Umt*0SwtM
Environment*! Protection .
A«*ncv         ,                  November 1984

Research and

Development

METHODOLOGY AND GUIDELINES

FOR RANKING CHEMICALS BASED

ON CHRONIC TOXICITY DATA
Prepared for
OFFICE OF EMERGENCY AND
REMEDIAL RESPONSE
Prepared by

Environmental Criteria and
Assessment Office
Cincinnati OH 45268

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                                  DISCLAIMER







    Mention  of  trade  names   or  c owner da 1  products  does  not  constitute



endorsement or recommendation for use.

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                            TABLE OF CONTENTS
                                                                      Page
1.  INTRODUCTION .....................  '

2.  CHRONIC TOXICITY RANKIN6 SYSTE* .................

3.  APPLICATION OF THE KETHODOlOGY ..................

4.  S0« CONCEPTUAL CONSIDERATIONS. ....••• ..........

5.  MODIFICATION  AND  APPLICATIONS  ..................
                                                           •  «•***
6.  REFERENCES ......................

                                         111

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                            LIST OF ABBREVIATIONS
ADI           Acceptable dally Intake
CERCLA        Comprehensive   Environmental   Response,   Compensation   and
              Liability Act of 1980-
CS            Composite score
CWA           Clean Hater Act
FEL           Frank effect level
ICRP          International Commission on Radlologlc  Protection
LDso          Dose fatal to 50* of test ail"*1?
LOAEL         Lowest-observed-adverse-effect level
MED           Minimum effective dose
NOAEL         No-observed-adverse-effect level
NOEL          No-observed-effect level
OERR          Office of Emergency and Remedial Response
OSWER         Office of Solid Haste and Emergency Response
RQ            Reportable quantity
RVj           Dose rating value
RVe           Effect rating value
                                      1v

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                                   PREFACE

    During  the  past three  years  the  Environmental  Criteria and  Assessment
Office. Cincinnati (ECAO-C1n) of the U.S. EPA has developed  a method  to  rank
chemicals based on  chronic  toxldty  data.   This ranking system reflects  two
primary attributes  of  every chemical:   the minimum effective  dose and  the
type of effect  elicited at  that dose.   Although based on observed toxldty
data, H 1s not considered to be a  health risk assessment.

    The purpose for  developing this  chronic toxldty  ranking  system was  to
provide the  U.S.  EPA with  the technical background  required  to adjust  the
RQs of hazardous  substances  designated 1n  Section 101(14) of the  Comprehen-
sive Environmental  Response, Compensation and  Liability Act of 1980  (CERCLA
or  "Superfund").   This  ranking system has  undergone  a  limited peer review
and a public review.  It may'have applications  to other areas of  Interest  to
the U.S. EPA and  other  regulatory  agencies  where ranking of chemicals based
on chronic toxldty Is  desired.

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                               1.  INTRODUCTION
    The  purpose  for  developing this chronic  toxldty  ranking system was  to
provide  the  U.S. EPA  with  the  technical  background  required to adjust  the
RQs of  hazardous  substances  deslgnaled  In Section 101(14) of the Comprehen-
sive  Environmental Response, Compensation and  Liability Act of 1980  (CERCLA,
or "Superfund").  Section 103  of CERCLA  requires  Immediate notification  from
any person  1n charge of a vessel or an  offshore  or  an onshore facility who
releases an amount of  a hazardous substance equal  to or greater  than  Us RQ.
Under Section  102(b),  the RQ  of any  hazardous substance  defined 1n  Section
101(14) of CERCLA 1s 1 pound unless a different RQ has been established  pur-
suant to Section 311(b) of the Federal Hater  Pollution Control Act.   This  1s
the statutory  RQ for  each  hazardous  substance unless and  until the Admin-
istrator of  the  U.S.  EPA promulgates  regulations   establishing that quantity
of any  hazardous  substance  the release  of  which  shall be reported pursuant
to Section  103 of CERCLA.  CERCLA also  permits the  U.S.  EPA to establish a
single  RQ  for each  hazardous  substance  regardless  of   the environmental
medium Into which the substance 1s  released.
    The strategy of  the  Office of  Emergency and Remedial  Response (OERR)  of
OSUER  1s to  adjust  the  Section  101(14) statutory  RQs  using  six   primary
criteria   (1gn1tab1l1ty,  reactivity,   cardnogenldty,   aquatic  toxldty,
acute mammalian  toxldty (oral, dermal. Inhalation)  and  chronic  toxldty)
and   three   other   factors   (blodegradatlon,   hydrolysis   and  photolysis).
(Chronic toxldty, for  the  purposes of  this  report,  1s  defined as toxldty
due  to  repeated or  continuous exposure  from a  single release  or  multiple
releases of a  designated  hazardous  substance.) For  each  criterion,   a five-
tiered  rating  scale  Is set up corresponding  with RQ values  of  1,  10.  100,
1000  and  5000 pounds  (X.  A.   B. C,  0).   Since this  f1ve-t1ered system was


0721B                               -1-                              03/11/85

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successfully used  1n  the CUA  and  the regulated community  1s  familiar  with
H,  CERCLA  uses  this  methodology.   Unlike  the CUA.  CERCLA  addresses  all
media, not only water.  Therefore, while the strategy selected to adjust the
RQs  of  the  designated hazardous  sJbstances  pursuant to  Section 101(14) of
CERCLA was  based  on  the  precedence established 1n assigning RQs pursuant to
the  CUA,  Instead  of  using aquatic toxldty as  the sole criterion for estpb-
                                                                         «
Ushlng  RQs,  health and  welfare  effects for  other  media  were also used to
adjust the  RQs.   Each  hazardous substance  1s  evaluated  according to the  pri-
mary criteria  and an  RQ value Is determined  for  each  applicable  criterion.
The  "primary  criteria"  RQ  for each  hazardous  substance 1s  the  lowest  value
of all  the  applicable  criteria.
                                       ,                               03/11/85
   0721B                               •*'

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                     2.  CHRONIC TOXICITY RANKING SYSTEM
    The  chronic  toxUUy ranking  system  reflects  two primary attributes  of
each chemical:
    1.  The MED  levels  for a  given" effect following chronic  exposures
        (mg/day for 70 kg man)  by  alternative  environmental  media  (air.
        water).
    2.  Type  of  effect at  the HED  (e.g.,  liver necrosis,  teratogenl-
        dty. etc.).
    The dose  rating for  a given chemical  1s  based upon the HEO  transformed
to values ranging from 1-10 using  the  graph given  1n  Figure  2-1.   Substances
having an effect at a  low  dose  (I.e.,  those that are  more  highly  toxic)  will
be given  a  high  rating on  this  graph,  while  those requiring  a high  dose
(less  toxic)  will  be  given a  low rating.   Similarly,  the  rating  for  the
observed effect  at  a given dose for  a given  chemical  will  range from  1-10
depending on  severity using Table  2-1. with 10 being  the most  severe.   These
values must be assigned on  a chemlcal-by-chemlca1 basis.
    A final composite  score  (CS)  1s determined by multiplying the dose  rat-
Ing by  the  effect rating.   The possible  range of  CSs Is  thus 1-100.   Using
this  scheme,  only  those  compounds   eliciting what  are judged to be  the  most
severe effects  at low levels  of  exposure would be  assigned high CSs;  com-
pounds that elicit minimal  effects  at  high doses would be assigned  low  CSs.
    The following text gives step-by-step details for  this  procedure:
                         s
    1.  Identify subchronlc or chronic NOAELs,  LOAELs or FELs* based on
        animal or  human  data from the available literature.  Note  the
        dose/exposure and the effect.
    2.  Convert all  NOAELs,  LOAELs and  FELs  to  units  of  mg/kg/day.
        Inhalation,   dietary  or  drinking water  exposure  data  will  be
        converted  to units  of  mg/kg/day doses  based  on the methods
        outlined previously (U.S. EPA.  1980).
    3.  If the NOAEL,  LOAEL  or FEL 1s  based  on subchronlc  exposure,  a
        corresponding chronic  value will be  estimated  by dividing  the
        subchronlc  value  by  10 or less.   This  1s  supported experi-
        mentally by Ue11  and NcColllster (1963) and HcNamara  (1976).

07218                               -3-                              03/11/85

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                                             MATIMO VALIItl FOR DOSES
            i
It

 t
                   •-
               >

               2
               P
                   J-

                   I

                   1

                   t
    • It IF IN MED < -3


    • -I.BtofMCD • •• IF-J < tafMtD < S


MVj • 1  IPfefMfD > J
                             -3-1-1        t        I       ?

                                                   bfl NUMAM MED linffM*!
                                                                I
                                                                S
                                      I
                                      4
o
OD
\
O
oo

OS
                               FIGURE  2-1


           Rating Values for Doses used  (o Rank Chronic  ToxUtty

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                                                      TABU Z-1

                       Rating Values for HOAEls.  LOAEls and fCls used to Rank Chronic Toxlclty


               Mimo                                     tmcT

                 1    f NfVMf INDUCTION Ofl OTHER BIOCHEMICAL CHANGE WITH MO PATHOLOGIC CHANGES AMD NO
                      CHANGE IN ORGAN WEIGHTS.
                 t
                      BUT NO OTHER APPARENT EFFECTS.
                                                                      WCKWSANWfWMTl.
                 •    IllVtHtiett CltiULAH CHAMOtit CtOUOY HittitHO.KYOHOftCCMAIIOt.OH MTTYCHAIHm,
                 f    NTCflOftt.ONMfTAHAilAiriTNNOA^AMEI^OfCtltMemOfOiraAMnMCTIOM. AMV
                      NEUROPATHY WITHOUT AIT A fit NT BEHAVIQUAL. SENSORY. ON fHYSIOlOOIC CHANGES.

                 f    Nf CROStf. ATHOWV. MWCMTflOHIV. ON M^TAM. AST A WITH A Of ft CT AW. I Of CUE «f NT Of
                      ORGAN FUNCTION*. ANY NEUROPATHY WITH A MEASURABLE CHANGE IN BEHAVIORAL.
                      SENSORY. OR fHVSIOLOGIC ACTIVITY.

                 •    NECROSIS. ATROPHY. HVFff RTMOmV. ON Kit TAW. ASIA WITM Df nWtTVf ONOAN UVSff UNCTION.
                      ANY NEUROPATHY WITH GROSS CHANOIS IN BEHAVIOR. SCNSOBV.ON MOTOR PEREORMANCE.
                      ANY DECREASE IN REPRODUCTIVE CAPACITY. ANY EVIDENCE O? FETOTOKICITY.
                                                              •
                 f   -.PRONOUNCED PATHOLOGIC CHANGES WITH WVtRE ORGAN OVTOJNCTfON . ANY NEUROPATHY
                     'WITH LOSS or BEHAVIORAL OR MOTOR CONTROL ON LOSS OP si NSORV ABILITY. REPROOUCTTVI
                      DYSFUNCTION. ANY TERATOOENIC EFf-ECT WITH MATERNAL 1ONICITY.

                ft    DC ATM ON PRONOUNCED LIFE SHORTENING. ANY TERATOOENIC f ffECT WITHOUT PONS Of
g                     MATERNAL TOKICITV.
o
CD

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  4.   The «Ds  based  on  animal  data -ni.
                                                         .*. Put
      KO in units of »g/day for a 70 kg man.*

  5   Assign  a dose  rating  value (IV,) to the  dose  associated  with
      the KO  as  described In Figure 2-1.
  6   Assign  an  effect  rating  value (RVe) to  the effect associated
      with  the "ED »s described In Table 2-1.

  7.  Calculate the CS as:

                           CS

  ,.   „ „.  than on,  K»  C
       be  selected D» the fellowln*
       .   If  adequate  cnronlc  dit.  are  available.  «1sr«g.rd
           based  on  subchronlc data.
       .   If  .ore  than  one HCD remains, select the BED uhlch 1s based
           on  the 'best' data.
           for a given route will  be used.
                         .." -Hh the  hlgheS, CS.

»s detailed 1. the f.IMm .«"-.  «.1.»  «U«1f1«.«". «he^ has r«.lt

,d ,„ a reasonable 41.tr1k.t1. .f CSs for the compounds  thus far
                 animal dose (mg/day) x (  an1mal weight


 .It the animal dose 1s  In.-gAg/day the^uman .dose  In^g/da, equals:

                                                          x 70 kg.
            animal dose (mgAg/day) x


                                                                     11/02/84
  07218

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    10   The  RQs  are then  assigned  based on  the  following relationship
        to CS:

                   Composite Score               *Q
                       81-100                         I
                       41-80                         10
                       21-40                         100
                        6-20                        1000
                        1-5                         5000
As detailed 1n the following section,  this classification  scheme has  result-

ed 1n a reasonable distribution of RQs for the compounds  thus  far analyzed.
  0721B
                                      -7-
                                                                       09/19/84

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                      3.   APPLICATION  OF  THE «THOOOl06Y
    To  date.  -260  compounds  have  been assessed  using  the  methodology
described  in  Chapter 2.   In  the  final   evaluation.  Insufficient data  were
available  to derive  CSs  on 81 cot-pounds. CSs were  derived by  analogy  for  47
conpounds. and  CSs were directly  derived from experimental data  on  the 116
remaining  compounds.   Histograms  were  constructed from  preliminary  evalua-
tions  showing  the  distribution  of  RVds. RVes  and  maximum  CSs.  and  are
given  1n  Figures  3-1.  3-2 and 3-3. respectively.   Although the final evalua-
tion  has  changed  several totals, the discussions  concerning these histograms
and.  more Importantly,  the conclusions reached are  the same.
    A reasonably  symmetric  distribution of  CSs  -as  obtained  (see  Figure
 3-3).  Histograms  of  the  RVds  and RVes  were  generated to  better  under-
 stand the distribution  of CSs and  to  suggest  ways in which  the  methodology
 could be modified to account  for  the available data.  As Indicated  In Figure
 3-1.   the distribution of  RVds  1s skewed, markedly toward the  lower  values.
 While this partially reflects  the distribution of  doses  In all the available
 data,  many  of  the  doses given  an  RV,  of  1 were  well  In  excess  of  1000
 mg/day.  suggesting that  U may  be  desirable  to expand  the RVd  scale,  at
 least  at the  lower  limit.   In  the distribution of RVes.  the  predominance
 of  RVes  of  10.  which  indicate  mortality  or  teratogenlc  effects  without
 signs If maternal toxldt'y. appears to reflect the nature of  the data  on  the
 105  compounds and may  not  be of  substantial  use  In  modifying the effects
 rating  scheme.   All  RVfts  derived  for  the "lOS  compounds,   not Just  those
 associated  with  the maximum CS.  are being reanalyzed to better  evaluate this
  assertion.
                                        .                               09/19/84
   07218                               ~B"

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               10-
                                  FIGURE 3-1
      Distribution  of  RVds  In  Raxlmum Composite  Scores  for  105  Compounds
0721B
                                    -9-
                                                                     09/19/84

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      i
                   i    !•«•••   7.   ••«
                                  FIGURE  3-2



      Distribution of  RV s  1n Haxlmun Composite Scores for  105 Compounds
0721B
                                    -10-
                                                                     09/19/84

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              1-
                          u.16   21-2S
                              10-20
11-3S   41-45    >K>
    S8-40    «f-K
                                 FIGURE 3-3

                          ComposUe Scores  for  105 Compounds
0721B
                                    -11-
                                                                     09/19/8*

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    In  addition to  examining  the  distribution  patterns  of  CSs,  RV.s  and
RV s.  1t  was also  determined If any  correlation existed between  reported-
acute  and  calculated-chronic  toxlclty values and if any  structural  correla-
tions  could  be  found vs.  the chronic  toxlclty  values.   These  determinations
were deemed  Important  since  acute mammalian toxlclty 1s a primary  criterion
In establishing  toxlclty  rating schemes,  and the Inclusion  of  chronic  toxl-
clty might possibly  be redundant.   This  latter  concern  Is  possibly  justified
given  the  relationships   between  acute  and  chronic  toxUUIes  noted  by
HeNamara (1976). Well and HcColllster  (1963) and  Ue1l et  al.  (1969).   Conse-
quently, for  the 105 compounds  on  which  maximum CSs were directly  derived,
the LOcQ  1n  experimental  mammals was  Identified  from the Registry of  Toxic
Effects of  Chemical Substances  (NIOSH,  1982)  and  converted  to  approximate
human  LDc.s  using  the cubed  root of  the  body  weight ratios as specified  In
point  4,  Chapter  2.  Preliminary  results  of  these analyses  are  given  1n
Figures 3-4.  3-5 and 3-6 for  aromatic*.^aliphatic* and Inorganics,  respec-
tively.  Although  an attempt  1s being  made to  more  critically  review  the
acute  toxlclty data, and statistical analyses will  be conducted,  no  correla-
tions  between maximum  CSs and minimum LD,Qs are  apparent.  That  1s  to  say,
the chronic  toxlclty of  a series  of chemicals  cannot  necessarily be  pre-
dicted  from  acute  toxldtles.  This  Is a  well  established  principle  In  the
                         j
field  of  toxicology.  Therefore, the  use  of chronic  toxlclty as a  ranking
tool Is not redundant.
    Although work on structural correlations Is In  a very  preliminary stage,
Figure  3-7  Indicates no  apparent correlation between  maximum CSs and  Upo-
phllldty for 21 substituted  benzenes.  In  this  figure, log of the  octanol/
water  partition  coefficient  given by  Hansch and  Leo (1981)  was  used  as  the
Index   of   I1poph1l1c1ty.   Analyses   of  other   structural   parameters   are
currently being conducted.
0721B
-12-
09/19/84

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    »    i.O-i
          4.0-1
          J.I-I
          2.0 H
          i.o H
          o.sH
                  e   •
                                          A

                                         A
e  CHicmo

•  MITKO

A  OTHER
                      ~T         i         i
                       10       20       ao
                         MAXIMUM COMPOSITE SCORE
                                AROMATICS

         10
                                FIGURE 3-4


            Composite Scores vs. H1n1«i» LD5(,s  for 28 Aromatic Compounds
07218
                                  -13-
                                                                  09/19/84

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     I
          f 0-,
          4.0-
          ....
           3.0-
           2.8-
        f
        I
           2.0-
                                          o  o
              -
           1.0-
           O.i-
 •  CMLORD

 o  OTHER
                        10       20       30

                               COMPOSITE SCORE

                                 ALIPHATIC*
T
 40
n
 •0
                                 FIGURE 3-5


           Composite Scores vs.  MlnlM- Utf for 33 Aliphatic Compounds
0721B
                                   -14-
                                                                   09/19/84

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  I
        4.0i
        I.S-
        3.0-
        2.5-
        2.0-
        1.5-
        1.0-
        0.5-
 I
10
 T
20
 1
30
                  I
                 40
                                                             I
                                                            K
                             COMPOSITE SCORE

                               INORGANICS
                               FIBURE 3-6
           Composite Scores vs. (Un^mum LDq_s  for. 25 Inorganic Compounds
0721B
-15-
                       09/19/84

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i
      n-
      n-
      t-
                                i
                                i
I

•
                                   MGURE 3-7



              ComposUe Scores  vs. Log P for ?1-Substituted Ben/enes

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                      4.  SOME CONCEPTUAL CONSIDERATIONS
    The development of  the quant Hat We  rating scheme for effects  (see  Table
2-1} and the combination of  this  scheme  with a quantitative  estimate  of  dose
(see Figure  2-1)  represent  a potentially  useful  Innovation  1n the analysis
and assessment of chronic toxlclty data.   The effects rating scheme 1s  based
on  a  combination of biochemical,  hlstologU.  physiologic  and  gross  effects
arranged 1n  Increasing  order  of  severity.   While the rating values assigned
to each type of effect  are essentially arbitrary, rating values of  1  to  3  or
4  have  been  generally regarded as  NOAELs, 5-7 as LOAELs and  7-10 as  FELs.
In  an  attempt  to allow for  the  necessary scientific judgment, the descrip-
tion of the  effects  Is  Intentionally  not  too detailed.   Although some  addi-
tional  modifications  and expansions  of  the  scheme  may  be desirable, the
application  of  the  scheme to  date suggests that  It would  be  a  mistake  to
attempt  to  catalogue  every   possible  specific  effect  which  chemicals can
Induce  and  to  associate each  effect  with a quantitative  value.   Also, the
                                         ^  ^
ranking  scheme  Is  not  organ  specific.   While  the  ICRP  (1977.  1979) has
addressed  the  problem  of organ  sensitivity to  specific  radlonuc.Hdes. and
their approach nay be useful In predicting the most  sensitive organ for  cer-
tain  radlonucUdes,  the  effects  rating  scheme  presented  1n  Table  2-1  Is
Intended to be applicable  across  target  sites.
    Nonetheless, the variation In organ  sensitivities 1s an  Important factor
In  defining  the BED  associated  with a  given dose  level for  a particular
toxicant.   This  1s  Illustrated  In Figure  4-1,  hypothetical  data  1n  which
NOELs.  NOAELs.  LOAELs  and FELs  are plotted on  a RVd  vs.  RV£ diagram.   At
low  doses  (I.e.,  high  RV s)  only  NOELs are  observed.    As  the  dose In-
creases (I.e..  the  RV^ decreases)  effect  ratings  become  Increasingly  high.
07218                               -17-                            09/19/84

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                       ECIESAMD
    tOAIL *
    NOAEL
          V 1-
          MOEL
                                 FIGURE 4-1



                Hypothetical MOELs.  HOAELs. LOAELS and FELs
0721B
                                   .18-
                                                                   09/19/84

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However,  at a gl«n «f'«t level, ~Utpl.  points  can b« e.pected a, the
„„« increases  -1th the point furthest  to the right  representing  the »«t
,,r,s1t1« organ or  species or  1r.cr.as1n, Incidence of  the tfftel.  The  slope
„,  the Hn, oravn  to the right of the effect  I...1 P«'nts an. l.l.r,Ktl.g
the .-axis to the  left of the .OILS represents  the 1.1— '«'"»  "  *»«
S,«r1t,  of  effect .Hh  Increasing  dose and «»  be  »«-d  the apparent
,e«r1t,  slope.  Ho«..r.  as  Illustrated In  ,**.  M.  the apparent sever-
uy .Lp. «y  »e a composite of .wtrll, slopes for  specific organs and/or
 spedes.
                                      ,a                            09/19/84
    07218                              -19'

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                    TftUE CUKVES rOM
                      PEMENTOHC
                       Oft SPECIES
                                       MED CURVE
                                 FIGURE  4-2

        Apparent BED Curve as a Composite of  True Curve for Different
                             Organs or Species
0721B
                                   -20-
                                                                   09/19/84

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                      5.  MOIFICATION AND APPLICATIONS

    The basic methodology outlined 1n Chapter 2 of  thU  report  was  developed

In  response  to  a specific  need.  Having  applied the  methodology to  -260

compounds, explored  some of  the conceptual  considerations  Inherent  1n  the

methodology,  and  received preliminary  comments  from  scientists  both  within

and outside of the Agency, the following modifications have been considered:
    1.  Derive  the  CS as  the SUB  rather  than  the  product  of  RVd  and
        RVe.

    2.  HodUy  the dose  rating  scheme to cover  a wider  range  of doses.
        As  Indicated  1n  Figure 3-1  and  discussed 1n Chapter  3  of this
        report,  several   studies  from which maximum  CSs were  derived
        Involved  dose levels well  1n excess  of 1000 mg/day. yet were
        still  assigned  the  minimum  RVd of  1.   The  revision  currently
        under  consideration  would   cover  10  log dose  units  from  10*
        mg/day  yielding  an  RVd  of  1  to  10'-  mg/day  yielding  an
        RVd  of  10.

    3.  Review  and  utilize  data on  pharmacok1net1cs  and other relevant
        data to  obtain  more  reasonable estimates  of  absorption from
        oral and  Inhalation  routes.  Th5  -current approach  assumes  50%
        absorption  from  Inhalation  exposures  and 100X  absorption from
        oral exposures.  These assumptions  were made rather than review-
        Ing  absorption data  In an  effort  to  minimize  the cost  of this
        project.   However,  these  assumptions may be misleading  particu-
        larly for metals.

     4.  Modify the effects  rating  scheme  giving more specific  guidance
        and/or  altering  some  of the  criteria.

     In  addition,  the  application  of the methodology  has suggested  that  the

 RV  vs.  RV   plot may  be useful  to other  Agency Offices  1n the estimation
   e    '    d
 of NOELs  or NOAELs- used 1n  the  derivation of  ADIs.   Kushner et al.  (1983)

 have recently  reviewed  the  use  of AOIs  1n  Superfund Implementation,  and

 Stara and coworkers  (Stara et al..  1980, 1981;  Oourson  and  Stara. 1983) have

 reviewed  more  general  problems with the estimation and application  of  ADIs

 In the regulatory process.   Two problems Involving  the  use  and  derivation of

 AOIs may be at  least partially alleviated  by  using  the  RVd  vs. RVg plot.
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First,  the Agency frequently  has  been criticized  for  not using all  of  the
available  data  1n estimating  the  NOAEL  from which ADIs  are  derived.   Using
the  RV   vs.  RV, plot  along  with  an  appropriate  statistical  method  for
estimating  the  apparent  severity  tlope and  the ^-Intercept  (I.e.,  maximum
NOEL),  all of  the  available  subchronlc  and  chronic  data  could  be  used.
Second, examples  have been  encountered  where  no  suitable NOAELs or  LOAELs
are available  from which an  ADI  could be derived.   In such cases, data  on
FELs and  NOELs  could be used  to estimate either the  maximum  NOEL or  a suit-
able  NOAEL (e.g.,  dose  associated  with an  RVg of  1  or  2).   Again,  this
would be  dependent  on the development of an  appropriate  mathematic model  to
estimate the severity slope and x-1ntercept.
    In addition to these  Immediate applications, U may be desirable  to con-
sider  expanding  the RV,  and  RV   plot  to  Include axes for  duration  of
exposure,  species and Incidence of response.  This, however,  would be  a very
complex undertaking  that should await  further  development and  applications
of the basic RVft vs. RVd plot.
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                               6.  REFERENCES
Dourson, H.L.  and J.F.  Stara.   1983.  Regulatory  history  and experimental
support  of   uncertainty   (safety)'  factors.   Reg.   T.«1c.1.   Pharmacol.
3: 224-238.

Hansch, C. and  A.J.  Leo.   1981.   Pomona College  Medicinal Chemistry  Project.
Seaver  Chemistry Laboratory. Claremont, CA.

 ICRP  (international  Collision on  Radlologlc  Protection).   1977.   Recommen-
 dations of  the  international  Contusion on  radlologlc  protection.   ICRP
 Pub.l.  26.  Pergamon Press.  Elmsford,  NY.  p. 50.

 ICRP  (International  Comlsslon  on  Radlologlc  Protection),   1979.  -Radio-'
 nucllde  release   Into  the environment:  Assessment of  doses to  man.   ICRP
 Publ.  29. Pergamon Press. Elmsford. NY.   p. 76.

  Ku.hn.r;  L.H.. «.C. Wards and V.  Pong.   1983.  The potential  use  of the ADI
  in  Superfund  Implementation,  mtre Corporation. McLean. VA.  p. 68.

  Samara.  I.P.   1976.   Concepts  1n health  evaluation  of  commercial  and
  industrial chemicals.   In:  New  Concepts 1n Safety  Evaluation:  Advances  in
  Modern Toxicology.  1(1): 61-115.

  NIOSH (National   Institute  for   Occupational  Safety  and  Health,.   1982.
  Registry of  Toxic  Effects of Chemical Substances.  U.S. DHE«. Cincinnati. OH.
                                        ,,                              03/11/85
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Stara, J.F., D. Kello and  P.R.  Durkln.   1)80.   Human health hazards associ-


ated  with  chemical  contamination  of  aquatic  environment.   Environ.  Health


Perspect.  34:  145-188.




Stara, J.F., H.I.  Dour son and  C.T.  DeRosa.   1981.   Water quality  criteria:


Methodology  and  applications.    In:  Conference  Proceedings:   Environmental


Risk  Assessment:   How  New Regulations  will  Affect  the  Utility  Industry.


Electric Power Research Institute. Palo Alto, CA.





U.S.  EPA.   1980.   Guidelines  and methodology  used  In  the preparation  of


health   effects  assessment  chapters of   the  consent  decree  water  quality


criteria.   Federal  Register.  45:  79318-79379.




 Hell, C.S.  and  D.O.  HcColHster.   1963.  Safety  evaluation  of  chemicals.


 Relationship  between  short- and  long-term  feeding studies 1n  designing  an


 effective toxUUy test.   Agrlc. Food Chen.   11: 486-491.




 Well.  C.S.. H.O.  Uoodslde,  J.R.  Bernard and  C.P. Carpenter.   1969.   Rela-
                                                                         •

  tlonshlps   between slngle-peroral.  one-week,  and  ninety-day  rat  feeding


  studies.   Toxlcol. Appl.  Pharmacol.  14:  426-431.
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