United States
Environmental Protection
Agency
Environmental Criteria and
Assessment Office
Research Triangle Park NC 27711
EPA-600/8-83-014A f
July 1983 **
External Review Draft
Research and Development
r/EPA
Health Assessment
Document for
Chromium
Review
Draft
(Do Not
Cite or Quote)
NOTICE
This document is a preliminary draft. It has not been formally
released by EPA and should not at this stage be construed to
represent Agency policy. It is being circulated for comment on its
technical accuracy and policy implications.
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EPA-600/8-83-014A
July 1983
External Review Draft
Health Assessment
Document for Chromium
NOTICE
This document is a preliminary draft. It
has not been formally released by EPA and
should not at this stage be construed to
represent Agency policy. It is being
circulated for comment on its technical
accuracy and policy implications.
U.S. Environment Protf~tion
Rc-^c.i V. '.'•••:•.-: •/
?/:,J So.h': L •-' Street
Chicago, Illinois 60604
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Research and Development
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
Research Triangle Park, NC 2771 1
July 1983
-------
DISCLAIMER
The report is an external draft for review purposes only and does not
constitute Agency Policy. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
U,S. Environmental Protectfcrt "Agency
ii
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PREFACE
The Office of Health and Environmental Assessment has prepared this health
assessment to serve as a "source document" for EPA use. This health assessment
document 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 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 response are placed in perspective with observed
environmental levels.
iii
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The Office of Health and Environmental Assessment (OHEA) of U.S. EPA is
responsible for the preparation of this health assessment document.
Dr. Si Duk Lee, as the Project Coordinator, had overall responsibility for
coordination and direction of the document, preparation and production effort.
The chapters addressing physical and chemical properties, sampling and analysis,
air quality and toxicity data were prepared by Life and Environmental Sciences,
Syracuse Research Corporation, Syracuse, NY. The principal authors of these
chapters are listed below.
Dr. Dipak Basu
Karen Blackburn
Dr. Bruce Harris
Dr. Michael W. Neal
Frederick W. Stoss
The OHEA Carcinogen Assessment Group (CAG) was responsible for preparation
of the sections on carcinogenicity. Participating members of the CAG are listed
below (principal authors of present carcinogenicity materials are designated
by •).
Roy Albert, M.D. (Chairman)
Elizabeth L. Anderson, Ph.D.
Larry D. Anderson, Ph.D.
Steven Bayard, Ph.D.
David L. Bayliss, M.S.
Chao W. Chen, Ph.D.
•Herman J. Gibbs, M.S., M.P.H.
Bernard H, Haberman, D.V.M., M.S.
•Charralingayya B. Hiremath, Ph.D.
Robert McGaughy, Ph.D.
*Debdas Mukerjee, Ph.D.
Dharm V. Singh, D.V.M., Ph.D.
Todd W. Thorslund, Sc.D.
iv
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The following individuals provided peer-review of this draft or earlier-
drafts of this document:
U.S. Environmental Protection Agency
Joseph Padgett
Office of Air Quality Planning and Standards
U.S. EPA
Karen Blanchard
Office of Air Quality Planning and Standards
U.S. EPA
Mike Waters, Ph.D.
Office of Health Research
Health Effects Research Laboratory
U.S. EPA
Jerry F. Stara, D.V.M.
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
U.S. EPA
Lester D. Grant, Ph.D.
Office of Health and Environmental Assessment
Environmental Criteria and Assessment Office
U.S. EPA
Carol Sakai, Ph.D.
Office of Health and Environmental Assessment
Reproductive Effects Assessment Group
U.S. EPA
External Peer Reviewers
Dr. Ann Baetjer
John Hopkins School of Hygiene
615 North Wolfe Street
Baltimore, MD 21218
Dr. Derek Hodgson
Professor, Chemistry Department
University of North Carolina
Chapel Hill, NC 27514
Dr. Marshall Johnson
Thomas Jefferson Medical College
Anatomy Department
1020 Locust Street
Philadelphia, PA 19107
-------
Dr. Magnus Piscator
University of Pittsburg
Graduate School of Public Health
Environmental Epidemiology
Pittsburgh, PA 15261
Dr. Bruce Stuart
Stauffer Chemical Company
Farmington Avenue
Farmington, CT 06032
Dr. Robert Tardiff
1*423 Trapline Court
Viena, VA 22180
Dr. Norman M. Trieff
University of Texas Medical Branch
Department of Pathology, UTMB
Gavleston, TX 77550
Dr. Jim Withey
Health Protection Branch
Dept. National Health and Welfare
Tunney's Pasture
Ottawa, Ontario
CANADA K1A 012
vi
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TABLE OF CONTENTS
Page
DISCLAIMER ii
PREFACE iii
LIST OF AUTHORS iv
TABLE OF CONTENTS vii
LIST OF TABLES xi
LIST OF FIGURES xiv
1. INTRODUCTION 1-1
2. SUMMARY AND CONCLUSIONS 2-1
2.1 BACKGROUND INFORMATION 2-1
2.2 ANALYSIS OF CHROMIUM 2-2
2.3 BIOLOGICAL SIGNIFICANCE AND ADVERSE HEALTH EFFECTS
OF CHROMIUM 2-3
2.3-1 Chromium Pharmacokinetics 2-3
2.3.2 Subcellular and Cellular Aspects of
Chromium Toxicity 2-4
2.3.3 Systemic Toxicity of Chromium 2-5
2.3.4 Chromium Carcinogenesis 2-5
2.3-5 Dermatological Aspects of Chromium 2-6
2.3.6 Chromium as an Essential Element 2-7
2.4 HUMAN BIOLOGICAL MONITORING 2-7
2.4.1 Chromium in Blood 2-7
2.4.2 Chromium in Urine 2-8
2.4.3 Chromium in Human Hair 2-9
2.5 HUMAN HEALTH RISK ASSESSMENT OF CHROMIUM 2-9
2.5.1 Health Effects Summary 2-9
2.5.2 Populations at Risk 2-10
3. BACKGROUND INFORMATION 3-1
3.1 CHEMICAL AND PHYSICAL PROPERTIES 3-1
vii
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TABLE OF CONTENTS (cont.)
3.2 PRODUCTION, USE, AND RELEASES TO THE ENVIRONMENT 3-6
3.2.1 Production of Chromium Compounds 3-6
3.2.2 Uses of Chromium and Its Compounds 3-6
3.2.3 Releases to the Environment 3-12
3.3 ENVIRONMENTAL FATE AND TRANSPORT 3-15
3.3.1 Air 3-15
3.3.2 Water and Sediments 3-17
3.3.3 Soil 3-19
3.4 LEVELS OF CHROMIUM IN VARIOUS MEDIA 3-20
3.4.1 Ambient Air 3-20
3.4.2 Aquatic Media 3-24
3.4.3 Aquatic Suspended Materials and Suspended 3-27
3.4.4 Soil 3-29
3.4.5 Food 3-29
3.4.6 Cigarettes 3-34
3.5 INDICES OF EXPOSURE AND DOSE-RESPONSE RELATIONSHIPS 3-34
3.5.1 Chromium in Blood 3-35
3.5.2 Chromium in Urine 3-37
3.5.3 Chromium in Human Hair 3-39
3.6 SUMMARY 3-40
4. SAMPLING AND ANALYSIS" 4-1
4.1 SAMPLING AND STORAGE 4-1
4.1.1 Air 4-1
4.1.2 Water 4-3
4.1.3 Soil and Sediments 4-4
4.1.4 Food 4-5
4.1.5 Biological Samples 4-5
4.2 SAMPLE PRETREATMENT 4-5
4.2.1 Wet and Dry Ashing 4-6
4.2.2 Precipitation 4-6
4.2.3 Solvent Extraction 4-7
4.2.4 Chromatographic Method 4-7
viii
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TABLE OF CONTENTS (cont.)
4.3 METHODS OF ANALYSIS 4-8
4.3.1 Atomic Absorption Spectrometry (flame) 4-12
4.3-2 Atomic Absorption Spectrometry (flameless) 4-12
4.3.3 Emission Spectroscopy 4-14
4.3.4 Neutron Activation Analysis 4-15
4.3.5 X-ray Fluorescence 4-16
4.3.6 Colorimetric 4-1?
4.3.7 Gas Chromatography 4-17
4.3.8 Chemiluminescence 4-18
4.3.9 Polarography 4-19
4.3.10 Mass Spectrometry 4-19
4.3.11 Catalytic Method 4-19
4.3.12 Liquid Chromatography 4-20
4.4 CONSIDERATIONS IN ANALYSIS 4-20
4.5 COMPARISON OF METHODS 4-22
5. CHROMIUM METABOLISM IN MAN AND ANIMALS 5-1
5.1 ROUTES OF CHROMIUM ABSORPTION 5-1
5.1.1 Chromium Absorption and Deposition by Inhalation 5-1
5.1.2 Gastrointestinal Absorption of Chromium 5-7
5.1.3 Chromium Absorption Through the Skin 5-9
5.2 CHROMIUM TRANSPORT, METABOLISM, DISTRIBUTION,
AND ELIMINATION 5-11
5.2.1 Transport and Metabolism 5-11
5.2.2 Distribution 5-14
5.2.3 Elimination 5-19
5.3 SUMMARY 5-22
6. CHROMIUM AS AN ESSENTIAL ELEMENT 6-1
6.1 CHROMIUM DEFICIENCY 6-1
6.2 GLUCOSE TOLERANCE FACTOR 6-4
6.3 SUMMARY 6-6
ix
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TABLE OF CONTENTS (cont.)
Page
7. CHROMIUM TOXICOLOGY 7-1
7.1 ACUTE EFFECTS OF CHROMIUM EXPOSURE IN MAN AND ANIMALS 7-1
7.1.1 Human Studies 7-1
7.1.2 Animal Studies 7-1
7.2 CHRONIC EFFECTS OF CHROMIUM EXPOSURE IN MAN AND ANIMALS 7-6
7.2.1 Evaluation of the Carcinogenicity of Chromium 7-6
7.2.2 Genotoxicity 7-86
7.2.3 Developmental Toxicity and Other Reproductive Effects ... 7-106
7.2.*J Chromium Hypersensitivity 7-112
7.2.5 Other Toxic Effects of Chromium 7-119
7.3 SUMMARY OF TOXIC EFFECTS OTHER THAN CANCER FOLLOWING
EXPOSURE TO CHROMIUM COMPOUNDS 7-140
8. CURRENT REGULATIONS AND STANDARDS 8-1
8.1 OCCUPATIONAL EXPOSURE 8-1
8.2 EXPOSURE TO CHROMIUM IN AMBIENT WATER 8-1
8.3 EXPOSURE TO CHROMIUM IN AMBIENT AIR 8-5
9. REFERENCES .-'... 9-1
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LIST OF TABLES
Table Page
3-1 Physical Properties of Selected Trivalent Chromium Compounds 3-3
3-2 Physical Properties of Selected Hexavalent Chromium Compounds .... 3-4
3-3 Manufacturers and Their Production Capacities of Sodium
Chromate and Sodium Bichromate 3-8
3-4 Principal United States Manufacturers of Chromic Acid 3-9
3-5 United States Chromium Consumption Pattern in 1979 3-10
3-6 Sources and Estimates of United States Atmospheric Chromium
Emissions in 1970 3-14
3-7 Regional Distribution of Principal Chromium Emissions 3-16
3-8 Five Forms of Chromium Transported in the Yukon and
Amazon Rivers 3-18
3-9 Total Chromium Concentrations Measured in the Ambient Air of
Selected Sites in the United States During 1977-1980 3-21
3-10 Chromium Levels in a Few Surface Waters and Groundwaters 3-25
3-11 Chromium Concentrations in U.S. Drinking Waters 3-26
3-12 Concentration of Chromium in Sediments 3-28
3-13 Chromium Content in Selected in United States' Soils 3-30
3-14 Chromium Content in Various U.S. Foods 3-31
3-15 Concentration of Chromium in a Few Commerical Grade Acidic
Foods 3-33
4-1 Analytical Methods for the Determination of Chromium 4-9
6-1 Estimated Adequate and Safe Intake (EASI) for Chromium 6-2
7-1 Inhalation Exposure of Mice to Chromium-Containing Dust 7-8
7-2 Carcinomas Produced with Chromium Compounds in Rats 7-13
7-3 Lung Tumors Found and Microscopically Confirmed 7-15
7-4 Exposure Schedule for Bioassay of Chromium Compounds by
Intrapleural Injection 7-18
xi
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LIST OF TABLES
Table Page
7-5 Compounds Reported to Have Been Tested for Carcinogenicity
by Intrapleural Implantation 7-20
7-6 Experimental Conditions Used to Study the Effect of Intrafemoral,
Intraperitoneal, and Intravenous Administration of Chromium 7-23
7-7 Levels of Hexavalent Chromium in Fractionated Residue Dust 7-2H
7-8 Compounds Reported to Have Been Tested for Carcinogenicity
by Intramuscular Implantation 7-27
7-9 Carcinogenicity of Chromium Compounds in Experimental Animals ... 7-30
7-10 Location of Chromate Manufacturing Plants Which Participated
in Epidemiologic Studies and Plants from Which Vital Statistics
Were Obtained for Each Study 7-37
7-11 Observed Number of Deaths, Standardized Mortality Ratios (SRMs),
and 95$ Confidence Limits (95% CL) for Deaths Due to Cancer of the
Trachea, Bronchus, and Lung and the Number of Reported Deaths
for Which No Certificate Could Be Obtained, By Year of Initial
Employment, Exposure Category and Total Duration Employed, For
Workers Initially Hired as Hourly Employees 7-^6
7-12 Lung Cancer in Workers in the Chromate Pigment Industry 7-58
7-13 Age-Specific Lung Cancer Death and the Gradient Exposure to
Total Chromium 7-71
7-1*1 Combined Age-Specific Lung Cancer Death Rates and Total
Chromium Exposure (in ng/m ) 7-73
7-15 Relative Carcinogenic Potencies Among 53 Chemicals Evaluated by
the Carcinogen Assessment Group as Suspect Human Carcinogens .... 7-79
7-16 Number of Cigarettes Smoked Per Day 7-83
7-17 The In Vitro Mutagenicity Bioassay of Chronic Compounds 7-87
7-18 Chromium Produced Clastogenic Effects and Cell Transformation ... 7-99
7-19 Teratogenic and Fetotoxic Effects of Chromium 7-109
7-20 Studies Suggesting NOAELS or NOELS 7-121
xii
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LIST OF TABLES (cont.)
Table
7-21 Clinical Findings in Workers Employed in Chromium-Plating
Plants 7-125
7-22 Perforation of Nasal Septum in Chromate Workers 7-127
7-23 Perforation of Nasal Septum in Chromate Workers 7-129
7-24 Nasal Medical Findings in a Chromium-Plating Plant 7-130
7-25 Medical Complaints of Workers in "hard" Chromium Electroplating
Plant 7-137
8-1 Recommended Occupational Standards and Recommended Criteria for
Chromium Compounds in the United States 8-2
8-2 Recommended Standards for Chromium in Ambient Waters in the
United States 8-3
8-3 Ambient Water Quality Criteria for the Protection of
Human Health 8-i*
8-U Calculated Ambient Water Quality Criteria for the Protection
of Aquatic Life 8-6
xiii
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LIST OF FIGURES
Figure
3-1
5-1
5-2
7-1
Simplified Flow Chart for the Production of Metallic Chromium
Rate of blood clearance of intravenously injected Cr(III)
51
Whole-body elimination of intravenously administered Cr(III)
Histogram representing frequency distribution of the potency
Page
3-7
5-15
5-21
indices of 52 suspect carcinogens evaluated by the Carcinogen
Assessment Group 7-78
xiv
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1. INTRODUCTION
The 1970 Clean Air Act and its 1977 amendment mandate EPA to regulate, under
Section 112, those pollutants that "may reasonably be anticipated to result in an
increase in mortality or an increase in serious irreversible, or incapacitating
reversible, illness." It also states that EPA must regulate, under Section 111
(d), those pollutants that "may reasonably be anticipated to endanger public
health or welfare."
For this reason, the Office of Air Quality Planning and Standards has
requested that the Environmental Criteria and Assessment Office prepare a scien-
tific assessment for chromium so that it can be determined whether the regulation
would be warranted under these sections of the Clean Air Act, since human expo-
sure to chromium has been a matter of public health concern. Therefore, this
chromium document will serve as a scientific data base for regulatory decision
making by the agency. The health assessment document should represent an inter-
pretive summary of relevant studies rather than a compendium of all available
papers.
The present document represents a comprehensive data base that considers
all sources of chromium in the environment, the likelihood for its exposure to
humans, and the possible consequences to man and lower organisms from its absorp-
tion. This information is integrated into a format that can serve as the basis
for qualitative and quantitative risk assessments, while at the same time identi-
fying gaps in our knowledge that limit accurate health assessment at this time.
Thus, it is expected that this document may serve the information needs of other
government agencies and the private sector that may be involved in decision
making and regulatory activities.
1-1
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2. SUMMARY AND CONCLUSIONS
2.1. BACKGROUND INFORMATION
Chromium is a metallic element which, when found in nature, is a stable
mixture of four separate isotopes. Inorganic chromium compounds occur in valence
states ranging from -2 to +6; however, in the environment the Cr(III) and Cr(VI)
states are the most stable. Chemically, the Cr(III) state is the most stable and
important form of inorganic chromium. Cr(VI) compounds are the most commercially
important form of chromium, and they also appear to be the most significant
chromium compounds from an environmental standpoint. Because Cr(VI) is readily
reduced in the presence of organic material, it is rarely found in nature apart
from deposition by anthropogenic sources.
Although chromite ore is not currently mined in the United States, several
chromium chemicals are domestically produced from imported ores. Sodium chro-
mate, sodium dichromate, and chromic acid are three of the more important
commercial chromium compounds produced in the United States. Metallurgical uses
constitute about 60% of the largest market demand for chromium. Chemical uses
are the second largest consumption sector at 21$, followed by refractory uses at
18$.
Chromium emissions are released into the air, water, and land environments
from a variety of industrial source categories. The largest chromium emission
sources to the air are ore -refining plants, coal combustion units, refractory
plants, and steel and alloy plants. Principal sources of chromium in water
systems include electroplating operations, leather tanneries, and textile manu-
facturing operations. Significant sources of chromium-containing solid wastes
2-1
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that are land disposed include chromite ore refining operations and chromium
chemical production plants.
Recent monitoring of the ambient air in many urban and rural area of the
country has shown 24-hour average chromium concentrations to be in the range of
0.0052 to 0.1568 (ig/m3. The maximum concentration determined during any one
o
measurement was about 2.U8 ng/nr. The chromium concentration in U.S. waters
varies with the type of surrounding industrial sources and the type of underlying
soils. An analysis of 383^ tap waters in representative U.S. cities showed a
chromium concentration ranging from O.1* to 8 ppb. Chromium levels in soils vary
with soil origin and the degree of contamination from anthropogenic chromium
sources. Tests on domestic soils have shown chromium concentrations ranging from
1 to 1000 ppm, with the average concentration ranging from 1H to about 70 ppm.
2.2. ANALYSIS OF CHROMIUM
Based on versatility, sensitivity, and precision, the three most important
methods that have found wide application for the analysis of chromium are
graphite furnace AAS, (atomic absorption spectrophotometry) x-ray fluorescence,
and neutron activation analysis. Of these three methods, graphite furnace AAS
has the advantage of being the least expensive method. The disadvantage of
graphite furnace AAS is that it cannot be used for simultaneous multi-element
analysis. X-ray fluorescence has the advantage over both neutron activation and
graphite furnace AAS analysis in that it can differentiate between the various
oxidation states of Cr without prior pretreatment of the samples. The use of
neutron activation analysis normally requires about a 2-week cooling period if
post-irradiation separations are not performed. Thus, the technique is not
suited for on-line or rapid analysis of chromium.
2-2
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The choice of a particular analytical method for Cr analysis is dictated by
several factors including the type of sample to be analyzed, concentration of Cr
in the sample, and the scope of the analysis. These factors, in combination with
others such as the desired precision and accuracy and the cost of analysis,
should be weighed in selecting a particular analytical method.
2.3. BIOLOGICAL SIGNIFICANCE AND ADVERSE HEALTH EFFECTS OF CHROMIUM
2.3.1. Chromium Pharmacokinetics. There is little specific information on the
deposition and adsorption of chromium by the lungs. As with other particles and
aerosols, deposition will depend on particle size and aerodynamic diameter. The
deposition of particles larger than 1 |im will be governed by gravitational
settling and impact. Deposition of these large particles will occur in the upper
portion of the respiratory tract. Deposition of smaller particles, £0.5 |im, is
predominantly governed by diffusion, and occurs in the deep portions of the
lungs. A portion of the chromium absorbed following inhalation may result from
mucocilliary clearance • of particles in the upper airways with subsequent
swallowing and gastrointestinal adsorption. It has been shown in experimental
animals, however, that the. efficiency of gastrointestinal adsorption is low and
of the order of <5%. All aspects of chromium metabolism are confounded by
limitations in current understanding of the role of valence state and chemical
form on interaction within biological systems. Chromium may be absorbed via the
skin, lungs, or gastrointestinal tract. Data relating to pulmonary absorption
are extremely fragmented, and quantification of absorption is not possible.
Dermal absorption has been better studied in that factors affecting the process
are more clearly delineated. Dermal absorption appears to be affected by valence
state, the particular salt employed, concentration applied, and pH. Gastro
2-3
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intestinal absorption is reported to be poor in all instances; however, data
relating to factors affecting gastrointestinal absorption are incomplete and
contradictory. Transport occurs primarily via plasma siderophilin, while Cr(VI)
penetrates red blood cells.
Reduction of Cr(VI) to Cr(III) appears to occur rapidly in biological
systems, while the mechanism and kinetics are not completely understood. Oxida-
tion of Cr(III) from tissue depots has been proposed, but not demonstrated.
Chromium, when given in excess amounts, accumulates with time. Lung, liver,
spleen, kidney, and bone marrow appear to be primary sites of deposition. Excre-
tion is primarily via the urine, and a small amount possibly excreted through the
gastrointestinal tract. Distribution and elimination kinetics appear to conform
to a three compartment model.
2.3.2. Subcellular and Cellular Aspects of Chromium Toxicity. Cr(VI) readily
crosses cell membranes. While early data indicate that cell membranes are
impermeable to Cr(III), later studies indicate that there is some transport, but
to a much smaller extent than with the hexavalent salts. Intracellularly, only
Cr(III) has been identified. Recent data suggest that Cr(IIl) may be the intra-
cellularly reactive species in mutagenesis. Acute studies indicate target organ
toxicity results from cellular necrosis once intracellular chromium reaches
critical levels. Effects of excess chromium on cellular metabolism following
either acute or chronic studies has not been investigated thoroughly.
The mutagenicity of chromium compounds has been examined in a wide variety
of in vitro assays such as the reverse and forward mutation, gene conversion, and
DNA modification tests. In general, soluble Cr(VI) compounds are less active
when metabolic activating systems are present and more active in their absence.
Insoluble Cr(VI) and Cr(III) compounds are generally less active in cellular
2-1
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mutagenicity assays. The reduction of Cr(VI) to Cr(III) by cellular agents
present in metabolic activation systems may explain Cr(VI)'s lack of mutagenic
activity. More recent evidence implicating both Cr(VI) and Cr(III) in induced
mutagenesis has been reported in DNA interaction and DNA polymerase infidelity
assays.
2.3.3. Systemic Toxicity of Chromium.
2.3.3.1. ANIMAL DATA — Ingestion of soluble Cr(Vl) solutions can cause
local irritation but, generally, chromium salts are relatively non-toxic when
administered orally. Acute exposures (intraperitoneal) result in kidney
failure, liver, heart, and brain micropathology. Chronic target organ effects
have not been described. Inhalation exposures result in characteristic lung
alterations, such as congestion, granuloma, and thickening of alveolar walls;
adverse effects in other organs following inhalation exposures have not been
reported.
2.3.4. Chromium Carcinogenesis. It is presumed that all forms of Cr(VI) are
carcinogenic but the degree of carcinogenicity is modified by the solubility of
the specific compounds. Using the International Agency for Research on Cancer
(IARC) criteria, animal studies have provided sufficient evidence for the
carcinogenicity of the following Cr(VI) compounds: calcium chromate, strontium
chromate, and zinc chromate. Both Cr(lII) and Cr(VI) compounds have been
ineffective in producing lung tumors by inhalation in animals. Similarly, nega-
tive results have been obtained following the ingestion of Cr(III). Chromium
has, however, been shown to be carcinogenic by intrabronchial, intrapleural,
intramuscular implantation, or subcutaneous injection. Cr(III) compounds have
2-5
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been studied less extensively than Cr(Vl); however, animal studies indicate that
Cr(VI) is more likely to be the etiologic agent in human chromium-related cancer.
The epidemiologic studies of chromium have demonstrated an association with
respiratory cancer in chromate-producing industries. The strength of the
association is evidenced by the high relative risks of lung cancer and the
consistency of results by different investigators in different countries.
Results of three epidemiologic studies of chrome pigment workers are also sugges-
tive of an association with lung cancer. Less clear, however, is the question of
which form of chromium is carcinogenic. One epidemiologic study of chrome
pigment workers (Davies, 1978, 1979) suggested that zinc chromate was carcino-
genic, while lead chromate was not. The data on the lead chromate pigment
workers, however, were limited by smal] sample size. Most of the epidemiologic
studies did not attempt to distinguish the carcinogenic species of chromium.
Using the IARC criteria, epidemiologic studies provide sufficient evidence
that chromium is a human carcinogen; also, the animal bioassay studies have
provided sufficient evidence for the carcinogenicity of Cr(VI). The carcino-
genic evidence of Cr(III) is inconclusive. Cr(VI) is mutagenic in multiple
tests while the data for Cr(lII) is inconclusive.
Using the IARC classification scheme, the level of carcinogenic evidence
available for the combined animal and human data would place chromium in Group 1,
meaning that there is decisive evidence for the human carcinogenicity of
chromium.
2.3.5 Dermatological Aspects of Chromium. Chromium reactions of the skin
can be classified as follows: primary .irritations, including ulcers (corrosive)
reactions), scars, and nonulcerative contact dermatitis; and allergic contact
dermatitis, including both eczematous and noneczematous (NAS, 1974). Contact
2-6
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dermatitis can be caused by both Cr(III) and Cr(VI) compounds, although most
cases reported are attributed to exposure to Cr(VI).
2.3.6. Chromium as an Essential Element. A number of clinical symptoms appear in
both humans and animals maintained on chromium deficient diets. Symptoms
reported in humans consist of glucose intolerance, weight loss, and confusion,
while in animals, decreased fertility, corneal opacity and aortic plaques have
also been observed. The symptoms in humans have been reported to be reversed in
some cases by supplementing the diet with chromium (III). Individuals prone to
chromium deficiency include the elderly, diabetics, pregnant women, malnourished
children, individuals who are offspring or siblings of diabetics, and persons
with early coronary heart disease. The Estimated Adequate and Safe Intake (EASI)
level for chromium ranges between 0.01 to 0.20 rag/day, depending on age (NAS,
1980), while the average human intake of chromium is 17 ng/day (range of 0 to
224 jig/day) (NAS, 1980). There is at present no Recommended Daily Allowance
(RDA) for this metal.
2.4. HUMAN BIOLOGICAL MONITORING
2.4.1. Chromium in Blood. Chromium is absorbed through both the respiratory
tract and gastrointestinal system (U.S. EPA, 1978). Exact values for chromium
absorption from the digestive tract are not known. Cr(III) is poorly absorbed,
whereas chromate is better absorbed (Mertz, 1969).
In the respiratory tract, water and serum soluble chromium(IV) is absorbed
into the blood system, whereas insoluble Cr(III) precipitates, particles and the
inert oxides and hydroxides of Cr(III) have long residence times in lung tissue
(U.S. EPA, 1978).
2-7
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Once in the blood stream, chromium compounds are bound by proteins (Gray and
Sterling, 1950). It has been shown that ionic Cr(Vl) (injected intravenously)
passes through the membrane of red blood cells and binds to the globin moiety of
hemoglobin. Hopkins and Schwartz (1964) reported that, in physiological
amounts, cationic Cr(III) is bound to siderophilin and transported to other
tissues.
Chromium disappears quickly from the blood and is taken up by other tissues
in the body, where it is concentrated much more heavily (by a factor of 10 to 100)
than in the blood. Therefore, blood levels of chromium are not a usable indi-
cator of chromium nutritional status (Mertz, 1969; Mertz and Roginski, 1971).
2.4.2. Chromium in Urine. A wide range of values for chromium content in urine
has been reported. Hambidge (1971) reported chromium levels in urine of 8.4 ppb
for adults and 5.5 ppb for children over a 24-hour period. Imbus et al. (1963)
reported median urinary concentrations of chromium for adult males of 3.77 |ig/&.
Renal excretion is the major pathway of chromium elimination, with >80% of
injected chromium excreted in this manner (Mertz, 1969).
Franchini et al. (1975) and Borghetti et al. (1977) reported on workers
exposed to chromium in the chromium-plating industries. They showed that urinary
excretion and renal clearance of diffusible chromium were two biological indices
to evaluate the degree of current exposure and the body burden of the compound,
respectively. Franchini et al. (1978) confirmed their earlier results with an
experimental investigation using rats.
Other authors have demonstrated a close relationship between the amount of
Cr(VI) in the air and urinary excretion (Gylseth et al., 1977) or urinary excre-
tion of the metal corrected for creatinine (Tola et al., 1977). Gylseth et al.
(1977) reported in an abstract that welders exposed to a concentration of
2-8
-------
0.05 mg/m^ (measured as chromium) had a urinary chromium concentration of
=40 \ig/i, measured after work. The duration of exposure was not reported.
2.4.3. Chromium in Human Hair. Schroeder and Nason (1969) reported a mean
chromium concentration of 0.69 + 0.063 ppm for women. Hambidge et al. (1972)
measured chromium concentrations at various distances from the hair root. They
reported that variation in the concentrations were due to past fluctuations in
chromium nutritional status. Hambidge and Rodgerson (1969) reported higher
levels of chromium in the hair of nulliparous women (0.2 to 2.81 ppm) than in the
hair of parous women (0.04 to 1.14 ppm). However, a later study by Hambidge and
Droegnueller (1974) found changes in hair chromium levels due to pregnancy not to
be statistically significant. Hambidge and Rodgerson (1969) reported that hair
chromium levels in 3- to 8-month-old infants were significantly higher than in
those of 2- to 3-year-old children. By the second year of life, mean chromium
levels in hair approached values present in older humans.
2.5. HUMAN HEALTH RISK ASSESSMENT OF CHROMIUM
2.5.1. Health Effects Summary. Although a number of epidemiologic studies have
found an association between exposure to chromium and lung cancer, the data that
could be used for estimating the cancer risk due to exposure to chromium are
limited to the study of Mancuso (1975). Mancuso (1975) reports age-specific lung
cancer mortality data for chromate production workers in terms of total elemental
chromium exposure. Using this information, CAG estimated the lifetime cancer
q
risk due to a constant exposure to air containing 1 jig/nr of elemental chromium
2-9
-------
to be 1.2 x 10 2. This is considered an upper-bound estimate, since it
is based on a model that is linear at low doses.
2.5.2 Populations at Risk. There is no toxicological information to
indicate that any specific subpopulation is highly sensitive to the toxic
effects of chromium. An additional burden of chromium may result from
environmental sources in individuals exposed to chromium in the workplace,
although predominant exposure would be from the workplace in most instances.
The National Institute for Occupational Safety and Health (NIOSH, 1975)
has estimated that 175,000 workers are exposed to Cr(VI), and 200,398
workers are exposed to Cr(III). The same individuals may be represented
in both groups of employees.
2-10
-------
3. BACKGROUND INFORMATION
3.1. CHEMICAL AND PHYSICAL PROPERTIES
Chromium was discovered in 1797 by the French chemist, Louis Vanquelin.
Metallic chromium is steel gray in color, melts at 1857 + 20°C, boils at 2672°C,
and has a specific gravity of 7.20 at 28°C (Weast, 1980). As found in nature,
chromium is a mixture of four stable isotopes of mass numbers 50, 52, 53, and 5*1.
The inorganic chemistry of chromium and its compounds has been extensively
studied. However, its physical or chemical forms and the mode by which they are
incorporated into biological systems are poorly characterized. Inorganic
chromium compounds occur in valence states ranging from -2 to +6. In natural
systems, the Cr(III) and Cr(VI) states are the two most stable forms of chromium.
Chemically, the Cr(III) state is the most stable and important form of
chromium. In neutral and basic solutions, Cr(III) forms binuclear and poly-
nuclear compounds in which adjacent chromium atoms are linked through hydroxy-
(OH) or oxo-(0) bridges. Interestingly, Cr(III) forms stable complexes with
amino acids and peptides (deMeester and Hodgson, 1977; deMeester et al., 1977).
Cr(III) also has a strong tendency to form hexacoordinated octahedral complexes
with ligands, such as water, ammonia, urea, ethylenediamine, halides, sulfates,
and organic acids. These relatively stable complex formations (Cotton and
Wilkinson, 1962) can prevent precipitation of Cr(III) at pH values at which it
would otherwise precipitate.
Cr(VI) exists in solution as hydrochromate, chromate, and dichromate ionic
species. The proportion of each ion in solution is dependent on pH. In strongly
basic and neutral pHs, the chromate form predominates. As the pH is lowered, the
hydrochromate concentration increases. At very low pHs, the dichromate species
3-1
-------
predominates. In the pH ranges encountered in natural water, the predominant
forms are hydrochromate ions (63.6$) at pH 6.0 to 6.2 and chromate ion (95.7$) at
pH 7.8 to 8.5 (Trama and Benoit, 1960). The oxidizing ability of Cr(VI) in
aqueous solution is pH dependent. The oxidation potential of Cr(VI) increases at
lower pHs. The ability of Cr(VI) to oxidize organic materials and the tendency
of the resulting Cr(III) to form stable complexes with available biological
ligands afford a reasonable mechanism by which chromium can interact with the
normal biochemistry of man (Towill et al., 1978).
The physical properties of a few environmentally significant chromium com-
pounds are shown in Table 3-1. The same parameters for the Cr(VI) compounds are
shown in Table 3-2. It should be mentioned that there is considerable disagree-
ment in the literature concerning the physical parameters given in Tables 3-1 and
3-2 and therefore 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 with moisture and air at high temperatures, impuri-
ties, and structural and compositional changes occurring during the experimental
determinations.
Reactions of Cr(III) in alkaline solution depend on the concentration of OH"
ions. When hydroxyl ions are added to Cr(III) solutions in quantities insuffi-
cient for precipitation, basic ions are formed, which then polymerize with the
formation of hydroxy- or oxy-bridged compounds as shown below:
3+ 2+
oi u»u_;_ f 01 ^ripu;/- j
(in solution)
F ( H n } Pr^n^rrfii ni i •<- r
L viipU yp-Vji — u— oi ^iipUV(-J L
(oxolation)
^ L^r^uHMHpu;,-J
°H" i
A standing
2 OH 2 4
(olation)
3-2
-------
U)
TABLE 3-1
Physical Properties of Selected Trivalent Chromium Compounds1
Compound Formula
Chromic acetate Cr(CH.COO) • H 0
332
Chromic chloride CrCl,
Chromic chloride, [CKH.OkCl-lCl • 2H-0
hexahydrate <2 1 Z 2
[Cr(H20)6]Cl3
Chromic formate, [Cr(HCOO) ] • 6H-,0
hexahydrate * i
Chromic oxide Cr_0,
Chromic phosphate, CrPO,. • 2H-0
hydrated CrPO,j • 6H20
Chromic sulfate Crp(SOj.)-
Chromic sulfate, Cr,(sok}_ • 15H 0
hydrated 2 M 3 2
Cr2(SO^)3 • 18H20
Density,
g/cm-5
NR
2.76 (15»C)
1.76
NR
NR
5.21
2.U2 (32.5°C)
2.121 (1lt°C)
3.012
1.867 (17°C)
1.7 (22»C)
Melting
Point, °C
NR
«1150
83
NR
decomposes
above 300
2266
NR
100
NR
100
-12H20, 100
Boiling
Point, °C
NR
1300
(sublimes)
NR
NR
NR
4000
NR
NR
NR
-10H20, 100
NR
Solubility
in Water, g/ 100 mi
slightly soluble
insoluble
58.5 at 25»C
soluble
soluble
insoluble
slightly soluble
insoluble
insoluble
soluble
120 at 20 »C
•Source: Weast, 1980; The Merck Index, 1976
NR = Not reported
-------
TABLE 3-2
Physical Properties of Selected Hexavalent Chromium Compounds8
Compound Formula
Ammonium chromate (NHj^)2 CrOj.
Ammonium di chromate (NHj.)2Cr207
Barium chromate BaCrOj.
Chromium (VI) oxide CrO_
Lead chromate PbCrOj,
Hercurous (I) chromate HgjCrOjj
M«r curie (II) ohromate HgCrOj.
Potassium chromate K-CrOj.
Potassium dichromate K2Cr20_
Sodium ohromate Ma CrOj.
Sodium dichromate Na^CrpO- • 2H-0
dihydrate
Density, b
g/'cm3
1.9112
2.15525
4.49825
2.7025
6.1215
NH
NR
2.73218
2.67625
2.72325
2.34825
Melting
Point, °C
180
decomposes
180
decomposes
decomposes
197
844
decomposes
decomposes
971
398
792
84.6
(incongruent)
Boiling
Point, "C
NR
NR
NR
decomposes
decomposes
NR
NR
NR
500
decomposes
NR
400
decomposes
Solubility in
Water, g/100 mi
40.5 at 30»C
30.8 at 15»C
3.4 x ID'1*
at 160»C
67.45 at 100°C
5.8 x 10~6 at
25 *C
very slightly
soluble
slightly soluble,
decomposes
62.9 at 20»C
4.9 at 0°C
102 at 100»C
87.3 at 30»C
180 at 20 "C
Source: Weast, 1980; Hartford, 1979
bThe lower figures indicate the tenperature («C) at which the densities were measured.
NR = Not reported
-------
Such ions are of the proper size to cross-link protein fibers and may play an
important part in the chemistry of tanning. The single hydroxyl-bridged rhodo
and erythro binuclear Cr(III) amine complexes also have been extensively studied
(Veal et al., 1973; Cline et al., 1981).
When a sufficient amount of a base is added to Cr(III) salt solution, a
hydrous oxide of indefinite compositipn, Cr2Og'xH20, is precipitated. On addi-
tion of more base to the hydrous oxide, the precipitate redissolves, probably due
O_Y _
to formation of complex ions of the type [Cr(OH)x3 (e.g., [Cr(OH)^] ,
[Cr(OH)6]3").
Cr(III) compounds are reduced to Cr(II) compounds by hypophosphites,
electrolysis, or reducing metals, such as Zn, Mg, and Al in acid solution. In
2_
basic solution, Cr(III) is readily oxidized to CrCK by hypochlorite, hypo-
bromite, peroxide, and oxygen under pressure at high temperature. Heating of
chromium compounds in air in the presence of alkalies also yields chromate. In
acid solution, Cr(III) is harder to oxidize and needs strong oxidizing agents,
such as concentrated HClOj., sodium bismuthate, and permanganate.
All Cr(VI) compounds except CrFfi are oxo-compounds. Cr(VI) rarely occurs in
nature, apart from anthropogenic sources, because it is readily reduced in the
presence of oxidizable organic matter. However, after it is introduced into
water, Cr(VI) frequently remains unchanged in many natural water sources because
of low concentration of reducing matter. Cr(VI) occurs most commonly in the form
of chromate or dichromate, both of which are produced on a large scale in
industry. The dissociation equilibrium of chromic acid solution indicates the
weaker acidity of E^CrO^. The dissociation of HpCr-O., appears to be that of a
strong acid. Acid solutions of dichromate are powerful oxidizing agents:
3-5
-------
2_
Cr>2°7 + 14H+ + 6e~ - > 2Cr+3
H20, E° = 1.33V
Dichromate salts are the leading commercial form of Cr(VI).
3.2. PRODUCTION, USE, AND RELEASES TO THE ENVIRONMENT
3.2.1. Production of Chromium Compounds. The industrial processes for the
production of chromium metal and the various compounds have been described by
Hartford (1979). A simplified flow chart depicting these processes appears in
Figure 3-1.
There has been no mining of chromite ore in the United States since 1961.
Chromium ore and ferrochrome alloys are imported mainly from the Soviet Union,
South Africa, Turkey, and Zimbabwe.
The two primary industrial compounds of chromium made directly from chrome
ores are sodium chromate and sodium dichromate. Secondary chromium compounds
produced in substantial quantities include potassium chromate and potassium
dichromate, ammonium dichromate, chromic acid, and various formulations of basic
chromic sulfate used principally for leather tanning. The United Stated manufac-
turers of the three important chromium compounds, their production capacity, and
the amount produced are discussed below.
The manufacturers of both sodium chromate and sodium dichromate and their
annual production capacity in 1982 are given in Table 3-3. The estimated produc-
tion capacity is based on a 100? sodium dichromate weight.
The manufacturers of chromic acid and their annual production capacity in
1982 are given in Table 3-4.
3.2.2. Uses of Chromium and Its Compounds. The United States consumption
pattern of chromium and its compounds for the year 1979 is shown in Table 3-5.
3-6
-------
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-------
TABLE 3-3
Manufacturers and Their Production Capacities of
Sodium Chromate and Sodium Bichromate3
Annual Production Capacity
Manufacturers in 1982, 10^ metric tons
Allied Chemical Corp. 65 (59)
Baltimore, MD
American Chrome and Chems., Inc. 45 (41)
Corpus Christi, TX
Diamond Shamrock 94 (85)b
Castle Hayne, NC
TOTAL 204 (185)
Source: SRI International, 1982; 1982 U.S. Industrial Outlook,
Chemical Marketing Reporter, 1982.
Diamond Shamrock will increase capacity to 118,000 tons
(106,200 Mg) in January 1983.
3-8
-------
TABLE 3-4
a b
Principal United States Manufacturers of Chromic Acid '
Annual Capacity in 1982,
•3 c
Manufacturers 10 metric tons
Allied Chemical Corp. 21
Baltimore, MD
Diamond Shamrock Corp. 24
Castle Haynes, NC
Source: SRI International, 1982; Hartford, 1979
Data on actual production of chromic acid are held to be
confidential to avoid disclosing proprietary
information on individual companies.
°The estimates for production capacity are based on a
100? chromic anhydride (CrO_) basis.
3-9
-------
TABLE 3-5
United States Chromium Consumption Pattern in 1979a
Quantity Consumed13'0 % Fraction of
10^ metric tons U.S. Consumption
Metallurgical
wrought stainless and heat 235 44
resisting steels
tool steels 6 1.1
wrought alloy steels 44 8.1
cast alloy steels 15 2.7
alloy cast irons 8 1.4
nonferrous alloys 15 2.7
other 6 1.1
Total 329 61.0
Refractories
chrome and chrome-magnesite 16 3.0
magnesite-chrome brick 23 4.2
granular chrome-bearing 42 7.8
granular chromite 16 3.0
Total 97 18.0
Chemicals
pigments
metal finishing
leather tanning
drilling muds
wood treatment
water treatment
chemical manufacture
textiles
catalysts
other
Total
Grand Total
29
24
18
5
7
7
9
4
<2
9
114
540
5.4
4.4
3.3
0.9
1.3
1.3
1.7
0.7
0.3
1.7
21.0
100
aSource: Hartford, 1979, Mineral Commodity Summaries, 1980.
Exclusive of scrap.
Columns may not total exactly due to rounding.
3-10
-------
It can be seen from Table 3-5 that metallurgical and chemical usages
constituted 82$ of the total United States chromium consumption in 1979.
Metallurgical grade chromite ore is usually converted into one of several types
of ferrochromium or other chromium metal that are alloyed with iron or other
elements, such as nickel and cobalt. A great variety of useful steels are
produced from these alloys. Because of their high melting points and chemical
inertness, chromite ore and chrome alloys are used by the refractory industry in
furnaces as linings, in the manufacture of furnace bricks, and as coating
materials to close pores and to join bricks within the furnace. Other uses of
chromite refractories include nonferrous alloy refining, glass making, and
cement processing. 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 (Hartford, 1979). In the future, growth in
chromium usage is expected in the metallurgical and chemical sectors. A recent
study (Morning, 1977) has projected a 3.4$ growth annually in the United States
chromium consumption, leading to a total chromium demand of 1 million tons
(900,000 metric tons) in the year 2000.
The consumption pattern of imported chromium for metallurgical, refractory,
and chemical usage is shown in Table 3-5. Chromium-containing pigments can be
primarily classified into chromate color pigments based on lead chromate,
Cr(III) oxide greens, and corrosion inhibiting pigments based primarily on zinc
chromate. In metal finishing, chromic acid is used in chromium plating of metal
surfaces. The chrome tanning of leather is one step in a complicated series of
operations leading from the rawhide to the finished product. The annual consump-
tion of hides by the leather industry is decreasing (Hartford, 1979), and the use
of Cr(VI) compounds for tanning purposes may be on the decline. Chromium
3-11
-------
chemicals, such as chromium lignosulfonates, are used in drilling muds during the
drilling of wells to combat fatigue corrosion cracking of drill strings
(Hartford, 1979). Chromated copper arsenate is widely used as a wood preserva-
tive, especially in treating utility poles, building lumber, and wood founda-
tions. Chromates are used to inhibit metal corrosion in recirculating water
systems, such as cooling towers, locomotives, and automobiles. Sodium
dichromate and various chromic salts are employed in the textile industry to
improve washfastness and to oxidize the dyed textile. A large number of chromium
compounds are used as catalysts in various chemical reactions. Barium and
calcium chromates are used as activators and dipolarizers in fused salt
batteries. Chromium dioxide (CrO?) is used as a ferromagnetic material in high-
fidelity magnetic tapes.
3.2.3. Releases to the Environment. Although the chromium industry in the
United States has adopted various pollution control measures, some release of
chromium compounds into the environment is occurring. Chromium compounds from
industrial operations enter the environmental air, water, and soil from several
sources. Kilns, smelting furnaces, boilers, leaching tanks, open boiling
vessels, plating tanks, and other installations emit dusts and mists containing
chromium to the atmosphere.
Chromium is a trace component of coal and oil and is released to the
atmosphere upon combustion of these fuels. Fly ash emitted from coal-fired power
plants contain 10 to 600 ppm chromium, depending on the type of boiler firing
(Block and Dams, 1976). For power plants equipped with electrostatic precipita-
tors (ESP) to prevent particulate emissions, the total chromium concentration in
the emission can be reduced (NAS, 1971*). Rinaldi et al. (1980) have shown that
the chromium concentration of particulates from controlled coal combustion may
3-12
-------
be higher than the chromium concentration of particulates from uncontrolled coal
combustion, due to preferential chromium enrichment on small particles that
escape the ESP device.
Wood contains chromium and it is likely that the burning of wood in fire-
places and campfires may contribute small amounts of chromium into the atmos-
phere. Forest fires would therefore be a potential non-anthropogenic source of
atmospheric chromium (NAS, 1971*). No estimate of the amount of chromium emitted
from forest fires could be obtained. However, Lantzy and MacKenzie (1979)
estimated chromium flux in the atmosphere from anthropogenic (industrial and
fossil fuel) and non-anthropogenic (continental dust, volcanic dust, and
volcanic gas) sources. The ratio of anthropogenic to non-anthropogenic atmos-
pheric flux of chromium was estimated to be 1.61. Incineration of municipal
refuse and sewage sludge is also expected to contribute small amounts of chromium
into the atmosphere (Rinaldi et al., 1980; Fiscus et al., 1978).
Asbestos mining is another source of chromium emissions to the atmosphere
since asbestos has been found to contain as much as 0.15? chromium (Towill
et al., 1978). The wearing of vehicular brake linings, therefore, represents a
potential source of chromium in the atmosphere. Catalytic emission control
systems in automobiles using copper chromite reduction catalysts represent
another source of chromium emissions to the atmosphere (IARC, 1980). Also, when
chromate chemicals are used as corrosion inhibitors in recirculating cooling
waters, some chromate is lost to the atmosphere as mist.
According to a GCA Corporation (1973) report, United States industrial and
inadvertent sources of chromium emissions into the atmosphere under controlled
operations amounted to 18,200 metric tons in the year 1970. The amount of
atmospheric chromium emissions from different sources is shown in Table 3-6.
Although the total estimated chromium emissions given by the two studies in
3-13
-------
TABLE 3-6
Sources and Estimates of United States
Atmospheric Chromium Emissions in 1970a
Chromium
Emissions, metric
GCA Estimates
Source
Industrial Sources:
refining
steel and alloy
material handling
chemical processing
refractory
Inadvertent Sources:
coal combustion
oil combustion
cement production
incineration
Asbestos Mining
Total
Uncontrolled
18,700
2,407
1,100
835
4,784
7,900
336
NR
NR
9
36,100
Controlled
11,200
595
750
106
1,650
1,420
336
254
143
0
16,500
tons/ year
Goldberg
Controlled
3,800
NR
NR
NR
6
7,030
69
NR
NR
7
10,900
Source: GCA Corporation, 1973; Goldberg, 1973
NR = Not reported
3-14
-------
Table 3-6 are somewhat comparable, there is a substantial difference in
estimated emissions from individual sources.
The geographical distribution of atmospheric chromium emissions in the
United States is presented in Table 3-7. It is evident from Table 3-7 that the
Great Lakes area, the Southeast and the East coast south from New York constitute
the bulk of atmospheric chromium emissions in the United States.
Chromium compounds occur in a variety of industrial wastewaters and poten-
tially may enter surface water and groundwater supplies. Wastewaters from
electroplating operations, leather tanning, and textile manufacturing represent
the types of chromium-containing streams that may ultimately enter surface and
groundwaters (Hartford, 1979). It has been estimated that 220 metric tons/year
are discharged in Southern California coastal waters (Schafer, 1977). Ottinger
et al. (1973) estimated that 6200 metric tons of chromium are lost annually in
the sludge of solvent-based paints and another 437 metric tons are discharged as
paint residues.
Solid waste streams containing Cr(VI) constitute the primary problem area
involving chromium solid wastes (Hartford, 1979). Wastes resulting from the
roasting and leaching steps in the chromate manufacturing process traditionally
contain residual Cr(VI). If landfilled, the residual Cr(VI) can slowly leach
into surrounding waters via desorption and disproportionation (Hartford, 1979).
An estimate of the total amount of chromium released into soil and groundwater as
a result of the leaching of chromium-containing solid wastes is not available.
3.3. ENVIRONMENTAL FATE AND TRANSPORT
3.3.1. Air. Little information exists in the literature regarding the nature of
the chemical species present in the atmosphere away from obvious sources of
3-15
-------
TABLE 3-7
Regional Distribution of Principal Chromium Emissionsa
EPA Region/States
I/CT,MD,MA,NH,RI,VT
II/NJ,NY,PR,VI
III/DE,MDfPA,VA,WV,DC
IV/AL,FL,GA,KY,MS,NC,SC,TN
V/IL,IN,MI,MN,OH,WI
VI/AR,LA,NM,OK,TX
VII/IA,KS,MO,NB
VIII/CO ,MT , ND ,SD ,UT , WY
IX/AZ,CA,NV,HA
X/AK,ID,OR,WA
TOTAL
Annual Chromium Emissions
From Sources in this Region,
metric tons (Mg)b
103
3,1^0
2,800
3,000
4, 830
74
177
107
174
898
15,300
Percent of Total
U.S. Chromium
Emissions
0.6
19.0
17.3
18.5
29.0
0.5
1.1
0.7
1.1
5.4
93.2
Source: GCA Corporation, 1973
Sources include ferrochrome production, refractory production, cement production,
chrome steel production, and coal and oil combustion.
3-16
-------
pollution. Under normal conditions, Cr(III) and Cr(0) in the air should not
undergo any reaction since these species are chemically inert (Towill et al.f
1978). Cr(Vl) in air could eventually react with dust particles or other
pollutants to form Cr(III) (NAS, 197*0. However, the exact nature of such
atmospheric reactions has not been extensively studied.
Low concentrations of chromium enter the atmosphere as a result of indus-
trial activities and soil-derived aerosols (Towill et al., 1978). Chromium is
removed from air by atmospheric fallout and precipitation. The total yearly
2 2
deposition of chromium in urban areas may vary from 0.12 ug/m to 3 Hg/m (Towill
et al., 1978). Depending upon the locale, between 44 and 96? of the total
deposition occurs by wet precipitation. In general, urban areas have higher wet
and total deposition than rural areas. Chromium concentration in a wet deposi-
tion may vary from 0.004 to 0.060 \ig/mi and 0.0006 to 0.034 (ig/fi, for urban and
rural areas, respectively (Towill et al., 1978). The precipitated chromium from
the air enters the surface water or soil.
Chromium particles of aerodynamic equivalent diameter <20 [im may remain
airborne for long periods and may be transported great distances by wind currents
and diffusion forces (Sehmel and Hodgson, 1976). Therefore, atmospheric
conditions play an important role in determining the chromium concentration
around emission sites; however, no data relating atmospheric chromium content to
atmospheric or meteorological conditions could be found in the literature.
3.3.2. Water and Sediments. Surface runoff, deposition from air, and release of
municipal and industrial wastewaters are the sources of chromium in surface
waters. Chromium may be transported in five forms (see Table 3-8) in surface
waters.
3-17
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TABLE 3-8
Five Forms of Chromium Transported in the Yukon and Amazon Rivers*
~~Percent Present Tn
Physical Form Amazon River Yukon River
In solution and organic complexes 10.4 12.6
Adsorbed 3.5 2.3
Precipitated and co-precipitated 2.9 7.2
In organic solids 7.6 13.2
In sediments 75.6 64.5
•Source: Towill et al., 1978
3-18
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It can be seen from Table 3-8 that most of the chromium in surface waters
may be present in particulate form as sediment. Some of the particulate chromium
would remain as suspended matter and ultimately be deposited in sediments.
DeGroot and Allersma (1973) found a chromium ratio in water to suspended matter
to be 1 to 2.3 for the Rhine River. In the heavily polluted Qishon-Gadura River
in Israel, chromium concentrations in water were <10 ppb, while sediment
contained from 220 to 610 ppm chromium (Towill et al., 1978).
The exact chemical forms of chromium in surface waters are not well defined.
Although most of the soluble chromium in surface water may be present as Cr(VI)
(Towill et al., 1978), a small amount may be present as Cr(III) organic complexes
(DeGroot and Allersma, 1978; Fukai, 1967). Schroeder and Lee (1975) studied the
transformation between Cr(III) and Cr(VI) in natural waters. They found that
only 3% of Cr(III) was oxidized by 0- in 30 days at ambient temperature. Cr(VI)
is the major stable form of chromium in seawater (Fukai, 1967); however, Cr(VI)
may be reduced to Cr(III) by organic matters present in water and may eventually
deposit in sediments. Lu and Chen (1976) found that chromium was not signifi-
cantly released from sediments into seawater under either oxidizing or reducing
conditions.
3.3.3. Soil. Most soil chromium is in mineral, absorbed, or precipitated form.
Chromium probably occurs as the insoluble Cr(III) oxide (Cr^O-j'nHpO) in soil, as
the organic matter in soil is expected to reduce any soluble chroraate to
insoluble Cr?0o. Chromium in soil can be transported to the atmosphere by way of
aerosol formation (John et al., 1973; Zoller et al., 197*0« Chromium is also
transported from soil through runoff and leaching of water. Runoff could remove
both chromium ions and bulk precipitates of chromium with final deposition on
either a different land area or a water body. In addition, flooding of soils and
3-19
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the subsequent anaerobic decomposition of plant matters may increase dissolution
of Cr(III) oxides in the soil (Towill et al., 1978).
3.4. LEVELS OF CHROMIUM IN VARIOUS MEDIA
3.4.1. Ambient Air. The chemical form of chromium in air depends on the source
of emission. The vast majority of chromium in the atmosphere, originating from
such sources as metallurgical production, coal and oil combustion, cement pro-
duction, and incineration, is usually in the Cr(III) or Cr(0) state. However, a
small amount of total chromium in the atmosphere may be present in the Cr(VI)
state. Chrome production, chrome plating, and cooling tower drifts are primary
examples of the sources of Cr(VI) in the atmosphere (Towill et al., 1978). The
mass median diameter of chromium in air particulate matter is in the range of 1.5
to 1.9 ^im (Cawse, 1974; Lee and von Lehmden, 1973). Chromate salts are often
used in the cooling tower water as a corrosion inhibitor. Therefore, cooling
tower drift consisting of water droplets formed mechanically within the towers
and carried by wind into the surrounding area may be a source of high Cr(VI)
concentrations in air. Air concentrations of chromium near a cooling tower at
the Oak Ridge Gaseous Diffusion Plant, Oak Ridge, Tennessee, were about 50 ng/m^
from distances up to 660 feet (200 m) from the tower (Alkezweeny et al., 1975).
p
Hourly chromium deposition was about 1 mg/m at 100 feet (30 m) and about
0.01 mg/m at 330 feet (1000 m) from the tower. Therefore, substantial amounts
of chromium may be present in the respirable particulate fraction and can be
deposited in the respiratory tract.
The concentrations of total chromium measured in the ambient air of many
urban and nonurban areas of the United States during 1977 to 1980 are given in
Table 3-9. The data in Table 3-9 were obtained from the U.S. EPA's National
3-20
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TABLE 3-9
Total Chromium Concentrations Measured in the Ambient Air
of Selected Sites in the United States During 1977-1980
Site
Grand Canyon, National Park, AZ
Los Angeles, CA
Water bury, CT
Atlanta, GA
Hawaii County, HId
Kansas City, KS
Iberville Parish, LA
Acadia National Park, ME°
Baltimore, MD
Worcester, MA
Bayonne, NJ
Newark, NJ
Niagara Falls, NY
Year
1977
1977
1978
1979
1977
1980
1977
1977
1978
1980
1977
1978
1980
1977
1977
1979
1977
1978
1979
1977
1978
1980
1978
1979
1980
1979
1980
Total Chromium Concentration, ^g/m
Arithmetic Maximum Observed
Mean5 Value0
0.0058
0.0188
0.0342
0.0326
0.0089
0.0062
0.0063
0.0167
0.0276
0.0191
0.0063
0.0059
0.0052
0.0052
0.1568
0.0935
0.0063
0.0099
0.0067
0.0105
0.0149
0.0123
0.0181
0.0129
0.0091
0.0389
0.01411
0.0134
0.0666
0.2178
0.1396
0.0441
0.0194
0.0216
0.0413
0.0724
0.0358
0.0159
0.0128
0.0052
0.0052
2.4870
0.4589
0.0167
0.0239
0.0166
0.0253
0.0324
0.0508
0.0301
0.0333
0.0369
0.5590
0.0603
3-21
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TABLE 3-9 (cont.)
Site
Total Chromium Concentration,
Arithmetic Maximum Observed
Year
Mean
b
Black Hills National Forest, SD
1978
0.0090
Value"
Akron, OH
Cincinnati, OH
Steubenville, OH
1977
1978
1979
1980
1977
1978
1979
1980
1978
1979
0.0126
0.0188
0.0166
0.0204
0.0083
0.0116
0.0451
0.0150
0.0517
0.1212
0.0610
0.0528
0.0389
0.0710
0.0377
0.0294
0.4316
0.0718
0.2602
0.6839
0.0295
Chattanooga, TN
Norfolk, VA
Tacoma, WA
1977
1978
1979
1980
1977
1978
1979
1980
1977
1978
1980
0.0122
0.0140
0.0112
0.0150
0.0067
0.0069
0.0083
0.0119
0.0099
0.0249
0.0104
0.0453
0.0463
0.0760
0.0705
0.0152
0.0158
0.0291
0.1456
0.0330
0.1425
0.0283
Source: Unpublished data in the National Aerometric Data Bank maintained by the
Monitoring and Data Analysis Division of EPA, Research Triangle Park, NC.
Values represent annual average.
°Values represent maximum 24 hour averages.
d
Background sites; all other sites are determined to be populated urban areas.
3-22
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Aerometric Data Bank, which is maintained by the Agency's Monitoring and Data
Analysis Division (MDAD) at Research Triangle Park, North Carolina. None of the
data in Table 3-9 have been previously published. The ambient chromium data have
been collected by monitoring networks operated by various State and local air
pollution control agencies as required by the Clean Air Act. After passing
editorial and validation checks which are performed by EPA regional offices, the
data are forwarded to MDAD for incorporation into the National Aerometric Data
Bank.
During the 1977 to 1980 period, the mean chromium concentration for the
urban areas given in Table 3-9 ranged from 0.0052 \ig/nr (the background level) to
0.1568 (ig/m^. The highest mean value of 2.U87 |ig/m^ was recorded in Baltimore,
Maryland in 1977. For the sites with >2 years worth of data, no discernible
upward or downward concentration trends are evident. For example, in Newark, New
Jersey, the mean chromium concentration dropped from 0.0181 ng/nr in 1978 to
0.0129 \ig/a^ in 1979 and to 0.0091 \ig/n? in 1980. However, in Norfolk, Virginia,
over the same period the chromium levels rose from 0.0069 ng/nr in 1978 to
0.0083 tig/m^ in 1979 and to 0.0119 rng/m3 in 1980. In Akron, Ohio, the mean
chromium concentration in 1978 was determined to be 0.0188 |ig/m . in 1979, the
concentration in Akron dropped to 0.0116 ng/nr but in 1980 it rose again to
0.0204 ng/m^. The mean chromium concentrations in nonurban, background areas
such as national parks ranged from 0.0052 ng/m3 to 0.0090 jig/m3 over the 1977 to
1980 period.
Specific industrial sources such as power plants, incinerators, and iron
and steel plants may signifi'cantly increase the atmospheric chromium concentra-
tions found in certain areas due to the relatively high chromium content of their
emitted particulate matter. Lee and von Lehmden (1973) reported the chromium
content of particulate emissions from coal-fired power plants to be between 1 and
3-23
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100 ppm, cement plants to be between 100 and 1000 ppm, iron and steel plants to
be between 10 and 100 ppm, and municipal incinerators to be between 100 and
1000 ppm.
3.4.2. Aquatic Media. The chromium levels detected in a few surface waters and
groundwaters are presented in Table 3-10. The amounts of chromium found in these
waters are usually related by the authors to anthropogenic input. For example,
it has been shown by Kopp and Kroner (1967) that water from Lake Michigan near
industrial discharge points contained a higher level of chromium than lake water
contaminated with lesser industrial input (5 to 19 ppb, compared to 2 to 4 ppb).
The valence of chromium in surface water can be either VI or III. Although
Cr(VI) is the more stable species in seawater, Fukai (196?) provided data to show
that both Cr(III) and Cr(VI) were present. Surface seawater contained Cr(III)
and Cr(VI) in the range of 0.02 to 0.14 ppb and 0.28 to 0.36 ppb, respectively,
while seawater at depths of 5, 500, and 1000 m contained about the same level
(0.2 ppb) of Cr(III) and Cr(VI).
In a survey of 14 groundwater and 69 surface water supplies in 83 United
States cities in Illinois, Indiana, Michigan, Minnesota, Ohio, and Wisconsin,
the chromium level in the raw waters used for drinking waters were found to range
between <5.0 and 17.0 ppb (see Table 3-11) (U.S. EPA, 1975).
The chromium concentration in various United States drinking water supplies
is presented in Table 3-11- In a survey of 2595 water samples from 969 water
supplies in the United States, only four samples showed chromium levels above the
detection limit of 50 ppb (McCabe et al., 1970). The maximum chromium concen-
tration in water detected in this survey was 80 ppb.
In a more recent survey (1974 to 1975) with an analytical method of better
sensitivity, 3834 tap waters from 35 geographical locations representative of
3-24
-------
TABLE 3-10
Chromium Levels in a Few Surface Waters and Groundwaters*
Source
Lake Tahoe
Colorado River
Columbia River
Mississippi River
Missouri River
Ohio River
U.S. surface waters
U.S. surface waters
Natural water, Oak Ridge, TN
Water near cooling tower,
Oak Ridge, TN
Uncontaminated stream, NY
Contaminated stream, NY
Uncontaminated well , NY
Contaminated well , NY
Illinois River
Spring water, CA
Well water, CA
Stream water, CA
Seawater , CA
Frequency of
Detection %
NR
12
87
23
10
20
25
25
NR
NR
NR
NR
NR
NR
NR
6
5
0
0
Cone, (ppb or \ig/i) in Samples
with Detectable Chromium Level
Average
<0.62
NR
NR
NR
NR
NR
<1
9.7
NR
NR
<10
1250
<10
6000
21
NR
NR
NR
NR
Range
<0.07 to <0.91
10 to 30
1 to 10
3 to 20
8 to 10
4 to 16
<1 to 19
1 to 112
50 to 120
2500 to 2790
NR
NR
NR
NR
5 to 38
0 to 21
0 to 13
NR
NR
Source: Towill et al., 1978
NR = Not recorded
3-25
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TABLE 3-11
Chromium Concentrations in U.S. Drinking Waters3
Water
Tap water, Dallas, TX
100 largest cities, U.S. (1962)
380 finished waters, U.S.
Concentration, in
Median
4b
0.4°
7.5b
g/J, or ppb
Range
1 to 20
0.2 to 35
1 to 29
(1962-1967)
3834 tap waters, U.S.
(1974-1975)°
83 Midwestern cities, U.S.6
115 Canadian municipalities
(1976-1977T
1.8
NR
<2.0
0.4 to 8g
<5.0 to 17.0
<2.0 to 4.1
Source: NAS, 1977
Average value; sampling date unavailable
Median value
Greathouse and Craun, 1978
iJ.S. EPA, 1975; sampling date unavailable
f
Mferanger et al., 1981
of areas had detectable levels
NR = Not recorded
3-26
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the U.S. population were monitored for metal content (Greathouse and Craun,
1978). The detection limit for Cr in this survey was 0.1 ppb. The results of
this survey, presented in Table 3-11, also indicated that 28$ of the area
surveyed had Cr levels above the detection limit. It should be mentioned that
the mean value of Cr in this study may be a little higher that reported since the
tap waters were not adequately flushed before collection.
In two surveys (1976 to 1977) of 115 municipalities across Canada
encompassing 63% of the Canadian population, the median and range of Cr concen-
trations were determined (Meranger et al.f 1979, 1981). The median and range
(within parentheses) of Cr concentrations in Canadian raw, treated, and distri-
buted waters were determined to be £2.0 (£2.0 to 5.0) ppb, £2.0 (£2.0 to
4.0) ppb, and £2.0 (£2.0 to 4.0) ppb, respectively.
3.4.3. Aquatic Suspended Materials and Sediments. The concentration of chromium
in suspended materials in several United States rivers was found to range between
37 and 460 ppm on a dry weight basis (Turekian and Scott, 1967). Chen et al.
(1974) determined the concentration in dry season suspended silts of Southern
California waters to be =500 ppm in "natural" areas and 2000 ppm in urbanized
areas.
Chromium concentrations determined for a variety of bottom sediments are
shown in Table 3-12. For the areas in the United States sampled, sediment
chromium levels ranged from about 1 to 450 ppm. An examination of Table 3-12
shows that the chromium concentration in sediments from several Wisconsin lakes
and Southern Lake Michigan does not significantly decrease with depth. A similar
finding concerning sediment chromium content was made by Bruland et al. (1974)
upon the analysis of chromium levels in sediments of different depths from the
Southern California basin. These studies of sediment chromium content versus
3-27
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TABLE 3-12
Concentration of Chromium in Sediments*
Chromium Concentration (ppm)
Area
Delaware Bay
New York City Bight:
Background
Sludge dumping area
Puget Sound
Houston ship channel , TX
Neches River, TX
Sabine River (low in
industrial activity)
TX-LA Border
Southern Lake Michigan:
surface sediments
sediments from >15 to
100 cm depth
estimated background
Illinois River
Non- industrial stream, IL
Buzzard Bay, MA
Wisconsin Lakes:
surface sediment
sediment from >50 cm depth
Median
NR
106
105
NR
NR
NR
NR
77
52
NR
17
6
33
NR
NR
Range
33 to 447
2 to 310
50 to 209
43 to 15*1
39 to 254
8 to 288
41 to 89
35 to 165
32 to 68
20 to 40
2 to 87
3 to 7
NR
1 to 49
0.8 to 35
•Source: Towill et al., 1978
NR = Not recorded
3-28
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depth appear to indicate that natural background chromium levels contribute
heavily to the chromium levels found in surface sediments.
The concentration of chromium in an incinerated sewage sludge ash was
determined to be 5280 ng/g. The concentrations of metals in ash residue after
incineration is =4 times those present in dried sludge (Fraser and Lum, 1983).
Therefore, sewage sludges are expected to contain high concentrations of
chromium.
3.4.4. Soil. The concentration of chromium in soil varies in accordance with
soil origin. Soils derived from nonserpentine areas can contain from traces to
300 ppm chromium. Soils derived from serpentine areas can contain up to 2% by
weight of chromium. The chromium concentrations in selected soils from various
parts of the U.S. are shown in Table 3-13. Most chromium in soils is apparently
insoluble. Extraction of soils with 2.5$ acetic acid, ammonium acetate at pH
4.8, and even with 0.1 N HC1 have shown that only 0.01 to 4$ of the total soil
chromium is extractable (Towill et al., 1978).
3.4.5. Food. The chromium content of a variety of foods is presented in
Table 3-14. The values given in Table 3-14 represent the average of several food
items in each category. It can be seen from this table that the chromium
concentrations in different categories of food determined by Schroeder et al.
(1962) were lower than the values determined by other investigators. It is not
known whether the observed discrepancies are due to geographical and seasonal
variations in trace element content of foods or due to errors in analytical
determinations.
The chromium content in acidic foods is often higher than other categories
of foods. The values of Cr content in a few commercial acidic foods which had
3-29
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TABLE 3-13
Chromium Content in Selected United States' Soils*
Location
Soil
Characteristic
Chromium content
ppm or mg/g
Range Median
Pennsylvania
Peninsular Florida
Florida
Missouri
New Jersey
Michigan
agricultural surface
and subsoil
surface and subsoil
surface and subsoil
on and off road soil
various soils
various surface soils
NR HI
<1 to 1000 50
<1 to 500 NR
NR 71
29 to 75 NR
3.2 to 17.6 NR
•Source: Towill et al., 1978
NR = Not recorded
3-30
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TABLE 3-14
Chromium Content in Various U.S. Foods
Sample
Mean Concentration
(ppm or [ig/g)
Reference
Fresh vegetables
Fresh vegetables
Fresh vegetables
Frozen vegetables
Canned vegetables
Fresh fruits
Fresh fruits
Fruits
Canned fruits
Dairy products
Whole fish
Meat and fish
Meat and fish
Sea foods
Sea foods
Grains and cereals
Grains and cereals
Fruit juices
0.14
0.03 to 0.05
0.14
0.23
0.23
0.09
0.19
0.02
0.51
0.10
0.05 to 0.08
0.23
0.11
0.12
0.47
0.01
0.22
0.09
Thomas et al., 1974
Schroeder et al., 1962
Toepfer et al., 1973
Thomas et al., 1974
Thomas et al., 1974
Toepfer et al., 1973
Thomas et al., 1974
Schroeder et al., 1962
Thomas et al., 1974
Schroeder et al., 1962
Okuno et al., 1978
Toepfer et al., 1973
Schroeder et al., 1962
Zook et al., 1976
Meranger and Soners, 1968
Schroeder et al., 1962
Toepfer et al., 1973
Meranger, 1970
3-31
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been in contact with stainless steel surfaces during harvesting, processing, or
preparation for market are shown in Table 3-15 (Stoewsand et al., 1979).
Jennings and Howard (1980) reported slightly higher levels of Cr in British
commercial alcoholic beverages than the Cr content in U.S. wines as given in
Table 3-15. The chromium contents in wines, beers, and spirits were reported to
be 0.45, 0.30, and 0.135 mg/£, respectively. However, it is difficult to assess
the daily chromium intake in the United States from the Cr content in individual
foods. The chromium contents in a selected diet composite were determined by
Kumpulainen et al. (1979). This study is the most recent diet study conducted
by FDA-USDA (personal communication with Dr. W.R. Wolf, USDA). The chromium
intake from typical American diets containing 43? fat was determined to be
62 + 28 |ig/day. The corresponding intake from typical American diets containing
25$ fat was determined to be 89 ^ 56 |ig/day.
3.4.5.1. BIOCONCENTRATION IN FOOD CHAINS -- Several authors have found that
chromium concentrations decrease in higher trophic level organisms in aquatic
ecosystems (Towill et al., 1978). For example, Mathis and Cummings (1973)
detected =10 ppm chromium in worms, =5 ppm in clams, =1.2 ppm in omnivorous fish,
and =1 ppm in carnivorous fish. Lack of assimilation of chromium is probably the
major reason that the organisms of the higher trophic levels contain lesser
amounts of chromium.
A bioconcentration factor (BCF) is the ratio of the concentration of a
chemical in aquatic species to the concentration in the water in which they live.
An appropriate BCF can be used with data concerning food intake to calculate the
amount of chromium which might be ingested from the consumption of fish and
shellfish. Residue data for a variety of inorganic compounds indicate that
bioconcentration factors for the edible portion of most aquatic animals is
3-32
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TABLE 3-15
Concentration of Chromium in a Few Commercial Grade Acidic Foods'
Commodity
Red cabbage
Red cabbage brine
Sauerkraut
Sauerkraut brine
Sauerkraut
Sauerkraut brine
Different brand
of honey
Vinegar
Hard cider
Cheese whey
Wine, Catawba
Wine, red concord
Wine, red concord
Container
glass
glass
can
can
flexible
pouch
flexible
pouch
glass
bulk
bulkb
bulk
lastiglass
( 1 year )
redwood
(8 months)
stainless
steel
(7 months )
Sample
PH
—
3.4
—
3.5
__
3.5
3.5 to 3-7
2.8
3.5
4.8
3.1
3.2
3.2
Cr Concentration,
ppm or jig/g (wet wt.)
2.6
10.3
0.3
0.3
0.2
0.2
0.04 to 0.18
0.01
0.004
0.01
0.02
0.07
0.02
fsource: Stoewsand et al., 1979
Before acidification
3-33
-------
similar, except that for some compounds bivalve molluscs (clams, oysters,
scallops, and mussels) should be considered a separate group. An analysis (U.S.
EPA, 1980b) of data from a food survey was used to estimate that the per capita
consumption of freshwater and estuarine fish and shellfish is 6.5 g/day
(Stephan, 1980). The per capita consumption of bivalve molluscs is 0.8 g/day and
that of all other freshwater and estuarine fish and shellfish is 5.7 g/day.
The BCF for Cr(VI) in fish muscle appears to be less than 1.0 (Buhler
et al., 1977; Fremm and Stokes, 1962), but values of 125 and 192 were obtained
for oyster and blue mussel, respectively (U.S. EPA, 1980c). For Cr(III), BCF
values of 116, 153, and 86 were obtained with the American oyster (Shuster and
Pringle, 1969)t soft shell clam, and blue mussel (Cappuzzo and Sasner, 1977),
respectively. It appears that the two valence states of chromium(III and VI)
have about the same BCF values, and that the geometric mean of 130 can be used for
bivalve molluscs. If the values of 0.5 (BCF for fish and mussels) and 130 (BCF
for bivalve molluscs) are used with the consumption data, the weighted average
bioconcentration factor for chromium in the edible portion of all freshwater and
estuarine aquatic organisms consumed by Americans can be calculated to be 16 on
the basis of per capita consumption of 0.8 g/day and 5.7 g/day for bivalve
molluscs, and fish and shellfish, respectively (U.S. EPA, 1980b).
3.4.6. Cigarettes. Chromium has been determined to be a component of cigarette
tobacco. Tobaccos grown in the United States have been found to have a chromium
content ranging from 0.24 to 6.3 mg/kg (IARC, 1980).
3.5. INDICES OF EXPOSURE AND DOSE-RESPONSE RELATIONSHIPS
Past exposure to low levels of chromium may be associated with higher than
normal levels of chromium in the hair. Creason et al. (1975), however, reported
3-34
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that this association is tenuous in young children and women, as a result of
variation in chromium levels related to age and pregnancy. Blood and urine
chromium levels have also been shown to be elevated following exposure to
chromium, although marked variation occurs in the linearity between exposure
levels and the levels in body fluids as a result of sequestering and release of
chromium from body depots. The only toxicologic index of exposure to chromium is
the development of perforated nasal septums. This occurs only in the presence of
Cr(VI) and is associated with exposure to levels of 0.1 mg/nr*; it is not known
whether lower exposure will also cause this disorder.
3.5.1. Chromium in Blood. Chromium is absorbed through both the respiratory
tract and gastrointestinal system (U.S. EPA, 1978). Exact values for chromium
absorption from the digestive tract are not known. Cr(III) is poorly absorbed,
whereas chromate is better absorbed (Mertz, 1969).
In the respiratory tract, water and serum soluble chromates are absorbed
into the blood system, whereas insoluble Cr(III) particles and the inert oxides
and hydroxides of Cr(III) remain in lung tissue (U.S. EPA, 1978).
Once in the blood stream, chromium compounds are bound by proteins (Gray and
Sterling, 1950). It has been shown that ionic Cr(VI) (injected intravenously)
passes through the membrane of red blood cells and binds to the globin moiety of
hemoglobin. Once inside the erythrocyte, chromium ions are unable to pass
through the cell membrane and move back into the plasma. Hopkins and Schwartz
(1961!) reported that, in physiological amounts, cationic Cr(III) is bound to
siderophilin and transported' to other tissues.
Chromium disappears quickly from the blood and is taken up by other tissues
in the body, where it is concentrated much more heavily (by a factor of 10 to 100)
3-35
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than in the blood. Therefore, blood levels of chromium are not a usable indica-
tor of chromium nutritional status (Mertz, 1969; Mertz and Roginski, 1971).
A wide range of values for chromium content in blood has been reported.
Schroeder et al. (1962) reported chromium levels in serum of 0.52 and 0.17 ppm,
whereas Doisey et al. (19&9, 1971) found a chromium concentration of 2 ppb in
serum. Other chromium values reported have ranged from 0.11 to 55 ppb in human
plasma, and from 5 to 54 ppb in red blood cells (Underwood, 1971). Imbus et al.
(1963), working with United States subjects, found blood chromium levels ranging
from 13 to 55 ppb with a median of 27 ppb, while Hamilton et al. (1973), studying
subjects from the United Kingdom, reported a blood level of 70 ppb chromium.
However, researchers have discovered, through the use of new technology in
flameless AAS analyses, that the amount of chromium in normal blood and urine is
in the range of 0.3 ppb, whereas previous measurements had shown 0.73 to 150 ppb.
It was considered by Guthrie et al. (1978), Kayne et al. (1978) and Anderson
(1981) that measurements made before 1978 are probably high as the result of
inadequate background correction for non-atomic absorption. Thus, measurements
of chromium in normal body fluids made before 1978 are probably useless (Toxic
Material News, 1982).
Kayne et al. (1978) used flameless AAS with a tungsten halogen light source
for background correction to determine the serum chromium levels in 8 normal male
subjects. The tungsten halogen light greatly improved the background correction
in the near UV region where chromium is detected as compared to the standard Dp
light source. With the elimination of non-atomic absorption, the mean level of
serum chromium was determined to be 0.1*1 \ig/l. These results were in agreement
with those of Versieck et al. (1978) in which serum chromium was determined by
neutron activation analysis. Serum obtained from 20 healthy subjects (duplicate
samples from 14 subjects) had a range of chromium levels from 0.0382 to 0.351
3-36
-------
with a mean value of 0.16 |ig/fi,. Using this data, the authors concluded that
normal human chromium levels in serum are in the sub-ppb range.
3.5.2. Chromium in Urine. A wide range of values for chromium content in urine
has been reported. Hambidge (1971) reported chromium levels in urine of 8.4 ppb
for adults and 5.5 ppb for children over a 24-hour period. Imbus et al. (1963)
reported median urinary concentrations of chromium for adult males of 3-77 ng/£.
Renal excretion is the major pathway of chromium elimination, with ^80$ of
injected chromium excreted in this manner (Mertz, 1969).
As discussed with chromium levels in serum, difficulties in determining the
low levels of chromium in urine were not resolved until 1978, and presently,
normal human levels of chromium are considered to be in the sub-ppb range
(Anderson, 1981). Using flameless AAS with background correction by either a
tungsten halogen lamp or a continuum source, echelle, wavelength modulated AA
system (CEW-AA), normal human urinary chromium levels were determined to be >1
\ig/i (Guthrie et al., 1978), >0.9 fig/A for most of 66 samples (Kayne et al.,
1978), and between 0.05 to 0.58 \ig/i for 48 males and 28 females (Anderson et
al., 1982). Veillon et al. (1979) obtained excellent agreement between chromium
determinations of pooled urine samples using CEWM-AA and chromium determinations
using stable isotope dilution methods measured by GC/MS. The mean values for the
respective methods were 0.34 + 0.1 and 0.32 + 0.02 fig/Jl. Increases in urinary
chromium in humans receiving a daily supplement of 200 \ig Cr as CrCl- ranged from
mean levels of 0.2 \ig/l prior to treatment to 1.02 and 1.13 V-g/Si after 2 and 3
months. This suggests that the high levels of urinary chromium reported in
earlier studies were not likely to have resulted from changes in chromium intake.
Although Anderson (1981) cautions against accepting absolute values for chromium
3-37
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from earlier studies, comparisons and trends determined in a given study may be
valid.
Franchini et al. (1975) and Borghetti et al. (1977) reporting about workers
exposed to chromium in the chromium-plating industries showed that urinary
excretion and renal clearance of diffusible chromium are biological indices to
evaluate the degree of current exposure and the body burden of the compound.
Franchini et al. (1978) confirmed their earlier results with an experimental
investigation using rats.
Other authors have demonstrated a close relationship between the amount of
Cr(VI) in the air and urinary excretion (Gylseth et al., 1977) or urinary excre-
tion of the metal corrected for creatinine (Tola et al., 1977). Gylseth et al.
(1977) reported in an abstract that welders exposed to a concentration of
0.05 mg/m (measured as chromium) had a urinary chromium concentration of
=40 ng/Jl, measured after work.
Krishna et al. (1976) studied 30 chrome workers who had nasal perforation.
Q
The atmospheric concentration of chrome ranged from 0.21 to 0.80 mg/m . Urine
samples from the workers were collected at the beginning of the day's shift and
again at the end of the day's shift. Before exposure, eight workers had a
concentration of chrome in the urine of j>0.20 ng/m£, whereas after exposure, 20
workers had such values. In an unexposed control group, there was no change in
the urine chrome values. While all the workers tested had nasal perforation, 66?
of them (20 of 30) had a urinary chrome concentration of 2:0.20 jig/ai£»
Mutti et al. (1979) studied 22 welders who worked with high chromium alloyed
electrodes. The concentration of the breathing zone levels of chromium, deter-
mined during the 1-month exposure monitoring period, ranged from 0.017 to
3 3
1.000 mg/m for total chromium, and from 0.002 to 0.350 mg/m as hydrosoluble
chromium. Urine samples from the workers were collected at the beginning and at
3-38
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the end of the experiment. These results suggest that the urinary concentration
of chromium at the end of a working period is affected by recent exposure to the
compound. At the same airborne concentration, the greater chromium body burden
is associated with greater excretion levels. Even after a week following the
last exposure, urinary chromium levels provide useful indications on body
burden.
Tandon et al. (1977) have reported urinary excretion of chromium among
electroplaters and polishers in an industrial setting. A total of 12 subjects
were examined. The range in duration of exposure to chromium in electroplating
processes ranged from 2 to 20 years (mean duration for 12 workers = 11.1 years).
Chromium levels in workers' urine samples taken before starting work ranged from
91 to 1116 \i&/l (mean value = 326.5 ng/£). Urinary chromium levels did not
necessarily correlate to duration of exposure, but a slight trend was indicated.
Subjective complaints included coughing, breathing difficulty, dermal itching,
depression, indigestion, body ache, and edema of the lower limbs. Mean urinary
chromium level in appropriate controls was 38.1 \ig/i (range: 0 to 78 \ig/SL).
Subjective complaints did not appear to correlate either with urinary chromium
levels or with duration of exposure. Urine samples collected at the end of the
work day, however, would perhaps have provided a better correlation between
exposure and complaints of illness.
3.5.3. Chromium in Human Hair. Schroeder and Nason (1969) reported a mean
chromium concentration of 0.69 + 0.063 ppm for women. Hambidge et al. (1972)
measured chromium concentrations at various distances from the hair root. They
reported that variation in the concentrations were due to past fluctuations in
chromium nutritional status. Hambidge and Rodgerson (1969) reported higher
levels of chromium in the hair of nulliparous women (0.2 to 2.81 ppm) than in the
3-39
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hair of parous women (0.04 to 1.14 ppm). However, a later study by Hambidge and
Droegnueller (197^) found changes in hair chromium levels due to pregnancy not to
be statistically significant. Hambidge and Rodgerson (1969) reported that hair
chromium levels in 3- to 8-month-old infants were significantly higher than in
those of 2- to 3-year-old children. Chromium is obtained through breast milk
during nursing. By the second year of life, mean chromium levels in hair
approached values present in older humans.
3.6. SUMMARY
Chromium is a metallic element which, when found in nature, is a stable
mixture of four separate isotopes. Inorganic chromium compounds occur in valence
states ranging from -2 to +6; however, in the environment the Cr(III) and Cr(VI)
states are the most stable. Chemically, the Cr(III) state is the most stable and
important form of inorganic chromium complexes. Cr(VI) compounds comprise the
most commercially important form of chromium, and they also appear to be the most
significant chromium compounds from an environmental standpoint. Because Cr(VI)
is readily reduced in the presence of organic material, it is rarely found in
nature apart from deposition by anthropogenic sources.
Although chromite ore is not currently mined in the United States, several
chromium chemicals are domestically produced from imported ores. Sodium chro-
mate, sodium dichromate, and chromic acid are three of the more important commer-
cial chromium compounds produced in the United States. Metallurgical uses
constitute about 60$ of the largest market demand for chromium. Chemical uses
are the second largest consumption sector at 21$, followed by refractory uses at
18$.
3-40
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Chromium emissions are released into the air, water, and land environments
from a variety of industrial source categories including fossil fuel combustion,
cement production, incineration, cooling towers, refractory production, leather
tanneries, steel and alloy production, electroplating, and chromite ore
refining. The largest chromium emission sources to the air are ore refining
plants, coal combustion units, refractory plants, and steel and alloy plants.
Principal sources of chromium in water systems include electroplating opera-
tions, leather tanneries, and textile manufacturing operations. Significant
sources of chromium-containing solid wastes that are land disposed include
chromite ore refining operations and chromium chemical production plants.
Recent monitoring of the ambient air in many urban and rural areas of the
country has shown annual average chromium concentrations to be in the range of
0.0052 to 0.1568 \ig/m . The maximum concentration determined during any one
24-hour measurement was about 2.48 ng/m . The chromium concentration in U.S.
waters varies with the type of surrounding industrial sources and the type of
underlying soils. An analysis of 3834 tap waters in representative U.S. cities
showed a chromium concentration range of from 0.4 to 8 ppb. Chromium levels in
soils vary with soil origin and the degree of contamination from anthropogenic
chromium sources. Tests on domestic soils have shown chromium concentrations
ranging from 1 to 1000 ppm, with the average concentration ranging from 14 to
about 70 ppm.
3-41
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4. SAMPLING AND ANALYSIS
Chromium is ubiquitous in the environment and is an essential micronutrient
for man. Therefore, the analysis of chromium encompasses a multitude of media,
namely, air, water, soil and sediments, foods, and a variety of biological solids
and fluids. Numerous methods are available for the determination of chromium in
these media. This section is intended to be a general overview of the available
methods commonly used for chromium analysis.
The analysis of chromium in a certain medium usually involves three distinct
steps, namely, sampling and storage, sample pretreatment, and analysis. The
individual step, as it pertains to the determination of chromium in various
media, is discussed below.
1.1. SAMPLING AND STORAGE
1.1.1. Air.
4.1.1.1. AMBIENT AIR — Dusts and fumes of chromium compounds in the
ambient air are usually collected by high volume sampler at a flow rate of about
20 to 30 m^ hr~1 (Demuynck et al.f 1976). Typical filter media include cellu-
lose, polyethylene, polystyrene, PVC, and glass-filter. The suitability of the
filtering media primarily depends on their background impurity level, particle
retention efficiency, and tendency to become clogged. Dams et al. (1972)
evaluated different filter materials and concluded that polyethylene filters are
most suitable for the collection of chromium particulates in atmospheric air.
4-1
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When size fractionation is required, multistage cascade impactors can be
used for the collection of aerosols (Broekaert et al., 1982; Winchester et al.,
1981). At a nominal sampling rate of 80 H min" f chromium particles of aero-
dynamic diameter in the range of 0.04 to 25 |im have been separated by this method
(Broekaert et al., 1982).
Although no specific information is available, it is reasonable to assume
that the filter paper protected from external contamination can be stored for an
indefinite period prior to chromium analysis.
4.1.1.2. OCCUPATIONAL AIR — Chromium in occupational air is collected in
a way similar to ambient air. A known volume of air is drawn through a polyvinyl
chloride (PVC) or cellulose filter to collect chromium. The sampling rate is
maintained at 1.5 H min~ (NIOSH, 1977). However, it has been determined by
Kneebone and Freiser (1975) that although the PVC filter can be stored for at
least 10 days, cellulose filters cannot be stored for more than several hours
without some loss of Cr(VI).
4.1.1.3. STATIONARY SOURCE — The sampling of chromium from stationary
sources, for example, stacks of refuse incineration and fossil fuel burning
facilities, can be done by collecting the sample isokinetically (Block and Dams,
1976; Greenberg et al., 1978). The sampling train typically consists of a copper
probe, a rotameter, a manometer, and a pump with a capacity of 20 nr hr~ . The
diameter of the nozzle is adjusted to the stack gas velocity to achieve iso-
kinetic sampling conditions (Block and Dams, 1976). Depending on gas tempera-
tures, glass-fiber, Teflon-fiber, and Whatman 41 filters have been used (Block
and Dams, 1976; Greenberg et al., 1978). However, the use of glass-fiber filters
may result in a high blank value for chromium (Greenberg et al., 1978).
4-2
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For studying distribution of particle size, the isokinetic sampling is
typically done in combination with a multi-stage cascade impactor
(e.g., Andersen cascade impactor) (Greenberg et al., 1978; Block and Dams,
1976). The different stages of the cascade impactor can be used to determine the
cutoff aerodynamic diameters of the collected particles.
The same method used for storing the filters from ambient air samples can be
used for the filters collected from the sampling of stationary sources.
4.1.2. Water.
4.1.2.1. DRINKING WATER — To collect distributed water samples from
household taps, the taps are typically run to waste at their maximum flow rate
for 5 minutes to clear the lines of overnight standing water (Meranger et al.,
1981). If suspended solids are suspected in the water, filtration is typically
done on location by passing the water samples through a 0.45 \an Millipore mem-
brane filter (Meranger et al., 1979). In order to get representative samples,
some investigators (Greathouse and Craun, 1978) have collected monthly samples
of finished water for a period of 1 year instead of one grab sample. The water
samples are collected in clean linear polyethylene screw-cap collection bottles.
Concentrated nitric acid (1 mJl/100 m£ water sample) is added to each bottle and
they are filled to the brim to avoid any air space. The filled and capped bottles
are transported in heavy plastic coolers containing gel-type freezer packs.
Immediately upon receipt in the laboratory, samples should be refrigerated at 4°C
(MSranger et al., 1981).
Recently, a novel method for preconcentration of trace metals in water
samples has been proposed by Smits and Grieken (1981). In this method, a
cylindrical plexiglass filtration unit consisting of a Nucleopore 0.4 urn
4-3
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pore-size membrane and a 2,2'-diaminodiethylamine (DEN)-cellulose filter has
been used. The Nucleopore filter was used to separate the suspended particles in
water and the DEN-cellulose filter allowed straightforward preconcentration of
trace cations by a simple filtration step. The collection efficiency for Cr(III)
by this method has been claimed to be 90-100$.
4.1.2.2. RAW AND SURFACE WATER — The sample collection, preservation,
transportation, and storage of raw and surface water samples are similar to those
for drinking water samples (Cranston and Murray, 1978; Pankow et al., 1977). A
more representative sample can be obtained by collecting several small samples
from different parts of the water body than by collecting one large sample at a
single point because of the inhomogeneity of the water body.
4.1.2.3. WASTEWATER — The sample collection, preservation, transporta-
tion, and storage of wastewater samples are similar to those for other water
samples. Grab samples (Larochelle and Johnson, 1978) are often collected but
wherever a process change is suspected, a 24-hour composite sampling is the
preferred or even necessary method.
4.1.3. Soil and Sediments. Grab samples are typically collected for the
analysis of chromium in soil and sediment. In order to evaluate the chromium
content in recent deposits, samples are collected from the upper few inches (2 to
3 inches) of sediment or soil (Pankow et al., 1977). The samples are usually
stored in polyethylene bags or bottles (Iwata et al., 1981; Pankow et al., 1977).
The samples are sieved through nylon sieves (2 mm) to remove gravel and leaves
(Iwata et al., 1981). The collected samples should be stored at 4°C or
-------
refrigerated during transportation and storage to minimize bacterial action
(U.S. EPA, 1979).
M.I.4. Food. No specific information for sample collection and storage of food
samples could be found in the literature. It is reasonable to assume that grab
samples collected in polyethylene bags or bottles and refrigerated during trans-
portation and storage should be an acceptable procedure for sample collection and
storage.
4.1.5. Biological Samples. Blood samples are typically drawn from donors with
10 mil vacutainers with disposable syringes and aluminum needles. Heparin is used
as the anticoagulant. Plasma samples can be obtained by centrifuging freshly
drawn heparinized whole blood. They can be transported at 4°C in polyethylene
tubes and frozen to -20°C during storage. Urine should be collected from donors
in polyethylene bottles, acidified, and stored at 4°C (Davidson and Secrest,
1972). Other solid tissue samples can be collected in polyethylene bags and
transported at 4°C. The tissue samples can be stored at -20°C.
4.2. SAMPLE PRETREATMENT
Sample pretreatment is often required as a technique to release the metal
from the sample matrix, and for concentration and separation from potential
interferences. A few of the typical pretreatment methods have been discussed
below. It should be emphasized that the pretreatment of samples is dictated by
the subsequent method of analysis, and in some cases the samples may not require
any pretreatment.
4-5
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4.2.1. Wet and Dry Ashing. This pretreatment method is often used for chromium
analysis in air particulate, biological samples, foods, soil, and sediment
samples in combination with atomic absorption, atomic emission, spectrophoto-
metric, and neutron activation analysis. In the wet digestion method, the sample
is digested with an acid or a mixture of acids depending on the sample matrix. A
number of acid(s) mixtures including HNOg, H2S04 (NIOSH, 1977), HN03/HF mixture
(Pankow et al., 1977), f^SO^/H^ mixture (Kumpulainen et al., 1979), HNOg/H202
mixture (Abu-Samra et al., 1975), HClO^/HgOg mixture (Davidson and Secrest,
1972), HNO-XHClOjj mixture (Gallorini et al., 1976), HN03/H2S01}/ HCIO^ mixture
(Kuennen et al., 1982; Feldman et al., 1967) and HNC^/HjSOjj mixture (Bryson and
Goodall, 1981) have been used. The two commonly used dry ashing procedures are
graphite furnace ashing (Meranger et al., 1979; Slavin, 1981) and low-
temperature oxygen plasma ashing (Kumpulainen et al., 1979). Some investigators
also have used a combination of dry and wet ashing for the pretreatment of
samples (Kumpulainen et al., 1979). Irrespective of the procedure, a particular
ashing method is always optimized to minimize matrix interference and maximize
the chromium yield from the sample.
4.2.2. Precipitation. The direct precipitation of chromium from aqueous solu-
tion by such reagents as hydroxyquinoline and tannic acid is generally not
suitable for environmental samples containing low chromium concentration.
However, the method of co-precipitation of chromium has been successfully used in
recent years. In this method, Cr(III) is co-precipitated with Fe(III) as
hydroxide at a pH of 8-8.5 (Cranston and Murray, 1978; Pik et al., 1981). The
co-precipitation of Cr(VI) has been accomplished by reducing Cr(VI) to Cr(III) by
the addition of Fe(II) and subsequent co-precipitation of hydroxides of Cr(III)
with Fe(II) at pH 8 (Cranston and Murray, 1978), or by co-precipitating Cr(VI) by
4-6
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Co(II) and ammonium pyrrolidinedithiocarbamate (APDC) addition (Pik et al.,
1981). The co-precipitated chromium is filtered from the solution and analyzed
by x-ray fluorescence or by flameless atomic absorption spectrometry.
4.2.3. Solvent Extraction. In this procedure, Cr(VI) is complexed with APDC at
a pH of 1.8-3.0 and extracted with an organic solvent, typically methyl isobutyl
ketone (MIBK). If Cr(III) is to be extracted, it must first be oxidized to
Cr(VI) with reagents such as silver nitrate and potassium peroxydisulfate or with
potassium permanganate and sodium azide (Towill et al., 1978). In the gas
chromatographic procedure, chromium is chelated with 1,1,1-trifluoro-2,4-
pentanedione or trifluoracetylacetone (HFTA) and the chelate is extracted into
benzene. This method has been used by a number of investigators (Lovett and Lee,
1976; Gosink, 1976).
4.2.4. Chromatographic Method. A number of chromatographic materials including
alumina, cation-exchange resin, anion-exchange resin, and chelating ion-exchange
resin have been used for the cleanup of impurities from chromium samples. In the
anion-exchange procedure, the solution containing Cr(VI) is allowed to pass
through the resin bed at an optimum pH. The Cr(VI) retained on the resin bed is
subsequently eluted with a suitable eluent. The major drawback of this procedure
is that the recovery of Cr(VI) is often poor. The problem, however, has been
alleviated by using an ascending flow technique or by in situ reduction of Cr(VI)
by Fe(II) (Pankow and Janauer, 1974). Marino and Ingle (1981) used medium
strength anion-exchange resin to obtain a satisfactory recovery of Cr(VI) from
the resin bed.
In the cation exchange procedure, the resin is used to retain the cationic
impurities while anionic Cr(VI) passed through the resin bed. This procedure has
4-7
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been used by Kneebone and Freiser (1975) for the analysis of Cr in occupational
samples.
The chelatory ion-exchange procedure was employed by Leyden et al. (1972)
to absorb quantitatively Cr(III) from a buffered solution. By this procedure,
Cr(VI) was detected by reducing it to Cr(IIl) with the addition of sodium bisul-
fite.
The alumina procedure has been used for the separation of both Cr(III) and
Cr(VI). Larochelle and Johnson (1978) adsorbed Cr(VI) on alumina column and used
HC1 for the subsequent elution of Cr(VI). Wolf et al. (1972), on the other hand,
used an alumina column for the separation of Cr(III). In this procedure, Cr(IIl)
is precipitated with other cations by the addition of excess 8-hydroxyquinoline.
The dried precipitate is dissolved in chloroform, diluted with an equal volume of
benzene, and passed through an activated alumina column. Chromium was eluted
with a mixture of chloroform and benzene.
4.3. METHODS OF ANALYSIS
Chromium can be determined by a variety of analytical methods. A few
analytical methods used for the determination of Cr are given in Table 4-1. It
should be emphasized that the detection limit and the percent-relative standard
deviation (% coefficient of variation) values given in Table 4-1 should be taken
as values representative of the specific pretreatment techniques and
instrumental methods used rather than definite data. For example, both the
detection limit and percent CV values obtained by the same instrumental method
may vary several-fold depending on the extent of preconcentration of the sample
and the method used for eliminating interferences. These values may also vary
considerably from laboratory to laboratory and even within the same laboratory.
4-8
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Catalytic method
TABLE 1-1
Analytical Methods for the Determination of Chromium
Method
Graphite furnace AA
Flame AA
Spectrophotometrio
Type of Sample
blood, urine, and other
biologic samples3
natural waters
raw, treated, and dis-
tributed water0
raw, treated, and dis-
tributed water0
natural waterd
blood, urine, and other
biologic samples6
tissue samples^
Preconcentration
none
co-precipitation
with Fe(OH)
none
APDC-MIBK
extraction
APDC-MIBK
extraction
an ion exchange
MIBK extraction
APDC-MIBK
extraction
Selectivity
total Cr
Cr(III); Cr(VI)
can be reduced
to Cr(III) by
Fe(II)
total Cr
Cr(Vl); Cr(III)
can be oxidized
to Cr(VI)
Cr(VI); Cr(III)
can be oxidized
to Cr(VI)
Cr(VI)
Cr(VI)
Cr(VI); Cr(III)
can be oxidized
Detection
Limit
0.1 ug/l
0.001 ug/l
2 ug/l
0.6 ug/l
0.05 ug/l
0.1 ug/l
10 ug/l
1.2 ug/l
* CV
(at sample
concentration)
5.2*
(10 ug/l)
5*
(0.14 ug/l)
15* (2 ug/l)
20* (2 ug/l)
5* (3 ug/l)
20* (0.1 ug/l)
15* (25 ug/l)
0.4* (800 ug/l)
Interference
Matrix interference
can be avoided by
wet ashing.
none reported
none reported
none reported
none reported
none reported
none reported
Fe, Hi and PO^
may interfere
3-
air particulates"
Neutron activation air psrtloulatesh
freshwater^
none
none
none
to Cr(VI)
Cr(VI)
total Cr
total Cr
1 ng 6* (<100 ug/l) Pb, Cu, Cr(III),
Fe(III), and V(?)
may interfere
30 ng/n 15* none reported
(1.3 ng/m3)
0.12 ug/l 21* (1.4 ug/l) none reported
-------
TABLE M-1 (oont.)
Analytical Methods for the Determination of Chromium
Method
Gas chromatography
(electron capture
detection)
Gas chromatography
(AAS detection)
Gas chromatography
(MS detection)
Liquid chromatography
(coulometric detection)
X-ray fluorescence
Type of Sample
natural waters
blood, serum, orchard
leaves
bloodm
natural water11
dried solution deposit0
Preconcentration
HTFA-benzene
extraction
HTFA-benzene
extraction
HTFA-benzene
extraction
1 i sample concen-
trated to 10 mi
none
Selectivity
Cr(III) and
Cr(III)
Cr(III)
Cr(VI)
total Cr
Detection
Limit
Cr(VI) 0.1 ug/l
<1 ng
0.5 pg
0.8 ug/l
1.5 ug/gP
* CV
(at sample
concentration)
2.6* (1.9 ug/l)
<6* (1 ng)
9* (10 ng/g)
<2* (90 ug/l)
'" ?.
Interference
none reported
none reported
none reported
SO,.'2, PO.3'
may inerflre
absorption by
(energy dispersive)
j_ X-ray fluorescence
I (energy dispersive)
Differential pulse
polarography
Emission spectroscopy
(inductively coupled
plasma source)
Mass spectrometry
surface water and drinking
waterq
natural waters
natural waters
variety of samples
chelating ion-
exchange membrane
none
none
none
Cr(III)
Cr(VI)
total Cr
total Cr
(1 jig/cm*1) matrix and dif-
ference in
particle size
may cause error
0.8 ug/l 10-15* excess alkali and
(1 ug/l) alkaline earth
metals may inter-
fere
10 ug/l 34* (61 ug/l) excess Cu(II) and
Fe(III) may inter-
fere
1.8-6 05* none reported
0.05-1 ug 20* (photo- Any species having
graphic) the sane m/e ratio
3* (electrical) as Cr nuclide may
0.5* (isotope interfere
dilution)
-------
Chemiluminescence
(lophine)
TABLE 1-1 (cont.)
Analytical Methods for the Determination of Chromium
Method
Chemil uminescence
Detection
Type of Sample Preconoentration Selectivity Limit
natural waters and orchard none Cr(III) 0.02 (ig/l
leaves1*
% CV
(at sample
concentration)
201 (at 2.3
ppm)
Interference
Fe(III), Fe(II),
Co(II), S032'.
and NO-" may
Interfere
natural waters'
ion exchange resin Cr(VI)
0.015
Pe(III), Fe(II),
Co(II), Cr(III),
Mnott", and
other cations and
anions may interfere
Davidson and Secrest, 1972
£r Cranston and Murray, 1978
Z? °M*ranger et al.f 1981
Sankow and Janauer, 1974
Veldman et al., 1967
fBryson and Goodall, 1981
^Kneebone and Freiser, 1975
T)emuynok et al., 1976
1Bhagat et al., 1971
•'salbu et al., 1975
T,ovett and Lee, 1976
, 1976
"Volf et al., 1972
"uarochelle and Johnson, 1978
°Camp et al., 1975
pKuhn, 1973
fyanGrieken et al., 1977
rCrosmun and Mueller, 1975
8Quinby-Hunt, 1978
Boumanns and deBoer, 1972
uAhearn, 1972
VElser, 1976
WHoyt and Ingle, 1976
*Marino and Ingle, 1981
-------
The following sections briefly describe some of the methods used for the analysis
of chromium.
1.3.1. Atomic Absorption Spectrometry (flame). This method has been used by
various investigators for the determination of Cr in surface water, sewage
effluent, and biological samples. The determination of Cr by the air-acetylene
flame is prone to interference by other elements (Thompson and Wagstaff, 1979).
This problem can be avoided by using nitrous oxide-acetylene flame but this
results in a decrease in the detection limit (Thompson and Wagstaff, 1979).
Therefore, most investigators have used air-acetylene flame for the determina-
tion of Cr. However, for samples with low Cr concentration, pretreatment of the
samples providing preconcentration of Cr and the reduction of the interfering
effects from other ions are required. Thompson and Wagstaff (1979) used an
evaporative technique on a hot plate to concentrate the sample 5-fold. A 2%
ammonium perchlorate solution (W/V) was used to suppress the interelement inter-
ference effects. Better methods for pretreatment of samples include
ion-exchange separation (Pankow et al., 1977; Pankow and Janauer, 1974), APDC-
MIBK extraction (Gilbert and Clay, 1973) and MIBK extraction (Feldman et al.,
1967). The flame AAS technique is not a preferable method for samples with very
low Cr concentration since this method has a much higher detection limit than
flameless AAS (Slavin, 1981).
4.3.2. Atomic Absorption Spectrometry (flameless). In the flameless AAS
method, the sample is atomized directly in a graphite furnace, carbon rod, or
tantalum filament instead of a flame. It is one of the most attractive methods
for the analysis of solid and liquid biological samples since the method does not
generally require sample preparation. Despite the high sensitivity of the flame
4-12
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less AAS method, it may suffer from certain disadvantages. For example, matrix
interference, background or nonspecific absorption effects, volatilization of
some Cr during dry ashing, and adsorption of Cr on the walls of crucibles during
dry ashing can cause error in analysis. The matrix interference effect in the
case of water samples can be overcome by chelation and solvent extraction
(Meranger et al., 1979, 1981) or by the co-precipitation technique (Cranston and
Murray, 1978), and in the case of biological samples, by wet disgestion (Davidson
and Secrest, 1972) prior to introduction of the sample into the graphite furnace.
Background correction for non-specific absorbance can be made with a deuterium
arc corrector (Cranston and Murray, 1978) or better yet, by continuum source,
echelle, wavelength-modulated, atomic absorption spectrophotometer (CEWM-AA)
(Kumpulainen et al., 1979). The volatilization of Cr during dry ashing at
temperatures of 700°C or higher, particularly during the analysis of complex
matrices such as food, may be substantial (Kumpulainen et al., 1979). Low
temperature ashing, for example, with oxygen plasma at 150°C, would eliminate
this problem and the problem of Cr adsorption on crucible walls. However, the
low temperature ashing may not be suitable for some biological samples (bovine
liver), and some biological materials such as brewer's yeast may contain acid
insoluble material that can strongly adsorb chromium (Kumpulainen et al., 1979).
However, these problems have been overcome by utilizing dry ashing at 500°C with
sulfuric acid and hydrogen peroxide as ashing acids (Kumpulainen et al., 1979).
The problems of sorption and volatilization can also be eliminated by the use of
"platform" technique described by Slavin (1981).
Versieck et al. (1978) reported that chromium levels in serum from normal
subjects was 0.16 jig/i, when determined by carefully conducted neutron activation
analysis. In a survey of previous reports of chromium levels determined by
flameless AAS, the range of values was 0.73 to 150 ng/&, and the levels tended to
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become lower as improvements in detection limits occurred. These results
prompted an intensive study of possible sources of artifacts in the flameless AAS
analysis of biological fluids by Kayne et al. (1978) and Guthrie et al. (1978).
Guthrie et al. (1978), in a study of the effects of purge gas, char temperature,
sample volume, and graphite tubes on the determination of low ppb levels of
chromium, demonstrated that all these parameters affected the background non-
atomic absorption, and that there was a direct correlation between background
absorption and the apparent chromium content of the sample. It was suggested
that the background correction was inadequate as the result of the low intensity
of the D lamp at the near UV wavelength used in chromium analysis. Kayne et al.
(1978) came to a similar conclusion, and modified the background correction by
replacing the usual D lamp with a tungsten halogen lamp. This modification
provided adequate background correction, and serum chromium levels determined
for 8 normal male subjects averaged 0.14 \ig/H, while most measurements from 66
randomly chosen urine samples were =0.9 ng/&. Guthrie et al. (1978), Kayne et
al. (1979), and Anderson (1981) warned that earlier reports of chromium levels in
urine and serum should be considered artificially high in light of these
findings.
4.3.3. Emission Spectroscopy. In emission spectroscopy, prepared samples are
excited with a flame, arc, spark, or plasma and the resulting light is dispersed
with a monochromator. The characteristic emission lines of the excited elements
are recorded electronically or on a photographic plate. Because of its better
sensitivity, inductively compiled plasma atomic emission spectrometry (ICP-AES)
has been more extensively used in recent years than the other modes of excitation
(Towill et al., 1978; Slavin, 1981). Since the sample is generally introduced
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into the plasma source by pneumatic nebulization, all solid and biological
samples require wet digestion prior to analysis. The wet digestion also tends to
minimize the matrix effects. A HF/HN03 digestion at 170°C has been employed for
the simultaneous multi-element analysis of air particulate matters (Broekaert
et al., 1982). Similarly, wet digestion by direct chelation with
1,1,1-trifluoro-2,4-pentaedione (also known as trifluoroacelytacetone) (HTFA) or
hexafluoroacetylacetone (HHFA) has been used for the cleanup and volatilization
of Cr in biological samples (Black and Browner, 1981) prior to ICP-AES analysis.
Recently, a direct atomization technique for raw agricultural crop samples has
been presented (Kuennen et al., 1982). The technique employs a 30-minute pres-
sure dissolution of sample composite with 6M HC1 at 80°C in linear polyethylene
bottles. The dissolved samples after proper filtration by Teflon filters can be
aspirated directly into the plasma source. Combined with real sample matrix
calibration technique, it has been suggested that this method provide comparable
recovery and precision as obtained by the more time-consuming conventional wet
ashing methods.
4.3.4. Neutron Activation Analysis. Neutron activation analysis is one of the
most sensitive modern analytical techniques for the determination of trace
elements. Neutron activation analyses are applicable to many kinds of environ-
mental samples including air particulates, dusts, soils, fresh and marine water,
sediments, biological liquids and solids, and foods. The samples are often
irradiated without prior chemical treatment. A detection limit of 0.12 ng/& in
freshwater (Salbu et al., 1975) and 0.2 jig/g in biologic materials (Spyrou
et al., 1974) has been reported for samples analyzed without chemical proces-
sing. Lower detection limits generally can be achieved if the samples are
chemically processed to separate and concentrate chromium. For example, in the
chemical processing of samples typically by ion-exchange separation, detection
4-15
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limits of 0.1 ng/fc for river water, 3 ng/& for seawater, and in the ppb range for
biological and environmental samples have been reported (McClendon, 1974;
Robertson and Carpenter, 1974).
One distinct advantage of this method is the reduced problems arising from
reagent contamination. Even if chemical processing is required, post-irradia-
tion contamination is of no consequence in introducing error to the final result„
In addition to the problem of acquiring a neutron source, this method has another
ph
disadvantage. Due to the intense x-ray or bremsstrahlung activity from Na,
3 Cl, K, 5 Mn, and ^ p in many samples, the irradiated samples usually must be
cooled for several weeks before measuring Cr concentration. However, chemically
separating the offending nucleides can reduce the cooling period to about
24 hours (McClendon, 1974).
4.3.5. X-ray Fluorescence. The x-ray fluorescence method is commonly applied
to solid samples. In this technique, the sample is bombarded with high energy
photons, for example, low energy x-ray or gamma photons or with particles such as
protons. The intensity of the characteristic emitted x-ray is currently measured
by two techniques, namely, energy-dispersive analysis and wavelength-dispersive
analysis. The resolution of wavelength-dispersive analysis is much better than
energy-dispersive analysis which often permits the former method to determine
the oxidation states of an element (Quinby-Hunt, 1978).
This technique is useful for trace analysis in solid samples, namely, air
particulates (collected on filters), sediments, biological specimens, and
filtered suspended solids from aqueous media. However, for aqueous samples,
sample preparation leading to the deposition of the element on a filtering medium
is required. This deposition can be done by a variety of methods. The obvious
and simple method is the evaporative drying of the sample on a Mylar film (Tanaka
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et al.f 1981). Other methods of sample deposition include retention on chelating
filters (Smits and Van Grieken, 1981), vapor filtration technique (Greathouse
and Craun, 1978) and co-precipitation (Pik et al., 1981). The last three methods
not only allow deposition of Cr on a filtering media, but also permit separation
and concentration of Cr from the aqueous phase during the deposition step.
Sample preparation in the case of. solid samples is an important requirement
for this method. In order to avoid absorption and scattering by sample matrix,
the size and shape of the particles on the films should be controlled by pressing
the deposits into thin wafers (Towill et al., 1978).
4.3.6. Colorimetric. The usual colorimetric method for the determination of Cr
involves oxidation of Cr(III) to Cr(VI), followed by complexation with diphenyl-
carbazide. However, the sensitivity of the method is such that samples with
relatively high Cr concentrations can be determined fay this method. This method
has been proposed by NIOSH (1977) for the determination of Cr in occupational
atmosphere. However, the NIOSH method of digesting the filter with 0.5 N H^O^
for the determination of Cr(VI) may not be suitable for use with welding fumes.
A carbonate leaching method has been described for the determination of Cr in
welding fumes and other complex matrices (Thomsen and Stern, 1979). Bryson and
Goodall (1981) have described a modified diphenylcarbazide spectrophometric
method for the determination of Cr in biological tissues.
4.3-7. Gas Chromatography. .
The gas chromatographic method is suitable for a variety of environmental
samples. The analysis of water samples by this method does not generally require
pretreatment before complexation (Lovett and Lee, 1976). Samples that are solid,
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namely, particulate matter, and biological samples are first digested to get Cr
in solution. The Cr is then quantitatively chelated with 1,1,1-trifluoro-2,4-
»
pentanedione (HFTA) or hexafluoroacetylacetone (HHFA) to form a thermally
Stable, volatile Cr(III) complex. To determine Cr(VI), it should be reduced to
Cr(III) by a reducing agent, such as sodium sulfite. The Cr(IlI)-HFTA or
Cr(III)-HHFA complex is extracted into an organic solvent, usually benzene or
hexane, and an aliquot is injected into the GC column. Recently a direct
chelation (without pretreatment) method has been described for biological
samples (Black and Browner, 1981).
The detection of Cr(III) complex can be accomplished by a variety of detec-
tors. The sensitivity of this method is dependent on the detector used. A
number of detectors including electron capture (Lovett and Lee, 1976), atomic
absorption (Wolf, 1976), mass spectrometric (Wolf et al., 1972), and ICP-AES
(Black and Browner, 1981) have been used.
The gas chromatography with any of the detection methods described has
excellent sensitivity for Cr determination, but the mass spectrometric method is
extraordinarily sensitive and specific.
4.3-8. Chemiluminescence. Luminal (5-amino-2,3-dihydrophthalazine-1,4-dione)
and lophine (2,4,5-triphenylimidazole) emits light when oxidized by hydrogen
peroxide. The first oxidation in basic solution is catalyzed by Cr(III) and the
second by Cr(VI). The design of different Chemiluminescence instruments for the
determination of Cr vary primarily in the technique for mixing the sample and
reagents. The three types of sample modules which are commonly used are discrete
sampling system, flow system, and centrifugal analyzer (Hoyt and Ingle, 1976).
All these sample modules have been used for the analysis of Cr (Towill et al.,
1978).
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The chemiluminescence method has been used primarily for the analysis of Cr
in water and in biological samples (Marino and Ingle, 1981; Hoyt and Ingle,
1976). The method is fast, economical, and has a high sensitivity. The sensi-
tivity can be further increased by preconcentration of the samples (Marino and
Ingle, 1981). However, this method has not been as widely used as some of the
other methods.
4.3.9. Polarography. Two recent variations of the method, namely, single-sweep
polarography and differential pulse polarography, have both been used for the
detection of Cr in natural waters (Whitnack, 1975; Crosmun and Mueller, 1975).
The polarographic method has a comparatively lower sensitivity than other
methods and is not currently popular for Cr analysis.
4.3.10. Mass Spectrometry. The spark-source mass spectrometric method is
applicable to virtually any matrix, but the results are only semiquantitative
(Towill et al., 1978). The precision and accuracy of this method can be greatly
improved by using the isotope dilution technique. This method has been used to
establish the Cr content in NBS bovine liver (Dunstan and Garner, 1977). The
mass spectrometric method is rarely used for the routine determination of
chromium.
1.3.11. Catalytic Method. This method has been used for the determination of
Cr(VI) in occupational samples (Kneebone and Freiser, 1975). In this method, the
microdetermination of Cr(VI) is done by means of Cr catalyzed oxidation of
o-dianisidine by hydrogen peroxide. The reaction rate is monitored spectro-
photometrically. This method has limited application (occupational samples)
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because of interferences by various cations, and it is rarely used for the
determination of Cr.
4.3.12. Liquid Chromatography. This method in combination with a coulometric
detection has been used for the determination of Cr in water samples (Larochelle
and Johnson, 1978). In this method Cr(VI) is separated by an alumina column and
the separated solution is passed through a flow-through coulometric detector.
Although the method has been purported to have good sensitivity and precision, it
has found little application in the analysis of chromium.
4.4. CONSIDERATIONS IN ANALYSIS
The determination of Cr in samples containing trace amounts of the compound
requires special precautionary measures from the initial sample collection step
to the final analytical manipulations of the samples. For example, contamination
of samples during collection should be avoided by the use of Cr-free equipment.
This is particularly true for the collection of biological samples. Biological
tissue samples are sometimes collected by hospital personnel who use stainless
steel scalpels, trays, utensils, etc. containing about 18? Cr. This may produce
unacceptable contamination in the samples. Similarly, sample containers should
be free from the possibility of sample contamination. Polyethylene bottles and
bags are particularly suitable as sample containers. Even with polyethylene
bottles, adsorption of Cr on the surface of the container from water samples may
be a serious problem. Therefore, acidification of aqueous samples prior to
storage is necessary to avoid adsorption losses.
The possibility of sample contamination and losses during analytical pre-
treatment of the samples should be avoided. Care should be taken that only
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reagents of the highest purity are used. Even so, the quantity added should be
limited to a minimum to avoid unnecessary buildup of contaminants. The use of
Cr-containing grinding or homogenizing equipment can introduce Cr-containination
into the samples. Grinding such samples with an agate mortar and pestle is a
better procedure. The analysis of Cr, especially in biological samples, is
complicated by extreme matrix effects, possible volatility of some Cr complexes,
and the inherent property of Cr-complexes to bind non-specifically to reaction
vessels, graphite tubes, or other equipment. The methods used to minimize these
problems have been discussed in section 4.3-2.
The problem of developing accurate data from Cr analysis, particularly in
food and biological samples, is amply illustrated by the large variations in the
interlaboratory comparison data (Towill et al., 1978). The problem is further
aggravated by the non-availability of Standard Reference Materials (SRM). Only
recently has the National Bureau of Standards (NBS) issued the Cr certified
materials, such as brewer's yeast (SRM-1569), bovine liver (SRM-1577), orchard
leaves (SRM-1571), spinach leaves (SRM-1570), pine needles (SRM-1575), and
tomato leaves (SRM-1573). In view of the absence of suitable comparison with
SRMs, the older data should be interpreted with skepticism.
Another problem in dealing with the analytical methods is their ability to
distinguish between Cr(III) and Cr(VI). This is particularly important since
Cr(VI) has been associated with health hazards, while Cr(III) is of substantially
less concern and is in fact necessary for the maintenance of a normal glucose
tolerance factor (Marino and Ingle, 1981). The problem for the determination of
the two oxidation states of Cr is not critical in foods, sediments, soils, and
biological samples, because Cr is genrally present in the Cr(III) state in these
samples. However, Cr may be present in both oxidation states in ambient and
occupational air, and in water samples. It should also be recognized that Cr(VI)
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may be present in both water soluble and water insoluble form in these samples.
It is necessary to distinguish these two forms of Cr(VI), as they may have
different genotoxic properties (Thomsen and Stern, 1979). Some of the methods
that distinguish between Cr(VI) and Cr(III) have already been discussed. The
analytical method for the determination of soluble and insoluble forms of Cr(VI)
in occupational air samples has been described by Thomsen and Stern (1979).
4.5. COMPARISON OF METHODS
Based on versatility, sensitivity, and precision, the three most important
methods that have found wide application are graphite furnace AAS, x-ray fluore-
scence, and neutron activation analysis. Of these three methods, graphite
furnace AAS has the advantage of being the least expensive method. The disadvan-
tage of graphite furnace AAS is that it cannot be used for simultaneous multi-
element determinations. Both neutron activation and x-ray fluorescence, on the
other hand, are commonly used for simultaneous multi-element analysis. X-ray
fluorescence has the advantage over both neutron activation and graphite furnace
AAS analysis in that it can differentiate between the various oxidation states of
Cr without prior pretreatment of the samples. The disadvantage of x-ray fluore-
scence is that it often requires time-consuming pretreatment of the samples. The
use of neutron activation analysis normally requires about a 2-week cooling
period if post-irradation separations are not performed. Thus, the technique is
not suited for on-line or rapid analysis of chromium.
The choice of a particular analytical method for Cr analysis is dictated by
several factors including the type of sample to analyzed, concentration of Cr in
the sample, and the scope of the analysis. These factors, in combination with
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others such as the desired precision and accuracy and the cost of analysis,
should be weighed in selecting a particular analytical method.
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5. CHROMIUM METABOLISM IN MAN AND ANIMALS
5.1. ROUTES OF CHROMIUM ABSORPTION
5.1.1. Chromium Absorption and Deposition by Inhalation. An important route of
exposure to chromium compounds is through inhalation of chromium containing
particles and aerosols. Although there are no specific data on the deposition of
chromium in the lungs, some general considerations of factors affecting deposi-
tion as presented in U.S. EPA (1982) would likely also apply to particles or
aerosols containing chromium. During inhalation (and exhalation) a portion of
the inhaled aerosol may be deposited by contact with airway surfaces or be
transferred to unexhaled air. The remainder is exhaled. The portion transferred
to unexhaled air may be either deposited by contact with airway surfaces or later
exhaled. These phenomena are complicated by interactions that may occur between
the particles, other gases such as endogenous ammonia, and the water vapor
present in the airways.
The mechanisms involved in the deposition of inhaled aerosols are affected
by physical and chemical properties, including aerosol particle size distribu-
tion, density, shape, surface area, electrostatic charge, hygroscopicity or
deliquescence, chemical composition, gas diffusivity and solubility, and related
reactions. The geometry of the respiratory airways from nose and mouth to the
lung parenchyma also influences aerosol deposition; the important morphological
parameters include the diameters, lengths, inclinations to vertical, and
branching angles of airway segments. These factors affect the extrapolation of
data between different species that have respiratory tracts of different
geometry. Physiological factors that affect deposition include breathing
5-1
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patterns, air flow dynamics in the respiratory tract, and variations of relative
humidity and temperature within the airways. Clearance from the respiratory
tract depends on many factors, including site of deposition, chemical composi-
tion and properties of the deposited particles, reaction products, mucociliary
transport in the tracheobronchial tree, macrophage phagocytosis in the deep
lung, and pulmonary lymph and blood flow.
Aerodynamic properties of aerosol particles depend upon a variety of
physical properties, including the size and shape of the particles and their
physical densities. Two important aerodynamic properties of aerosol particles
are the inertial properties, which are most important for particles larger than
0.5 M-m in diameter and are related to the settling speed in air under the
influence of the earth's gravity, and the diffusional properties, which are most
important for particles smaller than 0.5 |im in diameter and are related to the
diffusion coefficient (Fuchs, 1961). When particles are inhaled, their aero-
dynamic properties, combined with various anatomical and breathing charac-
teristics, determine their fractional deposition in various regions in the
respiratory tract.
The respiratory tract includes the passages of the nose, mouth, nasal
pharynx, oral pharynx, epiglottis, larynx, trachea, bronchi, bronchioles and
small ducts and alveoli of the pulmonary acini. With respect to respiratory
tract deposition and clearance of inhaled aerosols, three regions can be
considered: (1) extrathoracic, the airways extending from the nares down to the
epiglottis and larynx at the entrance to the trachea (the mouth is included in
this region during mouth breathing); (2) tracheobronchial region, the primary
conducting airways of the lung from the trachea to the terminal broncioles (i.e.,
that portion of the lung respiratory tract having a ciliated epithelium); and 3)
pulmonary region, the parenchymal airspaces of the lung, including the respira-
5-2
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tory bronchioles, alveolar ducts, alveolar sacs, atria, and alveoli (i.e., the
gas-exchange region) (Morrow et al., 1966).
The behavior of inhaled particles in the respiratory airways and their
alternative fate of either deposition or exhalation depend upon aerosol
mechanics under the given physiological and anatomical condition (Yeh et al.,
1976; DuBois and Rogers, 1968). Contact of particles with moist airway walls
results in attachment and irreversible removal of the particles from the air-
stream. The contact process can occur during inspiration or expiration of a
single breath or subsequently if a particle has been transferred to unexhaled
lung air (Engel et al., 1973; Davies, 1972; Altshuler, 1961).
There are five primary physical processes that lead to aerosol particle
contact with the wall of the airways. Gravitational settling occurs because of
the influence of the earth's gravity on airborne particles. This mechanism has
an important influence on the deposition of particles larger than 0.5 fim D .
36
Settling has an important role in the deposition of environmental aerosols in the
distal region of the bronchial airways and in the alveolar region. Impaction
dominates deposition of particles larger than 3 H*n D in the nasopharyngeal and
3.©
tracheobronchial regions (Pattle, 1961; Bohning et al., 1975). In this process,
changes in airstream direction or magnitude of air velocity streamlines or eddy
components are not followed by airborne particles because of their inertia. The
passages of the nose contain smaller airways, and the convective mixing spaces of
the nasal turbinates would be expected to collect some particles aa small as 1 or
2 urn D by impaction. Hence, impaction is an important process affecting the
3.6
inhalation deposition in the human airways of environmental aerosol particles
>1 jim in aerodynamic diameter. Deposition by diffusion results from the random
(Brownian) motion of very small particles caused by bombardment of the gas
molecules in air.
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Particles larger than 0.5 |im have relatively small diffusional mobility
compared with sedimentation or inertia; diffusion primarily affects deposition
of particles with physical diameters smaller than 0.5 ^m. Interception consists
of noninertial incidental meeting of a particle and the lining of the airway and
thus depends on the physical size of the particle.
Interception along with electrostatic attraction of particles to the walls
of the respiratory airways are probably minor mechanisms of deposition in most
circumstances. It is important to note that the diffusivity and interception
potential of a particle depend on its physical size, while the inertial proper-
ties of settling and impaction depend on its aerodynamic diameter. Chromium
absorption following inhalation exposures has received only limited attention.
The effects of valence state and chemical form on inhalation absorption are not
well defined. The problem is further complicated by the inability to clearly
differentiate between pulmonary absorption and subsequent absorption through the
gastrointestinal tract, and gastrointestinal absorption resulting from clearance
from the respiratory tract followed by swallowing. In addition, absorption is
often estimated by urinary excretion, and in many studies fecal contamination of
urine specimens has not been ruled out.
Langa'rd et al. (1978) exposed rats to zinc chromate(VI) dust at a concen-
tration of 7.35 mg/m . In initial studies whole blood chromium concentrations
were evaluated following 100, 250, and 350 minutes of exposure. Before initia-
tion of exposure, the mean blood chromium concentration was 0.007 ng/mJl.
Following exposure, values were 0.024, 0.22, and 0.31 jig/mi at 100, 250, and 350
minutes, respectively. These data indicate a very rapid pulmonary absorption of
a portion of the inhaled dose.
The next portion of the study involved four consecutive daily exposures of
6 hours duration to zinc chromate at a level of 7.35 mg/m . Blood concentrations
5-U
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appeared to peak after the second exposure session. Mean blood chromium values
from samples taken immediately after each exposure session were: 0.30, 0.56,
0.46, and 0.34 ng/mS, for days 1 through 4. The mean blood chromium level
following 2 months of exposure for 6.5 hours/day, 5 days/week was quite similar
(0.495 |ig/m&). There were no significant differences in absorption, as
reflected by blood chromium level, between the sexes or between day and night
exposure regimens.
Baetjer et al. (1959a) exposed guinea pigs via intratracheal administration
to 200 (xg chromium as sodium chromate(VI), potassium dichromate(VI), or chromic
chloride(III), all of which are water soluble salts. For the Cr(VI) compounds 10
minutes post-instillation, 15? of the dose remained in the lungs, 2Q% was found
in the blood, and 5% was distributed among various soft tissues. Clearance of
chromium upward from the trachea and subsequent swallowing is assumed to account
for the majority of the dose not found in the blood and tissues. During the first
24 hours, = 13? of the dose was excreted, 11? remained in the lungs, and 16$ was
found in the blood and other tissues. These data indicate that as much as 60? of
the administered dose may have been subsequently ingested. Similar data are not
available for inhalation exposures. After 140 days, chromium had been essen-
tially cleared from all tissues except lung and spleen. For chromic
chloride(III) 10 minutes post-instillation, 69? of the administered dose was
retained in the lungs, with 4? in the blood and other tissues combined. Twenty-
four hours post-exposure, the lungs retained 45? of the administered dose; lung
retention after 30 and 60 days was 30 and 12?, respectively.
Of the water soluble salts studied, Cr(III) is absorbed much more slowly
from the lungs than Cr(VI) possibly as a result of binding to extracellular
macromolecules. In addition, analyses of lungs from experimental animals and
human autopsy specimens indicate that water soluble salts undergo conversion to
5-5
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very insoluble moieties with long residence times in lung tissue (Baetjer et al.,
1959a). The characteristics and potential biological effects of these insoluble
Complexes which are only slowly released from lung tissue are unknown.
Wada et al. (1983) exposed male SD strain rats to CrCl at an atmospheric
concentration of 14.1 mg/m (Cr), and observed that the chromium was associated
with both high and low molecular weight proteins. The chromium which remained in
the lungs was associated with the high molecular weight fraction and this frac-
tion slowly decreased with time following exposure. The level of chromium
associated with the low molecular weight fraction remained constant for the 5
observation days following treatment; however, chromium associated with this
fraction accumulated with time in the liver. The authors suggested that the low
molecular weight protein was involved in the absorption and transport of chromium
following inhalation.
Visek et al. (1953) also studied the fate of 5 CrCl_ following intra-
tracheal instillation. Seven days post-exposure, 55% of the chromium was
excreted in the feces and 1% in the urine. These data agree with Baetjer
et al. (1959a), in that a large portion of the administered dose appears to have
been cleared to the gastrointestinal tract. Tissue concentrations in this study
indicated that =5$ of the administered dose was absorbed from the lungs.
No data are available which could be used to accurately estimate total
pulmonary absorption following inhalation exposure. The contribution of gastro-
intestinal absorption to body burden following inhalation or intratracheal expo-
sure is not clear. The assumption has been made that gastrointestinal absorption
is so poor that its contribution would be negligible. However, with one estimate
of pulmonary absorption at only 5% (Visek et al., 1953), gastrointestinal
absorption could play a significant role (Section 5.1.2). Although available
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data do indicate a significant effect of valence state on absorption, too few
examples have been studied to allow a thorough understanding of the process.
5.1.2. Gastrointestinal Absorption of Chromium. Gastrointestinal absorption of
chromium also appears to be dependent on valence state. Donaldson and Barreras
(1966) have examined absorption of 51CrCl3(III) and Na251CrOl|(VI) in rats and in
human patients. In conjunction with this study, they conducted a series of
in vitro evaluations to clarify factors affecting absorption.
Based on fecal excretion, mean absorption of orally administered Cr
compounds in human patients appeared to be -Q.H% for CrCl- and =10.6? for
NapCrOj,. Approximately 0.5 and 2.1$ of the doses of CrCl^, respectively, were
excreted in the urine after 2H hours. When CrCl- was administered intra-
duodenally, absorption of CrCl was not appreciably increased; however, intra-
duodenal administration of NaCrOj. resulted in an estimated 50% absorption.
In rats, *2% of the intragastric dose of both CrCl and Na-CrOj. appeared to
be absorbed based on fecal excretion (i.e., it was assumed that any radioactivity
not recovered in the feces represented the absorbed portion of the dose, although
it should be noted that the percision of these estimates may be questioned).
Jejunal administration increased apparent CrCl_ absorption to 8$, while NapCrOj.
was increased to =25$. Similar low levels of absorption of less than 1$ were
estimated by determining whole body counts 2 days after administration of radio-
labeled CrCl_ or NagCrOjj (Sayoto et al., 1980).
IH vitro studies by Donaldson and Barreras (1966) showed that CrCl., (Ill)
was bound by both neutralized and acid gastric juice, while Ha-CrO^ (VI) was
bound by acid gastric juice alone. Binding effectively prevented uptake by
intestinal rings. Acid gastric juice, in addition to binding Na^rO^ (VI), also
was capable of reducing Cr(VI) compound to Cr(III).
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-------
These absorption values must be considered rough estimates. Short-term
urinary excretion values cannot take into account either deposition of chromium
into body sinks or the potential contribution of intestinal excretion. Absorp-
tion estimates by difference from fecal excretion also cannot take into account
the potential role of enterohepatic cycling.
Mackenzie et al. (1958) administered either KgCrO^ (VI) or CrCl, (Ill) in
the drinking water of rats at a concentration of 25 mg/A. After 1 year of
exposure, animals receiving the hexavalent compound had average tissue levels
that were 9 times higher than those receiving the trivalent salt. This was
interpreted to indicate much greater gastrointestinal absorption of the hexava-
lent salt. The possible role of differences in elimination kinetics was not
addressed.
Mertz et al. (1965) administered a single dose of 0.15, 1.0, or 10 \ig
CrCl~/g body weight by stomach tube to rats. By comparing whole body radio-
activity 4 to 10 days after an intragastric dose with that following an intra-
venous dose, they suggest 2 to 3% as a rough estimate of gastrointestinal
absorption. Absorption was found to be independent of dose level or dietary
chromium history (deficient versus supplemented).
Visek et al. (1953) gave a single dose of CrCl (III) by gavage to rats.
Tissue distribution indicated <0,5% absorption after 4 days. Urinary excretion
suggested higher absorption estimates, but fecal contamination of the samples
was suspected.
MacKenzie et al. (1959) administered Na?CrOj, (VI) as a single dose by
stomach tube. Urinary excretion of 6$ of the dose after 14 days in fasted rats
and 3$ in non- fasted rats was observed and used as an estimate of absorption.
Blood chromium concentrations when rats were given Na^rO^ were 2-fold higher
51
than for animals given CrCl_. This is not surprising, since Cr(III) is cleared
5-8
-------
from the serum much more rapidly than Cr(VI) disappears from the erythrocytes.
Urinary excretion data for Cr(III) compound were not reported.
Additional evidence for the poor absorption of CrCl_ (III) was presented by
Mertz et al. (1965). They found that a 100-fold greater oral dose was required
to alter glucose tolerance in rats than the intravenous effective dose.
Ogawa (1976) examined differences in absorption and metabolism via several
routes of exposure using CrCl (III) and Na?CrO (VI) administered to rats. They
found gastrointestinal absorption to be 2.4 and 1.4$, respectively, for the two
salts. When animals were fasted for 48 hours, absorption of both salts was
increased to 11$.
Although precise quantitation of absorption efficiency is impossible, a
reasonable estimate from the available literature discussed above is that both
valence states are absorbed at efficiences of <5%.
5.1.3. Chromium Absorption Through the Skin. Percutaneous absorption of
chromium appears to be related to valence state, the particular salt employed,
and the concentration applied.
Mali (1963) conducted a series of in vitro and in vivo studies to determine
penetration of potassium dichromate(VI) and chromic sulfate(III) through the
skin (the source of skin was not mentioned). They found that neither compound
diffused spontaneously through intact, isolated epidermal membranes. The
diffusion constant for diffusion of the Cr(VI) compounds through dermis
C *)
(314 x 10~ cm /min) indicated unimpeded absorption; however, the diffusion
C 2
constant for the trivalent compound was 26.6 x 10 cm /min.
Significant amounts (30$) of Cr(III) were bound to dermal proteins in vitro,
while only very small amounts (1$) of Cr(VI) were bound (Mali, 1963). These
results were confirmed in human volunteers. It was found that in vivo potassium
5-9
-------
dichromate but not chromic sulfate penetrated intact epidermis. In addition,
reduction of Cr(VI) to Cr(III) in the skin tissue was demonstrated. The rate of
this reduction was pH dependent.
Samitz and Katz (1963, 196*0 presented additional data which indicate that
Cr(III) binds to skin in vitro, and that binding following exposure to Cr(VI)
salts is dependent upon reduction to Cr(III).
Samitz and Gross (1961) presented preliminary evidence that there is no
difference in absorption of potassium dichromate(VI) as compared to chromium
nitrate(III) in vivo in guinea pigs. Samitz and Shrager (1966) reported addi-
tional evidence that permeability of the skin to Cr(III) is dependent upon which
salt is employed. Their data indicate that absorption of chromic sulfate is
negligible, absorption of chromium nitrate is somewhat greater than chromic
sulfate absorption, and absorption of chromic chloride is as great as potassium
dichromate.
Wahlberg (1965) reported that absorption of a given salt is dependent upon
the concentration applied. In this study, application of 0.017 M to 0.239 M
solutions of Cr(III) resulted in percentages of absorption which were not statis-
tically different from absorption experiments under the same conditions for
Cr(VI). However, at concentrations from 0.261 to 0.398 M, significantly more of
the Cr(VI) compound was absorbed. Absolute absorption rates for chromic chloride
were maximal with application of 0.239 to 0.261 M solutions, reaching levels of
2
315 to 330 n moles Cr/hour/cm . In contrast, absorption rates of sodium dichro-
2
mate reached a maximum of 690 to ?25n moles Cr/hour/cm at a concentration of
0.261 to 0.398 M.
In conclusion, percutaneous absorption of chromium is dependent not only on
valence state, but is also affected by the anion, as well as the concentration
and pH of the applied solution.
5-10
-------
5.2. CHROMIUM TRANSPORT, METABOLISM, DISTRIBUTION, AND ELIMINATION
5.2.1. Transport and Metabolism. The mechanism of chromium transport is depen-
dent upon the valence state after reaching the bloodstream. Cr(VI) readily
crosses erythrocyte membranes. Kitagawa et al. (1982) demonstrated in vitro the
inhibition of Cr(VI) penetration into erythrocytes by U-acetamido-4'-isothio-
cyano-stilbene-2,2'-disulfonic acid, an inhibitor of anion transport. After
entry, the Cr(VI) undergoes reduction to Cr(III) and this reduction has been
investigated in other cell systems. In studies with cultured hamster fibro-
blasts, Levis et al. (1978) have shown that only Cr(III) could be identified
intracellularly following treatment with potassium dichromate. The mechanism
for intracellular reduction is not completely understood. Several investigators
have proposed a role for the mixed function oxidases. These proposals are based
upon the reduction of mutagenic activity following addition of microsomal
preparations to Cr(VI) (Gruber and Jennette, 1978; Lofroth, 1978; Petrilli and
DeFlora, 1978a). While rat liver preparations are very effective in reducing
mutagenic activity, lung preparations show only minimal activity (Petrilli and
DeFlora, 1978b). Addition of reduced cofactors, such as GSH, NADH, or NADPH,
also resulted in reduced activity. LSngard (1979) presented evidence that
although reduction of Cr(VI) may take place at any intracellular site where
electron donors are available (which includes the microsomes), the primary site
of reduction is within the mitochondria. In relation to chromium binding to
hemoglobin, Kitagawa et al. (1982) reported that the reduced cofactor GSH was
necessary for the in vitro binding of Cr(VI) to purified hemoglobin, suggesting
that either the chromium or the hemoglobin has been reduced for binding to occur.
Evidence that the reduction of Cr(VI) to Cr(III) may be of biological importance
was provided by Aaseth et al. (1982). Cr(VI) was shown to bind to erythrocytes
5-11
-------
under in vitro incubation conditions. When GSH was added to the incubation
media, the binding of chromium to the erythrocytes decreased as a result of the
reduction of Cr(VI) to Cr(III) and the inability of Cr(III) to penetrate the cell
membrane. Reduction of chromium binding was also observed when intracellular GSH
was decreased by the action of diethylmaleate. In this case, it was proposed
that the lower binding resulted from the failure to reduce Cr(VI) to Cr(IIl) in
the cytosol. Jennette (1982) demonstrated that a Cr(V) intermediate was formed
during the iri vitro reduction of Cr(VI) to Cr(III) by rat liver microsomes and
that this intermediate may be the chemically reactive form of chromium.
Localization In vivo of Cr(III) within the body cells of the rat appears to
be time dependent, with initial high concentrations within the cytosol and
subsequent translocation to mitochondrial and nuclear fractions (LSngard, 1979).
In addition, the partitioning of intracellular chromium appears to be dose
related. Tandon et al. (1979) found that chromium nitrate(III) doses of 1, 2 or
3 mg/kg administered intraperitoneally resulted in an increased percentage in
the mitochondrial fraction with increasing dose. Early hypotheses assumed
intracellular binding of Cr(III) to proteins; however, in vitro data developed by
Sanderson (1976) indicated that intracellular chromic ion exists in the form of
coordination complexes with small organic anions.
Transport of Cr(III) is facilitated by specific binding with siderophilin
(Hopkins and Schwartz, 196U). Following very large doses, binding with other
serum proteins occurs. Red blood cells appear to be essentially impermeable to
Cr(III). Impermeability of all cell membranes to Cr(III) compounds has been
traditionally accepted; however, Levis et al. (1978) have shown uptake of CrCl_
by cultured hamster fibroblasts. In addition, Tandon et al. (1979) have shown
significant intracellular levels of chromium following in vivo exposure to
Cr(III) nitrate.
5-12
-------
A number of investigators have demonstrated that in pregnant rodents
exposed to inorganic chromium only a very small fraction of the administered dose
is transported to the fetus in utero. Visek et al. (1953) gave Cr, as a single
dose, in the form of sodium chromate(VI) or chromium chloride(III) intravenously
to rats on days 15 to 20 of gestation. Fifty (iCi per dose was administered, and
specific activity ranged from 200 to 1250 |iCi/mg. Litters were examined 2*1 hours
post-injection. Regardless of chemical form or time of administration, recovery
of ^1Cr per total litter never exceeded 0.13$ of the administered dose.
Mertz et al. (1969) administered 5 Cr as chromium acetate(III) to rats.
Single doses were given either intravenously or by gavage at mating. Repeated
doses were given either by daily intubation during gestation or by administration
in the drinking water, at a concentration of 2 mg/8,. Five (iCi were given intra-
venously and either 5 or 250 |iCi by gavage. Specific activity ranged from 30 to
100 (iCi/iig. Pups were sacrificed no later than 3 hours following birth.
No Cr was detected in the young at birth following a single dose by either
route to the dam at mating. Repeated dosing by gavage during gestation resulted
in labeling of the litters at birth with from 0.5 to 1.5% of the mothers' total
body activity. Exposure of dams via the drinking water did not result in
51
transfer of Cr to the litters.
Matsumoto et al. (1976) examined placental transfer following subcutaneous
administration of CrCl-(III) to ICR mice. Six control mice were injected with
saline, 11 mice were injected with CrCl- (as Cr) at a dose of 9-76 mg/kg, and
6 mice were injected with 19.52 mg/kg. Mice were injected 9 times every other
day from the first to the sixteenth day of gestation.
Although there appeared to be a trend of increasing chromium in the pups
with dose, levels were not significantly different from controls for either dose
5-13
-------
group. The high dose dams did exhibit placental chromium concentrations that
were significantly elevated above controls.
51
In contrast to these studies, when Cr was administered to rats in the form
of glucose tolerance factor (a low molecular weight organic complex isolated from
yeast) by stomach tube during gestation, from 20 to 50% of the dam's radio-
activity was detected in the litters (Mertz et al., 1969). This is consistent
with the role of chromium as an essential trace element.
In conclusion, there are limited data that indicate transfer of small
amounts of chromium from mother to offspring when chromium is administered as a
salt during gestation. This appears to be true for both Cr(III) and Cr(VI)
salts. These data lend support to a hypothesis for chromium teratology which
relies on a mechanism other than direct interaction between chromium and the
fetus.
5.2.2. Distribution. Once absorbed, Cr(III) compounds are cleared rapidly
from the blood and more slowly from the tissues. This also indicates that blood-
chromium levels are inadequate indicators of body burden. Clearance of Cr(VI)
from the blood is slower, presumably due to uptake by erythrocytes followed by
reduction to the relatively impermeable Cr(III).
Hopkins (1965) injected 0.1 pig Cr (as chromium chloride )/100 g intra-
venously. The blood chromium content as a percent of the 15 minute blood concen-
tration at various time intervals was: 30 minutes, 94$; 1 hour, 87%; 2 hours,
69%; 4 hours, 66%; 8 hours, 47*; 24 hours, 17*; 48 hours, 9%; 96 hours, 5%.
Withey (1983) replotted this on semi-log paper and resolved the curve into
initial, intermediate, and terminal phases with respective half-lives of 0.56,
5.53 and 57 hours (Figure 5-1).
5-14
-------
I
8
<
Q.
o
z
iu
CC
»-
Z
uu
o
CC
UJ
CL
t % = 5.53 HOURS
= 57 HOURS
t % = 0 .56 \
HOURS \
I
20
I
40
I
60
I
80
1
100
HOURS AFTER INJECTION
Figure 5-1. Rate of blood clearance of intravenously injected Cr (III)
from male rats. Data from Hopkins (1965) as replotted by
Whitney (1983).
5-15
-------
Visek et al. (1953) compared clearance and distribution following intra-
venous injection of several chromium salts in rats. Four days following injec-
tion, NaCrO^ (III) blood levels were <0.02$ of the administered dose per gram of
blood and CrCl- (III) levels were 0.05$ of the administered dose per gram of
blood. In contrast, Na^rO^VI) levels 4 days post-injection represented 0.5255
of the administered dose per gram of blood. Nearly complete blood clearance for
this salt was not achieved until H2 days post-injection compared with only 7 days
for the trivalent salt.
Baetjer et al. (1959a) administered Na^rO^ (VI), K2Cr207 (VI), or CrCl3
(III) intravenously to guinea pigs. For the Cr(VI) salts, values of \ig Cr/10 gm
dry tissue/200 |ig Cr injected for erythrocytes 1 and 3 days post-injection were
28 and 31, respectively, and for plasma, 4 and 2, respectively. For the Cr(III)
salt, erythrocyte values at the 1 and 3 day time points were 1 and <1, respec-
tively, and plasma values were 5 and 3» respectively.
Visek et al. (1953) have reported organ distribution of several chromium
salts following intravenous injection in rats. Sodium chromite (NaCrCO (VI) was
concentrated in large quantities by the reticuloendothelial system, which in
combination with the liver accumulated 90$ of the dose. At 42 days post-
exposure, organs with detectable levels were: spleen > liver > bone marrow >
tibia epiphysis > lung > kidney. The liver and spleen contained 33 and 50$ of
their U day values, while the lung contained 10$. The extensive accumulation of
chromite in the reticuloendothelial system is postulated to be the result of the
formation of colloids by chromite at physiological pH.
Chromic chloride concentrated in the liver, spleen and bone marrow; once
deposited, it cleared very slowly. At 4 days post-exposure, CrCl exposed
animals had lower percentages of the total dose in their livers, spleens, and
bone marrow than those exposed to NaCrOp. More CrCl- than NaCrO? accumulated in
5-16
-------
the kidney, however. All organs gradually cleared chromite over the period of
the study. In contrast, the liver in CrCl--exposed rats was the only organ to
clear significant amounts of chromium over the study period (45 days).
Cr(VI) was picked up to a much smaller extent than either of the Cr(III)
salts. At the 42-day time point, <1? of the dose was found in the liver. For
comparison with the trivalent salts, 4-day tissue concentrations in animals
given sodium chromate were (% dose/g tissue): liver, 0.52%; spleen, 0.91?; bone
marrow, 0.56?; tibia epiphysis, 0.38$. At 42 days, corresponding values were:
liver, 0.07?; spleen, 4.8?; bone marrow, 0.16?; tibia epiphysis, <0.02?. The
increase in spleen concentration was attributed to erythrocyte destruction.
Hopkins (1965) examined the kinetics of distribution with trace quantities
of chromic chloride in the rat. Measured concentrations at 15 minutes post-
injection were highest in lung and kidney, followed by heart, pancreas, liver,
bone marrow, spleen, testis, and brain. The heart, lung, pancreas, liver, and
brain showed maximal levels at this 15-minute time point, and subsequently
declined. The spleen reached a maximum level 96 hours post-exposure and the
testis 4 hours post-exposure (300 times the initial level), while the kidney
concentration remained unchanged over 96 hours.
Following intratracheal administration of chromate to rats, highest concen-
trations were found in the lung, followed by liver, kidney, and spleen (Baetjer
et al., 1959a). In contrast to the injection studies, significant concentra-
tions were not found in bone.
Following a single oral dose of chromate administered by gavage, highest
concentrations were found in the liver, followed by the kidney and the spleen
(MacKenzie et al., 1959). When chromate was administered in the drinking water
for 1 year, highest concentrations were found in the spleen, followed by the
5-17
-------
kidney, liver, and bone. Year long administration of chromic chloride resulted
in the same type of distribution pattern with lower absolute quantities.
Generalizations regarding behavior of the two valence states are difficult
to make, since almost all testing has involved chromic chloride(III) and sodium
chromate(VI) or potassium dichromate(VI). The data of Visek et al. (1953)
showed differences in uptake and distribution between chromic chloride and
chromite; the behavior of other Cr(III) salts is difficult to anticipate. Data
from chromium chloride(III) do indicate that once absorbed, this salt is quickly
cleared from the bloodstream and has a long tissue residence time. Cr(VI) salts
have longer residence times in the blood and are more rapidly cleared from the
tissues. Comparisons of tissue distributions are difficult, because different
authors choose different organs to examine and time between exposure and analysis
varied considerably. In almost all instances, the following organs accumulated
significant amounts of chromium: liver, kidney, spleen, and bone marrow. In
addition, there are some data which indicate that the testis, heart, lung, and
brain accumulate considerable amounts. Tissue distribution does not appear to be
affected by the sex of the animal or by dietary history in terms of chromium
content.
In humans, Teraoka (1981) studied the distribution of 24 elements in 12
Japanese males. The samples obtained at autopsy were from seven workers exposed
to heavy metals and five subjects with no undue exposure. Although absolute
concentrations of chromium varied extensively between individuals, the greatest
concentrations of chromium were found in the Hilar lymph nodes and lungs followed
by spleen, liver, kidney, and heart which all contained approximately the same
level for each individual. The distribution patterns were similar for the seven
men occupationally exposed to metals and the unexposed control group. The
average level of chromium in the Hilar lymph nodes of unexposed men was 8.2 ppm
5-18
-------
as compared with 2400 ppm for the two chromium plating workers and 152 ppm for
the three chromate refinery workers. An airplane painter and stone mason who had
possible exposure to chromium had levels of 33 and 4.2 ppm, respectively. The
order of organ distribution appeared to be similar regardless of whether the
exposure to chromium was from occupational (high levels) or environmental (low
levels) sources.
Similarly, the highest levels of chromium were detected at autopsy in the
lungs of a worker who died of respiratory cancer 10 years after retiring from a
chromate manufacturing plant (Hyodo et al., 1980). The chromium levels in
different portions of the lungs of this worker varied from 616 to 7100 ng Cr/g
wet weight as compared to values of 19.3 to 881 ng Cr/g wet weight of similar
lung sections from five control subjects. The suprarenal gland, brain, and skin
also had relatively high levels of chromium as compared to the control values.
It was reported that Cr(VI) was more prevalent in the chromate worker; however,
the wet oxidation method, using hot nitric acid and perchloric acid, has the
potential of oxidizing Cr(III) to Cr(VI) and makes these results invalid.
5.2.3. Elimination. Hopkins (1965) examined the kinetics of single doses of 0.1
or 0.01 \ig Cr administered intravenously as CrCr_. Urinary excretion was
followed over 4 days, and an inspection of a semi-log plot of these data
indicated at least two elimination components, the first representing rapid
blood clearance of chromium and the second the slower elimination from soft
tissues. Hopkins data also indicate that, although the urine is the primary
route of excretion, the intestines also play a small role.
Mertz et al. (1965) followed the elimination of single doses of intra-
venously administered chromic chloride over a longer time period (72 days).
Whole body retention of chromium as a funtion of time was represented by a
5-19
-------
polynomial with three distinct regression terms (Figure 5-2). This evidence
supports a three compartment elimination process. The half-lives for chromium in
the three compartments were estimated from clearance rates to be 0.5 days,
5.9 days, and 83.4 days. At the end of 72 days, 13.5% of the original dose was
retained.
Onkelinx (1977) also followed elimination of an intravenous dose of chromic
chloride. Their data agree with Mertz et al. (1965), in that the plasma
disappearance curve could be described by the sum of three exponential compo-
nents, representing three compartments. Excretion has been quantified and 3
components have been identified. Urinary excretion represented 51 to 64$ of the
total excretion, fecal excretion 5 to 8%, and clearance of chromium into a body
"sink" 31 to 41$. The sink represents compartments with extremely long half-
lives .
In a comparison of Cr(VI) and Cr(III) elimination in rats, Sayoto et al.
(1980) administered radiolabeled Na2CrO|j or CrCl- to animals either by intuba-
tion or intravenous injection. Regardless of the route of administration, the
Cr(VI) compound was excreted more rapidly through the feces and urine. The
biologic half life for Na CrOj, and CrCl- after intubation was 22.24 and 91.79
days, respectively. The authors suggested that these findings indicated that
Cr(III) has a higher affinity for body constituents than Cr(VI).
Yamaguchi et al. (1983) studied the excretion of a Cr(III) and Cr(VI)
following subcutaneous administration to rats of Cr(NO )_ and KpCr^O™. Within 24
hours after treatment 93.6$ of the Cr(VI) was removed from the site of injection
while only 21.3$ of the Cr(III) was adsorbed. In 7 days, 48 and 8.0$ of the
Cr(VI) and Cr(III), respectively, were eliminated in the urine. The biologic
half-time of Cr(VI) in different organs was determined, with half-times for the
terminal component for lungs, liver, kidney, brain, heart, testes and blood
calculated to be 20.9, 15.7, 10.5, 9.6, 13.9, 12.9 and 13.9 days, respectively.
5-20
-------
100
20
ui
U
cc
UJ
0.
10
1 \
K-
j
t % = 5.9 DAYS
V t% = 0.5
1 1
10 20
~^-^_
DAYS
I I
30 40
t % = 83. 4 DAYS
"""»"*»•-. ^^__
!P^— ^
I I I
50 60 70
~-—-
I
80
DAYS AFTER INJECTION
Figure 5-2*1 Whole-body elimination of intravenously administered
^ Cr (III) in male rats (Mertz et al., 1965).
5-21
-------
Collins et al. (1961) examined chromium excretion in dogs dosed intra-
venously with chromium chloride or sodium dichromate. Acute exposures (dose not
stated) showed that 25% of the Cr(III) salt and 9$ of the Cr(VI) salt were
excreted in the urine within 4 hours. Less than 0.5% appeared in the bile.
In bile fistulated dogs, 1-day excretion values were 50% in the urine, 0.5%
in the bile, and 3.7% in the feces for the Cr(III) salt, and 20, 0.9, and 1.2$ of
the dose in urine, bile, and feces, respectively, for the Cr(VI) salt. Excreted
chromium was readily dialyzable indicating that, if the chromium was bound, the
molecule it was combined with was of small size or the binding was reversible.
Tubular reabsorption appeared to represent >63/& of the amount filtered.
Davidson et al. (197*0 examined kidney handling of chromium in normal human
subjects and in dogs (not pre-treated with chromium). Their results indicate
that in both dogs and man physiological quantities of chromium have a >99/6
reabsorption value. Their data also suggest that there is an active transport
mechanism in the renal tubule for chromium reabsorption. They hypothesize that
the normal filtered load for chromium may be close to the maximal reabsorption
rate. If this is the case, then any increase in plasma chromium concentration
would result in a significant increase in renal excretion of chromium.
5.3. SUMMARY
There are only limited experimental data available on the pharmacokinetics
of chromium. Absorption by inhalation exposure appears to occur rapidly,
although it is difficult to quantify the extent of absorption. A preliminary
estimate of pulmonary absorption, following disposition of CrCl into the lungs
by instillation, indicates that approximately 5% is absorbed. Following oral
exposure, gastrointestinal absorption was also low with estimates that only 5% or
5-22
-------
less of chromium was absorbed. In vitro studies indicate that gastrointestinal
juices have the capability to reduce Cr(VI) to Cr(III); however, there are
insufficient data from in vivo studies to demonstrate whether this reduction
process has the capacity to eliminate any differences in absorption between
ingested Cr(VI) and Cr(III) compounds. Percutaneous absorption of chromium
through unbroken skin is variable and dependent on valence as well as the
specific salt.
After absorption, chromium is transported by the blood with Cr(III) trans-
port facilitated by specific binding proteins in the blood. Cr(VI) on entering
the blood stream diffuses into the blood cells where reduction and binding to
cellular components occurs. Both absorbed Cr(III) and (VI) can be transported to
a limited extent to the fetus in utero after exposures of the dams, although the
data do not allow quantitative estimates of fetal exposure. Chromium transported
by the blood is distributed to other organs with greatest retention by the
spleen, liver, and bone marrow. The major deposition site following inhalation
exposure is the lungs, where chromium probably binds to the cellular material
before absorption can occur.
Absorbed chromium is eliminated from the body in a rapid phase representing
clearance from the blood and in a slower phase representing clearance from
tissues. Urinary excretion is the primary route of elimination accounting for
somewhat over 50$ of the eliminated chromium, while fecal excretion accounts for
only 5% of the elimination from the blood. The remaining chromium is deposited
into deep body compartments, such as bone and soft tissue. Elimination from
these tissues proceeds very slowly. Estimated half-lives for whole body chromium
elimination are 22 and 92 days for Cr(VI) and Cr(III), respectively.
5-23
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6. CHROMIUM AS AN ESSENTIAL ELEMENT
6.1. CHROMIUM DEFIENCY
The nutritional need for chromium as an essential element has been reviewed
by Golden and Golden (1981), Anderson (1981), Saner (1980) and Mertz (1974).
Mertz (197^) described the necessary components for considering an element as
essential. These components are: the element must be found in living matter, the
element must interact with living biological systems, and deficiency of the
element must produce a decrement in biological function. Indeed, chromium is
found in living matter, it does interact with living systems, and deficiency
syndromes are remedied with its supplementation.
The National Academy of Science (NAS, 1980) has summarized daily intakes of
chromium by persons in the United States as: dietary, a range of 37 to
130 ng/day with an average of 62 jig/day; air, a range of <0.5 to <4.0 of the
dietary intake; and drinking water, a range of 0 to 224 ug/day with an average of
17 jig/day. Mertz (1974) provided similar estimates that daily intake of chromium
in healthy humans was between 5 and 100 jig/day and that this intake resulted in
blood and urine levels of chromium of 0.5 to 5 and 5 to 10 ng/£, respectively.
Infants receive chromium through breast milk during nursing (Kumpulainen et al.,
(1980). These levels of chromium intake must be adequate since no serious
effects from chromium deficiency have been observed in the general populace. The
Estimated Adequate and Safe Intake (EASI) values for chromium, provided by the
National Academy of Science (NAS, 1980), are listed in Table 6-1. The lower EASI
values are based on the average United States daily intake from a mixed diet. No
Recommended Daily Allowance (RDA) has been issued.
6-1
-------
TABLE 6-1
Estimated Adequate and Safe Intake (EASI) for Chromium*
Age (years) EASI (mg/day)
Infants
Children
0
0
1
H
1
>
.0
.5
to
to
to
11
to 0.5
to 1.0
3
6
10
0
0
0
0
0
0
.01
.02
.02
.03
.05
.05
to
to
to
to
to
to
0
0
0
0
0
0
.04
.06
.08
.12
.20
.20
Adults 0.05 to 0.20
•Source: NAS, 1980
6-2
-------
Animal studies have been conducted to determine the effects of ingestion of
dietary chromium. Schroeder et al. (1964) maintained 54 male and 54 female mice
for life on drinking water containing 5 ppm of Cr(III). The mice exposed to
chromium had survival rates similar to those of control animals and mean body
weights that were 123/& of control values. In this study the food was devoid of
all trace metals. In an identical study using groups of 50 male and female Long-
Evans rats, Schroeder et al. (1965) observed increased longevity in the treated
animals. In studies of the effects of the absence of chromium in the diet,
Roginski and Mertz (1969) raised rats in plastic cages on low protein diets
containing less than 100 ppb chromium. A second group of rats were given a
chromium supplement of 2 ppm chromium in the drinking water. The chromium
supplemented rats had better weight gain than the chromium deficient animals.
This difference in weight gain was more striking if the animals were allowed free
access to an exercise wheel. When extreme care was taken to also prevent
airborne exposure to chromium of rats maintained on chromium deficient diets,
there was a high incidence of moderate hyperglycemia and glycosuria as compared
to animals on chromium supplemented diets. These studies suggest that small
amounts of dietary chromium were beneficial to the health of these rats. Preston
et al. (1976) maintained female guinea pigs on low protein diets containing
0.125, 0.5, or 50 ppm chromium along with adequate levels of vitamins and some
other trace metals. After 8 to 13 weeks of maintenance on these diets, the
animals were mated and allowed to deliver pups. Although the diets had no effect
on the survival of animals not mated, there was a significant decrease in
survival of mated animals on the low chromium diet (13 of 24 animals died) as
compared to animals on the low chromium supplemented diet (4 of 24 animals died)
and the high chromium supplemented diet (3 of 24 animals died). It was suggested
that the added stress of mating and pregnancy along with chromium deficiency
6-3
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resulted in the high level of mortality. Other parameters examined included
weight gain and glucose loading; serum cholesterol levels were not altered by
dietary chromium. It was concluded that chromium was beneficial to survival in
guinea pigs as was previously reported for mice and rats.
6.2. GLUCOSE TOLERANCE FACTOR
Chromium deficiency in the diet results in glucose intolerance in both the
experimental animals and humans (Saner, 1980). Schwarz and Mertz (1959) have
identified a glucose tolerance factor (GTF) which was required in rats to main-
tain normal rates of glucose removal from the blood stream. This factor has been
obtained from natural sources including brewer's yeast and hydrolyzed pork
kidney. In further studies, Mertz and Schwarz (1959) demonstrated that rats
maintained on some commercial diets had normal glucose removal rates, while
maintenance on other diets resulted in poor removal of glucose from the blood.
When the second diets were supplemented with GTF, glucose removal rates returned
to normal values. Mertz and Schwarz (1959) have identified Cr(III) as the active
agent in the GTF. It was further demonstrated that administration of a variety
of Cr(III) compounds to glucose intolerant rats resulted in an increase in the
rate of removal of glucose from the blood. In this assay, the less stable
Cr(III) compounds were most effective, and some Cr(VI) compounds were totally
without activity.
The effects of chromium on glucose metabolism were suggested to result from
chromium being a co-factor for insulin. Mertz et al. (1965) measured insulin
stimulated CO production in adipose tissue from chromium deficient rats
receiving supplements of 0.0, 0.01, 0.05, or 0.1 [ig Cr/100 g body weight. The
adipose tissue of rats receiving 0.05 ng Cr/100 g produced significantly more
6-4
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COp than tissues obtained from other groups. Farkas and Roberson (1965) per-
formed similar studies with measurements of glucose utilization in rat lenses
taken from animals on chromium deficient and supplemented diets. The chromium
treatment alone did not affect glucose utilization; however, chromium treatment
in conjunction with insulin significantly increased the utilization of glucose.
Administration of 2 ppm of chromium in the drinking water of rats also facili-
tated the insulin transport of amino acids into the heart and the incorporation
of amino acids into protein. Providing chromium supplements to rats increased
the animals' sensitivity to many of the effects of insulin.
Saner (1980) states that certain groups of persons may be prone to chromium
deficiency; these groups include the elderly, diabetics, pregnant women,
malnourished children, offspring and siblings of diabetics, persons with early
coronary heart disease and their offspring. Jeejeebhoy et al. (1977) have
described a female patient placed on total parenteral nutrition for 3 1/2 years
in whom chromium deficiency was indicated. Blood chromium levels were reported
as 0.55 ng/m£, and hair chromium levels as 154 to 175 ng/gm. In addition to
glucose intolerance, weight loss, neuropathy, elevated fatty acid levels,
reduced respiratory quotient, and abnormal nitrogen metabolism were reported.
Daily administration of 250 (ig chromium chloride for 2 weeks in the parenteral
infusate, followed by 20 jig/day maintenance, resulted in a reversal of symptoms.
Freund et al. (1979) report similar finding of chromium deficiency in a patient
receiving total parenteral nutrition. Supplementation of the infusate with 150
|ig chromium/day resulted in the reversal of the adverse clinical findings of
impaired glucose tolerance, weight loss, and confusion.
Chromium has been known to affect glucose tolerance in humans. Levin et al.
(1968) performed oral glucose tolerance tests on 9 male and 6 female elderly
subjects. Of the subjects tested, 10 daily dietary supplements with 150 fig/day
6-5
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chromium for 3 to 4 months resulted in normal glucose tolerance in four subjects.
The remaining six subjects still had abnormal tests after receiving the chromium
supplement. Glinsmann and Mertz (1966) observed improved glucose tolerance in
three of six diabetics given 150 to 1000 |ig of Cr(III) for 15 to 120 days. In a
similar study, Sherman et al. (1968) observed no change in the glucose tolerance
of ten diabetics who received chromium supplements of 100 |ig/day for 16 weeks.
In malnourished infants, Gurson and Saner (1971) and Hopkins et al. (1968)
observed dramatic increases in glucose removal and utilization following treat-
ment with Cr(III). To ensure that the improved glucose tolerance was the result
of chromium therapy, Hopkins et al. (1968) treated five infants in a manner
similar to the others with the exception that chromium was not administered.
These five infants showed no improvement in glucose tolerance. Dieatary chromium
appears to have some effect on human glucose tolerance; however, the therapeutic
effect of chromium supplementation on subjects with abnormal glucose tolerance
was variable.
6.3. SUMMARY
Animal studies have demonstrated that chromium deficient rodents gain less
weight and have a shorter lifespan than animals maintained on a diet containing
adequate chromium levels. Chromium deficiency results in glucose intolerance in
rats and this intolerance can be reversed by dietary treatment with Cr(Ill).
More effective in reversing glucose intolerance is a chromium complex which has
been isolated from brewer's yeast and designated as glucose tolerance factor
(GTF). GTF may be formed in mammals following ingestion of inorganic chromium.
Some humans with abnormal glucose tolerance, such as the elderly, diabetics, and
malnourished infants have responded to dietary supplements of chromium.
6-6
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Although the exact level of chromium needed for good health is not known, it is
assumed from the lack of observed effects of chromium deficiency that the average
American intake of 0.05 to 0.2 mg/day is adequate.
6-7
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7. CHROMIUM TOXICOLOGY
7.1. ACUTE EFFECTS OF CHROMIUM EXPOSURE IN MAN AND ANIMALS
7.1.1. Hunan Studies. Chromium metal is biologically inert and does not produce
toxic or other harmful effects in man or laboratory animals. When in contact
with the skin, compounds of chromium in the trivalent state combine with proteins
in the superficial layers, but do not cause ulceration (NAS, 1974).
Cr(VI) compounds are responsible for the majority of the health problems
associated with all chromium compounds. They are irritating and corrosive, and
may be absorbed cutaneously, by ingestion, or by inhalation. Acute systemic
poisoning is rare; however, it may follow deliberate or accidental ingestion or
result from absorption through broken skin (NAS, 1974).
Much of the information on the harmful effects of Cr(VI) is obtained from
occupational exposures, where the predominant effects are on the respiratory
system and skin (NAS, 197*0. As with most information derived in this fashion,
ejact knowledge about length of exposure, concentration of the chemical, and
other variables are not known, making it difficult to interpret the results or
assess any quantitative relationships between dose of chemical and its effect.
7.1.2. Animal Studies. Cr(III) compounds have a very low order of toxicity when
administered orally. Oral LD_ values for the rat have been reported as follows:
chromic chloride, 1.87 g/kg; chromium acetate, 11.26 g/kg; chromium nitrate,
3.25 g/kg (Smyth et al., 1969). Kobayashi et al. (1976) have determined oral
LD _ for chromium trioxide in mice and rats to be 135 to 177 mg/kg and 80 to
114 mg/kg, respectively. Animals died over a period of 3 to 35 hours.
7-1
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Symptomatology included diarrhea, cyanosis, tail necrosis, and gastric ulcer.
Surviving animals showed increases in liver and testes weight without micro-
scopic changes.
Cr(VI) is more acutely toxic. A primary effect of acute exposures is kidney
failure. Oral administration of high doses results in gastric corrosion. The
oral LD__ of sodium dichromate in humans has been reported as 50 mg/kg (NIOSH,
1979).
Kidney effects are the primary result of acute exposures to chromium by
various routes. Relevant studies are summarized in the following paragraphs.
Mathur et al. (1977) injected rabbits intraperitoneally with 2 mg/kg
chromium nitrate or potassium chrctnate daily for 3 or 6 weeks. After 3 weeks of
exposure, kidneys from animals dosed with chromium nitrate showed marked conges-
tion, extravasation of red blood cells in the intratubular spaces and tubular
necrosis. Further treatment, up to 6 weeks, did not produce any additional
changes.
The kidneys from animals given potassium dichromate showed marked conges-
tion and the walls of the small blood vessels were thickened. Glcmerular tufts
were shrunken in some places, while proliferation of endothelial cells,
obliterating the Bownan space, was seen in others. There was necrosis and
desquamation of the epithelium of the convoluted tubules. Red blood cells were
found in the intertubular spaces. Changes were similar whether animals were
exposed for 3 or 6 weeks.
Hunter and Roberts (1933) dosed monkeys subcutaneously with 1 to 5 mfc of a
2% solution of potassium dichrcmate. Two monkeys were dosed every 3 weeks; the
first dose was 1 mi, the second dose was 2 mi, the third and fourth doses were
4 mi, and the fifth dose was 5 mi. One monkey died following the final dose. The
7-2
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authors reported injury to the proximal and distal convoluted tubules and the
glcmeruli of the kidneys.
Kirschbaum et al. (1981) injected rats subcutaneously with 20 mg/kg sodium
chronate. Their data demonstrate that epithelial cell injury in the kidney
occurred 2 to 4 hours post-inject ion. They postulate that the interaction of
chromium with specific elements of the microfilamentous system, which are
responsible for directing intracellular flow of reabsorbed solutes, may be the
initial effect of chromium nephropathy. Baines (1965) also reports renal damage
following exposure of rats to acute, subcutaneous doses of potassium dichromate.
Berry et al. (1978) have examined localization of chromium within the kid-
ney. Rats were dosed by intraperitoneal injection with 0.1 mg potassium
dichronate/100 g body weight. Doses were given 5 times per week for 8 months.
Chromium was localized within cells of the proximal renal tubules, specifically
within lysosones. Chromium was retained throughout most of the study period,
being eliminated only when necrosis involved the entire cytoplasm of the tubule
cells.
Evan and Dail (197*0 also report data which indicate effects on the proximal
convoluted tubules following intraperitoneal administration of 10 or 20 mg/kg
sodium chromate and the formation of large lysosomal vacuoles in this region.
They also report effects on mitochondria! configuration shortly following
exposure.
Berndt (1976) reports in vitro data which indicate there may be species
differences in kidney susceptibility to chromium nephropathy. In kidney slices
from rats, effects were independent of valence state. Kidney slices from rabbits
were more sensitive to transport process inhibition by Cr(VI).
Mathur et al. (1977) documented effects in other target organs following
acute exposure to chromium. Rabbits were dosed intraperitoneally with 2 mg/kg
7-3
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chromiun as chromium nitrate or as potassium dichronate. Doses were given daily
and the animals were sacrificed after 3 or 6 weeks. Administration of Cr(III)
for1 3 weeks produced changes in the brain, including occasional neuronal
degeneration in the cerebral cortex, marked chromatolysis, and nuclear changes
in the neurones. Six weeks of exposure resulted in marked neuronal degeneration
in the cerebral cortex accompanied by neuronophagia, neuroglial proliferation,
and meningeal congestion.
Following 3 weeks of exposure to Cr(VI) , congestion with perivascular
infiltration by inflammatory cells was noted. In addition, some neurones in the
cortex showed pyknotic nuclei and dissolution of Nissl's substance. Neuro-
nophagia and focal neuroglial profileration were also evident throughout the
cerebral cortex. Changes following 6 weeks of exposure were similar. The
myocardium of animals exposed to Cr( III) for 3 weeks appeared to be normal.
However, following 6 weeks of exposure, the myocardium showed marked congestion
and degeneration of muscle fibers. Exposure to Cr(VI) for 3 weeks did not
produce any abnormalities. Exposure for 6 weeks produced changes similar to
those seen in animals exposed to the trlvalent salt.
Tandon et al. (1978) report hepatic changes in rabbits exposed to chromiun.
Exposure conditions were the sane as in the previous study. Exposure to Cr(III)
for 3 weeks produced marked congestion and dilation of the central veins and
sinusoids. Discrete foci of necrosis were noted in liver parenchjima. After 6
weeks, in addition to marked congestion, extensive hemorrhage was seen in the
parenchyma. Slight nuclear plecmorphism and mul tinucleated cells were noted in
the lobules. Bile duct proliferation, increased cellularity and proliferation
of fibroblasts around portal tracts were noted.
Exposure to Cr(VI) for 3 weeks produced more extensive pathology than did
Cr(III) exposure. The liver capsule was thickened and there was marked conges
. 7-4
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tion of central veins and adjacent sinusoids. Large areas of necrosis were seen
throughout the parenchyma. Changes seen following 6 weeks of exposure were
similar to those described following 6 weeks of exposure to the trivalent salt.
In summary, a number of organs appear to be targets for acute chromium
toxicity. Kidney effects are the best docunented, because they have received the
most intense study.
7-5
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7.2 CHRONIC EFFECTS OF CHROMIUM EXPOSURE IN MAN AND ANIMALS
7.2.1. Evaluation of the Carcinogenicity of Chromium
The purpose of this section is to provide an evaluation of the likelihood
that chromium is a human carcinogen and, on the assumption that it is a human
carcinogen, to provide a basis for estimating its public health impact
including a potency evaluation in relation to other carcinogens. The
evaluation of carcinogenicity depends heavily on animal bioassays and
epidemiologic evidence. However, information on mutagenicity and metabolism,
particularly in relation to interaction with ONA, as well as the
pharmacokinetic behavior, have an important bearing on both the qualitative
and quantitative assessment of carcinogenicity. The available information on
these subjects is reviewed in other sections of this document. This section
presents an evaluation of the animal bioassays, the human epidemiologic
evidence, the quantitative aspects of assessment, and finally, a summary and
conclusions dealing with all of the relevant aspects of carcinogenicity.
ANIMAL STUDIES
A number of animal studies have been performed to determine whether or not
chromium compounds are carcinogenic. In these studies metallic chromium and
salts of both the hexavalent and trivalent states were administered by various
routes. The discussions that follow are grouped by these various routes of
administration.
Inhalation Studies
Baetjer et al. (1959) exposed three strains of mice (strain A, Swiss, and
C57B1) having high, medium, and low spontaneous lung tumor incidences
respectively, to chromium-containing dust. The dust was similar to that found
in the chromium chemical manufacturing industry, containing 13.7% 003 and
7-6
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6.9% Cr203 along with other metal oxides. In addition to the chromium
compounds in the dust, I^C^Oy was added at a level of 1.0%. The
animals were exposed to the dust-laden atmosphere containing between 0.5 and 1
mg of total chromium 4 hours/day, 5 days/week, for an average of 39.7 weeks
(range of 16 to 58 weeks). Table 7-1 describes the specifics for each
exposure group. At death or termination of exposure, the lungs were examined
using a low power microscope, and abnormal tissues were submitted for
histologic confirmation of tumors.
The incidence of lung tumors was not different in exposed mice of any
strain as compared with approximately equal numbers of the appropriate strains
of unexposed mice of the same age. There was also no difference in those
strains having high spontaneous tumor incidence in regard to the average
number of tumors per mouse or the percent of mice with multiple tumors. The
lung tumors present in both control and treated animals were adenomas, which
appeared histologically to be similar; however, in exposed animals, the
adenomas developed slightly earlier in the strain A mice. Three additional
small groups of mice (two groups of 10 Swiss female mice and one group of nine
female strain A mice) were exposed to high concentrations of chromium dust
(7.8 to 13 mg Cr/m3) in a nose-only chamber 0.5 hours/day, 5 days/week, for
43, 52, and 20 weeks, respectively. Again, no increase in the incidence of
lung tumors was observed.
In a lifetime chronic study, Nettesheim et al. (1971) exposed 136 C57B1/6
mice of each sex 5 hours/day, 5 days/week, to an atmosphere containing
CaCr04 dust at a level of 13 mg/m3, with 95% of the particles less than
0.6 u in size. During the study, seven or eight mice were removed for interim
sacrifice at 6, 12, and 18 months; the sex distribution and exact number of
animals removed at each period were not stated. At autopsy, sections were
7-7
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TABLE 7-1 . INHALATION EXPOSURE OF MICE TO CHROMIUM-CONTAINING DUST
(Baetjer et al. 1959)
Strain
Swiss
Swiss
Swiss
Strain A
Strain A
Strain A
Strain A
C57B1
C57B1
Sex
F
M
F
F
F
F
M
M
F
Number of
Animals at
Start
11
10
127
34
45
110
52
50
61
Number of
Animals at
End
7
6
51
31
45
38
36
13
14
Duration of
Exposure
(weeks)
39
39
58
16
24
38
46
42
41
Estimate
of Total
Cr Inhaled
(mg of Cr)
520
520
692
141
210
359
406
667
589
7-8
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taken from all major organs, and with the exception of the lungs, it was
indicated that no increase in tumor incidence was observed. In the lungs,
tumors developed in six males and eight females, as compared with three males
and two females in the control group. The tumors were described as
alveologenic adenomas and adenocarcinomas, although the number of each type of
tumor was not enumerated. The authors claim in the discussion that CaCr04
exposure resulted in a significant increase in lung tumors; however, the
performance of statistical analysis was not described in the results. In a
review of this study, the International Agency for Research on Cancer (IARC
1980) maintained that no excess in treatment-related tumors was observed.
Because of difficulties in determining the number and sex of the animals
removed during the interim kills, it is impossible to perform independent
statistical analysis of this data.
Two other experimental groups in the aforementioned study were exposed to
CaCrffy dust following prior treatment with 100 R whole-body X-radiation or
infection by influenza virus. A slightly greater incidence of lung tumors was
observed after combined exposure to influenza virus, as compared with exposure
to CaCr04 alone. As a result of exposure to two potential cancer-producing
agents, these last two groups of animals cannot be used to provide any
supporting evidence for the carcinogenicity of chromium. With the limited
experimental detail presented in this study, it is not possible to determine
if the small increase in lung tumors represents a significant treatment-
related increase in tumor incidence.
In the study described previously, Baetjer et al. (1959) also exposed 110
(57 males and 53 females) mixed-strain rats (from Wistar and McCollum stock)
to the same chromium dust to which the mice were exposed; 100 rats (48 males
and 52 females) of similar age distribution were kept as controls. The level
7-9
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of chromium in the air was 1 to 1.5 mg/m^ w-jth exposure again for 4
hours/day, 5 days/week, for > 70 weeks. During the study, nearly half of the
experimental rats died, three developed lymphosarcomas involving the lungs,
while two additional suspected lymphosarcomas involving the lungs were also
identified. No rats developed bronchogenic carcinomas. The authors
considered these findings suggestive of a chromium-induced tumorigenic
response; however, since lymphosarcomas are common in these rats, the
experiment was repeated. In the second study (Steffee and Baetjer 1965),
Wistar rats were exposed to chromium-containing dust using the same regime as
described previously. Following autopsy, three alveologenic adenomas were
detected in the treated rats and two in the controls, and four lymphosarcomas
were present in both groups. From this second study, it was concluded that
lymphosarcomas in rats are not associated with exposure to chromium-containing
dust.
Also, Steffee and Baetjer (1965) exposed eight rabbits and 50 guinea pigs
to mixed chromium dust containing 1.5 to 2.0 mg of total chromium/m^ for 4
to 5 hours/day, 4 days/week, for 50 months and life, respectively. The mixed
chromium dust exposure consisted of 2 days/week exposure to roast dust [as
described previously by Baetjer et al. (1959) supplemented with 1.0% dry
K2Cr2°7 and tne m'ist of a 5-°?° section °f !<2Cr207» followed by a
1 day/week exposure to the mist of a 17.5% solution of ^CrO^, and a 1
day/week exposure to residue dust (roast dust from which Na2Cr04 was
extracted) supplemented with 1.0% dry I^C^Oy. There were no lung
tumors in the rabbits, and the incidence of lung tumors and other body tumors
was similar in the exposed and control guinea pigs. Under these experimental
conditions, inhalation of mixed chromium dust did not increase the incidence
of lung tumors.
7-10
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Laskin (1972) conducted a study in which rats (number and strain not
specified) were exposed by inhalation to air containing 2 mg/m^ calcium
chromate (VI). The total number of exposures were 589 over a period of R91
days. The author reported one squamous cell carinoma of the lung and larynx
and one malignant peritoneal tumor. Because of incomplete reporting of the
experiment, this study is considered to be inadequate to assess the
carcinogenicity of calcium chromate by inhalation.
Intratracheal Instillation Studies
In further attempts to illustrate a lung tumorigenic response from
chromium compounds, mixed chromium dust and chromium salts were instilled into
the tracheas of experimental animals. Baetjer et al. (1959) suspended a
chromium dust, similar in composition to that used in the inhalation studies,
in olive oil and zinc chromate and barium chromate in saline prior to
intratracheal instillation into strain A, Swiss, and C57B1 mice and mixed
breed rats (Wistar and McCollum stocks). The mice each received five to six
instillations of 0.01 to 0.05 mg of chromium at 4- to 6-week intervals, while
the rats received 15 instillation at the same dose at 2-week intervals. The
total duration of the studies was between 32 and 52 weeks. The mice treated
with chromium had a similar tumor incidence as age-matched controls, and the
rats in both the treated and control groups had no benign or malignant tumors.
In continuing work, Steffee and Baetjer (1965) treated 62 strain A mice with
0.01 to 0.03 mg chromium by intratracheal instillation of ZnCr04. The
instillations were performed at 2-week intervals for a total of six
injections, and the animals were observed until death. The incidence of lung
adenomas was 31 of 62 in the treated animals and 7 of 18 in the untreated
controls. In the controls treated with ZnC03, 3 of 12 animals developed
7-11
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lung adenomas. The incidence of lung tumors in treated animals was
statistically different from controls. In the same study, the instillation of
chromium dust, ZnCrO^ and PbCr04 into the tracheas of guinea pigs (13 to
21 animals/group) and rabbits (7 to 10 animals/group) produced no increase in
lung adenomas. Hueper and Payne (1962) also reported similar negative results
after instillation of SrCr04 or CaCrO^ suspended in gelatin; however, the
experimental detail in the report was insufficient for adequate evaluation.
There is no convincing evidence that intratracheal instillation of chromium
compounds results in the development of lung cancer.
Intrabronchial Implantation Studies
Laskin et al. (1970) investigated the carcinogenic effects of chromium
compounds using the intrabronchial pellet technique. The compounds used in
this investigation were: chromic chromate, chromic oxide, chromic trioxide,
calcium chromate, and process residue. Pellets were prepared from molten
mixtures of materials dispersed in equal quantities of cholesterol carrier.
These studies included material of differing solubilities and valences. A
total of 500 rats were under observation for periods up to 136 weeks. Lung
cancers that closely duplicate human pathology were found in these studies
(Table 7-2 ).
With the calcium chromate, eight cancers were found in an exposed group of
100 animals. Six of these were squamous cell carcinomas and the other two
were adenocarcinomas.
The National Institute for Occupational Safety and Health (NIOSH 1975)
criteria document on chromium (VI) described a written communication from L.S.
Levy in 1975 about an animal study done at Chester Beatty Research Institute,
London. Random-bred Parton Wistar rats of both sexes received a pellet in the
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TABLE 7-2 . CARCINOMAS PRODUCED WITH CHROMIUM COMPOUNDS IN RATS
(Laskin et al. 1970)
Material
Process Residue
Calcium Chromate
Chromic Chromate
Chromic Oxide
Chromic Tri oxide
Cholesterol Control
Number of
An i ma 1 s
100
100
100
98
100
24
Squamous Cells Adeno- Heptocellular
Carcinoma carcinoma Carcinoma
1 1
6 2 1
1
2
7-13
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left inferior bronchiolus via tracheotomy under anesthesia. The rats were
kept for 2 years. One hundred rats were set up for each of the
chromium-containing-material test groups. The pellets which were implanted
contained 2 mg of test material suspended 50/50 (w/w) in cholesterol.
Negative control groups received either blank metal pellets or pellets and
vehicle. Positive control groups received 3-methylcholanthrene. Lungs of all
rats either dying during the study or killed at its termination were examined
both macroscopically and microscopically. Apart from those in the lung,
tumors were similar both in type and number in all groups. The bronchial
tumors found and microscopically confirmed are given in Table 7-3 along
with the average induction periods. Additional lung tumors, not of bronchial
origin and not considered by the authors to be causally related to
implantations are also listed in Table 7~3 . The majority of bronchial
tumors were large keratinizing squamous cell carcinomas. Intrathoracic
invasions, particularly to the right lung in the hilar region, were common and
metastases to local lymph nodes and to kidneys were seen.
Squamous cell carcinomas were found in 8/100 ( P < 0.05) rats receiving
calcium chromate, 3/100 rats receiving zinc chromate (zinc potassium
chromate), 3/100 rats receiving chromic chromate dispersed in silica, and
1/100 rats receiving ground chromic acid. It may be that the chromic acid
implantation produced a carcinoma only because it was converted to a
less-soluble chromium (VI) material by reaction with cholesterol. Because of
its extremely great oxidizing ability, some of it may be have been chemically
reduced by cholesterol, forming chromic chromate. Calcium chromate produced
carcinomas in 5/100 (P < 0.05) rats when mixed with primene, and carcinomas in
7/100 (P < 0.05) rats when mixed with diphenylguanadine. Primene 81-R
benzoate and diphenylguanidine failed to produce tumors when administered by
7-14
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TABLE 7-3 . LUNG TUMORS FOUND AND MICROSCOPICALLY CONFIRMED
[Levy and Venitt (1975), NIOSH (1975)]
Experi-
mental Corn-
Group pound
No. No. Test Material
No. Bronchial Induction
Rats Carcinoma Period
in of Left in Days
Group Lung (Range)
Lung Tumors
not Associated
with Treatment
1 1 Ground chro- 100
mite ore
2 2 Bolton high
lime residue "
3 3 Residue after "
alumina pre-
cipitation
4 4 Residue from "
slurry tank-
free of
soluble Cr
5 5 Residue from "
vanadium
filter
6 6 Residue from 101
slurry
disposal tank
Sodium dichro- 100
mate dihydrate
Pulmonary aden-
oma of left lung
Anaplastic car-
cinoma of upper
left lung
Adenoma of right
lung
Fibrosarcoma of
upper left lung
8
9
10
lit
12
8
9
10
11
12
Sodium chromate "
Chromic acid "
(ground)
Chromic oxide "
Calcium chromate "
Chromic chloride "
hexahydrate
ii
1
0
8
0
560
604(473-734) P<0.05
Lymphoma of
right lung
*Zinc potassium cnromate.
tP-value is calculated using the Fisher Exact Test (one-tail).
(continued on the following page)
7-15
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TABLE 7-3 . (continued)
Experl
mental
Group
No.
13
14
21
22t
23
t24
25
26
15
16
28
20
17
18
19
27
Com-
pound
No.
13
14
15A
15B
16A
16B
17A
17B
15
16
28
20
17
18
19
27
No.
Rats
in
Test Material Group
Zinc chromate- "
type II*
Chrome tan "
Diphenyl- "
guanidine (DPG)
DPG + calcium "
Primene 81-R 100
benzoate
Primene + cal- "
cium chromate
Chromic chromate "
Chromic chromate "
dispersed in silica
Pellet + chol- 150
estorol
Blank Pellet
Pellet + chol- 100
estorol +
Kieselguhr
100% 3-MCA 48
100% 3-MCa
50% 3-MCA
25% 3-MCA
50% 3-MCA 50
Bronchial
Carcinoma
of Left
Lung
3
0
H
7
0
5
0
3
0
II
»
34
36
18
13
36
Induction
Period
in Days
(Range)
708(657-734)
656(502-732)
620(440-732)
698(666-730)
493(217-730)
498(270-701)
474(284-696)
517(297-698)
498(269-732)
Lung Tumors
not Associated
with Treatment
P<0.05
P<0.05
Adenoma of
right lung
Adenocarcinoma
of right lung
*ZTnc potassium cnromate.
tP-value is calculated using the Fisher
Exact Test (one-tail),
7-16
-------
themselves. No bronchial carcinomas were found in negative control groups or
in rats receiving sodium dichromate dihydrate or sodium chromate.
Intrapleural Injection Studies
Production of pulmonary tumors by the intrapleural injection of chromium
compounds has also been attempted. Hueper and Payne (Hueper 1955, Hueper
1958, Payne 1960a, Hueper and Payne 1962, Hueper 1961) described a series of
studies in rats treated by intrapleural injection of a number of hexavalent or
trivalent chromium compounds. Powdered metallic chromium was injected into
the pleural cavity of rats, guinea pigs, and mice under the dose schedule
described in Table 7-4 (Hueper 1955). No significant increase in tumor
incidence, either at the injection site or in other organs, was observed.
Payne (1960a) implanted chromite roast, from which the soluble NajjCrC^ was
extracted, into the pleural cavity of 35 rats. Each rat received 25 mg of
this material plus 50 mg of sheep fat, which corresponded to 2 mg of total
chromium, of which 0.4 was hexavalent chromium. None of the 35 control
animals developed tumors, while three of the treated animals developed
implantation site tumors. In an earlier study (Hueper 1958) using chromite
roast not leached of Na2Cr04, none of the 25 treated male Bethesda rats
developed implantation site tumors during 24 months; however, the early death
of nine of the treated animals appreciably decreased the animals at risk. No
implantation site tumors were observed within 24 months in 42 rats by Hueper
and Payne (1962) following eight implantations of 25 mg of trivalent chromium
acetate in gelatin over a 13-month period. Using a single implant of 2 mg of
K2Cr2°7 1nto tne Plural cavity, 1 of 39 rats developed a tumor at the
implantation site. In this study, only CaCr04 elicited a high tumor
incidence following implantation. Of the 14 rats treated with 12.5 mg of
7-17
-------
TABLE 7-4 . EXPOSURE SCHEDULE FOR BIOASSAY OF CHROMIUM COMPOUNDS BY INTRAPLEURAL INJECTION
Species
mice
mice
rats
rats
— rats
CO
rats
rats
rats
rats
guinea pigs
Strain
C57B1
Strain A
Bethesda Black
Bethesda Black
Bethesda Black
Bethesda Black
Bethesda Black
Osborne-Mendel
Osborne-Mendel
NR*
Number of Animals
50
55
25
35
42
39
14
25
25
26
Compound
metallic
chromium powder
mixed chromium dust
chromlte roast
chromlte roast
minus Na2CrO^
chromium acetate
K2Cr207
CaCr04
metallic
chromium powder
chromlte ore
metallic
chromium powder
Compound (mg)
0.001
1 or 2
25
25
25
2
12.5
16.8
36.7
67.2
Number of Injections
6 injections at 2
week intervals
4 Injections at 4
to 6 week Intervals
single Implant
single Implant
1n 50 mg of fat
8 Implantations over
13 months
single Implant
single Implant
6 Injections at
monthly Intervals
6 Injections at
monthly Intervals
6 injections at
monthly Intervals
Reference
Hueper 1955
Baetjer et
al. 1959
Hueper 1958
Payne 1960a
Hueper and
Hueper and
Hueper and
Hueper 1955
Hueper 1955
Hueper 1955
Payne 1962
Payne 1962
Payne 1962
*NR = Not reported.
-------
CaCr04» eight developed tumors at the site of implantation. These studies
suggest that intrapleural implantation of some hexavalent chromium compounds
might be carcinogenic, with CaCr04 producing the most dramatic response.
Hueper (1961) reports further evidence that many hexavalent chromium compounds
produce tumors upon intrapleural implantation, while trivalent compounds are
less effective; however, no experimental detail, including dose, was provided.
A summary of the tumor incidences reported are presented in Table 'J-H" .
Baetjer et al. (1959) also used intrapleural injection to assess the
carcinogenicity of mixed chromium dust, containing both trivalent and
hexavalent chromium, in male (30 animals) and female (25 animals) strain A
mice. The mice received four doses of dust suspended in olive oil, with each
dose containing 0.07 mg of chromium (Table 7-5 ). No increase in tumor
incidence or number of lung tumors per mouse was observed during the period
extending 52 weeks after the first treatment. Davis (1972) injected trivalent
chromite [FeO(CrAl)203l into the pleura! cavity of 25 BALB/c mice and
observed only small granulomas in the lungs. The animals were treated with a
single injection of 5 mg of finely ground ore (
-------
TABLE 7-5 . COMPOUNDS REPORTED TO HAVE BEEN TESTED FOR
CARCINOGENICITY BY INTRAPLEURAL IMPLANTATION*
(Hueper 1961)
Compound
Calcium chromate
Sintered calcium chromate
Strontium chromate
Lead chromate
Barium chromate
Sodium di chromate
Zinc yellow
Chromic chromate
Chromite roast
residue
Chromium acetate
Sheep fat controls
Valence
+6
+6
+6
+6
+6
+6
+6
+6, +3
+6, +3
+3
NA§
Number of Rats
with Tumorst
n
20
17
17
3
1
0*
22
26
5
1
0
Percent
57
49
74
9
3
0
63
74
14
3
0
tThere were 35 rats per group at the start.
§NA = not applicable.
7-20
-------
nor a greater number of tumors per tumor-bearing lung than the 72 control
mice. More recently, Stoner et al. (1976) and Shirnkin et al. (1978) reported
Similar negative results for trivalent 02(504)3 following
intraperitoneal administration to strain A mice. In this study, groups of 20
mice received 100, 50, or 20% of the maximum tolerated dose (2,400 mg/kg) in
24 injections given three times per week. The animals were examined for
tumors at the end of 30 weeks. In all of these studies, positive controls
were used to demonstrate the sensitivity of the strain A mouse to the
development of chemically-induced multiple lung tumors.
Although increased risk of lung cancer has been associated with the
chromium industry as discussed below, it has proven difficult to demonstrate a
carcinogenic response in the lungs of experimental animals. Trivalent
chromium compounds have not produced lung tumors after inhalation,
intratracheal implantation, or intrapleural implantation, while hexavalent
chromium was not carcinogenic by inhalation or intratracheal instillation.
Some hexavalent chromium compounds did produce tumors following intrabronchial
or intrapleural implantation; however, the small number of animals (14) used
by Hueper and Payne (1962) in the study of CaCrO/^ and the lack of detail in
the report of Hueper (1961), where a number of hexavalent chromium compounds
were reported to be carcinogenic, make it difficult to evaluate the
carcinogenicity of these compounds to rodent respiratory tissue. For these
reasons, the experimental studies of respiratory cancer in animal studies do
not provide substantial confirmation for the industrial observation. However,
the limited data does suggest that of the two valences, hexavalent chromium is
more likely to be the etiologic agent in chromium-induced cancer.
7-21
-------
Injection Studies For Sites Other Than Lung
Attempts have been made to demonstrate chromium-induced carcinogenesis in
other than respiratory tissue. In an early study, Hueper (1955) injected
either powdered chromium or chromite ore into the marrow cavity of the femur
of rats, rabbits, and dogs. The experimental conditions are described in
Table 7-6 . Of the animals treated, only one rat developed a tumor at the
site of injection, and other tumors observed in the treated and control groups
were not considered treatment-related. Similar negative results were obtained
by Hueper (1955) following intraperitoneal injection of chromium powder in
rats and mice and intravenous administration of chromium powder in mice, rats,
and rabbits. The experimental conditions used in these studies are also
presented in Table 7-6 . Although some tumors were present in treated rats,
these tumors were similar to those in the controls except for two treated rats
that developed unique insulomas of the pancreas after intraperitoneal
administration of powdered chromium, and two treated rats that developed lung
adenomas. While none were observed in the controls, the causal relationship
between chromium exposure and these tumors is highly questionable.
Injection site tumors developed in animals after subcutaneous
administration of chromium compounds in some, but not all, studies. Payne
(1960a) treated groups of 52 C57B1 mice (26 males and 26 females) with size
fractionated particles of chromium residue dust or chromic phosphate. The
animals received a single subcutaneous injection of 10 mg, after which they
were observed for life. The composition of the dust fraction as related to
trivalent and hexavalent chromium is presented in Table 7-7 . There was a
low incidence of injection site tumors (3 of 52) observed in animals treated
with the unfractioned residue dust, while no tumors were present in the
controls or animals treated with smaller particles, even though these smaller
particles had a higher proportion of hexavalent chromium. In a study of
7-22
-------
TABLE 7-6 . EXPERIMENTAL CONDITIONS USED TO STUDY THE EFFECT OF INTRAFFMORAL, INTRAPERITONEAL, AND INTRAVENOUS ADMINISTRATION OF CHROMIUM
(Hueper 1955)
Route
intrafemoral
Intrafemoral
Intrafemoral
Intrafemoral
"71 Intrafemoral
Intrafemoral
intraperitoneal
intraperltoneal
intravenous
intravenous
intravenous
Species
rats
rats
rabbits
dogs
rats
rabbits
mice
rats
mice
rats
rabbits
Strain
Osborne-Mendel
Wistar
Dutch
Mixed breed
Osborne-Mendel
Dutch
C57B1
Histar
C57B1
Wistar
NR*
Number of Animals
(M, F)
25 M
25 M
8 F
5 F
15 M, 10 F
4 F
50 M
25 M
25 M
25 M
8 F
Chromium
Compound
powdered chromium
powdered chromium
powdered chromium
powdered chromium
chromite ore
44% Cr203
chromite ore
44% Cr203
powdered chromium
powdered chromium
powdered chromium
powdered chromium
powdered chromium
Dose
100 mg
100 mg
140 mg
170 to 399 mg
followed in 24
months by 340
to 798 mg
36 mg
147 mg
1 mg/week
for 4 weeks
5 mg/week
for 6 weeks
0.25 mg/week
for 6 weeks
9 mg/week
for 6 weeks
2.5 mg/kg/week
for 6 weeks,
treatment repeated
4 months 1 ater
Duration of
Observation
24 months
24 months
3 to 58 months
60 months
24 months
20 to 50 months
21 months
NR*
18 months
NR*
3fi months
-------
TABLE 7-7 . LEVELS OF HEXAVALENT CHROMIUM IN
FRACTIONATED RESIDUE DUST
(Payne 1960a)
Material
Weight of Chromium as Cr/dose
Hexavalent (mg) Total (nig)
Vehicle
(tricaprylin)
Dust residue extracted
with H20
Dust residue
5 to 10
Dust residue
< 2
Chromic phosphate
0
0.037
0.17
0.45
0.003
0
0.50
0.69
0.68
2.64
7-24
-------
Identical design, Payne (1960b) treated mice with sintered 003, sintered
CaCr03, and CaCrO^ Only one injection site tumor was observed, and this
was in an animal treated with CaCr04. Roe and Carter (1969) reported that
20 weekly injections of CaCr04 at a dose of 5 mg for the first 2 weeks and
0.5 mg for the remaining 18 weeks resulted in a 75% (18 of 24) incidence of
injection site tumors. Although the title of Roe and Carter's (1969) article
and the legend to the tabulated results described the route of administration
as subcutaneous injection, the experimental section and the conclusion
describe the treatment as an intramuscular injection into the flank. As a
result of this uncertainty, it is unclear whether any chromium compound has
been demonstrated to produce injection site tumors following subcutaneous
administration.
Implantation Studies
Intramuscular implantation has also been used with varying success to
demonstrate that chromium compounds are carcinogenic. Hueper (1958) and Payne
(1960a) implanted chromite roast or chromium residue dust mixed with sheep fat
into the thigh of Bethesda black rats. The respective incidence of injection
site tumors was 3 of 31 for animals given 25 mg of chromite roast and 1 of 35
for animals receiving the same dose of dust. In both studies, no tumors were
present in the sheep fat-treated control animals. Payne (1960a) also
implanted 10 mg of chromium dust in the thigh of 52 C57B1 mice and observed no
injection site tumors. Hueper and Payne (1959) and Payne (1960b) used similar
techniques in the investigation of pure chromium compound. In a small study,
Payne (1960b) observed two injection site tumors in six Bethesda rats after
implantation of a gelatin capsule containing 12.5 mg of CaCrO^ In the
study by Hueper and Payne (1959), 25 mg of a chromium compound was mixed with
7-25
-------
sheep fat prior to implantation into groups of 35 Bethesda black rats. The
implantation site tumor incidence was 8 of 35 for CaCrO^ 8 of 35 for
Sintered CaCrO/^, 15 of 35 for Cr03, and 0 of 35 for BaCrO^ On
implantation of 10 mg of sintered CaCr04 into the thighs of 52 C57B1 mice,
nine implantation site tumors developed, however, only one tumor developed
following the implantation of CaCrO^. Hueper (1961) reported on the
development of implantation site tumors following treatment of rats with a
number of chromium compounds (Table 7-8 ); however, there was no
experimental detail in this report, including dose given, and thus, it is
difficult to relate this study to the other reports of implantation site
tumors. The intramuscular implantation technique has provided relatively
consistent findings that some hexavalent chromium compounds are tumorigenic in
laboratory animals.
Neither trivalent nor metallic chromium compounds have produced
implantation site tumors following intramuscular implantation. Hueper and
Payne (1962) implanted 25 mg of chromic acetate into the thigh of 35 Bethesda
black rats. After a 24-month observation period, only one animal developed an
injection site tumor. Using powdered chromium, Sunderman et al. (1974)
observed no tumors after 112 weeks in 24 male Fisher rats. Atomic absorption
spectroscopy indicated that each rat received 2 mg of dust. Similar results
were obtained by Hueper (1955) following repeated injection of powdered
chromium into the thigh of 25 C57B1 mice. Each animal received two injections
of 0.1 mg at 2-week intervals, and this was repeated 3 weeks later for a total
dose of 0.4 mg. No tumors developed in the 15 mice that survived 3 to 13
months. Although trivalent chromium was not tumorigenic following
intramuscular implantation, only one compound was tested under a limited
experimental protocol, and it is only speculative that zero valent and
7-26
-------
TABLE 7-8 . COMPOUNDS REPORTED TO HAVE BEEN TESTED FOR CARCINOGENICITY
BY INTRAMUSCULAR IMPLANTATION
(Hueper 1961)
Compound
Calcium chromate
Sintered calcium
chromate
Strontium chromate
Lead chromate
Barium chromate
Sodium di chromate
Zinc yellow
Chromic chromate
Chromite roast
residue
Chromium acetate
Sheep fat control
Valence
+6
+6
+6
+6
+6
+6
+6
+6, +3
+6, +3
+3
NAt
Number of Tumors*
9
12
15
1
0
0
16
24
1
1
0
Percent
25
34
43
3
0
0
46
69
3
3
0
*Tnere were 35 rats/group at tne start.
tNA = Not applicable.
7-27
-------
trivalent chromium would continue to give negative results with further
testing.
Oral Studies
Trivalent chromium has been tested for carcinogenicity by the oral route
in mice and rats. Schroeder et al. (1964) exposed a group of 108 (equal
numbers of male and females) Swiss mice to drinking water containing 5 ppm of
chromium as chromium acetate. The lifetime exposure to this level of chromium
had no effect on longevity of females, and only a slight decrease in longevity
in males. There was no increase in the tumor incidence in the treated animals
as compared with controls. In a similar study, Schroeder et al. (1965)
exposed 46 male and 50 female Long Evans rats to drinking water containing 5
ppm of chromium as chromium acetate. Again, lifetime exposure to this level
of chromium had only slight effect on longevity, with no increase in tumors in
treated as compared to control animals. It should be noted that only one dose
level of chromium was used in this study, and from the lack of overt signs of
toxicity, it may be concluded that higher dose levels could be tolerated.
Higher dose levels would increase the likelihood of detecting a carcinogenic
response from a weak carcinogen. Lane and Mass (1977) observed carcinogenic
activities of chromium carbaryl as well as synergistic activities with
benzo(a)pyrene in rats following tracheal grafting techniques.
Ivankovic and Preussman (1975) incorporated 0^03 into the diets of 60
male and female BD rats. The 0^03 was baked into bread at levels of 1,
2, or 5%, and fed to the rats 5 days/week for 2 years. The only effect of
treatment was a dose-dependent decrease in liver and spleen weight. Both the
longevity and tumor incidence in the treated animals were similar to that of
control animals. Again, the lack of major toxic effects of treatment may
7-28
-------
indicate that this chromium compound could have been tested at higher levels
in the diet. The author's commented that the negative may have resulted from
the poor absorption of chromium from the gastrointestinal tract.
Summary of Animal Studies
A summary of the animal carcinogenicity studies of chromium is presented
in Table 7-9 . At present, it has not been successful to induce tumors in
laboratory animals following exposure by inhalation and ingestion routes.
Both trivalent and hexavalent chromium have proven ineffective in producing
lung tumors by inhalation. Similar negative results have been obtained
following the ingestion of trivalent chromium; however, only low doses were
used and hexavalent chromium has not been tested. There is some evidence that
chromium, particularly some hexavalent chromium compounds, are carcinogenic
following subcutaneous injection or intrabronchial, intrapleural, or
intramuscular implantation; however, implantation site tumors have only
consistently been demonstrated using intramuscular implantation. Of all the
chromium salts, calcium chromate is the only one which has been found to be
carcinogenic in rats after intrabronchial and intramuscular implantations.
Calcium chromate, strontium chromate, and zinc chromate can produce local
sarcomas in rats at the site of application. Although the studies available
indicate that metallic chromium powder and trivalent chromium are not
carcinogenic, these compounds have been studied less extensively than
hexavalent chromium. The relevance of studies using intramuscular
implantation to human risk following inhalation or oral exposure to chromium
compounds is not clear; however, these animal studies may indicate that
hexavalent chromium is more likely to be the etiologic agent in human
chromium-related cancer. Using the International Agency for Research on
7-29
-------
TABLE 7-9 . CARCINOGENICITY OF CHROMIUM COMPOUNDS IN EXPERIMENTAL ANIMALS
VjJ
O
Route of
Administration Compound
inhalation chromium containing
dust
Inhalation chromium containing
dust
inhalation chromium containing
dust
inhalation CaCr04 dust
inhalation chromium containing
dust
Inhalation chromium containing
dust
Inhalation chromium containing
mist and dust
Species/Strain
mice/Strain A
mice/Swiss
m1ce/C57Bl
m1ce/C57B1
rats/mixed breed
Wlstar and McCollum
rats/Wistar
rabbits
guinea pigs
Dose Duration
as Chromium of Exposure
0.5 to 1 mg/m3 4 h/d, 5 d/wk
for 16 to 54 wk
0.5 to 1 mg/m3 4 h/d, 5 d/wk
for 39 to 58 wk
0.5 to 1 mg/m3 4 h/d, 5 d/wk
for 41 to 42 wk
4.33 mg/m3 5 h/d, 5 d/wk
for life
1 to 1.5 mg/m3 4 h/d, 5 d/wk
for > 70 wk
1 to 1.5 mg/m3 4 h/d, 5 d/wk
for life
1 to 5 to 2 mg/m3 4 to 5 h/d, 4 d/wk
for the life of
guinea pig or 50
months for rabbits
Findings
No increase in the
incidence of lung
tumors or number of
tumors /lung
No Increase in the
incidence of lung
tumors or number of
tumors/lung
No lung tumors
observed
6 of 136 males and 8
of 136 females
developed lung tumors
as compared with 3 of
136 females and 2 of 136
male controls; the
significance is not clear
Increased incidence of
lymphosarcomas
involving the lungs, 3
of 100 in experimental
and 0 of 85 in control
group
No change 1n lung
tumor Incidence
No increase in the
incidence of lung
tumors
Reference
Baetjer et al .
1959
Baetjer et al .
1959
Baetjer et al.
1959
Netteshelm
et al. 1971
Baetjer et al .
1959
Steffee and
Baetjer 1965
Steffee and
Baetjer 1965
(continued on the following page)
-------
TABLE 7-9
(continued)
Route of
Administration
Intratracheal
Intratracheal
Intratracheal
Instillation
Intratracheal
Instillation
Intratracheal
1ntniat1on
Intrapleural
Injection
Intrapleural
Injection
Intrapleural
Injection
Intrapleural
injection
Intrapleural
injection
Compound
chromium dust or
BaCrO-4 OP ZnCr04
ZnCro4
chromium
dust
ZnCrOa or
PbCr04
ZnCr04 or
PbCr04
Cr powdered metal
mixed chromium dust
FeO(CrAl)203
chromlte ore
Cr powdered metal
Species/Strain
mice/Swiss A
Swiss, C57B1
mice/Strain A
rats /mixed breed
Hi star and McCollum
rabbit
guinea pigs
m1ce/C57Bl
mice/Strain A
m1ce/Ba1b/c
rats/Osborne Mendel
rats/Osborne Mendel
guinea pigs
Dose
as Chromium
0.01 to 0.05 mg/
Injection
0.01 to 0.03 mg/
injection
0.02 ing/injection
2.3 to 2.8 mg/
Injection
0.7 to 0.86 mg/
0.001/mg
0.07 mg/1nject1on
1 mg
36.7 mg (of ore)
16.8 mg
67.2 mg
Duration
of Exposure
5 to 6 injections
at 4 to 6 wk
Intervals
6 Injections at
2 wk intervals
15 injections at
2 wk Intervals
3 to 5 Injections
at 3 mo Intervals
6 Injections at
6 wk intervals
6 Injections at
2 wk intervals
4 injections at
4 to 6 wk Intervals
single injection
6 Injections at
1 mo Intervals
6 injections at
1 mo intervals
Findings
No Increase in the
incidence of lung
tumors or the number
of tumors/lung
No statistical Increase
1n lung tumors, 31
No lung tumors
observed
No lung tumors
observed
No Increase 1n lung
tumor incidence
No significant Increase
1n Injection site
tumors
No Increase in lung
tumor Incidence or
number of lung tumors/
mouse
Only small
granulomas observed
No significant Increase
1n injection site
No significant increase
in injection site tumors
Reference
Baetjer et al .
1965
Steffee and
Baetjer 1965
Baetjer et al.
1959
Steffee and
Baetjer 1965
Steffee and
Baetjer 1965
Hueper 1955
Baetjer et al .
1959
Davis 1972
Hueper 1955
Hueper 1955
(continued on the following page)
-------
TABLE 7-9
(continued)
Route of
Administration
intrapleural
implant
Intrapleural
Implant
Intrapleural
Implant
Intrapleural
implant
Intrapleural
Implant
Intrabronchial
Intrafemoral
Intrafemoral
Compound
chromlte roast
minus Na2CrO$
K2Cr207
CaCr04
Cr(C2H302)3
chromlte roast
variety of
chromium compounds
metallic chromium
chromlte ore
Species/Strain
rats/Bethesda Black
rats/Bethesda Black
rats/Bethesda Black
rats/Bethesda Black
rats/Bethesda Black
rats/Parton
Wistar
rats/Osborne-Mendel
rats/Wistar
rabbits/Dutch
rats/Osborne-Mendel
rats/Dutch
Hose
as Chromium
25 mg (of roast)
0.35 mg
4.2 mg
5.2 mg/implant
25 mg (of roast)
2 mg
100 mg
100 mg
140 mg
15 mg
64 mg
Duration
of Exposure
single Implant in
sheep fat
single Implant 1n
in sheep fat
single Implant in
1n sheep fat
8 implants over
13 mo
single Implant
single Implantation
single injection
single Injection
Findings
3 of 35 animals
developed implant
site tumors; none
in controls
1 of 39 animals
developed implant
site tumors; none
in controls
8 of 14 animals
developed implant
site tumors, none
In controls
No Implantation site
tumors 1n 24 animals
No implant site
tumors
See Table
No injection site
tumors developed
except for a single
tumor 1n one rat
No Injection site
tumors
Reference
Payne 1960a
Hueper
and Payne 1962
Heuper
and Payne 1962
Hueper
and Payne 1962
Hueper 1958
Levy and
Venitt 1975
as reported
1n NIOSH
(1975)
Hueper 1955
Hueper 1955
(continued on the following page)
-------
TABLE 7-9 . (continued)
Route of
Administration Compound
Intrafemoral metallic chromium
1ntraper1toneal 02(804)3
intraperltoneal metallic chromium
1ntraper1tonea1 metallic chromium
Intravenous chromlte ore
Intravenous metallic chromium
Intravenous metallic chromium
Species/Strain
dogs/mixed breed
mice/Strain A
mice/C57Bl
rats/W1star
mice/Strain A
mice/C57Bl
rats/Wistar
rabbi ts/NR
nose
as Chromium
170 to 399 mg
f ol 1 owed by
340 to 798 ng
1.3 to 6.6 mg/
Injection
1 mg /Injection
5 mg/1nject1on
1.95 to 3 mg
0.25 mg/1njection
9.0 mg/inject1on
2.5 mg/kg
Duration
of Exposure
second treatment
given 24 mo
after first
24 Injections given
3/wk
4 Injections at
1 wk intervals
6 Injections at
1 wk intervals
single injection
6 injections at
1 wk intervals
6 injections at
weekly intervals
repeated in 4 mo
Findings
No injection site
tumors
No increase in lung
tumor incidence or
number of lung
tumors/mouse
No tumors observed
Pulmonary adenomas in
2 of 25 animals; none
in controls
No Increase in lung
tumor incidence or
number of lung tumors/
mouse
No tumors in mice
while tumors in rats
were identical to
controls
No adverse effects
after 36 months
Reference
Hueper 1955
Stoner et
al. 1976;
Shimkin et al .
1978
Hueper 1955
Hueper 1955
Shimkin and
Leiter 1940
Hueper 1955
Hueper 1955
-------
TABLE 7-9 . (continued)
—i
i
Route of
Administration
subcutaneous
Intramuscular
Intramuscular
Compound Species/Strain
chromium residue dust m1ce/C57B1
chromium residue dust,
5 to 10 p
chromium residue dust,
< 2 p
chromic phosphate
sinstered 003
sinstered CaCrO.3
CaCr04
metallic chromium mice/C57Bl
CaCr04 mice/C57Bl
sinstered CaCr04
Dose
. as Chromium
0.5 mg
0.69 mg
0.68 mg
2.64 mg
0.52 mg
0.37 mg
0.33 mg
0.1 mg
3.3 mg
3.3 mg
Duration
of Exposure
single injection
2 Injections at
2 wk intervals
repeated 3 wks later
single Implant
Findings Reference
3 of 52 animals Payne 1960a,b
receiving chromium
residue dust and 1 of
52 receiving CaCr04
developed injection
site tumors
No tumors in 25 Hueper 1955
animals
9 of 52 mice treated Payne 1960b
with sinstered CaCrO^
Intramuscular
intramuscular
intramuscular
chromium residue dust m1ce/C57Bl
metallic chromium
Cr(C2H302)3
rats/Fisher
10 mg (of dust)
2 mg
rats/Bethesda Black 5.2 mg
single implant
single Injection
single Implant
had implantation site
tumors, while 1 of 52
treated with CaCr04
developed tumors
No injection site
tumors developed
No tumors 1n 24
animals
1 Implantation site
tumors in 35
treated animals
Payne 1960a
Sunderman et
al. 1974
Hueper
and Payne 1962
-------
Cancer (IARC) classification scheme, this level of evidence in rats would be
sufficient for concluding that calcium chromate and some relatively insoluble
hexavalent chromium compounds are carcinogenic in animals.
7-35
-------
EPIDEMIOLOGIC STUDIES
Chromate Production
The early association of respiratory cancer with employment in the
chromate industry has been reviewed by Baetjer (1950a). The first case report
appeared in 1911, with a total of 122 reports of respiratory cancer in
chromate workers collected between this date and 1950. These cases were
predominantly in German and American industries, with only one case reported
in Scotland in 1890, and no cases reported in England or France. The workers
in the chromate industry were exposed to chromite ore (trivalent chromium) and
sodium monochromate, sodium bichromate, and chromic acid (hexavalent
chromium), along with other vapors and gases associated with the chromate
manufacturing process. The early German investigators suggested that
hexavalent chromium was the etiologic agent in respiratory cancer, since
respiratory cancer was not associated with the mining of trivalent chromite
ore. These early observations do not provide information on the relative
incidence of respiratory cancer in the chromate workers as compared with the
general population, nor were the studies sufficiently large or controlled to
support the conclusion that chromium exposure was related to respiratory
cancer. However, these early reports were the impetus for initiating a number
of epidemiologic studies of the chromate manufacturing industry in the United
States, Great Britian, and Japan. Although a relatively large number of
epidemiologic studies have been conducted of this industry, the individual
studies were often analyzing cancer incidence from the same cohort of workers.
In order to clarify the interrelationship of the cohorts in these studies, the
location of the plants from which each study derived its exposed population is
presented in Table 7-10 . It should be made clear that studies of the same
plant by different investigators often resulted in the vital statistics of
7-36
-------
TABLE 7-10
LOCATION OF CHROMATE MANUFACTURING PLANTS WHICH PARTICIPATE!! IN EPIOEMIOLORIC STUDIES AMI PLANTS FROM
WHICH VITAL STATISTICS WERE OBTAINED FOR EACH STUDY
Location
of
Plant
Machle
and
firegorlus
1948
Brlnton
et al.
1952
(also pub.
as part of
PHS 1953)
Mancuso
and
Hueper Mancuso
1951 1975
Baetjer
1950a
Hayes
et al .
1979
H111
and
Ferguson
1979
Taylor
1966
Enterllne
1974
Bldstrup
1951
Bldstrup
and
Case 1956
Alderson
et al .
1981
Hatanabe
Ohsakl and Korallus
et al. Fukuchl Satoh et et al 1.
1978 1975 al. 1981 198Z
filen Falls.
NY
Vjo
-~j
Jersey City, NJ
Plant »1 +
Plant 12 +
Baltimore,
MD +
Kearny, NJ +
Newark, NJ +
Palnes-
vllle, OH +
Bolton
England
Rutherglen
England
Eaglescllff
England
+t
wing page)
(continued on the
+ » Participating chromate manufacturing plants.
- = Non-participating chromate manufacturing plants.
* = The plant in the Watanabe and Fukuchl (1978) and the OhsaM et al. (1978) studies may be one 1n the same, 1t Is Impossible to tell from the
literature. Both plants were reported to be located on Hokkaido Island, Japan, however.
t - Plant #1 1n Jersey City, New Jersey 1s the larger of the two plants. Machle and r.regorius (1948) reported that It had 350 employees compared
to 150 employees 1n Plant 12.
-------
Table 7-10 . (continued)
BMnton
et al.
, , H1" Watanabe
Location and (also pub. and Hayes and Bldstrup Alderson Ohsakl and Korallus
of Gregorlus as part of Hueper Mancuso Baetjer et al. Ferguson Taylor Enterllne Bldstrup and et al. et al. Fukuchl Satoh et et al.
Plant 1948 PHS 1953) 1951 1975 1950a 1979 1979 1966 1974 1951 Case 1956 1981 1978 1975 al. 1981 1982
Hokkaido
Islands
I Tokyo,
*•*> Japan
CO
Leverkusen
W. Germany -- ---.._.
Verdingen,
W. Germany -- ---.___
*• - Participating chromate manufacturing plants. ~~ ~~—" ~~
- = Non-participating chromate manufacturing plants.
* = The plant In the Watanabe and Fukuchl (1978) and the Ohsakl et al. (1975) studies may be one 1n the same, 1t 1s Impossible to tell from the
literature. Both plants were reported to be located on Hokkaido Island, Japan, however.
t = Plant »1 1n Jersey City, New Jersey 1s the larger of the two plants. Machle and Gregorlus (1948) reported that 1t had 350 employees compared
to 150 employees 1n Plant 12.
-------
individual workers being used in more than one study. The result was that in
many cases, these epidemiologic studies verified the observations of previous
studies rather than adding evidence from additonally exposed population
groups.
In response to the early reports associating lung cancer with the chromate
industry, the industry initiated a retrospective epidemiologic study of the
seven chromate plants in the United States (Machle and Gregorius 1948). A
total of 1,445 workers were employed in the seven plants, with each plant
employing between 50 and 500 workers. The company group life insurance
records were used to determine cause of death. Adequate records were
available for six of the plants, and the cohort of men actively working in the
chromate industry consisted of 11,019 man-years of experience. In this
cohort, 156 deaths were observed, 32 of which were from lung cancer. An
additional 10 lung cancer deaths were reported of the 37 deaths from the plant
with work records unsatisfactory for the purpose of the epidemiologic
analysis. The period of study varied with each plant from 4 to 17 years,
depending on the availability of mortality data. Of the total deaths observed
in the chromate industry, 21.8% (42 of 193) were from lung cancer compared to
an expected 1.3% (10 of 733) as calculated from a comparable industrial group
not exposed to chromium (industrial life insurance policyholders for the year
1947, Metropolitan Life Insurance Co.). This is statistically significant at
P < 0.01. When examined individually, five of the seven plants were reported
to have respiratory cancer proportionate mortality ratios from 13 to 31 times
that expected. The crude respiratory cancer moraltity rate per 1,000 males
was also found to be significantly (P < 0.01) increased over the crude lung
cancer mortality rate of the group of life insurance holders. This was true
for both the age group 50 and under and the age group 50 and over. A slightly
7-39
-------
increased crude mortality rate from digestive system cancer was also reported
(1.18 per 1,000 versus 0.59 per 1,000,P <0.01).
Estimates of exposure were not made in this study, since analytical data
were not available for a large portion of the period studied, and work records
did not report the shifting of personnel to different positions in the plant
during the course of employment. A limitation to this study is that no age
adjustment was done in the comparison of the mortality rates of the control
group with the mortality rates of the exposed group. In this regard, however,
it should be noted that there was a dramatic difference in lung cancer
mortality between the chromate workers and the control group for both the 50
and under age category and the over 50 age category. Thus, it is unlikely
that a preponderance of older persons among the chromate workers was
responsible for the large difference in lung cancer mortality between the
chromate workers and the control group. Another limitation is that the
authors used a lung cancer mortality rate for oil refinery workers in 1933-38
for comparison with the chromate workers of 1930-47. Lung cancer increased
dramatically in U.S. males between 1930 and 1947 (about five times). Thus, it
is possible that the lung cancer mortality rate for the control group may have
a lower rate than what would have been found for the period 1930-1947.
However, the difference in lung cancer between the controls and the chromate
workers is so dramatically different, it is unlikely that this difference
could be explained by selection of a control group from a slightly different
time period than that of the exposed group.
Brinton et al. (1952) used the disability records between January 1, 1946
and December 31, 1950 of the seven United States chromate plants to determine
occupational diseases associated with the chromate industry. These data were
subsequently published as part of the Public Health Service (1953) report,
7-40
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"Health of Workers in a Chromate-Producing Industry." The cohort was limited
to men who belonged to the company disability plan, which prior to 1949 was
voluntary. After 1949, the participation was mandatory in all but two plants,
although participation in these plants was near 100% by the end of the study.
Only deaths that occurred within 1 year of beginning disability status were
included in this study, and the determination of the cause of death was made
solely on what was listed as "cause of death" on the death certificate. The
health experience of a "large group of industrial workers (predominantly
white)" was used for comparison. The incidence of most disabilities was
comparable between chromate workers and the reference population with the
exception of cancer. Cancer at all sites had an incidence of 7.1 per 1000 in
chromate workers and 0.7 per 1000 in the control populaiton (P < 0.01);
however, it should be pointed out that the actual number of individuals who
developed cancer was small (26 individuals) in the group of chromate workers.
Brinton et al. (1952) further studied the cancer experience in the chromate
industry using death records obtained from the group disability insurance plan
between the years 1940 and 1950. During this time, information was available
from two plants, while one plant had records from 1943 to 1950, three plants
from 1946 to 1950, and one plant from 1949 to 1950. During this 11-year
period, 44 deaths from cancer at all sites and 32 deaths from respiratory
cancer were observed. This corresponds to a 4.5-fold increase in cancer at
all sites and a nearly 29-fold increase in respiratory cancer in the chromate
workers as compared to males in the United States. There was an indication in
the data that the increased risk of respiratory cancer was greater in nonwhite
as compared to white chromate workers; however, the number of individuals was
small when the cohort of chromate workers was subjected to this further
subdivision. The authors commented on the limitations the study placed on
7-41
-------
the make-up of the cohort as a result of the use of death records obtained
solely from the company disability plan and suggested that the observed
increased risk of respiratory cancer represents a minimal value.
Baetjer (1950a, b) studied a cohort consisting of lung cancer patients in
two Baltimore hospitals to determine if employees of the local chromate plant
were overrepresented in this group. The records from Johns Hopkins Hospital
were examined from 1925 to 1946, and from Baltimore City Hospital from 1930 to
1948; 198 and 92 confirmed cases of lung cancer in males were obtained,
respectively, from each institution. Control groups consisted of age-matched
male patients with a hospital stay of >10 days chosen at random from the
hospital records. An additional control was used for Johns Hopkins; this
consisted of patients with cholelithiasis, since patients with this disease,
as well as lung cancer patients, may preferentially select a large medical
facility. At Johns Hopkins, 7 of 198 lung cancer patients had worked in the
chromate industry; none of the 226 randomly sampled controls and none of the
177 cholelithiasis controls had worked in the chromate industry. At the
Baltimore City hospital, 4 of 92 lung cancer patients and 0 of 499 control
patients reported exposure to chromium compounds. The percentage of chromate
workers in the lung cancer group was statistically significantly (P < 0.01)
greater than expected. If one were to calculate the unadjusted odds ratios of
having lung cancer and being exposed to chromium, the odds ratios would be
about 32 for the Johns Hopkins cases and about 23 for the Baltimore City
Hospital cases. Both are statistically significant (P < 0.05).
Mancuso and Hueper (1951) used the vital statistics found for all
employees who worked for >^ 1 year in the Painesille, Ohio chromate plant during
1931 to 1949 to investigate chromate production-associated lung cancer. Of
the 2,931 deaths of males in the county in which the plant was located, 34
7-42
-------
(1.2%) were from respiratory cancer, while of the 33 deaths among the chromate
workers, 6 (18.2%) were from respiratory cancer. This difference is
significant at P < 0.01. Mancuso and Hueper (1951) indicated that 95% of the
workers were exposed exclusively to insoluble chromite. Chemical analysis of
the organs of two deceased workers, one who had died from lung cancer and one
who had died from bladder cancer, revealed that the lungs appeared to be the
major storage depot for chromium, with approximately 390 and 250 ug of
chromium per 10 g of tissue detected in each individual respectively. The
high level of chromium in the first subject, the one who had died from lung
cancer, was still detected despite the fact that the individual had not been
exposed to chromium for a period of 3.4 years. Chromium levels measured in
the lungs of nonexposed individuals were nearly zero. Mancuso and Hueper
(1951) suggest that the presence of insoluble chromium in the lung may be an
etiologic factor in the observed higher incidence of cancer; however, the
present data are too limited to support this conclusion.
Mancuso (1975) followed the vital status until 1974 of 332 chromate plant
workers from his earlier study (Mancuso and Hueper 1951) who were employed
from 1931-1937. Over 50% of the 332 employees in this cohort had died by
1974. Mancuso divided this group of workers into those employed from 1931-32,
1933-34, and 1935-37. Mancuso found that 63.6, 62.5, and 58.3% of the cancer
deaths in the 1931-32, 1933-34, and 1935-37 groups, respectively, were lung
cancer deaths. The latency period for the lung cancer deaths was found to
cluster around 27-36 years. The author found that lung cancer deaths were
dose-related to insoluble (trivalent), soluble (hexavalent), and total
chromium exposure, and thus, the author concluded that lung cancer mortality
was associated with both trivalent and hexavalent chromium. Because workers
in this study were exposed to both trivalent and hexavalent chromium, and as
7-43
-------
exposure to one increased so did exposure to the other, an observed
dose-response to trivalent chromium may merely be a reflection of a
dose-response to hexavalent chromium or vice-versa. Thus, it is questionable
whether the author's conclusion with regard to a dose-response to both
hexavalent and trivalent chromium is correct. Furthermore, the lung cancer
death rates, which purport to show this dose-response, are based on very small
numbers, and thus the finding of dose-response is probably questionable. For
six deaths due to lung cancer, chromium levels well above control values were
found in the lungs as long as 15 months to 16 years and 3 months after last
exposure to chromium suggesting that the lung retains chromium for a
considerable period of time.
More recently, Taylor (1966) studied a group of 1,212 chromate workers for
24 years using Old-Age and Survivors Disability Insurance records. All of
these workers were employed in three United States chromate plants (Baltimore,
Maryland; Painesville, Ohio; and the larger of the two plants in Jersey City,
New Jersey) for 2.3 months during the 4-year period of 1937 to 1940. The vital
statistics of the group were obtained through 1960, and where deaths occurred,
the cause was determined from death certificates. Causes of death in this
cohort were compared with age and cause-specific mortality rates for civilian
males in the United States. The most dramatic increase in the standardized
mortality ratios (SMR) for chromate workers occurred in respiratory cancer,
with excesses of 8.5 times (71 observed and 8.3 expected) observed by the
termination of the study in 1960. Also, the length of experience in the
chromate industry, used as the only indication of the extent of exposure, was
compared with the incidence of lung cancer in this cohort. After 1937,
duration of employment was determined from insurance records, while prior to
this date, duration of employment was estimated by extrapolation from the
7-44
-------
age-specific employment experience of the cohort. Using this method to
determine length of exposure, Taylor found that respiratory cancer mortality
showed a dose-response by length of time exposed to chromate.
Enterline (1974) recalculated the expected deaths for the study by Taylor
(1966) but provided no explanation as to why this was done. Enterline
calculated a respiratory cancer SMR of 942 for the 20-year observation period
1940-1960. Taylor had calculated a respiratory cancer SMR of 850 for the
period 1937-1960. Enterline (1974) showed that the relative risk of
respiratory cancer was greater in workers in the age group <45 years (14.1
times) as compared with the older age group of 55 to 64 (6.8 times).
Enterline also showed that the risk of respiratory cancer'was highest shortly
after the cohort was identified, suggesting "a short latent period which is
probably the result of exposure to a very potent carcinogen."
Hayes et al. (1979) conducted a cohort mortality study of workers at a
Baltimore, Maryland chromium chemical production plant. The plant underwent
extensive changes in the mill and roast operation and bichromate operations in
1950 and 1951 when a new facility was built to house these operations and in
the chromic acid and special products operations in 1960 when a new facility
was built to house these operations. The new facilities were constucted for
the purpose of lowering employee exposure to chromium. In this study, vital
status was determined on newly hired workers between 1945 and 1974 who had at
least 90 days of employment. This cohort consisted of 2,101 employees, 1,803
laborers, and 298 managers, of which vital statistics were obtained for 88% of
the group as of 1977. A comparison of lung cancer in this cohort was made
using SMRs from the cause-specific mortality rates of Baltimore males and
tested for significance using Poisson probability distribution. Workers were
divided into two exposure groups; the high or questionable exposure group
7-44a
-------
consisted of employees who worked in the old facilities and workers of unknown
exposure, and the low exposure group consisting of workers employed only in
the new facilities. In this study, no information was available on the actual
levels of exposure or the extent of difference in exposure between the new and
old plants. Analysis of lung cancer mortality by specific jobs was done after
matching lung cancer cases by race, age, time of initial employment, and
duration of employment to employees that died from non-cancer causes.
The SMR for lung cancer in the entire cohort of hourly workers was 202
(95% confidence limits of 155 to 263), which was statistically significant
(P < 0.01). The SMRs for both short (90 days to 2 years) and long (>3 years)
term workers of the high and low exposure group are presented in Table 7-11 .
There was an apparent dose-response relationship, as associated with length of
employment, for the group initially hired 1950-59. The lung cancer SMR was
statistically significant (95% confidence limits did not include 1.00) for the
workers with "high and questionable exposure" employed >3 years, and who had
initially been employed 1950-59. In analyzing lung cancer by job description,
only workers in the special products department or employees who worked in
both the special products and bichromate departments, the so called "wet-end"
of the production process (the production process in the mill and roast
department is referred to as the "dry end"), showed a significantly (P < 0.05)
elevated relative risk of lung cancer of 2.6 and 3.3, respectively.
In a study of the same plant investigated by Hayes et al. (1979), Hill and
Ferguson (1979) used a novel statistical analysis in an attempt to demonstrate
any trends in the risk of lung cancer associated with the modernization of the
plant. The statistical method used was "probability window analysis" which
provided a method of comparing the number of cases of lung cancer in any equal
time period. In comparing the number of lung cancers prior to 1951 (the time
7-45
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TABLE 7-11 . OBSERVED NUMBER OF DEATHS, STANDARDIZED MORTALITY RATIOS (SMRs), AND 95% CONFIDENCE LIMITS (95% CL)
FOR DEATHS DUE TO CANCER OF THE TRACHEA, BRONCHUS, AND LUNG
AND THE NUMBER OF REPORTED DEATHS FOR WHICH NO CERTIFICATE COULD BE OBTAINED,
BY YEAR OF INITIAL EMPLOYMENT, EXPOSURE CATEGORY AND TOTAL DURATION EMPLOYED,
FOR WORKERS INITIALLY HIRED AS HOURLY EMPLOYEES
(Hayes et al. 1979)
Duration of
Employmentt
Cause of
Death
Low Exposure
Observed
No. of Deaths
Exposure Category*
SMR (95% CL)§
Questionable and- High Exposure
SMR (95% CL)§
Observed
No. of Deaths
Short
Long
Trachea, bronchus NA
and lung
Cause not NA
determinedll
Trachea, bronchus NA
and lung
Cause not NA
determined'!
INITIALLY HIRED 1945 to 1949
NA
NA
NA
NA
20
25
13
1.8
(1.1 to 2.7)
NA
3.0
(1.6 to 5.2)
NA
*Based upon whether work exposure was exclusively in a new facility. See text.
tDuration of employment, short (90 days to 2 years), long (>3 years).
§Calculated using an assumption that the observed number of deaths is distributed as a Poisson random
variable, P = 0.025, in each tail.
^ICause not determined are those reported deceased for whom no death certificate could be obtained. If these
are distributed by cause of death in a similar way as the known deaths (cancer of the trachea, bronchus,
and lung 15%) the reported SMRs would he increased slightly.
NA = Not applicable.
(continued on the following page)
-------
TABLE 7-11 . (continued)
Duration of
Employmentt
Short
Long
All
Low Exposure
Cause of Observed
Death No. of Deaths
Trachea, bronchus 2
and lung
Cause not 3
determinedfl
Trachea, bronchus 3
and lung
Cause not 0
determinedfl
Trachea, bronchus 0
and, lung
Cause not 0
determinedfl
Exposure Category*
Questionable and High Exposure
Observed
SMR(95% CL)<) No. of Deaths SMR (95% CL)§
INITIALLY HIRED 1950 to 1959
0.7 (0.1 to 2.6) 12 1.8
(0.9 to 3.1)
NA 7 NA
4.0 (0.8 to 11.7) 9 3.4
(1.6 to 6.5)
NA 0 NA
INITIALLY HIRED 1960 to 1974
NA 0 NA
NA 0 NA
*Based upon whether work exposure was exclusively in a new facility. See text.
tDuration of employment; short (90 days to 2 years), long (X3 years).
§Calculated using an assumption that the observed number of deaths is distributed as a Poisson random
variable, P = 0.025, in each tail.
HCause not determined are those reported deceased for whom no death certificate could be obtained. If these
are distributed by cause of death in a similar way as the known deaths (cancer of the trachea, bronchus,
and lung 15%) the reported SMRs would be increased slightly.
NA = Not applicable.
-------
of start up of the new bichromate plant) with those after 1951, Hill and
Ferguson (1979) report a statistically significant (P < 0.01) decline from 23
to 7, and the authors suggested that this reduced risk of lung cancer resulted
from the engineering improvements that took place in 1951. Comparing the time
periods 1932-41, 1942-51, 1952-61, and 1962-71 the number of bronchogenic
carcinoma deaths falling within these time periods ("windows") are 9, 7, 1,
and 0, respectively. The authors found a significant (P < 0.01) difference
when comparing the four groups under the null hypothesis that all classes have
equal probabilities of having cancer mortality. The Carcinogen Assessment
Group would agree with the review of this study by IARC (1980) in which they
stated that no conclusion on improved safety in this chromate plant could be
made, since the analysis only compared lung cancer cases and not rates of lung
cancer. Also, this analysis does not allow for the long latency period
generally associated with lung cancer in the chromate industry.
Chromate plants in both England and Japan have also been studied to
determine if there is an association between employment in this industry and
lung cancer. In an early survey, Bidstrup (1951) performed lung X-rays of 724
workers employed in the three chromate plants in England in 1949. This survey
detected only one case of lung cancer, while the expected number would have
been 0.4, as indicated from the mass radiography units of the Ministry of
Health. Of the 724 workers examined, 237 were employed for M5 years, and
although the numbers were too small for definite conclusions, Bidstrup (1951)
suggested that it was unlikely that a 25-fold increased risk of lung cancer,
as reported in studies of United States plants, was associated with employment
in the British plants. Bidstrup's study was a cross-sectional study of only
currently employed workers, however. Workers with lung cancer or with
symptoms of lung cancer have probably dropped out of the working population.
7-48
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Thus, the results are likely to be underestimates of what the difference in
the incidence or the risk of lung cancer in this group of workers would be.
Bidstrup and Case (1956) performed a follow-up study between 1949 and 1955
on the 723 workers who participated in the radiographic survey. During this
time, 217 workers were lost to the study as a result of change in employment.
Of the remaining men, all but 59 were alive in 1955 when the study was
terminated. The age and cause specific deaths of these chromate workers were
compared with the number expected based on the vital statistics for the male
population of England and Wales. There was no difference in either death
rates for neoplasms other than lung cancer or deaths from other causes;
however, for lung cancer, there were 12 observed deaths with only 3.3
expected. This increase of 360% was statistically significant (P = 0.005).
There was also a trend for greater risk in the age group <45 years (7 observed
and 1.3 expected); however, the numbers were too small to demonstrate if this
trend was statistically significant. The effects of place of residence,
social class, and smoking habits on lung cancer incidence were considered too
small to account for this 360% increase in risk. The authors note that this
study was of short duration and continued follow-up of this cohort would
probably give rise to an even greater increased risk of lung cancer. Of
interest in this study is the fact that the authors reported that 217 workers
were lost to follow-up because of change in employment. Change of employment
may well indicate a change in health status and thus may suggest that the
difference in lung cancer mortality again may be underestimated.
Alderson et al. (1981) conducted a cohort mortality study of workers at
three chromate plants in Great Britain. This was a follow-up of the earlier
studies by Bidstrup (1951) and Bidstrup and Case (1956). Subjects were
eligible for this study if they had had an X-ray examination at work, had
7-49
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worked for a minimum of one year's continuous service and were employed from
1948 to 1977. Two of the plants, those at Bolton and Rutherglen were closed
in 1966 and 1967, respectively. Following the closing of these two plants,
production became concentrated at the Eaglescliffe plant. The national
mortality rates for England and Wales were used to calculate expected
mortality for the plants at Bolton and Rutherglen. For all plants together
the observed lung cancer mortality to that expected was statistically
significant (observed/expected = 2.419, P < 0.001). For the individual
plants, the observed/expected ratio was not significant (observed/expected =
1.00 with 5 observed and 4.98 expected P < 0.44) at the Bolton plant while it
was significant (P < 0.001) at the Eaglescliffe (observed/expected = 2.156
with 36 observed and 16.20 expected) and Rutherglen (observed/expected = 2.854
with 75 observed and 26.28 expected) plants. It should be noted however that
the cohort at the Bolton plant was relatively small (number = 202) and not
large enough to be reasonably able to detect a difference between the observed
and the expected lung cancer deaths. It should also be noted that the
observed to expected nasal cancer mortality was statistically significant
(P < 0.05) at the Rutherglen plant. The authors were interested in
determining if plant modifications affected the relative risk of disease in
men in the earlier study by Bidstrup and Case (1956). The authors found that
the observed/expected ratio of lung cancer deaths decreased from 3.0
(P < 0.01) for those who worked before the plant modifications, to 2.0
(P < 0.005) for those who worked before and after the modifications, to 1.9
(P = 0.290) for those who worked after the modifications were completed.
Because of the confounding factors of age distribution of the workforce,
duration of employment, duration of follow-up, and the influence of
environment, the authors did a multivariate analysis of the data. For each
7-50
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individual, the analysis compared the risk of developing lung cancer based on
the following factors: duration of employment, duration of follow-up,
calendar period of employment, factory age at entry, and estimated degree of
chromate exposure. The authors found the greatest contribution to the risk of
lung cancer mortality to be that of duration of employment followed by
duration of follow-up, calendar period of employment, entry age, and estimated
degree of chromate exposure. In this study the authors reported that an
earlier report of the study cohort (case unpublished) presented data on the
smoking habits of the workers for 70 percent of the workers who had completed
a questionnaire. Results from this survey found that the percentage of heavy
smokers was lower for the study cohort than that reported for England and
Wales (Todd 1962). Thus, the authors concluded that there was no evidence
from the respondents to the questionnaire of a major risk of lung cancer due
to smoking compared to the population as a whole. Such a conclusion must be
considered questionable, however, considering that 30% of the cohort did not
respond. Other studies have found that the percentage of smokers among
nonrespondents to questionnaires is higher than among respondents (noil and
Hill 1964, Criqui et al 1979.
Watanabe and Fukuchi (1975) followed a group of 136 chromate production
workers who worked or had worked in a chromate production factory on Hokkaido
Island, Japan. The criteria for inclusion in the cohort was that one must be
exposed for more than 9 years to chromium compounds. The follow-up period was
14 years, from 1960 to 1973. Eight cases of lung cancer and two possible
cases of lung cancer were identified during the follow-up period. The author
did not state how the ten cases were identified. Seven of these ten cases had
died during the observation period, including the two questionable cases. The
date and cause of the deaths were ascertained by their death certificates
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and/or hospital records. Based on national vital statistics data, the
expected number of lung cancer deaths for this population would be 0.33. Thus
the observed number of lung cancer cases is 21.2 times greater (if the 2
questionable cases are counted with the observed lung cancer death) or 15.2
times greater (if only the five certain cases of lung cancer are counted).
Both observed numbers are significantly (P < 0.05) greater than expected,
however.
Ohsaki et al. (1978) studied the incidence of lung cancer in a cohort of
67 active chromate workers and 487 retired chromate workers at a factory on
Hokkaido Island in Japan. It is not known at this time whether this is the
same factory as was in the Watanabe (1975) study. The average exposure was
22.8 years (10 to 36 years), with 133 workers exposed for > 10 years. In this
population, the authors diagnosed 10 patients with lung cancer, and determined
from death records that an additional four cases had occurred. The incidence
of lung cancer in these chromate workers was 658 per 100,000 compared to 13.3
per 100,000 for the Japanese population. (It is presumed that the latter rate
is for the male population, although the authors did not state this
explicitly). No correction was made in this study for smoking habits, even
though all but two of the individuals with lung cancer were heavy smokers.
Sano and Mitohara (1978) reported that of 36 deceased chromate workers in
Tokyo, 19 died of cancer of the respiratory organs. Although this report
merely related case histories, the authors maintained that it supports the
risk of cancer associated with the chromate industry. Of particular interest
in this report were the total metal analyses of two workers exposed to
chromium who died of respiratory cancer. Along with excessive levels of Cr,
there were elevated levels of Ni, Co, Be, V, and Mn in the lungs, indicating
exposure to other possible carcinogens.
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Satoh et al. (1981) conducted a mortality and morbidity study of 896
workers engaged in the manufacture of chromium compounds for one or more years
during the period 1918 to 1975 at a plant in Tokyo, Japan. It was reported
that during the period 1934 to 1975, 84% of the chromium compounds
manufactured were hexavalent and 16% were trivalent. The plant was closed in
1975; workers were followed until 1978 or until death. Data on the cause and
date of death were collected from death certificates or other "reliable
written testimony." In addition to the 896 workers that were followed, there
were 165 chromium workers who were not included in the study due to a lack of
"necessary information." All of these were retired workers whose registered
permanent residence and current status were unknown and whose vital status as
of the end of 1978 could not be determined. Of these 165, approximately 80%
had left chromium work prior to 1949, and for 65% the date of birth was
unknown. The average number of years as a chromium worker for the 165 not
included in the study was about 7 years, less than the 10-year average for the
896 workers that were included in the study. The authors analyzed the
mortality data by four different time periods, 1918-49, 1950-59, 1960-69,
1970-78, and the overall time period 1918-78. They reported the observed and
expected number of deaths and SMR for various diseases and found that there
was an excess risk of lung cancer for each of the time periods (mortality
ratio = 9.5 for the 1918-78 time period, P < 0.005). No excess risk of death
from any other disease was found for any of the time periods or for the
overall time period. Satoh et al. also analyzed the data by length of working
experience (1-10 years, 11-20 years, and 21+ years) for the time periods
1950-1959, 1960-1969, and 1970-1978. For lung cancer deaths, but not for
deaths from "all other cancers," the ratio of observed to expected deaths
increased by length of working experience.
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Satoh et al. studied morbidity by examining health insurance records for
the period 1974 through 1977 to determine if any sickness occurred in the 81
chromium-exposed workers as compared with the 82 nonexposed workers in the
plant during that period. The author reported that although the numbers were
small, there was no apparent difference between the exposed and the nonexposed
groups in the number of cases for any major disease category. It should be
noted that respiratory cancer and perforation of the septum are compensate
and thus do not appear in the health insurance records. Three years after the
end of the chromium exposure, all 94 workers who had been exposed for 1 to 28
years (average 14.9 years) were given a complete series of liver and kidney
function tests. All values were reported to fall within the normal range
characteristic of Japanese males.
Korallus et al. (1982) reported the lung cancer SMRs for two West German
chromate-producing plants during the period 1948-1979. The population of
North Rhineland-Westphalia was used as the comparison group in calculating the
SMRs. The respiratory cancer SMRs for both plants, Leverkusen and Uerdingen,
1.92 and 2.24 respectively, were both statistically significant (P < 0.05) for
the period of the study. The authors reported that when the study period was
divided into six four-year intervals (1948-52, 1953-57, 1958-62, 1963-67,
1968-72, 1973-77) and one two-year interval (1978-79) that the respiratory
cancer SMRs for these intervals generally decreased in both plants over the
period of the study. This decrease was rather inconsistent in the Uerdingen
plant, however. Additionally, three subcohorts were defined: members with
beginning of exposure prior to January 1, 1948 (Group I), members exposed
before and after the "change in manufacture" (the change in manufacture began
in 1948 and was completed in 1957 at Leverkusen and in 1963 at Uerdingen)
(Group II), and members with beginning of exposure and after either "change in
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manufacture" or before this provided at least half the exposure time was after
completion of the changeover (Group III). The "change in manufacture"
represents the incorporation of the "no-lime" processing of the chrome ore
which is believed to result in a reduction of the carcinogen risk. For both
plants there was a clear drop in the lung cancer SMR from Group I to Group
III. For Uerdingen, the lung cancer SMRs were 2.76, 2.60, and 0.96 for Groups
I, II, and III. For Leverkusen, the corresponding lung cancer SMRs were 2.85,
1.97, and 0.54. In neither the Leverkusen plant nor the Uerdingen plant,
however, were the SMRs for Groups I, II, or III significantly different
(P < 0.05) from each other. Thus, the decrease in the respiratory cancer SMR
from Groups I to III might be due to chance. A reduction in nasal
perforations, symptomatic of chromium exposure, was also observed for Groups I
to III. This latter finding is statistically significant at P < 0.05 (chi
square test for linear trend in proportions) in both plants and would support
a conclusion of a decrease in chromium exposure from Group I to Group III.
Chrome Pigment Industry
Two studies have been conducted on the mortality in the chrome pigment
industry in which workers were exposed only to hexavalent chromium. Langard
and Norseth (1975) reported on three pigment plants in Norway that were in
operation between 1948 and 1972. One of the plants was brought on line only
in 1972, however, the year the study ended. Between these dates, 133 workers
were identified as being employed at the three plants. Of the 133, 24 had
been employed > 3 years, and of this cohort, six cases of cancer, three of
which were lung cancer and one which was gastrointestinal cancer, were
identified through the Cancer Registry of Norway. All three of the lung
cancer cases had been employed 5 years or longer. Two other cancer cases, one
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with prostate cancer and the other with nasal cancer were identified among the
133 workers. These cases did not qualify for membership in the cohort
employed for > 3 years, however. Data from the Cancer Registry indicated an
expected number of lung cancer cases among those employed of 0.079; thus, the
observed number of cases was 38 times that expected. Exposure levels as
determined by personal monitoring were reported for the plants for the year
1972, the year in which the study ended, with chromium levels in the two older
plants ranging between 0.04 and to 1.35 mg/m^, and levels in the new plant
between 0.01 and 0.08 mg/m3. The distribution of the number of employees
per year was not presented, although it was indicated that only seven or eight
employees worked in the plants between 1948 and 1950, with this number
increasing slowly to a level of 30 workers by 1972. Although an increased
risk of lung cancer was indicated, two of the individuals with lung cancer
were moderate to heavy smokers. Nevertheless, a relative risk of lung cancer
of 38 would not be explained by differences in smoking between the study
cohort and the Norwegian population.
Davies (1978, 1979) studied three chromate pigment plants in England, of
which plants A and B produced both zinc and lead chromate, while plant C
produced only lead chromate. The cohort of exposed workers consisted of
employees with _>. 1 year service that were first hired between 1933 and 1967
for plant A, 1948 through 1967 for plant B, and 1946 through 1961 for plant C
(these years were governed by the availability of complete employment
records), and for which vital statistics were available as of 1977. Using
these guidelines, 396, 136, and 114 subjects were obtained from plants A, B,
and C, respectively, and these groups were further subdivided into high and
medium exposure and low exposure groups. The observed mortality from lung
cancer in the different plants by exposure category was compared to the
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the expected mortality as calculated from national lung cancer mortality rates
for all males in England and Wales. These data are presented 1n Table
The exposure categories of high and medium were combined because they were
similar. Adjustments to the expected number of lung cancer death values were
made in the following manner: (1) the expected number of lung cancer cases was
adjusted upward because the proportion of unskilled and semiskilled workers in
the study population was higher than in the general population and these
persons are known to smoke more than the national average; (2) the expected
number Was adjusted downward for factory B and upward for factory C to reflect
the respective differences in local lung cancer mortality in comparison to the
national lung cancer mortality. The author did not state how these
adjustments were calculated. An elevated risk of lung cancer was present only
in the high exposure groups in plants A and B, while plant C, which
manufactured only lead chromate showed no elevated risk. Also, workers in
plant A that were hired after production modification in 1955 showed no
increased risk of lung cancer, even though there was a minimum follow-up
period of 15 years. The authors suggest that these data indicate that zinc
chromate was associated with the etiology of lung cancer, while lead chromate
was not, and although the data was limited by the small sample size, the
authors claim that engineering controls had effectively lowered the risk of
lung cancer in plant A.
Frentzel-Beyme (1983) reported that the observed number of lung cancer
deaths exceeded the expected among workers in five chronate pigment plants in
the Netherlands and West Germany. In only one factory, however, was this
excess statistically significant. The authors did not find a lung cancer
mortality dose-response by intensity of exposure or duration of exposure. The
numbers of deaths in each exposure category were rather snail, however.
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TABLE 7_12 • LUNG CANCER IN WORKERS IN THE CHROMATE PIGMENT INDUSTRY
(navies 1979)
High and Medium Exposure
Plant and Year of Number of Observed Expected
Initial Employment Men Lung Cancer Lung Cancer
Plant A
1932 - 1954 175 18t 8.17
^ 1955 - 1967* 62 0 1.14
CO
Plant B
1948 - 1967 116 7§ 1.43
Plant C
1946 - 1967 95 1 2.46
Low Exposure
Number of Observed Expected
Men Lung Cancer Lung Cancer
77 2 2
14 0 0.16
20 0 0.1
19 1 0.37
*Plant modification in Plant A in 1955 considerably reduced employee exposure to chromates.Thus, results
were divided into two time periods, 1932-54 and 1955-67, for the purpose of analysis.
tP < 0.01.
§P < 0.001.
-------
Chromium Plating
Royle (1975) studied mortality in the chromium plating industry of England
in a retrospective study between 1969 and 1972, and also reported on the first
2 years of a prospective study which began in 1972. Workers in this industry
are exposed to hexavalent chromium in the form of chromic acid mist and some
sodium dichromate dust. In the retrospective study, 1,238 chrome plating
workers employed for > 3 months were traced along with 1,284 manual laborers
used as controls. The control subjects were matched to the exposed workers
for sex and the last date they were known to be alive, while the subgroup of
workers that were currently employed in the chrome plating industry were also
matched for smoking habits. Similar success was achieved in tracing both
groups, and from the response to questionnaires, there was little difference
in the smoking habits of the groups. The death rate was higher in the chrome
plating group, with 109 deaths observed as compared to 85 in the control
group. In examining cause-specific deths, there was a significant (P < 0.05)
difference in the death rate for cancer at all sites, 3.15% in chrome platers
as compared to 1.63% in controls, while deaths from malignancy of the lung and
from malignancy of the gastrointestinal tract were each increased although not
significantly. Other causes of death were similar in the two groups. In a
small group (220 subj.ects) with high exposure, there was greater mortality
associated with employment of 1 year or more as compared with exposure for
less than 1 year. The results of the first 2 years of the prospective study
indicate an increased proportionate cancer mortality with 12 cancer deaths
(the tables indicate 12, although the text reports 9) of 33 deaths reported in
the chrome-exposed group compared with 3 cancer deaths of 19 deaths in the
control group.
In addition to the mortality study, Royle also conducted a morbidity study
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of the chrome plating workers. The controls were the same as those in the
mortality study. The author stated that detailed results of the morbidity
study would be published in a separate article. Among platers, it was
reported that there was a significant increase in the prevalence of a large
majority of different respiratory symptoms. The possible causes of this were
examined in some detail. In the course of this investigation, it was found
that a significantly larger proportion of controls (8.3%, 93 controls) than
platers (3.6%, 36 platers) had been engaged in asbestos processing. Thus, the
risk of lung cancer due to chromium exposure in platers compared to that of
the controls may have been underestimated. Results of this study are
inconclusive because of the relatively short (3 year) follow-up period in this
retrospective study, and because results from the prospective study are only
preliminary.
Okubo and Tsuchiya (1979) conducted a cohort study of 889 Tokyo chrome
platers an unspecified number of controls selected from the same factories as
the chromium platers. The follow-up period was April 1, 1970 to September 30,
1976. Vital statistics were ascertained using the records of the Tokyo Health
Insurance Society of the Plating Industry. The type of work and chromium
exposure history of the members of this society were investigated by a
questionnaire sent to the manager of each factory. The recovery rate of the
questionnaire was 70.5%. Survival information on retired subjects was
obtained from the offices of the Japanese family registration system. Among
the 889 male chromium platers, 19 deaths were observed or about 50% of that
expected. The expected number of deaths was calculated using the annual male
mortality rates, by age, for Tokyo. In contrast, the authors reported a
slightly higher percentage of deaths in the control group.
The authors noted that two possible types of error may have occurred in
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this study: 1) deaths from the chromium group were incorrectly assigned to
the control group and 2) the 30% of nonresponders may have represented a
significant number of factories where chromium-related deaths may have
occurred.
In addition to the problems noted by the author, the follow-up period for
this study, six years, is probably not long enough to be able to detect
differences in lung cancer mortality resulting from chromium exposure. Also,
the size of the cohort, 889, is relatively small to be able to detect
significant differences in lung cancer mortality.
Silverstein et al. (1981) found a statistically significant increase
(P < 0.001) in the lung cancer proportionate mortality ratios for both male
and female white employees in a die-casting and electroplating plant. In this
plant workers were exposed to chromium during electroplating, but nickel and
copper were also used to electroplate. The other operations of the plant were
zinc alloy die-casting and buffing, polishing, and metal cleaning of zinc and
steel parts. Because of the employees' exposure to other potential
carcinogens, no conclusion can be made from this study regarding the
association of chromium electroplating and lung cancer mortality.
Ferrochromium Workers
Langard et al. (1980) studied ferrochromium workers at a ferrochromium
plant in Norway who were predominantly exposed to trivalent chromium. In an
industrial hygiene study of the plant in 1975, ambient chromium levels of
between 0.01 and 1.34 mg/m3 were detected in the ferrochromium department,
and, of this chromium, it was determined that 11 to 33% was hexavalent. The
study consisted of 976 employees who worked for > 1 year, were alive after
1953, and initially employed prior to 1960. The study group was divided into
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10 subgroups by job description, with only 325 subjects specifically
associated with ferrochromium production and considered exposed to chromium.
Comparisons of cancer incidence for all sites and for different sites were
made between the Norwegian male population and ferrochromium worker population
using the Norwegian Cancer Registry. Poisson distribution was used to test
for statistical significance. A comparison of total mortality was also made.
Of the 10 job-related subgroups, only the ferrochromium workers had a
significant difference between the observed and expected number of lung cancer
cases (7 observed versus 3.1 expected, P < 0.05). Note: The statistical
significance was calculated by Langard et al. to be P = 0.08. CAG tested the
difference using the Poisson distribution and found the significance to be
P < 0.05. Total mortality and cancer incidence at all sites were similar to
the general population. The relative risk of lung cancer among the
ferrochromium workers as compared to the Norwegian male population, may be
underestimated, however, since the county in which the plant was located,
Hordaland, had an age-adjusted lung cancer incidence 58% that of Norway's lung
cancer incidence rate. If this 58% is multiplied by the expected number of
lung cancer cases calculated from national rates, this newly calculated
expected number is different from the observed at P < 0.01. If nonchromium
exposed workers in this plant were used as a control population, the risk of
lung cancer in chromium-exposed workers is increased to 8.5, which is
significant at P < 0.01. The ferrochromium workers were possibly exposed to
two other carcinogens, asbestos and polycyclic aromatic hydrocarbons; however,
this was unlikely to have been an important factor, the author indicated,
since a group of 243 ferrosilicon workers in the same plants were believed to
be exposed to these two known carcinogens to the same degree, and no increased
risk of lung cancer (0 observed and 2.78 expected) among them was observed.
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However, the sample size of ferrosilicon workers (Number = 243) would have to
be considered to small to be able to detect any signifiant excess of lung
cancer.
In studies of the ferrochromium industry in Sweden, Axelsson et al. (1980)
concluded that there was no association between employment in the
ferrochromium industry and risk of lung cancer. The study cohort consisted of
1,876 men employed for one or more years between 1930 and 1975, all of whom
were alive as of 1951. Observed cases were included for comparison if they
occurred 15 years after first exposure. The exposed population was compared
with males in the county in which the plant was located, and comparisons were
tested for significance by two-sided P-values using the Poisson distribution.
The workers were subdivided into four groups consisting of arc-furnaces;
transport, metal grinders, sampling; maintenance; and office workers. It was
estimated that these groups were exposed to 2.5, 0.5 to 2.5, 2.5, and 0
mg/m3 of Cr+3 and Cr°, and 0.25, 0.01 to 0.05, 0.05, and 0 mg/m3 of
Cr+6, respectively. Medical examination of employees during the last 3
years of the study detected three cases of perforated septum of the nose,
confirming that some exposure to Cr+6 had occurred in at least a portion of
the work force. No statistically significant difference in cancer mortality
between that observed in the workers and that expected based on national
mortality data was found. The only significant increase in cancer incidence
was an increase in respiratory cancer (4 observed and 1 expected, P = 0.038)
in the 315 maintenance workers. Of the four cases of respiratory cancer, two
were diagnosed as mesotheliomas, and the authors suggested that these may have
resulted from exposure to asbestos. It was also noted that the control
population was mainly rural dwellers, while the exposed group consisted of
urban dwellers, and that rural residents in Sweden generally smoked less.
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From the results of this study, the authors concluded that no association
existed between exposure to predominantly Cr"1"3 and Cr° and the development
of cancer. Because of the confounding due to smoking and exposure to
asbestos, no definite conclusions can be drawn from this study.
Summary of Epidemiologic Studies
Epidemiologic studies of chromate production facilities in the United
States, Great Britain, West Germany, and Japan have all found an association
between occupational exposure to chromium and lung cancer. Workers in the
chromate production industry are exposed to both Cr(III) and Cr(VI) compounds.
Most of the epidemiologic studies did not attempt to determine which chromium
compounds were the etiological agents. Three studies of the chrome pigment
industry, one in Norway, one in Great Britain, and the third in the
Netherlands and Germany, have also found an association between occupational
exposure to chromium and lung cancer. The predominant chromium exposure in
the chrome pigment industry is to Cr(VI). One study of the chromium plating
industry in England (Royle 1975) reported that workers exposed primarily to
Cr(VI) (chromic acid mist and some dichromate dust) had a significantly
(P < 0.05) higher mortality from cancer at all sites than the control group;
respiratory cancer mortality was not found to be elevated, however, and the
follow-up period was only for 3 years. Thus the results are inconclusive.
Results of a Japanese study (Okubo and Tsuchiya 1979) of chrome platers was
negative. A proportionate mortality study by Silverstein et al. (1981) of a
die-casting and electroplating plant where chromium was used to electroplate
found an excess of lung cancer mortality, but because of the presence of other
carcinogens in the plant, no conclusions regarding the association of chromium
and lung cancer can be drawn from this particular study. Two studies of the
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ferrochromium industry reported an increased risk of lung cancer mortality.
In most of the studies, smoking data was inadequate for any detailed
analyses with regard to smoking as a confounding variable with respect to lung
cancer. However, the lung cancer relative risks found by most of the studies
were higher than the risks that would be expected on the basis of difference
in smoking habits between the study group and the controls. The relative risk
of lung cancer for smokers in the United States as compared to nonsmokers is
about 10-fold (U.S. Department of Health and Human Sevices 1982). In
contrast, Brinton et al. (1952) found a relative risk of lung cancer mortality
for chromate production workers of about 29; the odds ratio (unadjusted) of
being a lung cancer case and being occupationally exposed to chromium was
calculated by the CAG from the data by Baetjer et al. (1959) to be about 32
for cases at the Johns Hopkins Hospital and 23 for cases at the Baltimore City
Hospital. Langard and Norseth (1975) calculated a risk of dying from lung
cancer for workers in the chrome pigment industry of 38. Lastly, in regard to
the issue of smoking as a confounding variable, the dose-response in terms of
length of time worked in the industry seen in the Hayes et al. (1979) and the
Taylor (1966) studies and the dose-response found by Mancuso (1975) in terms
of mg/m3-years of total chromium would not likely be explained by
differences in smoking habits between the study population and the comparison
population. Using the International Agency for Research on Cancer (IARC)
classification scheme for the assessment of human evidence of carcinogenicity,
the Carcinogen Assessment Group would classify the human evidence for chromium
as sufficient.
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QUANTITATIVE ESTIMATION
This quantitative section deals with the unit risk for chromium in air and
the potency of chromium relative to other carcinogens that the CAG has
evaluated. The unit risk estimate for an air pollutant is defined as the
lifetime cancer risk occurring in a hypothetical population in which all
individuals are exposed continuously from birth throughout their lifetimes to
a concentration of 1 ug/m3 of the agent in the air that they breathe. This
calculation is done to estimate in quantitative terms the impact of the agent
as a carcinogen. Unit risk estimates are used for two purposes: 1) to
compare the carcinogenic potency of several agents with each other, and 2) to
give a crude indication of the population risk which might be associated with
exposure to these agents, if the actual exposures are known.
The data used for the quantitative estimate can be of two types: 1)
lifetime animal studies, and 2) human studies where excess cancer risk has
been associated with exposure to the agent. It is assumed, unless evidence
exists to the contrary, that if a carcinogenic response occurs at the dose
levels used in a study, then responses will also occur at all lower doses with
an incidence determined by the extrapolation model.
There is no solid scientific basis for any mathematical extrapolation
model that relates carcinogen exposure to cancer risks at the extremely low
concentrations that must be dealt with in evaluating environmental hazards.
For practical reasons such low levels of risk cannot be measured directly
either by animal experiments or by epidemiologic studies. We must, therefore,
depend on our current understanding of the mechanisms of carcinogenesis for
guidance as to which risk model to use. At the present time the dominant view
of the carcinogenic process involves the concept that most agents that cause
cancer also cause irreversible damage to DNA. This position is reflected by
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the fact that a very large proportion of agents that cause cancer are also
mutagenic. There is reason to expect that the quanta! type of biological
response, which is characteristic of mutagenesis, is associated with a linear
non-threshold dose-response relationship. Indeed, there is substantial
evidence from mutagenesis studies with both ionizing radiation and a wide
variety of chemicals that this type of dose-response model is the appropriate
one to use. This is particularly true at the lower end of the dose-response
curve; at higher doses, there can be an upward curvature probably reflecting
the effects of multistage processes on the mutagenic response. The linear
non-threshold dose-response relationship is also consistent with the
relatively few epidemiologic studies of cancer responses to specific agents
that contain enough information to make the evaluation possible (e.g.,
radiation-induced leukemia, breast and thyroid cancer, skin cancer induced by
arsenic in drinking water, liver cancer induced by aflatoxin in the diet).
There is also some evidence from animal experiments that is consistent with
the linear non-threshold model (e.g., liver tumors induced in mice by
2-acetylaminfluorene in the large scale EDf)j study at the National Center
for Toxicological Research and the initiation stage of the two-stage
carcinogenesis model in rat liver and mouse skin).
Because it has the best, albeit limited, scientific basis of any of the
current mathematical extrapolation models, the linear non-threshold model has
been adopted as the primary basis for risk extrapolation to low levels of the
dose-response relationship.
The quantitative aspect of the carcinogen risk assessment is included here
because it may be of use in the regulatory decision-making process, e.g.,
setting regulatory priorities, evaluating the adequacy of technology-based
controls, etc. However, it should be recognized that the estimation of cancer
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risks to humans at low levels of exposure is uncertain. At best, the linear
extrapolation model used here provides a rough, but plausible estimate of the
upper-limit of risk; i.e., it is not likely that the true risk would be much
more than the estimated risk, but it could very well be considerably lower.
The risk estimates presented below should not be regarded as an accurate
representation of the true cancer risks even when the exposures are accurately
defined. The estimates presented may be factored into regulatory decisions to
the extent that the concept of upper risk limits is found to be useful.
Although there are many epidemiologic studies demonstrating that chromium
(Cr+6) is a potential human carcinogen, few of the studies provide adequate
exposure data for use in risk estimation. One study by Mancuso (1975)
provides what the CAG feels is limited but adequate information for this
purpose, however. The Mancuso study was based on a cohort of 332 white male
workers employed in a chromate plant between 1931 (when the plant began to
operate) and 1937 and followed to 1974.
In his study, Mancuso reported lung cancer death rates by levels of
exposure to soluble, insoluble, and total chromium concentrations. Because
only lung cancer mortality for total chromium exposure was reported by age
group, the CAG has used the only dose-response data for total chromium in its
risk estimation.
Exposure information in the Mancuso study was derived from an industrial
hygiene study of the plant conducted in 1949. In this study, time-weighted
averages of exposure to insoluble, soluble, and total chromium per cubic meter
were calculated for each occupation and for each worker in every department.
Using this data and company personnel records, Mancuso was able to calculate
an estimate of exposure to soluble, insoluble, and total chromium by duration
of exposure (in mg/m3-years) for each member of the 1931-37 cohort. The
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plant began operation In 1931. In 1949, after the industrial hygiene study
had been conducted, the company initiated a comprehensive program designed to
reduce exposure to employees and improve manufacturing efficiency. Until that
time, however, the company had not undertaken any programs for the purpose of
reducing employee exposure. It should be noted, however, that Bourne and Yee
(1950) who conducted the industrial hygiene survey in 1949 reported that "in
order to meet price and quality competition, improvements in equipment and
processes have been made periodically during the past 18 years, and it is the
universal experience of industrial hygiene personnel that greater process
efficiency is almost invariably associated with a more healthful working
environment. Therefore, there seems little doubt that atmospheric
contamination in the past was greater than in 1949." Nonetheless, no
concerted effort was made to reduce employee exposure until late in 1949 and
because this particular plant was a relatively modern plant at the time of the
industrial hygiene survey, it is unlikely that improvements in efficiency over
the period 1931 to 1949 would have reduced employee exposure to a great
extent. Thus, the GAG considers Mancuso's data to be a reasonable
approximation of what workers in the study cohort were exposed to during their
entire working history. We recognize the possibility that the exposure may be
slightly underestimated because it seems likely that a greater proportion of
the "total exposure" was contributed by the exposure prior to 1949 than post
1949.
The effects of underestimating the exposure concentration, along with
other uncertainties on the estimation of potency, will be addressed in the
Discussion section.
As stated in the previous paragraphs, the CAG used only Mancuso's data and
lung cancer deaths by total chromium exposure in its risk estimation. The
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CAG, however, believes that only some of the hexdvalent chromium compounds can
for certain be said to be carcinogenic. Thus, the risk estimate presented
here for total chromium will obviously underestimate the true risk from
exposure to those chromium compounds that are carcinogneic. The risk estimate
and carcinogenic potency of chromium as discussed in the following pages
places chromium in the first quartile of those carcinogens for which CAG has
done risk estimates. Thus, the potency of chromium compounds that are
carcinogenic is very high in comparison to that of other compounds for which
the CAG has done risk estimates. This, the CAG feels, is important
information, but it should be cautioned that it is to be used only in
conjunction with those chromium compounds evaluated by the CAG to be
carcinogenic.
Data Available for Estimating the Cancer Risk
Table 7-13 , which is taken directly from Mancuso (1975), presents the
age-specific lung cancer deaths, the corresponding person-years, and the range
of exposure to total chromium.
To estimate the lifetime cancer risk due to exposure to chromium, we
assume that an exposure, D (mg/m3-years) , as presented in Table 7-13 , is
equivalent to the continuous exposure d (ug/m3) calculated by
d = JL x __§. x 240 x 103 Ug/m3
24 365
where Le is the midrange in each age category, f is the fraction of time in
age exposed, and 8/24 and 240/365 are the fractions of a day and year,
respectively, that a worker spent at the plant. For instance, if D = 8
mg/m3-years, Le = 60, and f = 0.65, then d = 44.96 ug/m3. The
assumption of f = 0.65 implies that the cohort exposure to chromium began
7-70
-------
TABLE 7-13 • AGE-SPECIFIC LUNG CANCER DEATH AND THE GRADIENT EXPOSURE TO TOTAL CHROMIUM
(Mancuso 1975)
Exposure to Total Chromium (mg/m^-year)
Age <1.00 1.0-1.99 2.0-3.99 4.0-5.99 6.0-6.99 7.0-7.99 8+*
45-54 Deaths 1 2
Person-years 886 459
55-64 Deaths 1 3
Person-years 707 356
65-74 Deaths 1 1
Person-years 235 166
24330
583 348 159 140 262
14231
462 250 113 98 203
21103
182 80 42 41 81
*Data in the last column are not used in our risk assessment because the range of exposure in
this class is not known and it does not appear reasonable to assume that all three age groups had an
identical exposure distribution in this class.
-------
approximately at age 20. The assumption is that the particular exposure
pattern (unknown to us) leading to the cancer mortality rates as observed is
equivalent to the continuous constant exposure starting from the age when
exposure began. This assumption may or may not be realistic. However, it
would be more unrealistic to make a different assumption concerning the
exposure pattern when all that is given is an exposure which itself was
calculated by taking the weighted average of the duration of exposure for each
respective job the man had.
Since the person-year in each category presented in Table 7-13 is very
small, the exposure categories are combined as shown in Table 7-14 to
increase the statistical stability. The last column of Table 7-14 is given
for the purpose of identifying which exposure categories in Table 7-13 are
combined. The midrange of age and exposure concentration is used in
Table 7.^4 . Data in this table are used to estimate the lifetime cancer
risk due to chromium exposure.
Choice of Dose-Response Model
It has been widely recognized (e.g., Doll 1971) that the age-specific
incidence curve tends to be linear on doubly logarithmic graphs, or
equivalently, the age-specific incidence follows the mathematical form
where b and k are parameters that may be related to other factors such as
dose, and T may be one of the following three cases:
1. T is age when cancer is observed,
2. T is the time from the first exposure to observed cancer, or
7-72
-------
TABLE 7-14 . COMBINED AGE-SPECIFIC LUNG CANCER DEATH RATES
AND TOTAL CHROMIUM EXPOSURE (in ug/m3)
Age
50
50
50
60
60
60
70
70
Concentration
(ug/m3)* Death Person-year
5.66
25.27
46.83
4.68
20.79
39.08
4.41
21.29
3
6
6
4
5
5
2
4
1345
931
299
1063
712
211
401
345
Background Exposure Range
Ratet as Presented in Table 7-13
6.05 x lO-4
6.05 x ID'4
6.05 x lO-4
1.44 x IO-3
1.44 x IO-3
1.44 x ID'3
1.57 x IO-3
1.57 x IO-3
_< 1
2.0
6.0
<_ 1
2.0
6.0
1 1
2.0
.99
- 5.99
- 7.99
.99
- 5.99
- 7.99
.99
- 7.99
. r> ,
f = 0.65 in the formula described in the section "Data Available For Estimating the Cancer
Risk." The concentrations presented in this table are the averages of several exposure
categories weighted by corresponding person-years.
tBackground rate is estimated from 1964 U.S. Vital Statistics. The year 1964 is selected
because it is estimated that a large proportion of lung cancer deaths occurred during that year.
-------
3. T is the time from exposure to cancer minus the minimum time for a
cancer to be clinically recognized.
This model has been shown to arise from the somatic mutation hypothesis of
carcinogenesis (Armitage and Doll 1954, Whittemore 1978, Whittemore and Keller
1978). It has also been shown to arise from the epigenetic hypothesis when
the reversible cellular change is programmed to occur randomly (Watson 1977).
These authors and many others have used this model to interpret and/or
estimate potency from human data.
Since the data that could be used for risk estimation are limited, a
simple model that fits the data should be used. Therefore, the observed
age-specific incidence is assumed to follow the model
I(t,d) = B(t) + h(t,d)
where B(t) is the background rate at age t and h(t,d) = Q(d) tk-1 with
p
Q(d) = q.d + q d , a function of dose d.
Once the parameters q^ q2, and k are estimated, the lifetime
cancer risk associated with an exposure d by age t, taking into account the
competing risk, can be calculated by
t s
P(t,d) =/ h(s,d)exp{- [/ h(y,d)dy + A(s)]}ds
0 0
where exp[-A(s)] is the probability of surviving to age s and h(t,d) =
I(t,d) - B(t), the age-specific incidence after adjusting the background rate.
Estimation of the Risk Model
To estimate the parameters in h(t,d) we assume, as is usually done, that
the number of lung cancer deaths, X, at age t, follows the Poisson
7-74
-------
distribution with the expected value
E(x) = N x (B + Q(d) tk-!)
where N is the person-year associated with X, B is the background rate at age
t, and Q(d) = q^ + q2d2.
Using the BMDP computer program P3R and the theory relating the maximum
likelihood and non-linear least square estimation by Jennrich and Moore
(1975), the parameters q1 , q?, and k are estimated by the method of
maximum likelihood as q. = 1.11 x 10~7, q2 = 1.84 x 10"9, and k =
2.915.
Thus, the age-specific cancer death incidence at age t due to chromium
exposure d ug/m3 is given by
h(t,d) = Q(d) t
where
Q(d) = 1.11 x 10'7d + 1.84 x lO'V
The model fits the data well as one can see from the goodness of fit
statistic
X2 =z (0-E)2/E = 1.60
which has, asymptotically, a chi-square distribution with 5 degrees of freedom
under the model specified. The observed and predicted values used in
calculating X2 are (3, 2.5), (6, 7.2), (6, 5.1), (4, 3.11), (5, 6.7), (5,
4.1), (2, 1.4) and (4, 4.3).
Taking into account the competing risk, the lifetime probability of lung
cancer death due to exposure to chromium d ug/m3 is given by
7-75
-------
L
P(L,d) = / h(t,d)exp{-[(Q(d)/2.915) t2-915 + A(t)]}dt
o
where L is the maximum human lifetime and is mathematically equivalent to
infinity, since the probability of surviving beyond L is 0.
At low doses, approximately,
P(L,d) = d x P(L,1)
where P(L,1) is the lifetime cancer risk due to exposure to 1 ug/m^ of
chromium. The unit risk, P(L,1), has been adopted by the CAG as an indicator
of the carcinogenic potency of a chemical compound.
Calculation of the Potency at 1 ug/m3
To calculate the unit risk, P(L,1), we need to know exp[-A(t)], the
probability of surviving to age t. Since this probability can only be
estimated, it is assumed that the survival probability is constant over a
5-year interval as provided in the U.S. Vital Statistics.
Using this approximation and by integrating the formula, P(L,1), we have
P(L,1) = Z[exp(-3.87 x ICT* t^
exp(-3.87 x 10- t
= i.ie x in-2
where (t^j, t-j) is a 5-year interval and PJ is the probability of
survival up to the age t-j.j. PJ is assumed to be a constant over the
interval and is estimated from the 1975 U.S. Vital Statistics.
7-76
-------
Relative Potency of Chromium
Figure 7-1 1s a histogram representing the frequency distribution of
potency indices of 52 suspect carcinogens evaluated by the CAG. Table 7-15
presents the potency index for these 52 suspect carcinogens. The potency
index for a compounds is a rounded-off potency expressed in term of
(mMol/kg/day)'1. When human data are available for an agent, they have been
used to calculate the index. When no human data are available, animal oral
studies have been used in preference to animal inhalation studies.
Based on the occupational study and the assumption that the daily air
intake of a 70 kg man is 20 m3, the potency index for chromium 1s calculated
as 4 x lb+3, which lies in the first quartile of the distribution. This
provides the relative potency of chromium in comparison with other suspect
carcinogens evaluated by the CAG.
JJI scussion
The following discussions are intended to provide some insight about the
uncertainties on the estimated carcinogenic potency of chromium. No
statistical confidence limits can be meaningfully calculated because it is not
reasonable to assume that the exposures were measured without error.
1. As noted previously, the risk is estimated on the basis of the total
chromium obtained from all the soluble and insoluble chromium to which workers
were exposed. If indeed only some compounds of Cr+6 are carcinogenic, then
the potency presented above is likely to be underestimated. However, it is
difficult to evaluate the level of underestimation because the proportion of
the total chro-nium exposure that is carcinogenic is unknown. If one could
assume that the carcinogenic chromium compounds constituted half of the total
chromium exposure for each of the exposure groups in Table 7-13 , then the
7-77
-------
4th
quartile
3rd
quartile
2nd
quartile
1st
quartile
1x10
4x10
2x10
246
Log Of Potency Index
Figure 7-1 . Histogram representing frequency distribution of the potency
indices of 52 suspect carcinogens evaluated by the Carcinogen
Assessment Group.
7-78
-------
TABLE 7-15. RELATIVE CARCINOGENIC POTENCIES AMONG 53 CHEMICALS EVALUATED
BY THE CARCINOGEN ASSESSMENT GROUP AS SUSPECT HUMAN CARCINOGENS1»2»3
Compounds
Acrylonitril e
Aflatoxin B}
Aldrin
Ally! Chloride
Arsenic
B[a]P
Benzene
Benzidine
"leryl 1 iun
Cadmium
Carbon Tetrachloride
Chlordane
Chlorinated Ethanes
1,2-dichl oroethane
hexachloroethane
1,1, 2, 2-tetrachl oroethane
1 ,1 ,1-trichl oroethane
1,1 ,2-t rich! oroethane
Chi oroform
Chromium
OOT
Dichlorobenzidi ne
1 ,1-dichl oroethylene
Oieldrin
Slope
(mg/kg/day)"1
0.24(W)
2924
11.4
1.19x10-2
15(H)
11.5
5.2xlO-2(w)
234(W)
4.86
6.65(W)
1. 30X10-1
1.61
6.90x10-2
1.42x10-2
0.20
1.6x10-3
5.73x10-2
7x10-2
41
8.42
1.69
1.47x10-1(1)
30.4
Molecular
Weight
53.1
312.3
369.4
76.5
149.8
252.3
78
184.2
9
112.4
153.8
409.8
98.9
236.7
167.9
133.4
133.4
119.4
104
354.5
253.1
97
380.9
Potency
Index
1x10+1
9xlO+5
4x10+3
9x10"!
2x10+3
3x10+3
4x10°
4x10+4
4x10+1
7x10+2
2X10+1
7x10+2
7xlOn
3x10°
3x10+1
2x10-1
RxlOn
8x10°
4x10+3
3x10+3
4x10+2
1x10+1
1x10+4
Order of
Magnitude
0°9io
Index)
+1
-t-6
+4
0
+3
+ 3
+ 1
+5
-t-2
-t-3
+1
+3
0
+1
-1
+ 1
-H
+4
+3
+3
+1
+4
(continued on the following page;
7-79
-------
TABLE 7-15
(continued)
Compounds
Dinitrotoluene
Diphenylhydrazine
Epichlorohydrin
Bis(2-chloroethyl )ether
Bis(chloromethyl ) ether
Ethylene Dibromide (EDB)
Ethylene Oxide
Formaldehyde
Heptachlor
Hexachlorobenzene
Hexachl orobutadi ene
Hexachl orocycl ohexane
technical grade
alpha isomer
beta isomer
gamma isomer
Nickel
Nitrosamines
Dimethyl nitrosamine
Diethylnitrosamine
Di butyl nitrosamine
N-ni trosopyrrol i di ne
N-nitroso-N-ethylurea
N-nitroso-N-methyl urea
N-nitroso-di phenyl ami ne
PCBs
Slope
(mg/kg/day)"1
0.31
0.77
9.9xlO-3
1.14
9300(1)
8.51
0.63(1)
2.14xlO-2(I)
3.37
1.67
7.75xlO-2
4.75
11.12
1.84
1.33
1.15(W)
25.9(not by q*)
43. 5 (not by q*)
5.43 l
2.13
32.9
302.6
4.92xlO-3
4.34
Molecular
Weight
182
180
92.5
143
115
187.9
44.0
30
373.3
284.4
261
290.9
290.9
290.9
290.9
58.7
74.1
102.1
158.2
100.2
117.1
103.1
198
324
Potency
Index
6x10+1
lxlO+2
9X10-1
2x1 0+2
lxlO+6
2x1 0+3
3xlO+1
6X10-1
lxlO+3
5xlO+2
2X10+1
lxlO+3
3xlO+3
5xlO+2
4x10+2
7xlO+1
2xlO+3
4x1 0+3
9x10+2
2x10+2
4xlO+3
3x1 0+4
1x10°
lxlO+3
Order of
Magnitude
(1o9lQ
Index)
• +2
+2
0
+2
+6
+3
+1
0
+3
+3
+1
+3
+3
+ 3
+3
+2
+ 3
+4
+3
+2
+4
+4
0
+3
(continued on tne following page)
7-80
-------
TABLE 7-15
(continued)
Compounds
Phenols
2,4,6-trichlorophenol
Tetrachlorodloxin
Tetrachloroethylene
Toxaphene
Trichloroethylene
Vinyl Chloride
Slope
(mg/kg/day)'1
1.99xlO-2
4.25xl05
5.31X10'2
1.13
1.26xlO-2
1.75x10-2(1)
Molecul ar
Weight
197.4
322
165.8
414
131.4
62.5
Potency
Index
4x10°
lxlO+8
9x10°
5xlO+2
2xlOn
1x10°
Order of
Magnitude
0°9lp
Index)
+1
+8
+1
+3
0
0
Remarks:
1. Animal slopes are 95% upper-limit slopes based on the linear multistage model.
They are calculated based on animal oral studies, except for those indicated by I
(animal inhalation), W (human occupational exposure), and H (human drinking water
exposure). Human slopes are point estimate, based on linear non-threshold model.
2. The potency index is a rounded-off slope in (mMol/kg/day)"-^ and is calculated by
multiplying the slopes in (mg/kg/day)"^ by the molecular weight of the compound.
3. Not all the carcinogenic potencies presented in this table represent the same degree
of certainty. All are subject to change as new evidence becomes available.
7-81
-------
risk at low doses would be approximately twice as much as that estimated by
our model.
2. As indicated previously, there 1s a possibility that the use of 1949
hygiene data may result in a slight underestimation of what workers were
actually exposed to. However, because the plant was relatively modern at that
time, the underestimation is unlikely to be very considerable. If an
underestimation of 2 tines were assumed, then the unit risk would be reduced
from 1.2 x 10~2/ug/m3 to 6.0 x lCT3/ug/m3.
3. The risk presented in this report may be somewhat overestimated in the
sense that it is implicitly assumed that the smoking habits of chromate
workers were similar to the general white male population, while it is
generally accepted that the proportion of smokers is higher for industrial
workers (thus the higher background incidence rates) than for the general
population. As a sample calculation, we found that if the background rate of
lung cancer mortality for the cohort in Table 7-14 is increased by 40%,
then the corresponding unit risk would be reduced by about 25%, or from 1.2 x
10-2 to 8.7 x 10-3.
The background age-specific rate of lung cancer at ages 50, 60, and 70
could be 40% more than those presented in Table 7-14 , should it be assumed
that 80% of c-iromate workers are ever-smokers (individuals who smoke at least
100 cigarettes during their lifetimes) and only 50% of the general white male
population are ever-smokers. It could also result from other assumptions
about the smoking habit of the chromate workers and the general population.
For instance, the background rate could be increased by approximately 40%,
based on the age-specific cancer rates provided by Doll (1971), if the
proportion of smokers in each smoking level is distributed as follows:
7-82
-------
NUMBER OF CIGARETTES SMOKED PER DAY
0 1-14 15-24 25 or more
Chromate Workers 0.3 0.2 0.3 0.2
General Population 0.5 0.2 0.2 0.1
7-83
-------
SUMMARY
It is pressumed that all forms of Cr(VI) are carcinogenic but the degree
of carcinogenicity is modified by the solubility of the specific compounds.
Using the International Agency for Research on Cancer (IARC) criteria, animal
studies have provided sufficient evidence for the carcinogenicity of the
following Cr(VI) compounds: calcium chromate, strontium chromate, and zinc
chromate. Both Cr(III) and Cr(VI) compounds have been ineffective in
producing lung tumors by inhalation in animals . Similarly, negative results
have been obtained following the ingestion of Cr(III). Chromium has been
shown to be carcinogenic by intrabronchial, intrapleural, intramuscular
implantation, or subcutaneous injection; however. Cr(III) compounds have been
studied less extensively than Cr(VI); however, animal studies indicate that
Cr(VI) is more likely to be the etiologic agent in human chromium-related
cancer.
The epidemiologic studies of chromium have demonstrated an association
with respiratory cancer in chromate-producing industries. The strength of the
association is evidenced by the high relative risks of lung cancer and the
consistency of results by different investigators in different countries.
Results of three epidemiologic studies of chrome pigment workers are also
suggestive of an association with lung cancer. Less clear, however, is
question of which form of chromium is carcinogenic. One epidemiologic study
of chrome pigment workers (Davies 1978, 1979) suggested that zinc chromate was
carcinogenic while lead chromate was not. However, the data on the lead
chromate pigment workers was limited by small sample size. Most of the
epidemiologic studies did not attempt to distinguish the carcinogenic species
of chromium.
Although a number of epidemiologic studies have found an association
7-84
-------
between exposure to chromium and lung cancer, the data that could be used for
estimating the cancer risk due to the exposure to chromium are limited to the
study by Mancuso (1975). Mancuso (1975) reports age-specific lung cancer
mortality data for chromate production workers in terms of total elemental
chromium exposure. Using this information, CAG estimated the lifetime cancer
risk due to a constant exposure to air containing 1 ug/m^ of elemental
chromium to be 1.2 x 10"^. This is considered an upper-bound estimate,
since it is based on a model that is linear at low doses.
CONCLUSIONS
Using the IARC criteria, epidemiologic studies provide sufficient evidence
that chromium is a human carcinogen. Using IARC criteria, the animal bioassay
studies have provided sufficient evidence for the carcinogenicity of
hexavalent chromium. The carcinogenic evidence for trivalent chromium is
inconclusive. Hexavalent chromium is mutagenic in multiple tests while the
data for trivalent chromium is inconclusive.
Using the IARC classification scheme, the level of carcinogenic evidence
available for the combined animal and human data would place chromium into
Group 1, meaning that there is decisive evidence for the human carcinogenicity
of chromium.
7-85
-------
7.2.2. Genotoxicity.
7.2.2.1. JJJ VITRO MJTAGEMCITY — In an attempt to understand the funda-
mental biological activity of metals and its relationship to carcd.nogenesis,
numerous in vitro experiments have been conducted. Many of these studies attempt
to exploit the strong relationships between molecular events involved in muta-
genesis and carcinogenesis. In particular, the interaction of xenobiotics with
nucleic acids is believed to be a critical event in mutagenesis and/or cell
transformation. Cultures of mammalian cells and bacteria, as well as cell-free
systems, have been used to explore the potential mutageni city/carcino geni city of
chromiun salts. Although mutageni city assays employing bacterial tester strains
have received widespread use in screening compounds for mutageni city (e.g., Ames
assay), these assay systems have not been frequently employed for screening
metals. Nevertheless, positive results have been obtained with several metals in
both in vitro mutageni city assays and assays using DNA repair deficient bacteria.
A summary of the results obtained from in vitro mutagenicity assays of chromium
compounds are presented in Table 7-17.
In an early study of the mutagenicity of chromium in bacteria, Venitt and
Levy (1971*) tested three soluble Cr(VI) salts (Na2Cr04, KgCrO^, and CaCrO^) for
mutagenic activity using a spot test. Following application of each compound to
the plate at levels of 0.05, 0.10, or 0.20 jimol, a 3-fold increase was observed
in the number of reversion colonies in the tester organism E. coli WP2 (try").
Similar results were observed with both E. coli WP2 and WP2 uvrA (absence of
excision-repair) were exposed to Na^CrOj. in suspension, followed by removal of
the test compound and plating on minimal plates. Repair deficient E. coli WP2
(exrA, error prone DNA repair) and WP2 uvrA were compared with wild type E. coli
WP2 for mutagenic response in the spot test to KpCrOj.. Since all tester
7-86
-------
TABLE 7-17
The In Vitro Mutagenloity Bloassay of Chronic Compounds
Test
Reverse mutation E.
Reverse mutation E.
E.
Reverse mutation E.
E.
E.
Reverse mutation E.
E.
^j E.
i
GO
~~-j Reverse mutation E.
Reverse mutation E.
Reverse mutation E.
E.
Reverse mutation S.
Indicator
Orgmiam
coll W2 (try")
coll W>2 (try")
coll W2 uvrA
coll M>2 (try")
coll V*>2 uvrA
coll H?2 exrA
coll H>2
coll H>2 uvrA
coll CM571
coll Hs30R
coll Vi>2
coll K>2
coll B/r WP2
typhimiriia
Conpoir.d
Tested
Na_CrO,
K CrO,
I*— \>i\y ,
CSCrO,J
Na CrO,
Na,Crt)!
£ H
K CrO,
fCCrO?
2 H
2 "
KpCr.O-
JC Cr 0
K^Cr^oI
I— £ *
K 2Cr^
K2C"2°7
K CrO
2 1»
K2Cr20?
ohr ornate*
Valence
State
46
•*6
46
46
46
46
46
46
46
46
46
46
46
46
46
46
46
Metabolic
Activation
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
no
Dose
0.05, 0.10, and
0.20 [imol/plate
0.5 to 5 mg/nfc
0. 5 to 5 mg/ttt.
0. 05 fimol/plate
0. 05 nmol/plate
0. 05 n mol/plate
1. 0 x 10~^M
1.2 x 10 ,M
1.2 x lO'^M
13. 0 x 10"^M
13.0 x TO'^M
0. 5 |ig/nA
NR
NR
NR
TA92
Reverse mutation S.
typhlmurlun
diohr ornate*
chr ornate*
46
46
no
no
TA1 978. TA92
di chr ornate*
chr ornate*
diohr ornate*
46
46
46
no
yes
yes
NR
100 and 200
nmol/plate
100 and 200
nmol/plate
100 and 200
nmol/plate
100 and 200
nmol/plate
Application Response
spot test 4-
4-
4-
suspension assay +
suspension assay +•
spot test +
spot test 4
spot test 4-
suspension assay +•
suspension assay +
suspension assay
suspension assay 4-*
suspension assay +*
fluctuation test 4-
spot teat 4-
spot test
plate 4-
incorporation
plate +
incorporation
plate 4
incorporation
plate +
incorporation
plate
Incorporation
plate
incorporation
Refer en oe
Venitt and
Levy , 1 971
Venitt and
Levy , 1 971
Venitt and
Levy , 1 971
Nisid oka, 1975
Nakamtro et al .,
1978
Green et al . ,
1976
K an em at s u
et al., 1980
L of roth and
Ames, 1978
Lofroth, 1978
-------
TABLE 7-17 (oont .)
Indicator Compound
Test Or^nisn Tested
Reverse mutaticn S. typhlmurium K,Cr?07
TA1535, TA1537,
TA1538, TA100,
TA98
Reverse mutaticn S. typhlmuriun Na2Cr20_
Na_Cr_0,
2 27
Reverse mutaticn S. typhlmuriun Na.Cr-O-
TA1535, TA1537
TA98, TA100 CrO,
3
-~j CaCrO..
i ^
co K_Cr,(L
d. 2 f
2nCtQh'7t\W)y
«l e.
Na_Cr 0_
~2 2-y
Crt).
3
CaCrO,,
H
1C Cr,0_
2 2 Y
aiCrOa«3h(OH)_
Forward mutaticn S ohl aos acoharomyces K?Cr_0_
pom be
Forward mutaticn Chinese Hamster KpCr.O.
to 8-aaguanine V79 cells ZnCrO^
resistance FbCrO,.
Valence
State
46
46
46
46
46
46
46
46
46
46
46
46
46
46
46
46
46
Metabolic
Activation Dose
no
no
yes
no
no
no
no
no
yes
yes
yes
yes
yes
no
no
no
no
10 to
10 to
10 to
10 to
10 to
10 to
10 to
10 to
10 to
10 to
10 to
10 to
102nM
NR
10 ng/plate
80 ng/plate
200 ng/ pi ate
200 (ig/plate
200 tig/plate
200 (i ft/ pi ate
200 (ig/plate
200 |ift/ pi ate
200 us/ plate
200 ng/plate
200 lift/ pi ate
200 |ig/plate
0.35 to 0.78 lie/at.
1 to
5 to
4 Hft/nA
10 Hft/nA
Application Response
spot test
plate 4-
incorporation
plate
incorporation
plate 4-
incorporation
pi at e 4^
incorporation
plate 4-
incorporation
plate +
incorporation
plate 4-
incorporation
plate
Incorporation
plate
Incorporation
plate
incorporation
plate
incorporation
plate
incorporation
suspension 4-'
in culture medim +
in culture medim +•
In culture medium
Reference
Kanematsu
et al . , 1 980
DeFlora, 1978;
Petrilll and
DeFlora, 1978
Petrel 11 and
DeFlora, 1977,
1978
Bonatti et al .,
1976
New bo Id et al .,
1979
-------
TABLE 7-17 (cont.)
I
GO
Test
Gene conversion
Gene conversion
Reverse mutation
Reverse mutation
Reverse mutation
Reverse mutation
Indicator
Orgmism
S ohi aos accharom ycea
pom be
Saccharemyces
cerevisiae D7
E. coll (try") Cr
E. coll Ft30R
y
S. typhimuriun
TA98, TA1537,
TA1535, TA100
S. t yphimuri un
TA100
Compound
Tested
K2Cr207
Cr03
•2( 33 a^SO,, -210,0
Cr(CH3COO)-
CrtCCSO^.-^H-O
CrCl-«6fLO
CrK(SO,t)2.12H20
Valence
State
46
+6
+3
+3
+3
+3
+3
+3
+3
Metabolic
Activation Dose
no 102 to 105nM
no 10~2 to 10~3
no NR
no 130 x 10~3M
no/yes 20 mg/plate
no/ yes
no/ yes 800 ^g/ pi ate
no
no
Application Response
suspension +
suspension +
spot test*
suspension assay +•
plate
incorporation
plate
incorporation
plate
incorporation
Reference
Bonatti et al .,
1976
Fukunajp et al .,
1982
Venitt and
Levy, 1971
Natemiro et al .,
1978
Petrilli and
DeFlora, 1977
Petrilli and
DeFlora, 1978a,b
• = Refer to text for fvrtner information.
NR = Not reported
-------
organisms yielded approximately the sane mutagenic response regardless of the
presence or absence of DMA repair pathways, the authors concluded that chromium
directly interacted with DNA, with subsequent mispairing of bases occurring
during cell division. Other possible explanations for these results were not
considered. The soluble Cr(III) compound , Cr^SO^SO^ «2H20 [This was the
formula given in the report, although the test compound was probably
Cr?(SOi|)-?»K_SOi. «24H20.], gave negative results (specifics in experimental
protocol were not given), along with soluble salts of tungsten, molybdenum, zinc,
cadmiun, and mercury.
Nishioka (1975) obtained positive mutagenic results with K2Cr_07(VI) in a
suspension assay using the tester strain E. coli WP2 and WP2 uvrA, but not in the
tester strain E. coli CM,-™, . Since strain CMC_, is a re combination- deficient
— - 571
strain, it was postulated that metal mutagenesis needed seme component of the
recA allele. Positive results were also reported for K Cr 0 by Kanematsu et al .
(1980) in the spot test using strain E. coli WP2; however, E. coli B/r WP2 was
negative (no dose information was presented in this study). Nakamuro et al .
(1978) used E. coli HsSOR, a uvrA minus mutant requiring arginine , to study the
mutagenicity of K2Cr2CL(VI) and KjCrO^VI) , and Cr(CH3COO)3( Ill) in a suspension
assay. The respective mutagenic frequency of these compounds was 13^» ^5, and 30
Q
mutants x 10 viable cells. Although positive mutagenic responses were reported
for all test substances, the low survival of between iJ and 10$ at the doses which
were reported as mutagenic may lead to artifacts, particularly if spontaneous
revertants arise during growth on the trace levels of arginine used to supplement
the top agar, as suggested by Green (1976).
Green et al . (1976) also observed mutation in E. coli WP2 using a fluctua-
tion test. At levels of 0.5 (ig/md K^CrO^, '\H8 of 250 tubes were positive as
compared to 64 in controls. At a high dose of 2.5 ng/m2,f only 10 of 150 tubes
7-90
-------
were positive as compared with 31* tubes in the controls. The apparent anti-
mutagenic effect at the higher dose was attributed to the toxicity of the K?CrOj..
The mutagenicity of chromium compounds has been assessed in the Ames assay,
which uses specially constructed histidine dependent strains of Salmonella
typhijaurium; however, in the original report on the validation of this assay,
McCann et al. (1975) stated that the test was not suitable for metals as a
result of the high concentration of magnesium, citrate, and phosphate salts in
the media. Chromate and dichromate but not the chromic ion (the specific salt
was not mentioned) were reported in an abstract to cause frameshift mutations in
,3. typhimurium strains containing the his D3052 and his C3076 mutations, as well
as his G 46 strains containing the R factor. The greatest response was observed
in TA92 with five re vert ants/nmol Cr. Kanematsu et al. (1980) has reported
negative results with K^Cr^Q^ in the spot test using strains TA1535, TA100, TA98,
TA1537, and TA1538; however, the lack of exposure information in this report
makes it difficult to evaluate. In a recent study of the mutagenic activity of
chromic chromate (18.5$ Cr(VI), and 50$ total chromium) in S_. typhimurium strain
TA1535, Witmer et al. (1982) reported that mutagenic activity, expressed as
number of revertants - on test plates -f number of revertants on spontaneous
plates, was increased as the standard salt concentration of the minimal media was
reduced. At least a portion of this observed increased activity resulted from
the poor survival of the cells in the low salt media and the associated decrease
in the number of spontaneous colonies. Although the author suggested that
variation in the j>. typhimurium assay may be useful in further evaluation of the
mutagenic activity of inorganic compounds such as chromiun, further validation
of this method will be required before these results can be compared with the
other available data on mutagenicity of chromiun.
7-91
-------
In further studies, Lofroth (1978) found that chromate and dichromate were
mutagenic in strain TA1978 as well as TA92. On addition of a mammalian micro-
somal activation system (S-9 mix) prepared from the livers of Aroclor pretreated
male rats, the number of revertants decreased from 206 and 357 (assays without
activation system) to 89 and 89 (assays with activation system) for TA1978 and
TA92, respectively. In the absence of NADP in the S-9 mix, the inhibition of
chromium mutagenicity did not occur. It was also reported that addition of
Cr(VI) to an aqueous solution of NADP did not change the valence state of
chromium. It was concluded that NADP plus additional factors in the S-9 mix were
necessary to inactivate Cr(VI), possibly by reduction to Cr(III). Similarly,
Petrilli and DeFlora (1977) obtained positive responses with Na^Cr^d-, CrO-,
CaCrCL, and K Cr-CL when assayed in strains TA1537, TA1535, TA98, and TA100 at
levels between 10 and 200 |ig/plate. When the response was expressed as rever-
tants/jig of Cr(VI) , there was no statistically significant difference in the
activity of each of these compounds. The Cr(III) compounds, CrK(SO.)2 and CrCl_,
gave negative results.
DeFlora (1978) and Petrilli and DeFlora (1978a,b) further studied the
effect of metabolic activation on the mutagenicity of Cr(VI) and (III) . DeFlora
(1978) observed a decrease in the mutagenicity of Na?Cr_CL in S_. typhimurium
strain TA100 in the presence of S-9 mix prepared from rat liver. When Na_Cr20™
was added at 40 ng/plate, the number of revertant colonies decreased from 705 to
M20, 370, 283, 228, and 221 with the incorporation, respectively, of 0, 10, 20,
30, 40, and 50 \ii of S-9 fraction/pi ate. Petrilli and DeFlora (1978b) extend
these observations to the Cr(VI) compounds NapCapO-, CrCL, KpCrO^,
ZnCrOj»2i(OH)p (zinc yellow also contained 10$ CrO_), and PbCrCL'PbO, with muta-
genic activity in strains TA1535, TA1537, TA98, and TA100 detected in the absence
of S-9 mix but not in the presence of S-9 mix, prepared from rat liver. Little or
7-92
-------
no loss of rautagenic activity occurred when the added S-9 was prepared from lung
or muscle. Also, human plasma added to the top agar had no effect on chromium
mutagenicity, but lysates of erythrocytes did result in the loss of mutagenic
activity. The loss of mutagenicity was associated with reduction potential of
components in the S-9 mix, with reduced GSH, TPNH, and G6PD plus S-9 mix (to
generate TPNH) all inhibiting the mutagenicity of Cr(VI) . In a study using
varying levels of TPNH, the mutagenic response was correlated with the amount of
Na_Cr?07 (originally 52 |ig Cr(VI)Xplate) that remained as Cr(VI) . Conversely,
Cr(III) as CrK(S04)2, CrCl3, and CKNO^, which were inactive in the Ames assay,
were converted to active mutagens by the addition of nontoxic levels of the
strong oxidizer KMnOj. ( Petrilli and DeFlora, 1978a). The presence of this
oxidizing agent reversed the effect of S-9 mix on the mutagenicity of Cr(VI) .
These data supported the conclusions that the valence state of chromium was an
important factor in producing a mutagenic response in the Ames assay, and that
naturally occurring biological reducing agents were capable of reducing Cr(VI)
to Cr(III) . Although the studies show that Cr(VI) compounds produce a positive
response, these studies do not indicate whether Cr( III) or (VI) is the ultimate
mutagen which interacts with the DNA of the cell.
Cr(VI) compounds have also been demonstrated to be mutagenic in vitro in
eucaryotic test systems, while Cr(III) was inactive. Bonatti et al . (1976)
2 5
exposed yeast, Schizosaccharomyces pom be , to 10 to 10 \M of KpCr-O- in a
forward mutation assay and a test for gene conversion. Forward mutation was
observed in 7 of 480,054 colonies exposed to 10 (iM K^r^Oj for 7 hours, which
was not statistically increased from controls in which no mutants were observed
in 84,546 colonies; however, if comparison was made to the historical spontaneous
mutation rate (no mutants in 10 colonies), then chromium significantly
increased the mutation rate. In the study of gene conversion, there was a dose
7-93
-------
related increase in the four allelic combinations examined. The authors noted
that there were limitations in this study, but that the data suggest that K Cr 0
waa mutagenic under the test conditions.
Using another strain of yeast, Sac char omyces cerivisiae U?, Fukanaga et al.
(1982) examined the genetic activity of chromium trioxide. The compound was
-2 9
incubated with the cells at concentrations of 10 to 10 M for a period of
24 hours. Following incubation, the cells were plated to determine viability and
recombinance with cross-over in the ade locus. The highest concentration tested
caused nearly 100$ cell death while viability at the lowest concentration was
11%. The cross-over frequency in treated cells was dose dependent with the
_o
10~ M concentration resulting in a frequency of 1.4$ as compared to 0.02$ for
untreated cells. It was also reported that only growing and not resting cells
were susceptible to the effects of chromium, suggesting to the authors that
chromiixn may affect the fidelity of DNA polymerase.
Forward mutagenesis to 8-azaguanine resistance in cultured Chinese hamster
V79/1* cells was used by Newbold et al. (1979) to assess the genetic activity of
both Cr(VI) and (III). The highly soluble and slightly soluble Cr(VI) salts,
K?Cr_07 and 2iCrOj,, respectively, both produced dose related increases in
8-azaguanine resistant cell colonies, while the insoluble Cr(VI) compound,
PbCrOj., and the soluble Cr(III) compound, Cr(CH_COO)_, were inactive. The more
soluble KpCr_0_ was =5-fold more active than the ZnCrCL. It was stressed that
both the valence state and solubility of a chromium compound affected its muta-
genic potential. Although high solubility was necessary for a mutagenic
response, the authors suggested that low solubility would facilitate a carcino-
genic response, since compounds of lower solubility might remain in the body
longer, providing a low dose continuous exposure to chromium.
-------
7.2.2.2. EFFECTS CN DMA AND DNA REPLICATION — It is apparent from the
results of bioassays in both prokaryotic and eucaryotic systems that sane
chromiun compounds are mutagenic. In general, soluble Cr(VI) compounds were
positive in reverse and forward mutagenicity assays, while insoluble salts and
Cr(III) compounds are inactive. Metabolic activation inhibited the mutagenicity
of Cr(VI), probably by the reduction of the Cr(VI) to Cr( III) by cellular
reducing agents such as GSH. Other studies have been performed which indicate
that chromiun compounds interact with DNA and decrease the fidelity of DNA
polymerase, and this mechanism may participate in chromium induced mutagenesis.
The difference in the sensitivity of recombination deficient strains of
bacteria as compared to wild type to the toxic effects of chromium compounds has
been used as an indicator of DNA damage. Nishioka (1975) exposed both rec~ and
rec+ strains of Bacillus subtil is to K2Cr207(VI), K^rO^CVI), and CrCl^III) by
placing 0.05 n& of 0.05 M solution on a filter disc placed on the agar surface.
For the two Cr(VI) compounds, the zone of growth inhibition was greater for the
rec~ strains as compared with the rec+, indicating DNA damage, while there was no
difference in the size of the zone of inhibition in the assay of CrCl.. The
positive rec-effect with K^Cr 0 was diminished sharply when the reducing agent,
Na?SO,, was mixed with the test compound, indicating that the Cr(VI) oxidation
state was necessary to cause DNA damage. Similarly, Kanematsu et al. (1980), in
a survey of 127 metal compounds in the E. subtil is rec assay, reported that three
Cr(VI) compounds (KpCrCL, K^Cr 0„, and CrCL) were positive at 0.05 md of a 0.005
and 0.1 M solution, respectively, for the salts and oxide. Cr(III), Cr^SO^,,
was negative, and it was noted that the sample was toxic to the bacteria at the
dose tested.
Nakamuro et al. (1978) examined three Cr(VI) compounds (K2Cr20>, K^rO^,
and CrO_) and three Cr(III) compounds (Cr(CHLCOOK, Cr(NO_)_, and CrCl-) in the
7-95
-------
rec~ assay with J3. subtills. The compounds were tested using 0.02 md aliquots of
solutions between 3.2 x 10~1 to 1.6x 10" M for the Cr(VI) compound and 1.3 to
1.6 x 10" M for theCr(III) compound. All compounds tested were positive except
for CrCl (III). Although DNA damage as indicated by the rec effect was observed
with two of the Cr(III) compounds, the order of activities was
K2Cr2°7 > K2Cr°4 > Cr°3 > Cr(CH3°°)3 > Cr(NO_)_, with the Cr(VI) compounds being
more active than the Cr( III) compounds.
In an attempt to determine the mechanism of DNA damage induced by chromium,
Levis et al. (1978) examined the effects of KpCrpO™ exposure on DNA synthesis in
cultured BHK cells. The cells were treated with 10~3, 10"**, 10~5, and 10"6 M
K_Cr 0 for 1 to 4 hours, followed by determination of 3H-thymidine uptake into
DNA and the intracellular pools. At the two intermediate doses, increased
specific activity was observed in both the nucleotide pool and DNA, which was
attributed to chromium effects on the membrane transport of the exogenous labeled
thymidine. When DNA synthesis was adjusted for the changes in the specific
activity of the pools, transient and reversible inhibitions of DNA synthesis were
-6 -5
observed at 10 M, and ccmplete irreversible inhibition occurred at 10 M., It
was reported that inhibition of DNA synthesis occurred prior to, and to a greater
extent than, inhibition of protein or RNA synthesis. Although these effects on
DNA synthesis may be partly related to the effects of chromiun on the cellular
membrane, Raffetto (1977) reported evidence of direct interaction with DNA in
A18&jR cultured cells, as indicated by unscheduled DNA synthesis following
treatment with K-CrJD7 (VI). In cells treated for 1 hour with 16, 4, or 1 \ig
Cr(III)/m2, (as CrCl-), no increase was produced. This evidence suggests that at
least Cr(VI) can alter DNA synthesis by more than a single mechanism.
Loeb and coworkers (Sirova and Loeb, 1976; Loeb et al., 1977) have demon-
strated that chromiun compounds adversely affect the fidelity of DNA transcrip-
7-96
-------
tion. The compounds, CrCl- and CrOg, were incubated with avian myeloblastosis
virus DNA polymerase, a template with restricted base composition, and comple-
•32
raentary deoxynucleoside radiolabeled with J P and noncomplementary deoxynucleo-
side labeled with 3H. Following incubation, the error frequency was determined
to be greater when either metal compound was added to the incubation system as
compared to the controls. The error prone avian myeloblastosis virus DNA poly-
merase lacks exodeoxynuclease active for removal of noncomplementary base, thus
providing optimum conditions for detecting the nonfidelity of DNA synthesis. In
later studies, Tkeshelashvili et al. (1980) demonstrated a similar increase in
misincorporation of complementary bases using synthetic polynucleotides and CrO_
and CrCl in an assay system containing E. coli DNA polymerase. Both compounds
appeared to have approximately the same activity. Nearest neighbor analysis
indicated that the noncomplementary bases were incorporated as single base
substitution. Noncomplementary nucleotides were also incorporated with native
DNA from bacteriophage $x174 (am3) and E. coli DNA polymerase in vitro in the
presence of CrO_. Infidelity in DNA synthesis was detected by loss of an amber
mutation which was assessed by growth of infected strains of E. coli nonpermis-
sive and permissive for this mutation.
Tamino et al. (1981) examined the in vivo and in vitro binding of both
Cr(VI) (K_Cr207) and (III) (CrCl_) to DNA from cultured BHK cell, and i.n vitro to
commercial calf thymus DNA and synthetic polynucleotides. The interactions of
Cr(III) with these nucleic acids iji vitro was dependent on the G and C content,
with synthetic poly(G) and poly(C) binding 1.05 chromium ions per 100 nucleo-
tides. Iri vitro and in vivo reaction also changed the ultraviolet (UV) absorp-
tion spectra and thermal stability of the DNA. When Cr(VI) was used there was no
observed change in the UV spectra whether exposure occurred i_n vitro or i_n vivo.
The manner of treatment with Cr(VI) did affect the thermal stability of the DNA
7-97
-------
with in vitro exposure resulting in the same types of changes observed with
Cr(III), while little change in thermal stability occurred with in vivo exposure
to Cr(VI). The data indicate that Cr(III) has some capacity to cross biological
membranes and interact with cellular DNA, and that the types of interactions
between chromium and polynucleotides may be different for Cr(VI) and (III).
Although in vitro mutagenicity indicated that Cr(VI) compounds were
generally active and Cr(III) compounds nonactive, the assays of chromium induced
DNA damage in the rec assay, unscheduled DNA synthesis in mammalian cultured
cells, and increased jLn vitro infidelity of DNA synthesis indicated that at least
some activity is associated with both valence states (Nishioka, 1975; Nakamuro et
al., 1978; Raffeto, 1977; Loeb et al., 1977; and Tkeshelashvili et al., 1980).
7.2.2.3. CHROMIUM INDUCED CHROMOSOMAL ABERRATIONS AND CELL
TRANSFORMATIONS — Iri vitro, chromium has been shown to result in the appearance
of chromosomal aberrations and cell transformation (Table 7-18). Fradkin et al.
(1975) observed morphologic changes and loss of anchorage dependent growth in
BHK21 cells treated with 0.25 and 0.5 ng of CaCrO^»2HpO. Chromate transformed
cells maintain the ability to grow independent of anchorage even after the cells
were re-isolated and freed of exposure to CaCrO^»2ELO. Tsuda and Kato (1977)
observed morphologic transformation in primary hamster embryo cells after expo-
sure to K2Cr20,,(VI) at a level of 0.1, 0.2, and 0.5 \ig/wSi for 24 hours. The
transformation frequency increased from 0.179$ for the control cultures to
0.760, 2.86, and 2.70? for cells exposed to 0.1, 0.2, and 0.5 |ig/m!l, respec-
tively. A transformation frequency of 2.10$ was achieved with the positive
control, N-methyl-N'- ni tro-N-ni tros oguan i dine (MNNG) at a level of 0.5 \ig/mH.
Conflicting results of exposure to CrCl-(III) and K?Cr?0 (VI) on morphologic
transformation of BALB/c mouse fetus cells in culture was obtained in two experi-
7-98
-------
TABLE 7-18
Chromium Produced Clastogenlc Effects and Cell Transformation
Test
Cell transformation
Cell transf orm at i en
Cell transf crmaticn
Cell transf crmaticn
vj> Host mediated oell
V-D transf crmaticn
Clastogenic
Clastogenic
Clastogenic
Clastogenlc
Clastogenlc
Indicator
Cells
BHK21
primary embryo
hamster cells
BALB/o cells
primary embryo
hamster cells
primary embryo
hamster oells
BALB/c oells
CHO cells
mouse FM3A cells
hamster embryo
cells
V79 cells
Compound
Tested
CaCrO^O
K Cr20_
C- C. f
CrCl
K2Cr2°7
CaCrO,
K Cr04
ZnCrOjj
NaCrCv
CrCl
K2Cr207
K2Cr2°l
Na Cr267
K.CrCv
Na CrOu
CrO
CaC?Cv
CrClJ*
Cr(NO )
KCr(SOJ.
CKCOOOC)
K2?r2°7
CrO,
Cr2?S04)3
K2Cr2°7
C- C. \
K2Cr207
Valence
State
46
46
4-3
46
46
46
46
46
+3
46
46
46
46
46
46
43
+3
43
43
46
46
+3
46
46
Dose
0.25 and 0. 5 ug/mt
0.0, 0.1, 0.2, and
0.5 |ig/n£
0.04 and 0.4 tig/at
0. 015 and 0. 1 |ig/mt
0.006 mM
0.01 mM
0. 01mM
2.5 iig/100g body
weight on day 11
of gestation
0.04 and 0.4 ng/n*.
0.015 and 0.1 tig/mt
0. 1 and 0.3 ng/mt
0. 1 and 0.3 ng/nA
0.25 |ig/mfc
0.25 ng/mt
0. 1 and 0.25 \ig/JA
0.5 jig/ml
5 and 50 ng/nA
50 and 150 ng/mt
150 ng/nfc
5 and 20 |ig/n£
3.2x10^ to 3.2x10"^M
i.oxio^: to I.OXIO~;M
3.2x10 to 1.0x10~3M
0.5 iig/mi
0.35 to 0.8 |ig/nA
End point
Morphologic altera-
tions , loss of
anchorage dependent
growth
Morphologic altera-
tions
Morphologic altera-
tions
Increased suscep-
tibility to viral
tranf crmatlcn
Morphologic altera-
ations
Chromosomal aberra-
tions
Chromosomal aberra-
tions/ 100 cells
(17 in control cul-
tures )
Chromosomal aberra-
tions
Chromosomal aberra-
tions
Chromosomal aberra-
tions
Response
+
Transf crmatlcn
frequency increased
frcm 0. 76% for con-
trols to 2. 70< for
the high dose group
+«
+•
2 x control levels
2 x control levels
4 x control levels
+
4 at 0. 4 ug/mt
4- at both doses
36 and 56
58 and 169
42
41 and 65
60 and 62
102
21 and 31
1 5 and 21
32
38 and 39
4
4
+.
4
Reference
Fradldn
et al.,
1975
Tsuda and
Kato, 1977
Raffetto,
1977
Caato et
al., 1979
DiPaolo
and Casto,
1979
Raffetto,
1977
Levls and
Majone,
1979
Umeda and
Nishimura,
1979
Tsuda and
Kato, 1977
New bold
et al .,
1979
-------
TAB1£ 7-18 (cont.)
Test
Clastogenic
Clastogenic
Clastogenic
^,
i
— Clastogenic
o
o
Clastogenic
Clastogenic
Claatoganic
Clastogsnie
Claatogenic
Indicator
Cells
cul tired hum an
leukocytes
cultured human
lymphocytes
CHO cells
Don Chinese
hamster cells
cultured human
lymphocytes
polychromatic
erythrocytes from
NMRI mi 08
gel cells from
Boleophthalmus
dussunierl
human lymphocytes
human lymphocytes
Compound
Tested
K2Cr2°7
K2C™4
Cr(CH-COO),
Cr(NO )
CrCl J J
K Cr 0
CrCl* '
K Cr20-
Na_Cr20,
K-CrOj.
Na-Crfj,
cro
CrCl
Cr(NOJ
ff* M / On. V
ftX/ I \ Owj. ) A
CrfCOOCHp
CrCl «6H,0
Cr 2(*0~'
4fc,0
Ci°L
it— CrOi,
K2Cr207
CaCrCv
CrO,
K CrO,
<_ *T
Na Cr 0
CrO
Cr03
Valence
State
+6
+3
+3
+3
+6
+6
+6
+6
+6
+6
+6
+3
+3
4-3
4-3
4-3
4-3
46
46
46
46
46
46
46
46
46
Dose
0.125 to i». OxID^M
0.5 to 8. OXIOT'M
U to 32 x 10 M
£
32.0 x 10"7M
32.0 x 10 M
10 , to 10~?M
10"° to lO^M
0. 1 and 0.3 )ig/mt
0. 1 and 0. 3 (Jg/nA
0. 25 ng/nft
0.25 ng/n*
0.1 and 0.25 ng/nft
5 and 50 ug/nft
50 and 150 (ig/nA
150 ng/nfc
5 and 20 ng/nA
32 ug/nA
0.32 [ig/nA
0. 8 }ig/nA
0. 8 |ig/BA
0. 025 to 0. 1 (ig/nA
0.01 to 0.02 (ig/nA
0.025 to 0.1 jig/nA
2 x 48.5 fflg/kg, IP
2 x 24.25 mg/ kg, IP
2 x 12.12 mg/kg, IP
1 or 5 mg/kg IM
24 or 30. 5 ppm in
the aquaria! water
Occupational exposure
Occupational exposure
End point Response
Chromosomal abarra- +
tions +
4- ,
at >16 x 10 M
„
-
Chromosomal abbera- +
tions
Sister chromatid 4-
exchange 4
+
+
+
—
M
_
-
Sister chromatid +•
exchange
+,
+
4-
Sister chromatid +
ex: hangs +
*
Micron ucleus test 4-
+
-
Chromosomal aberra- +.
tions
+
Sister chromatid 4-
ewhanga
Chromosomal aberra- +•
tions
Reference
Nakamuro
et al .,
1978
Stella
et al.,
1982
Levls and
Majone,
1979
Ohno et al . ,
1982
Gomez-Arroyo
et al., 1981
Wild, 1978
Krishnaja
and Rege ,
Stella et al .
1982
Sarto et al .,
1982
IP = I ntra peritoneal injection
IM = Intramuscular injection
-------
ments by Raffetto (1977). Although both experiments showed an increase in the
number of transformed foci, this increase was not dose-related, and there was a
10-fold difference between the two experiments performed under similar condi-
tions. The authors suggest caution in interpreting these findings. Casto et al.
(1979), using a different experimental system, demonstrated that the Cr(VI)
compounds, CaCrOy, KpCr., and ZnCrO^, at concentrations of 0.006, 0.01, and
0.01 mM enhanced the virally induced transformation frequency of primary embryo
hamster cells. The increase in transformations was =2 for the Ca and K salts,
and 4 for the Zn salt. Other metals assayed that had no indication from the
literature of genotoxic properties did not enhance the rate of viral transforma-
tion.
Increase in cell transformation has also occurred in cells isolated from
hamster embryos exposed in utero to Cr(VI) (DiPaolo and Casto, 1979). Initially,
it was demonstrated that NaCr01»t»fLO at levels of 1.0, 2.5, and 5.0 jig/mi
increased the transformation frequency of isolated hamster embryo cells in
culture by 0.7, 2.1, and 3.W%, respectively. Following this initial study,
pregnant Syrian golden hamsters (number not reported) were given intraperitoneal
injections of NaCrO^ at 2.5 mg/100 g body weight on day 11 of gestation. It was
reported that cells isolated from embryos excised 2 days later produced elevated
numbers of transformed colonies; however, the data were not presented for these
studies. It was concluded that transplacental exposure to chrcmate resulted in
alterations of fetal cells.
A number of studies have also demonstrated that exposure of cells in culture
to either Cr(VI) or (III) compounds produces chromosonal aberrations. Raffetto
(1977) exposed BALB/c mouse cells to CrCl-dll) and K2Cr207(VI) for either 48 or
96 hours. Increase in the number of chromosomal aberrations was noted for Cr(VI)
at a level of 0.1 ug/md, but not for Cr(III) at the same level after a U8 hour
7-101
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exposure; however, with 96 hours of exposure, Cr(III) at 0. U ng/mJ, (O.OU
was also tested) and Cr(VI) at 0.1 and 0.015 (ig/mX, produced significant (PcO.05)
increases in the number of chromosomal aberrations. Newbold et al. (1979) also
detected dose dependent chromosomal damage with K Cr_0? at levels between 0.35
and 0.8 ng/m?, in V79 cells. Similar results were reported by Levis and Majone
(1979), in which both Cr(III) compounds [CrClg, Cr(N03)3> KCr(SO)||)2, and
Cr(COOCHj_] and Cr(VI) compounds (K2Cr2CL, Na2Cr207, K^rO^, Na^rO^, CrO_, and
CaCrCL) produced increases in chromosomal aberrations in CHO cells in culture.
Again, Cr(VI) compounds were more active, with positive responses obtained at
doses of 0.1 to 0.5 ng/mJl, while marginal positive responses with Cr(III)
occurred at doses of 5 to 150 |ig/mH. Although both valence states produced
chromosomal aberrations, only Cr(VI) induced increases in sister chromatid
exchange, and even the increase observed with Cr(VI) was small in comparison to
the response elicited by the positive control, Mitomycin C. Sister-chromatid
exchange was also observed by Ohno et al. (1982) in Don Chinese hamster cells
following treatment with the Cr(VI) compounds CrO , K^CrQ^, and K2Cr2CL at con-
centrations of 0.32, 0.8, and 0.8 fig/mS,, respectively. The Cr(III) compounds
CrCl •6H?0 and Cr_( SCLK'UfkO were less active than the Cr(VI) compounds at
levels of 32 and 6 [ig/m&, respectively, with the increases due to the sulfate not
significantly elevated over control values. Again, as in the previous study, the
levels of chromium induced sister-chrcmatid exchange was 10 times less than that
of the positive control, mitomycin C. However, in the study by Umeda and
Nishimura (1979), only the Cr(VI) compounds, K2Cr2
-------
The effectiveness of chromium compounds in producing chromosomal aberra-
tions was affected by the valence state of the compound. Tsuda and Kato (1977)
demonstrated that 0.5 ng/mSl of K Cr-CL produced chromosomal aberrations in 51 %
of hamster embryo metaphases examined; however, addition of the reducing agent,
Na SO , at a level of 0.645 |ig/mS, resulted in a decrease in abnormal metaphases
to 6%. This provides further evidence that Cr(VI) was more active than Cr( III)
in producing chromosomal aberrations.
Nakamuro et al . (1978) used peripheral blood human leukocytes in short-term
culture to elevate the clastogenic effects of a number of Cr(VI) and Cr(III)
salts. Following isolation and 24 hours of culture, the cells were exposed to
Cr(VI) (K2Cr20?, K2Cr04) and Cr(III) (Cr(CH3COC»3, CKNO^, CrCl^ chromium at
the respective concentrations of 0.125 to 4, 0.5 to 8, 4 to 32, 32, and
32 x 10"6 M. Significant increases (P<0.01) in total chromosomal aberrations
were observed at the higher doses with all compounds except CrtNO^)^ III) and
CrCl (III). It was apparent that human leukocytes responded similarly to other
cultured cells in regard to sensitivity to chromium induced chromosomal aberra-
tions.
In vivo clastogenic activity of KCrO^ has been observed in mice by the
micronucleus test (Wild, 1978). NMRI mice (4 animals of each sex) were treated
by two intraperitoneal injections of 0.0, 12.12, 24, 25, or 48.5 mg/kg of J^CrO^
in saline, followed in 6 hours by examination of bone marrow for micronucleus-
containing erythrocytes . Of the 1000 cells examined per mouse, there were 3.1,
4.8, 9.6, and 15.0/K micronucleated polychromatic erythrocytes in the control and
treated animals, respectively. The responses in the two highest dose groups
represent significant increases over control values. Chromosomal aberrations,
including breaks, fragments, rings, exchanges and unclassified makers, were
observed in the gills of the fish Boleophthalmus dussumieri after exposure to
7-103
-------
sodiun dichronate(VI) (Kushnaja and Rege, 1982). The number of total aberrations
increased from 1 to 6 and 16 after intramuscular injection of Na Cr~0 at doses
of 0.0, 1, and 5 rag Cr/kg, respectively. Increases in total aberrations of 0, 7,
and 7 were also observed when the fish were maintained in water for 96 hours
containing chromium at levels of 0.0, 24.0, or 30.5 ppm (the high dose level
killed 50% of the fish). Other heavy metals and mitomycin C also produced
chromosomal aberrations in this test system.
Human lymphocytes exposed either in vitro to chromium or isolated from
workers occupationally exposed to chromium have been used to investigate
chromium induced chromosomal damage. Increase in both sister chromatid exchange
and chromosomal aberrations were observed when cultured hunan lymphocytes were
exposed to the Cr(VI) compounds K^r^, CaCrO^, and CrO_ (Gomez-Arroyo, 1981;
Stella et al., 1982); however, the Cr(III) compound, CrCl , was totally inactive
(Stella et al., 1982) in this assay. In blood samples taken from workers in the
chromium plating industry (Stella et al., 1982; Sarto et al., 1982) there were
increases in chromosomal changes in the peripheral lymphocytes. Stella et al.
(1982) obtained blood samples from 12 male workers and 10 control donors not
exposed to chromium. There was no significant difference in the incidence of
sister chrcmatid exchange in the 5 older workers (24 to 47 years of age); how-
ever, in the 7 youngest workers (17 to 23 years of age) there was a significant
increase. The control subjects had an age associated increase in sister chroma-
tid exchange, while the level in the exposed population appeared constant. Sarto
et al. (1982) studied the peripheral lymphocytes of workers in two "hard" plating
(one of the plants was the same as that studied by Stella et al., 1982) and two
"bright" plating industries. In the "hard" plating industry, exposure was to
chromium alone, while in the "bright" plating industry the workers were also
exposed to nickel. As in the previous study, the younger workers had significant
7-104
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increases in chromosomal aberrations while the number of aberrations was not
significantly elevated from control levels in the older workers. There was also
a positive association between urinary chromium levels and the number of chromo-
somal aberrations in the two "hard" plating plants. The authors concluded that
these data support the genotoxicity of the soluble Cr(VI) ion.
7.2.2.4. SUMMARY — In vitro and in vivo assays of genotoxicity have tried
to clarify the mechanism of chromium carcinogenicity and have supported the
potential for Cr(VI) to be the active carcinogenic species. Cr(VI) has demon-
strated consistently postive mutagenic activity in a number of bacterial
systems. This activity was demonstrated in the absence of a metabolic activation
system. In the presence of a mammalian activation system, the mutagenic activity
of Cr(VI) disappeared. Because Cr(VI) shows only marginal, if any, mutagenic
activity, it was suggested that the mammalian enzymes or cofactors in the activa-
tion system reduced Cr(VI) to Cr(III). Both Cr(III) and Cr(VI) have been demon-
strated to interact with DNA in bacterial assays, and Cr(VI) has inhibited DNA
synthesis and increased unscheduled DNA synthesis in mammalian cells in culture.
In in vitro studies, both Cr(III) and Cr(VI) have increased the infidelity of DNA
replication. As observed with interaction with DNA, both valences of chromium
have been demonstrated to produce clastogenic effects in mammalian cells with
Cr(VI) being more active than Cr(III). The effects observed included a variety
of chromosomal aberrations, sister chromatid exchange, and the appearance of
micronuclei in polychromatic erythrocytes. Increased chromosomal damage also
has been observed in human lymphocytes cultured from subjects occupationally
exposed to chromium. For all the observed genotoxic effects, it has been
suggested that Cr(III) may be the predominant intracellular species a result of
the reduction of absorbed Cr(VI) by cellular components.
7-105
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7.2.3. Developmental Toxicity and Other Reproductive Effects.
7.2.3.1. DEVELOPMENTAL TOXICITY ~ Chromium salts have been shown to be
teratogenic and embryotoxic in mice and hamsters following intravenous or intra-
peritoneal injection. Golden hamsters were given single intravenous CrO (VI)
injections of 5, 7.5, 10, or 15 mg/kg on the eighth day of gestation (Gale,
1978), or an intravenous Cr03 dose of 8 mg/kg on day 7, 8, 9, 10, or 11 (Gale and
Bunch, 1979).
In the first study using mice, treatment groups were as follows: 15 dams
exposed to 5 mg/kg, 18 dams exposed to 7.5 mg/kg, 21 dams exposed to 10 mg/kg,
and H dams exposed to 15 mg/kg. In all but the 5 mg/kg group, dams exhibited
signs of chromium toxicity, including weight loss and tubular necrosis of the
kidneys. The highest dose was lethal to 75% of the dams.
Chromium given on the eighth day of gestation resulted in increased fetal
wastage at doses of >7.5 mg/kg (statistics not reported). The major external
anomaly noted was cleft palate. Incidence of cleft palate was significantly
elevated above the control level for all treated groups (method not stated). The
primary internal abnormality recorded was hydrocephaly, with an increased
incidence noted in all treatment groups. In addition, a wide range of skeletal
defects were noted.
In the second study, six pregnant female hamsters were treated in each time-
group with three concurrent controls. Fetal death was greatest in litters
treated on the seventh day of gestation when there was an 8H% incidence of
resorptions. Resorption incidence was elevated to a small degree on days 8 and 9
(20 and 13$, respectively), but was not affected on days 10 and 11.
As in the previous study, cleft palate was the primary external abnormality
recorded, occurring most frequently in litters from dams exposed on day 7 of
gestation and at elevated incidence rates with respect to controls on days 8 and
7-106
-------
9, but not on days 10 and 11 (determined based on tables of binomial confidence
limits). The only internal abnormalities noted were kidney defects in groups
exposed on days 7 or 8 of gestation. Group sizes were too small to establish a
significant difference from controls. As in the previous study, treated females
exhibited signs of chromium toxicity which included body weight loss and tubular
necrosis of the kidneys.
In a continuation of this work, Gale (1982) tested Cr(III) in noninbred
(LVG) and inbred (CB, LHC, SDH, MHA, and PD4) strains of hamsters for reproduc-
tive and teratological effects. The dams (10 animals/group) were treated by
intravenous injection on the 8th day of gestation with a single dose of 8 mg/kg
of Cr(III). On termination at day 15 of gestation, it was determined that
strains CB, LHC, and PD4 were resistant to any adverse effects of treatment. In
the other strains, LVG, LSH, and MHA there was an increased incidence of cleft
palate (33, 18, and 15 animals, respectively, while control groups had no more
than 1 pup/group with cleft palate) and other external abnormalities. The dams
of the strains with the highest incidences of fetal abnormalities also lost
weight during the period of gestation following treatment. Strain differences
were reported for the reproductive effects of other metal compound in these
animals; however, the genetic mechanism which results in these differences in
susceptability were not understood.
Matsumoto et al. (1976) administered chromium chloride (+3), 19.52 mg/kg
(as Cr) , intraperitoneally to ICR mice on day 7, 8, or 9 of gestation. Eight
control dams received a. saline injection. Treatment group sizes were 5, 6, and 7
on days 7, 8, and 9, respectively. The embryonic and fetal death rates were
elevated following treatment on days 8 and 9 (P<0.001, method not stated). The
incidence of external malformations was significantly greater than in controls
in litters of dams exposed on day 8 of gestation (PcO.001, method not stated).
7-107
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Recorded anomalies included exencephaly and open eyelids. In addition, there was
a small increase in skeletal defects in litters from dams treated on days 8 and
9.
In a second experiment, pregnant dams were given intraperitoneal injections
of chromium chloride at dose levels of 9.76, 14.64, 19.52, or 24.4 mg/kg as Cr on
day 8 of gestation. Group sizes were: control (11 dams), 9.76 mg/kg (13 dams),
14.64 mg/kg (13 dams), 19.52 mg/kg (7 dams), 24.4 mg/kg (9 dams). Fetal weights
were significantly reduced in all treatment groups (P<0.05, method not stated).
The incidence of external malformations was significantly greater than control
values for the 14.64 mg/kg dose group and all higher dose groups (P<0.05, method
not stated). Anomalies with greatest incidence in rats were open eyelids,
exencephaly, and acephalia. In addition, skeletal defects were noted in these
same groups.
lijima et al. (1979) dosed pregnant ICR mice with CrO (VI) by subcutaneous
injection. Mice were injected with a single 10 or 20 mg/kg dose on day 7, 8, 9»
10, or 11 of gestation. The 20 mg/kg dose was lethal to one-third of the dams.
In this group, a significant increase in external anomalies was recorded in
litters from dams exposed on day 8 of gestation. Cleft palate was the primary
abnormality. In addition, increased fetal and embryonic death rates were noted
in groups exposed to 20 mg/kg on day 8 or day 11.
The four studies discussed in the text above are summarized in Table 7-19.
As discussed previously (Section 5.1.4.), existing data indicate that
inorganic Cr(VI) and (III) are not transported across the placenta to any appre-
ciable extent during the period of organogenesis. These data indicate that the
observed teratogenic effects may well be the secondary result of maternal toxi-
city.
7-108
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TABLE 7-19
Teratogenic and Fetotoxic Effects of Chromium
Compound Route Species
CrO, i.v. hamster
CrO, i ,v . hamster
i
o
CrCl, i .p . mouse
CrO- i.v. hamsters
3 (strain
LVG)
hamsters
(strain
CB)
Dose
5, 7.5, 10,
or 15 mg/kg
on day 8 of
gestation
8 mg/kg on
day 7, 8, 9,
10, or 11 of
gestation
9.76, 14.64,
19.52, or 24.4
mg/kg on day
8 of gestation
8 mg/kg on day
8 of gestation
8 mg/kg on day
8 of gestation
Fetal Effects
increased fetal death in
7.5, 10, and 15 mg/kg
groups, increased incidence
of cleft palate in all
groups, hydrooephaly and
skeletal defects
increased fetal death
following administration
on day 7, increased
incidence of cleft palate
following administration on
days 7, 8, or 9
depression of fetal weights
in all Cr treated groups,
increase in rate of external
abnormalities for groups
treated with 14.64, 19.52,
or 24.4 mg/kg
increased incidence of cleft
palate
no effect
Maternal Effects Reference
depressed weight gain and Gale, 1978
kidney tubular necrosis
at all doses above 5 mg/kg
weight less, tubular necrosis Gale and Bunch, 1979
of kidneys
not reported Matsunoto et al., 1976
body weight loss Gale, 1982
no effect
-------
TABI£ 7-19 (oont.)
Teratogenio and Fetotoxlo Effects of Chromium
Conpound Route Species
hamsters
(strain
LHC)
hamsters
(strain
--J LSH)
i
— hamsters
0 (strain
PD4)
hamsters
(strain
MHA)
CrO. s.o. mouse
Dose
8 mg/kg on day
8 of gestation
8 mg/kg on day
8 of gestation
8 mg/kg on day
8 of gestation
8 mg/kg on day
8 of gestation
10 or 20 sag/kg
on day 7, 8, 9,
10, or 11 of
gestation
Fetal Effects Maternal Effects Reference
no effect no effect
increased incidence of cleft body weight loss
palate
no effect no effect
increased incidence of cleft body weight loss
palate
increase in external malfcr- lethal to 1/3 of dams lijiaa et alt, 1979
mations in 20 mg/kg group
when dosed on day 8, as well
as Increase fetal death when
dosed on day 8 or 11
-------
7.2.3.2. OTHER REPRODUCTIVE EFFECTS — Behari et al. (1978) examined the
effects of chromium on testicular tissue in rabbits. Animals were injected
intraperitoneally with chromium nitrate or potassium dichromate at doses of
2 mg/kg for 3 or 6 weeks. Both forms of chromium resulted in a decrease in
testicular succinic dehydrogenase at 3 and 6 weeks. Adenosine triphosphatase
was inhibited at both time points with both compounds, but the Cr(III) compound
resulted in more severe depression. Acid phosphatase was significantly
depressed at 6 weeks in anjjnals given the trivalent salt.
The administration of Cr(III) resulted in thickening of the tunia albuginea
and congestion of blood vessels following 3 weeks of treatment. In addition,
cells in the seminiferous epithelium showed degenerative changes. At the 6 week
time point, these degenerative changes were more pronounced, and there was a
complete absence of spermatocytes in the lumen. Cr(VI) produced mild edema of
the interstitial tissue of the testes at 3 weeks. Following 6 weeks of exposure,
edema was more marked and congestion of the blood vessels was noted. Although
the seminiferous epithelium appeared normal, the tubules were devoid of sperma-
tocytes .
Hopkins (1965) postulated that incorporation of chromium into sperm and
subsequent passage into the epididymis may be a problem. This hypothesis is
based upon observation of chromium uptake by testis, subsequent decline of tes-
ticular radioactivity, and subsequent increase in radioactivity in the
epididymis (see Section 5.2.2.). Gross and Heller (19^6) have reported
sterility in rats exposed to zinc chromate and potassium chronate in the diet
(Section 7.2.5.) .
7.2.3.3 SWWARY — Chromium has adversely affected fetal development and
male reproduction in experimental animals. Hamsters administered chromium
trioxide intravenously on day 8 of gestation had an increased incidence of cleft
7-111
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palates in the young when examined on day 15 of gestation. The malformations
were strain specific and associated with maternal toxicity. Maternal toxicity
was not observed in the strains where fetal malformation was not present.
Increases in external malformations also were observed in mice, following
subcutaneous administration of CrO_.
Other reproductive effects of chromium include testicular degeneration in
rabbits receiving 2 mg/kg/day for 6 weeks of either Cr(III) or Cr(VI) compounds
by intraperitoneal injection. The Cr(III) compound produced more severe effects
in this study than did the Cr(VI) compound (Behari et al., 1977). The relevance
of these observations to effects observed after environmental exposure are
questionable, since the route of exposure was not natural.
7.2.M. Chromium Hypersensitivity.
7.2.1.1. CHROMIUM SENSITIVITY AND CONTACT DERMATITIS — Chromic acid and
the chromates are powerful skin irritants, and, in lower concentrations, the
chromates are sensitizers (NAS, 197*O. Workmen exposed to the steam of boiling
dichrouate solutions developed an acute primary irritant contact dermatitis
(Schwartz et al., 1957; White, 1931*). White (193*0 described a diffuse erythema-
tous dermatosis that resulted from dichromate; seme progressed to an exudative
phase.
Various chromium compounds have been implicated in giving rise to allergic
dermatitis with varying degrees of eczema. Parkhurst (1925) reported the case of
a woman employed in blueprint production using a process in which a 156 potassium
dichromate solution was used as a fixative. A 0. 5% potassium dichromate solution
was rubbed on the right thigh of the woman, and soom after the application, there
was a local sensation of itching and burning. Twelve hours later, the patient
7-112
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developed a follicular erythematopapular deraatitis at the exposure site.
Itching and burning was reported when a similar application was made to the left
thigh.
Smith (1931) reported a case of chromium sensitization in a man who had been
hospitalized after occupational exposure to ammoniun dichrcmate. The patient
had ulcerations in the skin of both hands, and complained of asthma, and muscular
weakness and tenderness. He had a previous history of asthma and hay fever and
had further asthmatic attacks upon exposure to chromium. Following a patch test
P
with 1$ ammonium dichromate solution on a 1 cm area of normal skin on his
forearm, the man developed a mild erythema after 24 hours. After 3 days, the
erythematous area doubled in size, and there was the appearance of vesicles. An
intradermal injection of 0.1 m2, of a 0.5% aqueous solution of ammonium dichro-
mate was given in the right forearm 8 days later. Within an hour, the patient
developed a generalized pruritis with soreness at the injection site. This
progressed with the development of a vesicular erythematous dermatitis covering
the entire hands and lower parts of the forearm. In addition, he developed
diaphoresis and sibilant rales. These symptoms which required hospitilization
abated after his exposure to Cr(VI) ceased. Three control subjects who were
similarly injected showed no reaction.
Hall (19UU) reported on 132 aircraft workers who developed dermatitis after
contact with a primer consisting of a suspension of zinc chrcmate powder and
magnesium silicate in a xylene solution of certain resins, including a phenol-
formaldehyde resin. Those workers who had dermatitis from the primer and who
were allergic to zinc chromate pigment had a mean duration of employment of
7 months (range: 1 week to 9 years). A battery of patch tests showed that 90 of
the workers (68$) were sensitive to the zinc chromate pigment only. (Apparently,
the zinc chromate pigment was a mixture of zinc chrcmate and calcium carbonate.)
7-113
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Only a few workers had positive patch tests for other compounds encountered on
the job.
Forty-five cases of allergic contact dermatitis, observed in the Helsinki
area from 1945 to 1918, were reported by Pirila and Kilpio (1949). Positive
patch-testing with a 0.5% aqueous solution of potassium dichromate (pH 4.15) was
observed in 41 of the workers. The workers were involved in the following
occupations: 11 bookworkers, 10 cement and lime workers, 7 radio factory
workers using a photostatic procedure, 4 metal factory workers, 4 painters and
polishers, 3 fur workers, and 6 others.
Engebrigsten (1952) reported eight cases of cement eczema among 300 to 400
Norwegian workers exposed "more or less directly" to cement dust that contained
0.002 to 0.020% water-soluble Cr(VI), which was described only as "water-soluble
chromates." Positive patch testing was reported in 7 of 8 patients exposed to
0.5$ aqueous solution of potassium dichromate. Positive reactions to cement
patch tests were observed in 4 of 8 patients. Of the 10 persons who served as
controls, none gave any positive reactions. Engebrigtsen (1952) subsequently
tested the same eight patients with a cement slurry that had been washed free of
Cr(VI), and none of the people reacted positively.
Denton et al. (1954) patch tested a patient with a "strong specific hyper-
sensitivity to potassium chromate" with three solutions: (1) a 50 ppm solution
of potassium dichromate, (2) 1 ppm water-soluble Cr(VI) filtrate from American
Portland cement, and (3) 4 ppm water-soluble Cr(VI) filtrate from American
Portland cement. Each patch test resulted in an erythematous, edematous, and
papulovesicular reaction. There was no reaction to distilled water and none of
the control subjects reacted to any of the three Cr(VI) solutions.
Six out of 200 employees who worked in a diesel locomotive repair shop were
incapacitated by chromate dermatitis (Winston and Walsh, 1951). All were exposed
7-114
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to an alkaline diesel locomotive radiator fluid that contained 0.08$ sodium
dichromate. Positive patch testing was reported for both sodium dichromate
(pH 4.25) and the radiator fluid (pH 10).
Walsh (1953), in a summary report on chromate hazards in industry, described
the following patch test results: 2% "chromate acid" applied for 24 hours on
superficial skin abrasions produced a crusted lesion in 3 weeks; 0.5% sodium
dichrcmate, reapplied daily for 3 days, produced a crusted lesion in 3 weeks;
0.5% potassium chromate, applied 8 hours/day for 3 days, produced lesions in
3 days; 0.5% sodium chronate, 0.005$ sodium dichromate, and pure zinc chrcmate
also produced lesions in 3 days after being in contact with skin for 8 hours/day
for 3 days. Lead chronate did not produce a reaction after the same exposure
period. A 10$ solution of Cr(III) nitrate produced redness after the solution
was reapplied daily for 3 days.
Edmundson (1951) obtained only two positive reactions with patch testing in
56 men who had chrome ulcers. All men were said to have a history of chrome
dermatitis. He concluded that the presence of chrome ulcers did not necessarily
indicate sensitization.
Other investigators (Morris, 1955; McCord et al., 1931; Levin et al., 1959)
have demonstrated sensitization to other chromium compounds in workers employed
as tanners and lithographers. Many of the workers gave positive results for
patch tests.
There have been numerous case reports of contact dermatitis resulting from
exposure to a variety of chromium-containing products, such as matches, auto-
mobile primer paint, and fumes from welding rods (Fregert, 1961; Engle and
Calnan, 1963; Newhouse, 1963; Fregert and Ovrum, 1963; Shelley, 1964). In most
of these reports, the subjects developed a positive reaction to patch testing for
a solution of potassium dichrcmate.
7-115
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A study conducted in France by Jaeger and Pelloni (1950) demonstrated that
workers with cement eczema were sensitive to potassium dichronate. In their
study, the authors patch tested 32 patients with cement eczema and 168 patients
with eczema from other causes. Those with cement eczema gave positive patch
tests (9W to an aqueous 0.5% solution of potassium dichromate, while only 5% of
the other eczema patients exhibited positive reactions from the dichrcmate.
However, Perone et al. (1971*) reported that only 2 of 95 construction
workers who regularly worked with cement gave a positive reaction to patch
testing to a solution of 0.25$ potassium dichromate or a solution containing
H50 ng/g Cr(VI) extracted from cement. The authors suggested that the cement
dermatitis present in the construction workers was associated with the initia-
tive nature of the cement rather than a hypersensitivity.
There have been two reported cases of eczema in men who regularly worked
with cement and who each had a green tattoo which contained chromium (Cairns and
Calnan, 1962; Loewenthal, 1960). Both men developed a positive reaction to patch
testing to a solution of potassium dichrcmate (concentration range: 0.1 to 2%).
Negative results following patch testing were observed when the solution was
Cr(III) sulfate. The green pigment in one of the tatoos contained Cr(VI), but
the oxidation state of chromium in the other tattoo was not determined.
Krishna et al. (1976) reported that chrome workers exposed to 0.21 to
0.80 mg/nr Cr(VI) displayed various dermatologic disorders, including skin
ulcers, dermatitis, and nasal perforations. Dermatologic irritation has been
reported by Clausen and Rastogi (1977), in auto workshop employees exposed to
0.01 to 3.75 \ig/nr; by Tan don et al. (1977), in electroplaters, polishers, and
pigment workers; and by Spruit and Martin (1975), in offset printing employees
who came in contact with materials (usually inks) containing up to 60,000 ppm
chromium. Various dermatologic disorders among workers exposed to 0.001 to
7-116
-------
0.020 rag Cr/m in air and chromium on work surfaces have been reported by Lucas
and Kramkowski (1975). Chromium-induced dermatitis or eczema has been
*
associated with workers having contact with various chromium-containing lubri-
cants and oils (Rosensteel and Lucas, 1975; Weisenberger, 1976; Clausen and
Rastogi, 1977). Dermatitis associated with various chromium pigments and
coloring agents has been described by Scmov et al. (1976), Fisher (1977),
Fregert and Gruvberger (1976), Venediktova and Gudina (1976), and Evans
(1977a,b,c).
Allergic sensitization to chromium-containing compounds has been reported
by Burry and Kirk (1975) in several industrially exposed individuals, and by
Wahlberg and Wennersten (1977) and Kaaber and Deien (1977), who used potassium
dichrcmate in the patch tests. Husain (1977) showed sensitization in the
"general population" (not occupationally exposed), where, among 1312 patients
tested, 11.58? had contact sensitivity to 0.5$ potassium dichronate in a patch
test (15.59$ of the males reacted to the chromate as opposed to 8.18$ of females
tested).
Perisic and Jovovic (1977) have identified allergic contact sensitivity to
chromates among 219 Yugoslavian housewives. The incidence of allergic contact
sensitivity was confirmed in 43 cases (19.62$); the percentage of positive cases
was 31.44$ in women holding permanent jobs, 23.51$ in cleaners, and 14.58£ in
unemployed housewives. It was concluded by the authors that chromates contained
in a variety of household products used in routine cleaning operations are the
cause of allergic sensitivity to chromates in women. No control or reference
data were available.
Jovovic et al. (1977) have confirmed the allergic contact sensitivity of
shoemakers exposed to chrcmates in occupational settings. Sixty percent of the
shoemakers with allergic sensitivity showed a positive reaction to potassium
7-117
-------
dichrcmate. Allergic reactions in various glues to which the shoemakers were
exposed were also reported.
Exposure to chromium may sensitize certain individuals resulting in
asthmatic attacks upon subsequent re-exposure (NAS, 1 97*0 (see Section 7.2.5.1).
7.2.4.2. SENSITIVITY TO CHROMIUM IN PROSTHESES — In recent years, there
has been an increase in the use of metal-to-pi as tic prostheses in orthopedic
surgery. Many of the metal implants consist of alloys containing nickel,
chromiun, cobalt, and molybdenun.
Work by Swanson et al. (1973) and Coleman et al. (1973) has shown that when
two cobalt/chrome alloy surfaces rub together, cobalt and chrome are released
locally, pass into the blood and circulate throughout the tissue of the body, and
are finally excreted in the urine. In patients sensitive to metal, the vessels
supplying the bone in which the prosthesis is inserted may show obliterative
changes, and in theory, lead to death of the bone, with weakening of the fixation
between the bone and prostheses, and consequent loosening (Anonymous, 1976).
There is considerable conflicting evidence in this area, as Deutman et al.
(1977) reported metal sensitivity in H of 66 patients induced by metal alloy
implants following total hip replacement arthroplasty; however, positive patch
tests occurred only with cobalt and nickel, while tests with chromium were
negative. Brown et al. (1977) gave patch tests for chromium sensitivity to 20
patients with sterile loose hip replacements. Of these 20 patients, none were
positive for chromium sensitivity, and of 17 patients that were reoperated on,
none showed histologic evidence of delayed hypers ens itivity around the implant.
In addition, contact dermatitis and allergic sensitivity to chromium-
containing dental prostheses have been reported by Levantine (1974) and
Ovrutskii (1976).
7-118
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7.2.4.3. ANIMAL STUDIES ON CHROMIUM SENSITIVITY — Nunerous investigators
have demonstrated that sensitization of laboratory animals can be produced by
exposure to various chromium compounds, including both Cr(VI) and (III).
In studies of delayed dermal hyper-sensitivity to potassium chromate or
_ii
chromium chloride, guinea pigs treated with 2.4 x 10 M chromic sulfate
developed signifiant cross sections (Gross et al., 1968). The ability of Cr(III)
compounds to evoke an allergic reaction in chromium-sensitive guinea pigs
decreased gradually in the following order: chromic chloride > chromic nitrate >
chromic sulfate > chromic acetate > chromic oxalate (Scheiner and Katz, 1973).
According to the authors, this difference depended on the free Cr(III) concentra-
tion in the solution which, in turn, depended on the degree to which the Cr(III)
formed coordination complexes with the original ligands present; strong ligands
prevented the formation of complete antigens. Sensitization of guinea pigs with
chromium (III) sulfate (using Triton X-100) was 86$ successful, whereas sensiti-
zation with an aqueous solution of potassium chromate was successful in only %%
of the animals tested (Schwartz-Speck and Grundsmann, 1972).
Jansen and Barrens (1968) reported that guinea pigs could be sensitized to
both Cr(III) and Cr(VI) by the subcutaneous injection of aqueous solutions of the
appropriate chromium salts in a 1:1 emulsion with Freund's complete adjuvant.
Hicks et al. (1979) produced hypersensitization in guinea pigs with both
Cr(VI) and (III) salts. The contact sensitization potentials of the Cr(III)
complexes in guinea pigs were proportional to the release of chromium from the
complex (Schneeberger and Forck, 1974) .
7.2.5. Other Toxic Effects of Chromium. The literature concerning chronic
and subacute exposure to chromium consists primarily of reports of no observable
effect levels (NOEL) . Although the kidney and liver have been shown to be
7-119
-------
targets following acute exposures, reports of pathology in these organs
following long-term exposure via relevant routes were not found. There are two
reports which suggest effect levels following oral exposure; these studies are
summarized in the following text. The numerous studies which suggest free
standing NOAELs are of limited value as a result of experimental design and are
summarized in Table 7-20.
Gross and Heller (1946) reported that 0. 125/K K^rCL in the feed of rats was
tolerated without observable effects, 0.25% resulted in "subnormal condition",
including rough coat and "subnormal" young born to treated animals. Doses of 0.5
and 1$ resulted in diarrhea, rough dirty coats, and sterility. ZnCrOj. adminis-
tered in the feed at levels of 0.125, 0.25, 0.5, and 1.0$ resulted in subnormal
appearance, rough and dirty coats, and sterility at all dose levels. Group
sizes, duration of treatment, and criteria for determining sterility were not
reported.
Ivankovic and Preussman (1975) administered Cr 0 to rats in their feed.
The compound was prepared by incorporating it into bread dough at levels of 2 or
5%. In a 2-year study (600 feeding days), it was estimated that for the 2%
treatment level, males consumed 75 g/kg (25 g/animal) over the entire study
period and females consumed 72 g/kg (18 g/animal); at the 5% treatment level,
males consumed 180 g/kg and females 160 g/kg for the duration of the study. Body
weights were monitored and animals were maintained on normal rations following
the treatment period. At death, animals were autopsied and "all the important
organs" were studied for micro pat ho logy. In addition, a 90-day study was conduc-
ted also using bread levels of 2 or 5%. In this study, urinary protein, sugar,
bilirubin, blood, and sediment were monitored. During the last 30 days of the
study, treated animals were mated and the number of viable young produced in each
litter was recorded. At the end of treatment, blood samples were analyzed for
7-120
-------
TABLE 7-20
Studies Suggesting NGAELS or NOELS
Species
mouse
mouse
rat
(young)
rat
(young)
-•4
1 rat
KJ
dog
Route Con pound
drinking K0CrO,.
water 2 M
feed aiCrO,,
drinking fC_CrO,,
water 2 "
feed K-CrO,.
£. *T
feed Cr 0-
2 3
drinking K,CrO,.
water * ^
Dose Duration
100, 200, 300, N. S.
300, MOO, or
500 ppra
1) N. S.
300 and 500 ppm N. S.
0. 125J N. S.
0, 1, 2, or 9)t 2 years
0. 45, 2.25, 4 years
1.5, 6.75,
or 11.2 ppm
No. at End point a
Start Monitored
N. S. general appearance ,
reproduction
N. S. general appearance ,
reproduction
N. S. general appear an 09 ,
reproduction
N. S. general appearance ,
reproduction
60 / gross and micro-
group acopic pathology,
body weights
2 /group urinalysia Including
albumin, acetone,
bile plgnents
Result Reference
NCEL for all Gross and Heller, 19t6
doses
NCEL Gross and Heller, 19t6
NOLEL; slight Gross and Heller, 1946
roughness of
coal at 500 ppm
NCEL Gross and Heller, 1946
NCEL I van to vie and Preussman,
1975
NCEL Anwar et al., 1961
glucose, indican
erythrocytes , and
specific gravity;
gross and micro-
scopic pathology of
adrenals, bone
marrow, brain, heart,
intestine, kidney,
liver, lung,
mesenteric lymph
node, parathyroid,
pancreas, spinal cord,
spleen, stomach,
thyroid, and tonsils;
weights of liver
spleen and kidney
-------
TABLE 7-20 (cont.)
No. at
Species Route Conpotnd Dose Duration Start
rat drinking K_CrOtt 0, 0. U5, 2.2, 12 mo highest
water 1.5, 7. 7, 11 dose 9
and 25 ppm females ,
12 males
control
10 of
each sex,
all other
groups , 8
males, 8
females
End points
Monitored Result Reference
clinical blood NOEL MacKenzie et al., 1958
chemistry, body
weights gross and
microscopic patho-
logy
rat
cat
drinking CrCl,
water J
0, 25 ppm
feed
chroniun 50 to 100
carbonate, mg/ oat/ day
chromlun
phos phat e
cat
inhalation
chromium
carbonate
dust
from 3.3 to
to 83 mg/nr
average 58. 3
mg/nr
12 mo 12 males, clinical chemistry NOEL
9 females body weights, gross
and microscopic
pathology
1 to 3 10 organ weights NOEL
mo macrosoopic patho-
logy microscopic
pathogy of lung,
heart, liver, stonach,
spleen, pancreas,
kidney, brain,
sketal muscles
86 see- 2 gross and micro- NCEL
slons scoplc pathology
which
varied from
10 to 60
min and
a vera ged
28 mln
for one
cat and
57 min
for the
other
MacKenzie et al., 1958
Akatsuka and Fair hall,
193t
Akatsuka and Fair hall,
-------
blood sugar, serum protein, serum bilirubin, and haemoglobin. Erythrocytes and
leukocytes were counted. Liver, spleen, kidney, brain, and ovaries were weighed,
fixed, and sectioned at autopsy. In addition, lung, heart, pancreas, stonach,
small intestine, and urinary bladder were also fixed and sectioned.
In the 90-day study, the only treatment related effect was a depression of
spleen and liver weights. Spleen weights appeared to be depressed at both doses
in both sexes. Liver weights appeared to be depressed in both dose groups for
females and in high dose males. Statistical analyses were not reported. In the
2-year study, no treatment related effects were reported.
7.2.5.1. RESPIRATORY EFFECTS — Steffee and Baetjer (1965) exposed
rabbits, guinea pigs, rats, and mice to mixed chromate dust via inhalation or
intratracheal injection. Inhalation exposures were conducted 5 hours/day,
4 days/week throughout the lifespan of the animals. The average air concentra-
tion was estimated to be 3 to 4 mg of CrO_/m . The average weekly exposure was
estimated to be 53, 44, and 49 mg/hour for rabbits, guinea pigs, and rats,
respectively. The following exposure related effects were documented in the
lungs of exposed animals. Fifteen percent of the rabbits and rats in the
inhalation exposures, and rabbits and guinea pigs in the intratracheal groups
exhibited granulcmata. This lesion was found in only one control rat and in none
of the rabbits or guinea pigs. The incidence of alveolar and interstitial
inflammation was greater than controls in guinea pigs exposed via both routes.
Exposure related effects in liver, kidney, and spleen were not found.
Nettesheim et al. (1971) exposed mice to calcium chrcmate dust 5 hours/day,
5 days/week for life. The exposure concentration was 13 mg/m^ of CaCrCL. This
exposure concentration depressed weight gains. Exposed animals showed marked
alterations in the epithelium of the bronchial tree after 6 months of exposure.
These alterations were graded from epithelial necrosis and atrophy to marked
7-123
-------
hyperplasia. In addition, bronchiolization of alveoli (bronchiolar cells lining
alveolar walls) was observed. Another frequently observed effect was alveolar
proteinosis. In addition to lung effects, morphological changes were noted in
the tracheal submandibular lymph nodes. After 2 years of exposure, spleen and
liver were atrophied. Ulcerations in the stomach and intestinal mucosa were
noted occasionally.
Early historical recognition of the ulcerative property of Cr(VI) compounds
in humans is evidenced by several studies on the subject (BScourt and
Chevallier, 1863; Delpech and Hillairet, 1869; Legge, 1902).
Bloomfield and Blum (1928) reported on 23 men employed in six chromium
plating plants in the United States. Their findings are presented in Table 7-21.
They concluded that continuous daily exposure to chromic acid at concentrations
>0.1 mg/nr* is likely to cause nasal tissue injury. As can be seen from
Table 7-15, no concentrations <0.12 mg/nr were observed; hence, injury to nasal
tissue caused by lower concentrations could not be ruled out.
Four of 33 chromium platers were found to have septal perforation, although
the highest measured concentration of chromium trioxide in the workplace was
0.003 mg/m . Of the 33 workers, six had what the author considered to be normal
nqses. He suggested that in view of the low chromium concentration, the lesions
that resulted were due to exposure to periodic high concentrations of chromium
trioxide that occurred when ventilation of the tank failed (Lumio, 1953).
Anodizing operators exposed to concentrations of chromic acid mist ranging
from 0.09 to 1.2 mg/m (as CrO ) developed ulceration of the nasal passages and
atrophic rhinitis (Gresh, 19^; Zvaifler,
The United States Public Health Service conducted a study on workers in
seven chromate-producing plants in the early 1950s. The results are shown in
Table 7-22. Unfortunately, the results of the physical examinations on the
7-124
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TABLE 7-21
Clinical Findings in Workers Employed in Chromium-Plating Plants
Case
1
2
3
it
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Time Employed in
Chromiun-Platlng Time Over
Occupation Room, mo Tank, h/d
Chromiun plater
Chromim plater
Foreman plater
Foreman plater
Chromiun plater
Chromiun plater
Chromlun plater
Chromiun plater
Chromlun plater
Chromlun plater
Chromiun plater
Chromlun plater
Chromlun plater0
Chromiun plater
Nickel platerd
Backer
Backer
Backer
Wiper
6
20
7
8.5
3.5
0.75
0.25
7
3
36
5
0.75
12
0.67
1.5
8
0.75
0.75
1.5
U
4
2
3
4
7
7
7
7
4
6
6
4
2
0
0
0
0
0
Approximate
CrO. Expostre, Perforated Ulcerated
mg/m Septun Septun
1.5 ++
2.8 -H.
2.5 - -M-
2.5 - *+
5.6 - -M.
0.12
0.12
0.12
0.12
0.2
0.12
0.12
2.8
2.8
?
?
?
?
?
Inflamed
Mucosa" Nosebleed
•M. Yes
+ Yes
++ Yes
++ Yes
-M- Yes
•M. Yes
•M- Yes
++ Yes
++ No
++ No
+ Yes
+ No
No
No
+ Yes
+ Yes
+ No
+ No
+ No
Chrome
Holes
Yes
Yes
No
No
Yes
Yes
No
No
Yes
No
Yes
No
No
No
No
No
No
No
No
-------
TABLE 7-21 (cont.)
1
ON
Case
20
21
22
23
Occupation
Foreman6
Foreman6
Clerk6
Inspector6
Time Employed in
Chromlun-Plating
Room, mo
0
0
0
0
Time Over
Tank, h/d
0
0
0
0
Approximate
CrO, Exposure, Perforated Ulcerated
mg/m Septun Septun
0 -
0 -
0 -
0 -
Inflamed
Mucosa Nosebleed
+ No
+ No
No
+ No
Chrome
Holes
No
No
No
No
^Soiree: MAS, 1974a
c++, marked; +, alight; -, negative.
.Used vaseline In nose.
Cyanide burns
Worked in other departments of factory
mo = month; h = hoir; d = day
-------
—I
I
TABLE 7-22
Perforation of Nasal Septum in Chrcmate Workers*
All Workers
Time Worked
in Chroraate
Industry
<6 months
6 mont hs to
3 years
3 to 10 years
>1 0 years
TOTAL
Total
No.
41
117
370
369
897
Workers wi th
Perforation
No. %
1 2.4
46 39.3
205 55.4
257 69.6
509 56.7
White Workers
Total
No.
32
89
235
297
653
Workers with
Perforation
No. %
0 0
28 31.5
104 44.3
190 64.0
322 49.3
Nonwhite Workers
Total
No.
9
28
135
72
244
Workers with
Perforation
No.
1
18
101
67
187
*
11.1
64.3
74.8
93.1
76.6
•Source: NAS, 1974
-------
workers were not related to chromiun exposures, and hence, the data are of
limited usefulness (Federal Security Agency, 1953).
Mancuso (1951) reported on physical examinations of a random sample of 97
workers from a chromat e-eheraicaT plant. It can be seen from the results which
are presented in Table 7-23, that 61 of 97 workers ( 63%) had septal perforation.
The data suggested to the author that Cr(III) may be partly responsible for the
perforations; however, later studies have not provided support for this theory.
The results of examinations of nine workers in a chrome-pi at ing plant are
shown in Table 7-24. Analyses of air samples showed chromiun concentrations of
0.18 to 1.4 mg/m . Sane degree of nasal septal uloeration was seen in 7 of the 9
men, with 4 of 7 demonstrating frank perforations (Kleinfeld and Russo, 1965).
Unfortunately, the effects of chromium for a specific length of time at a fixed
concentration were not studied.
In a Russian study conducted by Kuperman (196*0, 10 apparently normal
persons were exposed to Cr(VI) aerosol concentrations of non-reported composi-
tion ranging from 0.0015 to 0.04 mg/m. Air containing Cr(VI) at 0.01 to
0.024 mg/nr sharply irritated the nose when inhaled for short periods of time.
The most sensitive person responded at a chromiun concentration of 0.0025 to
0.004 mg/m ; however, it was not known if this was a reaction to chromiun or to
the acidity of the aerosol.
Vigliani and Zurlo (1955) reported nasal septal perforation in workers
exposed to chromic acid and chromates in concentrations of 0.11 to 0.15 mg/m .
The lengths of exposure were not known. Otolaryngologic examinations of 77
persons exposed to chromic acid aerosol during chrome plating revealed 19$ to
have septal perforation and 48$ to have nasal mucosal irritation. These people
averaged 6.6 years of exposure to an air chromiun concentration of 0.4 mg/m . In
14 persons, papillonas of the oral cavity and larynx were foind. The diagnosis
7-128
-------
TABIJE 7-23
Perforation of Nasal Septum in Chronate Workers*
Ratio of
insol Cr*^ to Chromium Concentration,
sol Cr mg/nr (as Cr)
Workers in plant
<1.0:1 <0.25
0.26 to 0.51
£0.52
1.1 to 4.9:1 <0.25
0.26 to 0.51
>0.52
>5.0:1 <0.25
0.26 to 0.51
>0.52
TOTAL
Office workers 0. 06
No. Workers
Examined
4
7
8
9
32
15
7
2
13
97
4
Workers
Septal
No.
2
3
4
7
20
11
2
1
11
61
0
with
Perforation
%
50
43
50
78
63
73
29
50
85
63
0
•Source: MAS, 1974
insol = insoluble; sol = soluble
7-129
-------
TABLE 7-24
Nasal Medical Findings in a C hromi un-P lat ing Plant*
Case
1
2
3
4
5
6
7
8
9
Age, yr
30
19
19
18
47
U5
23
20
48
Duration of
Exposure, mo
6
2
12
9
10
6
1
0.5
9
Findings
Perforated septan
Perforated septun
Perforated septum
Perforated septum
Ulcerated septum
Ulcerated septun
Ulcerated septun
Moderate injection of septun and turbinates
Moderate injection of septun
"Source: MAS, 1974
7-130
-------
of papillona was confirmed by histologLc examination. There were no signs of
atypical growth or malignant degeneration (Hanslian et al., 1967).
Cohen et al. (197U) have identified a serious health hazard among workers in
a nickel-chrome plating area. Thirty-five of 37 (95/6) employees exposed to
•3
atmospheric concentrations averaging 0.0071 mg/m as total chromium were shown
to have developed significant nasal pathology and skin lesions characteristic of
exposure to chromic acid. The authors attributed the high incidence of adverse
health effects to the lack of emphasis on the implementation of good industrial
hygiene and personal hygiene. The mechanism postulated for the occurrence of the
observed nasal damage resulted from either long-term exposure to levels of Cr(VI)
below prescribed "safe" levels, or direct contact of the affected tissue resul-
ting from inadequate personal hygiene practices.
The literature suggests that chromiun compounds are responsible for a wide
variety of other respiratory effects. Studies done by German investigators
demonstrate mixed results from exposure to chromiun compounds. Fischer (1911)
and Lehmann (191U) reported that there were no marked clinical symptoms in
persons exposed to chromate dust. Other German investigators (Alwens and Jonas,
1938; Fischer-Was els, 1938; Koelsch, 1938; Lehmann, 1932; Mancuso, 1951) have
reported that prolonged inhalation of chrcmate dust caused chronic irritation of
the respiratory tract and resulted in such manifestations as congestion and
hyperemia, chronic rhinitis, congestion of the larynx, polyps of the upper
respiratory tract, chronic inflammation of the lungs, emphysema, tracheitis,
chronic bronchitis, chronic pharyngitis, and broncho pneumonia. X-ray findings
included enlargement of the hilar region (often on only one side), enlargement of
the lymph nodes, increase in perlbronchial and peri vascular lung markings , and
adhesions of the diaphragm. Letterer et al. (197*0 and Lukanin (1930) stated
that a characteristic pneunonoconiosis resulted from exposure to some chronates.
7-131
-------
With all of these studies, a correlation between symptomatology, physical signs,
length of exposure, and dose of chromium compounds was not available.
In contrast with the above findings, 897 workers in chromate-producing
plants in the United States had a higher incidence of severely red throats and
pneumonia, but did not show any increase in the incidence of other respiratory
diseases when compared with control groups. Although bilateral hilar enlarge-
ment was observed, there was no evidence of excessive pulmonary fibrosis in these
workers (Federal Security Agency, 1953). The various lung changes described in
these workers may represent a nonspecific reaction to irritating material or a
specific reaction to chromium compounds. Many of the conditions mentioned occur
widely in the general adult population (NAS, 197U).
Inhalation of massive amounts of chromic acid mist has resulted in acute
pulmonary complications. Meyers (1950) reported on two patients who were exposed
to an estimated chromic acid mist concentration of 20 to 30 mg/m . Symptoms
included cough, dyspnea, chest pain, and weight loss. The first patient
developed pulmonary edema, and the author stated that his exposure was more
severe and prolonged than the second patient who developed a slight pleural
effusion. In another study, Zvaifler (19^) reported atrophic rhinitis in 5 to
10$ of a group of workers exposed to the mist of a 5% chromic acid solution.
Hyperemia, congestion, swelling, and nasal inflammation recurred in some of
these persons.
Gomes (1972) examined 303 employers in 81 electroplating operations who
worked in Sao Paulo, Brazil. Over two-thirds of the workers had mucous membrane
or cutaneous lesions, with many of them having ulcerated or perforated nasal
septa. The duration of exposure was not stated, but the author mentioned that
the harmful effects were noted in less than 1 year. In addition, a direct
7-132
-------
correlation between workers exposed to a given airborne concentration of
chromiun (VI) and the development of harmful effects could not be made.
Cohen and Kramkowski (1973) and Cohen et al. (1971) examined 37 workers
employed by a chromium-pi at ing plant. Within 1 year of being employed, 12
workers experienced nasal ulceration or perforation. The airborne chromiun (VI)
concentrations ranged from <0.71 to 9.12 M.g/m .
In a chromiun plating plant where the maximun airborne chromiun (VI) concen-
tration was 3 ng/m , no ulcerated nasal mucosa or perforated nasal septa were
found; however, half of the 32 employees had varying degrees of mucosal irrita-
tion (Markel and Lucas, 1973). This was not thought to be significant by the
investigators, because the survey was carried out at the peak of the 1972 to 1973
influenza epidemic. The length of employment for the workers was as follows: >8
years, 15 workers; 4 to 8 years, 7 workers; 1 to 4 years, M workers; <1 year, 6
workers.
Machle and Gregorius (1948) reported an incidence of nasal septal perfora-
tion of ^3.5% in 354 employees who worked in a chronate-producing plant that
manufactured sodium chromate and bichromate. At the time of the study, airborne
•3
chromate concentrations ranged frcm 10 to 2800 jig/m . The plant has been in
operation for at least 17 years, and some employees had probably worked in the
plant when reverberatory furnaces, a prominent source of high chrcmate exposure,
were used.
Chromiun exposure in Australian shipyards, resulting from welding opera-
tions, has been reported by Bell (1976) to cause irritation to the nose and
throat at welding fume ranging from 0.006 to 0.05 mg/ . Lung biopsy specimens
from welders confirmed the presence of severe pneunoconiosis similar to that
reported by Stettler et al. (1977).
7-133
-------
Various other disease states such as asthma have been attributed to
chromium, but, in most cases, the etiologLc relation to chromium is doubtful
because of the presence of other chemicals (MAS, 1974). Asthma was reported as a
complaint among workers employed for >10 years in a ferrochromium plant in Norway
(Broch, 1950). Bronchial asthma was also reported in Russian bauxite workers,
where Cr(VI) was involved in the bauxite caking process (Budanova, 1976). A
clinical test for the diagnosis of actual or imminent bronchial allergic reac-
tions to Cr(VI) has been developed by Budanova and Makarova (1979). A correla-
tion was established between the concentration of leukocyte agglomerates in
blood stimulated by Cr(VI) , with 3% for a healthy control group versus =16$ for
workers with heavy bronchial asthma. It appears, then, that chromium sensitiza-
tion can occur after inhalation exposure as well as dermal exposure. In one
chromium-alloy plant, four cases of pulmonary disease with nodular fibrosis and
ventilatory impairment were reported by Princi et al. (1962), but no such cases
were found in another similar plant (Pierce and Scheel, 1965).
Bo vet et al. (1977) have suggested that workers exposed to chromium in
electroplating operations have increased frequencies of obstructive respiratory
disease. The lowest dynamic values of pulmonary function (e.g., vital ca'pacity,
forced vital capacity, forced expiratory volume, and forced expiratory flow)
were reported for those workers displaying the higher urinary chromium levels.
The effect of tobacco smoke on pulmonary function was minor compared to the
effect attributed to chromium exposure. Forced expiratory flow and forced
expiratory volume were the pulmonary functions decreased to the greatest extent
as a result of occupational exposure to chromium. The total number of workers
examined was 44, and no data on specific compounds, levels or duration of expo-
sure were reported.
7-134
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Capodaglio et al. (1975) demonstrated alterations in respiratory function
among bichromate and chromic acid production workers. Observed changes in chest
X-ray and respiratory function parameters were hypothesized to be the result of
exposure to chronate, and the extent of the reduced pulmonary function was
correlated to length of exposure. Data on the specific compounds and levels of
exposure were not reported in the only available review of this study (NIOSH,
1975).
Workers in a chromite mine and concentration plant developed pulmonary
markings (ground-glass types 1 and 2) that were attributed to chromite dust.
However, free silica dust was also present in the air. No clinical or roentgeno-
logic evidence of fibrosis was found in the chrcmate workers (Federal Security
Agency, 1953).
Royle (1975) has investigated the occurrence of various respiratory
symptoms among British electroplaters exposed to chromic acid. A total of 997
platers and 1117 controls completed a Medical Questionnaire on Respiratory
Symptoms. There was a significant (p<0.025) occurrence of attacks of bronchitis
in platers (28.2?) compared to controls (23.7*). Platers also had significantly
higher incidences of haemoptysis, perennial nasal catarrah, and Grade 2 habitual
winter cough and Grade 2 winter phlegm production. Ratative asthma was indicated
in 13.1? of the platers at a 2.5$ level of significance. Nasal and skin ulcers
were significantly higher in platers. Smoking histories were comparable in
intensity and longevity for both populations. No clinical testing or medical
examinations were performed to verify the findings of the Medical Questionnaire.
Controls were more frequently exposed to a variety of "dusts" in present or
previous employment situations or both, and were also exposed to asbestos much
more so than was the study population. Air samples taken between the years of
1969 and 1970 were <0.03 mg/nr in all but two cases (these were reported as
7-135
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<0.1 mg/m ) . Dust samples generally ranged from 0.3 to 97.0mg/g, but were
reported as high as 298 mg/g. Members of both the study and control populations
were exposed to a variety of additional compounds that could cause similar
symptoms (asbestos, cadmiun, nickel), a cu r cum stance that, detracts from the
overall quality of the study as does the use of medical questionnaires without
any medical examinations to substantiate these subjective findings.
Lucas and Kramkowskl (1975) have examined the occurrence of abnormal medi-
cal findings in a "hard" chromium electroplating processing plant. A total of 11
workers were screened for various medical complaints associated with exposure to
chromic acid in electroplating operations. Average age of the workers was 39
years (range 22 to 54) , with an average occupational exposure of 7.5 years (range
3 to 16 years). Average airborne chromium (VI) levels were reported as
•3 -3
0.004 mg/m , with a range of >0.001 to 0.020 mg/m , well within acceptable limits
of the current NIOSH standards. Ventilation systems appeared to be functioning
adequately, and work surfaces adjacent to the electroplating site were free from
contamination by chromium trioxide, CrO . A summary of medical findings is found
in Table 7-25. Despite the degree of protection offered by ventilation and
protective clothing and equipment, workers displayed a significant number of
adverse medical effects at presumably "safe" levels of exposure.
In addition, a fine nodular pneumoconiosis has been reported in a few
chromite miners in South Africa (Sluis-Cremer and duToit, 1968). The available
evidence suggests that the pneumoconiosis is due to deposition of chromite dust
in the lung tissue, and that the condition is benign and caused no fibrosis.
Other components of the ore, such as iron, may also have been responsible for the
observed fine nodular pneumoconiosis.
7.2.5.2. RENAL EFFECTS CF CHROMIUM —Several authors have reported kidney
damage following the deliberate ingestion or therapeutic application of chromium
7-136
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TABLE 7-25
Medical Complaints of Workers in "hard" Chromium Electroplating Plant3
Frequency Symptom
1 Nasal irritation
U Nasal soreness >c
6 Runny nose (chronic) 'G
4 Frequent nose bleeds
2 Ulceration of nasal septum
9 Scars indicating previous
ulceration of the nasal septum
1 Perforated nasal septun
5 Chronic coughing episodes
2 Pulmonary distress indicative
of emphysema
7 Current skin sores
9 Scars indicating healed chrome
ulceration on skin
5 Gastric distress
1 Chemical diabetes
1 Ocular pterygium on corneal
conjunctiva
1 Advanced renal carcinoma (1967
diagnosis; 1968, one kidney
removed; 1973, metastasized
to second kidney; 1971*, cobalt
treatment
^Source: Lucas and Kramkowski, 1975 " ~~
Previous to occurrence of nasal perforation.
Two occurences were attributed to cold outdoor temperatures.
Three individuals were reported as moderate to heavy smokers.
7-137
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compounds (Brieger, 1920; Godlman and Karotkin, 1935; Major 1922; Partington,
1950; Rambousek, 1913). Twelve persons died after the application of anti-
scabietic ointment in which sulfur had been replaced with Cr(VI). Necrosis of
the skin developed at sites of application and was followed or accompanied by
nausea, vomiting, shock, and coma. Urinalysis revealed albumin and blood.
Post-mortem findings included tabular necrosis and hyperemia of the kidneys
(Brieger, 1920).
Only one of the above studies (Goldman and Karotkin, 1935) was available for
review. It is difficult to determine if chromium has a direct toxic effect on
the kidneys or alters the normal homeostasis of the body, thereby exerting its
effect. Evidence to support the first view comes from a study conduted by Mutti
et al. (1979). They examined welders and chromium platers, and found that
workers with a higher degree of exposure to chromium showed a pattern of nephro-
toxicity, as evidenced by increases in the indices for renal tubular damage. The
length of exposure and concentration of chromium were not specified. It is
interesting to note that the workers who had a higher degree of exposure to
chromium also demonstrated higher urinary chromium values.
Pederson and Mersch (1978) reported the incident of a woman who ingested
10 mil of a 50% chromic acid solution with 150 mS, of Coca-Cola. Vomiting occurred
several times in the hospital, where gastric lavage was performed and activated
charcoal, magnesia, and milk were administered. Remedialysis was initiated 18
hours after ingestion. Blood samples were consistent with anemia, which was most
pronounced by the eighth day of hospitalization. Slight granulocytopenia was
observed on the third day. There was significant proteinuria (1.9 g) on the
first day.
Bilirubin levels rose during the first 3 days. One day after ingestion, the
patient was admitted to the renal unit; the serum chromium was 1.37 ug/mJl (2.9^
7-138
-------
mg Cr/SL whole blood) . Dialysis treatment was instituted, which accelerated the
removal of chromiun from the serum. During the patient's stay, no signs of
gastrointestinal or cerebral disturbance were noted. Hepatic function was
normal upon discharge, following a hospital stay of 11 days.
7.2.5.3. MIS CELLAN30 US TO HC EFFECTS —Mancuso (1951) reported that chro-
mate workers frequently showed excessive susceptibility to inflammatory and
ulcerative conditions of the gastrointestinal tract caused by ingestion of
chromium.
Hepatic injury, apparently due to exposure to chromic acid mist from plating
baths, has been reported ( Pascale et al., 1952). One woman who had been employed
for 5 years at a chromium plating factory was hospitalized with jaundice and was
found to be excreting significant amounts of chromium. A liver biopsy specimen
showed microscopic changes resembling those found in toxic hepatitis. Eight
coworkers were screened for urinary chromiun excretion in an effort to investi-
gate the possibility that the hepatic damage was of occupational origin. Four of
the workers were found to be excreting significant amounts of chromiun. In three
workers who had been exposed to chromic acid mists for 1 to 4 years , liver biopsy
specimens and a series of 12 hepatic function tests showed mild to moderate
abnormalities. The correlation of degree of hepatic injury with the concentra-
tion of chromic acid mist and information on controls were not available.
Frenkiel and Albert (1976) reported that traumatic injury of the tympanic
membrane and external auditory canal, and changes in middle ear mucosa were
suffered by a worker who had fallen into a vat of chromic acid. Extensive
chemical burns were sustained, along with a 20 decibel conductive hearing loss
stemming from an acid burn to the right tympanic membrane.
7-139
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7.3 SUMMARY OF TOXIC EFFECTS OTHER THAN CANCER FOLLOWING EXPOSURE TO CHROMIUM
COMPOUNDS.
Inhalation exposure is the most predominant route of exposure in industry to
chromiun compounds and the route most extensively investigated. Local effects on
the respiratory system are the primary toxic effects observed in workers exposed
to chromium in the atmosphere. Cr(VI) , in the form of chromic acid, has been
associated for many years with the development of perforations of the nasal
septun. The Implication of chromic acid as the causative agent results from the
common occurrence of this disorder in the chromium-pi at ing industry, where
exposure is restricted to this Cr(VI) compound. Other Cr(VI) compounds may also
participate in the etiology of perforated nasal septuns, since this disorder has
been reported in the chronate manufacturing industry, where the predominate
exposures are to Cr(III) and the Cr(VI) compounds, sodium chromate and sodium
dichrcmate; however, chromic acid mist may also be present in these plants. It
is interesting to note that nasal septun perforation has not been reported as an
occupational hazard in the chrcme leather tanning industry or the chrcme pignent
industry, both of which exclusively use Cr(VI) , although these industries are
associated with severe chromium dermatitis. The lack of perforated nasal septums
in these industries may result from differences in the physical or chemical form
of the chromiun, droplets in the tanning industry and participates in the pignent
industry as compared to the chromic acid mist generated in the plating industry.
The measurements of chromic acid associated with perforated septums in the
chrome-pi at ing industry is X).1 mg/m3 (see Table 7-21); however, it is not known
if lower concentrations are also effective. Also, severe irritation of the
throat and lower respiratory tract have been associated with chromiun compounds
at concentrations as low as 0.12 mg/m3. • Again, as with perforated nasal septum,
this respiratory tract irritation is primarily associated with Cr(VI) . Hyper-
7-1^0
-------
sensitivity may result from dermal or inhalation exposure to either Cr(VI) or
Cr(III); however, there is little information available on the levels of exposure
necessary to induce an allergic response.
Little information is available on systemic effects of inhalation of
chromium compounds, although Pascale et al. (1952) and Mutti et al. (1979)
reported liver injury in a chromate worker and kidney injury in a welder exposed
to chromium, respectively. Acute exposure of animals using a variety of routes
of administration (Section 7.1.2) have indicated that both Cr(VI) and Cr(III)
compounds can produce kidney and liver danage , although the dose levels employed
were relatively higi. From the evidence available from both human case reports
and animals studies, it can only be speculated whether the kidneys and liver may
be target organs following chronic exposure to chromium compounds.
Although inhalation studies of occupational exposure to chromium indicate
that exposure to some chromium compounds can result in perforation of the nasal
septum, irritation of the respiratory tract, pne uno coni osis, bronchitis, chronic
lung congestion, and possible liver and kidney damage (as supported by target
organ toxicity in acute animal studies) , there are insufficient data available to
make a quantitative risk assessment for either chromium as a class or individual
chromiun compounds from these inhalation studies. The only studies that provide
any exposure data (and this is of limited and questionable quality, since
measurements were not made contemporary with exposure and personal habits, such
as picking of the nose, may result in high local concentrations of chromiun) are
the studies of the occurrence of perforated nasal sept urns. Since perforated
nasal septun results from the local destruction of the mucous membrane of the
nose, this does not represent a systemic effect of chromium. Also, in the study
by Nettesheim et al. (1971), inhalation exposure of mice to chromiun resulted in
marked effects to the respiratory tract. These effects, including hyperplasia
7-TH
-------
and necrosis, were likely to have resulted from the severe local irritation of
the cells lining the air ways. It would not be expected that exposure to
chromium by any other route would result in this disorder, and although these
data can be used to derive an acceptable inhalation exposure level, they are
inadequate for determining safe levels of chromiun by all routes of exposure.
The limited information on other systemic effects of inhaling chromium, liver and
kidney damage, contains both insufficient exposure data and too few case reports
to form a firm association between exposure and effect.
There are only a few instances of human exposure to overtly toxic levels of
chromium compounds by ingestion, and these represent acute exposure to massive
doses which provide little information on the safe levels of chromium following
chronic exposure. A number of animal studies have been performed in which the
chromium compound was administered in the food, water, or by gavage. The acute
oral toxicity data indicate that Cr(VI) is approximately 2 or 3 orders of magni-
tude more toxic than Cr( III) , with the latter toxic at the level of g/kg body
weight (Section 7.1.2). The difference in valence state may be less relevant
following chronic or subchronic ingestion of chromiun, since it is suggested that
Cr(VI) is reduced to Cr(III) under the acid conditions of the stomach. The
determination as to whether Cr(III) or Cr(VI) is more toxic after chronic expo-
sure, however, cannot be made, since none of the studies employed a sufficiently
high dose to produce a toxic effect.
The only study in which an effect was observed was that of Ivankovic and
Preussman (1975) in which rats were fed diets containing 2 or 5% CrpO-tCr"1"-*), 5
days/week for 90 days. The only observed effect was a reduction in the weight of
the liver and spleen in the treated male rats as compared with liver and spleen
weights of control animals. Similar results were observed in female rats main-
tained on the same diet. Neither organ showed macroscopic or mi ores oo pic abnor-
7-142
-------
malities, and the authors concluded that these changes were not toxicologically
important. In a larger 2-year study using the same experimental procedure and 60
animals of each sex per group, Ivankovic and Preussman (1975) did not mention any
treatment-related changes in organ weight, although it was mentioned that no
signs of chronic toxicity were observed. Therefore, it is unclear whether the
slight change in organ weight observed in the small nunber of animals in the 90-
day study was the result of spurious observation due to the small group size, or
whether the 5% exposure level represents a true NOAEL (no-observed-adverse-
effect-level). No matter whether this 90-day study represents a NQftEL or an NCEL
(no-observed-effect-level) , the small group size makes this study very tenuous
as the basis for quantitative risk assessment.
In the absence of any data on effect levels following chronic exposure to
chromium, the U.S. EPA, in the Ambient Water Quality Criteria Document for
Chromium (U.S. EPA, 1980a), derived acceptably daily intake values (ADIs) of
0.175 and 125 mg/day/man for Cr(VI) and Cr(III), respectively. These ADIs were
derived by using the highest NCEL available for each valence state. For Cr(VI),
the study of MaoKenzie et al. (1958) was used, in which rats were exposed to
several levels of chromium in the form of KpCrOj. up to 25 ppm in the drinking
water for 1 year, while for Cr(III), the chronic study of Ivankovic and Preussman
(1975) was used, in which rats were fed diets containing up to 5% Cr20_ for 2
years. The ADIs for both Cr(VI) and Cr(III) were expressed as mg/d of the
compound administered. Although these ADIs were, derived, it is not apparent from
the toxi col ogle information available whether the ADIs are more appropriate for
the specific chromiun compounds tested, KpCrOj. and Cr_0_, rather than the general
classes of Cr(VI) and Cr(III) . This is particularly hard to determine, since no
toxic effects were observed in these chronic animals studies.
-------
8. CURRENT REGULATIONS AND STANDARDS
A number of recommended standards presently exist for permissible levels of
chromium in both air and water. The National Academy of Science (NAS, 1980) and
the U.S. Environmental Protection Agency (U.S. EPA, 1980a), in regard to ambient
water quality criteria, have stated that a distinction between the Cr(III) and
(VI) forms should be made when considering the formulation of regulations and
exposure criteria.
8.1. OCCUPATIONAL EXPOSURE
NIOSH (1973, 1975), OSHA (1978), and ACGIH (1981) have recommended various
exposure limits for chromium. These values are based on the chemical form of the
chromium compounds or their solubilities. Table 8-1 outlines the various United
States occupational standards for chromium compounds.
8.2. EXPOSURE TO CHROMIUM IN AMBIENT WATER.
A number of standards exist for chromium in ambient water or drinking water.
In general, the standards for occupational exposure to chromium in the air allow
for a greater uptake of chromium than by the uptake of chromium from drinking
water. The U.S. EPA (1980a) has estimated the daily intake of chromium from
drinking water to be 5 ng/day. Table 8-2 outlines various recommended or esta-
blished standards for chromium in the United States.
The U.S. EPA (1980a) recently proposed several ambient water quality cri-
teria for chromium. Based on methodology outlined in the Federal Register
(M5 FR 79353), acceptable daily intakes (ADIs), no-observable-adverse-effect
levels (NOAELs), and bioconcentration factors (BCFs) obtained from experimental
animal studies, separate water quality criteria were proposed. Table 8-3
8-1
-------
TABLE 8-1
Recommended Occupational Standards and Recommended Criteria for
Chromium Compounds in the United States
Chemical Form
Non- carcinogenic chromium (VI )a
Carcinogenic chromium (VI)
Chromic acid (as chromium trioxide)
Soluble chromic or chromous salt
Insoluble salts or chromium metal
Chromium metal
Chromium (II) compounds
Chromium (III) compounds
Chromium (IV) compounds
water soluble
water insoluble
Chromite ore
Chromium: soluble chromic and
chromous salts
Standard (^g/m^)
25 TWA
50 Maximum
1
50 TWA
100 Maximum
500 TWA
1000
500 TWA
500 TWA
500 TWA
50 TWA
50 TWA
50
500 TWA
Reference
NIOSH, 1975
NIOSH, 1975
NIOSH, 1973
OSHA, 1978
OSHA, 1978
ACGIH, 1981°
ACGIH, 1981
ACGIH, 1981
ACGIH, 1981
ACGIH, 1981
ACGIH, 1981
ACGIH, 1981
wIOSH listed "non-carcinogenic" chromium VI compounds as the monochromates and
dichromates (bichromates) of: hydrogen, lithium, potassium, rubidium, cesium,
ammonium, and chromic oxide (chromic acid anhydride).
NIOSH listed "carcinogenic" chromium VI compounds as all other chromium compounds not
included in the "non-carcinogenic" chromium VI listed above.
These are also known as the TLV values established by ACGIH.
ACGIH listed these classes of chromium compounds as substances associated with
industrial use that have been recognized as carcinogens.
8-2
-------
TABLE 8-2
Recommended Standards for Chromium
in Ambient Waters in the United States
Chemical Form
Chromium (VI)
Total Chromium
Medium
drinking water
total
domestic water
Criteria (\Lg/H)
50
50
Reference
U.S. Public Health
Service (USPHS), 1962
U.S. EPA, 1976
Total Chromium
Chromium (VI)
Chromium
supply
freshwater
(aquatic life)
livestock water
community water
systems and non-
community water
systems
100
1000
50
U.S. EPA, 1976
National Academy of
Science and National
Academy of Engineering
(NAS/NAE), 1972
40 CFR 141,11
8-3
-------
TABLE 8-3
Ambient Water Quality Criteria for
the Protection of Human Health3
Chemical NOAEL
Form (mg/£)
Chromium (III)b 50,000
i
"^ Chromium (VI) 25
Rat
NOAEL
(mg/d/kg)
1786
2.50
ADI
for man
(mg/d/man) BCF
125 16
0.175 16
Calculated
Criteria (|ig/&)
59,000
83
aSource: U.S. EPA, 1980a
Revised ADI and criterion. Published values (45 FR 79331) were incorrect. If exposure to trivalent chromium
results only from the eating of fish and shellfish, then the calculated ambient water criterion for chromium
(III) is proposed as 1200 mg/Jl (1.2 x 10
-------
summarizes the proposed U.S. EPA (1980a) ambient water quality criteria for the
protection of human health.
The U.S. EPA (1980a) also has proposed several ambient water quality cri-
teria for the protection of aquatic life. Table 8-4 summarizes the proposed
criteria for the protection of aquatic life.
8.3. EXPOSURE TO CHROMIUM IN AMBIENT AIR.
No federal or state (other than the state of Maine, i.e., 0.05 ng/nr for
mean annual and 0.3 \ig/fn for mean daily limits) ambient air chromium standards
have been proposed. No United States emission standards for chromium were found
in the available literature. TheU.S.S.R. recommends a "sanitary clearance zone"
of 1000 m for plants discharging 200 kg Cr(VI) per day, and 2000 m for plants
discharging 1000 kg per day (NAS, 197*0.
8-5
-------
TABLE 8-4
Calculated Ambient Water Quality Criteria
for the Protection of Aquatic Life*
Chemical
Form
Freshwater Life
24-hour Average Maximum
(Hg/fc) (|ig/fc)
Marine Life
24-hour Average
(|ig/A)
Maximum
(fig/A)
Chromium (III)
Chromium (VI)
44
(chronic value
toxicity)
0.29
NR
21
10,300 (acute
toxicity value)
18
NR
1260
•Source:U.S. EPA, 1980a
NR = Not recorded
8-6
-------
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