Methods to Develop Inhalation Cancer Risk
Estimates for Chromium and Nickel
Compounds

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                                             EPA-452/R-11-012
                                                October 2011
Methods to Develop Inhalation Cancer Risk
Estimates for Chromium and Nickel
Compounds
                 U.S. Environmental Protection Agency
               Office of Air Quality Planning and Standards
               Health and Environmental Impacts division
                 Research Triangle Park, North Carolina

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  Methods to Develop Inhalation Cancer Risk
Estimates for Chromium and Nickel Compounds
       Office of Air Quality Planning and Standards
         U.S. Environmental Protection Agency
          Research Triangle Park, NC 27711
                 December 2011

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                                          Table of Contents
1   Purpose	4

2   Chromium Compounds	4

  2.1    Background	4

  2.2    Approach for Estimating Inhalation Cancer Risks from Chromium Compounds	6

  2.3    Approach for Developing Speciation Profiles for Selected Source Types	6

  2.4    Chromium Speciation for Specific Source Types	7

    2.4.1    Coal Boilers	7

    2.4.2    Oil Boilers	7

  2.5    Uncertainties and Limitations	8

  2.6    Conclusions	9

3   Nickel and Compounds	10

  3.1    Background	10

  3.2    Approach for Estimating Inhalation Cancer Risks from Nickel Compounds	12

  3.3    Approach for Developing Speciation Profiles for Selected Source Types	13

    3.3.1    A. Approach to Derive Unit Risk Estimates: Electric Utility Report to Congress 1998	13

    3.3.2    B. Approach to Derive Unit Risk Estimates: NATA 2000	13

    3.3.3    C. Approach to Derive Unit Risk Estimates: Alternatives Based on  Speciation of Residual
    Oil Fly Ashes from Power Plants	14

  3.4    Uncertainties and limitations	15

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                                    List of Acronyms/Abbreviations
CDHS  California Department of Health Services




DHHS  Department of Health and Human Services




Cr (VI)  Hexavalent chromium, also denoted as (Cr+s)




Cr (III)  Trivalent chromium, also denoted as (Cr+3)




EGUs  Electric Utility Steam Generating Units




EPA    Environmental Protection Agency




IARC   International Agency for Research on Carcinogenicity




IRIS    Integrated Risk Information System




NATA  National Scale Air Toxics Assessment




NTP    National Toxicology Program




ROC   Report of the Carcinogens




RTR    Risk and Technology Review




TECQ  Texas Commission on Environmental Quality




UREs  Unit risk estimates




WHO  World Health Organization




XAFS  X-ray  absorption fine structure




XRD    Spectroscopy and x-ray diffraction

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       The purpose of this paper is to discuss the methods used to develop inhalation cancer risk
estimates associated with emissions of chromium and nickel compounds from coal- and oil-fired electric
utility steam generating units (EGUs) in support of EPA's Mercury and Air Toxics Standard (MATS).1
The derivation of cancer risk estimates is based on the speciation data available from selected source
types, and on the available unit risk estimates (UREs) reflecting the dose that corresponds to a specific
level of cancer risk. This document includes discussions for both emissions of chromium (Section 2) and
nickel (Section 3) compounds with regard to: (1) the methods and rationale used in previous analyses
(where applicable), (2) the methods used in the recent analysis for MATS (considering previous methods
and currently available data), and (3) a discussion of the uncertainties and/or limitations of the methods
used.  In this document, we consider the emissions of chromium compounds from both coal- and oil-fired
EGUs and the emissions of nickel compounds from oil-fired EGUs, since these are major contributors to
inhalation cancer risk estimates from each these source types.
2.1
      Chromium compounds occur in nature and are found primarily in the earth's crust. The largest
source of chromium is the ore mineral chromite, FeCR2O4 or MgCr2O4, where magnesium can substitute
for iron.2 Chromium can also be found in small concentrations in certain types of igneous rocks, coal, tar,
asphalt, and crude oil. Chromium compounds oxidation valences vary from -2 to +6, but only the 0, +2,
+3 and +6 valence states are common.3  However, the hexavalent state (Cr+6), also denoted as Cr (VI),
rarely occurs naturally, and is usually produced from anthropogenic sources (US EPA 1984).4 The
1 US EPA, 2011. National Emission Standards for Hazardous Air Pollutants from Coal- and Oil-fired
Electric Utility Steam Generating Units and Standards of Performance for Fossil-Fuel-Fired Electric
Utility, Industrial-commercial-Institutional, and Small Industrial-Commercial-Institutional Steam
Generating Units Rule.  Available online at http://www.epa.gov/ttn/atw/utility/utilitypg.html.
2 Guertin, Jacques, James A. Jacobs and Cynthia P. Avakian. Chromium (VI) Handbook. Independent
Environmental Technical Evaluation Group (IETEG). CRC Press, 2005. ISBN 9781566706087
3 Dayan AD and Paine AJ.  Mechanisms of chromium toxicity, carcinogenicity and allergenicity: review
of the literature  from 1985 to 2000. Hum and Experiment Toxicol 2001, 20:439-451.
4 US EPA, 1984. Health assessment document for chromium. Research Triangle Park, NC: Environmental
Assessment and Criteria Office, U.S. Environmental Protection Agency. EPA600883014F.

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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

trivalent state (Cr+3), also denoted as Cr (III), and the Cr(VI) state are the first and second most stable,
respectively, and thus the forms considered more important with regard to human health.5
      Chromium compounds are used in a variety of industrial applications and operations. They are
used in alloys, such as stainless steel; paint pigments; refractory bricks that line furnaces and kilns; wood
preservatives; production and processing of insoluble salts; in leather tanning; as catalysts for
halogenation, alkylation, and catalytic cracking of hydrocarbons; as fuel and propellant additives; and
more.6 Many of these applications use substances containing Cr(VI) compounds, including various
chromates, dichromates, and chromic acid.7 Disposal of chemicals containing chromium or burning fossil
fuels can also release chromium to the air, soil and water.  In addition, some industrial processes may
produce chromium emissions, wherein the hexavalent state is favored in an oxidizing alkaline
environment, and the trivalent state is favored in a reducing acidic environment.8 However the exact
distribution between the hexavalent and trivalent chromium states in the environment is unknown.
      In its 1998 IRIS Toxicological Review, the US EPA classified Cr(VI), including its compounds, as
"a known human carcinogen by the inhalation route of exposure" based on evidence from occupational
epidemiological studies consistently indicating dose-dependent associations between chromium inhalation
exposure and lung cancer, and on  supporting evidence from animal inhalation studies (US EPA, 1998)9.
Further support comes from a recent 2-year chronic bioassay conducted by the National Toxicology
Program (NTP) concluding that Cr(VI) is carcinogenic when ingested in drinking water. With regard to
trivalent chromium Cr(III), the 1998 IRIS Toxicological Review notes that while the evidence from the
occupational database "could be used to suggest that total chromium is carcinogenic by inhalation, animal
data support the human  carcinogenicity data only on hexavalent chromium". Thus, based on these
considerations the EPA  concluded that only Cr(VI) should be classified as a human carcinogen. Further
support for hexavalent chromium being the carcinogenic species is provided by a more recent, well-
conducted, epidemiological study by Gibb et al., (2000)10  showing dose-dependent associations between
exposure to hexavalent chromium and the development of lung cancer in workers.  The International
5 Dayan AD and Paine AJ.  Mechanisms of chromium toxicity, carcinogenicity and allergenicity: review
of the literature from 1985 to 2000. Hum and Experiment Toxicol 2001, 20:439-451.
6 Guertin J, Jacobs JA and Cynthia PA, 2005. Chromium (VI) Handbook. Independent Environmental
Technical Evaluation Group (IETEG). CRC Press. ISBN 9781566706087
7 Agency for Toxic Substances and Disease Registry (ATSDR), 2008. Toxicological Fact Sheet for
chromium. Available online atwww.atsdr.cdc.gov/tfacts7.pdf
8 Guertin, Jacques, James A. Jacobs and Cynthia P. Avakian. Chromium (VI) Handbook. Independent
Environmental Technical Evaluation Group (IETEG). CRC Press, 2005. ISBN 9781566706087
9 US EPA, 1998.  Integrated Risk Information Service (IRIS) assessment for hexavalent chromium.
Available at:  http://www.epa.gov/ncea/iris/subst/0144.htm.
10 Gibb HJ, PS Lees, et al. (2000). Lung Cancer Among Workers in Chromium Chemical Production.
American JIndMed 38(2): 115-26.

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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

Agency for Research on Carcinogenicity, or IARC, concluded that there are sufficient evidence for the
carcinogenicity of Cr(VI) compounds in humans based on the combined evidence from the
epidemiological, animal and mechanistic data available.  In agreement with the EPA, the IARC stated that
compounds of chromium III are not classifiable as to their carcinogenicity.::  Scientific views similar to
those of EPA and IARC are reflected in the NTP's 12th Report of the Carcinogens (ROC).12
      Cr (VI) has an inhalation unit risk estimate (URE)13 of 0.012 per (ig/m3, which means that inhaling
Cr(VI) in air at an average concentration of 1 (ig/m3 daily for a lifetime poses an estimated increased risk
of cancer of 12,000 in a million.14 This inhalation cancer potency value is among the highest values of
any of the hazardous air pollutants (HAPs) listed in the Clean Air Act.
      Based on the information in the previous section, we estimate cancer risks due to the inhalation of
all chromium compounds based on the exposure concentration of Cr(VI) alone.  Thus:

      Risk = ECCr * MFCr(vi) * URECr(vi)

      Where
       EC& is chronic exposure concentration for the mixture of all chromium compounds, MF Cr(vi) is the
mass fraction of the inhaled mixture which is hexavalent chromium, and URE Cr(vi) is the cancer unit risk
estimate for hexavalent chromium.
      As discussed above, the toxicity of chromium compounds is largely dependent on its oxidation
state (i.e., Cr(VI) vs. Cr(III), primarily) which is an important factor in evaluating the health effects from
exposure to chromium compounds. Where the specific compound or oxidation state of chromium is
11 International Agency for Research on Cancer (IARC), 1990. IARC monographs on the evaluation of carcinogenic
risks to humans. Chromium, nickel and welding. Vol. 49. Lyons, France: International Agency for Research on
Cancer, World Health Organization 49-256.
12 National Toxicology Program (NTP), 2011. Report on carcinogens. 12th ed. Research Triangle Park, NC: US
Department of Health and Human Services (DHHS), Public Health Service. Available online at
http ://ntp. niehs. nih. gov/ntp/roc/twelfth/roc 12 .pdf.
13 The inhalation Unit Risk Estimate (URE) represents the upper-bound excess lifetime cancer risk estimated to
result from continuous exposure to an agent at a concentration of 1 ng/m3 in air.
14 US EPA, 1998.  Study of Hazardous Air Pollutant Emissions from Electric Utility Steam Generating Units - Final
Report to Congress.  US EPA #453/R-98-004.  Available at http://www.epa.gov/ttn/caaa/t3rc.html.

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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

known and available, the appropriate dose response value may be applied for the purposes of risk
assessment. However, for generically reported chromium emissions where there is no information
provided regarding the oxidation state of the chromium, we generate "default" speciation profiles that
reflect the proportions of emissions that would likely be in the Cr(VI) and Cr(III) oxidation states.
Appendix A contains a paper by several EPA staff wherein available chromium speciation data for
different industrial categories of emission sources have been analyzed to develop default chromium
speciation profiles.  The following sections describe the data, analyses, limitations and conclusions
regarding chromium speciation for the two selected source types of coal-fired and oil-fired boilers.
        Based on source test data from 7 units, including 4 utility boilers and 3 industrial boilers (which
are similar in process to utility boilers but often smaller), an average of 12 percent hexavalent chromium
was derived to be used as the speciation default for coal-fired boilers without available chromium
speciation information. The average hexavalent chromium for the 4 utility boilers was 11 percent and the
range for the 4 tests was from 0.4 percent to 23 percent.15  Although the range of values was not reported,
the average hexavalent chromium for the 3 industrial boilers was 12 percent. (Emissions database
compiled November 30, 2000, in support of National Emission Standards for Hazardous Air Pollutants
for Industrial/Commercial/Institutional Boilers and process Heaters, Final Rule, 69FR55217 September
13, 2004). Because of the limited number of units tested, we chose the value of 12 percent (the highest
percent average of hexavalent chromium when considering both utility and industrial boilers) to be used
as the default for our analysis of potential chromium risks from coal-fired utility boilers.
      Based on source test data from 7 units, an average of 18 percent hexavalent chromium was derived
to be used as the speciation default for oil-fired boilers without available chromium speciation
information. The average hexavalent chromium for the  7 utility boilers was 18 percent, and the range for
the 7 tests was 5 to 34 percent.16
15 US EPA, 1998.  Study of Hazardous Air Pollutant Emissions from Electric Utility Steam Generating Units - Final
Report to Congress.  U.S. EPA #453/R-98-004. Available at http://www.epa.gov/ttn/caaa/t3rc.html.
16 US EPA, 1998.  Study of Hazardous Air Pollutant Emissions from Electric Utility Steam Generating Units - Final
Report to Congress.  U.S. EPA #453/R-98-004. Available at http://www.epa.gov/ttn/caaa/t3rc.html.

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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds
      The uncertainties and limitations associated with this analysis are related primarily to the speciation
profile data availability, and the assumptions made to generate the default speciation profiles.
Assumptions were made in this analysis in the: 1) selection of the compound species of chromium driving
cancer risks based on health effects information, and 2) selection of the appropriate percentage of the
chromium species driving cancer risk for derivation of the inhalation cancer risk estimates for chromium
emitting facilities. This section briefly describes the assumptions made and associated uncertainties and
limitations, and a qualitative characterization of the relative confidence (assigned as low, moderate or
high) regarding the used assumptions.
      A major limitation of this analysis is the small number of test data (i.e., speciation profile only
from 14 units) available to derive chromium default speciation profile  values for both coal- and oil- fired
EGUs. This data represents a very small portion of the units that exist within the respective source types
(approximately 1,200 combined coal- and oil-fired EGUs), which introduces great uncertainties when
making generalizations on how accurately the default profiles derived  in this analysis reflect actual
speciation profiles for coal- and oil-fired EGU emissions. With regard to selecting the appropriate
percent of chromium to use in the derivation of default speciation profiles based on the available
speciation data, we chose to calculate the percent average based on pooling similar test data from the
available units for coal- and oil-fired EGUs. Although this seems to be a reasonable  quantitative
approach given the limited data set, an alternative, and more conservative,  approach would consist on
selecting the maximum measured percentage of hexavalent chromium from the available data rather than
the average of the range (i.e., selecting 23 percent rather than 12 percent for coal-fired EGUs). Further,
speciation information showing coal  combustion emissions containing as much as 43 percent hexavalent
chromium17 indicates that past quantitative approaches could, in fact, underestimate hexavalent chromium
inhalation risks. However, another study of speciation of chromium in coal combustion showed
hexavalent chromium percentage levels  close to detection limits (i.e., 3-5 percent of total).18 Given the
high variability across the speciation data available, there is great uncertainty associated with percent
hexavalent chromium for either coal- or oil-fired EGUs.  Based on the available information, we have low
confidence in selecting a single percentage of hexavalent chromium to represent the true composition of
chromium in all EGU emissions.
17 Galbreath KC, Zygarlicke CJ. 2004.  Formation and chemical speciation of arsenic-, chromium-, and
nickel-bearing coal combustion PM2.5, Fuel Process Technol 85:701-726.
18 Huggins FE, Najih M, Huffman GP.  1999. Direct speciation of chromium in coal combustion by-
products by X-ray absorption fine structure spectroscopy, Fuel Process Technol 78:233-242.

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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

      With regard to the cancer risk, we selected hexavalent chromium as the species likely to be driving
cancer risks based on solid evidence from the health effects database for chromium and compounds.
Major scientific bodies that conduct thorough reviews on carcinogenic compounds (e.g., IARC, NTP)
agree that there are sufficient evidence for the carcinogenicity of Cr(VI) compounds in humans based on
the combined evidence from the epidemiological, animal and mechanistic data available. These reports
also state that compounds of chromium III are not classifiable as to their carcinogenicity. Based on this
information, we have high confidence on the assumption that hexavalent chromium is the carcinogenic
species and that the carcinogenic risk of chromium-emitting facilities is proportional to the mass of
hexavalent chromium contained in the emissions from those facilities.
      Based on the information above we have high confidence in the assumption that hexavalent
chromium is the carcinogenic species driving the risk of chromium-emitting facilities and thus we
consider a reasonable approach to derive default speciation profiles based on the mass of hexavalent
chromium contained in the emissions from chromium-emitting facilities. Nevertheless, the confidence in
the default speciation profiles is low because the profiles are based on a limited data set with a wide range
of percentages of hexavalent chromium across the different samples. An alternative, more conservative
approach would be to use the maximum measured percentage of hexavalent chromium rather than the
highest average of the range observed across samples (i.e., use of 23 percent rather than 12 percent
hexavalent chromium).

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3
.,

      Nickel (Ni) is a lustrous white, hard, ferromagnetic metal found in transition group VIII of the
Periodic Table. It has high ductility, good thermal conductivity, high strength, and fair electrical
conductivity. It constitutes approximately 0.009 percent of the earth's crust, making it the 24th most
abundant element.  Nickel can achieve several oxidation states including -1, O, +1, +2, +3, and +4, and
can be combined with many other elements to form different nickel compounds; however, the majority of
nickel compounds are nickel +2 species. Indirect sources, primarily coal and oil combustion, are
estimated to release from 85 to 94 percent of the total anthropogenic nickel emissions to the air. Nickel
compounds are used for nickel alloys, electroplating, batteries, coins, industrial plumbing, spark plugs,
machinery parts, stainless-steel, nickel-chrome resistance wires, and as catalysts.19
        Nickel and nickel compounds have been classified as human carcinogens. National and
international scientific bodies including the IARC (1990),20 the World Health Organization (WHO,
1991),21 and the European Union's Scientific Committee on Health and Environmental Risks (SCHER,
2006),22 agree that nickel compounds (including nickel sulfate), in general, are carcinogenic. In their 12th
Report of the Carcinogens, the NTP has classified nickel compounds as known to be human carcinogens
based on sufficient evidence of carcinogenicity from studies in humans showing associations between
exposure to nickel compounds and cancer, and supporting animal and mechanistic data. More
specifically, this classification is based on consistent findings of increased risk of cancer in exposed
workers, and supporting evidence from experimental animals that shows that exposure to an assortment of
nickel compounds by multiple routes causes malignant tumors at various organ sites and in multiple
species. The 12th Report of the Carcinogens states that the "combined results of epidemiological studies,
mechanistic studies, and carcinogenesis studies in rodents support the concept that nickel compounds
generate nickel ions in target cells at sites critical for carcinogenesis, thus allowing consideration and
19 US EPA, 1986.  Health Assessment Document for Nickel. EPA/600/8-83/012F. National Center for
Environmental Assessment, Office of Research and Development, Washington, DC.
20 International Agency for Research on Cancer (IARC), 1990. IARC monographs on the evaluation of carcinogenic
risks to humans. Chromium, nickel and welding. Vol. 49. Lyons, France: International Agency for Research on
Cancer, World Health Organization Vol. 49:256.
21 International Labour Organization/United Nations Environment Programme, World Health Organization (WHO),
1991. Nickel. In Environmental Health Criteria No 108 Geneva.
22European Commission, Scientific Committee on Health and Environmental Risks (SCHER), 2006. Opinion on:
Reports on Nickel, Human Health part. SCHER, 11th plenary meeting of 04 May 2006
[http://ec.europa.eu/health/ph_risk/committees/04_scher/docs/scher_o_034.pdf|.CHER 2006

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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

evaluation of these compounds as a single group". Although the precise nickel compound (or
compounds) responsible for the carcinogenic effects in humans is not always clear, studies indicate that
nickel sulfate and the combinations of nickel sulfides and oxides encountered in the nickel refining
industries cause cancer in humans. In agreement with the above mentioned scientific bodies, the US
Department of Health and Human Services (DHHS, 1994)23 has determined that nickel compounds are
known human carcinogens, and that another nickel compound, nickel metal, may reasonably be
anticipated to be a carcinogen. The EPA has only evaluated two nickel compounds for their carcinogenic
potential ~ nickel subsulfide and nickel refinery dusts ~ and has classified them both as group A, human
carcinogens. Another assessment for the carcinogenic potential of nickel and nickel compounds has been
developed by the California Department of Health Services (CDHS, 1991)24. With regard to speciation, it
is noted in this assessment that the available epidemiological data is inadequate to develop separate unit
risk factors for different nickel compounds, nevertheless the view of CDHS is consistent with
consideration of both insoluble and soluble nickel compounds, as a group, as carcinogenic based on the
available epidemiological evidence.

        The major scientific bodies mentioned above have recognized that there are potential differences
in toxicity and/or carcinogenic potential across the different nickel compounds. These differences are
believed to be  due, in part, to differences in solubility properties and/or different speciation of nickel
compounds that in turn make nickel ions be more or less available at target sites. The views of the
lARC's nickel review group (lARC's Working group Special Report 2009)25 is that in addition to the
release of nickel ions at target  sites, there may be other less understood factors that promote accumulation
of nickel ions  at critical target  sites and that given the available scientific evidence, it is difficult to predict
the relative carcinogenic hazard of nickel compounds. There have been different views on whether or not
nickel compounds, as a group, should be considered as carcinogenic to humans. Some authors believe
that water soluble nickel, such as nickel  sulfate, should not be considered a human carcinogen, based
primarily on a negative nickel  sulfate 2-year NTP rodent bioassay (which is  different than the positive 2-
year NTP bioassay for nickel subsulfide).26'27'28 Although these authors agree that the epidemiological
23 US Department of Health and Human Services (DHHS), 1994. Seventh annual report on carcinogens: Summary
1994. Research Triangle Park, NC: National Institute of Environmental Health Sciences (NIEHS), 262-269.
24 California Department of Health Services (CDHS), 1991. Health Risk Assessment for Nickel. Initial Statement
for Rulemaking, Proposed Identification of Nickel as a Toxic Air Contaminant - Technical Support Document, part
B. Available online at http://www.arb.ca.gov/toxics/id/summary/nickel_tech_b.pdf.
25 International Agency for Research on Cancer (IARC) Working Group: Special Report.  Policy; A review of
human carcinogens; Part C: metals, arsenic, dusts, and fibres. Lancet Oncol, 2009, 10:453-454.
26 Oiler A. Respiratory carcinogenicity assessment of soluble nickel compounds. Environ Health Perspect, 2002,
110:841-844.
27 Heller JG, Thornhill PG, Conard BR: New views on the hypothesis of respiratory cancer risk from soluble nickel
exposure; and reconsideration of this risk's historical sources in nickel refineries. J Occup Med Toxicol, 2009, 4:23.
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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

data clearly supports an association between nickel and increased cancer risks, they sustain that the data
are weakest regarding water soluble nickel.  A recent review by Grimsrud et al., (2010)29 highlights the
robustness and consistency of the epidemiological evidence across several decades showing associations
between exposure to nickel and nickel compounds (including nickel sulfate) and cancer.

        As mentioned above, the EPA has only derived URE values for nickel subsulfide and for nickel
refinery dusts. Nickel subsulfide has  a URE value of 0.00048 per (ig/m3, which means that inhaling
nickel subsulfide in air at an average concentration of 1 ug/m3 daily for a lifetime poses an estimated
increased risk of cancer of 480 in a million.  The nickel refinery dust has a URE value of 0.00024  ug/m3,
which suggests that this mixture may  have half the carcinogenic potency of nickel subsulfide. There are
two other available UREs that have both been derived for nickel compounds as a group. One was
developed by the California Department of Health Services (CDHS, 1991) and the other by the Texas
Commission on Environmental Quality (TCEQ, Development Support Document, 2011)30, with values of
0.00026 per uŁ/m3 and 0.00017 uŁ/m3, respectively.
      Based on past scientific and technical considerations, the determination of the percent of nickel
subsulfide (which has an IRIS URE value) versus nickel sulfate (with no available URE value) was
considered a major factor for estimating the  extent and magnitude of the risks of cancer due to nickel-
containing emissions. Thus, in previous analyses, we estimated cancer risks due to the inhalation of all
nickel compounds based on the estimated exposure concentration of nickel subsulfide alone. Thus:

      Risk = ECNl * MFNl subsuifide * URENl subsuifide

      Where
      ECNi is the chronic exposure concentration for the mixture of all nickel compounds, MFNl subsuifide is
the mass percentage of the inhaled mixture which is nickel subsulfide and URE Nl subsuifide which is the
cancer unit risk estimate for nickel subsulfide.
28 Goodman JE, Prueitt RL, Thakali S, and Oiler AR. The nickel iron bioavailability model of the carcinogenic
potential of nickel-containing substances in the lung. CritRev Toxicol 2011, 41:142-174.
29 Grimsrud TK and Andersen A. Evidence of carcinogenicity in humans of water-soluble nickel salts. J Occup Med
Toxicol 2010, 5:1-7. Available online at http://www.ossup-med.eom/content/5/l/7.
30 Texas Commission on Environmental Quality (TCEQ), 2011. Development Support Document for nickel and
inorganic nickel compounds. Available online at
http://www.tceq.state.tx.us/assets/public/implementation/tox/dsd7fmal/junel l/nickel_&_compounds.pdf
                                                                                               12

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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds
        Similar to chromium, the speciation data for nickel emissions from different source types is
limited. Several approaches have been considered by the EPA, over time, in the determination of the
cancer risks posed by the inhalation of nickel and nickel compounds emitted by large combustion sources
(including oil-combustion). The following subsections describe the data, analyses and assumptions
regarding nickel speciation for risk analysis derived in the past (A and B), and (C) potential approaches
based on recent nickel speciation data from oil-fired power plants.

        A speciation analysis performed by the Electric Power Research Institute31 using data dated from
1992 to 1994 on 5 sites with oil-fired utilities showed the presence of numerous nickel compounds and a
wide range of the percentages of different nickel species measured. This report indicated the following
general speciation profile:  soluble nickel compounds 25 to 60 percent, sulfidic nickel compounds 4 to 26
percent, metallic nickel compounds 0 to 4 percent, and oxidic nickel compounds 27 to 70 percent. Based
on these data, there were two proposed approaches to calculating nickel inhalation risk estimates from
these sources. The first approach used the assumption that the mixture of nickel compounds emitted by
oil-fired utilities was 50 percent as carcinogenic as nickel subsulfide (the nickel compound with the
higher cancer potency based on the existing IRIS UREs). The second approach was also based on the
application of the IRIS URE for nickel subsulfide, however it provided a suite of risk estimates depending
on the percentage of nickel subsulfide (ranging from 100 to 0 percent) believed to be present in the
emissions from oil-fired utilities.  The assumption used for both approaches was that only the nickel
subsulfide fraction contributes to the cancer risk.  The cancer risk due to the other nickel compounds was
considered as unknown, and thus not contributing to cancer from nickel-containing emissions.
       Based on previous analysis of some of the largest nickel-emitting combustion sources indicating
that at least 35 percent of total nickel emissions may be soluble compounds32, the EPA assumed that as
much as 65 percent of emitted nickel could be in the insoluble form and that all insoluble nickel could be
crystalline. Because the URE listed in IRIS for nickel subsulfide represents a form which is pure
31 US EPA, 1998.  Study of Hazardous Air Pollutant Emissions from Electric Utility Steam Generating Units - Final
Report to Congress. US EPA #453/R-98-004. Available at http://www.epa.gov/ttn/caaa/t3rc.html.
32 US EPA, 2001. National-Scale Air Toxics Assessment for 1996 - Appendix-G: Health Effects Information Used
in Cancer and Noncancer Risk Characterization for the NATA 1996 National-Scale Assessment, EPA-453/R-01-
003.  Available online at http://www.epa.gov/ttn/atw/sab/appendix-g.pdf.
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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

insoluble crystalline nickel, this assessment assumed that 65 percent of the total mass of emitted nickel
might be of this form, and thus might be carcinogenic. Thus, for the purposes of the 2000 NATA
assessment, the EPA assumed that 65 percent of emitted nickel was insoluble, that all insoluble nickel
was crystalline, and that the IRIS URE for nickel subsulfide could be applied to this portion.
        Recently, a nickel speciation analysis was conducted by the Electric Power Research Institute
(EPRI)33 on residual oil fly ashes (ROFA) obtained from stacks of utility boilers from two of the largest
oil-fired power plants in the country, which are located in Hawaii (Honolulu and Waiau, respectively).
The ROFA samples were analyzed using x-ray absorption fine structure (XAFS) spectroscopy and x-ray
diffraction (XRD). Speciation analysis results indicated that 80 to 95 percent of the total Ni present in the
ROFA samples was nickel sulfate hexahydrate (NiSO4.6H2O), and that approximately 20 percent of the
total Ni was present as a Ni-containing spinel compound, similar in composition to nickel iron oxide
(NiFe2O4). Sulfidic Ni compounds (such as nickel subsulfide) were not detected in this analysis. Given
that the ROFA samples tested did not contain nickel subsulfide, using an approach to derive unit risks
estimates similar to that used in past analysis (e.g., applying the URE for nickel subsulfide to the mass
emissions of all nickel compound) would result in a unit risk estimate equal to zero. Based on what we
know regarding the health effects of nickel compounds, as a group, making an assumption of no risk
associated with exposure to nickel-containing emissions would clearly not be health-protective.  For this
reason, we considered the following alternative approaches.
        1-  Using the same approach as 2000 NATA (see above section 3.3.2 B), which consists of using
           the IRIS URE for nickel subsulfide and assuming that nickel subsulfide constitutes  65 percent
           of the mass emissions of all nickel compounds.  While it does  not take the new speciation
           data into account, this approach was developed for NATA and RTR assessments years ago,
           and has been peer reviewed by the Science Advisory Board (SAB), each time receiving
           favorable reviews. It would also help to provide continuity and comparability between
           current and past assessments.  This is the approach used in assessments performed in support
           of MATS proposed in May 2011.
        2-  Considering a more health-protective approach. Based on the  consistent views of major
           scientific bodies (i.e., NTP in their 12th ROC, IARC, and other international agencies) that
33 Energy & Environmental Research Center (EERC), University of North Dakota, Final Report: Nickel Speciation
Analyses of Residual Oil Fly Ashes Using X-Ray Techniques, 2010. Electronic file available at:
http://oaspub.epa.gov/eims/eimscomm.getfile/?p_download_id=503933..
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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

           consider nickel compounds to be carcinogenic, as a group, we propose considering all nickel
           compounds as carcinogenic as nickel subsulfide.  This approach would include the
           application of the IRIS URE without a factor, assuming 100 percent of nickel compounds as
           carcinogenic as nickel subsulfide.
       3-  Considering alternative UREs. This approach would involve the direct application of URE
           values developed for nickel compounds as a group by governmental agencies other than the
           EPA rather than deriving a value based on the IRIS URE for nickel subsulfide. The
           application of the CDHS URE or TCEQ URE would be yield a unit risk estimate
           approximately two- to three-fold lower than using 100 percent of the IRIS URE for nickel
           subsulfide.

      The uncertainties and limitations associated with these analyses are related primarily to the
speciation profile data availability, and the assumptions made to generate the default speciation profiles.
Assumptions were made in this analysis to: 1) select the compound species of nickel driving cancer risks
based on health effects information, and 2) select the appropriate percentage of the nickel species driving
cancer risk for derivation of the inhalation cancer risk estimates for nickel-emitting facilities.  This section
briefly describes the assumptions made and associated uncertainties and limitations, and a qualitative
characterization of the relative confidence (assigned as low, moderate or high) on those assumptions.
      Similar to chromium, a major limitation of these analyses is the small number of test data (i.e.,
three individual nickel speciation analysis of only a few units) available to derive nickel default speciation
profile values for coal- and oil-fired units. Another source of great uncertainty is the lack of a speciation
profile patterns across the different nickel speciation analysis available, and the wide range of percentages
for the individual nickel species. Based on this information, we have low confidence in the derivation of
default nickel speciation profiles based on the available speciation data.
      With regard to the estimation of cancer risk from inhalation of nickel and compounds, we have in
the past selected nickel subsulfide as the species likely to be driving cancer risks based on health effects
evidence indicating that nickel subsulfide is carcinogenic in both humans and animals, and on the
potentially higher cancer potency of nickel subsulfide when compared to that of nickel refinery dusts (the
only other IRIS URE value available for nickel compounds). Although this approach was considered
reasonable at the time  (and consistent with approaches used for derivation of speciation defaults for other
compounds, such as chromium), an  alternative and more conservative approach would be based on
consideration of all nickel compounds, as a group, to be as carcinogenic as nickel subsulfide.
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Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

      It is important to note that the three existing URE values (i.e., derived by: IRIS, DCHS or TCEQ
with values of 0.00048, 0.00026 and 0.00017 (ig/m3, respectively), only vary by less than 3-fold, and that
using any of these three UREs would yield roughly similar risk estimates.
      Based on the views of the most authoritative scientific bodies, the EPA considers all nickel
compounds to be carcinogenic, as a group, and does not focus on nickel speciation or solubility as a
strong determinant of carcinogenicity. EPA will continue using the current IRIS URE for nickel
subsulfide as the preferred value for nickel compounds because IRIS derived values are at the top of our
hierarchy with respect to dose response information used in EPA's risk characterizations.  Nevertheless,
taking into account that there may be differences in toxicity and/or carcinogenic potential across mixtures
of different nickel compounds, and given that there have been two URE values derived for exposure to
mixtures of nickel compounds that are 2-3  fold lower than the IRIS URE for nickel subsulfide, the EPA
also considers it reasonable to use a value that is 50 percent of the IRIS URE for nickel subsulfide for
providing an estimate of the lower end of a plausible range of cancer potency values for different
mixtures of nickel compounds.
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United States                             Office of Air Quality Planning and Standards             Publication No. EPA-452/R-11-012
Environmental Protection                  Health and Environmental Impacts Division                                [October, 2011]
Agency                                          Research Triangle Park, NC

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