EPA/625/3-87/013
                                            July 1988
               Special Report on
        Ingested Inorganic Arsenic

   Skin Cancer; Nutritional  Essentiality
                    Principal Authors
 Tina Levine, Ph.D.
 Amy Rispin, Ph.D.
 Cheryl Siegel Scott, M.S.P.H
 Office of Pesticides and
  Toxic Substances
William Marcus, Ph.D.
Office of Drinking
  Water
Chao Chen, Ph.D.
Herman Gibb, M.P.H
Office of Research
  and Development
                    Technical Panel
Chao Chen, Ph.D.
Herman Gibb, M.P.H.
Frank Gostomski, Ph.D., Chairman
Tina Levine, Ph.D.
           William Marcus, Ph.D.
           Amy Rispin, Ph.D.
           Reva Rubenstein, Ph.D.
           Cheryl Siegel Scott, M.S.P.H.
              Risk Assessment Forum Staff

             ,!: oattn> Ph'D" J-D- Executive Director
            Judith S. Bellin, Ph.D., Science Coordinator
            Linda C. Tuxen, B.S., Technical Liaison
            RISK ASSESSMENT FORUM
   U.S. ENVIRONMENTAL PROTECTION AGENCY
             WASHINGTON, DC 20460

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                        Disclaimer








recommendation for use.

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                             Contents

Preface  	
External Peer Review	   v
EPA Risk Assessment Forum (1986-87)	  Xf
EPA Risk Assessment Council (1986-87)	  v"!
Science Advisory Board Review          	  Vl"
   I.  Overview  	

  II. Executive Summary
     A.  Background  	   	  5
     B.  Validity of Data from Taiwan	  %

     D.                           Dose-Response Assessment"'''.  I

     E.  Nutritional Essentiality  	     	   7
     F. Conclusion                  	   9
                     	           Q

 '"'  HannrIldRentifiCati0^and EPidemiologic Studies Suitable for	
       uose-Response Evaluation   	
    A.  Preliminary Considerations  .        	
    B.  Review of Studies  	  	   1'
        1. Taiwan Study  	'.'.'.'.	   1 ^
        2. Mexican Study	   12
        3. German Study	
    C.  Summary  	  	   ^

 IV.  Selected Elements of Hazard Identification	               17
    A.  Pathologic Characteristics and Significance of
       Arsenic-Induced Skin Lesions  . .  	

        1 - Description and Malignant Potential of Skin Lesions	   17
        2. Progression of Skin Lesions                      	   ]Q

    B.   lerrotoxS?1^ ^ of Arsenic-'nduced Skin Cancer ': I!   JI

        1. Introduction  	'.'.'.'.'.'.'.'.	   21
       2. Possible Mechanisms of Genotoxicity	   ?l

          o]iss^ge^RSk3enotox:city Data:n^Evaiuatin' ''   ,
    C.  Metabolism and Distribution                	
                                           ***
                               III

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                   Contents (continued)

 V.  Dose-Response Estimate for Arsenic Ingestion  	   27

     A.


     B.  Estimation of Risk       ,.._..                      ^
       1. Estimation of Risk using Taiwan Data   	   ^
       2 Comparison with Mexican Data  	
       3 Comparison with German Data	
     C.  Summary of Dose-Response Evaluation    	   ^Q
       1. Numerical Estimates  	   31
       2. Uncertainties   	   31
       3. U.S. Populations   	
                                                               33
 VI. Arsenic as an Essential Nutrient  	   33
     A.  Background 	   34
     B.  Animal Studies  	   34
        1. Data Summary 	   35
        2. Evaluation of Data  	  36
      C. Applicability to Humans  	  38
      D. Summary and Conclusions	
                                                               39
 VII.  Future Research Directions  	'  3g


              Skin Cancer  	:''''.	   -39
       C. Pharmacokinetics/Metabolism of Arsenic  	   ^
       D. Essentiality 	

Vl""  XpenS? A: Summary of  Epidemiologic Studies and Case
         Reports on Ingested Arsenic Exposure  .. .... ;
      Appendix B: Quantitative Estimate of Risk for Skm Cancer
         Resulting from Arsenic  Ingestion  ;	
         Appendix C: Internal Cancers Induced by Ingestion           gg
            Exposure to Arsenic  			
         Appendix D: Individual Peer Review Comments               ^
            on Essentiality	   97
       Aooendix E: Metabolic Considerations  	
                                                            ..115
   IX.  References 	
                                   IV

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                             Preface
                                       (EPA) Risk
 and to  ensure Itoto
 assessment  guidance.  To accompHsh this ThJ  SL  1   aPProPriate  risk
 assembles experts from throughoT he EPA'in a fnS  Assessmen*

 rert                                 ''
 estarncPe0o^

                                                         aa
 as Technical Panel members     partlc'Pate as consultants or, if appropriate,

 conSlgt^                      ^  many years within  EPA

these issues, a TechnS Panef on A,?   m9eSted arsenia To helP o\ve
Risk Assessment Fomm The Tlchnal P^n *!**  ^^ Within E ^ thl
report on arsenic health effe^^^^^^                              a

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                   External Peer Review

, draft of this report was reviewed at a
   rporates many of the peer
                                                      workshop of

                                                           the  current  draft
                                        comments.
Dr. Roy Albert
Department of Environmental Health
University of Cincinnati Medical Center

Dr. Julian B. Andelman
University of Pittsburgh
Graduate School of Public Health

Dr. John Bailar
Harvard University and
U.S. Department of Health and Human
   Services

 Dr. Mariano Cebrian
 Department of Pharmacology and
    Toxicology (Mexico)

 Dr. C.J. Chen
 Institute of Public Health
 National Taiwan University
 College of Medicine


  Dr. Philip Enterline
  Center for Environmental Epidemiology
  University of Pittsburgh

  Dr. KurtJ. Irgolic
  Department of Chemistry
  Texas A & M University
                                     Dr. Ruey S. Lin
                                     College of Medicine
                                     National Taiwan University

                                     Dr. Kate Mahaffey
                                     National Institute of
                                         Occupational Safety and Health

                                      Dr. Daniel B. Menzel
                                      Department of Pharmacology
                                      Duke Medical Center
                                      Dr. Paul Mushak
                                      Pathology Department
                                      University of North Carolina

                                      Dr. Forrest Nielson
                                      United States Department
                                          of Agriculture
                                       Grand Forks Human Nutrition Research
                                          Center

                                       Dr. Joseph Scotto
                                       National Institute of Health
                                       National Cancer Institute

                                       Dr. David Strayer
                                       Department of Pathology
                                       University of Texas Medical School
                                        vi

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              External Peer Review (continued)
Dr. Wen-Ping Tseng
Department of Medicine
National Taiwan University
College of Medicine

Dr. Marie Vahter
National Institute of Environmental
   Medicine
Karolinska Institute (Sweden)
Dr. Roland R. Weiler
Hazardous Contaminants Coordination
   Branch
Environment Ontario (Canada)

                               VII

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         EPA Risk Assessment Forum (1986-87)

      s of this report were reviewed by EPA's Risk Assessment Forum in
 c     1986 a'ndTn March 1987. In July 1987, the final report was submitted
to EPA's Risk Assessment Council for concurrence.

Forum Members
Peter W Preuss, Ph.D., Office of Research and Development, Cha.rman
     Argus. Ph.D., Office of Pesticides and Toxic Substances
       Barnes, Ph.D., Office of Pesticides and Tox,c Substances

       DeoCursoPnh Ph.S!Sc1e of Research and Development

          Ser^^
R?cha?d N Hil" M.D, Ph.D, Office of Pesticides and Toxic Substances
Carole Kimmel. Ph.D, Office of Research and Development
Arnold M. Kuzmack. Ph.D., Office of Water

Designated Representatives
James Baker, Region 8
Timothy  Barry, Office of Policy Planning and Evaluation
 Arnold Den. Region 9
 Kenneth  Orloff, Region 4
 Maria Pavlova, Region 2
 Patricia Roberts. Office of General Counsel

 STSSSMSS lolld Waste and Emergency Response
 Deborah Taylor. Office of the Administrator
 Jeanette Wiltse, Office of Air and Radiation

          EPA Risk Assessment Council (1986-87)

 John A  Moore, Office of Pesticides and Toxic Substances Chairman
  DarJel P Beardsley. Office of Policy  Planning and Burton
  Theodore M. Farber. Office of Pesticides and Toxic Substances
  Victor Kimm.  Office of Pesticides and Toxic Substances
  Hugh McKinnon, Office of Research and Development
  William Muszynski, Region 2
  Vaun A Newill, Office of Research and Development
  Peter W Preuss, Office of Research and Development
  Rosemarie Russo, Office of Research and Development
                                  VIII

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      EPA Risk Assessment Council (1986-87)
                         (continued)

Deborah Taylor, Office of the Administrator
Stephen  R. Wassersug, Region 3
Donald Clay, Office of Air and Radiation
Michael Cook, Office of Water.
Marciai Williams, Office of Solid Waste and Emergency Response
Terry Yosie, Office of the Administrator              response
                             IX

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           U S  Environmental Protection Agency
               Science Advisory Board Review

  Th qrisnce Advisory Board's (SAB) Environmental Health Committee was




comply.
                Chairperson

    Dr. Richard A. Griesemer
    Director, Biology Division
    Oak Ridge National Laboratory
    Oak Ridge, Tennessee
       Executive Secretary

Dr. Rick Cothern
Science Advisory Board (A-101F)
U.S. Environmental Protection
   Agency
Washington, D.C.
    Members

    Dr. Seymour Abrahamson
    Professor of Zoology and Genetics
    University of Wisconsin
    Madison, Wisconsin
     Dr. Gary P. Carlson
     Professor of Toxicology
     School of Pharmacology and
        Pharmacy Science
     Purdue University
     West Lafayette, Indiana

     Dr. John Doull
     Professor of Pharmacology and
        Toxicology
     University of Kansas Medical Center
     Kansas City, Kansas

     Dr. Philip E. Enterline
     Professor of Biostatistics
      University of Pittsburgh
      Pittsburgh, Pennsylvania
Dr. E. Marshall Johnson
Professor
Department of Anatomy
Jefferson Medical College
Philadelphia, Pennsylvania

Dr. Nancy Kim
Director, New York Dept. of Health
 Bureau of Toxic Substances
    Management
 Albany, New York
 Dr. Warner D. North
 Principal
 Decision Focus, Inc.
 Los Altos, California
  Dr. Robert Tardiff
  Principal
  Environ Corporation
  Washington, D.C.

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    Science Advisory Board Review (Continued)
Members (Continued)

Dr. Bernard Weiss
Professor, Division of Toxicology
University of Rochester
Rochester, New York
Dr. Ronald E. Wyzga
Program Manager
Electric Power Research Institute
Palo Alto, California
                           XI

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I. Overview

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Thomas in a June 21, 1988 memorandum to EPA off.ces.
   lT* is evidence 0(
                                                              as
                                          ,
     develop complete risk assessments for this element.

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 Background



 called into question  Second  thl nrimf           population has been
 ss &5?



R/sA Xissessmenf Forum Spec/a/ Report on Arsenic

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studies are needed to decide the question definitely.
















 judgments in light of the knowledge that:
      1   ingested inorganic arsenic is a class  A carcinogen resulting in an
         increased incidence of skin cancers.
      2  Only a fraction of the arsenic-induced  skin cancers are fatal.
      3". The non-fatal skin cancers remain of some concern
          risks.
       5  Arsenic may cause cancer in internal organs.
          humans.

   BCSon the Risk Assessment Council's review of the Forum's Report
   on inorganic arsenic, I  am recommending that:                    .nnmanin
       1 Risks of skin cancers  associated with the ingestion , o  "organic
          areenic be estimated  using a cancer  potency (slope factor)  of 5 x
          To-5 (ug/L)-i, derived in the Forum's Special  Report.
       o. , reaching risk management ***^






           the factors that influenced such a decision.

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                      II.  Executive Summary
  A.  Background
  nutritional requirement in the human Hipf T T  u  S?'C as an  essential"









  cancer guidelines (U.S  ?PA  iglej  taatseT nf 7?n9Sn Und6r EPA'S
                                            
 terms, the MLE of risk due to 1  ua/ka/dav nf    aiwanefe males)-  In other
 10-3 to P x  m-3  Th2    *   ^Q'Kg/aay of arsenic intake ranges from 1 *
                                     n       * TOt ful"








relent ^T^32^i^               ^Y^ a"d  *  of

populations, exposure" inforSonand ^the


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B. Validity of Data from Taiwan

                    ^
             and sk.n cancer in 40421 resioems or                tQ
              these data Is basi on
  exposure to this agent and human cancer.
  C  Biological Considerations for Dose-Response Assessment

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D. Dose-Response Assessment
                          .
                    AT

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T^gSSSfpSS" v*U7e dose-response assessment  using , a



1986), which set forth the principles that follow.
      No single mathematical  procedure is  recognized  as the most
      appropriate for low dose extrapolation  in carcinogenes.s When
      relevant biological evidence on mechanism  of action ex.sts (e.g.,
      rfhamTacokinetics  target organ dose), the models or procedures
      SyedshouW be consistent with the evidence. When data and
      SSon are limited,  however, and when *  unJtoirrty
      exists regarding the mechanism of carcinogenic action, models or
      procedures [which incorporate low dose linearity  are  preferred
      when compatible with the limited information.


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 E.  Nutritional Essentiality








































F.   Conclusion


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human populations, and an absence of significant information that provides a
                 8h    the estimated risks has to do with

                  ut  is lower than that for the  other primary skin tumors,
                                                           exposures to
                      estimates. Even in the absence of definitive biolog^l
                                                                    m
 data are needed to develop this premise.
                                     10

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     '"'
                         fon     o                   Studies
                         for Dose-Response Evaluation
  an association between arsenic exDosurP^nHcl  mcludes. manV reports of
  the Panel focused on three sudles  ThP P.  f,  T'?1' (see APPendix A),
  provided evidence of a causaf assodaon ht    Und that the Taiwan studV
  cancer in  humans, resulting Tn ?ts Sa-Kfn" arSen'C ^9eStl'n and skin
  carcinogen under  EPA's Seer ?ulS2 ^ (U S E^A" lSP TA  ""T1
  studies (Cebrian et al   1983- Fierz  iPR^f ch         ,     6)" Two other
  from arsenic ingestio^n were 'used for S       9 auSkm cancer response
  dose-response ?een in Se ^Taiwan study P'Sn W"h Predictins from the
  A.  Preliminary Considerations
                    8ccB*
discussed, creation o, ,hcoLfie
                                                       10 5tUd'eS are
             from the latter

                ^Se0nicff            n
 disease were more likely S^avS deJetoS I skin  PetrhSO/1S With Blackfoot
 not have Blackfoot disease Because ^Biacklot di^f   than perSOns who did
internal cancer are bn^y^vST^nS^A^"10, LngeStion and
studies by Chen et al  H98?  ioflR\  h APpendlx c- Additional data from the
cancer of'several s tes i?JS?lr2S!2 h" aSfCiatin between internal
dose-response estimation        In9est.on have been requested for use  in
                               11

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B   Review of Studies                                         .





exposed to arsenic in dnnj '"9 water and on     P        } As stated
 arsenic
                            t hough


  in thedlfterent wells ranged from 0.01 to  .   Pormed on . ,OM, population

                                                                   -
       which were counted as skin cancer.
                                     12

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2.  Mexican Study
                                       n                  oi 
                             13

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runoff into the water supply may have been an additional source of arsenic (in





































































































      arsenic contamination of the water supply.
                                        14

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                                              -
  lesions were observed in the control population. Also, there  was n
  of non-response (,.e., the number of individuals not present at the
  interview and/or examination is not reported).

  3.  German Study
                                                                  ur
 iub  or  <;b (40.4/c)  of the  patients. In patients  who  had  rec^ivpri  the





persons reported that they had looked "stained" sSrtS ^aftlr taking
                                       ^
                                 15

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C.  Summary
   The Taiwan (Tseng et al., 1968; Tseng, 1977), Mexican  (Cebnan et al.,
IQA? and German (Fierz, 1965) studies  have  been d.scussed in detail

 reSThft$Mexican  study found the prevalence of skin cancer increased  in a




















   this agent and cancer.
                                    16

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     IV.  Selected Elements of Hazard Identification
   This part summarizes biological information relating to the skin ran-
                         -"" " "-*-
7.  Description and Malignant Potential of Skin Lesions



carcinomas, mvasive squamous cell carcinomas, and "comb nedTesions "

                        17

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  Yeh et al. (1968) and Yen (1973) reported that arsenicsac|lehsypJr^eatJSeitS
SBM Si
cellular atypia and are morphologically benign-.Thus Yeh ( 973) dw c ed the
 Ssrsrs, K?
                             mos, frequent,,


   5The Tseng study is the epidem,olog,c study *gte*%g* f th8 Ca"Cer
     estimate associated with ingested arsenic (see Sections B and C).
                                18

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  2.  Progression of Skin Lesions
















 SI-STO                                 2?MS
 frequency of malignant transforms Jn,ho*ef  Sin "," ^T' 6

                e*


serve as biological markers        mdicatol-s of arsenic exposure, and can



3.  Case-Fatality Rate of Arsenic-lnduced Skin Cancer
                      sSnS^jrs^ s Teni9n,
 tumors are not considered  to hlve^Tpotenfel ? Dro^esf ^"Sf8 the beni9n
 malignancies of the same histogenic origin."         progress to  the associated
                             19

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              in

              co
              O)

              C.    <"
's
a;
               E"
               0
  a


  X
      S c =

      I'gg
      m to o


       = 1

      083
                        O

                        8
eport

pro
19

s r

20
-5 >s 
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                                                       ,
                                  ^^




















B. Genotoxicity 7
1.  Introduction

                              21

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Table 2.  Estimated Case-Fatality Rates for Nonmelanoma Skin Cancer by
         Cell Typea
   Race-sex
     group
    i
 White male

 White male
   Cell type
          
Squamous cell

Basal cell
Incidence
rate/
100,0003
65.5
202.1
21.8
115.8
Estimated
Mortality
rate/
I00,000b
0.8
0.2
0.3
 0.08
Estimated
case-fatality
rate0
1.2%
<0.1%
1 .4%

 White female   Squamous cell

 White female   Basal cell
 . - - - - - - - 
 asased on annual incidence rates, age-adjusted to the 1970 U.S. population (Scotto









   duration is relatively short and survival is good.
             does not appear to  induce chromosome aberrations in vivo ,n







  2   Possible Mechanisms of Genotoxicity
                                      22

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                          of
23

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The
         assay. "*
         vitro dose-response function for the induction of chromosomal
                       suss-^
                        used '" "*> eva'rti0^ .hTd^'no  wrmtt
                           ^^^
are therefore, genetically of no consequence.
  Aaents that are capable of breaking chromosomes are also capable of
        stS chromosome  rearrangements,  such  as  translocates or
            r r =^ suss  ssrss
             KM  oT rSrra
                                                             t
       ng Sith DMA synthesis and repair processes rather than by
 mutations, the need for two events is compounded by the need i for ^
 aKn to oroduce toxic effects on DMA synthesizing enzymes. With inc
 dose* many ceufwHI contain a single hit and the dose effect curve becomes
       size of any apparent "practical threshold" will be determined by the
 sio the target; i-e, if a high percentage of arsenic molecules interact
 wlh chromosomes to cause breaks, the targets are large nd the observed
 threshold is small  Although these observations suggest the existence OT a
                         is
                                                      a.
                                                  .
          of a nonlinear dose-responss relationship at low doses should be

        that s ng e arsenic-cell interactions may  start a process leading to
  Sgnancy, gene mutation may not be the only factor leading to low-dose
  linear dose-response relationships.

  C  Metabolism and Distribution  (See Appendix E)
       ent
                organic forms, and valence state-3 inorganic arsenicals are
                      a-z! =% sat
      mShySte v^ence state-3 compounds, it appears that methylat.on ,s a
                                24

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       f detxifyin9 inorganic forms. As more methyl groups are added  the
  compounds become less and less acutely toxic                  *wva, me
            *] tnere.are mar|y data gaps in our understanding  of  the body's
        tarTn'C> 9reat ftridSS have  been  made in recent years in  thl
        to speciate among valence states of arsenic. The picture that unfolds is
  as follows. Inorganic arsenic ( + 5) can be (reconverted in the  Wood  with
  ( + 3) - inorganic forms,  and  the latter can  be singularly  methylated  fc, fo m
  mono-methyl  arsen.c  (MMA); these are  enzymatic  and  nonenzymaS
  processes  It appears that arsenite, but not arsenate can enter live  Sat
  least m  vrtro) where a second  methyl  group  can be added- MMA becomes
  dimethyl arsenic (DMA) via a rate-limiting enzymatic process
    Under low-level exposures  to  arsenic,  there seems to'be a  balance
  between the amount entering the body and  the amount being excreted K
  MMA  nMfSenJClS IOSt frm  the body  in the uri"e as inorganic arsenSe
  a^nic is^fh  H' Vet uncharacterized. o^anic forms. A  small amoun of
  arsenic is lost by desquamation of the skin.
    With increasing arsenic intake there is suggestive evidence that therp i
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         animal in 8or calories diminished the cancer occurrence
                                  data are important for




                 Brass, siscss "
          quatively or qgantati.8ly, is uncertain, but
                                               further
study.

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  V.  Dose-Response Estimate for Arsenic Ingestion

A.  Introduction

  Dose-response  assessment develops  a  numerical expression for i
h:^t^fW,!e"-Pos-e.-d--inogenical eXPr<3SS'n ** '

1968, Tseng, 1977) for which the lowest dose level was about 10 ua/ka/dav
   Considerations Affecting Model Selection
                          there is no threshold for carcToaenic
                               ^^^^^
          e' '" de^idin9 between nonthreshold and threshold approaches
                   -e^
                            27

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due to S favors as the metabolism or pharmacok.net.es of arsen.c.
             in Methodology Relative to the 1984 Assessment
             JELd , JL <* or ^%SS"l
                                28

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  B. Estimation of Risk
  1.  Estimation of Risk Using Taiwan Data
2.  Comparison with Mexican Data
                             29

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the Mexican study.
3   Comparison with German Data
  socioeconomic conditions.
  C  Summary of Dose-Response Evaluation







   to 1  yg/kg/day of arsenic intake from water ranges from 1x10  to i.
                                 30

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                     " thS UPited States is un(ike'y to * greater than these
  2.  Uncertainties
















                                                      TOT 

3.  U.S. Populations
                                31

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    o.





ie^rs^s^^











       from L Taiwan study to the United States was reasonable.
                         r-srsr





   "n Comparison to the 500,000 cases occurring among whites.
                    32

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            VI.  Arsenic as an Essential Nutrient

A.  Background
                 ofar                  tO 6Valuate  the    s
                 of arsenic for humans-a  requirement that  ha<*
      been demonstrated in four mammalian species  In the absence
      of new data,  the  conclusion reached in  thf'tWrd  vohjme of
      Drinking Water and Health remains valid,  i.e., if 0 05 moTka o
                              H
                              h"man diet should provide a dailv
      does not aPprX'mate|y 25 to 50 3- The current^ American S2
                       presumed requirement (National Academy

      (1)  Information from experimental studies with rats  chicks
          mmipigs, and goats demonstrates  the plausibility" that
          arsenic  at least in inorganic form, is an essential nutrient
          wit^nthaniT f act'n has not been identified and  as
          esseSty      S' 'S ^^ tO 6Stablish ful|y arsnic

      (2>  hnm.n"1"110?1  es^iiamy  <* inorganic  arsenic  for
          humans  is not establ.shed. However, the history of trace
          element  nutrition shows that, if essentiality of an element
          for animals ,s  established,  it is highly probable ha
          humans also require the element. Accordingly, knowinq a
          mechanism of action is needed for a full interpretation o*
          the currently available animal data.           ^ewuon or
      (3)  The group consensus position is that, at this time it  is
         only possible to make  a general approximation  if

         foThuman0s  Sen
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       (4)  Elucidation of the role of arsenic in human nutrition win
           depend upon development of specific information in the
           following areas:
            biochemical and physiological mechanisms of action,
            biological  activity  and metabolic response to various
             chemical
            species of ingested arsenic, and
             dose-response relationships between animal species.
the risk assessment process.

B.  Animal Studies


                                          ss =te            s

      animals or diets.
                                   34

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                             ' * "" number f       *    r " ^maNer in



































2.  Evaluation of Data
                              Subcommittee on  Essentiality referred to a
                             srmmation of nutritional requirements






                                  and  adequacy of  the  basal diets is
                                 '" the .specificity  of the deficiencies
      significance of elevated zinc in the liver is not known.
                                 35

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         Framework for Determination of Nutritional Essentiality
                                  - Establish Plausibility of Animal Models
                                  - Use of Chemically Defined Diets, Animal
                                     Models
                                   - Characterize Specificity of Lesions
Empirical Observations
Reproducible Syndrome

Biochemical Lesions
Specific Biochemical Functions
Absolutely Dependent on Factor
Essentiality
rigorously established, even for animals.
C.  Applicability to  Humans
     workshoo but was unable to attend.)
                                       36

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                       * ws
37

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to be adequate.
D.  Summary and Conclusions

   on both the cancer and
                                       effects.
                                  38

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               VII.  Future Research Directions
                               >

  ^o^
  efforts among dSSSt parts of governmenfSfd^h? C0opteratin- ln additio"'
  integrated for optimal data development           Pf'    S6CtOr ShU'd be

  A. Epidemiologic Studies
                                                   *
                                                  a'TO "eeded
   ,
 B.  ^chanisms of Caroinogenesis fo, Arsenic-Induced Skin
C. Pharmacokinetics/Metabolism of Arsenic

                             39

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                 SonSs in biomethylation in different tissues

D.  Essentiality
   Elucidation of the role of arsenic in human nutrition will depend on the
development of specific information in the fo lowing areas.
      of ingested arsenic
      dose-response relationships  between animal species
                                      40

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                  Appendix A

Summary of Epidemiologic Studies and Case Reports
          on Ingested Arsenic Exposure    "eports
                     41

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Arsenical
Medicinals
(continued)
73
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medicinais exhibited the keratotic lesi
associated with arsenical poisoning.
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Six cases of basal cell carcinoma,
carcinoma in situ, or squamous cell
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of these patients had systemic cano
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keratosis on palms and soles.

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7 individuals tested
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Cases selected fror
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                            67

-------

-------
                Appendix B

Quantitative Estimate of Risk for Skin Cancer
      Resulting from Arsenic Ingestion
                  69

-------
                            Contents
                                                       	   71
List of Tables 	             72
List of Figures   	         73
 I.  Methodology  	   ?3
 II   Application to Taiwan Epidemiologic Study  	
III.  Use of the Mexican Data to Evaluate Taiwan's Dose-     	  yg
     Response Model  	
IV. Use of the German Data to Evaluate Taiwan's Dose-      	   ^
      Response Model  	
 V. Discussion of the Uncertainties of the Risk Estimates  	
                                                         	   87
 VI. Summary  	
                                    70

-------
                           Tables
 B-1        _
                                                t  risk (skin
      in Taiwan"""' ~' "a" a'""|J """ u
-------
             Figures
model, linear in dose .......................
Sffi^sjs^c^sss^      -
model, linear and quadratic in dose ......................
ssr-ttss.-trs;              *
of the model, linear in dose ..........................
                                * Ts
of the model, linear and quadratic in dose ..................

linear and quadratic in dose  .....................

linear and quadratic in dose .....................
                 72

-------
 I.    Methodology





 exposure to arsenic concentration d. Ve models Jhe ^oSing fo'm :   "^

                       F(t,d) = l-exp[-g(d)H(t)]















"    Application to Taiwan Epidemiologic Study




       (1)  LhlTrtality rate was the same in ^e  diseased
           cancer) persons as in the nondiseased persons.

           The population composition (with  respect to the risk
           factors of the skin cancer) remained constan  over time
           Th.s assumption .mplies that there was no cohort effect
           The skin cancer was not surgically removed
                                                  (skin
(2)
(3)
                       73

-------
procedure used for  estimating the actual  number of persons at risk  is

*         ,   i	...**.^i-ii-\he* tfrlQt ff^llnW
                                ^
                                dd,a,es, normalized o ,he reference













   were given  in  *9ur|s BJda4 show  the  analogous plots for females.
                                      74

-------
    Table B-1.
                Estimated  Distribution  of  the  Surveyed  Male
                Portion at Risk (Skin Cancer Cases? by Age Grow
                        nCentratl"n f Arsenic  '"  WeN Tater "n
          Arsenic
        concentration
           (ppm)
    Low (0-0.30)

    Medium (0.30-0.60)

    High (> 0.60)

    Unknown

    Total
2.714&
(0)0
1,542
(0)
2,351
(0)
4,933
(0)
11,540
(0)
	
935
(D
531
(2)
810
(18)
1,699
(3)
3,975
(24)
  653
  (4)
  371
 (18)
 566
 (56)

1,188
 (61)

2,778
(139)
 236
 (11)
 134
 (22)
 204
 (52)

 429
 (64)

1,003
(149)
 4,538
  (16)

 2,578
  (42)

 3,931
 (126)

 8,249
 (128)

19,296
 (312)
                       	                           \ ' ' "/	   ^*J




  "Estimated number of persons at risk
  cEstimated number of skin cancer cases observed.
  Low (0-0.30)

  Medium (0.30-0.60)

  High (> 0.60)

  Unknown

  Total
2,65 1&
(0)c
1,507
(0)
2,296
(0)
4,819
(0)
11,273
(0)
' '  .
1,306
(0)
742
(1)
1,131
(4)
2,373
(2)
5,552
(7)
    _^_
792
(3)
450
(9)
686
(33)
1,440
(13)
3,368
(58)
         239
         (2)

         136
         (8)
         207
         (22)

         435
         (27)

        1,017
         (59)
        4,988
         (5)
        2,835
         (18)
        4,320
         (59)
        9,067
         (42)

       21,210
        (124)
                                              '       \v^/      \ I.




Estimated number of persons at risk
cEstimated number of skin cancer cases observed.
                                75

-------
            Table B-3.  Conversion of Arsenic Dose
                       for Taiwanese  to Equivalent
                       Arsenic  Dose  for  U.S.
                       Populationsa
                   Taiwanese
                     (ppm)
                   Males
                  Females
                        0.17
                        0.47
                        0.80

                         0.17
                         0.47
                         0.80
U.S. person
(yg/kg/day)

   10.8
   29.9
   50.9
    6.8
   18.8
   32.0
             . -- - ---
             aAssumptions: A U.S. person weighs 70 kg and
              drinks 2 L of water daily; a Taiwanese male weighs
              55 kg and drinks 3.5 L of water daily; a Taiwanese
              female weighs 50 kg and drinks 2 L of water daily.
hypothesis that the coefficient corresponding to & is zero is rejected at p  <




                                                         SS
 estimate calculated on the basis or aai * JP     females: (1) the daily water
 that calculated on the bas.s ^^{JJ^SSTto that consumed by
            by Taiwanese males {3J5 _uaayj in r            particu|ar those
                                               migrate o'u,  Wn.
equivalent to 1.4 yg/
                                            a US.  reference person as
The lifetime risk is 8st,ma,l to
                  3.
                                    from
                                                      ^ ma|es) |or
                                          contaminated i,n 50 9/L o,
 to, the lour age       .
 respectively, 0.8.0 x 10 . 67

                 
                                                  for'males, and 0, 7.0
                                      ^          ^          ^
                               *e comment made b, MargoHs December
                                   76

-------
   Figure B-1.    Ob,vedland predictedskin cancerpreva.enceforTafwanesema.es

                                         " 39e;
             .2978
                          Observed
                          Prevalence
                           H = High Dose
                           M = Medium
                           L = Low
        .0088E-3
Figure  B-2.    Observed and predicted skin cancer prevalence forTaiwanese m
                                                               ~
                                                                     ales
     .0053E-3
                     Observed
                     Prevalence
                      H  = High Dose
                      M  = Medium
                      L  = Low
  H/

  /
/
                                  77

-------
Figure  B-3.
              use of the model, linear in dose.

           .1422
                10
                use of the model, linear and quadratic in dose.
           .1515
         |
           .0750
                       Observed
                       Prevalence
                        H  = High Dose
                        M = Medium
                        L  = Low
                                        78

-------
  Table B-4.
Results of Model
Data
  Linear
   Males:
               Doses (d):  0, 10.818,
   g(d) = (0.302525 x 10-7)d

   H(t) = (1-6.931)2-935
   In L = -614.551
   Unit risk (probability of skin cancer
   in lifetime due to 1 ng/kg/day
   of arsenic)
   = 5.0x10-3
                                   Fitting to Taiwan Skin Cancer
                                                  Quadratic
                    29.909, 50.909 ug/kg/daya
                          g(d) = (0.124707 x10-7)d
                                + 0.404871 x 10-9)d2
                          H(t) = (t - 6.873)2.950
                          In L = -610.088
                          Unit risk (probability of skin cancer
                          in lifetime due to 1 ng/kg/day
                         of arsenic)
                          = 2.3 x 10-3
  Females:
                   Doses (d): 0, 6.8,
  g(d) =  (0.682262 x 10'8)d
  H(t) = (t - 9.0)3.225
  In L = -348.041
  Unit risk (probability of skin cancer
  in lifetime due to 1 iig/kg/day
  of arsenic)
  = 3.4x10-3
                   18.8, 32.0 ug/kg/daya
                        g(d) = (0.157281 x 10-8)d
                               + 0.204076 x 10-9)d2
                        H(t) = (t - 9.0)3.231
                        In L = -344.365
                        Unit risk (probability of skin cancer
                        in lifetime due to 1 jig/kg/day
                        of arsenic)
                        = 1.0 x 10-3
ono   fr U'S- persons 
-------
Figure B-5.
                                  rhk for .U.S.
               linear and quadratic in dose



             .01
  Figure B-6.
                            Environmental Doses (yug/kg/day)
                 linear and quadratic in dose.
            .0046
                                           .7
                               Environmental Doses (/vg/kg/day)
                                         80

-------
  ra<,,ea.5.
                     0^0.3, P^ing to Taiwan SKn Cancer Data, Adiustec,  for
                 Linear
                                               Quadratic
                   Doses (d): 0, 10.818, 29.909, 50.909 ug/kg/dayc

  9(d) = (0.351576 X10-7)d              9(d)  =  (0.106619 X10-7)d

  H(t)  = (t-6.934,2.885                 Hm   + (-**64x10-9)d2
  ,  ,            '                     H(t) = (t - 6.867)2.903
  In L  = -596.744                      ,  ,
                                      In L = -590.501
  Unit risk: 4.0 x 10-3 (yg/kg/day)-'
  Females:
                                        Unit risk: 1.6 x 10-3 (ng/kg/day)-i


                       Doses (d): 0, 6.8, 18.8, 32.0 yg/kg/dayc
     from Tseng et al., 1968
cDose estimate for U.S. persons (see Table B-3).
                                                                   Chinese
years. However, since the
differed significantly ?n the
cancer in this age group js
                                       in format on
                                       "n S Syss
                                                                ' and * 60
                                                            years ld
                                                                   f Skin

 Table B-6.  Since th             re
 Taiwan data for both  genders were
 in yg/kg/day for the rSSSTTs
 same reason, it was  necessary to c
 of the reference U.S. person  This
                   ..            s
male (female) weighs 60 (55) kg and drinks 3 1
et al.,  1983). If  there  were an equal
reference Mexican  person would
                                                               experience,
                                                            'S PrVided '"
                                                  ,    Sender-specific,  the
                                            ^rS'ff tt.dSe e^ival^ts
                                                     ^ the model- For  the
                                                     dS6 0Stimate to that
                                                                 Mex''Can
                                                      wate'' da.ly (Cebrian
                                                        andfemales. e
                                                                      .
                                 81

-------
            Experience, Both Genders Combined
                                  A f,s* ttmt tr\ (\t(mrfi\
Control town
UL (observed) 0/201 a (0)t>
PK (observed) 0/201 (0)
Exposed town
unobserved) 0/187(0)
PK (observed) 0/187 (0)
UL (predicted) 0.08/1 87 (0.04)
	 	  	
aoata from Cebrian et al., 1983.
bprevalence in percentages.
0/73 (0)
0/73 (0)
1/68(1.5)
8/68 (1 1 .8)
0.7/68(1.0)
_ ..
                                              0/29 (0)
                                              0/29 (0)
                                             2/27 (7.4)
                                             6/27 (22.2)
                                             1.2/27(4.4)
                  0/15(0)
                  0/15(0)
                 1/14(7.1)
                 1/14(7.1)
               Table B-7.  Conversion  of  Arsenic
                           Dose for  Mexicans to
                           Equivalent Arsenic Dose
                           for U.S. Persons^
                   Mexican person
                       (ppm)
                       i
                       0.005

                       0.411
U.S. person
(pg/kg/day)
   0.26
   21.63
                aAssumptions:  A U.S. person weighs 70 kg
                  and  drinks 2 L of  water daily; a Mexican
                  person weighs 57 kg and drinks 3 L of water
                  daily.
response  data for both  genders
equivalents for the reference  U S .  pe son  anc re                  better
model, with linear and quadra^  ten in dose,  prov a      9      |jkelihood
                         ^         thecomybined (i.e., sex-b.ind)  data
are:
                g(d) = (0.564398 x 10-8)d + (0.435613 x 10-)d2
                                   82

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  and
                          H(t) = (t - 8.0)3.028





                                  ' *
                                                           o, 8 years
  carcinomas,  but for which no E Ln  9     -of ePldermo'd or basal cell

  diagnosis  of ulceraU lesions  n ^MeS'Ttudv T ^'f 8'  The

  d.agnosis of skin cancer in the Taiwan study          V corresPnds to the


  reference's0^" (fe^fne'dosf1-63-11^^ 3S the dose rate fer the
  1.5%,  and 7.4%.  The differences
                                                 resPectively: 0.0%,
                                 *               ,
     was conducted by Rerz ( 965? (See M ?, f C) SetWeen
study.)                     uaos;. (bee II.A.3. for  a description of this



                                            ww as
examined (total 262) by to?al dose         '" CanCef (total 21>  out of those
affect the response
                                              _n e study (e.g

                                             differences are likely to
rates at equivalent total                 osea

for each dose rate and exposure comb.naflEJSCg
                                                study
                                                         r6Spnse
                              83

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Follow-Up Study3
Fowler's solution Crucle__
(milliliters)
0-50
50 - 100
100 - 150
150 -200
200 - 250
250 - 300
300 - 350
350 - 400
400 - 450
450 - 500
500 - 600
600 - 700
700 - 1 ,000
1,000 - 1,500
1,500
	 respoiioB 	
0/24 ( 0.0)
2/45 ( 4.4)
2/24 ( 8.3)
1/12(8.3)
1/14(7.1)
1/31 ( 3.2)
1/17 ( 5.9)
2/11 (18.2)
2/11 (18.2)
0/7 ( 0.0)
1/18 ( 5.6)
1/14(7.1)
2/13 (15.4)
4/15 (26.7)
1/5 (20.0)
	 
Adjusted
response*3

0/24 ( 0.0)
2/45 ( 4.4)
6/98(6.1)
6/98 (6.1)
6/98(6.1)
6/98(6.1)
6/98 (6.1)
6/61 ( 9.8)
6/61 ( 9.8)
6/61 ( 9.8)
6/61 ( 9.8)
6/61 ( 9.8)
2/13 (15.4)
5/20 (25.0)
5/20 (25.0)
	 	 	  
       aResponse is given as no. oaroinomas/no. patients at risk, and, in



       SOURCE: Fierz, 1965.

dose  rate by  the total number of exposure  da^ Assuming , an  avenge
iUweight of 70 kg and a weight o  7.6  mg %  **^ to obtain an
solution,  we multiply the  total  dose '" 9'Kg  ,ytj    (FS).1 The prevalence
                    ff                  anlS  i. L,  read w, to.
                        for 20
                                            study, the  prevaience  rate ,s
                                        mg arsenic/mL FS) - 9.2 x 10- mL
    FS.
                                    84

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                                                                  B-8)
                                                * .



 V.   Discussion of the Uncertainties of the Risk Estimates
 Ih/Sp'eciarSrt' [gJ S^sf 4M *e  * pressed in
 elsewhere in  that document ) In  tht  t?'S  T" a"eady been Bussed
                             '                          Sc=  a
             ne quan,ltafce rlsk


        (1)  the  mortality rate  was the same  in the diseased /skin
            cancer) mdividuals as in the nondiseasec

                                 -.._ . ,v, i-ji_.^,woovj II KJIVIUUolS.
        (2)  the  population  composition  (with respect to the  risk
            factors of the skin cancer) remained constant over time
        (3)  the skin cancer was not surgically removed



mortality on the risk estimates.              S6SS the  'mpact of  differential



      PO  =  the skin cancer prevalence at age x

      PI  =  the skin cancer prevalence at age x +1

                             i the nondiseased persons in the  age-
h   =
             the^mortality rate in the diseased persons in the age-interval

             the age-specific skin cancer rate in the age-interval (x, x + 1)
                   F(t)= 1 -exp[- \   h(x)dx]
                                       ">

                                       of differential mortality on the
                               85

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  It is shown (Podgor and Leske, 1986) that the age-specific incidence rate,

h. satisfies the following equation.
                                        = P. exp(-m ) +

                                           
                        1-P,
                   (1 _pQ)h[exp(- TO,) - exp(-mQ-Kj\
                              mQ
                                         h
   From this equation, it is  possible to  investigate the effect of differential














  increase ranging  from about 2/0 to ^/ _w ,,.                    re|atjve
  two (rm  = 2mo) is assumed; from about 2 ^ to _49 /o          tjons are


                                                         ?
   hr7eH- thtLCarrSenicS fntake fro^ ^lood consumption" can affect the risk
                                     86

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     Fabte B-9.   Age-Specific Incidence  Rates Calculated  from  Age-
                 Specific  Prevalence with Equal  and Diffferential
                 Mortalities
Exposure
groupb
Low-dose



Mid-dose



Low-dose



Skin
Age
20-39
40-59
60-69

20-39
40-49
60-69

20-39
40-59
60-69

Cancer Age-Specific 1
Observed Equal
skin cancer mortality
prevalence m1 = m0
1.07x10-3
6.13x10-3
4.66x10-2

3.77x10-3
4.85x10-2
1.64X10-1

2.22x10-2
9.89x10-2
2.54x1 0-1

1.07x10-3
5.94x10-3
4.16x10-2

3.78x10-3
4.59x10-2
1.29X10-1

2.25x10-2
8.17x10-2
1.89X10-1

ncidencea
Differential mortality^
m-) = 2mo
1.09x10-3
(2)
6.04x10-3
(2)
4.84x10-2
(16)
3.85x10-3
(2)
5.30x10-2
(2)
1.57X10-1
(22)
2.29x10-2
(2)
8.39x10-2
(3)
2.34x10-1
(24)
n^ = 3m0
1.11x10-3
(4)
7.06x10-3
(2)
5.56x10-2
(34)
3.91x10-3
(3)
6.06x10-2
(3)
1.85X10-1
(43)
2.33x10-2
(4)
8.61x10-2
(5)
2.81X10'1
(49)
    Inn nJl ty rateS f?r those without skin cancer "B assumed to be 0 035 0 26
     and 0.25 respectively for the age-intervals 20 to 39, 40 to 59, and 60 to 69
    bForthe low exposure group, P0 = o, PI =  i.07xl0-3 for the age-interval 20 to
     fi3xio-3~P     2t'K^U=, 6-!3x10"3 for the age-interval  40-59; P0   =
     fiQ?Fnrn;h 1  = 4'66x10"2 for the age-interval  60* (assumed to be 60  to
     69). For other exposure groups, P0 and P-t are similarily defined
    The parenthesized values are the ratio (xlOO) of age-specific skin cancer
 purpose of discussion we will assume that a man in the study population ate
 one cup of dry rice and two pounds of potatoes per day and thaHhe amW
 of water required to cook the rice and potatoes was about   L  UndeTtnTs
 f f8?,1   ,etr'Sk alCU!f6d befre is overestimated by about 30% ('T J3 5
 L). This caculation considers only the water used for cooking- the arsenic
 content m the r,ce and potatoes  that might have been absorbed from    -
 arsemc ,s  not considered because of  the lack of information.  For a
                                      would  need
                                      of the diet
                                   certainly
VI. Summary

   This  section  presents  a dose-response analysis for  skin  cancer  from
exposure  to  inorganic arsenic  in drinking water.  Results base^Ton The
multistage theory  of carcinogenesis have been  obtained from  the  Taiwan
                                   87

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epidemiologic study and are compared to two studies in other environments
(Mexico- Cebrian et al., 1983; and  Germany: Fierz, 1965).  Compatibility of
results across studies (1) suggests the conclusion that arsenic exposure is the
likely causal factor in the increased prevalence of skin cancers  in these
studies- (2) provides additional statistical evidence for refinement of statistical
estimates;  and  (3) helps to identify potential sources of variability  and
environmental factors, or patterns of exposure, that may be influential.
   None of these studies  contains  all  of the  details  needed for  an  ideal
statistical analysis, such as: ages at times of initial exposure, termination  of
exposure, and first appearance of skin cancer; similar information on lesions
that may frequently precede appearance of skin cancer; number of subjects
with cancer at multiple sites; locations of cancers; and prior disease  including
those that lead to the use of Fowler's solution. Consequently, it is important to
glean  what  information  is  available  from each  study  for  purposes  of
complementarity as well as comparison.                              .   .
   Analysis of the Taiwan data  required estimation of  the  number  at risk in
each dose/aqe category because only response rates and marginal totals by
aqe qroups are provided. The estimated  values,  which fit the marginal data
closely  make possible the estimation of dose-response for the generalized
multistage model  by  means of maximum likelihood. The cancer response is
well  described  by a quadratic polynomial in dose   (with positive  linear
coefficient) for both male and female data. The minimum tumor induction time
is estimated at 7 and 9 years for  males and females, respectively; in both
 cases  the cancer response for time-to-tumor is best described by time of
 observation (minus induction time) to the third power. The  observed data in
 the Mexican study, taken at only one concentration of  arsenic in well  water,
 but collected for different exposure intervals, are consistent with predictions
 from the model using the Taiwan data.
    The data from the study in Germany consist of the response  of former
 dermatology patients who had been treated with Fowler's solution (a  0.5 /=
 solution of arsenic trioxide, which is  a relatively toxic form).  Patients were
 treated for up  to 26 years (many for  apparently a much shorter  period)  in
 intermittent dosing patterns specific to the  prescribed treatment   This is  m
 contrast to exposure to arsenic-contaminated well water which is likely to be
 consumed at a reasonably uniform rate over time.
    The published data do not include much information that could be useful
 for risk assessment.  Except for a few specific cases cited here, the data were
 summarized by response for total  dose. When compared to predictions from
 the model for Taiwan with total dose held fixed at values equivalent to total
 doses in  the German study, and then varied over a wide  range of possible
 exposure durations in the Taiwan  data, the  skin cancer prevalence values in
 the German study exceeded the values predicted.
    In conclusion, the lifetime  risk of  skin cancer for a 70-kg person who
 consumes 2 liters per day of  water contaminated with 1 ug/L of arsenic is
 calculated to range from 3 x 10-5 (on the basis of  Taiwanese females) to 7 x
  10-5 (on the basis of Taiwanese males); equivalent^, the lifetime risk due to
  1 pg/kg/day of arsenic intake from water ranges from 1 x 10-J to  2 x 10--*-
                                     88

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                  Appendix C

Internal Cancers Induced by Ingestion Exposure to
                   Arsenic
                     89

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  Internal Cancers Induced by Ingestion Exposure to
                          Arsenic

  As noted in the Technical Panel's Special Report on Ingested Inorganic
Arsenic areenic ingestion has been associated with cancer of internal organs
Chronic Senic ingestion has been reported to be asso-c.aec ' with cancer of

ar^a^^^

  IB^ ' b^StS^^1^:^^ 51:
 985, r98P6P)?nasopharynx (Prystowsky et al., 1978) OWney (Chen e  a , 985;
Nurse, 1978), and other internal organs (Rosset, 1958; Reyann.^' 1 97n8J
Chen et al  985). Many of these references are case reports, however, and
do not dlserve the attention given a well-designed ep.demiolog.c study.
   The Technical Panel felt it important to summarize the stud.es of Chen et
al  1985  1986) since these studies have been referred to  in the text of the

 Ss^^^

           zrstfn

                 ^
 stud? of lung, bladder, and liver cancer mortality cases and  random y
 Sampled  controls  from the endemic area. They  found  odd ratios ;  that were
 sianHicantly (p <  0.05)  elevated, and  rema.ned  much  the  same when
 adiusS i for other risk factors including cigarette  smok.ng.  Chen et al. (1985)
 fnSed a positive correlation between  the SMRs  of  those cancers which
 wee sianfficantly elevated and Blackfoot disease  prevalence rates. Also,
 SMRs we "greater in villages where only artesian  wells  were used  > the

 ^^SSTt?!^

                s
  andTnte^al cancer risk; however, the data is not sufficient to assess  the
  3ose-"?sPonse  For this purpose, it is necessary to have the  indiv.dua^
  studied  bv  Chen grouped by well-water arsenic concentra .on and age.
  Thesf data quite likely do (or did) exist, because they were ava.lable to Tseng
  II ?i (1968) Tor the skin cancer study. EPA is currently trying to obtain these

  data.
                                90

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                 Appendix D
Individual Peer Review Comments on Essentiality
                    91

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   Individual Peer Review Comments on Essentiality

  This appendix seeks to clarify some uncertainty in the workshop report of







arsenic essentiality."1
   The Subcommittee also
nutritional  essentiality. The
establishing essentiality as including:                       mnHp|o
        1)  performance of empirical observations in  animal models
           to establish the plausibility of nutritional essentiality,
        2)  establishment of a reproducible syndrome through the
           use of chemically defined diets in animal models;
        3)  definition of  biochemical lesions to  characterize the
           specificity of the lesions;
        4) establishment  of  specific  biochemical  functions
           absolutely dependent on the factor being investigated.










 position on tnis 'f^ue-    Arsenic (U S EPA, 1987) presents all of the post-

 workshop comments in full.
 I     Comments on Plausibility  of Arsenic  Essentiality in Animals

 A    Post-Workshop Comments on Essentiality [page numbers
       refer to the summary report of the Peer Rev/ew Workshop
       on Arsenic (U.S. EPA 1987)]
                 The section [in the peer review draft]  on  [essentiality] of
                 Irsenlc should  be  rewritten with a more positive emphasis
                 on the probable [essentiality] of arsenic. . . (p. E-17).
     1 Report of the EPA Risk Assessment Forum Peer Review Workshop on Arsenic,
      December 2-3, 1986.
                                   92

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        Mushak:   .  . .the overall  conclusion would  seem to be  that  it is

                  premature to conclude that essentiality is established (p  E-
                     uth            be enU9h ^'mental evidence
                    suggest that in some animals, diets low in arsenic
                                                            ,

                 what would be found in the normal human diet

                 Further, the supplementary arsenic is all inorganic whereas


                 oraaaniSceTh,',n 1? human  d'et is' '"  a" 'ikelihL, almost S
                 d M ^Jn r' ^ a,mUnt f inor9a"ic arsenic in the human
                 diet (excluding drinking water) is really quite small (perhaos

                 a few yg/day), but there are no apparent health effects S

                 have been observed in humans. The relevaricTofthe anima

                 experiments to humans is therefore not at all clear Sdtt

                 seems unrealistic to  believe  that  arsenic is needed  in
 B.   Oral Comments Drawn from EPA Notes of Meeting-



      '
        and histidine were cited as f^'^&^O^S^




      '









     '
        absence of a clear definition of a reproducible syndrome [general]


II.   Estimation of a Human Nutritional Requirement for Arsenic
  2 General discussion. Individual attribution uncertain
                                                           Arsenic,
                                93

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A   Post-Worfcshop Comments [page numbers refer to the
    summa% report of the Peer Review Workshop on Arsenic
    (U.S. EPA 1987)J
     Menzel-       the development of the estimate for the human daily
               reauirement  H          rf and  carefu, dehneatlon of  he
               S should be included. . . .uncomfortable about, providing
               a single estimate and would encourage the provision of a
               range  of values  citing the uncertainties in  the methods ;  o
               estimation and the interactions between arsen.c and methyl
               donor. . .availability in the diet (p. E-17).

      Straver   I feel  that a certain tone could  be struck by the report to
      StraV      ndicate that evaluating the question of  lower   imits fo
               arctic in drinking water is not so much a matter  of direct
               pS of essentiSy in any species. Rather, the fact that the
                Dossibi itv  of essentiality  has  been  raised by workers in
                Sy Disparate species and settings should deter us from
                Sting very low  limits even if proof of its essentially in man
                is  not forthcoming (p.  E-30).


 B   Oral Comments Drawn from Observers Notes of Meeting


   '
III.
            c
              er to make direct weight comparisons or to use
         conversions);  lack  of  a biochemical mechanism, and  lacK  or
         Sedge of arsenic requirements as a function of age. [general]

         Discussants  reached a consensus  that development of an order-
       "  ofTaSudeSmate of intake requirements is possible  However^
         SeTSt that  the factors  influencing the uncertainty  of such  an
         assessment (as listed  above) should be spelled out.  [general,
         subcommittee report 4]


       Use in Risk Assessments




                  he        sL cancer, and this is 'inappropriate. The nskrf
                  skin cancer is unlikely to be influenced  by  the possfce
                  essentfality of arsenic. The use of the risk model to regulate
                  Sfshould take into account such a P^W'^JJ^
                  does not appear to be a basis for doing so at this time (p.
                  E-6).
      4 Report of the EPA Risk Assessment Forum Peer Review Workshop on Arsenic,
       December 2-3, 1986.
                                    94

-------
 Menzel:
           As  a consequence of  the  agreement of  the  workshoo
           participants on the probable essentiality of arsen^ a new
           section will have to be added to deal with [the] problem [ol
           essentiality versus toxicity]	EPA should ace     the

           tPhPrh0f,Hhehn0'threShold  treatment of oncogenesis and
           the threshold phenomenon of essentiality	

           I see no need to abandon the no-threshold treatment for

           StTaT Tn *?, '^ arsenic r Other "^nera'smfght 
           essential. To not face this ,ssue directly will only encouraqe
Mushak.   ft ,s premature to factor essentiality  into risk assessment
          models for arsen.c exposure in human populations    ThSe
          is no inherent limitation on the use of  linear extrapoaX
          models for,  e.g., skin cancer, because  of  any thTeshdd
          implicit in a daily  required intake (p. E-21).       ""^snoia
                          95

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       Appendix E

Metabolic Considerations
       Prepared by:
     Dr. William Marcus
      Dr. Amy Rispin
          97

-------
                              Contents
                                                   	   99
List of Tables  	'  ' ' '	   99
List of Figures  	   	   100
,!;  Sp'Su^ve.s'of Arsenic; Chemica. Forms'and AvaNability  ...   100
     A.  Drinking Water 	         101
     B.  Ambient Air  	'.'.'....   101
     C.  Food   	             103
     D.  Occupational Exposed Groups	   1Q3
      E.  Total Daily Body Burden  	
 HI.  Metabolism, Bioavailability, and Toxicity 	   ^
      A  Toxicity of Arsenic Chemical Species   	   ^
      B. Absorption, Distribution, and Elimination  	   ^
      C  Detoxification via Methylation  	
      D  Human Metabolism and Enzyme Kinetics  	
  IV. Pharmacokinetics of Arsenic Metabo.ism and Its Implications.for     ^
      Oncogenicity  	
                                      98

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                                 Tables

 E-1    Percentage of inorganic arsenic in food: a preliminary analysis
 E-2    Daily arsemc body burden feg/day) in the United States
                                                                   102
                                                                   104
E-1


E-2


E-3
E-4
       Reproduction of arsenic
          lypoic acid   	
  Figures

I forms by
       Role of s-adenosylmethionine in methylation of
         arsenic III  ...
                                                                   107
E-5    Urinary excretion of arsenic (As) and its
                                                                   107
                                                                   110
                                99

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I.    Introduction

                                    of the rt*. associated  human
                                                               "
  11    Exposure Levels of Arsenic; Chemical Forms and Availab.lity






   arsenic are  via mgeshon of /odj". 7^r' ' auamented in proportion to
   (Weiler, 1987; IARC, 1986).
                                  100

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  A.   Drinking Water
                                                     SaltS in the tri'
                                     ,                      ,





                      '
 S.  Ambient Air





























C.   Food
                             101

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Table E-1.   Percentage of Inorganic
             Arsenic in Food: A
             Preliminary Analysis3
           Food
 Percentage of
Inorganic Arsenic
  Milk and dairy products
  Meat - beef and pork
  Poultry
  Fish - saltwater
      - freshwater
  Cereals
  Rice
  Vegetables
  Potatoes
  Fruits
      75
      75
      65
        0
       10
       65
       35
        5
       10
       10
            	
    oecaon of the arsenic content of basic food
   g?S b^sed on preliminary data from the Ontano
   Research Foundation and other sources.
  SOURCE: Weiler, 1987.
                       102

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  D.  Occupationally Exposed Groups











 E.   Total Daily Body Burden


                                               MS




III.  Metabolism, BioavailabilSty, and Toxicity
A.   Toxicity of Arsenic Chemical Species

                            103

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                 Table E-2.   Daily Arsenic Body
                             Burden (ug/day) in the
                             United States
                  Source
                               Usual
                                          Unusual
Water
Air

Food
Smoking
TOTAL
5
0.09

50d

55.09
100a
1.5 -45&
68
50
2 -6e
up to 224
                  aAt the ODW maximum containment level
                   (see Part II.A).
                  bNear industrial use sites such as smelter or
                   cotton gins (see Part II.B).
                  ^Occupational exposure.
                  dSee Part II.C.
                  e2 pg arsenic/package (Weiier, 1987;
                   I ARC, 1986).


while arsenate may interfere with phosphorylation  reactions  due to  its


cheS^^^








 B    Absorption, Distribution, and Elimination
                                    104

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                                                              *
   and control subjects, but eels of
                                               comParable for workers
 exposure to arsenic in toharm
 that some smokersln the ?9Ss
 each day. Although thec
 known  and the duration  of exoosurp
 completely defined  he Brune et a?
 inhaled arsenic binds irreveSy to

 hJWTuSS fiffi S
 water ranging  from 6 ng/L fc TSa   /L
concentrations increased in urine and
in concentrations in drink igt
biood unti, drinking water co'nceSions
                                             Ple>
                                                 a function of chronic

                                                      (1986>
                                                             is not
                                            -9!?UpS Of retirees is t
                                               ^ ** *  Prtion of
                                                    blood- urine- and
                                              Proportion to i
                                                            arsenic
                                                                in

 the body via  sweating and desquamo'n "' oTfhT llf'T ""? inated from
 excessively exposed to inorganic arsenic SIP hL^ r       humans not
 arsenic is generally found in skin hat and nfi ,.?,!* ft!sue concenfation of
 Kagey et al. (1977Ulsc ^studied womenTn ?t2" ^5ntd ftS andSith' 1968)'
 umbH,cal cord levels of arsenic were similar to ma Sna? SSs

                's-Scof as ^^?
 ss?^rr&^
 (inorganic) arsenic and used whole Sv rad ionSnh,Te ^- radiolabeled
 and clearance.  Initial concet^^                    y  * L djstribution
apatite crystals in bone     can aSc    ^ ^^ *"* PhosPnate in the
hair, and upper gastrointestinaTtrarTS M  ? c^umulatlon of arsenic in  skin,
keratin (Goyer 1^rointestinal tract * s binding of sulfhydryl groups of
vivo (Vahter and Marafante 1983) The
oral administration (Vahter et al   984? In
different pattern from that shown     '
                                                  r the tissues
                                                tained
                              105

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discussed above. The  highest
found in the kidneys lungs ^ 9|s
the longest retention time were me l
   Tissue retention of  arsenic  ;njhe
methylate  arsenic was  much '  J^f
methylate  arsenic (Vahter and Marat ante
injection with inorganic arsenic  a most 60 /          or          .
The major single binding  site wasJne"' !? "intestinal tract. To the extent that
was also retained  in the  kidney and gas  tesj  stribution and tissue
the marmoset monkey  may ^.fS^^the  normal detoxification




 that arsenic  is efficiently absorbea tnrouy      y         (eve|s Qf exposure
                                           a
                                            ntestinal walls, and lens.
                                                  k      hich doesn't
                                              ^Yn  species  which
                                              Seventy-two hours  atter
                                                    y         tjssues
                                             s^Dorj  inal dose. Arsenic
                                                      .
sites.
C   Detox/f/cat/on Via Metfiy/at/on
  'Methylation of inorganic ^arsenic is


                                                     arsenic methy,ation
   and detoxification are summarized Im
     Methylation appears Mn ^ta
   (Vahter and Envall.1 983). Bas
   al.  (1984)  hypothesized that me hylation
                                             .            ^

                                             model compounds, Cullen et
                                                arsenic III  requires  s-
                                                a               on  the
    arsenate was     fn\itro cellular uptake of the two

        o                                 at physiol9ic PH' arsenite is not
  ionized, whereas arsenate is charged                       sequences  of
     In  order to understand  react: on m echamsnv s        inMcubations Of
  methylation, Buchet and  auwery        .PTter^thylating capacity  of red
                                         arid  ,dney  r 05.^^
                                                         activity;  and s-
                                    106

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                 Source: Cullen etal., 1984.
                        HS
                        HS
                                                                HS ,
                                                             OH
                                  .
1
                                                      MeAs
  Figure  E-2.    R-Jaf dsr.osy.methionine in Cation of arsenic ,.
                Source: Cullen etal., 1984.





     S-Adenosylmethionine              --  As
   S-Adenosylhomocysteine
               MeAs
concentrations,  DMA formation was InhlbHeTiXe
                                  107

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accumulate in the system, showing that formation of DMA is a rate-limiting





 rabbits.  Perlodate-oxidized jjenosme ^PAD)  an         tratjon Qf the























   lead to decreased excretion of DMA m tneur   .       deficiencies lead  to
   the lungs, skin and liver. '"  ^J*0"'.^mes  These results in animals
                                     108

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                                                f
                                                        Distribution,
 D. Woman Metabolism and Enzyme Kinetics


















eliminate arsenic at levels of concern    numans  can  handle. detoxify, and



                            109

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Figure E-3.
Urinary concentrations of arsenic and its metabolites.
Source: Adapted fromBuchet et al., 198Z.
                                                             1400
       100
               725
                250             50
             Micrograms As per Day
                                                            1000
  saturation pattern would require that EPA obtain the raw data from Buchet's




  !2f of loTarS ffl%% in  people of adequate methy.ating capacrty

  (Fi?nrt9853)Lovell and Farmer  monitored urine for arsenic metabolites
  fonowinf ySn of  rg^J-c ^o se^of i^^-n, ^ P ^
                                     110

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Figure E-4.
              Source: Tarn et al., 1979



                1.5
                                           Day
                        Total arsenic




                        Inorganic arsenic




                  X    Monomethylarsenic compound




                  A   Dimethylarsinic acid
                                111

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MMA as observed by urmary excret,on_ ooes                    bQd   Qr
      workers exposed to high eve
 Urinary concen rations o  araenic and .s m          However_  whep  high
 with time nearly to that of  the  control popuh a                 inorganic



 exposure  (Figure E-5). Fu 'h:,t<,asf Ration  in concentration of
 evening  sampling  *0n8f concentration o.  its  methylated
-echan
                                 o? excreon o, metabolites indicates a

                                                      arsenic metabolites
                                                                  beon
                                     112

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   *""*
              Source: Foa et al., 1984.

                   As exposure
                er>d      resumption
                I        t
                      ' ArSen' Metabo"sm
                       ff
is melhylated enzymatically h the
                                              ' implications
                                   Koestzcor^.
                                          '    In!lr9a"'c
certain target tissues,  namely  he ^ ver  i.fn  lon9:terrT deposition in
gastrointestinal tract      name|y  tne  l.ver,  lung, skin, bladder,  and

or  pro,*. d9ficfent
                            113

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Engine to the manifestation of cardnogenic  sponM in
studies of certain highly expo^ groups (US EPA. 8^






to arsenic (in excess of 200 pg/day) "*cate Wat^^   d t  to chronjcally
be complete. However, even  , rh.human body accomm   ^      tQ much

elevated arsen.c levels,theJ"^"3'^3.^ Of time  Furthermore, the ability of
more inorganic arsen.c over  long^periods or^>me^             constitute a
the human organism to handle more than,500^ or buu ng   y   yhomeostatic

 stress to  the  body.  .^  ^^dftuen^rd0S-response assessment.
 mechanisms is cnt.cal to -mprovrng thei  cancer^^aos    H     t^ ^^ |ungj
   Appendix C summanas date on elevate^raes o^          tumQrs jn ^
 and bladder in Taiwan and also notes the occur      d fi  ,  t animalSi  one
 Rerz study. Extrapolatng from ^ stud,es an pr         protein-deficient

 SSSi'SSK SK  ^maTSAether the deposition patterns

 arematehed by confirmed incidence of internal cancer.
                                    114

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                         IX.  References
  Albores, A.; Cebrian, M.E.; Tellez I 
                               '
           Publica   "           
                  Proisction
                                                      <  -
                                                     f

                 Tech.
                                              endemic
Astrup P. (,968) Blackfoot disease. Ugeskr. Ueger 130 1807-1815
                                          ^^
                                       and death

                             115

-------
Biagini, R.E, Quiroga, G.C, Elias, V. (1974) Chronic hydroarsenism in ururau.

                                                                  S
       1 1 5  FPA Headauarters Library, Washington, D.C.
        Headquarters Library, Washington, D.C.
                                      116

-------

    microsomeson ,he
                                                        , MU,.  Re,
                                       ,,
       biologic,, ^wion                     iAS^*** *'
Cuz,k, J.; Evans, S.; Slllman. M.; Price Evans  D IIQnsi i/i'    ,
    internal mali9nancies. Br. J. Cancer ^904.^'  ed'Crnal a'56nfc an<1

                                              '  ru.ne. xylenes  and
                                  v              '             . B.W,
   arsenobelain.  the           onj,    t  of*    a,"d SV"""='S  of
   Tetrahedron Letters 13 1543-lS?         *e  W8stern rock
         hepatic angiosarcoL  Am  J fnd

                                                      b
                             117

-------
Sever.  L.  (-898, "bar d,,  chronlschen

                 U9"
                  Syph. 43:221-283 (transited
                             oondi"ons '

,or
       Organization.
                         France:  World
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                             Can-
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                             o? inorganic  arsenic.
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    Johnson. R.D.;
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        uide"''in adu"oSi diet samples. August
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                         1'  (1972) Leukemla '
Knoth, W. (1966) Arsentahandlung. Arch. Klin. Exp. Derm. 227228-234


    n^'^""^- RJ' Sumner' KW- D. C.: Boswell DC  Arch
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    (potassium arsenlte). Gastroenterology  es-l^-JS









Leonard,  A.; Lauwerys,  R.R.  (1980) Carcinogenicity  teratooeniritv  anH

    mutagenicity of arsenic. Mutat. Res  75-49-62      terat9en'city, and
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                                             *
M>csss
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-------
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  Popper,  H.; Thomas,  L.B.; Telles,  N.C.;  Falk,  H.;  Selikoff  IJ  (1978)

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        t                       Ion9"term arsenic in9est'n- Arch. Dermatol.
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                   ~
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  Reymann,  F.; Moller, R.; Nielsen, A. (1978) Relationship between  arsenic

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     SnH9 oc
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qrhmidt
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-------
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                                          f ***** ln m'Ce and <****
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                                 123

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                                      124

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