United States
Environmental Protection
1=1 m m Agency
EPA/690/R-07/030F
Final
9-26-2007
Provisional Peer Reviewed Toxicity Values for
Promethium
(CASRN 7440-12-2)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw
body weight
cc
cubic centimeters
CD
Caesarean Delivered
CERCLA
Comprehensive Environmental Response, Compensation and Liability Act

of 1980
CNS
central nervous system
cu.m
cubic meter
DWEL
Drinking Water Equivalent Level
FEL
frank-effect level
FIFRA
Federal Insecticide, Fungicide, and Rodenticide Act
g
grams
GI
gastrointestinal
HEC
human equivalent concentration
Hgb
hemoglobin
i.m.
intramuscular
i.p.
intraperitoneal
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
i.v.
intravenous
kg
kilogram
L
liter
LEL
lowest-effect level
LOAEL
lowest-observed-adverse-effect level
LOAEL(ADJ)
LOAEL adjusted to continuous exposure duration
LOAEL(HEC)
LOAEL adjusted for dosimetric differences across species to a human
m
meter
MCL
maximum contaminant level
MCLG
maximum contaminant level goal
MF
modifying factor
mg
milligram
mg/kg
milligrams per kilogram
mg/L
milligrams per liter
MRL
minimal risk level
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
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p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
PROMETHIUM (CASRN 7440-12-2) AND PROMETHIUM SALTS
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
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circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Promethium is the rarest of the rare earth elements that, as a class, also are referred to as
lanthanides. In general, the lanthanides can be radioactive or stable. However, promethium
probably does not occur in nature or in a stable form (Brzyska, 1996; Wells and Wells, 2001).
Seventeen isotopes of promethium, with atomic masses from 134 to 155 were identified.
Promethium-147, with a half-life of 2.6 years, generally was considered the most prevalent.
Promethium-145 is the longest lived, with a half-life of 17.7 years (Lide, 2007). Primary decay
products are neodymium (Nd) or samarium (Sm), depending on the isotope of promethium.
No toxicity or carcinogenicity assessments for promethium were available from IRIS
(U.S. EPA, 2007), HEAST (U.S. EPA, 1997), CARA (U.S. EPA, 1991, 1994), or the Office of
Water (U.S. EPA, 2006). Promethium had not been evaluated by ATSDR (2007) or IARC
(2007), or tested or scheduled for testing by NTP (2007). A toxicological review of the
lanthanides was identified, which derived toxicity values for several other lanthanides, but not
for promethium or its compounds (TERA, 1999). No occupational exposure limits were
recommended or promulgated for promethium by ACGIH (2007), NIOSH (2005), or OSHA
(2007).
This document was based on information obtained through comprehensive searches of
the following databases in June 1998 and 2007: TOXLINE (1965-2007), CANCERLINE (1970-
2007), MEDLINE (1966-2007), GENETOX, DART, CCRIS, CHEMID, RTECS, EMIC,
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ETICBACK, and TSCATS. Extensive tree-searching of acquired literature was performed to
identify pertinent data from the older literature.
This document has passed the STSC quality review and peer review evaluation indicating
that the quality is consistent with the SOPs and standards of the STSC and is suitable for use by
registered users of the PPRTV system.
REVIEW OF PERTINENT LITERATURE
Human and Animal Studies
No data regarding the oral or inhalation toxicity of promethium were located in the
available literature.
Human inhalation toxicity data on rare earth elements mainly consisted of case reports on
workers exposed to multiple lanthanides (Kappenberger and Buhlmann, 1975; Husain et al.,
1980; Sabbioni et al., 1982; Vocaturo et al., 1983; Colombo et al., 1983; Sulotto et al., 1986;
Vogt et al., 1986; Waring and Watling, 1990; Deng et al., 1991). Animal inhalation toxicity data
on rare earths mainly consisted of a few inhalation or intratracheal studies on some rare earth
mixtures and some single compounds (Schepers, 1955a,b; Schepers et al., 1955; Ball and
VanGelder, 1966; Abel and Talbot, 1967; Mogilevskaya and Raikhlin, 1967). However, because
separation and purification procedures prior to the 1950s yielded impure lanthanides (Wells and
Wells, 2001), we considered only those data generated since the newer purification methods
were instituted.
The pulmonary toxicity of inhaled rare earth compounds, in general, have been the
subject of debate, especially with regard to the relative contributions of radioactive contaminants
versus stable elements in the development of progressive pulmonary interstitial fibrosis (Haley,
1991; Wells and Wells, 2001). In particular, although it was known that stable rare earth
compounds could produce a static, foreign-body-type lesion consistent with benign
pneumoconiosis, there was uncertainty whether they also could induce interstitial fibrosis that
progressed after termination of exposure. A comprehensive assessment of the human and animal
data by Haley (1991) concluded that the evidence suggested inhalation exposure to high
concentrations of stable rare earths could produce lesions compatible with pneumoconiosis and
progressive pulmonary fibrosis, and that the potential for inducing these lesions was related to
chemical type, physiochemical form, dose, and duration of exposure. In a separate review,
Hirano and Suzuki (1996) also concluded that chronic inhalation of lanthanide dusts probably
caused pneumoconiosis in humans. However, no toxicity data specific to promethium were
identified.
Other Relevant Data
The gastrointestinal absorption and distribution of promethium (147Pm) was investigated
in adult and neonatal (2-day-old) rats and neonatal (2-day-old) swine that were treated by gavage
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and killed 1 week after treatment (Sullivan et al., 1984). Promethium was given as a single dose
but the administered form, doses, and kind of solvent were not reported, although the pH of the
solution was 2. Radioactivity was measured in the liver, kidney, and carcass of all animals;
urine and lungs of adult and neonatal rats; and skin and GI tract of neonatal rats. Fecal levels of
radioactivity were not determined. Total tissue retention after 7 days was 0.007, 5.4, and 3.4%
of the administered dose in the adult rats, neonatal rats, and neonatal swine, respectively. Most
of the dose retained by the neonatal rats was in the GI tract and skeleton (48.1% and 4.3% of
administered dose, respectively). No toxicity endpoints were evaluated in this study. Hazards
associated with ionizing radiation are not addressed here.
Carcinogenicity Data
No data regarding the carcinogenicity of promethium were located. Genotoxicity and
other supportive data relating to the potential carcinogenicity of promethium were not located in
the available literature. Hazards associated with ionizing radiation are not addressed here.
DERIVATION OF A PROVISIONAL SUBCHRONIC OR CHRONIC RfD FOR
PROMETHIUM COMPOUNDS
Derivation of a p-RfD for promethium or its compounds was precluded by the lack of
oral toxicity data.
DERIVATION OF A PROVISIONAL SUBCHRONIC OR CHRONIC RfC FOR
PROMETHIUM COMPOUNDS
Derivation of a p-RfC for promethium or its compounds was precluded by the lack of
inhalation toxicity data.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
PROMETHIUM COMPOUNDS
Weight-of-Evidence Descriptor
Available data on promethium or its compounds were insufficient for assessing possible
carcinogenicity. In accordance with U.S. EPA (2005) guidelines for substances with inadequate
human and animal data, promethium and its compounds were described as having "inadequate
information to assess carcinogenic potential". Hazards associated with ionizing radiation are not
addressed here.
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Quantitative Estimates of Carcinogenic Risk
Derivation of an oral slope factor or inhalation unit risk for promethium or its compounds
was precluded by the lack of data in humans and animals.
REFERENCES
Abel, M. and R.B. Talbot. 1967. Gadolinium oxide inhalation by guinea pigs: A correlative
functional and histopathologic study. J. Pharmacol Exp. Therap. 157:207-213.
ACGIH (American Conference of Governmental Industrial Hygienists). 2007. TLVs and BEIs.
Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure
Indices. ACGIH, Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Toxicological Profile
Query. ATSDR, U.S. Public Health Service, Atlanta, GA. On-line:
http://www.atsdr.cdc.gov/mrls/
Ball, R.A. and G. VanGelder. 1966. Chronic toxicity of gadolinium oxide for mice following
exposure by inhalation. Arch. Environ. Health. 13:601-608.
Brzyska, W. (1996) Lantanowce i aktynowce, pp. 40-41, Wydawnictwa Naukowo-Techniczne,
Warszawa (in Polish). Cited in Palasz and Czekaj 2000.
Lide D.R. (ed.). 2007. CRC Handbook of Chemistry & Physics, 87th edition. Taylor and Francis,
LLC, London. On-line: http://www.hbcpnetbase.com/7BookIIIN34
Colombo, F., M. Zanoni, G. Vocaturo et al. 1983. Pneumoconiosi da terre rare.
[Pneumoconiosis due to rare earth metals], Med. Lav. 74:191-197.
Deng, J.F., T. Sinks, L. Elliott, D. Smith, M. Singal and L. Fine. 1991. Characterization of
respiratory health and exposures at a sintered permanent magnet manufacturer. J. Ind. Med.
48:609-615.
Haley, P.J. 1991. Pulmonary toxicity of stable and radioactive lanthanides. Health Physics.
61:809-821.
Husain, M.H., J.A. Dick and Y.S. Kaplan. 1980. Rare earth pneumoconiosis. J. Soc. Occup.
Med. 30:15-19.
Hirano S. and K.T. Suzuki. 1996. Exposure, metabolism, and toxicity of rare earths and related
compounds. Environ Health Perspect 104 (Suppl l):85-95.
5

-------
9-26-2007
IARC (International Agency for Research on Cancer). 1997. Cumulative Index to the
Monograph Series. In: IARC Monographs on the Evaluation of Carcinogenic Risk to Humans,
Vol. 69, Polychlorinated Dibenzo-para-dioxins and Polychlorinated Dibenzofurans. IARC,
World Health Organization, Lyon, France. On-line:
http://monographs.iarc.fr/ENG/Monographs/vol69/volume69.pdf
Kappenberger, L. and A.A. Buhlmann. 1975. Lungenveranderungen durch «seltene erden».
(Lung lesions caused by "rare earths"). Schweiz. Med. Wochenschr. 105:1799-1801.
Mogilevskaya, O.Y. andN.T. Raikhlin. 1967. Rare earth metals. In: Izrael'son, Z.I. Ed.
Toxicology of the rare earth metals. Israel Program for Scientific Translations, Jerusalem,
p. 132-141.
NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to
Chemical Hazards. Viewed online (2007): http://www.cdc.gov/niosh/npg
NTP (National Toxicology Program). 2007. NTP Results Report
http://ntp.niehs.nih.gov:8080/index.html?col=010stat
OSHA (Occupational Safety and Health Administration). 2007. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Viewed on-line at
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p id=999
2
Palasz A. and P. Czekai. 2000. Toxicological and cvtophysiological aspects of lanthanides
action. Acta Biochimica Polonica 47:1107-1114. Polish Biochemical Society. On-line:
http://www.actabp.p1/pdf/4 2000/1107-1114s.pdf
Sabbioni, E., R. Pietra, P. Gaglione et al. 1982. Long-term occupational risk of rare-earth
pneumoconiosis: A case report as investigated by neutron activation analysis. Sci. Total
Environ. 26: 19-32.
Schepers, G.W.H. 1955a. The biological action of rare earths. II. The experimental pulmonary
histopathology produced by a blend having a relatively high fluoride content. A.M. A. Arch. Ind.
Health. 12:306-316.
Schepers, G.W.H. 1955b. The biological action of rare earths. I. The experimental pulmonary
histopathology produced by a blend having a relatively high oxide content. A.M. A. Arch. Ind.
Health. 12:301-305.
Schepers, G.W.H., A.B. Delahant and A.J. Redlin. 1955. An experimental study of the effects
of rare earths on animal lungs. A.M. A. Arch. Ind. Health. 12:297-300.
Sullivan, M.F., B.M. Miller and J.C. Goebel. 1984. Gastrointestinal absorption of metals (51 Cr,
65Zn, 95mTc, 109Cd, 113Sn, 147Pm, and 238Pu) by rats and swine. Environ. Res. 35:439-453.
6

-------
9-26-2007
Sulotto, F., C. Romano, A. Berra et al. 1986. Rare-earth pneumoconiosis: A new case. Am. J.
Ind. Med. 9:567-575.
TERA (Toxicology Excellence for Risk Assessment). 1999. Development of Reference Doses
and Reference Concentrations for Lanthanides. Prepared for: U.S. Bureau of Land Management,
National Applied Resource Sciences Center. On-line: http://www.tera.org/pubs/Lanthanides.pdf
U.S. EPA. 1988. Recommendations for and Documentation of Biological Values for Use in
Risk Assessment. Environmental Criteria and Assessment Office, Cincinnati, OH. PB-179874.
On-line: http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=34855
U.S. EPA. 1991. Office of Health and Environmental Assessment Chemical Assessments and
Related Activities. Office of Health and Environmental Assessment, Washington, DC. April,
1991. OHEA-I-127.
U.S. EPA. 1994. Office of Health and Environmental Assessment Chemical Assessments and
Related Activities. Office of Health and Environmental Assessment, Washington, DC.
December 1994. OHEA-I-127.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Office of
Research and Development, Office of Emergency and Remedial Response, Washington, DC.
July, 1997. EPA/540/R-97/036. PB 97-921199.
U.S. EPA. 2005. Guidelines for carcinogen risk assessment. Risk Assessment Forum,
Washington, DC; EPA/630/P-03/001F. Federal Register 70(66): 17765-17817. Available
online at http://www.epa.gov/raf
U.S. EPA. 2006. Drinking Water Standards and Health Advisories. Office of Water.
Washington, DC. August 2006, EPA 822-R-06-013. On-line:
http://www.epa.gov/waterscience/criteria/drinking/dwstandards.pdf
U.S. EPA. 2007. Integrated Risk Information System (IRIS). Online. Office of Research and
Development. National Center for Environmental Assessment, Cincinnati, OH.
http ://www. epa. gov/iri s
Vocaturo, G., F. Colombo, M. Zanoni, F. Rodi, E. Sabbioni and R. Pietra. 1983. Human
exposure to heavy metals: Rare earth pneumoconiosis in occupational workers. Chest. 83:780-
783.
Vogt, P., M.A. Spycher and J.R. Ruttner. 1986. Pneumokoniose durch «seltene erden» (cer-
pneumokoniose). [Pneumoconiosis caused by "rare earths" (cer-pneumoconiosis)]. Schweiz.
Med. Wochenschr. 116:1303-1308.
Waring, P.M. and R.J. Watling. 1990. Rare earth deposits in a deceased movie projectionist: A
new case of rare earth pneumoconiosis. Med. J. Aust. 153:726-730.
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9-26-2007
Wells W.H. and V.L. Wells. 2001. The Lanthanides, Rare Earth Metals. In: Patty's Industrial
Hygiene and Toxicology, Fifth Edition, Volume 3, E. Bingham, B Cohrssen, and C.H. Powell,
ed. John Wiley and Sons, Inc., New York, NY. p. 423-458.
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