EPA-540/1-86-020
                                          Office of Emergency and
                                          Remedial Response
                                          Washington DC 20460
Off'ce of Research and Development
Office of Health and Environmental
Assessment
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
                     Superfynd
&EPA
                      HEALTH  EFFECTS ASSESSMENT
                      FOR ARSENIC

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                                            EPA/540/1-86-020
                                            September 1984
       HEALTH  EFFECTS ASSESSMENT
                FOR ARSENIC
    U.S. Environmental Protection Agency
     Office of Research and Development
Office of Health  and  Environmental Assessment
Environmental Criteria and Assessment  Office
            Cincinnati.  OH  45268
    U.S. Environmental Protection Agency
  Office of Emergency  and Remedial Response
Office of Solid Waste and Emergency  Response
            Washington,  DC  20460
           U S  Environmental  Protection  Agency
                           - Street
           Chicago, Illinois  60b04

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                                  DISCLAIMER

    This  report  has  been funded  wholly  or  1n  part by  the United  States
Environmental  Protection  Agency under  Contract  No.  68-03-3112  to  Syracuse
Research Corporation.  It has been  subject  to  the Agency's  peer  and adminis-
trative review, and  It has been approved  for  publication as an EPA document.
Mention of  trade  names or commercial  products  does  not  constitute  endorse-
ment 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 arsenic.
All  estimates of  acceptable Intakes  and  carcinogenic potency  presented 1n
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-line literature searches of the Chemical
Abstracts,  TOXLINE,  CANCERLINE  and  the  CHEMFATE/OATALOG  data  bases.   The
basic  literature   searched   supporting  this   document  1s   current  up  to
September,  1984.    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 fol-
lowing  Office of  Health  and Environmental Assessment (OflEA)  sources  have
been extensively utilized:

    U.S.  EPA.   1980b.    Ambient  Water  Quality  Criteria  for  Arsenic.
    Environmental Criteria and Assessment  Office,  Cincinnati,  OH.  EPA
    440/5-80-021.  NTIS PB 81-117327.

    U.S.   EPA.    1983a.     Reportable   Quantity   for  Arsenic   (and
    Compounds).   Prepared by the Environmental  Criteria  and Assessment
    Office,  Cincinnati,  OH., OHEA,  for the Office of Solid  Waste and
    Emergency Response, Washington, DC.

    U.S.  EPA.   19835.    Review  of  Toxlcologlcal  Data  In  Support  of
    Evaluation  for  Carcinogenic  Potential  of  Arsenic and  Compounds.
    Prepared  by  the  Carcinogen  Assessment Group,  OHEA,  Washington DC.
    for the  Office of Solid Waste and Emergency Response, Washington DC.

    U.S.   EPA.    1984.    Health   Assessment  Document   for  Inorganic
    Arsenic.   Environmental   Criteria  and  Assessment  Office.  Research
    Triangle Park, NC.  EPA-600/8-83-021F.  NTIS PB 84-190891.

    The Intent 1n these assessments  1s to  suggest acceptable exposure levels
whenever  sufficient  data  were available.  Values were  not derived or  larger
uncertainty  factors were  employed  when  the  variable  data  were  limited  1n
scope tending  to  generate conservative (I.e.,  protective)  estimates.  Never-
theless,  the Interim values  presented reflect the  relative  degree of  hazard
associated with exposure or risk to the chemlcal(s) addressed.

    Whenever possible, two categories  of values  have been estimated for sys-
temic toxicants (toxicants for which  cancer  1s  not the endpolnt of concern).
The  first,   the AIS or  acceptable  Intake  subchronlc.  Is 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 llfespan).   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 Is
assumed.    Animal  data  used  for  AIS  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.
                                      111

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    The  AIC,  acceptable Intake  chronic,  Is  similar  1n  concept  to the  ADI
(acceptable  dally  Intake).   It  1s  an estimate  of  an  exposure  level  that
would  not  be expected  to  cause  adverse effects  when  exposure occurs for  a
significant portion  of  the Hfespan [see U.S.  EPA (1980a) for a  discussion
of  this  concept].   The  AIC  1s  route  specific  and  estimates   acceptable
exposure  for  a given  route 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  ranking  reportable  quanti-
ties; the methodology for their development  1s explained  In U.S.  EPA (1983c).

    For compounds for which there  1s sufficient evidence of  carc1nogen1c1ty,
AIS  and AIC values  are not derived.   For  a  discussion of risk  assessment
methodology  for  carcinogens refer  to  U.S.  EPA  (1980a).  Since cancer  1s  a
process  that  1s  not characterized by  a  threshold, any  exposure  contributes
an Increment of risk.   Consequently,  derivation of AIS  and AIC values would
be Inappropriate.   For carcinogens, q-)*s  have been computed  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 1s  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  the  quantitative estimates presented.   In
addition,  the  preface  defines the terminology  used  1n the text and  summary
tables.

    Arsenic and compounds have been classified as  Group A  compounds-based on
evidence for excess cancer  risk  for  skin and lung cancers  In humans  exposed
to  Inorganic  arsenic  compounds.   The  evidence for  the  cardnogenlcHy  of
arsenic 1n experimental animals 1s equivocal.  The U.S. EPA (1984)  used data
on skin cancer  In  people 1n Taiwan exposed to arsenic  1n  the drinking water
to estimate  a unit  risk based on  oral exposure  of  15.0  (mg/kg/day)"1.   A
unit  risk  of  4.29xlO"3  (ug/m3)  for   Inhalation  was  estimated  from  four
ep1dem1olog1cal  studies  concerning  respiratory cancers  1n workers  at  two
copper smelters.  Applying the assumptions discussed 1n Section  6.3.2.,  this
value corresponds to a unit  risk  of 50.1 (mg/kg/day)"1.

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                               ACKNOWLEDGEMENTS


    The  Initial  draft  of  this  report  was  prepared by  Syracuse  Research
Corporation under  Contract  No. 68-03-3112  for EPA's  Environmental  Criteria
and  Assessment  Office,  Cincinnati,  OH.   Or. Christopher  DeRosa and  Karen
Blackburn were the Technical Project Monitors  and  Helen  Ball  was the Project
Officer.  The final documents  In this  series  were  prepared  for the Office of
Emergency and Remedial Response.  Washington, DC.

    Scientists from  the  following  U.S. EPA offices  provided  review comments
for this document series:

         Environmental Criteria and Assessment Office, Cincinnati, OH
         Carcinogen Assessment Group
         Office of Air Quality Planning and Standards
         Office of Solid Waste
         Office of Toxic Substances
         Office of Drinking Water

Editorial review for the document  series was provided by:

    Judith Olsen and Erma Durden
    Environmental Criteria and Assessment Office
    Cincinnati. OH

Technical support services for the document series was provided by:

    Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
    Environmental Criteria and Assessment Office
    Cincinnati. OH
                                      v1

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                              TABLE OF CONTENTS

1.
2.


3.










4.










ENVIRONMENTAL CHEMISTRY AND FATE 	
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS ....
2.1.
2.2.
ORAL . 	 	
INHALATION 	
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 	
3.1.


3.2.


3.3.


3.4.
SUBCHRONIC 	
3.1.1. Oral 	
3.1.2. Inhalation 	
CHRONIC 	
3.2.1. Oral 	 ,
3.2.2. Inhalation 	
TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 	 ,
3.3.1. Oral 	 ,
3.3.2. Inhalation 	 ,
TOXICANT INTERACTIONS 	 , . . ,
CARCINOGENICITY 	 .
4.1.


4.2.


4.3.
4.4.
HUMAN DATA 	 ,
»
4.1.1. Oral 	
4.1.2. Inhalation 	
BIOASSAYS 	 ,
4.2.1. Oral 	
4.2.2. Inhalation 	
OTHER RELEVANT DATA 	
WEIGHT OF EVIDENCE 	
P^qe
. . 1
. . 3
. . 3
. . 4
. . 6
. . 6
. . 6
. . 9
. . 9
. . 9
. . 12
. . 12
. . 12
. . 12
. . 12
. . 14
, . 14
. . 14
. . 16
. . 24
, . 24
, . 25
, . 25
. . 26
5.  REGULATORY STANDARDS AND CRITERIA 	   27

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                           TABLE  OF  CONTENTS (cont.)

                                                                         Page

 6.  RISK ASSESSMENT	    28

     6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS) 	    28
     6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)	    28
     6.3.   CARCINOGENIC POTENCY (q-|*)	    28

            6.3.1.   Oral	    28
            6.3.2.   Inhalation	    29

 7.  REFERENCES	    31

APPENDIX: Summary Table for Arsenic	    48
                                     V111

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                               LIST OF TABLES

No.                               TUIe                                Page

3-1     Subchronlc Oral Toxldty of Arsenic	     7

3-2     Chronic Oral Toxlclty of Arsenic	    10

4-1     Age-Exposure-Specific Prevalence Rates for  Skin Cancer.  ...    15

4-2     Data from Table 8 of Enterllne and Marsh (1982) with
        Person-Years of Observation Added 	    18

4-3     Observed and Expected Deaths from Respiratory Cancer,
        with Person-Years of Follow-up, by Cohort and Degree of
        Arsenic Exposure	    19

4-4     Observed and Expected Lung Cancer Deaths and Person-Years
        by Level of Exposure, Duration of Employment, and Age  at
        Initial Employment	    20

4-5     Respiratory Cancer Mortality 1938-1978 from Cumulative
        Exposure to Arsenic for 1800 Men Working at the Anaconda
        Copper Smelter	    24

6-1     Combined Unit Risk Estimates for Absolute Risk Linear
        Models	    30
                                     1x

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                            LIST OF ABBREVIATIONS
ADI                Acceptable  dally Intake
AIC                Acceptable  Intake chronic
AIS                Acceptable  Intake subchronlc
BCF                Bloconcentratlon factor
CAS                Chemical Abstract Service
CS                 Composite score
ONA                Deoxyr1bonucle1c acid
1050               Median lethal dose
NOAEL              No-observed-adverse-effect level
ppm                Parts per million
STEL               Short-term  exposure limit
TLV                Threshold limit  value
TWA                Time-weighted average

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                     1.  ENVIRONMENTAL CHEMISTRY AND FATE

    Arsenic  (atomic  weight 74.92)  Is a  nonmetal  or metalloid  belonging to
Group VA  of  the  periodic  table.   Elemental  arsenic has a CAS Registry number
of 7440-38-2.  The major stable valences of arsenic are 3-, 3+ and 5+.
    Arsenic  can  enter  aquatic media through atmospheric  wet  and dry deposi-
tion  (Boyle  and Jonasson,  1973),  through runoff  from  soils  and  through
Industrial discharge  Into  surface waters.  The processes  that are likely to
dominate  the  fate  of  arsenic  1n aquatic  media  are chemical  speclatlon.
volatilization,  sorptlon  and  blotransformatlon   (Callahan  et  a!.,  1979).
Generally,  arsenate  (As*  )   1s   the  dominant  species  In aquatic  systems.
However,  the  speclatlon  of   arsenic  1n  natural  waters  1s  significantly
Influenced  by the  presence  of  biota 1n the  water bodies.  The  biological
activities  1n water  may  reduce  arsenate Into arsenlte  (As* )  and  finally
                                                              i
to methylated arsenlcals  (As~3)  (Callahan  et a!.,  1979).   In  the  presence
of  biological activity  or a  highly  reducing condition,  arsenic  1n  water
                                                    •
bodies may  be converted to methyl  arsenics (AsH3).  These  latter compounds
are  volatile  and  may  evaporate  from  water, accounting for  some   loss  of
arsenic.  In  polluted  water  bodies, arsenic may form  complexes  with organic
compounds present  1n  the water.  Various sorptlon  and  subsequent  precipita-
tion of both arsenate and  organic  complexes of arsenic may reduce the level
of arsenic 1n  water bodies.   Clay,  Iron  oxides, and partlculate  matters high
1n organic content  are excellent materials  for the  sorptlon  of  arsenic from
aquatic media (Callahan  et  al.,  1979).   The precipitated  arsenic  may  be
metabolized  by a  number   of  organisms  to  organic  arsenlcals,  thereby  In-
creasing arsenic mobility In  the aquatic media (Callahan et al.,  1979).
                                     -1-

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    The major  source of atmospheric  arsenic 1s  coal  combustion  (U.S.  EPA,
1980b).   Other  sources  Include  smelting operations,  dust  fnom  the  earth's
crust, and vaporization  of volatile compounds  (Graedel,  1978).   The dominant
atmospheric  species  appears  to  be   arsenic   trloxlde  (As-O-)  (Graedel,
1978).  The  principal  removal mechanisms  for  atmospheric arsenic  appear  to
be wet and dry precipitation  (Graedel.  1978).
    Arsenic can enter the soil from wet and  dry  precipitation of atmospheric
arsenic,  from  runoff of surface waters  and from  disposal   of  arsenic-con-
taining waters.  The fate  of  arsenic  1n soil  1s  Inadequately studied.   How-
ever, the fate may be dependent  on the  nature  of soil.  The  factors that may
significantly determine  the fate of soil arsenic  are  organic  matter content,
                                                     *      •
clay  content  and  mlcroblal activity capable of  metabolizing arsenic.   Soil
containing  high   levels  of  sorptlve  materials,  such  as  clay  or  organic
matter, are likely to retard the Teachability  of  arsenic In  soils.  However,
                                                              i
arsenic may  leach Into  groundwater  from soils  with  low sorptlve  capacity.
Indirect evidence suggests that  leaching of arsenic from soils  Into  ground-
water may be quite common (Page,  1981).
    The BCFs for  arsenic 1n  aquatic  organisms have been determined by  a few
Investigators and  have  been found  to   vary  from 333-6000 (Callahan  et  al.,
1979).
                                     -2-

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           2.   ABSORPTION FACTORS  IN  HUMANS  AND  EXPERIMENTAL  ANIMALS
2.1.   ORAL
    Absorption of arsenic from  the GI  tract 1s  predominantly governed by the
solubility  of  the  specific  compound  administered  and  the  dosing  rate.
Coulson et  al.  (1935)  reported that solutions  of  either  trlvalent or penta-
valent  soluble  Inorganic arsenic compounds were  almost  completely  absorbed
from  the  GI  tracts  of  rats.   Solutions of arsenic  trloxlde have  been  re-
ported to  be  88% absorbed In rats (Urakabo et  al.,  1975;  Dutk1ew1cz, 1977),
90%  absorbed  1n  pigs   (Munro  et al.,  1974),  and 98%  absorbed  1n  monkeys
(Charbonneau et al., 1978).  Absorption  1s  reduced when  the  arsenic  trloxlde
Is  administered  as  a  suspension, with  40% of  the  administered  dose  being
absorbed by rabbits and 30% by rats  (Arlyoshl and Ikeda,  1974).
    Coulson et  al.  (1935) and  Ray-Bettley  and  O'Shea (1975) estimated  that
>95% of the Inorganic  arsenic  that man consumes 1s absorbed.  Slightly lower
                                                             >
estimates may be obtained from  the study of Mappes (1977), who  observed that
one human  subject  given a dally  dose  of -0.8 mg  trlvalent  arsenic  excreted
~70% of the dally  dose 1n the  urine each day.   Mappes  (1977) reported that,
1n contrast to  the high  absorption  of soluble  Inorganic  arsenic,  Insoluble
arsenic  trlselenlde  (As2Se3)  passed  through  the GI  tract  with  negligible
absorption.   Buchet  et  al.  (1981)  reported that  human  volunteers  treated
with  sodium  met a   arsenlte  that   provided  arsenic  at  125-1000  yg/day
excreted 60%  of their  dally dose 1n  the urine.  Steady  state was  achieved
within 5 days.
    Arsenic 1s present  In crustaceans  and fish  1n  a  highly complexed organic
form  known as  "shrimp"  arsenic.   The  pharmacoklnetlcs  of  this  form  of
arsenic have  been  Investigated  recently In  considerable detail  (LeBlanc  and
Jackson,  1973; Westoo  and Rydalv, 1972;  Munro,  1976; Edmonds et  al.,  1977;
                                     -3-

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Penrose et al., 1977; Crecellus, 1977; Edmonds and  Francesconl,  1977).   Col-
lectively, these studies  suggest that  "shrimp"  arsenic appears  to  be  exten-
sively absorbed and rapidly excreted as an  Intact organoarsenlcal  complex  by
man and animals and, therefore,  does not  appear  to be a health threat.
2.2.   INHALATION
    Absorption  of  arsenic  from the  respiratory tract  Is  governed  by  the
specific  chemical  compound  and, In  the  case  of  aerosols or  dusts, the  par-
ticle  size.   Particles  smaller than  1-2  ym  1n diameter  are  deposited  1n
the alveoli  and may, thus, be  absorbed  through the  respiratory epithelium.
Larger particles are predominantly  deposited  1n  the upper  respiratory  tract,
expelled by retrodHary movement,  and swallowed.
    The effect  of  solubility on the pulmonary retention  of arsenic compounds
was  Investigated  by Inamasu et al.  (1982),  who administered single  1ntra-
tracheal  doses  of  -2 mg  of  arsenic  as  arsenic  trloxlde (slightly soluble)  or
                                                              i
calcium arsenate (nearly  Insoluble)  to rats.  Groups  of  4-5 rats were  killed
at  Intervals  from  15  minutes  to 7 days after  treatment  and the  amount  of
                                                    *
arsenic  retained  1n  the  lungs  was measured.   At   15 minutes  after  treat-
ment,  the  amounts  of  arsenic recovered  from the  lungs  were  1146  and
620 yg,  respectively,  1n the calcium  arsenate  and  arsenic  trloxlde  treated
rats.  By 24 hours post-treatment,  almost  all the  arsenic trloxlde had been
cleared from  the lungs,  but -50X of the  calcium arsenate was retained.  Very
little  additional   clearance  of  calcium arsenate  was  observed  by  7  days
post-treatment,  while  the small amount of  arsenic  trloxlde remaining  at the
end  of  24 hours had been cleared.   These data  suggest that arsenic trloxlde
Is absorbed by  the  lung  to  a much greater extent than  1s calcium arsenate.
     Similar  conclusions  were  reached by  Pershagen  et  al.  (1982),  who  admin-
istered  4 weekly Intratracheal  doses of  arsenic trloxlde,  arsenic  trlsulflde
                                     -4-

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and calcium  arsenate  at  doses of 0.3, 0.5  and  0.5  mg arsenic, respectively,
to  Syrian  golden hamsters. ' In  animals  sacrificed Immediately  after  treat-
ment, the  lung  contents  of arsenic were 386, 755 and  866  mg/kg  1n the above
three treatment  groups,  respectively.  At  the  end  of the  fourth treatment,
lung contents  of arsenic were -0.3,  3.0 and 800 mg/kg,  respectively.  Mor-
tality and severe  lung  damage occurred only  1n  the calcium arsenate treated
hamsters.
    Outk1ew1cz  (1977) observed  similar tissue distribution  dynamics  1n rats
following  either  Intratracheal  or Intravenous administration  of pentavalent
arsenic. Indicating  extremely rapid  absorption  across the  respiratory epi-
thelium.  Rapid absorption has also been observed  1n  rats  and mice following
exposure  to   condensation  aerosols  of  arsenic  trloxlde   (1.0,   3.7  or  46
vg/m3)  (Rozenshteln,  1970)  or  a  solid aerosol  of  fly  ash  containing  180
yg  arsenlc/m3  (Bencko and  Symon, 1970).   Pinto et  al.  (1976)  found that,
                                                             i
1n  workers at  a copper  smelter, urinary  excretion  of  38-55  yg arsenic/1
occurred 1n  men  exposed to  atmospheric concentrations  ranging  from 3-295
                                                   *
vg/m3.   Smith  et  al.   (1977)  reported that  urinary  levels  of  trlvalent,
pentavalent,   methyl- and  dimethylarsenic   1n  copper  smelter  workers  were
directly  correlated   with  atmospheric  concentrations.   In  a  quantitative
study, Holland  et  al. (1959) found  that,  within 4  days,  75-85%  of  the  de-
posited  arsenHe was absorbed  from  the lungs  of  a group  of   lung  cancer
patients who  Inhaled arsenlte-contalnlng  aerosols  or  smoke  from arsenlte-
contalnlng  cigarettes.
                                     -5-

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                3.  TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
    In general,  the  rat 1s not a good  model  for  arsenic toxldty.  Lanz  et
al. (1950)  found  that,  1n contrast to  other  mammals,  the rat stored 79%  of
an  Intramuscularly  administered  arsenic dose  bound  to hemoglobin  1n red
blood cells.   Cats  were  found  to accumulate  5.6% 1n the  blood,  and  dogs,
chicks,  guinea  pigs  and  rabbits  stored <0.27% 1n  the blood.  This binding
results  1n  an  extremely slow excretion  of  arsenic  by rats  as compared with
other species,  Including man, following Intravenous  administration (Ducoff
et al.,  1948;  Mealey et  al., 1959).   Blood levels are  much  higher In rats
(125 ppm)  than  1n guinea pigs  (4  ppm), rabbits  (1.5  ppm)  or hamsters (2.5
ppm) following  administration of  diets  containing 50 mg  arsenic tMox1de/kg
diet for  21 days (Peoples,  1975).   For this  reason,  toxldty  data 1n rats
cannot be reliably extrapolated to man.  The  subchronlc  and chronic  toxldty
of arsenic  depends  principally on  the  chemical  form,  physical  state, par-
                                                              i
tlcle size and  solubility  of  the  material   tested.   Generally,   Inorganic
trlvalent arsenic 1s  regarded to  be  more  toxic  than the pentavalent  form.
Methylated  forms  appear  to  be less toxic and "shrimp" or "fish" arsenic  Is
generally regarded as non-toxic (NAS, 1977; Pershagen  and Vahter, 1979; WHO,
1981).
3.1.   SUBCHRONIC
3.1.1.   Oral.    The  subchronlc  oral  toxldty of  arsenic Is  summarized   In
Table 3-1.  Byron et al. (1967)  administered  diets containing  0,  5, 25,  50
or 125 mg  arsenic/kg  diet,  as either  sodium arsenHe  or  sodium arsenate,  to
groups of three male and  three female beagle  dogs for up to 2 years.   Sodium
arsenHe was more toxic  than  sodium arsenate,  with  5/6 dogs 1n  the  high-dose
group dying or  becoming moribund following  3-9  months  of   treatment.  The
no-effect level was  50 mg/kg diet  for  both compounds.
                                     -6-

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                                                                   TABLE  3-1

                                                      Subchronlc  Oral  Toxtclty  of  Arsenic
Compound
Sodium
arsentte
Sodium
ar senate
Arsenlc(III)
oxide
Species/
Strain
dog/beagle
dog/beagle
rat/Ulstar
Dose
0, 5. 25. 50
or 125 mg
arsenic/kg diet
0, 5. 25. SO
or 125 mg
arsenic/kg diet
0, 0.125. 12.5
or 62.5 mg
arsenlc/ft h^O
Length of
Exposure
up to 2 years
up to 2 years
7 months
Effects Reference
t
Slight to moderate anemia, anorexia, Itstlessness, Byron et al.. 1967
and decreased body weight In high-dose group.
5/6 died between 3 and 9 months, and all were
dead by 19 months. No effects at doses of
<50 mg/kg diet.
At a dose of 125 mg/kg diet, one dog had severe Byron et al.. 1967
weight loss and died by 13.5 months. All had
mild anemia and granular Iron-positive pigment
In liver macrophages. No effects at a dose of
<50 mg arsenic/kg diet.
Slightly decreased water consumption In high-dose Ishlntshl et al.. 1980;
group. Dose-related Increase In absolute and Hlsanaga, 1982
relative liver weight, degenerative changes In
Calcium
arsenate
(probably)


NR
human
human/
Infants
3 mg/day
NR
2-3 weeks
•a few
months*
Arsenlc(III)  human
oxide or
arsenic
trtsulftde
             2.5 mg arsenic/
             day or 10.3 mg
             arsenic/day,
             respectively
                  dally for
                  several
                  months or
                  •Intermit-
                  tently1  for
                  up to 15 years
liver, and sloughing of the kidney tubular
epithelium.

Facial edema and anorexia In 187/220.  Less than
10X with exanthemata, desquamatlon. and
hyperplgmentatton.  Approximately 20X with
peripheral neuropathy.

Coughing, rhlnorrhea. conjunctivitis, vomiting.
dtaiVhea, melanosls. fever, abdominal swelling.
hepatomegaly, anemia, granulocytopenla. abnormal
electrocardiograms.' Increased density at
eptphyseal ends of long bones.  Symptoms were
reversible, except for a retardation of ulnar
growth.  Follow-up Indicated Increased Incidences
of leukomelanoderma. keratosls. mental retardation.
growth retardation and epilepsy.

Polyneuropathles In -SOX of 74 patients.  Hyper-
pigmentation and hyperkeratosts.
Nlzuta et al.. 1956
Nasahlkl and Hldeyasu. 1973;
Okamura et al., 1956;
Satake. 1955; Nagal et al..
1956
                                                                      Tay and Sean.  1975

-------
    Ish1n1sh1 et al. (1980) and Hlsanaga  (1982) administered  0,  0.125,  12.5,
or 62.5 mg  arsenlc/l drinking water,  as  arsenlc(III)  oxide, to  Wlstar  rats
for 7 months.   Most of the arsenic-treated  rats  had cloudy  swelling of  the
hepatocytes, spotty coagulatlve necrosis,  proliferation  of  Interlobular  bile
ducts, and  angltls  of  adjacent  blood vessels.   Sloughing  of   the  tubular
epithelium was observed In the kidneys from all  three treatment  groups.
    Two studies  In humans present  useful dose-response  Information  (Mlzuta
et al.,  1956; Tay and Seah,  1975).  Tay  and  Seah  (1975)  Investigated  74
patients   1n  Singapore  who   had  Ingested  arsenic-containing  antlasthmatlc
herbal preparations  for periods  ranging  from <6 months  to (Intermittently)
15 years.   Doses  were  estimated to be  2.5  mg arsenic/day  as  arsenlc(III)
oxide or  10.3 mg  arsenic/day as  arsenic sulfldes.   The organ  systems  In-
volved were  cutaneous  (91.9%), neurological  (51.3%),  GI  (23%),  hematologlcal
(23%) and  renal  and others (19%);  5.4% of the patients  had  Internal  mallg-
                                                             *
nancies.   The major effects,  occurlng  In  more than  10% of the subjects, were
generalized  hyperplgmentatlon (arsenic melanosls),  hyperkeratosls of  palms
                                                   •
and  soles,  "raindrop"  deplgmentatlons,  palmar  and  plantar  hyperhldrosis,
multiple  arsenical  keratoses,   sensorlmotor  polyneuropathy,   fine   finger
tremors,  persistent  chronic  headache, lethargy,  weakness and Insomnia, psy-
chosis,  gastritis  or   gastroenteritis,   mild  Iron  deficiency   anemia  as  a
result  of   toxic  marrow  suppression,  and  transient  albumlnurla  without
azotemla.   The  Internal malignancies  consisted of  two  squamous-cell  carci-
nomas of  the lungs, one squamous-cell carcinoma  of  the  gall  bladder  and one
hemanglosarcoma  of the  liver.  Mlzuta et  al. (1956)  observed similar neuro-
logical effects  1n people  who consumed ~3 mg arsenic/day 1n  contaminated soy
sauce for 2-3 weeks.
                                     -8-

-------
 3.1.2.    Inhalation.   A gaseous arsenic  compound,  arslne. has  a  high acute
 toxlclty  and can  be  formed  1n  the  environment under conditions  of low pH,
 high  reducing  potential  and low  oxygen pressure,  or   as  a  by-product of
 Industrial  processes  (Callahan  et  al., 1979;  ACGIH,  1980).   Other Investi-
 gators  have  Indicated  that  airborne  arsenic compounds  are  associated  with
 skin  lesions, cardiovascular and respiratory effects,  and peripheral neuro-
 pathy,  but no  adequate exposure Information  Is  available for  any of these
 studies  (Stoklnger,  1981;  IARC, 1980;  ACGIH, 1980; U.S.  EPA,  1980b; NIOSH,
 1975).
 3.2.   CHRONIC
 3.2.1.    Oral.   The chronic oral toxlclty of  Inorganic  arsenic compounds 1s
 summarized  In Table  3-2.   The most  common  effects observed  In humans  were
 skin  lesions,  peripheral   vascular  disease   and  peripheral  neuropathy.   In
 experimental   animals,   decreased   survival   without  apparent   cause  was
 frequently  observed.   The  only  species,  other than  human,  1n  which  dermal
 pathologies  were observed was the mouse,  and  these changes  were  relatively
 mild  and  did  not Include  skin  cancers.  Peripheral  neuropathies  were  not
 observed  1n any  experimental  animals tested.  Hepatic  degenerative changes
 and renal damage were frequently observed In rats, but not 1n other species.
    Tseng  (1977)  Investigated the relationship between  blackfoot  disease,  a
 peripheral  circulatory  disease characterized  by gangrene of the extremities,
 and the  arsenic concentration 1n drinking water  of residents  of  the south-
 west  coast  of  Taiwan.   A  total of  40,421  Individuals  In 37  villages  were
 Included  In the  study.  Arsenic concentrations  ranged   from 0.001 to  1.82
mg/i.    The  overall   prevalence  rate  for blackfoot  disease was  8.9/1000,
with a positive  correlation between  the prevalence rate  and  arsenic concen-
 tration and duration  of  Intake.   This study  established a  NOAEL  of  0.001-
0.017  mg/a for blackfoot disease.

                                     -9-

-------
                                                                           TABLE 3-2

                                                                Chronic  Oral  Toxlclty  of Arsenic
o
i
Compound
Arsenlc(III)
oxtde
Sod tin
arsenlte
Sodium
arsenate
Sodlun
arsentte

Sodium
arsentte
Sodium
arsenate
Lead
arsenate
Species/
Strain
•Ice/Swiss
rats/NR
rats/NR
rats/Long-
Evans

mice/CD
rats/Utstar
rats/Utstar
Dose
0.01X In
drinking water
0. 15.63, 31.25.
62.5. 125 or
250 *g arsenic/
mg diet
0. 15.63. 31.25.
62.5. 125. 250
or 400 mg
arsenic/kg diet
5 tig/ml H20

5 vg/M H20
100 mg arsenic/
kg diet
100 or 399 mg
arsenic/kg diet
Length of
Exposure
•lifetime"
2 years
2 years
-2 years

-1 years
29 Months
29 Months
Effects ' Reference
Slight hyper ker at os Is with occasional areas of Baronl et al.. 1963;
epidermal hyperplasla. Shubtk et al.. 1962
Decreased survival and body weight and enlargement Byron et al.. 1967
of common bile duct at high-dose level. Slight
decrease In body weight and enlargeMent of common
bile duct at 125 mg/kg diet.
400 mg arsenic from sodium arsenate produced
approximately the same effects as 250 mg arsenic from
sodium arsentte. Slight decrease In survival and
body weights and enlargement of the conmon bile
ducts In 250 mg/kg diet group.
No effect on growth, longevity or hlstopathology. Schroeder et al., 1968
Increased serum cholesterol and decreased serum
glucose In males.
Decreased survival rates and longevity. No treat- Schroeder and Balassa. 1967
ment-related htstopathologlcal effects.
No effects on survival, body weight gain, food Kroes et al.. 1974
consumption, blood hemoglobin levels, erythrocytes.
gross anatomy or histology.
In the high-dose group, males had decreases In blood
hemoglobin values and packed cell volumes. Food
                                                                    consumption and body weight  were decreased  and
                                                                    mortality was  Increased In both sexes.   Htstopatho-
                                                                    loglcal  changes fncluded enlarged bile  ducts.
                                                                    bile duct proliferation, pertcholangltls,
                                                                    cholangloftbrosls.  and Intranuclear  eoslnophlllc
                                                                    Inclusions. In  the kidneys.  No effect at a  dose
                                                                    of 100 mg/kg diet.

-------
                                                               TABLE  3-2 (cont.)


1
1
Compound
NR
NR
Species/
Strain
human/NA
human/NA
Arsentc(III) human/NA
oxide
NR - Not
reported
Bose
O.S98 mg
arsenlc/l
H20
0.01-1.82 mg
arsenic/ft HjO
8.8 mg/day

Length of
Exposure
IS years
>4S years
28 Months

Effects
Leukomelanoderma. hyperkeratosls. chronic coryia,
abdominal pain, Raynaud's syndrome
Hyperptgmentatton, keratosls. sktn cancer.
blackfoot disease
Characteristic dermal lesions and peripheral
neuropathy

' Reference
Zaldlvar and Ghat. 1980;
Borgono and Grelber. 1972;
Zaldlvar. 1974; Borgono
el al., 1977
Tseng et al.. 1968;
Tseng. 1977
Silver and Ualmun. 1952

NA . Not applicable

-------
3.2.2.   Inhalation.   Chronic  Inhalation  exposure  to  arsenic   compounds
results 1n  symptoms  similar  to those observed following oral  exposure.   For
example.  Landau  et  al.  (1977) reported  a direct  relationship between  the
length  and  Intensity of  exposure of  smelter workers  to  airborne  arsenic,
predominantly as arsenic trloxlde, and alterations  In peripheral  nerve func-
tion.   No studies  were  available  1n which exposure  levels are characterized
to an extent sufficient for the determination  of  dose-response relationships.
3.3.   TERATOGENICITY AND OTHER REPRODUCTIVE  EFFECTS
3.3.1.   Oral.  Hood et al.  (1977)  reported  that oral administration  of  120
mg  sodium arsenate/kg  bw to mice during  pregnancy  had  less  of an  effect on
prenatal mortality,  reduction 1n fetal  weight,  or  the  occurrence  of  fetal
malformations  than  did  Intraperltoneal   administration  of  40  mg/kg  bw.
Hatsumoto et al. (1973a,b) reported  that  oral  doses  of  up  to 40 mg/kg bw/day
for  3  consecutive  days  resulted 1n  decreased  fetal  weights;  however,  admln-
                                                              i
1strat1on  of  diets containing  up  to 100  mg  arsen1te/kg   diet   (~5  mg/kg
bw/day) throughout  pregnancy  had  no effect on the  offspring  (Kojlma,  1974).
Baxley  et al.  (1981) Indicated that a single  oral  dose  of 40-45  mg/kg bw on
any  gestation day  between days  8-15  will  produce adverse effects 1n develop-
ing mice.
3.3.2.   Inhalation.   No  data pertinent  to  the  teratogenldty  or   other
reproductive  effects  of  Inhaled  arsenic were located  1n  the  available
literature.
3.4.    TOXICANT INTERACTIONS
     The  best-known  Interactive  effect   of   arsenic Involves  a  protective
effect  In  cases  of  selenium poisoning.   Hoxon  (1938)  found   that  5  mg
arsenlc/i  H-0,  as  sodium  arsenlte,  prevented  liver   damage  In   rats  fed
                                     -12-

-------
diets containing  15 mg  selenium/kg  diet.   In  a  later study  Dubols  et al.
(1940)  determined  that  sodium arsenHe  and  sodium arsenate  were equally
effective, but that the arsenic sulfldes were  Ineffective.
                                    -13-

-------
                             4.  CARCINOGENICITY
4.1.   HUMAN DATA
4.1.1.   Oral.    Numerous   arsenic   compounds,    particularly    trlvalent
Inorganics, have  been associated with  lung and  skin  carcinomas   1n  humans.
Tseng et al.  (1968) and Tseng  (1977)  surveyed  40,421  residents  of Taiwan who
consumed  artesian well  water   containing  0.01-1.8  mg  arsenlc/l for  45-60
years.  A dose-response relationship  (Table 4-1)  was  established  between the
prevalence of skin cancer  and  arsenic consumption, based on arsenic  concen-
trations 1n different wells and length of exposure (age).   The  overall  Inci-
dence of  skin cancer  was  10.6/1000,  with  a maximum  Incidence  of 209.6/1000
1n males over 70 years of age.
    Arsenic sulfldes and arsenic trloxlde have also  been associated with the
development  of  malignancies  1n 74   patients  1n  Singapore (Tay and  Seah,
1975).  These patients  had consumed  herbal preparations containing  arsenic
for  up  to  15   years.   Malignancies  of  the   skin  were  reported  1n  6/74
patients, and malignancies of  the Visceral  organs 1n 4/74.
    In  contrast,  Morton  et al.  (1976)  found  no Increase 1n  skin  cancer
Incidences In an  area of  Oregon where  arsenic levels 1n the drinking  water
are  high.   No  Increase  1n Internal  malignancies was  observed  1n  patients
treated  with  arsenlcals  for  various  skin diseases,  although  an  Increased
Incidence of  basal-cell  carcinoma  was observed  1n females  (Reymann  et  al.,
1978).
    Cuzlck et al. (1982)  reported on  a cohort  study of patients treated with
Fowler's solution  (potassium arsenlte).   They  found an  excess  of both  fatal
and  nonfatal  skin  cancers, often  associated  with  other  signs   of  chronic
arsenic  poisoning.   They  hypothesized  the existence  of a susceptible  sub-
population that  Initially develops  dermatologlcal symptoms, followed  by the
development of skin cancers.

                                     -14-

-------
                                   TABLE  4-1
            Age-Exposure-Specific  Prevalence  Rates  for Skin Cancer3
Exposure In ppm&
0-0.29
(0.15)
0.30-0.59
(0.450)
>0.6
(1.2)

20-39
(30)
0.0013
0.0043
0.0224
Aqe
40-59
(50)
0.0065
0.0477
0.0983
*

>60
(70)
0.0481
9.1634
0.2553
aSource: Tseng et al., 1968
''Range given by authors.  Midpoint Is 1n parentheses.
                                     -15-

-------
4.1.2.   Inhalation.   Numerous  Investigators  have  reported  an  association
between  occupational   exposure  to  arsenic  and  the  development  of  tumors.
This  exposure  Is presumably  largely by  the  respiratory  route.   Pinto  and
Bennett  (1963)  failed to  find  an association  between  arsenic exposure  and
tumor formation  1n  copper  smelter  workers;  however, a follow-up  study  found
an Increase  1n  deaths  from all  cancers, particularly respiratory cancer,  at
th1,s  smelter  (Pinto   et   al.,  1978).   Numerous  other  Investigators   have
reported an  Increase  1n lung cancer  among  arsenic-exposed workers,  but  the
exposure  concentrations  are  Insufficiently characterized  for use   1n  risk
assessment  (Axelson et al.,  1978;  Lee and  Fraumenl,  1969; Rencher  et  al.,
1977; Tokudome  and  Kuratsune,  1976;  Osburn,  1969; Pershagen  et  al.,  1977;
H111 and Fanlng, 1948; Perry et  al., 1948;  Ott  et al., 1974).
    The  U.S.  EPA (1984) used an  absolute-risk  linear  model  applied to  the
data  from  four epldemologlcal  studies  Involving  copper  smelters.   Those
studies  are  briefly reported  here;  however, U.S. EPA  (1984)  provides a more
exhaustive  discussion  of  these  studies and  other  studies  that did  not lend
themselves to quantitative risk  assessment.
    The  four  studies  from which  the  U.S.  EPA  (1984)  derived  unit  risks  for
respiratory  cancer  all  deal  with   different  cohorts  of  workers  at  the
Anaconda  copper smelter   1n  Montana  (Brown  and Chu,  1983;  Lee-Feldste1n,
1983; H1gg1ns  et al., 1982)  or  the ASARCO smelter 1n Tacoma,  WA (Enterllne
and Marsh, 1980, 1982).
    In  the  Tacoma,  WA,  case, Enterllne and Marsh  (1980,  1982)  studied  the
vital statistics of a  cohort  of male workers who were employed 1n the period
1940-1964.   Since work-related  exposure for >1  year was  required for Inclu-
sion  1n  the cohort,  follow-up did not  begin until  1941  and extended through
                                     -16-

-------
1976.   The  cohort Initially contained  2802 Individuals.  The  vital  statis-
tics  of 51  could  not  be verified, so  final  studies Involved  2751  persons;
results  are  presented  In  Table  4-2.   During  this  period,  1061  deaths
occurred.  A significant Increase  1n deaths due  to  cancers  (all respiratory)
was  noted.  Arsenic  exposure  for  each  worker  was estimated on  the  basis  of
average urinary arsenic of workers In each  department  factored by the length
of  time each  worker  remained  1n  that  department.  When  estimated  this  way,
Enterllne and  Marsh   (1980,  1982)  observed a  dose-related  response  between
estimated arsenic exposure and the Incidence of lung cancer.
    The other  ep1dem1olog1cal  studies  concern statistics that  were  gathered
from  workers   at   the  Anaconda  copper   smelter   In  Montana.   Lee-Fe1dste1n
(1983)  studied the mortality of workers  from this plant from 1938-1977.   The
8045  workers  were assigned to  cohorts  on  the basis of  length  of  exposure:
cohort  1  worked >25  years,  cohort 2,  15-24  years,  cohort  3,  10-14  years,
cohort  4, 5-9  years  and cohort 5,  1-4  years.   SMRs were calculated  by  com-
paring  the  Incidences  of 13 causes  of  death among  the workers  to  those  of
the  combined male  populations  of  three  western states.   Of  the 13  causes  of
death considered,  only death  due  to respiratory  cancer  showed  a significant
Increase 1n the ratio of observed  to expected  deaths coupled with a positive
gradient related to length of  employment (Table 4-3).
    Brown and  Chu  (1983)  further  discussed the  data and conclusions  of the
Lee-Feldste1n   (1983)  study,  particularly  regarding   the   suitability  of
applying the  multistage  theory  of cancer  to  these  data (Table 4-4).  They
Indicated that  the observation  of an  Increasing risk  of  lung  cancer  mor-
tality  at Increasing  age of Initial exposure  and the  observation  that  mor-
tality  appeared  to   be  Independent  of  time  after  exposure  ceased  were
evidence that  arsenic acts  as  a late-stage carcinogen.
                                     -17-

-------
                                  TABLE 4-2

                Data from Table 8 of Enterllne and Harsh (1982)
                    with Person-Years  of  Observation Added
Cumulative Exposure3       Person-Years         Observed            Expected
    iig/m'-years           of Observation*1       Deaths              Deaths
                                               0 Lag
          91.8                10,902               8                 4.0
         263                  21,642              18                11.0
         661                  14,623              21                10.3
        1381                  13,898              26                14.1
        4091                    9398              31                12.7

                           	10-Year Lag 	
          91.8                27,802              10                 6.4
         263                  16,453              22                12.5
         661                  11,213              26                11.5
        1381                    9571              22"               12.4
        4091                    5423              24                 9.7
Exposures are 1n  yg/m3  —  years  estimated by the formula  (I yg/i-years)
 (0.304)  where  I  Is  mean  urinary  exposure Index  from  Enterllne and  Marsh
 (1982) and 0.304  Is the  relation  between  urinary  and  airborne arsenic  esti-
 mated by Pinto et al.  1977.

bFurn1shed by Dr. Enterllne (personal communication to  U.S.  EPA, 1984)
                                     -18-

-------
                                  TABLE 4-3

          Observed and Expected Deaths from Respiratory Cancer,  with
     Person-Years of Follow-up, by Cohort  and Degree of Arsenic  Exposure3
Maximum Exposure to Arsenic (>12
Years of
Exposure
25 years*
15-24
<15 years
Heavy
Obs/Expc
13/2.5
9/1 .3
11/2.4

P-Yd
2400
2629
6520
Medium
Obs/Exp
49/7
13/4.0
31/9.3

P-Y
6837
6509*
24,594
months)13
L1qht
Obs/Exp
51/16.3
16/ 8.6
69/31


P-Y
14,573
12,520
78,245
aSource:  Lee-Feldste1n, 1983

bThe  1562  men who  worked <12 months  1n their  category of maximum  arsenic
 exposure were not Included 1n this table.

C0bserved/Expected

^Person-years  of  follow-up  furnished by  Dr.  Lee-Feldste1n  (personal  com-
 munication to U.S.  EPA, 1984).
                                     -19-

-------
                                TABLE 4-4

      Observed and Expected Lung Cancer Deaths and Pers.on-Years by
Level of Exposure, Duration of Employment, and Age at Initial Employment*
Duration of Employment (years)
Age at Initial
Employment
H1qh Exposure Level
<20 Obs
Exp
Pyr
20-29 Obs
Exp
Pyr
30-39 Obs
Exp
Pyr
40-49 Obs
Exp
Pyr
50^. Obs
Exp
Pyr
0-9
Group
0
0.001
206
0
0.008
624
0
0.030
398
0
0.083
210
0
0.066
78.0
10-19

0
0.009
408
0
0.051
637
0
0.077
207
0
0.054
80.0
0
0.027
23.2
20-29

0
0.065
588
2
0.164
495
3
0.106
155
0
0.034
49.1
0
0.0
0.0
30-39

3
0.249
499
0
0.277
308
0
0.053
59.1
0,
0.007
6.88
0
0.0
0.0
40+

0
0.193
172
2
0.082
64.4
0
0.001
0.86
0
0.0
0.0
0
0.0
0.0
Medium Exposure Level Group
<20 Obs
Exp
Pyr
20-29 Obs
Exp
Pyr
30-39 Obs
Exp
Pyr
40-49 Obs
Exp
Pyr
0
0.010
1801
0
0.035
2636
0
0.167
1939
0
0.167
1190
0
0.039
1763
0
0.118
1622
0
0.473
1137
0
0.414
448
1
0.171
1500
2
0.331
1099
1
0.329
438
1
0.098
98.9
4
0.591
1206
4
0.717
951
3
0.161
194
3
0.010
12.1
1
0.597
579
7
0.514
654
0
0.045
68.2
0
0.0
0.0
                                   -20-

-------
                               TABLE  4-4  (cont.)
Duration of Employment (years)
Age at Initial
Employment
<50+


Low Exposure
<20


20-29


30-39


40-49


50+


Obs
Exp
Pyr
Level
Obs
Exp
Pyr
Obs
Exp
Pyr
Obs
Exp
Pyr
Obs
Exp
Pyr
Obs
Exp
Pyr
0-9
0
0.262
295
Group
0
0.056
8524
0
0.115
9951
0
0.390
5218
2
1.29
3703
3
1.62
1945
10-19
0
0.076
71.2

0
0.117
5249
0
0.334
4724
3
0.802
2218
1
1.18
1319
2
0.385
371
20-29
0
0.011
14.5

1
0.478
4038
2
0.892
2965
1
0.937
1364
1
0.344
386
0 "
0.041
65.4
30-39
0
0.0
0.0

1
1.59
3175
5
1.74
2117
0
0.662
715
l'
0.035
52.7
0
0.0
0.0
40+
0
0.0
0.0

3
1.57
1376
6
0.796
834
1
0.062
74.6
0
0.001
2.00
0
0.0
0.0
*Source: Brown and Chu, 1983
                                     -21-

-------
    In another study of  the  same smelter, H1gg1ns et al.  (1982)  reported  on
a sample of  1800  workers,  277 from a "heavy exposure category" and  a  random
sample (20%)  of  the remaining known  workers.   Workers  with at least  1  year
of work  experience  were entered  Into   the  study.  Smoking  histories  were
obtained.  SMRs were calculated by comparison with the  white  male population
of Montana and also of the United  States.   Estimates of workroom  atmospheric
concentrations of  arsenic  for 52  smelter departments  were based on  Indus-
trial hygiene records for the years 1943-1965 or  by  analogy with  those areas
In which the  concentrations  were  known.  The  departments were  classified
Into four categories  based  on atmospheric arsenic concentration:   low,  <100
vg/ma;   medium,    100-499    vg/ma;    high,   500-4999    »ig/m3;    or    very
high, >5000 yg/m3
    The  data  were analyzed  by five exposure/follow-up  methods  that  differed
primarily In the  amount of  overlap  permitted  between exposure   period  and
                                                             i
follow-up period.  Data  analysis method  I  was the primary method  used by the
authors  and  Included the  worker's arsenic exposure  up  to  the time  he  was
entered  Into the  cohort with follow-up  from  day of  entry until  1978.   No
overlap  between  exposure and follow-up  occurred.  Method  IV,  exposure  from
date  hired  until  1964  and follow-up from 1964-1978,  also had  no  overlap.
Complete  overlap  was  permitted  1n  methods II  and V.   Method  II  Involved
exposure  from date  hired  through 1964  and  follow-up  from  1938-1964  and
              \
method V Involved  exposure from  date  hired to  termination and follow-up from
1938-1978.   Partial  overlap  occurred  with method  III;  exposure from date of
hire to  1964 and follow-up from 1938-1978.
    Analysis  of  the data obtained  (presented  In Table  4-5)  resulted  1n the
following  conclusions:   (1)  that  exposure  to  arsenic  In the workroom was
strongly correlated with  excess  mortality  due  to  respiratory  cancer;  (2)
                                     -22-

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                                  TABLE  4-5
        Respiratory  Cancer  Mortality  1938-1978  from  Cumulative  Exposure
        to  Arsenic for  1800 Hen Working at  the  Anaconda Copper  Smelter3
Cumulative
Exposure
pg/m3-years
0-500
(250)b
500-2000
(1250)
2000-12,000
(7000)
>12,000
06,000)
Person-Years
of Observation
13,845.9
10,713.0
11,117.8
9015.5
Observed
Deaths
4
9
27C
40C
Expected
Deaths
5.8
t
5.7
6.8
7.3
aSource:  H1gg1ns et al., 1982
^Numbers 1n parentheses Indicate assumed average exposures.
C51gn1f1cant at 0.01 level
                                     -23-

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exposure  to other  occupational  contaminants,  such  as  sulfur  dioxide  and
asbestos  did  not appear  to  cause excess  deaths  due to  respiratory  cancer;
(3) smoking accounted for only  a  small  fraction of  excess respiratory cancer
deaths;  (4)  the  SMRs reflected Increased  Incidences  of  excess  lung  cancers
positively correlated with exposure category; and (5) that  SMRs  dropped sub-
sequent  to  1923 when  additional  methods  were Instituted  that  resulted  1n
Increased arsenic fume and dust recovery.
4.2.   BIOASSAYS
4.2.1.   Oral.   Animal  bloassays  with  a variety  of  arsenic compounds  have
generally produced negative  results.   Hueper  and  Payne (1962) and  Baronl  et
al. (1963)  administered 0.0034%  or  0.01% arsenic  tMoxIde In  the  drinking
water   to  mice.   No Increase  1n tumor  Incidence was observed at either dose
level.  In a similar study,  Kanlsawa and Schroeder  (1967, 1969}  administered
5  mg  sodium arsen1te/l drinking  water  to mice  or 5  mg  sodium  arsenate/J.
                                                              >
to  rats  over  their entire Hfespan  without  producing any  Increase  1n tumor
Incidence.  Hueper and  Payne (1962) found  that  drinking water  levels  of  up
to  34 mg  arsenic  tr1ox1de/l  had  no  effect  on  tumor  Incidences 1n  rats.
Both  sodium  arsenate and sodium  arsenlte  were found to  be  Ineffective 1n a
2-year  feeding   study  In dogs  fed  diets  containing arsenic,  as  at  levels
between  5-125 mg/kg  diet  (Byron et  al., 1967).   Shlrachl  et al.  (1983)
reported  that sodium arsenlte did not  Induce renal  tumors  (species  unspeci-
fied)   but did Increase  the  Incidence of d1methyln1trosam1ne-1n1t1ated kidney
tumors.   These  authors,  therefore,  considered   arsenlte  to  be  a  tumor
promoter.
    Other Investigators have reported  tumorlgenlc  effects  of  arsenic treat-
ment.    Schrauzer et  al.  (1978)  reported  that an  unspecified  arsenic com-
pound,  at a concentration of  2 mg/l drinking water, fa-lied  to  Increase the
                                     -24-

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number  of  treated  female  mice  bearing mammary  adenocardnomas,  but  the
growth rate  and  Incidence of multiple  tumors  In tumor-bearing animals were
Increased.   Knoth  (1966/1967),  In a  brief  and  Incomplete  report, found an
Increase In adenocardnomas of the skin, lung, peritoneum and  lymph  nodes of
mice dosed with arsenic  trloxlde  or  Fowler's solution (1% arsenic  trloxlde)
orally once per week for  5 months.
4.2.2.   Inhalation.  Ish1n1sh1 et al.  (1976,  1977)  administered  15 weekly
Intratracheal Instillations of arsenic  trloxlde  (0.26 mg), copper  ore  (3.95%
arsenic), or  refinery  flue condensate  (10.5%  arsenic)  to W1star-K1ng  rats.
Tumor  Incidences  were  not  Increased  over  those  of  controls  during  the
Ufespan of  the animals.   Berteau  et  al. (1978) exposed female mice to a 1%
aqueous aerosol of  sodium arsenlte,  20-40 minutes/day,  5  days/week, for 55
weeks.  No  significant  Increase 1n  tumor  Incidence  was  observed.  In con-
trast, a  single  Intratracheal Instillation  of  Bordeaux  mixture (4% calcium
                                                             >
arsenate) resulted  1n  the Induction  of  lung tumors 1n 9/15 rats  (Ivankovlc
et al., 1979).
4.3.   OTHER RELEVANT DATA
    Singh  (1983)  tested  sodium arsenlte  for  mltotlc  gene  conversion  and
reverse mutation  1n Saccharomyces cerevlslae  07.  Under  the  conditions of
this  assay,  sodium arsenlte  was  weakly  positive for reverse mutation  and
negative for mUotlc gene conversion.
    Arsenic compounds have  been  observed to produce chromosomal damage both
in  vitro  and  in  vivo  (Petres and  Hundelker,   1968;  Petres  et  al.,  1970,
1972).  Walker and Bradley  (1969) reported that  arsenate Increased  the  total
frequency of  exchange  chromosomes In  OrosophHla melanogaster treated with
selenocystlne.  Petres  et al.  (1970)  studied lymphocytes from  34 patients at
the University of  Freiburg Skin  Clinic, 13 of  whom had received  extensive
                                     -25-

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arsenic therapy  up  to 20 years  before.   There was a remarkable  Increase  1n
the frequency of aberrations observed  1n  the  arsenic-treated  group.   Beckman
et al.  (1977) found  an  Increase 1n gaps, chromatld  aberrations,  and  chromo-
some aberrations 1n  short-term cultured leukocytes from mine  workers  exposed
to arsenic at the Ronnskar smelter  1n  northern Sweden.
4.4.   WEIGHT OF EVIDENCE
    IARC  (1980)  has  found  that  "there 1s  Inadequate  evidence for the  car-
c1nogen1c1ty of  arsenic  compounds  1n  animals.  There 1s  sufficient evidence
that Inorganic  arsenic  compounds are  skin  and lung  carcinogens  1n humans."
Applying  the  criteria proposed  by the  Carcinogen Assessment  Group  of  the
U.S. EPA  for calculating the  overall  weight of evidence  for  cardnogenlcHy
to humans  (Federal Register, 1984), arsenic 1s most  appropriately classified
1n Group A - Human Carcinogen.
                                     -26-

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                     5.   REGULATORY  STANDARDS  AND  CRITERIA
    ACGIH  (1980)  has  established   a   TWA  of  0.2  mg/m3  for  arsenic  and
soluble arsenic  compounds,  as  measured as arsenic, and  the  compound arslne.
Arsenic  trloxlde  1s  classified  as  an  "Industrial   Substances  Suspect  of
Carcinogenic  Potential  for  Man"  and  no TWA has  been established.   NIOSH
(1973)  recommended  a TWA  of  O.OS  mg  arsen1c/m3  as  a  workplace  air  stan-
dard.   This   was changed  to  a  15-mlnute  celling  of  0.002  mg/m3  (NIOSH,
1975).   In  1978,  OSHA  established  a  standard  of 0.01  mg/m3 for  airborne
Inorganic arsenic (U.S.  EPA, 1980b).
    The  U.S.   PHS  established  a maximum allowable   level  of 50  yg/SL  for
arsenic In drinking  water  supplied  by  Interstate carrier water  supplies  In
1942.   This  standard was  continued  when the  U.S.  EPA  Drinking  Water  Stan-
dards  became  effective  1n  June of  1977.   The U.S. "EPA (1980b) has  subse-
quently  recommended   a  criterion  of  22  ng/i,   which  would  result  1n  an
                                                             t
estimated excess cancer  risk of 10~9.
                                     -27-

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                             6.  RISK ASSESSMENT
6.1.   ACCEPTABLE INTAKE SUBCHRONIC (AIS)
    Arsenic has  been  determined  to be carcinogenic to humans  and  data exist
from which  carcinogenic potencies  have been  estimated.   It  1s,  therefore,
Inappropriate to determine  an AIS for arsenic.
6.2.   ACCEPTABLE INTAKE CHRONIC (AIC)
    Arsenic has  been  determined  to be carcinogenic to humans  and  data exist
from which  carcinogenic potencies  have been  estimated.   It  1s,  therefore.
Inappropriate to determine  an AIC for arsenic.
6.3.   CARCINOGENIC POTENCY (q^)
6.3.1.    Oral.  As described 1n  Chapter 4, numerous  studies  have  Implicated
arsenic 1n the etiology of human cancer.   Since arsenic  has  not consistently
produced  tumors  1n animals.  1t  1s  necessary to rely  on  human data  for  the
derivation of a  unit  risk.   Tseng  et al.  (1968)  found a  positive correlation
                                                              i
between the  levels of arsenic  1ngest1on  and the development  of  skin cancer
In  southwest  Taiwan.   The  U.S.  EPA  (1984) fH the Incidence  of" skin cancer
data to  a model generated for  estimating the cance'r  rate as a  function  of
drinking  water   arsenic  concentration.   A unit risk  of  15.0 (mg/kg/day)'1
was  estimated,  assuming  that  humans  drink  2 I  of  water/day  and  that
absorption  of  arsenic  1s  100%.   A detailed  discussion  of  the data  and
assumptions  employed  In the  estimation  of this  carcinogenic  potency can  be
found 1n U.S. EPA  (1984).
    The  Issue of  risk associated with oral  arsenic  exposure  1s currently
being reevaluated  (U.S.  EPA,'1985).   This  assessment  should  be evaluated for
possible  Impact  on  the  present  document  when   H  becomes  available  1n
reviewed, final  form.
                                     -28-

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6.3.2.   Inhalation.   The U.S.  EPA  (1984) applied  the  data  from the  eplde-
ra1olog1cal studies of copper  smelting  1n  Montana (Brown and Chu, 1983;  Lee-
Feldsteln, 1983; H1gg1ns et al.t  1982)  and Washington  (Enterllne and  Marsh,
1980, 1982)  to an absolute risk  linear model and  estimated  unit risks  for
these studies  as  summarized  In Table 6-1.   The  U.S.  EPA (1984) provides an
1n-depth  discussion  of  this  risk  assessment.   The  geometric  mean  of  the
several   unit  risks  1s  4.29x10"*  (yg/m3)"1.   Applying  the  assumptions
that  humans   weigh  70   kg,  Inhale  20  ma/day   and  absorb  30%  of   Inhaled
arsenic, a unit risk  of  50.1  {mg/kg/dayr* 1s calculated (U.S. EPA, 1984).
                                    -29-

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                                  TABLE 6-1

         Combined Unit Risk Estimates for Absolute Risk Linear Models3
  Exposure
   Source
Unit R1skb
Geometric Mean
  Unit R1skb
  Final
Estimated
Unit R1skb
Reference
Anaconda
(Montana)
smelter
ASARCO
(Washington)
smelter
1.25xlO"»


2.80x10"'


4.90x10"'




6.81xlO"»c

7.60xlO"'c
                                 2.56x10"'
  7.19x10"'
                                                 4.29x10"'
                                Brown and Chu,
                                1983

                                Lee-Feldste1n,
                                1983

                               .Hlgglns
                                et al., 1982
              Enterllne and
              Marsh, 1980
aSource:  U.S. EPA. 1984

bUn1t risk values presented as

cUn1t  risk  estimated  from  data   gathered  using  two  different  follow-up
 periods
                                     -30-

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                                7.  REFERENCES

ACGIH  (American  Conference  of Governmental  Industrial Hyg1en1sts).   1980.
Documentation of the  Threshold Limit  Values for Substances  1n  Workroom Air,
4th ed. with supplements through  1981.   Cincinnati,  OH.   p.  4-27.   (Cited in
U.S. EPA, 1983a)

Ar1yosh1, T. and T. Ikeda.   1974.   On  the  tissue distribution and  the excre-
tion of  arsenic  1n rats  and  rabbits  of administration with arsenical  com-
pounds.  0. Hyg.  Chem.  20: 290.  (Cited 1n U.S. EPA, 19805)

Axelson, 0.,  E.  Dahlgren,  C.D.  Jansson and  S.O.  Rehnlund.   1978.   Arsenic
exposure  and  mortality:   A   case-referent   study   from  a   Swedish  copper
smelter.  Br. J.  Ind.  Med.   35: 8-15.   (Cited In U.S. EPA,  1983b)
                                                             t
Baronl, C.,  G.J. Van  Esch  and U.  Safflottl.   1963.   Cardnogenesls  tests of
two  Inorganic  arsenlcals.    Arch.  Environ. Health..  7:  668-674.  (Cited In
U.S. EPA, 1983a,b)

Baxley, M.N., R.D.  Hood,  G.C.  Vedel,  W.P.  Harrison  and  G.M.  Szczech.   1981.
Prenatal toxlclty  of  orally  administered  sodium arsenlte  1n  mice.   Bull.
Environ. Contam.  Toxlcol.   26: 749-756.  (Cited 1n  Lederer  and Fensterhelm,
1983)

Beckman, G.,  et  al.   1977.   Chromosome aberrations In  workers exposed  to
arsenic.  Environ.  Health Perspect.   19: 145.   (Cited 1n U.S.  EPA,  1980b)
                                     -31-

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Bencko, V. and  K.  Symon.   1970.  The  cumulation  dynamics  1n some tissue of
hairless  mice  Inhaling arsenic.   Atmos.  Environ.   4: 157-161.   (Cited In
U.S. EPA.  1980b)

Berteau,  P.E.,  3.0.  Flom,  R.L.  D1mm1ck and  A.R.  Boyd.   1978.   Long-term
study  of  potential  cardnogenldty  of  Inorganic  arsenic aerosols  to mice
Toxlcol. Appl.  Pharmacol.   45:  323.   (Abstr.)   (CHed  1n U.S. EPA, 1983b)

Boyle,  R.W.  and  I.R. Jonasson.  1973.   The  geochemistry  of  arsenic and Us
use as  an Indicator element 1n geochemlcal  prospecting.   J. Geochem. Expl.
2: 251-296.  (Cited 1n U.S.  EPA, 1983b)

Brown,  C.C.  and  K.C. Chu.  1983.   Implications  of  the multistage theory of
carclnogenesls  applied  to occupational  arsenic  exposure.   J.  Natl.  Cancer
Inst.  70: 455-463.  (Cited In  U.S. EPA,  1984)

Buchet,  J.P.,   R.   Lauwerys  and  H.   Roels.   1981."   Urinary   excretion  of
Inorganic  arsenic  and  Its  metabolites  after  repeated Ingestlon  of  sodium
meta  arsenlte   by   volunteers.   Int.  Arch.  Occup.   Environ.   Health.  48:
111-118.  (CHed 1n U.S. EPA,  1984}

Byron,  U.R., G.W.  Blerbower,   J.B. Brouwer and W.H.  Hansen.  1967.   Patho-
logical changes In rats and dogs from  two-year feeding of  sodium  arsenlte or
sodium  arsenate.   Toxlcol. Appl.   Pharmacol.   10: 132-147.   (CUed 1n  U.S.
EPA, 1980b, 1983a,b)
                                     -32-

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Callahan,  H.A.,   H.M.  SUmak,  N.W.  Gabel,  et  al.    1979.   Water-Related
Environmental Fate  of  129  Priority  Pollutants,  Vol.  I.   OWPS,  OWWM,  U.S.
EPA, Washington,  DC.  EPA-440/4-79-029a.   (CUed  1n U.S. EPA, 1983a)

Charbonneau,   S.M.,  K.  Spencer,  F.  Bryce  and  E.   Sandl.   1978.   Arsenic
excretion by  monkeys  dosed  with  arsenic-containing  fish or  with Inorganic
arsenic.  Bull.  Environ.  Contain. Toxlcol.  20: 470-477.  (Cited 1n U.S. EPA,
1980b)

Coulson, E.J., et al.  1935.   Metabolism 1n the rat  of the naturally occur-
ring  arsenic  of   shrimp  as  compared with arsenic trloxide.   J.  Nutr.   10:
255-270.  (CHed  1n  U.S.  EPA,  1980b)

Crecellus,   E.A.    1977.   Changes   1n   the  chemical   spedatdn  of  arsenic
following  1ngest1on  by   man.   Environ.  Health.  Perspect.   19:  147-150.
(Cited 1n U.S. EPA,  1984)

Cuzlck,  J.,  S.  Evans, M. Glllman and  O.A. Price Evans.   1982.   Medicinal
arsenic and  Internal malignancies.   Br.  J.  Cancer.   45(6):  904-911.   (Cited
In U.S. EPA,  1983b)

Dubols, K.P., et  al.  1940.   Further studies on  the effectiveness of arsenic
1n preventing selenium poisoning.   J.  Nutr.  19: 477.   (CHed 1n U.S. EPA,
1980b)
                                     -33-

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Ducoff, H.S., W.B. Neal,  R.L.  Straube,  L.O.  Jacobson and A.M. Brues.   1948.
Biological  studies  with  arsenic.   II.  Excretion and  tissue localization.
Proc.  Soc.  Exp. B1ol.  Med.   69:  548-554.   (Cited  In NAS,  1977;  U.S.  EPA,
19805)

Dutklewlcz, T.  1977.   Experimental  studies  on arsenic absorption routes  In
rats.  Environ.  Health Perspect.   19:  173.   (Cited 1n  U.S. EPA, 1980b)

Edmonds,  J.S. and  K.A. Francesconl.  1977.   Methylated  arsenic  from  marine
fauna.  Nature 265:  436.  (Cited  In  U.S.  EPA,  1984)

Edmonds,  J.S.,  K.A. Francesconl,  J.R. Cannon.  C.L.  Raston,  B.W.  Skelton and
A.H.  White.   1977.    Isolation,  crystal  structure and .synthesis of arseno-
betalne,  the  arsenical constituent  of  the western  rock lobs»ter, Panullrus
longlpes  cygnus George.  Tetrahedron Lett.   18:  1543-1546.   (CHed 1n  U.S.
EPA, 1984}

Enterllne,  P.E.  and   G.H.   Harsh.    1980.    Mortality   studies  of  smelter
workers.  Am. J. Ind.  Med.  1:  251-259.   (CHed 1n U.S. EPA,  1984)

Enterllne, P.E. and G.M.  Marsh.   1982.  Mortality  among workers exposed  to
arsenic and  other  substances 1n a  copper  smelter.   Am.  J.  Ep1dem1ol.   116:
895-910.  (Cited 1n U.S. EPA, 1984)

Federal Register.  1984.   Environmental  Protection Agency.   Proposed  guide-
lines for carcinogenic risk assessment.   Federal  Register.   49: 46294-46299.
                                     -34-

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Graedel, I.E.  1978.  Chemical Compounds 1n the Atmosphere.  Academic Press,
NY.  p. 1-49.

Hlgglns,  I., K.  Welch  and  C.  Burchflel.   1982.   Mortality of  Anaconda
smelter workers  In relation to arsenic and other exposures.  Ann Arbor, MI.,
Dept. of Epidemiology,  Univ.  of Michigan,  1982.  (Cited  In U.S. EPA, 1984)

Hill. R.H. and E.L.  Fanlng.   1948.   Studies  1n the Incidence of cancer 1n a
factory handling Inorganic compounds of arsenic.  I. Mortality experience 1n
the factory.   Br.  J. Ind.  Med.  5:  1.   (Cited  1n U.S. EPA, 1983b)

Hlsanaga, A.   1982.  Chronic  toxldty  of  arsenous  add 1n rats with special
reference to  dose  response.  Fukuoka  Igaku Zasshl.   73(1):  46-63.  (Eng.)
(Cited 1n U.S. EPA,  1983a)                                   »

Holland,  R.H.,  et  al.   1959.   A  study  of   Inhaled  arsenic - 74  1n  man.
Cancer Res.   19:  1154.   (Cited 1n U.S.  EPA, 19805)

Hood,  R.D.,  G.T.  Thacker and  B.L.  Patterson.  1977.   Effects  1n  the mouse
and  rat  of   prenatal  exposure to  arsenic.   Environ.  Health  Perspect.   19:
219-222.  (Cited In U.S.  EPA,  1980b)

Hueper, W.C.   and W.W.  Payne.   1962.   Experimental  studies 1n metal cardno-
genesls.  Chromium,  nickel,  Iron,  arsenic.  Arch.  Environ.  Health.  5: 445.
(Cited In U.S. EPA,  1983b)
                                     -35-

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IARC  (International  Agency  for  Research  on  Cancer).   1980.   Arsenic and
arsenic  compounds,   in:  Some Metals  and  Metallic  Compounds.   IARC  Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to Humans.   IARC,
WHO, Lyon, France.   23:  39-142.   (Cited  1n  U.S.  EPA,  1983b)

Inamasu,  T.,  A.  Hlsanaga  and N.  Ish1n1sh1.   1982.   Comparison  of  arsenic
trloxlde and calcium arsenate retention  1n the rat lung after  Intratracheal
Instillation.  Toxlcol.  Lett.  12:  1-5.   (CHed  1n  U.S.  EPA, 1984)

Ishlnlshl, N., K. Osato, Y. Kodama and E.  KunHake.  1976.  Skin effects and
carclnogenldty  of  arsenic  trloxlde:  A  preliminary experimental  study  1n
rats.   ITK  Effects and Dose-Response  Relationships  of Toxic  Metals,  G.F.
Nordberg, Ed.  Elsevler Scientific, Amsterdam,  p. 471-479.  (Cited 1n  IARC,
1980; U.S. EPA, 1983b)                                         ,

Ish1n1sh1, N., Y. Kodama,  K.  Nobutomo,  K.  and A.  Htsanaga.  1977.  .Prelimi-
nary experimental study on  carclnogenldty of  arsenic  trloxlde 1n  rat  lung.
Environ. Health Perspect.   19: 191-196.   (Cited  1n  U.S.  EPA, 1983b)

Ishlnlshl,  N.,   M.  Tomlta  and   A.  Hlsanaga.   1980.   Chronic  toxlclty  of
arsenic  trloxlde In  rats  with special  reference  to  liver  damages.   Fukuoka
Igaku Zasshl.  71(1):  27-40.  (Eng.)   (Cited 1n  U.S.  EPA, 1983a)

Ivankovlc,  S.,   G.  Elsenbrand  and R.   Preussmann.   1979.   Lung   carcinoma
Induction 1n BD  rats after single  Intratracheal Instillation  of an arsenic-
containing  pesticide  mixture formerly  used 1n  vineyards.  Int.  J.  Cancer.
24: 786-788.  (CHed 1n U.S. EPA, 1983b)
                                     -36-

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Kanlsawa, H. and H.A. Schroeder.  1967.  Life term  studies  on  the  effects  of
arsenic, germanium, tin, and vanadium on spontaneous tumors  1n mice.   Cancer
Res.  27: 1192.  (Cited  In U.S.  EPA,  1983b)

Kanlsawa, M. and H.A. Schroeder.   1969.   Life term studies  on the effect  of
trace elements  on  spontaneous  tumors  1n mice  and rats.   Cancer  Res.  29:
892.  (Cited 1n U.S.  EPA,  1983b)

Knoth,  W.    1966/67.    Arsenic  treatment.   Arch.  KUn.  Exp.  Derm.    227:
228-234.  (Ger.)  (Cited In IARC,  1980;  U.S.  EPA,  1983D)

KoJIma,   H.   1974.    Studies  on  development  pharmacology  of arsenlte.  II.
Effect of arsenlte on pregnancy, nutrition and hard tissue.  Pol.  Pharmocol.
Japon.  70:  149-163.   (Cited 1n  Lederer  and Fensterhelm,  1983) *

Kroes.  R.,  M.J. Van  Logten,  J.M. Berkvlns,  I.  deVcles and G.J.  van  Esch.
1974.  Study on the carc1nogen1c1ty of lead arsenate and sodium  arsenate and
on  the   possible  synerglstlc  effect of  diethylnltrosamlne.   Food  Cosmet.
Toxlcol.  12: 671-679.  (Cited  1n  U.S.  EPA, 1983a,b)

Landau,   E.,  et al.   1977.  Selected noncarclnogenlc  effects  of  Industrial
exposure to  Inorganic arsenic.   U.S. EPA, Washington,  DC.   EPA 569/6-77-018.
(Cited 1n U.S.  EPA,  1980b)

Lanz, H.,  Jr., P.U.  Wallace and  J.G.  Hamilton.   1950.   The  metabolism  of
arsenic   In   laboratory  animals  using  As74  as a  trace.   Univ.  Calif.  Pub.
Pharmacol.   2:  263-282.   (Cited  1n NAS,  1977)
                                     -37-

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LeBlanc, P.J. and  A.L.  Jackson.   1973.   Arsenic 1n marine  fish  and  Inverte-
brates.  Mar. Pollut. Bull.   4:  88-90.   (Cited 1n U.S.  EPA,  1984)

Lederer,  W.H.  and  R.J.  Fensterhelm,  Ed.   1983.  Arsenic.   Proc.  Arsenic
Symp., 1981, Galthersburg, HD.   Van Nostrand Relnhold  Company,  NY.

Lee, A.M.  and  J.F. Fraumenl, Jr.   1969.   Arsenic and respiratory cancer  1n
men: An  occupational study.   J.   Natl.  Cancer Inst.   42:  1045.  (Cited  1n
U.S. EPA, 19835)

Lee-Fe1dste1n,  A.   1983.   Arsenic and respiratory  cancer  In  man:  Follow-up
of  an  occupational  study.    In:  Arsenic  --  Industrial,  B1omed1cal   and
Environmental Perspectives, W. Lederer and  R.  Fensterhelm,  Ed.   Van  Nostrand
Relnhold. New York.  (Cited In U.S. EPA,  1984}               J

Nappes, R.  1977.  Versuche zur Auscheldung  von  Arsen  1n  Ur1n.   [Experiments
on excretion of  arsenic  In  urine.]  Int. Arch.  Occup. Environ.  Health.   40:
267.  (Cited 1n U.S. EPA,  1980b)

Masah1k1,  0.  and  A.  Hldeyasu.    1973.   Ep1dem1olog1cal   studies   on   the
Morlnaga powdered  milk  poisoning  Incident:  Final report of  the Joint  pro-
ject team  from Hiroshima and  Okayama  Universities for  survey  of the  Senol
area.  Jap. J.  Hyg.  27: 500.  (Cited In  U.S. EPA. 1980b)

Matsumoto,  N.,  T.  Oklno,  H. Katsunuma  and  S.  I1J1ma.   1973a.   Effects  of
Na-arsenate  on the growth and development  of the foetal mice.   Teratology.
8: 98.  (Cited 1n Lederer and Fensterhelm, 1983)
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Matsumoto,  N.,  T.  Oklno,  H.  Katsumuma  and S.  I1J1ma.   1973b.   Effects  of
Na-arsenlte  on  the growth  and  development  of the  foetal  mice.   CongenU.
Anom. Curr. LH.  13:  175-176.   (Cited 1n Lederer  and Fensterhelm,  1983)

Mealey,  J., Jr.,  G.L.  Browne!!  and  W.H.  Sweet.   1959.   Rad1oarsen1c  1n
plasma,  urine,  normal tissues,  and  1ntracran1al  neoplasms.   Arch.  Neurol.
Psychiatry.  81: 310-320.  (Cited 1n NAS, 1977)

Hlzuta, N.,  et  al.  1956.   An  outbreak of acute arsenic poisoning  caused  by
arsenic  contaminated  soy  sauce  (shoyu):  A clinical  report  of  220 cases.
Bull. Yamaguchl  Med. Sch.  4: 131.   (Cited 1n U.S.  EPA,  1980b, 1983a)

Morton, W.t  6.  Starr, D.  Pohl,  J.  Stoner, S.  Wagner  and  P.  Heswlg.  1976.
Skin  cancer  and  water   arsenic  1n  Lane  County,   Oregon.  ,Cancer.   37:
2523-2532.  (Cited In  U.S.  EPA,  1980b, 1983b)
                                                     *
Moxon, A.L.   1938.   The effect  of  arsenic on the toxldty of  selenlferous
grains.  Science.  88: 81.   (Cited  In U.S.  EPA. 1980b)

Munro,  I.C.   1976.   Naturally  occurring  toxicants   1n   foods   and  their
significance.  CUn. Toxlcol.  9: 647-663.   (Cited  1n U.S. EPA, 1984)

Munro,  I.e.,  S.M.  Charbonneau,  E.  Sandl,  K. Spencer,  F. Bryce  and   H.C.
Grlce.  1974.  Biological availability of arsenic from  fish.  Toxlcol. Appl.
Pharmacol.  29:  111.  (Abstr.)   (Cited 1n U.S.  EPA, 1980b)
                                     -39-

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Nagal,  H.,  R.  Okuda,  H.  Nagaml,  A.  Yagl,  C.  Mori  and H.  Wada.   1956.
Subacute-chronU  "arsenic"  poisoning   1n  Infant   —   Subsequent   clinical
observations.   Ann.  Pedlat.  2:  124-132.  (Cited 1n  U.S.  EPA,  1980b)

NAS (National Academy  of Sciences).   1977.   Medical and biologic effects  of
environmental  pollutants: Arsenic.   NAS, Washington, DC.

NIOSH  (National  Institute  for  Occupational   Safety  and Health}.    1973.
Criteria  for  a  Recommended  Standard...Occupational  Exposure  to  Inorganic
Arsenic.  U.S. DREW, PHS, CDC,  Cincinnati,  OH.   (Cited In ACGIH,  1980)

NIOSH  (National  Institute  for  Occupational   Safety  and Health).    1975.
Criteria  for  a  Recommended  Standard...Occupational  Exposure  to  Inorganic
Arsenic.  DHEW (NIOSH) Publ. No. NIOSH  75-149.   U.S.  DHEW,  PHS,  CDC,  Cincin-
nati, OH.  (Cited 1n U.S. EPA,  1983a)
                                                    «
Okamura, K.,  et  al.   1956.  Symposium on arsenic poisoning by powdered milk
(2).  Dlagnos. Ther.  9: 240.  (Jap.)   (Cited  1n U.S.  EPA,  1980b)

Osburn, H.C.  1969.   Lung  cancer  In a mining district  1n  Rhodesia.   S. Afr.
Med. J.  43: 1307.   (Cited  In U.S.  EPA,  1983b)

Ott,  M.G.,  B.B.  Holder and H.L.  Gordon.   1974.    Respiratory  cancer  and
occupational  exposure  to  arsenlcals.    Arch.  Environ. Health.  29:  250-255.
(Cited 1n U.S. EPA,  1983b)
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Page, 6.W.  1981.  Comparisons of groundwater and surface water for patterns
and  levels  of  contamination  by  toxic  substances.    Environ.  Sd. Technol.
15: 1475-1481.

Penrose,  W.R.,  H.B.S.  Conacher,  R.  Black,  et  al.    1977.   Implications of
Inorganic/organic Interconverslon on fluxes  of  arsenic  In marine food webs.
Environ. Health Perspect.   19:  53-59.   (CUed 1n U.S.  EPA, 1984)

Peoples,  S.A.   1975.   Review  of  arsenical  pesticides.  In:  Arsenical Pesti-
cides,  E.A.  Wool son,  Ed.   ACS Symp.  Ser.  7.   Am.  Chem.  Soc., Washington,
DC.  (Cited 1n NAS,  1977)

Perry,  K.,  R.G.  Bowler,  H.M.  Buckell,  H.A.  Druett and  R.S.F.   Schilling.
1948.   Studies  1n the Incidence  of  cancer  1n  a factory handling  Inorganic
                                                              i
compounds of  arsenic.   II. Clinical and  environmental  Investigations.   Br.
J. Ind. Med.  5: 6.   (Cited In  U.S.  EPA, 1983b)
                                                    «

Pershagen,  G.   and  H.   Vahter.    1979.    Arsenic.   A  toxlcologlcal  and
epIdemlologUal  appraisal.   Llbertryck,   Stockholm,  Sweden,  SNV  PM-1128
(CHed In U.S. EPA,  1984)

Pershagen, G., C.G.  Ellnder and A.M. Bolander.   1977.  Mortality 1n a region
surrounding  an  arsenic   emitting- plant.    Environ.  Health  Perspect.   19:
133-137.  (Cited 1n  U.S.  EPA,  1983b)
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Pershagen,  G.,  B.  L1nd  and  N.E.  Bjorklund.   1982.   Lung  retention  and
toxlclty  of  some  Inorganic  arsenic  compounds.   Environ.  Res.  29: 425-434.
(CHed 1n U.S.  EPA,  1984)

Petres,   3.  and  M.   Hundelker.    1968.   "ChromosomenpulveMsatlon"  nach
Arsene1nw1rkung auf  Zellkulturen 1n vitro.  Arch. Klin. Exp. Dermatol.  231:
366.  {CHed 1n U.S.  EPA,  1980b)

Petres, 3., et al.  1970.  Chromosomenaberratlonen an menschllchen Lymphozy-
ten be1  chronlschen  Arsenschaden.   Dtsh. Hed.  Wochenschr.   95:  79.    (CHed
In U.S. EPA, 1980b)

Petres.  J., et   al.   1972.   Zum  Elnfluss  anorganlschen  Arsens auf  die
DNS-Synthese menschllcher  Lymphocyten  in vltr.   Arch. Derm.  Forsch.  242:
343-352.  (CHed In  U.S.  EPA, 1980b)
                                                                  *

Pinto, S.S. and 8.M. Bennett.  1963.  Effect of arsenic trloxlde exposure on
mortality.  Arch.  Environ. Health.  7:  583-591.   (CHed  1n U.S.  EPA,  1980b,
19835)

Pinto,  S.S.,  et  al.   1976.   Arsenic  trloxlde  absorption  and  excretion  1n
Industry.  J.  Occup.  Hed.   18:  677.   (Cited  In U.S. EPA, 1980b)

Pinto, S.S., P.E.  Enterllne, V. Henderson and M.O. Varner.   1977.  Mortality
experience  1n  relation to  a measured  arsenic  trloxlde  exposure.  Environ.
Health Perspect.  19:  127-130.   (CHed  1n U.S. EPA, 1984)
                                     -42-

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Pinto, S.S.,  V.  Henderson and  P.E.  interline.   1978.   Mortality experience
of arsenic-exposed workers.  Arch. Environ. Health.  33: 325-332.  (Cited 1n
U.S. EPA, 1983b)

Ray-Bettley, F. and  J.A.  O'Shea.   1975.  The absorption  of arsenic  and Us
relation  to carcinoma.   Br.  J.  Dermatol.   92: 563.   (Cited 1n  U.S.  EPA,
1980b)

Rencher, A.C., M.W. Carter and D.W. McKee.  1977.  A retrospective epidemic-
logical  study  of  mortality  at  a  large western copper  smelter.   J. Occup.
Med.  19: 754-758.   (CUed In U.S.  EPA,  1983b)

Reymann, F., R. Holier and A.  Nielsen.   1978.   Relationship between arsenic
Intake  and  Internal  malignant  neoplasms.   Arch.  Dermatol.   114:   378-381.
(CHed 1n U.S. EPA, 1983b)                                   »

Rozenshteln, I.S.   1970.   Sanitary toxlcologlcal  assessment  of  low concen-
trations  of arsenic trloxlde  1n  the atmosphere.   Hyg. SanH.   34: 16-21.
(Cited 1n U.S. EPA, 1980b)

Satake,  S.   1955.   Concerning the  cases  of   arsenic  poisoning  caused  by
prepared  powdered  milk.    Jap.  J.  Pub.   Health.   2:  22-24.   (CUed  1n U.S.
EPA. 1980b)

Schrauzer.  6.N., D.A.  White,  J.E.  HcGlnness, C.J. Schneider  and L.J.  Bell.
1978.  Arsenic and  cancer: Effects of  Joint administration of arsenlte and
selenlte  on  the  genesis   of  mammary  adenocarclnoma 1n  Inbred  female C3H/ST
mice.  Bloorg. Kh1m.  9(3): 245-253.   (CUed  1n  U.S. EPA, 1983b)

                                     -43-

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Schroeder,  H.A.  and  J.O.  Balassa.    1967.   Arsenic,  germanium,  tin,  and
vanadium 1n mice: Effects on  growth,  survival,  and tissue levels.  J. Nutr.
92: 245-252.  (Cited 1n  U.S.  EPA,  1983a)

Schroeder, H.A., M.  Xanlsawa,  O.V.  Frost and M.  HHchener.   1968.   German-
ium,  tin,  and arsenic  1n rats:  Effects  on  growth,  survival, pathological
lesions, and Hfespan.   J. Nutr.   96:  37-45.   (Cited  1n  U.S. EPA,  1983a)

Sh1rach1, D.Y., M.G. Johansen, J.P. McGowan and S.H. Tu.  1983.   Tumor1gen1c
effect  of  sodium arsenlte 1n rat kidney.   Proc.  West.  Pharmacol. Soc.  26:
413-415.  (CA 99: 117554u)

Shublk,  P.,  U. Safflottl, W.  L1J1nsky,  et al.   1962.   Studies  on the  tox-
1c1ty  of  petroleum waxes.   Toxlcol.  Appl.  Pharmacol.   4(suppl.):  1-62.
(CHed  In U.S. EPA,  1983a)

Singh,  I.   1983.  Induction  of  reverse mutation and mltotlc  gene conversion
by  some metal  compounds  1n  Saccharomyces  cerevlslae.  Hutat.  Res.  117(1-2):
149-152.

Smith,  T.3.,  E.A.   Crecellus,  and J.C.  Reading.   1977.   Airborne  arsenic
exposure  and  excretion  of  methylated arsenic  compounds.    Environ.  Health
Persp.   19: 89-93.   (CHed 1n U.S. EPA, 1980b)

Stoklnger,  H.E.   1981.   The  metals: Arsenic.  .In: Patty's  Industrial  Hygiene
and Toxicology,  Vol. II, 3rd  ed.,  C.O.  Clayton and F.E. Clayton,  Ed.   John
Wiley and  Sons,  Inc., NY.  p. 1517-1531.  (CHed 1n U.S. EPA,  1983a)
                                     -44-

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I   I
     Tay,  C.H.  and  C.S.  Seah.    1975.   Arsenic  poisoning  from anti-asthmatic
     herbal preparations.   Hed.  J.  Aust.   2:  424.   (Cited  1n  U.S.  EPA, 1983a,b)

     Tokudome,  S.  and M.  Kuratsune.   1976.   A  cohort  study  on mortality  from
     cancer and other causes among  workers  at a metal refinery.  Int. J.  Cancer.
     17:  310-317.   (Cited 1n  U.S.  EPA,  1983b)

     Tseng, W.P.   1977.   Effects  and  dose-response  relationships of skin  cancer
     and  blackfoot disease with arsenic.  Environ. Health Perspect.  19:  109-119.
     (Cited In  U.S. EPA,  1980b,  1983a,b)

     Tseng, W.P.,  H.H.  Chu,  S.W.  How,  J.M.  Fong,  C.S.  L1n and S.  Yeh.   1968.
     Prevalence of  skin  cancer  In an  endemic  area of  chronic  arsenlclsm  1n
     Taiwan.  J.  Natl.  Cancer  Inst.   40:  453-463.   (Cited  1n  U.S.  EPA,  1980b,
     1983a,b,  1984)
                                        *

     Urakabo,  G.,  et al.   1975.    Studies  on  the  fate "of  poisonous  metals  In
     experimental  animal  (V).  Body  retention and excretion of arsenic.   J.  Food
     Hyg. Soc.  Jap.  16:  334.   (Jap.)   (Cited In U.S. EPA,  1980b)

     U.S.  EPA.   1980a.   Guidelines  and Methodology  Used  In  the Preparation  of
     Health  Effects  Assessment  Chapters  of  the Consent   Decree  Water  Quality
     Criteria.   Federal  Register.   45:  79347-79357.

     U.S.  EPA.   1980b.   Ambient  Water  Quality Criteria  for Arsenic.   Environ-
     mental Criteria  and Assessment  Office,  Cincinnati,  OH.  EPA  440/5-80-021.
     NTIS PB 81-117327.
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I   I
     U.S.  EPA.  1983a.   Reportable Quantity  for  Arsenic  (and  Compounds).   Pre-
     pared  by the  Environmental  Criteria and Assessment  Office,  Cincinnati, OH,
     OHEA for  the Office of Solid Waste and Emergency Response, Washington, DC.

     U.S. EPA.   1983b.   Review of lexicological  Data In Support of Evaluation for
     Carcinogenic Potential of Arsenic  and Compounds.   Prepared by the Carcinogen
     Assessment  Group,  OHEA,  Washington, DC  for  the  Office of  Solid  Waste and
     Emergency Response, Washington, DC.

     U.S. EPA.   1983c.   Methodology and Guidelines for Reportable Quantity Deter-
     minations  Based on  Chronic  Toxldty Data.   Prepared  by  the Environmental
     Criteria  and Assessment  Office,  Cincinnati,  OH, OHEA for the Office of  Solid
     Waste  and Emergency Response,  Washington, DC.

                                                                   i
     U.S.   EPA.    1984.   Health   Assessment   Document  for  Inorganic  Arsenic.
                             *
     Environmental  Criteria  and  Assessment Office,  Research Triangle. Park, NC.
     EPA-600/8-83-021F.  NTIS PB  84-190891.

     U.S.  EPA.  1985.   Acceptable Dally  Intakes  for  Volatile Organic Chemicals,
     Inorganic  Chemicals  and  Synthetic Organic Chemicals.  Criteria and  Standards
     Division, Office of Drinking Water.   Draft Federal Register Notice.

     Walker,   G.W.R.  and  A.M.  Bradley.    1969.   Interacting  effects  of sodium
     monohydrogenarsenate  and selenocystlne on crossing over  1n DrosphUa melano-
     qaster.   Can.  J. Genet.  Cytol.  11:  677.   (Cited  1n  U.S. EPA,  1980b)
      U.S. Environments!  Protection Agency
      Rs         •'•--  "
     230 South Co,.
     Chicago, lliir.u;s   60C-J4
                                           -46-

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' •  1
  Westoo,  G. and  M.  Rydalv.   1972.  Arsenic  levels  1n foods.  Var Foda.   24:
  21-40.   (In Swedish with  English  summary).   (Cited  In U.S.  EPA,  1984)

  WHO (World Health  Organization).  1981.   Environmental  Health Criteria  18:
  Arsenic.   International Program on Chemical Safety.  Geneva.   (Cited  In  U.S.
  EPA,  1984)
                                      -47-

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