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o
Biomarkers
o
In Vivo (Oral)
o
In vivo (inhalatlor)>
o
In Vitro
Figure 4-3. Visual summary of tagging structure for ADME and PK/PBPK
studies.
4.2. METHODS FOR DOSE-RESPONSE ASSESSMENT
4.2.1. Selecting Endpoints for Dose-Response Assessment
1 Based on the SEM (Appendix C) and assessments conducted by others, the NTP inhalation
2 cancer bioassay studies for cobalt sulfate and cobalt metal NTP (19981: NTP (20141 were
3 considered most appropriate for dose-response analysis. Key scientific issues related to MOA and
4 the dose response assessment are outlined in Section 2.4. In addition, statistical and biological
5 information will be used to try to identify BMR levels, and the appropriate dose metrics for animal-
6 to-human extrapolation. If supported by the available data, EPA may develop separate IURs for
7 water-soluble and water-insoluble cobalt compounds, as was done by other agencies (Table 2-2).
8 If this is done, EPA will define a water solubility limit to guide IRIS users as to which IUR to apply
o
Pharmacokinetic
(ADME)
o
Supplemental
(ADME/PBPK)
o
PK/PBPK Models
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for their specific needs. EPA may also develop additional IURs for certain subsets of cobalt
compounds or develop a single IUR to address all cobalt compounds.
Also considered is whether there are opportunities to quantitatively integrate the evidence.
Tumors of the lung and other tissues were reported in both male and female rats and mice by NTP
(20141. and NTP (19981. Examples of quantitative integration include (1) combining results for an
outcome across sex (within a study); (2) characterizing effects that occur on a continuum (e.g.,
precursors and benign tumors that progress to malignant tumors); (3) conducting a meta-analysis
or meta-regression of multiple studies; and (4) estimating the risk of getting one or more tumors
for any combination of tumors observed in a single bioassay. In addition, mechanistic evidence
that influences the dose-response analyses will be highlighted. This includes evidence related to
susceptibility or evidence informing the potential shape of the dose-response curve (i.e., linear, or
nonlinear dose response as described in the EPA Guidelines for Carcinogen Assessment U.S. EPA
(2005all. Mode(s) of action information relevant to dose-response analysis will be summarized,
including any pathway interactions relevant to understanding overall risk. For cancer dose-
response of animal data, relevant biological considerations are:
• Is there evidence for direct mutagenicity?
• Is there evidence of a nonlinear mechanism at low dose?
• Does tumor latency decrease with increasing exposure?
• If there are multiple tumor types, which cancers have longer/shorter latency periods?
• Are incidence data or individual-level available?
• While benign and malignant tumors of the same cell or tissue of origin are generally
evaluated together, was there an increase only in malignant tumors?
4.2.1.1. Data Extraction and Dose Standardization
Data will be extracted from the NTP inhalation cancer bioassay studies for cobalt sulfate
and cobalt metal NTP (19981:NTP (20141 into EPA's version of Health Assessment Workspace
Collaborative (HAWC, https://hawcprd.epa.gOv/l. a web-based software application designed to
manage and facilitate the process of conducting health assessments. Because the focus of the
current assessment is to develop one or more cancer IURs for inclusion in the IRIS database, tumor
data (along with any other data relevant to dose-response, such as animal survival rates and
individual-level data) will be prioritized for data extraction. Raw data for NTP studies are available
in the Chemical Effects in Biological Systems database (https://cebs.niehs.nih.gov/ceb s/). In
addition to HAWC, data will be stored in other formats necessary for dose-response modeling and
assessment data presentation (i.e., Excel, BMDS, Word). For quality control, data extraction is to be
performed by one member of the evaluation team and independently verified by at least one other
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member. Discrepancies in data extraction will be resolved by discussion or consultation with a
third member of the evaluation team.
For the dose-response assessment, exposures will be standardized to common units of
mg/m3 elemental cobalt This involves performing a molecular weight conversion from the parent
compound to cobalt The 2-year inhalation cancer bioassay of cobalt metal NTP (20141 does not
require unit conversion since concentration was measured in units of elemental cobalt. However,
the air concentrations presented in the NTP (19981 2-year inhalation cancer bioassay of cobalt
sulfate heptahydrate were in units of mg/m3 anhydrous cobalt sulfate (C0SO4), and not the
heptahydrate or hexahydrate (which it was shown to dehydrate to under the experimental
conditions). This conclusion was based on a review of the assessment analytical details in the NTP
report and Behl etal. (20151. and correspondence with study authors Bucher et al. fin Press!. To
convert from concentrations presented in NTP (19981 to concentrations of elemental cobalt, the
molecular weight ratio of Co (MW=58.933) to CoS04(MW=154.996) will be applied.
All assumptions used in performing dose conversions will be documented in the
assessment Dosimetry adjustments, including converting to continuous chronic exposure from
workday/workweek exposure used in the bioassays and application of model-derived lung
dosimetry factors, will also be documented.
4.2.2. Conducting Dose-Response Assessments
EPA uses a two-step approach for dose-response assessment that distinguishes analysis of
the dose-response data in the range of observation from any inferences about responses at lower,
potentially more environmentally relevant exposure levels U.S. EPA (2012bl: U.S. EPA f2005a. §31:
1) The first step is an analysis of dose and response in the range of observation of the
experimental or epidemiologic studies. The preferred approach for the first step is to use
dose response modeling to incorporate as much of the data set as possible into the analysis
to derive a point of departure (POD) near the lower end of the observed dose range without
significant extrapolation.
2) The second step is extrapolation to lower doses. The extrapolation approach considers
what is known about the agent's mode of action. When multiple estimates can be
developed, the strengths and weaknesses of each are presented. In some cases, they may be
combined in a way to best represent human cancer risk.
When sufficient and appropriate human and laboratory animal data are both available for
the same outcome, human data are generally preferred for the dose response assessment because
their use eliminates the need to perform interspecies extrapolations. Findings from human studies
were evaluated but considered less suitable for dose-response primarily due to lack of well-
characterized quantitative exposure estimates and certain study evaluation concerns (e.g., limited
duration and confounding from other exposures). Therefore, the results of the cobalt SEM (see
Appendix C) indicate that animal data represent the most appropriate evidence available for
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estimating an IUR(s) and these data will be used for dose-response analysis. When there are
multiple tumor types, the final IUR(s) will attempt to address overall cancer risk.
4.2.2.1. Dose-Response Analysis in the Range of Observation
For conducting a dose-response assessment, pharmacodynamic ("biologically based")
modeling can be used when there are sufficient data to ascertain the mode of action and
quantitatively support model parameters that represent rates and other quantities associated with
the key precursor events of the modes of action. If an applicable pharmacodynamic model is not
available to assess health effects associated with inhalation exposure to cobalt, empirical dose-
response modeling will be used to fit the data (on the apical outcomes or a key precursor events) in
the range of the observed data. For this purpose, EPA has developed a software tool (Benchmark
Dose Software, BMDS) that includes a standard set of models fhttp://www.epa.gov/ncea/bmds)
that can be applied to typical data sets, including those that are nonlinear. In situations where
there are alternative models with significant biological support, the users of the assessment can be
informed by the presentation of these alternatives along with the models' strengths and
uncertainties. The EPA has developed guidelines on modeling dose-response data, assessing model
fit, selecting suitable models, and reporting modeling results [see the EPA Benchmark Dose
Technical Guidance U.S. EPA f2012bl1.
U.S. EPA BMDS is designed to help model dose-response datasets in accordance with EPA
Benchmark Dose Technical Guidance U.S. EPA f2012b). With the nonlinear approach of cancer data
analysis based on Guidelines for Carcinogen Risk Assessment U.S. EPA f2005all. a BMCL (for
inhalation exposure data, as is the case for this assessment) is computed using a model selected
from the BMDS suite of models using statistical and graphical criteria. Linear analysis of cancer
datasets generally uses the multistage model, with degree selected following a U.S. EPA Statistical
Workgroup technical memo available on the BMDS website
fhttps://cfpub.epa.gov/ncea/bmds/recordisplay.cfm?deid=308382). Modeling of cancer data may
in some cases involve additional, specialized methods, particularly for multiple tumors or early
removal from observation. For example, when survivals are different across exposure groups
and individual-level data are available, models that include time-to-tumor information may be
useful. Also, additional judgment or alternative analyses may be used if these procedures fail to
yield results in reasonable agreement with the data. For example, modeling may be restricted to the
lower exposure levels, especially if there is competing toxicity at higher concentrations.
For each modeled response, a POD from the observed data should be estimated to mark the
beginning of extrapolation to lower exposure levels. The POD is an estimated exposure level
(expressed in human equivalent terms, e.g., PODhec for inhalation data) near the lower end of the
observed range without significant extrapolation to lower concentrations. For linear extrapolation
of cancer risk, the POD is used to calculate an inhalation unit risk (IUR), and for nonlinear
extrapolation, the POD is used in calculating an RfC. The response level at which the POD is
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calculated is guided by the severity of the endpoint. If linear extrapolation is used, selection of a
response level corresponding to the POD is not highly influential, so standard values near the low
end of the observable range are generally used (for example, 10% extra risk for cancer bioassay
data, 1% for epidemiologic data, lower for rare cancers). Nonlinear approaches consider both
statistical and biologic considerations. For dichotomous data, a response level of 10% extra risk is
generally used for minimally adverse effects, 5% or lower for more severe effects in experimental
animals. For continuous data, a response level is ideally based on an established definition of
biologic significance. In the absence of such definition, one control standard deviation from the
control mean is often used for minimally adverse effects, one-half standard deviation for more
severe effects. The point of departure is the 95% lower bound on the dose associated with the
selected response level.
EPA has developed standard approaches for determining the relevant exposure level to be
used in the dose-response modeling in the absence of appropriate pharmacokinetic modeling.
These standard approaches (limited here to inhalation cancer) also facilitate comparison across
exposure patterns and species:
• Intermittent study exposures will be standardized to a daily average over the duration of
exposure. For chronic effects, daily exposures are averaged over the lifespan. Exposures
during a critical period, however, are not averaged over a longer duration U.S. EPA (2005a ,
S3.1.11: 91. S3.21. Note that this will typically be done after modeling because
the conversion is linear.
• Exposure concentrations will be standardized to equivalent human terms (via a common
internal dose metric for animals and humans) to facilitate comparison of results from
different species. Inhalation exposures are scaled using dosimetry models that apply
species-specific physiologic and anatomic factors and consider whether the effect occurs at
the site of first contact or after systemic circulation U.S. EPA f2012al: )4. §31.
The preferred approach for dosimetry extrapolation from animals to humans is through
PBPK modeling. Methods for lung dosimetry are described in Methods for Derivation of
Inhalation Reference Concentrations and Application of Inhalation Dosimetry U.S. EPA
1), and in EPA's MPPD Technical Support Documentation and User's Guide U.S. EPA
£2022).
In the absence of study specific data on, for example, inhalation rates or body weight, the
EPA has developed recommended values for use in dose response analysis U.S. EPA
f 19881.
For additional dose-response considerations specific to this assessment, see Studies that
Meet SEM PECO Criteria.
4.2.2.2. Extrapolation: Unit Risk
An IUR is calculated to facilitate estimation of human cancer risks when low-dose linear
extrapolation for cancer effects is supported, particularly for chemicals with direct mutagenic
activity or those for which the data indicate a linear component below the POD. Low-dose linear
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extrapolation is also used as a default when the data are insufficient to establish the mode of action
U.S. EPA (2005al If the currently available data on cobalt compounds (or specific tumors resulting
from cobalt exposure) are judged as sufficient to "ascertain the M0A[s] and conclude that it is not
linear at low doses and the agent [cobalt] does not demonstrate mutagenic or other activity
consistent with linearity at low doses ...Where alternative approaches with significant biological
support are available for the same tumor response and no scientific consensus favors a single
approach, [the] assessment may present results based on more than one approach (e.g., both low-
dose linear and reference concentration approaches)" U.S. EPA (2005al Both approaches may also
be used when there are multiple MOAs identified. When multiple approaches are presented, the
assessment will describe the strengths and uncertainties of each before selecting and justifying a
final estimate.
4.2.2.3. Extrapolation: Reference Concentrations
Reference value derivation is EPA's most frequently used type of nonlinear extrapolation
method. Although it is most commonly used for noncancer effects, this approach is also used for
cancer effects if there are sufficient data to ascertain the MOA and conclude that it is not linear at
low doses. For these cases, reference values for each relevant route of exposure are developed
following EPA's established practices U.S. EPA (2005a. §3.3.4): in general, the reference value is
based not on tumor incidence, but on a key precursor event in the MOA that is necessary for tumor
formation. If a reference value approach is presented as an alternative to the IUR, reference value
derivation will be performed in accordance with current EPA guidelines U.S. EPA (19981: U.S. EPA
f!9961: t n I i \ i I' 94); LU> I ! \ l I" 1); 1LSJ IW.i '0021: IJ.S. EPA (20111: U.S. EPA (201.4a1
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(inhalation studies). (NTPTR471). Research Triangle Park, NC.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
NTP (National Toxicology Program). (2014). NTP Technical Report on the Toxicology
Studies of Cobalt Metal (CAS No. 7440-48-4) in F344/N Rats and B6C3F1/N Mice
and Toxicology and Carcinogenesis Studies of Cobalt Metal in F344/NTac Rats and
B6C3F1/N Mice (Inhalation Studies). (TR-581). Research Triangle Park, NC.
httpsi//ntp.nielis.iiili.gov/iitp/litdocs/It rpts/tr581 508.pdf.
NTP (National Toxicology Program). (2016). Monograph on cobalt and cobalt compounds
that release cobalt ions in vivo. In Report on carcinogens. (CAS No. 7440-48-4).
Research Triangle Park, NC.
https://ntp.niehs.nih.gov/ntp/roc/monographs/cobalt final 508.pdf.
NTP (National Toxicology Program). (2021). Report on carcinogens, fifteenth edition:
Cobalt-related exposures. Research Triangle Park, NC: U.S. Department of Health
and Human Services, National Institutes of Health, National Toxicology Program.
https://ntp.niehs.nih.gov/ntp/roc/content/profiles/cobalt.pdf.
OEHHA (California Office of Environmental Health Hazard Assessment). (2019). Cobalt
metal powder. Available online at littps://oehha.ca.gov/chemicals/cobalt-metal-
powder (accessed February 16, 2022).
OEHHA (California Office of Environmental Health Hazard Assessment). (2020). Cobalt and
cobalt compounds cancer inhalation unit risk factors. Technical support document
for cancer potency factors: Appendix B. Sacramento, CA: California Environmental
Protection Agency, Office of Environmental Health Hazard Assessment, Air,
Community, and Environmental Research Branch, Air Toxics Hot Spots Program.
https://oehha.ca.gov/media/downloads/crnr/cobaltcpfl00220.pdf.
Osman. D: Cooke. A: Young. TR: Deei . I nm. N1: Warren. Ml. (2021). The
requirement for cobalt in vitamin B12: A paradigm for protein metalation [Review].
Biochim Biophys Acta Mol Cell Res 1868: 118896.
Ozaki. K: Haseman. IK: Hailev. IR: Maronpot. RR: Nvska. A. (2002). Association of adrenal
pheochromocytoma and lung pathology in inhalation studies with particulate
compounds in the male F344 rat-the National Toxicology Program experience.
Toxicol Pathol 30: 263-270. Imi)://dx.doi.org/10.1080/019262302753559605.
Palmes. ED: Nelson. N: Laskin. S: Kuschner. M. (1959). Inhalation toxicity of cobalt
hydrocarbonyl. Am Ind Hyg Assoc J 20: 453-468.
http://dx.doi.org/10.1080/00028895909343751.
Pomi ^ I \limaro. B: Broggi. F: Marmot «r I t hini. F: Colognato. R: Rossi.
F, (2009). Genotoxicity and morphological transformation induced by cobalt
nanoparticles and cobalt chloride: an in vitro study in Balb/3T3 mouse fibroblasts.
Mutagenesis 24: 439-445. ¦Ldoi.org/10.1093/rniitage/gep02.
RSC (Royal Society of Chemistry). (2022). Cobalt(II) carbonate; ChemSpider ID10123.
Available online at A^w.chemspider.com/Chemical-Structure. 10123.html
(accessed March 11, 2022).
Sauni. R: Ok ia. A: Kerttula. R: Pukkala. E. (2017). Cancer incidence among
Finnish male cobalt production workers in 1969-2013: a cohort study. BMC Cancer
17: 340. http://dx.doi.org/10.1186/sl288S-017-3333-2.
ScholAR Chemistry. (2009). Cobalt (II, III) oxide: Material safety data sheet. Rochester, NY.
https://www.mccsd.net/cms/lib/NY02208580/Centricitv/Shared/Material%20Saf
This document is a draft for review purposes only and does not constitute Agency policy.
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etv%20Data%20S!ieets%20 MSDS /MSPS%20Sheets Cob 00 QO.p
df.
Slack, IF; Kimball, BE; Shedd, KB. (2017). Cobalt: chapter F of critical mineral resources of
the United States—economic and environmental geology and prospects for future
supply. US Geological Survey Professional Papers F: F1-F40.
http://dx.doi.org/10.3133/ppll
Si.mh I [ hiu s I [ mu nal. SK: Mason. MP: Ziu u'.1 I ' 'isc, IP. (2014). The cytotoxicity
and genotoxicity of soluble and particulate cobalt in human lung fibroblast cells.
Toxicol Appl Pharmacol 278: 259-265.
http://dx.doi.Org/10.1016/i.taap.2014.05.002.
Smith. MT: Guvton, KZ: Gibbons, CF: Fritz, 1M; Portiei ^ 1: iisvii, I: tVMarini, DM: Caldwell,
h IxhIocJlKI I vUTibei IN {V cherJBi St:e, warL B Wi B
VI: Straif. K. (2016). Key characteristics of carcinogens as a basis for organizing data
on mechanisms of carcinogenesis [Review]. Environ Health Perspect 124: 713-721.
http://dx.doi.org/10.1289/ehp.1509912.
Suh. M: Thompson. CM: Brorbv. GP: Mittai. L. iz: Proctor. DM. (2016). Inhalation cancer risk
assessment of cobalt metal [Review]. Regul Toxicol Pharmacol 79: 74-82.
http://dx.doi.Org/10.1016/i.yrtph.2016.05.009.
TCEO (Texas Commission on Environmental Quality). (2017). Development support
document: Cobalt and cobalt compounds.
https://www.tcea.texas.gOv/assets/public/implementation/tox/dsd/Final/cobalt.p
df.
Ton. TT: Ko\ i I 1 ^ dada. TN: Chhabria. RM: Shocklev. KR: Flagh i \ rrish. KE:
Herbert. RA: Behl. iiierhoff. Ml: Sills, RC: Pandiri, AR. f20211. Cobalt-induced
oxidative stress contributes to alveolar/bronchiolar carcinogenesis in B6C3F1/N
mice. Arch Toxicol 95: 3171-3190. lmi)://dx.doi.org/10.1007/s00204-021-U * 1 Ju
5.
Tuch.M u ^ U usen. MV: Villadsen ^ !•]. (1996). Incidence of lung cancer among
cobalt-exposed women. Scand J Work Environ Health 22: 444-450.
U.S. EPA (U.S. Environmental Protection Agency). (1988). Recommendations for and
documentation of biological values for use in risk assessment [EPA Report].
(EPA600687008). Cincinnati, OH.
http://cfpub.epa.gov/ncea/cfm/recordisplay.
U.S. EPA (U.S. Environmental Protection Agency). (1991). Guidelines for developmental
toxicity risk assessment. Fed Reg 56: 63798-63826.
U.S. EPA (U.S. Environmental Protection Agency). (1994). Methods for derivation of
inhalation reference concentrations and application of inhalation dosimetry [EPA
Report]. (EPA600890066F). Research Triangle Park, NC.
https://cfpub.epa.gov/ncea/risk/recordisplay.cfin H-'B&CFII^ ' 11 J029&
> ' ^ M ^ ' 'U)63'l7.
U.S. EPA (U.S. Environmental Protection Agency). (1996). Guidelines for reproductive
toxicity risk assessment (pp. 1-143). (EPA/630/R-96/009). Washington, DC: U.S.
Environmental Protection Agency, Risk Assessment Forum.
https://www.epa.gov/sites/production/files/2014-
11 Uocumem "nidelines repro toxicitv.pdf.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
U.S. EPA (U.S. Environmental Protection Agency). (1998). Guidelines for neurotoxicity risk
assessment [EPA Report] (pp. 1-89). (ISSN 0097-6326
EISSN 2167-2520
EPA/630/R-95/001F). Washington, DC: U.S. Environmental Protection Agency, Risk
Assessment Forum, http://www.epa.gov/risk/guide1ines-neurotoxi city-risk-
assessment.
U.S. EPA (U.S. Environmental Protection Agency). (2002). A review of the reference dose
and reference concentration processes. (EPA630P02002F). Washington, DC.
https://www.epa.gov/sites/production/files/2014-12/documents/rfd-final.pdf.
U.S. EPA (U.S. Environmental Protection Agency). (2005a). Guidelines for carcinogen risk
assessment [EPA Report]. (EPA630P03001F). Washington, DC.
https://www.epa.gov/sites/production/files/2Q13-
09/docume ncer guidelines final 3-25-05.pdf.
U.S. EPA (U.S. Environmental Protection Agency). (2005b). Supplemental guidance for
assessing susceptibility from early-life exposure to carcinogens [EPA Report].
(EPA/630/R-03/003F). Washington, DC: U.S. Environmental Protection Agency,
Risk Assessment Forum, https://www.epa.gov/risk/supplemental-guidance-
assessing-susceptibilitv-early-life-exposure-carcinogens.
U.S. EPA (U.S. Environmental Protection Agency). (2008). Provisional peer reviewed
toxicity values for cobalt (CASRN 7440-48-4) [EPA Report]. (EPA/690/R-08/008F).
Cincinnati, OH. https://cfpub.epa.gov/ncea/pprtv/recordisplay.cf 1=338894.
U.S. EPA (U.S. Environmental Protection Agency). (2011). Recommended use of body
weight 3/4 as the default method in derivation of the oral reference dose.
(EPA100R110001). Washington, DC.
https://www.epa.gov/sites/production/files/2013-09/documents/recommended-
use-of-bw34.pdf.
U.S. EPA (U.S. Environmental Protection Agency). (2012a). Advances in inhalation gas
dosimetry for derivation of a reference concentration (RfC) and use in risk
assessment (pp. 1-140). (EPA/600/R-12/044). Washington, DC.
https://cfpub.epa.gov/ncea/risk/recordisplay.cfm?deid=244650&CFID=50l
&.€ FTP K E N = 17139189.
U.S. EPA (U.S. Environmental Protection Agency). (2012b). Benchmark dose technical
guidance [EPA Report]. (EPA100R12001). Washington, DC: U.S. Environmental
Protection Agency, Risk Assessment Forum, https://www.epa.gov/risk/benchmark-
dose-technical-guidance.
U.S. EPA (U.S. Environmental Protection Agency). (2014a). Guidance for applying
quantitative data to develop data-derived extrapolation factors for interspecies and
intraspecies extrapolation [EPA Report]. (EPA/100/R-14/002F). Washington, DC:
Risk Assessment Forum, Office of the Science Advisor.
https://www.epa.gov/sites/production/files/2015-01/docun' 7-final.pdf.
U.S. EPA (U.S. Environmental Protection Agency). (2014b). Substance registry services
[Database]. Washington, D.C. Retrieved from
https ipiib.epa.gov/sor internet/registry/substreg/searchandretrieve/substa
ncesearch/search.do
U.S. EPA (U.S. Environmental Protection Agency). (2015). Peer review handbook [EPA
Report] (4th ed.). (EPA/100/B-15/001). Washington, DC: U.S. Environmental
This document is a draft for review purposes only and does not constitute Agency policy.
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Protection Agency, Science Policy Council, https://www.epa.gov/osa/peer-review-
handbook-4th-edition-2015.
U.S. EPA (U.S. Environmental Protection Agency). (2018). An umbrella Quality Assurance
Project Plan (QAPP) for PBPK models [EPA Report]. (0RD QAPP ID No: B-0030740-
QP-1-1). Research Triangle Park, NC.
U.S. EPA (U.S. Environmental Protection Agency). (2019). ChemView [Database]. Retrieved
from https://chemview.epa.gov/chemview
U.S. EPA (U.S. Environmental Protection Agency). (2020a). 2017 National Emissions
Inventory (NEI) data (April 2020 version) (Version April 2020). Washington, DC: US
Environmental Protection Agency. Retrieved from https://www.epa.gov/air-
emissions-inventories/2017-national-emissions-inventorv-nei-data
U.S. EPA (U.S. Environmental Protection Agency). (2020b). Benchmark Dose Software
(BMDS). Version 3.2: User guide [EPA Report]. (EPA/600/R-20/216). Washington,
DC: U.S. Environmental Protection Agency, Office of Research and Development.
https://nepis.epa.gov/Exe/ZyPURL.cgi?Dock< 3T2.txt.
U.S. EPA (U.S. Environmental Protection Agency). (2020c). ORD staff handbook for
developing IRIS assessments (public comment draft) [EPA Report]. (EPA/600/R-
20/137). Washington, DC: U.S. Environmental Protection Agency, Office of Research
and Development, Center for Public Health and Environmental Assessment.
https://cfpub.epa.gov/ncea/iris drafts/recordisplay.cfm?deid=350086.
U.S. EPA (U.S. Environmental Protection Agency). (2020d). Toxicology testing in the 21st
century (Tox21). Available online at https://ntp.niehs.nih.gov/go/tox21 (accessed
May 4, 2021).
U.S. EPA (U.S. Environmental Protection Agency). (2021). CompTox chemicals dashboard.
Washington, DC. Retrieved from https://comptox.epa.gov/dashboard
U.S. EPA (U.S. Environmental Protection Agency). (2022). Multiple-path Particle Dosimetry
(MPPD) model: EPA technical support documentation and user's guide (EPA MPPD
2022 v.2.0).
Whit s!; ¦-v 1 > ien. KM: Niehoff. NM: Carroll. R: Saudi > (2019). Metallic air pollutants
and breast cancer risk in a nationwide cohort study. Epidemiology 30: 20-28.
http://dx.doi.Oi ItMtH S H00000000000917.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
APPENDIX A. CHEMICAL AND PHYSICAL
PROPERTIES OF INCLUDED FORMS
A.l. KEY COMPOUNDS IDENTIFIED DURING SCOPING
Table A-l. Chemical identity and physicochemical properties of cobalt
Characteristic or property
Value3
Reference
Chemical structure
Co
U.S. EPA (2021)
CASRN
7440-48-4
U.S. EPA (2021)
Synonyms
cobalt element
U.S. EPA (2021)
Color/form
hard, lustrous, silver-gray metal
U.S. EPA (2021)
Molecular formula
Co
U.S. EPA (2021)
Molecular weight (g/mol)
58.933
U.S. EPA (2021)
Density (g/cm3)
8.9 at 20°C
ATSDR (2004)
Boiling point (°C)
3,000
U.S. EPA (2021)
Melting point (°C)
1,500
U.S. EPA (2021)
Heat of formation (kJ/mol)
427.7 (gas)
NCBI (2021)
Log Kow
ND
NA
Koc(L/kg)
ND
NA
Henry's law constant
(atm-m3/mol)
ND
NA
Solubility in water (g/L)
2.9 x 10"3
OEHHA (2020)
Vapor pressure (mmHg)
1 at 1,910 °C
ATSDR (2004)
NA = not applicable; ND = no data.
a When available, average experimental values are reported from U.S. EPA (2021) Chemicals Dashboard (Cobalt
DTXSID1031040): https://comptox.epa.gov/dashboard/chemical/details/DTXSID1031040.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Table A-2. Chemical identity and physicochemical properties of cobalt oxide
Characteristic or property
Value
Reference
Chemical structure
Co2+ O2"
U.S. EPA (2021)
CASRN
1307-96-6
U.S. EPA (2021)
Synonyms
cobalt(ll) oxide, cobaltous oxide, FCO
178, (oxido)cobalt, Zaffre, C.I. 77322,
C.I. Pigment Black 13, cobalt black,
cobalt monoxide, cobaltoxid
U.S. EPA (2021)
Color/form
olive-green or gray solid
U.S. EPA (2021)
Molecular formula
CoO
U.S. EPA (2021)
Molecular weight (g/mol)
74.932
U.S. EPA (2021)
Density (g/cm3)
6.45
ATSDR (2004)
Boiling point (°C)
ND
NA
Melting point (°C)
1,935
NCBI (2021)
Heat of formation (kJ/mol)
-237.9
NCBI (2021)
Log Kow
ND
NA
Koc(L/kg)
ND
NA
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
4.88 x lO"3 at 20°C
NCBI (2021)
Vapor pressure (mmHg)
ND
NA
NA = not applicable; ND = no data.
Table A-3. Chemical identity and physicochemical properties of hexanoic acid,
2-ethyl-, cobalt(2+) salt
Characteristic or property
Value3
Reference
Chemical structure
H 0
h3c^ ch3
U.S. EPA (2021)
CASRN
136-52-7
U.S. EPA (2021)
Synonyms
cobalt(2+) bis(2-ethylhexanoate); 2-ethylhexanoic
acid cobalt(2+) salt; bis(2-ethylhexanoate) de
cobalt; cobalt 2-ethylhexanoate; cobalt bis(2-
U.S. EPA (2021)
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Characteristic or property
Value3
Reference
ethylhexanoate); cobalt(ll) 2-ethylhexanoate;
cobalt octoate; cobaltous 2-ethylhexanoate;
cobaltous octoate; hexanoate, 2-ethyl-, cobalt;
Octlife Co 12; Octlife Co 8; Versneller NL49
Color/form
blue liquid
NCBI (2021)
Molecular formula
C16H30C0O4
U.S. EPA (2021)
Molecular weight (g/mol)
345.345
U.S. EPA (2021)
Density (g/cm3)
1.01
NIP (2016)
Boiling point (°C)
decomposes at 90
NCBI (2021)
Melting point (°C)
53-84 at 100.5- 101.325 kPa
ECHA (2022)
Heat of formation (kJ/mol)
ND
NA
Log Kow
2.96 at 20°C
ECHA (2022)
Koc(L/kg)
ND
NA
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
40.3 at 20°C
ECHA (2022)
Vapor pressure (Pa)
5
ECHA (2022)
NA = not applicable; ND = no data.
Table A-4. Chemical identity and physicochemical properties of cobalt nitrate
Characteristic or property
Value
Reference
Chemical structure
0" 0
/ -
G=N+ O N
\ \
0 0
Co +
U.S. EPA (2021)
CASRN
10141-05-6
U.S. EPA (2021)
Synonyms
cobalt(ll) nitrate; cobalt dinitrate; cobalt
bis(nitrate); cobaltous nitrate; nitric acid,
cobalt(2+) salt
U.S. EPA (2021)
Color/form
red solid
ATSDR (2004)
Molecular formula
Co(NOb)2
U.S. EPA (2021)
Molecular weight (g/mol)
182.941
U.S. EPA (2021)
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Characteristic or property
Value
Reference
Density (g/cm3)
2.49
ATSDR (2004)
Boiling point (°C)
NA
NA
Melting point (°C)
decomposes at 100-105
ATSDR (2004)
Heat of formation (kJ/mol)
-420.5
NCBI (2021)
Log Kow
ND
NA
Koc(L/kg)
ND
NA
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
670
OEHHA (2020)
Vapor pressure (mmHg)
ND
NA
NA = not applicable; ND = no data.
Table A-5. Chemical identity and physicochemical properties of cobalt nitrate
hexahydrate
Characteristic or property
Value
Reference
Chemical structure
O O"
// /
O M+ 0 N* Co '
\ . \\
0 0
h2o h2o h2o
h2o h2o h2o
U.S. EPA (2021)
CASRN
10026-22-9
U.S. EPA (2021)
Synonyms
cobalt(2+) nitrate--water
U.S. EPA (2021)
Color/form
red solid
NCBI (2021)
Molecular formula
Co(N03)2x6 H20
U.S. EPA (2021)
Molecular weight (g/mol)
291.031
U.S. EPA (2021)
Density (g/cm3)
1.88
NCBI (2021)
Boiling point (°C)
decomposes at 74
NCBI (2021)
Melting point (°C)
55
NCBI (2021)
Heat of formation (kJ/mol)
ND
NA
Log Kow
ND
NA
Koc(L/kg)
ND
NA
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Characteristic or property
Value
Reference
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
1,338 at 0°C
NCBI (2021)
Vapor pressure (mmHg)
ND
NA
NA = not applicable; ND = no data.
Table A-6. Chemical identity and physicochemical properties of cobalt
bromide
Characteristic or property
Value
Reference
Chemical structure
9 +
Rr Co
br Br
U.S. EPA (2021)
CASRN
7789-43-7
U.S. EPA (2021)
Synonyms
cobalt(ll) bromide, cobalt
dibromide, cobaltous bromide
U.S. EPA (2021)
Color/form
green solid
U.S. EPA (2021)
Molecular formula
CoBr2
U.S. EPA (2021)
Molecular weight (g/mol)
218.741
U.S. EPA (2021)
Density (g/cm3)
4.909
NCBI (2021)
Boiling point (°C)
927
AR.TEAM (2022)
Melting point (°C)
678
NCBI (2021)
Heat of formation (kJ/mol)
-220.9
NCBI (2021)
Log Kow
ND
NA
Koc(L/kg)
ND
NA
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
1,132 at 20°C
NCBI (2021)
Vapor pressure (mmHg)
ND
NA
NA = not applicable; ND = no data.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Table A-7. Chemical identity and physicochemical properties of cobalt
carbonate
Characteristic or property
Value
Reference
Chemical structure
0
_ 2 +
Co
U.S. EPA (2021)
CASRN
513-79-1
U.S. EPA (2021)
Synonyms
carbonic acid, cobalt(2+) salt (1:1),
cobalt(ll) carbonate
U.S. EPA (2021)
Color/form
reddish paramagnetic solid
U.S. EPA (2021)
Molecular formula
C0CO3
U.S. EPA (2021)
Molecular weight (g/mol)
118.941
U.S. EPA (2021)
Density (g/cm3)
4.13
CADENAS (2022)
Boiling point (°C)
ND
NA
Melting point (°C)
decomposes at 427
CADENAS (2022)
Heat of formation (kJ/mol)
-722.6
CADENAS (2022)
Log Kow
-1.192
RSC (2022)
Koc(L/kg)
ND
NA
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
11.4 x lO"3
OEHHA (2020)
Vapor pressure (mmHg)
ND
NA
NA = not applicable; ND = no data.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Table A-8. Chemical identity and physicochemical properties of cobalt
chloride
Characteristic or property
Value3
Reference
Chemical structure
cr co2+ cr
U.S. EPA (2021)
CASRN
7646-79-9
U.S. EPA (2021)
Synonyms
cobalt(ll) chloride, cobalt
dichloride, cobaltous chloride
U.S. EPA (2021)
Color/form
blue solid
ATSDR (2004)
Molecular formula
C0CI2
U.S. EPA (2021)
Molecular weight (g/mol)
129.83
U.S. EPA (2021)
Density (g/cm3)
3.4
NCBI (2021)
Boiling point (°C)
1,050
U.S. EPA (2021)
Melting point (°C)
411
U.S. EPA (2021)
Heat of formation (kJ/mol)
-311.07
Lavut et al. (1989)
Log Kow
0.8494
Alpha Chemicals (2020)
Koc(L/kg)
23.74
Alpha Chemicals (2020)
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
450
OEHHA (2020)
Vapor pressure (mmHg)
75 at 818°C
NCBI (2021)
NA = not applicable; ND = no data.
a When available, average experimental values are reported from U.S. EPA (2021) Chemicals Dashboard (Cobalt
chloride DTXSID9040180): https://comptox.epa.gov/dashboard/chemical/details/DTXSID9040180.
Table A-9. Chemical identity and physicochemical properties of cobalt
hydrocarbonyl
Characteristic or property
Value
Reference
Chemical structure
0+
cr
_ J
0—C—Co—C—0+
iiv
o+
U.S. EPA (2021)
CASRN
16842-03-8
U.S. EPA (2021)
This document is a draft for review purposes only and does not constitute Agency policy.
A-7 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Characteristic or property
Value
Reference
Synonyms
carbon monooxide-cobalt
U.S. EPA (2021)
Form
flammable gas with offensive odor
ACGIH (2001c)
Molecular formula
C4HC0O4
U.S. EPA (2021)
Molecular weight (g/mol)
171.981
U.S. EPA (2021)
Relative gas density
5.93
NIOSH (2019)
Boiling point (°C)
10
DOE (2018)
Melting point (°C)
-26
ACGIH (2001c)
Heat of formation (kJ/mol)
-569.2
NIST (2021a)
Log Kow
ND
NA
Koc(L/kg)
ND
NA
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
0.5
ACGIH (2001c)
Vapor pressure (atm)
>1
NIOSH (2019)
NA = not applicable; ND = no data.
This document is a draft for review purposes only and does not constitute Agency policy.
A-8 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Table A-10. Chemical identity and physicochemical properties of cobalt oxide
(II, HI)
Characteristic or property
Value
Reference
Chemical structure
C0O.C02O3
NCBI (2021)
CASRN
1308-06-1
U.S. EPA (2021)
Synonyms
cobaltic-cobaltous oxide, cobalto-
cobaltic oxide, cobalto-cobaltic
tetroxide, cobaltosic oxide, cobalt
tetraoxide, tricobalt tetraoxide
U.S. EPA (2021)
Color/form
black antiferromagnetic solid
U.S. EPA (2021)
Molecular formula
C03O4
U.S. EPA (2021)
Molecular weight (g/mol)
240.797
NCBI (2021)
Density (g/cm3)
6.07
ATSDR (2004)
Boiling point (°C)
decomposes at 900
ScholAR Chemistrv (2009)
Melting point (°C)
895
ScholAR Chemistrv (2009)
Heat of formation (kJ/mol)
ND
NA
Log Kow
ND
NA
Koc(L/kg)
ND
NA
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
1.6 x 10"3
OEHHA (2020)
Vapor pressure (mmHg)
ND
NA
NA = not applicable; ND = no data.
Table A-ll. Chemical identity and physicochemical properties of cobalt
carbonyl
Characteristic or property
Value
Reference
Chemical structure
o+
0+^ c- ^0+
0 = C^ l2^C=0
Co
0^ C" ^0+
0+
U.S. EPA (2021)
CASRN
10210-68-1
U.S. EPA (2021)
Synonyms
dicobalt octacarbonyl
U.S. EPA (2021)
This document is a draft for review purposes only and does not constitute Agency policy.
A-9 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Characteristic or property
Value
Reference
Color/form
orange solid, white when pure
ATSDR (2004)
Molecular formula
Co2(CO)8
U.S. EPA (2021)
Molecular weight (g/mol)
341.946
U.S. EPA (2021)
Density (g/cm3)
1.73 at 18°C
ATSDR (2004)
Boiling point (°C)
decomposes at 52
ACGIH (2001b)
Melting point (°C)
51
ACGIH (2001b)
Heat of formation (kJ/mol)
-1,249.3
NISI (2021b)
Log Kow
ND
NA
Koc(L/kg)
ND
NA
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water
insoluble
ACGIH (2001b)
Vapor pressure (torr)
1.5
ACGIH (2001b)
NA = not applicable; ND = no data.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
A.2. ADDITIONAL COBALT COMPOUNDS USED TO SUPPORT DERIVATION
OF INHALATION UNIT RISK ESTIMATES
Table A-12. Chemical identity and physicochemical properties of cobalt
sulfate
Characteristic or property
Value3
Reference
Chemical structure
Co2+ 0_
0
0— =0
M
0
U.S. EPA (2021)
CASRN
10124-43-3
U.S. EPA (2021)
Synonyms
cobalt(ll) sulfate, cobalt
monosulfate, cobalt sulphate,
cobaltous sulfate, sulfuric acid,
cobalt (2+) salt
U.S. EPA (2021)
Color/form
red or pink solid
NCBI (2021)
Molecular formula
C0SO4
U.S. EPA (2021)
Molecular weight (g/mol)
154.99
U.S. EPA (2021)
Density (g/cm3)
3.71
NCBI (2021)
Boiling point (°C)
735 - decomposition temperature3
NCBI (2021)
Melting point (°C)
97a
NCBI (2021); U.S. EPA (2021)
Heat of formation (kJ/mol)
-888.3
NCBI (2021)
Log Kow
ND
NA
Koc(L/kg)
ND
NA
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
383
NCBI (2021)
Vapor pressure (mmHg)
ND
NA
NA = not applicable; ND = no data.
a Several online databases, including PubChem and the Hazardous Substances Databank, contain conflicting data
including that 735 °C is the melting point and decomposition temperature for cobalt (II) sulfate (while also
reporting 97 °C as a melting point).
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
33 Table A-13. Chemical identity and physicochemical properties of cobalt sulfate heptahydrate
Characteristic or property
Value3
Reference
Chemical structure
h2o
h2o
o h2o
u 0 II
o=s—cr
h2o 0 c°2+ h2o
h2o
U.S. EPA (2021)
CASRN
10026-24-1
U.S. EPA (2021)
Synonyms
cobalt(ll) sulfate heptahydrate;
cobalt monosulfate heptahydrate;
cobaltous sulfate heptahydrate;
sulfuric acid, cobalt(2+) salt,
heptahydrate
U.S. EPA (2021)
Color/form
pink or red crystalline solid
NCBI (2021)
Molecular formula
CoS04 x 7 H2O
NCBI (2021)
Molecular weight (g/mol)
281.09
U.S. EPA (2021)
Density (g/cm3)
1.95
NCBI (2021)
Boiling point (°C)
Becomes anhydrous at 420 (°C),
turning into cobalt sulfate15
NCBI (2021)
Melting point (°C)
NDb
NA
Heat of formation (kJ/mol)
ND
NA
Log Kow
ND
NA
Koc(L/kg)
ND
NA
Henry's law constant (atm-m3/mol)
ND
NA
Solubility in water (g/L)
604 at 3°C
NCBI (2021)
Vapor pressure (mmHg)
ND
NA
NA = not applicable; ND = no data.
a When available, average experimental values are reported from U.S. EPA (2021) Chemicals Dashboard (Cobalt sulfate
heptahydrate DTXSID7020340): https://comptox.epa.gov/dashboard/chemical/details/DTXSID7020340.
bSeveral online databases, including PubChem and the Hazardous Substances Databank, contain conflicting data
including that 735 °C is the melting point and decomposition temperature for cobalt (II) sulfate (while also reporting 97
°C as a melting point).
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
APPENDIX B. SURVEY OF EXISTING TOXICITY
VALUES
B.l. METHODS
1 Table B-l lists websites which were searched for relevant human health reference values
2 for various compounds of cobalt, along with indications of the results of the search. In addition to
3 these sources, the ToxVal database on the Chemicals Dashboard
4 fhttps://comptox.epa.gov/dashboard/chemical lists/TOXVAL V5] was also searched for both
5 reference values and potential points of departure (PODs) for development of values.
Table B-l. Sources searched for human health reference values for cobalt and
cobalt forms
Source
Search Results
Query and/or link
ACGIH
See table of non-cancer values
in HAWC
ACGIH. 2001. 2001 TLVs and BEIs: Based on documentation of
the threshold limit values for chemical substances and physical
agents and biological exposure indices. Cincinnati, OH:
American Conference of Governmental Industrial Hygienists.
AIHA
See table of non-cancer values
in HAWC
AIHA. 2019. 2019 ERPG/WEEL Handbook. Fairfax, VA: American
Industrial Hygiene Association. [Latest list of values.]
AIHA. 2002 (and updates). 2002 Emergency Response Planning
Guidelines. Fairfax, VA: American Industrial Hygiene Association.
[Details used in deriving values.]
ATSDR
See table of non-cancer values
in HAWC
http://www. atsdr.cdc.gov/toxDrofiles/index.asD
httos://www.atsdr.cdc.gov/mrls/mrllist.asD
EPA
CompTox
Chemicals
Dashboard
See table of non-cancer values
in HAWC and Table B-2
httDs://comotox.eoa.gov/dashboard
CT DEEP
See table of non-cancer values
https://eregulations. ct.gov/eRegsPortal/Browse/getDocument?g
in HAWC
uid={00D6A654-0300-CC47-9B95-397D2AD21304}
DFG
No values found
httos://series. Dublisso.de/sites/default/files/documents/series/
mak/lmbv/Vol2021/lss2/Doc002/mbwl 2021 eng.odf
EPA/NRC
AEGL
No values found
https://www.epa.gov/aegl/access-acute-exposure-guideline-
levels-aegls-values#chemicals
Health
Canada
No values found
https://publications.gc.ca/collections/collection 2021/sc-
hc/H 129-108-2021-eng.pdf
This document is a draft for review purposes only and does not constitute Agency policy.
B-l DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Source
Search Results
Query and/or link
https://www.canada.ca/en/services/health/publications/healthy
-living,html
http://publications.gc.ca/site/archivee-
archived.html?url=http://publications.gc.ca/collections/Collectio
n/H46~2~36~134E,Ddf
HSA
See table of non-cancer values
https://www.hsa.ie/eng/publications and forms/publications/c
in HAWC
hemical and hazardous substances/chemical agents and carci
nogens code of practice 2021.html
IDEM
See table of non-cancer values
in HAWC
https://www.in.gov/idem/toxic/2343.htm
ID DEQ
24-h acceptable ambient
concentrations for cobalt
(0.0025 mg/m3), cobalt
carbonyl, and cobalt
hydrocarbonyl (0.005 mg/m3)
https://adminrules.idaho.gov/rules/current/58/580101.pdf
IFA
See table of non-cancer values
in HAWC
https://limitvalue.ifa.dguv.de/WebForm gw2,aspx
IRIS
No values found
http://www.epa.gov/iris/
JSOH
No values found
https://www.sanei.or. ip/?mode=view&cid=328
MassDEP
No values found
https://www.mass.gov/service-details/massdep-ambient-air-
toxics-guidelines
MDH
No values found
https://www.health.state.mn.us/communities/environment/risk
/guidance/air/table, html
MlEGLE
See table of non-cancer values
https://www.michigan.gov/documents/dea/dea-rrd-chem-
in HAWC
CleanupCriteri pdf
NATICH
Compendium of state values
based on prior occupational
exposure limits, last updated in
1993
https://nepis.epa.gov/Exe/ZyPDF.cgi/2000NS7S. PDF?Dockey=200
0NS7S.PDF
NC DEQ
No values found
https://files.nc.gov/ncdea/Air%20Quality/rules/rules/D1104.pdf
NDEP
See table of non-cancer values
https://ndep.nv.gov/resources/risk-assessment-and-toxicology-
in HAWC and Table B-2
basic-comparison-levels
NIOSH
See table of non-cancer values
in HAWC
http://www.cdc.gov/niosh/npg/npgdcas.html
https://www.cdc.gov/niosh/pubs/criteria date desc nopubnum
bers.html
https://www.cdc.gov/niosh/idlh/intridl4.html
NYSDEC
No values found
https://www.dec.ny.gov/docs/remediation hudson pdf/techsup
pdoc.pdf
OAQPS
No unique results
https://www.epa.gov/fera/dose-response-assessment-assessing-
health-risks-associated-exposure-hazardous-air-pollutants
This document is a draft for review purposes only and does not constitute Agency policy.
B-2 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Source
Search Results
Query and/or link
OEHHA
See table of non-cancer values
in HAWC and Table B-2
http://www.oehha.ca.gov/tcdb/index.asp
https://oehha.ca.gov/air
Ontario MOL
See table of non-cancer values
https://www.labour.gov.on.ca/english/hs/pubs/oel table.php
in HAWC
ORDEQ
See table of non-cancer values
in HAWC
https://www.oregon.gov/deq/FilterDocs/airtox-abc.pdf
OS HA
See table of non-cancer values
in HAWC
https://www.osha.gov/chemicaldata/
PAC
Database
See table of non-cancer values
in HAWC
https://edms.energy.gov/pac/Search
PPRTV
See table of non-cancer values
https://www.epa.gov/pprtv/provisional-peer-reviewed-toxicity-
in HAWC and Table B-2
Publications
Quebec
See table of non-cancer values
in HAWC
http://legisquebec.gouv.qc.ca/en/showdoc/cr/S-
2.1,%20r,%2013?csi scan 9222d36c6a354dc6=BO9xyrMZ+270U
P3iOMGuODOkZjgFAAAAXrM3HA==&bcsi scan filename=S-
2.l,%20r.%2013&bcsi scan 3222d36c6a3S4dc6=KXzmpPueuN0L
lAjnJOBlZerr85YMAAAAyhrPTg==&bcsi scan filename=S-
20r.%2013
Rl DEM
See table of non-cancer values
http://www.dem.ri.gov/programs/benviron/air/pdf/airtoxgl.pdf
in HAWC
RIVM
No values found
https://www.rivm.nl/bibliotheek/rapporten/711701092.pdf
https://www.rivm.nl/bibliotheek/rapporten/609021044.pdf
See table of non-cancer values
https://www.rivm.nl/bibliotheek/rapporten/711701025.pdf
in HAWC
Safe Work
Australia
See table of non-cancer values
in HAWC
https://www.safeworkaustralia.gov.au/exposure-
standards#exposure-standards-in-australia
SWCAA
24-h acceptable source impact
levels for cobalt metal
(0.00017 mg/m3), cobalt
carbonyl, and cobalt
hydrocarbonyl (0.00033
mg/m3)
http://www.swcleanair.org
TCEQ
See table of non-cancer values
in HAWC and Table B-2
https://www.tcea.texas.gov/toxicology/dsd/final
https://www.tcea.texas.gov/remediation/trrp/trrppcls.html
USAPHC
Critical, marginal, and
negligible military exposure
guidelines based on other
agencies' values
https://phc.amedd.army.miI/topics/envirohealth/hrasm/Pages/T
G230,aspx
VT DEC
See table of non-cancer values
in HAWC
https://dec.vermont.gov/sites/dec/files/aac/laws-
regs/documents/AQCD%20Regulations%20ADOPTED Decl3201
8,pdf#page=127
This document is a draft for review purposes only and does not constitute Agency policy.
B-3 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Source
Search Results
Query and/or link
WA State
Dept. of
Ecology
24-h acceptable source impact
level of 0.0001 mg/m3
Iittpsi//apps,Ieg,wa,gow/WAC/defauIt,aspx?cite=173-460-lS0
Worksafe
See table of non-cancer values
https://worksafe.govt.nz/topic-and-industrv/work-related-
in HAWC
health/monitoring/exposure-standards-and-biologica (-exposure-
indices/
ACGIH = American Conference of Governmental Industrial Hygienists; AEGL = Acute Exposure Guideline Levels;
AIHA = American Industrial Hygiene Association; ATSDR = Agency for Toxic Substances and Disease Registry; BEI =
biological exposure index; CT DEEP = Connecticut Department of Energy & Environmental Protection; DFG =
Deutsche Forschungsgemeinschaft, German Research Foundation; EPA = Environmental Protection Agency; ERPG
= Emergency Response Planning Guideline; HSA = Health and Safety Authority; IDEM = Indiana Department of
Environmental Management; ID DEQ= Idaho Department of Environmental Quality; I FA = Institutfur
Arbeitsschutz, The Institute for Occupational Safety and Health; IRIS = Integrated Risk Information System; JSOH =
Japan Society for Occupational Health; MassDEP = Massachusetts Department of Environmental Protection; MDH
= Minnesota Department of Health; Ml EGLE = Michigan Environment, Great Lakes & Energy; MOL = Ministry of
Labour; NATICH = National Air Toxics Information Clearinghouse; NC DEQ = North Carolina Department of
Environmental Quality; NDEP = Nevada Division of Environmental Protection; NIOSH = National Institute for
Occupational Safety and Health; NRC = National Research Council; NYSDEC = New York State Department of
Environmental Conservation; OAQPS = Office of Air Quality Planning and Standards; OEHHA = California Office of
Environmental Health Hazard Assessment; OR DEQ = Oregon Department of Environmental Quality; OSHA =
Occupational Safety and Health Administration; PAC = Protective Action Criteria; PPRTV = Provisional Peer-
Reviewed Toxicity Value; Rl DEM = Rhode Island Department of Environmental Management; RIVM =
Rijksinstituut voor Volksgezondheid en Milieu, The Netherlands Institute for Public Health and the Environment;
SWCAA = Southwest Clean Air Association; TCEQ = Texas Commission on Environmental Quality; TERA -
Toxicology Excellence for Risk Assessment; TLV = threshold limit value; USAPHC = United States Army Public
Health Center; VT DEC = Vermont Department of Environmental Conservation; WEEL = Workplace Environmental
Exposure Level.
This document is a draft for review purposes only and does not constitute Agency policy.
B-4 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
B.2. SUMMARY OF EXISTING TOXICITY VALUES
1 A summary of inhalation reference values and cancer risk ranges is presented in Figure B-l.
2 Details on the derivation of the inhalation cancer toxicity values are presented in Table B-2. Details
3 on the available non-cancer values displayed in Figure B-l can be found in HAWC. see "Non-cancer
4 reference values for inhalation exposure to cobalt and compounds" under "Attachments."
This document is a draft for review purposes only and does not constitute Agency policy.
B-5 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Cobalt Inhalation Reference Values and Cancer Risk Estimates
February 2022
10,000.0
1,000.0
100.0
10.0
1.0
0.1
0.01
0.001
0.0001
0.00001
0.000001
0.0000001
0.00000001
£
O)
E,
6
E
o
o
ACUTE
Short Term
0)
>
n
a
~ PAC-3 CoC03
PAC-3 Co(N03)2 x 6 H20
"N. /v- PAC-2 C0CO3
PAC-3 Co(N03)2
- PAC-3 CoBr2 PAC.3 Cob|2
NIOSH IDLH* r PAC-3 CoO
Jk- PAC-3 CO3O4
¦!— paC-3 Co
- PAC-2 CoCI, -W- PAC-3 CBCo20B
PAC-2 CofNOsfcAL PAC-2 CofNOjkx 6H20
HAC-2 CoBr2 p*p 9 p ^
PAC-2 CoO -4R- "AC-2 C03O4
PAC-2 C8Co208/^'~ ERPG-3 C4CoO,
~ PAC-2 Co -'&¦ C4Co04
PAC-1 Co(N03)2 x 6 H20
PAC-1 CsCOzOs <"> PAC-1 C4CoO„
PAC-1 Co(N03)2* PAC-1 CoBr2
PAC-1 C0CO3 Z PAC-1 Co 0> I
PAC-1 C03O; -T- PAC-1 CoCI2 O —4
PAC-1 CoO ^ |
ra ACGIH-TLV (TWA)* inorganic Co
Subchronic
Chronic
OSHA-PEL Cal/OSHA-PEL (TWA)*
(TWA)* C8Co208 & C4C0O4
NIOSH-REL (TWA)*
C8Co208 & C4C0O4
ACGIH-TLV (TWA)*
C8Co208 & C4C0O4
| Avg. of Other State Values^.
TX-ReV (1 hr)
-0
NIOSH-REL (TWA)* inorganic Co |
Cal/OSHA-PEL (TWA)* inorganic Co
I
OEHHA Cancer Range soluble Cov
RIVM TCA
TX-ReV (24 hr)
| Avg. of Other State Values ] t
ATSDR-MRL (> 1yr)
PPRTV p-RfC (Subchronic)
TX-ReV (Chronic)
Tf"
PPRTV p-RfC (Chronic)
TCEQ Cancer Range
| Avg. of Other State Values |— ~
PPRTV Cancer Range
OEHHA Cancer Range insoluble Co
r|
ERPG-3
ERPG-2
PAC-3
PAC-2
PAC-1
NIOSH IDLH*
NIOSH-REL (TWA)*
ACGIH-TLV (TWA)*
OSHA-PEL (TWA)*
Cal/OSHA-PEL (TWA)*
TX-ReV (1 hr)
TX-ReV (24 hr)
- TX-ReV (Chronic)
ATSDR-MRL (> 1yr)
- PPRTV p-RfC (Subchronic)
- PPRTV p-RfC (Chronic)
- RIVM TCA
Avg. of Other State Values
PPRTV Cancer Range
TCEQ Cancer Range
OEHHA Cancer Range insoluble Co
OEHHA Cancer Range soluble Co
O <"
c £
® Q
2 a
® VI
F ®
IN K
<0
a
D
O
o
O
n
3
Q-
~tc
i—
a?
c
<13
o
10 100 1,000
Duration (hours)
10,000 100,000 1,000,000
Indicates an occupational value; expert judgement necessary prior to applying these values to the general public.
Figure B-l. Available noncancer and cancer toxicity values for inhalation exposure to cobalt.
This document is a draft for review purposes only and does not constitute Agency policy,
B-6 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Table B-2. Details on the derivation of existing inhalation cancer toxicity values for cobalt and cobalt compounds
Toxicity
Cobalt Form(s)
Toxicity
Health Effect
Point of
Qualifier
Source
Notes on
Review
Value Name
Value
Departure
Derivation
Status
NDEP BCL
Cobalt
3.12 x 10"7
Cancer
9 (mg/m3)1
PPRTV IUR
U.S. EPA
Calculated3
Final
mg/m3
(2008)
NDEP
(2017)
PPRTV IUR
Soluble cobalt
9 (mg/m3)1
Alveolar/bronchiolar
0.3 mg/m3
NOAEL
Bucheret
Duration
Provisional
sulfate
adenomas and
al. (19991
adjusted,
U.S. EPA
hexahydrate,
carcinomas in female
0.012 mg Co/m3
NOAELadj
and NIP
MW adjustment15
(2008)
applied to
rats exposed to cobalt
(1998)
additional
sulfate hexahydrate
0.0095 mg Co/m3
NOAELhec
HEC adjusted0
compounds
0.011 mg Co/m3
BMDL
OEHHAIUR
Cobalt metal and
7.7
Alveolar/bronchiolar
1.25 mg/m3
NOAEL
NIP(2014)
Duration
Final
water-insoluble
(mg/m3)1
adenomas and
adjusted:
OEHHA
compounds
carcinomas in male
0.23 mg/m3
NOAELadj
(6.2-h/24-h) x
(2020)
mice exposed to
(5-d/7-d)
cobalt metal
0.26 mg/kg-d
ADD
ADD adjustedd
0.01122 mg/kg-d
BMDLos
CSFa = 0.05 -f
4.46 (mg/kg-d)1
CS Fa
BMDLos
27 (mg/kg-d)1
CSFh
CSFh calculated6
IUR calculated'
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Toxicity
Value Name
Cobalt Form(s)
Toxicity
Value
Health Effect
Point of
Departure
Qualifier
Source
Notes on
Derivation
Review
Status
Water-soluble
cobalt compounds
0.86
(mg/m3)1
Lung and adrenal
tumors in female rats
exposed to
aerosolized cobalt
sulfate
0.01504 mg/kg-d
3.32 (mg/kg-d)1
13.41 (mg/kg-d)1
3.0 (mg Co/kg-d)1
BMDLos
CS Fa
CSFh
MW-adjusted
CSF
NIP (1998)
CSFa = 0.05 -f
BMDLos
CSFh calculated8
MW adjustedh
III R calculated1
TCEQIUR
Cobalt compounds
6 (mg/m3)1
Alveolar/bronchiolar
adenomas and
carcinomas in female
rats exposed to cobalt
sulfate hexahydrate
0.3 mg/m3
0.012 mg Co/m3
0.0095 mg Co/m3
0.011 mg Co/m3
NOAEL
NOAELadj
NOAELhec
BMDLio
NIP (1998)
and U.S.
EPA (2008)
Duration
adjusted),
MW adjustment
HEC adjustedk
Calculated1
Final
TCEQ
(2017)
Alveolar/bronchiolar
adenomas and
carcinomas in female
rats exposed to
aerosolized cobalt
metal
1.25 mg/m3
0.223 mg/m3
0.132 mg/m3
0.108 mg/m3
LOAEL
LOAELadj
LOAELhec
BMDL
NIP(2014)
and Suli et
al. (2016)
This document is a draft for review purposes only and does not constitute Agency policy.
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Toxicity
Value Name
Cobalt Form(s)
Toxicity
Value
Health Effect
Point of
Departure
Qualifier
Source
Notes on
Derivation
Review
Status
ADD = average daily dose; ADJ = adjusted; AT = averaging time; BCL = basic comparison level; BMDL = benchmark dose level; BWa = animal body weight; BWh
= human body weight; Co = cobalt; C0SO4X 6 H2O = cobalt sulfate hexahydrate; CSFa = animal cancer slope factor; CSFh = human cancer slope factor; ED =
exposure duration; EF = exposure frequency; EPA = Environmental Protection Agency; ET = exposure time; HEC = human equivalent concentration; IR =
inhalation rate; IIIR = inhalation unit risk; LOAEL = lowest-observed-adverse-effect level; MW = molecular weight; NDEP = Nevada Division of Environmental
Protection; NOAEL = no-observed-adverse-effect level; NTP = National Toxicology Program; OEHHA = California Office of Environmental Health Hazard
Assessment; PPRTV = Provisional Peer-Reviewed Toxicity Value; RDDR = regional deposited dose ratio; TCEQ = Texas Commission on Environmental Quality;
TR = target risk; URF = unit risk factor.
a BCL = TR x AT 4 (ET x EF x ED x URF) = (106 x 70 y x 365 d/y x 24 h/d) 4 [24 h/d x 350 d/y x 26 y x 9 (nig/m3)"1] = 3.12 x 10"7 mg/m3.
b NOAELadj = NOAEL x (6 h 4 24 h) x (5 d 4 7 d) x [Co atomic mass 4 (C0SO4x 6 H20) MW] = 0.3 mg/m3 x (6-h 4 24-h) x (5-d 4 7-d) x (58.933 g/mol 4 263.08
g/mol) = 0.012 mg Co/m3.
c NOAELhec = NOAEUdj x RDDR = 0.012 mg Co/m3 x 0.79 = 0.0095 mg Co/m3.
d ADD = 0.0345 m3/d x(BWt 0.025 kg)2/3 x NOAELadj 4- BW = 0.0345 m3/d x (0.0485 kg 4 0.025 kg)2/3 x 0.23 mg/m3 4 0.0485 kg = 0.26 mg/kg-d.
e CSFh = CSFa x (BWh 4 BWa)1/4 = 4.46 (mg/kg-d)1 x (70 kg 4 0.0485 kg)1/4 = 27 (mg/kg-d)-1.
f IUR = CSFh x IR 4 BW = 27 (mg/kg-d)^x 20 m3/d 4 70 kg = 7.7 (mg/m3) ^
sCSFh = CSFa x (BWh 4 BWa)1/4 = 3.32 (mg/kg-d)1 x (70 kg 4 0.2633 kg)1/4= 13.41 (mg/kg-d)-1.
h MW-adjusted CSF = CSFh x [Co atomic mass 4 (C0SO4X 6 H2O) MW] = 13.41 (mg/kg-d)-1 x (58.9 g/mol 4 263.1 g/mol) = 3.0 (mg Co/kg-d)1.
' IIIR = CSFx IR 4 BW = 3.0 (mg Co/kg-d^x 20 m3/d 4 70 kg = 0.86 (mg Co/m3)1.
J NOAELadj = NOAEL x (6 h 4 24 h) x (5 d 4 7 d) x [Co atomic mass 4 (C0SO4x 6 HzO) MW] = 0.3 mg/m3 x (6-h 4 24-h) x (5-d 4 7-d) x (58.933 g/mol 4 263.08
g/mol) = 0.012 mg Co/m3.
k NOAELhec = NOAEUdj x RDDR = 0.012 mg Co/m3 x 0.79 = 0.0095 mg Co/m3.
LOAELhec = LOAELadj x RDDR = 0.223 mg Co/m3 x 0.592 = 0.132 mg Co/m3.
1 NTP 1998 IUR = 0.1 4 BMDLio= 0.140.011 mg/m3 =9.1 (mg/m3)"1.
NTP 2014 IUR = 0.32 4 BMDL = 0.32 4 0.108 mg/m3 = 3 (mg/m3)1.
The two derived lURs were averaged to arrive at the final value: [9.1 (mg/m3) 1+ 3 (mg/m3)"1] 4-2 = 6 mg/m3.
This document is a draft for review purposes only and does not constitute Agency policy.
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APPENDIX C. SYSTEMATIC EVIDENCE MAP
C.l. SYSTEMATIC EVIDENCE MAP (SEM) SPECIFIC AIMS
• Develop a systematic evidence map (SEM) to identify epidemiological (i.e., human) and
toxicological (i.e., experimental animal) literature that report reporting effects of inhalation
exposure to cobalt or cobalt compounds and cancer.
o The SEM includes searches for studies published since the October 2020 inhalation
'unit risk estimates' (URE) or 'inhalation unit risk' (IUR) developed by California
EPA OEHHA (2020). The SEM also includes a survey of prior assessments U.S. EPA
("20081: OEHHA C20191: OEHHA C20201: TCEO C20171: NTP C20161: ATSDR C20041
to ensure consideration of studies cited to develop cancer hazard conclusions or
develop inhalation unit risk estimates.8
• Evaluate studies that meet SEM PECO criteria to identify studies most suitable for deriving
an inhalation unit risk (IUR) for water-soluble and water-insoluble compounds of cobalt
Prioritized studies from this evaluation are those that appear at least as suitable for IUR
derivation as the NTP rodent cancer bioassays NTP (2014.1998) used in prior assessments
U.S. EPA (~2Q08"):OEHHA f20191:QEHHA f20201:TCEQ f20171.
• Conduct study evaluation (evaluating risk of bias and sensitivity) and data extraction for
prioritized epidemiological and toxicological studies.
• Identify supplemental material in the literature published since October 2020 or cited in the
prior assessments listed above that may potentially inform dose-response analysis, clarify
what is known currently about the cancer mode of action, inform conclusions on potential
susceptibility, or help elucidate key science issues. Supplemental material content includes
mechanistic in vitro, in vivo, ex vivo, or in silico studies; toxicokinetic and absorption,
distribution, metabolism, and excretion (ADME) studies; pharmacokinetic (PK) or
physiologically based pharmacokinetic (PBPK) model studies; studies using non-inhalation
route of exposure; non-mammalian model systems; exposure assessment studies with no
health outcomes reported; mixture studies; human case studies and case reports; animal
cancer studies using less than subchronic duration exposures; studies or reports with no
original data; and conference/symposium abstracts or poster presentations, and studies
assessing noncancer health outcomes. Studies considered PECO-relevant that also contain
supplemental information are tagged as such.
8 The full 2022 IARC Monograph on" Carcinogenicity of cobalt, antimony compounds, and weapons-grade
tungsten alloy" was not publicly released at the time of preparing this SEM but will be surveyed for any
missing citations when it becomes available.
This document is a draft for review purposes only and does not constitute Agency policy.
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C.2. POPULATIONS, EXPOSURES, COMPARATORS, AND OUTCOMES
(PECO) CRITERIA AND SUPPLEMENTAL MATERIAL TAGGING
1 PECO criteria are used to focus the research question(s), search terms, and
2 inclusion/exclusion criteria used in a SEM or systematic review. The SEM PECO criteria are
3 presented in Table C-l. In addition, studies containing supplemental material are inventoried
4 during the literature screening process using the categories presented in Table C-2.
This document is a draft for review purposes only and does not constitute Agency policy.
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Table C-l. Example Populations, Exposures, Comparators, and Outcomes (PECO) Criteria
Populations
Human: Any population and lifestage (occupational or general population, including in pregnant women, infants, children, adolescents and
adults).
Animal: Nonhuman mammalian animal species (whole organism) of any lifestage (including fetal, early postnatal, adolescents and adults).
Studies of transgenic animals are tracked as mechanistic studies under "potentially relevant supplemental material".
Note: Studies meeting PECO criteria may also contain information on susceptible populations. When this occurs, these studies are also tagged
as having information pertinent to susceptible populations. This typically happens during preparation of the literature inventory or full text
extraction.
Exposures
Relevant forms for Clean Air Act: cobalt aluminate (1345-16-0), cobalt bromide (7789-43-7), cobalt carbonate (513-79-1), cobalt
carbonyl (10210-68-1), cobalt chloride (7646-79-9), cobalt (7440-48-4), cobalt hydrocarbonyl (16842-03-8), cobalt naphtha (61789-51-
3), cobalt nitrate (10141-05-6), cobalt oxide (1307-96-6), cobalt oxide (II, III) (1308-06-1), andhexanoic acid, 2-ethyl-, cobalt(2+) salt
(136-52-7). Many of these compounds do not have cancer toxicity information, thus other water-soluble and water-insoluble cobalt
compounds that do have inhalation cancer evidence are included within the scope of this review, e.g., cobalt sulfate, cobalt hydroxide, and
cobalt sulfide. Radioactive isotopes (i.e., 60Co) and vitamin B12 are considered out of scope.
Human: Anv quantitative exposure to cobalt via the inhalation route, aside from acute or verv short fdavsl duration. Studies of
developmental exposure are also included. Studies will also be included if biomarkers of exposure are evaluated (e.g., measured compound
or metabolite levels in tissues or bodily fluids) and the exposure route can be inferred as primarily inhalation.
Animal: Anv quantitative exposure to cobalt via the inhalation route for anv subchronic and chronic exposure duration. Studies of
developmental exposure are also included. Studies involving exposures to mixtures will be included only if they include exposure to a
relevant form of cobalt alone. Non-inhalation routes, including oral, dermal or intravenous, are tracked as "potentially relevant
supplemental information."
Comparators
Human: Referent populations exposed to lower fwithin the studvl levels of cobalt. The results of the comparisons must be presented with
sufficient detail of quantitative modeling (e.g., regression coefficients presented with statistical measure of variation). Case reports
describing findings in 1-3 people are tagged as "potentially relevant supplemental information."
Animal: A concurrent control sroup exposed to vehicle-onlv treatment and/or untreated control.
Outcomes
Any cancer-related effect on any system.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Table C-2. Categories of Potentially Relevant Supplemental Material
Category (Tag)
Description
Typical Assessment Use
Pharmacokinetics Data Potentially Informative to Assessment Analyses
Classical pharmacokinetic (PK) or
physiologically based
pharmacokinetic (PBPK) model
studies
Classical Pharmacokinetic or Dosimetry Model Studies: Classical PK or dosimetry
modeling usually divides the body into just one or two compartments, which are not
specified by physiology, where movement of a chemical into, between, and out of
the compartments is quantified empirically by fitting model parameters to ADME
(absorption, distribution, metabolism, and excretion) data. This category is for
papers that provide detailed descriptions of PK models but are not PBPK models.
The data are typically the concentration time-course in blood or plasma after oral
and or intravenous exposure, but other exposure routes can be described.
Physiologically Based Pharmacokinetic or Mechanistic Dosimetry Model Studies:
PBPK models represent the body as various compartments (e.g., liver, lung, slowly
perfused tissue, richly perfused tissue) to quantify the movement of chemicals or
particles into and out of the body (compartments) by defined routes of exposure,
metabolism, and elimination, and thereby estimate concentrations in blood or target
tissues.
A defining characteristic is that key parameters are determined from a substance's
physicochemical parameters (e.g., particle size and distribution, octanol-water
partition coefficient) and physiological parameters (e.g., ventilation rate, tissue
volumes).
PBPK and PK model studies are included
in the assessment and evaluated for
possible use in conducting quantitative
extrapolations. PBPK/PK models are
categorized as supplemental material
with the expectation that each one will be
evaluated for applicability to address
assessment extrapolation needs and
technical conduct. Specialized expertise
is required for their evaluation.
Standard operating procedures for
PBPK/PK model evaluation and the
identification, organization, and
evaluation of ADME studies are outlined
in An umbrella Quality Assurance Project
Plan (QAPP) for PBPK models U.S. EPA
(2018).
Pharmacokinetic (ADME)
Pharmacokinetic (ADME) studies are primarily controlled experiments, where defined
exposures usually occur by intravenous, oral, inhalation, or dermal routes, and the
concentration of particles, a chemical, or its metabolites in blood or serum, other
body tissues, or excreta are then measured.
These data are used to estimate the amount absorbed (A), distributed (D),
metabolized (M), and/or excreted (E).
ADME data can also be collected from human subjects who have had environmental
or workplace exposures that are not quantified or fully defined.
ADME data, especially metabolism and tissue partition coefficient information, can
be generated using in vitro model systems. Although in vitro data may not be as
definitive as in vivo data, these studies should also be tracked as ADME. For large
evidence bases it may be appropriate to separately track the in vitro ADME studies.
ADME studies are inventoried and
prioritized for possible inclusion in an
ADME synthesis section on the chemical's
PK properties and for conducting
quantitative adjustments or
extrapolations (e.g., animal-to-human).
Specialized expertise in PK is necessary
for inventory and prioritization.
Standard operating procedures for
PBPK/PK model evaluation and the
identification, organization, and
evaluation of ADME studies are outlined
in An umbrella Quality Assurance Project
This document is a draft for review purposes only and does not constitute Agency policy.
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Category (Tag)
Description
Typical Assessment Use
*Studies describing environmental fate and transport or metabolism in bacteria or
model systems that are not applicable to humans or animals should not be tagged.
Plan (QAPP) for PBPK models U.S. EPA
(2018).
Supplemental Evidence Potentially Informative to Assessment Analyses
Mechanistic endpoints
Studies that do not meet PECO criteria but report measurements that inform the
biological or chemical events associated with phenotypic effects related to a health
outcome. Experimental design may include in vitro, in vivo (by various routes of
exposure; includes all transgenic models), ex vivo, and in silico studies in mammalian
and nonmammalian model systems. Studies using New Approach Methodologies
(NAMs, e.g., in vitro high throughput testing strategies, read across applications) are
also categorized here. Studies where the chemical is used as a laboratory reagent
(e.g., as a chemical probe used to measure antibody response) generally should not
be tagged.
Mechanistic evidence can also help identify factors contributing to susceptibility;
these studies should also be tagged "susceptible populations."
[Notes: During screening, especially at the title and abstract (TIAB) level, it may not
be readily apparent for studies that meet P, E, and C criteria if the endpoint(s) in a
study are best classified as phenotypic or mechanistic with respect to the 0 criteria. In
these cases, the study should be screened as "unclear" during TIAB screening, and a
determination made based on full-text review (in consultation with a content expert
as needed). Full-text retrieval is performed for studies of transgenic model systems
that meet E and C criteria to determine if they include phenotypic information in
wildtype animals that meet P and 0 criteria that is not reported in the abstract.]
Prioritized studies of mechanistic
endpoints are described in the
mechanistic synthesis sections; subsets of
the most informative studies may become
part of the units of analysis. Mechanistic
evidence can provide support for the
relevance of animal effects to humans
and biological plausibility for evidence
integration judgments (including MOA
analyses, e.g., using the MOA framework
in the US EPA Cancer Guidelines 2005a)).
Non-PECO animal model
Studies that report outcomes in animal models that meet the outcome criteria but do
not meet the population criteria in the PECO.
Depending on the endpoints measured in these studies, they can also provide
mechanistic information (in these cases studies should also be tagged "mechanistic
endpoints").
This categorization generally does not apply to studies that use species with limited
human health relevance (e.g., ecotoxicity-focused studies are typically excluded).
Studies of non-PECO animals, exposures,
or durations can be summarized to inform
evaluations of consistency (e.g., across
species or routes or durations),
coherence, or adversity; subsets of the
most informative studies may be included
in the unit of analysis. These studies may
also be used to inform evidence
integration judgments of biological
plausibility and/or MOA analyses and thus
Non-PECO route of exposure
Epidemiological or animal studies that use a non-PECO route of exposure, e.g.,
injection studies or dermal studies if the dermal route is not part of the exposure
criteria.
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Category (Tag)
Description
Typical Assessment Use
This categorization generally does not apply to epidemiological studies where the
exposure route is unclear; such studies are considered to meet PECO criteria if the
relevant route(s) of exposure are plausible, with exposure being more thoroughly
evaluated at later steps.
may be summarized as part of the
mechanistic evidence synthesis.
Acute or short-term duration
exposures
Given the focus on cancer, acute exposure durations (defined as animal studies of
<1 d) or short-term (defined as animal studies of <90 d/13 weeks) are considered
supplemental.
Susceptible populations
Studies that help to identify potentially susceptible subgroups, including studies on
the influence of intrinsic factors such as sex, lifestage, or genotype to toxicity, as well
as some other factors (e.g., health status). These are often co-tagged with other
supplemental material categories, such as mechanistic or ADME. Studies meeting
PECO criteria that also address susceptibility should be co-tagged as supplemental.
*Susceptibility based on most extrinsic factors, such as increased risk for exposure due
to residential proximity to exposure sources, is not considered an indicator of
susceptible populations for the purposes of IRIS assessments.
Provides information on factors that
might predispose sensitive populations or
lifestages to a higher risk of adverse
health effects following exposure to the
chemical. This information is summarized
during evidence integration for each
health effect and is considered during
dose-response, where it can directly
impact modeling decisions.
Background Information Potentially Useful to Problem Formulation and Protocol Development
(These studies fall outside the scope of IRIS assessment analyses)
Human exposure and
biomonitoring (no health
outcome)
Information regarding exposure monitoring methods and reporting that are
unrelated to health outcomes, but which provide information on the following:
methods for measuring human exposure, biomonitoring (e.g., detection of chemical
in blood, urine, hair), defining exposure sources, or modeled estimates of exposure
(e.g., in occupational settings). Studies that compare exposure levels to a reference
value, risk threshold or assessment points of departure are also included in this
category. Studies related to environmental fate and transport are typically tagged as
background materials unless otherwise described in the assessment-specific
protocol.
* Assessment teams may want to subtag studies that describe or predict exposure
levels versus those that present exposure assessment methods.
This information may be useful for
developing exposure criteria for study
evaluation or refining problem
formulation decisions.
Notably, providing an assessment of
typical human exposures (e.g., sources,
levels) falls outside the scope of an IRIS
assessment.
Mixture study
Mixture studies use methods that do not allow investigation of the health effects of
exposure to the chemical of interest by itself (e.g., animal studies that lack exposure
Mixture studies are tracked to help
inform cumulative risk analyses, which
may provide useful context for risk
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Category (Tag)
Description
Typical Assessment Use
to chemical of interest alone or epidemiology studies that do not evaluate
associations of the chemical of interest with relevant health outcome(s)).
* Methods used to assess investigation of the exposure by itself may not be clear
from the abstract, in particular for epidemiology studies. When unclear, the study is
advanced to full-text review to determine eligibility.
assessment but fall outside the scope of
an IRIS assessment.
Case reports or case series
Human studies that present an investigation of a single exposed individual or group
of < 3 subjects that describe health outcomes after exposure but lack a comparison
group (i.e., do not meet the "C" in the PECO) and typically do not include reliable
exposure estimates.
Tracking case studies can facilitate
awareness of potential human health
issues missed by other types of studies
during problem formulation.
Noncancer health outcomes
Studies assessing noncancer health outcomes.
Out of scope for the assessment but
tracked to facilitate any assessment work
conducted by others in understanding
potential non-cancer health publication
trends.
Reference Materials
Records with no original data
Records that do not contain original data, such as other agency assessments,
informative scientific literature reviews, editorials, or commentaries.
Studies that are tracked for potential use
in identifying missing studies, background
information, or current scientific opinions
(e.g., hypothesized MOAs).
Posters or conference abstracts
Records that do not contain sufficient documentation to support study evaluation
and data extraction.
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C.3. METHODS: LITERATURE SEARCH STRATEGIES
C.3.1.Database Search Term Development
The literature search focused on the chemical name (and synonyms, trade names, and
metabolites/degradants of interest) and was date limited to studies published after 2019
(Addendum 1). The literature search was completed on December 16, 2021. This date was selected
to cover new studies published since the 2020 CalEPA cobalt assessment OEHHA (20201. which is
the most recent US Federal or State assessment conducted. No language restrictions were applied.
Chemical synonyms were identified by using the "Find Chemical Synonyms" feature in SWIFT
(Sciome Workbench for Interactive computer-Facilitated Text-mining) Review Howard et al.
(20161. In brief, this feature automatically creates a PubMed-formatted chemical search using
(1) the common name for the chemical as presented in the Tox21 chemical inventory list U.S. EPA
(2020dl: (2) the Chemical Abstract Services Registry Number (CASRN); (3) synonyms from the
ChemlDPlus database, which currently contains chemical names and synonyms for over 400,000
chemicals; and (4) removal of ambiguous or short alphanumeric terms that could lead to false
positives. This search is manually reviewed to ensure that any synonyms listed in EPA's Dashboard
U.S. EPA (20211 as "valid" or "good" are included. The PubMed search created from SWIFT Review,
along with additional synonyms identified from EPA's Dashboard, is shared with EPA information
specialists to develop search strategies tailored for each of the databases below, as each database
has its own search architecture. Full details of the search strategy for each database are presented
in the Addendum 1.
C.3.2.Database Searches
The databases listed below are searched by an EPA information specialist Retrieved
references are imported into the EPA's Health and Environmental Research Online (HERO)
database and undergo a round of deduplication in HERO9.
• Web of Science (Thomson Reuters)
• PubMed (National Library of Medicine)
The literature search is updated throughout SEM development. In addition to the databases
listed below, a variety of other resources are subsequently searched using customized processes
(see "Other Resources"). One process described in "Other Resources" is to review prior
9 Deduplication in HERO involves first determining whether a matching unique ID exists (e.g., PMID, WoSID,
or DOI). If one matches one that already exists in HERO, HERO will tag the existing reference instead of
adding the reference again. Second, HERO checks if the same journal, volume, issue and page number are
already in HERO. Third, HERO matches on the title, year, and first author. Title comparisons ignore
punctuation and case
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assessments of cobalt carcinogenicity to identify studies meeting the current SEM PECO criteria
that would have been missed by the date limited database search described above.
The unique studies are imported into SWIFT Review software Howard et al. f20161 to
identify those references most likely to be applicable to a human health risk assessment In brief,
SWIFT Review has pre-set literature search strategies ("filters") developed by information
specialists that can be applied to identify studies that are more likely to be useful for identifying
human health content from those that likely do not (e.g., environmental fate). The filters function
like a typical search strategy where studies are tagged as belonging to a certain filter if the terms in
the filter literature search strategy appear in title, abstract, keyword or Medical Subject Headings
[MeSH) fields content The details of the search strategies that underlie the filters are available
online. For this SEM, filters for human, animal (human health models) and in vitro evidence were
used. Studies not retrieved using the search strategies are not considered further. Studies that
include one or more of the search terms in the title, abstract, keyword, or MeSH fields are exported
as a Research information Systems (RIS) file for uploading into the screening software as described
below in "Screening Process." Application of the SWIFT Review evidence stream filters to the initial
search results (12/16/2021) reduced the number of studies for title and abstract screening from
29,833 to 4,589.
C.3.3.Searching Other Resources
The literature search strategies described above are designed to be broad, but like any
search strategy, studies may be missed (e.g., cases where the specific chemical is not mentioned in
title, abstract, or keyword content; ability to capture "gray" literature that is not indexed in the
databases listed above). Thus, in addition to the database searches, the sources below are used to
identify studies that may have been missed based on the database search. References that appear to
meet the PECO criteria are uploaded into the screening software, annotated with respect to source
of the record, and screened according to PECO as described below. Searching of these sources is
summarized to include the source type or name, the search string (when applicable), the URL
(when available and applicable), number of results, and number of unique references not otherwise
identified from database searching (Addendum 2).
• For studies screened as 'included' based on full text review, manual review of the citation
list of each study was then conducted at the title and abstract level.
• Review of the reference list from final or publicly available draft or finalized assessments
(e.g., EPA IRIS [Integrated Risk Information System], EPA PPRTV [Provisional Peer
Reviewed Toxicity], ATSDR [Agency for Toxic Substances and Disease Registry]
Toxicological Profile, NTP [National Toxicology Program], California EPA, TCEQ [Texas
Commission on Environmental Quality], IARC [International Agency for Research on
Cancer]). Assessments are identified from the database search, the resources listed in
Appendix B, or from the EPA CompTox Chemicals Dashboard ToxVal database U.S. EPA
(20211. Citation review of these materials is focused on the most pertinent section, i.e.,
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presentation of the human health literature, focusing on primary data studies pertinent to
cancer.
• European Chemicals Agency (ECHA) registration dossiers to identify data submitted by
registrants fattoi //echa.europa.eu/information-on-chemicals /information-from-existing-
substances-regulation.
• EPA ChemView database U.S. EPA (20191 to identify unpublished studies, information
submitted to EPA under Toxic Substances Control Act (TSCA) Section 4 (chemical testing
results), Section 8(d) (health and safety studies), Section 8(e) (substantial risk of injury to
health or the environment notices), and FYI (For Your Information, voluntary documents).
Other databases accessible via ChemView include EPA's High Production Volume (HPV)
Challenge database (https://iaspub.epa.gov/oppthpv/public_search.html_page) and the
Toxic Release Inventory database.
• National Toxicology Program (NTP) Chemical Effects in Biological Systems (CEBS) database
of study results and research projects.
• The Organisation for Economic Cooperation and Development (OECD) eChemPortal to
retrieve results for OECD Screening Information DataSet (SIDS) and High Production
Volume (HPV) Chemicals (https://www.echemportal.org/echemportal/).
• References identified by technical consultants, during peer-review, and during public
comment periods (when applicable).
C.3.4.Non-Peer-Reviewed Data
IRIS assessments rely mainly on publicly accessible, peer-reviewed studies. However, it is
possible that unpublished data directly relevant to the PECO may be identified during assessment
development In these instances, the EPA will try to get permission to make the data publicly
available (e.g., in HERO); data that cannot be made publicly available are not used in IRIS
assessments. In addition, on rare occasions where unpublished data would be used to support key
assessment decisions (e.g., deriving a toxicity value), EPA may obtain external peer review if the
owners of the data are willing to have the study details and results made publicly accessible, or if an
unpublished report is publicly accessible (or submitted to EPA in a non-confidential manner) U.S.
EPA (20151. This independent, contractor driven, peer review would include an evaluation of the
study similar to that for peer review of a journal publication. The contractor would identify and
select at least three scientists knowledgeable in scientific disciplines relevant to the topic as
potential peer reviewers. Persons invited to serve as peer reviewers would be screened for conflict
of interest In most instances, the peer review would be conducted by letter review. The study and
its related information, if used in the IRIS assessment, would become publicly available. In the
assessment, EPA would acknowledge that the document underwent external peer review managed
by the EPA, and the names of the peer reviewers would be identified. In certain cases, IRIS will
assess the utility of a data analysis of accessible raw data (with descriptive methods) that has
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undergone rigorous quality assurance/quality control review (e.g., ToxCast/Tox21 data, results of
NTP studies not yet published) but that have not yet undergone external peer review.
Unpublished data from personal author communication can supplement a peer-reviewed
study as long as the information is made publicly available. If such ancillary information is acquired,
it will be documented in the Health Assessment Workspace Collaborative (HAWC,
https://hawcprd.epa.gOv/l or HERO project page (depending on the nature of the information
received). HAWC is a web-based software application designed to manage and facilitate the
process of conducting health assessments.
C.4. METHODS: LITERATURE SCREENING PROCESSES
CA.l.Title/Abstract and Full Text Screening
The studies identified from the database searches and application of SWIFT Review filters
are imported into SWIFT-Active Screener (https://www.sciome.eom/swift~activescreener/l for
title and abstract (TIAB) screening. SWIFT-Active Screener is a web-based collaborative software
application that utilizes active machine learning approaches to reduce the screening effort Howard
et al. [20201. TIAB screening is conducted by two independent reviewers and any screening
conflicts are resolved by discussion between the primary screeners with consultation by a third
reviewer, if needed. For citations with no abstract, articles are initially screened based on the
following: title relevance (title should indicate clear relevance), and page length (articles two pages
in length or less are assumed to be conference reports, editorials, or letters). Eligibility status of
non-English studies is assessed using the same approach with online translation tools or
engagement with a native speaker.
The machine learning screening process is designed to prioritize references that appear to
meet PECO-criteria or supplemental material content for manual review (i.e., both types of
references are screened as "include" for machine learning purposes). Screening continues until
SWIFT-Active Screener indicates that it was likely at least 95% of the relevant studies are
identified, a percent identification often used to evaluate the performance of machine learning
applications and considered comparable to human error rates Bannach-Brown et al.
f2Q181:Howard et al. f20161:Cohen etal. (20061. Any studies with "partially screened" status at the
time of reaching the 95% threshold are then fully screened. Studies identified as meeting PECO
criteria "unclear" or supplemental material during TIAB screening in SWIFT-Active Screener are
then imported into DistillerSR software fhttos://www.evidencepartners.com/products/distillersr-
svstematic-review-software /1. In DistillerSR, these studies underwent another round of TIAB
screening to separate PECO-relevant studies from studies containing only supplemental material.
The utility of studies classified as "unclear" was determined. Studies that met PECO or a specific
type of supplemental content were tagged accordingly and added to the evidence stream.
In DistillerSR, both TIAB and full-text screening is conducted by two independent reviewers
and any screening conflicts resolved by discussion between the primary screeners with
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consultation by a third reviewer, if needed. Conflicts between screeners in applying the
supplemental tags, which primarily occur at the TIAB level, are resolved by similarly, erring on the
side of over-tagging based on TIAB content. Full-text references are sought through the EPA's HERO
database for studies screened as meeting PECO criteria or "unclear" based on the TIAB screening.
References that are not able to be procured within 45 days of attempt are determined to be
unavailable.
The screening decisions are then imported into HAWC's Literature Review Module, where
the screening and tagging results are visualized in interactive literature tag trees where additional
tagging can be conducted, e.g., more details on the nature of mechanistic or ADME studies.
C.4.2.SuppIementaI Material Tagging
Supplemental material records (Table C-2) can be identified at either the TIAB or full-text
levels. Conflicts between screeners in applying the supplemental material tags are resolved by
discussion and consultation with a third reviewer (as needed), erring on the side of over-including
at the TIAB level when the article content is relatively unclear.
It is important to emphasize that articles tagged as supplemental material are not
necessarily excluded from consideration in an assessment. The tagging structure is designed to
ensure that supplemental material studies are categorized for easy retrieval while conducting the
assessment Studies that meet the PECO criteria are those most likely to be used to derive toxicity
values and thus will undergo subsequent individual study evaluation and data extraction. In
contrast, the impact on the assessment conclusions of individual studies tagged as supplemental
material is often difficult to assess during the screening phase of the assessment These studies
could emerge as being critically important to the assessment and need to be evaluated and
summarized at the individual study level (e.g., cancer MOA or ADME studies). Supplemental
materials might be helpful to provide context (e.g., summarize current levels of exposure, provide
hazard evidence from routes or durations of exposure not pertinent to the PECO) or they might not
be cited by the assessment (e.g., individual studies that contribute to a well-established scientific
conclusion). The tagging inventory is intended to inform a systematic identification of key science
issues and refine the assessment evaluation plan (i.e., approach for analysis of mechanistic and
ADME/PK/PBPK content, or consideration of susceptible populations). When tagged during title
and abstract screening, it may not be clear whether the chemical of interest is reported in the study
(i.e., abstracts might not describe all chemicals investigated). In such cases, studies are still tagged
with the expectation that additional screening would clarify if the studies are considered pertinent
to address the specific aims of the assessment
C.4.3.Multiple Publications of the Same Data
When there are multiple publications using the same or overlapping data, all publications
will be included, with one selected for use as the primary study; the others will be considered as
secondary publications with annotation in HAWC indicating their relationship to the primary
record during data extraction. For epidemiology studies, the primary publication is most often the
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one with the longest follow-up, the largest number of cases, or a factor relevant to study evaluation.
For animal studies, the primary publication will typically be the one with the longest duration of
exposure, or with the outcome(s) most informative to the PECO. For both epidemiology and animal
studies, the assessments will include relevant data from all publications of the study, although if the
same data are reported in more than one study, the data will only be extracted once. For
corrections, retractions, and other companion documents to the included publications, a similar
approach to annotation is taken and the most recently published data are incorporated in the
assessments.
C.4.4.Literature Flow Diagrams
The results of the screening process are posted on the project page for the assessment in
the HERO database fhttps://heronetepa.gov/heronet/index.cfm/proiect/page/project id/14781.
Results are also summarized in a literature study flow diagram and interactive HAWC literature
trees (where additional tagging can be documented and visualized, e.g., more details on the nature
of mechanistic or ADME studies).
C.5. METHODS: LITERATURE INVENTORY PREPARATION
During title/abstract or full-text level screening in DistillerSR, studies that meet SEM PECO
criteria or a category of supplemental information are categorized based on evidence type (human,
animal, mechanistic, PBPK, etc.). Next, study design details for studies that meet SEM PECO criteria
are summarized and a more granular tagging of supplemental material is conducted as described
below. The results of this tagging are referred to as a literature inventory.
C.S.l.Studies That Meet SEM PECO Criteria
Human and animal studies that met SEM PECO criteria after full-text review are briefly
summarized in tabular format Summaries are done by one team member and quality checked by at
least one other team member. For non-English studies online translation tools (e.g., Google
translator) or engagement with a native speaker can be used to summarize studies at the level of
the SEM literature inventory. Fee-based translation services for non-English studies are typically
reserved for studies considered potentially informative for dose response, a consideration that
typically occurs subsequent to the SEM during preparation of the draft assessment
Assessing Suitability for Dose-Response Based on Study Design Considerations
The studies that meet SEM PECO criteria are evaluated with respect to the considerations
below to identify studies that may be suitable for developing an IUR.
• Studies with chronic exposure durations or including exposure during reproduction or
development, are prioritized over studies with shorter-term exposure durations.
• Animal studies using a species that is considered a relevant human surrogate.
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• Studies with a broad exposure range and multiple exposure levels are preferred to the
extent that they can provide information about the shape of the exposure-response
relationship [see the EPA Benchmark Dose Technical Guidance, §2.1.1 U.S. EPA (2012b)]
and facilitate extrapolation to more relevant (generally lower) exposures.
• For human studies, studies for which quantitative exposure measurements were available
and exposure-response results are presented in sufficient detail (e.g., standardized
mortality rate or relative risks, numbers of cases/controls, etc) are prioritized. Studies
based exclusively on duration of exposure analyses (i.e., longer versus shorter exposure
duration) are typically not considered suitable for dose response unless additional
information on exposure can be incorporated.
• For epidemiological studies, studies that used biomarker measurements in tissues or bodily
fluids as the metric for exposure were only considered suitable for dose-response analysis if
data or PBPK models are available to extrapolate between the reported biomarker
measurement and the level of exposure.
• For both animal and human studies, whether the nature of the outcomes/endpoints
assessed were interpretable with respect to potential adversity, was considered. Typically,
apical or clinical measures ("phenotypic") are preferred over other endpoints for dose
response. However, "mechanistic" endpoints can be useful in dose-response analyses when
they can be reasonably established as predictive of, or strongly associated with, phenotypic
outcomes interpreted as adverse.
• High or medium confidence studies are highly preferred over low confidence studies (see
"Study Evaluation" below).
In addition to the broad criteria presented above, attributes of animal studies that met the
SEM PECO criteria are compared to the NTP inhalation cancer bioassays for soluble and insoluble
cobalt compounds NTP f2014.1998) used by prior assessments to develop cancer inhalation unit
risk values OEHHA f2Q2Q. 2019: TCEO f2017: U.S. EPA [20081 Only studies considered to be
comparable to (or an improvement over) the NTP studies will be considered for dose-response. Key
study attributes of the NTP studies are presented in (Table C-3).
Table C-3. Preferred design features of animal dose-response studies of
inhalation exposures to cobalt compounds.
Attribute
Preferred design feature
Rationale
Exposure duration
At least 2 years
Tumors in NTP (2014,1998) were late-onset. Prefer chronic
exposures to observe tumors.
Exposure design
Cyclical daily or workweek
exposure
Prefer studies to inform chronic continuous exposure. NTP (2014,
1998) exposed animals for 6 hours/day, 5 days/week.
Measurement of
exposure
Measures of particle size
(i.e., MMAD). Analytical
validation of chamber air
concentration
Particle size information is necessary for inhalation dosimetry, dose-
response modeling, and human extrapolation. Analytical validations
should be comparable to NTP protocols.
Number of
exposure groups
At least 3 (excluding
controls)
NTP {2014,1998) utilized 3 groups.
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Attribute
Preferred design feature
Rationale
Animal sex
Both male and female
NTP (2014.1998) utilized both sexes.
Animal
species/strain
A species that is a relevant
or reliable human surrogate
NTP (2014.1998) utilized F344 rats and B6C3F, mice.
Number of
animals/groups
At least 50
NTP (2014,1998) utilized 50 animals per group.
Dose range
At least two concentration
groups below 5 mg Co/m3
5 mg/m3 is the highest concentration group in the NTP (2014) study
of insoluble cobalt metal. Tumor incidences were high at this
concentration. Data at lower levels (which are more environmentally
relevant and near the modeled benchmark response rate) are
preferred.
Measurement of
health outcome
Tumor incidence per group,
with adenomas/carcinomas
listed separately.
NTP (2014,1998) reports tumor incidence per group, with adenoma
and carcinomas presented separately.
Individual-level
data
Individual-level animal
tumor and survival data.
NTP (2,014,1998) provides individual-level data and poly-3 survival
statistic. Individual-level data are needed for time-to-tumor
modeling. NTP also reported changes in survival rate as a function of
concentration and time.
Study evaluation
Tumor data considered
medium or high confidence
Both NTP reports NTP f1998): NTP C2014) were considered hiah
confidence
(https://hawc.epa.gov/summary/visual/assessment/100500295/NTP-
Cancer-Bioassays/)
Study Evaluation
Epidemiological or animal studies that are prioritized from the analysis of suitability for
dose response will undergo study evaluation. When available, study evaluations from prior
assessments (e.g., RoC Monograph) were used to identify major limitations that would preclude the
study from being considered suitable for dose-response in this assessment Studies considered
suitable for dose-response - such as the NTP rodent cancer bioassays N] 8); NTP (20141 -
undergo full study evaluation using IRIS methodology - a domain-based approach to evaluate
studies. The detailed approaches are described in the Office of Research and Development (ORD)
Staff Standard Operating Procedures for Developing Integrated Risk Information System (IRIS)
Assessments (Version 1.0, October 2020, referred to as the "IRIS Handbook") U.S. EPA f2020cl.
The key concerns for the review of studies are potential bias (factors that affect the
magnitude or direction of an effect in either direction) and insensitivity (factors that limit the
ability of a study to detect a true effect; low sensitivity is a bias towards the null when an effect
exists). Each outcome or grouping of related outcomes within a study is judged independently by
two or more ORD staff reviewers using the HAWC Study Evaluation module. Reviewers reach a
consensus judgment (with conflict resolution by an additional reviewer, as needed) for each
evaluation domain and overall confidence determination. Judgments could differ from one outcome
to another within the same study, and with the overall study confidence determination. During
review, for each evaluation, domain reviewers reach a consensus judgment of good, adequate,
deficient, not reported, or critically deficient. It is important to emphasize that evaluations are
performed in the context of the study's utility for identifying individual hazards. Limitations
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specific to the usability of the study for dose-response analysis are useful to note, but they do not
contribute to the study confidence classifications. Once the evaluation domains have been rated, the
identified strengths and limitations are considered collectively to reach a study confidence
classification of high, medium, or low confidence, or uninformative for a specific health outcome.
This classification is based on the reviewer judgments across the evaluation domains and considers
the likely impact that inadequate reporting or the noted deficiencies in bias and sensitivity have on
the outcome-specific results. The specific limitations identified during study evaluation are carried
forward to help inform the synthesis within each body of evidence for a given health effect. Health
outcomes evaluated as uninformative are considered unusable for hazard and dose-response given
that the findings of interest are considered to be uninterpretable based on the identified flaws.
These studies have no impact on evidence synthesis or integration conclusions but may be used to
highlight research gaps.
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(a) Individual evaluation domains
Epidemiology
Animal
In vitro
• Exposure measurement
• Outcome ascertainment
• Participant selection
• Confounding
• Analysis
• Selective reporting
• Sensitivity
• Allocation
• Observational bias/blinding
• Confounding
¦ Attrition
• Chemical administration and
characterization
• Endpoint measurement
• Results presentation
• Selective reporting
• Sensitivity
¦ Observational bias/blinding
¦ Variable control
• Selective reporting
• Chemical administration and
characterization
• Endpoi nt measurement
• Results presentation
• Sensitivity
(b) Domain level judgments and overall study rating
Domain judgments
Judgment
Interpretation
0 Good
Adequate
Deficient
® Critically
Deficient
Appropriate study conduct relating to the domain and minor
deficiencies not expected to influence results
A study that may have some limitations relating to the domain, but
they are not liKely to be severe or to have a notable impact on results
Identified biases or deficiencies interpreted as liKely to have had a
notable impact on the results or prevent reliable interpretation of
study findings
A serious (law identified that makes the observed effect(s)
uninterpretabie. Studies with a critical deficiency are considered
"uninformative" overall.
Overall study rating for an outcome
Rating
Interpretation
High
Medium
Low
Uninformative
Mo notable deficiencies or concerns identified: potential for bias
unlikely or minimal; sensitive methodology
Possible deficiencies or concerns noted but they are unlikely to have a
significant impact on results.
Deficiencies or concerns were noted, and trie potential for substantive
bias or inadequate sensitivity could have a significant impact on trie
study results or their interpretation
Serious flaw(s) makes study results uninterpretabie but may be used
to highlight possible research gaps
Figure C-l. Overview of Integrated Risk Information System (IRIS) study
evaluation process, (a) individual evaluation domains organized by evidence type.,
and [b] individual evaluation domains judgments and definitions for overall ratings
(i.e., domain and overall judgments are performed on an outcome-specific basis),
1 Data Extraction of Study Methods and Results
2 Data will be extracted from prioritized studies into EPA's version of Health Assessment
3 Workspace Collaborative (HAWC, https://hawcprd.epa.gOv/l. a web-based software application
4 designed to manage and facilitate the process of conducting health assessments. Because the focus
5 of the current assessment is to develop a cancer IUR for inclusion in the IRIS database, tumor data
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(along with any other data relevant to dose-response, such as animal survival rates and individual-
level data) are prioritized for data extraction. Data are also be stored in other formats (i.e., Excel,
BMDS, Word). See Section 4.2.1 "Selecting Endpoints for Dose-Response Assessment"
For quality control, data extraction is be performed by one member of the evaluation team
and independently verified by at least one other member. Discrepancies in data extraction are
resolved by discussion or consultation with a third member of the evaluation team.
C.5.2.SuppIementaI Material
The results of the supplemental material tagging (Table C-2) conducted in DistillerSR are
imported into the Literature Inventory module in HAWC, where more granular sub-tagging within a
type of supplemental material content category is conducted during assessment development
(including after preparation of the SEM). A single study can have multiple tags. Tagging judgements
in HAWC are made by one assessment member and confirmed during preparation of draft
assessment by another member of the assessment team.
C.6. RESULTS: LITERATURE SCREENING RESULTS
The database searches yielded 29,833 references in HERO after duplicate removal
(Figure C-l). Application of the SWIFT Review literature search filters (available online from
Sciome Company) for "human", "animal (human health models)", and "in vitro" evidence reduced
the number of studies for consideration to 4,588 after duplicate removal. The studies were
screened in SwiftActive Screener using predictive relevance, resulting in 2095 studies being
manually screened to identify 742 studies that were considered potentially PECO relevant or
supplemental ("included" for the purposes of machine learning) and 1353 references that were
manually excluded. After manually reviewing these 2095 references, screening was stopped
because SWIFT ActiveScreener indicated at least 95% of the relevant studies are identified, a
percent identification often used to evaluate the performance of machine learning applications and
considered comparable to human error rates Bannach-Brown et al. f20181:Howard et al.
f2Q16):Cohen etal. f2006). More specifically, in this project screening stopped when a predicted
96% of relevant studies were identified.
Separately, over 1600 unique records were identified from the other sources searched and
compared to the 4588 that were initially uploaded into SWIFTActive Screener, yielding 502 unique
records. These 502 studies, as well as the 742 studies previously identified as potentially PECO
relevant or supplemental, were imported into DistillerSR for a total of 1244 studies screened at
TIAB level. During TIAB screening in DistillerSR, 62 were included for full-text review, 826 were
tagged as supplemental material, and 399 were excluded as not relevant to PECO.
During full-text review, 19 studies were considered PECO relevant (11 animal studies and 8
human studies), 22 studies were excluded, and 22 studies were tagged as supplemental material.
The PECO relevant human and animal studies were then assessed for suitability for dose response
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(Table C-4, Table C-5). Literature search results are summarized graphically in Figure C-l and in an
interactive version in Figure C-2.
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Cobalt Compounds Literature Searches (December 2021)
PubMedr 12/16/2021
(n = 7,442)
WoS, 12/16/2021
(n = 28,676)
Following duplicate removal, SWIFT Review used to analyze 29,833 records from database searches
Identification of potentially relevant records based on application of SWIFT-Review evidence stream tags for
human, animal (human health models), and in vitro evidence, n = 4,589.
Following additional duplicate removal in SWIFT Active, n = 4,588.
TIAB Screen in SWIFT Active (n = 4,588)
742 records met SEM PECO or considered
supplemental material
Excluded (n = 3846]
1353 records manually screened and excluded
2493 records predicted as not relevant in SWIFT
Active (and not manually screened)
Records identified from other sources {n = 1834)
Reference list from
existing assessments
(ASTDR, CalEPA, NTP, PPRTV)
(n = 1834)
Reference list from
included studies (n = 93}
ECHA
(n = 303)
NTP CEBS
(11=10)
QECD Echem
(n = 4)
EPA Chemyiew
(n = 14)
Comptox
(n = 0)
Identification of potentially relevant records based on citation from assessment cancer sections or potential PECO
relevance based on Title scan, n = 502.
T
Title & Abstract Screen in DistillerSR^
(n = 1244)
Included after Full-Text Screening (n = 19)
Animal {n = 11); Human (n = S)
Full-Text Screen in DistHlerSR (n = 62)
Excluded, did not meet all PECO criteria (n = 377)
Tagged as supplemental material (n = 304]
Sum of TIAB excluded or supplemental [n = 1,181)
Excluded (n = 22)
Not PECO relevant (n = 17)
Unable to obtain full text {n = 5}
Tagged as supplemental material (n = 22)
Sum of full-text excluded or supplemental (n = 44)
Tagged as Supplemental Material
TIAB + Full text + Inventory (n = 826)
• Mechanistic (including in vivo/in vitro/ex vivo/in silico studies,}
(n = 187)
• Non-mammalian model systems (n = 7)
• Non-PECO route of exposure (n = 115}
• Noncancer epidemiology or in vivo sub chronic/chronic animal
study (n = 235)
• Cancer studies with less than subchronic exposure (n = 3)
• Medical therapeutic studies (n = 18)
• Medical implantation studies (n = 15)
• Hypoxia-induction studies {n = 115)
• ADME (n = 65)
• PBPK (n = 0)
• Exposure characteristics (no health outcome assessment) (n =
49)
• Mixture studies (n = 44)
• Records or other assessments with no original data (n = 66)
• Case reports (n = 34)
• Conference abstract (n = 4)
• Errata/retracted (n= 1)
Figure C-2. Study Flow Diagram
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Studies can be tagged to multiple supplemental tags, therefore, total number of supplemental subtags is
greater than the total number of supplemental references.
©
Animal
^19
Inclusion
826
Supplemental
Cobalt (inhalation) (2022}
Human
4245
Q
Manually Excluded
Exclusion
2493
Excluded by Machine Learning
Figure C-3. Literature tree. Click here for interactive version.
This document is a draft for review purposes only and does not constitute Agency policy.
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1
2
3
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
C.7.LITERATURE INVENTORY
C. 7.1. Characterizing Epidemiological Studies for Dose-Response Analysis
Six epidemiological studies were identified that met the SEM PECO criteria, which were
developed to identify studies of cancer in relation to quantitative estimates of exposure Mur et al.
(1987]; Moulin et al. (1998]; Tuchsen et al. (1996]; Sauni et al. [2017]; White etal. [2019]; Kresovich
et al. (20191 (Table C-5). Four of the epidemiological studies involved workers, and included
evaluations of: malignant tumor (ICD-8 140-209] mortality in an electrochemical plant workers
Mur et al. (19871: lung cancer in a case-control study nested in a cohort study of workers in the
French hard-metal industry Moulin et; 8]; lung cancer in women exposed to cobalt-
aluminum spinel in a retrospective cohort study Tuchsen 3]; and multiple cancer types
(including lung] in Finnish cobalt production workers Sauni etal. (20171. The remaining two
studies assessed breast cancer in relation to environmental exposure to air pollutants including
cobalt (participants of the U.S.-wide Sister Study White etal. (20191. and participants of the Cancer
Care in Chicago study Kresovich et al. (201911.
Among the epidemiological studies, 3 had been included in the NTP RoC Monograph Cobalt
and Cobalt Compounds that Release Cobalt Ions In Vivo NTP (20161: the summary of study strengths
and limitations presented in the RoC Monograph Mur et a []; Moulin et al. (19981: Tuchsen et
al. (19961: Kresovich et al. (20191 were used to evaluate this set of studies for suitability for dose-
response analysis. For the 3 studies published after the RoC Monograph Sauni etal. (20171: White
et al. (20191: Kresovich et al. (20191. a targeted evaluation based on the considerations outlined in
the IRIS Handbook U.S. EPA (202Pel.and summarized in section 8.5 was performed. This targeted
evaluation revealed concerns in all 3 studies that precluded their use for dose-response, namely the
lack of individual-level exposure information, and the potential for confounding by co-exposures to
other carcinogens. These limitations are summarized in Table C-4. As the 3 earlier studies
evaluated in the RoC Monograph also had limitations, none of the human studies were deemed to
be more suitable for dose-response compared to the NTP animal cancer bioassay studies.
C. 7.2. Characterizing Animal Studies for Dose-Response Analysis
Eleven animal studies were identified that met SEM PECO criteria, including three NTP
Toxicity Reports NTP (19911: N 98]; NTP (20141 and six associated publications Bucher etal.
(19901: Bucher etal. (19991: Ozaki etal. (20021: Behl etal. (20151: i et al. (20151: Ton etal.
(20211. The two remaining publications had been considered in prior assessments Kerfoot (19731:
Palmes el ) and no new cancer bioassays were identified. The NTP rodent cancer
bioassays NTP (19981:NTP (20141 were both considered high confidence (Figure C-3], and the six
associated publications Bucher et al. (19901:Bucher et al. (19991:Ozaki etal. (20021:6efal etal.
(2015]:Hong et al. (20151:Ton et al. (20211 weNational Toxicology Program (Nr 08351: NTP
(20141 based on comparisons outlined in Table C-3. All other studies were determined to be
inadequate for dose-response for multiple reasons, with short exposure durations being the most
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
1 common rationale (see Table C-5). The three subchronic studies fNTP (1991). Kerfoc IX and
2 Palmes ) contained no tumor dose-response data. In addition, Kerfoot (19731. and
3 Palmes had insufficient study designs and data reporting.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Table C-4. Analysis of Human Studies Meeting PECO Criteria for Suitability for Dose-Response.
Study
Study design and
population
Exposure
Endpoints
Study evaluation observation
Suitability for dose-
response
Muretal. (19871
Cohort of
electrochemical plant
workers producing
cobalt and sodium
(1950-1980)
Occupational
categories (whole
cohort, general
services,
maintenance, sodium
production, cobalt
production)
Malignant
tumor
mortality, lung
cancer
mortality
"Exposure duration: 60% worked greater than 10
years; 75% hired before 1975. Confounding: Likely
inadequate control for smoking; however, likely co-
exposure to nickel and arsenic with no control for
coexposures. Strengths: Cobalt production workers
exposed primarily to cobalt compounds.
Limitations: Small number of exposed cases; high
loss to follow-up (20%); potential for selection bias
due to left truncation" (page 49 from RoC
Monograph, NIP (2016).
Study quality concerns identified in the
confounding and sensitivity domains (page 47 from
RoC Monograph, NIP (2016).
Not suitable for dose-
response
Main limitations
related to
confounding,
sensitivity and
selection bias
Moulin et al.
(1998)
Nested case control
study of French hard-
metal industry workers
(10 facilities, 1968-
1991). 5777 males,
1682 females
Job-exposure matrix,
320 job periods and
semi-quantitative
estimation of
exposure to cobalt
and to tungsten
carbide
All cancer
mortality, lung
cancer
"No information on actual exposure level or
average exposure duration for the cohort.
Confounding: Potential concern for exposure to
other lung carcinogens, which were not controlled
in the cobalt alone analyses. Strengths: Exposure-
response analyses with multiple exposure metrics;
JEM validated for atmospheric concentrations of
cobalt; incident cohort reducing the potential for
left truncation; internal analysis reducing the
impact of the reported HWE; and lagged analysis.
Limitations: Potential confounding by coexposures
classified only as "ever/never" in the JEM" (page 51
from RoC Monograph, NIP (2016)
Study quality concerns identified in the
confounding domain (page 47 from RoC
Monograph, NIP (2016)
Not suitable for dose-
response
Main limitations
related to
confounding from
exposure to other
carcinogens.
Tuchsen et al.
(1996)
Retrospective cohort of
two Danish porcelain
factories, 874 women
Dust and airborne
concentrations (only
for certain years)
All-cause
mortality,
organ- specific
"Employment in factories/departments with or
without cobalt. Confounding: No control for
smoking; however, smoking data on subset of
Not suitable for dose-
response
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Study
Study design and
population
Exposure
Endpoints
Study evaluation observation
Suitability for dose-
response
occupationally exposed
to cobalt (and 520
women not exposed)
cancer
incidence
(including lung
and breast
cancer)
workers suggests that smoking was not associated
with exposure. Strengths: Population exposed
primarily to cobalt compounds alone; only female
population with data on cobalt. Limitations: Small
number of exposed cases. Differential selection out
of the cohort could have occurred as the authors
mentioned that records of ill persons may have
been removed potentially resulting in an
underestimate of the true incidence of cancer."
(Page 47 from RoC Monograph, NIP (2016) 'This
study had low sensitivity to detect an effect
because of (1) small numbers of exposed cases in
this relatively small cohort and (2) potentially
combining workers with high and low exposures
together, which could dilute any effect and bias the
results towards the null. In addition, no lagged
analyses were reported. A concern about
differential selection also exists in this study. The
authors suggested that removal of records of ill
persons was known to take place in Danish
manufacturing. The possibility of differential
selection out of the cohort could have resulted in
an underestimation of the true incidence of lung
cancer in this study."
Study quality concerns identified in the sensitivity
domain (page 47 from RoC Monograph, NIP
(2016)
Main limitations
related to low
sensitivity
Sauni et al.
(20171
Cohort study of male
cobalt production
workers (Finland, 1969-
2013). 995 men with
26083 person-years.
Occupational
categories
Cancer
incidence
(including lung,
tongue, other
cancer types)
Male worker cohort stratified by age and exposure
level. Strengths: routine stationary measurements
and personal sampling with worker history verified.
Smoking data available. Limitation: potential
confounding by other carcinogens, namely nickel.
No information on alcohol consumption.
Study quality concerns: confounding and sensitivity
Not suitable for dose-
response
Main limitations
related to potential
confounding and
limited
generalizability.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Study
Study design and
population
Exposure
Endpoints
Study evaluation observation
Suitability for dose-
response
White et al.
(2019)
The Sister Study (US-
wide prospective
cohort) of 50,884
women.
U.S. EPA National Air
Toxics Assessment
Breast cancer
General population study with estimated exposure
to ambient toxic pollutants. Strengths: Large study
population. Limitations: Exposure to cobalt
estimated based on national air pollutant data. No
measurement of actual cobalt exposure levels.
Potential confounding by other air pollutants.
Study quality concerns: specificity of exposure and
confounding
Not suitable for dose-
response
Main limitations
related to potential
confounding due to
exposure to other
carcinogens.
Kresovich et al.
(2019)
Breast Cancer Care in
Chicago (population-
based cohort study)
study of 696 women.
U.S. EPA National Air
Toxics Assessment
Breast cancer
General population study with estimated exposure
to ambient toxic pollutants. Strengths: Health
outcome (breast cancer) medically verified.
Limitations: Exposure to cobalt estimated based
on national air pollutant data. No measurement of
actual cobalt exposure levels. Potential
confounding by other air pollutants. Study quality
concerns: specificity of exposure and confounding
Not suitable for dose-
response
Main limitations
related to potential
confounding due to
exposure to other
carcinogens.
1
Table C-5. Analysis of Animal Studies Meeting PECO Criteria for Suitability for Dose-Response.
Study
Species,
strain, sex
Dur.
Design
Air
measurements
Sample
size/group
Cone
(mg/m3)
Outcome
measure
Suitability for dose-response
NTP (1998)*
F344 rats,
B6C3Fi mice
M, F
2 yr
6h/day,
5d/week
Particle size and
mg/m3 validation
50
0
0.114
0.38
1.14
Tissue pathology
(quantitative)
Suitable for dose-response.
Chronic study. Tumors observed. Individual
animal data available. Large sample size.
NTP (2014)*
F344 rats,
B6C3Fi mice
M, F
2 yr
6h/day,
5d/week
Particle size and
mg/m3 validation
50
0
1.25
2.5
5.0
Tissue pathology
(quantitative)
Suitable for dose-response.
Chronic study. Tumors observed. Individual
animal data available. Large sample size.
NTP (1991)
F344 rats,
B6C3Fi mice
M, F
90 d
6h/day,
5d/week
Particle size and
mg/m3 validation
10
0
0.114
0.38
1.14
3.8
Tissue pathology
(quantitative).
No tumors
observed.
Not suitable for dose-response. Subchronic
study. No tumors observed. Small sample
size limits power to observe rare effects.
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
11.4
Kerfoot {1973}
Mini, swine
(sex not
specified)
90 d
6h/day,
5d/week
No particle or air
validation
presented
5
0
0.1
1
Tissue pathology
(qualitative). No
tumors
observed.
Not suitable for dose-response.
Insufficient data (animal specification, air
and outcome quantitation). Subchronic
study. No tumors observed. Small sample
size and few exposure groups. No individual
animal data available.
Palmes et al.
{1959}
Albino rats
(M), guinea
pigs, dogs
90 d
6h/day,
5d/week
Gaseous cobalt
hydrocarbonyl. Air
mg/m3validation
41 control,
75 exposed
(rats)
0
9
Tissue pathology
(qualitative),
hematology,
pharmacokinetic
s
Not suitable for dose-response. Insufficient
data (outcome quantitation). Subchronic
study. No tumors observed. Single high
exposure group (above 5 mg/m3). No
individual animal data available.
* Related studies include Bucher et al. {1990), Bucher et al. {1999), Ozaki et al. {2002), Be
il et al. {2015), Hong et al. {2015), and Ton et al. {2021).
1
This document is a draft for review purposes only and does not constitute Agency policy.
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
ADDENDUM 1. LITERATURE SEARCH STRATEGY
(DATE LIMITED TO 2019- 2021)
Search
Search Strategy
Results
and Date
wos
(TS=("cobalt" OR "7440-48-4" OR "10124-43-3" OR "Cobaltsulfat" OR "7646-79-9" OR
"Cobaltous chloride" OR "Dichlorocobalt" OR "1317-42-6" OR "71-48-7" OR "6147-53-1" OR
"917-69-1" OR "513-79-1" OR "10210-68-1" OR "21041-93-0" OR "21158-51-0" OR "61789-51-
3" OR "10141-05-6" OR "10026-22-9" OR "1308-04-9" OR "1307-96-6" OR "1308-06-1" OR
"10026-24-1" OR "Cobaltic acetate" OR "Dicobalt octacarbonyl" OR "Cobalt(ll) hydroxide" OR
"Cobaltous hydroxide" OR "Cobalt(ll) acetate" OR "Cobalt(ll) acetate tetrahydrate" OR
"Cobalt(lll) acetate" OR "Cobalt(ll) carbonate" OR "Cobalt(ll) chloride" OR "Cobalt(ll)
hydroxide" OR "Cobalt(ll) mesoporphyrin" OR "Cobalt(ll) naphthenate" OR "Cobalt(ll) nitrate"
OR "Cobalt(ll) nitrate hexahydrate" OR "Cobalt(ll) oxide" OR "Cobalt(lll) oxide" OR "Cobalt(ll)
sulfate" OR "Cobalt(ll) sulfate heptahydrate" OR "Naftolite" OR "Cobaltdinitrat" OR "Cobaltous
nitrate" OR "Cobaltous oxide" OR "C.I. Pigment Black 13" OR "Cobaltoxid" OR "Cobaltic oxide"
OR "Dicobalt oxide" OR "Cobaltosic oxide" OR "Cobaltic-cobaltous oxide" OR "Cobalto-cobaltic
oxide" OR "Tetraoxyde de tricobalt" OR "Tricobalttetraoxid" OR "tricobalt tetraoxide" OR
"Tricobalt tetraoxide" OR "Tricobalt tetroxide" OR "Cobaltous sulfate heptahydrate" OR
"cobalt element" OR "cobalto") AND (PY=2019-2021))
28,676
12/16/2021
PubMed
"cobalt"[tw] OR "7440-48-4"[rn] OR "10124-43-3"[tw] OR "Cobaltsulfat"[tw] OR "7646-79-
9"[tw] OR "Cobaltous chloride"[tw] OR "Dichlorocobalt"[tw] OR "1317-42-6"[tw] OR "71-48-
7"[tw] OR "6147-53-l"[tw] OR "917-69-l"[tw] OR "513-79-l"[tw] OR "10210-68-l"[tw] OR
"21041-93-0"[tw] OR "21158-51-0"[tw] OR "61789-51-3"[tw] OR "10141-05-6"[tw] OR "10026-
22-9"[tw] OR " 1308-04-9"[tw] OR "1307-96-6"[tw] OR "1308-06-l"[tw] OR "10026-24-l"[tw]
OR "Cobaltic acetate"[tw] OR "Dicobalt octacarbonyl"[tw] OR "Cobalt(ll) hydroxide"[tw] OR
"Cobaltous hydroxide"[tw] OR "Cobalt(ll) acetate"[tw] OR "Cobalt(ll) acetate tetrahydrate"[tw]
OR "Cobalt(lll) acetate"[tw] OR "Cobalt(ll) carbonate"[tw] OR "Cobalt(ll) chloride"[tw] OR
"Cobalt(ll) hydroxide"[tw] OR "Cobalt(ll) mesoporphyrin"[tw] OR "Cobalt(ll) naphthenate"[tw]
OR "Cobalt(ll) nitrate"[tw] OR "Cobalt(ll) nitrate hexahydrate"[tw] OR "Cobalt(ll) oxide"[tw] OR
"Cobalt(lll) oxide"[tw] OR "Cobalt(ll) sulfate"[tw] OR "Cobalt(ll) sulfate heptahydrate"[tw] OR
"Naftolite"[tw] OR "Cobaltdinitrat"[tw] OR "Cobaltous nitrate"[tw] OR "Cobaltous oxide"[tw]
OR "C.I. Pigment Black 13"[tw] OR "Cobaltoxid"[tw] OR "Cobaltic oxide"[tw] OR
"Dicobalt oxide"[tw] OR "Cobaltosic oxide"[tw] OR "Cobaltic-cobaltous oxide"[tw] OR
"Cobalto-cobaltic oxide"[tw] OR "Tetraoxyde de tricobalt"[tw] OR "Tricobalttetraoxid"[tw] OR
"tricobalt tetraoxide"[tw] OR "Tricobalt tetraoxide"[tw] OR "Tricobalt tetroxide"[tw] OR
"Cobaltous sulfate heptahydrate"[tw] OR "cobalt element"[tw] OR "cobalto"[tw])
AND (2019/01/01:3000[dp])
7,442
12/16/2021
Unique items were discovered using the search strategy above.
29,833
Number of records after application of SWIFT Review tags for human, animal (human health
models), and in vitro evidence
4,589
TOTAL
Number of records after an addition round of de-duplication SWIFT Active
4,588
1
This document is a draft for review purposes only and does not constitute Agency policy.
Addendum 1-1 DRAFT-DO NOT CITE OR QUOTE
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1
2
3
4
5
6
7
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9
10
11
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13
14
15
16
17
18
19
20
21
22
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27
IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
ADDENDUM 2. PROCESS AND RESULTS FOR
SEARCHING AND COLLECTING EVIDENCE FROM
OTHER RESOURCES
Process
Review of reference lists from existing assessments (final or publicly available draft) and
journal studies considered relevant to PECO based on full-text screening
Citations from cancer sections of prior assessments were compiled and reviewed manually
by scanning the titles for those that appear to meet the PECO criteria. Any unique records
identified from these sources are formatted in an RIS file format, imported into DistillerSR,
annotated with respect to source, and screened as outlined previously in "Literature Screening
Processes".
Reference lists from journal articles are also reviewed manually by scanning the titles for
those that appear to meet the PECO criteria. This is only done for journal articles that meet PECO
criteria based on full-text review and not for journal articles tagged as supplemental material.
European Chemicals Agency
A search of the ECHA-registered substances database is conducted using the CASRN. The
registration dossier associated with the CASRN number is retrieved. The general information page
and all subpages included under the Toxicological Information tab are downloaded in PDF format,
including all nested reports that have unique URLs.
At this stage, each study summary is reviewed for inclusion on the basis of the PECO
criteria. When a study summary considers relevant reported data from a study or lab report, a
citation for the full study is generated in HERO, and it is verified that the study is not already
identified from the database search (or searches of "other sources consulted") prior to moving
forward to screening.
EPA ChemView
A search of the EPA ChemView database U.S. EPA f20191 using the chemical CASRN is
conducted. The prepopulated CASRN match and the "Information Submitted to EPA" output option
filter is selected before generating results. If results are available, the square-shaped icon under the
"Data Submitted to EPA" column is selected, and the following records are considered:
• High Production Volume Challenge Database (HPVIS)
This document is a draft for review purposes only and does not constitute Agency policy.
Addendum 2-1 DRAFT-DO NOT CITE OR QUOTE
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
• Human Health studies (Substantial Risk Reports)
• Monitoring (Includes environmental, occupational and general entries)
• TSCA Section 4 (Chemical testing results)
• TSCA Section 8(d) (Health and safety studies)
• TSCA Section 8(e) (Substantial Risk)
• FYI (Voluntary documents)
All records for ecotoxicology and physical & chemical property entries are excluded. When
results are available, extractors navigate into each record until a substantial risk report link is
identified and saved as a PDF file. If the report cannot be saved, due to file corruption or broken
links, the record is excluded during full-text review as "unable to obtain record." Most substantial
risk reports contain multiple document IDs; thus, citations are derived by concatenating the unique
report numbers (OTS, 8EHD Num, DCN, TSCATS RefID, CIS) associated with each document along
with the typical author organization, year, and title. Once a citation is generated, the study is moved
forward to DistillerSR, where it is screened according to PECO criteria.
NTP Chemical Effects in Biological Systems
This CEBS database is searched using the chemical CASRN
fhttPsi //manticore.niehs.nih.gov/cebssearchl All non-NTP data are excluded using the "NTP Data
Only" filter. Data tables for reports undergoing peer review are also searched for studies that have
not been finalized (httpsi / /ntp.niehs.nih.gov/data/tables /index.html) on the basis of a manual
review of chemical names.
OECD Echem Portal
The OECD Echem Portal fhttps://hpvchemicals.oecd.org/Ul/Search.aspxl is searched using
the chemical CASRN to retrieve results for OECD Screening Information DataSet (SIDS) and High
Production Volume (HPV) Chemicals (https://www.echemportal.org/echemportal/). Only database
entries from those resources are included, and entries from all other databases are excluded in the
search. Final assessment reports and other relevant SIDS reports embedded in the links are
captured and saved as PDF files.
This document is a draft for review purposes only and does not constitute Agency policy.
Addendum 2-2 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
1 Results of Searching Other Resources
Source
Source address
Search terms
Search date
Total unique
number of
results
retrieved
Records not
otherwise
identified that were
screened in
DistillerSR
Review of reference lists of studies
considered relevant to PECO based
on full-text screening.
NA
NA
7/15/2022
93
34
Review of reference lists from
existing assessments (final or
publicly available draft)
NA
NA
3/24/22
1,834
465
EPA CompTox Chemicals Dashboard
version to retrieve a summary of any
ToxCast orTox21 high throughput
screening information
Iittps://comptox, epa.gov/dashboard
7440-48-4; 1345-16-0
7789-43-7; 513-79-1;
10210-68-1; 16842-03-8;
7646-79-9; 61789-51-3;
1307-96-6; 1308-06-1;
136-52-7; 10141-05-6;
10026-22-9; 10124-43-3
3/16/2022
0
0
ECHA
https://echa.europa.eu/da/informatio
nicals/registered-substances
7440-48-4; 1345-16-0;
7789-43-7; 513-79-1;
10210-68-1; 16842-03-8;
7646-79-9; 61789-51-3;
1307-96-6; 1308-06-1;
136-52-7; 10141-05-6;
10026-22-9; 10124-43-3
3/17/2022
303
0
EPA ChemView
https://chemview.epa.gov/chemview
7440-48-4; 1345-16-0;
7789-43-7; 513-79-1;
10210-68-1; 16842-03-8;
7646-79-9; 61789-51-3;
1307-96-6; 1308-06-1;
136-52-7; 10141-05-6;
10026-22-9; 10124-43-3
3/15/2022
14
0
This document is a draft for review purposes only and does not constitute Agency policy.
Addendum 2-3 DRAFT-DO NOT CITE OR QUOTE
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IRIS Assessment Plan and Protocol for Cobalt and Cobalt Compounds (Cancer, Inhalation)
Source
Source address
Search terms
Search date
Total unique
number of
results
retrieved
Records not
otherwise
identified that were
screened in
DistillerSR
NTPCEBS
httpsi//manticore,niehs, nih.gov/cebss
earch/
7440-48-4; 1345-16-0;
7789-43-7; 513-79-1;
10210-68-1; 16842-03-8;
7646-79-9; 61789-51-3;
1307-96-6; 1308-06-1;
136-52-7; 10141-05-6;
10026-22-9; 10124-43-3
3/16/2022
10
0
OECD Echem Portal
https://hpvchemicals.oecd.org/ll I/Sear
ch.aspx
7440-48-4; 1345-16-0;
7789-43-7; 513-79-1;
10210-68-1; 16842-03-8;
7646-79-9; 61789-51-3;
1307-96-6; 1308-06-1;
136-52-7; 10141-05-6;
10026-22-9; 10124-43-3
3/17/2022
4
4
PECO = Populations, Exposures, Comparators, and Outcomes; NA = not applicable; POD = point of departure; ECHA = European Chemicals Agency; NTP
CEBS = National Toxicology Program Chemical Effects in Biological Systems; OECD = Organisation for Economic Co-operation and Development.
This document is a draft for review purposes only and does not constitute Agency policy.
Addendum 2-4 DRAFT-DO NOT CITE OR QUOTE
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