EPA-600/8-87/048F
APRIL 1990
FINAL
NONCARCINOGENIC EFFECTS OF CHROMIUM:
UPDATE TO HEALTH ASSESSMENT DOCUMENT
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
RESEARCH TRIANGLE PARK, NC 27711
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DISCLAIMER
This document has been reviewed in accordance with U.S. Environmental Protection
Agency policy and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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CONTENTS
Page
TABLES v
AUTHORS vii
ABBREVIATIONS x
PREFACE xi
1. INTERPRETIVE SUMMARY AND CONCLUSIONS 1-1
1.1 CHROMIUM OXIDATION STATES AND THEIR
PERSISTENCE IN THE ENVIRONMENT 1-1
1.2 SAMPLING AND ANALYTICAL METHODOLOGY
FOR EACH OXIDATION STATE AT RELATIVELY
LOW LEVELS 1-2
1.3 DEGREE OF EXPOSURE TO CHROMIUM IN THE
ENVIRONMENT 1-3
1.4 COMPOUND DISPOSITION AND KINETICS 1-4
1.5 THE ESSENTIALITY OF CHROMIUM 1-5
1.6 EFFECTS OF CHROMIUM EXPOSURE ON
RESPIRATORY AND RENAL SYSTEMS 1-5
2. INTRODUCTION 2-1
3. BACKGROUND INFORMATION 3-1
3.1 CHEMICAL AND PHYSICAL PROPERTIES 3-1
3.2 PRODUCTION, USE, AND RELEASE TO
THE ENVIRONMENT 3-3
3.2.1 Production of Chromium Compounds 3-9
3.2.2 Uses of Chromium and Its Compounds 3-9
3.2.3 Releases Into the Environment 3-9
3.3 ENVIRONMENTAL FATE, TRANSPORT, AND
CONCENTRATIONS 3-13
3.3.1 Air 3-13
3.3.2 Soil 3-15
4. QUANTITATIVE ANALYSIS OF CHROMIUM IN
BIOLOGICAL AND ENVIRONMENTAL MEDIA 4-1
4.1 TOTAL CHROMIUM ANALYSIS IN BIOLOGICAL
AND ENVIRONMENTAL MEDIA 4-1
4.1.1 Biological Media Sampling Steps in
Total Cr Measurements 4-1
4.1.2 Instrumentation Methods 4-4
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CONTENTS
Page
4.2 BIOLOGICAL/ENVIRONMENTAL APPLICATIONS
OF ATOMIC SPECTROSCOPIC TECHNIQUES ........... 4-7
4.2. 1 Neutron Activation and X-Ray
Fluorescence Methods ........................ 4_7
4.2.2 Neutron Activation Analysis of Cr
in Various Media ........................... 4.7
4.2.3 Quality Assurance/Quality Control
(QA/QC) Protocols ........................ 4_10
4.3 CHEMICAL SPECIATION ANALYSIS OF
Cr IN BIOLOGICAL AND ENVIRONMENTAL MEDIA ...... 4-12
4.4 SUMMARY AND OVERVIEW ...................... 4_16
5. COMPOUND DISPOSITION AND KINETICS ............... 5-1
5.1 MECHANISMS FOR REDUCTION OF HEXAVALENT
CHROMIUM COMPOUNDS ........................ 5_1
5.2 ABSORPTION AND DISTRIBUTION .......... ... ..... 5.5
5.3 EXCRETION ............................ !!.'!." 5-6
5.4 METABOLIC MODELS AND BIOLOGICAL HALF-TIME . . . . 5-7
6. HEALTH EFFECTS ................................ 6_!
6.1 THE ESSENTIALITY OF CHROMIUM ...... ......... 6-1
6.2 RESPIRATORY EFFECTS ................. 6-19
6.3 RENAL EFFECTS ..................... \ ........ 6_22
6.4 CHROMIUM SENSITIVITY ............. ........... 6-25
6.5 DEVELOPMENTAL TOXICITY ................ 6-26
6.6 OTHER EFFECTS ....................... .' .' ..... 6_27
6.7 FACTORS MODIFYING TOXICITY ...... .... ........ 6-27
6.8 SUMMARY AND CONCLUSIONS ............. ...... 6-28
7. REFERENCES
IV
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TABLES
Number Page
3-1 Chemical and physical properties of chromium ............. 3-2
3-2 Oxidation states of selected chromium compounds and
their major physical properties ....................... 3-4
3-3 Composition of typical ferrochromium alloys
and chromium metal (percent) ....................... 3-8
3-4 Major chromium uses and key chromium chemicals
involved ..................................... 3-10
3-5 List of commercially produced secondary chromium
chemicals and their general uses ...................... 3-11
3-6 Sources and estimates of united states atmospheric
chromium emissions .............................. 3-12
3-7 Chemical plant particle size results ..................... 3-14
3-8 Number of NADB observations exceeding 0. 1
total chromium according to year ...................... 3-15
3-9 NADB sites exceeding 0.3 fig/m3 total chromium
from 1977 to 1983 ............................. . . 3-16
3-10 Highest measured total chromium concentrations
for the year 1984, jug/m3 ........................... 3-17
4-1 Sample collection and processing factors in
total chromium analysis ........................... 4-3
4-2 Biological and environmental Cr analyses using
atomic spectral analyses ........................... 4-8
4-3 Recent neutron-activation and x-ray fluorescence
analysis for Cr measurements ........................ 4-11
4-4 Recent uses of standard reference materials in
chromium analysis ............................... 4-13
4-5 Recent chemical speciation methods for chromium
in various media ................................ 4-16
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TABLES
Number
Page
5-1 Activity (percent of dose) of 51CR in rats
after intratracheal administration of Na2CrO4 .............. 5.4
6-1 Summary of inhalation studies on human
exposures to chromium compounds .................... 6_2
6-2 Animal studies on chromium effects, disposition,
and pharmacokinetics _
6-3 Urinary excretion of beta2-microglobulin in
relation to exposure levels of Cr(VI) among
present chromeplaters
VI
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AUTHORS
The main authors responsible for preparation of this update document on
chromium are:
Si Duk Lee
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
MD-52
U.S. EPA
Research Triangle Park, NC 27711
Paul Mushak
811 Onslow Street
Durham, NC 27705
Magnus Piscator
The Karolinska Institute
Department of Environmental Hygiene
P.O. Box 60400
S-104 01 Stockholm, Sweden
Winona Victery
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
MD-52
U.S. EPA
Research Triangle Park, NC 27711
The following individuals provided review of a prior draft version of
this update:
U.S. Environmental Protection Agency
Daniel Bivins
Office of Air Quality Planning and Standards
MD-13
U.S. EPA
Research Triangle Park, NC 27711
Karen Blanchard
Office of Air Quality Planning and Standards
MD-12
U.S. EPA
Research Triangle Park, NC 27711
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Frank Butler
Environmental Monitoring Systems Laboratory
MD-77A
U.S. EPA
Research Triangle Park, NC 27711
Rob Elias
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
MD-52
U.S. EPA
Research Triangle Park, NC 27711
Herman Gibb
Office of Health and Environmental Assessment
Carcinogen Assessment Group
RD-689
U.S. EPA
Washington, DC 20460
Ronald E. Myers
Office of Air Quality Planning and Standards
MD-13
U.S. EPA
Research Triangle Park, NC 27711
Mary-Jane Selgrade
Health Effects Research Laboratory
MD-82
U.S. EPA
Research Triangle Park, NC 27711
External Reviewers
Joel Barnhart
American Chrome and Chemical
P.O. Box 9912
Corpus Christi, TX 78469
Larry Fishbein
Environ Corporation
1000 Potomac St., N.W.
Washington, D.C. 20007
vm
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Kaye Kilburn
University of Southern California
School of Medicine
913 Hoffman Research Building
2025 Zonal Avenue
Los Angeles, CA 90003
Erik Lindberg
Department of Occupational Medicine
Swedish National Board of Occupational Health and Safety
S-171 84
Solna, Sweden
Gordon Loewengart
Allied Signal
P.O. Box 1021 R
Morristown, NJ 07690
Robert M. Lollar
University of Cincinnati
Mail Location 4
Cincinnati, OH 45221
Paul Mushak
811 Onslow Street
Durham, NC 27705
Gunnar Nordberg
University of Umea
Dept. of Environmental Medicine
Umea, Sweden
F. William Sunderman, Jr.
University of Connecticut
School of Medicine
Farmington, CT 06032
IX
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ABBREVIATIONS
AAS
AIRS
Cr(m)
Cr(VI)
DPC
EPA
ETA-AAS
FEFx
FEVt
FVC
HAD
IAEA
ICP-ES
i.p.
i.t.
i.v.
LOEL
MIG
MMA
MMAD
NAA
NADB
NADPH
ND
NR
NIOSH
PAM
RDA
SAROAD
SRM
TIG
TR-XRF
VC
Atomic absorption spectroscopy
Aerometric Information Retrieval System
Trivalent chromium
Hexavalent chromium
Diphenyl carbazide method for Cr(IV) analysis
U.S. Environmental Protection Agency
Electrothermal atomic absorption spectroscopy,
synonymous with graphite furnace AAS
Forced expiratory flow, x indicates amount
already exhaled
Forced expiratory volume, t indicates duration,
usually one second
Forced vital capacity, performed with a
maximally forced expiratory effort
Health Assessment Document
International Atomic Energy Agency
Inductively coupled plasma-emission spectroscopy
intraperitoneal
intratracheal
intravenous
Lowest observed effect level
Metal inert gas, a welding process
Manual metal arc, another welding process
Mass median aerodynamic diameter
Neutron activation analysis
National Aerometric Data Branch
Reduced nicotinamide adenine diphosphate
Not detected
Not reported
National Institute for Occupational Safety and
Health
Pulmonary alveolar macrophage
Recommended Daily Allowance
Storage and Retrieval of Aerometric Data,
replaced in 1987 by AIRS
Standard reference materials
Tungsten inert gas, another type of welding
Total reflection Xray analysis
Vital capacity
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PREFACE
The Office of Health and Environmental Assessment has prepared this health assessment
on the non-carcinogenic effects of chromium to serve as a source document for EPA use. The
health assessment was developed for use by the Office of Air Quality Planning and Standards to
support decision making regarding possible regulation of chromium as a hazardous air pollutant.
In the development of the assessment document, the scientific literature has been
inventoried, key studies have been evaluated, and summary/conclusions have been prepared so
that the chemical's toxicity and related characteristics are qualitatively identified. Observed
effect levels and other measures of dose-response relationships are discussed, where appropriate,
so that the nature of the adverse health responses is placed in perspective with observed
environmental levels.
The relevant literature for this document has been reviewed through June, 1986. Selected
studies of more recent publications through December, 1989 have been incorporated in the
sections on toxicity.
Any information regarding sources, emissions, ambient air concentrations, and public
exposure has been included only to give the reader a preliminary indication of the potential
presence of this substance in the ambient air. While the available information is presented as
accurately as possible, it is acknowledged to be limited and dependent in many instances on
assumption rather than specific data. This information is not intended, nor should it be used, to
support any conclusions regarding risks to public health.
If a review of the health information indicates that the Agency should consider regulatory
action for this substance, a considerable effort will be undertaken to obtain appropriate
information regarding sources, emissions, and ambient air concentrations. Such data will provide
additional information for drawing regulatory conclusions regarding the extent and significance
of public exposure to this substance.
XI
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1. INTERPRETIVE SUMMARY AND CONCLUSIONS
The purpose of this update is to address several technical issues related to
noncarcinogenic health effects of chromium compounds that require further clarification.
Material previously used for the 1984 document has been reviewed and cited, when
appropriate. This update to the 1984 Health Assessment Document (HAD) addresses the
following issues:
(1) Oxidation states and persistence of these states in the environment.
(2) Sampling and analytical methodology to differentiate these oxidation states and
amounts at submicrogram ambient air levels.
(3) Degree of human exposure to chromium in the environment, both short and
long-term.
(4) In vivo reduction of Cr (VI) to Cr (III).
(5) Effects from environmentally relevant levels on pulmonary function and on
kidney function.
These issues are addressed in this section of the update. The remaining material can be used
to supplement this discussion. Approximately 200 new references were reviewed for
consideration in this update to the 1984 HAD for chromium, many of which have been
published since the completion of the 1984 HAD.
1.1 CHROMIUM OXIDATION STATES AND THEIR PERSISTENCE IN
THE ENVIRONMENT
The most chemically stable state for chromium is trivalent chromium [Cr(III)], which
comprises most of the total chromium in the environment. Hexavalent chromium [Cr(VI)] is
readily reduced to Cr(III) and, in the presence of organic material and particularly at lower
pH levels, forms stable Cr(III) complexes. Under certain conditions, Cr(III) will oxidize to
Cr(VI). The important variable in this reaction is the presence of manganese oxide, which is
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reduced as Cr(m) is oxidized. Cr(HI) also is oxidized to Cr(VI) when ore containing Cr(IV)
is roasted at high temperatures. The type and amounts of chromium valence states in the
ambient environment are not well characterized. The oxidation state of chromium in the
ambient air most likely depends on the proximity to sources that emit one form over the
other, or mixtures of both. Because Cr(ffl) is found naturally in the earth's crust, most of the
airborne chromium in areas not source-dominated is probably of the trivalent state, but this
has not been tested empirically. Additional research is needed to develop quantitative data
and mathematical descriptions for predicting the chemical attenuation of chromium in the
environment. For now, however, the available data indicate that, in the absence of a nearby
source of Cr(VI), chromium exists primarily as Cr(III) in an atmospheric environment that is
normally slightly acidic. It appears that Cr(VI) exists primarily in the fine particle phase.
This conclusion was reached based on limited data from a few source-specific locations,
where Cr(VI) accounted for about 35% of the total mass and 85% of the particle mass smaller
than 10 )Ltm.
1.2 SAMPLING AND ANALYTICAL METHODOLOGY FOR EACH
OXIDATION STATE AT RELATIVELY LOW LEVELS
Reliable monitoring methods to speciate chromium oxidation states, Cr(III) and Cr(VI),
at ambient air levels of less than 1 ^g/m3 are not available. Several research methods are
being developed that may be amenable to routine monitoring of Cr(VI). Some of the more
prominent problems with the existing methods include the following:
(1) the presence of other atmospheric contaminants that interfere in the sampling and
collection procedure;
(2) losses during sample pretreatment;
(3) oxidation/reduction of the chromium in the sample during analysis;
Some comparative studies presented in the analytical section of this update suggest ways to
mitigate some of these problems, but at the expense of accuracy and sensitivity. In general,
the methods used routinely to monitor total chromium in ambient air, such as neutron
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activation analysis, a nondestructive technique, are accurate and sensitive to relatively low
total chromium levels (less than 1 /*g/m3). Pretreatment of the sample and use of other
collection methods to determine oxidation state lack the sensitivity to measure these species at
the levels found commonly in ambient air. In conclusion, the speciation of chromium in
ambient air cannot be determined with any degree of confidence with currently available
instrumentation.
1.3 DEGREE OF EXPOSURE TO CHROMIUM IN THE
ENVIRONMENT
Little new information was found on the types of chromium and compounds occurring in
the environment. As noted above, analytical methods available for differentiating Cr(III)
from Cr(VI) in occupational settings are not sufficiently sensitive or selective for ambient air
monitoring. Accordingly, knowledge about the forms of chromium emitted and the transport,
transformation, and persistence of these species is the main tool that can be used to estimate
the abundance of each oxidation state in specific environments.
The primary sources of emissions of hexavalent chromium appear to be chemical
manufacturing and cooling towers. Based on estimated total chromium emissions and percent
Cr(VI), these two source categories account for approximately 80% of total Cr(VI) emitted.
Theoretically, much of this may be transformed into Cr(III) over a protracted period of time;
however, populations close to these sources would be at a greater risk of exposure to Cr(VI)
than would the general population.
Manual metal arc (MMA) welding generates three to four times more fumes per
kilograms of welded stainless steel than metal inert gas (MIG) welding at the same power; the
total chromium contents of MMA welding fumes ranges from 2.4 to 7.0%, 40 to 90%
appears in a hexavalent and soluble form. MIG welding fumes may contain 4 to 15%
chromium, but most of it is in the trivalent or metallic form.
The most recent data available from EPA's National Air Data Branch (NADB, n.d.) for
total chromium show that the highest measured 24-hr chromium level nationwide was
0.6 /ig/m3, in Camden, NJ. With the use of standard meteorological dispersion factors, the
24-hr reading translates into a 1-hr level of 1.5 /tg/m3. The maximum annual mean
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(arithmetic), also in Camden, for 1984 was 0.08 jug/m3. But on average, annual levels
nationwide rarely exceed the limit of detection i.e., 0.005 pg/m3. The monitoring sites were
not located in areas typically dominated by chromium emissions. EPA currently is
conducting atmospheric dispersion modeling to improve estimates of exposure to chromium
for the general public.
1.4 COMPOUND DISPOSITION AND KINETICS
In the 1984 HAD, the data base for evaluating the in vivo reduction of Cr(VI) to Cr(m)
was very limited, and no conclusions could be drawn about the importance of such
conversions for metabolism and toxicity of Cr(VI) compounds.
In recent years, much work has been performed on in vivo reduction, and some valid
characterizations now can be made. Many efficient systems for in vivo reduction of Cr(VI)
exist (Petrilli and De Flora, 1988). The respiratory system, as well as the gastrointestinal
tract, provide physiologic environments which have the potential to reduce significant
amounts of Cr(VI). Any Cr(VI) that is taken up into the blood may be reduced in the
plasma; and if Cr(VI) passes into the red cells, these have a large capacity to reduce Cr(VI)
to Cr(ffl), which will be bound and stored in the cells. Cr(VI) reduction can occur in the
cytosol. Ascorbic acid (Vitamin C) is a reducing agent that plays an important protective role
against Cr(VI) toxicity in human beings (Korallus, 1986) and experimental animals (Suzuki,
1988; Ginteretal., 1989).
The lack of certain kinetic information about reduction of Cr(VI) to Cr(ffl) makes it
difficult to complete a characterization of the efficiency of Cr(VI) reduction since it will be
dependent on the dose and the nature of the reduction environment (e.g., gastric juices have
peak reductive capacity 2 to 4 hrs after a meal and reaching a minimum between meals and at
night). In general most Cr(VI) would be expected to convert to Cr(III) with absorption and
distribution showing much more Cr(IH) present than Cr(VI). Cr(VI) is preferentially
absorbed, however. Studies to date have not definitively shown that Cr(VI) survives long
enough for excretion although kidney toxicity is greater with Cr(VI) exposure than with
Cr(in).
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1.5 THE ESSENTIALITY OF CHROMIUM
Cr(m) is essential for animals and human beings since it potentiates insulin action in
peripheral tissue. Chromium deficiency may cause changes in the metabolism of glucose and
lipids. In some studies, dietary supplementation with chromium reverses changes in glucose
tolerance and serum lipids. Chromium deficiency is difficult to diagnose since at present no
good indicator for tissue-level chromium exists.
1.6 EFFECTS OF CHROMIUM EXPOSURE ON RESPIRATORY AND
RENAL SYSTEMS
In much of the literature published since the completion of the 1984 Chromium HAD,
together with earlier studies, qualitative information on the association between respiratory
tract irritation and Cr(VI) exposure was reported. Few of the available studies, however,
provide quantitative concentration-response data on chromium health effects.
Three studies on chromeplaters seem to provide some quantitative information on upper
respiratory irritation after exposure to Cr(VI) as chromic acid. In the study of Cohen et al.
(1974), nasal ulcers and perforations were associated with total chromium concentrations of
1.4 to 43.9 /ig/m3, averaging 7.1 j*g/m3, and Cr(VI) concentrations of 0.09 to 9.1 fig/m3,
averaging 2.9 /*g/m3. Ninety-five percent of the 37 workers studied exhibited pathologic
changes in nasal mucosa and in a concentration-duration response. More than half of the
workers employed less than one year had nasal pathology that was more severe than simple
redness of the nasal mucosa. Almost all the workers (35 of 37) employed longer than one
year had nasal tissue damage. The authors noted the lack of good industrial hygiene
practices, implicating direct contact, such as touching of the nose with chromium-
contaminated hands, as a potentially important route of exposure. A subsequent study by
Lucas and Kramkowski (1975) revealed similar results. Cr(VI) concentrations ranged from 1
to 20 /*g/m3, averaging 4 j*g/m3. However, the authors attributed the nasal pathology
primarily to direct contact. Lindberg and Hedenstierna (1983) also found similar effects on
nasal pathology and subjective symptoms. They reported reddening of the nasal mucosa at 1
to 2 jig/m3 and nasal irritation (chronic and nasal septal ulceration and perforation) in two-
thirds of the subjects at concentrations from 2 to 20 /*g/m3. All workers with nasal ulceration
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had been exposed to chromic acid mist, which contained Cr(VI) at 20 ^g/m3 or greater near
the baths. For pulmonary function measurements, changes in vital capacity and forced
expiratory volume at one sec (FEVj) were seen from Cr(VI) exposures greater than 2 /*g/m3.
Cr(VI) exposure as low as 4 to 6 jtg/m3 can result in renal effects. Elevated urinary
excretion of 02-microglobulin is an indicator of nephrotoxicity. Lindberg and Vesterberg
(1983b) observed increased elimination of this protein in chromeplaters exposed to 8-hr shifts
of 4 to 20 ^g/m3 Cr(VI). The effect is probably reversible since former chromeplaters did
not have an elevated concentration of either 02-microglobulin or albumin in their urine.
In another study, Saner et al. (1984) did not find increased urinary 02-microglobulin
levels in tannery workers in comparison to referent control workers. However, comparison
of urinary chromium concentrations of the tannery workers in this study versus the
chromeplaters in the Lindberg and Vesterberg (1983a,b) study suggests that the latter had
distinctly higher chromium exposures than the former.
Hexavalent chromium compounds may cause skin lesions by direct contact, but exposure
to such compounds can also cause sensitization, which may lead to dermatitis and eczema.
Chromium allergy is mainly an occupational problem and not common in the general
population.
In conclusion, transient and subtle effects on the airways and renal effects have been
observed in chromeplaters exposed subchronically to chromic acid mist containing Cr(VI) in
air at concentrations greater than 1 jig/m3. Such effects include: reddening of nasal mucosa
starting at 1 to 2 /zg/m3; nasal irritation (ulceration, perforation) at 2 to 20 ^g/m3, changes in
pulmonary function (FEY^ at levels >2 Mg/m3; and renal proteinuria at 2 to 20 ^g/m3. The
o
1 ^g/m level, therefore, appears to represent the lowest observed-effect level (LOEL)
associated with exposure to chromic acid. It is difficult to specify whether 1 /*g/m3 should
also be identified as the lowest observed adverse effects (LOAEL) level. The observed
effects between 1 and 2 ^g/m3 may not constitute functional impairment of human activity,
but could be an early indicator of altered normal functioning that might lead to a progression
to more serious health effects if long-term sustained exposure occurred at this level.
However, the data by Lindberg and Hedenstierna (1983) did not indicate any chronic effects.
The data on other chromium compounds do not clearly identify a LOEL.
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Chromic acid represents the worst case since it is highly soluble and reactive. By
applying an uncertainty factor of 10 because LOAELs are used rather than NOAELs (no-
observed-adverse-effect-levels), exposure to 0.1 j*g Cr(VI)/m3 should not cause irritation of
the airways or other local or systemic effects. Cr(VI) will be reduced to Cr(III) in the lungs,
and that chromium species will be retained in the lungs, showing a tendency to increase with
age.
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2. INTRODUCTION
In August 1984, the U.S. EPA's Environmental Criteria and Assessment Office (ECAO)
completed an in-depth review of the scientific literature on chromium and its compounds for
the Office of Air Quality Planning and Standards. Published as the Health Assessment
Document (HAD) for chromium (U.S. Environmental Protection Agency, 1984a), it was the
scientific data base to be used for regulatory decision making by the Agency and as an
interpretive summary of all relevant scientific studies. The HAD considered all sources of
chromium in the environment, the likelihood for human exposure, and the possible
consequences to man and lower organisms from its absorption. The information was
integrated into a format that could serve as the basis for qualitative risk assessments; at the
same time, it identified gaps in scientific knowledge that limited accurate health assessment.
Notwithstanding the in-depth analysis, peer-review processes, and multiple revisions of
the 1984 Chromium HAD, several salient scientific questions concerning noncarcinogenic
effects remained unanswered. To address those issues, a new literature review was initiated
in selected areas, key studies were reanalyzed, and some of the conclusions of the original
HAD were reassessed. Approximately 200 additional references were reviewed for possible
inclusion in the revised HAD. Although this additional material and the reanalysis of
previously reviewed data add considerably to understanding the effect of chromium on human
health, many of the questions still are not answered completely, though the confidence in the
evaluation has increased markedly. In this update the following technical issues have been
addressed:
• Types and persistence of chromium compounds in the environment
• Adequacy of the sampling and analytical methods as a means of evaluating the
types and amounts of chromium in environmental and controlled study exposures
• Transformation rates of chromium compounds in the environment
• Exposure parameters associated with the key studies
• In-depth review of pulmonary effects
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• Concentration-response relationships of acute, subchronic, and chronic respiratory
effects, including chemical and physical properties of the active chromium species
that influence deposition, absorption, and other pharmacokinetics.
In this update, all key references cited in the 1984 document were reviewed again and
compared with their descriptions in the HAD. Sometimes no changes were made; in some
instances, the original descriptions were revised.
Several other assessments of health effects of trivalent and hexavalent chromium have
been prepared by EPA (U.S. Environmental Protection Agency, 1984b,c; Syracuse Research
Corporation), World Health Organization (1988) and the ATSDR Tox Profile on Chromium
(Syracuse Research Corporation, 1989) are available. Carcinogenic potency of different
valence states of chromium is also under consideration (U.S. Environmental Protection
Agency, 1987). In addition, there is a recent summary chapter (Hertel, 1986) which is useful
for review purposes.
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3.1 CHEMICAL AND PHYSICAL PROPERTIES
Chromium is one of the most important metals used in industry today. Discovered in
1797 by the French chemist Louis Vanquelin, chromium was a key ingredient in the industrial
revolution. Table 3-1 lists its chemical and physical properties.
Although chromium exists in several oxidation states, from -2 to +6, chromium +3 and
+6 [Cr(III) and Cr(VI)] have been studied extensively, and the other species have been
investigated only moderately in research chemistry. The action of these two forms on
biological systems is characterized poorly. The intermediate oxidation states of chromium,
+4 and +5, also may have an important role in interactions with biological systems, but until
recently, virtually no biological research had been conducted on these chemical species.
Cr(III) is the most stable form of chromium. In neutral and basic solutions, Cr(III)
forms binuclear and polynuclear compounds in which adjacent chromium atoms are linked
through hydroxy- (OH) or oxo- (O) bridges. Interestingly, Cr(III) forms stable complexes
with amino acids and peptides. Cr(III) also has a strong tendency to form hexacoordinated
octahedral complexes with ligands, such as water, ammonia, urea, ethylenediamine, halides,
sulfates, or organic acids. These relatively stable complex formations (Cotton and Wilkinson,
1980; Kiilunen et al., 1983) can prevent precipitation of Cr(III) at pH values at which it
would otherwise precipitate, and at normal pH values further oxidation of Cr(III) is unlikely
(Hartford, 1986).
Cr(VI) exists in solution as hydrochromate, chromate, and dichromate ionic species.
The proportion of each ion in solution is dependent both on pH and on concentration
(Pourbaix, 1974). In strongly basic and neutral pH values, the chromate form predominates.
As the pH is lowered, the hydrochromate concentration increases. At very low pH, the
dichromate species predominates. In the pH ranges encountered in natural water, the
predominant forms are hydrochromate ions (63.6%) at pH 6.0 to 6.2 and chromate ions
(95.7%) at pH 7.8 to 8.5. The oxidizing ability of Cr(VI) in aqueous solution is pH-
dependent. The oxidation potential of Cr(VI) increases at lower pH. The ability of Cr(VI) to
oxidize organic materials and the tendency of the resulting Cr(III) to form stable complexes
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TABLE 3-1. CHEMICAL AND PHYSICAL PROPERTIES OF CHROMIUM
Property
Value
Atomic weight
Isotopes, %
50
52
53
54
Crystal structure
Density at 20°C, g/cm3
Melting point, °C
Boiling point, °C
Vapor pressure 130 Paab,°C
Heat of fusion, kJ/mol
Latent heat of vaporization at bp kJ/molb
Specific heat at 25°C, kJ/(mol-K)b
Linear coefficient of thermal expansion at 20 °C
Thermal conductivity at 20°C, W/(m-K)
Electrical resistivity at 20°C, /*-m
Specific magnetic susceptibility at 20°C
Total emissivity at 100°C, nonoxidizing atm, in %
Reflectivity, R
A, nm
%
Refractive index
a
\
Standard electrode potential, valence 0 to 3+, V
lonization potential, V
1st
2nd
Half-life of 51Cr isotope, days
Thermal neutron scattering cross section, m2
Elastic modulus, GPac
Compressibility, at 10-60 TPad
51.996
4.31
83.76
9.55
2.38
body-centered cube
7.19
1875
2680
1610
13.4-14.6
320.6
23.9 (0.46 kJ/kg-K)
6.2 x 10"6
91
0.129
3.6 x 10'6
0.08
300, 500, 1,000, 4,000
67, 70, 63, 88
1.64-3.28
2570-6080
0.71
6.74
16.6
27.8
6.1x 10-28
250
70 x 10'3
fTo convert Pa to mmHg, multiply by 0.0075.
^o convert J to cal, divide by 4.184.
-------
with available biological ligands afford a reasonable mechanism by which chromium can
interact with the normal biochemistry of man.
The solubility of a specific chromium compound can be an important factor in
determining its health effects from welding fumes and similar mixture of chromium particles.
Studies of water solubility (determined by shaking 30 minutes at room temperature) have
shown that, in welding fumes, only Cr(VI) compounds are water soluble, and some of these
only slightly so (Stern, 1982). Some Cr(VI) and all Cr(IH) and Cr(O) compounds are not
water soluble.
The physical properties of various chromium oxidation states and of several
environmentally significant trivalent and hexavalent chromium compounds are shown in
Table 3-2. Because of the considerable disagreement in the literature concerning the physical
parameters given in this table, these values should be accepted with reservation. The
disagreement in the values is possibly due to the reactions of these compounds with other
substances, namely the moisture and air at high temperatures, impurities, and structural and
compositional changes occurring during the experimental determinations. The composition of
typical ferrochromium alloys and chromium metals is given in Table 3-3. General
information on the chemistry of chromium can be found in the 1984 HAD (U.S.
Environmental Protection Agency, 1984a).
3.2 PRODUCTION, USE, AND RELEASE TO THE ENVIRONMENT
Considerable information is available on production, use, and release of chromium into
the environment. Much less information is available on the forms of chromium in the
environment. Although it is assumed that Cr(IH) and Cr(VI) comprise most of the total
environmental chromium, the biological importance of the other oxidation states cannot be
ruled out completely.
This section focuses mainly on new information not presented in the 1984 HAD.
3.2.1 Production of Chromium Compounds
According to the U.S EPA's 1984 report (Radian Corporation, 1984) on chromium
emission factors, chromite ore has not been mined commercially in the United States since
3-3
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1961, when the U.S. Defense Production Act was phased out, eliminating government
subsidization of chromite mining activities. The United States owns chromite deposits in
Maryland, Montana. North Carolina, California, Wyoming, Washington, Oregon, Texas, and
Pennsylvania; however, the low chromium content of these deposits precludes economical
mining. In 1982, the U.S. imported 456,000 metric tons (507,000 tons) of chromite, mostly
from South Africa (54.6 percent), the Phillipines (13.8 percent), Finland (8.9 percent),
Madagascar (8.1 percent), the U.S.S.R (6.7 percent), Turkey (6.3 percent), Albania
(0.8 percent), and Pakistan (0.6 percent).
In 1984, the U.S. annual production capacity of sodium chromate and sodium
dichromate was 204,000 metric tons. Chromic acid annual production capacity totaled
38,000 metric tons (Myers et al., 1986). The industrial processes for the production of
chromium metal and compounds were described adequately in the previous document (U.S.
Environmental Protection Agency, 1984a).
3.2.2 Uses of Chromium and Its Compounds
The 1984 Chromium HAD (U.S. Environmental Protection Agency, 1984a) noted that
metallurgical and chemical usages constituted 82% of the total U.S. chromium consumption
in 1979. The major chromium chemicals, uses, and the number of production sites are
presented in Tables 3-4 and 3-5. As noted in the 1984 Chromium HAD, the pattern of
chromium consumption in the United States has been consistent over the last 20 years.
However, the use of chromite and chrome alloys in the refractory industry is beginning to
decline as open-hearth furnaces are replaced by basic-oxygen furnaces. In the future, growth
in chromium usage is expected in the metallurgical and chemical sectors.
3.2.3 Releases Into the Environment
As seen in Table 3-6, comfort cooling towers account for the largest number of sources
emitting Cr(VI) compounds. With an estimated 38,000 sources, the estimated 7.2 to
206 metric tons per year amounts to a relatively significant contribution of the total
hexavalent chromium emissions, but on a site-by-site basis, most of the individual towers do
not appear to be significant sources of hexavalent chromium emissions, averaging a maximum
of 0.005 metric tons per year. Although the combustion of coal and oil represents the largest
3-9
-------
TABLE 3-4. MAJOR CHROMIUM USES AND KEY
CHROMIUM CHEMICALS INVOLVED
Chromium Chemical
Use Area
Key Chromium
Chemicals Involved
Paints and Pigments
Leather Tanning Liquor
Metal Finishing and Plating
Corrosion Inhibitors
Catalysts
Drilling Muds
Wood Preservatives
Textile Mordants and Dyes
Chrome Yellow8
Chrome Orange3
Chrome Oxide Green
Molybdate Orange*
Chrome Green
Basic Chromium Sulfate
Chromic Acid
Zinc Chromate
Zinc Tetroxychromate
Strontium Chromate
Lithium Chromate
Cadmium Chromate
Copper Chromate
Magnesium Dichromate
Nickel Chromate
Copper Chromite
Chromium Lignosulfonate
Chrome Copper Arsenate
Chrome Zinc Chloride
Chromic Chromate
Chromic Chloride (hydrated)
Chromic Fluoride
Chromic Lactate
aContains lead chromate.
Source: Radian Corporation (1984).
3-10
-------
TABLE 3-5. LIST OF COMMERCIALLY PRODUCED SECONDARY CHROMIUM
CHEMICALS AND THEIR GENERAL USES
Chromium Chemical8
Number of
Production
Sitesb
General Uses
Chromic acid (Chromium trioxide)
Chromium acetate
Chromium acetylacetonate
Chromium monoboride
Chromium carbide
Chromium carbonyl
Chromium chloride, basic
Chromium chloride
Chromium diboride
Chromium difluoride
Chromium dioxide
Chromium 2-ethylexanoate
(Chromic octoate)
Chromium fluoride
Chromium hydroxide
Chromium hydroxy diacetate
Chromium hydroxy dichloride
Chromium naphthenate
Chromium nitrate
Chromium oleate
Chromium oxide (Chrome oxide green)
Chromium phosphate
Chromium potassium sulfate
(Chrome alum)
Chromium sulfate
Chromium sulfate, basic
Chromium triacetate
Chromium trifluoride
Chrome lignosulfate
Potassium chromate
Potassium dichromate
Lead chromate
Zinc chromate
Ammonium dichromate
Barium chromate
Calcium chromate
Cesium chromate
Copper chromate, basic
Magnesium chromate
Strontium chromate
Iron chromite
Electroplating
Printing and dyeing textiles
Catalysts, antiknock compounds
Unknown
Metallurgy
Catalysts
Metal treatment
Metal treatment
Unknown
Catalysts
Magnetic tape
Unknown
Mordants, catalysts
Pigments, catalysts
Unknown
Unknown
Textile preservative
Catalysts, corrosion control
Unknown
Pigments
Pigments, catalysts
Photographic emulsions
Catalysts, dyeing, tanning
Tanning
Unknown
Printing, dyeing, catalysts
Drilling muds
Metal treatment
Tanning, dyeing, pigments
Pigments
Corrosion control
Printing, pyrotechnics
Pyrotechnics
Corrosion control
Electronics
Wood preservative
Refractory, catalysts
Corrosion control pigment
Refractory
EList does not include sodium chromate and sodium dichromate, which are primary chemicals.
"Several sites produce multiple chromium chemicals.
Source: Radian Corporation (1984).
3-11
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TABLE 3-6. SOURCES AND ESTIMATES OF UNITED STATES
ATMOSPHERIC CHROMIUM EMISSIONS
Source Category
Combustion of Coal and Oil
Chromium Chemical Manufacturing
Chemical Manufacturing
Cooling Towers
Petroleum Refining Cooling Towers
Specialty/Steel Production
Primary Metal Cooling Towers
Chromeplating
Comfort Cooling Towers
Textile Manufacturing Cooling
Towers
Refractory Production
Ferrochromium Production
Sewage Sludge Incineration
Tobacco Cooling Towers
Utility Industry Cooling Towers
Chrome Ore Refining
Tire and Rubber Cooling Towers
Glass Manufacturing Cooling Towers
Cement Production
Municipal Refuse Incineration
NATIONWIDE TOTAL
Estimated
Number of
Sources
Many
2
2,039
475
18
224
4,000
38,000
51
10
2
133
16
6
6
40
3
145
95
Chromium
Emissions
(Metric
Tons/Yr)
1,723
18
43
32
103
8
700
7.2-206
0.1
24
16
13
0.2
1.0
4.8
0.2
0.01
3
2.5
2
Estimated
Cr(VD
(%)
0.2
67
100
100
2.2
100
-100
100
100
1.3
5.4
<0.1
100
100
<0.1
100
100
0.2
0.3
,700-2,900
Sources: Myers et al. (1986); Nelson et al. (1984); Radian Corporation (1984); U.S. Environmental Protection
Agency (1987).
3-12
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source category of total chromium emissions, only about 0.2% of these emissions are
hexavalent chromium, or 5.4 metric tons Cr(VI) annually. Chemical manufacturing,
petroleum-refining cooling towers, primary metal, and chromeplating represent the major
Cr(VI) source categories. However, the maximum average of each individual source is less
imposing; for instance, the emission average for petroleum-refining cooling towers is only
0.4 metric tons per year.
3.3 ENVIRONMENTAL FATE, TRANSPORT, AND
CONCENTRATIONS
3.3.1 Air
Chromium occurs in the atmosphere primarily in two oxidation states, Cr(in) and
Cr(VI). The forms and uses are shown in the previous tables. In the environment under
typical atmospheric conditions, as theorized by Seigneur (1986) and others, Cr(VI) may be
reduced to Cr(III) at a significant rate by vanadium (V2+, V3 + , and VO2+), Fe2+, HSO3-
and As(IH). Conversely, the oxidation of Cr(III) to Cr(VI) may occur in the atmosphere at a
significant rate only if (1) Cr(III) is emitted as a chromium salt and not Cr2O3 and (2) at least
1 % of Mn in atmospheric aerosols is present as MnO2. The time required for these reactions
to occur in the environment, given all the other species present, is unknown. Butler et al.
(1986) and others reported that chromium occurred in the smaller particle size fractions.
Table 3-7 shows the combined results from two kilns at a chemical plant for a total of six
impactor measurements. The mean aerodynamic diameter particle size classes are: greater
than 10 f*m, 2 to 10 ^m, and less than 2 /*m. Eighty-five percent of the total Cr(VI) was
contained in the two smaller size classes, which contained only 35% of the total mass.
Similar data were reported by Cox et al. (1985), who determined by scanning electron
microscopy that the submicron particles and aggregates of the particles contained the most of
the hexavalent chromium.
In general, 24-hr ambient air chromium levels, at monitoring sites not necessarily
located near chromium emissions, rarely exceed 0.1 jig/m3. In EPA's National Aerometric
Data Branch (NADB, n.d.) inventory of daily chromium monitoring, only 8 observations at
173 sites exceeded 0.1 jttg/m3 as a 24-hr average in 1984. Table 3-8 lists the number of
3-13
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TABLE 3-7. CHEMICAL PLANT PARTICLE SIZE RESULTS
CrfVn extracted
Size
fraction
mm
>10
2-10
<2
Total
Particulate Mass
mg
39.9
6.6
18.4
64.9
%of
total
62
10
28
100
Mg
84.2
197.8
286.1
568.1
% of
total
chromium
15
35
50
100
Crfim extracted
Mg
349
511
621
1,481
% nf
total
chromium
23
35
42
100
Source: Butler et al. (1986).
observations exceeding 0.1 /*g/m3 from 1977 through 1984. In fact, only about 50 24-hr
observations out of the entire data set have exceeded 0.3 ^g/m3 chromium from 1977 to
1984. Table 3-9 shows the 26 sites at which those 50 observations occurred. Table 3-10,
containing the most recent information available from EPA's NADB, lists 24-hr values for
total chromium, measured by neutron activation analysis, for the 13 highest sites, taken from
an examination of 173 site records for the year 1984. From these sites, which make up the
nationwide network, the highest observed 24-hr total chromium concentration was 0.6 ^g/m3
(in Camden, NJ). Additionally, chromium emissions from only 7 of the 173 sites exceeded
»2
0.1 pg/m , but these monitors generally are not located near sources that emit significant
quantities of chromium (Myers et al., 1986).
3.3.2 Soil
Bartlett (1986) investigated the chemistry of chromium in soils. He found that the key
parameter for oxidizing Cr(HI) to Cr(VI) was fresh manganese oxide, which becomes reduced
as the Cr(III) is oxidized. According to Bartlett, this phenomenon has not been reported
previously because dried, stored, lab-dirt samples had been studied. In such samples,
reducing organics are released, and manganese oxides are reduced or occluded temporarily.
3-14
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TABLE 3-8. NUMBER OF NADB OBSERVATIONS EXCEEDING 0.1 jig/m3
TOTAL CHROMIUM ACCORDING TO YEAR8
Number 1977 1978 1979 1980 1981 1982 1983 1984
28 21 19 17 18 17 29 8
aNADB Chromium Inventory from 1977-1984; total of 2,106 possible yearly maxima.
Bartlett noted that the federal toxicity test using acetic acid eliminates the possibility of
finding Cr(VI) in most soils.
Whether or not Cr(m), naturally present in soil or added to it, is oxidized depends upon
the interaction between the chemical forms of the chromium and the manganese oxides. If
the Cr(III) is "moderately available," the regulating factor appears to be the "freshness" of the
manganese oxide surfaces, which is related to quantities of oxidizable organic substances and
to soil temperature, moisture, aeration, and drying. Strongly bound Cr(III) may remain
reduced in soils, although small amounts may be oxidized. Organic forms are more easily
oxidized than insoluble oxides. Reduction of Cr(VI) added to soils occurs readily if the soil
pH is low and an organic energy source is available. Because soils are not equilibrium
systems, reduction of Cr(VI) and oxidation of Cr(IH) may occur at the same time in the same
soil sample.
3-15
-------
TABLE 3-9. NADB SITES EXCEEDING 0.3 jig/m3 TOTAL
CHROMIUM FROM 1977 TO 1983
Site
Steubenville, OH
East Chicago, EL
Pasadena, CA
Clarion Co., PA
Greenville, SC
Columbia, SC
Huntington, WV
Torrance, CA
Niagara Falls, NY
Baltimore, MD
Cincinnati, OH
Abilene, TX
Camden, NJ
New Orleans, LA
Corpus Christi, TX
(2 locations)
Brownsville, TX
Wichita, KS
Kansas City, KS
Shawnee, KS
Year
1977
1979
1977
1977
1977
1977
1977
1977
1977
1979
1979
1980
1982
1983
1979
1980
1980
1981
1981
1981
1981
1981
1982
1983
1983
1983
No. of
samples
21
28
24
32
25
27
11
6
29
30
26
6
19
23
28
53
19
30
30
33
36
51
58
56
42
57
Maximum
observation
Mg/m'
2.0550
0.6839
1.0750
0.5600
0.4052
0.4031
0.3045
0.3742
0.3153
0.5590
0.4589
0.5794
0.4310
0.4466
0.4316
0.9100
0.4037
0.3461
1.0710
0.7300
0.3500
0.3900
0.3500
0.4000
0.4400
0.3900
Arithmetic
mean
«/«>
0.5251*
0.1212*
0.1170
0.0400*
0.1475*
0.0311
0.0360*
0.0885*
0.0306
0.0389
0.0935
0.2264
0.1019
0.0854
0.0451
0.0400
0.0903
0.0603
0.0436
0.1200
0.0700
0.0300
0.0150
0.0420
0.0320
0.0260
aValue derived from data that did not meet SAROAD criteria, i.e., at least five valid 24-hr measurements per
quarter or 9 of 12 monthly composites.
Source: Derived from NADB data files (n.d.).
3-16
-------
TABLE 3-10. HIGHEST MEASURED TOTAL CHROMIUM CONCENTRATIONS
FOR THE YEAR 1984, jig/m3
Site
Camden, NJ
Reading, PA
Dundalk, MD
Baltimore, MD
(1st site:
Fire Department)
Youngstown, OH
St. Louis Park, MN
Columbus, GA
Cleveland, OH
(2nd site:
Broadway Avenue)
Erie, PA
Philadelphia, PA
Maximum
observation
0.6017
0.3530
0.3442
0.3197
0.1649
0.1594
0.1502
0.1183
0.0993
0.0839
2nd
maximum
0.2190
0.1466
0.1386
0.2271
0.0163
0.0318
0.0052a
0.1053
0.0466
0.0428
Arithmetic
mean
0.0834
0.0618
0.0497
0.0626
0.0181
0.0114
0.0184
0.0332
0.0161
0.0188
Geometric
mean
0.0249
0.0369
0.0278
0.0236
0.0085
0.0064
0.0071
0.0221
0.0096
0.0108
(2nd site:
Edgemont and
Auburn Streets)
Milwaukee, WI
(1st site:
Greenfield Avenue)
Huntington, WV
Chattanooga, TN
(2nd site:
East llth Street)
0.0767
0.0717
0.0713
0.0416
0.0220
0.0200
0.0149
0.0128
0.0134
0.0103
0.0075
0.0082
*Apparent error in the data analysis.
Source: Calculated from the files of EPA's National Aerometric Data Branch (NADB, n.d.).
3-17
-------
-------
4. QUANTITATIVE ANALYSIS OF CHROMIUM IN
BIOLOGICAL AND ENVIRONMENTAL MEDIA
Chromium analysis poses a number of problems in the acquisition of dose-effect and
dose-response relationships for this element. First, levels of the element in biological media
are at the trace and ultra-trace level, even under conditions of occupational, environmental, or
accidental exposure. Secondly, chromium's toxicological and biological behavior is closely
linked to its chemical form, notably the valency state. Thirdly, environmental trans-
formations in the valency of this element can occur after dispersal as can artifactual changes
of oxidation state during sampling and analysis.
This chapter update for chromium analysis has two major sections: total chromium
analysis in biological and environmental media and chemical speciation measurements in
various biological and environmental media.
4.1 TOTAL CHROMIUM ANALYSIS IN BIOLOGICAL AND
ENVIRONMENTAL MEDIA
In many cases, it is sufficient to simply measure the total chromium content of various
media while in other circumstances it may not be readily feasible to do chemical form
speciation. In the analysis of human physiological fluids, for example, the biochemical
milieu and the presence of variably bound chromium species rules out methodologies which
permit simple partitioning of valence state in monitoring of general populations.
4.1.1 Biological Media Sampling Steps in Total Cr Measurements
In total chromium analyses, preservation of specific chemical species of chromium is not
a compelling problem, and precautions to be taken are basically those for most elements at the
ultra-trace level in biological and environmental media. Measurements of total chromium in
biological media entail potential hazards of sample contamination, sample loss, and other
variables which affect precision and accuracy.
4-1
-------
Sample Collecting Steps
Specifics of the sample collection method are determined by the nature of the testing
matrix itself. Since media background levels are at the picogram and subnanogram levels,
extremely scrupulous care to avoid sample contamination must be taken. It is strongly
recommended at the outset that only well-trained personnel with experience in ultra-trace
analysis of elements and associated field work be employed for total chromium analysis
(Versieck et al., 1982; Behne, 1981). Sample collection steps are summarized in Table 4-1.
Ordinary blood collection needles can contaminate blood samples by 2 to 3 orders of
magnitude because of their leachable chromium content. Similarly use of surgical steel blades
for soft tissue sampling must be avoided (Versieck et al., 1982).
Various sample collection alternatives which avoid contamination are available.
Versieck et al. (1979) used a plastic polypropylene over-the-needle catheter while Halls and
Fell (1981) used a plastic cannula to collect whole blood. All-plastic syringes with silanized
needles in a butterfly-type configuration are reported to be satisfactory (Veillon et al., 1984).
Similarly, collection containers can provide opportunities for both contamination as well
as sample loss - the latter by transfer of chromium from bulk matrix to the vessel wall. Fell
et al. (1980) advise against use of any containers which have not been thoroughly evaluated
for Cr release. Chromium levels in serum are so low that even conventional acid washing of
blood tubes is inadequate. Extended boiling in Cr-free acids and surface silanization of high-
purity quartz tubes are recommended for serum collection and processing (Veillon, 1988).
Spot urine samples (ca. 25 ml) are collected best in rigorously acid-washed plastic containers.
Similarly, 24-h collections should employ 2-L polypropylene plastic bottles washed and rinsed
in low-chromium acids and chromium-free deionized water.
Collection procedures similar to that for biological media are required for environmental
samples such as natural waters, while grossly contaminated samples, such as from Superfund
waste sites, may allow somewhat less stringent care (see, Aleckson et al., 1986).
Laboratory Processing of Samples
Ideally, laboratories in which biological chromium analyses are done should be 'ultra-
clean' facilities as described by Patterson and Settle (1976). Such facilities are appropriate
for picogram level measurements of chromium in serum. Otherwise, a laboratory meeting
4-2
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'Class 100' standards should be used. Finally, only highly trained, experienced laboratory
personnel using chromium-free reagents and laboratory ware and using laboratory
performances assessment procedures (see below) should be employed in such analyses.
Reagents for chromium analysis are a chronic source of problems in the laboratory, requiring
constant testing of chromium-free-certified reagents. Methods which minimize or avoid
reagent use are desirable if they also meet traditional analytical performance criteria.
Serum chromium analysis is especially demanding since this medium usually has
chromium levels lower than other biological matrices (Versieck et al., 1979). Dry ashing at
elevated temperature is preferable if wet reagent decomposition produces chronically high and
unacceptable blank values (Ottaway and Fell, 1986). Similarly, urinary chromium analysis by
direct sampling can be used with appropriate safeguards (Kumpulainen et al., 1983; and
Veillonetal., 1982).
Potential loss of chromium during sample degradation steps has plagued many methods
and laboratories (Ottaway and Fell, 1986). Careful wet ashing of media with mixtures of
nitric-perchloric-sulfuric acids can minimize chromium loss during mineralization. The
charring step in conventional muffle furnace ashing is acceptable below 500°C while the
charring step in the graphite furnace of atomic absorption spectrometry is acceptable below
1200°C.
4.1.2 Instrumentation Methods
One can divide instrumental methods for total chromium analysis into those involving
atomic absorption/emission spectroscopy and those involving nonatomic spectroscopic
techniques. The former principally includes atomic absorption spectrometry in the flameless
(electrothermal atomization-atomic absorption spectrometry, ETA-AAS) mode and the newer
method of inductively coupled plasmatomic emission spectrometry (ICP-AES). For this
discussion, the latter will include X-ray fluorescence analysis with various modes of excitation
and various configurations of neutron activation analysis.
Hundreds of chromium methodology studies have been described in the literature over
the years, either as chromium-specific or multi-element measurements. The broad features of
these various methods have been reviewed (e.g., Anderson, 1981; Kumpulainen et al., 1984).
The vast majority of these have not been evaluated critically regarding their accuracy and
4-4
-------
precision by present laboratory practice criteria. It is also the current view (e.g., Veillon,
1988; Ottaway and Fell, 1986) that limitations in methods before 1978 or so, particularly
those using ETA-AAS, are not reliable, and values of concentrations are too high.
Consequently, only the most recent representative techniques are presented in this update
material.
Atomic Absorption/Emission Spectrometric Techniques
The various atomic spectroscopic methods now applied to total chromium measure-
ments differ markedly in their instrumentation specifics, their sample preparation requirements
and their specifications of sensitivity, complexity of operation, and overall cost.
ETA-AAS and Related Methods
Two major factors which affect the usefulness of ETA-AAS for total chromium
measurements at the trace and ultra-trace levels concern the adequacy of chromium detection
limits in all sampling cases and spectrochemical interferences from matrix backgrounds in
various biological and environmental samples.
The reported chromium detection limits for ETA-AAS range considerably, with a lower
end to the range for final analytical solutions of ca. 0.1-0.2 jtg/L (e.g., Ottaway and Fell,
1986). This detection limit is often adequate for urinary analysis of exposure subjects and
measurements in contaminated environmental samples but may not be adequate for serum
chromium analyses in unexposed human populations. Even this detection limit, 0.1-0.2 jig/L,
demands very careful attention to analytical parameters using ETA-AAS, and may require use
of a platform (Slavin et al., 1983) and pyrolytic graphite furnace tubes (Veillon et al., 1984).
The issue of background matrix interference in most commercially available ETA-AAS
systems, especially those older systems using deuterium arc background correction, can be a
serious one when dealing with very low chromium concentrations. Even at charring
temperatures adequate to decompose organic matter, various inorganic salts will often remain
to produce a background signal at the atomization step (e.g., Guthrie et al., 1978). It appears
that background interference problems in the general flameless AAS analytical approach to
human biological monitoring have contributed to earlier levels which are now known to be
too high by at least 10-fold (Veillon, 1988).
4-5
-------
The basic problem is the use of deuterium arc correction devices for controlling
background interferences for analysis of an element such as chromium where the principal
atomic absorption line is compensated poorly, i.e., 357.9 nm. The deuterium arc method
generally is applicable for element lines at or below ca. 300 nm. To offset this problem,
steps can be taken which in some cases further reduce the overall sensitivity. Use of a
tungsten-halogen correction lamp will provide much better results, while adjusting balance in
signals of older units to suppress background will enhance background noise.
Owing to the above interference problems, it is frequently not possible to do direct
analyses of chromium in serum, urine, and other fluids. Although such forms of
measurement are claimed periodically (see, e.g., Ping et al., 1983), most trace analysis
laboratories prefer use of sample pretreatment steps. The trade-off is the level of reagent
blank in chemical treatment steps versus interference problems from spectrochemical
interferences.
As an alternative, O'Haver (1984) has attempted to enhance AAS sensitivity using a
continuum, rather than a typical narrow-line, source via an Echelle spectrometer and a 300 W
Xenon short-arc excitation continuum source. Detection limits appear to approximate that of
narrow-line sources, and there is the added advantage of doing simultaneous analysis of other
elements (Lewis et al., 1985).
Overall, AAS in the flameless mode is more appropriate for those samples where levels
are > 1 ^g/L in final solution than for those below this reference value, as often encountered
in human sera and natural waters. In the latter case, a high level of expertise and proficiency
of the analytical staff are required.
ICP-ES Methods
This newer method, based on plasma excitation of the element atom and measurement of
the resulting emission line(s), has made various inroads into the place of ETA-AAS methods
for environmental sample analysis. Applications to biological monitoring of human
populations have been more limited, due to relative sensitivities in methods. For occupational
screening of urine samples, ICP-ES is probably adequate since its detection limit is 1-5 jig/L.
This limit is one order of magnitude less sensitive than needed for clinical background
4-6
-------
samples. One inherent difficulty is spectral interference which requires dilution of fluids with
deionized water. This markedly reduces the level of sensitivity.
4.2 BIOLOGICAL/ENVIRONMENTAL APPLICATIONS OF ATOMIC
SPECTROSCOPIC TECHNIQUES
Table 4-2 presents illustrative applications of atomic spectroscopic methods to biological
and environmental media. ETA-AAS analyses of human biological fluids by both direct
analysis and via sample pretreatment have been the basis of a large number of methodology
reports in the literature. The approaches of Dube (1988) and Saryan and Reedy (1988) are
typical of approaches using no matrix degradation. The report of Veillon (1988) shows a
good detection limit for serum chromium using degradation of organic matrix. Levels of
chromium in urine and serum are often measurable with ETA-AAS methods, especially in
cases of chromium poisoning.
4.2.1 Neutron Activation and X-Ray Fluorescence Methods
These two types of instrumental analysis differ considerably from those described above.
First, they have multi-element capability and, second, they tend to be more complex and
expensive in their basic equipment packages. This is especially so for the different types of
neutron activation analysis and those forms of X-ray analysis involving sample irradiation
with high-energy beams, such as the proton beam (PIXE) and the synchrotron, linear
polarized beam.
4.2.2 Neutron Activation Analysis of Chromium in Various Media
In traditional neutron activation analysis ashed larger samples or unmodified small
quantities are irradiated in a neutron flux; the samples are set aside to permit decay of
radiation; and the generated radioisotope quantitated radiometrically after chemical
separations. Nuclear reactor irradiation of small amounts of processed biological material,
using neutron fluxes of 1010-1015 neutrons/cm2/sec. and bombardment times of up to
12 days and subsequent radiochemical measurement have been reported for chromium in
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serum (Versieck and Cornells, 1980), urine (Cornells et al., 1975), lung tissue (Landsberger
and Simsons, 1987), and bone (Grynpas et al., 1987).
The neutron activation approach is relatively tedious in that it requires sample-decay
time sufficient to allow sample handling for subsequent isolation and/or analysis of the
chromium species. The 51Cr isotope has a half-life of 27.8 days and a photopeak of
320 keV. The radiochemical separation technique is exacting. However, the direct,
thermal/epithermal energy band analysis used in instrumental neutron activation analysis
(INAA), which uses machine calculation of gamma-ray net peak areas and translation to
chromium concentration, employs more technical equipment. Given the special requirements
of this methodology in terms of equipment and operator expertise, its principal use is
providing reference analysis data rather than routine measurements.
X-ray fluorescence analysis in its various configurations can bridge the gap between
routine laboratory needs for chromium measurements and the specialized research or reference
facility. The ordinary form of X-ray fluorescence analysis, be it energy-dispersive or wave-
length dispersive as to detection configuration, is usually appropriate for analysis of larger
quantities of sample having chromium levels in the parts-per-million (ppm) range and above.
There are, however, newer variations on the conventional X-ray fluorometric approach which
have somewhat more flexibility for chromium measurement in environmental and biological
samples, especially in regard to sensitivity.
In PIXE X-ray spectrometry, samples under a high vacuum are irradiated with a proton
beam of 2 to 3 MeV energy via a tandem Van de Graaff accelerator. Detection is by a low-
energy photon detector fabricated with either a germanium or a lithium-doped silicon detector
core (Tanaka et al., 1987; Maenhaut et al., 1987) and coupled with a pulse height analyzer
interfaced with a microcomputer. Sample powders or ash can be used. In the PIXE
approach, analysis error is introduced by overlap from large neighboring peaks. Using a
variety of National Bureau of Standards (NBS) standard reference materials (SRMs), PIXE
was shown by Maenhaut et al. (1987) to yield results which were within 5% of the reference
values.
In the variant of total reflection X-ray analysis (TR-XRF) which is a form of energy-
dispersive X-ray spectroscopy, ash and film samples are analyzed readily. The
instrumentation configuration to achieve this includes an X-ray generator, a fine focus tube
4-9
-------
and a multiple-reflection module. The high-energy portion of the primary X-ray beam is
intercepted by the multiple-reflection module and only energy < 20 keV is passed to impinge
upon the optically flat support. When analyzing chromium at low levels, Compton and
Rayleigh background scatter must be reduced to enhance detection power (von Bohlen et al.,
1987). Detection limits are ppm or less, and the technique is as accurate as AAS and ICP-
ES methods (e.g., Gerwinski et al., 1987).
A particularly sensitive variation of X-ray analysis uses the synchrotron beam which
irradiates the sample. An intense, linearly polarized beam provides an irradiation
fluorescence and permits use of tunable, wavelength-dispersive monochromators, which are
inherently more sensitive than the conventional energy-dispersive system. The linear
polarization feature also reduces the problem of background scatter. Overall, sensitivity is
greater. However, the relative restriction of this irradiation source to physics research
facilities limits its usefulness to conventional laboratories.
Illustrative applications of neutron activation analysis and X-ray fluorescence to
biological and environmental chromium analysis are given in Table 4-3. Landsberger and
Simsons (1987) examined samples of lung autopsy tissue using Canadian Medical Research
Council reference material (hepatopancreas) to validate accuracy. The mean level of lung
chromium was 8.6 ppm, dry weight. The mean value for the NAA analysis of reference
material was 2.4 ppm vs. the reference value of 2.5 ppm. Bone ash representing cancellous
bone from human femoral heads (N=23, 300 mg) was analyzed by instrumental neutron
activation analysis with a detection limit of <5 ppm and a range of < 5 to < 10 ppm was
found (Grynpas et al., 1987). Using PIXE with a 2.4 MeV proton beam and eight different
NBS standard reference materials processed in two forms (form A was a powder, form B was
an acid digest dried film), it was found that single-target multiple run precision was 2 to 5%
for chromium and other heavy elements, and overall accuracy was within 5% of reference
levels (Maenhaut et al., 1987). Total reflection X-ray spectrometry was used to analyze
content of chromium and other elements in municipal waste incinerator ash in the form of
either digests or leachates (Gerwinski et al., 1987). The levels of chromium in both forms
were validated by comparisons with AAS and with ICP-ES. Synchrotron irradiation X-ray
analysis was tested for its use in measurement of chromium and other metals in biological
materials using SRM milk powder as a reference material (Giauque et al., 1987). The X-ray
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method showed chromium as <0.6 ppm vs. an NBS reference value of 0.003 when samples
of 500 mg were used.
4.2.3 Quality Assurance/Quality Control (QA/QC) Protocols
The elements of an idealized QA/QC framework include close adherence to the use of
internal and external control materials and other proficiency standards (Aitio and Jarvisalo,
1984; Schelenz et al., 1989). A number of standard reference materials which have been
validated for chromium and should be an integral part of any laboratory's QA/QC program,
are summarized in Table 4-4.
Chromium levels in a variety of standard reference materials are known. These include
samples from such sources as the National Institute of Science and Technology (formerly
NBS) SRM program and the many samples of the International Atomic Energy Agency
(IAEA) program. The IAEA program has a total of 11 samples for chromium validation. Of
these, six are clinical/biological in nature, and five are for environmental assessment.
Overall, the data in Table 4-4 indicate that when many laboratories using many
approaches are evaluated for chromium analysis, the variability is large as one gets down to
the low levels in biological media. This is seen when one examines results of the IAEA H-9
human diet testing, using seven laboratories and three of the most commonly used methods.
4.3 CHEMICAL SPECIATION ANALYSIS OF CHROMIUM IN
BIOLOGICAL AND ENVIRONMENTAL MEDIA
The various chromium valence species and other chemical forms show marked
differences in biological activity. Hexavalent chromium [Cr(VI)] is assumed to be more toxic
than trivalent chromium [Cr(III)] owing to the relatively potent carcinogenic character of
various salts in the lung.
Whatever the value of chemical speciation analyses, they are also fraught with analytical
hazards. This is because of the valence lability of Cr(VI) various reactions to include:
environmental transformations of Cr(VI) to Cr(III) or the reverse once emitted to various
environmental compartments; the in vivo conversion to the rather more innocuous trivalent
state after filtration to urine or in other media, e.g., lung fluids and blood; and artifactual
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transformation between valencies during analysis at lower pHs (reduction) or the reverse in
alkaline media conditions.
Harzdorf (1987) has classified two types of chromium speciation techniques presently in
use: those which measure one or more forms directly, e.g., spectrophotometry and
electrochemical techniques, e.g., polarography. In these cases, hexavalent chromium has
discrete spectral and electrochemical characteristics.
The majority of the methods are those where specificity is based on separation of forms,
e.g., Cr(VI) from Cr(III) inorganic anions and followed by some metal-specific but not form-
specific detection, e.g., ETA-AAS. With form-specific detection speciation efficiency is a
matter of separation power for the valency forms. Chelation-extraction separations, using
such common agents as 1,5-diphenylcarbazide or its derivatives, are based on complexation
between the chelant, the hexavalent form, and measurement of chromium through ETA-
AAS. Chromatographic separations are also known, using ion chromatography in its various
configurations. Illustrative recent applications of the above types of analysis for biological
and environmental analyses are presented in Table 4-5.
Chromium speciation of the hexavalent and trivalent states in serum has been reported
by Urasa and Nam (1989) using NBS reference serum for comparison. Separation was by
cation/anion dual chromatography with a plasma emission detector for specific quantitation.
The total chromium value, which is what was actually certified and not various forms therein,
accorded closely to the reference material, while speciation gave a roughly 50:50 distribution
of Cr(VI) vs. Cr(III) with a sum close to the reference total.
Other biological media have been subjected to attempted speciation via chromatographic
approaches. Minoia and Cavalleri (1988) used anion exchange chromatographic separation
with an AAS detector to examine urine for forms of chromium present. No Cr(VI) was
detected which would be expected based on earlier studies. Similarly, Suzuki (1987)
combined anion-exchange high-performance liquid chromatography with AAS detection to
provide a sensitive system (2-5 ng detection limit) for examining reducing activity in vitro of
Cr(VI) in various experimental animal media. In rat plasma, hemolysate and liver
supernatant, various rates of Cr(VI) reduction were measurable. These data further support
the notion that chromium valency is quite labile in mammals. Direct measurement of Cr(VI)
in serum was done using the method of polarography as described by Harzdorf (1987) for the
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pH range of 9-12. The detection limit for the method is 20-50 parts-per-billion. This
approach was also applied successfully to waste water, sediments arid river waters. The
results show also that serum will reduce Cr(VI) when it is added as the simple anion.
Environmental applications of form-specific methodology are known also. Besides those
mentioned already, Subramanian (1987) applied chelation-extraction to measurement of
Cr(VI) in tap water supplies, using ammonium pyrrolidine carbodithioate in methylisobutyl
ketone as the extraction system. The level of Cr(VI) in welding fumes is of particular
concern from a worker health perspective, and a number of reports have described analyses to
measure such a form. In the illustrative approach of Brescianini et al. (1988), anion-
exchange chromatography in tandem with ETA-AAS as a metal detector was used, and the
method was examined using reference fume material from the Danish Welding Institute.
In general, the value of speciation may lie more in environmental assessment than
examining in vivo behavior of specific forms taken into the body. It is known for example,
that one cannot easily examine chromium workers for form-variable chromium exposures,
since chromium from all sources is found in urine as the trivalent form (Minoia and Cavalleri,
1988). Enough of a reduction potential exists that one cannot relate form-variable chromium
in serum to exposure or biotransformation rates (Harzdorf, 1987). Thus, it would not be
useful to speciate chromium in human tissues since reports show significant reduction of
Cr(VI) in tissue and cell preparations (Suzuki, 1987).
The application of methods for environmental speciation, however, would be governed
by the relative red-ox power of the medium in which the chromium is found. Chromium in
complex waste mixtures where oxidizable material is mixed with Cr(VI) along with acid
wastes would be apt to eventually convert to reduced element. Similarly, alkaline wastes co-
occurring with Cr(III) and strong oxidants would proceed toward oxidation over extended
time. "Chromium-clean" systems may be more amenable to speciation analysis, taking into
account the long timeframes in which chromium is apt to be present in such media.
4.4 SUMMARY AND OVERVIEW
Total chromium analysis in biological media is feasible if full account of the many
analytical hazards are taken. For chromium in serum of the general population, specialized
4-16
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laboratories using highly-stringent techniques are probably required. Urinary chromium and
chromium in biological samples other than sera/plasma are higher in concentration and are
more forgiving of laboratory limitations.
With these caveats in mind, it appears that flameless A AS is probably the best method
for total chromium analysis in samples where extremely high sensitivity is not needed. Other
methods have been noted, although they become increasingly more complex and less routine
in application as one proceeds through the list. ICP-ES is generally less sensitive than ETA-
AAS, but it is a multi-element measure; and this may be of considerable value in some cases.
Neutron activation analysis with or without laborious chemical separation steps is mainly a
reference procedure as are some of the X-ray fluorescence approaches using high-energy
irradiation beams to activate chromium.
Chromium is still a trace and ultra-trace element in most media, and its analysis requires
use of good laboratory practices and a stringent QA/QC protocol. Such a protocol should
partake of the variety of standard reference materials for biological and environmental method
validations.
Chromium speciation techniques are feasible, but their value to biological assessments
are circumscribed owing to valence state lability of Cr(VI) and Cr(III) in bioredox systems.
Urinary chromium does not preserve original exposure forms, especially in the workplace.
Environmental applications may be more promising if one can first characterize the pH
of the entire environmental medium and the presence of other redox-active species. Some
environmental media may be simple enough to permit speciation e.g., population exposures
through inhalation of airborne Cr(VI) paniculate. However, valence stability of chromium on
collection filters in high-volume air samplers or even personal samplers would have to be
validated.
4-17
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-------
5. COMPOUND DISPOSITION AND KINETICS
Human beings are exposed to two main forms of chromium. Trivalent chromium,
Cr(III), is a stable form which as an organic complex is present in some foodstuffs and is
regarded as an essential factor in insulin-mediated glucose metabolism. Cr(III) also occurs in
food bound to proteins. The body stores of chromium in the general population are derived
from dietary intakes. Air exposure results in an accumulation in the lung with age (Schroeder
et al., 1962; Kollmeier et al., 1985; Raithel et al., 1988; Paakko et al., 1989) due to the
strong complex binding properties of Cr(III). Hexavalent chromium, Cr(VI) only exists in
oxyanions as hydrochromate, chromate, or dichromate. Exposure in the working environment
is via air and sometimes via skin. Small amounts also may be present in the ambient air.
Chromate ions will pass easily through membranes utilizing the same pathways as sulfate
ions.
The term Cr(VI) will be used in the following text, but it is the fate of the chromate
ion, CrO4"2, which is being described. The reduction mechanism of Cr(VI) to Cr(III) must
be understood before describing chromium metabolism. This topic was briefly discussed in
the 1984 HAD, but extensive research since the completion of that document makes it
possible to give more valid information. This information is needed for risk evaluation.
5.1 MECHANISMS FOR REDUCTION OF HEXAVALENT CHROMIUM
COMPOUNDS
Section 3.3.1 mentions that in ambient air Cr(VI) will be reduced to Cr(III). Oxidation
of Cr(III) to Cr(VI) is less likely to occur. The fate of chromium in soil was discussed in
Section 3.3.2, Cr(VI) will be reduced to Cr(III) in acid soils, but the possibility of
Cr(III) oxidation to Cr(VI) by oxidizing agents, e.g., manganese oxide, was pointed out.
Hexavalent chromium compounds may be inhaled and absorbed in workplace
environments and in ambient air near point sources. These compounds will be subjected to
several reducing environments in the respiratory tract. The fate of hexavalent chromium has
been discussed by Petrilli et al. (1986a). Some reduction to Cr(III) may occur in the lumen
5-1
-------
of the terminal airways by contact with epithelial lining fluid. In the alveolar region, human
and rat macrophages have the capacity to engulf Cr(VI) compounds in particle form and also
the capacity to reduce Cr(VI) to Cr(III), which eventually will be transported away by
mucociliary transport (Petrilli et al., 1986b). Some chromium will be transported by
macrophages via the lymph to lymph nodes. It is known that hilar lymph nodes of humans
contain high concentrations of chromium (Bartsch et al., 1982). The reducing capacity of
alveolar macrophages is even higher than that of liver cells (Petrilli et al., 1986b). Cells
from bronchial or lung tissue of rats and humans seem to have some capacity to reduce
Cr(VI), but much less than that in the liver (Petrilli et al., 1985). This intracellular reduction
is enzyme-catalyzed similar to what has been seen in liver cells. Further evidence for
reducing mechanisms in the lung has been provided by Suzuki (1988) and Suzuki and Fukuda
(1989), who studied the reducing capacity of cell-free lavage fluids from rat lungs and
postulated ascorbic acid, which is present in the surfactant layer of the alveoli to be one
important reducing agent. Suzuki (1988) estimated that the ascorbic acid present could reduce
about 8 fig Cr(VI) per gram of lung tissue, which was higher than the capacity of liver cells;
no comparison was made with lung macrophages. Most Cr(VI) is reduced to Cr(III) in the
respiratory system before Cr(VI) can penetrate into lung tissue cells. If the reducing capacity
is overwhelmed, as may occur in occupational exposure, additional soluble compounds of
Cr(VI) may be absorbed by these cells and result in systemic absorption.
The ingestion of Cr(VI) for instance as small amounts in drinking water, raises the
question of whether any will be absorbed in that form since the saliva and gastric juice of
humans seems to have a high capacity to reduce Cr(VI) to Cr(III) (De Flora et al., 1987;
De Flora et al., 1989). Donaldson and Barreras (1966) found that after a tracer dose of
Na251CrO4 was administered p.o. to fasting humans about 2% of the dose was found in urine
compared to 0.5% after a dose of Cr(III), thus, some chromate was absorbed. After
intraduodenal infusion in four patients, more chromate was absorbed than after passage
through the stomach. The acidity of gastric juice was an important factor since less
Cr(VI) was reduced by achylic persons (Donaldson and Barreras, 1966). De Flora et al.
(1987) observed that while the reduction of Cr(VI) was favored by the acidic gastric
environment, the reaction appeared to depend on the presence of thermostable reducing agents
in the gastric juice, the presence of which varied widely according to the intake of food.
5-2
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Oral uptake of Cr(VI) compounds may occur in occupational exposures, but assuming
normal dietary habits even relatively large amounts may be reduced efficiently. The
efficiency of Cr(VI) reduction is one factor for consideration. The rate of Cr(VI) reduction,
as well as the time Cr(VI) is available for absorption is another factor for consideration.
De Flora et al. (1987) showed that the amount of reducing agent present in gastric juice
cycled with the patterns of food ingetion (the highest levels correlating with 3 to 4 hours after
meals. On the other hand, Cr(VI) reduction was less pronounced by a factor of ten in fasting
individuals and at night irrespective of pH variations. De Flora et al. (1987) estimated that
more than 10 mg of Cr(VI) could be reduced daily by human gastric juice although the
kinetics of the system with this capacity were not discussed.
Cr(VI) absorbed into the blood will be reduced in the plasma by proteins. Ascorbic acid
also may play a role (Korallus, 1986). These results were obtained by experimental studies
on human serum. Ascorbic acid also is effective in the treatment of acute poisoning by
Cr(VI) compounds (Korallus et al., 1984). One liter of plasma can reduce 2 mg of Cr(VI) to
Cr(III) (Korallus, 1986). Experience from studies on exposed workers indicates that
circulating Cr(VI) is filtered through the glomerulus and excreted. Slight renal tubular
damage occurs at exposures resulting in low blood or plasma levels. The plasma reduction
rate in vivo may not always be rapid enough for complete reduction. Further evidence for the
beneficial effects of ascorbic acid is given by Ginter et al. (1989) who showed that ascorbic
acid protected against toxicity from orally administered dichromate in guinea pigs (see also
6.7).
Cr(VI), which has not been reduced in the plasma, may pass into the red cells.
Cr(VI) will be reduced to Cr(III) in the red blood cell by binding to hemoglobin and thiols,
especially glutathione (Lewalter et al., 1985).
Table 5-1 shows the distribution of chromium in rats given intratracheal installations of
3.5 and 87 jug of radioactive Cr(VI) as sodium dichromate (Weber, 1983). A large part of
the dose is retained in the lungs - the clearance being more rapid after the smaller dose. The
concentrations are similar in serum, but in the erythrocytes a larger percentage of the dose is
found after the higher dose. This indicates that the reduction in plasma was relatively more
efficient after the lower dose.
5-3
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TABLE 5-1. ACTIVITY (PERCENT OF DOSE) of 51Cr IN RATS AFTER
INTRATRACHEAL ADMINISTRATION OF Na2CrO4
Dose (jLtg Cr/kg)
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Erythrocytes
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0.34
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0.45
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1.4
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0.94
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1.8
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0.64
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5.40
17.40
87
18.5
0.49
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0.39
0.97
0.065
0.76
0.41
5.5
27.1
(Source: Weber, 1983).
Reduction in plasma and red cells is, thus, a further step in detoxifying chromate ions.
If any chromate ions are left in the circulation, they will either be excreted via the kidneys or
taken up by other organs. Minoia et al. (1983) noted that reduction may occur in the urinary
tract. Cr(VI) could not be found in urine from human beings exposed to chromates,
however, Ginter et al. (1989) found that vitamin C protected against toxicity from orally
administered dichromate in guinea pigs (see also 6.7).
Metabolism of Cr(VI) in liver cells has been extensively studied. A number of enzyme
systems, thiols, and other reducing agents are involved (Wiegand et al., 1984a; Petrilli et al.,
1985; De Flora et al., 1985; Connett and Wetterhahn, 1985; Mikalsen et al., 1989).
Mitochondria, microsomes, and cytosol all have reduction capacity. According to De Flora
et al. (1985), DT-diaphorase, a cytosolic enzyme, is mainly responsible for intracellular
reduction. Cr(VI) is reduced in intact cells and microsomal and mitochondrial preparations,
and a reactive intermediate Cr(V) is formed (Wetterhahn Jennette, 1982; Arslan et al., 1987;
Rossi et al., 1988; Wetterhahn et al., 1989).
5-4
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Thus, several different systems in the mammalian body are capable of reducing Cr(VI),
but the capacity and kinetics of these systems, especially in the lung, are not well
characterized.
5.2 ABSORPTION AND DISTRIBUTION
The absorption of Cr(III) from food seems to be dependent on dietary intake.
Chromium absorption is inversely related to dietary intake. Anderson and Kozlovsky (1985)
estimated that the absorption was about 2% when the dietary intake was 10 jug and about
0.5% at an intake of 40 jug, i.e., about 0.2 jug was absorbed daily. Urinary chromium
excretion was not related to dietary chromium intake. However, daily chromium intake was
less than 40 jug in this study. Similar results were obtained by Bunker et al. (1984) who
reported net absorption of 0.6 jug when the intake was 24.5 jug. Increased chromium
absorption with decreased intake is an efficient mechanism for ensuring relatively constant
amounts of absorbed chromium.
With regard to absorption of inhaled chromium compounds, there are many factors to be
taken into account. Cr(III) is slowly cleared from the lungs of guinea pigs, rabbits, and rats,
and very little seems to be absorbed (Al-Shamma et al., 1979; Wiegand et al., 1984b;
Edel and Sabbioni, 1985). The higher Cr(III) content in lung may come from the
environment and remains undissolved (Hyodo et al., 1980). The increase in chromium levels
with age in man indicates that retained Cr(III) may have a long half-time in the lungs
(SchroederetaL, 1962).
The water solubility of Cr(VI) compounds is complex and ranges from compounds with
high solubility, e.g., chromic acid (chromium trioxide), to those with low solubility,
e.g., lead chromate. Animal experiments have shown that after exposure to soluble chromate
(e.g., sodium chromate) via inhalation or intratracheal instillation, there is an uptake of
Cr(VI) in blood (Langard et al., 1978; Bragt and van Dura, 1983; Wiegand et al., 1984b;
Edel and Sabbioni, 1985), whereas lead chromate was poorly absorbed (Bragt and van Dura,
1983). Thus, biological monitoring of chromium in urine and blood of workers exposed to
lead chromate may not be indicative of previous exposure. The chromium retained is likely
to be in the reduced form. In all animal studies listed, the doses administered are much
larger than the expected exposure to human beings from ambient air.
5-5
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Absorbed chromium is mainly retained in the liver, spleen and kidneys. Chromium is
absorbed from the alveoli, gastrointestinal tract, and skin as Cr(VI) (Hyodo et al., 1980).
Muscle and fat retain only small amounts of chromium after exposure to Cr(VI). Such tissues
do not have a reducing capacity. Five days after a single intravenous administration to rats of
Cr(in) as chromium chloride, the highest concentrations of chromium were in the kidney,
liver, spleen, and bone. The Cr(VI) distribution included the same four organs plus blood
and intestine (Sayato et al., 1980). The plasma component of blood contains much more
Cr(ffi) than the red cells (Edel and Sabbioni, 1985; Sayato et al., 1980). Cr(m) has a high
binding activity for transferrin in plasma, and Cr(VI) is permeable into red cells where it
binds to hemoglobin. In human beings without occupational exposure, the highest
concentrations are in the lung. Among internal organs, the highest concentrations are in the
liver, kidney, and pancreas (Hyodo et al., 1980). In a worker exposed to chromates who
died 10 years after the last exposure, the chromium concentrations in the lung, liver, and
kidney were several times higher than in controls (Hyodo et al., 1980).
Cr(III) is not absorbed after dermal exposure, but workers exposed to chromic acid and
soluble chromates may absorb Cr(VI) via skin (Lindberg and Vesterberg, 1983a).
5.3 EXCRETION
Absorbed chromium, Cr(ffl) and Cr(VI), will be excreted mainly by the kidneys.
Wiegand et al. (1984b) found that after intratracheal instillation to rats of about 0.1-0.5 mg of
Cr(VI) as chromate or 0.1 mg of Cr(m) as the chloride about 16 and 8% of the dose,
respectively had been excreted after 4 hours. Edel and Sabbioni (1985) gave groups of rats
intratracheal installations of 0.01 mg Cr(VI) as chromate and 0.01 mg of Cr(III) as chloride,
respectively. After seven days about 20 and 4% of the respective doses had been excreted via
urine. Bryson and Goodall (1983) gave repeated weekly injections of 3.5 /zg of Cr(IH) and
Cr(VI) to mice and found that after 14 weeks the body burden of chromium was nine times
higher after Cr(HI) treatment.
After intratracheal instillation chromium also will be found in feces, which is mainly
due to mucociliary clearance from the respiratory tract to the gastrointestinal (Gl) tract. In
the rat study by Edel and Sabbioni (1985), 24 percent of Cr(VI) and 36 percent of Cr(HI)
administered by intratracheal instillation had been eliminated in the feces after seven days.
5-6
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After injection of Cr(EI) or Cr(VI) compounds, the excretion is via kidneys (Sayato et al.,
1980). Sayato et al. (1980) showed that 25 days following injection of Cr(VI) and Cr(III) in
rats, urinary excretion was twice fecal excretion — the urinary being 60% of the Cr(VI) dose
and 50% of the Cr(IH) dose. The excretion was more rapid in urine and feces for Cr(VI).
Following oral administration the biological halflife for Cr(VI) was 22.2 days and for Cr(III)
was 91.8 days.
There are also many studies on urinary excretion of chromium in workers exposed to
different chromium compounds (Mutti et al., 1984; Randall and Gibson 1987; Angerer et al.,
1987; Welinder et al., 1983; Sjogren et al., 1983; Kalliomaki et al., 1981; Aitio et al., 1984;
Lindberg and Vesterberg, 1983a). Elevated concentrations of chromium (not speciated) in
urine have been seen after exposure to Cr(III) sulfate (Aitio et al., 1984; Randall and Gibson,
1987) and after exposure to Cr(VI) compounds with excretion generally being much higher
after exposure to soluble compounds (Angerer et al., 1987; Mutti et al., 1984; Lindberg and
Vesterberg, 1983a). However, Aitio et al. (1984) concluded that in the tannery workers,
absorption from the (Gl) tract could account for most of the increase in urine excretion of
chromium. Lindberg and Vesterberg (1983a) noted that among workers with obvious signs of
dermal exposure to chromic acid, urine chromium was higher than expected from air levels.
Chromate can damage the renal tubules, and slight tubular dysfunction has been seen in
workers exposed to Cr(VI) (Lindberg and Vesterberg, 1983b). This indicates that the
glomerular filtrate can contain chromate, which will be taken up by tubular cells.
Section 5.1 stated that Cr(VI) has not been found in urine from workers exposed to chromate,
which provides evidence for reduction to Cr(III) in the renal tissue and in the urinary tract.
5.4 METABOLIC MODELS AND BIOLOGICAL HALF-TIME
No simple model exists for the kinetics of Cr(VI) in the lungs or after systemic
absorption. Since the efficiency of the numerous reduction mechanisms may be
dose-dependent, the fate of a large dose, such as in animal experiments or working
environments, cannot be applied to exposures in the general population. Based on knowledge
about the reduction kinetics of Cr(VI), it is likely that most Cr(VI) which can be inhaled from
ambient air or ingested with drinking water will be reduced before systemic absorption can
5-7
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occur. Even if there is absorption, further reductions to Cr(III) will occur in the blood and
certain blood-receiving organs .
The lung is the critical organ for toxicity from inhaled chromium, and models may be
developed in the future for the fate of Cr(VI) compounds in that organ. Type of compound,
e.g., solubility, dose and pulmonary reduction systems are examples of factors that must be
included in such models.
It is easier to predict the fate of the stable Cr(III). Onkelinx (1977) gave rats of
different ages single intravenous injections of labelled CrCl3, the dose was 0.76 /*g of
chromium per animal. The animals were followed up to four months. A three-compartment
model was proposed. Plasma chromium had a short half-time during the first 6 to 8 hours,
and then passed into a phase with a longer half-time. In bone, kidney, liver, and spleen,
chromium was taken up and retained for longer periods. It also was noted that age played a
role for chromium turnover, which fits with the finding that in human beings a decrease in
chromium levels occur with age.
A human model was proposed by Lim et al. (1983), who gave six subjects a single
intravenous injection of radioactive Cr(III) as the chloride and observed them for
three months. The plasma pool was considered to be in equilibrium with three compartments
having fast, medium, and slow turnovers. The slow compartment was mainly made up by
chromium stored in the liver and had a half-time of 3 to 12 months.
The biological half-time of Cr(III) in rats after oral exposure was estimated to be
92 days (Sayato et al., 1980). In human beings a longer half-time of 192 days has been
estimated (Sargent et al., 1979). As discussed by World Health Organization (1988),
chromium turnover will be influenced by a number of factors, e.g., insulin and glucose.
5-8
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6. HEALTH EFFECTS
It was shown in Chapter 5 that many factors are involved in the metabolism of
hexavalent chromium [Cr(VI)] compounds. Type of compound and magnitude of dose are
two important factors which must be taken into account when the health effects of chromium
exposure are discussed. In Chapter 4, it was pointed out that it is difficult to determine
accurately chromium species in air and other media, and it must be assumed that the exposure
levels of Cr(VI) reported in some studies are not always accurate. In this chapter the main
emphasis will be on the human health effects from exposure to Cr(VI), since it already has
been well documented that low level exposure to trivalent chromium Cr(III) does not
constitute a health hazard (U.S. Environmental Protection Agency, 1984a; World Health
Organization, 1988). Since Cr(III) is regarded as an essential element, the essentiality also
will be discussed. The carcinogenicity of Cr(VI) will be reexamined by the U.S. EPA's
Carcinogen Assessment Group in a separate update document. Table 6-1 gives information
on some studies which are not mentioned in the text or are only briefly discussed with regard
to health effects, exposure, and kinetics. The basis for the risk assessment will be human
studies. There also are a large number of toxicity studies on experimental animals. Some of
these studies are summarized at the end of the chapter in Table 6-2.
6.1 THE ESSENTIALITY OF CHROMIUM
Experimental animal studies and clinical studies indicate that Cr(III) is needed for
normal glucose metabolism and that chromium deficiency results in impaired glucose
tolerance, which can be reversed by chromium administration (U.S. Environmental Protection
Agency, 1984a). The basic mechanism is probably that chromium potentiates insulin in
peripheral tissues; no data indicate that chromium plays a role in pancreatic insulin production
(World Health Organization, 1988).
6-1
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Lipid metabolism also may be affected by chromium deficiency, since low-density
lipoprotein cholesterol (LDL-C), which is regarded as a risk factor in the development of
cardiovascular disease, was lowered after chromium supplementation (World Health
Organization, 1988).
Offenbacher and Pi-Sunyer (1988) recently have reviewed available data on chromium
in human nutrition, and there are both positive and negative results with regard to the effect
of chromium supplementation on glucose and lipids. The main problem is the lack of a good
indicator for chromium levels in the body. Thus, it is difficult to select individuals with
chromium deficiency. Of special interest for this document is whether excessive exposure to
Cr(III) will have any influence on glucose and lipids. Such a study was performed by
Randall and Gibson (1988), who determined insulin, total cholesterol, triglycerides, LDL-C,
and HDL-C in serum from 72 tanner workers exposed to Cr(III). Compared to 52 controls
with a similar age distribution there were no significant differences for any of these
parameters. These workers had an average exposure time of about 11 years and elevated
serum concentrations of chromium (Randall and Gibson, 1987).
Wang et al., 1989 studied subjects participating in a health screening program at a
university. Thirty persons participated; 18 males and 12 females, ranging from 31 to
66, and all had serum cholesterol levels about 2000 mg/1. They were divided into three
groups, 10 persons in each. No data are given on the age and sex distribution within these
groups. One group was given supplements of 50 /*g Cr(III) as the chloride 5 days a week for
12 weeks; another group was given yeast tablets corresponding to 9 /*g Cr(III); the third
group served as controls. There were no changes in insulin levels, but slight reductions were
noted in LDL-C and total cholesterol in both chromium-supplemented groups, compared to
the controls. It is difficult to assess the validity of the authors' claim that there were
significant changes in the supplemented groups. The supplemented intake of complex
chromium from yeast was quite low.
These studies support the conclusions by Offenbacher and Pi-Sunyer (1988). In people
with normal dietary habits and without metabolic diseases, the intake of chromium is probably
adequate for maintaining tissue concentrations of chromium so that glucose and lipid
metabolism are not impaired. Excess chromium will not cause any metabolic disturbances.
6-18
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The active compound, originally called "glucose tolerance factor", has not yet been
wholly characterized. Recently, Yamamoto et al. (1989) isolated a chromium-binding
substance from livers of rabbits who had received dichromate injections. This compound
enhanced glucose oxidation and lipogenesis in adipocytes, and removal of Cr(III) resulted in
loss of activity. The molecular weight of the chromium-binding substance was 1500, and it
was rich in aspartate and glutamate.
A daily intake of 50-200 jig Cr(III) has been suggested in the 1980 RDA. Several
studies in the United States have shown that the actual daily intake is probably between 25
and 75 jug (Offenbacher and Pi-Sunyer, 1988). It cannot be excluded that chromium
deficiency may exist in certain populations, especially among elderly people.
6.2 RESPIRATORY EFFECTS
It has been well documented that high exposure to certain hexavalent chromium
compounds, especially chromic acid (chromium trioxide), has caused severe effects on the
upper airways (U.S. Environmental Protection Agency, 1984a; World Health Organization,
1988). Cr(VI) compounds at lower levels may cause irritation in the airways and functional
impairment of the lungs. Evaluation of the levels at which such effects may occur previously
have not been possible, however.
During recent years several papers have appeared, which together with some earlier
data, make it possible to get a better understanding of effects from low-level exposure to
Cr(VI). Studies have been performed on workers exposed to chromic acid during chrome-
plating and on welders, which may be exposed to Cr(VI) when welding stainless steel.
Studies on welders have given valuable information on the kinetics of Cr(VI) in human
beings, but it is difficult to use such groups for an evaluation of respiratory effects since
welding fumes contain many other gases and particles which may affect the respiratory tract.
It also may be difficult to determine accurately the amount of Cr(VI) in such complex
mixtures. In contrast, there is very specific exposure to chromic acid mist near the plating
baths.
Thirty-seven chromeplaters were studied by Cohen et al. (1974). Total chromium in air
was determined by atomic absorption spectrophotometry (no details given) and Cr(VI) by the
6-19
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Abell and Carlberg (1974) method. As mentioned in Chapter 4 this method may give too low
values due to reduction of Cr(VI). Samples were collected in the breathing zone of the
workers (sampling time not stated). The concentration of total chromium varied from not
detectable to 49.3 /*g/m3 and that of Cr(VI) from not detectable to 9.1 ^g/m3.1 The mean
concentrations were 7.1 and 2.9 jug/m3, respectively. The workers were given a
questionnaire and an examination of the nasal system and skin. Pulmonary function was not
studied. The control group was 15 workers in the same plant but without exposure to
chromium. Whereas none of the controls had a history of nasal sores, 62 percent of the
exposed group reported that symptom. Also, other symptoms indicating severe nasal
irritation were much more common among the chromeplaters. Inspection of the nasal mucosa
showed that 95% of the exposed workers had pathological changes, compared to 7% among
the controls. Eleven percent showed septal perforations. The severity of the mucosal
changes seemed to increase with exposure time, but it is noteworthy that among workers
exposed less than one year 57% had relatively severe changes. No attempt was made to
relate individual exposures to nasal changes; and since air levels were measured only once,
they would give little information on previous exposure. Assuming that the determination of
chromium was relatively accurate, this study indicated that exposure to relatively low
concentrations of chromic acid had caused severe local changes in the nasal mucosa. The
authors pointed out that additional exposure resulted from transfer by hand from contaminated
surfaces; thus, poor personal hygiene was an important factor.
A similar study on 11 chromeplaters was reported by Lucas and Kramkowski (1975).
The concentrations of [Cr(VI)] varied from < 1 to 20 jug/m3 with an average of 4 jug/m3.
Nasal changes, including perforations, were noted, and poor hygiene resulting in direct
contact was considered as an important factor in this plant. The levels of Cr(VI) reported in
these two studies are lower than those reported earlier to cause nasal lesions.
More recently, Lindberg and Hedenstierna (1983) studied 104 chromeplaters from
13 workplaces. Air measurements with personal samplers were performed on 84
chromeplating workers on 13 different days. For the remaining 20 subjects, exposure was
assumed to be similar to that measured for a fellow worker doing identical work in the same
In another section of that report the lowest concentrations are reported to be 1.4and 0.019 /ig/m3, respectively.
6-20
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areas. To evaluate the variations in exposure on different days, measurements were
performed with personal air samplers on 11 subjects at three factories during an entire work
week. Air measurements were performed with stationary equipment at five chrome baths
during a total of 19 days. Sampling was done with glass fiber filters that were leached in an
alkaline buffer solution at pH 12. After buffering to pH 4, Zephiramin was added, and the
Zephiramin-Cr(VI) complex was extracted with methyl isobutyl ketone and analyzed by
atomic absorption (Fukamachi et al., 1975). The limit of detection was 0.2 /*g Cr(VI) per
filter, which corresponded to a Cr(VI) concentration of 0.2 /*g/m3 during an 8-hr sampling
period.
Forty-three subjects were studied with regard to the upper airways. They were exposed
to chromic acid only with no exposure to other irritants. Exposure times ranged between
0.2 to 23.6 years. Nineteen office workers constituted a control group. When exposure was
1-1.9 jug/m3 of Cr(VI), 4 of 10 workers complained of diffuse nasal symptoms, whereas none
of 9 workers exposed to less than 1 jLtg/m3 had such symptoms. Among 24 workers with
mean exposures of 2-20 /*g/m3 there were more pronounced symptoms like stuffy noses and
nosebleeding. Inspection of the nasal mucosa revealed mucosal changes in 11 of 19 workers
exposed to less than 2 ^g/m3, atrophy in four cases but no ulcerations. None of the control
group showed atrophy. Among 24 workers with higher exposure, atrophy was more common
and 11 had ulcerations or perforations of the nasal septum. Ulcerations appeared in two
subjects after less than one year of exposure. The data also indicated that peak exposures are
of significance. This study by Lindberg and Hedenstierna (1983) confirms that nasal irritation
and mucosal changes occur at relatively low concentrations of chromic acid and that there is a
threshold around an average exposure of 1 jug/m3.
There are a few earlier studies on lung function in chromeplaters. Bovet et al. (1977)
and Franchini et al. (1977) made spirometric studies, but air concentrations of Cr(VI) were
not measured. They used urinary chromium as an exposure index. Bovet et al. (1977) found
that a high urinary chromium (> 15 /*g/g creatinine) was related to a decrease in spirometric
values (e.g., VC, FEVj 0). Franchini et al. (1977) reported that 12 out of 18 workers had a
decrease in spirometric values. The urinary chromium averaged about 17 /Ltg/1 in that group.
Lindberg and Hedenstierna (1983) studied respiratory symptoms and lung function in
104 chromeplaters; some details of that study have already been given. Forty-three workers
6-21
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were exposed almost exclusively to chromic acid, and 61 also were exposed to some other
irritating chemicals. As controls, a group of 119 auto mechanics was selected. That group
had been examined earlier with the same methods and by the same personnel as in the present
study. To study short-term effects of exposure, spirometry was performed on Monday
morning and Thursday morning and afternoon. In six nonsmokers with average exposures
above 2 ^g Cr(VI)/m3, there were significant decreases in FVC, FEVLO, and FEF^ from
Monday morning to Thursday afternoon as well as from Thursday morning to Thursday
afternoon. The morning values were slightly lower on Thursday than on Monday, but the
difference was not statistically significant. In 10 workers with average exposures below
2 ^g Cr(VI)/m3, there were no changes in spirometric values from Monday morning to
Thursday afternoon. In 48 smokers there was a small but significant decrease in FVC, but
there was no significant change in FEVj 0 or FEF^.^.
To study long-term effects of exposure to chromic acid the Monday morning values for
nonsmokers and smokers were compared to the corresponding values from the control group.
No differences between the groups was demonstrated. An additional analysis was made by
multiple linear regression taking height and age into account. Exposure time correlated well
with age, but no significant difference between the exposed group and the control group was
shown. This study indicates that reversible effects on lung function can occur when exposure
is above 2 Mg/m3, but chronic effects do not seem to occur even after long-term exposure.
6.3 RENAL EFFECTS
Injection of chromates into experimental animals has been used to produce renal tubular
damage. Early in this century several cases of renal damage after accidental ingestion or
therapeutic applications of Cr(VI) compounds were reported (U.S. Environmental Protection
Agency, 1984a).
Thus, renal effects have been searched for in exposed workers. Mutti et al. (1979)
reported an increased excretion of beta-glucuronidase and protein in welders and
chromeplaters with high urinary chromium (above 30 Mg/g creatinine). This concentration
may correspond to at least 10 ^g Cr(VI)/m3 in the air.
6-22
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Littorin et al. (1984) studied a group of welders with an average chromium excretion of
6 pig/g creatinine (morning) and 11 fig/g creatinine (after work). They determined several
indices of tubular toxicity but did not find any evidence of tubular dysfunction. The levels of
Cr(VI) in air were not reported.
Lindberg and Vesterberg (1983b) examined the urinary excretion rate of proteins in
24 men currently working as chromeplaters, 27 former chromeplaters, and 37 referents who
were divided by age for comparison with each of the chrome workgroups. Some of the men
in the referent group were used in each comparison based strictly on their age distribution.
The chromeplaters ranged in age from 20 to 70 years with a mean age of 36. Their
chromium exposure by air was monitored by personal exposure monitors. The 8-hr mean
value ranged between 2 and 20 jLtg/m3 and averaged 6 jug/m3. The exposure period ranged
between 0.1 and 25 years with the mean of 5.3 years and median of four years. The former
chromeplaters had worked in less modern plants between 1940 and 1968. The exact exposure
level was not known but was presumably quite high since 7 of the 27 had permanent
perforation of the nasal septum. The 37 men used as referents were selected from those
working at the same company but not in the chromeplating facility. The men ranged in age
from 18 to 80 years. Ten individuals over 60 were excluded to form the referent group for
the current chromeplaters, and 10 of the youngest individuals were excluded, to form the
referent group for the former chromeplaters. Thus, the age distributions of the four groups
were similar though values obtained from 17 referents were used twice.
Urine collection was performed midway through the workweek. The urine was
collected after the subjects had drunk a glass of water containing bicarbonate that promoted
formation of alkaline urine; this was necessary to minimize the risk of degradation of beta2~
microglobulin. Protein analysis for urinary beta2-microglobulin and albumin was performed
by sensitive methods. The detection limit for beta2-microglobulin was below 2 jug/1 and
<2 mg/1 for albumin. In addition, all urines were analyzed for cadmium since concurrent
cadmium exposure could result in elevated beta2-microglobulin excretion. None were found
to have cadmium exposure. Elevated beta2-microglobulin (defined as >0.30 mg/1) was found
in five current chromeplaters compared to one in their control group. There was a significant
difference in the excretion of beta2-microglobulin between current chromeplaters and their
controls - the mean values being 230 and 150 jug/1, respectively. There was no difference
6-23
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between former chromeplaters and their controls. Table 6-3 suggests a dose-response
relationship between air levels and renal effects. The authors concluded this study
demonstrates that renal toxicity may occur from chronic, low level chromium exposure.
Theeffect may be reversible, however, since former chromeplaters did not differ from
controls of similar age with regard to excretion.
Chromeplaters were also studied by Verschoor et al. (1988). Twenty-one chromeplaters
and 38 welders exposed mainly to Cr(VI) were compared to 16 boilermakers exposed mainly
to metallic chromium and 63 nonexposed workers. The average ages were 39, 41, 38 and
35 years, respectively. A large number of tests for both renal glomerular and tubular
function were performed, e.g., creatinine and beta2-microglobulin in serum, albumin, betar
microglobulin, retinol-binding protein (RBP) and some enzymes in urine. There were no
abnormal findings with regard to tubular function or albumin excretion. Though the authors
claimed a slight difference in glomerular function between the workers exposed to Cr(VI) and
the other two groups, the data does not substantiate that the difference is of biological
significance. The average excretion of chromium was 9, 3, 1 and 0.2 ^g/g creatinine in the
chromeplaters, welders, boilermakers, and nonexposed workers respectively which indicates
that the chromeplaters had a relatively low exposure to Cr(VI). However, no data were given
on air concentrations of chromium. This study offers further support of a threshold for renal
effects of chromium.
Renal function was also studied by Franchini and Mutti (1988). The subjects were
43 workers with a mean age of 41 years, who were exposed to Cr(VI) in a plant producing
chromates and dichromates. Exposure was high, since the median value for urinary
chromium was 26 Mg/g creatinine. Compared to a control group (n=30) all workers with
urinary chromium below 15 ^g/g RBP and albumin. In the group of workers with urinary
chromium above 15 /*g/g creatinine, the mean RBP excretion was about twice as high as in
the control group. A dose-response relationship could not be established. Additional
evidence for tubular damage was obtained by measuring renal antigens in the urine. In
workers with high urinary chromium, a highly signficant increase in the excretion of these
antigens were noted. A threshold for renal effects of chromium is supported.
Saner et al. (1984) reported a significantly lower excretion rate of urinary beta^
microglobulin in tannery workers (n=18) and in a control group (n=16) used than in normal
6-24
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TABLE 6-3. URINARY EXCRETION OF BETA2-MICROGLOBULIN IN RELATION
TO EXPOSURE LEVELS OF Cr(VI) AMONG PRESENT CHROMEPLATERS
Cr(VI)
/Ag/nr
11-20
4- 8
2- 3
Age
N
5
13
6
Urine beta2-m
Mean
39
37
29
mg/1
0.23 - 130
0.04 - 0.44
0.06-0.18
Source: Lindberg and Vesterberg (1983b).
adults (n=12). However, essentially equivalent average urinary beta2-microglobulin/
creatinine ratios were found for the tannery workers and the control group. The average
urinary chromium concentration was 6.6 /xg/1. There is no information on the level of
exposure to Cr(VI).
6.4 CHROMIUM SENSITIVITY
Sensitivity to chromium compounds has been widely reported in the research literature
dating back to 1869 when Delpech and Hillairet (cited in Joules, 1932) described five cases of
asthma in chromium workers. Cirla (1985) reviewed the literature on chromium sensitivity
and noted that asthma, which can be a manifestation of hypersensitivity, could be induced by
exposure to chromium compounds during chrome plating, galvanic processes, and stainless
steel welding. Although (Cr(VI) is considered the sensitizing determinant of chromium skin
allergy, Cr(IH) has also been associated with sensitization because of its ability to bind and
denature proteins. However, in the work reviewed in Cirla (1985), asthmatic symptoms/
sensitization were seen only in some subjects exposed to Cr(VI). Data for two subjects are
presented as examples by Cirla (1985). The Cr(III) exposure (compound not stated) of
o
260 fj.g/m3 for 30 min had virtually no effect, whereas exposure to 150 /*g/m Cr(VI)
(unknown compound) for 30 min "provided immediate asthmatic reactions".
6-25
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Using radioactive compounds, Fitzgerald (1982) noted that Cr(IH) binds protein haptens
and cannot penetrate the skin membranes, whereas Cr(VI) can penetrate skin membranes and
is reduced to Cr(ffl). When Cr(III) is injected subcutaneously, it may cause a reaction such
as dermal irritation (Naruse et al., 1982). Burrows (1984) concluded from a review of the
literature that in those people with eczematous skin disease, 5- to 10 percent were sensitive to
dichromate (CrVI) compounds as determined by a positive patch test; the ratio of male to
female respondents was 3 to 1.
The prevalence of chromium sensitivity was studied more extensively by Peltonen and
Fraki (1983). Two groups were studied: one consisted of 822 healthy volunteers, including
110 workers who had some exposure to chromium; the second group consisted of
2,981 hospital patients, including 499 with possible occupational exposure to chromium. In
the first group, chromium allergy, as determined by a positive two-day patch test with
0.5 percent potassium dichromate (CrVI), was observed in 10 of the 110 chromium-exposed
workers (9 percent). Among 712 persons without known occupational exposure, four showed
positive reactions (0.6 percent). In this 5-year patient study (Peltonen and Fraki, 1983)
6.8 percent of the men and 2.8 percent of the women reacted positively. Among the
occupational^ exposed segment, 20 percent of the men and 8 percent of the women
responded; only 1.3 percent of a separate group composed of 390 patients with atopic
dermatitis responded. Chromium sensitivity is, thus, mainly an occupational problem. In
contrast to nickel, chromium metal does not sensitize people, which makes it unlikely for
members of the general population to be sensitized. One source may be shoes if Cr(VI) has
been used for tanning.
6.5 DEVELOPMENTAL TOXICITY
It was concluded earlier that injections to experimental animals of Cr(III) or Cr(VI)
compounds could cause embryotoxic and teratogenic effects (U.S. Environmental Protection
Agency, 1984a). At that time there were no data on effects of orally administered chromium.
Trivedi et al. (1989) gave pregnant mice potassium dichromate in drinking water daily during
the gestation period. The concentrations in the water were 250, 500 and 1000 mg/1 as
potassium dichromate, the ingested daily amounts were calculated to be 1.8, 3.6 and 7.0 mg
6-26
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of Cr(VI) respectively, which corresponds to about 60, 120 and 200 mg/kg b.w. Dose-
dependent effects on fetal development such as decreased litter sizes, malformations and
increased resorption were noted. The doses were very high and there is still a lack of data on
teratogenic effects at low levels of oral exposure.
6.6 OTHER EFFECTS
With the exception of the kidney there are no conclusive data that indicate that in human
beings internal organs are affected by absorbed chromium (VI) compounds (U.S.
Environmental Protection Agency, 1984a; World Health Organization, 1988).
6.7 FACTORS MODIFYING TOXICITY
Ginter et al. (1989) studied the effect of ascorbic acid status on the toxicity of Cr(VI).
They used guinea pigs, which like human beings cannot synthesize this vitamin. In animals
with a low intake of ascorbic acid for 8 weeks, regarded as marginally deficient, injections of
potassium dichromate (8 mg/kg b.w.) caused significantly more chromosome aberrations in
bone marrow cells than in animals with a high intake of ascorbic acid. The tissue levels of
ascorbic acid were about 10 times higher. In another experiment, guinea pigs were given
potassium dichromate in drinking water (28 mg/1) for 24 days. The daily intake of the
dichromate was estimated to be about 8 mg/kg b.w. Dichromate exposure did not cause any
changes in tissue concentrations of ascorbic acid in animals on low or high intake of ascorbic
acid, but there were significant decreases in some liver microsomal enzyme activities in the
ascorbic acid-deficient animals. In this study, the animals on high intake of ascorbic acid had
tissue concentrations of ascorbic acid 2-3 times higher than those seen in the deficient
animals. In the bone marrow there were no effects in animals on high intake of ascorbic
acid, whereas in deficient animals there was a significant increase in micronuclei in
polychromatic erythrocytes, indicating a mutagenic effect.
6-27
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6.8 SUMMARY AND CONCLUSIONS
Recent data (Lindberg and Hedenstierna, 1983) support earlier findings (Cohen et al.,
1974; Lucas and Kramkowski, 1975) that in occupational settings air concentrations above
2 ^g/m3 of Cr(VI) as chromic acid are highly irritating to the nasal mucosa and can induce
morphological changes. Even average concentrations of 1-2 Mg Cr(VI)/m3 seem to be
irritating, but peak exposures are probably of great importance. Chromic acid is a highly
soluble and reactive compound, which may represent the worst case. Chromates and dichro-
mates will show irritating properties related to water solubility. Slight changes in lung
function were seen during work at exposure levels of 2-20 Mg Cr(VI)/m3. These changes are
probably reversible since it was not possible to demonstrate long-term effects (Lindberg and
Hedenstierna, 1983).
Reversible effects on the kidney seem to appear at exposure levels above 4 Mg
Cr(VI)/m3 (Lindberg and Vesterberg, 1983b), corresponding to 10-15 Mg Cr/1 in urine.
From the available data, a LOEL of 1 Mg Cr(VI)/m3 is the best estimate for occupational
exposure to chromic acid. At that level there should be no systemic effects, only minor
irritation of the upper airways.
With regard to the general r opulation a life-time exposure to a level of 0.1 ^g
Cr(VI)/m3 should not cause irritation of the airways or other local or systemic toxic reactions.
That estimate is based on the properties of chromic acid, which in ambient air will be only a
minor part of the total chromium, Cr(ffl) being the most common form.
However, the reduction of Cr(VI) to Cr(III), which has a long retention time in the
lungs, may lead to an accumulation of Cr(IH) in the lungs, and it is reasonable to lower the
acceptable level to 0.01 /*g Cr(VI)/m3. Since it is very difficult to determine small amounts
of chromium species in air, a level of 0.05 Mg of total chromium per m3 is recommended.
This will ensure low concentrations of Cr(VI) since Cr(III) is the major form of total
chromium in air.
6-28
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