzene contributions
of each of the pertinent environmental sources to an individual's
total daily benzene uptake.

     Benzene is emitted to the environcent from petroleum refineries
and coke ovens, the two major sources of commercial benzene produc-
tion, and from chemical manufacturing facilities, the major avenue of
benzene consumption.  Benzene is  highly volatile, and there is there-
fore a considerable potential for evaporitive emissions to the atmo-
sphere during production,  storage, transport, and use of the com-
pound.  Facilities which produce  benzene and .its major by-products
(styrene, phenol, and cyclohexane) are primarily located near the
major domestic sources of  oil and coal, i.e., in the Gulf Coast
States and the Middle Atlantic States, respectively, and emissions
from these sources will be greatest  in these areas.  The majority of
benzene transport in the U.S. is  between these centers of production
and consumption, and thus, losses during transport are largely re-
stricted to the interconnecting transportation routes.  Emissions
from all of these sources  in 1971 have been estimated to be as much
as 738 million pounds (42  percent of total quantified U.S. benzene
emissions).

     Benzene is a component of gasoline, and motor vehicle emissions
are thought to constitute  the greatest source of benzene emissions.
Atmospheric emissions from this source contained an estimated 1 bil-
lion pounds in 1971 (57 percent of total 1971 emissions).   Benzene is
also emitted to the environment by evaporation of gasoline during
transfer.  Additional losses result  froa evaporation of benzene-
containing solvents and from oil  and fuel spills.

     Data on atmospheric benzene  levels are scarce, as there has been
no routine program for monitoring atmospheric pollution by this com-
pound.  Reported values range from 3 to 900,000  ^ig/m-*, although
levels at the high end of  this range were measured in areas where
production, use, or disposal of benzene was thought to create a local
air pollution problem.  A  conservative estimate  for the national
average urban benzene concentration  is 50

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     Data on levels on benzene in food are extremely limited*although
benzene has been measured qualitatively in a large number of food-
stuffs.  Eggs have been found to contain high levels (1900 Hg/kg) of
the compound.  Daily dietary benzene intake has been estimated to be
as much as 250 ug.

     Benzene has been detected in b percent of the 113 U.S. water
supplies surveyed in the National Organics Monitoring Survey (NOMS).
The median concentration for all samples ranged from less than 0.1
to 0.2 ng/1.  The highest concentration was 1.8 pg/1*  Benzene was
detected in four of ten drinking water supplies iu the National Or-
ganics Reconnaissance Survey (KORS).  Concentrations in these four
water supplies ranged from 0.1 to 0.3 ug/1.

     Inhalation of benzene is the most frequent cause of industrial
benzene poisoning, and thus inhalation has been the most intensely
studied exposure route.  At ambient airborne concentrations,  up to
80 percent of inhaled benzene may be absorbed by the lungs.  However,
studies in which persons were exposed to benzene contrations  over
1000 times higher than urban ambient levels revealed a steady-state
absorption rate of about 45 percent.  The rate of benzene uptake
via the gastrointestinal tract is believed to be high, although no
conclusive data are available.  It has been conservatively assumed,
therefore, that 1CJ percent of the ingested benzene is absorbed.
Dermal absorption is insignificant under ambient environmental con-
ditions.

     After inhalation exposure as much as half or as little as 10
percent of the benzene absorbed by the body is excreted unchanged
through the lung.  Most of the remainder is excreted as metabolites
in the urine.  Metabolism takes place in the liver, and possibly also
in the bone marrow.  The major metabolic products are phenol  and its
congeners.

     The total daily benzene uptake and the percent contribution to
this total uptake from each of these environmental .ources have been
calculated for an adult male in an urban setting.  These calculations
are based upon average concentrations in the various  environmental
media (air, food, and water), and estimated consumption and absorp-
tion rates for these media and the benzene contained therein.   Based
upon the assumptions utilized, air is the predominant source  of ben-
zene absorbed by the general populations.  This  source  contributes
more than 65 percent of the total daily benzene uptake  at all drink-
ing water concentrations considered.  Drinking water contributes less
than 3 percent at benzene concentrations of 10 ug/1,  and well below 1
percent at assumed urban ambient average conditions.
                                 vi

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                         TABLE OF CONTENTS
LIST OF TABLES

LIST OF FIGURES                                               Viii

1.0  INTRODUCTION                                                1
     1.1  Background                                             2
     1.2  Approach                                               3

2.0  BENZENE INPUT TO THE ENVIRONMENT                            4
     2.1  Benzene Production, Storage and Transport              4
     2.2  Commercial Uses of Benzene                             8
     2.3  Contamination From Petroleum and Petroleum-
            Derived Fuels                                        9

3.0  ENVIRONMENTAL SOURCES OF BENZENE EXPOSURE                  12
     3.1  Benzene Concentrations in Ambient Air                 12
     3.2  Benzene Concentrations in the Diet                    16
     3.3  Benzene Concentrations in Drinking Water              .19
     3.4  Benzene Intake From Smoking                           22

4.0  ABSORPTION, RETENTION, AND ELIMINATION OF BENZENE
       IN HUMANS                                                23
     4.1  Absorption Characteristics                            23
          4.1.1  Pulmonary Absorption                           23
          4.1.2  Gastrointestinal Absorption                    27
          4.1.3  Dermal Absorption                              27
     4.2  Metabolic Pathways                                    28'
     4.3  Retention Characteristics                             30
     4.4  Elimination Characteristics                           31

5.0  SOURCE CONTRIBUTIONS TO DAILY BENZENE UPTAKE IN
       KUMANS                                                   33
     5.1  Approach                                              33
     5.2  Basic Assumptions                                     34
     5.3  Estimated Daily Benzene Uptake                        34
     5.4  Identification of Critical Receptors                  41

6.0  REFERENCES                                                 42
                                vii

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                          LIST OF TABLES

Table Number                                                Page So.

    2-1     Distribution of U.S. Benzene Emissions, 1971          5

    2-2     Upper Limit of Benzene Losses from By-Prcduct
            Manufacturing in 1971                                 7

    3-1     Benzer.e Concentrations in Air                        14

    3-2     Atmospheric Benzene Expsoures Attributable to
            Major Emission Sources:  Number of Persons
            Exposed at Various Concentrations                    15

    3-3     Foods Reported to Contain Benzene                    18

    3-4     Benzene Concentrations in Drinking Water             20

    4-1     Snnmary of Reported Pulmonary Absorption
            Rates for Benzene                                    25

    5-1     Basic Assumptions Employed in the Calculation
            of Individual Source Contribution Factors            35

    5-2     Representative Environmental Benzene Exposure
            Levels                                               37

    5-3     Calculation Sequence in Determining Source
            Contribution Factors                                 38

    5-4     Estimated Daily Benzer.e Uptake                       39
Figure Number

    4-1     Proposed Pathways of Human Benzene Metabolism        29
                                v
                                 iii

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1.0  INTRODUCTION




     The Office of Drinking Water (ODW) within the United States




Environmental Protection Agency (EPA)  in accordance with the Safe




Drinking Water Act as amended has promulgated National Interim Pri-




mary Drinking Water Regulations for a  number of physical, chemical,




biological and radiological contaminants in potable water systems.




These interim standards, which specify maximum contaminant levels




(MCLs) for substances in drinking water, will be replaced by final




Primary Drinking Water Regulations as  more definitive information




describing the health risks associated with each contaminant is




accumulated and analyzed.




     Because of a paucity of data on the occurrence of various




organic chemicals in drinking water supplies and the associated risks




to human health, and uncertainties over appropriate methods  of treat-




ment, the only organic chemicals for which MCLs were specified in the




Interim Primary Drinking Water Regulations were selected pesticides.




In order to be able to specify MCLs for additional organic contami-




nants in the final Primary Drinking Water Regulations,  EPA has pub-




lished Special Monitoring Regulations,  and in accordance with  these




regulations, is conducting a National  Organics  Monitoring Survey




(NOMS) of drinking water supplier in 113 U.S.  cities.




     The MITRE Corporation/METREK Division has  been assisting  the




Criteria and Standards Division, Office of Drinking Water in the




identification of the frequency of occurrence  of benzene in  the

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various environmental media, characterization of the benzene levels




in these media,  and determination of the relative benzene contribu-




tion of each of  the pertinent environaentsi sources to an individ-




ual's total daily benzene uptake.  The source contribution model




utilized in this study identifies those er.vironmerttal sources afford-




ing the greatest potential for exposure to benzene, enabling the most




effective regulatory action to be initiated.




1.1  Background




     Benzene is  widely distributed throughout the environment.   The




compound is a component of petroleum and light oil produced froQ




coal, and it is  produced commercially free both of these sources.




Benzene is also  a component of gasoline.  Benzene is highly volatile




and therefore the production and use of the conpouni, and of gaso-




line, offer substantial opportunity for atmospheric benzene emis-




sions.  Consequently benzene appears to be ubiquitously distributed




in the atmosphere.   Benzene has also been detected in a number  of




U.S. waterways and  community water supplies and in sooe foods.




     Because of  the multiple exposure pathways, the relative contri-




butions to an individual's daily benzene uptake arising from s-pecific




environmental media are being defined.  IP. this way, if benzene




appears to pose  a significant health risk as a result of exposure via




daily drinking water intake alone, or if drinking water intake  con-




tributes significantly to the total daily benzene uptake,  ther.  an




intensive review ar.d analysis of the probles will be initiated.

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1.2  Approach

     In order to properly assess the health significance of the

ingest ion of benzene contaminated drinking water, it is necessary to

define the contributions to an individual's total daily benzene up-

take from each major source of exposure.   These source contribution

factors can be defined in threi successive steps, i.e.,

     •  define and quantify the major environmental sources of ben-
        zene exposure,

     «  determine the absorption/raetaboiisra/retention and elimination
        characteristics of benzene in man via each exposure route,
        and

     •  estimate total daily uptake of benzene in can, bssed on anci-
        ent exposures and absorption/retention characteristics.

By examining the percent contribution to  the total uptake from each

route of exposure, one can calculate the  source contribution factors

for each type of benzene exposure.  In this way,  the significance of

benzene exposure via drinking water can be assessed in view of the

other possible exposure routes.

     This report defines the percent contribution to the total daily

benzere uptake from all the major environments]  sources  of exposure.

The report does not, however, consider or evaluate the toxicologf.cal

implications of such benzene uptake.  Those instances when critical

data weie insufficient or lacking are pointed out in the text.

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2.0  BENZENE INPUT TO THE ENVIRONMENT




     Benzene is emitted to the environment from petroleum refineries




and coke ovens, the two major production sources, and chemical isanu-




factoring facilities;  by evaporation of benzene during storage and




transport and during use of bcr.zcr.e as a solvent; and by evaporation




of petroleum-based fuels.  Combustion of fossil fuels may also be an




important source of benzene emissions, although the contribution from




this source has not been quantified.  Many of the industrial emission




sources are located near the major domestic sources of oil and coal




(in the Gulf Coast and Middle Atlantic states,  respectively).  The




quantitative and geographical distributions of  benzene emissions from




the major quantified emission sources are shown in Table 2-1.




2.1  BenzeneProduction, Storage and Transport




     Benzene has been commercially produced from light oil (generated




by the carbonization of coal to coke) sinca 1849 and fron petroleum




since 1941 (Ayers and Muder, 1964).  The compound is still derived




from both sources but petroleum currently supplies most of the ben-




zene produced in the U.S.  Approximately 92 percent is derived from




this source (Mara and Lee,  1977).   As of early  1975,  the total capac-




ity of U.S. benzene production facilities was 1.74 billion gallons




(12.7 billion pounds)  per year (SRI, 1975).  Actual production of




chemical benzene in 1975 was 8.04  billion pounds (USITC,  1977).   U.S.-




benzene production capacity was .more than doubled during the decade




from 1963 to 1973 (SRI, 1975).

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                             TABLE 2-1
           DISTRIBUTION OF U.S. BENZENE EMISSIONS, 1971
    Origin
      Priraary
Geographic Location
 Quantity
(106 Ibs.)
Commercial Benzene
Production, Storage,
and Transport
Gulf Coast States,
Middle Atlantic
 States
   80'
                                                          a
By-product
Manufacture
Gulf Coast States,
Middle Atlantic
 States
  658'
Oil Spills
Oceans, Rivers
   23
Motor Vehicle
Emissions
Approximates
Population
Distribution
 1000
Total of quantified
emissions
                              1761
 One percent of tot&l 1971 benzene production,

3Upper limit (see Table 2-2).
SOURCE:  Adapted frca Howard and Durkin,  1974,

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     Although the Compilation of Air Pollution EmissionFactors (EPA,




1973) states that "there are essentially no emissions from petroleum




reforming operations" the high volatility of benzene suggests that




some degree of evaporative loss during production, storage,  transfer




and transport is almost inevitable.   Benzene is normally stored and/




or transported in steel tanks, 55-gallon metal drums, tank trucks and




barges (Erskine, 1972) and there is  a potential for vapor emission




during transfer to and from each of  these containers.  In addition,




the rupture of a benzene container may result in high local  atmo-




spheric benzene levels, the absolute magnitudes of which will depend




upon the extent of benzene loss and  local physical conditions.   Quan-




titative estimates of the total benzene emissions from these sources




are not available; however, Howard and Durkin (1974) have assumed




that economic constraints on benzene loss would limit emissions to 1




percent or less of the total quantity produced.  The majority of ben-




zene production facilities are located near major domestic sources of




oil (in the coastal areas of Louisiana and Texas) and coal (predomi-




nantly in Ohio and Pennsylvania) (Howard and Durkin, 1974);  there-




fore, the quantity of benzene emissions associated with  production




will be greatest in these areas.  Benzene transport is mainly  from




the Gulf Coast States to the Middle  Atlantic states, and thus,  losses




during transport will be largely restricted to the major intercon-




necting transportation routes (Howard and Durkin, 1974;  as indicated




in Table 2-1).

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                             TABLE 2-2
                  UPPER LIMIT OF BENZENE LOSSES
              FROM BY-PRODUCT MANUFACTURING IN 1971
                             a
  By-Product
Styrene
Phenol
Cyclohexane
Maleic Anhydride
Detergent Alkylate
Aniline
Dlchlorobenzene
DDT
All Other Non-
 fuel Usesc
Consumption
 (106 Ibs.)
  3709
  1610
  1311
   325
   323
   297
    94
    43

   676
                        8388(7712°)
Percent      Upper Limit of
 Yield     Lossesb (106 Ibs.)
   97             111
   82             290
  100               0
   57             140
   80              65
   93              21
   85              14
   60              17
                                 658
a
 Quantity not accounted for by end-product yield.
 Losses may not only be benzene but  also process intermediates.
>«
"Includes synthesis of anthraquinone,  benzene hexachloride,
 chlorobenzene (for use other than as  an intermediate for DDT,
 aniline, and phenol manufacture), diphcnyl,  nitrobenzene (other
 than for aniline), cunene (other  than for phenol),  and ethylbenzene
 (other than for styrene); and solvent uses.
JTotal excluding "Other Konfuel Uses".
SOURCE:   Adapted from Howard and  Durkin,  1974.

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2.2  Commercial Uses of Ben z e n e




     Chemical manufacture accounts for most of the benzene used in




the U.S. (more than 7.7 billion pounds,  or 92  percent of the total




U.S. consumption,  in 1971 [Howard and  Durkin,  1974]).  The manufac-




turing processes used in the production of benzene-derived chemicals




vary widely in efficiency; 100 percent of the  theoretical yield of




cyclohexane is produced, whereas a yield of 57 percent is attained in




maleic anhydride production (Table 2-2),  The  difference between the




maximum potential yield of these benzene by-products (100 percent)




and the actual yield, has been used to develop an upper bound of 658




million pounds for the 1971 benzene emissions  from facilities manu-




facturing the principal by products (Howard and Durkin,  1974;  as




shown in Table 2-2).




     The geographical distribution of  the aajor benzene by-product




manufacturing facilities is not uniform.  The  majority of these




facilities are located in the Gulf Coast states (24  of the 49 U.S.




manufacturing facilities are located in Texas, Louisiana,  Missis-




sippi, and Alabama; 14 of these are at the site of a benzene produc-




tion facility) and the Kiddle Atlantic States  (New Jersey, Pennsyl-




vania, West Virginia, and Maryland have 14 such facilities).   Texas




alone has 20 such manufacturing facilities (Howard and Durkin,  1974).




     Benzene is used to some extent as an ingredient in paint  brush




cleaners, paint and varnish recovers,  and other multicomponent  sol-




vent formulations  (Gosselin et si., 1976).   The compound is  an
                                 8

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excellent solvent for rubber,  and has been used as such in rubber




manufacture (Mara and Lee,  1977) and in rubber cements (Ayers and




Muder, 1964).   Benzene will be emitted to the atmosphere by evapora-




tion during use of these products, and'may also be emitted to streams




and rivers via disposal of  these products in domestic and industrial




wasrewater.



2.3  Contamination from Petroleum and Petroleum-Derived Fuels




     Benzene is a component of petroleum and of gasoline and other




fuels which are derived from petroleum (Howard and Durkin, 1974).




Before 1974, most gasoline  produced in the U.S. contained less than 1




liquid volume (Iv) percent  benzene (1.3 percent by weight), although




concentrations as high as 2 Iv percent were reported (Runion, 1975).




Sanders and Maynard (1968)  analyzed regular and premium gasolines and




found them to contain 1.35  and 0.81 percent benzene by weight,




respectively.   As the average  lead content of U.S. gasoline has de-




creased, however, it has been  necessary to increase the benzene con-




centration to maintain the  same average octane rating.  More recent




estimates (PEDCo Environmental, Inc., 1977) of the average benzene



content of U.S. gasoline range from 1.24 to 2.5 Iv percent.




     The concentrations of  benzene in U.S. gasolines are limited by




both the refinery process methods used and economic considerations.




Because of the refinery methods utilized,  most gasolines  produced in




the U.S. contain between 15 and 35 percent aromatic-rich reforaatea,




whereas European gasolines  generally contain 85 to 90 percent

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refortnates (Runion, 1975).  Furthermore, selective separation of ben-




zene is economically practical, as it offers a much higher return to




the refiner than when benzene is sold as a fuel component (Runion,




1975).




     Howard and Durkin (1974) have calculated the total 1971 benzene




motor vehicle emissions based on total hydrocarbon emissions of 2.94




billion pounds.  If it is assumed that evaporated gasoline consti-




tutes 20 percent by weight of the total emissions, and benzene con-




stitutes 1 percent of these vapors, then benzene emissions from




gasoline evaporation would amount to 58.8 million pounds.  In addi-




tion, benzene constitutes 2.15 percent by volume of the hydrocarbon




exhaust emissions from a reciprocating (piston)  engine (Schofield,




1974).  This is about 4 percent by weight (Howard and Durkin, 1974).




Therefore, the amount of benzene in the hydrocarbon exhaust  emissions




(the remaining 80 percent of the total hydrocarbon emissions) would




be about 941 million pounds, and the total 1971  motor vehicle benzene




emissions would be about 1 billi-rn pounds (Table 2-1).  From these




projections, motor vehicle emissions were projected to be the largest




source of atmospheric benzene in 1971.  The geographic distribution




of these emissions would vary with traffic density and would there-




fore be approximately the same as that of U.S.  population.   Evapora-




tion of gasoline during pumping and bulk loading operations  will  also.




result in atmospheric benzene emissions;  however,  these emissions




have not been quantified.
                                  10

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     Environmental benzene contamination may also result from oil and




fuel spills and from the evaporation and incomplete combustion of




benzene-containing fuels other than gasoline.   The total influx of




oil into the oceans from routine discharges  from tankers, tanker




accidents, leaks during storage, pipeline breaks,  disposal of spent




lubricants, incompletely burned fuels,  and untreated industrial and




domestic sewage is estimated to be between 11  and  12 billion pounds




per year (Blutner et al., 1971).  Ascuming that the concentration of




benzene in these discharges is the same as the average concentration




in crude oil (0.2 percent by weight, Howard  and Durkin,  1974), the




total annual emission of benzene into the oceans is 22 to 24 million




pounds.
                                 11

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3.0  ENVIRONMENTAL SOURCES OF BENZENE EXPOSURE




     Although many potential sources of environmental benzene con-




tamination have been identified, monitoring data that would allow




prediction of the extent of the benzene exposure of the general pop-




ulation attributable to these sources are extremely limited.  Benzene




levels have been measured in the ambient air and water in a number of




locations throughout the western world and in a small number of food-




stuffs.  The results of these measurements can be used to develop




tentative estimates of average ambient environmental Levels and expo-




sure rates.




3.1  Benzene Concentrations in Ambient Air




     The ambient concentration of benzene in urban air is estimated




to range from about 4 to 200 Hg/"^; (Altshuller, 1969; Bertsch et




al., 1974; Pilar and Graydon, 1973).  This estimate is based on a




very small body of data, as the level of benzene in ambient air is




not routinely monitored.  Concentrations of airborne benzene reported




in the literature range from a trace to 900,000 pg/m-* for areas as




widely dispersed as Zurich, Switzerland; Vancouver, Canada; Edison,




New Jersey; and Iberville Parish Louisiana (Grob and Grob, 1971;




Williams, 1965; RTI #9, 1976; RTI #2, 1977).  Values at the upper end




of this range probably do not reflect conditions encountered by a




large majority of the population, however, as eany of the reported




atmospheric benzene concentrations were measured in areas where pro-




duction use, or disposal of organic chemicals was thought to produce
                                  12

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a local air pollution problem.  A summary of reported benzene levels




in air is presented in Table 3-1.




     Mara and Lee (1977) calculated the number of persons exposed to




benzene from each of the major emission sources in selected concen-




tration ranges above 0.1 ppb (0.32 jig/m-*) and the total exposure



(in ppb-person-years) attributable to each source.  The results are




shown in Table 3-2.




     Schewe (1977) estimated the average atmospheric benzene concen-




trations in four U.S. cities (Dallas, Los Angeles, St. Louis, and




Chicago) based upon estimated automotive emissions, area, and average




wind conditions.  The estimated concentrations ranged from 3.0




(Dallas) to 13.8 jig/n^ (Chicago).  However, these estimates are con-




tradicted by reported levels in Los Angeles and other cities (Table




3-1), and a more realistic estimate of the average urban value is




about 50 jig/m^.  This high benzene concentration is primarily




associated with high levels of motor vehicle traffic.




     Evaporative emissions froa gasoline service stations are also




responsible for a large amount of human exposure to atmospheric  ben-




zene, through exposure of both nearby residents and customers, espe-




cially those using self-service facilities.  Based upon limited  data,




Runion (1975) reported that gasoline vapor concentrations to which




service station attendants were exposed were less  than 10 ppau




Assuming benzene constituted 1 lv percent of these vapors, thie  cor-




responds to a benzene concentration of 320
                                13

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     The use of benzene-containing solvents and the misuse of gaso-




line as a solvent cleaner for machine parts, paint brushes, hands,




etc., probably results in the greatest short-term atmospheric benzene




levels encountered by the general public (Runion, 1975).  Limited




testing in an enclosed room with no positive ventilation showed that




when gasoline is used in this way, concentrations of 100 ppra total




hydrocarbons (about. 3200 fig/ra^ benzene) would be reached frequently




in the breathing zone, and momentary peaks-would be as high as 500 to




1000 ppra total hydrocarbons (16 to 32 mg/m-* benzene).




     Reclamation of spent solvents may be another source, however



minor, of atmospheric benzene.  In May 1970 the Maryland State Health




Department contracted with the Thiokol Chemical Company to collect




and analyze air samples from a small v&lley nenr Elkton, Maryland.




It was believed that higher-Chan-normal concentrations of various




solvents would be found due to the presence of a reclamation facility




in the vicinity (Capurro, 1973).  Benzene was found in the "...air of




the valley within two miles of the plant," in "...the blood of people




in the valley," and in water from a nearby creek.   A maximum atmos-




pheric concentration of 73,375 ng/m-* was reported.




3.2  Benzene Concentrations in the Diut




     According to Mr. Corbin Miles, Chief of the GRAS* Review




Branch of the Food and Drug Administration,  exposure to benzene  via
 Generally regarded as safe.
                                 16

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Che diet is not considered to be a problem of the general population

(Miles, 1977).  However, benzene has been detected in fruits, nuts,

vegetables, dairy products, meat, poultry, eggs, fish, and several

different beverages (Table 3-3), and is thought to occur naturally

(possibly at a flavor component) in many or all of the foods in which

it is found.  Concentrations of benzene have been measured in only a

small number of these foods:  butter (0,5 jig/kg; Siek and Lindsay,

1970); cooked beef (2 to 19 |ig/kg; National Cancer Institute, 1977);

eggs (500 to 1900 |ig/kg*; MacLeod, 1976; MacLeod and Cave, 1976);

haddock (100 to 100 ng/kg; Merritt, 1972); and Jamaican Rum (120

US/kg; Liebich et al., 1970),  The benzene level in heated lamb, mut-

ton, and veal, and in chicken, is less than 10 fag/kg (Herritt, 1972).

     In some cases, ,the concentration of benzene in foods may be af-

fected by food preparation techniques.  Chang and Peterson (1977)

found large amounts of benzene in the volatile fraction of boiled

beef and canned beef stev.  It has been speculated that the cooking

of meats causes an increase in their benzene content due to the

breakdown of the aromatic amino acids (phenylalaninc and tyrosine)

(FASEB, 1977).  However, the benzene concentration ir. nonirradiated

haddock (stored for 14 days) was found to be twice as great as that

in irradiated haddock (stored for 30 days) (Merritt,  1972).
 f
 Calculated from the fraction of benzene in total  egg volatilec
 (0.1 to 0.38 percent) and the fraction of volatiles ir. the whole egg
 (0.05 percent) for a 50 g egg.
                                  17

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                             TABLE 3-3
                 FOODS REPORTED TO CONTAIN BENZENE
    Fruits
Apple
Citrus Fruits
Cranberry and Bilberry
Currants
Feyoa and Guave
Pineapple
Strawberry
Tomato

    Nuts

Filbert (roasted)
Peanut (roasted)
Macademia Nut

Vegetables

Beans
Leek
Mushroom
Onion (roasted)
Paraley
Potatoe
Soya Bean
       (cooked)
Dairy Products

Butter  (0.5)1!2
Bleu Cheese
Cheddar Cheese
Other Cheese
Meat, Fish and Poultry^

Beef (cooked) (2 to 19)3
Chicken (
-------
     It has been estimated that an individual's dietary benzene in-




take from beef, eggs, and rum alone, may be as high as 250 fig/day




(National Cancer Institute, 1977).  Of the foods in which benzene




levels have been quantified, eggs are the most significant source;




one egg may contain as much as 100 ug of benzene.




3.3  Benzene Concentrations in Drinking Water



     The literature does contain a small number of references to ben-




zene concentrations in drinking water (Table 3-4).  Benzene was one




of a number of organic drinking water contaminants identified in U.S.



cosaunity water supplies in the National Organics Monitoring Survey




(MOMS) of the U.S. Environmental Protection Agency (See Table 3-4);




MOMS Phase I; Phase II; Phase III).  The majority of water supplies



tested were located in urban areas.  The nedian benzene concentration




was less than 0.2 H8/l«  Benzene was detected in only about 6 percent




of the 113 water supplies surveyed.  These results essentially veri-




fied the drinking water benzene concentrations reported In the earli-




er National Organics Reconaissance Survey (U.S. Environmental




Protection Agency, 1975).  Benzene was detected in 4 of 10 water



supplies surveyed, in concentrations ranging froa 1.0 to 3.0 pg/1.




     An analytical study of tap water derived fro:: the Mississippi




River compared chemicals in the water with substances in waste efflu-




ents of 60 industries discharging wastes into the river (U.S.  Envi-




ronmental Protection Agency, 1972).  A total  of 53 organic chenicals




were detected in the effluent  from 11 of the  plants monitored.
                                19

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Although a trace of benzene was found in the tap water, it was not




detected in the effluent from any of the facilities,  suggesting a




source of contamination other than the industrial waste.




     Dovty et al.,  (197S) thermally extracted low molecular weight




organi.cs from water samples obtained at the intake of a Kew Orleans




area municipal water treatment plant, in the effluent from the clari-



fier before chlorination, and at the tap.   Values or  various organics




were reported as relative percent abundance in a gas  chromatogram.




Absolute concentrations were not determined.  The samples tcken from




the Mississippi River at the plant entrance had a relative percent




abundance of a combination of benzene, carbon tetrachloride, and




dichloroethane (which were inseparable chromatographically) of 12.17




while the value for this same combination from the clarifier effluent




was 3.26 and from New Orleans tap water was 36.61.  The high relative




abundance of this mixture in tap vater was  apparently the result of




chemical disinfection using chlorine and aaaonia.   Commercially




bottled artesian water and deionized, charcoal-filtered tap water




processed by a commercial filter unit,  were also" sampled  and ana-




lyzed.  The relative percent abundance of benzese was 16.16 in the




bottled artesian water and 2.17 ia the deionizec charcoal-filtered




water.




     Samplings of the effluent fro'a five benzene production and/or




consumption facilities revealed concentrations  iron less  than 1.0  to




179 jig/1 benzene in the effluent from the plants.   However,  theae
                                21

-------
concentrations soon dissipated, as samples from downstream receiving




waters had lower benzene concentrations, ranging from less than 1.0




to 13.0 jig/1 (Batteile-Colunbus Laboratories, 1977)*




3.4  Benzene Intake From Smoking




     One source that could be of significance to selected individuals




is the vapor phase of tobacco smoke*   The quantity of benzene in one




AO ml pull of cigarette smoke is 6.1  |ig (Newsome et al., 196S).




Assuming 15 pulls per cigarette, an individual smoking one pack of




cigarettes each day would inhele 667«95 rog of benzene each year from




smoking alone.
                                 22

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4.0  ABSORPTION, RETENTION,  AND ELIMINATION OF BENZENE IN HUMANS




     Benzene can be absorbed into the body after inhalation, inges-




tion, and, to some extent,  dermal contact.  Approximately half of the




absorbed benzene is rapidly eliminated as  unchanged benzene via the




pulmonary route, and a small amount of benzene is eliminated in the




urine.  The remainder is metabolized to a  number of different com-




pounds, or retained at various sites.  Benzene is retained for the



longest time in the fatty tissues and bone marrow*




     Metabolism of benzene takes place pricarily in the liver{ mainly




producing phenolic compounds.  The toxic effects associated with ben-




zene exposure are thought to be caused by  one or more of these meta-




bolic products.  The metabolites conjugate with glycine,  sulfuric




acid, and glucuronic acid,  and are subsequently eliminated in the




urine.  The following sections describe the primary absorption,




retention, and elimination mechanisms for  benzene.




4.1  Absorption Characteristics




     Inhalation of benzene  vapors is the predominant cause of benzene




poisoning and is therefore  the subject  of  most  phsrmacokinetic




studies.  Benzene is rapidly and efficiently  absorbed from the lungs




and presumably also from the GI tract.   Denial  absorption  is  an




insignificant route of uptake under ambient environmental  conditions.



     4.1.1  PulmonaryAbaorptipn




     Because of the high vapor pressure  of  benzene (100 cm Hg at




26.075°C [Ayers and Muder,  1964J) most  incidents  of  human  benzene




poisoning in the workplace have been attributed  to inhalation (NIOSH,






                                  23

-------
1974).  Therefore, most of the research on benzene absorption has
focused on uptake from the lung.  A summary of the reported pulmonary
benzene absorption rates is given in Table 4-1.
     Determinations of the rate of pulmonary benzene absorption have
been based upon human exposures to airborne concentrations ranging
from 80 to 19140 mg/m^.  These concentrations are at least three
orders of magnitude higher than ambient atmospheric levels.  Under
the conditions of these studies, absorption rates varied from 20 to
68 percent, although values found in the older literature are as high
as 85 percent (Srbova et al.,  1950).  The mean absorption rate for
benzene, based on the results  of the eight studies reported in Table
4-1, is about 45 percent.
     The rate of pulmonary absorption,  at least at these intake
levels, is dependent upon the  duration  of exposure, and is presumably
also dependent upon the concentration of benzene in the inhaled air.
Srbova and coworkers (1950) reported that 81 percent of the benzene
in inhaled air containing 306  ing/ur* of  the compound was absorbed
through the lungs of one subject after  5 minutes of exposure,  whereas
the absorption rate declined to 52.5 percent after 15 minutes, and
remained at approximately this level thereafter.  In similar studies
with additional subjects (Srbova et al., 1950; Noraiyaraa and Nomiyaraa,
1974b), absorption rates continued to decline very slowly,  reaching
an apparent steady state after 2 to 3 hours.  This decrease in ab-
sorptive efficiency is thought to be due to increasing saturation  of
the blood and tissues with benzene (Srbova et al., 1950;  Nomiyaaia  and
                                 24

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                            Table 4-1

            SUMMARY OF REPORTED PULMONARY ABSORPTION
                        RATES FOR BENZENE
Percent
Absorption
20.42a
20-50
28-34

45. 8,48. Oa
.46
47
53-63
63
Concentration
(ng/m3)
191-255
150-350
19140
*
166-198
320
112
80-100
b
Duration
of Exposure
4 hours
2-3 hours
—

4 hours
5 hours
5-7 ninutes
3-4 hours
>2 hours
                                                     Reference


                                              Nomiyama and Noniyarns,  1969

                                              Srbova et al.,  1950

                                              Duvoir et al.t  1946

                                              Nomiyama and Nomiyania,  197Ab

                                              Teisinger et al., 1952

                                              Hunter, 1966

                                              Hunter and Blair, 1972

                                              Fiserova-Bergerova et al.f  1974
values for males and females,  respectively.
Not specified.
                               25

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Nomiyama, 197AB).  If this is the case, then at much lower atmo-




spheric concentrations,.such as those ordinarily encountered by the




general population, the degree of saturation achieved at an equilib-




rium state will be quite low (since metabolism and elimination of




must of the absorbed benzene is fairly rapid;  See section 4.1.4) and




the absorption rate should never drop far below the initial value (60




to 80 percent based on studies of Srbova et al..  1950;  Fiserova-




Bergerova et al., 1974).   Although the absorption rates given  in




Table 4-1 do not show a clear dependence upon  concentration, as would




be required to confirm this reasoning, a comparison of  absorption




rates and concentrations utilized suggests that there were signifi-




cant differences in the methods utilized and/or considerable varia-




bility in individual physiological parameters  of  the test subjects.




Because of the uncertainty over pulmonary absorption kinetics  in the




ambient exposure situation, two values, 80 and 45 percent,  will be




used in subsequent calculations.




     One study (Nomiyama and Nomiyama, 1969) revealed significant




differences in the absorption rates of males and  females.  It  was




suggested that females would therefore be more susceptible  to  benzene




intoxication.  However, a more recent study by the same authors




(Nomiyama and Noniyaraa, 1974b) failed to confirm  the original  re-




sults.




     An individual's degree of physical activity  nay be an  important




mediating factor.  Egle and Gochberg (1976) observed an inverse
                                 26

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relationship between the degree of benzene uptake and the ventilatory




rate in dogs.




     4.1.2  G as t ro int e s t i n a 1Absorption




     Acute benzene poisoning due to ingestion of the compound is rel-




atively uncommon (Gosselin et al., 1976),  therefore little or no re-




search has been undertaken to determine the rete of gastrointestinal




absorption.  However, because benzene is raiseible with organic sol-




vents and fairly soluble in water (the solubility in water is 820




Hg/l) (NIOSH, 1974;  Howard and Durkin, 1974), it can be estimated




that nearly 100 percent  of a small quantity of ingested benzene would




be absorbed.  This estimate is supported by the high initial pulmon-




ary absorption rate. The presence of food in the GI tract may inhib-




it complete benzene absorption,  since the compound may bind with or




be otherwise sequestered within bulk food materials.  However, 100



percent will be considered a reasonable value for GI absorption.




    .4.1.3  Derma1 Absorp t ion




     Dermal contact  with benzene should not be appreciable under




ambient environmental conditions,  although exposure may result from




occasional contact with  gasoline and benzene-containing solvents.




Benzene may be slowly absorbed through the skin (Hanke et  al., 1961),




although in one study,  in which subjects arms were iraeersed in ben-




zene for 25 to 35 minutes, no evidence of  dermal aboorption was  ob-




tained (Conca and Haltagliati,  1955).   Given the extent of deraal
                                 27

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exposures to benzene for the general population, deraal absorption




can be considered insignificant.




4.2  Metaboilc Pathways




     The proposed scheme of benzene metabolism in huoans (Figure 4-1)




has been inferred from in vivo studies with mice, rats and rabbits,




and in vitro studies with isolated tissues and tissue fractions from




these animals (Gibson, 1971; NIOSH, 1974; Howard and Durkin, 1974).



The metabolic end-products shown In Figure 4-1 have been identified




in the urine of benzene-exposed persons (Teislnger et al., 1952;




Hunter and Blair, 1972).  The relative proportion of metabolic



products has been determined in laboratory animals (Rusch et al.,




1977) but similar data from humans are not available.




     Oxidation of benzene to the arene oxide (benzene-1,2-oxide) is




thought to be the initial metabolic step although this has not been




conclusively demonstrated (Gibson, 1971).  The arene oxide is then




converted to one of three liydroxylated benzene derivatives; phenol,



trans-benzenediol (trans-1,2-dlhydro-l,2-dlhydroxybenzcne) , or S-(l,




2-dihydro-2-hydroxyphenyl)glutathione.  The latter Is converted to




phenylmercapturic acid.  Phenol may be conjugated with sulfates,



glycine, and glucurcnides or converted to quinol  dihydroquinone




(hydroquinone) and conjugated.   trans-Benzenedlol is also excreted in




conjugated form.   Catechol (pyrocatechol), formed froa both phenol




and trans-benzenediol,  is transformed  to either hydroxydihydroquinone




(hydroxyquinol) or trans, trans-muconic acid.   Catechol and
                                 28

-------
                                          S-Glu-Cys-Gly
                                                               S-CH2-CH-COOH

                                                                    NH-CO-CH,
                                           %  ,    t
              S-(l,2-dihydro-2-hydroxyphenyl}glutathione
                                                        Phenylmercapturic Acid
   Benzene     Benzene-1,2-oxide

Excretion via
    Lung
                          IH
             OH

             S-
             OH
 trans-Benzcned iol   Catechol
(trana-l,2-dihydro-(Pyrocatechol)
1,2-d ihydroxybenzene
                                                                  trans,trons-

                                                                  Muconic Acid
                 Phenol
                                   Excretion via
                                       Urine
                                                        Kyd roxydIhydroquinone
                                                          (Hydroxyquinol)
          Quinol Dihydroquinone
               (Hydroquinone)
   SOURCE:  Adapted from Truhaut,  1968; Gibson,  1971; Howard and Durkin, 1974.
                                  FIGURE 4-1
           PROPOSED PATHWAYS OF HUMAN BENZENE METABOLISM
                                      29

-------
hydroxyquinol are also eliminated as conjugates.  Conjugated phenol


appears to be the primary metabolic end-product in humans (Hunter and
       <

Blair, 1972).


     Benzene metabolism takes place mainly in the liver (Gibson,


1971; Howard and Durkin, 1974) although it is not restricted to this


organ.  Experiments with mice suggest that benzene is also metabo-


lized in bone marrow (Andrews et al., 1977).


4.3  Retention Characteristics


     The presence of benzene in the body is, for the most part, high-


ly transient (Howard and Durkin, 1974; Srbova et al., 1950; Hunter


and Blair, 1972; Fiserova-Bergerova et al., 1974).  Benzene is re-


tained for the longest period in those tissues which exchange the


compound most slowly with the blood, i.e., fat and bone marrow


(Fiserova-Bergerova et al., 1974; Hunter and Blair, 1972), although


the available evidence suggests that the compound is almost complete-


ly eliminated from these compartments within a few days after the


cessation of exposure (Fiserova-Bergerova et al., 1974; Howard and


Durkin, 1974).  Parke and Williams (1953) found only 2.6 percent of a


benzene dose in rabbit fat after two days.  Most of the remaining


tissues appear to freely equilibrate with the blood (Fiserova-


Bergerova et al., 197.4).


     Andrews and coworkers (1977) obtained evidence suggesting that


benzene is metabolized within the bone marrow of the mouse.   If human
                                 30

-------
bone marrow also has the capacity to metabolize benzene, then benzene




lifetime within the marrow will be shorter than that dictated by ex-




change kinetics.  However, metabolites thereby produced may be




responsible for some of the toxic consequences of benzene exposure.




4.4  Elimination Characteristics




     The primary routes of elimination of benzene from the body are




excretion, as benzene, from the lung, and as phenolic compounds in




the urine.  Srbova and coworkers (1950) determined that 30 to 50 per-




cent of the absorbed benzene is eliminated as benzene by the lungs.




Furthermore, the rate of elimination via this route was seen to de-




cline rapidly, obeying a logarithmic relationship (indicating thac




the rate of benzene removal from the blood is proportional to the



blood-benzene level).  In 10 subjects, 16.4 to 41.6 percent of the




absorbed benzene was eliminated via the lungs in 5 to 7 hours.




     Elimination via the kidney is the second main route of benzene




excretion, although in this case the major excretion products are




phenol and its congeners, produced in the liver and possibly also in




the bone marrow.  Only 0.1 to 0.2 percent of the absorbed  benzene




dose is eliminated as benzene in the urine.




     Following relatively short exposures (several hours),  up to 87.1




percent of the absorbed benzene has been found to be eliminated with-




in 50 hours cs phenol (free and conjugated) by the urinary route




(Hunter and Blair, 1972).  As with pulmonary benzene excretion,  the
                                 31

-------
rate of phenol excretion in the urine  is  proportional  to the absorbed




benzene dose (and therefore the level  in  the blood)  (Hunter  and




Blair, 1972).
                                32

-------
5.0  SOURCE CONTRIBUTIONS TO DAILY BENZENE UPTAKE IN HUMANS

     To evaluate the potential health risks associated vith benzene

in drinking water, it is necessary to ascertain an individual's total

dose of benzene, froia all exposure sources, and to determine the rel-

ative magnitude of the benzene contribution from drinking water.

5.1  Approach

     The method employed in this study to estimate the degree to

which each major environmental source of benzene exposure contributes

to an individual's total daily uptake is based on probable exposure

cocditions (i.e., ambient benzene levels) as veil as  absorption rates

for each exposure route.  The method consists of a five—step process:

     o  Definition of ambient concentrations of benzene for the major
        exposure source (i.e., air, food, and drinking water)

     o  Determination of daily benzene intake from each exposure
        source according to the relationship

                      1i ° ci " (Benzene>£

        where 1^ is the daily benzene intake from each source,  C^
        is the consumption per day of each source (i.e., air, food,
        drinking water), and (Benzene)^ is the concentration of
        benzene in each source i

     o  Calculation of the amount of benzene absorbed from each ex-
        posure source:

                         Ui » Ii •  Aj

        where U^ is benzene uptake for each exposure  source i,  Ij
        is daily benzene intake from each source i, end A: is the
        fraction of benzene absorbed for each particular exposure
        route j (i.e., inhalation or ingescion)
                                  33

-------
     o  Calculation of the total daily benzene uptake (Uc):
U
 t
                            i • Aj) -SU£
        for all appropriate pairs of i and j

     o  Determination of percent (?£> of total daily uptake (Ut)
        provided by each of the three exposure sources (i.e., source
        contribution factors):
                        Pi
                             »t
5.2  Basic Assumptions

     Several assumptions were made in defining the amount of each

source material consumed each day.  Reference Kan (ICRP, 1975) values

are utilized for daily air and food consumption rates.  Values for

daily consumption of drinking water are those suggested by NAS (1977)

as conservative estimates (see Table 5-1).

       Pulmonary and gastrointestinal absorption rates utilized in

subsequent calculations are specified in Table 5-1.  Two pulmonary

absorption rates have been used.  The first, 80 percent, is the ap-

proximate initial rate in humans exposed to high atmospheric concen-

trations (see Section A. 1.1).  The second pulmonary rate, 45 percent,

is the average steady-state value measured  in the same studies.  The

gastrointestinal absorption rate is a worst case estimate but is jus-

tified, to some extent, by a number of considerations (see Section

4.1.2).

5.3  Esticated Daily Benzene Uptake

     The relative contribution from each exposure route (i.e., air

food, drinking water) to an individual's total daily benzene uptake

                                  34

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was determined by using the estimated average environmental benzene




occurrence levels and absorption rates in the calculation sequence




previously described.  Several concentrations of benzene in drinking




water were selected to represent the range of empirically determined




values.  The benzene concentrations are thought to be representative




of average and maximum urban values.  The level in food is a crude



estimate (see Section 3.2).  Table 5-2 provides the exposure values




used in subsequent calculations.  Table 5-3 provides an example of




the actual calculation sequence employed.  In Table 5-4, the source




contribution factors for air, food, and drinking water are indicated




for an average adult.




     Based upon the assumed urban ambient exposure levels, air is the



predominant source of absorbed benzene, contributing over 65 percent




of the total daily uptake at even the highest drinking yater concen-




trations utilized.  Assuming the benzene concentration in air is 50




fig/n^ (the estimated urban average) and the pulmonary absorption




rate is 80 percent, drinking water contributes 1.7 percent of the




daily uptake of benzene when the benzene concentration is 10 |ig/l,




0.1 percent at 1 pg/l, and well below 0.1 percent at 0.1 and 0.3




pg/1, the values presumed to represent average ambient conditions.




Using the low estimate of pulmonary benzene absorption (45 percent)




adds at most 1.7 percent to the source contribution factor for water.



At the estimated maximum ambient urban air-benzene level of 200




   a-', greater than 88 percent of the total daily benzene uptake is
                                 36

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-------
contributed by this source at all drinking water levels utilized and




less than 1 percent is contributed by drinking water.




     The distribution of benzene in the atmosphere is apparently




highly non-uniform.  Because gasoline combustion is a major source of




benzene emissions, concentrations of benzene in air are presumed to




generally be higher in areas with high traffic density (urban areas)




than in areas with low traffic density (rural areas).  This has not




yet been confirmed, as ambient benzene levels in rural areas have not




been reported.  Atmospheric concentrations of benzene are also ex-




pected to vary on a regional basis, that is, levels will generally be




higher in areas near benzene production and by-product manufacturing




facilities (particularly the Gulf Coast and Middle Atlantic States)




than in other areas of the -country.  Whether or not these same fac-




tors also affect drinking water benzene concentrations has not been




determined.




     Smoking may be a major source of absorbed benzene.  The results




of one study indicate that a person may inhale as much as 91.5 fig of



benzene per cigarette or 1830 fig/pack.  The latter figure is higher




than the total daily benzene intake from air (at 50 pg/m^),  food




and drinking water.  The percentage of benzene absorbed from the




inhaled smoke has not been determined.




     Benzene intake during use of gasoline as a solvent cleaner may




also be significant.  A person exposed to a gasoline concentration of




lOOppm (3200 ng/m^ benzene)  as a result of this practice would

-------
inhale about 3840 jig of benzene per hour*, and would absorb 1728 to

3072 ug/hour.

5.4  Identification of Critical Receptors

     As mentioned in Section 4.0, there is some evidence to suggest

that females are more susceptible to benzene intoxication than males.

These results have been attributed to the female's higher percentage

of body fat.  Koaiyama and Nomiyama (1969) reported that female sub-

jects absorbed benzene frca the lungs more than twice as efficiently

as males; however, this result was contradicted by a more recent

study (Komiyaaa and Nomiyama, 1974b).  In another study by these

authors (Noraiyama and Xomiyama, 1974a), the.percentage of absorbed

benzene excreted by the respiratory route was three times higher .in

men than in vonen and, therefore, women excreted a greater proportion

as urinary metabolites.  This is presumably supported by Hunter and

Blair's (1972) finding in men that as the proportion of body fat

increases, the proportion of benzene excreted as urinary phenol also

increases.  These results say indicate an increased susceptibility  in

women, since the toxic effects of benzene may be due,  at least  in

part, to one or core of the metabolic products (Andrews et  al.t

1977).
*Assuuning a coxsusption rate  of  1.2 ro^ air/hr during  "light
 activity" <1CRP,  1975).
                                41

-------
6.0  REFERENCES

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Andrews, L.S., E.W. Lee, C.M. Witmer, J.J. Kocsis, and R. Snyder,
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Chang, S.S. and R.J. Peterson, 1977.  "Sycposium:   the basis of
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                                 42

-------
Egle, J.L. and B.J. Gochberg, 1976.  "Respiratory retention of in-
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-------
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-------
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