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EPA/63 5/R-08/018
www.epa.gov/iris
TOXICOLOGICAL R
OF
HALOGENATED PLATINUM SALTS AND
PLATINUM COMPOUNDS
11 Review Draft. This information is distributed solely for the
purpose of pre-dissemination peer review under applicable information quality guidelines. It has
not been formally disseminated by EPA. It does not represent and should not be construed to
Agency determination or policy. It is being circulated for review of its technical
science policy implications.
In Support
In teg i ' ¦" *
lary Information on the
)nnation System (IRIS)
January, 2009
NOTICE
U.S. Environmental Protection Agency
Washington, DC

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DISCLAIMER
This document is a preliminary review draft for review purposes only. This information
is distributed solely for the purpose of pre-dissemination peer review under applicable
information quality guidelines. It has not been formally disseminated by EPA. It does nui
represent and should not be construed to represent any Agency determination or policy. Mention
of trade names or commercial products does not constitute endorsement or recommendation for
use.
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CONTENTSCTOXICOLOGICAL REVIEW OF HALOGENATED PLATINUM SALTS
AND PLATINUM COMPOUNDS
DISCLAIMER	 ii
LIST OF TABLES	vi
LIST OF FIGURES	
LIST OF ABBREVIATIONS AND ACRONYMS			viii
FOREWORD			x
AUTHORS, CONTRIBUTORS, AND REVIEWERS			xi
1.	INTRODUCTION			 1
2.	CHEMICAL AND PHYSICAL INFORMATION			3
3.	TOXICOKINETICS			17
3.1.	ABSORPTION			17
3.1.1.	Oral			17
3.1.2.	Inhalation			20
3.1.3.	Dermal	22
3.2.	DISTRIBUTION	22
3.2.1.	Oral			22
3.2.2.	Inhalation			25
3.2.3.	Dermal			27
3.2.4.	Other Routes			27
3.3.	METABOLISM....		28
3.4.	ELIMINATION...,		28
3.4.1.	Oral	28
3.4.2.	Inhalation	29
3.4.3.	Dermal	31
3.4.4.	Other Routes	32
3.5 BIOLOGICALLY BASED TOXICOKINETIC MODELS	32
i; > IDENTIFICATION	39
4. i. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL
CONTROLS	39
: : : ' al	39
4.1.2. Inhalation	39
4.1.2.1.	Soluble Pt Forms	42
4.1.2.2.	Insoluble Pt Forms	67
4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS IN
ANIMAL S—ORAL AND INHALATION	69
4.2.1.	Oral	69
4.2.1.1.	Subchronic	69
4.2.1.2.	Chronic	70
4.2.2.	Inhalation	70
4.2.2.1. Subchronic	70
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4.2.2.2. Chronic	70
4.3.	REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION	71
4.3.1.	Oral	71
4.3.2.	Inhalation	71
4.4.	OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES AND
OTHER HAZARD IDENTIFICATION IS SUES	 2
4.4.1.	Acute Exposure Studies		; 2
4.4.1.1.	Oral	72
4.4.1.2.	Inhalation			74
4.4.1.3.	Dermal			75
4.4.2.	Short-term Exposure Studies			75
4.4.2.1.	Oral			75
4.4.2.2.	Inhalation			80
4.4.3.	Drug Studies		.. 	81
4.4.3.1.	Pharmacokinetics of Pt Anticancer Drugs	81
4.4.3.2.	Anticancer and Adverse Effects of Pt Anticancer Drugs	85
4.4.3.3.	Mode of Action for Nephrotoxicity of Pt Anticancer Drugs	89
4.5.	MECHANISTIC DATA AND OTHER f	S IN SUPPORT OF
THE MODE OF ACTION			90
4.5.1.	Sensitization Studies	90
4.5.1.1.	Soluble Pt Salts			90
4.5.1.2.	Insoluble Pt Forms	101
4.5.2.	Genotoxicity Studies	 	102
4.6.	SYNTHESIS OF MAJOR NONC AN EFFECTS	108
4.6.1.	Oral	108
4.6.2.	Inhalation	109
4.6.2.1.	Sensitization Effects	109
4.6.2.2.	Other Adverse Effects (Respiratory Irritation, Nephrotoxicity,
Neurotoxicity, Ototoxicity)	1 14
4.6.3.	Mode of Action Information	115
4.6.3.1.	Sensitization	115
4.6.3.2.	Other Considerations for Mode of Action	126
4.6.3.3.	Mode of Action Summary	129
4.7.	EVALUATION OF CARCINOGENICITY	130
-7.1. Summary of Overall Weight-of-Evidence	130
¦ : 7.2. Synthesis of Human, Animal, and Other Supporting Evidence	131
: 7.3. Mode of Action Information	131
¦i. • ¦' SUSCEPTIBLE POPULATIONS AND LIFE STAGES	131
-r.8.1. Possible Childhood Susceptibility	131
4.8.2.	Possible Gender Differences	132
4.8.3.	Other	132
5. DOSE-RESPONSE ASSESSMENTS	133
5.1.	ORAL REFERENCE DO SE (RfD)	133
5.1.1. Choice of Principal Study and Critical Effect - with Rationale
and Justification	133
5.2.	INHALATION REFERENCE CONCENTRATION (RfC)	135
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5.2.1.	Choice of Principal Study and Critical Effect - with Rationale
and Justification	135
5.2.2.	Methods of Analysis - Including Models (PBPK, BMD, etc.)	144
5.2.3.	RfC Derivation - Including Application of Uncertainty Factors (UFs)	147
5.2.4.	Previous RfC Assessment	150
5.3.	UNCERTAINTIES IN CHRONIC ORAL REFERENCE DOSE (RfD)
AND INHALATION REFERENCE CONCENTRATION (RfC)	 !'¦
5.4.	CANCER ASSESSMENT	
6.	MAJOR CONCLUSIONS IN THE CHARACTERIZATION OK HAZARD
AND DOSE RESPONSE		,...158
6.1.	HUMAN HAZARD POTENTIAL			158
6.2.	DOSE RESPONSE			160
6.2.1.	Noncancer/Oral			160
6.2.2.	Noncancer/Inhal ati on			161
6.2.3.	Cancer/Oral and Inhalation	 ... 	164
7.	REFERENCES			165
APPENDIX A. SUMMARY OF EXTERNA L I't.f.K kEVIEW AND PUBLIC
COMMENTS AND DISPOSITION	A-1
APPENDIX B. BENCHMARK DOSE (BMD) ¦ING	B-l
B. 1. SUMMARY OF BMDS MODELING RESULTS FOR Pt USING THE
OUTCOME OF SPTs FROM AN OCCUPATIONAL EXPOSURE STUDY	B-l
B. 1.1. Exposure Metrics.		B-l
B. 1.2. Approach for Dost-: - > Modeling and Results	B-4
B.1.3. Selection of POD	B-7
B.2. IN SEN SITIVIT Y TO BMDS MODEL IN FITTING THE INCIDENCE
OF POSITIVE. SKIN PRICK TESTS FOR Pt IN CATALYST WORKERS
USiNG DIFFERENT Pt DOSE METRICS	B-9
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LIST OF TABLES
2-1. Physical properties of Pt and selected Pt compounds	 ....4
2-2. Major uses of selected Pt compounds	
2-3.	Pt concentrations in air samples			
3-1.	Parameters and values in ICRP (1981) Pt biokinetics model..		35
3-2.	Default parameter values for ICRP (1994) model of absorptiu
particulates			38
4-1.	Prevalence of allergic symptoms			51
4-2. Pt specific and nonspecific allergic results			52
4-3. Pt sensitization in CPO workers and exposure to d	Pt
compounds in different work environments	55
4-4. Incidences of positive hexachloroplatinate SPT results among current workers
in different work areas in a U.S. precious metal reclamation facility in 1981	59
4-5. Symptoms, test results and relative risk of symptoms by Pt SPT result	60
4-6. Summary of selected enc ' " ' altli surveys of catalyst plant workers	62
4-7. Acute oral toxicity of Pi compounds in rats	73
4-8. Exposures, estimated <¦¦¦: • ;.. s, and effects in Sprague-Dawley rats exposed
to Pt compounds in drinking water or diet	77
4-9. Summary of pharmacokinetics properties for Pt anticancer drugs	83
4-10. Toxic effects associated with Pt anticancer drugs	89
4-11	Summary of genotoxicity studies of Pt compounds	103
iry of human epidemiology studies of allergic sensitization to Pt	112
5-i.	Concentration of soluble Pt for each exposure group in German catalyst
production workers	145
B-l. Number of observations of soluble Pt, as measured by stationary air monitors,
for each exposure group by year	B-2
B-2. Three different dose metrics for representing air concentrations of soluble Pt
in each of three exposure groups of German catalyst production workers
from Merget et al. (2000)	B-3
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B-3. BMD modeling results employing the pooled geometric mean of 1992 and
1993 stationary air monitoring data of soluble Pt as an exposure metric	B-6
B-4. BMD modeling results employing the mid-median of 1992 and 1993 stationary
air monitoring data of soluble Pt as an exposure metric	B-6
B-5. BMD modeling results employing the pooled median of 1992 and 1993 stationary
air monitoring data of soluble Pt as an exposure metric	 	 : ¦¦
B-6. BMD modeling results employing the pooled arithmetic mean of 1992 and :
stationary air monitoring data of soluble Pt as an exposure metric	B-7
LIST OF FIGl I
3-1. ICRP (1981) model of Pt toxicokinetics		33
3-2. Generic ICRP (1994) model of Iranspoit of particles deposited in regions of
the respiratory tract	 ... .		37
3-3. Generic ICRP (1994) model of absorption of particles deposited in the
respiratory tract	38
B-l. BMD modeling results employing the pooled geometric mean of 1992
and 1993 stationary air monitoring data of soluble Pt as an exposure
metric to support results Table B-3	B-9
B-2. BMD modeling results employing the mid-median of 1992 and 1993 stationary
i a of soluble Pt as an exposure metric to support Table B-4	B-12
rnlts employing the pooled median of 1992 and 1993 stationary
i of soluble Pt as an exposure metric to support Table B-5	B-l 5
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LIST OF ABBREVIATIONS AND ACRONYMS
AIC	Akaike's information criterion
AOO	acetone and olive oil
API	al-Proteinase inhibitor
AAS	atomic absorption spectrometry
BMC	benchmark concentration
BMCL	benchmark concentration, lower 95% confiu
BMD	benchmark dose
BMDL	benchmark dose, lower 95% confidence lim
BMDS	benchmark Dose Software
BMR	benchmark response
BSA	bovine serum albumin
CASRN	Chemical Abstracts Service Registry V
( HO	Chinese hamster ovary
CI	confidence interval
CPO	chemical process operator
CV	coefficient of variation
DF	deposition fractions
DMSO	diniethy 1 sill f oxide
DNCB	2,4-dinitrochlorobenzene
FEF	forced expiratory flow
FEV	forced expiratory volume
FVC	forced vital capacity
GFR	glomerular filtratic" r^tc
GI	gastrointestinal
GM	geometric mean
GSD	geometric standard deviation
USA	human serum albumin
IARC	International Agency for Research on Cancer
ICRP	International Commission on Radiological Protection
IFN	interferon
II.	interleukin
ICP-MS	inductively coupled-mass spectrometry
IRIS	Integrated Risk Information System
KLH	keyhole limpet hemocyanin
LCL	lower confidence limit
LD50	median lethal dose
LOD	Limit of detection
LOQ	limit of quantitation
LOAEL	lowest-observed-adverse-effect level
MCV	mean corpuscular volume
MDI	methane-4,4'-diisocyanate
MIIC	major histocompatibility complex
MMAD	mass median aerodynamic diameter
MN	micronucleus
NOAEL	no-ob served-adverse-effect level
NIST	National Institute of Standards and Technology
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OSHA
OVA
PBMC
PBPK
PCA
PCNA
PD
PEF
PEFR
PGE
PBA
PLN
PM
POD
POR
Pt
RAST
RfC
RfD
ROS
SD
SE
SPT
SPTC
TLV
TMA
TNF
TPC
TWA
IF
U.S. EPA
Occupational Safety and Health Administration
ovalbumin
peripheral blood mononuclear cells
physiologically based pharmacokinetic
passive cutaneous anaphylaxis
proliferating cell nuclear antigen
provocative dose
peak expiratory flow
peak expiratory flow rate
Pt group element
phytohemagglutin
popliteal lymph node assay
particulate matter
point of departure
prevalence odds ratios
platinum
radioal 1 ergenosorbent test
reference concentration
reference dose
reactive oxygen species
Standard deviation
Standard error
skin prick test
skin prick test i
threshold limit
trimellitic anhv<-i >
uncertainty factor
it c ]Fr"'**-onmental Protection Agency
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FOREWORD
The purpose of this Toxicological Review is to provide scientific support and rationale
for the hazard and dose-response assessment in IRIS pertaining to chronic exposure to
halogenated platinum (Pt) salts and Pt compounds. It is not intended to be a comprehensive
treatise on the chemical or toxicological nature of halogenated Pt salts and Pt compounds.
The intent of Section 6, Major Conclusions in the Characterization of Hazard and Dose
Response, is to present the major conclusions reached in the derivation of the reference dose,
reference concentration, and cancer assessment, where applicable, and to characterize the overall
confidence in the quantitative and qualitative aspects of hazard and dose response by addressing
the quality of data and related uncertainties. The discussio	the limitations
of the assessment and to aid and guide the risk assessor in the ensuing steps of the risk
assessment process.
For other general information about this assessment or other questions relating to IRIS,
the reader is referred to EPA's IRIS Hotline at (202) 566-1076 (phone), (202) 566-1749 (fax), or
hotline.iris@epa.gov (email address).
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER/AUTHOR
Andrew A. Rooney, Ph.D.
Office of Research and Development
National Center for Environmental Assessment
Research Triangle Park, NC.
AUTHORS
Channa Keshava, Ph.D.
Office of Research and Development
National Center for Environmental Assessment
Research Triangle Park, NC.
Allan Marcus, Ph.D.
Office of Research and Development
National Center for Environmental Assessment
Research Triangle Park, NC.
Amanda Persad, Ph.D., DABT
Office of Research and Developrr
National Center for Environmenta! Assessment
Research Triangle Park, N
Reeder Sams, Ph.D.
Office of Research and De v s <
National Center for Environmental Assessment
Research Triangle Park, NC.
AUTHORS/CON TR1B V TORS
Andrew K. Hotchkiss, Ph.D.
Office of Research and Development
National Center for Environmental Assessment
Research Triangle Park, NC.
Janice S. Lee, Ph.D.
Office of Research and Development
National Center for Environmental Assessment
Research Triangle Park, NC.
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J. Michael Davis, Ph.D.
Office of Research and Development
National Center for Environmental Assessment
Research Triangle Park, NC.
MaryJane Selgrade, Ph.D.
Office of Research and Development
National Environmental Effects Research Laboratory
Research Triangle Park, NC.
Julie Klotzbach, Ph.D.
Gary Diamond, Ph.D.
Peter McClure, Ph.D., DABT
Daniel Plewak, B.S.
Syracuse Research Corporation
Syracuse, NY.
Under Interagency Agreement No. DN 89939822-01-0
of Energy.
REVIEWERS
This document and the accompanying JUL-VAkJ UUlIili iary has been reviewed by EPA
scientists, interagency reviewers from other federal agencies, and the public, and peer reviewed
by independent scientists ex	; "a. A summary and EPA's disposition of the comments
received from the ii	?r reviewers and from the public is included in
Appendix A of the	of halogenated Pt salts and Pt compounds.
INTERNAL
Susan Reith
Office of Research and uevelopment
National Center for Environmental Assessment
Ted Berner
! ii: :¦ . earch and Development
National Center for Environmental Assessment
Glinda Cooper, Ph.D.
Office of Research and Development
National Center for Environmental Assessment
Marion Hoyer
Office of Air and Radiation
Office of Transportation and Air Quality
PA and U.S. Department
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1. INTRODUCTION
This document presents background information and justification for the Integrated Risk
Information System (IRIS) Summary of the hazard and dose-response assessment of halogenated
platinum (Pt) salts and Pt compounds. IRIS Summaries may include oral reference dose (RfD)
and inhalation reference concentration (RfC) values for chronic and other exposure durations,
. .
and a carcinogenicity assessment.
The RfD and RfC, if derived, provide quantitative information for -. r s		 ssments
for health effects known or assumed to be produced through a nonlinear (pre ;; i ; ¦ o lold)
mode of action. The RfD (expressed in units of mg/kg-day) is defined as an estimate (with
uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human
population (including sensitive subgroups) that is likely to be without an. appreciable risk of
deleterious effects during a lifetime. The inhalation RfC (expressed in units of mg/m3) is
analogous to the oral RfD, but provides a continuous inhalation exposure estimate. The
inhalation RfC considers toxic effects for both the respiratory system (portal-of-entry) and for
effects peripheral to the respiratory system (extrarespiratory or systemic effects). Reference
values are generally derived for chronic exposures (up to a lifetime), but may also be derived for
acute (#24 hours), short-term (>24 hours up to 30 days), and subchronic (>30 days up to 10% of
lifetime) exposure durations, all of which are derived based on an assumption of continuous
exposure throughout the duration specified. Unless specified otherwise, the RfD and RfC are
derived for chronic exposure duration.
The carcinogenicity assessment provides information on the carcinogenic hazard
potential of the substance in question and quantitative estimates of risk from oral and inhalation
exposure may be derived. The information includes a weight-of-evidence judgment of the
likelihood that the agent is a human carcinogen and the conditions under which the carcinogenic
effects may be expressed. Quantitative risk estimates may be derived from the application of a
low-dose extrapolation procedure. If derived, the oral slope factor is a plausible upper bound on
;tiv ¦, imate of risk per mg/kg-day of oral exposure. Similarly, an inhalation unit risk is a
i ¦;: :.)le upper bound on the estimate of risk per jig/m3 air breathed.
Development of these hazard identification and dose-response assessments for
naiogenated Pt salts and Pt compounds has followed the general guidelines for risk assessment as
set forth by the National Research Council (1983). EPA Guidelines and Risk Assessment Forum
Technical Panel Reports that may have been used in the development of this assessment include
the following: Guidelines for the Health Risk Assessment of Chemical Mixtures (U. S. EPA,
1986a), Guidelines for Mutagenicity Risk Assessment (U.S. EPA, 1986b), Recommendations for
and Documentation of Biological Values for Use in Risk Assessment (U.S. EPA, 1988),
Guidelines for Developmental Toxicity Risk Assessment (U.S. EPA, 1991), Interim Policy for
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Particle Size and Limit Concentration Issues in Inhalation Toxicity (U.S. EPA, 1994a), Methods
for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry
(U.S. EPA, 1994b), Use of the Benchmark Dose Approach in Health Risk Assessment (U.S. EPA,
1995), Guidelines for Reproductive Toxicity Risk Assessment {U.S. EPA, 1996), Guidelin for
Neurotoxicity Risk Assessment (U.S. EPA, 1998), Science Policy Council Handbook: Risk
Characterization (U.S. EPA, 2000a), Benchmark Dose Technical Guidance Document (U.S.
EPA, 2000b), Supplementary Guidance for Conducting Health Risk Assessment of Chemical
Mixtures (U. S. EPA, 2000c), A Review of the Reference Dose and Refer e. < ~ titration
Processes (U.S. EPA, 2002), Guidelines for Carcinogen Risk Assessment : ! 'A, 2005a),
Supplemental Guidance for Assessing Susceptibility from Early-Life Kxpu.... ^ lo Carcinogens
(U.S. EPA, 2005b), Science Policy Council Handbook: Peer Review (U.S. EPA, 2006a), and .4
Framework for Assessing Health Risks of Environmental Exposures to Children (U. S. EPA,
2006b).
The literature search strategy employed for this compound was based on the Chemical
Abstracts Service Registry Number (CASRN) and at least one common name. Any pertinent
scientific information submitted by the public to the IRIS Submission Desk was also considered
in the development of this docum	ture was reviewed through August 2008.
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2. CHEMICAL AND PHYSICAL INFORMATION
Pt is a third row transition metal and is a member of the Pt group metals (ruthenium,
rhodium, palladium, osmium, iridium, and Pt) (Giandomenico and Matthey, 1996).	ge
concentration in the rocky crust of the earth is approximately 0.001-0.005 mg/kg (Wnkj, iv9 1).
Elemental Pt is a silver-gray, lustrous, ductile, malleable metal (O'Neil, 2001). Pt metal is
chemically stable in air even at high temperatures and is unaffected by most acids (Czerczak and
Gromiec, 2001; WHO, 1991). When present in compounds, Pt exists most commonly in the
+2 and +4 oxidation states (Czerczak and Gromiec, 2001; Giaiuiomenico and Matthey, 1996).
Chemical structures and selected chemical and physical properties of halogenated Pt salts and Pt
compounds are listed in Table 2-1.
Pt is found in nature both in the metallic form and in minerals such as sperrylite,
cooperate, braggite, ferroplatinum, moncheite, rustenburgite, and vvsoiskite (Rentier et al., 2005;
Seymour and O'Farrelly, 2001; WHO, 1991). During manufacture, Pt group metals in the ore
are first concentrated, and are then treated with a highly oxidizing acid solution, such as aqua
regia, hydrochloric acid-chlorine, or hydrochloric acid-bromine, to dissolve some or all of the Pt
group metals (Rentier et al., 2005; Czerczak and Gromiec, 2001; Seymour and O'Farrelly, 2001).
Hexachloroplatinic and tetrachloroplatinic acids are water-soluble forms of Pt salts that can be
produced in this process (see Table 2-1 for structures). The metals are then separated out using
selective dissolution and precipitation techniques. Pt is typically precipitated from solution
through the addition of ammonium chloride, which precipitates ammonium hexachloroplatinate
from solution under refinery conditions.
Both soluble and insoluble Pt compounds can be present in environmental and
occupationa ;¦ i pies. Soluble Pt is measured with quantitative techniques after extracting
samples into ; solution (e.g., water, dilute hydrochloric acid, or nitric acid). Therefore, soluble
Pt is an opei	..ally-defined fraction of Pt in which many different species of Pt can be present
depending on the extraction solution (see Analysis ofPt in Ambient Air and Source Samples
below for further discussion). In this document, the term soluble Pt compounds primarily
includes Pt(SO.t):, tetraamine Pt dichloride (TPC) ([Pt(NH3)4]Cl2), and the halogenated Pt salts,
c " »unds for which there are published kinetic or toxicity data. When samples contain
haiugcnated Pt salts, these compounds are likely to be a portion of the soluble Pt reported
because of their solubility in water and other common extraction solutions (see Table 2-1 for
solubility of individual compounds). Pt salts of any of the halogen elements are collectively
referred to as halogenated Pt salts. Salts of the ions [PtCl4]2" and [PtCl6]2" are the most important
commercial Pt compounds, although there are also Pt salts of other halides (e.g., bromine)
(Cotton and Wilkinson, 1988; Cleare et al., 1976). Halogenated Pt salts are generally considered
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Table 2-1. Physical properties of Pt and selected Pt compounds
Name
Pt
Pt(ll) oxide
Pt(IV) oxide
Pt(II) chloride
Pt(IV) chloride
CASRN
7440-06-4
12035-82-4
1314-15-4
10025-65-7
13454-96-1; 37773-49-2
Synonyms
Platin; platinum black;
platinum sponge; liquid
bright platinum
Platinum oxide;
platinum monoxide
Platinum dioxide;
platinic oxide; Adam's
catalyst
Platinum dichlotide;
platinous chloride; muriate of
platinum
Platinum tetrachloride;
platonic chloride
Structure
Pt
Pt=0
0=pt=0
Cl\
Pt—CI
cix 7ci
Pt
CI ci
Molecular weight
195.078
211.08
227.08
265.98
336.89
Molecular formula
Pt
PtO

PtCl2
PtCl4
Halogenated Pt salt
No
No

No; halogenated Pt, not a salt
Yes
Form
Silver-gray, lustrous,
malleable, and ductile
metal; also prepared as a
black powder and spongy
masses
Black tetrahedral
iwder;
Hexagonal crystals
Grayish-green to brown
powder; hexagonal crystals
Red-brown cubic crystals
Melting point
1,768.2°C (boiling point
= 3,825°C)
325°C (decomposes)
450°C
581°C
327°C (decomposes)
Density
21.5 g/cm3
.4.1 g/cm3
11.8 g/cm3
6.0 g/cm3
4.30 g/cm3
Water solubility3
Insoluble
Insoluble
Insoluble
Insoluble
142 g/100 g H20 at 25°C
Other solubility3
Insoluble in mineral and
organic acids; reacts with
aqua rcgia
Insoluble in ethanol;
soluble in aqua regia
Soluble in concentrated
acid and dilute alkaline
solutions
Insoluble in ethanol; soluble
in hydrochloric acid and
ammonium hydroxide
Soluble in ethanol
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Table 2-1. Physical properties of Pt and selected Pt compounds
Name
Tetraamine Pt dichloride
Clsplatln
Carlioplatin i Pt cllnltrate
CASRN
13933-32-9
15663-27-1
41575-94-4
18496-40-7
Synonyms
Tetraammine platinous
chloride; tetraammine-
dicMoroplatinum(II);
tetraammineplatinum(II)
chloride; TPC
cis-Diamminedichloroplatinum;
n'.v-platinum II; cis-DDP; CACP;
CPDC; DDP; briplatin; cismaplat;
cisplatyl; citoplatino; lederplatin;
neoplatin; platamine; platinex;
platiblastin; platinol; platinoxan;
platistin; randa
acid platinum complex;
¦'. arboxylato) platinum) II);
CBDCA; JM-8; Paraplatin
Not available
Structure
h3n nh3
\ / f 1
Pt CI
/ \ L J2
h3n nh3
CI—Pt-NH,
!
0
2+
Pt
0^ „0~ 0^ +-0
N N
1- 1-
0 0
Molecular weight
334.109
inn
371.25
319.088
Molecular formula
[Pt(NH3)4]Cl2
PtC6H604(NH3)2
Pt(N03)2
Halogenated Pt salt
No halide is pre sen
ion and not a liganc
coordinated to Pt (I
and Hughes, 1999;
et al., 1976); thereto, *
halogenated complex st.:;
No
No
Form
White, crystalline powder
Deep yellow solid
White crystals, soluble in water
Not available
Melting point
250°C (decomposes)
270°C (decomposes)
Not available
Not available
Density
Not available
Not available
Not available
Not available
Water solubility3 : ; "¦ ; ti;, HO
0.253 g/100 g H20 at 25°C
Approx. 15 mg/mL
Not available
Other solubility3 M' i '; ¦. ¦: ¦: ¦. - ; i ethanol
Insoluble in most common solvents;
soluble in dimethyformamide
Not available
Not available
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Table 2-1. Physical properties of Pt and selected Pt compounds
Name
TetracMoroplatinic(II)
acid
Hexachloroplatinic(IV) acid
Potassium tetracfaioroplalimite
iiiun hexachloroplatlnate
CASRN
Not available
16941-12-1
10025-99-7
16921-30-5
Synonyms
Dihydrogen
tetrachloroplatinate(II)
Hexachloroplatinic acid
hexahydrate; dihydrogen
hexachloroplatinate(IV)
tetrachloroplatinate(II); platinous
potassium chloride; potassium
platinochloride; potassium
chloroplati::::'
Potassium hexachloroplatinate(IV);
Platinic potassium chloride;
potassium platonic chloride
Structure
O O
x ¦ /
CM X
CL
o O
CM
1	1
+
X
L™__J
CI CI
r +i \/2-
H CI	Pt—C
¦ ^ n/ ^
CI CI
r . Cl\ P
K Pt\
LK 2 / \
CI CI
CI CI
r .i \/»
K 2 C' /P\ C'
CI CI
Molecular weight
336.90
409.81
.^.09
485.99
Molecular formula
H2PtCl4
2PtCl6.6H20
K2PtCl4
2PtCl6
Form
Not available
Brownish-yellow hygroscopic
crystals
Ruby-red crystals
Orange-yellow ciystals or yellow
powder
Halogenated Pt salt
Yes
Yes
Yes
Yes
Melting point
Not available
60°C
500°C (decomposes)
250°C (decomposes)
Density
Not avai
2.43 g/cm3
3.38 g/cm3
3.5 g/cm3
Water solubility3
Not avai
140 g/100 g H20 at 18°C
Soluble in water
0.77 g/100 g H20 at 20°C
Other solubility3
Not
Soluble in ethanol and ether
Soluble ethanol and ether
Insoluble in ethanol
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Table 2-1. Physical properties of Pt and selected Pt compounds
Name
Platinum(IV) sulfate
Transplatln
Sodium hexacMorojsiatinate | Ammonium hexachloroplatinate
CASRN
7446-29-9
14913-33-8
16923-58-3
16919-58-7
Synonyms
Platinic sulfate; Sulfuric
acid, platinum(4+) salt
(2:1)
trans-Diamminedichloroplatinum;
trans-diamminedichloro-
platinum(II); trans-DDP;
trans-dichlorodiammineplatinum;
trans-dichlorodiammine-
platinum(II); trans-platinur
diammine dichloride;
trans-plati
dichloride
Disodium hexachloroplatinate;
sodium hexachloroplatinate
Ammonium chloroplatinate;
ammonium platinic chloride;
ammonium platinum chloride;
ammonium hexachloroplatinate(IV);
diammonium hexachloroplatinate(2-);
diammonium platinum hexachloride;
platinate(2-), hexachloro-
diammonium, (OC-6-11)-; platinum
ammonium chloride; quatemium-17;
platinic sal ammoniac
Structure
1 1
O O
x\ //
CO
/ \
O O
i I
IO
ID
+
c
NH—Pi—NH3
CI CI
+1 \ /2.
a CI	Pt—CI
L "2 n/\
CI CI
CI CI
r .i
NH4 2 CI Pt CI
CI CI
Molecular weight
387.204
300.04
453.78
443.88
Molecular formula
Pt(S04)2
PtCl2(NH3)2
Na2PtCl6
(NH4)2PtCl6
Halogenated Pt salt
No

Yes
Yes
Form
Hygroscopic, greenish-
black mass
Pale yellow solid
Yellow, hygroscopic crystals
Orange-red crystals or yellow powder
Melting point
Not available
Decomposes at 270°C
Not available
Decomposes at 380°C
Density
Not available
Not available
Not available
3.065 g/cm3
Water solubility3
Soluble in water
0.036 g/100 g H20 at 25°C
53 g/100 gH20 at 16°C
0.5 g/100 gH20 at 20°C
Other solubility3
r, ¦ T: ible in dilute acids,
nfcohol. ether
Soluble in dimethyl sulfoxide and
dimethyl formamide
Soluble in alcohol
Practically insoluble in alcohol
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Table 2-1. Physical properties of Pt and selected Pt compounds
Name
Sodium
tetrachloroplatinate
Ammonium
tetrachloroplatinate
Ammonium hexabromt ¦ ¦
Oxallplatln
CASRN
10026-00-3
13820-41-2
17363-02-9

>4-3
Synonyms
Platinate(2-), tetrachloro-,
disodium, (SP-4-1)-;
disodium
tetrachloroplatinate;
platinous sodium chloride;
sodium chloroplatinite;
sodium
tetrachloroplatinate(II)
tetrahydrate
Ammonium platinous
chloride; ammonium
chloroplatinate(II);
bis(ammonium)
tetrachloroplatinate! 2-);
diammonium
tetrachloroplatinate;
platinate(2-),
diammoniuir
Ammonium
(IV); Platina
diammoniun:
AClUlUlllVJIJlClllilCllt'
(SiJ-4-2-( lR-trans))-( 1,2-Cyclohexanediamine-
N,N')ethanedioato(2-)-0,0')platinum; 1 -OHP;
Dacplat; Eloxatin; JM-83; Oxalato(lR,2R-cyclo-
hexanediammine)platinum(II); Oxalate
(trans-1 -1,2-cyclohexanediamine)platinum(II);
oxalatoplatin; oxalatoplatinum;
IR,2R| -1,2-Cyclohexanediamine-N,N')
oxalate(2-)-0,0')platinum; platinum,
([1R,2R] -1,2-cyclohexanediamine-.kappa.N,
kappa. N') ethanedioato(2-)-kappa01, kappa 02)-,
(SP-4-4)-
Structure
r i c'\/'
CI CI
r - C'\ /'
[ nh;
;.;i
i
CM
	 J
Br Br
U
Br	Pt—Br
p/\
Br Br
XZ ZI
/2l\
o o
) {
o o
Molecular weight
454.93
372.v7
710.58
397.29
Molecular formula
Na2PtCl4.4H20
(NH:! 1
(NH4)2PtBr6
PtCgH14N204
Halogenated Pt salt
Yes
Yes
Yes
No
Form
Red prisms
Dark ruby-red crystals
Powder
Colorless, thin triangular plates with truncated
vertices
Melting point
100°C
140-150°C (decomposes)
Decomposes at 145°C
Not available
Density
Not available
2.936 g/cm3
Not available
Not available
Water solubility3
Soluble in water
Soluble in water
0.59 g/100 g H20 at 20°C
7.9 mg/mL
Other solubility3
Soluble in ethanol
Insoluble in alcohol
Not available
Not available
Tor solubility, quantitaih c Aila fire reported in the table when available in the sources examined.
Sources: ChemlDplus (2007, 2006); Hamelers et al. (2006); Lide (2005); Czerczak and Gromiec (2001); Lewis (2001); O'Neil (2001); Johnson Matlhey (2000).
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soluble and both their solubility and toxicity appear to be related to the halogen-ligands
coordinated to Pt and the negative charge of these complexes (Nischwitz et al., 2004; Ravindra et
al., 2004; Rosner and Merget, 2000; Cleare et al., 1976). There is a distinction between the
halogenated Pt salts and ([Pt(NH3)4]Cl2), a Pt compound in which halide is present as an ion and
not a ligand coordinated to Pt; therefore, [Pt(NH3)4]Cl2 is a halogenated complex, not a
halogenated Pt salt (Linnett and Hughes, 1999; Cleare et al., 1976). The terms insoluble Pt or
insoluble Pt compounds principally refer to the following compounds for which there are
published kinetic or toxicity data: Pt metal, Pt oxide (PtO), Pt dioxide (PtC	Pt dichloride
(PtCl2).
Analysis ofPt in Ambient Air and Source Samples
Since the toxicity of some metals, including Pt, is h	chemical
species in which they are present, analytical techniques need to be 	 that have the ability to
identify and quantify the species of metals present. These techniques are not readily available
and frequently involve research-grade analytical instrumentation and expertise. In the absence of
routine laboratory methods for speciation, Pt concentrations in both environmental media and in
source samples are most frequently reported as t^t~f - .e., Pt in all chemical forms and
oxidation states that were present in the sample) ; < ¦; v, > ;'t is measured in samples following
complete sample digestion followed by quantitative determination often using inductively
coupled-mass spectrometry (ICP-MS) (Barefoot and Van Loon, 1999). To provide qualitative
information regarding the chemical nature of Pt compounds in a sample matrix, investigators
have frequently measured soluble and insoluble Pt. These studies involve extracting samples
into a solution (e.g., water, dilute hydrochloric acid, or nitric acid) followed by filtration to
exclude small Pt-containing particles that are not in solution. The soluble fraction is an
operationally-^ lined fraction of Pt in which many different species of Pt can be present
depending on i sk: extraction solution. When extracting into water, Pt salts with halogen- or
nitrogen-donoi ngands can be present and in the presence of slightly or highly acidic solutions,
Pt can be oxidized and brought into solution (WHO, 1991). As such, characterization of Pt from
environmental samples as "soluble Pt" does not provide information regarding the chemical
species present in a sample. Techniques available from other disciplines are being developed for
a i ition to environmental samples in order to identify and quantify the species of metals
present (e.g., X-ray absorption fine structure techniques).
Production and Uses ofPt and Pt Compounds
Primary production of Pt (production from mining) in the United States during 2004 was
4,040 kg (worldwide production was 214,000 kg) (George, 2006). The Stillwater Mine and East
Boulder Mine located in south-central Montana are the only primary sources of commercial Pt in
the United States (George, 2006). Over 70% of the world's primary production of Pt takes place
at the Bushveld complex of South Africa (George, 2006; Renner et al., 2005; Seymour and
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O'Farrelly, 2001). Secondary production (recovery and recycling) of Pt group metals has
become increasingly important due to the rising prices of these metals (George, 2006, 2004;
Johnson Matthey, 2006b; Rennet" et al., 2005). Secondary production of Pt in the United States
was 3,080-5,130 kg during 2004 (George, 2004). Total U.S. imports and exports of Pt in ...1 -05
were 86,400 and 20,000 kg, respectively (George, 2006). Workers in the primary and seco; i "
production of Pt may be expected to be exposed to similar conditions since similar selective
dissolution and precipitation processes are used in these industries.
The two major uses of Pt metal are in jewelry and automotive emission control catalysts
(catalytic converters), which represent approximately 30 and 46%, respecth
worldwide demand for Pt as of 2005-2006 (Johnson Matthey, 2007, 2006a; Renner et al., 2005).
Use in jewelry has been declining in recent years due to the rising price of Pt (George, 2006,
2004). Pt-based catalysts have been used in gasoline-fueled vehie m ' : U.S. since 1975. The
Pt content of catalysts used in gasoline-fueled vehicles has decreascu uum the amounts used in
the 1970s due to improvements in catalyst formulations. The Pt content of catalytic converters
used in gasoline-fueled vehicles also changes over time depending on the price of Pt and
technological issues (e.g., emissions reduction strategies). Pt-based catalysts (e.g., oxidation
catalysts and catalyzed wall-flow filters) are bei-1... m-¦. .isingly employed to reduce emissions
from diesel vehicles and nonroad engines. Pt is also commercially available as an additive to
diesel fuel (i.e., in liquid form), which can be used as an after-market additive for diesel fleets.
Other commercial applications of Pt metal include oxidation catalysts in the manufacture of
acetic acid, nitric acid, sulfuric acid, and other chemicals; thermocouples; electrical contacts and
devices; electrodes; high temperature electrolysis; medical and dental materials; laboratory and
industrial apparatus; resistance thermometry; high temperature equipment for use in the glass
industry; mA ^eramic coatings (Renner et al., 2005; Czerczak and Gromiec, 2001; Lewis, 2001;
O'Neil, 2001, Seymour and O'Farrelly, 2001). Pt oxidation catalyst technology also is used in
other emissi - :< »ntrol applications such as gas turbines (WHO, 1991).
Hexachloroplatinic acid is the most important of the commercial Pt compounds (Renner
: : 2005). It is prepared by treatment of Pt sponge (metallic Pt in a colloidal form) with aqua
regit! or moderately concentrated hydrochloric acid saturated with chlorine (Renner et al., 2005;
. ¦ ^ak and Gromiec, 2001). Hexachloroplatinic acid is used in the manufacture of most Pt
»unds and for impregnating catalyst support materials (Renner et al., 2005; Lewis, 2001).
In catalytic converters for gasoline-fueled vehicles, metallic forms of Pt and other Pt-group
elements (e.g., palladium and rhodium) are contained in a 90% aluminum oxide coating of a
honeycomb-type support material made of a high melting point ceramic material (Palacios et al.,
2000). In the manufacture of catalytic converters, hexachloroplatinic acid, palladium chloride,
and rhodium chloride are impregnated into the aluminum oxide coating and then converted to the
metallic forms by reduction in a hydrogen gas stream at high temperatures (Ravindra et al.,
2004).
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The presence of Pt in dental materials and medical treatments represents a separate
category of Pt usage wherein exposure is intentional and the potential toxicity of the form of Pt
used may relate to its medical role. The Pt anticancer drugs currently approved for clinical use
are cisplatin, carboplatin, and oxaliplatin (see Table 2-1 for chemical structures), although a large
number of carboplatin analogues have been developed and tested to various degrees in clinical
trials (Sanderson et al., 1996). These drugs have been used to treat testicular, ovarian, head amr
neck, bladder, lung, prostate, and cervical cancer (Seymour and O'Farrelly, 2001; Giandomenico
and Matthey, 1996). They are especially effective against testicular tumors, where long-term
remission is achieved in 90% of patients treated. Section 4.4.3 (Drug Studies) provides an
overview of pharmacokinetic properties of some of the Pt anticancer drugs and adverse effects
associated with their use. A comprehensive review of their pharmacokinetic and toxicological
properties is beyond the scope of this document, because they are not expected to represent a
significant source of environmental exposure to Pt. Another medical use of metallic Pt is in
noble metal dental alloys that also contain silver, gold, and palladium (Benemann et al., 2005;
Herr et al., 2003; Wataha et al., 1995). Pt content in noble metal dental restorations is known to
vary, and has been reported to be as high as 20% (Herr et al., 2003).
Major uses of selected Pt compounds are listed in Table 2-2.
Table 2-2. Major uses of st
jounds


Name

Use
Platinum) IV) oxide
1314-15-4
Hydrogenation catalyst (by forming Pt black)
Platinum(II) c
10025-65-7
Preparation of Pt salts
Cisplatin
15663-27-1
Chemotherapeutic agent
Carboplatin
41575-94-4
Chemotherapeutic agent
HexacMoropl;
16941-12-1
Manufacture of most Pt compounds; impregnating
catalyst support materials; electroplating; etching zinc for
printing; manufacture of Pt mirrors, indelible ink, and
ceramics; in microscopy; as a catalyst for the manufacture
of S03
Potassium tetracMoroplatinate(II)
10025-99-7
Manufacture of Pt(II) compounds
Potassium hexachloroplatinate(IV)
16921-30-5
In photography; laboratory reagent
j.	et al. (2005); Lewis (2001); O'Neil (2001); Seymour and O'Farrelly (2001).
Release ofPt from Vehicles Equipped with Catalytic Converters
Vehicles equipped with catalytic converters are thought to represent one of the main
sources of Pt in ambient air, especially in areas heavily populated with automotive vehicles
(Fritsche and Meisel, 2004; Lesniewska et al., 2004; Ranch et al., 2004; Schins et al., 2004;
Gomez et al., 2002; Moldovan et al., 2002; Gomez et al., 2001; Ranch et al., 2001; Zereini et al.,
2001; Ranch and Morrison, 2000; Rosner and Merget, 2000; Alt et al., 1993). A comparison of
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Pt concentrations in air and airborne-dust samples collected in Germany in 1988 (when catalytic
converters were introduced in Germany), 1989, 1992, 1997, and 1998 showed a trend for a
continuous increase in Pt concentrations during this period (Zereini et al., 2001). The difference
in mean Pt concentrations between air samples collected in 1988 (3 pg/m3) and 1998 (147 . ^/m3)
was about 49-fold (Zereini et al., 2001). Although similar studies of airborne Pt concentration
trends in the U.S. were not located, sediment-based data from an urban lake near Boston ,
Massachusetts (Upper Mystic Lake) support a similar increase in Pt concentrations following
widespread use of catalytic converters in the U.S. (Rauch and Hemond, 2003). Deposition rates
from 1940 to 1980 were 0.5-0.8 jig/m2 year (±0.5 standard deviation	>er Mystic
Lake. The deposition rate increased after the introduction of catalytic 10 urn
(Artelt et al., 1999a). Since very small amounts of Pt are emitted from catalysts, measurements
are usually limited to total Pi		...e few studies reporting measurements of soluble Pt,
investigators have extracted tuples into dilute acid solutions (Moldovon et al., 2002; Artelt et
al., 1999b). These solutions were filtered to exclude small metallic Pt particles from being
considered soluble. In spite of this precaution, metallic Pt that exists on particles smaller than
the pore size of the filter were reported as soluble Pt (Artelt et al., 1999b). As discussed earlier
in this chapter, the use of an acidic extraction solution can bring some Pt species into solution
that were not initially present as strictly water-soluble Pt. A further challenge in interpreting
these data is the complex matrix effects provided by motor vehicle exhaust particulate matter
(PM). Motor vehicle PM is a largely organic matrix that can provide a hydrophobic coating for
trace metals present in the exhaust stream. Extracting this organo-PM in a slightly acidic
solution is not expected to liberate all of the relevant Pt in the matrix. When present,
halogenated Pt salts would be part of the soluble Pt fraction; however, since no data are available
on the Pt species present in the soluble Pt fraction, these data do not provide information on the
emissions or ambient concentrations of halogenated Pt salts.
Estimates of the fraction of the total Pt emitted from catalytic converters as soluble Pt
compounds have ranged from <1 to <10% (Moldovan et al., 2002; Artelt et al., 1999b). Pt
oxides have been estimated to account for <5% of Pt emitted (see review by Rosner and Merget,
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2000). As discussed above, the Pt species in the soluble Pt fraction reported in these studies
have not been identified. Laboratory experiments have demonstrated the formation of soluble Pt
salts after incubating nanocrystalline metallic Pt attached to aluminum oxide particles in
physiological saline solutions (Nachtigall et al., 1996).
Levels of Pt in the Environment and Potential for Human Exposure
Levels of total Pt detected in ambient air samples collected in various '-.ur, . - ::
world are shown in Table 2-3 (see Ravindra et al., 2004 for a review of envir	)
element [PGE] levels). The ultralow levels of Pt in environmental media po;.<. \ -
difficulties that have precluded the determination of the chemical form of Pt in .uiiiicui
samples (Ljubomirova et al., 2008; Nischwitz et al., 2004, 2003). Therefore, concentrations of
total Pt are generally reported and even when there are data on soluble Pt, speciation data are not
available to determine the percentage represented by halogenated Pt salts. The Pt levels in
ambient air samples shown in Table 2-3 have values in the ap,>'"'" ;'nate range of 1-500 pg Pt/m3
(1 x 10"6 to 500 x 10"6 ug Pt/m3) with a maximum range of 2 Pt/m3 in Probst et al. (2001).
While most studies of Pt in the environment have been performed in Europe, one recent study of
ambient Pt in the U.S. reported concentrations of airborne Pt ranging from 6 to 9 pg Pt/m3
(Ranch et al., 2005). In contrast, air samples from manufacturing workplaces using Pt have
shown much higher values. For example, Merget (2000) reported approximate lower and upper
quartile values of 930 and 3,490 ng soluble Pt/m3 (0.93 and 3.49 ug soluble Pt/m3) for personal
air samples collected from hig:.	3 workers in a German catalyst production plant. Baker
etal. (1990) reported concenti < '	irborne Pt in a U.S. precious metals reclamation plant
3	1
that were also in the ug/m range. Mean air concentrations of Pt salts for sampling locations
were between i: m .¦ M ug Pt/m3 (Baker et al., 1990).
'Measured air concentrations of Pt were reported as "salts"; therefore measurements are assumed to be equivalent to
soluble Pt in Baker et al. (1999). The ranges of measurements within a sampling location, SDs, and analytical
methods were not reported.
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Table 2-3. Pt concentrations in air samples
Region
Special features
Pt concentration
(pg/m3, unless Indicated
otherwise)
Reference
California, USA
—
<0.05
Johnson et al., 1975
Boston, USA
Urban area, PMi0
6.9 ± 1.9
Rauch et al, 2005
Tsukuba, Japan
—
14-184 ng/g
Mukai et al., 1990
Dortmund, Germany
Urban areas
0.02-5.1
Alt et al., 1993
Dortmund, Germany
Highway
30
Alt et al., 1993
Munich, Germany
Bus, tramway
0-43.1, mean: 7.3
Schierl and Fruhmann, 1996
Graz, Austria
Tunnel dust
11.0 ±3.8
Schierl and Fruhmann, 1996
Bruck/Mur, Austria
Tunnel dust
13.0 ±3.8
Wegscheider and Zischka, 1993
Stuttgart, Germany
Urban area, 1997
68 ng/g
He Inters and Mergel, 1998
Czech Republic
Various sites
9-62
Vlasankovaetal., 1999
Italy
—
6.4-38.8
Caroli et al., 2001
Germany
Background level
<2
Rosner and Merget, 2000
Rome
Heavy traffic areas
7.8-38.8
Petrucci et al., 2000
Copenhagen
Heavy traffic, 1993
13
Probst et al., 2001
Copenhagen
Heavy traffic, 1995-1997
250-2,740
Probst et al., 2001
Madrid, Spain
—
<0.1-57.1, mean: 12.8
Gomez et al., 2001
Madrid, Spain
Urban area, PMi0
Mean: 7.3
Gomez et al., 2002
Madrid, Spain
Ring road area, PI*
Mean: 17.7
Gomez et al., 2002
Goteborg, Sweden
Urban area, PMi0

Gomez et al., 2002
Goteborg, Sweden
Ring road area, PI*;,,,
Mean: 4.1
Gomez et al., 2002
Rome
Urban area, PM10
Mean: 8.6
Gomez et al., 2002
Rome
Ring road area, PR'
Mean: 8.1
Gomez et al., 2002
Madrid, Spain
Highway, PMi0
15-19
Gomez et al., 2003
Munich, Germany
—
4.4-42.4, mean: 13.6
Dietl et al., 2000
Munich
Tramway, 1993-1994
Mean: 7.3
Schierl, 2000
Munich
Tramway, 1995-1996
Mean: 21.5
Schierl, 2000
Germany

3
Zereini et al., 2001
Germany
1998
147
Zereini et al., 2001
Frankfurt, Germany
PMjo, 2001, major street
8.7-28.4, mean: 15.7
Zereini et al., 2004
Frankfurt, Germany
PMio, 2001, side street
4.1-9.5, mean: 6.2
Zereini et al., 2004
Frankfurt, Germany
PMio, 2001, nonurban
3.0-7.9, mean: 5.2
Zereini et al., 2004
Goteborg, Sweden
Urban area, PM10
0.9-19
Rauch et al., 2001
Vienna, Austria
PM10
4.3
Kanitsar et al., 2003
Vienna, Austria
<30 fim
38.1
Kanitsar et al., 2003
Buenos Aires, Argentina
PM10
2.3-47.7, mean: 12.9
Bocca et al., 2006
Buenos Aires, Argentina
Road dust
123.8-486.3 ng/g
Bocca et al., 2006
Bialystok, Poland
Tunnel dust
23.3 ±3.8 ng/g
Lesniewska et al., 2004
Bialystok, Poland
Road dust
35.9-110.9 ng/g
Lesniewska et al., 2004
Perth, Australia
Road or tunnel dust
53.84-440.46 ng/g
Whitely and Murray, 2003
London
Road dust
101.6-764.2 ng/g
Ward and Dudding, 2004
Source: Modified from Ravindra et al. (2004).
Recent research efforts to determine levels of Pt and other PGEs (e.g., palladium and
rhodium) in soils adjacent to heavily traveled roads or sediments receiving runoffs from roads
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indicate that concentrations of PGEs may exceed background levels by a factor of 100 or more
(Zereini et al., 2007; Whiteley and Murray, 2005; Ek et al., 2004; Fritsche and Meisel, 2004;
Lesniewska et al., 2004; Ranch et al., 2004; Ward and Budding, 2004; Kylander et al., 2003;
Whiteley and Murray, 2003; Gomez et al., 2002, 2001; Ranch et al., 2001; Ranch and Morrison,
2000). Based on a review of reported levels of Pt and other PGEs in road dust, soil, vej,
rainwater, and bodies of water and their sediments, Ravindra et al. (2004) concluded that levc
of Pt and other PGEs in the environment have been increasing in parallel with the increased use
of Pt and other PGEs in automobile catalysts. Although the Ravindra et al. (2004) conclusions
are largely based on exposure data from Europe, lake sediment data from Massachusetts support
the same trend for increased levels of Pt and other PGEs in parallel with automobile catalyst use
in the U.S. (Ranch and Hemond, 2003). Data from the U.S. indicate that PGE concentrations in
roadside soil and dust are comparable to European studie	>1; Hodge and Stallard,
1986). Furthermore, the data from samples in the U.S. suppon hum easing concentrations of Pt in
roadside dust over time with higher Pt and PGE concentrations closer to roads with heavier
traffic patterns (Ely et al., 2001; Hodge and Stallard, i 986).
The above information on Pt emissions ana environmental levels indicate the potential
for exposure of the general population in the U.! : ; trope to Pt in one or more forms.
Because of the increasing use of automobile catalytic converters since the 1970s, there has been
some expectation that human exposure to Pt - >; .: i i - ly be increasing, particularly for people who
spend considerable time in the proximity of roadways. However, several studies of urinary
levels of Pt as a marker of Pt exposure have not found consistent correlations between elevated
levels of Pt in urine and expot	xaffic (see Benemann et al., 2005; Ravindra et al., 2004;
Herr et al., 2003 for review). For example, multiple regression analyses of urinary Pt levels in
samples of the German population (people not expected to have occupational exposure to Pt)
found that the number of noble metal dental restorations was a significant explanatory variable,
whereas traffic-related variables were not (Benemann et al., 2005; Herr et al., 2003). These
findings indicate that exposure to Pt through dental alloys currently may be a more significant
ire pathway for the general population than traffic-related exposures. Several other studies
. .. ; ound that nonenvironmental sources of Pt exposure (e.g., dental alloys and Pt from
i ¦ ¦:.(i seses including breast implants) may confound estimates of true environmental exposures
raj, 2004; Merget et al., 2002). Because Pt can enter into the food chain, there is an
expectation that exposure to Pt can also occur through the diet (Jorhem et al., 2008; Frazzoli et
al., 2007). A study of Pt levels in the diet of 84 German children indicated that dietary intake of
Pt ranged from <0.81 to 32 ng Pt/kg-bw/week, with a median value of 2.3 ng Pt/kg-bw/week
(Wittsiepe et al., 2003). The daily intake estimates for children in the Wittsiepe et al. (2003)
study of German diets (about 0.33 ng Pt/kg-bw/day) were lower than daily estimates for adults in
dietary intake studies of adults in the U.K. (2.9 ng Pt/kg-bw/day; Ysart et al., 1999) and Australia
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(20.1 ng Pt/kg-bw/day; Vaughan and Florence, 1992). Data on dietary levels of Pt for adults or
children in the U.S. were not located.
Bioavailability ofPt in the Environment
Although Pt and other PGEs in automobile exhaust are expected to be predominar
water-insoluble metallic or oxide forms, there is evidence that environmental transformation to
more soluble forms can occur to a limited extent via oxidation by organic materials in sediments
or soils such as humic acids, a transformation that may be enhanced due to the ultrafme nature of
the emitted particles (Sures and Zimmermann, 2007; Ravindra et al., 2004). Conjugatic
microbially produced ligands (siderophores) may enhance the bioavailability and increase the
mobility of Pt compounds in the environment (Dahleimer et al., 2007). Transformation to more
soluble forms is expected to increase the bioavailability of Pt. Uptake of Pt and other PGEs by
plants and aquatic organisms has been demonstrated; thus, entry of Pt into the food chain is
expected to some extent (e.g., Hooda et al., 2008; Sures an'4 Z:mmermann, 2007; Ek et al., 2004;
Ravindra et al., 2004). Although these studies demonstrate - -depositional transformation of
Pt and clear PGE uptake, there are no speciation data on environmental Pt in these studies to
identify the Pt compounds associated with greater bioavailability. Two recent in vitro studies
(Colombo et al., 2008a, b) have compared bioavailability of Pt in road dust to the bioavailability
of powdered automobile catalyst using artificial digestive and lung fluids (see Section 3.1.1 and
3.1.2 for complete study details). Colombo et al. (2008a, b) report that Pt in roadside dust is 7-
50 times more bioavailable thun Pt from, the powdered automobile catalysts. However, no
speciatk	"	he particular Pt compounds that were more bioavailable.
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3. TOXICOKINETICS
Toxicokinetic data are available for a number of soluble Pt compounds (principally
?t[S().t]2, the halogenated Pt salts PtCU, (NH4)2PtCl6, and K^PtCU) and insoluble Pt compounds
(Pt metal, Pt(>2, and PtCl 2). As discussed in detail in Chapter 2, measurements of soluble Pt are
obtained using quantitative techniques after extracting samples into a solution (e.g., water, dilute
hydrochloric acid, or nitric acid). Therefore, soluble Pt is an operationally-defined fraction of Pt
in which many different species of Pt can be present depending on the extraction solution.
Reported estimates of oral absorption of insoluble Pt metal (Pt-AM); complex) or soluble Pt
such as the halogenated Pt salt PtCU are <1% of the dose (Arte	1 " ; ^svore et al.,
1975b, c). Inhaled soluble and insoluble Pt compounds are clt	atory tract by
mucociliary transport and absorption (Moore et al., 1975a). Soluble PtCSO t); is cleared from the
lung more rapidly than insoluble Pt metal and Pt(>2, suggesting greater absorption of soluble Pt
compounds such as PK SO t h (Moore et al., 1975a). A consistent pattern of tissue distribution of
Pt (i.e., highest concentrations in kidney, liver, spleen) was observed following absorption of
soluble (e.g., Pt[S04]2 or the halogenated Pt salts PtCU, N a 2 PtCl,,) and insoluble (e.g., Pt metal,
PtCl;, Pt-AI2O5 complex) Pt compounds (Artelt et al., 1999a; Reichlmayr-Lais et al., 1992;
Massaro et al., 1981; Lown et al., 1980; Hoi brook et al., 1975; Moore et al., 1975a, b; Yoakum et
al., 1975). Parenteral studies with PtCl4 indicate that Pt accumulates in the fetus (Moore et al.,
1975a, b), suggesting that Pt is transported across the placenta for at least one soluble Pt
compound. Fecal excretion of unabsorbed Pt is the dominant excretory pathway for ingested
soluble and insoluble Pt compounds (Artelt et al., 1999a; Moore et al., 1975a, b, c). Absorbed Pt
is excreted in feces and urine (Moore et al., 1975b, c). Inhaled soluble Pt forms (Pt[SO.i]2 and
the halogen; ; = t salt PtCU) are excreted from the body more rapidly than insoluble Pt forms
, slower excretion of insoluble forms may, in part, reflect slower
clearance from the lung.
3.1, ABSORPTION
3.1.1. Oral
nusuipuun uf dietary Pt was estimated in a study of 21 Australians in which Pt levels
weie reported for hair, blood, urine, and feces (Vaughan and Florence, 1992). The study also
analyzed total Pt content in a variety of foods obtained from a 1986 Market Basket Survey after
the foods had been prepared by normally prepared cooking processes. For both dietary and
human samples, Pt concentrations were determined by adsorptive voltammetry (limit of
detection [LOD] not reported) and speciation or identification of individual Pt compounds was
not reported. The reported mean concentrations of Pt in hair, blood, urine, and feces were
4.90 ± 4.76 ug/kg tissue, 0.60 ± 0.39 |ig/L, 0.25 ± 0.25 |ig/L, and 8.65 ± 5.13 ug/kg, respectively.
Concentrations of Pt in urine showed the widest variation with a 46-fold range (0.02-0.92 |ig/L)
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that is only slightly reduced when normalized to creatinine concentration to correct for dilution
(0.03-0.82 jig/g creatinine). The authors estimated the daily intake of 1.44 ug Pt/day (20.6 ng
Pt/kg-bw/day) using a hypothetical diet and their measurements of Pt concentrations in food
(ranging from 8.11 ug/kg for liver to 0.13 ug/kg for full-cream milk). Using the 20.6 ng
Pt/kg-bw/day dietary estimate, and the concentration of Pt excreted in urine, the author
estimated that 42-60% of the dietary Pt was absorbed (Vaughan and Florence, 1992). Othe
quantitative estimates of amounts and rates of gastrointestinal (GI) absorption of Pt compounds
in humans have not been reported. The Vaughan and Florence (1992) estimate i ; ¦; roximately
50 times the Pt absorption measured in rodents, and the authors suggest that the	relative
absorption may reflect the greater bioavailability of the Pt found in dietary sources. The
absorption estimate is based on dietary estimates based on a hypothetical diet, and the authors
note that human absorption measurements from subjects receiving diets with known Pt
concentrations is required to make more reliable conclusions on absorption.
Colombo et al. (2008a, b) used a physiologically based extraction test with artificial
digestive and lung fluids to study the potential i uptake of PGEs from roadside dust in vitro
(the artificial lung fluid results are described below m Section 3.1.2 Inhalation). Material
analyzed included: (1) a Certified Reference Material sample of road dust with a maximum
particle size of 90 urn from the Institute of Reference Materials and Measurements; (2) powdered
automobile catalyst with maximum particle size of 74 um from the National Institute of
Standards and Technology (NIST): and (3) PGE-hydroxides for Pt, palladium, and rhodium
(Pt[OH]2, Pd[OH]2, Rh[OH|<) mixed 4:88 with alumina powder to simulate PGEs released from
catalysts. Bioavailability i : . igestive tract was estimated with the use of a physiologically
based extraction test perfoiiiicu ,ii two phases to simulate the passage of material through the
acid conditions of the stomach and the near-neutral conditions of the small intestine (Colombo et
al., 2008a). Concentrations of PGEs in these environmental samples before and after the
physiologically based extraction test were determined by ICP-MS. The percent of Pt that is
bioavailable in the reference sample of road dust was estimated at 15.5-17% based on the results
of the physiologically based extraction test (Colombo et al., 2008a). In contrast, the authors
reported that 0.1-0.3% of the Pt from powdered catalyst and 0.01% of the Pt from the simulated
PGE released from automobile catalyst was bioavailable. The authors suggest that PGEs in road
dust are likely to have been transformed to more soluble compounds in the environment;
however, the study did not include characterization of individual Pt compounds.
Studies in rats indicate that only a very small fraction of the administered oral dose of
PtCl4, a soluble halogenated Pt salt, is absorbed. Moore et al. (1975b, c) administered a gavage
dose of tracer amounts of [191'193PtCl4] to male CD-I rats (n = 20) and measured whole-body
retention kinetics by whole-body counting of [191Pt] gamma activity for 28 days following
dosing. Whole-body retention exhibited approximately bi-phasic, first-order kinetics, with an
initial rapid phase that coincided with relatively high rates of fecal excretion of Pt (contributed
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by excretion of unabsorbed Pt). Based on extrapolation of the terminal phase of whole-body
retention kinetics to the time of dosing (this phase would be expected to be minimally influenced
by excretion of unabsorbed Pt), absorption was estimated to have been <1% of the administered
dose (this value presumably represents a group mean; SD was not reported).
Artelt et al. (1999a) administered a gavage dose of a suspension of Pt-coated .
particles to female Lewis rats (n = 8) and measured amounts of Pt recovered in'
8 days following the Pt dose. The Pt-coated particles were produced to be similar
particulates emitted from automobile exhaust catalytic converters, which consi
metal complexed to AM); particles. The Pt-AM); particles were produced by
onto A1203 powder (<5 urn particle size), followed by calcinating (at 473-737°K) in the presence
of oxygen, followed by reduction in hydrogen. The resulting complex	; ¦ i ¦¦¦< ntent of
approximately 3.1% (w/w). The solubility of Pt in the complex way approximately 0.4% in
distilled water and 10% in 0.9% NaCl (i.e., isotonic). The Pt dose administered to the animals
was 1,030 ug Pt (contained in 33.3 mg of the Pt-Al203 complex). Pt concentrations in tissues
and urine (collected in metabolic cages) were measured by atomic absorption spectrometry
(AAS) (LOD = 0.5 jig/g tissue; limit of quantitation [LOQ] = 1 jig/g tissue) and/or ICP-MS
(LOD = 7.5 ng/g tissue; LOQ =15 ng/g tissue). Based on recovery of Pt in tissues (blood,
femur, kidney, liver, lung, spleen, washed GI tract) 8 days following the dose and cumulative
excretion, absorbed Pt was estimated to have been approximately 0.11% of the administered
dose (this value presumably represents a croup mean; SD was not reported).
Detection of Pt in kidney and other tissues following oral exposures to Pt compounds
provides additional evidence - a	on of Pt (Artelt et al., 1999a; Reichlmayr-Lais et al.,
1992; Lown et al., 1980; Hot brook et al., 1975; Moore et al., 1975b, c). These studies are
described in g	ter detail in Section 3.2.1.
The R ilmayr-I.ais et al. (1992) study is particularly pertinent because it directly
compared the tribution of Pt following oral exposure to a relatively soluble (PtCl4) or
insoluble (PtCl?) Pt compound. Reichlmayr-Lais et al. (1992) exposed male Sprague-Dawley
(nine rats per dose) to PtCl; or PtCU in the diet (ad libitum) at concentrations of 0, 0.01,
5, 1.0, 5.0, 10, or 50 mg Pt/kg diet for 4 weeks. The corresponding group mean Pt
not reported), determined from measurements of food consumption, were 0, 0.004,
0 , 0.041, 0.21, 0.42, 2.0, 4.0, and 21 mg Pt/animal in animals exposed to PtCl; and 0, 0.004,
0.020, 0.040, 0.21, 0.41, 2.0, 4.1, and 21 mg Pt/animal in animals exposed to PtQU. Pt
concentrations (mg/kg tissue dry weight) in various tissues (adipose, brain, femur, heart, kidney,
liver, muscle, plasma, spleen, testes, carcass) were measured at the conclusion of exposure by
AAS (LOD was not reported). The highest tissue concentrations of Pt were found in kidney,
which increased with increasing Pt dose. Concentrations in kidneys of animals exposed to PtCl;
or PtCl4 were similar; the group mean concentration ratios (PtC^PtCU) for the five exposure
groups for which concentrations were reported (0.5, 1, 5, 10, and 50 mg Pt/kg diet) were 1.4, 1.5,
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0.73, 0.75, and 0.81. These results provide supporting evidence of absorption of Pt during
exposures to PtCl; or PtCU in the diet. Although quantitative estimates of the fractions of the
dose absorbed were not reported, the comparison of Pt levels in kidney suggests that absorption
of soluble PtCl4 and relatively insoluble PtCl; were similar.
In summary, results of the Moore et al. (1975b, c) study suggest that oral absorption of
the water-soluble Pt compound, PtCl 4, is <1% of the administered dose. Results from the Artelt
et al. (1999a) study suggest that absorption of an oral dose of a Pt-Al203 com pie a:
approximately 0.11% of the Pt dose. The Pt solubility of this complex in isotonic sodium
chloride solution was approximately 10% (Artelt et al., 1999a). Based on these limited
observations, oral absorption of both soluble and insolu	be <1% of an
administered dose. Similar tissue concentrations obser	: nilar oral doses of
relatively soluble (PtCU) or insoluble (PtCl;) Pt compo ' 	-	olubility did not
substantially affect absorption (Reichlmayr-Lais et al., 1992).
3.1.2. Inhalation
Quantitative studies of amounts and rates ot adsorption of inhaled Pt compounds in
humans have not been reported. Colombo et al. (2008a, b) used a physiologically based
extraction test with artificial digestive and lung fluids to study the potential human uptake of
PGEs from roadside dust in vitro (the artificial digestive fluid results are described above in
Section 3.1.1 Oral). Material analyzed included: (1) a Certified Reference Material sample of
road dust with a maximum nartide size of 90 [im from the Institute of Reference Materials and
Measurements; (2) powdered automobile catalyst with maximum particle size of 74 [im from the
NIST; and (3) PGE-hydrokit;^ .or Pt, palladium, and rhodium (Pt[OH]2, Pd[OH]2, Rh[OH]3)
mixed 4:88 with alumina powder to simulate PGEs released from catalysts. In Colombo et al.
(2008b), bioavailability in the lung was estimated with the use of two simulated lung fluids in
vitro: (1) Gamble's solution representative of interstitial fluid of the deep lung, and (2) artificial
representative of more acidic environment in the lung. The percent of Pt that
and therefore bioavailable, in the reference sample of road dust was estimated at
/ 36% in the artificial lysosomal fluid (Colombo et al., 2008b). In contrast, the
i ' - Pt from powdered catalyst and the simulated PGE released from automobile
5t in the artificial lysosomal fluid was <5% bioavailable (data from Figure 2 in Colombo et
al., 2008b). The bioavailability in the higher pH (7.4) Gamble's solution was considerably lower
(<0.5%) compared to the lower pH (4.5) artificial lysosomal fluid for all the PGEs. The authors
suggest that Pt compounds in road dust are likely to have been transformed to more soluble
compounds in the environment; however, the study did not include characterization of individual
Pt compounds
As is generally the case for inhaled particulates, absorption of inhaled aerosols of Pt
compounds that are deposited in the respiratory tract are expected to be influenced by size of the
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inhaled particles and solubility as well as the size-dependent pattern of regional deposition
within the respiratory tract (Bailey and Roy, 1994; James et al., 1994). Fine particles (<1 jim)
deposited in the bronchiolar and alveolar region can be absorbed after extracellular dissolution or
may be ingested by phagocytic cells and transported from the respiratory tract. Larger panicles;
(>2.5 jim) that are deposited, primarily, in the ciliated airways (nasopharyngeal and
tracheobronchial regions) can be transferred by mucociliary transport into the esophagus ar ;
swallowed. Studies in animals have observed retention kinetics of inhaled Pt aerosols typical c
mucociliary clearance of particles from the respiratory tract, combined with absorption of
particles deposited in the deeper regions of the respiratory tract. For example, Moore et al.
(1975a) exposed CD-I rats (81 animals per compound, sex not reported), nose-only for
48 minutes, to aerosols of [191,193Pt] as insoluble Pt02 (7-8 mg/m3) or Pt metal (7-8 mg/m3), or
as soluble PtC'U (5 mg/m3) or Pt(SO.t): (5-6 mg/m3). The aerodyr - ¦ meter of the
particulate aerosols was reported as "nearly 1.0 jim" (this value appeals iu have been calculated
based on the nebulizer droplet size and concentration of the nebulizing solution). Whole body
retention kinetics of [191Pt] were measured by whole-body counting of [191Pt] gamma activity for
up to 20 days following exposure. Fast and slow phases of whole-body retention kinetics of Pt
were evident for all four Pt compounds (see Section 3.4.2). The fast phase occurred during the
first 24 hours following exposure and coincided with the appearance of relatively large amounts
of Pt in feces (relative to urine) indicative of mucociliary clearance of Pt initially deposited in the
respiratory tract. Initial lung burdens were reported as 14% of initial body burden (coefficient of
variation [CV] = 34%) following exposure to Pt metal and 16% (CV = 30%) of initial body
burden following exposure to . v™.al lung burdens for other Pt compounds were not
reported). During the fast of elimination, approximately 37% of the initial lung burden
was eliminated from the lung following exposure to Pt metal. The corresponding fast phase
elimination was 43% following exposure to Pt©2 and 26% following exposure to Pt(SO.t): (these
values presumably represent group means; values for SD were not reported). Pseudo-first-order
elimination half-times of Pt from the lung for the slow phase were approximately as follows: Pt
"i "-h1 19 days; PO2, 8 days; and Pt(SO.t):, 4 days. These estimates are based on reported data
1 ¦			 ¦. :¦ : ition for the period 2-16 days postexposure reported in Table 1 of Moore et al.
. ¦.: i - for PtCl4 were not reported. The above half-times suggest that soluble Pt(S04)2
eared from the lung more rapidly than the less-soluble Pt metal or PtO;.
Artelt et al. (1999a) exposed female Lewis rats (four animals/dose) to aerosols of a
Pt-AM); complex (see Section 3.1.1 for more detailed description of study) having a mass
median aerodynamic diameter (MMAD) of 1.3 urn (geometric standard deviation [GSD] not
reported), and Pt content of 2.7%. The exposure was nose-only, 5 hours/day, 5 days/week for
13 weeks to 4 or 12 mg/m3 of the Pt-AM); aerosol (approximately 0.1 or 0.3 mg Pt/m3). Urine
and fecal Pt were measured 3 times during the exposure, and Pt in tissues (adrenals, blood,
bronchial lavage fluid and cells, femur, kidney, liver, lung, spleen, stomach) was measured at the
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conclusion of the 90-day exposure. Pt in tissues and excreta were measured by ICP-MS
(LOD = 7.5 ng/g tissue; LOQ = 15 ng/g tissue). The estimated mean total amounts of Pt
recovered in all tissues (including lung) and excreta were 776 and 1,390 ug in animals exposed
to 0.1 or 0.3 ug Pt/m3, respectively. These represent estimates of the total amounts of Pt
deposited in the respiratory tract during the exposure. Of these amounts, Pt in feces amounted to
approximately 98%; and approximately 1% was recovered in lung, and 1% was recovered in
urine and tissues other than lung. The mean amount of Pt in lung at the conclusion of the study
was 5.19 ug (SD = 0.48, approximately 0.67% of total) and 17.8 ug (SD : .... approximately
1.3% of total) in animals exposed to 0.1 or 0.3 mg Pt/m3, respectively. Pi - vail ability was
estimated as the total amount of Pt recovered in bone, kidney, liver, splee.., ,..v>macfi, and urine,
expressed as a fraction of the body burden (i.e., sum of tissues, urine plus lung). Estimated mean
bioavailability percentages were 31.4 and 22.7% (SD not reported) in the animals exposed to
0.1 or 0.3 mg Pt/m3, respectively. Since absorbed Pt may have been excreted in feces (Artelt et
al., 1999a; Moore et al., 1975b, c), this represents a minimum estimate of the fraction of the body
burden that had been absorbed.
In summary, based on the results of the Moore et al. (1975a) rat study, following
inhalation of soluble and relatively insoluble tornis of i't aerosols (approximately 1 [im particle
size), Pt deposited in the lung was eliminated from the lung by mucociliary clearance to the GI
tract and by absorption from the lung. Basec < surements of lung clearance kinetics during
days 2-16 after exposure (i.e., beyond the early mucociliary clearance phase of elimination),
soluble Pt(SO.t): appeared to be absorbed more rapidly from the lung than the less-soluble forms,
Pt metal and Pt02. The Artelt .	. 9a) study provides a quantitative estimate of the total
amount of Pt deposited in mag and amounts retained in and absorbed from the lung during a
90-day expose to an aerosol of a Pt-AM)* complex (approximately 1.3 urn particle size). Of
the total ami ::i, estimated to have been deposited in the respiratory tract during the exposure,
approximate i 1 •% was recovered in feces, approximately 1% was recovered in lung, and 1%
was recovered in urine and tissues other than lung.
Ai,i, Dermal
ies are available that provide information on the absorption of Pt when exposure
occurs from dermal contact with environmentally relevant Pt compounds.
3.2. DISTRIBUTION
3.2.1. Oral
The tissue distribution of Pt following oral administration of soluble (Pt[SO.t]: and the
halogenated Pt salt PtCl.t) or insoluble (PtCl; and Pt metal) Pt compounds, localizes primarily to
soft tissues, with the highest residual concentrations achieved in kidney, liver, and spleen (Artelt
et al., 1999a; Reichlmayr-Lais et al., 1992; Massaro et al., 1981; Lown et al., 1980; Holbrook et
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al., 1975; Moore et al., 1975a, b). Similar patterns of distribution (i.e., highest concentrations in
kidney, liver, spleen) were observed for these four soluble and insoluble Pt compounds.
Reichlmayr-Lais et al. (1992) exposed male Sprague-Dawley rats (nine rats per dose) to
PtCl; or PtCl4 in the diet (ad libitum) at concentrations of 0.5, 1.0, 5.0, 10, or 50 mg Pt/kg elk-'
for 4 weeks. The corresponding group mean Pt intakes (SD not reported), determined from
measurements of food consumption, were 0.21, 0.42, 2.0, 4.0, and 21 mg Pt/animal in anim - -
exposed to PtCl2 and 0.21, 0.41, 2.0, 4.1, and 21 mg Pt/animal in animals exposed to PtCl4. Pt
concentrations (mg/kg tissue dry weight) in various tissues (adipose, brain, femur, heart, kidney,
liver, muscle, plasma, spleen, testicles, carcass) were measured at the conclusion of exposure by
AAS (LOD and LOQ not reported). The highest tissue concentrations were found in kidney,
which increased with increasing Pt dose. Concentrations in kidneys of animals exposed to PtCl2
or PtCl4 were similar; the group mean concentration ratios (PtCliiPtCU) for the five exposure
groups for which tissue concentrations were reported (0.5, 1, 5, 10, or 50 mg Pt/kg diet) were
1.4, 1.5, 0.73, 0.75, and 0.81 (calculated from group mean data reported in Tables 4 and 5 of
Reichlmayr-Lais et al., 1992). Tissue distribu "	so similar in rats exposed to PtCl2 or
PtCl4, apparent from comparison of the ratios ol trie Ft concentration in tissues compared to that
of plasma (calculated from group mean data rep re.'-. -; Tables 4 and 5 of Reichlmayr-Lais et al.,
1992). For example, tissue:plasma Pt concentration (jig Pt/g dry tissue) ratios in rats exposed to
10 mg Pt/kg diet as PtCl2 were: kidney, 226; liver, 9; spleen, 7; femur, 6.5; skeletal muscle, 3.5;
heart, 3.0; and brain, testes, and fat, <1.5. Tissue:plasma Pt concentration (jig Pt/g dry tissue)
ratios in rats exposed to 10 mg Pt/kg diet as PtCl4 were: kidney, 300; liver, 15; femur, 12;
spleen, 8.5; skeletal muscle, 3.5; brain, 4.5; heart and testes, 3.0; and fat, <1.5. These results
suggest that ti;	-; > - on of Pt absorbed during exposures to PtCl2 or PtCl4 in the diet are
similar.
observations of the kidney having the highest residual concentrations of
x>sure to PtCl4 are consistent with those reported by Moore et al.
lie CD-I rats described in detail in Section 3.2.1. Following a single oral tracer
14], [191Pt] gamma activity was detected above background only in kidney and
Micentrations were not reported). Moore et al. (1975c) reported the highest
trations in kidney following intravenously-administered [191PtCl4] from the same study
xtion 3.2.4).
Holbrook et al. (1975) exposed male Sprague-Dawley rats (2-16 animals per dose) to
Pt(S04)2 or PtCl4 in drinking water (ad libitum) at concentrations of 106 or 319 mg Pt/L
(Pt[S04]2), and 319 mg Pt/L (PtCl4). Total Pt doses were reported as 26 or 80 mg Pt/rat during
the exposure to Pt(S04)2 and 60 mg Pt/rat during the exposure to PtCl4. Concentrations
(jig Pt/g wet) of Pt in tissues (blood, brain, heart, kidney, liver, spleen, testes) were determined
immediately following 8 or 9 days of exposure. Pt in tissues was measured by emission
spectroscopy; the detection limit of this method was reported in Yoakum et al. (1975) as 0.01-
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i at
dto:
0.05 ug/electrode. The highest concentrations of Pt were in kidney in animals exposed to
Pt(SO.t): or PtCl4. In animals exposed to Pt(SO.t):, kidney Pt concentrations (jig Pt/g wet weight)
were 0.26 ± 0.05 (SD, n > 4) following exposure to 106 mg Pt/L and 4.5-4.7 jig/g (n = 2)
following exposure to 319 [ig Pt/L. The latter kidney concentrations were similar to that
observed in animals exposed to PtC'U at a similar dose (60 mg Pt/rat as PtCl4, compared
Pt/rat as Pt[SO.t]:): 4.8 ± 0.5 ug/g (SD, n > 4). Tissue:blood Pt concentration (jig Pt/g wet
tissue) ratios in animals exposed to 106 mg Pt/L of Pt(SO.t): (25 mg Pt/rat) were r- j ¦ ? vs
(calculated from group mean data reported in Table 4 of Holbrook et al., 1975): kidney, 5; liver,
1; testes, 0.8; spleen, 0.4; heart, 0.4; and brain, not detected. Tissue:blood Pt coii^cmration ratios
in animals exposed to 319 mg Pt/L of Pt(S04)2 (80 mg Pt/rat) were as follows: kidney, 21; liver,
4; heart, 1; spleen, 0.6; brain, 0.07; and testes, not detected. Tissue:blood Pt concentration ratios
in animals exposed to 319 mg Pt/L PtCU (60 mg Pt/rat) were as follows: kidney, 21; liver, 10;
spleen, 1; and brain, heart, and testes, not detected.
Holbrook et al. (1975) also compared the tissue distributions of Pt in rats following a
single gavage dose (382 mg Pt/kg) or intraperitoneal dose (113 mg Pt/kg) of Pt(SO.t):. Data
were obtained from survivors of a 14-day lethality study, and the doses administered were close
to the median lethal dose (LD50). The highest Pt concentration following the oral dose was in
kidney. Tissue:blood Pt concentration (jig Pt/g wet tissue) ratios in animals exposed to the oral
dose ofPt(S04)2 were as follows (calculated from group mean data reported in Table 5 of
Holbrook et al., 1975): kidney	1; liver, 0.7; heart, 0.3; testes, 0.15; and brain, 0.03.
Concentrations of Pt in liver were substantially higher following the intraperitoneal dose;
tissue:blood Pt concentration umua wac as follows: kidney, 37; liver, 34; spleen, 16; heart, 3;
testes, 1; and brain, 0.6.
Lown et al. (1980; Massaro et al., 1981) reported tissue concentrations in male Swiss
.
mice at various times following single or repeated doses of Pt(S04)2. In the single-dose study,
mice (40 animals/dose) received a gavage dose of 144 or 213 mg Pt/kg (7-day I. Do? and LD2s
respectively). Pt concentrations (jig/g wet weight) in tissues (blood, brain [cerebellum,
cerebrum, brain stem], kidney, liver, lung, muscle, spleen, testes) were determined on 10 animals
v: : aours, 1 day, 3 days, and 7 days following the dose. Tissue Pt concentrations were measured
: 1 AS (detection limits were not reported). The highest concentrations in tissues were
rved in kidney, liver, spleen, and lung. For example, 3 days following the 144 mg Pt/kg
dose, tissue:blood concentration ratios were approximately: kidney, 3.0; liver, 2.3; spleen, 1.4;
lung, 0.9; and other tissues (testes, muscle, brain), <0.3. In animals that received the 213 mg
Pt/kg dose, tissue:blood concentration ratios on day 3 were approximately: kidney, 1.4; liver,
2.6; spleen, 1.3; lung, 0.6; and other tissues (testes, muscle, brain), <0.3. In the repeated-dose
study, mice (n = 100) received gavage doses of 109 mg Pt/kg as Pt(S04)2 (7-day LD0i) every
3 days for a total of 10 doses (Lown et al., 1980). A subset of the mice were sacrificed (n = 10)
3 days following 2, 4, 6, 8, or 10 doses, and tissue Pt concentrations were determined. Three
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days following 10 daily doses of 109 mg Pt/kg, tissue:blood concentration ratios were:
kidney, 8; lung, 8; spleen, 2; liver, 0.9; and testes, 0.5.
Artelt et al. (1999a) reported Pt levels in various tissues in female Lewis rats (n = 80),
following a single gavage dose of Pt metal (1,030 ug Pt), administered as a particulate
suspension of Pt-AM); complex (see Section 3.1.1 for detailed description of this stud)
highest concentrations (jig/g wet tissue) were observed in kidney (0.08 ± 0.02 SD), spleen
(0.0056 ± 0.0013 SD), liver (0.0035 ± 0.0008 SD), and lung (0.0022 ± 0.0005 SD). Tissue:bk
Pt concentration ratios were approximately: kidney, 5; spleen, 0.4; lung, i md liver,
0.2 (calculated from group means reported in Table 12 of Artelt et al., 1999;:?). Artelt et al.
(1999a) also reported urinary and fecal excretion of Pt following intravenous administration of
K^PtCU; this study is summarized in the discussion of Pt excretion (see Section 3.4.4).
In summary, the tissue distribution of Pt absorbed following oral administration appears
to be similar for soluble and less-soluble compounds, based on the results of studies conducted
on relatively soluble compounds of Pt (PtCl4, Pt[S04]2) and less soluble compounds (PtCl2,
Pt-AM); complex) (Artelt et al., 1999a; Lown
1975b, c). The highest tissue concentrations
concentrations in kidney were 5-20 times th< t o:
conducted in rats, the results of one o
of Pt in kidney, liver, spleen, and lun
0; Holbrook et al., 1975; Moore et al.,
n kidney, liver, spleen, and lung. Pt
.though most studies have been
•use also found the highest concentrations
1980). Following intravenous
administration of soluble PtCU to rats, the highest concentrations of Pt were also observed in
kidney (Moore et al., 1975c). A direct comparison of the distribution of tissue distributions of Pt
in rats following a single gavage dose (382 mg Pt/kg) or intraperitoneal dose (113 mg Pt/kg) of
Pt(SO.t): showed substantially higher concentrations of Pt in liver (relative to blood) following
the intraperitoneal dose, compared to the oral dose (Holbrook et al., 1975).

3.2.2.
ve studies of the tissue distribution of inhaled Pt in humans have not been
sue distribution of Pt following exposures to aerosols of Pt metal or as a Pt-AM);
een studied in CD-I Lewis rats (Artelt et al., 1999a; Moore et al., 1975a). Moore
	.1/ . determined tissue distribution of Pt in CD-I rats (n = 87, sex not reported),
..ing 48-minute nose-only exposures to an aerosol of [191,193Pt] as insoluble Pt metal (7-
8 mg/m3). The aerodynamic diameter of the particulate aerosol was reported as "nearly 1.0 jim"
(see Section 3.1.2 for a more complete description of this study). The highest Pt concentrations
(based on [191Pt] gamma activity) were found in the respiratory tract, kidney, and bone (data
comparing tissue distribution of soluble and insoluble forms were not reported). Tissue:blood
concentration ratios 8 days following the exposure were: lung, 2,000; kidney, 69; bone, 13;
liver, 1.4; and brain, heart, muscle, and spleen, <0.5. Although the Moore et al. (1975a) study
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also exposed rats to aerosols of PtCU, PtO;, or Pt(SO.t):, tissue distribution was reported only for
animals exposed to Pt metal.
Artelt et al. (1999a) exposed female Lewis rats (four animals/dose) to aerosols of Pt
metal bound to aluminum oxide particles (MMAD: 1.3 jim) and observed the highest am. -«its
of Pt in lung, kidney, and liver (see Section 3.1.2 for a more complete description of this sti: J \ *
The exposure was nose-only 5 hours/day, 5 days/week for 13 weeks to 4 or 12 mg/m3 of thi r;
A1203 aerosol (approximately 0.1 or 0.3 mg Pt/m3). At the conclusion of exposure to 12 mg/m
of the Al;OyPt aerosol (approximately 0.3 mg Pt/m3), the tissue:blood Pt lev-. : tg/organ or
tissue) were as follows (calculated from group mean data reported in Table 8 ^ , .rtelt et al.,
1999a): lung, 214; liver, 1.6; kidney, 0.5; spleen, 0.07; and femur, 0.07. Assuming relative
masses (percent of body weight) of liver (4%), kidney (0.8%), lung (0.6%), and blood (5%) in
the rat (Davies and Morris, 1993), corresponding tissue:blood Pt concentration ratios were
approximately: lung, 1,900; kidney, 3.4; and liver, 2.1. Similar tissue:blood ratios were
observed after intratracheal instillation of A^Os/Pt particulate suspensions (Artelt et al., 1999a).
Ultrafme particles (diameters <0.1 jim) of insoluble materials can contribute very little to
the overall mass of airborne PM in urban air, but at low gravimetric concentrations (less than
about 125 jig/m3) when aggregation is impeded, large numbers of ultrafme particles can exist
(Oberdorster, 2001). The only published information on the tissue distribution inhaled ultrafme
Pt particles is a report of an experiment examining the Pt content of different tissues in one male
F344 rat sacrificed 0.5 hours after a 6-hour exposure to ultrafme particles (count median
diameter =13 nm; GSD = 1.7"! of Pt metal at a concentration of about 110 jig/m3 (Oberdorster,
2001; Oberdorster et al., 2000). Pt content in tissues was determined by ICP-MS (LOD reported
as 10 pg/g tissue) and expio^ou. as a percentage of the total Pt detected in several tissues (lungs,
blood, trachea, liver, and kidney). Tissue:blood Pt concentrations ratios were: lung, 10,000;
liver, 77; and kidney, 3 (based on data from Table 7 of Oberdorster, 2001). The results
demonstrated that Pt was transported to the liver, but it is uncertain if the particles themselves
were transported or if some of the particles were dissolved in the lung before transport of Pt to
, : : er. Direct comparisons of the disposition of ultrafme and larger-sized particles of Pt
following inhalation exposure are not available.
The localized distribution of Pt within tissues and cells is largely unknown. In female
rats, following intratracheal administration of Pt metal, administered as a particulate
suspension of a Pt-AM); complex, approximately 2-5 %o of Pt in plasma was associated with
complexes of molecular weight <60 kDa, the remaining fraction was associated with higher
molecular weight complexes (Artelt et al., 1999a). When rat plasma was incubated with
K2PtCl4, high molecular weight complexes ranging from 60 to 900 kDa were observed. A
relatively large complex in the 63-83 kDa range may have included serum albumin. High
molecular weight complexes (>63 kDa) were also the dominant complexes found in lung tissue
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and bronchiolar lavage cells, following intratracheal administration of Pt metal (suspension of
Pt-AM); complex) to female Lewis rats (Artelt et al., 1999a).
In summary, based on the results of studies conducted in rats on relatively insoluble Pt
metal (Moore et al., 1975a) and a Pt-AM); complex (Artelt et al., 1999a), inhaled Pt deposits in
the respiratory tract, undergoes mucociliary clearance to the GI tract, and is absorbed into "
Pt absorbed from the lung distributes primarily to kidney, liver, and bone. Concentrations < ^ !;
in kidney were approximately 40 times greater than in liver of rats, following an inhalation
exposure to Pt metal (Moore et al., 1975a). The above observations pertain to particles of
approximately 1 urn in size. Following exposure to ultrafme particles (e.g., 13 nm) of Pt metal,
the Pt concentration in liver was 30 times that of the kidney (Oberdorster, 2001; Oberdorster et
al., 2000). Although limited to a single observation made in one rat, these results suggest that
the tissue distribution of inhaled ultrafine particles of Pt r ;n:,7 n ¦ be predicted from the
observed distribution of large (e.g., 1 jim) particles.
3.2.3.	Dermal
No studies are available that provide information on the distribution of Pt when exposure
occurs from dermal contact with I
3.2.4.	Other Routes
Studies of tissue di	ag parenteral dosing of rats with PtCU or
Pt(SO.t): indicate that absorbed Pt distributes primarily to soft tissues, with the highest
concentrations achieved in kit	„. „, and spleen (Holbrook et al., 1975; Moore et al., 1975c,
b; Durbin, 1960). Tissue:blood concentrations 7 days after a tracer intravenous dose of
[i9i,i93ptci4] administered to CD-I rats were: kidney, 11; spleen, 4; adrenal, 2; liver, 2; pancreas,
1.3; bone, 0.7; fat, 0.25; and brain, 0.04 (Moore et al., 1975b, c). Holbrook et al. (1975)
compared tissue distributions of Pt in male Sprague-Dawley rats following a single gavage dose
(382 mg Pt/kg) or intraperitoneal dose (113 mg Pt/kg) of Pt(SO.t):. Data were obtained from
survivors of a 14-day lethality study and the doses administered were close to the LD50. The
1 Pi Micentration was in kidney following the oral dose. Tissue:blood Pt concentration
: tissue) ratios in animals exposed to the oral dose of Pt(S04)2 were as follows
(calculated from group mean data reported in Table 5 of Holbrook et al., 1975): kidney, 5;
spleen, I; liver, 0.7; heart, 0.3; testes, 0.15; and brain, 0.03. Concentrations of Pt in liver were
substantially higher following the intraperitoneal dose; tissue:blood Pt concentration ratios were
as follows: kidney, 37; liver, 34; spleen, 16; heart, 3; testes, 1; and brain, 0.6.
Maternal-fetal transfer of intravenously-administered Pt has been studied in rats.
Following an intravenous tracer dose of 191PtCl4 administered on day 18 of gestation, the
fetus maternal blood ratio was 0.03 (Moore et al., 1975b, c). From this same study, maternal
tissue:blood ratios were: kidney, 12; liver, 4, placenta, 2.6; and ovary, 1.4.
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In summary, tissue distribution of absorbed Pt following intravenous injection of soluble
PtCl4 in the rat was similar to that observed following oral or inhalation exposures, with the
highest tissue concentrations (outside of the lung and GI tract) observed in kidney, liver, and
spleen (Moore et al., 1975b, c). A direct comparison of the distribution of tis " '	s of
Pt in rats following a single gavage dose or intraperitoneal dose of Pt(SO.t): showed substantially
higher concentrations of Pt in liver (relative to blood) following the intraperi
compared to the oral dose (Holbrook et al, 1975).
3.3. METABOLISM
As an element, Pt is neither created nor destroyed within the body, however, Pt
compounds (e.g., PtCl4) can participate in chemical reactions s	igand
exchange, and formation of revisible and covalent complexes wiiii aiimiu iuus, peptides, and
nucleic acids. Pt forms complexes with amino, carboxyl, imidazole (e.g., histidine), and
sultliydry! (e.g., cysteine) groups on amino acids (NAS, 197' a result, Pt can form
complexes with proteins, nucleic acids, and free amino acids, in rats, high (>60 kDa) and low
(<60 kDa) weight complexes of Pt have been odserved in plasma and lung tissue or rats,
following intratracheal administration of a suspension of Pt-AM); complex (Artelt et al., 1999a,
see Section 3.2.2). Absorbed Pt compounds may participate in redox reactions; however,
experimental evidence of this for environmental forms of Pt was not located. Although there is
evidence suggesting limited environmental transformation of metallic Pt within soil (Sures and
Zimmerman, 2007; Ravindra et ni,, 2004), data on the potential for transformation of metallic Pt
within experimental animals e. 		 .vere not located.
3.4. ELIMINATION
3.4.1. Oral
Studies of the routes or kinetics of elimination of Pt in humans following oral exposure to
Pt compounds have not been reported. Studies in rodents have shown that absorbed Pt is
excreted in feces and urine (see Section 3.4.4 for a discussion of intravenous studies). Oral
absorption of Pt administered as PtCl4 or a Pt-AM); complex has been estimated to be <1%
, 1999a; Moore et al., 1975b, c; see Section 3.1.1 for more detailed description of
these studies). As a result, during the first 1-2 days following ingestion of these Pt compounds,
fecal excretion of unabsorbed Pt is likely to contribute substantially to Pt excretion. Absorbed Pt
is also excreted in feces. Evidence for this derives from studies of intravenously administered
PtCl4 and Pt-Al203 complex (Artelt et al., 1999a; Moore et al., 1975c; see Section 3.4.4 for more
complete description of these studies).
Rates of elimination of orally administered PtCl4 or Pt(SO.t): have been measured in mice
and rats. Lown et al. (1980; Massaro et al., 1981) reported tissue concentrations in male Swiss
mice at various times, up to 7 days following a single dose of Pt(S04)2. Elimination half-times
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estimated from data for mice that received 144 mg Pt/kg were: blood, 3.3 days; kidney,
2.2 days; and liver, 2.1 days. Moore et al. (1975b, c) measured whole-body retention profiles of
Pt in male CD-I rats, following single oral tracer doses of [191'193PtCl4], Less than 1% of the oral
[191Pt] dose remained in the body 3 days after the dose. Fecal excretion was the dominant
excretory pathway during the 11-day observation period; however, the contribution of the
urinary pathway increased with time. The urine:feces excretion ratio was approximately
0.01 during the first 2 days following the dose and increased to approximately 0.2 on day 8
following the dose (calculated from data presented in Figure 6 of Moore et al, 1975b). Moore et
al. (1975b, c) also reported data on whole-body elimination and excretion of Pt following an
intravenous tracer dose of [191'193PtCl4] and observed a much larger contribution of the urinary
pathway to excretion (i.e., urine:fecal ratio of 1-2.5; see Section 3.4.4. for a more detailed
description of this study). These observations suggest that Pt e\cr : - in feces following the oral
dose ofPtCU derived from both unabsorbed Pt and absorbed Pt.
Artelt et al. (1999a) administered a gavage dose of a	. of Pt-coated AM);
particles to female Lewis rats (n = 8) and measured amounts of Pt recovered in tissues and urine
8 days following the Pt dose (see Section 3.1.1 for more detailed description of the study). The
Pt dose administered to the animals was 1,030 jj: ; . ng of the Pt-AM); complex). Most of
the administered Pt was excreted during the first 24 hours following the dose. Fecal excretion
was the dominant pathway; urine:fecal ratios were approximately 0.001 (based on data presented
in Figures 5 and 6 of Artelt et al. 1999a).
3.4.2. Inhalation
Schierl et al. (1998 ,	...,ared urinary Pt excretion in two male Pt refinery and catalyst
production workers who were subject to a single 4-hour exposure to estimated concentrations of
approximately 1.7 ug Pt/m3 (Subject A) or 0.15 ug Pt/m3 (Subject B). Schierl et al. (1998) report
that exposure was predominantly to (NH.t);PtClt1 by handling dry powder; however, no Pt
speciation or exposure measurements were reported. Urinary Pt (ng Pt/g creatinine) was
measured for the First 4 days following the exposure and periodically for the subsequent
6 months. Pt content in all samples (urine or air) was quantified by adsorptive v ol tain met ry
(LOD was reported to be 2 ng/L urine and 2 pg/m3 air). Based on these observations, a urinary
excretion half-time was estimated to be 50 hours (95% confidence interval [CI]: 36-66). A
second, slow elimination component was observed in Subject A; the estimated half-time was
24 days (95% CI: 18-33).
Schierl et al. (1998) also reported urinary Pt levels measured in 34 Pt refinery and
catalyst production workers (32 males) who were exposed primarily to K^PtCU and Pt(NO.O:
Estimated average exposures based on periodic air sampling were: stationary sampling,
1.2 jig/m3 (range: 0.2-3.4); and personal sampling, 2.5 jig/m3 (range: 0.8-7.5). Urinary Pt
excretion was 16-6,270 ng/g creatinine among currently exposed workers (n = 18) and 10-
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170 ng/g creatinine among workers formerly exposed (exposure ceased 2-6 years earlier; n = 4),
compared to 1-12 ng/g creatinine among a reference control group of workers who were not
exposed to Pt (n = 12). The persistence of urinary Pt levels above those of the reference control
group, 2-6 years following cessation of exposure, suggests the existence of a more slowly
eliminated fraction of body burden that may not be reflected in the above elimination lialf-t';
estimates.
Rates of elimination of soluble (Pt(S04)2, or the halogenated Pt salt PtCl4) and insolubl
(Pt metal and PtO; ) Pt compounds have been measured in rats. Moore et al. (1975a) measured
the kinetics of whole-body elimination and urinary and fecal excretion in CD-I rats (n = 87, sex
not reported) following 48-minute, nose-only exposures to aer . .>.. : ' v > ) iim". Pt was
eliminated in the feces and urine. Fecal excretion was the dominant pain way of excretion during
the first 3 days following exposure (indicative of mucociliary clearance of Pt initially deposited
in the respiratory tract). Whole-body elimination kinetics exhibited at least two phases: an early
fast phase, reflecting mucociliary clearance and fecal excretion of Pt initially deposited in the
respiratory tract, followed by a slower phase(s), reflecting excretion of absorbed Pt. The slow
phase elimination of Pt was more rapid following inhalation of soluble forms (PtCl4, Pt[S04]2)
than following inhalation of insoluble forms (Pt02, Pt metal). The pseudo-first-order elimination
half-times for body burden, estimatec ::' h i data collected after the first 5 days following
cessation of exposure were as follow!. > ;014, 9 days; Pt(S04)2, 10 days; Pt02, 44 days; and Pt
metal, 32 days (estimated from digitization of Figures 1 and 2 of Moore et al., 1975a). The
slower elimination of the insoluble forms may, in part, result from slower clearance from the
lung. This ie '• ""ported by the kinetics of Pt retention in the lung that were observed in this
study. Pseu . ¦¦¦¦¦. "st-order elimination half-times of Pt from the lung for the slow phase were
approximate i ':: follows: Pt metal, 19 days; Pt02, 8 days; and Pt(S04)2, 4 days (estimates are
based on reported data on lung retention for the period 2-16 days postexposure (from Table 1 of
Moore et al, 1975a); data for PtCl4 were not reported. The above half-times suggest that soluble
Pt(S04)2 is cleared from the lung more rapidly than the less-soluble forms of Pt (Pt metal and
PtO: ). Fecal excretion was the predominant excretory route for all four Pt compounds; however,
the relative contribution of the urinary route increased with time after the inhalation exposure.
Urine:fecal excretion ratios for each of the Pt compounds were <0.1 during the first 2 days
following exposure and increased to 0.6-0.8 by day 5. These results are consistent with a
substantial mucociliary clearance of Pt from the respiratory tract to the GI tract during the first
1-2 days following inhalation exposure. The slow-phase, whole-body elimination half-time of
9 days for Pt inhaled as PtCl4 was similar to the whole-body elimination half-time observed
following intratracheal administration of PtCl4, approximately 10 days (Moore et al., 1975b, c).
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Artelt et al. (1999a) exposed female Lewis rats (four animals/dose) to aerosols of Pt
metal bound to aluminum oxide particles (MMAD: 1.3 jim; see Section 3.1.2 for a more
complete description of this study). The exposure was nose-only 5 hours/day, 5 days/week for
13 weeks to 4 or 12 mg/m3 of the Pt-AM); aerosol (approximately 0.1 or 0.3 mg Pt/m3). Urine
and fecal excretion of Pt was determined on days 8, 28, and 90 of exposure. Fecal excretio ^
the dominant excretory pathway; urine:fecal excretion ratios ranged from 0.002 to 0.004 (b
on group mean data reported in Table 9 of Artelt et al., 1999a).
In summary, data on elimination of inhaled Pt compounds in hum ;; ::: ;;;' limited to a
study of Pt refinery and catalyst production workers (Schierl et al., 1998). This study observed
Pt in urine of workers who were exposed predominantly to (NH4)2PtCl6 and observed what
appeared to be biphasic excretion kinetics with fast- and slow-phase half-times of approximately
50 hours and 24 days, respectively. The study also observed Pt in urine of workers 2-6 years
after cessation of exposure primarily to K2PtCl4 and PtCNOj);. The persistence of urinary Pt
excretion 2-6 years following cessation of exposure suggests the existence of a more slowly
eliminated fraction of body burden that may not be reflected in the above elimination half-time
estimates. The observation of faster and slower phases of urinary excretion of Pt in humans is
consistent with similar observations of multi-phasic elimination of inhaled Pt metal, PtO;, PtCl4,
or Pt(SO.t): in rats (Moore et al., 1975a). The pseudo-first-order elimination half-times for the
body burden in rats were approximately 9 days for PtCl4, 10 days for Pt(S04)2, 44 days for Pt02,
and 32 days for Pt metal (Moore et al.. 1975a). The slow-phase urinary excretion half-time
estimated for a worker exposed predominantly to (NH4)2PtCl6 (24 days; Schierl et al., 1998) falls
within this range observed in l„	 	.es conducted in rats exposed to aerosols of Pt metal,
PtO;, PtCl4, Pt(S04)2, or Pl complex have shown that fecal excretion is the dominant
excretory route for these Pt compounds following inhalation exposure; however, the relative
contribution of the urinary route increases with time after the inhalation exposure (Artelt et al.,
1999a; Moore et al., 1975a). These results are consistent with mucociliary clearance of Pt from
the respiratory tract to the GI tract during the first 1-2 days following inhalation exposure.
V ving this early phase of mucociliary clearance, fecal excretion of absorbed Pt continues to
in* - i'oute to fecal Pt excretion. Evidence for fecal excretion of absorbed Pt derives from studies
; i >?!; avenously administered PtCl4 and Pt-Al203 complex (Artelt et al., 1999a; Moore et al.,
, see Section 3.4.4 for more complete description of these studies).
3.4.3. Dermal
No studies are available that provide information on excretion of Pt when exposure
occurs from dermal contact with Pt compounds.
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3.4.4. Other Routes
Moore et al. (1975b, c) measured whole-body retention kinetics and urinary and fecal
excretion of Pt following a single intravenous administration of a tracer dose of [191'193PtCl4] to
male CD-I rats (n = 20). Whole-body retention for the first 28 days following the d .. ; :
measured by whole-body counting of [191Pt] gamma activity; urine and fecal Pt was >
measured by counting [191Pt] gamma activity of samples collected in metabolic cat
pseudo-first-order whole-body elimination half-time was approximately 10 days
digitization of data presented in Figure 4 of Moore et al., 1975b). Data on i :; le and fecal 191Pt
activity for the first 14 days following the dose were reported; urine:fecal e etion ratios ranged
from 1 to 2.5 during this period (estimated from data presented in Figure 6 Moore et al.,
1975b).
Artelt et al. (1999a) measured urinary and fecal excretion of Ptfor 10 days following a
single intravenous administration of 500 ug Pt as K2PtCl.t to female Lewis rats (n = 8). Pt in
excreta was measured by ICP-MS (see Section 3.1.1). Approximately 50% of the administered
dose was excreted in urine in 10 days and 41% Kcreted in feces (these values presumably
represent group mean, SD values were not reported).
In summary, the above studies (Artelt et al., 1999a; Moore et al., 1975b, c) provide
evidence for fecal excretion of Pt following absorption of K^PtCU or PtCU, and provide evidence
for urine:fecal excretion ratios of absorbed Pt that range from 1 to 2.5. The nearly comparable
rates of urinary and fecal excretio ; ;' ; lat were observed following intravenous
administration of PtCl4 suggest that the much lower urinefecal excretion ratios (e.g., <0.1)
observed during the first 1-2 days following inhalation exposures to this compound (Moore et
al., 1975a) are contributed ,,.,,c-ociliary clearance of Pt deposited in the respiratory tract to the
GI tract.
3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS
The International Commission on Radiological Protection (ICRP, 1981) developed a
u ^ i icompartmental model of the toxicokinetics of Pt in humans (Figure 3-1). This model was
developed for the purpose of estimating radiation doses resulting from absorbed radioactive Pt
nucleotides and, therefore, simulates the post-absorption distribution and excretion of Pt (i.e.,
irrespective of the chemical or physical form ingested or inhaled). The model is reportedly based
largely on the data reported in Moore et al. (1975a, b) and Yoakum et al. (1975); however,
specific connections between parameter values and the latter studies are not discussed in detail in
ICRP (1981). Information on calibration and evaluation of the model is not discussed in ICRP
(1981) and does not appear available elsewhere.
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Absorption
F = 95%, t1/2 = 8 days
S = 5%, t1/2 = 200 days
The ICRP (1981) model simulates the kinetics of elimination of absorbed Pt.
Absorbed Pt enters a transfer compartment, from which Pt is distributed
(ti/2 = 0.25 days) to kidney (10%), liver (10%), spleen (1%), adrenals (0.1%), and
other tissues (58.9%). Biphasic elimination of Pt from tissues is simulated as fast
(F, 11/2 = 8 days, 95% of burden) and slow (S, tia = 200 days, 5% of burden) first-
order excretion in urine and feces, in a 1:1 mass ratio.
Figure 3-1. ICRP (1981) model of Pt toxicokinetics in humans.
The ICRP (1981) model includes several compartments including a central (transfer)
compartment that receives absorbed Pt (e.g., from the GI tract or respiratory tract), and other
compartments representing the kidney, liver, spleen, adrenals, other tissues, feces, and urine.
Each tissue is composed of two subcompartments, representing pools of Pt that are assumed to
make faster (ti/2 = 8 days) or slower (ty2 = 200 days) contributions to Pt excretion kinetics.
Excretion of Pt in feces and urine is represented with direct transfers from each tissue to excreta
(urine:feces ratio = 1:1). This approach accounts for the relative contribution made by the Pt
burdens in each tissue to excretion, rather than providing a simulation of physiological pathways
of excretion (i.e., transfer directly from kidney to urine, transfer from liver to feces, transfer from
other tissues to urine via a central compartment). Transfers of Pt from the central compartment
to tissues and from tissues to excreta are assumed to follow first-order kinetics. Each transfer is
represented with a single rate coefficient (day"1). Age-dependency of transfer or other factors
that might affect intercompartment transfer rates (e.g., differences between Pt compounds) are
not represented in the model. The total transfer rate from the central compartment to all
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destinations combined is assumed to be 2.77 day"1 (ti/2 = 0.25 day). Values for transfer
coefficients from the central compartment to tissues and tissue compartments are based on
assumed deposition fractions (DFs) or instantaneous fractional outflows of Pt between
compartments, where the transfer coefficient to a specific tissue or compartment ( IT
by:
TP= />/•', • TP ALL
M* W •/
This approach establishes mass balance with respect to
5ma:
YTP1 = TP ALL
]q. (3-2)
DFs and corresponding transfer coefficients calculated fr
are presented in Table 3-1.
i-1 for each compartment
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Table 3-1. Parameters and values in ICKP (1981) Pt biokinetics model
Parameter
DF
Half-time
(day)
Mate
(day"1)
Description
TRTl
1.000
0.25
2.77
Transfer to tissues
TRKI(l)
0.095
0.25
2.63 x 101
Transfer to kidney(l)
TRKI(2)
0.005
0.25
1.39 x 10~2
Transfer to kidney(2)
TRLI(l)
0.095
0.25
2.63 x 101
Transfer to liver(l)
TRLI(2)
0.005
0.25
1.39 x 10"2
Transfer to liver(2)
TRSP(l)
0.010
0.25
2.63 x 10"2
Transfer to spleen(l)
TRSP(2)
0.001
0.25
1.39 x 1(T3
Transfer to spleen(2)
TRAD(l)
0.001
0.25
2.63 x 10~3
Transfer to adrenal(l)
TRAD(2)
0.000
0.25
1.39 x 10~4
Transfer to adrenal(2)
TROT(l)
0.560
0.25
1.55
Transfer to other tissue(l)
TROT(2)
0.029
0.25
8.17 x W2
Transfer to other tissue(2)
KI(1)FE
1.000
200
3.47 x 1(T3
Kidney(l) to feces
KI(1)UR
1.000
8
8.66 x W2
Kidney(l) to urine
KI(2)FE
1.000
200
3.47 x 10~3
Kidney(2) to feces
KI(2)UR
1.000
8
8.66 x 10~2
Kidney) 2) to urine
LI(1)FE
1.000
200
3.47 ;
Liver(l) to feces
LI(1)UR
1.000
8
8.66 x iu
Liver(l) to urine
LI(2)FE
1.000
200
3.47 x 10~3
Liver(2) to feces
LI(2)UR
1.000
8
8.66 x 10"2
Liver(2) to urine
SP(1)FE
1.000
200
3.47 x 10"3
Spleen) 1) to feces
SP(1)UR
1.000
8
8.66 x 10-2
Spleen) 1) to urine
SP(2)FE
1.000
200
3.47 x 10"3
Spleen(2) to feces
SP(2)UR
1.000
8
8.66 x W2
Spleen(2) to urine
AD(1)FE
1.000
200
3.47 x 1(T3
Adrenal(l) to feces
AD(1)UR
1.000
8
8.66 x 10"2
Adrenal(l) to urine
AD(2)FE
1.000
200
3.47 x 10"3
Adrenal) 2) to feces
AD(2)UR
1.000
8
8.66 x 10"2
Adrenal(2) to urine
OT(l)FE
1.000
200
3.47 x 1(T3
Other tissue(l) to feces
OT(l)UR : 1.000
8
8.66 x 10"2
Other tissue(l) to urine
OT(2)FE ! 1.000
200
3.47 x 10"3
Other tissue(2) to feces
OT(2)UR i 1.000
8
8.66 x W2
Other tissue(2) to urine
Tissue compartments aie composed of faster (1) and slower (2) pools for Pt excretion. Rates are first-order
constants (day"1) calculated as: rate = ln(2)/ti/2
AH = adrenal; DF = deposition fraction; KI = kidney; FE = feces; LI = liver; SP = spleen; TR = transfer
c rtmerit; UR = urine
Although the ICKP (1981) model is intended to simulate the distribution and elimination
of absorbed Pt, other ancillary models developed by ICRP can be applied to estimate the
absorbed dose inputs to the post-absorption kinetics model. ICRP (1981) assigned a value of
0.01 (i.e., 1%) for the GI absorption fraction of all Pt compounds and based this assignment on
the Moore et al. (1979b, c) study of relatively soluble PtCl.t. ICRP (1994) developed a generic
model for simulating lung deposition and clearance of inhaled particulates in humans. The
model can be implemented to simulate deposition, retention, and absorption of inhaled Pt, when
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specific parameters values for inhaled particle size and Pt absorption are used in the model. The
general form of the model represents the respiratory tract as a series of compartments
representing the extrathoracic, bronchial, bronchiolar, and alveolar-interstitium regions of the
tract (Figure 3-2). Each compartment is assigned age- and particle-size-dependent DFs (i....
fraction of inhaled particles deposited in each compartment). Nose- and mouth-breathing
pathways are simulated, which vary in relative contribution, depending on age and activity ;
Within each compartment, particulates can be deposited, sequestered into tissue, transported to
other compartments (i.e., mechanical clearance), or dissolved and absorbed (Figure 3-3).
Transport between compartments is assumed to follow first-order kinetics and, for Pt, are
independent of the chemical or physical form of the Pt compound that is inhaled. Dissolution
and absorption parameters in the model are chemical specific; ; - sorption paraine iers for Pt are
presented in Table 3-2. ICRP (1981) assigned all Pt compounds to the fast absorption category,
in which dissolution rate is assumed to be 100 day"1 (ti/2 « 10 minutes). The basis for this
categorization is reported in ICRP (1981) as the observation reported in Moore et al. (1975a) that
"platinum whether inhaled as the metal, the i : . sisulfate is rapidly translocated from the
lungs". This categorization reflects a revision in the l( KP (1981) report from a previous
categorization in which Pt compounds; were classified into clearance categories as follows:
oxides and hydroxides, Y (pulmonary absorption tm = 365 days); halides and nitrates, W
(pulmonary absorption ti/2 = 90 days) : ¦::? other, D (pulmonary absorption ti/2 = 30 minutes).
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Anterior
Nasal
Bronchi
Bronchioles
Alveolar
Inters itium
Sequestered in Tissue
Extrathoracic
0.001
LN
ET
ET
SEQ
0.01
0.01
bb
SEQ
0.00002
Surface Transport

0.03
ET,
10
B^SEQ

bb2


bb.-
0.0001
bb.
0.001
AU
0.02
AU
100
AL
Thoracic
Exhaled Air
Gl tract
AI = alveolar-interstitial; BB = bronchial; bb = bronchiolar; ET = extrathoracic;
LN = lymph nodes; SEQ = sequestered; TH = thoracic
The ICRP (1994) model simulates surface transport (e.g., mucocilliary) and
sequestration into tissues. Numbers are default values for first order rate
constants (day"1) and represent combined rates of transport by all contributing
mechanisms (e.g., mucocilliary, macrophages) in each compartment.
Figure 3-2. Generic ICRP (1994) model of transport of particles deposited in
regions of the respiratory tract.
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The generic ICRP (1994) model of absorption includes: dissolution (s);
transformation, in which the particle in the initial state, with dissolution rate sp, is
transformed at rate spt to a form having a dissolution rate st; and binding, which
results in absorption rate, St,; unbound dissolved materials are absorbed
instantaneously. Each process acts, at the same rates, on all compartments in each
region of the respiratory tract except ETi (see Figure 3-2), where no absorption
occurs. Absorption parameter values are grouped into classes (fast, moderate,
slow), to which specific chemical compounds are assigned (see Table 3-2).
Particle transport rates are the same for particles in the initial and transformed
states; however, bound material is not subject to particle transport.
Figure 3-3. Generic ICRP (1994) model of absorption of particles deposited
in the respiratory tract.
Table 3-2. Default parameter values for ICRP (1994) model of absorption of
inhaled particulates
Parameter
Absorption behavior class
F (fast)
M (moderate)
S (slow)
Initial dissolution rate (d1), sp
100
10
0.1
Transformation rate (d1), sDt
0
90
100
Transformed dissolution rate (d1), st
-
0.005
0.0001
Fraction to bound state, fb
0
0
0
Absorption rate from bound state (d1), sb
-
-
-
Initial dissolution half-times range from approximately 10 minutes (F) to 7 days (S). Transformed dissolution half-
times range from approximately 140 days (M) to 19.5 years (S). Prior to ICRP (1981), Pt compounds were
classified as follows: oxides and hydroxides, Y (pulmonary absorption ti/2 = 365 days, k « 0.00190 day"1); halides
and nitrates, W (pulmonary absorption ti/2 = 90 days, k « 0.00770 day"1); and all other, D (pulmonary absorption
ti/2 = 30 minutes, K « 33.3 day"1).
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4. HAZARD IDENTIFICATION
4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL
CONTROLS
4.1.1.	Oral
A single case study reports effects of intentional ingestion of a photographic solutio
containing 600 mg of potassium chloroplatinite (a synonym for the halogenated Pt salt potassium
tetrachloroplatinate K^PtCU) by a 31-year-old man (Woolf and Ebert, 1991). Toxic effects
included acute oliguric renal failure, metabolic acidosis, fever, muscle cramps, gastroenteritis,
and rhabdomyolysis. Abnormal laboratory finding included elevated liver enzymes and blood
neutrophil and eosinophil counts. All signs and symptoms of toxicity resolved within 6 days
with supportive medical management. No additional reports of oral exposure of humans to Pt or
Pt compounds were identified.
4.1.2.	Inhalation
Pt-group metals are refined through a sei' ¦;:: ¦ ¦¦; . ;;; lization and precipitation processes
involving acids (usually hydrochloric acid) to obtain puim^d halogenated metal salts, and, with
further processes, the elemental metals. Refinery workers are expected to be exposed to various
types of PGE salts and metals, and other airborne non-PGE respiratory irritants, depending on
their job responsibilities (Merget et al., 2000; Maynard et al., 1997; Biagini et al., 1985a).
Numerous case studies am miological studies of occupational exposure to halogenated Pt
salts and Pt compounds art. : ible. Studies can be generally categorized based on Pt
compound class (e.g., soluble or insoluble); however, for most occupational exposures, it is
unlikely tha v< >: kers are exposed to a single Pt compound or class of Pt compounds.
Occi m i >nal exposures to Pt compounds in refineries and catalyst production plants are
to a mixture of soluble Pt compounds (mainly halogenated Pt salts in the form of
chloroplatinates) and insoluble Pt compounds (principally Pt metal, PtO, and PtO;) (Merget et
al 1 QQQ) Exposure measurements of Pt concentrations in occupational studies are generally
: tal Pt or soluble Pt. As discussed in detail in Chapter 2, total Pt (i.e., Pt in all
chemical forms and oxidation states present in the sample) is measured following complete
sample digestion with quantitative determination often using ICP-MS (Barefoot and Van Loon,
1999). Determination of soluble Pt requires the additional step of sample extraction into a
solution (e.g., water, dilute hydrochloric acid, or nitric acid). The soluble fraction is an
operationally-defined fraction of Pt in which many different species of Pt can be present
depending on the extraction solution. As such, characterization of Pt from occupational or
environmental samples as "soluble Pt" does not provide information regarding the chemical
species present in a sample. When samples contain halogenated Pt salts, these compounds are
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likely to be a portion of the soluble Pt reported because of their solubility in water and other
common extraction solutions (see Table 2-1). In this document, the term soluble Pt compounds
primarily includes Pt(S04)2, tetraamine Pt dichloride ([Pt(NH3)4]Cl2), and the halogenated Pt
salts. However, no occupational studies were identified that report speciation of Pt compoi
analytical characterization of Pt compounds, specific measurements of halogenated Pt
compounds, or estimations of the fraction of soluble Pt represented by halogenated Pt
compounds.
Most case reports and older studies reporting health effects associated with F; p ¦¦¦¦¦:¦ ire
attribute health effects to halogenated Pt salts based on processes utilized in the refti.....-, wi r t;
however, these studies do not report exposure data (e.g., Jarabek et al., 1984; Dally et al., 1980;
Milne et al., 1970; Parrot et al., 1969; Roberts, 1951). The work environment of a Pt refinery or
Pt catalyst production plant where individuals become sensitized t ;; ' ' pounds involves
exposure to halogenated Pt salts, mainly chloroplatinates (e.g., ami nun mm hexachloroplatinate,
sodium hexachloroplatinate, potassium hexachloroplatinate, and chloroplatinic acid), because
these compounds are required for the processes involved (Merget, 2000; Merget et al., 1999;
Parrot et al., 1969; Hunter et al., 1945). For example, inhalation exposure to Pt compounds in a
Pt refinery includes exposure to the complex halogenated Pt salt ammonium hexachloroplatinate
([NT Lj]2PtC*l0) or sodium hexachloroplatinate (NaPtC'U) because Pt is precipitated in the form of
one of these complex halogenated salts in whatever method is used in refining (Parrot et al.,
1969; Hunter et al., 1945).
Even in occupational studies that contain some exposure measurements, data are
generally restricted to semi -	n itative measures such as percent of measurements where air
concentrations exceeded 2 liable Pt/m3 (e.g., Calverley et al., 1995). Five epidemiological
studies repo'"* K'^h health effects and Pt exposure measurements including data on total and
soluble Pt (I : : ;t et al., 2000; Linnett and Hughes, 1999; Bolm-Audorff et al., 1992; Baker et
al., 1990; Bi<. . : et al., 1990). No occupational studies were identified that report speciation of
Pt compounds, analytical characterization of Pt compounds, or specific measurements of
alogenated Pt compounds. Although inhalation is considered to be the predominant route for
lal exposure, the potential for a dermal exposure component cannot be ruled out.
nkplace atmospheres in precious metal refineries in the United States (Baker et al., 1990) and
South Africa (Calverley et al., 1995) frequently exceeded the Occupational Safety and Health
Administration (OSHA) occupational limit for Pt salts of 2 ug soluble Pt/m3, but lower
exposures to Pt salts are expected in modern PGE catalyst production plants due to more uniform
production processes and implemented protective measures (Merget et al., 2000).
Health and toxic effects in humans repeatedly exposed to Pt metal or Pt compounds by
inhalation are documented in numerous case reports and epidemiologic studies and include
respiratory irritation and effects associated with allergic sensitization. Other adverse health
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effects (e.g., those effects not related to respiratory irritation or allergic sensitization) have not
been reported.
Individuals with halogenated Pt-salt allergic sensitization showed progression to
moderate or severe asthma with continued exposure (Merget et al., 1999). For halogenated Pr
salts and other sensitizers, effects of work-related allergic sensitization may be severe and
disabling (Friedman-Jimenez et al., 2000). Severe cases of allergic sensitization to halogenated
Pt salts included workers with bluish skin due to insufficient oxygen in blood, feeble pulse, anc
extreme difficulty breathing, which required the subject to remain upright to breathe (Roberts,
1951). The effects and time-course of allergic sensitization to halogenated Pt salts are consistent
with an IgE-mediated, Type I response (see Section 4.6.3.1, Sensitization for additional details).
Data on the health effects of chronic Pt exposure in workers following the development of Pt
allergic sensitization are complicated by the practice of medically terminating or transferring
workers to areas with lower Pt exposure (e.g., Merget et al, 2001, 2000; Calverley et al., 1995;
Brooks et al., 1990). Although no deaths were reported for Pt-specific allergic sensitization, two
cases of occupational asthma leading to death lurve been reported after medical recommendations
to permanently cease exposure to other low molecular weight sensitizers (isocyanates) had been
given but not followed (Friedman-Jimenez et al., 2000). Even following the work practice of
medical termination, about 50% of workers with allergic sensitization to halogenated Pt salts
continue to experience symptoms such as asthma and shortness of breath on exertion several
years after removal from exposure (Merget et al., 1999, 1994).
Signs and symptoms consistent with respiratory irritation and allergic sensitization have
been observed in workers exp„	r „ .n several types of work environments, including
photographic studios using halogenated Pt salts (Hunter et al., 1945); jobs applying halogenated
Pt salts by brush to anodes (Harris, 1975); refinement of Pt involving halogenated Pt salts (Raulf-
Heimsoth et al., 2000; Santucci et al., 2000; Linnett and Hughes, 1999; Newman Taylor et al.,
1999; Calverley et al., 1999, 1995; Merget et al., 1999, 1996, 1994, 1991, 1988; Niezborala and
Gamier, 1996; Bolm-Audorff et al., 1992; Brooks et al., 1990; Baker et al., 1990; Venables et al.,
Biagini et al., 1985a; Jarabek et al., 1984; Hughes, 1980; Dally et al., 1980; Cromwell et
- ; i 79; Cleare et al., 1976; Milne, 1970; Parrot et al., 1969; Roberts, 1951; Hunter et al.,
'"¦!. I and exposure to halogenated Pt salts in the production of Pt catalysts (Cristaudo et al.,
. Merget et al, 2002, 2001, 2000, 1999, 1996, 1995; Raulf-Heimsoth et al, 2000).
Numerous epidemiology and case studies report that inhalation exposure to Pt
compounds, specifically halogenated Pt salts, is associated with the development of allergic
sensitization; other toxic effects associated with inhalation exposure of humans to Pt compounds
have not been reported (review and detailed discussion of available evidence is provided below
in Section 4.1.2.1, Soluble Pt Forms). In contrast to the numerous publications on exposure to
soluble Pt compounds, very little information is available on health effects of insoluble Pt
compounds (details are discussed in Section 4.1.2.2, Insoluble Pt Forms). However, the
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available evidence from studies of inhalation of insoluble Pt compounds has not demonstrated
effects.
1luble forms ofPt:
enerally not
e is some evidence that
city and solubility of
terature) appear to be
4.1.2.1. Soluble Pt Forms
As discussed above, many case reports and epidemiology studies provide evidence that
workers exposed to halogenated Pt salts develop allergic sensitization to Pt compounds.
Information to characterize the exposure-response relationship for the development of
halogenated Pt salt sensitivity is available from five epidemiological studies (Merget et al., 2000;
Linnett and Hughes, 1999; Bolm-Audorff et al., 1992; Baker et al., 1990; Brooks et al., 1990);
details of these five studies are provided in Section 4.1.2.1.2 (Toxicit
epidemiological evidence ofPt allergic sensitization). Although *
characterized in the available occupational studies beyond sc
halogenated Pt salts may have different sensitizing potencies. The'
halogenated Pt salts (compounds generally considered soluble in th
related to the halogen-ligands coordinated to	icgative charge of these complexes
(Nischwitz et al., 2004; Ravindra et al., 2004; Kosner and Merget, 2000; Cleare et al., 1976). In
particular, results of the retrospective study by Linnett and Hughes (1999) suggest that
chloroplatinate salts are allergenic, as are chloroplatinates in combination with tetraamine Pt
dichloride, but tetraamine Pt dichloride does not show any strong evidence of being a sensitizer.
A high incidence of allergic sensitization to halogenated Pt salts was observed among refinery
workers exposed to chloronlatinates (106 of 270 workers) or to chloroplati nates with co-
exposure to tetraamine Pt iride (5 of 31 workers), but no cases were observed among
39 workers exposed to tetM.-ninne Pt di chloride alone in the production of automotive catalysts
(study details provided in Section 4.1.2.1.2, Toxicity of soluble forms ofPt: epidemiological
evidence ofPt allergic sensitization). Similar results were reported by Steinfort et al. (2008) in a
prospective study of workers at a catalyst manufacture plant in Melbourne, Australia, where no
cases of positive skin prick test (SPT) were noted among workers with reported exposure to
tetraamine Pt di chloride. The authors report that tetraamine Pt di chloride, palladium, and
rhodium were utilized in the plant, but do not report any speciation data to identify specific Pt
compounds. Steinfort et al. (2008) report three air measurements of between 10 and 20 g/m3, but
do not list methods used to measure Pt, whether the reported concentrations were total or soluble,
or limits of detection. Of the 112 total workers, the authors reported that 71 had exposure to
tetraamine Pt dichloride, 41 were in the high-exposure areas, and 26 of the high-exposure
workers had at least two examinations. None of the 26 workers had a positive SPT or symptoms
of allergic sensitization to Pt based on forced expiratory volume in 1 second (FEVi) or general
respiratory symptoms. Although the authors report that exposure was to tetraamine Pt
dichloride, the SPT was performed with hexachloroplatinic acid (1.471 g/kg).
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Supportive evidence for the allergenic activity of halogenated Pt salts also is provided by
dermal and parenteral studies conducted in animals (Dearman et al., 1998; Schuppe et al.,
1997a, b, 1992); evidence for airway effects of inhaled halogenated Pt salts (specifically to salts
of hexachloroplatinate) is provided by studies in monkeys (Biagini et al., 1986, 1985b, 198""
Parenteral studies in animals also provide evidence supporting the findings of Linnett and
Hughes (1999) and Stein foil et al. (2008) that tetraamine Pt di chloride may not have
sensitization properties (Schuppe et al., 1997b). Details of animal studies are provided in
Section 4.5.1.1, Sensitization Studies, Soluble Pt Salts.
Additional supportive evidence on the variable allergenic potency of soluble Pt
compounds comes from a study by Cleare et al. (1976) on 18 refinery workers with known Pt
sensitivity and on the characterization portion of a study of 22 catalyst production plant workers
with Pt sensitivity in Cristaudo et al. (2005). In the Cleare et al. (¦ ¦ • ;¦ m: dy, SPTs (defined in
detail in Section 4.1.2.1.1 below) were performed on workers using zi uui'erent Pt compounds
(including some isomers); however, not all compounds were	11 workers. No
information on the study population, other than that workers were employed in a Pt refinery and
were known to be sensitive to halogenated Pt salts (specifically to salts of hexachloroplatinate),
was reported. For each compound tested, the in- ¦¦¦¦;¦ : was conducted by injecting a volume of
approximately 3 x 10"6 ml. of a solution containing 10"" g/mL of the specific compound (e.g., a
dose of approximately 10"15 g). If no reaction was observed within 10 minutes, a 10-fold higher
concentration was used; this steo-wise orocess was continued until a positive response was
observed or the maximum test solution concentration of 10'3 g/mL was reached. Ammonium
hexachloroplatinate [(NH4)2 rt:€l6] was used as the positive control. Results were presented for
individual workers. Two	did not show a positive reaction to ammonium
hexachlorop,',t;,i'ite and were used as negative controls; these workers also did not show a
positive SP -¦¦ ¦. ther Pt compounds tested. Results of the SPT in the remaining 16 workers
' allergic reaction was related to the number of chlorine atoms in a
lalogenated Pt salts. Sensitivity showed the following order of decreasing allergenicity:
6] « (NH4)2[PtCl4] > Cs2[Pt(N02)Cl3] > Cs:[Pt(NO:hCl:] > Cs2[Pt(N02)3Cl] >
)4j (inactive). Other nonallergenic Pt compounds in this study included
i3>2Cl2]; ^ra«5-[Pt(NH3)2Cl2]; c7v-[Pt(CH3NH3)2Cl2]; *ftms-[Pt(CH3NH3)2Cl2];
fraws-[Pt(CH2OHNH2)2Cl2; c7s-(Pt(NFl3)2( 112()2 )2(N()3 )2; and [Pt(NH3)4]Cl2. Exchanging
bromine for chlorine appeared to reduce the allergenicity, with a similar distribution of potency
as for the chlorine-containing compounds.
In a study of 153 workers in a catalyst production plant reported by Cristaudo et al.
(2005), workers were subject to a medical questionnaire, SPT to common aeroallergens, SPT to
chloride salts of Pt ( H2[PtClt1], K2[PtCl4], Na2[PtClt1]) and other PGEs (IrCl3, RhCl3, PdCl2), and
patch tests to H;[Pt('*l,,] and PdCl2. The SPTs to common allergens were performed with
16 common diagnostic inhalants including dusts, pollens, molds, animals, and controls. No
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exposure data were reported; however, the authors separated workers into three categories based
on exposure potential (high—workers on the production and refining side of the plant; low—
workers in all other production areas; and no—office workers outside the production area).
Positive SPTs were reported for 22 of the 153 workers to one or more of the PGEs at varioi
concentrations. None of the 11 office workers had a positive SPT, while 14/105 or 13.3%
workers in the low-exposure group had a positive SPT to halogenated Pt salts and 9/37 or 24.3%
of workers in the high-exposure group had a positive SPT to halogenated Pt salts. All of the
workers with a positive SPT were positive to hexachloroplatinic acid (EyPtCle]) a»: ;ie/: authors
suggest that their data support the use of hexachloroplatinic acid as the most import;.... ^ . salt to
test for allergy to halogenated Pt salts. A subset of the 22 workers positive to hexachloroplatinic
acid were positive to all other PGE salts tested except for palladium, which was negative in all
SPTs and only positive in one individual by patch test. P -.. results for SPT to H2[PtCl6],
K2[PtC'l.t], Na2[PtClt1], IrCls, RI1CI3, are as follows: seven workers were positive to FI2[
only, eight workers were positive to all halogenated Pt sans tested., three workers were positive
to H2[PtCl6] and Na2[PtCl6], four workers were positive to n2[m. it>] and K2[PtCl4], two workers
were positive to all five PGEs, and one individual was positive to all but RI1CI5.
Forty workers had positive SPTs to the common allergens and Cristaudo et al. (2005)
used this information to separate the workers into four groups based on response to all etiological
tests (negative, positive to common allergens, positive to halogenated Pt salts, and positive to
both common allergens and halosenated Pt salts). Symptoms of eczema did not differ
substantially between groups	i > > jvalence). Symptoms of rhinitis were low in workers
classified as negative (5.1%) ana. iu0i; m all allergic groups (90.6, 73.3, and 87.5% in workers
positive to common allergens, halogenated Pt salts, and both common allergens and halogenated
Pt salts, respectively). The prevalence of asthma and urticaria was higher in workers with
halogenated Pt salt allergy only (asthma—46.7%; urticaria—26.7%) and workers with
halogenated Pt salt allergy and positive response to common allergens (asthma—37.5%;
urticaria—25.0%). The authors analyzed age, atopy, smoking, and years at work by univariate
multivariate analyses to assess these variables as potential risk factors for predicting positive
SPT to halogenated Pt salts. They did not detect any effect of age, but found a slight increase in
prevalence for atopy (adjusted odds ratio = 2.2, 95% CI = 0.8-6.0). The prevalence of positive
SPTs to halogenated Pt salts was almost equal between smokers and nonsmokers (adjusted odds
ratio =1.1, 95% CI = 0.4-3.0). The workers were separated into two categories based on years
on the job (0-5 and 6-30 years). Workers with >6 years of work had an increased risk of
developing a positive SPT to halogenated Pt salts (adjusted odds ratio = 3.2, 95% CI = 1.2-8.9).
Cleare et al. (1976) noted that most of the nonallergenic Pt compounds were neutral
(nonionic) compounds, with the exception of K2[Pt(N02)4]. Cleare et al. (1976) proposed that Pt
complexes with strongly bound ligands (e.g., K2[ Pt(N()2).t]; cw-[Pt(NH3)2Cl2]) having poor
leaving abilities (e.g., N02, NH3, which are not easily displaced by a nucleophile) are not
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allergenic, presumably due to little or no reaction with proteins. As discussed in Section 4.6.3.1
{Mode of Action, Sensitization), allergenic Pt compounds are expected to be haptens, compounds
that elicit an allergenic response only when attached to a large carrier molecule (typically, a
protein) (Rosner and Merget, 1990). Findings by Linnett and Hughes (1999) on the occurn ;
of allergic disease in workers exposed to chloroplatinates, but not in workers exposed tc
tetraamine Pt dichloride, support the results of Cleare et al. (1976) showing that allerget
potential may be related to the degree of chlorination. However, the Linnett and Hughes (L _ -
study does not include exposure data on the particular Pt compounds to which workers are
exposed; workers were instead classified by work area without speciated Pt exposure data.
Results of studies in animals provide supportive data on the relationship of allergenic potential
and the degree of chlorination (Murdoch and Pepys, 1986, 1985, 1984a, b; Schuppe et al., 1997a,
1992); study details are provided in Section 4.5.1.1 {Sensitization Studies, Soluble Pt Salts).
Together, results of these studies suggest that highly chlorinated forms of halogenated Pt salts
(such as hexachloroplatinate and tetrachloroplatinate salts) may have a relatively higher potential
to induce sensitization than less-chlorinated forms. However, results of the Cleare et al. (1976)
study also indicate that halogenated Pt salts with other halogens as ligands (e.g., bromine) may
also have allergenic activity.
In summary, an association between exp ^ ¦ workers to halogenated Pt salts and the
development of allergic sensitization is indicated by numerous case reports and epidemiology
studies. The available studies susaest that halogenated Pt salts induce allergic sensitization
resulting in asthma, rhinitis, conjunctivitis, and dermatitis. However, all soluble Pt compounds
may not have allergenic activi.,. „			.ice from the retrospective epidemiology study by Linnett
and Hughes (1999) and fro... SPT study by Cleare et al. (1976) and Cristaudo et al. (2005)
suggest that allergenic activity of halogenated Pt salts may differ among the compounds.
Supporting evidence for compound-specific allergenic activity is also available from studies in
animal (see Section 4.5.1.1).
4,I .2.1,1. Toxicity of soluble forms of Pt: diagnosis of Pt allergic sensitization. Most cases of
Pt are thought to be due to Type I, immediate onset, IgE-mediated immune
enated Pt salts (Murdoch and Pepys, 1987; Murdoch et al., 1986; Biagini et
al., 1986; Hughes, 1980; Cromwell et al., 1979; Pepys et al., 1979). Briefly, IgE-mediated Type
I hypersensitivity reactions involve IgE-mediated release of histamine and other mediators from
degranulation of mast cells and basophils. The reaction is classified as "immediate", because the
mediators released by degranulation act quickly to produce effects. Initial exposure to an
allergen (also known as "sensitizing exposure") is required for IgE antibodies to be produced and
sensitization effects to occur on subsequent exposures (although not necessarily the next
exposure). As discussed in Section 4.6.3.1 {Mode of Action Information, Sensitization), the
clinical presentation of halogenated Pt salt sensitization is consistent with an IgE-mediated
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reaction (see Section 4.6.3.1 for additional details on Type I hypersensitivity reactions).
However, evidence suggests that non-IgE mechanisms may also be involved in some of the
hypersensitivity responses to halogenated Pt salts. Results of a study on the passive transfer (via
serum) of halogenated Pt salt-allergy to non-exposed humans and monkeys suggest that an
additional IgG-mediated mechanism may be involved in the development of halogenated Pt salt
allergy (Pepys et al., 1979; study details are summarized in Section 4.5.1.1.2). IgG-mediated
hypersensitivity reactions are classified as Type II or Type III. Unlike IgE-medi ;
hypersensitivity reactions, Type II- and Type Ill-mediated reactions do not	lediate
degranulation of mast cells and basophils. Details of IgG-mediated mechai:;111: .
hypersensitivity are discussed in Section 4.6.3.1. In addition, evidence that	t salts
(specifically to salts of hexachloroplatinate) can produce respiratory effects in the absence of
IgE-mediated sensitization was reported in a study in monkeys by Biagini et al. (1985b) (see
Section 4.4.2 for study details).
The diagnosis of sensitization to halogenated Pt sans, as reviewed by Merget (2000), is
based on the occurrence of respiratory or dermal symptoms in tne work place, documentation of
disease status (asthma, rhinitis, conjunctivitis, urticaria), and a positive SPT (discussed in detail
below) with a hexachloroplatinate salt. Asthma is usually documented with tests of lung
function (e.g., FEVi, forced expiratory flow [FEF], peak expiratory flow [PEF]), or bronchial
responsiveness to nonspecific stimuli (e.g., methacholine, histamine, or cold air) or specific
stimuli (e.g., in this case, halogenated Pt salts). The pathogenesis of bronchial
hyperresponsiveness and asthma involves several mechanisms, including inflammation,
enhanced neuromuscular :(-;3S, and allergic reactions (Barnes, 1989); thus, although
bronchial hypeixesponsive.^.,., may be mediated through a Type I hypersensitivity reaction,
bronchial hyperresponsiveness also may occur in the absence of an IgE-mediated response (see
Sections 4.6.3 for additional details). To definitively demonstrate bronchial hyperresponsiveness
to a halogenated Pt salt, a bronchial challenge test must be performed using that specific
stimulus. The specific stimulus test examines the effect of inhalation (typically 10 breaths) of
^bulized solutions containing that substance on baseline pulmonary function test results. A
;sponse to an allergen is typically defined as a 15-20% decrease in FEVi from baseline
(Melillo et al., 1991). Although bronchial responsiveness testing using a specific stimulus
provides evidence of bronchial reactivity (but not the mechanism producing the effect) to that
specific agent, a severe reaction may occur; therefore, bronchial challenge tests are often
conducted using nonspecific stimuli to decrease medical risks. The nonspecific stimulus test
involves inhalation of increasing doses of a nonspecific challenge agent (most commonly
methacholine). Pulmonary function tests are conducted after each dose, until reaching a dose
that produces a 15-20% drop in FEVi from baseline (called the provocative dose or PDi5 or
PD2o); the response to a nonspecific stimulus is quantified by the PD. Nonspecific stimuli do not
produce bronchial responsiveness through an IgE-mediated mechanism.
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SPTs are routinely performed to diagnose sensitivity to specific halogenated Pt salts
(Merget, 2000). Unlike bronchial responsiveness, which involves several mechanisms and may
occur in the absence of an IgE-mediated mechanism, SPTs only detect Type I, IgE-mediated
sensitization. SPTs are conducted by applying a small amount of the test substance to the ¦¦; in;
the skin is then pricked, introducing the test substance into the epidermis. If IgE-antibodies to a
specific allergen are present, the allergen will induce degranulation of mast cells and basop ^
resulting in the local release of histamine and other mediators. The response, which typically
occurs within 10-15 minutes, is observed as a raised, blanched center surrounded by an area of
erythema (e.g., a wheal and flare). The criterion for a positive response typically is a wheal with
a diameter of at least 3 or 4 mm (Merget, 2000). Since most cases of allergic sensitivity to Pt are
thought to be due to IgE-mediated immune mechanisms (see Section 4.63.1,Mode of Action
Information, Sensitization), sensitivity to specific Pt compounds can be detected through SPTs.
However, as discussed above and in Section 4.6.3.1, a non-IgE mechanism of sensitivity to
halogenated Pt salts cannot be ruled out. Thus, if sensitivity to halogenated Pt salts is
predominantly mediated in an individual through, a non-IgE mechanism (e.g., possibly an IgG
mechanism), sensitivity would not be detected, using tne SPT.
As reviewed by Merget and Rosner (1990), demonstration of sensitization by SPT to
halogenated Pt salts has a high specificity, and in subjects with positive responses to unspecified
bronchial challenges and ongoing exposure, SPTs to halogenated Pt salts have a high sensitivity.
For example, among the 13 cases of workers who developed a positive SPT to Pt in a 5-year
prospective study of 115 high-exposure catalyst production workers, all displayed symptoms
(rhinitis, asthma, or dermatitis.,,	the symptoms were not work-related in a few of these
cases (Merget et al., 2000; study details provided in Section 4.1.2.1.2). An additional six
subjects in this group developed work-related symptoms, but did not display positive SPT results
(Merget et al., 2000). In a retrospective study of 406 U.K. refinery workers exposed to
chloroplatinates, 110 cases of halogenated Pt salt allergy were identified; of these, 100 were SPT
positive to Pt (Linnett and Hughes, 1999). Among the 10 Pt SPT negative cases, 1 was positive
in a patch test, 1 was positive in a "specific" bronchial challenge test (the study report did not
identify challenge agent used, although "specific" implies a chloroplatinate salt), 1 had work-
related upper respiratory symptoms, and 7 had bronchospasms at work.
Merget et al. (1991) further explored the relationship between SPT to hexachloroplatinate
and bronchial challenge tests with specific (hexachloroplatinate) and nonspecific (methacholine)
stimuli in Pt refinery workers. A total of 35 workers from two Pt refineries were initially
referred to a pulmonary clinic due to work-related symptoms of Pt sensitization (asthma,
conjunctivitis, rhinitis); of these, 27 agreed to participate in Pt SPT and Pt specific and
nonspecific bronchial challenge tests. Tests were performed an average 15 months (range 0-
132 months) after the workers had been removed from the refining area (reasons for removal
were not provided in the report), although 19 workers reported that they still had "occasional"
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contact with Pt salts. Test results, however, were not reported based on current or previous
exposure, and no quantitative information on exposure was reported. Results of testing showed
that 16/27 workers tested positive for all three tests (Pt SPT, Pt bronchial challenge, and
methacholine bronchial challenge). Test results of the remaining 11 workers were as follows:
2 workers tested positive to Pt and methacholine bronchial challenge, but negative to Pt SPT;
4 workers tested positive to Pt bronchial challenge, but negative to methacholine bronchial
challenge and Pt SPT; 1 worker tested positive to Pt SPT (weak response) and methacholine
bronchial challenge, but negative to Pt bronchial challenge; 3 workers tested positive to
methacholine positive challenge, but negative to Pt bronchial challenge and Pt SPT; and
1 worker tested negative in all three tests. A positive correlation was observed between the
response to the Pt SPT and Pt bronchial challenge test (r = 0.66; p < 0.0008; n = 27), but no
correlation was observed between the response to Pt SPT and methacholine bronchial challenge
(r = 0.05; /rvalue reported as not significant; n = 27). Results of this study show that the Pt SPT
response does not always predict the respiratory response to inhaled hexachloroplatinate.
After removal from exposure, SPT sensitivity to hexachloroplatinate and asthmatic
bronchial responses to halogenated Pt salt and methacholine challenges persist in most workers
over a 2-year period. Merget et al. (1994) examined the effect of removal from exposure on Pt
SPT sensitivity and bronchial challenge tests in 24 Pt refinery workers who had experienced
work-related asthma symptoms. Quantitative data on exposure were not reported. Workers were
examined on two occasions; SPT to hexachloroplatinate and bronchial challenge tests to
hexachloroplatinate and methacholine were conducted at both examinations. At the initial
assessment, 11 workers had ci	. .r..'Sure to Pt salts and 13 workers had been removed from
exposure for an average ol ^ i iu^nths (range 1-61 months). All 24 workers tested positive in the
hexachloroplatinate bronchial challenge test and 23 workers tested positive in the methacholine
bronchial challenge test; results of the SPT to hexachloroplatinate conducted at the initial
assessment visit were not reported. The average time between the first and second assessments
was 20 months (range 8-100). At the second assessment, 17 of the 24 workers reported that they
~";'l experienced symptoms of asthma. SPT to hexachloroplatinate converted from positive to
- native in three workers and from negative to positive in one worker. The response to
mchial challenge with hexachloroplatinate and methacholine did not change from the initial
assessment. The three workers converting from positive to negative in the hexachloroplatinate
SPT had positive responses to bronchial challenges tests with hexachloroplatinate and
methacholine at the second assessment.
Other responses to halogenated Pt salts include elevations in nonspecific histamine
release, Pt-specific IgE levels, and total IgE levels in Pt SPT-positive compared with Pt
SPT-negative subjects (Merget et al., 1988; Biagini et al., 1985a; Cromwell et al., 1979).
Histamine release and Pt-specific IgE levels are not thought to be useful in diagnosing individual
cases of halogenated Pt salt allergy, because the nonspecific high binding affinity of
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h ex a c 111 orop 1 a t i n at e to IgE antibodies is a confounding factor in using Pt-specific IgE to identify
halogenated Pt salt allergy (Merget, 2000). The role of total IgE in halogenated Pt salt allergy is
also unclear. It may represent a risk factor (i.e., individuals with elevated total IgE may be more
likely to become SPT positive). Alternatively, total IgE may be associated with exposure
reported by Merget et al. (2000, 1999), because ongoing Pt exposure causes an increase in 1>
IgE (Merget et al., 1999). However, total serum IgE can be influenced under several condi : ¦i.-,
including atopy (e.g., individuals with a hereditary disposition to develop Type I hypersensitivity
to common environmental allergens), seasonal variations in pollens, and exposure (variable or
continuous) to other non-Pt allergens (such as animal dander) (Goldsby e\ n 3a). Thus,
since total serum IgE can be influenced by many factors and may vary o\ ? i:; >' ti response to
those factors, use of total serum IgE to diagnose Pt allergy is limited. Ne, Ts are routinely performed to diagnose sensitivity to specific halogenated Pt
bronchial responsiveness, which involves several mechanisms and may occur in
f an IgE-mediated mechanism, SPTs only detect Type I, IgE-mediated
Results of a study by Merget et al. (1991) show that the Pt SPT response does not
always predict the respiratory response to inhaled hexachloroplatinate. The data also support the
hypothesis that a non-IgE mechanism may be involved in the response of some individuals,
based on the finding that positive hexachloroplatinate bronchial challenge was observed in a few
workers testing negative for hexachloroplatinate in the SPT.
4.1.2.1.2. Toxicity of soluble forms of Pt: epidemiologic evidence of Pt allergic sensitization.
Five epidemiologic studies provide information on the characteristics of exposure-response
relationships for the development of halogenated Pt salt sensitivity in Pt refinery workers
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(Linnett and Hughes, 1999; Bolm-Audorff et al., 1992; Baker et al., 1990; Brooks et al., 1990)
and Pt catalyst production workers (Merget et al., 2000; Linnett and Hughes, 1999). Studies are
described in more detail, as follows, and are evaluated for use in developing an RfC for chronic
inhalation exposure to halogenated Pt salts (see Sections 4.6 and 5.2). Although there are
numerous additional reports of occupational exposure that provide strong supportive evidence
for respiratory and sensitization effects of inhaled Pt compounds, exposure measurements or
quantitative estimates of exposure were not reported in these studies (Watsky, 20
al, 2005; Merget et al, 2002, 2001, 1999, 1996, 1995, 1994, 1991, 1988;
2000; Santucci et al., 2000; Newman Taylor et al., 1999; Calverley et al., 1(
and Gamier, 1996; Venables et al., 1989; Biagini et al., 1985a; Jarabek et al..
1980; Hughes, 1980; Cromwell et al., 1979; Cleare et al., 1976; Harris, 1975,
Milne, 1970; Parrot et al., 1969; Roberts, 1951). Since data from ' ¦ ' dies do not allow for
characterization of the shape or slope of the dose-response relationsnip iui halogenated Pt salt
sensitivity, additional details on these studies are not summarized in this report.
Bolm-Audorff et al. (1992): Pt Refinery Workers
A cross-sectional study of the employees of a Pt refinery in Germany used a cohort of
65 subjects (63 men and 2 women) that was divided into three exposure categories (high,
moderate, and low) on the basis of predicted Pt exposure level (Bolm-Audorff et al., 1992). The
mean age of the staff was 37.2 years (SD = 10.8 years), and mean duration of employment (i.e.,
exposure to Pt) was 8.9 years (range 1-40 years). Exposure categories were defined based on the
job location of workers, rather than personal air monitoring data. The high-exposure category
consisted of 21 workers in the Pt refinery division of the plant. The moderate-exposure category
consisted of 21 workers involved in the refining of gold, silver, palladium, iridium, and osmium,
but not Pt. r;:workers were expected to have been exposed to Pt as "bystanders" because the
refining of these other metals took place in the same building as the refining of Pt. The low-
exposure categuiy comprised 21 tradesmen and employees involved in alkaline dissolution of
metallic Pt. Analysis of Pt in total dust was conducted in 1984 and 1986 using two 3.5-hour
tionary monitors. The location of the stationary monitors was identified as the "separation
uunt"; however, the location of the monitors relative to the work areas that define the exposure
groups was not indicated in the study report. The report also did not indicate the number or
frequency of measurements taken. Analysis of two 3.5-hour stationary air monitor readings of Pt
in total dust in 1984 showed soluble Pt concentrations <0.20 ug soluble Pt/m3 (the detection
limit). In 1986, two 2-hour measurements revealed soluble Pt concentrations of 0.08 and 0.10 ug
soluble Pt/m3. Two 1-hour personal air-monitoring measurements, taken from filter press
workers in 1986, showed soluble Pt concentrations of <0.05 ug soluble Pt/m3 (detection limit) in
total dust. The study report did not indicate if the two filter press workers were included in the
study, or the location of the "filter press" relative to the three exposure locations. The study
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report also did not indicate the chemical analytical methods used to determine air concentrations
of total or soluble Pt and made no mention of particle sizes in the air samples. No information
was provided regarding the chemical species present or further characterization of Pt beyond the
soluble Pt reported. Bolm-Audorff et al. (1992) reported that plant records indicated that'
plant was in long-term compliance with the German regulatory exposure standard (8-hc
weighted average [TWA]) of 2.0 ug soluble Pt/m3.
Occupational and nonoccupational histories were collected by questionnaire, including
the presence of allergy symptoms (conjunctivitis, rhinitis, coughing/expectoration, and
respiratory distress). Measures of lung function (FEVi and FEF25-75) and pulmonary resistance
were recorded before and after a Monday shift as well as after the following Friday shift. Assays
for nonspecific allergy symptoms and specific allergic sensitization to halogenated Pt salts
included a SPT with six common allergens and 10"3Mthe halogenated Pt salt dipotassium
hexachloroplatinate (K.;PtClt1). Levels of serum IgE and Pt-specific IgE were determined, as was
histamine release from whole blood following incubation with K2PtCl6. Prevalence data were
analyzed using % -tests, and mean values were ' red using t-tests. Lung function data at
different times were compared using the Wilcoxon test for matched pairs. Results of the
symptom and medical exams are presented in TV 'K/:, : : and 4-2, respectively.
Table 4-1. Prevalence of allergic symptoms
Symptoms
Hi«h exposure
Moderate exposure
Low exposure
Work-related
11/211'
1/23
3/21
Non-work-related3
2/21
5/23
3/21
No symptoms
8/2 lb
17/23
15/21
	
'Non-work-related symptoms were judged as such if they also occurred at home.
hp < 0.01 compared to either the moderate- or low-exposure groups; no estimates of workplace air Pt concentrations
CM)cn.cnced b> the high-, moderate-, and low-exposure groups of workers were available.
992).
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Table 4-2. Pt specific and nonspecific allergic results
Knd point
Symptom status
Work-related
Non-work-relateci
No symptoms
SPT—K2PtCl6
9/14a
2/10
1/40
SPT—other allergens
2/13
4/10
13/4' ?
Total IgE (U/mL)
230.4 ±296.9b'd
48.6 ±35.4
I08-2 ±- —
Pt-specific IgE (percent binding)
10.8 ± 11.3°
2.4 ± 1.3
4.6 ±3.6
Histamine release (percent of maximum)
17.3 ±20.9
15.6 ± 12.5
19.0 ±14.8
*p < 0.01 compared to either the "non-work-related" or "no symptoms" columns.
hp < 0.05 compared to the "non-work-related" column.
cp < 0.05 compared to either the "non-work-related" or "no symptoms
dThe study report did not indicate if values were reported as means ± SO or means ± SI
Source: Bolm-Audorff et al. (1992).
Symptoms (including conjunctivitis, rhinitis, coughing, and respiratory distress) assessed
as work-related by the subjects were reported significantly more often in the high-exposure
category, compared to the moderate- or low-exposure categories (Table 4-1). Allergic symptoms
assessed by subjects as non-work-related (also including conjunctivitis, rhinitis, coughing, and
respiratory distress) did not occur more frequently in the high-exposure category, compared with
the lower exposure categories. In subjects with work-related symptoms, the average latency
between the initial exposure and the appearance of symptoms was 4.8 years (SD = 3.9 years,
range = 1-13 years). Latencies were not different between different symptom types. Positive Pt
SPT results were more frequent in the group with work-related symptoms (Table 4-2). Subjects
with work-related symptoms showed sensitivity to environmental allergens less frequently than
did those without work-related symptoms. Mean levels of total and Pt-specific IgE were higher
in the group v us; work-related symptoms. Lung function tests in employees exposed to Pt salts
with work-reL.-i symptoms showed normal function on Monday morning. In the course of the
Monday work shift and work week, there was a significant fall in FEVi from 100.7 to 95.9% of
¦ -dieted values, and other respiratory flow values were similarly affected, most notably
FEF'25, which fell to 95.1 and 73.4% of the predicted values by Monday and Friday after shift,
respectively. Measures of airway resistance remained unchanged.
This study reports the occurrence of cases of allergic sensitization to halogenated Pt salts
in a workplace in which air concentrations of soluble Pt appeared to have been below the
German occupational exposure limit of 2 ug soluble Pt/m3 (8-hour TWA), although details of the
methods used to measure Pt and to determine "soluble" Pt were not included in the study report.
The maximum reported concentration among the limited number of air samples collected from
the workplace was 0.1 ug soluble Pt/m3. However, the exposure data are too limited to reliably
estimate the air concentrations experienced by the three exposure categories of workers and
personal air monitoring was only done for a 1-hour period for two filter press workers. Thus, no
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characterization of the shape or slope of the exposure-response relationship for development of
allergic sensitization to halogenated Pt salts was provided, and a no-observed-adverse-effect
level (NOAEL) for allergic sensitization to halogenated Pt salts was not identified. The
characterization of Pt allergic sensitization did not include specific respiratory challenge to Pt or
nonspecific respiratory challenge, but did include basic lung function, Pt-specific and total IgE,
histamine release, and SPT to the halogenated Pt salt hexachloroplatinate. In addition, important
factors, such as smoking status and years of exposure, were apparently not included in the
analysis.
Linnett and Hughes (1999): Pt Refinery and Catalyst Production Workers
In a retrospective study of medical surveillance data collected over a - - ;ar period at a
Pt processing company in the United Kingdom (Linnett and Hughes, 1999), the allergenicity
potentials of two soluble Pt forms, halogenated Pt salts (chloroplatinates) and tetraamine Pt
dichloride ([Pt(NH3)4]Cl2), were studied in workers involved in three different operations at the
same site. Workers in the Pt group metal refinery area were chemical process operators (CPO,
n = 270) who refined Pt and other PGEs from ore using processes involving concentrated HC1
dissolution, ammonium hexachloroplatinate precipitation, and thermal reduction of
hexachloroplatinate to Pt metal. Soluble Pt in air samples from the refinery area were reported to
consist solely of chloroplatinates. No data on Pt speciation were provided to substantiate that Pt
exposure in the refinery area was restricted to chloroplatinates. Workers in the tetraamine Pt
dichloride lab (n = 31) made t -Pt dichloride from chloroplatinic acid in a closed reactor
vessel to ultimately produce a	:r of tetraamine Pt dichloride. Operations with the dust
were carried out with respiratory protection. Soluble Pt in air samples was considered by the
authors to contain both chloroplatinates and tetraamine Pt dichloride. No data on Pt speciation
were provided to substantiate that Pt exposure in the tetraamine Pt dichloride lab included both
chloroplatinates and tetraamine Pt dichloride. Workers in the third area (n = 39) made
automobile catalysts by impregnating a coated substrate with a solution rich in tetraamine Pt
dichloride and other PGE elements and firing the material to attain thermal reduction to the
ii i...;: ;: metals. The authors state that tetraamine Pt dichloride was expected to be the only
soluble Pt form to which the automobile catalyst workers were exposed. No Pt speciation data
.. (. i '. ided to substantiate that tetraamine Pt dichloride was the only form of Pt present. Air
samples were collected by personal air monitoring in work areas (see Table 4-3). The frequency
of sampling was not reported. Sampling times in the refinery work areas were reported as
"short", but not otherwise specified. For the other two work areas, samples were collected for an
entire shift and reported as an 8-hour TWA. Samples were collected on a 25-mm filter with a
7-hole sampling device equipped with a pump (2 L/minute). Filters were dissolved in 0.12 M
HC1 and analyzed for soluble Pt by electrothermal atomic absorption spectrophotometry. More
specific chemical analysis to identify the soluble Pt forms in the air samples was not mentioned.
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Information regarding particle sizes in the air samples was not provided. Sensitization was
defined as one or more of the following: (1) a repeatable positive SPT to Pt compounds
including (NH4)3PtCl6, Na2PtCl6, Na2PtCl4, and tetraamine Pt dichloride, (2) a positive "specific"
bronchial challenge test (the study report did not indicate the test substance used, although
"specific" implies a chloroplatinate salt), (3) work-related symptoms and assessment by an
occupational physician, or (4) a positive patch test. SPTs were conducted with two halogenate
Pt salts [(NH4)2PtCl6 and Na2PtCl6] and tetraamine Pt dichloride at concentrations of 10"3 g/mL,
and the positive criteria was a weal diameter >2 mm of vehicle control (g' x i ol carbol saline).
If a negative Pt SPT was obtained in a worker presenting with symptoms, i ;/i and FEF
variables were measured to ascertain a relationship with work. One symptomatic worker who
was Pt SPT negative was diagnosed as sensitized with a specific bronchial challenge test. No
mention was made in the report of operational details of t	>r of the actual use of this
test in diagnosing a case of sensitization.
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Table 4-3. Pt sensitization in CPO workers and exposure to different soluble
Pt compounds in different work environments

Pt group metal refining
Tetraamine Pt clicMoricle
synthesis
Catalyst production
Number of subjects
270
(257 men; 13 women)
31
(31 men; 0 women)
39
(39 men; 0 wom '
Number of sensitization cases
106
5
0e
Median latency3 to
sensitization (mo)
12.6
36.9
Not applicable
Latency range (mo)
1.0-107.9
7.1-51.7
Not applicable
Chemical exposure'
chloroplatinates only
chloroplatinates and |tetraamine Pt dichloridc
tetraamine Pt dichloridc only
Total number of air samples
collected0
(personal air monitoring)
380
H" | 176
I
Soluble Pt concentration
Number of samples in range (cuiieciea oeivvcen 1989 and 1991)
<0.5 ng soluble Pt/m3 d
335 (88%)
67 (52%)
107 (61%)
0.5-<1.0 \ig soluble Pt/m3
21 (6%)
12 (9%)
38 (22%)
1.0-<2.0 \ig soluble Pt/m3
15 (4%)
14(11%)
16 (9%)
2.0-<5.0 \ig soluble Pt/m3
7 (2%) [ 25 (19%)
10 (6%)
5.0-<10.0 \ng soluble Pt/m3
1 (<1%)
9 (7%)
2 (1%)
>10.0 \ig soluble Pt/m3
1(<1%)
3 (2%)
3 (2%)
aNumber of months between initial exposure and development of sensitization.
bPt compounds in the work environment in the different areas of the refinery were determined by work conditions.
No data were provided that demonstrate specific Pt compounds and measurement of Pt concentrations in each work
area are only reported as "airborne soluble platinum"; no further speciation data were provided. However, the
authors state that exposure in the refinery was restricted to chloroplatinates, that the tetraamine Pt dichloridc lab was
a mixed exposure to chloroplatinates and tetraamine Pt dichloridc, and that the catalyst production area was to
tetraamine Pt dichloridc only.
" Sampling times in the refinery work areas were reported as "short", but not otherwise specified. For the other two
work areas, samples were collected for an entire shift and reported as an 8-hour TWA.
''Concentrations in these groups of samples were reported only as <0.5 \ig soluble Pt/m3. No information on
detection limit was provided.
eSPTs were performed using (NH4)2PtCl6, Na2PtQ6, Na2PtCl4, and tetraamine Pt dichloridc.
Source: Linnett and Hughes (1999).
mpling (8-hour TWA concentrations) and prevalence data for allergic sensitization
PO workers only) are given in Table 4-3. Although demographic data concerning age and
smoking habits were reported, as well as the medians and ranges of the time to diagnosis for the
cases of allergic sensitization, no information on the duration of employment for the workers in
the three groups was provided. The results demonstrate a high prevalence of Pt salt sensitivity
(106 sensitized/270 CPO workers [39%]) in a workplace in which chloroplatinates were
described as being likely to be the only soluble Pt forms present. The 270 CPOs were the most
heavily exposed workers in the Pt group metal refining area; an additional 136 workers (these
workers are not included in the 270 CPOs) in the refining area who were expected to have much
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less exposure showed a lower prevalence of allergic sensitization (4/136, 3%). In the combined
group of 406 chloroplatinate workers (270 CPOs and 136 non-CPOs), 110 cases of halogenated
Pt salt allergy were identified, with 100 testing positive by SPT to halogenated Pt salts. Among
the 10 cases with a negative Pt SPT, 1 was positive in a patch test, 1 was positive in a "sp s dc"
bronchial challenge test (the test substance was not identified in the study report), 1 had wo; <,
related upper respiratory symptoms, and 7 had bronchospasms at work. The study did not r- ¦¦¦<
the Pt SPT results for the 270 CPO group, although 106/270 were reported as sensitized.
Personal air monitoring data in the refining work area indicated that the c ' rial limit of
2.0 ug soluble Pt/m3 was exceeded in only 9/380 samples (2%) collected _ year period
(Table 4-3). In contrast, soluble Pt concentrations exceeded 2.0 jig/m3 in 37/130 samples (28%)
collected from the tetraamine Pt dichloride synthesis area (where tetraamine Pt dichloride was
expected to be the predominant soluble Pt form) and 5/31 CPO workers showed Pt salt
sensitization (16%). No cases of sensitization (to either halogenated Pt salts or tetraamine Pt
dichloride) occurred in the 39 catalyst production workers, whose exposure to soluble Pt was
expected to have been restricted to tetraamine Pt dichloride. aoiuoie Pt concentrations exceeded
2.0 jig/m3 in 15/176 samples (9%) in this catalyst production area where exposure was expected
to be limited to tetraamine Pt dichloride. The ci	; probability of sensitization for a 5-year
period was 51% in CPOs classified by the authors as exposed to chloroplatinates alone, 33% in
tetraamine Pt dichloride lab workers (classified as exposed to a mix of chloroplati nates and
tetraamine Pt dichloride), and 0% in workers classified as exposed to tetraamine Pt dichloride
alone (i.e., catalyst production workers). The study authors concluded that tetraamine Pt
dichloride may not be allergen.. 	gh the limited number of workers who were classified as
exposed to tetraamine Pt diuu^de alone (n = 39) and the lack of information on duration of
employment limits the confidence in this conclusion.
Atopics were excluded from employment as CPOs in the Pt processing company;
therefore, atopy could not be evaluated as a risk factor for development of halogenated Pt salt
sensitization. There was no evidence of an effect of age at the start of employment as a risk
^-tor; however, smoking was a risk factor for the development of halogenated Pt salt
v;: isitization. For workers in the Pt group metal refining area (classified as exposed to
oroplatinates alone), smokers of 1-19 cigarettes/day were 2.19 times more likely to develop
halogenated Pt salt sensitization (p < 0.01) and smokers of >20 cigarettes/day had 3.24 times
higher risk (p < 0.001) relative to nonsmokers. Data for the relative risk of smokers to
nonsmokers in the tetraamine Pt dichloride lab (classified as mixed exposure to chloroplatinates
and tetraamine Pt dichloride) were not provided. The relative risk of developing Pt sensitization
was significantly lower (0.33 relative risk; 0.14-0.78 95% CI) for workers in the tetraamine Pt
dichloride lab relative to the workers in the Pt group metal refining area if smoking was not
considered. When adjusted for smoking, the relative risk of developing Pt sensitization did not
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differ between workers in the tetraamine Pt dichloride lab and the Pt group metal refining area
(0.47 relative risk in the tetraamine Pt dichloride lab; 0.20-1.12 95% CI).
Data from this study do not characterize the shape or slope of the exposure-response
relationship for halogenated Pt salt allergic sensitization and do not identify a NOAEL (an
exposure level to a pertinent soluble Pt form that produced no cases of sensitization). A key-
limitation to the usefulness of this study for developing a chronic inhalation RfC is that, although
median latencies to sensitization were reported for the refining and tetraamine Pt die > i: de
synthesis workers, no information was provided concerning the duration of
workers in any of the three groups. However, the results clearly show that ¦
concentrations of chloroplatinates, predominantly <0.5 ug soluble
concentration for 335/380 or 88% of collected air samples from th ;
associated with a very high prevalence of workers who developed .
provide limited evidence that tetraamine Pt dichloride may not be aiicigemu.
soluble Pt concentrations were reported as number and percent of samples above and below
0.5 ug soluble Pt/m3 rather than actual concen " ere are no data on the actual
concentration of samples below 0.5 ug soluble Ft/nr. ine characterization of Pt sensitization
included specific respiratory challenge and diagnosis of Pt-related symptoms at work by a
physician as Pt-specific SPT to halogenated Pt salts ([NH4]2PtCl6, Na:PtCl„, and Na2PtCU) and
tetraamine Pt dichloride.
Baker et al. (1990); Brooks e( at. (1990): Pt Refinery Workers
A cross-sectional h.	an evaluating workers for halogenated Pt salt allergy
was conducted in 1981 in - ¦	.J. precious metals reclamation plant (Baker et al.,
1990, Brooks et al., 1990). Workers were administered a medical questionnaire for symptoms of
the eyes (symptoms were not specified), nose (itchy and/or runny nose), chest (wheeze, cough,
shortness of breath, chest tightness), and dermatitis (symptoms were not specified); use of a
severity scale in this survey was not reported. Physical examinations of workers included
spirometry (forced vital capacity [FVC ], FEVi, FEVi/FVC) before and after a work shift, cold
: i bronchial inhalation challenge (measuring the post-challenge change from baseline for FEVi
.- lowing inhalation of cold air), and skin prick testing to halogenated Pt salts (sodium
nexachloroplatinate [Na;Pt('*l,,] and ammonium hexachloroplatinate [(NH4)2 PtCl,,]) and three
common aeroallergens (ragweed, timothy, and dust). Serum concentrations of total IgE and IgE
specific for halogenated Pt salts were measured by a radioal 1 ergenosorbent test (RAST). The
plant had been in operation for about 13 years at the time of the study in 1981 (e.g., from
approximately 1968 to 1981). The subjects included 107 of the 123 employees in 1981 ("current
workers") and 29 former employees. Medical records for the plant indicated that 49 workers had
been terminated from 1971 to 1979 due to suspected halogenated Pt salts allergy; the 29 former
workers in the study were among the 49 medically terminated workers. The latencies between
¦" rted air
¦ ¦¦ - were
ati on, and they
ncuuise airborne
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employment termination and the 1981 medical examination were 7-107 months (average =
5 years). The current workers had a mean age of 33.7 years and a mean duration of employment
of 70.8 months (SDs or ranges for these means were not reported): 99 were men and 8 were
women; 65% were current or ex-smokers. The terminated workers (28 men and 1 woman) had a
mean age of 36.5 years and a mean duration of employment of 61.2 months; 97% were curr.MM
ex-smokers.
"Pt salt concentrations" were reported (as an 8-hour TWA) for air samples collectec :;
number of work areas by the company during several workdays between 1977 and 1979; the
number of sampling days varied with sampling location and ranged from 1 to 9 days. The air
samples were collected by stationary air sampling techniques; personal air samples for workers
in this study were not collected. The study report did not specify the analytical methods used to
determine the Pt salt concentrations in the collected air 		 ; or report the LOD. No mention
of acid extraction of filters or detection systems was made. Requests for more information on
the air sampling and analytical techniques were sent to the siuuy authors in March 2005, but no
replies were received within 1 year of that request. Under me assumption that Pt salt
concentrations reported were soluble Pt, analysis of Pt salt concentrations in workplace air
samples indicated that 50-75% of the samples ir , work areas exceeded the OSHA TWA
permissible exposure limit (2.0 ug soluble Pt/m'). The geometric mean air concentrations of Pt
salts (with number of sampling days, n, indicated in parentheses) in the recovery,
recovery/sampling, refinery, refinery tray, and warehouse areas were 5.3 (n = 9), 2.7 (n = 4),
10.7 (n = 3), 27.1 (n = 4), and 8.(3 (n = 8) ug soluble Pt/m3, respectively, compared with values of
0.5 (n = 1), 0.4 (n = 3), an< ; u J) ug soluble Pt/m3 in the residue, analytical laboratory, and
administrative office air coiiaiu^ning unit areas, respectively (Baker et al., 1990). SDs or ranges
for these memc were not reported; thus, measures of the variability of Pt salt concentrations in
the air samp .. ¦ e not available.
Posi ; .. PT results to halogenated Pt salts (Na2PtCl6 or [NH4]2PtCl6 concentrations
ranging from 10"9 to 10"3 g/mL) were found in 23 workers (17% overall; 15/107 current workers
n ^n/T . j "'09 terminated workers [28%]), compared with 1 positive result in 45 control
were University of Cincinnati employees. The control subject showing a positive
halogenated Pt salt was a scientist who had worked with Pt salts in the past; the
other control subjects had no known exposure to Pt salts. Among current workers, positive Pt
SPT results occurred in all areas of the facility except the administrative offices (Table 4-4). The
occurrence of sensitization to halogenated Pt salts was correlated with mean air concentrations in
the current employees' work areas (Spearman correlation = 0.71;/? = 0.11), but not to a
statistically significant degree using a significance criterion ofp< 0.05. However, a logistic
regression analysis indicated that the risk of a positive SPT to Pt was statistically significantly
increased (p = 0.01) 1.13 times with 1-ug/m3 increments in exposure concentration (the report
did not specify if adjustment for smoking was made in this analysis).
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Table 4-4. Incidences of positive liexachloroplatinate SPT results among
current workers in different work areas in a U.S. precious metal reclamation
facility in 1981
Work area
Mean air concentration3
(|tg Pt/m ' as Pt salts)
Incidence of workc:
with positive Pt SPT
Residue/recovery
0.5/5.3
1/15 (7%)
Refinery
10.7
2/14 (14%)
Refinery, tray area
27.1
2/3 (67%)
Chemical products/salts
Not reported'
3/22 (14%)
Analytical laboratories
0.4
2/19(11%)
Warehouse/stores
8.6 : ; (33%)
Maintenance
Not reported' ¦ : 2 (25%)
Manager/office
0.6 0/15
Other (electrician, boiler operator)
Not reported' !¦ (25%)
Total
07 (14%)
'Geometric means of 8-hour TWA concentrations measured with 	™,,.™ during 1-9 sampling
days between 1977 and 1979 (see text). SDs or ranges for these means were not reported.
bAir concentrations for these work areas were not reported and apparently were not measured.
Sources: Baker et al. (1990); Brooks et al. (1990),
Results of the symptoms survey, pulmonary function test, cold air challenge, aeroallergen
test, and total IgE analysis by , ¦ - 'T result (positive or negative) and work status (current or
former) are summarized in Table 4-5. Current workers with positive SPT results for halogenated
Pt salts were more likely to report rhinitis symptoms, asthma symptoms, or dermatitis, and to
display positive results in a cold-air challenge, than current workers with negative SPT results to
Pt, as indica' ~J hy statistically significantly increased prevalence odds ratios (PORs) for rhinitis
symptoms (!¦¦¦ . 5% CI: 1.8-37.8), asthma symptoms (11.3, 95% CI: 2.3-54.6), reported
dermatitis (] .. 95% CI: 2.2-72.8), and positive cold-air challenge (7.7, 95% CI: 1.5-38.3)
(Baker et al, 1990). In addition, among current workers, current or past smokers were more
ave a positive SPT result for halogenated Pt salts than nonsmokers (POR= 9.0, 95%
CI: 1.2-69.3).
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Table 4-5. Symptoms, test results and relative risk of symptoms by Pt
SPT result

Current workers
Former workers

Symptom or test
result
Incidence In
workers with
positive Pt SPT
Incidence In
workers with
negative Pt SPT
Incidence In
workers with
positive Pt SPT
Incidence In
workers with
negative Pt SPT
POR*
Rhinitis symptoms
13/15 (87%)
33/92 (37%)
3/8 (38%)
7/21 (33%
13
, 0.001)
Asthma symptoms
10/15 (77%)
18/92 (22%)
4/8 (50%)

1.3
¦¦ 0.001)
Reported dermatitis
5/15 (33%)
8/92 (9%)
2/8 (25%)

12.6
(p = 0.001)
FEVi/FVC < 70%
2/15 (13%)
4/92 (5%)
4/8 (50%)
.
1.9
(p = 0.52)
Positive cold air
challenge
5/15 (33%)
6/92 (7%)
4/X(50%) 4/21(19%)
7.7
(p = 0.003)
Elevated total IgE
4/15 (27%)
7/92 (8%)
'21 (19%)
3.5
(p = 0.54)
Positive
aeroallergen SPTb
6/15 (40%)
29/92 i
2/8 (25%)
	'21 (29%)
1.5
(p = 0.01)
"Prevalence odds ratio (FOR) of positive versus negativ : ;
aeroallergen test status and smoking (current, past, or never).
bAeroallergens tested were ragweed, timothy, and dust.
Source: Baker etal. (1990).
;rs (current workers only), adjusted for
Results of the RAST analysis for Pt-specific IgE showed Pt-specific RAST binding
(expressed as a percentage of total IgE) in sera of positive and negative Pt SPT workers of
7.0 ±1.4 and 4.3 ± 0.7% (means ± standard error [SE],p < 0.001), respectively; the value in
eight contro mteers was 4.2 ± 0.8%. According to the study authors, using a value of two
SEs above t-.. : Mean in control volunteers to define an abnormal value (e.g., a value of 5.8%), 20
of 22 positive Pt SPT workers had abnormal RAST values, compared to 8 of 94 negative Pt SPT
workers (Brooks et al., 1990). PORs for the RAST analysis were not reported. Results of the
inalvsis on a subset of the current (13/15) and former (6/8) workers with positive Pt SPT
re also reported by Biagini et al. (1985a); however, at the time of the Biagini et al. (1985a)
study, samples from all workers were not available for analysis.
In 1982, SPTs for halogenated Pt salts were repeated in 74 of the 107 current workers and
12 of the 29 medically terminated workers (Brooks et al., 1990). The 12 medically terminated
workers showed the same results in 1981 and 1982: 5 were negative and 7 were positive.
Among the 74 "current workers" who were evaluated in 1981 and 1982, 7 showed positive Pt
SPT results in 1981. In 1982, these 7 workers still had positive Pt SPT results, and an additional
5 workers also had positive Pt SPT results (i.e., 5 of the 67 subjects with negative results in 1981
were converted to Pt SPT sensitive in 1982).
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The results from this cross-sectional health examination of workers in a U.S. Pt refinery
(Baker et al., 1990; Brooks et al., 1990) provide strong evidence that exposure to halogenated Pt
salts in workplace air increases the risk of allergic sensitization and associated respiratory and
dermal symptoms. The follow-up results (Brooks et al., 1990) are consistent with those of
Merget et al. (1999, 1994), suggesting that allergic symptoms and Pt SPT sensitivity dc
necessarily disappear following removal from exposure. The cross-sectional desii
usefulness of the results for developing an RfC for halogenated Pt salts. Althoiii,
concentrations were measured for the 15 office workers who were found to be nonser
cross-sectional design does not allow assessment of the subsequent health status
or the status of office workers who may have left the workplace before the survey. Thus, a
reliable NOAEL for halogenated Pt salt allergic sensitization was not identified in this study. In
addition, the characterization of Pt sensitization was largely based on SPT to hexachloroplatinate
and did not include specific respiratory challenge to hexachloroplatinate. Data included
nonspecific respiratory challenge to cold air, basic lung fur	i -specific and total IgE,
histamine release, SPT to common aeroallergens, and smoking status.
Merget et al (2000): Catalyst Production Workers
A prospective cohort study was conducted between 1989 and 1995 in a catalyst
production plant in Germany (Merget et al., 2000); additional details of the study are also
reported in Merget (2000) and Rosner and Merget (2000). The study initially enrolled
166 subjects, and over the 5-year period, added 142 new employees. Over the course of the
study, 308 subjects were recruited, 98 either refused to participate or left the study, and 4 were
excluded from the study because of a positive SPT to the halogenated Pt salt,
hexachloroplatinate. Over the approximate 5-year study period, the number of employees who
had at least two study examinations was 275. Using a system based on job location and title,
subjects were grouped into four exposure categories: high- (n = 115), persistent-low- (n = 51),
ii	¦ )\v- (n = 61), and no-exposure (n = 48) (see Table 4-6 for selected demographic
exposure groups). The high-exposure category included production line workers
i engaged in maintenance or demolition of production lines. Persistent-low-
kers worked within the catalyst production department, but were not in the
production lines and included office workers, wash coat preparation workers, and staff involved
in quality control, chemical analysis, or the warehouse. Intermittent-low-exposure workers were
those who only entered the catalyst production building on an intermittent basis. Workers who
never entered the catalyst production building were assigned to the no-exposure control group.
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Table 4-6. Summary of selected Midpoints in health surveys of catalyst plant
workers

Exposure group
High
Persistent low
Intermittent low
No
Group size (n)
115
51
61

Age (in years; mean, 95% CI)
Males (n, %)
Smokers (n, %)
Ex-smokers (n, %)
Nonsmokers (n, %)
32 (30-34)
115 (100%)
53 (46.1%)
38 (33%)
24 (20.9%)
32 (29-35)
48 (94.1%)
16(31.4%)
12 (23.5%)
23 (45.1%)
39 (36-42) i 38 (35-41)
60 (98.4%) j 41 (85.4%)
18(29.5%) i '<6 (33.3%)
19(31.1%) ; 6 (33.3%)
24 (39.3%) 16(33.3%)
Time in plant before first survey3
Job exposure before first survey3
Time between 1st and final survey3
31 (17-45)
21(15-27)
33 (29-37)
72 (49-95)
43 (30-56)
46 (40-52)
144 (124-164)
91 (75-107)
43 (38-48)
i_3 (100-146)
39 (33-45)
Exposure (ambient-air)
(ng soluble Pt/m3)
1992
14; 8/41; 16b
6.6; 4.2/7.5
0.05; 0.03/0.05; 8
1993
37; 12/64; 12
0.4: 0.3/1.3; 8
All <0.13; 4
Exposure (personal-air)c (ng
soluble Pt/m3)
1993
177; 93/349; 22

	
rmed
Not performed
Positive SPT allergen1
Initial survey
19


13
11
Final survey


12
12
Positive SPT - Pf
Initial survey

0
0
0
Final survey

lf
0
0
Total IgE (kU/mL; mean, 95%
CI)
Initial survey
33 (30-90)
36 (31-108)
33 (29-66)
26 (23-66)
Final survey
37 (33-114)
31 (27-137)
40 (35-121)
34 (29-118)
FEVi (% predicted)
Initial survey
101 (99-103)
103 (100-106)
104 (100-108)
106 (102-110)
Final survey
100 (97-103)
103 (100-106)
102 (98-106)
103 (99-107)
FEVi <90% predicted (n)
Initial survey
20
7
14
4
Final survey
22
9
13
6
Bronchial hyperresponsive-
Initial survey
2.3 (2.1-4.2)
1.5 (1.3-3.4)
2.5 (2.2-4.8)
2.5 (2.2-4.9)
ness dose-response slope8
(%/mg, 95% CI)
Final survey
2.3 (2.1-3.1)
1.4 (1.2-2.6)
2.1 (1.9-5.1)
2.1 (1.8-5.7)
Bronchial hyperresponsive-
ness8 (number of workers with
PDis <1 mg histamine, %)h
Initial survey
8(7.1%)
1 (2.1%)
6 (9.8%)
1 (2.1%)
Final survey
7 (6.9%)
1 (3.4%)
3 (6.0%)
0
Symptoms1 before exposure
Initial survey
19
11
14
7
Symptoms after exposure but
before study
Non-workJ
5
6
12
1
Work
5
2
1
0
Symptoms during study
Non-work
23
3
3
1
Work
15
3
0
3
'Presented as the mean number of months with 95% CI in parentheses.
'Presented as the median concentration; lower/iipper-quartile concentration and number of samples, as reported.
cPersonal-air assessments were performed in 1993 only, and only in the high-exposure group.
dAllergens used were cat dander, grass and birch pollen, dust mite, and air-bome fungus.
Conversion from negative-to-positive SPT for 10~2 M hexachloroplatinic acid.
fThis subject was misclassified as "low-exposure" and admitted to occasional direct contact with Pt salts.
'Bronchial hyperresponsiveness was not assessed in 16 (7%), 13 (12%), and 11 (9%) of workers in the high-, persistent-
low-, and intermittent-low-exposure groups, respectively.
hPD15 is the dose of histamine causing a 15% decreased in FEVi in bronchial hyperresponsiveness tests.
'Symptoms included wheezing, rhinitis, burning eyes, and dermatitis.
J"Non-work" and "work" indicate whether symptoms were work-related.
Source: Merget (2000).
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Health surveys of subjects were conducted at several time periods, including initial
survey (start of study), at intervals of 6 months during the first year and afterward at yearly
intervals including the final survey at the end of the study (most subjects received 4
5 examinations over the course of the study). The mean durations of employment at the time of
the initial health survey (with ranges noted in parentheses) were 21 (15-27) months, 43 (30-56)
months, 91 (75-107) months, and 123 (100-146) months for the high-, persistent-low-,
intermittent-low-, and no-exposure groups, respectively. The mean time between the initial and
final survey per subject for the groups (in order of decreasing exposure) were 33 (29-37)
months, 46 (40-52) months, 43 (38-48) months, and 39 (33-45) months. Health survey
endpoints included self-reported allergic symptoms (shortness of breath/wheezing, rhinitis,
conjunctivitis, and dermatitis) with medical follow-up if needed; analysis of serum Pt
concentrations; SPTs to five common allergens (cat dander, grass and birch pollen, dust mite,
and air-borne fungus) plus the halogenated Pt salt, hexachl oropl atinate; lung function tests
(FEVi); bronchial responsiveness to histamine); and total and common allergen-specific serum
IgE (by RAST). The primary outcome variable was SPT conversion (SPTC), the change from a
negative-to-positive response in the SPT to halogenated Pt salts, which the authors considered
evidence of sensitization to halogenated Pt salts. Predictive factors for SPTC were determined
using a multivariate model, incorporating exposure category, age, smoking status, atopy,
preexisting asthma symptoms, total IgE, FEVi, and bronchial hyperresponsiveness as well as
various employment history van ah
Stationary (work area) exposure assessments were conducted in 1992 and 1993 (Merget,
2000; Merget et al., 2000; Rosner and Merget, 2000). Sampling periods for these assessments
varied between 12 and 17 hours. Thus, the reported air concentrations from the stationary air
samples repre 112- to 17-hour TWA concentrations. The study author indicated that there
were three 8-1 >¦		 shifts during the 24-hour production in the plant, and therefore, there were no
differences between work shifts or workplace activity (email from Dr. Rolf Merget, Research
Institute for Occupational Medicine, Institutions for Statutory Accident Insurance and
tion, University Hospital Bergmannsheil, Ruhr University, Bochum, Germany to Andrew
U.S. EPA, dated September 23, 2008). Total and soluble Pt concentrations were
determined by standard methods (either inductively coupled plasma emission spectrometry or
graphite furnace AAS); detection limits were 0.025 ng soluble Pt/m3 in 1992 and 0.13 ng soluble
Pt/m3 in 1993 due to the use of different analytical methods in the 2 years (Merget, 2000).
Soluble Pt was defined by the amount of Pt assayed in a 70-mM HC1 acid extraction of each
sample. Additionally, personal-air sampling assessments were conducted in 1993 in high-
exposure subjects. Merget et al. (2000) noted that only 22 personal air measurements were
made, indicating that personal air measurements were not made for all workers in the high-
exposure category (n = 115 subjects). The sampling period for each personal-air assessment was
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8 hours, and the detection limit was reported as "about 20 ng/m3" (Merget et al., 2000). No
information on particle size distribution in the collected samples was reported. No information
was provided regarding the chemical species present or further characterization of Pt beyond the
soluble Pt reported.
Results for the exposure assessments and selected endpoints are presented in Table 4-6.
The ratio of total to soluble Pt was reported to be approximately 10:1 in most air samples. In the
catalyst production area (high-exposure), the numbers of samples collected in 1992, 1993, and
the 1993 personal-air assessment were 16, 12, and 22, respectively. Median concentrations (with
lower- and upper-quartile values noted in parentheses) for the stationary air samples from the
high-exposure catalyst production areas were 0.014 (0.008, 0.041) ug soluble Pt/m3 in 1992 and
0.037 (0.012, 0.064) ug soluble Pt/m3 in 1993 (Merget, 2000). Median (and lower- and upper-
quartile) concentrations in personal air samples were markedly his -: : 77 (0.093, 0.349) ug
soluble Pt/m3 (Merget, 2000). For the low-exposure areas (subjects in the persistent-low and
intermittent-low groups), median (and lower- and upper-qi	-titrations were
0.0066 (0.0042, 0.0075) ug soluble Pt/m3 in 1992 and O.OOu^t (u.uuuj, 0.0013) ug soluble Pt/m3
in 1993. The maximum concentrations in the iow'-exposure areas were 0.0086 ug soluble Pt/m3
in 1992 and 0.0015 ug soluble Pt/m3 in 1993 (Merget audRosner, 2001). For the no-exposure
areas, median concentrations (and lower and upper quartiles) were 0.00005 (0.00003, 0.0005) ug
soluble Pt/m3 in 1992 and all values were <0.00013 ug soluble Pt/m3 in 1993 when a different
detection system was used. Concentrations of soluble Pt in stationary and personal-air samples
were highly variable: 100- and ! ,000-foid ranges of soluble Pt concentrations were recorded in
the stationary and personal-an 	r.	ollected in the high-exposure group, respectively. The
threshold limit value (TLV) of 2.0 (.ig/in3 was exceeded in 3 of the 78 total exposure
measurements made; all three were recorded in the personal-air sampling assessments in the
catalyst production (high-exposure) area. Since only 22 personal air measurements were made
(e.g., measurements were not made for all 115 workers in the high-exposure category), data that
wouH "How analysis for a correlation between individual personal air monitoring data and
:; i ltcome do not appear to have been collected by Merget et al. (2000).
sera were made from six workers; three workers from the high-exposure group with SPT
conversion to halogenated Pt salts and three workers from the low- or no-exposure groups with
no SPT conversion to halogenated Pt salts. Blood samples for analysis were obtained 5-8 times
during the 5-year study. Sera Pt was measured by adsorptive voltammetry, with a detection limit
of 0.2 ng/L. Merget et al. (2002) found no correlation between Pt concentrations in sera with
allergy outcome.
The percentage of smokers was higher (approximately 46%) in the high-exposure
category compared to the low- and no-exposure groups (approximately 30-33%). Based on the
et al. (2002) reported results of the sera analysis for Pt and examined the
Pt concentration in sera to allergy outcome. A total of 38 measurements of Pt in
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incidence of positive SPT to non-Pt allergens at the initial survey, the incidence of atopy was
similar across all three categories, with positive SPT to non-Pt allergens in 19/115 (16.5%),
10/51 (19.6%), and 13/61 (21.3%) workers in the high-, persistent low- and intermittent low-
exposure groups, respectively. At the beginning of the study, all subjects were Pt SPT-negative
(Table 4-6). SPTC occurred (n = 13; 11.3% of subjects) only in the high-exposure category
these 13 subjects, 10 were newly hired employees and 3 had been employed for 68, 16, and
10 months prior to the initial survey. Nine of the 13 subjects showed SPTC during the thin ,_i.r
of the follow-up; the remaining showed SPTC during years 1, 2, 4, and 5 af : the initial survey
(incidence of SPTC was 4.1 per 100 person-years, and slightly higher for newly employed
subjects). One subject in the low-exposure category did show SPTC conve..,..on, but this subject
was found to be misclassified as to exposure category after admitting to performing occasional
high-exposure tasks. Due to the uncertainty surrounding this misclassified worker, they were not
considered further. Work- and non-work-related new allergy symptoms occurred more
frequently in the high-exposure category (Table 4-6). No subject with a negative Pt SPT and
new symptoms showed a positive Pt SPT upon follow-up exam. The study authors reported that
results of pulmonary function tests (FEVi percent ot predicted), bronchial hyperresponsiveness
tests (dose-response slope and number of worke v,:; : PDi5 <1 mg histamine), and total IgE
did not differ between exposure categories (Table 4-6).
The multivariate analysis showed a strong association (p = 0.011) between exposure and
SPTC; less-pronounced associations with SPTC included smoking (p = 0.054), total IgE
(p = 0.036), and FEVi (percent predicted) (p = 0.041) (Merget et al., 2000). Age-adjusted
relative risks for developing u r_.„	... t SPT in the high-exposure category were elevated for
smokers compared with noii^uio^ers and ex-smokers (odds ratio = 3.9, 95% CI = 1.6-9.7). Age-
adjusted rel?*""3 risks for developing a positive Pt SPT in the high-exposure category were not
elevated for i iduals with lower FEVi values (below 90% of predicted value; odds ratio =1.1,
95% CI = 0. >) or with elevated total IgE (>100 kU/L; odds ratio =1.1, 95% CI = 0.8-1.6).
Intervention procedures prevented determining how many subjects with SPTC developed allergic
symptoms. Neither atopy, bronchial hyperresponsiveness (slope), nor pre-existing asthma were
significantly predictive for halogenated Pt salt sensitization.
The Merget et al. (2000) prospective health survey of workers in a catalyst production
plant provides information on the relationship between exposure to chloroplatinates and the
development of allergic sensitization to halogenated Pt salts. Merget et al. (2000) state that the
concentration of soluble Pt in the low-exposure group areas may be defined as "safe" because no
cases of Pt-specific allergic sensitization were observed in workers in these areas. No cases of
sensitization occurred in the 5-year period in 111 workers ("persistent" and "intermittent" low
groups) who worked in areas with median concentrations of 0.0066 ug soluble Pt/m3 in 1992 and
0.0004 ug soluble Pt/m3 in 1993. Therefore, the exposure concentration in the low-exposure
areas represents a NOAEL, although the authors do not use that language. There was 1 subject
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in the original 112 workers in this group who became sensitized, but the subject admitted to
occasional direct contact with Pt salts (see Table 4-6). Merget et al. (2000) is the only study
among the available epidemiologic studies on allergic sensitization to halogenated Pt salts with a
prospective design. Consistent with the superior detection capabilities of prospective :- ¦>! 5
compared with cross-sectional or retrospective designs, the study identified the lowesl
level associated with a statistically significant increased prevalence of sensitized subjects (i
the lowest-observed-adverse-effect level [LOAM.]): 13/115 catalyst production ("high-
exposure") workers developed Pt-specific allergic sensitization in the 5-year r¦¦;;. d. Median
concentrations in stationary air samples in the catalyst production area were O.u i ; and 0.037 ug
soluble Pt/m3 in 1992 and 1993. The median value for personal air monitoring data was
0.177 ug soluble Pt/m3, suggesting that stationary air sampling may have underestimated
exposure in this work area. A multivariate analysis of explanatory ¦ ¦ :s for SPTC found
that, in addition to exposure category, smoking, total Tg.Fi, and FFV i, wcic statistically significant
variables. Smokers in the high-exposure group showed a significantly elevated, age-adjusted
risk for developing sensitization, compared with non smokers and ex-smokers (odds ratio = 3.9,
95% CI = 1.6-9.7). This result confirms results rrom otner studies indicating that smokers have
greater risks for sensitization to halogenated Pt salts iiuin nonsmokers (Calverley et al., 1995;
Venables et al., 1989).

The 100- and 1,000-fold range of concentrations within the collected stationary air and
personal air samples for the hieh-exoosure group suggests a fair amount of variance across time
or space in the high-exposure :;; The air concentrations reported by Merget et al.
(2000) are lower than the lowt„, Vv un^uce air concentrations associated with increased
prevalence of halogenated Pt salt allergic sensitization in the cross-sectional study by Baker et al.
(1990), 0.4, 0.5, and 5.3 (.ig soluble Pt/m3; however, the analytical methods and limits of
detection used to determine the Pt concentrations in Baker et al. (1990) were not reported. The
Pt air concentrations reported by Merget et al. (2000) are also lower than airborne Pt
concentrations reported in the retrospective study by Linnett and Hughes (1999). However, the
. ^ om Linnet and Hughes (1999) are limited to percent of measurements above 0.5 fig
3
soluble Pt/m' and percent of measurements below 0.5 ug soluble Pt/m with no information on
josure values of concentrations below 0.5 fig soluble Pt/m3. The fact that Merget et
00) present lower exposure concentration data than the occupational studies in Pt refineries
may be related to the quantitative and qualitative differences in exposure to halogenated Pt salts
between refineries and catalyst production plants (Merget et al., 2001, 2000). Pt exposure in a
catalyst production plant is lower and at a more consistent level than in a refinery because the
production process in a catalyst production plant is more uniform and the protective measures are
intensified (Merget et al., 2001). Among the five available occupational studies that report Pt
exposure concentrations and health effects, only Merget et al. (2000) is a study of workers in a
catalyst production plant; the other four studies (Linnett and Hughes, 1999; Bolm-Audorff, 1992;
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Baker et al., 1990; Brooks et al., 1990) are of workers in Pt refineries. Another limitation of
using the data in this study to estimate dose-response relationships for chronic lifetime exposure
is that the duration of exposure necessary for development of sensitization among the
13 sensitized workers in the high-exposure group was less than chronic, although somewhat
variable (9 converted during year 3, with the remainder converting in years 1, 2, 4, and 5).
Additional limitation of this study is that it examined a relatively narrow population: adult males
healthy enough to work. Subjects in the exposed groups were predominantly (94-100%) males,
whereas the no-exposure group had fewer (85%) males. Another liiuitatioii of this study is that
only the concentration producing sensitization can be estimate	.. ' oentration to
elicit an allergic response (which is likely much lower than thai needed to produce sensitization)
in sensitized individuals is not known.
4.1.2.2. Insoluble Pt Forms
Insoluble forms of Pt (Pt metal and PtCh) are genenmy considered to be inert, thus
leading to the use of alloys containing Pt metal in prostheses, including breast implants (ACGIH,
2001; Gebel, 2000; WHO, 2000, 1991). In contrast to the numerous studies evaluating adverse
health effects associated with exposure to soluble Pt compounds, only one report evaluating the
health effects of human exposure to inhaled insoluble Pt compounds was identified (Hunter et
al., 1945). Findings of this study suggest that insoluble Pt compounds do not induce allergic
sensitization. No studies have been reoorted on possible respiratory responses (e.g., nasal or
pulmonary inflammatory responses) or other human health effects to repeated exposure to
airborne particles with Pt metal or Pi oxides. Studies evaluating the allergenic potential of
insoluble Pt compounds in uiiiuuls were not identified (see Section 4.5.1.2, Sensitization Studies,
Insoluble Pt Forms).
Hunter et al. (1945) reported that occupational asthma was not observed in workers
primarily involved in a process involving very heavy exposure to dust of Pt metal, but that
asthma and other signs of allergy were observed in workers exposed to complex halogenated Pt
salts. Workers from four refineries were recruited for this study. The main process used at each
refinery was reported as follows: refinery A, a wet process involving sodium chloroplatinate;
refinery B, a wet process involving precipitation of ammonium chloroplatinate which was then
nery C, dry ammonium chloroplatinate was "handled"; and refinery D, ammonium
chloroplatinate was precipitated and then ignited to form spongy Pt. Air monitoring was
conducted at multiple locations at each refinery. The duration of sample collection was reported
as "usually during the whole of the operation", but specific information on the duration of
sample collection (e.g., over several hours, daily work shift, or several days) was not provided;
furthermore, it was not clear from the study if the same collection duration was used at all
sampling locations. Total Pt in samples was determined by a colorimetric assay following acid
extraction of filters; the LOD ranged from 0.5 to 10 fig Pt per sample, depending on the specific
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method used (a "micro-reading technique" was used for samples with low total Pt). The ranges
of total Pt concentrations in air for work areas involving Pt salts were estimated by study authors
as 7-20 fig Pt/m3 at refinery A, 1.6-50.2 fig Pt/m3 at refinery B, 1.5-1,700 Pt fig/m3 at refinery
C, and 0.9-3.2 fig Pt/m3 at refinery D. Total Pt air concentrations at work locations involved in
sieving spongy Pt (a process that generates metallic Pt dust) were estimated at 400 fig Pt/m ^
refinery A and 960 fig Pt/m3 at refinery C; estimates of Pt concentrations in air of work areas
conducting sieving of spongy Pt at refineries B and D were not reported.
At total of 114 workers from four refineries were enrolled in the stud1.'. orkers were
described as having "contact with" Pt salts (Hunter et al., 1945). The remaining 23 workers were
presumably exposed to metallic Pt dust during the process of sieving spongy Pt; however, the
study does not include specific information regarding exposure of this group, including
identification of the specific non-salt Pt compounds involved in the exposure (other than
"metallic Pt dust"), the potential for these workers to be exposed to complex Pt salts during
normal operations at the refinery, or history of exposure to complex Pt salts prior to the study.
All participating workers were interviewed for history of nasal symptoms (sneezing, runny nose)
or symptoms of asthma (chest tightness, wheeze, or shortness of breath). Chest x-rays were
taken, and a physical examination was conducted. Blood samples were obtained from all study
participants and were analyzed for percent hemoglobin and counts of red blood cells, total white
blood cells, polymorphonuclear leukocytes, and eosinophils. SPTs to sodium chloroplatinate
were conducted in 16 of 24 workers at refinery A (the remaining workers were unwilling to
participate); Pt SPT were not conducted on workers at refineries B, C, or D. The report did not
specific if the SPT was condik		 ..alogenated Pt salts (hexachloroplatinate or
tetrachl oropl ati nate). Data on smoking history of workers was not reported. No asthma
symptoms were reported by the 23 workers involved in sieving spongy Pt; no additional
information on health outcomes for this group was reported. Of the 91 workers exposed to
complex Pt salts, 52 workers reported symptoms of asthma and 13 workers were diagnosed with
emphysema (based on chest x-ray). Dermatitis, located on exposed areas (hands, forearm, face,
~~~J x~:is observed in 13 workers. Positive SPT to sodium chloroplatinate was observed in
10 of the 16 workers participating in this test; however, the study did not report the exposure
letallic Pt dust or complex Pt salts) for any of the 16 workers. Eosinophilia was
reported in 43 of 91 workers, but exposure-related effects were not observed for the other
hematological variables assessed in this study.
It is possible that repeated exposure to dusts of Pt metal or Pt oxides can lead to
respiratory irritation, inflammation, or other more serious respiratory lesions, especially at
concentrations that overload respiratory clearance mechanisms, as has been observed with other
relatively insoluble and inert airborne materials (see Li et al., 1996; Oberdorster, 1994). For
example, at high exposure levels, inhalation of insoluble nickel compounds (such as nickel oxide
and nickel subsulfide) may result in decreased pulmonary clearance of these compounds, leading
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to increased lung retention and the increased potential for local adverse effects (see
Section 4.5.1.2 for additional information). However, no specific data on the potential
respiratory irritation effects of exposure to Pt metal or Pt oxide dust in humans are available.
4.2. SUBCHRONIC AND CHRONIC STUDIES AND CANCER BIOASSAYS .
ANIMALS—ORAL AND INHALATION
4.2.1. Oral
4.2.1.1. Subchronic
Few studies on the toxicity of subchronic oral exposure of laboratory animals to Pt
compounds have been reported. A single 90-day oral drinking water study u..,-, 11^,1 i tCU in
Sprague-Dawley rats (n = 4) was included as part of a series of otherwise short-term (1 and
4 weeks) exposure studies conducted by Holbrook and coworkers (Hoibrook et al., 1976, 1975;
Holbrook, 1976). Data on body weight or organ weight in rats exposed PtCU for 90 days were
not reported. Exposure information and estimated doses in the Holbrook studies are provided in
Table 4-8 in the discussion of short-term exposure data in Section 4.4.2.1. The study only
reported data on two hepatic microsomal enzymes indicative of hepatic cytochrome P450
activity and found that aniline hydroxylase activity was increased by 28% relative to control
(p < 0.05; mean and SD not reported), but no change in aminopyrine demethylase activity was
found. As discussed in Section 4.4.2, exposi m./ uj PtCl4 for shorter periods (1-4 weeks) was
associated with either a decrease or no change in the activities of the two hepatic microsomal
enzymes reported, while this 90-day exposure was associated with an increase in one enzyme.
Therefore, the conflicting and inconsistent effects of PtCl4 on these endpoints are difficult to
interpret and do not reflect u u^rly adverse effect on the liver in the absence of additional
information o" potential hepatotoxicity such as histopathology or standard biochemical
endpoints. Li m., ations in study design (e.g., a single dose tested, lack of comprehensive
endpoints) do ; < h: allow for identification of other potential target organs or dose-response
relationships, or comparisons of the relative potency of more-soluble (e.g., PtCl.t) and less-
)ounds (e.g., PtO;).
i a related palladium compound (Pd[NH3]4Cl2) at doses ranging from 0.05 to
5 mg/kg-day reduced body weight gain, decreased prothrombin time, and decreased serum levels
of urea and P-lipoproteins, although specific dose-response data were not reported. Increased
serum concentrations of urea were also reported, and it is unclear which of the reported effects
were associated with Pt compounds and which were associated with palladium compounds.
Histopathological examinations of tissue were not conducted. No additional details were
reported (e.g., rat strain, sex, number of animals, preparation of dosing material, magnitude of
effect). Since methods and results of the Roshchin et al. (1984) study are poorly reported, it is
Roshchin et al. (1984) reported that a 6-month dietary exposure of rats to Pt and
im powder at doses of 50 mg/kg-day as well as a 6-month dietary exposure to
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also unclear if treatment-related effects are specific for oral exposure or inhalation exposure,
which was also evaluated in this study (see Section 4.2.2.1, Inhalation, Subchronic).
In summary, there are a few toxicity studies of animals following subchronic oral
exposure to Pt or Pt compounds, but limitations in design (e.g., no histopathology in the studies
by Holbrook and colleagues) or reporting (e.g., the report by Roshchin et al., 1984) do not
definitive identification of health hazards.
4.2.1.2. Chronic
No studies on the effects of chronic oral exposure of ar	le Pt
compounds were identified.
4.2.2. Inhalation
4.2.2.1. Subchronic
Animal toxicology studies involving repeated inhainuon exposure to Pt compounds are
limited to a single inadequately reported study by Roshchin ei ai. 11984) and studies evaluating
sensitization effects of inhaled halogenated Pt salts of hexachloroplatinate (Biagini et al., 1986,
1983).
Roshchin et al. (1984) reported	tsure of rats to ammonium chloroplatinate at a
concentration of 18.6 mg/m3 for 6 months (daily exposure duration not reported) appeared "to be
toxic." Further clarification or descriotions of toxic effects specifically attributed to inhaled Pt
exposure were not reported.
Biagini et al. (1986, 1983) exposed cynomolgus monkeys to (NH4)2PtCl6 for 6 hours/day,
5 days/week for 12 weeks uuti u, Na:PtCl„ 4 hours/day, biweekly, for 12 weeks. Since the
primary goal of these studies was to evaluate sensitization effects, comprehensive toxicity
endpoints (e.g., gross pathology, histopathology, biochemistry, hematology, signs of toxicity)
were not evaluated; additional details are described in Section 4.5.1, Sensitization Studies.
In summary, there are a few toxicity studies of animals subchronically exposed by
cion to Pt compounds, but limitations in design (e.g., no histopathology in the studies by
Biagini and colleagues) or reporting (e.g., the report by Roshchin et al., 1984) do not allow
	ive identification of health hazards other than allergic sensitization.
4.2.2.2. Chronic
No studies on the effects of chronic inhalation exposure of animals to soluble or insoluble
Pt compounds were identified.
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4.3. REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION
4.3.1.	Oral
Studies investigating the reproductive effects of oral exposure to Pt compounds were not
identified. The effect of oral exposure to Pt compounds on development and neonatal g . w; ii
was reported in studies by D'Agostino et al. (1984) and Massaro et al. (1981). These st<,;<.
however, do not adequately evaluate the potential developmental effects, because dams wei
only exposed on a single day during gestation or lactation and comprehensive development;
endpoints (e.g., external, skeletal, or visceral malformations) were not examined. Although
developmental effects were only assessed for acute oral exposure, results (exposure-related
decreased body weights in offspring) indicate that Pt compounds may be toxic to the developing
fetus and neonate.
D'Agostino et al. (1984; Massaro et al., 1981) administered a single gavage dose of
Pt(SO.t): (200 mg Pt/kg) to pregnant ICR Swiss mice (nine dams per uuse group) on days 7 or 12
of gestation, or on day 2 postpartum. Pups from dams that received the Pt(SO.t): dose and pups
from control dams were cross-fostered. Litters from control and treated dams were culled to
three males and three females prior to commencement of nursing. Culled pups from treated
dams were fostered to treated and control dams; culled pups from control dams were fostered to
treated and control dams. The only maternal endpoint evaluated was offspring retrieval latency
(i.e., time to retrieve offspring from scattered locations to the nest), assessed during the first
2 hours of the light phase of the light cycle on day 3 postpartum. Offspring were evaluated for
body weights at several intervals up to postpartum day 45, gross activity (activity field
observations) on day 8 postpartum, and open field activity (e.g., ambulations, rearings, passive
avoidance) and performance on a rotarod, on days 60-65 postpartum. Offspring from dams that
received the dose of Pt( SOt); on gestational day 7 or 12 had significantly (p < 0.05)
decreased bi : . /eights, compared to controls, up to postpartum day 45. Mean body weights
were 1.42 ± (: 1 g at birth in the pups born to dams exposed to Pt(SO.t): on day 12 of gestation
and fostered by exposed dams, and 1.75 ± 0.21 g in pups from control dams fostered by control
dams (i.e., 23% decrease in treated versus control). On day 45 postpartum, corresponding mean
body weights were 25.1 ± 4.6 g in treated offspring and 29.0 ± 4.4 g in control offspring (15%
decrease). The only other reported exposure-related effect was for statistically significantly
(p < 0.05) reduced neonatal activity for treated pups on postpartum day 2 (group means and SD
were not reported).
4.3.2.	Inhalation
No studies on the potential reproductive/developmental effects of inhalation exposure of
animals to soluble or insoluble Pt compounds were identified.
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4.4. OTHER DURATION- OR ENDPOINT-SPECIFIC STUDIES AND OTHER
HAZARD IDENTIFICATION ISSUES
4.4.1. Acute Exposure Studies
4.4.1.1. Oral
Acute lethality following oral administration to rats has been reported for seve
compounds, as summarized in Table 4-7 (WHO, 1991; Roshchin et al., 1984; Lown et al., 1980;
Holbrook, 1976; Holbrook et al., 1975). Experimental details of the acute oral toxicity studies in
rats are largely unavailable, with the exception of the reports by Holbrook et al. (1975) and
Roshchin et al. (1984). Holbrook et al. (1975) reported that Sprague-Dawley rats were observed
for a 14-day observation period after dose administration, but did not report the range of actual
doses administered or the number of rats per dose groups. Roshchin et al. (1984) reported that
acute oral administration of fine dusts of Pt group metals (Pt and palladium particles of 1-5 urn
diameters) at a dose of 25 mg/kg produced no deaths in rats and caused slight necrotic changes in
the GI epithelium, hepatocytic granular dystrophy, and epithelial swelling in renal convoluted
tubules, but did not report further experimental details for this study or for the rat LD50 values for
PtCl;, PtCl4, or (NH4)2PtCl6 in Table 4-7. The rat LD50 values in Table 4-7 indicate that
halogenated Pt salts (e.g., salts of tetrachloropla ;;;;* ; -or hexachloroplatinic acid) generally
have higher acute oral toxicity potencies than ncm: t compounds (e.g., Pt©2, PtCl;,
Pt( SO.t >2) and that the water solubility of nonionic Pt compounds can influence acute oral
toxicity potency (e.g., water-soluble PtCL has a higher acute oral toxicity potency than relatively
insoluble PtCl;).

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Table 4-7. Acute oral toxicity of Pt compounds in rats
Compound
LDso(:iiig/kg)a
I Dm (mg Pt/kg)
Reference
Pt02
>3,400
>2,950
Holbrook et al., 1975
>8,000
>6,900
Holbrook, 1976
PtCl2
>1,330
>975
Holbrook et al., 1975
>2,000
>1,450
Holbrook, 1976
3,423
2,500
WHO, 1991; Roshchin et al, 1984
PtCl4
240
140
Holbrook, 1976
276
160
WHO, 1991; Roshchin et al, 1984
<640
<370
Holbrook et al., 1975
Pt(S04>2 (H20)4
1,010
430
Holbrook, 1976; Holbrook etal., 1975
(NH4)2PtCl4
125-212
65-110
WHO, 1991
(NH4)2PtCl6
195
85
WHO, 1991; Roshchin ci ai., 1984
H2PtCl6
40-50
14-19
Ward etal., 1976
Na2PtCl6
25-50
10-20
Johnson Matthey, 1978b (as cited in WHO, 1991)
Na2Pt(OH)6
500-2,000
285-1,140
Johnson Matthey, 1978a (as cited in WHO, 1991)
K2PtCl4
50-200
20-95
Johnson Matthey, 1981a, b (as cited in WHO, 1991)
amg of Pt compound.
Limited acute oral toxicity data for mice support the hypothesis that halogenated Pt salts
have higher acute oral toxicity potencies than nonionic Pt compounds. Lown et al. (1980) and
Massaro et al. (1981) administered single gavage doses of Na;Pt('*l,, or Pt(SO.t): to male ICR
strain Swiss mice (10 an	>up) and reported 7-day LD50 values (actual doses
administered were not reported;. me /-aay LD50 value for Na:PtCl„ was 82.5 mg Pt/kg body
weight (95% confidence limit [CL]: 72.1, 108.5). The 7-day LD50 value for Pt(S04)2 was
280.5 mg Pt ¦ . > ody weight (95% CL: 237.6, 320.1). Acute LD50 values for Pt compounds
administered by parenteral routes are generally lower than those reported for oral administration,
complete absorption of orally administered compounds (WHO, 1991).
The kidney appears to be a target of acute high-level exposure to insoluble Pt as
lielial swelling in the convoluted tubules of the kidney (Roschin et al.,
1984). However, an noted above, study details in Roshchin et al. (1984) do not discriminate
between effects observed with exposure to Pt or palladium. Although additional data on
potential renal effects of oral exposure are not available, rat deaths from acute intraperitoneal
exposure to hexachloroplatinic acid (H;PtClt1) have been attributed to renal failure and
necrotizing renal tubular lesions throughout the renal cortex (Ward et al., 1976). As part of a
study of Pt anticancer agents, Ward et al. (1976) administered single intraperitoneal doses of
hexachloroplatinic acid to male Fischer 344 rats (two animals per dose group) and reported
14-day LD50 values (actual doses administered were not reported). The LD50 value for
hexachloroplatinic acid was estimated to be 40-50 mg/kg (approximately 14-19 mg Pt/kg;
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confidence limits not reported). Severe lesions were reported in the kidney and thymus, mild
lesions were reported in the peritoneal cavity, and no lesions were reported in the other organs
evaluated (liver, intestine, and bone marrow). No additional information was provided on the
peritoneal lesions or the thymic lesions; however, thymic lesions are consistent with stress
associated thymic atrophy expected in an LD50 study.
No direct evidence has been reported implicating neurotoxicity of Pt compounds. The
only information available on the potential neurotoxicity of Pt compounds is limited to finding
of effects on gross neurobehavioral endpoints. Decreased activity, classific .;s "behavioral
effects" by the study authors, was observed in mice exposed to acute oral Prf SOth at sublethal
doses (Lown et al., 1980). In this study, male ICR Swiss mice (40 animals Fv,* dose) received a
gavage dose of 144 or 213 mg Pt/kg (7-day LD„, and LD2J, respect,vely) as P,(S04)j Open field
behavior was observed at 4 hours, and 1, 3, or 7 days foil :. - / dosing. Immediately following
the observations, animals were sacrificed and Pt concentr : *.¦: (jig/g wet weight) in tissues
(blood, brain [cerebellum, cerebrum, brain stem], kidney, lives, lung, muscle, spleen, testes) were
determined on 10 animals at each observation lime (see Section j.z.l for discussion of tissue Pt
measurements). Open field explorations (ambulations and rearings) were marginally depressed
in mice exposed to single oral doses of approximately 144 and 213 mg Pt/kg body weight as
Pt( SO.t >2, with the most pronounced effects observed 4 hours after exposure. Effects did not
correlate with brain levels of Pt. In another study of rats exposed to acute oral doses of
(NHthPtCLt, signs of toxicity included hvookinesia, piloerection, diarrhea, convulsions, labored
respiration, and cyanosis (Degussa, 1989, as cited in WHO, 1991). Additional experimental
details on Degussa (1989) are not available.
oraiation is available regarding the acute inhalation toxicity of Pt compounds.
1984) reported that no lethality occurred in rats exposed to ammonium
at concentrations up to 564.6 mg/m3 (exposure duration not reported) and
ine at concentrations up to 678 mg/m3. Increased serum protein (p < 0.001),
).001), and cholesterol (p < 0.001) and decreased urea (p < 0.002) and lactic acid
were observed by Roshchin et al. (1984); however, it is unclear which dose or
compound the effects were associated with. Methods and results of Roshchin et al. (1984) were
poorly described and further information on the degree of change for endpoints in treatment or
control groups were not reported; no additional details were reported (e.g., rat strain, sex, number
of animals, and preparation of dosing material).
Using a primate animal model, Biagini et al. (1985b) reported that acute inhalation
exposure to 'Na;Pt('*l,, altered pulmonary function, producing peripheral and central airway
constriction. Cynomolgus monkeys were challenged with serially increasing concentrations of
aerosolized solutions of Na2PtCl6 (0, 0.5, 2.5, 25, and 50 mg/mL). All aerosols had a MM AD of
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1.0-1.5 uni, with GSDs of 1.7-2.0. Bronchoprovocation challenges were performed for
1 minute (15 breaths), with increasing concentrations administered at 10-minute intervals.
Bronchoprovocation challenge with Na2PtCl6 increased average pulmonary flow resistance and
decreased pulmonary dynamic compliance (e.g., the extent to which the lungs can expand)
dose-dependent fashions. Increases in average pulmonary flow resistance ranged from
approximately 140 to 690% and decreases in pulmonary dynamic compliance ranged from
approximately 2 to 45% of control levels at concentrations of 0.5 and 50 mg/mL, respective. :
Dose-dependent reductions in maximal effort flow-volume performance param : rs (peak
expiratory flow rate [PEFR], FEV05/FVC, FEF50/F¥C, and FEF25/FVC) were also observed,
indicating both peripheral and central airway bronchoconstriction. Acute inhalation exposure to
Na2PtCl6 did not affect respiratory rate. Companion studies evaluating the sensitization effects
of acute inhalation exposure of animals to Pt compounds ¦¦¦ !<¦¦ ¦¦¦¦¦¦.... . i >.n Section 4.5.1,
Sensitization Studies {Biagini etal., 1986, 1983).
4.4.1.3. Dermal
Dermal irritancy of several Pt compounds was examined as part of a larger study of
palladium, lead, manganese, and Pt compounds in a standard rabbit patch test for irritancy in
intact and abraded skin (Campbell et al., 1975). Test material was applied to 2 x 2 cm closely
clipped sites on the dorsolateral surface of each of six male albino rabbits (intact on one side and
abraded on the other) weighing between 2 and 3 kg. Pt compounds included Pt dichloride
(PtCh), Pt tetrachloride (PtCU), and Pt dioxide (PtO;). The authors state that test materials in the
powder state were mixed with water (0.1 g powder with 0.1 g water) and that liquid materials
were applied directly in 0.1 ml . quantity, but specific concentrations of the Pt compounds tested
were not otherwise reported. Each application was immediately covered with gauze and secured
with tape for 24 hours. After 24 hours, the covering was removed, test sites were washed and
dried, evaluated, and then valuated again following an additional 48 hours. A four-point rating
scale (0-1 nonirritant and nontoxic for cellular components of skin; 1-1.9 mild irritant and mild
. J:: ? r toxin; 2-4 irritant and cellular toxin) was employed and means reported for each of the
Pt compounds were as follows: 0 intact and 0 abraded for PtO;; 0.2 intact and 0.6 abraded for
: : ; . and 1.8 intact and 2.6 abraded for PtCl4. Under the test conditions, the two non-soluble Pt
. .. , muds were rated nonirritants and PtCU, the only soluble compound tested, was rated a mild
irritant with evidence of cellular toxicity in abraded skin.
4.4.2. Short-term Exposure Studies
4.4.2.1. Oral
Few studies on the toxicity of short-term oral exposure of laboratory animals to Pt
compounds have been reported. Short-term oral exposure studies are available for PtCU,
Pt(S04)2, (NH4)2PtCl6, and Pt02 (Reichlmayr-Lais et al., 1992; Roshchin et al., 1984; Lown et
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al., 1980; Holbrook, 1976; Holbrook et al., 1976, 1975). Results of available studies identify the
kidney as a target organ for halogenated Pt salts and Pt compounds; however, available data are
inadequate to fully characterize nephrotoxic effects or to define the exposure-response
relationship for nephrotoxicity. Furthermore, available studies do not evaluate coinpr rc
toxicity endpoints, such as histopathology or standard biochemical and hematological
or provide dose-response data.
A series of experiments conducted by Holbrook and coworkers (Holbrook et al., 1976,
1975; Holbrook, 1976) evaluated the effects of repeated exposure of male Sprague-Dawley rats
to Pt compounds in drinking water or diet on body weight gain, organ weights (liver, kidney,
spleen, heart, and testes), and activities of two hepatic microsomal enzymes (aniline hydroxylase,
aminopyrine demethylase) indicative of hepatic cytochrome P450 activity. Histopathology
effects and effects on standard biochemical or hematological endpoints were not evaluated in
these studies. Exposure information and estimated doses in the Hoiuiuur. studies (Holbrook et
al., 1976, 1975; Holbrook, 1976) are provided in Table 4-8. Daily dose estimates (mg/kg-day)
were not reported in these studies. Because data on body weight and food and water
consumption were incompletely reported, the estimated doses shown in Table 4-8 are based on
U.S. EPA (1988) reference values	isumption in male Sprague-Dawley rats.
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Table 4-8. Exposures, estimated doses, and effects in Sprague-Dawley rats exposed to Pt i-ompou
water or diet
iking
Compound
Medium
Exposure
duration
(days)
N
Exposure concentration3
Estimated c
(mgPt/kg-t- ¦ ?
Effects
(nimol/l. or kg)
(mg Pt/L or kg)
Body weight
gain
Change In organ
welghtc
Microsomal
enzyme activity'1
PtCl4
Water
8-9
12
1.63
318
44.1
No change
No change
No change/
Decreased6
PtCl4
Water
8-9
4
2.45
495
68.6
uecreasea
Not reported
No change
PtCl4
Water
29-31
8
0.54
105
14.6
No change
No change
No change
PtCl4
Water
29-31
12
1.63
318
44.1
Decreased
(1st wk only)
Increased
(kidney only)
No change
PtCl4
Water
90-91
4
0.54
105
i 1.6
Not reported
Not reported
Increased'
Pt(S04)2
Water
8-9
8
1.63
318
44.1
Decreased
No change
Decreased8
PtCl4
Food
29-31
12
5.90
1,151
99.2
No change
Not reported
No change
PtCl4
Food
29-31
4
13.2
2,575
222
No change
Not reported
Increased11
Pt(S04)2
Food
29-31
4
5.90
1,151
99.2
No change
Not reported
No change
PtO.
Food
29-31
4
29.8
5,813
501
No change
Not reported
No change
body weight (for subchronic exposure, male Sprague-Dawley rat; U.S. EPA, 1988)
for subchronic exposure, male Sprague-Dawley rat; U.S. EPA, 1988)
aExposure concentration, mmol/L or mg/L drinking water; mmol/kg or mg/kg food
bmg/kg-day = mg/L drinking water x 0.037 L water/day/0.26'
mg/kg-day = mg/kg food x 0.023 kg food/day/0.267 kg
"Organ weight taken of liver, kidney, spleen, hea
dAniline hydroxylase and aminopyrine demethyla
eHolbrook et al. (1975) reported that activity of aniline hydroxylase was decreased by 21% and that no effects on aminopyrine demethylase activity were observed.
However, a later report of the same study (Holbrook et al., 1976) reported no change in either enzyme following exposure to 1.63 mM PtCl4 for 8-9 days.
' Aniline hydroxylase activity was increased (p < 0.05; mean and SD not reported) by 28%, compared with control, but no change in aminopyrine demethylase
activity was found.
'Aniline hydroxylase activity v*. as decreased (p < 0.05; mean and SD were not reported) by 21%, compared with control, but no change in aminopyrine demethylase
activity was found.
''Aminopyrine demet	creased (p < 0.1; mean and SD were not reported) by 22%, compared with control, but no change in aniline hydroxylase
activity was found.
Sources: Holbrook (
(1976, 1975).
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Results of the drinking water studies are summarized in Table 4-8. No effect on body
weight gain was observed for rats exposed to 1.63 niM PtCl4 for 8-9 days, or 0.54 niM PtCl4 for
29-31 days. Body weight gain was reduced by approximately 25% in rats exposed to 2.45 niM
PtCl4 in drinking water for 8-9 days (SD and statistical significance were not reported).
Exposure for 29-31 days to 1.63 niM PtCl4 resulted in a 20% reduction in body weight gain
during the first week of exposure only; decreases in weight gain were accompanied by a 20%
reduction in food and water consumption (SD or statistical significance not reported). Body
weight gain was decreased by 14% (SD or statistical significance not reported) in rats exposed to
1.63 niM Pt(SO.t): for 8-9 days. Data on body weight gain in rats exposed to 0.54 mM PtCU for
90-91 days were not reported. Exposure to 0.54 mM PtCU in drinking water for 29-31 days did
not affect weights of any of the five organs investigated (liver, kidney, spleen, heart, and testes);
organ weight data for rats exposed to 0.54 mM PtCU for 90-91 days (see Section 4.2.1.1 for
complete discussion of the subchronic exposure portion of this study) or 2.45 mM PtCU for 8-
9 days were not reported. No changes in organ weights were observed in rats exposed to
1.63 mM rat PtCl4 or 1.63 mM Pt(S04)2 for 8-9 days. However, exposure to 1.63 mM rat PtCl4
for 29-31 days resulted in a slight increase in kidney weight as a percentage of body weight,
from 0.85% in controls to 0.92% in the PtCl4 group (8% increase; p < 0.05; SD not reported)
(Holbrook et al., 1975), but no changes in weights of other organs were observed. Reported
results for activities of aniline hydroxylase and aminopyrine demethylase provide mixed
evidence for induction of hepatic cytochrome P450 with 90-91 days of exposure to 0.54 mM
PtCl4: aniline hydroxylase activity was increased by 28% compared with control (p < 0.05), but
aminopyrine demethylase activity was unchanged (Table 4-8). With shorter durations of
exposure (8-9 or 29-31 da,?tCl4 or Pt(S04>;, no consistent evidence for exposure-related
changes in these hepatic enzymes was found (see Table 4-8). In the absence of histological
examinations or other endpoints indicative of liver damage, the evidence for PtCl4 induction of
hepatic cytochrome P450 is not judged to be an adverse effect on the liver.
Holbrook et al. (1976, 1975; Holbrook, 1976) also exposed Sprague-Dawley rats to PtCl4,
4)2, or PtO; in the diet for 29-31 days (exposures, estimated doses, and results are
:.>!iarized in Table 4-8). No discemable effects on body weight were found for any of the
.. ' i >¦ : - ;d groups of rats. No data on the effect of dietary exposure on organ weights were
;d for any group. Exposure to PtCl4 in the diet (13.2 mmol/kg diet or 222 mg Pt/kg body
weight-day) was associated with a 22% increase in hepatic microsomal aminopyrine
demethylase activity (p < 0.10, SD not reported), but no other changes in microsomal enzyme
activities were observed for the other groups exposed to Pt compounds in the diet.
As further evidence for an effect of PtCl4 on hepatic cytochrome P450 activity, Holbrook
et al. (1976) reported a dose-dependent increase in hexobarbital sleeping time in male Sprague-
Dawley rats (number of animals per dose group were not reported) following two daily
intraperitoneal doses of PtCl4 ranging from 14 to 56 uniol Pt/kg-day (2.73-10.9 mg Pt/kg-day);
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the increase was 51 ± 15 (SD)% (p < 0.05%) at the highest dose (22.0 mg Pt/kg-day). The
increase in hexobarbital sleeping time is indicative of a decrease in metabolism of hexobarbital
by cytochrome P450.
In summary, the Holbrook (1976) and Holbrook et al. (1975) studies provide s ve
evidence for the possibility of kidney toxicity in rats exposed tol .63 niM PtCU in drin	^ aier
(=44.1 mg Pt/kg-day) for 29 days (i.e., 8% increase in relative kidney weight), but no
histopathological examinations of kidney or any other organs were conducted. The > i • ¦ ;; i tsi stent
effects (i.e., increase, decrease, and no change) reported in these studies on activities ' uie
hepatic microsomal enzymes, aniline hydroxylase and aminopyrine demethylase, arc uiiiicult to
interpret and do not reflect a clearly adverse effect on the liver. Limitations in study design (e.g.,
few doses tested, lack of comprehensive endpoints) do not allow for identification of other
potential target organs or dose-response relationships, or risons of the relative potency of
more-soluble (e.g., PtCU, Pt[S().t];) and less-soluble Pt compounds (e.g., PtC^).
Reichlmayr-Lais et al. (1992) exposed Sprague-Dawiey nils (nine animals per dose
group) for 4 weeks to PtCh or PtCl.t in diet at concentrations of 0, 0.01, 0.05, 0.1, 0.5, 1, 5, 10,
and 50 mg Pt per kg diet. Using an average body weight (based on an average initial body
weight of 35 g and the average total body weight gain over 4 weeks for each treatment group)
and the total Pt intake reported for the 4-week exposure period for each treatment group, daily Pt
doses were estimated at 0.001, 0.006, 0.01, 0.06, 0.1, 0.5, 1, and 6 mg Pt/kg-day for the 0.01,
0.05, 0.1, 0.5, 1, 5, 10, and 50 mg Pt groups, respectively, for both PtCl; and PtQU groups. The
following assessments were made on animals at the conclusion of exposure: food consumption,
body weight, hematology (i.e., erythrocyte count, mean corpuscular volume [MCV], hematocrit,
hemoglobin), and plasma creatinine concentration. Pt concentrations in tissues (adipose, brain,
carcass, femur, heart, kidney, liver, muscle, plasma, spleen, testes) were measured by AAS (see
Section 3.2.1 for summary of tissue Pt data). Body weight gain and food intake were unaffected
by dietary exposure to PtCl; and PtCl.t. No treatment-related effects on hematological
parameters (erythrocytes count, hematocrit, MCV, and hemoglobin) were observed in any PtCl;
¦: . - - ' trend (p < 0.06) was observed in rats treated with PtCU for decreased erythrocytes
		 ¦ ¦1'! .- id hematocrit. Approximate maximum percentage decreases observed in the highest
:¦ ¦¦•'¦ <^ \ group were 13% for mean erythrocyte count (5.11 ± 0.50 [SD] x 106/jiL versus
j.ou _l xj.^5 x 106/jiL in the control group) and 13% for mean hematocrit (29.1 ±3.3 versus
32.9 ±3.1 in the control group). Plasma creatinine was also significantly (p < 0.05) increased in
the 6 mg PtCU group (1.45 ± 0.19 mg/dL versus 0.7 ± 0.47 [SD] mg/dL in control), indicating
altered renal function. No other measure of renal function or additional information on potential
histopathological changes to the kidney or other organs was reported. Decreased erythrocyte
count and increased creatinine clearance indicate that the 4-week dietary exposure to PtCU, but
not PtCl2, may adversely affect the hematopoietic system and the kidney at the doses tested.
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Reduced activity (marginally reduced rearing and exploratory activity) were observed in
rats exposed to repeated oral dose of 109 mg Pt/kg body weight as Pt(S04): (1-10 doses over
30 days) (Lown et al., 1980).
In summary, short-term oral studies (Reichlmayr-Lais et al., 1992; Roshchin et c >1 4;
Holbrook, 1976; Holbrook et al., 1976, 1975) provide evidence for the kidney as a possible
target of toxicity of soluble Pt compounds in rats (i.e., PtCl4, Pt [ S().t];), but are limited in scope
and did not include histopathological examinations. Evidence in support of this conclusion
include observations of an 8% increase in relative kidney weight in rats exf i o 1.63 mM
PtCl4 in drinking water for 29 days (=44.1 mg Pt/kg-day; Holbrook et al., 19', , cuid an increase
in plasma creatinine concentration in rats exposed to 50 mg Pt per kg diet a.> a tCl4 in diet for
4 weeks (»6 mg Pt/kg-day; Reichlmayr-Lais et al., 1992). The studies provide less convincing
evidence that the liver is a potential toxicity target of repeated oral exposure to soluble Pt
compounds. Changes in activities of the hepatic microsomal enzymes (e.g., aniline hydroxylase
and aminopyrine demethylase) have also been observed in rats exposed to PtCl4 or Pt(S04)2 in
drinking water at concentrations of 1.63 or 2.4 : n r¦¦¦>. < ¦¦¦ : 4.1 or 68.6 mg Pt/kg-day) or to PtCl4 in
food at a concentration of 13.2 mmol/kg food («222 mg Pt/kg-day; Holbrook et al., 1976, 1975);
however, the observed changes have not been consistent in direction (i.e., increase or decrease in
enzyme activity) or repeatable across oral exposure studies. The observation that intraperitoneal
dosing with PtCl4 prolonged hexobarbital sleeping time in rats provides further evidence that
PtCl4 may alter in vivo cytochrome P450 activity (Holbrook et al., 1976), but the toxicological
significance of these liver effects (i.e., their connection to a mode of action for toxicity in the
liver or other tissues) in association with oral exposures to PtCl4 or Pt( S()4 h cannot be
determined from the available information. One of the studies reported a trend for decreased
erythrocyte number and hematocrit in rats treated exposed to PtCl4 in the diet for 4 weeks, with
decreases of approximately 13% for erythrocyte count and hematocrit in rats exposed to 50 mg
PtCl4 per kg diet («6 mg Pt/kg-day; Reichlmayr-Lais et al., 1992). These observations suggest
;: in addition to kidney, the liver and blood may be potential target tissues for oral exposures
; n Juble Pt compounds. However, limitations in study design (e.g., few doses tested, lack of
comprehensive assessment of endpoints, including histopathology of potential target tissues) do
:. ; ow for more definitive identification of target organs, characterization of dose-response
relationships, or comparisons of relative potency of more-soluble (e.g., PtCl4, Pt[S04]:) and less-
soluble Pt compounds (e.g., Pt02).
4.4.2.2. Inhalation
No studies on the effects of short-term inhalation exposure of animals to soluble or
insoluble Pt compounds were identified.
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4.4.3. Drug Studies
Drags containing Pt are used frequently to treat cancers of the testes, ovaries, breast,
lung, head, and neck (Screnci and McKeage, 1999; WHO, 1991; I ARC 1987, 1981). The Pt
anticancer drags currently approved for clinical use are cisplatin (c /s-dichlorodianiniitie Pt).
carboplatin (diamminecyclobutane-dicarboxylato-Pt), and oxaliplatin (cis-1,2-cyclohexane-
diamine-N,N'-oxalato-2-0,0'-Pt), although a large number of carboplatin analogues have t y;
developed and tested to various degrees in clinical trials (Sanderson et al., 1996). The extensiv
clinical experience with Pt anticancer drags provides a large body of information regarding
adverse effects of those Pt compounds in humans at high doses and generally after acute or short-
term parenteral exposure. Although no studies are available examining possible associations
between inhalation exposure to Pt anticancer drags and specific adverse health effects,
information on adverse effects associated with parenteral ;¦;: ¦ i < al exposure to Pt anticancer
drags in human subjects indicates the potential for a range of Pi-induced adverse health effects.
Adverse effect profiles of the Pt anticancer drugs vary wim specific compound (as discussed in
Section 4.4.3.2 and summarized in Table 4-10). Predominant toxic effects of the three main
parenteral forms of Pt anticancer drags include nephrotoxicity (cisplatin), ototoxicity (cisplatin),
neurotoxicity (cisplatin and oxaliplatin), myelotoxicity (carboplatin), gastrointestinal toxicity (all
three of the main parenteral forms), and allergic sensitization (all three of the main parenteral
forms) (Hartmann and Lipp, 2003). Treatment of humans and animals with the newer,
experimental oral Pt anticancer drug JM216 has been associated with myelosuppression and
gastrointestinal toxicity, but riot ototoxicity. However, due to the limited clinical experience
with these drugs, the neph oi u:, neurotoxic, and sensitization potential of JM216 or the other
experimental oral drugs ha^ uui oeen established (Screnci and McKeage, 1999; Sessa et al.,
1998; McKeage, 1995). The precise mechanism of anticancer activity of the Pt anticancer drags
has not been fully elucidated, although the mechanism appears to involve the inability of tumor
cells to repair special intra-strand DNA cross-links that are formed by cisplatin (Hartmann and
Lipp, 2003; Lawley and Phillips, 1996; WHO, 1991). Anticancer activity is highly dependent
;ron chemical structure and spatial orientation, as indicated by the lack of anticancer activity by
; f i ; trans isomer of cisplatin (Hartmann and Lipp, 2003; Lawley and Phillips, 1996; Arany and
firstein, 2003; WHO, 1991). As described below, although Pt anticancer drugs share similar
structures, they differ in pharmacokinetic and toxicity profiles (Hartmann and Lipp, 2003).
4.4.3.1. Pharmacokinetics of Pt Anticancer Drugs
Treatment with parenteral Pt anticancer drags typically involves a course of intravenous
or intraperitoneal injections, most commonly administered by intravenous infusion lasting from
minutes to 24 hours (Calvert et al., 1993). As shown in Table 4-9, the pharmacokinetic
properties of Pt anticancer drags vary with specific compound. Pt anticancer drugs vary widely
with respect to binding to plasma proteins; >90% of administered cisplatin is irreversibly bound
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to plasma proteins, compared to approximately 24-50% for carboplatin and 85% for oxaliplatin
(Hartmann and Lipp, 2003; Chabner et al., 2001). The distribution of the cisplatin, carboplatin,
oxaliplatin, and JM40 (an experimental oral Pt anticancer drug) appears to be biphasic (e.g., an
initial phase, a, which reflects distribution from the blood to tissues with high perfusion, ar
second phase, P, which reflects the time required for tissue concentrations to reach eqi
with the blood). Cisplatin, carboplatin, and JM40 are rapidly distributed within the body, v -!;
initial distribution half-lives of 0.22, 0.37, and 0.2 hours, respectively; whereas the initial
distribution of oxaliplatin is much slower, showing an initial distribution half-life of 7.3 hours
(Chabner et al., 2001; Graham et al., 2000; Calvert et al., 1993). Pt anticancer drugs are widely
distributed in the body. At steady state, oxaliplatin has the largest volume of jim; ibution (295-
812 L), followed by carboplatin (176 L), JM40 (62 L), and cisplatin (52 L) (C^wm et al., 2000;
Calvert et al., 1993). Similar tissue distribution of Pt has been reported for cisplatin and
carboplatin, with the highest concentration of Pt observed in the kidney for cisplatin and
carboplatin (Chabner et al., 2001; Tinker et al., 1990). For cisplatin, Pt appears to concentrate in
the kidney in areas of functional and histological damage (Arany and Safirstein, 2003; McKeage,
1995). Penetration into the central nervous system is poor for all Pt anticancer drugs (Chabner et
al., 2001). Cisplatin has been rep	tita in humans and rats (Hartmann and
Lipp, 2003; Pascual et al., 2001).
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Table 4-9. Summary of pharmacokinetics properties for Pt anticancer drugs
Property
Cisplatin
Carboplatin
Oxaliplatin
JM40
Route of administration
Parenteral
Parenteral
Parenteral
Oral
Binding to plasma proteins
>90%a,b
24—50%b
80-87%3'b,c
NA
Distribution half-life a
0.22 hrc
0.37 hrc
7.3 hrc

Distribution half-life P
0.72 hrc
1.93 hrc
239 hr0

Initial volume of distribution
10Ld
10 Ld
NA

Volume of distribution at
steady-state
52 Ld
176 Ld
295-812 Lc,d

Tissue distribution
Kidney, liver,
intestine, testes3
Kidney, liver, lung,
spleen, testes6


Crosses placenta
Yesb'8
NA


CNS penetration
Poor3
Poor3

NA*
Primary elimination routes
Renal excretion
(GFR and tubular
secretion) and
metabolism3,13
Renal excretion
(GFR)bd
Renal cxu&uuii
(GFR) and
metabolism3
Renal excretion and
metabolism3,11
Total body clearance
0.35 L/hrd

0.96 L/hrc
0.54 L/hrd
Terminal half-life
57 '",i
10.5-26 d3,b,c
4.1 dd
"( hahtier et al. (2001).
' Hartmann and Lipp (2003).
"Graham et al. (2000).
dCalvert et al. (1993).
"Tinker et al. (1990).
'Data on the tissue distribution ( : e. <	drug, JM216, in mice (following oral administration) show
distribution to the kidney, liver,	(demonstrating poor central nervous system penetration), with
the highest tissue concentration ui ^i. 		in to the testes was not examined (Bates et al., 1996).
8Pascual et al. (2001).
'Information on the specific mechanism of renal excretion of JM40 was not identified in the retrieved literature.
'McKeage (1995).
GFR = glomerular filtration rate; NA = information not available in the retrieved literature
Physiologically based pharmacokinetic (PBPK) models of the Pt anticancer agents have
harmacokinetics of various Pt anticancer agents (e.g., cisplatin) have been
characterized with empirical models. The empirical models have been derived by fitting
mathematical expressions (e.g., first-order rate equations) to data on plasma concentrations of Pt
or urinary excretion of Pt in humans following single or multiple doses of Pt compounds. The
models were derived to estimate specific pharmacokinetic parameters relevant to prediction of
dosing regimes needed to achieve therapeutic levels of the agents (e.g., distribution and
elimination half-times, volumes of distribution, clearances, area under plasma concentration-time
profiles, binding constants). The models do not identify or parameterize specific physiological
compartments (e.g., tissues). Examples of empirical models for several anti-cancer agents are
presented in Table 4-9.
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Metabolism and binding of Pt anticancer drags appears to relate to the reactivity of the
leaving groups. Pt anti-cancer agents (e.g., derivatives of cisplatin) include a variety of diamine-
Pt (II) or Pt(IV) compounds having the general structures ci4PtX2(NHR2)2] or ci4PtX4(NHR2)2],
respectively, where R is an organic moiety and X is a leaving group (CI in cisplatin). Thes
compounds undergo a variety of nonenzymatic ligand exchange reactions with amino
proteins and nucleic acid bases (Reedijk, 2003; Calvert et al., 1993). The reactions occur by
hydrolysis of the non-amine leaving group, which yields reactive intermediates (e.g.
[PtCl(H20)(NH3)2]+ from cisplatin) leading to the formation of Pt-adducts (Reedijk, :! >).
Reactivity is related to stability of the leaving group relative to that of the donor group
(N03"< SOf" < CI"; Calvert et al., 1993). Relatively high stability of S-donor ligands results in
formation of Pt-sulfur complexes with sulfur amino acids (e.g., cysteine, methionine) in proteins
and peptides (e.g., glutathione). Formation of Pt-DNA adducts (e.g., Pt-guanine) may involve
migration of Pt from a sulfur ligand intermediate (Reedijk, 2003). The affinity of Pt for sulfur is
the main pharmacologic rationale for the use of thiol agents (e.g., di ethyl dithi ocarbaniate,
thiosulphate) for mitigating toxicity of cisplatin and related anticancer agents (McKeage, 1995;
Calvert et al., 1993). Pt( TV) anticancer agents (e.g., iprorplatin, tetraplatin) can undergo
intracellular reduction to Pt(II) species (Calvert et al., 1993). Reduction may influence reactivity
of diamine-Pt compounds with DNA (Reedijk, 2003; Calvert et al., 1993). The exact
mechanisms for the reduction have not been elucidated; however, redox potential of diamine-Pt
complexes is influenced by substituents on the amine groups (Reedijk, 2003).
Pt anticancer drugs are eliminated through a combination of metabolism and renal
excretion, with most metabolites formed through non-enzymatic reactions (Calvert et al., 1993).
Renal excretion is the predominant excretory route, with a high percentage of administered dose
eliminated i" urine (Chabner et al., 2001; Graham et al., 2000; Calvert et al., 1993). For
cisplatin, ap mately 43% of the administered dose is recovered in the urine (compound
measured in Of.; was not specified) within 5 days (Chabner et al., 2001) and approximately
65% of carboplatin is excreted unchanged in the urine within 48 hours of administration of a
single intravenous dose (Calvert et al., 1993). Renal excretion of cisplatin is by glomerular
ind active proximal tubular secretion by organic anion and cation transport mechanisms
(Arany and Safirstein, 2003; Hartmann and Lipp, 2003; McKeage, 1995). However, since the
renal elimination of carboplatin and oxaliplatin has been reported to closely approximate the
glomerular filtration rate, it appears that carboplatin and oxaliplatin do not undergo significant
tubular reabsorption or secretion (Hartmann and Lipp, 2003; Graham et al., 2000; Calvert et al.,
1993). As discussed in Section 4.4.3.3, the higher nephrotoxic potency of cisplatin, compared to
carboplatin and oxaliplatin may, in part, be related to its renal tubular secretion. Cisplatin,
oxaliplatin, and JM40 also are eliminated by metabolism, whereas metabolism does not
significantly contribute to the elimination of carboplatin. Pt has been reported to be excreted in
breast milk following treatment with cisplatin (De Yries et al., 1989). The terminal elimination
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half-life for cisplatin, carboplatin, and JM40 are 5.4, 5.8, and 4.1 days, respectively (Graham et
al., 2000; McKeage et al., 1995; Calvert et al., 1993). Compared to cisplatin and carboplatin,
oxaliplatin is eliminated much more slowly, with a terminal elimination half-life ranging from
10.5 to 26 days (Hartmann and Lipp, 2003; Chabner et al., 2001; Graham et al., 2000).
Studies conducted on the anti-cancer drugs, cisplatin and carboplatin, provide evidence
for transdermal absorption of these compounds. Dermal application of carboplatin dissolved ii;
dimethylsulfoxide (DMSO) or cisplatin dissolved in dimethylformamide (DMF) delay the onset
of adjuvant arthritis in rats induced by subcutaneous injections of an arthrit	1.,
1991). These observations suggest that these Pt compounds and/or comple	nts
were absorbed transdermally.
In summary, the pharmacokinetics of Pt anticancer drugs a-i v- v i.i 1 i &b >. unu uvpwiu un the
specific chemical in question. The distribution of cisplatin, carboplatin, aim j ivl40 is more rapid
than for oxaliplatin. Although all Pt anticancer drugs undergo wide distribution, the volume of
distribution of oxaliplatin is much larger than that of cisplatin, carboplatin, or JM40. The highest
organ concentration of Pt is observed in the kidney for cisplatin and carboplatin. Cisplatin,
oxaliplatin, and JM40 are eliminated through metabolism and renal excretion, whereas
carboplatin is primarily eliminated by renal exci ¦?!. : he mechanisms of renal excretion for
cisplatin are glomerular filtration and tubular secretion, whereas carboplatin and oxaliplatin are
primarily excreted via glomerular filtration. The renal tubular secretion of cisplatin may play an
important role in the higher relative nenhrotoxicity of cisplatin compared to other Pt anticancer
drugs (see Section 4.4.3.2 for derailed discussion of cisplatin-induced nephrotoxicity).
Oxaliplatin is eliminated from	_ 		.nuch more slowly than cisplatin, carboplatin, or JM40.
4.4.3.2. An	. .¦ ,. ¦. 'verse Effects of Pt Anticancer Drugs
Anticancer chemotherapeutic agents, such as the Pt anticancer drugs, are typically
administered at maximum tolerated doses with respect to adverse effects; as such, serious
toxicity is commonly associated with administration of therapeutic doses (Ishibashi et al., 2003).
-: ^ igh the Pt anticancer drugs are structurally similar, toxicity profiles differ. Cisplatin is
:: i i.:.:ily associated with nephrotoxicity, neurotoxicity, and ototoxicity, whereas myelotoxicity
iominant for carboplatin, and neurotoxicity is predominant for oxaliplatin (Arany and
ein, 2003; Hartmann and Lipp, 2003; Links and Lewis, 1999; Screnci and McKeage,
1999; Cersosimo, 1993). For example, a 97% prevalence of peripheral neuropathy (paraestheias,
dysaetheisa, and sensory ataxia) was reported in a clinical trial of 107 patients with colorectal
cancer treated with oxaliplatin, whereas a 47% prevalence of peripheral neuropathy (paraesthesia
and sensory ataxia) was reported in a clinical trial of cisplatin in 292 ovarian cancer patients and
a 6% prevalence was found in a trial of carboplatin in 428 patients with various tumor types
(Screnci and McKeage, 1999). In general, Pt anticancer drugs are not classified as hepatotoxic
drugs, although mild, reversible increases in liver function tests have been reported (Hartmann
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and Lipp, 2003). The major toxicities associated with Pt anticancer drugs in humans have been
well-described.
Information on the characteristics of cisplatin-induced nephrotoxicity has been
summarized in reviews and is based on data from humans and experimental animals (H
and Lipp, 2003; McKeage, 1995; Calvert et al., 1993). Cisplatin-induced nephrotoxicity ;
characterized by degenerative lesions of the proximal and distal convoluted tubules of the
corticomedullary junction and the outer stripe of the medulla (Hartmann and Lipp, 2003;
McKeage, 1995). Acute histopathological changes include cellular necrosis, s ; , : M ining of the
epithelium, hydropic degeneration, nuclear hyperchromasia, and congestion ui vasa recta.
With chronic damage, cellular atrophy, tubular dilatation, nuclear atypia, and : -(u;rstitial
inflammation are observed (McKeage, 1995). The initiating event is a proxii,.«. tabular lesion,
which results in decreased proximal tubular reabsorption of water - n : s um, followed by
alterations in distal tubular reabsorption, renal vascular resistance, ieiiai uiood flow, and
glomerular filtration rate (GFR) (McKeage, 1995). Hypomagnesemia and potassium and
calcium wasting may result from prolonged renal damage (McKeage, 1995). The most sensitive
indicators of cisplatin-induced nephrotoxicity are changes in creatinine clearance, and urinary
activities of alanine aminopeptidase and N-acetyt-p 4) ducosamidase (Hartmann and Lipp,
2003). Reduced renal toxicity of cisplatin through a combination of NaCl infusion and mannitol-
induced water diuresis is thought to be due to suppression of the formation of "aquated" species
in the renal tubule (Calvert et al., 1993). Tubular epithelial damage may be related to the renal
accumulation, urinary excretion, and renal tubular secretion of cisplatin (McKeage, 1995).
Differences in renal handling of carboplatin and oxaliplatin (e.g., compounds do not undergo
tubular secretion) may contribute to the reduced nephrotoxicity of these agents relative to
cisplatin (McKeage, 1995); severe nephrotoxicity is uncommon in patients treated with
carboplatin and only rarely observed for oxaliplatin (Hartmann and Lipp, 2003). It has also been
proposed that the reduced nephrotoxicity of carboplatin and oxaliplatin may be due to reduced
reactivity of the leaving group (e.g., NH3, RNH2; not easily displaced by a nucleophile)
(Hartmann and Lipp, 2003; Calvert et al., 1993).
Several reports indicate that hypersensitivity reactions to Pt anticancer drugs occur (see
jpherd, 2003). Symptoms of hypersensitivity reactions include respiratory
3ms (wheeze and dyspnea), GI discomfort (abdominal cramps and diarrhea), and rashes
(pruritus, urticaria, facial erythema, and edema) (Hartmann and Lipp, 2003). In sensitive
patients, hypersensitivity reactions are reported to occur after the administration of multiple
intravenous courses of Pt anticancer drugs (Hartmann and Lipp, 2003; Markman et al., 2003).
Hypersensitivity reactions to carboplatin, typical of a Type I, IgE-mediated mechanism and
ranging in severity from mild to severe, were reported in 16% of the 194 patients treated
intravenously with carboplatin for ovarian cancer in a Greek hospital over a 10-year period
(Polyzos et al., 2001). Also, in a clinical trial study of cisplatin in which 30 patients were
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administered a dose of 75 mg/m2, 1 had to be removed from the study for hypersensitivity, and
4 were removed for renal toxicity (Sabbatini et al., 2004). Intravenous oxaliplatin induced
hypersensitivity reactions in 17 of 124 patients (13%), with reactions observed after 2-
17 administrations (Brandi et al., 2003). Hypersensitivity reactions to oxaliplatin have also been,
reported in case studies (Bhargava et al., 2004; Thomas et al., 2003). Based on the overall
clinical experience with Pt anticancer drugs, the incidence of hypersensitivity reactions : ¦
estimated as 5% for cisplatin, 2-9% for carboplatin, and <1% for oxaliplatin (Lim et al, 2004).
Cross-sensitivity is possible among the Pt anticancer drugs (Hartmann and Lipp, 2003).
Results of a study by Markman et al. (2003) suggest that patients with a prior history of systemic
hypersensitivity reactions to medications or environmental exposures may be predisposed to
allergic reaction to Pt anticancer drugs. Since hypersensitivity from therapeutic treatment with
Pt anticancer drugs prevents further use in patients wit!	- esensitization
protocols have been developed in order for patients to c	cancer drug therapy
(Bhargava et al., 2004).
Peripheral neurotoxicity is one of the major adverse enects associated with cisplatin and
oxaliplatin, occurring in approximately 50% of patients treated with cisplatin and nearly all
patients treated with oxaliplatin (Screnci and M< s • o.. .. 1999). Neurotoxicity associated with
administration of carboplatin is generally mild and occurs in approximately 5% of patients
(Screnci and McKeage, 1999). Symptoms O; : ¦. ixicity include numbness and tingling,
paraesthesia of the upper and lower extremities, reduced deep-tendon reflexes, and leg weakness
with disturbances in gait (Hartmann and Lipp, 2003). Neurotoxicity is characterized by slowing
of sensory nerve conduction ; iongation or disappearance of sensory nerve latency, absence or
reduction in sensory action potential, and normal motor conduction (McKeage, 1995).
Histopatholo<"'H]y, changes include degeneration and loss of medium- to large-sized
myelinated : ¦¦., axonal degeneration, and degeneration of myelin sheaths (McKeage, 1995).
Cellular cha i . in the dorsal route ganglia included reduced cell size, increased
multinucleolization, and hypertrophy of satellite cells (McKeage, 1995). The underlying
lechanism for peripheral neuropathy of Pt anticancer drugs has not been identified (Hartmann
2003; McKeage, 1995).
Administration of therapeutic doses of cisplatin is also associated with ototoxicity,
characterized by tinnitus and bilateral high-frequency hearing loss (Hartmann and Lipp, 2003;
Chabner et al., 2001; McKeage, 1995). The incidence of cisplatin-induced ototoxicity ranges
from 11 to 91% (McKeage, 1995). At therapeutic doses, carboplatin rarely causes ototoxicity,
with a reported incidence of 1.1% (Hartmann and Lipp, 2003). Oxaliplatin has not been reported
to induce ototoxicity (Hartmann and Lipp, 2003). Cisplatin-induced histological effects are
primarily cochlear damage with hair cell loss, although some studies suggest nerve damage and
degenerative changes to the spiral ganglia and cochlear nerve (McKeage, 1995).
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In addition to adverse effects associated with therapeutic use of Pt anticancer drugs,
cisplatin has been classified by the International Agency for Research on Cancer (I ARC) (1987)
in cancer Group 2 A, probably carcinogenic to humans, based on inadequate evidence of
carcinogenicity in humans and sufficient evidence of carcinogenicity in animals (incre
incidence of tumors in rats and mice following multiple intraperitoneal injections). AI
cancer bioassays are available for other Pt anticancer drugs, positive results from genotoxic
studies suggest possible carcinogenic activity. Based on the mechanism of anticancer activity
(e.g., the formation of intra-strand DNA cross links), it is anticipated that all Pt anticancer drugs
are potentially genotoxic. Cisplatin, carboplatin, and other Pt anticancer drugs have been shown
to induce mutations in both in vitro and in vivo assays, although the mutagenic activity of
cisplatin appears to be higher than that of the other Pt anticancer drugs (Sanderson et al., 1996).
A large database exists with strong evidence for genotoxic potential of cisplatin and other
anticancer Pt compounds. For the Pt anticancer compounds, gcnoiu.\ii_uv is determined by
valency, conformation, and structure. Square planar t /s-compounds, sush as cytostatic drug
cisplatin, are the potent genotoxins and much more so than their /ram-isomers. Furthermore,
among anticancer Pt compounds there is evidence that Pt(lV) compound genotoxicity arises from
reduction to its divalent Pt (II) species. Cisplatin[tv'.s-Pt (NH3 )2C1;] has been extensively studied
as an anticancer therapeutic drug in the pharmaceutical industry.
The predominant toxic effects associated with the main parenteral Pt anticancer drugs and
the oral drug JM216 are summarized in Table 4-10, along with other less predominant effects.
The predominant toxic effect or effects are defined as those adverse effects that are considered
dose-limiting for clinical use (e.g., due to the severe nature of the effect, higher doses cannot be
administered). Treatment puuents with therapeutic doses of cisplatin and carboplatin has been
associated with nephrotoxicity, neurotoxicity, ototoxicity, myelotoxicity, GI toxicity (primarily
nausea and vomiting), and hypersensitivity. For cisplatin, the predominant toxic effects are
nephrotoxicity, neurotoxicity, and ototoxicity, and for carboplatin, the predominant toxic effect
is myelotoxicity. The predominant toxic effect associated with oxaliplatin is neurotoxicity,
although myelotoxicity, GI toxicity, and hypersensitivity have also been reported with
therapeutic use. All three of the parenteral drugs have been reported to induce hypersensitivity.
Use of the experimental oral drug, JM216, in clinical trials has been consistently associated with
myelotoxicity and GI toxicity, but the nephrotoxic, neurotoxic, and hypersensitization potentials
of JM216 are uncertain due to conflicting reports and lack of information (see Table 4-10). This
uncertainty may reflect the limited clinical experience with this drug.
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Table 4-10. Toxic effects associated with Pt anticancer drugs
Toxicity
Cisplatin3
Carboplatin3
Oxaliplatin3
JM216
Nephrotoxicity
~
•
•
./_b
Neurotoxicity
~
•
~
•/—*
Ototoxicity
~
•
—
—
Myelotoxicity
•
~
•
A
GI toxicity
•
•


Hypersensitivity
•
•

able
A Predominant toxic effect.
• Effect has been observed, but is not considered predominant.
— Toxic effect not observed.
aHartmann and Lipp (2003).
bSessa et al. (1998) stated that the nephrotoxicity of JM216 was "comparable to that of i.v. carboplatin in mice".
McKeage (1995) reported that "JM216 exhibits "no nephrotoxicity" in animals or humans.
cScrenci and McKeage (1999) stated that JM216 has been "associated with infrequent peripheral neurotoxicity in early
phase clinical trials." McKeage (1995) reported that JM216 exhibits "no pfirmberal neurotoxicity."
dMcKeage (1995).
4.4.3.3. Mode of Action for Nephrotoxicity of Pt A ntkaneer Drugs
Information pertaining to the mode of acuui. ucp.irotoxicity is restricted to studies on
Pt anticancer drugs. Cisplatin, carboplatin, fn- ; platin are associated with nephrotoxicity in
patients at standard therapeutic doses; howevei, uspiatin is considered to be the most
nephrotoxic of these three drugs. It has been proposed that differences in nephrotoxic potency is
related to differences in th< k-hi handling of these drugs; cisplatin undergoes renal excretion by
glomerular filtration and a ; oximal tubular secretion (Arany and Safirstein, 2003;
Hartmann and Lipp, 2003; McKeage, 1995), whereas carboplatin and oxaliplatin do not appear
to undergo s icant tubular secretion (Hartmann and Lipp, 2003; Graham et al., 2000; Calvert
et al., 1993) . ^ 5 principal site of cisplatin toxicity is the proximal tubule; thus, proximal tubular
secretion of cisplatin provides a plausible pathway for entry of cisplatin into cells where
degenerative tubular lesions are initially observed (Arany and Safirstein, 2003; Hartmann and
Lipp, 2003; McKeage, 1995). Renal toxicity of cisplatin is reduced by administration of
mannitol, which increases urine flow rate and thereby flushes the kidney and decreases the
transit time of cisplatin in the kidney (WHO, 1991). Based on these observations, the renal
accumulation and toxicity of cisplatin is likely related to renal transport mechanisms. Unlike
carboplatin or oxaliplatin, renal tubular secretion is the major excretory pathway for cisplatin;
thus, tubular epithelial damage is Pt compound-specific and may be related to the renal
accumulation, urinary excretion, and renal tubular secretion of cisplatin (McKeage, 1995).
Although the mode of action of cisplatin-induced nephrotoxicity has not been identified,
several possible mechanisms have been proposed. Like other nephrotoxic heavy metals (e.g.,
mercury), cisplatin is likely to interact with sulfhydryl compounds, leading to depletion of
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intracellular glutathione and other protein and nonprotein sulfhydryls, and oxidant stress
(Hartmann and Lipp, 2003; McKeage, 1995). Cisplatin also upregulates several cytokines in the
kidney, leading to recruitment of inflammatory cells, which can injure surrounding renal tissue
(Arany and Safirstein, 2003). Induction of gene products, possibly leading to apoptosis, lia ' >
been proposed to play a role in cisplatin-induced nephrotoxicity (Arany and Safirstein, 2003;
Hartmann and Lipp, 2003).
Genotoxic damage by intercalation of DNA or oxidant-induced damage may also be an
important component of stress-induced changes by cisplatin. The primary lesion produced by
cisplatin in cancer cells is intrastrand binding to adjacent purine bases, whict
secondary structure of DNA, inhibiting replication (Arany and Safirstein, 2003). This lesion is
not produces by the tram isomer, which is neither nephrotoxic nor antineopkwuv (Arany and
Safirstein, 2003). It is unknown if cisplatin, or other Pt compounds, produces DNA damage in
kidney cells.
In summary, information on the potential for Pt compounds to produce nephrotoxicity is
limited to data on the Pt anticancer drugs. The nephrotoxic potential of the experimental oral Pt
anticancer drugs has not been determined due to the limited clinical experience with these drugs.
The precise mechanism of nephrotoxicity associated with Pt anticancer drugs has not been
established, although nephrotoxic potency is compound-specific and appears to be related to
renal excretory mechanisms and therefore, cisplatin has higher nephrotoxicity due to its unique
renal excretion among Pt comoounds studied. The relevance of the proposed mode of action
derived for Pt anticancer drags to induce nephrotoxicity is unknown for oral exposure to
environmental forms of Pt coi..t		 Renal toxicity has not been associated with occupational
exposure to Pt compounds. ;Uiuitional information on the nephrotoxicity of other Pt compounds
from the studies by Holbrook (1976) and Holbrook et al. (1975) indicates the possibility of
kidney toxicity in rats exposed to PtCU in drinking water (i.e., 8% increase in relative kidney
weight); however, histopathological confirmation of kidney injury was not attempted in these
studies and no data are available on the mechanisms of renal excretion for environmental Pt
5, with the exception of the Pt anticancer drugs, the nephrotoxic potential for Pt
not been established.
HANISTK DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF
ACTION
4.5.1. Sensitization Studies
4.5.1.1. Soluble Pt Salts
Animal studies have evaluated sensitization effects of halogenated Pt salts following
inhalation, dermal, and parenteral exposure, providing limited evidence to support the numerous
reports of allergic sensitization to halogenated Pt salts in groups of occupationally exposed
workers. The results of the three available animal studies of inhalation exposure to Pt (Biagini et
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al., 1986, 1985b, 1983) support the possibility that co-exposure to ozone may promote the
development of allergic sensitization to halogenated Pt salts. Although inhalation exposure
studies are the most relevant to occupational exposure, demonstration of sensitization by dermal
and parenteral routes provides additional supportive data.
4.5.1.1.1. Inhalation studies. Sensitizing effects of inhaled halogenated Pt salts
investigated in two subchronic exposure studies (Biagini et al.,1986, 1983) and c
exposure study (Biagini et al.,1985b) in primates. The results of the acute exposure study are
summarized in Section 4.4.1.2, Acute Inhalation Exposure Studies, and the subcl,, ~ .posure
studies are described below.
Biagini et al. (1983) exposed groups of three or four cynomolgus monkeys to sodium
hexachloroplatinate (Na2f>t('*l,,) by nose-only inhalation a . i ntrations of 200 and
2,000 jig/m3, 4 hours/day, biweekly, for 12 weeks. Repo i ¦: .; M ADs and GSD for the aerosols
were 1.61 urn and 2.03 for the low-exposure group and l.z/ urn ;.nid2.09 for the high-exposure
group. Another group of four monkeys was exposed biweeKiy ror i2 weeks to a percutaneous
dose of 20 mg T^PtCl,, in water applied to a 7 • 7 cm shaved, abraded area (uncovered) on the
intrascapular region of the back. The control group had eight nonexposed monkeys. Monkeys
were evaluated pre- and postexposure with pulmonary function tests that included measurement
of pulmonary resistance, dynamic compliance, PEF, FVC, FEVs, and FEFs 2 weeks following
the end of exposure. Sodium hexachloroplatinate SPTs (administered to shaved areas of the
chest and stomach) were administered pre- and postexposure with serially diluted doses of
1 x 10"3-1 x 10"7 g/mL in k: :;u '.';iven to monkeys pretreated for 15 minutes with an intravenous
dose of 5% Evans blue dye. ^..dine bronchoprovocation values were determined with a
nebulized sa,;"e solution prior to provocation with N^PtCl,,-
No s ... i ;¦ '. .cant differences were seen in comparisons between pre- and postexposure SPTs
toNa2PtCl6 < ntrol or treated monkeys (Biagini et al., 1983). Postexposure measurements of
pulmonary function following bronchoprovocation with nebulized saline showed no significant
differences among groups. Bronchoprovocation with increasing doses of Na2Pt('"l,, (0-
62.5 mg/mL) showed marked effects on pulmonary function in all control and treated animals
when compared to baseline values. When bronchoprovocation data for the 62.5 mg/mL
challenge dose of Na2f>tCl„ were compared across groups, the pulmonary function parameters in
the percutaneous and 2,000 jig/m3 groups were not different than controls (monkeys in these
three groups showed similar responses to T^PtCl,,)- However, significant increases in
pulmonary resistance and decreases in FEV in 0.5 seconds/FVC ratios were observed in the
200 jig/m3 exposure group, when compared to controls. However, given the small number of
animals in the control (n = 8), 200 fig/m3 (n = 3), and 2,000 fig/m3 (n = 4) groups, results of
pulmonary function tests are difficult to interpret with respect to the dose-response relationship.
This study showed that neither inhalation nor dermal exposure to Na2PtCl6 (at the doses used) for
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12 weeks affected skin prick sensitivity or baseline pulmonary function in cynomolgus monkeys.
Bronchoprovocation tests with 'Na;Pt('*l,, showed effects in all monkeys including controls, but
these effects were more pronounced in the 200-jig/m3 group.
In a follow-up study, Biagini et al. (1986) exposed groups of cynomolgus monkeys h-
inhalation to 200 jig/m3 ammonium hexachloroplatinate ([ NFI4]2PtC*lt,) (group 1, n = 8),
200 jig/m3 (NH4)2PtCl6 plus 1 ppm ozone (group 2, n = 8), or 1 ppm ozone alone (group 3, -
for 6 hours/day, 5 days/week, for 12 weeks. Ozone was chosen for its ability to produce
respiratory inflammation and irritation following inhalation. MMADs and G : = for the aerosols
were reported to be 0.94 urn and 2.03 for group 1 and 1.07 urn and 1.89 for 2.
Immediately after, and 2 weeks following exposure, animals were given met! < n >line and
Na2PtCl6 bronchoprovocation tests and Na2PtCl6 SPTs. In addition, b	llected for
serum analysis for total and Pt-specific antibodies. No effects on aniruat nauui ui body weight
were observed. SPT to Na2PtCl6 conversion (from negative to positive; was seen in (positive
tests/total tests) 1/8, 4/8, and 0/7 monkeys in groups 1, 2, and 3, respectively. No differences
were seen in total IgE, total IgG, or Pt-specific IgE antibodies. Pulmonary function tests were
normal among all monkeys following 12 weeks of exposure. However, Na2PtCl6 and
methacholine challenge effects on pulmonary reactivity were significantly different from
preexposure values in monkeys from group 2 ([NH4]2PtCl6 plus ozone) but not groups 1 or 3.
These results suggest a synergistic effect of inhalation exposure to (NH4)2PtCl6 plus ozone on the
development of sensitization to hexachloroplatinate. These results also provide support for the
hypothesis that airway damage from exposure to irritant materials in combination with exposure
to halogenated Pt salts may pi\			 development of allergic sensitization. Although no data
are available on co-exposure to other relevant irritants or adjuvants such as diesel exhaust
particles, the animal data suggesting that ozone promotes development of allergic sensitization to
Pt supports the human data on increased probability of developing Pt hypersensitivity among
smokers (Merget et al., 2000; Baker et al., 1990; Linnett and Hughes, 1999; see Section 4.1.2.1
4,5,1.1.2, Dermal and parenteral studies. Exposure of volunteers and animals by dermal and
'¦¦i: iv : : ites also provide supportive evidence for the sensitization effects of halogenated Pt
Results of a study on the passive transfer (via serum) of halogenated Pt salt-allergy to
non-exposed humans and monkeys provide evidence of a possible IgG-mediated mechanism in
the development of halogenated Pt salt allergy (Pepys et al., 1979). Serum was collected from
six Pt refinery workers with positive SPT to (NH4)2PtCl6 and ammonium "tetrachloroplatinite"
(e.g., ammonium tetrachloroplatinate, or (NH4)2PtCl4; as indicated in Table 2-1, tetrachloro-
platinite is a synonym for tetrachloroplatinate); one worker was asymptomatic and five had
work-related symptoms of asthma. Serum from each sensitized worker and from non-exposed
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control subjects (number of control subjects was not reported) was injected 2.5 cm apart on the
forearm of three male volunteers. After 24-48 hours, heat-treated serum (e.g., serum heated at
56°C for 2 hours) from the sensitized workers and controls were injected into the opposite
forearm of the volunteers. SPTs with (NH4)2PtCl4 were performed at the injection sites on. both
arms 3-4 hours after injection. For the passive transfer studies in monkeys, serum from
sensitized and control workers was injected into sites on the thorax and abdomen of two me
rhesus monkeys. After 24 hours, heat-treated serum was injected, and SPTs with (NH4)2PtCl4
were performed 3-4 hours after injection. Positive SPT results to (NFl4)2PtCl4, as indicated by a
wheal and flare response, were observed in all three volunteers injected with unheated sera; for
two volunteers, a positive response was observed for sera from 4/6 sensitized workers, and for
one volunteer, a positive response was observed for sera from 5/6 workers. The serum from each
sensitized worker produced a positive SPT to (NH4)2PtCl	¦	 )lunteer. Responses
to sera from controls were not reported. For heat-treated serum, a uaiv-umy response to SPT
with (NFI4)2PtCl4 was observed in one volunteer for heat-	om 3/6 workers, and no
response to SPT with (NH4)2PtCl4 was observed in the two omer volunteers. In monkeys, no
positive SPTs to (NFI4)2PtCl4 were observed, using mtracutanous injections of (NH4)2PtCl4, a
positive response was observed for sera from 2/6 sensitized workers in both monkeys, and
positive results were observed for heat-treated sera from sensitized workers in one monkey
(individual monkey data were not reported). The study authors hypothesized that the positive
(NFl4)2PtCl4 SPT response to heat-treated sera may be due to the presence of a heat-stable
antibody, such as IgG. However involvement of an IgG-mediated mechanism, at least in some
individuals, in the developmcs			..ization to halogenated Pt salts has not been established.
Schuppe et al. (195 /u> Evaluated the potential for Na2PtCl„ to induce hypersensitivity
following repeated dermal applications in mice. Groups of 4-6 female naive BALB/c mice were
treated with 2.5 mg sodium hexachloroplatinate (Na;Pt('*l,,) in acetone by topical application to
the dorsum of both ears (1.25 mg applied to each ear; application area was not reported) for
4 consecutive days; the control group was treated with acetone. Mice were sacrificed 24 hours
iV ¦ i le last treatment. An initial immune response was demonstrated by comparison of the
number oF cells with proliferating cell nuclear antigen (PCNA+ cells) in fluid drained from
ph nodes in treated compared to vehicle control animals. The total number of
~ cells in mice treated with Na2PtCl„ was 22.8 times greater than observed in control mice,
indicating that dermal application of Na2PtCl„ induced an initial immune response. To evaluate
the response to re-challenge with Na2PtCl6, naive mice were initially sensitized by topical
application (to the right ear only) of 0 or 1.25 mg Na2PtCl6 in acetone for 4 or 8 consecutive
days. On weeks 1, 4, 8 (4-day group only), and 20 (8-day group only) following completion of
the initial sensitizing treatment, a single re-challenge dose of 0 or 0.5 mg Na2PtCl6 in acetone
was applied to the left ear; the response was evaluated by measuring left ear thickness 24 and
48 hours after re-challenge. At all re-challenge time points, a significant (p < 0.05 or 0.01,
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compared to acetone re-challenge controls) increase in 24- and 48-hour left ear thickness was
observed on re-challenge with 'Na;Ptn,, in the 4- and 8-day groups, with maximal left ear
swelling at 48 hours (p < 0.01). No increase in ear thickness was observed in sensitized animal
re-challenged with acetone only. Histological evaluation of left ear tissue 48 hours after re
challenge with 'Na;Ptn,, (4- or 8-day group not specified in the study report) showed der
edema and infiltration of mononuclear and polymorphonuclear inflammatory cells. In contrast, a
single application of 0.5 mg Na2PtCl6 or repeated application of acetone (number of doses were
not reported) in naive mice did not produce histopathological changes to ear tissue.
Topical application of ammonium tetrachloroplatinate, ammonium hexachloroplatinate,
or cisplatin elicited a secretion profile of cytokines from cultured lymphocytes similar to
secretion profiles elicited by other respiratory allergens such as trimellitic anhydride (TMA)
(Dearman et al., 1998). Groups of female BALB/c mice (5 for each treatment groups and 10 for
vehicle controls) were treated with 50 u L of ammonium tetrachloroplatinate ([NFL^PtCU),
ammonium hexachloroplatinate ([ NFI4]2PtC*lt,), or cisplatin Cc/.v-^NffO^tCK]) (0, 0.25, 0.5, or
1% in DMSO). Solutions were applied to a ¦¦¦; ; re;1: n (area of the application site was not
reported) of the abdomen; a second treatment was administered after 5 days. On day 10 after the
first treatment, 25 ul . of the test solution was applied to the dorsum of each ear for 3 consecutive
days. Concurrent controls were treated with 10% TMA or 1% 2,4-dinitrochlorobenzene (DNCB)
in acetone and olive oil (AOO) or with AOO alone. Unlike DNB, TMA was previously shown
to increase total serum IgE (indicating an IgE-mediated response). Auricular lymph nodes were
drained 13 days after the initial treatment, and cells from the fluid were cultured. Culture media
was analyzed for interleukin (	, 			 I10 (cytokines associated with initiation and
maintenance of an IgE-me^via^a response) and INF-y (a cytokine associated with inhibition of
IgE antibody production) after 12, 24, and 48 hours in culture. In cells from mice treated with
the three Pt 	founds or TMA, dose-related increases in II.-4 and II.-10 production were
observed (statistical significance not reported; data presented graphically); only a minimal
response was observed for DNCB. In contrast, DNCB induced a pronounced production of
INF-y, whereas a much weaker response was observed for the three Pt compounds or TMA.
These results are consistent with the human data indicating a Type I, IgE-mediated, immediate
hypersensitivity mechanism of action for halogenated Pt salts.
Using the popliteal lymph node assay (PLN), Schuppe et al. (1992, 1997b) evaluated the
sensitizing potencies of Pt compounds. All studies were conducted in the absence of adjuvant,
and Pt compounds were administered as the free compound (e.g., the compounds were not
conjugated to or co-administered with albumin).
Schuppe et al. (1992) evaluated the primary and secondary PLN response, including
T cell-dependence, in a series of experiments. To evaluate the dose-response relationship of the
primary PLN response to (NH4)2PtCl6, groups of six C57BL/6 mice (sex not reported) were
administered a single subcutaneous injection of 2, 9, 45, 90, 180, or 360 nmol (equivalent to 0.9,
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4, 20, 40, 80, or 169 fig) of (NH4)2PtCl6 in saline into one hind footpad; control mice received an
injection of saline. Indices for weight and cell counts of PLNs (derived by comparison of the
response of the injected versus untreated side for each animal) were determined on day 6 after
injection (data presented graphically). Increases in PLN weight and total cell indices w
observed, with statistically significant increases (p < 0.05 or 0.01) in both variables ; ;
doses > 20 fig; maximal increases in weight and cell counts were observed at doses > 40 ug.
Similar results were observed for mice treated with sodium hexachloroplatinate (Na2Pt€l6) (data
were not presented in the study report). Evaluation of the time-course of the primary PLN
response showed that maximal increases in PLN weight and cell count wer iserved 6 days
after injection. In a study on the secondary PLN response, mice were pritiK^ with saline or
80 nmol (equivalent to 82 fig) Na2PtCl6 in saline by subcutaneous injection to one hind footpad
and re-challenged 6 weeks later with saline or 36 nmol (equivalent to 16 (.ig) Na2PtCl6 injected
into the same footpad. The PLN count index in mice primed with Na2PtCl6 and re-challenged
with Na2PtCl6 were significantly increased compared to mice primed with saline and challenged
with the same dose of Na2PtCl6 (data were presented graphically; on day 2,p>0 .005; on day 6,
p > 0.05), indicating a secondary PLN response. The primary PLN response appeared to be
dependent on the presence of T cells. Following e protocol for evaluation of the primary
PLN response as described above, NMRI +/nu (T cell normal) and NMRI nu/nu (T cell deficient)
mice were administered priming doses of 40, 80, or 169 fig (NH4)2PtCl6 in saline or saline. The
PLN cell count index was significant	"		 )f
Schuppe et al. (19S^/ compared the primary PLN response to (NH4)2PtCl6 in the
following st^'*1" of mice: BAI.Cc, DBA/2, C57BL/5, B10.S, C3H/He, and NMRI. Based on
BALC/c mit : < ire highest responders, and B10. S, C3H/He, and NMRI were the lowest
responders. The potency of Pt compounds to induce a primary PLN response was assessed in
;t.-77h- .-f c ^ C57BL/5 and BALC/c mice (Schuppe et al., 1992). In C57BL/5 mice, equimolar
doses (90 nmol) of Na2PtCl„ and (NH4)2PtCl6 produced similar increases in the PLN cell count
index (6.8 ± i .2 and 6.2 ± 1.2 in the Na2PtCl6 and (NH4)2PtCl6 groups, respectively; mean ± SD).
In BALC/c mice, increases in the PLN cell count index were higher for (NHthPtCl,, (9.3 ± 1.6)
than for Na2PtCl„ (5.9 ± 1.0) (statistical significance was not reported). Also in BALC/c mice,
67 nmol cisplatin (the study report stated that higher concentrations were not available) produced
a primary PLN response, with a cell count index of 3.8 ± 0.9 (cw-[Pt(NH3)2Cl2]) was not
assessed in C57BL/5 mice).
Results of the studies by Schuppe et al. (1992) demonstrate that Na2PtClt1, (NH4)2PtCl6,
and cisplatin, in the absence of adjuvant priming, induce an immune response in mice, and
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(NH4)2PtCl6 in T cell normal mice ce
observed in T cell deficient m„„ v_„;a presented graphically).
increases m
weight and cell count indices, all strains mounted a primary PLN response;

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suggest that T cells are required for a response to occur. Furthermore, the degree of response
varies in magnitude across mouse strains.
Schuppe et al. (1997b) further explored the sensitizing properties of different Pt
compounds in groups of 5-6 BALB/c mice. Using the PLN assay as described above (Schuppe
et al., 1992), the potencies of equimolar doses (90 nmol) of Na2PtCl„, N^PtC'U, or potassium
tetrachloroplatinate (K2PtCl4), and of increasing doses (45-900 nmol) of tetraamine Pt dichloride
([Pt(NH3)4]Cl2) to induce a primary PLN response were evaluated on day 6 after
injection. All Pt compounds were dissolved in saline; control mice were admini;...	.inc.
Na2PtCl6, Na2PtCU, and K2PtCl4 induced significant (p < 0.01) increases in the PLN cell count
index compared to saline control (data presented graphically). For mice treated with
[Pt(NH3)4]Cl2, the cell count index was unaffected by treatment, except for a slight increase
(p < 0.05) in mice treated with a 90 nmol dose; however, since no response was observed at
substantially higher (up to 900 nmol) doses, the response to the 90 iiinui uuse was not considered
to be treatment-related by investigators. Phenotyping of PLN cells showed that the majority of
proliferating cells in mice treated with Na2PtCl6 1' ! or K2PtCl4 were CD4 T cells.
Taken together, results of the studies by Schuppe et al. (1997b, 1992) demonstrate that
Na2PtCl6, (NH4)2PtCl6, Na2PtCl4, K2PtCl4, and iv v^ PtfNHshCK], in the absence of adjuvant
priming, induce an immune response in mice; however, [Pt(NH3)4]Cl2 did not exhibit
immunogenic activity. The lack of immune response with [Pt(NH3)4]Cl2 in the PLN assay in
mice is consistent with results '	-;v. miology study by Linnett and Hughes (1999) showing
that no cases of sensitization were observed among 39 workers exposed to [Pt(NH3)4]Cl2 in the
production of automotive <	; ";>:s (study details provided in Section 4.1.2.1.2, Toxicity of
soluble forms ofPt: epidemiological evidence ofPt allergic sensitization). Similar results were
reported by Steinfort et al. (2008) in a prospective study of workers at a catalyst manufacture
plant in Melbourne, Australia, where no cases of positive SPT were reported among workers
with reported exposure to [Pt(NH3)4]Cl2. However, the Linnett and Hughes (1999) and Steinfort
et al. (2008) studies does not include exposure data on the particular Pt compounds to which
--~rh:rs are exposed and workers are instead classified by work area without speciated Pt
¦. ¦¦¦¦¦':Mire data. Results also suggest that the PLN response primarily involves T cells and may
; ; v ; > \ magnitude with the specific mouse strain tested.
Immunoglobulin (IgE) responses to parenteral injections of Pt compounds ([NH4]2PtCl4,
[NH4]2PtCl6, [Pt(NH3)4]Cl2, Cs2Pt[N02]Cl3, K2Pt[CN]4, cw-[Pt(NH3)2Cl2]) have been studied in
the Hooded Lister rat (Murdoch and Pepys, 1986, 1985, 1984a, b).
Murdoch and Pepys (1984a) immunized female rats (6-8 animals per group) with
intraperitoneal injections of a conjugate of Pt with bovine serum albumin (Pt-BSA) or ovalbumin
(Pt-OVA). All animals received an intraperitoneal injection of heat-killed Bacillus pertussis
(1010 bacilli) as adjuvant. The conjugates were formed by mixing BSA or OVA with an
ammonium salt of PtCl4 ([NH4]2PtCl4), which yielded conjugates having a Pt content ranging
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from approximately 1.7 to 9.9 moles Pt/mole protein. An initial dose of 100 ug of each
conjugate was administered, followed by a boost dose of 10 jig of the conjugate. Corresponding
Pt doses of the conjugates (initial 100 ug dose) ranged from 1.5 to 7.6 ug Pt, based on Table 1 of
Murdoch and Pepys (1984a). Following immunization, serum was harvested and tested for
activity in a passive cutaneous anaphylaxis (PCA) test in which female Hooded List.,
received an intradermal injection of serially diluted serum from the immunized rats
24 hours latter by a challenge dose of 1 mg free halogenated Pt salt ([NH4]2PtCl4)
together with Evans blue dye (in 1% in saline), injected into the tail vein. PCA titers
assessed by observation of blueing of the dermal injection site, indicative ^ extras
leakage of the dye from the vascular compartment and increased vascular permeability to
macromolecules. Total serum IgE and Pt-specific serum IgE were determined in immunized
rats. Pt-specific serum IgE was determined using a RAST specific for halogenated Pt salts
([NH4]2PtCl4 conjugated to human serum albumin [HSA-Sephrose]). injections of the free
halogenated Pt salt failed to produce a response in the PC	ions of Pt-BSA or
Pt-OVA conjugates produced a response in the i'CA test wnen tne immunization and challenge
were to homologous conjugates (i.e., Pt conjugated to tne same protein) or to heterogeneous
conjugates (i.e., Pt conjugated to protein differei;; ; i 			 le immunization). The PCA response
appeared to be directed against the Pt moiety in the conjugates based on the following:
(1) immunization with Pt-OVA resulted in a positive PCA response to Pt-BSA or Pt-OVA
challenge, but no response to BSA alone; and (2) immunization with Pt-conjugates, but not with
BSA or OVA alone, resulted in elevation in serum levels of Pt-specific IgE. Furthermore, the
antibody response to Pt-BSA „ VA conjugates showed specificity to the conjugates relative
to free halogenated Pt salt based on the observations that the response to a subsequent challenge
dose of Pt-pr«tem conjugates in the PCA assay was much greater than the response to injected
(NH thPtCLs > a response to the free halogenated Pt salt was not detected in the PCA assay).
Immunization with Pt-conjugates had no effect on total IgE levels in serum. These results
suggest that Lister rats can develop Pt-specific antibodies to injected (intraperitoneal) Pt-BSA or
-OVA conjugates and that the antibody response shows specificity to the Pt moiety of the
irdoch and Pepys (1984b) examined the effect of Pt compounds on sensitization of rats
to OVA. Female Hooded Lister rats (6-8 animals per group) were immunized with
intraperitoneal injections of OVA alone or OVA together with one of the following Pt
compounds (OVA and Pt were injected at different sites to avoid conjugation): (NH4)2PtCl4,
(NH4)2PtCl6, [Pt(NH3)4]Cl2, cw-PtCl2(NH3)2, or Cs2[Pt(N02)Cl3], Doses were 10, 100, or
1,000 ug compound; the corresponding Pt doses for the 10 jig dose of each compound were
approximately: 5.1, 4.4, 5.8. 6.5, or 3.2 ug Pt, respectively. All animals received heat-killed
B. pertussis (1010 bacilli/animal) as adjuvant. Animals received a boost injection of OVA
21 days following the initial immunization. Following the initial and boost immunization, serum
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was harvested and tested for activity in a PCA test in which OVA was the challenge antigen.
Total serum IgE and OVA specific serum IgE (RAST) were determined in immunized rats.
Immunization with OVA together with Pt compounds produced an enhanced response in the
PCA assay, compared to the response that followed immunization with OVA alone. Th
enhanced response was evident after immunization with (NH4)2PtCl4, (NH4)2PtCl6, or
Cs2[Pt(N02)Cl3] and only after the boost injection of OVA. Sensitization was not detected
following immunization with OVA together with [Pt(NH3)4]Cl2. Immunization with
c7s-PtCl2(NH3)2 resulted in reduced antibody response in the PCA test, which v.. , attributed to
observed toxicity in the immunized rats (i.e. weight loss). Immunization witu v> . A together
with (NH4)2PtCl4 or (NH4)2PtCl6 resulted in enhanced serum levels of OVA-specific IgE.
Immunization with Pt compounds had no enhancing effect on total IgE levels in serum. These
results suggest that Lister rats can develop antibodies to injected (:	oneal) OVA and that
this response is enhanced by co-administration of OVA and certain Pt-compounds. The
responses occurred with (NH4)2PtCl4 and (NH4)2PtCl6, and	xtent with
Cs2[Pt(N02)Cl3] (this compound did not produce art enhancement of serum OVA-specific IgE
levels).
Murdoch and Pepys (1986) examined the kinetics of the IgE response to repeated doses
of (NH4)2PtCl4 in animals sensitized to OVA. Female Hooded Lister rats (8 animals per group)
were immunized with intraperitoneal inj ecti< :': ., f OVA alone or OVA together with
(NH4)2PtCl4. Doses were not reported and were noted to have been optimized for an IgE
response, based on previous studies (Murdoch and Pepys, 1984b). OVA was injected on days 1
and 21 (boost), without ad . ;; > i (heat-killed B. pertussis and/or aluminum hydroxide gel). The
Pt compound was injected vday 1) or 3 times/week for 3 weeks. Following immunization,
serum was b'>™»sted and tested for total serum IgE and IgG, and OVA-specific serum IgE
(RAST), am . i vity in a PCA test in which OVA was the challenge antigen. Injection of
adjuvant ale : ';.id no effect on serum total IgE levels. Injection of (NH4)2PtCl4, in the absence
of adjuvant treatment, had no effect on total serum IgE levels. A single injection of (NH4)2PtCl4
together with adjuvant also had no effect in total serum IgE; however, repeated injections of
(NH i.bPtCl4 elevated serum total IgE and OVA-specific IgE. The enhanced IgE response
increased in magnitude with repeated dosing with (NH4)2PtCl4 and declined after cessation of
dosing. Activity on the PCA test correlated (r = 0.892) with serum OVA-specific IgE. These
results show that the enhanced IgE response to injected (intraperitoneal) OVA produced by
(NH4)2PtCl4 increases with repeated dosing and declines after cessation of the exposure.
Murdoch and Pepys (1985) examined cross-reactivity of IgE antibodies produced in
response to immunization with Pt-OVA conjugate to various Pt compounds. Female Hooded
Lister rats (number of animals per group was not reported) were immunized with intraperitoneal
injections of a Pt-OVA conjugate prepared from OVA and (NH4)2PtCl4, together with heat-killed
B. pertussis (1010 bacilli/animal) as adjuvant. The conjugates had a Pt content ranging from 5 to
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8 moles Pt/mole protein. An initial dose of 100 ug of each conjugate was administered, followed
by a boost dose of 10 ug. Following the initial and boost immunization, serum was harvested
and tested for activity in a PCA test in which the challenge dose was either 50 ug of Pt-BSA
conjugate or 50 ug of one of the following Pt compounds: (NH4)2PtCl4, (NH4)2PtCl6,
Cs2[Pt(N02)Cl3], [Pt(NH3)4]Cl2, K2Pt(CN)4, or c7v-PtCl:(NH3>;. The corresponding Pt doses of
the free (i.e., not conjugated) Pt compounds were approximately 26.2, 22.0, 15.9, 29.2, 25.8, or
32.5 ug, respectively. Pt-specific serum IgE (RAST) levels were determined in immunized rats.
Immunization with Pt-OVA resulted in a positive response on the PCA test to a challenge with
Pt-BSA conjugate, (NH4)2PtCl4, or (NH4)2PtCl6, and negative response to a challenge with
Cs2[F>t(N()2)Cls], [Pt(NH3)4]Cl2, K2Pt(CN)4, or c/s-PtCl2(NH3)2. Immunization with Pt-OVA
conjugate resulted in enhanced serum levels of Pt-specific IgE, which cross-reacted with both Pt-
OVA and Pt-BSA conjugate (RAST inhibition). These results suggest that Lister rats can
develop antibodies to injected (intraperitoneal) Pt-OVA conjugate and that this response
sensitizes the rats to both Pt-BSA conjugates as well as free (NH4)2PtCl4 and (NH4)2PtCl„. The
cross-reactivity of the antibodies produced in response to immunization with Pt-OVA is more
pronounced with free (NH4)2PtCl4 and ( NH4)2PtCl(, than with Cs2[Pt(N02)Cl3], [Pt(NH3)4]Cl2,
K2Pt(CN)4, or c7s-PtCl2(NH3)2 (i.e., no reactivity was detected with the latter four Pt-compounds
in this study).
In summary, the studies conducted by Murdoch and Pepys (1986, 1985, 1984a, b) in the
Hooded Lister rat provide evideni ; ; > traperitoneal injection of Pt-compounds, either as
protein-conjugates or as free halogenated Pt salts, can trigger production of IgE-specific
antibodies that sensitize the animal to subsequent exposures to the Pt compounds. Specific
findings from these studies that support this conclusion are as follows:
(1)	Immunization of rats with intraperitoneal doses of Pt-protein conjugates (e.g.,
Pt-OVA, Pt-BSA) results in sensitization to heterologous challenge with Pt-protein
conjugates.
(2)	Antibodies produced in response to immunization with Pt-OVA cross-react with
Pt-BSA, (NH4)2PtCl4, or (NH4)2PtCl„ and to a lesser extent (if at all) to
1 -2[Pt(N02)Cl3], [Pt(NH3)4]Cl2, K2Pt(CN)4, or c«-PtCl2(NH3)2.
nsitization of rats to OVA can be enhanced by injections of the free halogenated Pt
salts (NH4)2PtCl4, (NH4)2PtCl6, or Cs2[Pt(N02)Cl3], and to a lesser extent (if at all) to
[Pt(NH3)4]Cl2, c7s-PtCl2(NH3)2; the enhanced sensitization to OVA that occurs with
(NH4)2PtCl4, (NH4)2PtCl6, or Cs2[Pt(N02)Cl3] is further increased with repeated
doses of the Pt compounds.
(4) The above responses were observed only in animals that received adjuvant and were
more pronounced for the more highly chlorinated Pt compounds examined in these
studies (e.g., [NH4]2PtCl4 or [NH4]2PtCl6) compared to less chlorinate compounds
(e.g., Cs2[Pt(N02)Cl3], [Pt(NH3)4]Cl2 K2Pt[CN]4, cw-PtCl2[NH3]2).
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The lack of sensitization following immunization with OVA together with [Pt(NH3)4]Cl2
is consistent with results of Schuppe et al. (1997b) in mice showing the lack of immune response
with [Pt(NH3)4]Cl2 in the PLN assay and results of the epidemiology study by Linnett and
Hughes (1999) showing that no cases of sensitization were observed among 39 workers ex;,
to [Pt(NH3)4]Cl2 in the production of automotive catalysts (study details provided in
Section 4.1.2.1.2, Toxicity of soluble forms ofPt: epidemiological evidence < , / ;1 :
sensitization).
4.5.1.1.3. In vitro studies: effects on human immune cells in culture. The s; 					 i cts of
several Pt compounds ([NH4]2PtCl6, [NH4]2PtCl4, PtCl4, PtCl;, sodium hexai
[Na2PtI6], and cisplatin) on spontaneous and phytohemagglutin (PHA)-stimuitiioa pivynxvfation of
human peripheral blood mononuclear cells (PBMC; PBiV	: i! >< lymphocytes and
monocytes, including B and T immune cells) and release of sevena uy lumiies, tumor necrosis
factor (TNF)-a, interferon (IFN)-y, and 11 .-5 were evalua	7 M) and high (10"4 M)
concentrations (Di Gioacchino et al., 2004). Low concentrations or txNH4)2PtCl6 and
(NH4)2PtCl4 inhibited both spontaneous and PHA-stimulated PBMC proliferation and low
concentrations of cisplatin inhibited PHA-stimulated proliferation. No effects on spontaneous or
PHA-stimulated proliferation were observed for PtCl4, PtCl2, or Na2PtIt>. TNF-a release was
inhibited only by the high concentration of (NH4)2PtCl6. IFN-y release was inhibited by low and
high concentrations of (NH4)2PtCk and fNH4)2PtCl4 and the high concentration of Na2Ptl6.
IF-5 release was inhibited at the high concentration for (NH4)2PtClt1, (NH4)2PtCl4, and Na2PtI„
and enhanced for the low and		titrations of PtCl4. PtCl2 did not affect cytokine release.
These results indicate the i^i;ovv*ng potency for immune cell responses of the tested Pt
compounds: (NH4)2PtCle > (NH4)2PtCl4 > Na2PtIt, and cisplatin > PtCl4 > PtCl2. Thus, cells
involved in the sensitization response may be directly affected by Pt compounds.
. vitro study of Pt and PGEs was conducted to investigate the effect of PGEs on
antigen presentation by human dendritic cells, and explore the potential role of dendritic cells in
•nerating an allergic response to PGEs (Paolucci et al., 2007). Monocyte-derived human
>'!< idritic cells were obtained from peripheral blood samples from healthy donors and incubated
i der appropriate culture conditions to produce mature and immature dendritic cells. Dendritic
cells were cultured in the presence of 10 iiM concentrations of the following Pt, palladium, and
rhodium compounds: Na2PtCl4-3H20, Na2PtCl,/6H20 , Na2PdCl4, Na2PdClt1-6H2(), RhCl3,
Na3RhClt1- 12FFO. Preliminary experiments were performed on all six PGEs and the
hexachlorinated compounds of Pt, palladium, and rhodium were then used to treat dendritic cells
prior to measuring several markers of dendritic cell activation: expression of cell membrane
differentiation markers (CD80, CD86, and major histocompatibility complex [MHC]-II),
expression of the high affinity receptor Fce-RI, antigen presentation of grass pollen (in co-
cultures of T cells, dendritic cells, and raw grass pollen from individuals allergic to grass pollen),
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and endocytosis. All three PGEs increased expression of CD 86 (a T-cell activator), T^PtCl,,
and Na2PdCl„ increased expression of CD80 (a co-stimulator and T-cell activator), and
Na2PtCl6'6H20 also increased cell surface expression of MHC-II Incubation with Na2PtCl6 and
Na2PdCl„ increased the T-cell proliferation in the presence of grass pollen, suggesting thai both
compounds increase the efficiency of antigen presentation to antigens for existing allergies.
Na2PtCl„ increased endocytosis by mature dendritic cells, but did not affect immature cells. ;
three PGEs also increased the expression of Fce-RI, increased the production of IL-5, and had i
effect on TI .-4 or INF-y. The authors conclude that PGEs have an
dendritic cells that may increase the response to allergens.
In vitro exposure to hexachloroplatinic acid (FFPtCl,,) (0.0	x been shown to
enhance reactive oxygen species (ROS) production in human neut	ired by
lucigenin-enhanced chemiluminescence (Theron et al., 2(	production
from neutrophils or phagocytes in general has been implicated in biuuuiuu nypcnesponsiveness
in some cases of asthma (Barnes, 1989). In the presence of HbPiCU, neutrophils also inactivated
al-proteinase inhibitor (API) (Theron et al., 2004). API is involved m the protection of airways
from infective and inflammatory insult, and reductions m API are associated with bronchitis and
asthma (Hiemstra, 2002; Stockley et al., 2002). * nc ^ itro IhPtC'l,,-induced ROS production
by neutrophils takes place in the absence of traditional markers of neutrophil proinflammatory
reactions such as the generation of eicosanoids and prostanoids, the release of the granule
enzyme elastase, or the mob	. : ! ,2+ from either intracellular or extracellular stores.
Rather than pro-inflammatory, Theron et al. (2004) characterized the effects of FFPtCl,, as pro-
oxidative actions dependent o			itrophil NADPH oxidase and attenuated by inhibitors of
the electron transporter. Siiu^ui pro-oxidative interactions with neutrophils were also found with
palladium, but not with the pt compound, cisplatin, or other PGEs (rhodium and osmium).
4.5.1.2. Insoluble Pt Forms
As reviewed earlier in Section 4.1, insoluble forms of Pt (Pt metal and PK>2) are
generally considered to be inert (ACGIH, 2001; Gebel, 2000; WHO, 2000, 1991). Limited
.ii ; .-live evidence that insoluble Pt compounds are inactive as sensitizing agents is provided by
of the in vitro study by Di Gioacchino et al. (2004), showing that PtCl2 does not have
le effects on human PBMC proliferation or cytokine release. No additional studies on the
potential allergenic effects of inhaled insoluble Pt compounds were identified.
In acute exposure experiments, mice (either 8 weeks or 18 months of age) exposed for
6 hours to ultrafme Pt metal particles at inhaled concentrations of about 110 jig Pt/m3 showed no
inflammatory responses in the lungs (Oberdorster, 2001). Pt metal particles in the test
atmospheres were reported to have count median diameters of approximately 25 nm. When
pretreated with an intratracheal instillation of elastase to induce emphysema, the young mice still
showed no signs of pulmonary inflammation following 6 hours of exposure, but the aged mice
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showed a mild inflammatory response in the lungs (a slight increase in neutrophil count and the
appearance of microscopic lymphocytic infiltrations around the peribronchiolar spaces). No
additional studies regarding the potential irritation effects of inhaled insoluble Pt compounds
were identified.
Although data are lacking regarding the potential of inhaled insoluble Pt compounds to
produce sensitization effects, it is possible that repeated exposure to dusts of Pt metal or Pt
oxides can lead to respiratory irritation, inflammation, or other more serious respiratory lesions,
especially at concentrations that overload respiratory clearance mechanisms, as has been
observed with other relatively insoluble and inert airborne materials (see ; : '= al, 1996;
Oberdorster, 1994). Particle overload, which results from altered macropii^v, clearance of
inhaled particles, is associated with enhanced lung accumulation of particles, pulmonary
inflammation, and epithelial cell proliferation (Tl . ST, 2000). As a result of increased
accumulation, the potential for local adverse effects is enhanced. Thus, for insoluble and poorly
soluble particulate compounds, exposure levels leading to particle overload may result in
increased toxicity. Data on toxicity and clearance of soluble and insoluble compounds of
another metal, nickel, in rodents suggest a role for particle overload in toxicity of insoluble metal
particulates (Hsieh et al., 1999a, b); however, data on potential particle overload for insoluble Pt
compounds are not available (see Section 3.1.2 and 3.2.2 for discussion of available studies).
The relevance of rodent data on particle overload to humans is unclear as rodent species may be
more susceptible than larger mammals and humans to alterations in pulmonary clearance that
result in increased retention of insoluble particles (Snipes, 1996).
4.5.2. Genotoxicity Studk:
Several Pt compounds have been studied for their genotoxic potential, although the
database is limited. The available studies on the genotoxicity of Pt compounds include
comparisons of the activities of Pt compounds in mutation assays with Escherichia colt (Gebel et
al., 1997; Kanematsu et al., 1980; LeCointe et al., 1979), Salmonella typhimurium (Uno and
7, 1993; Kanematsu et al., 1980; LeCointe et al., 1979), Bacillus subtilis (Kanematsu et al.,
1;; Chinese hamster ovary (CHO) cells at the HGPRT locus (Johnson et al., 1980; Taylor et
. i ¦179a) and mouse lymphoma cells at the TK locus (Sandhu, 1981). Also available are
> on micronuclei formation in human lymphocytes (Gebel et al., 1997), meiotic disturbance
in Saccharomyces cerevisiae (Sora et al., 1986), and enhancement of transformation of Syrian
hamster embryo cells by an adenovirus, SA7 (Casto et al., 1979). Results from these studies are
summarized in Table 4-11.
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Table 4-11. Summary of genotoxicity studies of Pt compounds
In vitro gene mutation assays
Test


Concentra-
Results


compound
Test system
Cells/strain
tion
-S9
+S9
Comments
Reference
K2PtCl4
S. typhimurium (reverse
mutations)
TA100
Not specified
+
NP

LeComteetal.,

S. typhimurium (reverse
mutations)
TA98, TA100
0.8-100
nmol/plate
+
+

Uno and
Morita, 1993

E. coli (SOS chrome
test)
PQ37
6-781 (iM
+
NP

Gebel et al„
1997

Bacteriophage 1
(forward mutation to
virulence in E. coli)
/.GY14 in
lysogenic E. coli
GY4854 and
indicator strain
GY3646
Not specified



LeCointe et al.,
1979

S. cerevisiae (meiotic
disturbance disomic or
diploid spores)
DIS13
5-100 ill


;reased
loid only)
Sora et al.,
1986

CHO cells (HGPRT
locus)
CHO

+/-
JNF

Johnson et al,
1980

CHO cells (mutations at
the HGPRT locus)
CHO-S,
auxotropMc for
proline


NP

Taylor et al.,
1979a

Human peripheral
lymphocytes
(micronuclei)
Lymphocyte
5-300 (iM
+
NP

Gebel et al.,
1997
PtCl4
S. typhimurium
TA1535,
TA100, TA98,
TA1537,
TA1538
Not specified
+
NP
+ in TA 98
Kanematsu et
al., 1980

E. coli (reverse
mutations, spot test)
WP2 her try
Not specified
-
NP

Kanematsu et
al., 1980

J7 cnu ccqs chrome
PQ37
8-481 (iM,
+
NP
50%
cytotoxicity
>120 (iM
Gebel et al.,
1997

/• ¦ (rec assay)
H17 (rec+), M45
(rec")
5-500 mM
+
NP
effective
concentration
= ImM
Kanematsu et
al., 1980

•gaster (sex-
sssive lethal
mil unions)
Canton-S males
0.3 mM for
72 hr or
1.5 mM for
48 hr
+
NP
in feeding
solution
Woodruff et
al., 1980

Mouse lymphoma cells
(forward mutation at the
TK locus)
L5178Y
50-100 (iM
+
NP

Sandhu, 1979

Human peripheral
lymphocytes
(micronuclei)
Lymphocyte
10-60 (iM
+
NP

Gebel et al.,
1997

Syrian hamster embryo
cells (enhancement of
transformation by
adenovirus, SA7)
SHE
15-120 (iM
+
NP

Casto et al.,
1979
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Table 4-11. Summary of genotoxicity studies of Pt compounds
In vitro gene mutation assays
Test
compound
Test system
Cells/strain
Concentra-
tion
Results
Comments
i i-rence
-S9
+S9
H2PtCl6
S. typhimurium
TA98, TA100
0.8-100
nmol/plate
-
+
+ with S9 in
TA 98
I. 1
Monta, 1993
B. subtilis (rec assay)
H17 (rec+), M45
(rec")
5-500 mM
+
NP
effective
concentration
10 mM
Kanematsu et
aL, 1980
EyptGg
E. coli (SOS
Cfaromotest)
PQ37
11-367 (iM

NP
50%
cytotoxicity
>92 nM
Gebel et al.,
1997
S. typhimurium
TA97a, TA98,
TA100, TA102
5-500 (ig/plate


»
Hunger et al.,
1996
K2PtBr6
S. typhimurium (reverse
mutations)
TA98, TA100
0.8-100 nmol/
plate



Uno and
Morita, 1993
(NH4)2PtCl6
S. typhimurium
TA1535,
TA100, TA98,
TA1537,
TA1538
Not specified
+
NP
+ in TA98,
others in-
conclusive
Kanematsu et
al., 1980
S. typhimurium
TA97a, TA9!
TA100, TA1U-
_
+
+

Bunger et al.,
1996
B. subtilis (rec assay)
H17 (rec+),
M45 (rec")
5-500 mM
+
NP
effective
concentration
= 100 mM
Kanematsu et
al., 1980
(NH4)2PtCl6
E. coli (reverse
mutations, spot test)
WP2 her try
Not specified
+
NP

Kanematsu et
al., 1980

Not specified
-
NP

Kanematsu et
al., 1980
(NH4)2PtCl4
S. typhimurh ; FA98,
FA102
5-500 (ig/plate
+
+

Bunger et al.,
1996
[Pt(NH3)4]Cl2
S. typhimurium (reverse
mutations)
TA100
Not specified
-
NP

LeCointe et al.,
1979
S. typhimurh
TA98, TA100
0.8-100 nmol/
plate
-
-

Uno and
Morita, 1993
< acteriophage 1
' i brward mutation to
irulence in E. coli)
/.GY14 in
lysogenic E. coli
GY4854 and
indicator strain
GY3646
Not specified

NP

LeCointe et al.,
1979

CHO cells (mutations at
the HGPRT locus)
CHO
0-6,600 (iM
-
NP

Johnson et al.,
1980
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Table 4-11. Summary of genotoxicity studies of Pt compounds


In vitro gene
mutation assays



Test


Concentra-
Results


compound
Test system
Cells/strain
tion
-S9
+S9
Comments
Reference
PtCl2
E. coli (SOS
Chromotest)
PQ37
19-1,213 (iM

NP
50%
cytotoxicity
>606 (iM
1997

Mouse lymphoma cells
(forward mutation at the
TK locus)
L5178Y
50-800 (iM

NP

Sandhu, 1979
Pt(NH3)2
(N02)2
Pt(S04)2
Mouse lymphoma cells
(forward mutation at the
TK locus)
L5178Y; CHO-
S, auxotrophic
for proline
1-20C



Sandhu, 1979

CHO cells (mutations at
the HGPRT locus)

1-50C



Taylor et al.,
1979a
+ = Positive; - = negative/no change; NP = assay not performed
Mutagenic properties of 16 Pt compounds were studied using S. lyphimurium TA98 and
TA100 (Uno and Morita, 1993). Mutagenic activity was found in some Pt compounds, including
Pt(C5H12N2)Cl2, Pt(en)Cl2, [ F (N113 )3 C1 ] - Pt C" Lt, and K2[ PtClj], both in the presence and absence
of S9 mix in TA98 and TA100 strains. When the same compounds were tested using a different
solvent, DMSO, it was found that the" :vere much less mutagenic and less toxic compared to
distilled water as a solvent for both T , -¦> and TA100 strains. Other compounds such as
Ba[Pt(CN)4].4H20, K2[PdCl4], CM-pt(NH.02(NO2)2, K:[R(C:().th].2H:(), [Pt(NH3)4]Cl2, and
K2[Pt(N02).t].H20 did not show significant mutagenicity in either strain with or without S9 mix
(Uno and Morita, 1993). The authors suggest two possibilities for this difference in the result. It
is possible thai " i.e structure of the Pt complex in DMSO is different from that in distilled water.
Displacement of the chloride ligant with DMSO can occur when they are dissolved in DMSO,
giving ionic sy^ies that react less strongly with bacteria. It is also possible that the bacterial
3ptibility is changed in the presence of a solvent quantity of DMSO.
	• halogenated Pt salts [K2PtCl6, (NH4)2PtCl4, (NH4)2PtCl6] were evaluated for
using S. typhimurium strains (TA97a, TA98, TA100, and TA102) both in the
F,v.,v™v «..« absence of metabolic activation. All three compounds caused higher rates of
rtvv-ioe mutation in all of the tester strains, but (NH4)2PtCl4 was the most potent among the three
compounds tested. Cytotoxicity of these Pt compounds was analyzed using mouse fibroblasts
(L929) and human embryonic lung (L132) cell lines. Cytotoxic effects of the three Pt
complexes, measured as ED50, occurred at test concentration of 0.2 niM (Bunger et al., 1996).
Gebel et al. (1997) compared several Pt compounds in the bacterial SOS chromotest
using E. colt PQ37 and have shown the following order for the induction of P-galactosidase
activity, an index for DNA repair mechanisms induced in response to DNA damage (induction
factor values [fold increases from controls] are noted in parentheses): PtCl4 (4.54) > K2PtCl4
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(3.63) > PtCl: (1.42) > K2PtCl6 (1.01). The mechanism of mutagenic activity is believed to occur
through the reaction with DNA by displacement of both chlorine atoms and subsequent chelate
formation between N7(G) and 06(G) sites. Gebel et al. (1997) also performed micronucleus
(MN) assay in human peripheral lymphocytes from healthy donors aged 25-35 years using
various Pt compounds. A significant increase in number of MN was obtained in PtCU exposed
cells to different concentrations (0-60 iiM). A significant increase in MN was also observe : ; =
K2PtCl4 compound at higher dose (150 iiM) tested. The highest dose (300 iiM) was toxic. No
significant increase in MN was observed in two other Pt compounds t ' ' r\ and PtCl;).
The order of potency for these compounds with respect to the inductk	¦;: uclei in
primary cultures of human peripheral lymphocytes (lowest effective concentrations are noted in
parentheses): PtCl.t (20 iiM) K.;PtCU (150 iiM). As mer	:	tCl2 nor
K;Pt('*l,, induced micronuclei in these assays (Gebel et <
Male Drosophila melanogaster were treated by feeding 0.3 or t. j mM PtCU (n = 33
versus n = 29 in controls) in a 1% glucose solution for <	ours, respectively, with
an objective of identifying recessive sex-linked lethal mutations as a result of exposure to PtCl4
(Woodruff et al., 1980). Both 0.3 and 1.5 mM treatments with PtCU induced significant
increases in recessive lethal mutations compared to control frequencies. PtCU was also tested for
induction of mutation (TK locus) in mouse lymphoma cells (Sandhu, 1979). PtCU induced
mutation frequencies at doses ranging from 25 to 150 iiM that were significantly greater than the
spontaneous mutation frequencies'
Pt compounds showing mutagenic . : ^ with the available data: PtCU, K2PtCU
Results from various genotoxicity assays support the findings by Gebel et al. (1997) that
PtCl4 and K2PtCU have genotoxic potential. PtCU induced mutations in mouse lymphoma cells
(Sandhu, 1979), in />. melanogaster (Woodruff et al., 1980), and in S. typhimurium strain TA98,
but not in strains TA100, TA1535, TA1537, or TA1538 (Kanematsu et al., 1980). PtCU also
induced micronuclei in human peripheral lymphocytes (Gebel et al., 1997). PtCU enhanced
transformation of Syrian hamster embryo cells by the adenovirus, SA7 (Casto et al., 1979), and
produced positive results in the B. subtilis rec assay at lower concentrations than H2PtCU or
-j i ; ;PtCl6 (Kanematsu et al., 1980), but did not induce mutations in E. coli strain WP2 her try
-.m;' riatsu et al., 1980). K2PtCU induced diploid spores in S. cerevisiae strain DIS13 (Sora et
al., iy86) and mutations in S. typhimurium strains TA98 and TA100 (Uno and Morita, 1993;
LeCointe et al., 1979), but did not consistently induce mutations at the HGPRT locus in CHO
cells (Johnson et al., 1980; Taylor et al., 1979a) or in the bacteriophage 1 assay (LeCointe et al.,
1979). In addition, Pt(SO.i): may also have some genotoxic potential, as evidenced by the
finding that it induced mutations in CHO cells (Taylor et al., 1979a). However, this conclusion
is based on only one study that is currently available.
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Pt compounds without significant mutagenic activity: PtCh, H2P1CI6, [Pt(NH3)4]Ch, K2PtBr^,
K2PtCl6
Studies conducted on PtCl; and tetraamine Pt dichloride ([Pt(NH3)4]Cl2) consistently
have shown no significant genotoxic activities. PtCl2 did not induce mutations at the TK us in
mouse lymphoma cells (Sandhu, 1979) or at the HGPRT locus in CHO cells (Taylor et al.,
1979a). [Pt(NH3)4]Cl2 did not induce HGPRT mutations in CHO cells (Johnson et al., 1980),
reverse mutations in S. typhimurium strains TA 98 or TA100 (Uno and Morita, 1993; LeCointe
et al., 1979), or mutations in the bacteriophage 1 assay (LeCointe et al., 1 ;; , /ailable data on
most chloroplatinate compounds present little evidence of genotoxicity p<	.;nd, in some
cases, present conflicting evidence from the limited available studies. H2 , ; 1 not
consistently induce mutations in E. coli strain WP2 her try (Kanematsu ul. .u., . 50) or in
several strains of S. typhimurium (Uno and Morita, 1993; Kanematsu et al, 1980), but did
produce positive results in the B. subtilis rec assay (Kane ;m et al, 1980). (NH4)2PtCl6
induced mutations in E. coli strain WP2 her try (Kanenun .« v. ;.H., 1980) and S. typhimurium
strain TA98, but not in strains TA100, TA1535, TA1537, or TA1538 (Kanematsu et al., 1980).
(NH4)2PtCl6 produced positive results in the . btilis rec assay at a concentration that was 100-
fold higher than the lowest effective concentiauun ibr i'tCl4 (Kanematsu et al., 1980).
(NH4)2PtCl6 and (NH4)2PtCl4 induced mutations m o. typhimurium strains TA97a, TA98,
TA100, and TA102 (Bunger et al., 1996). K2PtCle did not induce mutations at the HGPRT locus
in CHO cells (Taylor et al., 1979a). K;PtCl,, did, however, induce mutations in S. typhimurium
strains TA97a, TA98, TA100, and TA102 (Bunger et al., 1996). K2PtBr6 (a hexabromoplatinate
salt) did not induce mutati: 'i typhimurium strains TA 98 or TA100 (Uno and Morita,
1993), but no other genoto a. < lata were found for this compound.
A laree database exists with strong evidence for genotoxic potential of cisplatin and other
anticancer P. . ipounds. Because they are not environmentally relevant compounds, the studies
related to gt :? dc potential of cisplatin and other anticancer Pt compounds are not discussed in
this toxicological review.
In summary, several Pt compounds have been tested for their mutagenic activity and
genotoxic potential. Limited data are available on mutagenicity and genotoxicity of soluble or
insoluble Pt compounds. Soluble Pt compounds such as PtCl4 and K2PtCl4 have yielded positive
results for gene mutation and other genotoxic battery of assays and appear to have mutagenic
activity. However, other soluble Pt compounds such as H2PtCl6, [Pt(NH3)4]Cl2, K2PtBr6, and
K2PtCl„, and insoluble Pt compounds such as PtCl2 have yielded conflicting results from
different studies or negative results with no significant mutagenic activity. It is important to note
that few studies have been performed for each compound (as few as one study per compound).
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4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS
4.6.1. Oral
Information on the noncancer health effects in humans following acute-, short-term-,
subchronic-, or chronic-duration oral exposure to Pt or Pt compounds is limited to a single r. ¦
report of intentional ingestion of a photographic solution containing 600 mg of potassium
chloroplatinite by a 31-year-old man (Woolf and Ebert, 1991). Reported adverse effect
acute oliguric renal failure, metabolic acidosis, fever, muscle cramps, gastroc
rhabomyolysis. Clinical findings from this single case report suggest that ad u
kidney, muscle, and the GI tract are potential outcomes of acute toxicity of p- ;: ,
chloroplatinite. As discussed below, additional information on the
compounds is provided in the clinical literature on Pt anticancer a;
No chronic exposure animal studies have been identi
reported that have comprehensively examined histopathological, b
endpoints of oral exposure to Pt or Pt compounds. Available studi
target organ for soluble and insoluble Pt comp
insufficient to fully characterize toxicity outo
al. (1984) observed epithelial swelling in
administration of 25 mg/kg fine powde:
however, it is unclear if the swelling was as;
s. uiu/nvi
ty of Pt
Although additional data on pot
intraperitoneal LD50 values
death due to renal failure an
etal., 1976). In short-ter
by 8% in rats exposed >3
0-day studies have been
emical, and clinical
dentify the kidney as a
hough the available information is
s or dose-response relationships. Roshchin et
convoluted tubules in rats following acute oral
up metals (Pt and palladium; 1-5 urn diameter);
with one or the other metals, or both,
ts of acute oral exposure are not available, rat
for hexachloroplatinic acid were associated with
zing renal tubular lesions throughout the renal cortex (Ward
are studies, relative kidney weight was significantly increased
PtCl4 in drinking water for 29 days (approximately 44.1 mg
Pt/kg-day), but no effects on kidney weight were observed in rats exposed to 0.54 niM PtCU in
drinking water for up to 29 days (reported data inadequate to estimate daily dose) or to 1.63 niM
PK SO.vh in drinking water for 8-9 days (reported data inadequate to estimate daily dose;
i - )ok et al, 1975). Decreased renal function, as indicated by increased plasma creatinine
concentration, was observed in rats exposed to 50 mg Pt per kg diet as PtCU (equivalent to
;imately 6 mg Pt/kg-day) for 4 weeks; no information regarding other measures of renal
in or potential histopathological changes to the kidney were reported (Reichlmayr-Lais et
al, 1992).
The above observations of outcomes indicative of nephrotoxicity are consistent with
toxicokinetic studies on soluble and insoluble environmentally relevant Pt compounds and the
clinical literature on Pt anticancer agents. Results of toxicokinetic studies in experimental
animals show that the highest tissue concentration is reached in the kidney following oral
exposure to soluble [Pt(SO.t): and PtCU] or insoluble [PtCU and Pt metal] Pt compounds (Artelt
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et al., 1999a; Reichlmayr-Lais et al., 1992; Massaro et al., 1981; Lown et al., 1980; Holbrook et
al., 1975; Moore et al., 1975a, b; Yoakum et al., 1975) (Section 3.2.1).
Other adverse effects reported for acute and subchronic oral exposure to environmentally
relevant Pt compounds include decreased activity (exploration and rearing) (Lown et al., : <>0),
hypokinesia, piloerection, diarrhea, convulsions, labored respiration, cyanosis (Degussa, 1989, as
cited in WHO, 1991), reduced body weight gain (Holbrook et al., 1975), decreased prothrombin
time (magnitude of response not reported) (Roshchin et al., 1984), increased as well as decreased
serum levels of urea, and decreased P-lipoproteins (magnitude of response not reported)
(Roshchin et al., 1984). However, these effects are nonspecific and do not lead to the
identification of other potential target organs. Available information on endpoints other than
hypersensitivity is insufficient to evaluate whether the acute and subchronic oral toxicity profiles
(e.g., effects or potency) differ between soluble and insoluble Pt compounds.
No studies investigating the reproductive effects c	e to Pt or Pt compounds
in experimental animals were identified. The available developmental studies are inadequate to
characterize potential effects since dams were not exposed ror xne enure gestational period and
comprehensive developmental endpoints (e.g., external, skeletal, or visceral malformations) were
not examined (D'Agostino et al., 1984; Massaro et al., 1981). However, based on a reduction in
fetal weight and reduced neonate activity, results indicate that oral exposure of mice to Pt(SO.t):
is toxic to the developing fetus. Insufficient information is available to describe a dose-response
relationship.
4.6.2. Inhalation
4.6.2.1. Sensitization Effi
Allergic sensitization to Pt compounds has long been recognized as an occupational
hazard for halogenated Pt salts and was first reported in photographic studio workers by Karasek
and Karasek (1911). As reviewed previously (Section 4.1.2, Studies in Humans—Epidemiology,
Case Reports, and Clinical Controls, Inhalation), numerous case reports and epidemiological
~"tt demonstrate that occupational exposure to Pt compounds produces allergic sensitization
' : ;i'r!.e subjects. Evidence suggests that halogenated Pt salts are responsible for allergic
: zation rather than insoluble forms of Pt, although data are not always available to identify
lual Pt compounds. Effects associated with allergic sensitization, have been reported in
workers exposed to Pt in several types of work environments, including photographic studios
(halogenated Pt salts), anode production (applying halogenated Pt salts by brush to anodes),
refinement of Pt (halogenated Pt salts), and production of Pt catalysts (involving halogenated Pt
salts).
WHO (2000) lists the following range of effects following occupational exposure to
halogenated Pt salts: allergic asthma (an inflammatory disorder of the airways that results in
shortness of breath), rhinitis (runny nose and sneezing), cough, wheeze, dyspnoea (or difficulty
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breathing) and cyanosis (bluish skin due to insufficient oxygen in blood) characteristic of severe
asthma, watering of the eyes, itching, urticaria (swollen itching skin), and contact dermatitis
(itching skin eruptions). Among the various effects characteristic of Pt-specific allergic
sensitization, five main effects (asthma, rhinitis, conjunctivitis, urticaria, and dermatitis) are
reported in numerous studies that identify health effects in workers exposed to halogenated Pt
salts (Cristaudo et al., 2005; WHO, 2000, 1991; Merget, 2000; Merget et al., 2000, 1999, 1988;
Calverley et al., 1999, 1995; Bolm-Audorff et al., 1992; Baker et al., 1990; Pepys, 1984; Pepys et
al, 1972; Marshall, 1952; Hunter et al, 1945).
Individuals with halogenated Pt-salt allergic sensitization show pi ¦;.	derate
or severe asthma with continued exposure (Merget et al., 1999). For halog,	and
other sensitizers, effects of work-related allergic sensitization may be severe and disabling
(Friedman-Jimenez et al., 2000). Severe cases of allergic sensitization to halogenated Pt salts
include workers with bluish skin due to insufficient oxygen in blood, feeble pulse, and extreme
difficulty breathing requiring the subject to remain upright to breath (Roberts, 1951).
Halogenated Pt salt allergy is characterized by .. ;;¦
-------
human health hazard from occupational exposure to airborne halogenated Pt compounds (WHO,
2000, 1991). Several epidemiologic studies have found increased prevalences of workers with
allergic sensitization in chloroplatinate-contaminated workplaces with estimated air
concentrations <2 ug soluble Pt/m3 (Merget et al., 2000; Linnett and Hughes, 1999; Bolm-
Audorff et al., 1992; Baker et al., 1990). Reported air concentrations of soluble Pt cor
associated with cases of halogenated Pt salt allergy are summarized in Table 4-12. The Bol
Audorff et al. (1992) study did not include sufficient detail in the exposure measurements t»..
estimate air concentrations for the three exposure categories in the study. The Linnett and
Hughes (1999) study did not characterize the Pt exposure beyond soluble Pt. Although no Pt
speciation data were provided to substantiate the form of Pt present,
divided worker exposure into three categories by workspace: chloro
exposure to chloroplatinates and tetraamine Pt dichloride, and tetrai
No information is provided regarding the chemical species present
Pt beyond the soluble Pt reported in Merget et al. (2000) or the Pt s,
is presented as soluble under the assumption that Pt salt concentrations reported were soluble Pt.
See Section 4.1.2.1.2, Toxicity of Soluble Forms of Pt: Epidemiologic Evidence of Pt Allergic
Sensitization, for more detailed st
uglics (1999)
e, mixed
^ Pt di chloride alone,
er characterization of
in Baker et al. (1990) that
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Table 4-12. Summary of human epidemiology studies of allergic sensitization to Pt
Reference
Study description
Outcomes
Baker etal., 1990
Design: cross-sectional
Subjects: current workers (n = 107, 92% male) at a
precious metals secondary refinery and former
workers (n = 29) who were terminated from work
because of respiratory tract symptoms between the
period 1971-1979
Outcome measure: SPT (Na2PtCl6)
Exposures: stationary air monitors (8-hr TWA,
collected 1977-1979; method and LOD not reported);
exposure measurements not reported for all work areas
(e.g., stores)
Prevalence was 0 and 11% in areas that had air concentrations of soluble Pt of 0.6 or
0.4 |xg/m3, respectively, and combined sensitization data were reported for some areas that do
not distinguish which exposure data applies to members of that combined group:
Work area
Air (GM)
(fig soluble Pt/m3 )
Prevalence of
sensitization
Refinery, tray area
27.1
2/3 (67%)
Refinery
10.7
2/14 (14%)
Warehouse
8.6
1/3 (33%)
Stores
ND
Recovery
5.3
1/15 (7%)
Recovery, sampling
2.7
Residue
0.5
Manager/office
0.6
0/15 (0%)
Analytical laboratories
0.4
2/19(11%)
Linnett and Hughes,
1999
Design: retrospective
Subjects: workers (CPOs) at a precious metal
secondary refinery (n = 340, 96% male) employed
during the period 1976-1995
Outcome measure: SPT (Na2PtCl6, [NI1 i|2PtCl„.
Na2PtCl4, [Pt(NH3)4]Cl2) (compounds used in the SPT
differed by year)
Exposures: personal air monitors, analyzed for Pt by
electrothermal AAS (LOI) not reported), collected
1989-1991
Prevalence was 51%) in areas that had air concentrations of soluble Pt <0.5 jxg/m3 in 88%o of
personal air samples (335/380 sampled 1989-1991):
Work area/Pt exposure
Air
(Hg soluble Pt/m3 )
Prevalence of
sensitization
PGM refinery/H2PtCl6
<0.5 (88%)
>2 (2%)
106/170 (51%)
tetraamine Pt dichloride
laboratory/H2PtCl6,[Pt(NH3)4]Cl2
<0.5 (52%)
>2 (28%)
5/31 (16%)
Catalyst production/[Pt(NH3)4]Cl2
<0.5 (61%)
0/39 (0%)
Merget et al., 2000
Design: prospective
Subjects: workers precious metal refinery (n = 275,
96% male) employed during the period 1989-1995
Outcome measure: SP T (I I2PtCl6)
Exposures: Stationary air monitors (median 12-17 hr
TWA) or personal air samples (TWA), analyzed for Pt
bv ICP-MS (LOD 0.025 ng soluble Pt/m3) or AAS
(LOI) 0.13 ng soluble Pt/m3) collected in 1992 and
1993
Prevalence was 11%> in high-exposure group that had median air concentrations of soluble Pt
of 0.177 (xg/m3 (personal, sampled 1993) and 0.014 (xg/m3 (stationary, sampled 1992-1993):
Exposure category
Air (median)
(fig soluble Pt/m3 )
Prevalence of
sensitization
High
0.014 -0.037 (stationary)
0.177 (personal)
13/115 (11%)
Low
0.0004-0.0066
(stationary)
0/111 (0%)
No exposure
0.00005
0/48 (0%)
AAS = atomic absorption spectrometry; CPO = chemical process operator; GM = geometric mean; ICP-MS = inductively coupled plasma/mass spectrometry; LOD = limit of
detection; PGM = platinum group metals; TWA = time weighted average
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The allergenic activity of halogenated Pt salts is supported by three inhalation exposure
studies in primates and a larger number of dermal and parenteral exposure studies in
experimental animals. The results of the three available animal studies of inhalation exposure to
Pt (Biagini et al., 1986, 1985b, 1983) support the possibility that co-exposure to ozone may
promote the development of allergic sensitization to halogenated Pt salts. As reviewed in
Section 4.5.1 (Sensitization Studies), Biagini et al. (1986) reported sensitization in 1/8 monl . /
following subchronic exposure to inhaled hexachloroplatinate alone and in 4/8 monkeys ex, ,¦.
to hexachloroplatinate plus ozone, compared to 0/7 in those receiving ozone alone. Studies
assessing the potential sensitizing effects of inhaled hexachloroplatinate in monkeys were
conducted in a small number of animals, thus limiting the power to detect sensitization.
Furthermore, the length of the latency period to develop sensitization to hexachloroplatinate in
monkeys has not been determined; therefore, it is unclear how the exposure duration may have
affected response rate. However, even with these limitations, Biagini et al. (1986) detected
sensitization in 1/8 monkeys exposed to hexachloroplatinate by inhalation for 12 weeks. A low
response rate is consistent with the characteristics; of a Type I allergic response in humans, in
which only a fraction of exposed individuals are expected to become sensitized (see Section
4.6.3.1, Mode of Action Information, Sensitization). Dermal application of hexachloroplatinate
to mice induced dermal hypersensitivity and a lymphocyte secretion profile of cytokines
consistent with an allergic response (Dearman et al., 1998; Schuppe et al., 1997a) and parenteral
exposure of rats and mice to hexachloroolatinate induced sensitization (Schuppe et al., 1997b,
1992; Murdoch and Pepys, 1986, 198 ; 84a, b). Results of the Schuppe et al. (1997b) study in
mice and the Murdoch and Pepys (1985, 1984b) studies in rats showing that tetraamine Pt
dichloride ([Pt(NH3)4]Cl2) did not exhibit immunogenic activity are consistent with results of the
epidemiology study by Linnett and Hughes (1999) showing that no cases of sensitization were
observed among 39 workers exposed to [Pt(NH3)4]Cl2 in the production of automotive catalysts.
Similar results were reported by Stein foil et al. (2008) in a prospective study of workers at a
catalyst manufacture plant in Melbourne, Australia, where no cases of positive SPT were
reported among workers with reported exposure to [Pt(NH3)4]Cl2. However, the Linnett and
1999) and Stein foil et al. (2008) studies does not include exposure data on the particular
compounds to which workers are exposed and workers are instead classified by work area
without speciated Pt exposure data. Although available data are inadequate to characterize the
exposure level-response relationship for induction of halogenated Pt salt allergy in animals
exposed by inhalation, results provide evidence to support the numerous reports of allergic
sensitization to halogenated Pt salts in groups of occupationally exposed workers.
The allergenic activity of Pt is compound-dependent, since sensitization effects appear to
be restricted to the halogenated Pt salts and there is no evidence of allergic sensitization
following exposure to insoluble Pt compounds. Data suggest that sensitization to the
halogenated Pt salts may be related to the halogen-ligands coordinated to Pt and the negative
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charge of these complexes (Nischwitz et al., 2004; Ravindra et al., 2004; Rosner and Merget,
2000; Cleare et al., 1976). The reactivity of these Pt coordinated halogen-ligands with proteins is
important in the generation of Pt-specific immune response because low molecular weight
chemicals such as Pt must act as haptens by binding with larger endogenous substances bef u
they can generate an allergic response (see Sections 4.6.3.1.1-3 for a detailed description o:<
haptens and the Type I allergic response). Support for the importance of this reactivity of I;
coordinated halogen-ligands is provided by evidence that suggests tetraamine Pt dichloride :;
not cause Pt-specific allergic sensitization. Results of the retrospective occupational exposure
study by Linnett and Hughes (1999) show that exposure to tetraamine Pt dichloride alone was
not associated with sensitization in workers, whereas mixed exposure to tetra ; < - e Pt dichloride
and halogenated Pt salts (chloroplatinates) was associated with allergic sensiu^uon. Halide is
present as an ion in tetraamine Pt dichloride ([Pt(NH3)4]Cl2) and not a ligand coordinated to Pt;
therefore, [Pt(NH3)4]Cl2 is a halogenated complex, not a halogenated Pt salt (Linnett and
Hughes, 1999; Cleare et al., 1976). The Pt in [Pt(NH3)4]Cl2 is bonded to nitrogen and ligand
substitution necessary to react with proteins is extremely slow and may not take place on a
biologically relevant timescale (Cleare et al., 1976). SPT results in sensitized Pt refinery
workers showed that activity in the SPT, or inflammation in individuals already sensitized to
halogenated Pt salts, was directly related to the number of chlorine atoms in a series of
halogenated Pt salts, with the highest activity ¦:> ¦. , IgE-mediated inflammation) associated with
ammonium hexachloroplatinate and ammonium tetrachloroplatinate (Cleare et al., 1976).
Several soluble Pt compounds that were not halogenated Pt salts, including tetraamine Pt
dichloride, yielded negative SPT results. Results of the Schuppe et al. (1997b) study in mice and
the Murdoch and Pepys (1^„, . -,84b) studies in rats showing that tetraamine Pt dichloride did
not exhibit immunogenic activity provide supporting evidence for the findings of Linnett and
Hughes (1999) and Cleare et al. (1976). Tetraamine Pt dichloride doesn't show any strong
evidence of being a sensitizer. Data from Cleare et al. (1976) also show that non-halogenated
soluble Pt compounds such as K;PtCNO;)4 were negative in the SPT. Limited evidence also
)ports the lack of allergenic potential of insoluble Pt compounds. Hunter et al. (1945) reported
xupational asthma was not observed in workers primarily exposed through processes that
involved very heavy exposure to airborne, insoluble, Pt metal. Furthermore, results of the in
vitro study by Di Gioacchino et al. (2004) indicate that insoluble PtCl; did not have immune
effects (proliferation or cytokine release from on isolated human PBMCs), whereas soluble
halogenated Pt salts demonstrated immune activity in this model.
4.6.2.2. Other Adverse Effects (Respiratory Irritation, Nephrotoxicity, Neurotoxicity,
Ototoxicity)
Respiratory Irritation. Inhalation exposure to insoluble Pt compounds has the potential
to produce respiratory irritation and/or inflammation. Respiratory irritant or inflammatory
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activity from chronic inhalation exposure to insoluble Pt forms is supported by the following
observations: (1) pulmonary inflammation in aged emphysematous rats acutely exposed to
ultrafine Pt particles (Oberddrster, 2001), and (2) a correlation between Pt concentrations in
nasal lavage fluid and markers of nasal inflammation (increased neutrophils and epithelial cells)
in a group of children (Schins et al., 2004). Although the Schins et al. (2004) study suppofl:
potential for Pt to produce respiratory irritation or inflammation, a link between concentrati ¦-.: n
the nasal lavage fluid and air concentrations of Pt was not demonstrated, and corrc
findings of the correlation between Pt concentrations in nasal lava
of nasal inflammation are not available.
Acute exposure to halogenated Pt salts has been shown
airway. Using a primate animal model, Biagini et al. (1985b) :
exposure to 'Na;Pt('*l,, altered pulmonary function, producing pciip
constriction (see Section 4.4.2 for complete study details). Since 1
animals with no prior exposure to 'Na;Pt('*l,, or any other Pt o
that Na2PtCl6 can produce direct effects on the
sensitization to Pt. Furthermore, the authors o
eased markers
luce direct effects on the
i that acute inhalation
i\ and central airway
study was performed in
, results provide evidence
me absence of IgE-mediated
lucie t the response was not indicative of
irritation because respiratory rate was not affected by treatment.
Nephrotoxicity, Neurotoxicity, and Ototoxicity. As summarized in Section 4.6.1.
(Synthesis of Major Noncancer Effects, Oral), oral exposure of animals to soluble and insoluble
Pt compounds and the clinical exoerience with Pt anticancer drugs identify the kidney as a
potential target organ for toxicity of Pt compounds. Other adverse effects commonly associated
with parenteral adniinistra : . . . acer drug include neurotoxicity and ototoxicity (see
Section 4.4.3, Drug Studie.,,. However, occupational exposure studies and case reports do not
identify nephrotoxicity, neurotoxicity, or ototoxicity as adverse effects of inhalation exposure to
soluble or insoluble Pt compounds. Furthermore, no evidence for effects (other than
sensitization) was reported in short-term inhalation studies in animals, although comprehensive
toxicity endpomts (e.g., gross pathology, histopathology, biochemistry, hematology, signs of
ere not evaluated and no routine 90-day or chronic toxicity studies of soluble or
impounds are available other than studies of the Pt anticancer drugs discussed in
... .... Mode of Action Information
4.6.3.1. Sensitization
4.6.3.1.1. Type I allergic responses. The symptoms and time-course of the hypersensitivity
response to halogenated Pt salts are typical of an IgE-mediated, Type I allergic reaction.
However, the possibility that a second, non-IgE-mediated mechanism, is responsible for some
cases of allergic sensitization to halogenated Pt salts is suggested by several lines of evidence
including pulmonary effects of Pt compounds in naive monkeys (Biagini et al., 1985b) and the
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failure of skin prick testing to identify all workers displaying symptoms of allergic sensitization
to halogenated Pt salts (see Section 4.6.3.1.4 Utility of the SPT as an endpoint for further
discussion of non-Type I mechanisms). Although immune-mediated hypersensitivity reactions
are not completely understood, the following general scheme of Type I reactions is well accepted
(Descotes, 2004; Goldsby et al., 2003b). Upon initial contact with an allergen, B lymphocytes
produce specific antibodies, probably of the IgG isotype. The B lymphocytes undergo class;
switching to produce IgE antibodies of the same specificity. Antibodies of the IgE isotype can
bind to high affinity receptors on membrane surfaces of mast cells and basophils thr„^u the Fc
portion of the antibody. Mast cells and basophils with membrane-bound IgE are considered to
be sensitized. Upon subsequent exposure to the same antigen, although not necessarily the next
exposure, antigen binds to the Fab portion of the antibody on sensitized cells, triggering cellular
degranulation. Symptoms of Type I hypersensitivity reactions (e.g., asthma, rhinitis, urticaria,
conjunctivitis, dermatitis, and anaphylaxis) are caused by degranulation products, including
histamine, leukotrienes, prostaglandins, and proteases, and may be localized or systemic,
depending upon the extent of mediator release. "	; xiiators released by degranulation
act quickly to produce effects, Type I allergic	ermed "immediate hypersensitivity
reactions", even though the symptom-free latency period after initial antigen exposure may last
for several years.
Type I hypersensitivity reactions can be diagnosed through skin prick testing or
determination of serum levels of Pt antigen-specific IgE by RAST testing. Detailed information
on the use of the SPT in the diagnosis of Type I hypersensitivity reactions to Pt compounds is
provided in Section 4.1.2.1 1 : deity of soluble forms of Pt: diagnosis of Pt allergic
sensitization) and Section .. ^A .4 (Utility of the SPT as an endpoint to identify Pt-specific
sensitization). The RAST test appears to be less sensitive than the SPT in the clinical diagnosis
of Pt IgE-mediated allergy. Due to the high affinity of Pt compounds to IgE antibodies, a high
degree of non-specific binding interferes with detection of Pt-specific antibodies (Merget, 2000;
Biagini et al, 1985a). Thus, although Pt-specific IgE antibodies have been identified by RAST
"'-u-~is in skin test positive workers (Murdoch et al., 1986; Biagini et al., 1985a; Cromwell et
al., 1979), RAST test results are not considered sensitive enough for individual diagnosis of
hd:-mediated hypersensitivity to Pt compounds.
Symptoms of allergic sensitization (asthma, rhinitis, conjunctivitis, urticaria, and
dermatitis) and the time-to-onset of effects (e.g., symptom-free latency period) in exposed
workers are consistent with the effects and time-course observed for a Type I allergic reaction
(Section 4.1.2, Studies in Humans—Epidemiology, Case Reports, Clinical Controls—Inhalation).
The clinical presentation of halogenated Pt salt sensitization meets the following criteria
for a Type I allergic response: (1) symptoms occur only after a symptom-free latency period;
(2) only a fraction of exposed subjects become sensitized; (3) sensitivity increases over time and
sensitized individuals react to low exposure levels; and (4) SPTs using halogenated Pt salts (e.g.,
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[NH.t]:PtCl„ and Na:PtCl„) as the test chemical on atopic and non atopic controls yield negative
results (WHO, 1991; Rosner and Merget, 1990).
(1) Symptoms occur only after a symptom-free latency period: Data from the
occupational studies suggests that sensitization can develop over an exposu	i
of several months to over 13 years (Cristaudo et al., 2005; Merget et al., 20'	f-
Heimsoth et al., 2000; Linnet and Hughes, 1999; Bolm-Audorff et al.,
et al., 1988). Merget (2000) states that most cases of allergic sensitiza
halogenated Pt salts develop within several years of exposure. How eve
periods less than 1 month have also been reported; a latency period of 1
reported in an abstract by Dally et al. (1980), and a 17-day latenc
reported by Pepys et al. (1979).
(2)	Only a fraction of exposed subjects become sensitized: Early occupational studies of
allergic sensitization to halogenated Pt salts in Pt refineries report prevalence of
sensitization as high as 57% (Hunter et al., 1945) and 73% (Roberts, 1951) based on
symptoms of sensitization. More recent studies that used positive SPT to halogenated
Pt-salts to determine sensitization to halogenated Pt-salts have reported sensitization
prevalences between 12.4 and 38.5% (Brooks et al., 1990 reported 14% in a U.S.
refinery; Murdoch et al., 1986 reported 12.4% in a South African refinery; Merget et
al., 1988 reported 38.5% in a German refinery; Bolm-Audorff et al., 1992 reported
18.7% in a German refinery).
(3)	Sensitivity increases over time and sensitized individuals react to low exposure levels:
Data on the health effects of chronic Pt exposure in workers following the
development of Pt allergic sensitization and the potential for increased sensitivity
over time is complicated by the practice of medically terminating or transferring
workers to areas with lower Pt exposure (e.g., Merget et al., 2001, 2000; Calverley et
al., 1995; Brooks et al., 1990). Individuals with halogenated Pt-salt allergic
sensitization show a progression of symptom severe asthma with continued exposure
(Merget et al., 1999; Hunter et al., 1945). Most occupational studies show that
sensitized individuals react to low exposure levels and the results of the SPT provide
the best quantitative data of the increased sensitivity of workers sensitized to
ed Pt salts. Brooks et al. (1990) reported positive SPT to halogenated Pt
nsitized workers at concentrations as low as 10"8 g/mL. Merget et al. (1991)
ative specific bronchial provocation tests with halogenated Pt salts as low as
; : o (10~8 g/mL).
(4)	SPTs using halogenated Pt salts (e.g., [NH4]2PtCl6 andNa2PtCl$) as the test
on atopic and non atopic controls yield negative results: The SPT to
halogenated Pt salts is commonly performed at concentrations in the range of
10"3 g/mL (e.g., SPT were performed to [NH4]2PtCl6, Na:PtCl„, and Na2PtCU at
10"3 g/mL in Linnett and Hughes, 1999 and to H;PtClt1 at 4.1 x 10"3 g/mL and Merget
et al., 2000). At that concentration (i.e., 10"3 g/mL) control subjects are negative in
SPT to halogenated Pt salts. Atopics without occupational exposure to halogenated
Pt salts are negative in the SPT and false positive SPTs are generally not reported as
the test is very specific for halogenated Pt salt allergy (Merget et al., 1991; reviewed
in Merget, 1990). In Books et al. (1990), one of the few studies to test a range of
concentrations for the SPT, control subjects were negative at test concentrations
ranging from 10"9 to 10"3 g/mL, with the exception of a biologic scientist that had
previously worked extensively with Pt salts.
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Individuals with halogenated Pt-salt allergic sensitization showed progression to
moderate or severe asthma with continued exposure (Merget et al., 1999). For halogenated Pt
salts and other sensitizers, effects of work-related allergic sensitization may be severe and
disabling (Friedman-Jimenez et al., 2000). Severe cases of allergic sensitization to halogenated
Pt salts included workers with bluish skin due to insufficient oxygen in blood, feeble pulse, ai: "
extreme difficulty breathing requiring the subject to remain upright to breath (Roberts, 195 :
Although no deaths have been reported for Pt-specific allergic sensitization, two cases of
occupational asthma leading to death were reported after medical recommendations ;¦
permanently cease exposure to other low molecular weight sensitizers (isocyanates) i;u.a jeen
given but not followed (Friedman-Jimenez et al., 2000). Even following the work practice of
medical termination, about 50% of workers with allergic sensitization to halogenated Pt salts
continued to experience symptoms such as asthma and shortness O' - ath on exertion several
years after removal from exposure (Merget et al., 1999, 1994).
Several occupational exposure studies provide data	tportive of an
IgE-mediated mode of action for sensitization effects of haiogenaxed Pt salts. An association
between elevated total serum IgE levels and sensitization has been reported in exposed workers
(Merget et al., 1988; Murdoch and Pepys, 1987; Murdoch et al., 1986; Biagini et al., 1985a).
Merget et al. (2000) reported an association between SPTC and total IgE (p = 0.036); however,
the authors reported that total IgE did not differ between exposure categories. In workers
removed from exposure, total serum IsE levels were significantly reduced (Merget et al., 1999,
1994). Although attempts to identify Pt-specific IgE antibodies by RAST analysis have not
yielded consistent results, possibly due to interference from nonspecific reactions of Pt halide
complexes with immunoglobulins (Merget et al., 2000; Cleare et al., 1976), Pt-specific IgE
antibodies h',v*> been identified by RAST analysis in skin test positive workers (Murdoch et al.,
1986; Biagini et al., 1985a; Cromwell et al., 1979). The existence of Pt-specific antibodies is
also supported through passive transfer of skin test reactivity; positive SPT reactions were
observed in both humans and monkeys using sera from sensitized workers (Pepys et al., 1979;
Freedman and Krupey, 1968). Taken together, results of occupational exposure studies strongly
indicate that sensitization effects for halogenated Pt salts are generally mediated through an
IgE-mediated mode of action.
4.6.3.1.2. Type II, Type III, and Type IV allergic responses. An additional IgG-mediated
mechanism may be involved in the development of halogenated Pt salt allergy, as proposed by
Pepys et al. (1979) (study details are provided in Section 4.5.1.1.2). IgG-mediated
hypersensitivity reactions are classified as Type II or Type III. In Type II hypersensitivity
reactions, IgG or IgM antibodies are produced in response to antigens bound to cells. Type II
reactions can be intrinsic (e.g., the antigen is a cell-attached endogenous substance) or extrinsic
(e.g., the antigen is a foreign body adsorbed onto a cell). The IgG or IgM antibodies bind to
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these antigens, initiating an inflammatory response and other events leading to cell lysis and
death (Goldsby, et al., 2003a). In Type III hypersensitivity, the antigen and antibody (IgG or
IgM) form a soluble immune complex (aggregations of antigens and IgG and IgM antibodies) in
the blood. The antibody-antigen complexes are then deposited in various tissues (typically, skin,
kidney, and joints), resulting in a reaction at the sites of antibody-antigen complex depc
(Goldsby et al., 2003a).
Unlike the preceding three types, Type IV reactions are mediated by activa
rather than antibodies. Much has been learned about T cells since the four hypersensi
classifications were originally proposed. As a result, the Type IV responses can now be divided
into three subtypes, mediated by different populations of T cells, CD4 T helper (Th) 1 and
Th2 cells, and CD8+ cells (Janeway et al., 2005). These CD4 cells recognize modified
extracellular proteins presented in the context of MHC-II molecules and activate macrophages,
which release a variety of cytokines and chemokines, leading to inflammation characterized by
the influx of neutrophils. CD8+ T cells are cytotoxic and attack cells bearing modified
intracellular proteins that are presented on the cell surface in the context of MHC-I antigens.
Thl and CD-8 reactions generally occur 24-48 hours after exposure in a previously sensitized
individual and are thus referred to as delayed-tyr.; .. ? sensitivity. Hypersensitivity
pneumonitis includes both Thl and CD-8 responses (Greenberger, 2008). Th2 cells facilitate the
antibody class switch to IgE and mobilize and activate eosinophils and mast cells. Chronic
responses in allergic asthma are. in Dart, attributable to Th2 cells.
endogenous
conventi
by th'
licit
4.6.3.1.3. Low molecular weight chemicals such as Pt act as haptens to produce sensitization.
For low molecular weight uiouuoals (<1,000 kDa), such as halogenated Pt salts, to induce a
hypersensitiv';tv' reaction, the chemical must act as a hapten, binding to a large molecular weight
tance to form an antigenic complex (Rosner and Merget, 1990). Unlike
tein allergens (e.g., dust-mites), low molecular weight chemicals are too small
be recognized by the immune system as foreign and are therefore too small to
sponse without forming a complex with a larger molecule. The probability
molecular weight chemical would be a sensitizer depends on the reactivity of the
A given chemical must be reactive enough to complex with larger molecules, usually
host proteins, to be a sensitizer. This chemical-protein complex is then recognized by the
immune system, which may result in the generation of hapten-specific immune responses (Sarlo
and Clark, 1992).
Low molecular weight chemical sensitizers are typically electrophiles, or proelectro-
philes, capable of reacting with hydroxyl, amino, and thiol groups on proteins (Karol et al.,
2001). The reactivity of chemical sensitizers may also contribute to allergenicity by cross-
linking individual proteins and forming new epitopes. For well-studied low molecular weight
chemicals, such as the isocyanates, data indicate that chemicals become conjugated to serum
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albumin, glutathione, and other proteins of the airway and skin epithelium upon inhalation
(Karol et al., 2001; Wisnewski et al., 2001). The specific protein or proteins responsible for
haptenization of halogenated Pt salts in humans is not known. In animals studies, OVA was
successful in forming an allergen when conjugated to ammonium tetrachloroplatinate
([NT Lj]2PtC*Lt) as evidenced by positive specific RAST against the Pt moiety wlit
challenged to (NH4)2PtCl4 conjugated to OVA (Murdoch and Pepys, 1984b). Ti-
the failure of free (NH4)2PtCl4 to induce Pt-specific IgE following immunization
intraperitoneal, intramuscular, intradermal, intravenous, intratrach
the same conditions, even in the presence of adjuvants.
Consistent with current scientific knowledge of allergeniciiy of low
chemicals, Cleare et al. (1976) hypothesized that the strength of the Pt ligand bond and the
reactivity of the Pt compound with endogenous proteins play a sig	determining
the allergic potential of Pt compounds. Linnett and Hughes (1999; iiypuUicsizcu that, in humans,
the most likely site of the Pt chemical-protein bond would be to the sulfur in methionine groups
on HSA. Furthermore, the authors identify the chloride ions in chloroplatinate as comparatively
labile leaving groups that allow substitution by sulfur- or nitrogen-containing ligands to occur on
a biologically relevant time scale. By contrast, the authors suggest that substitution in tetraamine
Pt dichloride is extremely slow and formation of a Pt-protein complex with this compound would
be reduced and may not form under normal occupational exposure (Linnet and Hughes, 1999).
4.6.3.1.4. Utility of the SPT as an endpoint to identify Pt-specific sensitization. SPTs are
routinely used in the diagnosis 			 .../ation to halogenated Pt salts in conjunction with work-
related symptoms of allergy, puunonary function tests, and specific and nonspecific bronchial
challenge tests. As discussed in detail in Section 4.1.2.1.1 {Toxicity of soluble forms ofPt:
diagnosis of Pt allergic sensitization), SPTs detect only Type I, IgE-mediated sensitization.
Since most cases of allergic sensitivity to Pt are thought to be due to IgE-mediated immune
mechanisms (see Section 4.6.3.1, Mode of Action Information, Sensitization), sensitivity to
specific Pt compounds can be detected through SPTs in many sensitized individuals. For
. : ' i u-le, among the 13 cases of workers who developed a positive SPT to Pt in a 5-year
ctive study of 115 high-exposure catalyst production workers, all displayed symptoms
is, asthma, or dermatitis), although the symptoms were not work-related in a few of these
cases (Merget et al., 2000). No subject with a negative SPT and new work-related symptoms
(n = 6 in the high-exposure group) showed a positive SPT upon follow-up exam (Merget et al.,
2000). In a retrospective study of 406 U.K. refinery workers exposed to chloroplatinates,
110 cases of halogenated Pt salt allergy were identified; of these, 100 were SPT positive (Linnett
and Hughes, 1999). Among the 10 SPT-negative cases, 1 was positive in a patch test, 1 was
positive in a specific bronchial challenge test, 1 had work-related upper respiratory symptoms,
and 7 had bronchospasms at work.
;.StS tO
' ;e under
..Jght
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Sensitization would not be detected using the SPT if the response to halogenated Pt salts
in a subset of sensitized individuals is mediated through a non-IgE mechanism. Results of a
study by Merget et al. (1991) found that Pt SPT does not always predict the respiratory response
to hexachloroplatinate (study details provided in Section 4.1.2.1.1). The data support the
hypothesis that a non-IgE mechanism may be involved in the respiratory response in sc
individuals, based on the finding that positive hexachloroplatinate bronchial challenge was
observed in a few workers testing negative in the hexachloroplatinate SPT. Similar findings
have been reported for other chemicals with known allergic sensitization properties. For
example, immunologic respiratory effects have been observed in workers expose
diisocyanate; however, the association between diisocyanate-specific IgE antibodies and
respiratory symptoms appears to be variable or absent (Kimber and Dearman, 2002; Redlich and
Karol, 2002; Kimber et al., 1998). Furthermore, four iinnumological 1 v-mediated respiratory
syndromes (one IgE- mediated and three IgG-mediated) have been identified for the respiratory
sensitizer TMA (Grammer et al., 1998). Thus, it is possible that multiple mechanisms are
involved in sensitization to hexachloroplatinat . ? uilogenated Pt salts.
Additional support that at a least a portion trie anergic sensitization to Pt is non-IgE-
mediated is provided by a study examining the r.¦¦¦¦:> is i:y response of methacholine and
Na2PtCl„ in naive (i.e., not previously exposed to Na2Pt(*lt, or other Pt compounds) cynomolgus
monkeys (Biagini et al., 1985b). Male monkeys (n = 24) were evaluated for pulmonary
responsiveness to inhaled (nebulized) aerosols of methacholine (0, 0.1, 0.5, 1.05, or 6.25 mg/mL
in phosphate buffered salinel or Na2PtCl6 (0, 0.5, 2.5, 25, or 50 mg/mL in saline). For both test
agents, MMADs ranged fr; a< : 1 no 1.5 um, with GSD s of 1.7 2.0. Bronchial challenges for
each dose of methacholine , ,a2PtCl,, were performed for 1 minute (15 breaths). The study
report did not specify how each agent was administered, although bronchoprovocation agents are
typically adi;: :s i; tered using a breathing tube. Monkeys were anesthetized for all challenge tests.
Tests were f; ? i ondueted with methacholine, followed 2-3 weeks later by tests with Na2PtCl6 in
the same monkeys. The following pulmonary function variables were assessed following
-~ure to each dose of challenge agent: average pulmonary resistance ( R|); dynamic
x (CLdy„); PEFR; FVC, FEV0.5/FVC (F¥C0.5/F¥C); FEFs at 50 and 25% of vital
normalized for FVC (FEF50/F¥C and FEF25/FVC); and respiratory rate. All pulmonary
mi test results were reported graphically. For measures of airway mechanical status at tidal
breathing (Rt and Cmyn), effects of methacholine and Na2PtClt1 were similar. Both agents
produced dose-dependent increases in RL, with maximal increases (relative to the pre-challenge
response on the test day) at the highest dose tested of approximately 550% for methacholine and
almost 700% for Na2PtClt1. Both agents also produced dose-dependent decreases in Cmyn, with a
maximal decrease of approximately 50% (for methacholine and Na2PtClt1) at the highest
challenge dose. Methacholine and Na2PtClt1 also produced dose-dependent decreases in airflow
in central and peripheral airways under maximal expiratory conditions (FVC0.5/FVC and PEFR)
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and under conditions of low lung volumes (FEF50/F¥C and FEF25/FVC); however, the decreases
were significantly greater compared to those observed for methacholine (p < 0.05). Since
respiratory rate was not affected by either treatment, the study authors concluded that neither
challenge agent stimulated respiratory irritant receptors. Results of this study indicate that both
methacholine and 'Na;Pt('*l,, produce peripheral and central airway bronchoconstriction; hov . ,
they appear to act, at least in part, through different mechanisms. Furthermore, since this si;y
was performed in animals with no prior exposure to Na2PtCl6 or any other Pt compound, results
provide evidence that Na:PtCl„ can produce airway effects in the <	" - nediated
sensitivity to Pt.
Since SPTs detect IgE-mediated sensitization, other factor;	' :: circulating
levels of IgE antibodies to hexachloroplatinate could potentially affect SPT results. For
example, Merget et al. (1994) reported that in a few work	.ire, SPT to
hexachloroplatinate converted from positive to negative, although >uc>.v wuikcis still tested
positive in bronchial challenge tests to hexachloroplatina	loline. This finding is
consistent with the hypothesis that low circulating levels 01 ri-specinc IgE antibodies following
an exposure-free period may not be sufficient to yield a measurable response to detect
sensitization by hexachloroplatinate SPT. For example, in some individuals sensitized to
diisocyanate, decreased circulating di i socy an ate- speci ii c IgE levels have been observed
.
following an exposure-free period (Kimber and Dearman, 2002; Tee et al., 1998).
4.6.3.1.5. Correlation between Pi sensitization and asthma/atopy toward other allergens. The
data examining the correlation			„ sensitization and asthma/atopy toward other allergens
are limited to a few epider...v,.v,t,.c studies in occupationally exposed workers (Merget et al.,
2000; CalverW st al., 1999; Bolm-Audorff et al., 1992; Baker et al., 1990). Some studies have
shown equa . , ¦ xluced sensitivity to environmental allergens in halogenated Pt salt-exposed
populations > Dared to nonexposed controls (e.g., Merget et al., 2000), while others have
shown an increase in sensitivity to environmental allergens with Pt-salt exposure (Calverley et
al., 1999). The in vitro studies of human dendritic cells by Paolucci et al. (2007) suggest that
Na;PtCl„, and some palladium and rhodium compounds, may act on dendritic cells in an
adjuvant-like way such that exposure results in an increased allergic response to allergens.
Occupational data may be confounded by the exclusion of atopic individuals from high-exposure
jobs, thereby selecting for reduced sensitivity to the development of allergies or asthma.
Common nonspecific irritants such as smoke and diesel exhaust are likely to exacerbate the
asthmatic condition, as reflected in reports that both nonspecific and specific bronchial
responsiveness persist in a considerable number of sensitized workers after removal from the
workplace or from high-exposure workplace areas (Merget et al., 1999, 1994). In a recent
review of the epidemiological literature examining the relationship between environmental
asthma triggers (e.g., tobacco smoke, outdoor air pollutants, pollen) and asthma incidence,
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Gilmour et al. (2006) suggest that complex organic molecules in diesel exhaust may act as
allergic adjuvants and exacerbate asthma or increase the likelihood of developing allergic asthma
(Gilmour et al., 2006). This hypothesis is supported by results of studies in humans and rodents
showing that diesel exhaust particles acted as an adjuvant, enhancing the IgE-mediated re^; «nse
to allergens (ragweed in human subjects—Diaz-Sanchez et al., 1997; OVA in mice Lovik et al.,
1997). Diesel exhaust particles also acted as an adjuvant producing an IgE-mediated response in
9/15 subject challenged with diesel exhaust particles and keyhole limpet heniocv	H),
whereas no individuals (0/10) developed anti-KLH-specific IgE when ex]	:
(Diaz-Sanchez et al., 1999). However, the potential for the diesel exfiaun		-	y„,unt
and exacerbate asthma in Pt sensitized individuals has not beei
4.6.3.1.6. Relevance of acute versus chronic exposures and of repeated versus single
exposures in the development of Pt sensitization. The information from the available
epidemiologic studies is inadequate to specify the duration of exposure or exposure
concentrations necessary to induce halogenated Pt salt allergic sensitization. In the only study
from which a NOAEL can be identified for halogenated Pt salt sensitization (Merget et al.,
2000), exposure estimates for workers in the high-exposure group (in which 13/115 workers
developed halogenated Pt salt sensitization as assayed by SPT during a 5-year period) were
highly variable (100- and 1,000-fold variations were reported for stationary air and personal air
samples) and individual pt	>i les were not collected for each worker in the study. It
is unclear from the data wl	)pment of sensitization was better associated with high
concentrations that the wo may have intermittently experienced or with a central tendency
measure of air concentratit.-,,..^erienced across the period of occupation. The data provide
some information that the workplace conditions may have been sufficient to require less than a
"chronic" di : ? -; ;' >n for the development of sensitization; nine of the high-exposure workers
became sen; ; ¦¦¦ d during year 3 of the study, while the others did so in years 1, 2, 4, and
5 (Merget et al., 2000). However, the high-exposure workers were employed in their jobs for
1"" months before the initial survey in the study. As discussed in Section 4.6.3.1 (Mode of
¦" : '// Information, Sensitization), a Type I hypersensitivity response requires more than one
. are before symptoms develop. Symptoms may develop after relatively few exposures or
svelop after several years of exposure, as reported by Merget et al. (2000). In general, as
the sensitization dose of an allergen increases, the dose needed to elicit a response on re-
challenge decreases (Hostynek and Maibach, 2004; Scott et al., 2002). However, several factors
may affect this relationship, including frequency of exposure, single versus multiple exposures,
and biological half-life of the allergen (Scott et al., 2002). A further complication in identifying
threshold doses for sensitization and elicitation (e.g., re-challenge) involves the mechanism of
sensitization. Studies examining the dose-response relationship for sensitization indicate that
humoral responses (e.g., B cell-mediated) are induced in response to high doses, whereas, cell-
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mediated responses (e.g., T cell-mediated) are induced with lower doses (Constant and Bottomly,
1997). Given the many factors that may influence the sensitization and elicitation thresholds,
coupled with variations in worker exposure, the relationship between the dose of halogenated Pt
salts needed to produce sensitization and the dose needed to elicit a response on re-challenge has
not been established. The exposure data from Merget et al. (2000) for the high-exposure gt =¦: :
identify an occupational exposure concentration associated with sensitization, as 13/115 wc -
in the high-exposure group developed Pt-specific allergic sensitization as determined by positive
SPT during the 5-year study. The dose of hexachloroplatinic acid : . ; or the SPT
represents the elicitation dose in this study. A single dose level w,	licitation in the
SPT; therefore, no information on the dose-response for elicitatioi	m Merget et al.
(2000).
4.6.3.1.7. Relationship between exposure levels associated with *en\(uzm$vn and the
subsequent exposure levels required to elicit a respom	s experimental evidence
to characterize the relationship between the dose required to inauce anergic sensitization (i.e.,
induction or sensitization dose) via respiratory exposure and the subsequent dose required to
elicit the allergic response (i.e., challenge or elic; > n. ose). However, the elicitation dose is
generally lower than the dose required to induce sensitization for both contact and respiratory
sensitization (Arts et al., 2006; Rosner and Merget, 2000). The relationship between the dose-
response curves for sensitization and elicitation are better studied for dermal exposure in allergic
contact dermatitis. There is a clear inverse correlation between the strength of the sensitization
and the subsequent dose required to elicit a contact hypersensitivity response in humans
(Friedmann, 2007). The sU'c*%ui of sensitization is, in turn, related to the potency of the allergen
and the dose that reaches the skin (Friedmann, 2007). The slopes of dose-response relationships
for sensitization in the induction of allergic contact dermatitis from certain chemicals have been
shown to be similar to the slopes for elicitation dose-response relationships, albeit elicitation
curves are shifted to lower ranges of the dose axis (Scott et al., 2002; Friedmann, 1994, 1990).
le SPT responses in Pt-sensitized individuals indicate that concentrations that
reaction are, for many cases, 3 orders of magnitude lower than the maximum
concentration which elicits no response in nonsensitized subjects, and that, for rare cases,
the difference may be as much as 6 orders of magnitude. For example, in a study of 107 actively
employed refinery workers and 30 former workers, Biagini et al. (1985a) reported the following
distribution of the elicitation doses required for a positive SPT result2 among the 23 sensitized
2 Note the concentration reported is the lowest concentration associated with a positive SPT to (NH4)2PtCl6.
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individuals: 10"3 g/mL (n = 2); 10"4 g/mL (n = 3); 10"5 g/mL (n = 4); 10"6 g/mL (n = 9); 10"7
g/mL (n = 3); 10"8g/mL (n = 1); and 10"9 g/mL (n = 1). The elicitation doses ranged from 10"9 to
10"3 g/mL.
4.6.3.1.8. Cross-sensitivity between Pt and other metals for sensitization. No data were located
to describe the structure-activity relationship between Pt and other Pt group metals (i.e.,
palladium, ruthenium, rhodium, osmium, iridium, and Pt). Studies in rats (Murdoch and Pepys,
1985, 1984a, b; study details provided in Section 4.5.1.1.2) indicate that OVA-Pt specific IgE-
antibodies are not cross-reactive to chlorinated salts of other PGEs. On the other hand, several
occupational studies demonstrate sensitization to other PGEs in humans that have a known
allergic sensitization to halogenated Pt salts (Cristaudo et al., 2005; Murdoch and Pepys, 1987;
Murdoch et al., 1986). A similar sensitization to halogenated Pt sii; i¦¦¦ : f k; >ther PGEs (Pt and
palladium) as well as gold (gold sodiumthiosulfate) was observed in a analytical chemist testing
various metal plating solutions (Watsky, 2007).
In occupational situations (including Pt refineries ana caxaiysx production and recycling
facilities) where exposure to halogenated Pt salts takes place with co-exposure to halogenated
salts of other PGEs, a subset of individuals with positive SPT to Pt have been shown to have a
positive SPT to other PGEs. A survey of 306 South African Pt refinery workers found cross-
sensitivity by both SPT and RAST to chlorinated salts of other PGEs in workers that were SPT
positive to hexachloroplatinate salts (Murdoch et al., 1986; Murdoch and Pepys, 1987). The
authors report that in addition to Pt, refinery workers are known to be exposed to comparable
levels of palladium and rhodium salts and that in all cases, refinery workers are exposed other
PGEs (Murdoch and Pepy.., ,). Therefore, most Pt refinery studies cannot discriminate
between trap ^rr>ss-sensitivity (i.e., individuals with specific IgE antibodies to Pt that also bind
and thereby cross-react to other PGEs) and simultaneous development of separate, specific,
hypersensiti :;to multiple PGEs. No information was reported on symptoms of sensitization
or on Pt or other PGE exposure levels at the refinery in Murdoch et al. (1986) or Murdoch and
were performed to detect sensitivity to hexachloroplatinate and to
Its (not specified) of ruthenium, iridium, rhodium, and palladium. In the 306 total
<9 (12.7%) were SPT positive to Pt and a subset of workers that were sensitized to Pt
were also sensitized to other PGEs with the following results: two workers (0.6% of 306 total
workers) tested positive to palladium; five (1.6% of 306 total) workers tested positive rhodium;
6 (1.9% of 306 total) workers tested positive to iridium; and four (1.3% of 306 total) workers
tested positive to ruthenium. Similar results were obtained with compound-specific RAST
assays. Cross-reactivity to chlorinated salts of iridium (IrCls) and rhodium (RhCh) was also
found in some of the 22 workers with positive SPT or patch test to hexachloroplatinic acid
among the total population of 153 workers tested in a catalyst manufacturing and recycling
factory (Cristaudo et al., 2005). No information was reported on Pt or other PGE exposure levels
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at the factory. While 22 of the 153 workers (14.4%) were SPT positive to Pt, only 3 (2.0% of the
153 total) workers were also SPT positive to iridium and 2 (1.31% of the 153 total) of these
workers were also SPT positive to rhodium. No worker in the Cristaudo et al. (2005) or
Murdoch and Pepys (1987) studies demonstrated sensitization to a PGE that was not also SI
positive to Pt.
As described above, respiratory allergic sensitization as indicated by a posit
been shown for all PGEs except osmium, and it is restricted to individuals who ar
to Pt and in each case occupational exposure to the PGEs takes place in the presence <
halogenated Pt salts (Cristaudo et al., 2005; Murdoch and Pepys, 1987; Murdoch et al, 1986).
However, there is evidence that other PGEs, especially palladium, are sensitizers independent of
co-exposure with Pt compounds. Palladium is a well-known contact sensitizer, particularly from
the use of palladium in dental materials (see review in Kielhorn et a!., 2002). Evidence of the
respiratory sensitizing capacity of palladium is largely limited to occupational studies where co-
exposure with Pt cannot be ruled out. There is a single case study of respiratory sensitization to
palladium (demonstrated by positive SPTs a	inspiratory challenge to Pd[NH3]4Cl2)
where it could be demonstrated that exposure was to palladium compounds alone (Daenen et al.,
1999). In the case of palladium, there may be a cross-reactivity of antibodies to palladium and
nickel, and there is evidence that individuals with nickel allergy are more susceptible to
developing allergic sensitization to palladium (Kielhorn et al., 2002).
In summary, several occupational studies demonstrate respiratory sensitization to other
PGEs in humans that have a known allergic sensitization to halogenated Pt salts. There is
insufficient information to n - tine if positive SPTs to other PGEs represent cross-sensitization
of Pt-specific antibodies rather than separate, specific allergic responses to each PGE or if co-
exposure to lh important to the development of sensitization to other PGEs. In addition, unlike
palladium, there is no evidence that individuals with allergic sensitivity to other metals or PGEs,
are more lik ; > develop sensitization to Pt compounds.
4.6.3.2. Other Considerations for Mode of Action
4.6.3.2.1. Relevance of particle size to qualitative and quantitative toxicity characteristics of
Pt Particle size is an important determinant of deposition, retention, and absorption in the
respiratory tract (Oberdorster, 2001, 1994; Oberdorster et al., 2000). Inhalation exposure to Pt
has been studied in experimental animals, but no studies examining the relationship between
particle size and toxic effects were located. Presumably, smaller particles will be deposited
deeper into the respiratory tract, where absorption may be more efficient. Whether Pt particles
deposited in the lung undergo transformation to other compounds, including whether or not such
particles could function as a hapten and react with native proteins to become capable of
producing allergic sensitization, is not known (Oberdorster, 2001).
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The effect of particle size has been investigated for respiratory sensitization to diphenyl-
methane-4,4'-diisocyanate (MDI) in guinea pigs (Pauluhn et al., 2000). Respiratory sensitization
was examined for intradermal injections (3 x 0.3% MDI) or a 15-minute inhalation exposure to
135 mg MDI/m3 of a small particle aerosol (1.7 um MM AD) or a large particle aerosol (3.1
MMAD). There was a greater response to the large aerosol for sensitization by either'
intradermal or inhalation route. The authors hypothesized that the greater sensitiza
of the large aerosol may be related to a greater fraction of deposition of the larger ]
within the upper respiratory tract. The relevance of particle size for the sen ;: on effects of
halogenated Pt salts is unknown.
4.6.3.2.2. Utility of biomarkers of Pt exposure. Overall, the util.iy v, biomo>mviing for Pt
exposure is limited, as levels of urinary/serum Pt in nonoccupational^ ca^uscu populations are
generally low and highly variable (for review, see Begerow and Duiicmaii, 2000). Additionally,
analysis of Pt in biological samples indicates only the concentration of elemental Pt, and not the
specific chemical compounds to which exposure occurred. Other sources of Pt exposure (e.g.,
dental alloys, Pt-containing drugs, and Pt from prostheses including breast implants) may
confound estimates of true environmental exposures (M ah a raj, 2004; Merget et al., 2002). In a
recent environmental survey of 1,080 German adults, regression analysis revealed that levels of
Pt in urine were significantly correlated with the number of teeth with noble metal dental alloy
restorations, more frequent coffee consumption, and upper social class status, but not with
traffic-related variables (Benemartrt et al., 2005).
In an occupational stut, ,.„„ers in a catalytic converter production and recycling
plant, Petrucci et al. (2005, uio^jred Pt in airborne PM, and blood, urine, and hair of
106 exposed workers, 21 control workers from the plant's administrative offices, and
25 unexposed ltrols. Health symptoms or Pt allergic sensitization information were not
recorded in th vudy. The report makes no mention of controlling for Pt exposure from dental
devices. Environmental air samples were taken in various sites throughout the plant and
sociated with specific work processes. Sampling times ranged from 13 to 57 hours and
^articles were collected using pumps equipped with a PMio sampling head to measure
/ith a diameter below 10 um. Personal air sampler devices worn by individual workers
ill week were also used for all sites and most processes for which environmental samples
were collected. Analysis of biological and environmental samples was performed by high
resolution-ICP-MS and quantitative-ICP-MS with a detection limit of 0.018 ng/m3 for airborne
samples and 1-3 ng/L for biological samples. Concentrations of total and soluble Pt were highly
correlated between stationary samplers and personal sampling devices (r2 = 0.9667). A strong
correlation was also observed between Pt concentrations from environmental air samples and Pt
concentrations in urine and hair, but not in blood. The authors suggest that urine samples may be
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a viable method of biomonitoring occupational Pt exposure, and that blood is not a suitable for
monitoring Pt exposure.
A recent study examined levels of various metals, including Pt, and markers of nasal
inflammation in nasal lavage fluid (e.g., neutrophil and epithelial cell counts and II.-8 levels)
sampled from 67 children (Schins et al., 2004). Children, who were selected from a larger o." t
of 283 children (the basis of selection was not provided in the study), were classified into ft :
groups (A, Bl, B2, and C) based on area of residence; subjects in group A lived in a small city in
a rural region in Germany (representing the control population), and subjects in groups Bl, B2,
and C lived in two major cities in Germany. "Personal characteristics" for participating subjects
were obtained through parent-completed questionnaires. Subjects with hay fever or a specific
allergy, diagnosed based on questionnaire and a positive SPT to five common allergens (not
reported), were excluded from the study. Nasal lavage was conducted on all participants and
analyzed for total cell counts, differential counts (neutrophils, eosinophils, monocytes,
lymphocytes, and epithelial cells), II .-8, and concentrations of Pt, vanadium, chromium
(measured by sector field ICP-MS; LOD for Pt was 0.01 ng/L). Air monitoring data (daily
averages) on traffic-associated air pollutants (airDorne fM, NO, NO2, and CO) were obtained
from an air quality monitoring agency, but were not verified in this study. Statistically
significant correlations were found between concentrations of Pt (but not concentrations of
vanadium or chromium) in the nasal lavage 1 :n; and two cell concentrations associated with
inflammation (neutrophil counts [r = 0.40,/? < 0.001] and epithelial cell counts [r = 0.41,
p < 0.0001]). No significant correlations were found between concentrations of any of the
metals and 11 .-8 concentration			 „„jal lavage fluid samples. Air monitoring data indicated
that area Bl had significant ui&her air pollutant levels (PM, NO, NO2, and CO) and area C had
significantly '""her NO2 and CO levels than area A, but no correlations were found between
these indice - ir pollution and the concentrations of Pt, vanadium, or chromium in fine or
coarse PM s^n: nes from the locations. Concentrations of vanadium, chromium, and Pt in nasal
lavage fluids were detectable in 64, 73, and 93% of the children, respectively, but significant
differences between locations were not found. Although the results show a correlation between
Pt concentrations in nasal lavage fluid and neutrophil and epithelial cell counts associated with
nasal inflammation, they do not clearly establish whether Pt itself or some other compound or
material caused the effect. In addition, the results are limited to the markers of inflammation
examined (i.e., differential cell counts from nasal lavage and TI.-8) and data were not collected
on a more extensive set of cytokines or other inflammatory indicators, nor do they distinguish
what form or forms of Pt (e.g., Pt metal, oxides, or soluble halogenated compounds) were
present. Although nasal (or pulmonary) inflammation from airborne Pt particles is plausible, the
study was unable to conclusively demonstrate inflammation and did not show an association
between Pt exposure and Pt concentrations in nasal fluid. Without a more clearly demonstrated
association between Pt exposure and effect, or corroborative findings from other studies, the
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results provide inadequate evidence to establish nasal inflammation or Pt concentrations from
nasal lavage as biomarkers of Pt exposure.
4.6.3.2.3.	Potential for olfactory nerve uptake. Certain metals gain access to the central
nervous system via uptake by the olfactory nerve. In rodents following intranasal instillation,
certain metals (including manganese, cadmium, nickel, zinc, and mercury) are taken up by the
primary olfactory neurons in the olfactory epithelium of the nose and transported along the
neurons to the olfactory bulbs in the brain (Persson et al., 2003; Tjalve and Henriksson, 1999;
Tjalve et al., 1996). Some metals (e.g., manganese and nickel) appear to be transported via this
olfactory pathway to other parts of the brain, whereas other metals (e.g., cadmium and mercury)
are not (Tjalve and Henriksson, 1999). Data examining the ability of Pt metal or Pt compounds
to be transported via this olfactory pathway to the brain were not located. Furthermore, available
data do not provide evidence of neurotoxicity in humans or animals exposed to inhaled soluble
or insoluble Pt compounds.
4.6.3.2.4.	Bioaccumulation of Pt and implications for health effects. No data associating the
bioaccumulation of Pt to adverse health effects ^ ¦ < ¦;< :. \-1 * . However, two points suggest the
need for further consideration. First, studies in rats show that inhaled Pt is preferentially
distributed to kidney, liver, spleen, and bone, which suggests the potential for accumulation in
these organs (Moore et al., 1975a). Second, a study of occupationally exposed workers showed
elevated levels of urinary Pt. 2-6 years following removal from exposure (Schierl et al., 1998).
Although these findings suggt,			^accumulation of Pt is possible, the health effects (if any)
of this accumulation are ho. — <-n.
4.6.3.3. Mo.. . •¦-¦"Action Summary
Expo;-:: o of humans and experimental animals to halogenated Pt salts and Pt compounds
demonstrates that the immune system is a target organ to halogenated Pt salts. Available data
demonstrate that allergic sensitization to Pt compounds is associated with exposure to
halogenated Pt salts and do not support sensitization from exposure to insoluble or
nonhalogenated Pt compounds. The symptoms and time-course of the allergic sensitization
response to halogenated Pt salts are typical of IgE-mediated, Type I allergic response. Data from
both humans and animals demonstrate that allergic sensitization results from inhalation exposure.
Although data on dermal exposure in humans are lacking, animal data (Kimber and Dearman,
2002; Dearman et al., 1998; Schuppe et al., 1997a) suggest that dermal exposure may also
contribute to respiratory allergic sensitization to soluble halogenated Pt compounds.
Research supports a mode of action for low molecular weight compounds, such as
soluble halogenated Pt compounds, to act as haptens to produce allergic sensitization (Sarlo and
Clark, 1992). Because soluble halogenated Pt compounds are too small to be recognized by the
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immune system, they must bind to a larger endogenous substance to form an antigenic complex
(Rosner and Merget, 1990). Therefore, the probability that a given Pt compound would be a
sensitizer depends on the strength of the Pt ligand bond and its ability to react with endogenous
proteins (Linnett and Hughes, 1999; Cleare et al., 1976). The fact that evidence of sensitize:?
is restricted to halogenated Pt salts supports the importance of the reactive halogen grou
Specific proteins involved with the Pt-protein complex have not been identified; however,
Linnett and Hughes (1999) hypothesized that, in humans, the most likely site of the Pt chemical-
protein bond would be the sulfur in methionine groups on HSA.
When the immune system recognizes the Pt-protein complex, B Ij	luce
specific antibodies to the Pt compound. These B lymphocytes undergo ck™	aom the
initial IgG isotype to produce IgE antibodies with the same specificity. The IgE antibodies bind
to surface receptors of mast cells and basophils and are thereby distributed in mucosal and
epithelial tissues where these cell types are normally located. Individuals with these specific IgE
antibodies to halogenated Pt salts are then considered to be sensitized and will be positive for
specific IgE tests such as the SPT. Subsequent exposure to the same halogenated Pt salts results
in binding by the IgE on the cell surface and triggers degranulation and cellular release of
histamine, leukotrienes, prostaglandins, and proteases. The extent of release of inflammatory
mediators (number of cells involved, affinity of IgE antibodies, etc.) determines the extent of
response and contributes to a local or systemic allergic response.
Symptoms of IgE-mediated, Type I allergic responses include asthma, rhinitis, urticaria,
conjunctivitis, dermatitis, and anaphylaxis. These symptoms occur only after a symptom-free
latency period during whics; - - llergic sensitization is taking place. The epidemiologic data
suggest that sensitization can develop over an exposure period of several months to 13 years
(Cristaudo et al., 2005; A<1er«et et al., 2000; Linnet and Hughes, 1999).
CARCINOGENICITY
of Overall Weight-of-Evidence
l's Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a), the cancer
ita are inadequate for an assessment of human carcinogenic potential," is
iate for halogenated Pt salts and Pt compounds. Cancer studies in humans and cancer
ays in animals exposed to soluble or insoluble Pt compounds were not found. As
discussed in Section 4.5.2 (Genotoxicity), soluble Pt compounds (PtCU, Pt[S().t];, K^PtCU,
H;Pt('*l,,) produced gene mutations in prokaryotic and eukaryotic test systems, including
bacteriophage, bacteria, CHO cells, and mouse lymphoma cells. However, there is no direct
evidence to indicate that exposure to halogenated Pt salts or Pt compounds are carcinogenic in
animals or humans, with the exception that intraperitoneal exposure of rats or mice to cisplatin
produced increased incidences of animals with tumors. Insoluble PtCh tested negative for gene
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mutations in the E. coli SOS chromotest, mouse lymphoma forward mutation test, and human
lymphocyte micronuclei test.
Cisplatin has been classified by I ARC (1987) in cancer Group 2A, probably carcinogenic
to humans, based on inadequate evidence of carcinogenicity in humans and sufficient evidence
of carcinogenicity in animals (increased incidence of tumors in rats (leukemia) and mice (lung
adenomas) following multiple intraperitoneal injections). Although no cancer hioassavs are
available for other Pt antitumor drugs, mutagenicity assays suggest possible <	activity
similar to that of cisplatin (Sanderson et al., 1996).
4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence
Cancer studies in humans and cancer bioassays iu animal* exposed to ov«uble or insoluble
Pt compounds were not found, with the exception of ra	with cisplatin.
4.7.3. Mode of Action Information
There is inadequate evidence to indicate that exposure xo naiogenated Pt salts or Pt
compounds is carcinogenic in animals or humans, with the exception of the evidence for the
carcinogenicity of cisplatin in rats and mice. Thus, possible modes of carcinogenic action of
halogenated Pt salts and Pt compounds are not discussed herein.
4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES
4.8.1. Possible Childhood Susceptibility
No data were locate Hoarding potential increased susceptibility of children in the
development of allergic se>:. >n to halogenated Pt salts. The database for developmental
studies of Pt is limited to a single study involving acute gavage dosing of pregnant ICR Swiss
mice with Pt(SO.i); (D'Agostino et al., 1984; Massaro et al., 1981; see Section 4.3.1). Although
comprehensive developmental endpoints were not examined, the results for Pt(S04)2 (exposure-
related decreased body weights in offspring) indicate that Pt compounds may be toxic to the
developing fetus and neonate. Schins et al. (2004), investigating the relationship between Pt
concentrations in nasal lavage fluid and markers of nasal inflammation in a group of children,
found statistically significant correlations between Pt concentrations in the nasal lavage fluid and
neutrophil and epithelial cell counts, although no association was demonstrated between Pt
concentrations in nasal fluid and air. However, results of this study do not provide any
information regarding the potential for increased susceptibility of children to allergic
sensitization to halogenated Pt salts. The epidemiology studies that have examined health
outcomes associated with occupational exposures to Pt compounds provide no information on
childhood susceptibility.
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4.8.2.	Possible Gender Differences
No data were located regarding potential gender differences in the development of
allergic sensitization to halogenated Pt salts.
4.8.3.	Other
Available epidemiological evaluations of Pt allergic sensitization were primarily
conducted in populations of adult workers (>90% males) at Pt refineries and Pt catalyst
production plants. More susceptible adults are likely to have been selected out of the work force
at these facilities (i.e., healthy worker effect). Given the narrow focus of these studies on
relatively healthy adult males, the susceptibility of females, children, immune-compromised
subjects, or elderly to sensitization to halogenated Pt salts cannot be determined from these
studies.
No other data were located examining the relative sensitivities among potentially
sensitive populations with regard to development of allergic sensitization to halogenated Pt salts,
with the exception that smokers in refineries (Calverley et ai., iyyo; Baker et al., 1990; Venables
et al., 1989), in a combined refinery and catalyst production plant (Linnett and Hughes, 1999),
and in a catalyst production plant (Merget et al., 2000) have increased risk for developing
sensitization compared with nonsmokers. It is possible that asthmatic individuals may be at
special risk to develop sensitivity to halogenated Pt salts. Merget (2000) reported that
preexisting asthma or bronchial hvoerresponsiveness was not a risk factor for allergic
sensitization to halogenated Pf salts in a prospective study of German catalyst production
workers, but cautioned that th _ 			 jf workers with these preexisting conditions were low in
this study. Although no data are available on co-exposure to other relevant irritants or adjuvants
in the worke™ 
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5. DOSE-RESPONSE ASSESSMENTS
5.1. ORAL REFERENCE DOSE (RfD)
5.1.1. Choice of Principal Study and Critical Effect - with Rationale and Justif
Oral exposure studies of halogenated Pt salts and Pt compounds are not adequate ior the
determination of an RfD. The human data available on the oral toxicity of halogenated Pt salts
and Pt compounds are limited to a single case study report of the toxic effects resulting from of
intentional ingestion of a photographic solution containing 600 mg of potas
tetrachloroplatinate (Cl.tK.2Pt) by a 31-year-old man (Woolf and Ebert, 1991). This individual
exhibited elevated liver enzymes, acute oliguric renal failure, metabolic acidosis, fever, muscle
cramps, gastroenteritis, rhabomyolisis, and elevated serum levels of neutrophils and eosinophils
following ingestion of the photographic solution. All signs of toxicity resolved within 6 days of
supportive medical care. No additional reports of oral exposure of humans to halogenated Pt
salts or Pt compounds were identified.
The kidney may be a target organ for some Pt compounds based on the limited available
short-term and subchronic drinking water and dietary exposure studies in animals (Reichlmayr-
Lais et al., 1992; Roshchin et al., 1984; Hoi brook, 1976; Holbrook et al., 1976, 1975). However,
the available animal data involved exposure to several different Pt compounds, employed few
dose levels, and there are no comprebcn~-ve subchronic or chronic toxicology studies that
include even basic endpoints such as ¦¦¦?< logy. In short-term exposure studies, relative kidney
weight was increased by 8% in rats e . - ¦> :d to PtCU in drinking water (approximately 44 mg
Pt/kg-day) for 4 weeks (Holbrook et al., 1975). Decreased renal function, as indicated by
increased plasma creatinine concentration, was observed in rats exposed to PtCU in the diet
(approximately 6 mg Pt/kg-day) for 4 weeks (Reichlmayr-Lais et al., 1992). Although additional
data on potential renal effects of oral exposure are not available, rat intraperitoneal LD50 values
of 40-50 mg/kg for hexachloroplatinic acid were associated with death due to renal failure and
: otizing renal tubular lesions throughout the renal cortex (Ward et al., 1976). The above
n :v.. i ations suggestive of nephrotoxicity are consistent with oral toxicokinetic studies in
!1 i i,;.: ¦: is demonstrating renal accumulation of soluble [Pt(SO.th and PtCU] and insoluble [PtCl ;
; f ^ metal] environmentally relevant Pt compounds (Artelt et al., 1999a; Reichlmayr-Lais et
«i., i5>92; Massaro et al., 1981; Lown et al., 1980; Holbrook et al., 1975; Moore et al., 1975a, b;
Yoakum et al., 1975). Extensive clinical experience with parenteral exposure to cisplatin and
other Pt-containing anticancer drugs also identified the kidney as a target organ for accumulation
and toxicity of these compounds after parenteral exposure (Hartmann and Lipp, 2003).
Possible hepatotoxicity associated with oral exposure to Pt compounds is suggested by
changes in activities of two hepatic microsomal enzymes (aniline hydroxylase and aminopyrine
demethylase) observed in rats exposed to PtCU or Pt(SO.t): in drinking water or food (Holbrook
et al., 1976, 1975); however, the observed changes were not consistent in direction (i.e., increase
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or decrease in enzyme activity) or repeatable across oral exposure studies. Reichlmayr-Lais et
al. (1992) also reported a trend for decreased erythrocyte number and hematocrit in rats exposed
to PtCl4 in the diet for 4 weeks. No studies on the effects of chronic oral exposure of animals to
halogenated Pt salts or Pt compounds were identified.
A series of short-term exposure studies conducted by Holbrook and coworkers (Holbrook
et al., 1976, 1975; Holbrook, 1976) evaluated the effects of repeated exposure of male Sprague-
Dawley rats to three Pt compounds (PtCl4, Pt[S04]2, and Pt02) for durations of approximately
1 or 4 weeks in drinking water or 4 weeks via the diet. Data show small increases in kidney
weight in rats exposed to PtCl4 and Pt(SO.t): in drinking water; however, only rats exposed to
1.63 niM PtCl4 in drinking water (=44.1 mg Pt/kg-day) for 4 weeks demonstrated a statistically
significant increase in kidney weight (i.e., 8% increase in relative kidney weight, p < 0.05). The
authors suggested that dietary administration of (PtCl4, Pt[S04]2, and PtO?) for 1 week may have
decreased activity of hepatic microsomal enzymes (aniline hydroxylase and aminopyrine
demethylase), while exposure for 4 weeks or longer had no effect or increased activity (Holbrook
et al., 1976). However, the inconsistent effects (i.e., increase, decrease, and no change) reported
in these studies on activities of the hepatic microsomal enzymes (see Table 4-8) are difficult to
interpret and do not reflect a clear effect on the 1; '' e observation that intraperitoneal dosing
with PtCl4 prolonged hexobarbital sleeping time in rats provides further evidence that PtCl4 may
alter in vivo cytochrome P450 activity (Holbrook et al., 1976). Limitations in study design (e.g.,
few doses tested, lack of comprehensive evaluation of endpoints such as histopathology, or the
absence of evaluation of standard biochemical or hematological parameters) do not allow for
identification of other potential target organs, characterization of dose-response relationships, or
comparisons of the relative potency of more-soluble (e.g., PtCl4, Pt[SO.t]:) versus less-soluble Pt
compounds (e.g., PtC^).
Reichlmayr-Lais et al. (1992) exposed Sprague-Dawley rats for 4 weeks to PtCl; or PtCl4
in diet at estimated daily doses of 0.001-6 mg Pt/kg-day. A trend (p < 0.06) was observed in rats
treated with PtCl4 for decreased erythrocyte number and hematocrit with approximately 13%
decreases observed in the highest dose PtCl4 for both measures. Plasma creatinine was
significantly (p < 0.05) increased by approximately threefold in the 6 mg Pt/kg-day PtCl4 group,
i i ¦ '¦1 , icing altered renal function. No other measure of renal function or additional information
o , ential histopathologic^! changes to the kidney or other organs was reported. Decreased
erythrocyte count and increased creatinine clearance indicated that 4-week dietary exposure to
PtCl4, but not PtCb, may adversely affect the hematopoietic system and the kidney at the doses
tested.
Roshchin et al. (1984) evaluated the effects of a 6-month dietary exposure of rats to Pt
and palladium powders at doses of 50 mg/kg-day, as well as a 6-month dietary exposure of rats
to (NH4)2PtCl6 and a related palladium compound (Pd[NH3]4Cl2) at doses ranging from 0.05 to
5 mg/kg-day. Treatment effects included reduced body weight gain, decreased prothrombin
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time, increased and decreased serum levels of urea, and decreased P-lipoproteins, although
specific data on dose-response were not reported. Histopathological examinations of tissues
were not conducted. No additional details were reported (e.g., rat strain, sex, number of animals,
preparation of dosing material, magnitude of effect). Because the methods and results of i;
Roshchin et al. (1984) study were not completely reported, it is unclear if the treatment-related
effects observed were from Pt or palladium compounds. In addition, it is unclear if effects . ;
specific for oral exposure or inhalation exposure, which was also evaluated in this study.
In summary, available animal studies identify the kidney as a potential target organ for
the toxicity of soluble and insoluble Pt compounds, although the available information is
insufficient to fully characterize toxicity outcomes or dose-response relationships. Roshchin et
al. (1984) observed epithelial swelling in renal convoluted tubules in rats following acute oral
administration of 25 mg/kg fine powder of Pt group metals (Pt and/or palladium; 1-5 urn
diameter). Although additional data on potential renal effects of acute oral exposure are not
available, rat intraperitoneal LD50 values of 40-50 mg/kg for hexachloroplatinic acid were
associated with death due to renal failure and necrotizing renal tubular lesions throughout the
renal cortex (Ward et al., 1976). In short-term exposure studies, relative kidney weight was
statistically significantly increased by 8% in rats exposed to 1.63 niM PtCU in drinking water for
29 days (approximately 44.1 mg Pt/kg-day) (Holbrook et al., 1975). Decreased renal function, as
indicated by increased plasma creatinine concentration, was observed in rats exposed to 50 mg Pt
per kg diet as PtCU (equivalent to approximately 6 mg Pt/kg-day) for 4 weeks (Reichlmayr-Lais
et al., 1992). These observations are consistent with toxicokinetic studies demonstrating that
both soluble and insoluble environmentally relevant Pt compounds accumulate in the kidney
following oral exposure to	[Pt(SO.t): and PtCU] or insoluble [ PtCl; and Pt metal] Pt
compounds (Artelt et al, 1999a; Reichlmayr-Lais et al., 1992; Massaro et al., 1981; Lown et al.,
1980;Holbr. . ;t al., 1975; Moore et al., 1975a, b; Yoakum et al., 1975). Derivation of an RfD
based on ne;;: ? h oxicity from this relatively limited database of studies would likely result in a
cumulative uncertainty factor (UF) of 10,000 or greater (database, subchronic to chronic,
LOAEL to NOAEL, animal to human, and human variation). Therefore, an oral RfD was not
derived for Pt.
5.2. INHALATION REFERENCE CONCENTRATION (RFC)
5.2.1. Choice of Principal Study and Critical Effect - with Rationale and Justification
Effects in humans resulting from inhalation of Pt include respiratory irritation and effects
associated with allergic sensitization. Typical Pt allergic sensitization to halogenated Pt salts
includes a range of effects. WHO (2000) lists the following pattern of effects following
occupational exposure to halogenated Pt salts: allergic asthma (an inflammatory disorder of the
airways that results in shortness of breath), rhinitis (runny nose and sneezing), cough, wheeze,
dyspnoea (or difficulty breathing) and cyanosis (bluish skin due to insufficient oxygen in blood)
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characteristic of severe asthma, watering of the eyes, itching, urticaria (swollen itching skin), and
contact dermatitis (itching skin eruptions) Among the various effects characteristic of Pt-specific
allergic sensitization, five main effects (asthma, rhinitis, conjunctivitis, urticaria, and dermatitis)
are reported in numerous case reports and occupational studies that identify health effects in
workers exposed to halogenated Pt salts (Cristaudo et al., 2005; WHO, 2000, 1991; Merget.
2000; Merget et al, 2000, 1999, 1988; Calverley et al, 1999, 1995; Bolm-Audorff et al, 19
Baker et al., 1990; Pepys, 1984; Pepys et al., 1972; Marshall, 1952; Hunter et al., 1945).
Additional reports provide support for one or more of the above effects (e.g., asthma—Merget et
al., 1996, 1995, 1994, 1991; Brooks et al., 1990) or other related effects such as respiratory
difficulties (Karasek, 1911), inflammatory changes in the respiratory tract (Merget et al., 1996;
Roberts, 1951), bronchospasms (Calverley et al., 1999), and bronchial hyperactivity (Merget et
al., 1991; Brooks et al., 1990; Biagini et al., 1985a). H ... 	ited to respiratory
irritation or allergic sensitization have not been reported in occupational studies involving
inhalation exposure to Pt compounds.
Symptoms consistent with allergic sensitization nave oeen onserved in workers exposed
to Pt in several types of work environments including photographic studios using halogenated Pt
salts (Hunter et al., 1945); jobs applying halogenated Pt salts by brush to anodes (Harris, 1975);
refinement of Pt involving halogenated Pt salts (Raulf-Heimsoth et al., 2000; Santucci et al.,
2000; Linnett and Hughes, 1999; Newman Taylor et al., 1999; Calverley et al., 1999, 1995;
Merget et al ., 1999, 1996, 1994, 1991, 1988; Niezborala and Gamier, 1996; Bolm-Audorff et al.,
1992; Baker et al., 1990; Brooks et al., 1990; Venables et al., 1989; Biagini et al., 1985a; Jarabek
et al., 1984; Dally et al., 1980; Hughes, 1980; Cromwell et al., 1979; Cleare et al., 1976; Milne,
1970; Parrot et al., 1969; Roberts, 1951; Hunter et al., 1945); and exposure to halogenated Pt
salts in the promotion of Pt catalysts (Cristaudo et al., 2005; Merget et al., 2002, 2001, 2000,
1999, 1996, 1 " ; Raulf-Heimsoth et al., 2000). Allergic sensitization from occupational
exposure via ini tiation to halogenated Pt compounds is a well-established human health hazard
Although the particular Pt compound or compounds involved in many occupational
exposures has not been conclusively demonstrated, evidence suggests that allergic sensitization
is restricted to halogenated Pt salts (Merget and Rosner, 2001; WHO, 2000, 1991). One factor
contributing to the identification of chloroplatinates as relevant compounds in Pt-specific allergic
sensitization is knowledge of the chemistry involved in the production of Pt compounds in
refineries and catalyst production plants. For example, inhalation exposure to Pt compounds in a
Pt refinery includes exposure to halogenated Pt salts (either the complex halogenated Pt salt
ammonium hexachloroplatinate, (NH.t):Pteit1, or sodium hexachloroplatinate, NaPtCl,,) because
Pt is precipitated in the form of a complex halogenated Pt salt in whatever method is used in
refining (Parrot et al., 1969; Hunter et al., 1945).
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Another factor in the identification of Pt compounds responsible for Pt-specific allergic
sensitization is the test used to identify Pt-specific allergy. The SPT used to identify individuals
with allergic sensitization involves applying a small amount of the challenge substance to the
skin, and then the skin is pricked to introduce the substance into the epidermis (described in
detail in Section 4.1.2.1.1). Use of the SPT to identify workers with Pt-specific allergic
sensitization involves positive response to challenge with chlorinated Pt salts. Therefore, the test
for sensitization to Pt compounds is, by definition, a determination of sensitization to chloriiUi., 1
Pt salts, rather than to soluble Pt compounds in general.
Additional SPT data suggest that Pt-specific allergic sensitization is associated with
halogenated Pt salts, rather than chlorinated Pt salts. In a study of workers with Pt-specific
allergic sensitization, Cleare et al. (1976) demonstrated that the SPT was positive to halogenated
Pt salts including Pt salts with either chlorine or bromine ligands. These results also provide
some evidence that halogenated Pt salts may have different sensitizing potencies. Cleare et al.
(1976) reported increasing response associated with an increasing number of chlorine atoms (i.e.,
a stronger response to hexachloroplatinic acid [H2PtCl6] than to Pt tetrachloride [PtCl4]) among
chlorinated Pt compounds. The results from Cristaudo et al. (2005) also support the increasing
allergenicity of Pt compounds associated with ir > number of chlorine atoms, where 22 of
153 workers were SPT positive to H^PtCle and £ , ,»f these 22 individuals had positive SPTs
to Na2PtCl6 (11/22) and K2PtCl4 (12/22).
In vitro and experimental animal data also provide evidence that Pt-specific allergic
sensitization is associated with exposure to halogenated Pt salts. Proliferation and cytokine
release in response to halo . '.,.;: ed Pt salts were demonstrated an in vitro study reporting immune
responses associated with .> iK - pic sensitization in isolated human PBMCs (Di Gioacchino et al.,
2004). Siipp'^^ e evidence for the allergenic activity of halogenated Pt salts is also provided by
evidence foi ; = s> :'gic sensitization and airway effects of inhaled hexachloroplatinate in monkeys
(Biagini et a- : 86, 1985b, 1983). Dermal and parenteral studies conducted in animals provide
further support of the allergenicity of halogenated Pt salts (Dearman et al., 1998; Schuppe et al.,
b, 1992).
striction of Pt-specific allergic sensitization to halogenated Pt salts, rather than just
soluble Pt is supported by data from Cleare et al. (1976) demonstrating that non-halogenated
soluble Pt compounds such as K;Pt(NO;)4 were negative in the SPT in individuals positive to
halogenated Pt salts. No studies were located that demonstrate a positive SPT to a non-
halogenated Pt compound.
As reviewed earlier in Section 4.1, insoluble forms of Pt (Pt metal and Pt02) are
generally considered to be inert and not anticipated to be associated with allergic sensitization
(ACGIH, 2001; Gebel, 2000; WHO, 2000, 1991). In contrast to the numerous studies evaluating
health effects associated with exposure to soluble Pt compounds, only one report evaluating the
health effects of human exposure to inhaled insoluble Pt compounds was identified (Hunter et
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al., 1945). Findings of this study suggest that insoluble Pt compounds do not induce allergic
sensitization. Limited evidence also supports the lack of allergenic potential of insoluble Pt
compounds. Hunter et al. (1945) reported that occupational asthma was not observed in workers
primarily exposed through processes that involved exposure to airborne, insoluble Pt metal.
Furthermore, results of the in vitro study by Di Gioacchino et al. (2004) indicate that insolu" *
PtCb did not have immune effects associated with allergic sensitization (proliferation or cy; ' e
release from isolated human PBMCs), whereas halogenated Pt salts demonstrated immune
activity in this model.
Data suggest that sensitization to the halogenated Pt salts may be related to the halogen-
ligands coordinated to Pt and the negative charge of these comple:	:t al., 2004;
Ravindra et al., 2004; Rosner and Merget, 2000; Cleare et al., 197' -> >¦¦¦¦¦ ty of these Pt
coordinated halogen-ligands with proteins is important in the gene; ; ^	sific immune
response because low molecular weight chemicals such as Pt must aui as Haptens oy binding with
larger endogenous substances before they can generate an «	>nse (see
Sections 4.6.3.1.1-4.6.3.1.3 for a detailed description of haptens and the Type I allergic
response). Support for the importance of this; reactivity of Pt coordinated halogen-ligands is
provided by evidence suggesting that tetraamme Pt dichloride may not cause Pt-specific allergic
sensitization. Results of the retrospective occupational exposure study by Linnett and Hughes
(1999) show that exposure to tetraamine Pt dichloride alone was not associated with sensitization
in workers, whereas mixed exposure to tetraamine Pt dichloride and halogenated Pt salts
(chloroplatinates) was associated with allergic sensitization. Similar results were reported by
Steinfort et al. (2008) in a i votive study of workers at a catalyst manufacture plant in
Melbourne, Australia, whtic uc ^ases of positive SPT were reported among workers with
reported exposure to f Pt(Nf113)4]C1 r- It is important to note that the Linnett and Hughes (1999)
and Steinfort et al. (2008) studies do not include exposure data on the particular Pt compounds to
which workers were exposed, and workers were instead classified by work area without
speciated Pt exposure data. Halide is present as an ion in tetraamine Pt dichloride
i.; i H3 )-t]Cl;) and not a ligand coordinated to Pt; therefore, [Pt(NH3)4]Cl2 is a halogenated
:: : ''.'iex, not a halogenated Pt salt (Linnett and Hughes, 1999; Cleare et al., 1976). The Pt in
'1! iOtlCl; is bonded to nitrogen and ligand substitution necessary to react with proteins is
lely slow and may not take place on a biologically relevant timescale (Cleare et al., 1976).
Parenteral studies in animals also provide evidence supporting the findings of Linnett and
Hughes (1999) that tetraamine Pt dichloride may not have sensitization properties (Schuppe et
al, 1997b).
In summary, the allergenic activity of Pt is compound-dependent and sensitization effects
appear to be restricted to the halogenated Pt salts. There is no evidence of allergic sensitization
following exposure to insoluble Pt compounds. Although exposure data in occupational studies
are only characterized to the extent that soluble Pt concentrations are reported, the specificity of
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the SPT used to identify Pt-specific allergic response demonstrates that occupational allergic
sensitization from exposure to Pt compounds is to chlorinated Pt salts. Furthermore, the wider
application of Pt-specific allergic sensitization to halogenated Pt salts rather than chlorinated Pt
salts is suggested by the data from Cleare et al. (1976) and Cristaudo et al. (2005) demonstrating
that workers with Pt-specific allergic sensitization may have a positive SPT to chlorin
brominated Pt salts.
Most of the case reports and occupational studies that detail Pt allergic sensitization
not contain exposure data. Five epidemiologic studies do provide some exposure information on
total and soluble Pt along with relative incidence of allergic sensitization to halogenated Pt salts
in Pt refinery workers (Linnett and Hughes, 1999; Bolm-Audorff et al, 1992; Baker et al., 1990;
Brooks et al., 1990) and Pt catalyst production workers (Merget et al., 2000; Linnett and Hughes,
1999). These studies are discussed below.
Bolm-Audorff et al. (1992) described a cross-sectional study of the employees of a Pt
refinery in Germany in which a cohort of 65 workers w	hree exposure categories
(high, moderate, and low) on the basis of predicted Pt exposure icvei. Exposure categories were
defined based on the job location of workers, rather than personal air monitoring data. The
incidence of work-related symptoms (conjunctivitis, rhinitis, coughing, or respiratory distress)
was elevated in the high-exposure group (11/21) relative to the moderate- (1/23) and low-
exposure (3/21) groups; however, a NOAEL for allergic sensitization to halogenated Pt salts was
not identified. Individuals with work-related symptoms of respiratory allergy had a higher
incidence of positive SPT with K :PtC1;, than workers in the other exposure groups (64.3, 20.0,
and 2.5% respectively) as well as higher total IgE and Pt-specific IgE levels. This study reported
the occurrence of cases of ^i^uzation to halogenated Pt salts in a workplace in which air
concentrations of soluble Pt appeared to have been below the German occupational exposure
limit of 2 ug soluble Pt/m3 (8-hour TWA). However, the exposure data are too limited to
reliably estimate the air concentrations experienced by workers in the three exposure categories
and the personal air monitoring was only done for a 1-hour period with two filter press workers,
lus, no exposure-response relationship for development of Pt allergic sensitization can be
innett and Hughes (1999) studied the incidence of allergic sensitization associated with
exposure to two types of soluble Pt compounds, halogenated Pt salts (principally
chloroplatinates) and tetraamine Pt dichloride ([Pt(NH3)4]Cl2), in a retrospective study of
medical surveillance data collected over a 20-year period at a Pt processing facility in the United
Kingdom. Exposure categories were defined based on different operations at the same site
involving: (1) chloroplati nates in the refinery area, (2) tetraamine Pt dichloride in the
autocatalyst production area, or (3) a mixed exposure to chloroplati nates and tetraamine Pt
dichloride in the tetraamine Pt dichloride production laboratory. No data on Pt speciation were
provided to substantiate that Pt exposure in the refinery area was restricted to chloroplati nates,
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that there was mixed exposure in the laboratory, or that exposure in the autocatalyst production
area was restricted to tetraamine Pt dichloride. The characterization of Pt sensitization included
specific respiratory challenge and diagnosis of Pt-related symptoms at work by a physician as
Pt-specific SPT to halogenated Pt salts ([NH4]2PtCl6, Na:PtCl„, and Na^CLt) and tetraamine Pt
dichloride. The results show that the cumulative probability of allergic sensitization was
50% after 5 years of exposure in the refinery area where only 2.4% of over 8,000 air sampl
were above 2 ug soluble Pt/m3 and Pt exposure was primarily to chloroplatinates. Similarly, th
cumulative probability of allergic sensitization was 33% after 5 years of exposure in the refinery
area where 28.5% of over 511 samples were above 2 ug soluble Pt/m3 and exposure was to both
chloroplatinates and tetraamine Pt dichloride. In the autocatalyst production area, where air
concentrations of soluble Pt were intermediate and tetraamine Pt dichloride was the primary
compound, the authors calculated a zero probability of allergic set ¦¦¦¦¦¦¦¦¦¦¦¦ n. Thus, tetraamine Pt
dichloride does not show any strong evidence of being a sensitizer. No exposure-response
relationship for development of Pt allergic sensitization to	Pt salts can be derived
from this study and the study does not identify a NOAEL.
Baker et al. (1990) and Brooks et al. (1990) reported results from a single cross-sectional
health study evaluating workers for allergic sensitization to halogenated Pt salts in workers in a
U.S. precious metals reclamation plant in 1981 (Baker et al., 1990; Brooks et al., 1990). Pt salt
concentrations were reported (as an 8-hour TWA) for air samples collected by the company in a
number of work areas during several wor kdays between 1977 and 1979; the number of sampling
days varied with sampling location and ranged from 1 to 9 days. The air samples were collected
by stationary air sampling tec!	l	, r jrsonal air samples for workers in this study were not
collected. The study report did not specify the analytical methods used to determine the Pt salt
concentrations in the collected air samples or report the limit of detection. Among current
workers, positive SPT results were reported in all areas of the facility, except the offices and the
incidence of allergic sensitization to halogenated Pt salts was correlated with the mean air
concentrations of the individuals work areas (Spearman correlation = 0.71; p = 0.11). Work area
concentrations of Pt salts were higher (0.6 fig Pt/m3 Pt salts) for the group of 15 office workers
who were not sensitized than for groups of workers who were sensitized (e.g., 0.4 fig Pt/m3 for
tl :-1 s ilytical laboratories). Thus, a reliable NOAEL for allergic sensitization to halogenated Pt
s; 'as not identified in this study, and the cross-sectional design does not allow assessment of
the subsequent health status of these workers or the status of office workers who may have left
the workplace before the survey. Additionally, no information was provided as to the exclusion
of atopic individuals or those with positive SPTs prior to employment in the designated work
areas.
The study by Merget et al. (2000) tested baseline allergenic sensitivity to halogenated Pt
salts among 275 new and current workers with reassessment after 5 years of follow-up.
Conversion to a positive SPT to the halogenated Pt salt hexachloroplatinic acid result over the
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5-year period was used as an indicator of allergenic sensitization to halogenated Pt salts. For the
exposure assessment, workers were assigned to different exposure categories (high, persistent
low, intermittent low, no exposure) based on job title and location within the plant. Air
monitoring samples were available to quantify Pt exposure to soluble Pt for each category tar
limited personal monitoring samples were available for the high-exposure group. The stud'
analyses excluded atopic individuals and workers with a positive SPT at the start of the stu<
Of the 115 workers in the high-exposure category, 13 (11.3%) developed a positive SPT
response at the end of the 5-year follow-up period. Median concentrations (with lower- and
upper-quartile values noted in parentheses) for the stationary air samples from the high-exposure
catalyst production areas were 0.014 (0.008, 0.041) ug soluble Pt/m3 in 1992 and 0.037 (0.012,
0.064) ug soluble Pt/m3 in 1993. Personal air monitoring data was limited to 1993 and only
collected from the high-exposure group. The median value (with lower- and upper-quartile
values noted in parentheses) for personal air monitoring data was 0.177 (0.093, 0.349) ug soluble
Pt/m , suggesting that stationary air sampling may have underestimated exposure in work areas.
Other than one misclassified case in the persistent low-exposure category, no positive SPT
responses were reported in the other exposure categories. For the low-exposure areas (subjects
in the persistent-low and intermittent-low groups), median (and lower- and upper-quartile)
concentrations were 0.0066 (0.0042, 0.0075) (.ig soluble Pt/m3 in 1992 and 0.0004 (0.0003,
0.0013) ug soluble Pt/m3 in 1993.
The allergenic activity of haloeenated Pt salts is supported by three inhalation exposure
studies in primates and a larger numb - ¦ i dermal and parenteral exposure studies in
experimental animals. The results of the three available subchronic animal studies of inhalation
exposure to Pt (Biagini et al., 1986, 1985b, 1983) support the possibility that co-exposure to
ozone may pr'""ote the development of allergic sensitization to halogenated Pt salts. As
reviewed in ^on 4.5.1 {Sensitization Studies), Biagini et al. (1986) reported sensitization in
1/8 monkey: :. 11 owing subchronic exposure to inhaled ammonium hexachloroplatinate alone
and in 4/8 monkeys exposed to ammonium hexachloroplatinate plus ozone, compared to 0/7 in
those receiving ozone alone. A low response rate is consistent with the characteristics of a Type
I allergic response in humans, in which only a fraction of exposed individuals are expected to
become sensitized (see Section 4.6.3.1, Mode of Action Information, Sensitization). Dermal
application of sodium hexachloroplatinate to mice induced dermal hypersensitivity and a
lymphocyte secretion profile of cytokines consistent with an allergic response (Dearman et al.,
1998; Schuppe et al., 1997a) and parenteral exposure of rats and mice to various chloroplatinates
(e.g., Na2PtCl6, [NH.t]:PtClt1, [NH^PtCU, K2PtCl4,) induced sensitization (Schuppe et al.,
1997b, 1992; Murdoch and Pepys, 1986, 1985, 1984a, b). Results of the Schuppe et al. (1997b)
study in mice and the Pepys et al. (1985, 1984b) studies in rats showing that tetraamine Pt
dichloride ([Pt(NH.04]('l;) did not exhibit immunogenic activity are consistent with results of the
epidemiology study by Linnett and Hughes (1999) showing that no cases of sensitization were
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observed among 39 workers exposed to [Pt(NH3)4]Cl2 in the production of automotive catalysts.
Although available data from animal studies are inadequate to characterize the exposure level-
response relationship for induction of allergic sensitization to halogenated Pt salts in animals
exposed by inhalation, these studies do demonstrate the potential allergic sensitization by
halogenated Pt salts in experimental animals, and thus support the numerous reports of allergic
sensitization to halogenated Pt salts in groups of occupationally exposed workers.
Smoking was identified as a risk factor in the development of Pt-specific
sensitization in several occupational studies of workers in Pt refineries and catalyst production
plants (Cristaudo et al., 2005; Merget et al., 2000; Linnett and Hughes, 1999; Calverley et al.,
1995; Baker et al., 1990; Yenables et al., 1989). However, it is clear that nonsmokers develop
allergic sensitization to halogenated Pt salts in the same occupational environments as do
smokers (i.e., Pt refineries as in Linnett and Hughes, 199'	i i : , 1990; Brooks et al.,
1990; Yenables et al., 1989; and catalyst production plan	¦ ido et al., 2005; Merget et
al., 2000). The adjusted prevalence odds ratio for develo	ensitization to
halogenated Pt salts for smokers relative to nonsmokers ranges irom i.l to 4.66 (OR 1.1, 95%
CI 0.4-3.0 for workers in a catalyst production plant reported by Cristaudo et al., 2005; OR 4.66,
95% CI 1.55-14.0 for workers in a Pt refinery reported by Yenables et al., 1989). The major
effect of smoking as a risk factor appears to be that it decreases the time to developing allergic
sensitization. Venable et al. (1989) reported that after 3 years of occupational exposure, there
was approximately 75% probabilitv that nonsmokers would develop symptoms of allergic
sensitization to halogenated Pf salts, whereas it only took 1 year of exposure for smokers to reach
the same probability of devek:.f	„,_rtoms of allergic sensitization to halogenated Pt salts.
Linnett and Hughes (1999; icpoued similar relative decrease in the time to sensitization for
smokers such that nonsmokers had a cumulative probability of developing allergic sensitization
to halogenated Pt salts of approximately 20% after 2 years and smokers reached the same 20%
probability in <1 year. Merget et al. (2000) reported that 13/115 workers in the high-exposure
group developed allergic sensitization to halogenated Pt salts (as determined by positive SPT)
... 5 years of the prospective study and no workers in the low-exposure category (0/111)
. ...>ped allergic sensitization to halogenated Pt salts. At least 1 of the 13 workers that
j'. 'ped allergic sensitization to halogenated Pt salts developed a positive SPT in each of the
5 years of the study (Merget et al., 2000). The Merget et al. (2000) study identified smoking as a
risk factor for developing Pt-specific allergic sensitization with an age-adjusted relative risk of
3.9 for individuals in the high-exposure category (95% CI 1.6-9.7). Merget et al. (2000) did not
adjust the report of SPT positive individuals in the high-exposure group for smoking
(13/115 workers in the high-exposure group developed Pt-specific allergic sensitization as
determined by a positive SPT). An adjustment for smoking as a risk factor may result in a
reduced adjusted incidence of workers with Pt-specific allergic sensitization; however, it is
unlikely that it would effect the identification of the exposure level of the high dose group as a
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LOAEL. Therefore, inclusion of smokers in the Merget et al. (2000) data is also unlikely to
affect the identification of the exposure level of the low dose group as the NOAEL.
As described above, several epidemiologic studies have found an increased prevalence of
workers with allergic sensitization in halogenated Pt salt-contaminated workplaces with
estimated air concentrations <2 ug soluble Pt/m3 (Merget et al., 2000; Linnett and Hughes, 1999;
Bolm-Audorff et al., 1992; Baker et al., 1990). However, only Merget et al. (2000) provided
adequate exposure assessment data with sufficient documentation of health effects to establish a
dose-response relationship. Therefore, the prospective cohort study among German catalyst
production workers (Merget et al., 2000) was used as the principal study for the derivation of the
chronic RfC. Pt-specific allergic sensitization, as measured by the development of a positive
SPT, was deemed a specific endpoint that resulted from exposure to halogenated Pt salts.
The Merget et al. (2000) study was selected as the principal study for the derivation of
the chronic RfC for a number of reasons. First, Merget et al. (2000) state that at the
concentration of soluble Pt in the low-exposure group no Pt-specific allergic sensitization was
observed in workers in these areas. Therefore, although the authors did not identify a NOAEL,
the exposure concentration in the low-exposure areas can be considered a NOAEL. The
exposure concentration in the low-exposure groiu) i vlerget et al. (2000) represents the only
reliable NOAEL among the five studies with some exposure information and relative incidence
of allergic sensitization to halogenated Pt sal: :¦ ,e;. nd, Merget et al. (2000) provided the most
complete exposure data and the only exposure data that can be linked to allergic sensitization for
the development of dose-response assessment among the available studies. Bolm-Audorff et al.
(1992) included only six total exposure measurements; each sample was obtained from <4 hours
of sampling; and the measuicuiwts could not be directly related to the three categories of
exposure (hi"11. moderate, and low) used by the researchers. Linnett and Hughes (1999)
provided rel - - frequency of exposure levels above and below 2 fig/m3 of soluble Pt, but
absolute cor- i rations were not reported. Baker et al. (1990) and Brooks et al. (1990) did not
icentrations of soluble Pt for all work areas associated with positive SPTs and reported
xntration (0.6 fig/m3 soluble Pt) in an area associated with no positive SPTs (0/15 in
m in other work-areas associated with positive SPT (e.g., 2/19 and 0.4 fig/m3
in the analytical laboratories). Third, Merget et al. (2000) identified the lowest median
workplace Pt air concentrations (i.e., 0.014 and 0.037 fig soluble Pt/m3) associated with a
statistically significant increase in the incidence of workers with allergic sensitization to
halogenated Pt salts. Fourth, Merget et al. (2000) provided more data on duration of exposure
than the other available studies. This is, in part, related to the fact that Merget et al. (2000) was
the only study with a prospective experimental design that increased the sensitivity of detecting
affected individuals compared with the retrospective and cross-sectional design of the other
studies. In addition, Merget et al. (2000) presented information on the time between the initial
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and final survey as well as the duration of working at the same occupation for individuals who
were employed at the start of the study.
Thus, the prospective cohort study among German catalyst production workers (Merget
et al., 2000) was used as the principal study for the derivation of the chronic RfC. Pt-specif
allergic sensitization, as measured by the development of a positive SPT, was selected as th
critical effect resulting from exposure to halogenated Pt salts. No cases of sensitize
developed during the 5-year period in 111 workers (persistent and intermittent lov
groups) who worked in areas with reported median air concentrations of 0.0066 ug soluble Pt/m3
in 1992 and 0.0004 ug soluble Pt/m3 in 1993. Therefore, exposure in the low-exposure group
(persistent and intermittent) represents a NOAEL. In addit	1 ¦¦': f:; the high-
exposure group developed allergic sensitization as determi:	Suring the 5
years of the study and therefore, exposure in this group represents a LOAEL. Reported median
concentrations in stationary air samples in the high-exposuic wiuum wvtv u.uit and 0.037 [ig
soluble Pt/m3 in 1992 and 1993.
5.2.2. Methods of Analysis - Including Models (PBPK, HMD, etc.)
Exposure data from a prospective cohort study among German catalyst production
workers (Merget et al., 2000) were considered for benchmark dose (BMD) modeling for the
development of Pt-specific allergic sensitization, as measured by the incidence of a positive SPT
to hexachloroplatinic acid resultina from exposure to halogenated Pt salts. No individuals in the
low- and no-exposure groutis had a positive SPT, and therefore, exposure concentrations in the
low-exposure group were considered a NOAEL. The available data are of marginal adequacy
for BMD modeling because only three exposure groups (high, low, and no exposure) are
available and only one of these groups has a non-zero response. A large degree of uncertainty
exists when modeling data sets that do not contain at least two non-zero response levels, because
a wide range of curves can be drawn through a single point and a control value (Barnes et al.,
1995). Therefore, BMD modeling was performed for comparison purposes only and the
" ")AKL from the low-exposure group was utilized to derive a point of departure (POD). A
"x mailed discu ission of modeling for each exposure metric is presented in Appendix B. The
:¦: -dieted concentrations associated with 10% extra risk (and the lower 95% confidence limits or
BMC I . io) from these models are consistent with the choice of the NOAEL from the low-
exposure group to derive a POD.
Airborne Pt concentrations were measured for each of the exposure groups using
stationary air sampling in 1992 and 1993. Personal air monitoring was performed in 1993 in the
high-exposure group only (see Section 4.1.2.1.2 Toxicity of soluble forms ofPt: epidemiologic
evidence of Pt allergic sensitization for study details). Personal air monitoring data were not
used for modeling because of the small sample size and the fact that data collection was
restricted to a single year in the high-dose group only.
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The raw exposure data used to generate Figure 1 in Merget et al. (2000) were obtained
from the lead author of the study and used to calculate the arithmetic means (pooled and
unpooled across years), geometric means (pooled and unpooled across years), medians (pooled
and unpooled across years), and mid-medians of Pt air concentrations for the three groups of
workers in the high-exposure, low-exposure, and no-excess-exposure categories based on tl ; >
work locations. A detailed discussion of the derivation of these exposure metrics is present :
Appendix B. The exposure data from stationary air samplers in 1992 and 1993 show a large
degree of variation both within years and between years (Table 5-1). The arithmetic mean across
both years is thought to be the most appropriate representative value for the general class of
exposure measurements presented in Merget et al. (2000). Although the geometric mean is a
convenient parameter for describing the central tendencies of lognormal distributions, the
arithmetic mean concentration is the most appropriate representative value to estimate an
individual's long-term average exposure (Crump, 1998; Mage, 191 /; The choice of the
arithmetic mean concentration as the appropriate exposure measure uerives from the need to
estimate an individual's long-term average exposure. Thereiore, tne arithmetic mean across both
years (52.9, 3.37, and 0.048 ng soluble Pt/nr tor tne mgn-, low-, and no-exposure groups,
respectively) was selected as the most appro; ¦ : -, metric for these exposure measurements.
Table 5-1. Concentration of soluble Pt for endi exposure group in German catalyst
production workers
Exposure
group
Arithmetic mean3
(ng soluble Pt : ¦ :

c mean3
e Pt/m3)
Median3
(ng soluble Pt/m3)
Incidence of
workers with
positive SPT
1992
1993

1992
1993
Pooled
1992
1993
Mid-
median
Pooled
High
Mean or
median
61.6
41.4
jz..y
20.7
27.7
23.5
13.5°
36.5d
25.5
18.0
13/115
SEb

9.62
19.7
1.38
1.34
1.25
NA
NA
NA
NA
n

12
28
16
12
28
16
12
28
28
Low
Mean or
median
6.06
0.675
3.37
5.78
0.376
1.48
6.55e
0.400f
3.48
2.45
0/111
SEb
0.664
0.211
0.773
1.13
1.62
1.53
NA
NA
NA
NA
N
8
8
16
8
8
16
8
8
16
16
No
Mean or
median
0.047
0.050
0.048
0.044
0.050
0.046
0.045
0.050
0.048
0.050
0/48
."ib
0.007
0.000
0.005
1.150
1.000
1.097
NA
NA
NA
NA
n
8
4
12
8
4
12
8
4
12
12
aAll of the statistics in this table were calculated directly from the raw data used to generate Figure 1 in Merget et al., 2000 as
provided by Dr. Merget.
bSEs are provided here, but the quartiles provided in Appendix B were regarded as more appropriate indicators of heterogeneity
and variability in the medians and mid-medians. See Appendix B for further discussion.
"Calculated value equivalent to 0.014 jig soluble Pt/m3 reported in Mergetet al., 2000.
Calculated value equivalent to 0.037 jig soluble Pt/m3 reported in Mergetet al., 2000.
Calculated value equivalent to 0.0066 jig soluble Pt/m3 reported in Mergetet al., 2000.
'Calculated value equivalent to 0.0004 jig soluble Pt/m3 reported in Mergetet al., 2000.
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As described above, although allergic sensitization from occupational exposure via
inhalation to halogenated Pt salts is a well-established human health hazard (WHO, 2000, 1991),
most of the case reports and occupational studies that demonstrate allergic sensitization to Pt
compounds do not contain exposure data. Even in the available epidemiologic studies that
demonstrate increased prevalences of workers with allergic sensitization to halogenated Pt¦¦¦/'I
with associated exposure data (Merget et al., 2000; Linnett and Hughes, 1999; Bolm-Audoi:: <:(
al., 1992; Baker et al., 1990), the measurements of Pt compounds are limited to determination of
soluble Pt/m3 or total and soluble Pt/m3 and are not further characterized. Although t
particular Pt compound or compounds involved in many occupational exposures has not been
conclusively demonstrated, evidence suggests that allergic sensitization is restricted to
halogenated Pt salts. In each case, the work environment of a	i >alyst
production plant where individuals become sensitized to Pt compouna> mvuivra exposure to
chloroplatinates (e.g., ammonium hexachloroplatinate, potassium ncxaauuroplatinate, and
chloroplatinic acid), but the analytical methods only genetically identify soluble Pt compounds.
One factor contributing to the identification of chloroplati nates as relevant compounds in
Pt-specific allergic sensitization is knowledge of the chemistry involved in the production of Pt
compounds in refineries and catalyst production plants. Inhalation exposure to Pt compounds in
a Pt refinery includes exposure to the complex halogenated Pt salt ammonium
hexachloroplatinate (NH4)2PtCl6 or sodium hexachloroplatinate NaPtCl,, because Pt is
precipitated in the form of one of these complex halogenated salts in whatever method is used in
refining (Parrot et al., 1969; Hunter e .j. 1945).
Another factor in the identification of Pt compounds responsible for Pt-specific allergic
sensitization is the test used to identify Pt-specific allergy. The SPT used to identify individuals
with allergic digitization involves applying a small amount of the challenge substance to the
skin, and th< ¦.;. : skin is the pricked to introduce the substance into the epidermis. Detailed
information on. the use of the SPT in the diagnosis of allergic sensitization is provided in Section
4.1.2.1.1 Toxicity of soluble forms of Pt: Diagnosis of Pt allergic sensitization and Section
4.6.3.1.4 Utility of SPT as an endpoint to identify Pt-specific sensitization. Use of the SPT to
identify workers with Pt-specific allergic sensitization involves positive response to challenge
with chlorinated Pt salts (e.g., hexachloroplatinic acid [H2PtCl6] in Merget et al., 2000;
ammonium hexachloroplatinate [CNH-thPtCl,,], sodium hexachloroplatinate [Na:PtCl„], and
sodium tetrachloroplatinate [N^PtCU] in Linnett and Hughes, 1999, potassium
hexachloroplatinate [K.;Pt('*l,,] in Bolm-Audorff et al., 1992; and ammonium hexachloroplatinate
[(NH4)2PtCl6] and sodium hexachloroplatinate [Na2PtCl6] in Baker et al., 1990). Therefore, the
test for sensitization to Pt compounds is, by definition, a determination of sensitization to
chlorinated Pt salts, rather than to soluble Pt compounds in general, although the exposure data
only identifies soluble Pt compounds. The study by Cleare et al. (1976), comparing the
responses to various Pt compounds as determined by the results of the SPT in workers with
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known allergic sensitization to Pt, is particularly useful in further refining which Pt compounds
are important to Pt-specific allergic sensitization. Cleare et al. (1976) demonstrated that the SPT
was positive to halogenated Pt salts with increasing response associated with an increasing
number of chlorine atoms (i.e., a stronger response to hexachloroplatinic acid [H;Pt('*l,,] than to
Pt tetrachloride [PtCU]) among chlorinated Pt compounds. Exchanging bromine for chlorine in
halogenated Pt salts also resulted in positive SPTs, with a similar distribution of potency for
brominated Pt salts relative to the number of bromine atoms (Cleare et al., 1976). Data from
Cleare et al. (1976) also show that non-halogenated soluble Pt compounds such as K;PtCNO;)4
were negative in the SPT. A recent study by Cristaudo et al. (2005) found a similar result where
22 of 153 workers were SPT positive to FI2PtC*lt, and a subset of these 22 individuals had positive
SPTs to Na2PtCl6 (11/22), K2PtCl4 (12/22), IrCl3 (3/22), and RhCh (2/22). Limited evidence
also supports the lack of allergenic potential of insoluble Pt compounds. Hunter et al. (1945)
reported that occupational asthma was not observed in workers primarily exposed through
processes that involved very heavy exposure to airborne, insoluble Pt metal. Furthermore,
results of the in vitro study by Di Gioacchino '	•) indicate that insoluble PtCl2 did not
have immune effects (proliferation or cytokine release trom on isolated human PBMCs),
whereas halogenated Pt salts demonstrated immune activity in this model. In summary, although
exposure data in occupational studies are only characterized to the extent that soluble Pt
concentrations are reported, the specificity of the SPT used to identify Pt-specific allergic
response demonstrates that occupational allergic sensitization from exposure to Pt compounds is
to chlorinated Pt salts. Furthermore, the data from Cleare et al. (1976) and Cristaudo et al.
(2005) demonstrated that Pt-sensitized workers as determined by a positive SPT to one
halogenated Pt salt may have a positive response to other halogenated Pt salts including
brominated l>t "fits. Therefore, the exposure data on soluble Pt/m3 from Merget et al. (2000) and
the positive SPT to the halogenated Pt salt hexachloroplatinic acid is used to derive an RfC for
halogenated ; ¦ i v:Jts,
Merget et al. (2000) was selected as the principal study (Section 5.2.1) and the
development of Pt-specific allergic sensitization as determined by a positive SPT to
hexachloroplatinic acid was selected as the critical effect as a measure of allergic sensitization to
halogenated Pt salts. The arithmetic mean exposure level of the low-exposure group of 3.37 ng
soluble Pt/m3 from Merget et al. (2000) represented the NOAEL used to derive the POD for the
development of an RfC for halogenated Pt salts.
5.2.3. RfC Derivation - Including Application of Uncertainty Factors (UFs)
The incidence of positive SPT to hexachloroplatinic acid was selected as the critical
effect as a measure of allergic sensitization from the prospective health survey of workers in a
German catalyst production plant (Merget et al., 2000) and exposure data from that study were
used to derive the RfC for halogenated Pt salts for the reasons described above. The data from
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Merget et al. (2000) were of marginal adequacy for BMD modeling because only three exposure
groups (high, low, and no exposure) were available and only one of the exposure levels had a
non-zero response. Therefore, the BMD modeling was done for comparison purposes only, and
the RfC is based on a NOAEL of 3.37 ng soluble Pt/m3. Because the RfC is a standard
applicable to continuous lifetime exposure, EPA guidance (U.S. EPA, 1994b) provides
mechanisms for adjusting for differences between 8 hour, 5 days/week occupational exposures
and non-occupational 24 hour, 7 days/week predicted exposures using the following equation:
NOAELadj = NOAEL (mg/m3) x (VEho/VEt
where:
NOAEL adj is the dosimetrically adjusted NOAEI
NOAEL is the TWA occupational exposure level
VEho is the human occupational default minute v
VEh is the human ambient default minute volume (20 m3/da
Therefore:
NOAEL = 3.37 ng soli
= 3.37 x 10"6
NOAELadj =3.37 x 10"6 mg soluble Pt/m" x (10 m3/day / 20 m3/day) x 5 days / 7 days
= 1.20 x 10"6 n.5 sviuuio . i/m3
A total UF of 1,000 was applied to this POD to derive the RfC: 10 for consideration of
interindividual variability (UFh: human variability), 10 for extrapolation from a subchronic
study (UFS), and 10 for database deficiencies (UFD). The rationale for the application of the UFs
is described below.
A default factor of 10 was used to account for variation in susceptibility among members
of the human population (UFH). The population examined in the Merget et al. (2000) study was
oi i rs in a German catalyst production plant. As the working population may be healthier than
the general population (i.e., the "healthy worker effect"), this population is not expected to
ent the variation in susceptibility among the general population. Insufficient information is
available to predict potential variability in susceptibility among the general population to
sensitization from inhaled halogenated Pt salts.
A default factor of 10 was used to account for uncertainty in extrapolating from a
subchronic to chronic (UFS) exposure duration since the Merget et al. (2000) study, which was
selected as the principal study, is 5-year prospective cohort study. The prevalence of the critical
effect (i.e., positive SPT as a measure of allergic sensitization to halogenated Pt salts) increases
with increasing exposure duration. However, the information from available epidemiologic
W1 WJLJLWWi- was observed;
ly); and
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studies is inadequate to specify the duration of exposure necessary to cause allergic sensitization
to halogenated Pt salts. The duration of exposure necessary to develop allergic sensitization is
likely to depend on exposure dose, frequency of exposure, and biological half-life of the allergen
(Scott et al., 2002), as well as interindividual variation. As discussed in Section 4.6.3.1 Mode of
Action Information, Sensitization, a Type I hypersensitivity response requires more than on
exposure to develop a response. Hypersensitivity, in general, may develop after relatively i. ¦
exposures or after years of exposure (as in the data from Merget et al., 2000). There is evidenc
of allergic sensitization to Pt developing within an exposure duration range of 1 to 108 months
from the retrospective analysis of Pt refinery workers by Linnett and Hughes (1999) and a range
of 1 to 5 years in the prospective study by Merget et al. (2000). Ten of the 13 individuals who
became sensitized to halogenated Pt salts in the Merget et al. (2000) study were newly employed
workers and 3 had already worked at the plant before the initial survey (for 68, 16, and
10 months). One of the 13 workers who developed Pt-specific allergic sensitization (i.e.,
positive SPT) did so during the first year and another worker developed sensitization the second
year. Nine workers developed allergic sensitization in the third year, and the last two became
sensitized in years 4 and 5 of the study. An incidence rate of 5.9 per 100 person-years was
calculated for newly employed workers, and an incidence rate of 2.1 per 100 person-years was
calculated for those who had already worked at the plant before the initial survey. In summary,
although allergic sensitization may develop with relatively few exposures, evidence suggests that
the likelihood of developing allereic sensitization to halogenated Pt salts increases with
increasing exposure duration and a UF was, therefore, used to account for uncertainty in
extrapolating from a subchroii...		.ic exposure.
A UFd of 10 was used to account for deficiencies in the Pt database. The database
includes multiple case reports as well as several epidemiological studies of allergic sensitization
from inhalation exposure to halogenated Pt salts to support the prospective cohort study among
German catalyst production workers selected as the key study (Merget et al., 2000). Although
inhalation exposure is probably the most common route of exposure for the development of
llergic sensitization to compounds in general, data support the development of allergic
ion and respiratory effects including allergic asthma to some chemicals following
exposure alone (Kimber and Dearman, 2002). Available data from occupational studies
do not allow the determination of the relevance of dermal exposure in the development of
allergic sensitization to halogenated Pt salts. Results from animal studies provide evidence to
support the numerous reports of allergic sensitization to halogenated Pt salts in groups of
occupationally exposed workers including the development of hypersensitivity following dermal
application of hexachloroplatinate to mice (Dearman et al., 1998; Schuppe et al., 1997a). In
addition to the relevance of dermal exposure to the development of allergic sensitization to
halogenated Pt salts, there are two major sources of uncertainty associated with deficiencies in
the database. First, there is a lack of data on the potential for inhalation exposure to Pt
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compounds to cause adverse effects other than allergic sensitization. There are no inhalation
developmental toxicology studies, and the data on reduced body weights in offspring from the
only oral developmental study (acute exposure to Pt[S04]2 with limited toxicological endpoints)
in the database suggests that Pt compounds may be toxic to the developing fetus and neonate.
The inhalation (and oral) toxicity database is also lacking a two-generation reproductive toxicity
study. Second, there are animal data showing that inhalation exposure to Pt compounds
(including PtCl4, Pt[S04]2, Pt02, and Pt metal) results in preferentially distribution of Pi l,'
kidney, liver, spleen, and bone (Moore et al., 1975a).
The potential for Pt accumulation in the kidney is of particular concern because there is
some evidence of potential nephrotoxicity associated with Pt compounds following oral exposure
(i.e., increased kidney weight and decreased renal function, as indicated by increased plasma
creatinine concentration, in rats exposed to PtCl4, (Holbrook et al., 1975; Reichlmayr-Lais et al.,
1992). Interpretation of the animal data suggesting nephrotoxicity is complicated by inadequate
study design, limited number of Pt compounds tested, and fe v. ;: . .. levels such that data were
not sufficient for characterizing a dose-response. However, the above observations suggestive of
nephrotoxicity are consistent with oral toxict ¦ in'/tic studies in animals demonstrating renal
accumulation of soluble [Pt(S04)2 and PtCUj and insoluble [PtCl2 and Pt metal] environmentally
relevant Pt compounds (Artelt et al., 1999a; Reichlmayr-Lais et al., 1992; Massaro et al., 1981;
Lown et al., 1980; Holbrook et al., 1975; Moore et al., 1975a, b; Yoakum et al., 1975) and the
clinical literature on Pt anticai , ..gents (particularly the nephrotoxicity associated with
cisplatin). The analysis of the scientific information available for Pt compounds as a whole
supports the utilization of. ^ ^ase UF of 10.
A I,IF was not needed for extrapolation from animals-to-humans or from a LOAEL to a
NOAEL ;.u> human dat? c,m«orting a NOAEL was used as the POD.
The chronic RFC for halogenated Pt salts was calculated as follows:
RfC = NOAELadj - UF
10"6 mg soluble Pt/m3 1000
10"9 or 1 x 10"9 mg soluble Pt/m3 (rounded to one significant figure)
Note that the RfC applies to halogenated Pt salts as available evidence does not support
allergic sensitization to insoluble forms of Pt (e.g., Pt02 or Pt metal) or non-halogenated soluble
Pt compounds. The use of the RfC for Pt compounds other than halogenated Pt salts is not
recommended as the similarity between these compounds and other soluble forms of Pt
compounds is unknown.
5.2.4. Previous RfC Assessment
A previous IRIS assessment was not available for halogenated Pt salts and Pt compounds.
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5.3. UNCERTAINTIES IN CHRONIC ORAL REFERENCE DOSE (RfD) AND
INHALATION REFERENCE CONCENTRATION (RfC)
Risk assessments need to portray associated uncertainty. The following discussi. ;
identifies uncertainties associated with the RfC for halogenated Pt salts. As presented ear!i
Sections 5.2.2 and 5.2.3, UFs were applied to the POD in order to derive the RfC. Factors
accounting for uncertainties associated with a number of steps in the analyses were adopted to
account for a diverse population of varying susceptibilities, extrapolating "	lie to
chronic exposure duration, and database deficiencies. These extrapolatio : v,.\:; 11 v out with
current approaches to inform individual steps given the limited occupati OliUl UUIU Uii AJLtt-AW genated
Pt salts and Pt compounds.
A limited range of toxicology data is available for the hazard assessment of halogenated
Pt salts and Pt compounds, as described throughout the previous chapters (Chapters 4 and 5).
For the oral exposure route, human data are restricted to a single case report of intentional
ingestion of a photographic solution containing potassium tetrachloroplatinate (Cl4K2Pt). No
chronic studies (of either oral or inhalation exposure) in animals exposed to Pt compounds are
available and only limited subchronic or short-term animal studies of oral exposure to Pt
compounds were identified. The kidney may be a target organ for some Pt compounds based on
data suggesting an 8% increase in relative kidney weight in rats exposed to PtCl4 in drinking
water (Hoibrook et al., 1975), increased plasma creatinine concentration indicating decreased
renal function in rats exposed to PtCL, (Reichlmayr-Lais et al., 1992), and toxicokinetic studies
in experimental animals dt n > - > rating renal accumulation of soluble and insoluble Pt
compounds. The available, ^uuios were not suitable for quantitation of effects for various
reasons incl"H: basic endpoints such as histology. Derivation of an RfD for nephrotoxicity
from the available data would likely result in a composite uncertainty factor of 10,000 or greater
(database, subchronic to chronic, LOAEL to NOAEL, animal to human, and human variation).
The lack of a study or studies with adequate dose-response data to derive an RfD with less
uncertainty represents a critical data gap in the oral database given the effects demonstrated.
The inhalation database includes several acute and subchronic exposure studies in
cynomolgus monkeys designed to investigate allergic sensitization associated with exposure to
Pt compounds, several epidemiologic studies (including a single prospective occupational study
from which a NOAEL can be identified for development of allergic sensitization to halogenated
Pt salts [Merget et al., 2000]), and numerous case reports of workers who developed Pt
sensitization after occupational exposure to Pt compounds. There are few acute or subchronic
inhalation toxicity studies of animals exposed to Pt compounds, but limitations in study design or
reporting do not allow identification of health hazards other than allergic sensitization. Although
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the allergenic activity of halogenated Pt salts is supported by inhalation, dermal, and parenteral
exposure studies in experimental animals, the available animal data are inadequate to
characterize the exposure level-response relationship for induction of allergic sensitization to
halogenated Pt salts. Three animal studies of allergic sensitization to Pt by inhalation exposure
were located (two subchronic exposure study in primates by Biagini et al. [1986, ! 983 j and one
acute study by Biagini et al. [1985b] also in primates). These primate studies su
possibility that co-exposure to ozone may promote the development of allergic sensitization to
halogenated Pt salts. Critical data gaps have been identified and uncertaintie ;;;¦:¦¦¦. with
data deficiencies are more fully discussed below.
There are several sources of uncertainty that relate to exposure and the exposure
measurements of Pt compounds. The first is the identification of the ]	. compound or
compounds associated with allergic sensitization. Althoi	' Sutaiuz.aiiuii from
occupational exposure via inhalation to halogenated Pt salts is o wwcsutulished human health
hazard (WHO, 2000, 1991), most of the case reports and	itudies that demonstrate
allergic sensitization to Pt compounds do not contain exposure data, r.ven in the available
epidemiologic studies that demonstrated an increased prevalence of workers with allergic
sensitization to halogenated Pt salts and include! ¦ " re data (Merget et al., 2000; Linnett and
Hughes, 1999; Bolm-Audorff et al., 1992; Baker et al., 1990), the measurements of Pt
compounds are limited to determination of soluble Pt/m3 or total and soluble Pt/m3 without
characterization of the par	;! ¦< unds present. Although exposure data in occupational
studies is only characterized to the extent that soluble Pt concentrations are reported, the
specificity of the SPT used to 	... .-specific allergic response demonstrates that
occupational allergic senski^uud from exposure to Pt compounds is to chlorinated Pt salts. The
data from C,Mre et al. (1976) demonstrated that among occupationally exposed workers an
individual w -: positive SPT to one halogenated Pt salt may also have a positive response to
other haloge: -4 Pt salts including brominated Pt salts.
The second source of exposure-related uncertainty is derived from evidence suggesting
variation in the potency of different halogenated Pt salts to induce Pt-specific allergic
sensitization. Results of challenges to various halogenated Pt compounds using the SPT in
sensitized Pt refinery workers suggest that the degree of allergic reaction was related to the
number of chlorine atoms in a series of chlorinated Pt salts, with the highest activity (i.e.,
IgE-mediated inflammation) associated with greater number of chlorine atoms (Cleare et al.,
1976). Exchanging bromine for chlorine appeared to reduce the allergenicity, with a similar
distribution of potency as for the chlorine-containing halogenated Pt salts (Cleare et al., 1976).
The results from Cristaudo et al. (2005) also support the increasing allergenicity of halogenated
Pt salts associated with increasing number of chlorine atoms, where 22 of 153 workers in a
catalyst processing plant were SPT positive to H;PtClt1 and a subset of these 22 individuals had
positive SPTs to Na2PtCl6 (11/22) and K2PtCl4 (12/22). Data suggest that sensitization to the
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halogenated Pt salts may be related to the strength of the Pt ligand bond of halogen-ligands
coordinated to Pt and the ability of these complexes to react with endogenous proteins (see
Section 4.6.3.1.1 for a detailed description of haptens and the Type I allergic response)
(Nischwitz et al., 2004; Ravindra et al., 2004; Rosner and Merget, 2000; Linnett and Hughes,
1999; Cleare et al., 1976). The potential variation in sensitizing potency among halogens
salts is complicated by the lack of exposure data to specifically identify the halogenated Pt sal'
associated with the development of allergic sensitization.
The third source of uncertainty in the exposure measurements of Pt < >; > ;: )ounds is the
variation in the exposure measurements from Merget et al. (2000). Exposure data from the
stationary air samplers were collected for sampling times that varied between 12 and 17 hours.
Thus, the reported air concentrations from the stationary air samples represent 12- to 17-hour
TWA concentrations. Although the study author indicated that there were three 8-hours shifts
over the 24-hour production in the plant and that there were no differences between work shifts
or workplace activity (email from Dr. Rolf Merget, Research Institute for Occupational
Medicine, Institutions for Statutory Accident Insurance and Prevention, University Hospital
Bergmannsheil, Ruhr University, Bochum, Germany to Andrew A. Rooney, U.S. EPA, dated
September 23, 2008), there are no data on potential fluctuations in Pt concentrations throughout
the workday. The Pt air concentration data from stationary monitors was highly variable,
particularly in the high-exposure dose groups. Exposure estimates for workers in the high-
exposure group were highly variable (100- and 1,000-fold variations were reported for stationary
air and personal monitoring air samples, respectively). The variation in exposure measurements
contribute to the uncertain:, v ; ciated with exposure levels necessary for the development of
Pt-specific allergic sensitization in the workers described in Merget et al. (2000). The variation
of Pt air cotv",tration measurements in the low-exposure group was lower (60-fold overall,
2.5-fold in t i ^iitples from 1992, and 11.5-fold in the samples from 1993) than the variation in
the high-exp' -e group. This variability is due, in part, to the temporal variability of the
concentrations from one day to another as well as the spatial heterogeneity due to the placement
of the monitors at different locations within the plant. The number of monitors also depends on
le dose group. The variability of Pt concentrations from personal monitors is even
larger because it also includes variability introduced by the movement of workers among the
several areas of the plant. Epidemiologists often call this statistical variation in exposure
"measurement error" or "exposure misclassification error". It may also include analytical error,
but this is typically a relatively small component. The typical effect of exposure measurement
error on dose-response models is to attenuate or flatten the apparent effect of dose on response
(Carroll et al., 1995). In lab animal toxicology studies, the doses are determined with relatively
much greater precision than in epidemiologic studies such as Merget et al. (2000). Exposure
measurement in Merget et al. (2000) is not much more variable than in some other studies. If it
were possible to precisely measure the individual exposures, the typical result would be a steeper
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dose-response curve than would be calculated by using a single-number summary of the
exposure distribution, whether it is the arithmetic mean, median, geometric mean, mid-median,
or any other single statistic to characterize the entire distribution of exposures. There are a
number of computational statistical methods for adjusting dose-response for exposure
measurement error, but these are not implemented in a NOAEL or in BMD Software (BMDS) if
BMD modeling had been utilized to derive the POD. Consequently, there are a number of
exposure considerations that contribute to uncertainties in the assessment.
Consideration of the available dose-response data to determine an ' ; n = te of inhalation
exposure that is likely to be without an appreciable risk of adverse health effects over a lifetime
led to the selection of a prospective health survey of workers in a German catalyst production
plant (Merget et al., 2000) as the principal study, and the increased incidence of Pt sensitization
to halogenated Pt salts as the critical effect for deriving the RfC for halogenated Pt salts.
Although several epidemiologic studies have found an increased prevalence of workers with
allergic sensitization in halogenated Pt salt-contaminated workplaces with estimated air
concentrations <2 ug soluble Pt/m3 (Merget et al., 2000; Linnett and Hughes, 1999; Bolm-
Audorff et al., 1992; Baker et al., 1990), only the study by Merget et al. (2000) provided
adequate exposure assessment data with sufficient health effects data to establish a dose-response
relationship.
The derived RfC was quantified using a NOAELAdj for the POD. The exposure data are
of marginal adequacy for BMD modelinu because only three exposure groups (high, low, and no
exposure) were available from the Merget et al. (2000) study and only one exposure group had a
non-zero response as no indiv			 „ther the low or no-exposure groups had a positive SPT.
Therefore, the use of a NG,	was used for the POD rather than a POD identified by an
effect level concentration (i.e., benchmark concentration [BMC]) because of the large degree of
uncertainty in modeling data sets that do not contain at least two non-zero response levels as an
unlimited range of curves can be drawn through a single point and a control value (Barnes et al.,
1995). A POD based on a LOAEL or NOAEL is, in part, a reflection of the particular exposure
~ titration observed in an occupational study or the exposure concentration or dose at which
¦ifi i-ii iual study was conducted. It lacks characterization of the dose-response curve and for this
j u > is less informative than a POD defined by an effect level concentration (i.e., BMC)
ed from BMD modeling of appropriate dose-response data.
Heterogeneity among humans is another uncertainty associated with extrapolating doses
from occupational exposure studies to non-occupational exposures of the general population.
Uncertainty related to human variation also needs consideration in extrapolating dose from a
subset or smaller-sized population (e.g., one sex or a narrow range of life stages typical of
occupational epidemiologic studies, to a larger, more diverse population). Human variation may
be larger or smaller; however, Pt-specific data on human variation in the development of allergic
sensitization to examine the potential magnitude of over- or under-estimation is unavailable.
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Consideration of smoking as a risk factor represents an uncertainty associated with
extrapolating doses associated with the development of Pt-specific allergic sensitization from
occupational exposure studies to non-occupational exposures of the general population. Several
occupational studies of workers in Pt refineries and catalyst production plants identify smoking
as a risk factor in the development of allergic sensitization to halogenated Pt salts (Merget n. "
2000; Linnett and Hughes, 1999; Calverley et al., 1995; Baker et al., 1990; Yenables et al.,
1989). However, it is clear that nonsmokers develop allergic sensitization to halogenated Pi 	s
in the same occupational environments as do smokers (i.e., Pt refineries as in ¦=ett and
Hughes, 1999; Baker et al., 1990; Brooks et al., 1990; Yenables et al., 1989; catalyst
production plants as in Cristaudo et al., 2005; Merget et al., 2000). The adjusted prevalence odds
ratio for developing allergic sensitization to halogenated Pt salts for smokers relative to
nonsmokers ranges from 1.1 to 4.66. The Merget et al. (2000) study identified smoking as a risk
factor for developing Pt-specific allergic sensitization with an age-adjusted relative risk of 3.9 for
individuals in the high-exposure category (95% CI 1.6-9.7). The major effect of smoking as a
risk factor appears to be that it decreases the time to developing allergic sensitization. Yenable
et al. (1989) reported that after 3 years of occupational exposure, there was approximately 75%
probability that nonsmokers would develop symptoms of allergic sensitization to halogenated Pt
salts, whereas it only took 1 year of exposure for smokers to reach the same probability of
developing symptoms of allergic sensitization to halogenated Pt salts. Merget et al. (2000)
reported that 13/115 workers in the high-exposure group developed allergic sensitization to
halogenated Pt salts (as determined by positive SPT) during 5 years of the prospective study and
no workers in the low-exposure category (0/111) developed allergic sensitization to halogenated
Pt salts. At least 1 of the 13 workers who developed allergic sensitization to halogenated Pt salts
developed a positive SPT in each of the 5 years of the study (Merget et al., 2000). Merget did
not adjust the report of SPT positive individuals in the high-exposure group for smoking
(13/115 workers in the high-exposure group developed Pt-specific allergic sensitization as
determined by a positive SPT). An adjustment for smoking as a risk factor may result in a
~~~' ~ :4 "^>7-ted incidence of workers with Pt-specific allergic sensitization; however, it is
t would effect the identification of the exposure level of the high dose group as a
LOAEI.. Therefore, inclusion of smokers in the Merget et al. (2000) data is also unlikely to
effect the identification of the exposure level of the low dose group as the NOAEL.
Data gaps have been identified with regards to general toxicity studies from either oral or
inhalation exposure to halogenated Pt salts or other Pt compounds. Although limited animal
studies are available that were designed to examine allergic sensitization associated with
halogenated Pt salts, the database lacks oral or inhalation exposure subchronic and chronic basic
toxicology studies for halogenated Pt salts or other Pt compounds. The database lacks a
multigenerational reproductive toxicity study and neurotoxicity studies. Limited developmental
toxicity data are available for oral exposure to Pt(S04)2, and no developmental toxicity studies
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are available for Pt compounds by the inhalation route of exposure. Although the database of
case reports and occupational studies supporting allergic sensitization resulting from inhalation
exposure to halogenated Pt salts is adequate, information on the role of dermal exposure in the
development of allergic sensitization and respiratory effects including allergic asthma is not
available. Inhalation exposure is probably the most common route of exposure for the
development of allergic sensitization to compounds in general; however, some data support the
development of allergic sensitization and respiratory effects including allergic asthma to some
chemicals following dermal exposure alone (Kimber and Dearman, 2002^ ; ail able data from
occupational studies do not allow the determination of the relevance of di a: exposure in the
development of allergic sensitization to halogenated Pt salts. Results froi.. animal studies
provide evidence to support the numerous reports of allergic sensitization to halogenated Pt salts
in groups of occupationally exposed workers including the develo .';s ,/ hypersensitivity
following dermal application of hexachloroplatinate to mice (Deal man ct al., 1998; Schuppe et
al., 1997a). The lack of a sufficient study to derive an RfD represents a critical data gap in the
oral database given the potential fornephroti ^ ^ a..!,:^sted by the toxicokinetic studies
demonstrating renal accumulation of soluble [Ft(SU4)2 and PtCU] and insoluble [PtCl; and Pt
metal] environmentally relevant Pt compounds, the clinical literature on Pt anticancer agents
(particularly the nephrotoxicity associated with cisplatin), and the evidence for increased kidney
weight and increased plasma creatinine concentration in rats exposed to PtCl4.
The use of a positive response in the SPT to hexachloroplatinic acid represents an
uncertainty as a measure of allergic sensitization resulting from exposure to halogenated Pt salts.
As discussed in Section 4j - ¦ : - < Utility of the SPT as an endpoint to identify Pt-specific
sensitization, close to 10% ^ j/i i0) of workers identified as having allergic sensitization to
halogenated l>t "fits had a negative SPT in the retrospective study of 406 U.K. refinery workers
reported by ; : ^ r.Jt and Hughes (1999). Among the 10 SPT-negative cases, 1 was positive in a
patch test, 1 : , positive in a specific bronchial challenge test, 1 had work-related upper
respiratory symptoms, and 7 had bronchospasms at work. The SPT detects IgE-mediated, Type-I
and responses may be attenuated in individuals that have had prolonged
icontact with the allergen due to reduced levels of IgE. This should not be the case
;ers, who would be exposed weekly. In addition, the positive SPTs to Pt reported in
-up studies as much as 4 years after individuals who had been terminated from their
employment (and presumably their exposure to Pt) due to the development of allergic symptoms
(Merget et al., 1999) suggest that a period of reduced exposure to Pt is not responsible for the
failure of SPTs to identify all individuals sensitized to halogenated Pt salts. The potential for a
second, non-IgE-mediated, mechanism to be responsible for allergic sensitization in some
individuals is suggested by the existence of both IgE-mediated and non-IgE-mediated
hypersensitivity responses to known sensitizers such as diisocyanate (Kimber and Dearman,
2002; Redlich and Karol, 2002; Kimber et al., 1998). Although specific bronchial challenge
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(i.e., measurements of hypersensitivity following direct inhalation of Pt compounds) represents
the best measure of allergic sensitization, it is rarely done due to the difficulty in performing the
assay and the possibility of anaphylactic reactions, and therefore, the health risk associated with
the assay in sensitized individuals.
5.4. CANCER ASSESSMENT
As discussed in Section 4.7, studies addressing the carcinogenic effects of Pt or Pi
compounds upon which to base a cancer assessment are unavailable. In accordance v.iui U.S.
EPA (2005a) Guidelines for Carcinogen Risk Assessment, there is "inadequate information to
assess the carcinogenic potential' of halogenated Pt salts and Pt compounds. Cancer studies in
humans and cancer bioassays in animals exposed to soluble or insoluble Pt compounds were not
found. As discussed in Section 4.5.2 (Genotoxicity), genotoxicity data were limited; however
some soluble Pt compounds (PtCU, Pt[SO.t]:, K^PtCU, (NH.thPtCU) produced gene mutations in
prokaryotic and eukaryotic test systems, including bacteriophage, bacteria, CHO cells, and
mouse lymphoma cells, whereas others such as H,>Pt€l6. K^PtC'l,,, and K2PtBr6, have yielded
conflicting results from different studies or negative results with no significant mutagenic
activity. Insoluble PtCl; tested negative for gene mutations in the E. colt SOS chromotest,
mouse lymphoma forward mutation test, and human lymphocyte micronuclei test. There is no
direct evidence to indicate that exposure to environmentally relevant Pt or Pt compounds is
carcinogenic in animals or humans: however, intraperitoneal exposure of rats or mice to the anti-
cancer compound cisplatin nrorinced increased incidences of animals with tumors.
Cisplatin has been cUu		..ie International Agency for Research on Cancer (I ARC,
1987) in cancer Group 2A,p-i uo^bly carcinogenic to humans, based on inadequate evidence of
carcinogenicity in humans and sufficient evidence of carcinogenicity in animals (increased
incidence of tumors in rats (leukemia) and mice (lung adenomas) following multiple
intraperitoneal injections). Although no cancer bioassays are available for other Pt antitumor
drugs, mutagenicity assays suggest possible carcinogenic activity similar to that of cisplatin
(Sanderson et al., 1996).
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6. MAJOR CONCLUSIONS IN THE CHARACTERIZATION OF HAZARD AND DOSE
RESPONSE
6.1. HUMAN HAZARD POTENTIAL
The two major uses of Pt compounds are in jewelry and automotive emission control
catalysts (catalytic converters), which represent approximately 30 and 46%, respectively, of the
worldwide demand for Pt as of 2005-2006 (Johnson Matthey, 2006a; Rentier et al., 2005). The
use of Pt as a fuel-borne catalyst in diesel fuel vehicles in recent years presents another potential
source of environmental Pt. Evidence suggests that vehicles equipped with catalytic converters
represent a significant source of Pt in ambient air, especially in areas heavily populated with
automotive vehicles (e.g., Fritsche and Meisel, 2004). Estimates of the fraction of the total Pt
emitted from catalytic converters as soluble Pt compounds have ranged from <1 to <10%
(Moldovan et al., 2002; Artelt et al., 1999b). As discussed in Chapter 2, analytical challenges
have so far precluded the determination of the chemical species of Pt released from catalytic
converters or Pt in ambient air samples. An;	dques are being developed that may
provide speciation information to inform the use of this RfC to source emissions data and
ambient samples.
The presence of Pt in dental materials an- - v . il treatments represents a separate
category of Pt usage wherein exposure is intentional and the potential toxicity of the form of Pt
used may relate to its medical role. Insoluble forms of Pt (Pt metal and PtO;) are generally
considered to be inert, thus leading to the use of alloys containing Pt metal in prostheses,
including breast implants (ACGIH, 2001; Gebel, 2000; WHO, 2000, 1991). A comprehensive
review of pharmacokinetic and toxicological properties of Pt anticancer drugs is beyond the
scope of thir ''—anient, because they are not expected to represent a significant source of
enviroiinieii - • posure to Pt.
Limi;. : )xieokinetic studies in rodents have examined the absorption, distribution,
metabolism, and elimination of Pt compounds. In rats, both soluble and insoluble Pt compounds
are poorly absorbed following oral exposure. Reported estimates of oral absorption of PtCU and
Pt metal (Pt-Al203 complex) are <1% of the administered dose (Artelt et al., 1999a; Moore et al.,
1975b, c). Inhaled soluble and insoluble Pt compounds are cleared from the respiratory tract by
mucociliary transport and absorption (Moore et al., 1975a). Soluble Pt(SO.t): is cleared from the
lung more rapidly than insoluble Pt metal and PtO;, suggesting more rapid absorption of soluble
Pt compounds such as Pt(S04)2 following inhalation (Moore et al., 1975a).
Once absorbed into the body, both soluble (e.g., PtCU) and insoluble (e.g., Pt metal) Pt
compounds tend to accumulate primarily in the kidney, liver, spleen, and bone (Artelt et al.,
1999a; Reichlmayr-Lais et al., 1992; Massaro et al., 1981; Lown et al., 1980; Holbrook et al.,
1975; Moore et al., 1975a, b; Yoakum et al., 1975). Pt concentrations in kidney were 5-40 times
that of liver following oral or inhalation exposure. Following inhalation exposure to ultrafme
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particles (e.g., 13 nm) of Pt metal, the Pt concentration in liver was 30 times that of the kidney
(Oberdorster, 2001; Oberdorster et al., 2000), suggesting that the tissue distribution of inhaled
ultrafine particles of Pt metal may be different than the observed distribution of large (e.g., 1 um)
particles. Parenteral studies with PtCU indicate that Pt accumulates in the fetus (Moore et al,
1975a, b), suggesting that other soluble Pt compounds may be transported across the placer
As an element, Pt is neither created nor destroyed within the body; however, Pt compounds v ^ ,
PtCl4) can participate in chemical reactions such as hydrolysis, ligand exchange, and formation
of revisible and covalent complexes with amino acids, peptides, and nucleic acid ; > forms
complexes with amino, carboxyl, imidazole (e.g., histidine), and sulfhydryl (e.g., uy^ieine)
groups on amino acids (NAS, 1977). As a result, Pt can form <	with proteins, nucleic
acids, and free amino acids. Absorbed Pt compounds may par	'©actions;
however, direct evidence for this is limited to data from anticancer therapeutics, while data on
environmentally relevant Pt compounds is lacking.
Following oral exposure, fecal excretion of unabsoroeu r'i is me dominant excretory
pathway for ingested soluble and insoluble Pt compounds (.*\neu et ai., 1999a) and absorbed Pt
is excreted in both feces and urine (Moore et al, 1975b, c). Data on elimination of inhaled Pt
compounds in humans is limited to a study of Pt refinery and catalyst production workers
(Schierl et al., 1998). This study reported Pt in urine of workers who were exposed
predominantly to (NH4)2PtCl6 and noted what appeared to be bi-phasic excretion kinetics with
fast and slow phase half-times of approximately 50 hours and 24 days, respectively. The study
also reported the persistence of urinary Pt excretion 2-6 years following cessation of exposure,
suggesting the existence o; ; n m e slowly eliminated fraction of body burden that may not be
reflected in the above elimiiiuu^i half-time estimates. The observation of faster and slower
phases of urinary excretion of Pt in humans is consistent with similar observations of multi-
phasic elimination of inhaled Pt metal, Pt©2, PtCU, or Pt(SO.t): in rats (Moore et al., 1975a).
Inhaled soluble Pt forms such as PtCl4 are excreted from the body more rapidly than insoluble Pt
forms such as Pt02; however, slower excretion of insoluble forms may, in part, reflect slower
-1 -----n- fro m the lung.
i'-: :\: rous case reports have been published describing workers who developed
symptoms consistent with Pt-specific allergic sensitization after occupational exposure to Pt
compounds by inhalation (reviewed in WHO, 1991). Health effects in humans include
respiratory irritation or symptoms of allergic sensitization such as asthma (shortness of breath),
rhinitis (runny nose and sneezing), conjunctivitis (burning and itching eyes), urticaria (rash), and
dermatitis (itching skin eruptions) (Cristaudo et al., 2005; Merget, 2000; Merget et al., 1999,
1995; Calverley et al., 1999, 1995; Bolm-Audorff et al., 1992; Baker et al., 1990; Merget et al.,
1988; Pepys et al., 1972; Hunter et al., 1945). Symptoms consistent with allergic sensitization
have been observed in workers exposed to Pt in several types of work environments including
photographic studios using halogenated Pt salts (Hunter et al., 1945); jobs applying halogenated
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Pt salts by brash to anodes (Harris, 1975); refinement of Pt involving halogenated Pt salts (Raulf-
Heimsoth et al., 2000; Santucci et al., 2000; Linnett and Hughes, 1999; Newman Taylor et al.,
1999; Calverley et al., 1999, 1995; Merget et al., 1999, 1996, 1994, 1991, 1988; Niezborala and
Gamier, 1996; Bolm-Audorff et al., 1992; Baker et al., 1990; Brooks et al., 1990; Venables et al.,
1989; Biagini et al., 1985a; Jarabek et al., 1984; Dally et al., 1980; Hughes, 1980; Cromwell
al., 1979; Cleare et al., 1976; Milne, 1970; Parrot et al., 1969; Roberts, 1951; Hunter et al.,
1945); and exposure to halogenated Pt salts in the production of Pt catalysts (Cristaudo et a
2005; Merget et al, 2002, 2001, 2000, 1999, 1996, 1995; Raulf-Heimsoth et al, 2000). Health
effects not related to respiratory irritation or allergic sensitization have not been reported in
occupational studies involving inhalation exposure to Pt compounds.
Allergic sensitization from occupational exposure via inhalation to halogenated Pt salts is
a well-established human health hazard (WHO, 2000, 1991). Sevi	.miiologic studies have
found increased prevalences of workers with allergic sensitization m naiogenated Pt salt-
contaminated workplaces with estimated air concentrations <2 (.ig soluble Pt/m3 (Merget et al.,
2000; Linnett and Hughes, 1999; Bolm-Audorf f ci al., 1992; Baker et al., 1990). However, only
Merget et al. (2000) provided adequate exposure assessment data with sufficient health effects
data to establish a dose-response relationship. Although exposure data in available occupational
studies are only characterized to the extent that soluble Pt concentrations are reported, the
specificity of the SPT used to identify Pt-specific allergic response demonstrates that
occupational allergic sensitization from exposure to Pt compounds is to chlorinated Pt salts.
Furthermore, the data fron	i .s ¦: : 976) demonstrated that the SPT among occupationally
exposed workers may also res;,..	r„itive response to other halogenated Pt salts, such as
brominated Pt salts.
The of action for allergic sensitization to halogenated Pt salts following inhalation
exposure is • > r to be primarily an IgE-mediated, Type I allergic reaction based on the
symptoms a^ : i ne-course of the hypersensitivity response. However, the possibility that a
second, n on - IgE -in ed i a ted, mechanism is responsible for some cases of allergic sensitization to
halogenated Pt salts is suggested by several lines of evidence including pulmonary effects of Pt
compounds in naive monkeys (Biagini et al., 1985b) and the failure of skin prick testing to
Modify all workers displaying symptoms of allergic sensitization to halogenated Pt salts.
	»OSE RESPONSE
6.2.1. Noncancer/Oral
The database for oral exposure to halogenated Pt salts and Pt compounds in humans is
limited to a single case report of the toxic effects of intentional ingestion of a photographic
solution containing 600 mg of potassium tetrachloroplatinate (CUK^Pt) (Woolf and Ebert, 1991),
and several short-term drinking water and dietary studies in rats (Reichlmayr-Lais et al., 1992;
Roshchin et al., 1984; Holbrook, 1976; Holbrook et al., 1976, 1975). All signs of toxicity
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(elevated liver enzymes, acute oliguric renal failure, metabolic acidosis, fever, muscle cramps,
gastroenteritis, rhabomyolisis, and elevated serum levels of neutrophils and eosinophils) from the
individual in the case report resolved within 6 days of supportive medical care follow in
ingestion of the photographic solution.
Possible hepatotoxicity associated with oral exposure to Pt compounds is suggested by
changes in activities of two hepatic microsomal enzymes (aniline hydroxylase and aminopyrine
demethylase) observed in rats exposed to PtCl4 or Pt(S04)2 in drinking water or food (Holbrook
et al., 1976, 1975); however, the observed changes were not consistent in d motion (i.e., increase
or decrease in enzyme activity) or repeatable across oral exposure studies. .mo studies on the
effects of chronic oral exposure of animals to Pt or Pt compounds were identified.
The limited available short-term and subchronic drinking water and dietary exposure
studies in rats suggest that the kidney may be a target organ for some Pt compounds. Oral
toxicokinetic studies in rats demonstrate renal accumulation of soluble [Pt(SO.th and PtCU] and
insoluble [PtCh and Pt metal] environmentally relevant Pt compounds (Artelt et al., 1999a;
Reichlmayr-Lais et al., 1992; Massaro et al., 1981; Lown et al., 1980; Holbrook et al., 1975;
Moore et al., 1975a, b; Yoakum et al., 1975). The potential for Pt accumulation in the kidney is
of particular concern because there is some evidence of potential nephrotoxicity associated with
Pt compounds following oral exposure (i.e., increased kidney weight and decreased renal
function, as indicated by increased plasma creatinine concentration, in rats exposed to PtCl4)
(Holbrook et al., 1975; Reichlmavr-Lais et al., 1992). However, data are restricted to a limited
number of Pt compounds, few doses were examined in the existing studies, and no
comprehensive subchronic or .	ideology studies have been conducted and therefore,
there is a lack of basic toxkui^cal data such as histology. Derivation of an RfD for
nephrotoxicity from the available data would likely result in a composite UF of > 10,000
(database, sub ; onic to chronic, LOAEL to NOAEL, animal to human, and human variation).
The lack of a ¦¦¦; ¦ xiy or studies with adequate dose-response data to derive an RfD with less
uncertainty represents a critical data gap in the oral database given the potential effects that have
demonstrated.
ncer/Inhalation
Allergic sensitization from occupational exposure via inhalation to halogenated Pt salts is
a well-established human health hazard (WHO, 2000, 1991). There are numerous case reports
and occupational studies of workers who develop allergic sensitization to halogenated Pt salts;
however, most studies do not include adequate exposure assessment. Of the available data with
exposure estimates, several epidemiologic studies found increased prevalences of workers with
allergic sensitization in halogenated Pt salt-contaminated workplaces with estimated air
concentrations <2 ug soluble Pt/m3 (Merget et al., 2000; Linnett and Hughes, 1999; Bolm-
Audorff et al., 1992; Baker et al., 1990). However, only Merget et al. (2000) provided adequate
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exposure data along with sufficient health effects data to establish a dose-response relationship.
Although available data from animal studies are inadequate to characterize the exposure level-
response relationship for induction of allergic sensitization to halogenated Pt salts in animals
exposed to Pt compounds via inhalation, the allergenic activity of halogenated Pt salts in humans
is supported by three inhalation exposure studies in primates and a larger number of dermal
parenteral exposure studies in experimental animals.
Consideration of the available dose-response data to determine an estimate of inhalation
exposure that is likely to be without an appreciable risk of adverse health effects over a lifetime
led to the selection of a prospective cohort study among German catalyst production workers
(Merget et al., 2000) as the principal study and the development of Pt-specific allergic
sensitization as measured by the incidence of a positive skin prick test (SPT) to
hexachloroplatinic acid as the critical effect for deriving ;.ni RfC for halogenated Pt salts. The
arithmetic mean exposure concentration of workers in the low-cxpubiue group in this study
represents aNOAEL of 3.37 ng soluble Pt/m3.
Because the RfC is a standard applicable to continuous n retime exposure, a
dosimetrically adjusted NOAEL (NOAELadj) or l x iu J mg/m3 was derived from the
occupationally identified NOAEL. The RfC was derived from the NOAELadj as the identified
POD. A POD based on a LOAEL or NOAEL is, in part, a reflection of the particular exposure
concentrations or doses at which a study was conducted. A POD so derived does not make use
of the dose-response relationship, and for this reason, is less informative than a POD defined as
an effect level concentration (i.e., BMC) obtained from benchmark dose-response modeling.
The RfC of 1 x 10" p: ... m3 was calculated from a NOAELadj of 1 x 10"6 mg/m3 for
development of allergic se>-, ;ation to halogenated Pt salts as determined by positive SPT to
hexachlorop,Qti«ic acid (Merget et al., 2000). Note that the RfC applies to halogenated Pt salts
as available ...^ : .;nce does not support allergic sensitization to insoluble forms of Pt (e.g., PtO;
or Pt metal) .. ? : > ¦ m-halogenated soluble Pt compounds. The use of the RfC for Pt compounds
other than halogenated Pt salts is not recommended as the similarity between these compounds
and other soluble forms of Pt compounds is unknown. A total UF of 1,000 was used: 10 for
intraspecies variability, 10 for subchronic to chronic extrapolation, and 10 for database
deficiencies.
Heterogeneity among humans is an uncertainty associated with extrapolating doses from
animals to humans. Uncertainty related to human variation needs consideration, also, in
extrapolating dose from a subset or smaller sized population, say of one sex or a narrow range of
life stages typical of occupational epidemiologic studies, to a larger, more diverse population.
Human variation may be larger or smaller; however, Pt-specific data to examine the potential
magnitude of over- or under-estimation are unavailable. Therefore, insufficient information is
available to predict potential variability in susceptibility among the population; thus, a human
variability uncertainty factor of 10 was applied. A 10-fold UF was used to account for
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uncertainty in extrapolating from a subchronic to chronic exposure duration. Data gaps have
been identified with uncertainties associated with database deficiencies with regards to a lack of
general toxicity studies, as well as a lack of reproductive and developmental toxicity studies.
Therefore, a database uncertainty factor of 10 was applied, noting the extensive support for
Pt-specific allergic sensitization in humans as observed in the principal study, and the
effects observed in animals, but the general lack of toxicity studies on any other endpoint.
The overall confidence in this RfC assessment is low. Confidence in the princif
(Merget et al., 2000) is low. It is a well-designed, well-conducted, and well-reported prospective
epidemiologic study that provided an exposure estimate that represents a NOAEL indicating that
no cases of allergic sensitization to halogenated Pt salts developed over a 5-year period in
workers in a German catalyst production facility at an exposure concentration of 3.37 ng soluble
Pt/m3. The high variation in exposure measurements (i.e., 100-fold variation in the stationary air
samples used for derivation of the RfC and 1,000-fold variation in the personal air samples) and
lack of speciation of the soluble Pt measurements reported in Merget et al. (2000) contribute to
low confidence in the exposure measurements. BMD modeling of the exposure measurements
reported in Merget et al. (2000) was performed for comparison purposes only as the data are of
marginal adequacy for BMD modeling because only three exposure groups (high, low, and no
exposure) are available and only one of these groups has a non-zero response. Therefore, the
NOAEL from the low exposure group in Merget et al. (2000) was utilized to derive a POD for
the development of an RfC for halogenated Pt salts. Confidence that Pt-specific allergic
sensitization is associated with halogenated Pt salts is high because of the specificity of the SPT
for the individual halogens ."; = ts used in Merget et al. (2000) and the other occupational
studies with exposure data ^iiu^tt and Hughes, 1999; Bolm-Audorff et al., 1992; Baker et al.,
1990). Confi^rtce in the database for allergic sensitization from exposure to halogenated Pt
salts is high, whereas confidence in the overall toxicity from exposure to halogenated Pt salts is
low. The df: ; - ;e of case reports and occupational studies provide strong evidence that allergic
sensitization is the critical effect from inhalation exposure to halogenated Pt salts. In addition,
animal studies provide further support for allergic sensitization from exposure to halogenated Pt
salts. However, several factors limit the overall confidence in the database. The available
exposure-response information for the development of allergic sensitization to halogenated Pt
salts covers a period of only 5 years, and therefore, a less-than-lifetime exposure duration. In
addition, there is a complete lack of information on whether inhalation exposure to halogenated
Pt salts or other forms of Pt may induce other systemic, reproductive, developmental, or
neurotoxicological effects. In addition, the available occupational data on Pt-specific allergic
sensitization are from healthy adult workers (predominately male). The potential susceptibility
of young, aged, or asthmatic populations is unknown. The overall confidence in the chronic RfC
of low reflects the variation in the exposure data and confidence in the database.
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The elicitation dose is generally lower than the dose required to induce sensitization for
both contact and respiratory sensitization (see Section 4.6.3.1.7 Relationship between exposure
levels associated with sensitization and the subsequent exposure levels required to elicit a
response for discussion) (Arts et al., 2006). A single dose level of hexachloroplatinic acid
(4.1 g/L) was used for elicitation in the SPT; therefore, no information on the dose-response ~
elicitation is available from Merget et al. (2000). Data from other refinery workers with all. :
sensitization to Pt, demonstrate that the elicitation doses required to produce a positive SPT to
(NH4)2PtCl6 ranged from 10"9 to 10"3 g/mL (Biagini et al., 1985a). These data suggest that an
RfC, derived with standard methods involving application of uncertainty factors to a reliable
NOAEL for the induction of halogenated Pt salt sensitization, may not prevent elicitation
responses in some previously sensitized individuals. As such, the RfC is expected to be
protective against developing allergic sensitization to halogenated Pt salts, but it is not expected
to be protective for exacerbation of symptoms in previously sensitized individuals.
6.2.3. Cancer/Oral and Inhalation
Under the Guidelines for Carcinogen
for halogenated Pt salts and Pt coi
and to calculate quantitative canci
: Assessment (U.S. EPA, 2005a), the database
[equate to assess human carcinogenic potential
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Wegscheider, W; Zischka, M. (1993) Quality assurance in environmental research: emissions and fate of platinum.
Pre senilis' J Anal Chem 346:525-529.
Whiteley, J; Murray, F. (2003) Anthropogenic platinum group element (Pt, Pd and Rh) concentrations in road dusts
and roadside soils from Perth, Westem Australia. Sci Total Environ 317(1-3):121—135.
Whiteley, J; Murray, F. (2005) Autocatalyst-derived platinum, palladium and rhodium (PGE ; : ;; :	i basin
and wetland sediments receiving urban runoff. Sci Total Environ 341(1-3): 199-209.
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Switzerland. Environmental Health Criteria No. 125. Available online .
http://www.inchem.org/documents/ehc/ehc/ehcl25.htm.
WHO. (World Health Organization). (2000) Platinum. Chapter 6.11, In: Airqunli(\ guidelines for Hurope. 2nd ed.
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http://www.euro.who.int/document/aiq/6_llplatinum.pdf.
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Immunol 1(2): 169-175.
Wittsiepe, J; Schrey, P; Whilhelm, M; et al. (2003) Dietary intake of platinum and gold by children from Germany
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Woolf, A; Ebert, T. (1991) Toxicity after self-poisoning by ingestion of potassium chloroplatinite. J Toxicol Clin
Toxicol 29(4):467-472.
Yoakum, A; Stewart, P; Sterrett, J. (:'1 / ¦ td development and subsequent survey analysis of biological tissues
for platinum, lead, and manganese content, tnviron Health Perspect 10:85-93.
Ysart, G; Miller, P; Crews, H; et al. (1999) Dietary exposure estimates of 30 elements from the UK Total Diet
Study. Food Addit Contain 16(9):391-403.
Zereini, F; Wi C; Alt, F; et al. (2001) Platinum and rhodium concentrations in airborne particulate matter in
Germany fron ; ' .'. .. -1998. Environ Sci Technol 35:1996-2000.
Zereini, F; Alt, x , ivi esserschmidt, J; et al. (2004) Concentration and distribution of platinum group elements (Pt, Pd,
Rh) in airborne particulate matter in Frankfurt am Main, Germany. Environ Sci Technol 38(6): 1686-1692.
Zereini, F; Wiseman, C; Puttmann, W. (2007) Changes in palladium, platinum, and rhodium concentrations, and
their spatial distribution in soils along a major highway in Germany from 1994 to 2004. Environ Sci Technol
4l(2):451-456.
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APPENDIX A. SUMMARY OF EXTERNAL PEER REVIEW AND PUBLIC
COMMENTS AND DISPOSITION
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APPENDIX B. BENCHMARK DOSE (BMD) MODELING
B.l. SUMMARY OF BMDS MODELING RESULTS FOR Pt USING THE OUTCOME
OF SPTs FROM AN OCCUPATIONAL EXPOSURE STUDY
This appendix summarizes the results of a dose-response assessment carried out using
data from a prospective cohort study of German catalyst production workers categorized into
three exposure groups (high, low, and no exposure to Pt) and then evaluated for Pt-specific
allergic sensitization resulting from exposure to halogenated Pt salts, as measured by a SPT to
hexachloroplatinic acid (Merget et al, 2000). All available dichoiomous models in U.S. EPA's
Benchmark Dose Software (BMDS, version 1.40d) were fit to the data in accordance with U.S.
EPA (2000c) BMD methodology.
B. 1.1. Exposure Metrics
Airborne Pt concentrations were determined for e,	e exposure groups using
stationary air sampling results from 1992 and 1993, and personal air monitoring results from
1993 in the high-exposure group only (see Section 4.1.2.1.2 Toxicity of soluble forms ofPt:
epidemiologic evidence ofPt allergic sensitization for study details). Personal air monitoring
data were not used for BMD modeling because of the limited nature of these data (i.e., personal
air monitoring data were collected only in 1993 and in the high-dose group only). All of the
BMDS models available were fit employing each of the following exposure metrics from
stationary air monitoring data that reported concentrations of soluble Pt (in ng/m3) in the work
areas of the high, low, and no exposure groups in the catalyst production plant:
Arithmetic Mean Pt for 1992
Arithmetic mean Pt for 1993
Arithmetic mean Pt pooled for 1992 and 1993
Geometric mean Pt for 1992
Geometric mean Pt for 1993
:¦¦¦'©metric mean Pt pooled for 1992 and 1993
, ; edian Pt for 1992
Median Pt for 1993
Median Pt pooled for 1992 and 1993
Mid-median, unweighted average of 1992 and 1993 medians
The original data as provided by the principal investigator, Dr. Merget, were used to calculate the
above statistics as possible exposure metrics for airborne concentrations of soluble Pt. The
number of Pt air samples from each worker exposure area during each year is shown in
Table B-l:
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Table B-l. Number of observations of soluble Pt, as measured by
stationary air monitors, for each exposure group by year

Year
Exposure group
1992
1993
None
8
4
Low
8
8
High
16
12
In deriving the exposure metrics described above, calculating a pooled median was
somewhat problematic. The individual exposure measurements were obtained from Merget,
ranked from smallest to largest within each exposure group across years, and then the middle
observation in the combined set was selected as the median. The 1992 and 1993 data in the
high- and no-exposure groups showed considerable overlap, and pooling the data for both years
within each of these exposure groups seemed reasonable. However, the 1992 and 1993 data in
the low-exposure group did not overlap, so that pooling data across these 2 years was a matter of
concern. Therefore, another exposure metric was constructed, the mid-median, that dealt with
this concern. To derive the mid-median, the unweighted average of the medians from 1992 and
1993 was calculated. This is a reasonably robust statistic whose values were consistent with
other pooled statistics (median or geometric mean) for both the high-exposure and no-exposure
groups. Access to the raw data, instead of the highly aggregated data in the box plots from the
figures in Merget et al. (2000), allowed detailed comparison and evaluation of several candidate
exposure metrics. The mid-median and the pooled median are probably the more robust
estimates with respect to characterizing the distribution of Pt air concentrations than are
geometric n
Exposure metrics were derived from the actual air concentrations of Pt measured at
locations within the catalyst production facility described in Merget et al. (2000). BMDS models
appli ::>!¦. 
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Table B-2. Three different dose metrics for representing air concentrations
of soluble Pt in each of three exposure groups of German catalyst
production workers from Merget et al. (2000)


Arithmetic mean3
(ng soluble Pt/m"*)
Geometric mean3
(ng soluble Pt/m3)
Median3
(ng soluble Pt/m3)
Exposure
group
1992
1993
Pooled
1992
1993
Pooled
1992
1993
Mid-
median
Pooled

Measure
of central
tendency
61.6
41.4
52.9
20.7
27.7
23.5
13.5
36.5
25.5
18.0

SE
34.0
9.62
19.7
1.38
1.34
1.25


NA
NA
High
LCL or
25th
percentile11
<0.13
20.2
12.5
10.4
14.4
14.8


NA
9.0

UCL or
75th
percentile11
134
62.5
93.3
41.5
53.0



NA
52.5

ii
16
12
28
16
12


12
28
28

Measure
of central
tendency
6.06
0.675
3.37
5.™""
0.376
1.48
6.55
0.400
3.48
2.45

SE
0.664
0.211
0.773
: 5
1.62
1.53
NA
NA
NA
NA
Low
LCL or
25th
percentile11
4.49
0.176
1.722
:¦ i
0.120
0.594
4.25
0.225
NA
0.40

UCL or
75th
percentile11
7.63
1.17

7.68
1.18
3.67
7.45
1.30
NA
6.55

ii
8
8
16
8
8
16
8
8
16
16

Measure
of central
tende
0.047
0.050
0.048
0.044
0.050
0.046
0.045
0.050
0.048
0.050

SE

000
0.005
1.150
1.000
1.097
NA
NA
NA
NA
No
LCLm
25th
percentile"

350
0.038
0.032
0.050
0.038
0.03
0.05
NA
0.035

UCL or
75th
percentile11
0.065
0.050
0.059
0.061
0.050
0.056
0.055
0.05
NA
0.05

n
8
4
12
8
4
12
8
4
12
12
aAll of the statistics in this table were calculated directly from the raw data used to generate Figure 1 in Merget et
al. (2000) as provided by Dr. Merget.
bSEs were regarded as not relevant for characterizing the variability of the robust order statistics (medians, mid-
medians) used here as air exposure metrics. Quartiles are provided as more appropriate indicators of heterogeneity
and variability for the medians and mid-medians, i.e., the 25th percentile instead of a lower confidence limit (LCL)
and the 75th percentile in place of an upper confidence limit. See the text for further discussion.
For the no-exposure group in 1992, the median air concentration was 0.045 ng/m3 soluble
Pt, which was not otherwise adjusted for the LOD of 0.05 ng/m3. For the same exposure group
in 1993, the LOD was 0.13 ng/m3, with all concentrations observed in the no-exposure group
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below this limit. Employing the LOD of 0.13 ng/m3 as a typical value for the non-detects seems
less credible than using a smaller value; therefore, the same median concentration of 0.05 ng/m3
observed in 1992 was employed for 1993, although this made little difference in the analyses.
The Pt air concentration data from stationary monitors exhibits a highly dispersed
distribution, particularly in the high-exposure group. This is due, in part, to the tempor
variability of the concentrations from one day to the next, as well as to the spatial heterogeneity
resulting from the placement of monitors at different locations throughout the plant. The numb... f
of monitors employed also varied from year to year and was not consistent .. oss exposure
groups. The variability in the distribution of Pt concentrations from person m air monitors is even
larger than for stationary monitors because personal monitors include addit,v,..al variability
introduced by movement of workers among several areas of the plant. Epidemiologists often call
this variability in exposure "measurement error" or "exposure misclassification error". This
variability may also include analytical error, but this is typically small relative to other sources of
variability. The typical effect of exposure measurement error on dose-response models is to
attenuate or flatten the apparent effect of dose ¦	: (Carroll et al., 1995).
In animal toxicology studies, doses are determined with greater precision than in
epidemiologic studies such as Merget et al. (200 1; * ; >sure measurements in Merget et al.
(2002) were not much more variable than in other similar studies. If it were possible to precisely
measure the individual exposures., the typical result would be a steeper dose-response curve than
what was observed, and consequently, a smaller BMC and BMCL for the same benchmark
response (BMR) than would have been calculated by using a single summary statistic to
represent the entire exposure distribution. A number of computational statistical methods exist
for adjusting dose-response for exposure measurement error, but these have not been currently
implemented <« MMDS. Consequently, uncertainty in the measurement and characterization of
exposure is - ^.-er factor in selecting an appropriate UF for the derivation of the RfC.
B.1.2. Approach for Dose-Response Modeling and Results
The amount of dose-response information contained in these data is very limited. The
entire dataset is represented by only three pairs of measurements in the form (x, y), where x is
the exposure metric and y is the response (i.e., the incidence of positive SPT). These exposure-
response data pairs can be represented as follows: (no-exposure metric, 0), (low-exposure
metric, 0), and (high-exposure metric, 13/115). These data suggest the following regarding the
dose-response relationship:
(1)	the shape of the response at low doses is very flat, essentially a nonlinear function
that increases rapidly above the low-exposure metric; thus, one may expect BMDS to
estimate 0 as the background response;
(2)	the typical BMDS model that can fit these data is sublinear, essentially, below a
straight line drawn from (low-exposure metric, 0) to (high-exposure metric, 13/115);
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(3) most dose-response functions that increase sufficiently rapidly with increasing dose
above the low-exposure concentration will satisfy the BMDS model selection
criterion (Akaike's Information Criterion [AIC] within 2 units of the minimum AIC,
p > 0.10), but model fitting is still useful in eliminating those models that do not fit
adequately, and thus do not need to be considered in evaluating uncertainty associated
with model selection.
No a priori reason exists to choose data from a single year (i.e., 1992 or 1993), and thus exciuue
data from the other year. Therefore, only dose metrics representing a combination of the 2 years
(i.e., pooled geometric means, mid-medians, pooled medians, and pooled arithmetic means) were
considered for use in dose-response modeling. However, exposure metrics representing data
from individual years were modeled for comparison purposes.
The BMR was defined as a 10% increase in extra ri	:	o clear
biological rationale for selecting an alternate BMR for these data. Employing each of the seven
exposure metrics in fitting all available BMDS models yielded very similar BMC and BMCLio
values (i.e., all BMCLio values were between 12.9 and 49.4 ng/m3 soluble Pt). The highest
BMCL io value of 49.4 ng/m soluble Pt resulted from the use of the arithmetic mean of pooled
data from 1992 and 1993, and was approximately 4 times higher than the lowest BMCLio value
of 12.9 ng/m3 of soluble Pt resulting from the use of the median of pooled data from 1992 and
1993. The BMD modeling results for exposure metrics employing the pooled geometric means,
mid-medians, pooled medians, and proW arithmetic means are presented below in Tables B-3,
B-4, B-5, and B-6.
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Table B-3. BMD modeling results employing the pooled geometric mean of
1992 and 1993 stationary air monitoring data of soluble Pt as an exposure
metric
Model
Power
AIC
P
Df/7
BMC10
BMCL10
Weibull
18
83.151
1.0000
2
23.3
16.3
Multistage
(Weibull Integer Power)
8
83.151
1.0000
2
23.1
21.9
7
83.151
1.0000
2
23.1
21.7
6
83.151
1.0000
2
23.0
21.5
5
83.151
1.0000
2
22.9
21.0
4
83.152
0.9999
2
22.7
20.5
3
83.158
0.9983
2
22.5 2
19.5
2
83.257
0.9739
2
22.1
17.8
1
84.798
0.6530
2
22.0
14.4
Gamma
6.62 ± 128
85.151
0.9986
1
22.7
16.2
Logistic
NAa
85.151
0.9996
1
23.3
20.9
Log-Logit
6.16 ±348.
85.151
0.9994
1
23.0
16.0
Probit
NA
85.151
0.9995
1
23.2
20.2
Log-Probit
1.65 ± 162
85.151
0.9995
1
22.5
14.8
aNA means that a model statistic cannot or will not be calculated. The gray shaded models did not attain the model
selection criteria used for BMDS.
Df = degrees of freedom
Table B-4. BMD modeling results employing the mid-median of 1992 and
1993 stationary air monitoring data of soluble Pt as an exposure metric
Model
Power
AIC
P
Df/7
BMC10
BMCL10
Weibull
18
83.151
1.0000
2
25.3
19.6
Multistage
(Weibull Integer Power)
8 A
83.151
1.0000
2
25.1
23.8
1
83.151
1.0000
2
25.0
23.6
6
83.151
1.0000
2
25.0
23.2
5
83.153
0.9997
2
24.8
22.8
4
83.160
0.9977
2
24.7
22.2
3
83.219
0.9832
2
24.4
21.2
2
83.643
0.8833
2
24.1
19.5
1
86.572
0.3990
2
25.5
16.7
Gamma
9.92 ± 283
85.151
0.9984
1
24.8
19.3
Logistic
NAa
85.151
0.9994
1
25.3
22.0
Log-Logit
8.79 ± 922
85.151
0.9995
1
25.1
19.4
Probit
NA
85.151
0.9994
1
25.2
22.1
Log-Probit
2.30 ±76
85.151
0.9995
1
24.1
18.2
aNA means that a model statistic cannot or will not be calculated. The gray shaded models did not attain the model
selection criteria used for BMDS.
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Table B-5. BMD modeling results employing the pooled median of 1992 and
1993 stationary air monitoring data of soluble Pt as an exposure metric
Model
Power
AIC
P
Dip
BMC10
BMCL10
Weibull
12
85.151
1.0000
1
17.8
13.8
Multistage
(Weibull Integer Power)
8
83.151
1.0000
2
17.7
16.8
7
83.151
1.0000
2
17.7
W 16.6
6
83.151
1.0000
2
17.6
16.4
5
83.152
0.9997
2
17.5
16.1
4
83.160
0.9977
2
17.4
L15.7
3
83.218
0.9833
2
17.3
15.0
2
83.640
0.8838
2
17.0 3
13.8
1
86.572
0.3989
2
18.0
11.8
Gamma
9.82 ±234
85.151
0.9983
1
17.5
13.6
Logistic
NAa
85.151
0.9994
1
17.9
16.1
Log-Logit
8.77 ± 547
85.151
0.9995
1
17.7
13.7
Probit
NA
85.151
0.9994
1
17.8
15.6
Log-Probit
2.30 ±234
85.151
0.9995
1
17.5
12.9
aNA means that a model statistic cannot or will not be calculated. The gray shaded models did not attain the model
selection criteria used for BMDS.
Table B-6. BMD modeling results employing the pooled arithmetic mean of
1992 and 1993 stationary air monitoring data of soluble Pt as an exposure
metric
Model
Power
AIC
P
Dip
BMC10
BMCL10
Weibull
18
83.151
1.0000
2
52.5
36.7
Multistage
(Weibull Integer Power)
8
83.151
1.0000
2
52.0
49.4
7
83.151
1.0000
2
51.9
48.9
6
83.151
1.0000
2
51.8
48.2
5
83.151
1.0000
2
51.5
47.4
4
83.152
0.9999
2
51.2
46.1
3
83.158
0.9983
2
50.7
44.0
2
83.259
0.9733
2
49.7
40.2
1
84.804
0.6518
2
49.5
32.4
Gamma
6.59 ± 143
85.151
0.9995
1
51.2
36.5
Logistic
NAa
85.151
0.9995
1
52.5
47.0
Log-Logit
6.21 ±502
85.151
0.9994
1
51.7
36.2
Probit
NA
85.151
0.9995
1
52.1
45.4
Log-Probit
1.67 ± 125
85.151
0.9995
1
50.7
33.3
aNA means that a model statistic cannot or will not be calculated. The gray shaded models did not attain the model
selection criteria used for BMDS.
B.1.3. Selection of POD
For each fitted model, BMDS provided an overall goodness-of-fit test (x2) and an AIC
value. The goodness-of-fit test is a measure of the model fit based on the log-likelihood at the
maximum likelihood estimates for the parameters. Models with %2p values > 0.1 were
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considered to have adequate fits. The AIC is a measure of the model fit based on the log-
likelihood at the maximum likelihood estimates for the parameters. Within the subset of models
that exhibit adequate fit, models with lower AIC values are preferred. The "best-fit" model
selection criteria are described in detail in EPA's Benchmark Dose Technical Guidance
Document (U.S. EPA, 2000c). As seen in Tables B-3 through B-6, almost all of the models:
provide an adequate fit to the data, and for all practical purposes, many of the models provi - :
nearly perfect fit to the data with virtually indistinguishable values of AIC. Therefore, other
criteria must play a role in model selection. Perhaps, most importantly, is juti:.: nt about the
power or exponent in the model. The simplest situation is that of the multisti- ¦ :: todel
(equivalently, the Weibull model with an integer value for the exponent or power). Only one
parameter is to be estimated from the data in the multistage or fixed-power muuus. In this case,
the background response is virtually constrained to be 0. If one as	.at sensitization to Pt
exposure is a strict threshold phenomenon, then the highest possible puwei provides the best
approximation to a jump from no response below the threshold concentration to a positive
response above the threshold. This is unlikely to be the case, however, and would probably be
rejected if there were more dose groups between trie low Pt exposure and high Pt exposure
groups (discussed previously as a consequence of so-called exposure measurement error). An
alternative is to choose the smoothest curve from no response to response that still provides a
near-perfect fit to the data. Among all such possibilities, the models with a perfectp value (to
within 4 decimal places) are shown in the above tables highlighted in yellow, and the resulting
BMCL io values from these models are presented below. No additional information exists on
which to base a choice of the i					...
• The pooled geometric mean air Pt with BMCLio = 21.0 ng Pt/m3 in Table B-3, using
a multistage (monomial or single term only) model of degree 5.
'"'ie olid-median air Pt for 1992 and 1993 with BMCLio = 23.2 ng Pt/m3 in Table B-4
;e (monomial or single term only) model of degree 6.
ie median of pooled or combined air Pt from 1992 and 1993 with
vlCl.,0 = 16.4 ng Pt/m3 in Table B-5 using a multistage (monomial or single term
ly) model of degree 6.
• The arithmetic mean of pooled or combined air Pt from 1992 and 1993 with
BMCL io — 47.4 ng Pt/m3 in Table B-6 using a multistage (monomial or single term
only) model of degree 5.
• The BMCLio values from these models presented above are consistent with the choice
of a NOAELadj as a POD; however, as noted in Section 5.2.2. Methods of Analysis
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Including Models (PBPK, BMD, etc.), BMD modeling is not recommended when
data sets do not contain at least two non-zero response levels.
B.2. IN SEN SITIVITY TO HMDS MODEL IN FITTING THE INCIDENCE OF
POSITIVE SKIN PRICK TESTS FOR Pt IN CATALYST WORKERS USING
DIFFERENT Pt DOSE METRICS
The incidence data do not allow selection for a unique best model. The models sho
below demonstrate that the standard multistage monomial (using only a single polynomial term)
can provide a virtually perfect fit to the data, within a relatively small range of BMDs and
benchmark dose, lower 95% confidence limits (BMDLs) across these best-fitting models. We
show the BMDS output for the lowest-order multistage mo	¦¦ improvement
in model fitting seems possible (Figure B-l).
Multistage Model with 0.95 Confidence Lev
13
it
<
s=
g
ti
ro
0.3
0.25
0.2
0.15
0.1
0.05
Multistage
BMD Lower Bound
~~)r


10
15
BMDL
20
BMD
25
dose
Lv
Figure B-l. BMD modeling results employing the pooled geometric mean of
1992 and 1993 stationary air monitoring data of soluble Pt as an exposure
. .. support results Table B-3.
Multistage Model. (Version: 2.5; Date: 10/17/2005)
Input Data File: U:\IRIS\PLATINUM\MERGET2000.(d)
Gnuplot Plotting File: U:\IRIS\PLATINUM\MERGET2000.pit
Tue Feb 26 03:24:38 200£
SPT POSITIVE GEOMETRIC MEANS PT MULTI STAGE MODEL DEG 5
Observation # < parameter # for Multistage model.
The form of the probability function is:
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P[response] = background + (1-background)*[1-EXP(
-betal*doseAl-beta2*doseA2-beta3*doseA3-beta4*doseA4
beta5*doseA5-beta6*doseA6-beta7*doseA7-beta8*doseA8)]
The parameter betas are not restricted
Dependent variable = SPT
Independent variable = GEOMMEAN
User specifies the following parameters:
Beta
1) =
0
Beta
2) =
0
Beta
3) =
0
Beta
4) =
0
Beta
6) =
0
Beta
7) =
0
Beta
8) =
0
Total number of observations = 3
Total number of records with missing ¦< ~ . = 0
Total number of parameters in model =
Total number of specified parameters = 7
Degree of polynomial = 8
Maximum number of iterations
Relative Function Convergence : ¦ ¦¦ en set to: le-00£
Parameter Convergence has bee : ' ' o: le-008
:ial Parameter Values

md =
0

1) =
1 Specified
sta
2) =
1 Specified
sta
3) =
1 Specified
sta
4) =
1 Specified
sta
5) =
0
sta
6) =
1 Specified
~eta
7) =
1 Specified
Beta
8) =
1 Specified
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Beta(1) -Beta(2)
^3) -Beta(4) -Beta(6) -Beta(7) -Beta(8)
have been estimated at a boundary point, or have been
specified by the user,
and do not appear in the correlation matrix )
Beta (5)
Beta(5)	1
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Parameter Estimates
Confidence Interval
Variable
Upper Conf. Limit
Background
Beta (5)
4.38152e-008
Estimate
0
1.67377e-00E
Std. Err.
NA
1. 38153e-008
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
95.0% Wald
Lower Conf. Limit
Model
Full model
Fitted model
Reduced model
AIC:
Analysis of Deviance
Log(likelihood) # Param's
-40.5756
-40.5756
-52.3129
83.1513
P~value
<.0001
Dose
23.5000
1.4800
0.0460
Est. Prob.
0.1130
0.0000
Chi A2
0.
Fit
;peci:ea v-oserved	Size
13	115
0	111
u.uuu 0	48
P-value = 1.0000
Scaled
Residual
-0.000
-0.004
-0.000
Benchmark Dose Compute
L
BMD
BMDL
0.1
Extra risk
0. 95
22 .8979
21.0349
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Multistage Model with 0.95 Confidence Level
Multistage
BMD Lower Bound
04:29 02/26 2008
Figure B-2. BMD modeling results employing the mid-median of 1992 and
1993 stationary air monitoring data of soluble Pt as an exposure metric to
support Table B-4.
Multistage Model. (Version: 2.5; Date: 10/17/2005)
Input Data File: U:\IRIS\PLATINUM\MERGET2000.(d)
Gnuplot Plotting File: U:\IRIS\PLATINUM\MERGET2000.plt
Tue Feb 26 04:29:56 200£
SPT POSITIVE MID-MEDIANS PT MULTISTAGE MODEL DEG 6
Observation # < parameter # for Multistage model.
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl-beta2*doseA2-beta3*doseA3-beta4*doseA4-
beta5*doseA5-beta6*doseA6-beta7*doseA7-beta8*doseA8)]
The parameter betas are not restricted
Dependent variable = SPT
Independent variable = MIDMEDIAN
User specifies the following parameters:
Beta(1) =	0
Beta(2) =	0
Beta ( 3) =	0
Beta(4) =	0
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Beta ( 5) =
Beta ( 7) =
Beta ( 8) =
Total number of observations = 3
Total number of records with missing values
Total number of parameters in model = 9
Total number of specified parameters = 7
Degree of polynomial = 8
= 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-OOf
Parameter Convergence has been set to: le-008
Inputs Initial
Parameter
Values
Background =
0

Beta (1) =
1
Specified
Beta (2) =
1
Specified
Beta ( 3) =
1
Specified
Beta ( 4) =
1
Specified
Beta ( 5) =
1
Specified
Beta ( 6) =
0

Beta ( 7) =
1
Specified
Beta ( 8) =

Specified
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background -Beta(l) -Beta(2)
-Beta(3) -Beta(4) -Beta(5) -Beta(7) -Beta (8)
have been estimated at a boundary point, or have been
specified by the user,
and do not appear in the correlation matrix )
Beta(6)
Beta(6)	1
Parameter Estimates
Confidence Interval
Variable	Estimate
Upper Conf. Limit
Background	0
Beta(6)	4.36306e-010
1.14215e-009
Std. Err.
NA
3.60129e-010
95.0% Wald
Lower Conf. Limit
-2.69534e-010
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
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Analysis of Deviance Table
Model	Log(likelihood) # Param's Deviance Test d.f. P-value
Full model	-40.5756	3
Fitted model	-4 0.57 57	1 0.000172036	2
0 . 9999
Reduced model	-52.3129	1 23.4746	2
AIC:	83 . 1514
Goodness of Fit
Dose	Est. Prob. Expected Observed
25.5000	0.1130	13.000	13	1.000
3.4800	0.0000	0.000	0	).009
0.0480	0.0000	0.000	0	1.000
ChiA2 = 0.00	d.f. = 2	P-value =
Benchmark Dose Compul
Specified effect =
Risk Type	=
Confidence level =
BMD =
RMHT =
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Multistage Model with 0.95 Confidence Level
Figure B-3. BMD modeling results employing the pooled median of 1992 and
1993 stationary air monitoring data of soluble Pt as an exposure metric to
support Table B-5.
Multistage Model. (Version: 2.5; Date: 10/17/2005)
Input Data File: U:\IRIS\PLATINUM\MERGET2000.(d)
Gnuplot Plotting File: U:\IRIS\PLATINUM\MERGET2000.plt
Tue Feb 26 05:19:16 2008
SPT POSITIVE MEDIAN PT MULTISTAGE MODEL DEG 6
Observation # < parameter # for Multistage model.
The form of the probability function is:
P[response] = background + (1-background)*[1-EXP(
-betal*doseAl-beta2*doseA2-beta3*doseA3-beta4*doseA4-
beta5*doseA5-beta6*doseA6-beta7*doseA7-beta8*doseA8)]
The parameter betas are not restricted
Dependent variable = SPT
Independent variable = MEDIAN
User specifies the following parameters:
Beta(1) =	0
Beta(2) =	0
Beta ( 3) =	0
Beta(4) =	0
Beta(5) =	0
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Beta ( 7) =	0
Beta ( 8) =	0
Total number of observations = 3
Total number of records with missing values = 0
Total number of parameters in model = 9
Total number of specified parameters = 7
Degree of polynomial = 8
Maximum number of iterations = 250
Relative Function Convergence has been set to: le
Parameter Convergence has been set to: le-008
User Inputs Initial Parameter Val
Background
Beta
Beta
Beta
Beta
Beta
Beta
Bet
Bet
Specified
Specified
Specified
Specified
Specified
Specified
Asymptotic Corre
^ * * * fp]
-Beta(3) -Beta(¦
h;
specified by the u;
ameter Estimates
-Beta(2)
stimated at a boundary point, or have been
¦ ipear in the correlation matrix )
round -Beta(1)
-Beta(8)
±
Parameter Estimates
Confidence Interval
Die	Estimate
Conf. Limit
Background	0
Beta(6)	3.52693e-009
9 . 23267e-009
Std. Err.
NA
2 . 91115e-009
95.0% Wald
Lower Conf. Limit
-2 . 17881e-009
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
1/27/2009
Analysis of Deviance Table
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Model
Full model
Fitted model
0.9999
Reduced model
AIC:
Log(likelihood) # Param's Deviance Test d.f.
P~value
-40.5756
-40.5757
-52 . 3129
83.1514
0.000169335
23.4746
Dose
18.0000
2.4500
0.0500
Est. Prob.
0.1130
0.0000
0.0000
Goodness of Fit
Expected Observed	Si;
13.000
0. 000
0. 000
13
0
0
al
Chi A2
0. 00
d.f.
P~value
1
Benchmark Dose Computation
Specified effect =	0 . 1
Risk Type	=	Ext
Confidence level =
BMD =	1
BMDL =
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