Untod State*
 EnrirenfMrtal PraMk
 Agamy
 Region III
 Tachnical Guidance Manual
 Risk Assessment
Ofltoa <* PoNution Prevention andTcodo SubataneM
    Air, Radiation and Tadw OivWon
       Philadelphia, PA 19107
          Chemical  Indexing System
for the Toxic Chemical  Release Inventory
         Part I: Chronic Index
                                                  IPA Contact Dr. Dtbn L Forman
                EPA
                Region III
                                                         Air, Radiation and Toxics Division
                                                          November 1993
The TRI database contains information about chemical releases and transfers from industrial manufacturers and
processors (primary Standard Industrial Classification (SIC) codes 20-39) to environmental msdia. Since 1987, facilities
meeting established thresholds have been required to report release data according to sesiion 313 of the Emergency
Planning and Community Right~to-Know Act of 1886 (EPCRA)1. To date, however, Agency tracking and analysis of tf?®
data has generally been limited to an evaluation of the relative amounts of chemicals released without regard f$r
differences in chemical toxicity3. This guidance document presents a method for evaluating EPCRA chemical releases
in terms of their toxicity and is intended to support enforcement targeting and strategic planning efforts with a metre
realistic evaluation of these chemical releases.  The intent of this process is to place emphasis on the most toxic
chemic&l releases reported under EPCRA §313. Furthermore, the technique provides a standard tool which reflects the
dynamic operating system of EPCRA program development and scientific growth. The method also fulfils the EPA Region
.'// mandate to utilize best science in its decision-making processes. The guidance is intended to be used as a screen/rig
toot to improve the quality and consistency of enforcement targeting and strategic planning for the EPCRA program in
Region III.  (EPA/903/R-93/002)                                                              •.
L BACKGROUND

       To date, analysis of the Tadc Chemical Release
inventory Database (TRI) hat generally been limited to
comparisons of  the  relative  amounts  of chemical
releases without  regard for differences in chemical
toxicity*. While som+methods have attempted to define
relative toxicity in terms of ordinal or categorical scoring
systems, the large uncertainties, inherent in the analysis.
have limited the usefulness  of the  results3'4.  This
guidance  serves  as a   refinement  of previous
methodologies3** and offers  a scheme for  media-
specific, multi-component  Chemical Indexing which
utilizes  a dose-based  approach to rank TRI chemical
                   releases. In this paper," the first component of the Index
                   is  presented.  It is termed  a Multiple Component
                   'Chronic Index* since it 'a based on botir cancer and
                   chronic noncencer effects of EPCRA chemicals. The
                   results of the Chronic Index are intended to be used as
                   a supplemental screening tool to refine planning and
                   enforcement targeting efforts and focus resources on
                   the most compelling problems. While the results of
                   Phase I are intended as a priority screening tool for
                   hazard identification, Phase II of the project focuses on
                   evaluating the relative risks of targeted releases.

                         The Chronic Index is based on a combination
                   of TRI emissions data and an estimate of relative dose,
                                                      U.S. Environmental Protection Agency
                                                      Region 5, Library (PL-12J)
                                                      77 West Jackson Boulevard, 12th Floor
                                                      Chicago, IL  60604-3590

-------
 rather then an ordlnat or categorical scoring system. In
 Ms way, the resutMrart^retafarrm sensitivity to
 experimented dam bypouenlng the relative intervals
 between ad/acant calculated Index vafcea*. Moreover,
 because the result* of the Max am intended for heard
 identification, the vaft/ea ara necessarily independent of
 calculated exposure and subsequent risk values7.

        Subsequent  development  of  the  Chemical
 Indexing System will include consideration of the acute
 toxicologic  effects and potential chemical fate of TRI
 chemicals  (see Figure  1).  The Chemical Index is
 intended  to enable identification of specific facilities
 estimated to contribute the greatest amount of toxic
 releases  to the  environment and as  the  project
 progresses, a database of Index values assigned to
 each EPCRA facility will be collected for use with GIS
 mapping.
    Ptese I:
     Phase II:
        Eifosire/Ksi issesswt
        Ecologiat
           Figure 1: Scope end Objectives

        Upon completion of Phase I of this project,
Phase II will appry risk assessment methodologies to
evaluate the specific human health exposure scenarios,
and fate and transport modelling to assess  exposure
point  concentrator*  of  targeted  chemicaia.  The
epidemiotogic  liteOftfa witt also  be  consulted  to
support evaluations concerning possible causa and
effect  relationships.  This aspect provide* additional
support  to decision-makers  in the  evaluation  of
perceived versus actual adverse health impacts of 77V
emissions. Ecological considerations are also included
in the overall assessmentof ffie predicted impact of the
TRI release.
2. METHODS

2.1.  Primary  Qa*««*»;  The TFU database  (TH/S) is
mainlined by the US. EPA to Research Triangle Park,
NC and is a/so a component Hie of the National Library
of Medicine's TOXNET system. Agency access to the
database and downloading procedures are available.
Public access to TRI can be obtained by writing to:

       U.S. EPA
       P.O. Box 70268
       Washington, D.C. 20024-0266
       Attention: TRI Public Inquiry

       In order to estimate the relative toxicity of TRI
chemicals, a consistent criterion for  comparison is
required. The IRIS database of oral Reference Doses
(RfD) and Cancer Slope Factors (CPF) was selected as
the baseline for toxicity comparison for several reasons.
Firstly, the database provides quantitative estimates of
toxicity  which  are  derived  using  a  consistent,
established procedure. This serves to standardize errors
inherent in the database. Secondly, the RfD and CPF
approval processes an endorsed by the EPA and an
nationalty recognized aa a score*  of relative toxicity
data, This serves to support futun actions which might
be based on the results of the Indexing procedure. For
access to the IRIS  database,  contact  the Risk
Information Hotline at (SI3) 569-7254.

       The IRIS database provides oral toxicity factors
for most EPCRA chemicals. However, because IRIS
supports alt EPA programs  with limited resources, IRIS
toxicity data an not always available for ail  EPCRA
chemicals.
   WWWpmwS^fe'

   ~;% "H^IPGk^f1

         ***
  : / & ^ f   frj V >
      F&n 2: Most Distribution of INRetoua
             far a UA Stole (Iffl990)
Figure 2 shows a sample dataset reported in one U.S.
State for the 1990 reporting year (RY1990) when more
than 50% of the pounds reported  were released to the
air medium. Of this amount, up to 87% of the fugitive

-------
to
 emission*  can be  uccountad lot using the toxicity
 information in IfUS. About 50%  of the point source
 emissions can be expntnci in terms of IRIS toxicity
 data (see Figure 3).

        It is important to point out that depending on
 the industrial processes used and the availability  of
 toxicity information, thepercentago of chemical releases
 expressed in terms of the Chronic Index may vary from
 year to year. Nevertheless, each calculated facility index
 may be tracked to evaluate trends. Estimates of  acute
 toxicity and chemical fate will be incorporated into the
 Index in forthcoming updates of  this guidance which
 will serve to improve the percentage of TRI releases
 measured by the Index. Moreover, it is understood that
 the EPA-RfD  (Reference   Dose)  and   EPA-CRAVE
 (Carcinogen   Risk    and   Verification  Endeavor)
 workgroups approve new chemicals monthly and care
 should be taken to include the new chemicals as they
 become available.

       In the absence of primary toxicity data (IRIS),
 the  reported chemical releases are termed 'residual
 releases'  and are ranked according to  the  mass
 released (Ib/yr). This list is then examined for candidate
 chemicals which may possess toxicity information from
 secondary sources.

 2.2. Secondary Datasets:  Secondary sources of toxicity
 data are investigated for possible  inclusion of residual
 chemicals  not  represented  by  IRIS toxicity   data.
 Generally, a provisional toxicity factor from a secondary
 source is investigated if a compound is identified in the
 top 90 percentile  of the residual releases.

       Some  examples of secondary sources include
 the  Health  Effects   Assessment  Summary  Tables
 •HEAST), provisional factors derived from intra- or inter-
Agency sources,  such as  the Environmental Criteria
Assessment Office, Office of Pollution Prevention and
 Toxic Substances and the  National Toxicology Program,
 or the general literature. While this is not an exhaustive
 listing of secondary sources, the preferred hierarchy of
 toxicity sources is commensurate with the most to least
 •igorous level of Agency review.

       In the absence of primary or secondary toxicity
data, the  residual releases  are ranked according to
pounds released per year and the ranking Is included
as a corollary to the Chronic Index report
                                                                         Figure 3: Chronic Tenacity Distribution
                                                                                 (US. Stale) KY1990
                                                              2.3. Emphasis of Carcinogens  vs. Non-Carcinogens:
                                                              The Index System includes an adjustment to account for
                                                              the policy relationship between carcinogenic  versus
                                                              noncarcinogenic regulations.  This adjustment is not
                                                              intended to  imply  biological  significance  of the
                                                              individual toxic effects,  but  is  included to remain
                                                              consistent with Agency policies regarding regulation of
                                                              risk and hazard  levels  for  carcinogens and non-
                                                              carcinogens. The adjustment is based solely on Agency
                                                              policy which outlines the conditions  for acceptable
                                                              heard and risk levels.

                                                                     For  noncarcinogens  regulated  under the
                                                              Superfund Program, the National Contingency Plan
                                                              (NCP) recommends concentrations to which the human
                                                              population,  including sensitive  subgroups,  may  be
                                                              exposed without adverse effect during a lifetime or part
                                                              of a lifetime, incorporating an adequate margin of
                                                              safety.* Thus, the acceptable exposure level occurs at
                                                              levels where there Is no lasting deleterious effect. This
                                                              has generally been interpreted as those concentrations
                                                              equivalent to a hazard index of

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       FofcarcMTogem regulated under the Superfund
Program, tf» NCP tmam Hat for the purpose of hazard
identification, •accapHt* exposure levets are generally
concentration level* Ihet represent  an excess upper
bound lifetime cancer /Mr to an Individual of between
iff4 and  Iff1  using information on the relationship
between dose and response-* In addition to Superfund,
other Agency programs also recommend this risk range
for hazard Identification of carcinogens. For example,
rulemaking  pursuant  to   The   Clean  Air  Act
Ammendmenta of 1990 discuss screening carcinogens
for the early reduction plan at a risk level oflxlff4
10
        Thus,  in accordance with policy  statements
regarding hazard identification, the hazard index level of
1 and the risk level of 1 x Iff* represent  acceptable
limits for this purpose. The Chronic Index is computed
in  accordance  with  these policy  statements  by
expressing the dose for noncarcinogens at a hazard
index * 1 and the dose for carcinogens at 1 x Iff* risk
(approximately equivalent to a hazard index » 0.04)".

       Additional  refinements  of  the System will
include grouping of the noncarcinogenic toxicity data in
terms of target organ toxicity and if deemed appropriate,
the development of an appropriate weighting system.
3. ALGORITHMS

3.1.   Derivation  of  the  Chronic  Index  LOTUS
spreadsheets were developed for dam handling and
analysis. The TRI release data was combined with the
corresponding IRIS-approved oral RfD and/or CPF value
to ootain an estimate of the relative  toxicity of the TRI
release.  The resultant estimate is termed the Chronic
Index.

        The algorithm is based on the assumption that
adverse health effects resulting from exposure to either
carcinogens or noncarcinogens is due to some dosage
received by the organism. Since  the present form of
IRIS toxicity dam  doe* not lend tee* to direct
comparison of carcinogenic and  noncarcinogenic
doses, a method was derived which normalizes the two
dose scales.  The  resultant  standardization permits
comparison  and  equivalency  ranking   of   both
carcinogenic and noncarcinogenic TRI releases.

        Reference points for determining relative hazard
are  identified  according to Agency policies  cited
above8*10.  The reference point for noncarcinogenic
doae it caJcutated at a hazard index of 1 and the
reference point for carcinogenic dose it equivalent to 1
x tor* risk.

       Following dose calculation for carcinogens, the
calculated doses are adjusted according to the weight
of evidence (WOE) scheme developed by the EPA14.
TheWOEclassHicationa of A, B1, B2, C-B2", and C are
represented by mathematically equivalent intervals, A -
3/3,  8 -  2/3 and C -  1/3. The B2 category  was
considered the lower limit of the A-B interval and the
value for B1 was assigned an average valueijetween A
and B. The WOE value for the C-S2" category was also
derived by assigning an  average value for the  B-C
interval. Hence  the  numerical  WOE values  were
assigned:  1.00, 0.84, 0.67, 0.51 and 0.34, respectively.
Class D and E compounds generally do not possess
cancer potency factors and are assigned a value  of o.
The complete algorithm is presented in Appendix 3.

        77)8 oral carcinogen dose (d) is calculated at
a reference risk of 1 x Iff4, by solving the equation used
to derive the q.1 values. Thus,
                                                        where
                q »
                de
                risk
                          ziak » l -•'**
              cardnogonte potency factor
              eardnogenlc dose
               1 x 19* as the reference risk value.
                Noncarcinogenic dose is expressed as the oral
         reference dose (RfD) equivalent to a hazard index of 1.
         Thus,
                tfosei
                    'He
         where
                                                - 1
         Dose units for both carcinogenic and noncarcinogenic
         scales an  converted from  per  mgi(kg/day)  and
         mgfkgfd to mgld by dividing or multiplying by 70 kg,
         respectively.

                If a compound possesses both noncarcinogenic
         and carcinogenic toxicity factors,  the total dose is
         calculated according to the following equation:
         where

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Dosee
                      -  Total Chronic
                      "  Noncerdnoganic Dote
                      .»  Carcinogenic Dote
        For the purpose of equivalent comparisons, all
toxicity factors are expressed in terms of dose and as
a  result,  a constant  dose-based  toxicity factor  is
calculated for  each  compound  listed in the  IRIS
database.

        The TRI chemical releases are converted from
the units Ibfyr to mg/d to correspond to the calculated
dose units of mg/d using the following conversion
factors:
        1 year
        11b chemical
        1 kg chemical
                 365 days
                 0.435 kg chemical
                 1 x 10* mg chemical
       The TRI release (mg/d) for each compound is
divided by the calculated chronic doser (mg/d). The
resultant values (Chronic Indices) are ranked and target
chemicals are identified which simultaneously account
for both carcinogenic and noncarcinogenic toxicity. It is
Important to note that Single Component Indices (I.e.
noncarcinogenic  or  carcinogenic)  may  also  be
calculated and ranked to identify target chemicals for
specific endpoints of concern1'. Those chemicals which
do not possess primary or secondary toxicity factors an
evaluated   as residual  releases  and  an  ranked
according to the mass released for each TRI category.

3.2.  Facility Targeting: LOTUS spreadsheets  which
utilize the  Chronic Index to identify specific facilities
lave also  been developed. For example, the analysis
may include a ranked list of facilities responsible for the
highest toxic  relemtei indicated by their Chronic
indices. The total releases for these chemicals in each
geographic entity (I.e.  county, zipcode zone, census
iract,  etc.)  are summed, ranked  and those facilities
estimated  to  have the largest  contribution  to each
entity's emissions maybe identified. These facilities may
also be characterized by related data including SIC
codes and descriptions, parent  company names, and
participation in the 33150 program17.

        EPA'S 33/50 Program target* 17 priority toxic
pollutants and asks industry nationwide to voluntarily
reduce releases of these chemicals 33% by the end of
1992 and 50% by the end of 1995.  While these are
national goals, each company selects Us own individual
reduction goals.  The  Program  is multi-media  and
advocates pollution prevention (source reduction) as the
preferred method for reducing releases.

4. LIMITATIONS

4.1. Dataset reconciliation: Several discrepancies were
noted in reconciling the two datasets, IRIS and the
EPCRA chemical  list  EPCRA allows reporting  of
chemical classes as well as individual chemicals. Thus,
most metals an  reported  both  as elements  and
compounds,   e.g.   manganese   or  manganese
compounds. The chemical nature of the 'compound' is
not specified according to EPCRA. Since IRIS provides
toxicity information for'specific compounds or elements,
the Information which  corresponds to the generalized
EPCRA reported  re/eases for metals do not coincide.
Thus, in order to maximize the data useability from both
databases, metals which an reported on TRI as either
elentants or compounds an summed and assigned the
toxicity factor available in IRIS.

        While this approach may tend to overestimate
the Chronic Index of some reported metal releases, it is
consistent with the  purposes described above. Both
enforcement  and planning  activities can  use  this
information as a screening tool to assist in determining
the need for action. Should the decision to take action
arise, then other sources of data should be Investigated
in depth to obtain more realistic estimates.

4.2.  Valence State:  Compounds which exist in more
than one valence state, e.g. chromium (Cr) or  arsenic
(As)   an  particularly  problematic.  In  the  case  of
chromium, for example, IRIS possesses specific toxicity
factors for Cr(lll)  and Cr(vT),  but EPCRA onty requires
general reporting of  Cr nleases as  chromium  or
chromium compounds. Thus, the TRI database does not
distinguish between nleases of the less toxic Cr(lll) and
the mon toxic Cr(VJ). In order to develop a conservative
estimate of the Chronic Index, the toxicity factor for the
mon toxic compound is used in the calculation. This
limitation  should be  considered  in  evaluating  the
effectiveness of this approach for certain media.

-------
 4.3. exposure rout* mite ertfa^oaurv/Muffin?/torn
 soU deposition  of at •mtofata may constitute  the
 primary route of chemical exposure for tome type* of
 industrial source**, «* direct  inftaJation route may
 contribute to expoaun to air emissions from other
 source types. This exposure convept would argue for
 the inclusion of inhalation rather than oral toxicity data.
 However,  because many TRI  compounds  do  not
 possess inhalation  toxicity data (RtC)  for noncancer
 endpoints, some other value, such as an oral RfD,
 would be required as a default tor missing inhalation
 values. The  combination of data from two exposure
 routes may result in an inordinate weighting of those
 chemicals which possess inhalation RtCs compared to
 those  which  are represented by oral RfDs. Thus,  the
 usefulness of the resultant Index as representative of
 TRI releases  and as a comparative indicator is limited.
 Further study will include a distributional comparison of
 existing FtfCs and RfDs to determine the existence of
 differences in relative toxicity between the two routes of
 exposure.

 4.4. BioavailabiHtv (foodlwater): The relative toxicity of
 some compounds depends on the vehicle of ingestion,
 i.e. food or water and toxicity values  may be listed
 separately on the IRIS database. Generally, compounds*
present in water are more bioaveJIaUe and more toxic
 when ingested with water. In order to provide some
 measure of consistency, if two values are reported in
 IRIS, the drinking water oral toxicity factor is  used to
 calculate the  Index.

 4.5. Standard Dose Scale: The methodology presented
 in this analysis assumes acceptance of the current RfD
 and CRAVE workgroup processes. While each process
 contains elements of uncertainty which stem both from
subjective judgements and calculated mathematical
 error,  the resultant  Chronic  Index   scale   merely
 compares one Index  value to another. Thua, errors
inherent in the approval processes  an tost  likety to
influence the results of the Chronic Index ranking. Aa
 these accepted processes an refined1*3**1, the Index
 method will adopt the outputs of the new procedures.
5. CONCLUSION

       As with  all systems which attempt  to utilize
imperfect data to achieve conclusions, this system also
possesses its contingent of limitations. When utilizing of
results of this process, it la incumbent upon the  user
that the information is applied in the context of these
limitations.

       Oespto Its limitations, this approach provides a
current best-sconce  approach to support ongoing
decision-making  processes.   Moreover,  since  the
method assigns  a  constant  toxicity factor to each
chemical,  it permits tracking of the toxicity reductions in
releases reported for Individual chemicals or facilities
from year  to year.  The method also allows for inclusion
of new information  as it becomes available, both in
terms of toxicity and governmental regulations.

REFERENCES

1. Public Law 99-09, Frtfe III, f 313, October 17, 1986,
100 Stat 1741, 42 U.S.C. § 11023; See also U.S. EPA
(1992) Toxic Chemical Release Reporting: Community
Right-to-Know; Subpart B-Reporting Requirements 40
C.F.R. § 372.22.

2. US. EPA (1990) Toxics in the Community National
and Local Perspectives, OPPTS, EPA 56014-90417.

3. U.S. EPA (1992) Region  III  1991 Merit Project:
Comparison  of  Toxics Release  Inventory Airborne
Carcinogenic Releases with Observed Human Cancer
Mortality Rates, Final Report submitted from Jeffrey J.
Burke, Protect Manager to Henry P. Brubaker, Program
Analyst, (August 8, 1992).

4. U.S. EPA (1989) Toxic Chemical Release Inventory
Risk Screening Guide, Volume I: The  Process and
Volume II: Appendices, EPA 560(2-89/002, Version 1.0,
OPPTS, Juty 1989.

5. Forman, D. L  (1993)  U.S.  EPA Region HI Toxicity
Index Prototype for Targeting TRI Chemical Releases, in
Proceedings Toxics Release Inventory (TRff Data Use
Conference March 29-31,1993, Chicago, IL EPA/745-R-
93-004, pp. 205-208.

6. Stevens, S. S.  (1946)  On  the Theory of Scales of
Measurement, Science 103:677-680.

7.  National  Academy  of  Sciences  (1983)  Risk
Aamsment in the Federal Government Manageing the
Process. National Academy Press, Washington, B.C.

8.40 C.FJJ. § 300.430(9)(2)(i)(A)(1) /at Of July 1,1992],

9.40 C.F.R. § 30Q.430(9)(2)(l)(A)(2) /at Of Juty 1, 1992].

-------
 70. U.S. EPA (1992) National Emission Standards for
Hazardous Air Pollutant* Compliance Extensions for
Early Reductions; Final Rule,  57 Fed,  fleer. 67987,
December 29, 1992.

 11. See Appendix A: Calculation of Carcinogen Hazard
Index.

 12. U.S. EPA (1993) Reference Dose (RfD): Description
and Use in Health  Risk  Assessment,  Background
Document 1A, Integrated Risk Information System (IRIS).

13.  U.S.  EPA   (1991)  General  Quantitative  Risk
Assessment Guidelines for Noncancer Health Effects,
ECAO-CIN-538, Second External Review Draft

14. 51 Fed. Reg. 33992, September 24, 1986 Guidelines
-or Carcinogen Risk Assessment

 15. U.S. EPA (1992) Risk Assessment Issue Paper for
Carcinogenicity Characterization for Trichloroethylene
(CASRN 79-01-6), Tetrachloroethylene (CASRN 127-18-
 i), and Styrene  (CASRN 100-42-5),  ECAO, Technical
Support Center.

1 6. U.S. EPA (1992) Toxic Release Inventory Geographic
Risk Analysis System (TIGRAS), Region VII, Kansas City,
 17. U.S. EPA (1992) The 33/50 Program: Forging an
 Alliance for Pollution Prevention, Office of Prevention,
Pesticides and Toxic Substances, EPA-741-K-92-001.

 1 8. U.S. EPA (1990) Methodology for Assessing Health
risks Associated with Indirect Exposure to Combustor
Emissions, Interim Final, OHEA, EPA/60016-90/003.

19. Alien,  B.D.,  Kavlock, RJ.,  Klmmei,  CA and
Faustman EM (submitted) Dose Response Assessment
for Developmental Toxicity: II. Comparison of Generic
Benchmark Dose Estimates with NQAELa. Fundamentals
zf Applied Toxicology.
                      •

20. U.S. EPA (1992). Working Paper for Considering
Oraft Revisions to the U.S. EPA Guidelines for Cancer
Risk, Review Draft, EPA 600/AP-92/003.

21. Knauf, L, and Hertzberg, fl.C. (1990) Statistical
Methods for Estimating Risk  for Exposure Above the
Reference Dose,  ECAO,  C/nc/nnatf, OH., EPA 600/8-
riO/065.
22. U.S. EPA (1992) Toxic Chemical Release Reporting:
Community Right-to-Know; Subpart  D-Specific  Toxic
Chemical Listings, 40 C.F.R. 5 372.65.
Aeknowladgamanta:

Tha Air, Radiation and  Toxic* Division  would Ilk* to axpnw*
appreciation for lha con«tructfnt ravhws and suggestions ncoivtd
from tha following IndMduafa:

Raglon III Toxtcohojat* Quality Clrcla: Roy Smith, Samoa/ Rotonberg.
Jatfary Burka, Dawn lovan, Batty-Ann Qulnn. Nancy Rloa, Young-Moo
Kim, Jannifar Hubbvd, Reginald Harris.

Raglon III, AR7D: Jamaa Bakar

OPPT: Joa Uannda,  Vanaaaa Vu, Emla Falka, Maurice Zeoman,
Elizabeth Margotcha*, Mary Hanry, Joa Cotruvo, Bill Waugh, Dick
Wormall, Nlcholaaa Bowaa, Susan Hazan, Loran Hall.

OflO: Ufcn CogHano
For additional information, (215) 597-3175.
                                                         Approved by. _
                  Thomas u. Maslany, Director
                  Air, Raqiation and Toxics Division

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                                          Aoa«ndbt A

Carcinogenic Hazard Infer Calculation: The quantitative relationship between the noncarcinogenic and
carcinogenic scales may tw described by individually ranking the two scales and comparing the values
at designated scale points such as percentiles.

       Based on policy issues discussed In Section 2.3, reference po/nts denoting acceptable limits for
the purpose of hazard identification are established at a risk level oflx Iff* for carcinogens and a hazard
index of 1 for noncarcinogens. Using the approach outiined !n Section 3.1, doses are calculated for each
scale and the resultant dose values are rank ordered from most toxic (lowest acceptable dose) to-'feast
toxic (highest acceptable dose). The order statistic for percentiles 1-99 are calculated for both the ranked
carcinogenic dose scale and the ranked noncarcinogenic dose scale, as (n+fJp/f 00 where n« number
of observations and p= percentile1 and the value corresponding to each order statistic is recorded.  The
ratio of carcinogenic dose to noncarcinogenic dose at each percentile expresses the differences in
magnitude at regular scale intervals as shown in Figure A. 1.

An example of the hazard index equivalent to 1 x Iff4 risk may be calculated using the 50th percentile. The
hazard equal to a carcinogenic risk of 1 x Iff* may be calculated as
                     ~   ^     ,  L,   ^    (reference hazard x penerOBeG )
                     CardnogenlG Hazard --		     •	—
where
               percent9ee * 50th percentOe of carcinogen doses at reference risk
               percentfe^ SOth percentile of noncardnoffonic doses »t reference htxard
               reference hazard » 1
        The ratio of percentiles from the carcinogenic and noncarcinogenic data using both IRIS and
HEAST values1, suggests that carcinogenic hazard is more restrictive then noncarcinogenic hazard in a
ratio of about 0.04:1, or 25 fold. Figure A. 1. shows a scatterpiot of the scale ratios.
                            Figure A. 1.: Scatterpiot of Dose Ratio values
    Smdteor, Q.W. and Cochrw W.O. (1979) SWMfctf Mtttndt, m EA, to** SM UntonHf Pntt, Am*, lew*.

                                                    HEASTllfUSctomnt»n
-------
Table A.1. belowshow$ the mean +/- 9S% confidence limits for thit data. Kit important to emphasize that
tf» reiatfve emphaal* employed by this methodology does not imply biological significance regarding
severity of effect Instead, it provide* a mechanism lor assessing chronic toxic effects within the confines
of Agency pollcy with regard to regulations concerning carcinogens and noncarcinogens".

        The following analysis describes the relative  emphasis of carcinogens and noncarcinogens
according to Agency pollcy statements tor the entire percentile distribution of dose ratios shown in Figure
A.1.  Those ratios occurring at the  extremes of the percentile distribution, i.e. greater than the 75th
percentile (Quartile 4) or less than the 25th percentile (Quartile 1) exhibited the greatest variability. Dose
ratios calculated for values between the 25th and 75th percentiles (Quartiles 2 and 3) demonstrated good
agreement.
Table A. 1: Descriptive Statistics for CPF:RfD quartiles
Quartile
1
2
3
4
2and3
1,2,3 and 4
N
25
25
25
24
50
99
Mean of Dose Ratios
(+/-95% Cl)
97.8 (4, 192)
29.2 (27, 31)
16.7 (15, 18)
15.2 (12, 19)
23.0 (21,25)
23.9 {22, 26)
S.EM
45.5
1.1
0.8
1.7
1.1
1.1
Variance
a1.
51716.9
28.1
16.1
71.4
61.1
118.8
Correlation
i»
0.21
0.68
0.68
0.30
0.59
0.57
p-value
0.023
<0.001
<0.001
0.006

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                                         Chronic Max Algorithm
                  Chronic Index -
mass x kg/lb
x mgjkg
dlyr
i 1
i
[Ip^*™]
, i
x*w .32
Mv J
where         mess = TRI mass (Ib/yr)
              risk = 1 x 1O4 » reference risk
              WOS =» carcinogenic weight of evidence
              CPFa = oral cancer potency factor (mg/kg/dayf1
              RfD - oral reference dose (mg/kg/day)
              bw * body weight (70 kg)
              d/yr - 365 - (conversion factor)
              mg/kg - 7.000,000 - (conversion factor)
              kg/lb m 0.453 » (conversion factor)
                                            10
                                                        U.S. Environmental Protection Agency
                                                        Region 5, Library (PL-12J)
                                                        77 West Jackson Boulevard, 12th Floor
                                                        Chicago, IL   60604-3590

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