TECHNICAL REPORT DATA
                           ffteat rtmd liuaucnons on Me reverse txfort compithns)
1. REPORT NO.
  FPA/60Q/a-8Q/Q86
4. TITLE AND SUBTITLE
 Updated Health  Effects Assessment for Benzene
                                                           3. RECIPIENT'S ACCESSION NO
                                                            PB90-U2381/AS
                                                           k. REPORT DATE
                                                           t. PERFORMING ORGANIZATION CODE
7. AUTMOR(S)
                                                           I. PERFORMING ORGANIZATION REPORT NO.
 PERFORMING ORGANIZATION NAME AND ADDRESS
                                                           10. PROGRAM ELEMENT NO.
                                                           11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
 Environmental Criteria  and Assessment Office
 Office of Research and  Development
 U.S. Environmental Protection Agency
 Cincinnati. OH  45268    	_____^_
                                                           13. TYPE OF REPORT AND PERIOD COVERED
                                                           14. SPONSORING AGENCY CODE
                                                              EPA/600/22
IS SUPPLEMENTARY NOTES
16. ABSTRACT
   This report summarizes  and evaluates information  relevant to a preliminary interim
 assessment of adverse  health effects associated with  specific chemicals or compounds.
 The Office of Emergency and Remedial Response  (Superfund) uses these documents in
 preparing cost-benefit analyses under Executive Order 32991 for decision-making under
 CERCLA.  All estimates of acceptable intakes and carcinogenic potency presented in
 this document should be considered as preliminary and reflect limited resources
 allocated to this  project.   The intent in these assessments is to suggest acceptable
 exposure levels whenever  sufficient data are available.   The interim values presented
 reflect the relative degree of hazard associated with exposure or risk to the
 chemical(s) addressed.  Whenever possible, two categories of values have been
 estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
 concern).  The first,  RfDs or subchronic reference  dose, is an estimate of an exposure
 level that would not be expected to cause adverse effects when exposure occurs during
 a limited time interval.   The RfD is an estimate of an.exposure level that would not
 be expected to cause adverse effects when exposure  occurs for a significant portion
 of the lifespan.   For  compounds for which there is  sufficient .evidence of
 carcinogenicity, qi*s  have been computed, if appropriate, based on oral and
 inhalation data if available.
7.
                               KEY WORDS AND DOCUMENT ANALYSIS
                 DESCRIPTORS
                                              b.IDENTIFIERS/OPEN ENDED TERMS
                                                                        c.  COSATI Field/Croup
8. DISTRIBUTION STATEMENT

  Public
                                              IB. SECURITY CLASS 
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                                            EPA/600/8-89/086
                                            August, 1989
          HEALTH EFFECTS ASSESSHENT
                 FOR BENZENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
      OFFICE OF RESEARCH AND DEVELOPMENT
    U.S. ENVIRONMENTAL PROTECTION AGENCY
            CINCINNATI. OH  45268

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                                  DISCLAIMER

    This  document  has been  reviewed  In  accordance with  the U.S.  Environ-
mental  Protection  Agency's   peer  and administrative  review  policies  and
approved  for  publication.   Mention  of  trade names  or commercial  products
does not constitute endorsement or recommendation for use.
                                      11

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                                    PREFACE


    This report  summarizes  and evaluates Information relevant  to  a  prelimi-
nary  Interim  assessment of adverse  health  effects associated  with  benzene.
All  estimates  of acceptable  Intakes and carcinogenic  potency  presented  In
this  document  should  be   considered  as  preliminary  and  reflect  limited
resources  allocated   to  this   project.   Pertinent  toxlcologlc   and  environ-
mental data were located through on-Hne  literature  searches  of the  TOXLINE,
CANCERLINE   and  the  CHEMFATE/DATALOG  data  bases.    The  basic  literature
searched supporting  this  document  Is current  up to March, 1987.   Secondary
sources of  Information have also been relied  upon  1n  the  preparation of this
report  and  represent  large-scale   health  assessment  efforts  that  entail
extensive  peer  and   Agency  review.   The  following  Office  of  Health  and
Environmental Assessment (OHEA) sources  have been extensively  utilized:

    U.S. EPA.    1979.   Carcinogen   Assessment  Group's  Final  Report  on
    Population  Risk   to Ambient  Benzene Exposures.    Prepared by  the
    Office  of  Health and  Environmental  Assessment, Carcinogen Assess-
    ment Group,  Washington, DC,  for the Office  of A1r  Quality  Planning
    and Standards, Research Triangle Park,  NC.   EPA-450/5-80-004.   NTIS
    PB82-227372.

    U.S. EPA.    1980a.   Ambient  Mater  Quality Criteria  Document  for
    Benzene.    Prepared  by  the  Office  of  Health  and   Environmental
    Assessment,  Environmental  Criteria  and  Assessment  Office,  Cincin-
    nati,  OH,   for   the Office  of  Water  Regulations  and  Standards,
    Washington, DC.   EPA 440/5-80-018.   NTIS PB 81-117293.

    U.S. EPA.   1983a.  Reportable  Quantity for  Benzene.   Prepared  by
    the  Office of  Health  and  Environmental  Assessment,  Environmental
    Criteria  and  Assessment Office, Cincinnati, OH,  for  the Office  of
    Solid Waste and  Emergency  Response,  Washington, DC.

    U.S. EPA.  1983b.  Review of Toxlcologlc Data  1n Support  of Evalua-
    tion for Carcinogenic Potential  of Benzene.  Prepared  by  the Office
    of  Health   and   Environmental   Assessment,  Carcinogen   Assessment
    Group,  Washington,  DC  for  the  Office of  Solid Waste and  Emergency
    Response, Washington,  DC.

    U.S. EPA.   1985a.  Drinking Water  Criteria  Document for  Benzene.
    Prepared  by  the  Office of Drinking  Water,  Washington,  DC.   Final
    Draft (on Public Comment).   NTIS PB86-118122.

    U.S. EPA.   1985b.   Interim Quantitative Cancer Unit  Risk  Estimates
    Due to  Inhalation of Benzene.   Prepared by  the Office  of  Health  and
    Environmental Assessment,   Carcinogen  Assessment Group, Washington,
    DC, for the  Office  of  A1r  Quality Planning  and  Standards,  Research
    Triangle  Park,  NC.  Internal  Report.
                                      111

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    The Intent 1n these assessments 1s to  suggest  acceptable  exposure  levels
for  noncarclnogens  and  risk  cancers/potency   estimates   for   carcinogens
whenever sufficient data were  available.   Values  were not derived  or  larger
uncertainty  factors  were employed  when  the  variable data  were limited  1n
scope, which  tended  to  generate  conservative (I.e., protective)  estimates.
Nevertheless,  the  Interim values  presented reflect  the  relative  degree  of
hazard or risk associated with  exposure to  the chemical(s)  addressed.

    Whenever  possible,  two  categories of values  have been estimated  for
systemic  toxicants   (toxicants  for  which  cancer  Is  not  the  endpolnt  of
concern).  The first,  RfD$  (formerly AIS)  or  subchronlc  reference dose,  1s
an estimate of an exposure level  that would not be expected  to cause  adverse
effects when  exposure  occurs  during  a limited time Interval (I.e.,  for  an
Interval that  does  not  constitute  a  significant  portion  of  the  Hfespan).
This type of  exposure  estimate has  not been extensively used,  or  rigorously
defined, as  previous risk  assessment efforts have been  primarily directed
towards  exposures  from  toxicants 1n  ambient air  or water  where  lifetime
exposure  1s  assumed.   Animal   data  used   for   RfD$  estimates   generally
Include exposures with  durations  of 30-90  days.   Subchronlc human data  are
rarely available.  Reported  exposures  are usually  from chronic  occupational
exposure situations  or  from reports  of   acute accidental  exposure.   These
values  are   developed   for   both   Inhalation  (RfD$i)   and  oral  (RfD$Q)
exposures.

    The  RfD  (formerly  AIC)  1s   similar  In  concept and  addresses  chronic
exposure.  It Is an estimate of an  exposure level  that  would not be expected
to cause adverse  effects when exposure occurs for a significant  portion  of
the llfespan  [see  U.S.  EPA  (1980b) for  a  discussion of this  concept].   The
RfD  Is route-specific  and  estimates  acceptable  exposure  for  either  oral
(RfDn,)  or   Inhalation   (RfDj)  exposure  with   the  Implicit  assumption  that
exposure by other routes 1s  Insignificant.

    Composite  scores  (CSs)  for  noncardnogens  have also  been  calculated
where  data   permitted.   These  values  are  used  for Identifying  reportable
quantities   and  the  methodology for  their  development  1s  explained  In  U.S.
EPA (1984).

    For compounds for which  there Is  sufficient evidence  of  carclnogenlclty,
RfD$ and  RfD values are not derived.  For a discussion  of  rUk  assessment
methodology  for  carcinogens   refer  to  U.S.   (1980b).   Since  cancer  1s  a
process that  Is  not  characterized by  a  threshold, any exposure contributes
an  Increment  of  risk.   For   carcinogens,  q-j*s  have  been  computed,  1f
appropriate, based on oral and Inhalation data 1f  available.
                                      1v

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                                   ABSTRACT
    In order  to  place  the risk assessment evaluation  1n  proper  context,  the
reader Is  referred to  the  preface of  this  document.  The  preface  outlines
limitations applicable to all documents of this  series as well  as the appro-
priate Interpretation and use of quantitative estimates presented.

    Considerable  human data  are  available  Unking  Inhalation   exposure  to
benzene  with  leukemia.   A  carcinogenic   slope   for  Inhaled   benzene   of
2.9xlO~2    (mg/kg/day)"1  may   be   estimated   using  data   from   several
ep1dem1olog1cal  Investigations.   Animal  data concerning  the  cardnogenldty
of Inhaled benzene are corroborative.

    Data   regarding cancer  Incidence  1n  humans following  oral   exposure  to
benzene were not  located.  Animal  studies clearly  associate  oral  exposure  to
benzene with  Increased Incidences  of  several  types  of cancer.   A  carcino-
genic  slope  of  2.9xlO~2  (mg/kg/day)"1  was  estimated  for  oral   exposure  to
benzene.    This   value  was   obtained  by   route   extrapolation  using   the
Inhalation occupational data.

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                             TABLE OF CONTENTS

                                                                       Page
1.  ENVIRONMENTAL CHEMISTRY AND FATE	       1

2.  ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 	       3

    2.1.   ORAL	       3
    2.2.   INHALATION	       3

3.  TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	       5

    3.1.   SUBCHRONIC	       5

           3.1.1.   Oral	       5
           3.1.2.   Inhalation	       5

    3.2.   CHRONIC	       7

           3.2.1.   Oral	       7
           3.2.2.   Inhalation	       8

    3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS	      10

           3.3.1.   Oral	;	      10
           3.3.2.   Inhalation	      10

    3.4.   TOXICANT INTERACTIONS	      12

4.  CARCINOGENICITY	      13

    4.1.   HUMAN DATA	      13

           4.1.1.   Oral	      13
           4.1.2.   Inhalation	      13

    4.2.   BIOASSAYS	      17

           4.2.1.   Oral	      17
           4.2.2.   Inhalation	      22

    4.3.   OTHER RELEVANT DATA	      24
    4.4.   WEIGHT OF EVIDENCE	      25

5.  REGULATORY STANDARDS AND CRITERIA 	      27
                                     vl

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TABLE OF CONTENTS (cont.)
                                             Page
RISK ASSESSMENT 	
6.1. SUBCHRONIC REFERENCE DOSE (RfD$) 	
6.2. REFERENCE DOSE (RfD) 	
6.3. CARCINOGENIC POTENCY (q-|* or UNIT RISK SLOPE). . . .
6.3.1. Oral 	
6.3.2. Inhalation 	
REFERENCES 	
DIX Summarv Table for Benzene 	
. . 30
. . 30
. . 30
. . 30
. . 30
. . 31
. . 33
. . 56

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                               LIST OF TABLES

No.                               TUIe                                Page

4-1     Incidences of Leukemia and Zymbal Gland and Mammary
        Gland Carcinomas 1n Sprague-Dawley Rats Given Benzene
        by Gavage	      18

4-2     Incidences of Neoplastlc Lesions 1n F344/N Rats Adminis-
        tered by Gavage	      19

4-3     Incidences of Neoplastlc Lesions 1n B6C3F1 Mice Adminis-
        tered Benzene by Gavage	      20

4-4     Incidences of Hematopoletlc Tumors In Mice Exposed to
        Benzene Vapors by Inhalation	      23

5-1     National Occupational Exposure Limits for Benzene 	      28

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                             LIST OF  ABBREVIATIONS
ADI                     Acceptable dally Intake
bw                      Body weight
CAS                     Chemical Abstract Service
CS                      Composite score
NOEL                    No-observed-effect level
ppm                     Parts per million
RfO                     Reference dose
RfOj                    Inhalation reference dose
RfOg                    Oral reference dose
RfD$                    Subchronlc reference dose
RfD$i                   Subchronlc Inhalation reference dose
RfD$o                   Subchronlc oral reference dose
SMR                     Standardized mortality ratio
STEL                    Short-term exposure limit
TWA                     Time-weighted average
                                      1x

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                     1.  ENVIRONMENTAL CHEMISTRY AND FATE

    The physical  and  chemical properties  and  environmental  fate of  benzene
(CAS No. 71-43-2) are  given below:
    Chemical class:
    Molecular weight:
    Vapor pressure:

    Water solubility:
    Octanol/water partition
    coefficient:
    B1oconcentrat1on factor:
    Soil sorptlon coefficient (Koc)
    Half-lives 1n Air:
                Mater:
         Surface soil:
     monocycllc aromatic  hydrocarbon
     78.12
     95.2 mm Hg at 25°C
     (Callahan et al.,  1979)
     1750 mg/l at 25°C
     (Banerjee et al.,  1980)
     135 (recommended value)
         (Hansch and Leo, 1985)
     132 (Banerjee et al., 1980)
     12.6 (Mackay, 1982)
     -26.7 (Vowles and  Mantoura,  1987)
     -6 days (Atkinson, 1985)
     3-23 days (Lay et  al., 1985;
     Wakeham et al., 1983)
     0.3-1.6 days (Jury et al.,  1984)
    In  water,  the  dominant   fate  determining  processes  for  benzene  are
predicted to  be volatilization and blodegradatlon.   In an aquatic  modeling
study, U was  estimated  that  32% of benzene  1n water  1s  lost  by blodegrada-
tlon, 66%  loss  occurs by volatilization  and  2% remains In water  (Mackay et
al., 1985).  The overall half-life  (from  all  loss  processes)  of  benzene In a
marine ecosystem during  winter,  spring and summer and  1n  a pond during fall
was  found  to  be  13, 23,  3.1  and  5  days, respectively  (Lay  et al.,  1985;
Wakeham et al., 1983).
0037H
-1-
08/31/89

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    In surface  layers  of  soil, the  dominant  removal  process Is expected  to
be volatilization.  The volatilization half-lives for benzene 1n soil  (1 and
10 cm  deep)  were  estimated  to be  0.3  and 1.6  days,  respectively (Jury  et
al.,  1984).  Considering Its reasonably high water  solubility and  reasonably
low soil-water  distribution coefficient (Vowles  and Mantoura, 1987),  benzene
1s expected to  leach from subsurface  soil.  Conlgllo et  al.  (1980)  reported,
however,   only  an  8.5% frequency  of occurrence  of benzene  1n groundwater
samples  throughout the United States,  compared with  a 70%  frequency  for
chloroform.  Therefore,  both  volatilization and blodegradatlon may  account
for the primary  loss of  benzene from soil before It has the chance to leach
appreciably from  soil  to  groundwater.  The overall  half-life  of benzene  1n
groundwater was estimated  to be 0.3-1.0 years  (Zoeteman  et al.,  1981).
    The dominant  removal  mechanism  of atmospheric benzene  1s   Us reaction
with photochemically generated  hydroxyl radicals.   The  atmospheric  half-life
reported   above   1s  based   on  a  reaction  rate  constant  of  1.28xlO~12
cm3/molecule-sec  at  25°C  (Atkinson,  1985) and  an  average  hydroxyl  radical
concentration   of  106  molecules/cm3.    A  half-life   of  6  days   In  air
suggests   that  benzene  would be transported long distances  In  air from  Us
sources of emission.
0037H                               -2-                              08/31/89

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           2.   ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL  ANIMALS
2.1.   ORAL
    Sabourln  et  al.  (1987)  Investigated the  gastrointestinal  absorption of
benzene In F344/N and  Sprague-Dawley  rats  and B6C3F1  mice.   All test animals
were  13-week-old males  and  were  given  single  gavage  (0.5-300   mg/kg)  or
IntraperHoneal  (0.5-150 mg/kg) doses  of  14C-benzene 1n corn  oil.  Cumula-
tive excretion of radioactivity  was measured  1n expired air, urine and feces
for 48 hours  after  treatment.  Using a  formula for  determining gastrointes-
tinal absorption  that Incorporates excretion  data following oral  and Intra-
perltoneal  treatment,  gastrointestinal  absorption  was  measured  at  >97% at
all dose levels 1n both  strains of rats and B6C3F1 mice.
2.2.   INHALATION
    Sabourln  et  al.  (1987) exposed young  adult male  F344/N rats  and B6C3F1
mice  by   nose   only  to  14C-benzene   1n  air  at   26-2600  vg/l  (26-2600
mg/m3)  for  6  hours.   Respiratory  volume  was  measured   and  the  Inhaled
dosage  of  radlolabeled  benzene was  estimated.  The proportion  of  Inhaled
14C-benzene retained was estimated as  the amount of  radioactivity retained
1n  the carcass  at  the end of the  exposure  period or  as  the  amount of radio-
activity  excreted  over  a  56-hour  postexposure period.    Retention  values
decreased  from 33 to 15% 1n rats and from  50  to  10%  In  mice as the exposure
concentration was Increased from 26 to 2600 yg/l.
    Data regarding the Inhalation  absorption  of benzene  by  humans  suggest an
absorption factor of -50%.  Nomlyama and  Nomlyama  (1974) exposed  three  men
and  three  women  to  benzene  at  52-62  ppm (166-198  mg/m3)  for 4  hours  and
estimated  respiratory  retention.   Respiratory uptake  (the difference between
the  concentration of  benzene  In  Inhaled  and  exhaled  air  expressed as  a
percent of the  concentration  1n  Inhaled  air) was  measured  at  46.9%  with
little difference between men and women.

0037H                               -3-                              04/12/88

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    Srbova et  al.  (1950) exposed  volunteers  to  47-110  ppm  (150-351  mg/ma)
benzene for up to 3 hours and  estimated  mean  respiratory absorption (uptake)
at 53.8%, using a method of estimation similar  to that  described by Nomlyama
and Nomlyama (1974).
    Hunter  and  Blair  (1972)   exposed  human  volunteers  to  63-405  mg/m3
benzene  for  various  lengths   of   time  and measured  the  concentrations  of
benzene  1n  Inhaled  and  exhaled  air.   Benzene   retention,  estimated  from
graphs  of Inhaled  and  exhaled concentrations,  was -44%.   In  an  earlier
experiment (Hunter,  1968),  benzene retention was estimated at  55-60% using
concentrations  of 100-120 mg/ma.
0037H                               -4-                              04/12/88

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                3.   TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
                                 /
3.1.   SUBCHRONIC
3.1.1.   Oral.   Wolf  et al.  (1956)  dosed  groups  of  10  female  Wlstar  rats
(~2.75 months  old)  with benzene at 1, 10,  50  or 100 mg/kg  by gavage 5 days/
week for 187  days  to  study effects  on the hematopoletlc system.  The control
group, consisting  of  20  matched animals,  received  only the  vehicle,  which
was an olive  oil solution emulsified with  5-10% aqueous  solution of acacia.
No  effect  on  the  hematopoletlc  system was seen at  the 1  mg/kg  level,  very
slight leukopenla  was  observed  at  the  10 mg/kg  level,  and  leukopenla  and
erythrocytopenla were noted at both the 50 and 100 mg/kg levels.
    Pertinent  data regarding  the  effects of subchronlc  oral  exposure  of
humans to benzene were not located 1n the available literature.
3.1.2.   Inhalation.  In  a series  of experiments,  Delchmann  et  al.  (1963)
exposed groups  of  -40 male and  female Sprague-Dawley rats  to benzene vapors
at  levels  of  15-831  ppm  (48-2655  mg/m3)  for 5-13  weeks.   Rats  exposed  to
>61 ppm  (195  mg/ma),  5 hours/day,  ~5 days/week  over a period  of 38-46  days
developed significant  leukopenla after 1-4 weeks  of  exposure.   Rats exposed
to  benzene  vapors  at 47  ppm  (150  mg/m3), 7  hours/day for 180  days  over  a
period of  245  days  had slight  or  moderate leukopenla,  which began  at  7-8
weeks of exposure  and persisted  to  the  end of the  study.   Likewise,  leuko-
penla was  observed  among  rats  exposed   to 44  ppm  (141  mg/m3)  benzene,  7
hours/day,  5  days/week  for 8  weeks.   Leukopenla  was  not observed 1n  groups
of  rats  exposed  to  benzene  levels  <31  ppm  (99 mg/m3),  7  hours/day,  ~5
days/week for  periods of  88-126  days.   There  were no  overt  signs of  toxlc-
1ty, effects  on  body  weight gain, anemia  or gross pathologic  changes  at  any
exposure level  (15-831  ppm benzene).  Rats  exposed to either  61  or 831  ppm
of  benzene vapors  were  examined  for  bone marrow changes,  but  there were  no
0037H                               -5-                              04/12/88

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differences  when  compared  with  control  animals.   No  differences  between
treated and  control rats  were observed  during extensive  hlstopathologlcal
examination of control  rats and those exposed to 15,  31  or  47  ppm benzene.
    Wolf et al.  (1956)  exposed groups of 10-25 male and female  Wlstar  rats,
5-10 male  guinea pigs  and  1-2 male rabbits to  benzene  vapors at  levels  of
>88  ppm (>281 mg/m3,  for   rats  and  guinea  pigs)  and >80  ppm  (>256  mg/m3,
for  rabbits), respectively,   7  hours/day,  5   days/week  for  204-269  days.
Leukopenla was   seen  In all   three  species at  these exposure  levels.   In
addition,   rats  exposed  to >88  ppm  benzene  had  Increased spleen  weights;
guinea  pigs  exposed to >88 ppm  had growth depression. Increased  spleen  and
testes  weights and unspecified hlstopathologlc  changes  1n the  bone  marrow;
and  rabbits  exposed to  >80 ppm had  unspecified hlstopathologlc  changes  1n
the  kidneys  and  testes.  In the  same study, rats exposed  to  benzene vapors
at  2200 ppm   (7030  mg/m3)  had  depressed  growth and unspecified  hlstopatho-
loglc changes In the spleen and bone  marrow,  1n addition  to the effects also
seen at the lower exposure  levels.
    No  hematologlc  effects  were seen  1n  rats,  guinea  pigs  or  dogs exposed to
benzene vapors at  a level   of  17.6 ppm  (56.2  mg/m3)  continuously  for  up  to
127 days (Jenkins et al., 1970).
    Green   et  al.  (1981) exposed  a  group  of  11  or  12 male  CD-I  mice  to
benzene vapors at  a level   of  302  ppm (965 mg/m3), 6 hours/day,  5 days/week
for  26  weeks.  Treatment-related  effects Included -50% mortality  by  the  end
of  the  study, as  well  as  marked  lymphocytopenla,  anemia  and  reduction  of
bone marrow and spleen cellularlty and spleen weight.
     In  a more recent  study (Ward et  al., 1985), groups  of  150 CD-I mice/sex
and  50  Sprague-Dawley  rats/sex were  exposed  to benzene  at 1, 10,  30 or  300
ppm  (3, 32,  96  or 958 mg/m3),  6  hours/day,  5  days/week for  <13  weeks.


0037H                               -6-                              04/13/88

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Blood counts and clinical chemistry  tests  were  performed  on animals from all
groups,  complete  hlstopathologlcal  examinations  were performed  on controls
and  300  ppm group  animals,  and limited hlstopathologlcal  examinations  were
performed on  10  and 30 ppm  group  animals.  At 300 ppm,  rats  had leukopenla
and  decreased bone marrow  cellularlty,   and  mice  had  leukopenla,  anemia,
testlcular  atrophy,  decreased  spermatogenesls,   ovarian  cysts  and  thymlc
atrophy.  No  significant  effects  were  observed  In  either  species at  10 or
30 ppm.
    Pertinent  data  regarding  the  effects  of subchronlc  Inhalation exposure
of humans to benzene were not  located In the available literature.
3.2.   CHRONIC
3.2.1.   Oral.  NTP (1986)   administered  benzene  In  corn  oil  by  gavage to
groups  of  50  male  and 50  female F344/N  rats and  equal  numbers  of  B6C3F1
mice,  5  days/week  for  103  weeks.   Dosage  levels  were  0,  50,  100 and  200
mg/kg/day for  male  rats  and  0, 25,  50  and 100  mg/kg/day  for  female rats and
mice  of  both  sexes.   Significantly  reduced survival  was  observed near  the
end  of  the  study  In  high-dose male and  middle- and  high-dose  female  rats.
All  treated  groups  of male  rats  exhibited  a  statistically  significant  and
dose-dependent lymphocytopenla throughout  most  of the  study.  A  similar  but
less  consistent  trend was   noted  1n female rats.   Lymphold depletion  was
observed  1n  the  spleens  of  all  treated  groups  of  rats;  a  dose-related
lymphold  depletion  was  observed  1n the  splenic follicles  (both sexes  of
rats)  and  thymus   (male  rats).   Hyperplasla   of  the adrenal  occurred  In
low-dose  rats  of both  sexes,  hyperplasla of   the  Zymbal  gland  occurred In
low-dose male  and middle-dose  female rats, and  hyperkeratosls and acanthosls
occurred 1n  the forestomachs  of high-dose male  rats.
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    Male and  female mice  1n  the high-dose  group had  significantly  reduced
survival  near   termination  of  the   study.   Lymphocytopenla  was evident  1n
middle- and high-dose male mice  for  most  of  the  study,  but results In female
mice were equivocal.  Hyperplasla of  the  bone  marrow occurred 1n all  treated
groups of mice  and  adrenal  hyperplasla occurred  1n  at  least  one sex  at each
exposure level.   Hyperplasla  and hyperkeratosls  of  the  forestomach,  hyper-
plasla of  pulmonary alveolar epithelium,  Zymbal  gland,  harder Ian  gland  and
preputlal gland, and epithelial  hyperplasla  and senile atrophy  of  the ovary
were  Increased  1n  Incidence  1n  some  treated groups.   These  effects  were
attributed to treatment with benzene.
3.2.2.   Inhalation.   Snyder  et  al.  (1980)  examined  the  heinatotoxlc  and
carcinogenic effects of  benzene  to  mice by  exposing  groups  of 50 male AKR/J
mice  to  filtered  air  or  air  containing  100  ppm  (319  mg/m21) benzene,  6
hours/day,  5 days/week  for  life  (up to 505  days).   There was no significant
difference  1n  median  survival  or  rate  of  weight  gain  between  treated  and
control  mice.   From  the  first  week  of  exposure  through  the  end   of  the
experiment, marked  Increase 1n lymphocytopenla and slight, but statistically
significant, anemia were reported for treated mice.   Bone marrow hypoplasla
was observed  In 10/50 treated mice and 1n  1/50  controls.   Similar but more
severe effects  on  these parameters  were  reported In AKR  mice 1n an  earlier
study  conducted  at  a higher  exposure level  of  300 ppm  benzene  1n the same
laboratory (Snyder et al., 1978).
    Snyder  et  al.  (1980)  also  exposed groups of  40 male C57B1/6J  mice to
filtered air  or air containing  300 ppm (958  mg/ma)  benzene,  6 hours/day, 5
days/week for life  (up  to  488 days).   A decreased survival rate was reported
for treated  mice,  with  a median  survival  of  41 weeks  for  the treated group
and 75 weeks for the  control group.  Body  weight  gain  of  treated mice was


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depressed relative to controls.  From the  first week  of  exposure through the
end of  the experiment, marked  lymphocytopenla and anemia  were  observed  In
treated mice relative  to  controls.   Bone marrow hyperplasla was  observed  In
13/40 benzene-exposed mice and 1n none of the corresponding control mice.
    In an  earlier  experiment by Snyder  et al. (1978),  Sprague-Dawley  rats,
tested similarly  at  300  ppm (958 mg/m3)  benzene,  exhibited a  trend  toward
anemia and had  a  milder  lymphocytopenla than  had either  AKR mice (Snyder  et
al., 1978) or C57B1 mice (Snyder et al., 1980) at  the  same exposure level.
    There are numerous reports of  the effects  of  chronic  Inhalation exposure
to  benzene  1n  humans.  Chronic  exposure  of  humans  to benzene  vapor  causes
pancytopenla, which  Is a reduction  of blood erythrocytes,  leukocytes  and
thrombocytes (platelets)  (U.S.  EPA,  1980a;  IARC,  1982;   ACGIH,  1980;  NIOSH,
1974).   In  early  (mild)  cases  of chronic  benzene  poisoning,  a  decrease  1n
only one type of blood element may  occur (anemia,  leukopenla  or thrombocyto-
penla), and  the disease appears to  be  reversible on  cessation  of exposure.
Severe pancytopenla  (aplastlc anemia)  as a result of  exposure  to benzene  1s
often associated  with  a  marked  reduction  In  bone  marrow  cellularlty  (U.S.
EPA,  1980a;  IARC,  1982).   The  best evidence for  the   causal  relationship
between  benzene  exposure and   pancytopenla   Is  derived  from  occupational
studies  1n  which  the  appearance  of pancytopenla  In  workers occurred  after
the use  of  benzene  was  Instituted,  and  ceased  after benzene  was  replaced
with another solvent  (U.S. EPA,  1980a).  According to NIOSH  (1974),  occupa-
tional  exposures   to  benzene  at  300-700  ppm (958-2236 mg/m3)  have  been
linked consistently with  blood dyscraslas  (Greenburg,  1926;  Savllahtl,  1956;
Vlgllanl  and Salta,  1964).   The  lower limit of exposure  that will result  1n
hematologlc effects 1n humans 1s not  well  defined,  but 1s thought to be <100
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ppm {Hardy and  Elklns,  1948;  Pagnotto et al., 1961;  Pagnotto,  1972).   There
1s some  evidence  for  Impairment of  the  Immune system In humans  chronically
exposed to benzene (Lange et al.,  1973;  Smollk et  al., 1973).
    An additional  consequence of chronic benzene  exposure  1s  the  Induction
of acute  myelogenous  leukemia  In  humans  (Section 4.1.)  (U.S. EPA,  1980a;
IARC,   1982).   According to IARC  (1982),  there Is  sufficient  evidence  that
benzene 1s carcinogenic  to humans.
3.3.    TERATOGENICITY  AND OTHER REPRODUCTIVE  EFFECTS
3.3.1.   Oral.  Pregnant mice were  given gavage doses  of benzene at  levels
of 0.3,  0.5  or 1.0 ml/kg/day  (790,  1320  or  2640  mg/kg/day) on days 6-15  of
gestation  (Nawrot  and  Staples,  1979).   Increased  mortality  among  the  dams
and Increased  resorptlon of  embryos  occurred at  >0.5  ml/kg/day.  At  the  1
mg/kg/day dose  level  (given  on days  6-15 or  days  12-15  of  gestation),  there
was no statistically significant change  1n the Incidence  of  malformations.
3.3.2.   Inhalation.    In   most   Inhalation   teratogenlclty   experiments,
benzene  was  not  teratogenlc  and was  fetotoxlc  only at level;;  of  exposure
that   were  also maternotoxlc  (U.S.  EPA,  1980a; IARC, 1982).    In  one  study,
however,   evidence  of  fetotoxUHy  was  observed  1n  mice 1n  the  absence  of
maternotox1c1ty  (Hurray et  al.,  1979),  and  In   another  study,  suggestive
evidence  of   teratogenlc potential  was  observed  In rats  at  maternotoxlc
exposure levels (Kuna  and Kapp, 1981).
    Hurray  et  al.  (1979)  exposed  CF-1  mice  and  New   Zealand  rabbits  to
benzene  vapors at  a  concentration  of 500  ppm (1597 mg/m3).   Groups  of  35
and 37 mice were  exposed to  room air or  500  ppm benzene, respectively, for 7
hours/day, on  days  6-15 of  gestation.  Groups of  20  rabbits  were exposed  to
room  air  or  500  ppm  benzene  for  7  hours/day, on  days  6-18  of  gestation.
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Changes  1n  body  weight  and  overt  signs  of  tox1c1ty were  not  observed  In
exposed  animals  of  either   species,  nor  were  differences  1n  numbers  of
resorptlons or  viable fetuses observed.   Mean  fetal  body  weight was signifi-
cantly  lower   (p<0.05)  1n  Utters   from benzene-exposed  mice,  but  not  1n
Utters  from  benzene-exposed rabbits.   Utters of  benzene-exposed mice had
statistically  significant  Increases  In  several  minor  skeletal  variants
considered  to  be Indicative  of  delayed  development,  but not  1n  major  mal-
formations.  Treatment-related effects  were not seen  1n  Utters  of benzene-
exposed rabbits.
    Kuna and Kapp (1981)  exposed pregnant Sprague-Dawley  rats  to benzene  by
Inhalation  on  days  6-15 of  gestation.   Hated  females were exposed to  0 ppm
(17  females),  10  ppm  (32  mg/m3,   18   females),   50  ppm  (160  mg/m3,  20
females) or 500  ppm  (1597  mg/m3,  19 females)  for  7  hours/day.  No  overt
signs of  toxlclty were seen  In  any  of  the pregnant  dams  except  for  reduced
weight gains on days 5  through 15 of gestation 1n the 50 and 500 ppm groups.
No differences  were  seen  In maternal erythrocyte,  leukocyte  or differential
leukocyte counts, or  1n Implantation efficiencies or  number  of resorptlons.
Mean crown  rump length was  significantly reduced  (p<0.05)  1n  Utters  of dams
exposed  to  500 ppm,  and  mean fetal  body weights  were  reduced  (p<0.05)  1n
both the 50 and 500 ppm groups.   Delayed ossification occurred  at 50  and 500
ppm, and four  fetuses  (from four Utters) of  the  500 ppm group had skeletal
variants or anomalies; one  fetus had  exencephaly,  one had angulated Mbs and
two had  out-of-sequence ossification of  the forefeet.   In addition,  Utters
from the  high-dose  group  contained  three fetuses  with  dilated  lateral  and
third  brain ventricles.   Historical  Incidences   of exencephaly,  angulated
ribs,  out-of-sequence ossification  of the forefeet,  and  dilated  lateral  and
third  brain  ventricles   were very   low  1n  control  rats;  these  specific
abnormalities  had not  previously occurred together  1n a  single experiment.

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In  the  50 ppm  group,  delayed ossification of  the  rib cage and  extremities
was seen.  No anomalies were noted 1n the lowest dose or  control  Utters.
    Keller and  Snyder  (1986) Investigated  the  effects of maternal  exposure
to  benzene  on  the  development  of  the hematopoletlc  system  1n  fetuses  and
offspring of  Swiss-Webster  mice.   Mated  mice  were exposed to 0,  5,  10  or  20
ppm  (0,  16,   32  or  64  mg/m3),  6  hours/day on  days 6-15  of  gestation.   A
dose-related  Increase 1n  fetal  differentiated erythrold  colony-forming  cells
(CFU-E) was  observed  at 5  and  10 ppm; a  decrease  1n CFU-E was  noted  at  20
ppm.  Some significant changes  1n  CFU-E and GM-CFU-C were  observed  1n 2-day-
old  neonates and  6-week-old adults  following  in  utero  exposure,  but  no
pattern  of  response was  discerned  and  the biological  significance of  the
results 1s unclear.
3.4.   TOXICANT INTERACTIONS
    Benzene  metabolism,  and  therefore benzene  toxldty,  may  be altered  by
simultaneous  exposure  to  some other solvents  (e.g.,  xylene, toluene).  These
other  aromatic  solvents  are oxidized  by many  of   the  same  hepatic enzyme
systems that metabolize benzene (Ikeda et  al.,  1972).  Since benzene metabo-
lites rather  than the  parent compound are suspected  of  Inducing  bone marrow
toxldty.  Inhibition  of  benzene  metabolism (hydroxylatlon) by  toluene  may
Increase  the toxlclty  of  benzene (Andrews et  al.,  1977;  U.S. EPA,  1980a).
This  synerglsm  might  possibly  explain  the failure to  Induce   leukemia  In
animals with exposure to benzene alone (NAS, 1976).
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                             4.  CARCINOGENICITY
4.1.   HUMAN DATA
4.1.1.   Oral.  Pertinent  data  regarding the cardnogenldty  of  benzene by
oral exposure to humans were not located In the  available literature.
4.1.2.   Inhalation.   IARC  (1982)  has  summarized  many  case  studies   that
suggest a causal  relationship  between  exposure  to benzene by  Inhalation  and
leukemia 1n  humans  (Delore and Borgomano,  1928;  Bowdltch and Elklns,  1939;
Hunter, 1939;  Mallory  et  al., 1939;  OeGowIn,  1963; Tareeff  et al.,  1963;
V1gl1an1 and  Salta, 1964;  Goguel  et  al.,  1967;  Aksoy  et  al.,  1971,  1972;
Aksoy, 1980; Ludwlg and Werthemann,  1962;  Galavottl and  Tro1s1,  1950; Nlssen
and Soeborg Ohlsen, 1953;  D1 Gugllelmo and lannaccone,  1958;  Rozman  et  al.,
1968;  Bryon  et al.,  1969; Fornl  and  Horeo,  1969; Glrard  and Revol,  1970;
Goldstein,   1977).   Because  these  studies  are  secondary  to several epide-
miology studies  for assessing  human cancer  risk  associated with  Inhalation
exposure to benzene,  these case  studies  will  not  be  discussed  further.
These data  are more completely  reviewed by IARC  (1982)  and Goldstein  (1977).
    A  number  of epidemiology  studies  have associated occupational  exposure
to benzene (either alone or  1n  conjunction with other  organic  solvents)  with
an Increased  Incidence of  leukemia  (Aksoy, 1977,  1980;  Aksoy et al.,  1971,
1972.  1974;  Infante et  al.,  1977a,b;  Ott et  al.,  1978;  Ishlmaru  et  al.,
1971; V1gl1an1, 1976;   Flshbeck et  al.,  1978; Thorpe, 1974; McMlchael  et  al.,
1975;  Monson  and  Nakano,  1976;  Tyroler et al.,  1976;  Brandt  et al.,  1978;
Flodln et al.,  1981;  Harden et al.,  1981; Greene et al., 1979; Rushton  and
Alderson,  1980, 1981;  Tabershaw and Lamm,  1977;  Rlnsky  et  al., 1981,  1987;
Wong et al., 1983).  Only  studies  Important 1n  risk assessment are discussed
1n this section.  The  other  epidemiology  studies  are reviewed  In IARC (1982)
and U.S. EPA (1978a, 1980a).
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    Aksoy/(1977) examined the effect of benzene  exposure  on  the Incidence of
leukemia or  "preleukemla"  among a  group  of  28.500  workers  employed  In  the
shoe  Industry  of Turkey.  The  mean duration of  employment  and mean  age of
this  cohort  were  9.7  years  (range,  1-15  years)  and 34.2 years,  respec-
tively.  Benzene exposure was  reported to  have occurred  In  small,  poorly
ventilated  work  areas,  with  peak   exposures   of   210-650  ppm  (671-2078
mg/m3).   Of   the 28,500  subjects   studied,   34  cases  of leukemia  or  pre-
leukemla were  Identified.  This corresponds  to an annual  leukemia  Incidence
of  -13/100,000  workers, which  yields  a  relative risk of  ~2  when  compared
with  the  annual  estimate  of  6/100,000 for  the general  population.   In  a
later follow-up  study, eight additional cases of  leukemia were reported,  and
there  was  suggestive evidence  of   an  Increase  1n  other  malignant  diseases
(Aksoy, 1980).
    Infante et  al.   (1977a,b)  examined the  leukemogenlc  effects of  benzene
exposure on a cohort of 748  white males exposed  to the  solvent during  the
manufacture  of  a  rubber  product  from  1940-1949.    Vital  statistics  were
obtained for  75% of  the cohort through mid-1975.  When compared with  either
of  two separate  control populations,  the  general  American  population  and
workers 1n  another   Industry not  using benzene, a  statistically significant
(p<0.002)  excess  of  leukemia  was  found.   Infante et  al.  (1977a) reported a
5-fold excessive risk of all leukemia  and  a  10-fold  excessive risk  of myelo-
cytlc  and  monocytlc   (probably  myelomonocytlc)  leukemlas  combined.  The  lag
period for  chronic  myelocytlc   leukemia (one case)  was 2 years from Initial
benzene exposure,  while the lag  period for  acute  myelocytlc  and  monocytlc
leukemia (six  cases) was 10-21  years.   The  work  environment was reported to
be  free of contamination by solvents other  than benzene.   The air concentra-
tions  of   benzene  were  generally   below  the  recommended  limits  In  effect


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during the  period  of the  study  (I.e.,  100 ppm  1n 1941, 50 ppm  In  1947,  35
ppm 1n 1948, 25 ppm 1n 1957 and 10 ppm 1n 1969).
    Rlnsky et  al.  (1981)  published a follow-up  report  to  the  Infante et al.
(1977a,b) studies  using  the  same cohort but with  vital  status data  obtained
for 98%  of  the  workers  compared  with  75% In the Infante et  al.  (1977a,b)
reports.   Among  748  workers  exposed  to  benzene  for >1  day between  1940 and
1950,  seven workers  died of  leukemia.   Based  on  U.S.  death  rates  standard-
ized  for age,  sex  and  calender  time  period,  1.25  leukemia  deaths  were
expected, resulting  1n  a statistically  significant  SHR  of   560 (p<0.001).
The mean  duration  of  exposure to  benzene  was brief;  and  437 (58%)  of the
workers were  exposed  for <1  year.   In  workers exposed  for >5 years, deaths
from  leukemia  resulted  In an  SMR of 2100.  Had four  additional  known cases
been  Included  (they were  excluded for technical  reasons),  the  SMR would have
been  3780.   The Investigators estimated  past  exposure and concluded that,
although generally TWA exposures  fell within permissible limits 1n  effect  at
the time  of  exposure,  benzene  concentration  occasionally  rose  to  several
hundred ppm 1n some areas of the plant.
    Rlnsky et  al.  (1987)  have published an update  of risk assessment  of  a
cohort of 1165 rubber workers,  as  reported by Infante  et al.  (1977a,b) and
Rlnsky  et  al.  (1981).    In   order  to   reduce  the  uncertainties  posed  by
estimates of  group exposures, Individual   work  histories  were compiled and
cumulative exposures were estimated  for  each employee  In the  cohort  based  on
the available  past Industrial hygiene measurements.   Standardized  mortality
ratios were determined  for leukemia  by  four cumulative  exposure categories
(I.e.,  <40,   40-200,   200-400  and  >400   ppm    •  years)  and  a   marked,
progressive   Increase   In   standardized  mortality  ratios was   observed  with
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Increasing cumulative dose.  There was no apparent  pattern  for  nine  leukemia
deaths with regard  to  latency,  which ranged from under 5 years  to more  than
30 years.
    Ott  et  al.  (1978)  used  a retrospective cohort analysis to examine  the
mortality of  594  Individuals occupatlonally exposed  to benzene In  chemical
manufacture during  1940-1973.  Three  deaths  attributable  to leukemia  (two
acute  myelogenous   leukemia  and  one  myeloblastlc  leukemia)  were  reported
among  the  594 workers  compared with  0.8 case  of  expected  leukemia  deaths
(excluding  lymphocytlc  or monocytlc cell  types),  based  on Incidence  data
from  the third National  Cancer  Survey   (SMR=375).   The  difference  between
observed  and  expected   Incidence   had   marginal   statistical   significance
(p<0.05).  The  TWA benzene  concentration to  which  the  three   subjects  who
died of leukemia were exposed was  estimated  to  be <10  ppm  (32 mg/m3).
    Wong et al. (1983)  examined  the mortality data of  7676 workers  employed
for >6  months  In  the period  January 1,  1946  to December  31, 1975  1n seven
chemical plants  In  which exposure  to benzene  occurred.    A  total  of  4602
workers  were  exposed to  benzene.    The  exposed group  was  divided  Into  two
categories; those  exposed continuously  (exposed at  least  3 days/week)  vs.
those  exposed  Intermittently.   Air  concentrations  and  TWA  exposures  to
benzene  were  estimated.   The remaining 3074 workers  constituted an  Internal
control  group.   VHal  statistics  were compiled  through  December 31,  1977;
1036  of  the  7676  workers  had  died  and death certificates  were  obtained for
1013  (97.8%).   SMRs were calculated for  several causes of  death  using  data
from  the United States  population  for comparison.   SMRs  were  slightly  but
not statistically  significantly >100 for  lymphatic  and  hematopoletlc cancer,
and within  the general  category of  hematopoletlc  cancer,  specifically  for
leukemia,  non-Hodgk1ns  lymphoma and  non-Hodgk1ns   lymphopoietic cancer  when


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compared with  the  general population.   However,  the relative risk  of  death
from  lymphatic  and hematopoletlc  cancer  was significantly  Increased with  a
dose-response  relationship  between  excess  cancer  risk  and  cumulative  dose
when  compared  with  data from  Internal  controls.   The  Investigators  noted
that  deaths  from  hematopoletlc  cancers  were  unusually  low 1n  the  control
cohort.
    Only a small proportion  of  exposed  Individuals  actually develop leukemia
and It  has been  suggested that there Is  a  sensitive subpopulatlon, possibly
with  some metabolic   Idiosyncrasy   that  allows  the  formation   of  reactive
metabolites at a specific cellular  target.   Blattner et  al. (1976) described
a  family  Involving  a  father  and  four  of  five  siblings  with  chronic
lymphocyctlc   leukemia.   They  all  had   been employed  1n  the  dry  cleaning
business since the-1940s, a period during which benzene was widely used.
4.2.   BIOASSAYS
4.2.1.   Oral.   Maltonl  and  Scarnato  (1979)  observed  Increases  1n  Zymbal
gland  and  mammary  gland  carcinomas  1n  female  Sprague-Dawley  rats   and
leukemia In male rats  administered  benzene  by  gavage.   Three groups of  30 or
35  animals  of each  sex  were  treated  4-5  times/week for  52 weeks at  dose
levels  of  either 50 or  250  mg/kg bw.   The control group,  consisting of 30
male and 30  female rats, received olive  oil  only.   The  tumor Incidences for
this study are summarized 1n Table 4-1.
    More  recent  evidence for  the  cardnogenlclty  of   benzene   to  orally-
exposed  animals  was provided  by  the  2-year NTP  (1986) gavage  study  using
rats and mice.   Details of  the  protocol and tumor  Incidences  are presented
In  Tables  4-2 (rats)  and 4-3  (mice).   In  rats, benzene  administration was
associated with  Zymbal  gland carcinomas  and  squamous  cell paplllomas  and
0037H                               -17-                             08/31/89

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carcinomas of the oral cavity and of  the  skin.   In mice,  benzene administra-
tion  was  associated  with  malignant  lymphoma,  particularly  In males,  and
tumors of  the  Zymbal  gland, lung,  harderlan  gland, preputlal gland,  ovary,
mammary gland and possibly the  liver.
4.2.2.   Inhalation.  A  statistically  significant  Increase  1n hematopoletic
neoplasms was  reported  for male C57B1/6J  mice  (n=40)  exposed by  Inhalation
to  300 ppm  (958 mg/m3)  benzene,  6  hours/day,   5  days/week for  488  days
(Snyder et a!.,  1980).   These  tumor Incidences are  summarized In  Table 4-4.
In  the  same  study,  there  was  no Increase 1n tumors  In  50 male AKR/J  mice
exposed  to  100  ppm  (319  mg/m3)  benzene  under  the  same exposure  schedule
(see Table 4-4).  Snyder et al.  (1980)  also  failed to find  a  statistically
significant Increased  Incidence  of  tumors  1n male  Charles  River CD-I  mice
(number not specified)  exposed  to  100 or  300 ppm  of benzene under  the same
exposure  schedule  previously  described;  however,   myelogenous   (myelold)
leukemia  was  observed  1n  two  CD-I  mice  exposed  to  300  ppm  of  benzene.
Leukemia was  observed 1n  1/40  male Sprague-Dawley  rats  exposed to  benzene
vapors at a  level  of  100  ppm, 6  hours/day,  5 days/week  for  life  (Snyder et
al., 1980).   Because  leukemia  Is seldom  observed  In CD-I mice  and  Sprague-
Dawley  rats,  the  authors  concluded  that  benzene  exposure may  have  been
responsible for these  cancers.
    A  major  continuing study (CronkHe  et al.  1984,  1985;  Cronklte,  1986)
provides a basis on which a reproducible model can  be  built.  In  this study
C57B1/6 BNL and  CBA/Ca  mice were exposed  to  0,  10, 25,  100, 300 or  400 ppm
(0,  32,  80,  319,   958  and  1276  mg/m3),  6  hours/day,   5  days/week  for  16
weeks  followed  by  lifetime observation.   This exposure regimen  was  selected
because  the  authors  thought  H  most   closely   paralleled  likely  human
exposure.   Human ep1dem1olog1cal  studies  1n the  literature reported  that


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occupatlonally-exposed persons  were  exposed for -15% of their Hfespan  and
16 weeks  represent ~15?C  of  the Hfespan for  mice.   The C57B1/6 and  CBA/Ca
mouse  strains  were chosen for  this  study  because  of their  low  spontaneous
rates of acute myeloblastlc  leukemia,  the disease most  frequently associated
with benzene exposure In humans.
    Preliminary results  associate  benzene with  leukemia In both strains  of
mice  at  concentrations  >25  ppm.   An  elevated  Incidence  of  leukemia  was
associated with  CBA/Ca  mice  exposed  by the same schedule  to >100 ppm  (319
mg/m3).  No  dose-related effect Information  1s  available for evaluation  at
this point.
4.3.   OTHER RELEVANT DATA
    Benzene  has  been tested  extensively  for genotoxlc  properties.   Benzene
was not mutagenlc  1n several bacterial  and  yeast systems. Including  Salmo-
nella typhlmurlum both 1n the presence  and  absence  of an exogenous  metabolic
activating  system  (Lyon, 1976;   Dean,  1978;  Shahln  and  Fournler,  1978;
Lebowltz  et  al.,  1979;  Kaden  et   a!.,   1979),   Saccharomyces   cerevlslae
(Cotruvo et  al.,  1977)  and  Escher1ch1a  coll  (Rosenkranz and  Lelfer,  1980).
A  preliminary  study suggests that benzene  oxide,  a  postulated  Intermediate
metabolite of  benzene,  might be  mutagenlc  In  S.  typhlmurlum (IARC,  1982).
Benzene was  also  negative In the sex-linked recessive  lethal  mutation assay
with Drosophlla melanoqaster  (Nylander  et  al., 1978) and the  mouse lymphoma
forward mutation assay (Lebowltz et al., 1979).   Equivocal  results  have been
obtained 1n  assays for  clastogenlc effects  of benzene  on  mammalian  chromo-
somes in  vitro,  but  accumulated  data  seem  to suggest  that  benzene  metabo-
lites may  be responsible In  those cases with positive  results  (IARC, 1982;
Koizumi et al., 1974; Horlmoto, 1976;  Gerner-Smldt  and  FMedrlch, 1978; Diaz
et  al.,  1979;  Horlmoto  and  Wolff,  1980).    Several  Investigators  have
reported positive  results 1n mouse  mlcronucleus assays  following  treatment

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    x
wfth benzene  (Lyon,  1976; D1az et  al.,  1980; HHe et  al.,  1980; Meyne and
Legator,  1980).    Benzene-Induced   chromosomal  aberrations  1n  bone marrow
cells  from rabbHs  (K1ssl1ng  and  Speck,  1971),  mice  (Meyne  and  Legator,
1978, 1980) and  rats (Dean, 1969;  Philip  and Krogh Jensen, 1970; Lyapkalo,
1973; Lyon,  1976; Dobrokhotov  and Enlkeev,  1977;  Anderson and  Richardson,
1979) have also been  reported.
    Numerous  Investigators  have   examined  the  effect  of  benzene   on  the
chromosomes  of  bone marrow cells  and  peripheral  lymphocytes  from  both
symptomatic and asymptomatic workers with either a  current or a  past history
of  exposure  to   benzene.   Many  of  these  Investigators  found  significant
Increases-  In  chromosomal  aberrations  In both  symptomatic  and  asymptomatic
groups,  some of which persisted for years after cessation of exposure (IARC,
1982; Poll1n1 and  Colombl,  1964a,b;  Poll1n1  et al., 1964, 1969;  Polllnl and
B1scald1,  1976,  1977;  Fornl et  al.,  1971a,b;  Fornl  and Moreo,  1967, 1969;
Hartwlch et al.,  1969;  Sellyel  and Kelemen,  1971;  Erdogan and  Aksoy, 1973;
Hudak and  Gombosl, 1977; Van den Berghe  et al., 1979;  Tough and  Court Brown,
1965; Tough et  al., 1970;  Funes-Cravloto  et al.,  1977;  Plcclano, 1979;
Hartwlch and  Schwanltz,  1972;  Khan  and Khan, 1973;  Fredga  et al., 1979;
Sarto et al.,  1984)).
4.4.   WEIGHT OF  EVIDENCE
    The case  reports  reviewed  by IARC  (1982)  and  Goldstein (1977)  relating
cardnogenlclty  In  humans  with   exposure   to benzene, coupled with  the
epldemlologlcal studies  by Infante et  al.  (1977a,b),  Rlnsky  et al. (1981,
1987) and  Ott et  al.  (1978)  provide sufficient  direct  human evidence for the
cardnogenlclty of benzene.
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    Animal bloassays,  which  demonstrate  Increased  Incidence of  many  tumor
types  In  orally-exposed  rats  and  mice   (Maltonl  and Scarnato,  1979;  NTP,
1986)  and  suggest   Increased  Incidence  of  hematopoletlc  tumors  1n  mice
exposed by  Inhalation  (Snyder  et  al.,  1980;  Cronklte et  al.,  1984,  1985;
CronkHe,  1986), may be considered corroborative data that are supportive of
a  carcinogenic   role  for  benzene.    Applying   the  criteria  for  weight  of
evidence  adopted  by the  U.S.  EPA  (1986a), benzene  Is  appropriately desig-
nated a Group A human carcinogen.
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                     5.   REGULATORY STANDARDS AND  CRITERIA

    Regulations  and  recommended  guidelines  reported  by  15  countries  for
limiting occupational exposure  to benzene are summarized  1n Table  5-1.   The
current ACGIH (1986) THA-TLV for benzene Is 10 ppm (30 mg/m3).
    The  U.S.  EPA  (1980a)  has  estimated  ambient  water  concentrations  of
0.066,  0.66  and  6.6  vQ/l  associated  with excess  cancer risks  of  10"7,
10~6  and  10~5,   respectively.   These  estimates  are  based  on  an  earlier
CAG  analysis  (U.S.  EPA,   1978b),   which  used   the  epidemiology  studies
performed by Infante et al. (1977a,b), Aksoy (1977) and Ott et  al. (1978).
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                                  TABLE 5-1
             National Occupational Exposure UrnUs  for  Benzene3
Country
Australia
Belgium
Czechoslovakia
Finland
Hungary
Italy
Japan
The Netherlands
Poland
Romania
Sweden
Switzerland
United States
OSHA

ACGIH
NIOSH
Year
1978
1978
1976
1975
1974
1978
1978
1978
1976
1975
1978
1978
1980
1987
1983
1980
Concentration
(mg/ma) (ppm)
30
30
50
80
32
20
30
80
30
30
50
15
30
6.5
NR
NR
NR
3.2
1.5
30
75
3.2
10
10
NR
NR
10
NR
10
25
10
NR
NR
5
10
2
10
25
50
1
5
10
25
1
Interpretation
TWAb
TWAb
TWA
celling (10 minutes)
TWAb
TWAC
TWAb
celling
TWAb
ceH1ngb
max1mumb
TWAb
maximum (15 minutes)
TWAb
TWA
celling
peakd
TWA
STEL
TWA
STEL
celling (60 minutes)
Status
guideline
regulation
regulation
regulation
regulation
regulation
guideline
guideline
guideline
regulation
regulation
guideline
guideline
regulation
regulation
regulation
regulation
regulation
regulation
guideline
guideline
guideline
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                               TABLE  5-1  (cent.)
Concentration
Country

USSR
Yugoslavia
Year

1980
1971

(mg/m3)
5
50

(ppm)
NR
15
Interpretation

celling5
ceH1ngb
Status

regulation
regulation
aSources: ACGIH, 1983; ILO, 1980; NIOSH, 1980; OSHA, 1980; IARC, 1982
bSk1n Irritant notation added
cMay be exceeded 5 times/shift as long as average does not exceed value
dPeak limit above celling — 10 minutes
NR * Not recorded
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                             6.  RISK ASSESSMENT
6.1.   SUBCHRONIC REFERENCE DOSE  (RfD.)
                                     d
    Benzene 1s a known carcinogen for which data  are  sufficient  for  estimat-
ing carcinogenic  potency.   Therefore,  It Is  Inappropriate  to calculate  an
oral or Inhalation RfDg for benzene.
6.2.   REFERENCE DOSE (RfD)
    Benzene 1s a known carcinogen for which data  are  sufficient  for  estimat-
ing carcinogenic  potency.   Therefore,  1t 1s  Inappropriate  to calculate  an
oral or Inhalation RfD for  benzene.
6.3.   CARCINOGENIC POTENCY (q.,*  or  UNIT RISK  SLOPE)
6.3.1,   Oral.  Oral  cancer  data Include a 52-week gavage study  using  rats
by  Haltonl  and Scarnato (1979)  and  a  103-week  gavage  study using  rats  and
mice sponsored by  the NTP  (1986).   Benzene was clearly  carcinogenic In  rats
and In  mice 1n these studies.   Benzene Is  an EPA  Group A carcinogen,  which
means  that  human data are  sufficient  to support  a causal association between
exposure and  cancer.   Therefore, 1t  1s  more  appropriate to  base  estimation
of carcinogenic potency on  human  rather  than animal data.
    U.S.  EPA  (1978b)  derived  a   slope  factor  of   0.024074  (ppm)'1   for
Inhalation  exposure  to benzene  based  on the  epidemiology studies  by  Aksoy
(1977),  Infante et  al.  (1977a,b)  and  Ott  et  al.  (1978).   In  estimating
excess  cancer  risk   associated  with  benzene  In  ambient  water,  U.S.  EPA
(1980a)  chose the  Inhalation  unit  risk  slope developed  by CAG  (U.S.  EPA,
1978b)  over  an  estimate  of  carcinogenic  potency  derived   from  the  first
positive  oral rat  study   (Maltonl  and  Scarnato,  1979).   The reasoning  for
this  decision 1s  that  1t   Is  more  appropriate  to base risk assessment  on
human  rather  than  animal data,  even  1f  route-to-route extrapolation  Is
Involved, when sufficient  human data are available.

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    In a  later CAG  assessment (U.S.  EPA,  19855),  an  Inhalation unit  risk
slope  of   2.60xlO"2  (ppm)"1  was  developed  from the  ep1dem1olog1cal  data
of Rlnsky  et al.  (1981),  Wong et  al.  (1983) and Ott  et al.  (1978).   This
estimate was considered as  "single best Judgment unit  risk  estimate"  by CAG
(U.S.  EPA,   1986b).   U.S.  EPA (1986b)  stated  that  this  slope  factor  was
equivalent  to  2.8xlO~r  (mg/kg/day)"1.    A  slope  factor  for  oral  exposure
was  calculated to  be  5.6xlO~2   (mg/kg/day)"1,  by  dividing the  Inhalation
unit risk slope with absorption factor for Inhalation (0.5).
    In a  recent CRAVE  meeting (March  1,  1988), the oral  slope factor  for
benzene  has  been  verified  to   be  2.9xlO~2  (mg/kg/day)"1  based   on  the
occupational  data  that  served   as  the  basis  of   the  slope  estimate  for
Inhalation  exposure  (Aksoy,  1977;  Ott  et al.,  1978;  Rlnsky et  al.,  1981).
The   unit    risk   for   oral   exposure   was   calculated   to   be   8.3xlO~7
(vg/l)"1  (U.S.  EPA,  1988).   It  should be  noted  that  the  more  recent
study  of  Rlnsky et  al.  (1987) has  not been  reviewed  by the U.S.  EPA and,
therefore,  results -from   this study   have  not  been  Integrated  Into  the
quantitative assessment that has  been verified by the CRAVE work group.
6.3.2.   Inhalation.  The U.S. EPA (1980a)  derived a cancer-based criterion
for  human  exposure to  benzene from the  epidemiology  studies of Infante  et
al.  (1977a,b), Ott  et  al.  (1978)  and Aksoy  (1977),  In  which a  significantly
Increased Incidence of  leukemia was observed for workers  exposed to benzene
principally  by  Inhalation.    Using  these  epidemiology   studies,  U.S.  EPA
(1978b) calculated  a  dose-response curve with a slope  of 0.024074  units  of
lifetime  risk/unit  (ppm)  of  continuous  exposure  to  atmospheric  benzene.
This  corresponds  to  a  slope  factor   of   7.52xlO~3   (mg/m3)"1.   Assuming
an Inhalation  rate  of  20  mVday  for a  70 kg  man, the  unit  risk  also  may  be
expressed as 3.76xlO~4 (mg/day)'1  or 2.6xlO~2 (mg/kg/day)'1.
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    In  a  later  evaluation  by  CAG (U.S.  EPA,  1985b),  an  Inhalation  slope
factor  of  2.60xlO~2  (ppm)"1  was  developed  from  the  epldemlologlcal  data
of  Rlnsky  et  al.  (1981),  Wong  et al.  (1983)  and  Ott  et  al.  (1978)  (see
Section  6.3.1.).   This  slope factor  transforms  to  2.8xlO~2  (mg/kg/day)"1
as determined by U.S. EPA (1986b).  The  Inhalation  carcinogenic:  slope  factor
for benzene was  verified by  the  CRAVE work group of EPA on March  1, 1988 to
be  2.9xlO"2  (mg/kg/day)"1,   based  on  the occupational  results  obtained  by
Rlnsky et al.  (1981), Ott et  al.  (1978)  and  Aksoy (1977).   The corresponding
Inhalation  unit   risk   Is    calculated   to   be  8.3xlO~*   (yg/m3)"1   (U.S.
EPA, 1988).
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Aksoy,  M.    1977.   Leukemia   In  workers  due  to   occupational  exposure  to
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Aksoy,  M.    1980.    Different  types  of  malignancies  due   to  occupational
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Gerner-Smldt, P. and  U.  FMedrlch.   1978.  The mutagenlc effect  of  benzene,
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Glrard,  R.  and L.  Revol.   1970.  The  Incidence of  exposure  to benzene  1n
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Greenburg,  L.   1926.   Benzol   poisoning as  an  Industrial  hazard.  VII.
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PolUnl,  G.  and  G.P.  Blscaldl.   1977.   Investigations  of  karyotype 1n  the

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                                 •
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U.S. EPA.  1978b.  Estimation of Population Cancer Risk  from  Ambient  Benzene
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Wong, 0..  R.W.  Morgan,  M.D. Whorton.  1983.  Comments  on  the NIOSH study of
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0037H
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