Methods to Develop Inhalation Cancer Risk 

Estimates for Chromium and Nickel 

Compounds
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
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
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
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+6)

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
1 Purpose

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

2 Chromium Compounds

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 Background

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

 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 

 The 

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

5

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

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)

 However the exact 

distribution between the hexavalent and trivalent chromium states in the environment is unknown.

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, wellconducted, epidemiological study by Gibb et al., (2000)10

 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 at www.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 J Ind Med 38(2): 115-26.

showing dose-dependent associations between 

exposure to hexavalent chromium and the development of lung cancer in workers. The International 
Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

6

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.

11 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 μg/m3

, which means that inhaling 

Cr(VI) in air at an average concentration of 1 μg/m3 daily for a lifetime poses an estimated increased risk 

of cancer of 12,000 in a million.

14

2.2 Approach for Estimating Inhalation Cancer Risks from Chromium 

Compounds

 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) * URE Cr(VI)

Where

ECCr 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.

2.3 Approach for Developing Speciation Profiles for Selected Source Types

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/roc12.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 μg/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.
Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

7

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.

2.4 Chromium Speciation for Specific Source Types

2.4.1 Coal 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

2.4.2 Oil Boilers

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

8

2.5 Uncertainties and Limitations 

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

 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 byproducts by X-ray absorption fine structure spectroscopy, Fuel Process Technol 78:233-242.

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

9

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.

2.6 Conclusions

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).
3 Nickel and Compounds

3.1 Background

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

 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

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

11

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

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 

IARC’s nickel review group (IARC’s Working group Special Report 2009)

. 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.

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

 23US 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 Oller A. Respiratory carcinogenicity assessment of soluble nickel compounds. Environ Health Perspect, 2002, 

110:841-844. 27Heller 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.

Although these authors agree that the epidemiological 
Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

12

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

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 μg/m3

, which means that inhaling 

nickel subsulfide in air at an average concentration of 1 μg/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 μg/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)

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.

30

3.2 Approach for Estimating Inhalation Cancer Risks from Nickel Compounds

, with values of 

0.00026 per μg/m3 and 0.00017 μg/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 nickelcontaining 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 = ECNi * MFNi subsulfide * URENi subsulfide

Where

ECNi is the chronic exposure concentration for the mixture of all nickel compounds, MFNi subsulfide is 

the mass percentage of the inhaled mixture which is nickel subsulfide and URE Ni subsulfide which is the 

cancer unit risk estimate for nickel subsulfide.

 28 Goodman JE, Prueitt RL, Thakali S, and Oller AR. The nickel iron bioavailability model of the carcinogenic 

potential of nickel-containing substances in the lung. Crit Rev Toxicol 2011, 41:142-174. 29Grimsrud 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.com/content/5/1/7. 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/dsd/final/june11/nickel_&_compounds.pdf
Methods to Develop Inhalation Cancer Risk Estimates for Chromium and Nickel Compounds

13

3.3 Approach for Developing Speciation Profiles for Selected Source Types

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.

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

A speciation analysis performed by the Electric Power Research Institute31

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

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

 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. 32US 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.

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

14

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. 

3.3.3 C. Approach to Derive Unit Risk Estimates: Alternatives Based on Speciation of

Residual Oil Fly Ashes from Power Plants.

Recently, a nickel speciation analysis was conducted by the Electric Power Research Institute

(EPRI)33

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.

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.

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

15

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.

3.4 Uncertainties and limitations 

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

16

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 μg/m3

, respectively), only vary by less than 3-fold, and that 

using any of these three UREs would yield roughly similar risk estimates.

3.5 Conclusion

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.
United States

Environmental Protection

Agency

Office of Air Quality Planning and Standards

Health and Environmental Impacts Division

Research Triangle Park, NC

Publication No. EPA-452/R-11-012

[October, 2011]