CHROMIUM
Agency for Toxic Substances and Disease Registry
U.S. Public Health Service
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ATSDR/TP-88/IO
TOXICOLOGICAL PROFILE FOR
CHROMIUM
Date Published — July 1989
Prepared by:
Syracuse Research Corporation
under Contract No. 68-C8-0004
for
Agency for Toxic Substances and Disease Registry (ATSDR)
U.S. Public Health Service
in collaboration with
U.S. Environmental Protection Agency (EPA)
Technical editing/document preparation by:
Oak Ridge National Laboratory
under
DOE Interagency Agreement No. 1857-B026-A1
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DISCLAIMER
Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry.
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FOREWORD
The Superfund Amendments and Reauthorization Act of 1986 (Public
Law 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of significant
human exposure for the substance and the associated acute,
subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and chronic
health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may present
significant risk of adverse health effects in humans."
This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
iii
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Foreword
Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.
The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. We
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
James 0. Mason, M.D., Dr. P.H.
Assistant Surgeon General
Administrator, ATSDR
iv
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CONTENTS
FOREWORD iii
LIST OF FIGURES ix
LIST OF TABLES xi
1. PUBLIC HEALTH STATEMENT 1
1.1 WHAT IS CHROMIUM? 1
1.2 HOW MIGHT I BE EXPOSED TO CHROMIUM? 1
1.3 HOW DOES CHROMIUM GET INTO MY BODY? 2
1.4 HOW DOES CHROMIUM AFFECT MY HEALTH? 3
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN
EXPOSED TO CHROMIUM? 3
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
HEALTH EFFECTS? 4
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
MADE TO PROTECT HUMAN HEALTH? 8
2. HEALTH EFFECTS SUMMARY 9
2.1 INTRODUCTION 9
2.2 LEVELS OF SIGNIFICANT EXPOSURE 10
2.2.1 Key Studies and Graphical Presentations 10
2.2.1.1 Inhalation 10
2.2.1.2 Oral 16
2.2.1.3 Dermal 21
2.2.2 Biological Monitoring as a Measure of
Exposure and Effects 24
2.2.3 Environmental Levels as Indicators of
Exposure and Effects 27
2.2.3.1 Levels found in the environment 27
2.2.3.2 Human exposure potential 27
2.3 ADEQUACY OF DATABASE 29
2.3.1 Introduction 29
2.3.2 Health Effect End Points 30
2.3.2.1 Introduction and graphic summary 30
2.3.2.2 Description of highlights of graphs 30
2.3.2.3 Summary of relevant ongoing research .... 34
2.3.3 Other Information Needed for Human
Health Assessment 35
2.3.3.1 Pharmacokinetics and mechanisms of
action 35
2.3.3.2 Monitoring of human biological samples .. 36
2.3.3.3 Environmental considerations 36
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Com
3.
4.
rents
CHEMICAL AND PHYSICAL INFORMATION
3 . 1 CHEMICAL IDENTITY
3 . 2 PHYSICAL AND CHEMICAL PROPERTIES
TOXICOLOGICAL DATA
4 . 1 OVERVIEW
4 . 2 TOXICOKINETICS
4 . 2 . L Absorption
4.2.1.1 Inhalation
4.2.1.2 Oral
4.2.1.3 Dermal
4.2.2 Distribution
4.2.2.1 Inhalation
4.2.2.2 Oral
4.2.2.3 Dermal
4.2.2.4 Other routes of exposure
4.2.3 Metabolism
4.2.4 Excretion
4.2.4.1 Inhalation
4.2.4.2 Oral
4.2.4.3 Dermal
4.2.4.4 Other routes of exposure
4 . 3 TOXICITY
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Inhalation
4.3.1.2 Oral
4.3.1.3 Dermal
4.3.2 Systemic/Target Organ Toxicity
4.3.2.1 Respiratory tract effects
4.3.2.2 Immune system effects excluding
hypersensitivity
4.3.2.3 Chromium hypersensitivity and
skin effects
4.3.2.4 Nervous system effects
4.3.2.5 Kidney effects
4.3.2.6 Liver effects
4.3.2.7 General toxicity not discussed in
other sections
4.3.3 Developmental Toxicity
4.3.4 Reproductive Toxicity
4.3.4.1 Inhalation
4.3.4.2 Oral
4.3.4.3 Dermal
4.3.4.4 General discussion
4.3.5 Genotoxicity
4.3.5.1 Human
4.3.5.2 Nonhuman
4.3.5.3 General discussion
4.3.6 Carcinogenicity
4.3.6.1 Inhalation
4.3.6.2 Oral
4.3.6.3 Dermal
4.3.6.4 General discussion
4 . 4 INTERACTIONS WITH OTHER CHEMICALS
1~
. . . 3.
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vi
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Concents
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL . 03
5.1 OVERVIEW „,
5 . 2 PRODUCTION ' ' .' 83
5.3 IMPORT 84
5.4 USE ...:.-..-.-. '.'.'.'.'.'.'.'.'.'. 84
5.5 DISPOSAL 85
6. ENVIRONMENTAL FATE 87
6 .1 OVERVIEW '.'.'.'.'.'.'.'.'.'.'.'.'. 87
6.2 RELEASES TO THE ENVIRONMENT '.'. 87
6.3 ENVIRONMENTAL FATE '.'.'.'.'.'.'.'.'.'.'.'.'.'.'. 88
7. POTENTIAL FOR HUMAN EXPOSURE 9L
7.1 OVERVIEW '.'.'.'.'.'.'.'.'.'.'.'.'.'.'..'. 91
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 91
7.2.1 Air ' 91
7.2.2 Water 91
7.2.3 Soil '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'. 92
7.2.4 Foodstuffs 92
7.2.5 Other Media ' 92
7.3 OCCUPATIONAL EXPOSURE 94
7.4 POPULATIONS AT HIGH RISK '.'.'.'.'.'.'.'.'.'.'.'.'. 94
8. ANALYTICAL METHODS 97
8 .1 ENVIRONMENTAL AND BIOMEDICAL SAMPLES".'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'. 97
9. REGULATORY AND ADVISORY STATUS 103
9.1 INTERNATIONAL 103
9.2 NATIONAL '.'.'.'.'.'.'.'.'.'.'.'.'.'.'.'. 103
9.2.1 Regulations 103
9.2.1.1 Air '.'.'.'.'.'." 103
9.2.1.2 Water 103
9.2.1.3 Non-media-specific 104
9.2.2 Advisory Guidance 104
9.2.2.1 Air '.'.'.'.'.'.'.'. 104
9.2.2.2 Water ' 105
9.2.3 Data Analysis ' ' 105
9.2.3.1 Reference doses 105
9.2.3.2 Carcinogenic potency 106
9.3 STATE 107
10. REFERENCES 109
11. GLOSSARY 131
APPENDIX: PEER REVIEW 135
vii
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LIST OF FIGURES
1.1 Health effects from breathing chromium
[primarily chromium(VI)] 5
1.2 Health effects from ingesting chromium
[primarily chromium(III) and chromium(VI)] 6
1.3 Health effects from skin contact with chromium
[primarily chromium(VI)] 7
2.1 Effects of chromium-- inhalation exposure
[primarily chromium(VI) unless otherwise specified] 11
2.2 Levels of significant exposure for chromium--inhalation
[primarily chromium(VI) unless otherwise specified] 12
2.3 Effects of chromium(VI)--oral exposure 17
2.4 Levels of significant exposure for chromium(VI)--oral 18
2.5 Effects of chromium(III)--oral exposure 19
2.6 Levels of significant exposure for chromium(III)--oral 20
2.7 Effects of chromium(VI)--dermal exposure 22
2.8 Levels of significant exposure for chromium(VI)--dermal 23
2.9 Relationship between water-soluble chromium(VI)
concentration in the workroom air (CrA) and daily
increase in urinary chromium levels (CrU)
(pre-exposure values were subtracted from
end-of-shift values) 25
2.10 Linear relationship between the airborne hydrosoluble
chromium concentration and the chromium concentration
in blood and urine at the end of a 5-day shift in
workers of a dichromate plant 28
2.11 Availability of information on health effects of
chromium(VI) and (III) (human data) 31
2.12 Availability of information on health effects of
chromium(VI) (animal data) 32
2.13 Availability of information on health effects of
chromium(III) (animal data) 33
ix
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LIST OF TABLES
3.1 Chemical identity of chromium metal [chromium(O)] 38
3.2 Physical properties of chromium and selected
trivalent compounds 39
3.3 Physical properties of selected hexavalent chromium
compounds 41
4.1 Acute lethality of chromium compounds 55
4.2 Condition of the nose and subjective symptoms in groups
with different mean values of exposure and with different
highest exposure values 58
4.3 Genotoxicity of chromium compounds in vitro 71
4.4 Genotoxicity of chromium compounds in vivo 72
4.5 Age-specific lung cancer deaths and gradient exposures to
total chromium 75
4.6 Incidence of lung tumors in rats following intrabronchial
implantation of various chromium compounds 79
6.1 Sources and estimates of U.S. atmospheric chromium
emissions 89
7.1 Chromium content in various U.S. foods 93
8.1 Analytical methods for chromium determination in various
sample matrices 98
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1. PUBLIC HEALTH STATEMENT
1.1 WHAT IS CHROMIUM?
Chromium is a naturally occurring element that is found in soil and
in volcanic dust and gases. It is found in the environment in three
major states: chromium(O), chromium(III), and chromium(VI). Chromium
(III) occurs naturally in the environment, while chromium(VI) and
chromium(O) are generally produced by industrial processes. The metal
(chromium(O)] is a steel-gray solid with a high melting point. Chromium
is used mainly for making steel and other alloys. In the form of the
mineral chromite, it is used by the refractory industry to make bricks
for metallurgical furnaces. Chromium compounds produced by the chemical
industry are used for chrome plating, the manufacture of pigments,
leather tanning, wood treatment, and water treatment.
1.2 HOV MIGHT I BE EXPOSED TO CHROMIUM?
For most persons, exposure to small amounts of chromium results
from breathing air and ingesting drinking water and food containing
chromium. Chromium has been found in at least 386 of 1,177 hazardous
waste sites on the National Priorities List (NPL) . Much higher exposure
to chromium occurs to people working in certain chromium industries
(occupational exposure) and to people who smoke cigarettes. The two
largest sources of chromium emission in the atmosphere are from the
chemical manufacturing industry and combustion of natural gas, oil, and
coal. Other sources of chromium exposure are as follows:
• cement-producing plants, since cement contains chromium;
• the wearing down of asbestos brake linings from automobiles or
similar sources of wind-carried asbestos, since asbestos contains
chromium;
• incineration of municipal refuse and sewage sludge;
• exhaust emission from catalytic converters in automobiles;
• emissions from air conditioning cooling towers that use chromium
compounds as rust inhibitors;
• wastewaters from electroplating, leather tanning, and textile
industries when discharged into lakes and rivers; and
• solid wastes from the manufacture of chromium compounds, or ashes
from municipal incineration, when disposed of improperly in
landfill sites.
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2 Section 1
Some consumer products that contain small amounts of chromium are:
• some inks, paints, and paper;
• some rubber and composition floor coverings;
• some leather materials;
• magnetic tapes;
• stainless steel and a few other metal alloys; and
• some toner powders used in copying machines.
Occupational sources of chromium exposure mainly occur in industries
that produce the following:
• stainless steel products (from welding),
• chromates (chemicals made from chromium and used in chemical
industries),
• chrome plated products,
• ferrochrome alloys,
• chrome pigments, and
• leather (from tanning).
Examples of additional occupations that have potential for chromium
exposure include:
• painters
• workers involved in the maintenance and servicing of copying
machines and in the disposal of some toner powders from copying
machines
• battery makers,
• candle makers,
• dye makers,
• printers, and
• rubber makers.
1.3 HOW DOES CHROMIUM GET INTO MY BODY?
• Because small amounts of chromium occur in many foods, most
chromium enters the body from dietary intake.
• Some chromium exposure occurs from breathing air and drinking
water, but exposure from these sources is normally small compared
to intake from food. However, exposure from breathing chromium may
increase for people living near industrial sites where chromate is
produced or used, and exposure from drinking water may increase due
to passage of corrosive water through steel alloy pipes or plumbing
containing chromium.
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Public Health Statement 3
1.4 HOW DOES CHROMIUM AFFECT MY HEALTH?
Chromium is considered to be an essential nutrient that helps to
maintain normal metabolism of glucose, cholesterol, and fat in humans.
Signs of chromium deficiency in humans include weight loss and
impairment of the body's ability to remove glucose from the blood, as
measured by the glucose tolerance test. The minimum human daily
requirement of chromium for optimal health is not known, but a daily
ingestion of 50-200 micrograms (pg) per day (0.0007-0.003 milligram of
chromium per kilogram of body weight per day) has been estimated to be
safe and adequate. Brewer's yeast and fresh foods are good sources of
chromium. Individuals eating diets containing large amounts of highly
processed foods, especially white bread and refined sugar, may consume
less than the suggested dietary level of chromium. The long-term effects
of eating diets low in chromium are difficult to evaluate.
There are three major forms of chromium, which differ in their
effects on health. One major form, hexavalent chromium [chromium(VI)],
is irritating, and short-term high-level exposure can result in adverse
effects at the site of contact, such as ulcers of the skin, irritation
of the nasal mucosa and perforation of the nasal septum, and irritation
of the gastrointestinal tract. Chromium(VI) may also cause adverse
effects in the kidney and liver. The second major form of chromium,
trivalent chromium [chromium(III)], does not result in these effects and
is the form that is thought to be an essential food nutrient when
ingested in small amounts, although very large doses may be harmful.
Chromium in food is mostly trivalent. The third major form is metallic
chromium [chromium(O)]. Exposure to chromium(O) is less common and is
not well characterized in terms of levels of exposure or potential
health effects.
Long-term exposure of workers to airborne levels of chromium higher
than those in the natural environment has been associated with lung
cancer. Lung cancer may occur long after exposure to chromium has ended.
Although it is not clear which form of chromium is responsible for this
effect in workers, only compounds of chromium(VI) have been found to
cause cancer in animal studies. Based on evidence in humans and animals,
compounds of chromium(VI) should be regarded as probable cancer-causing
substances in humans exposed by inhalation. Evidence for other chromium
compounds is inconclusive. Inhalation exposure to chromium may result in
additional adverse effects on the respiratory system and may affect the
immune system. Whether the effects on the immune system seen in
experiments with animals would change a person's resistance to disease
is not known.
Long-term studies in which animals were exposed to low levels of
chromium compounds [particularly chromium(III) compounds] in food or
water have not resulted in harmful health effects.
1.5 IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE BEEN EXPOSED TO
CHROMIUM?
Chromium (III and VI) can be measured in the hair, urine, serum,
and red blood cells, but, because chromium(III) is normally present at
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4 Section 1
low levels in these tissues and fluids, measurements for chromium are
not very useful for determining slight elevations in chromium exposure
over the low levels normally present in the environment. With relative.
high exposure levels (usually occupational), chromium levels in the
urine and red bl'ood'cells provide indications of exposure to compounds
of hexavalent chromium but not trivalent chromium compounds.
1.6 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS?
Figures 1.1, 1.2, and 1.3 show the relationship between exposure to
chromium and known health effects. In the first set of graphs, labeled
"Health effects from breathing chromium," exposure is measured in
milligrams of chromium per cubic meter of air (mg/m3). In the second and
third sets of graphs, the same relationship is represented for the known
"Health effects from ingesting chromium" and "Health effects from skin
contact with chromium." Exposures are measured in milligrams of chromium
per kilogram of body weight per day (mg/kg/day).
In all graphs, effects in animals are shown on the left side,
effects in humans on the right. The first column, called short-term,
represents health effects from exposure lasting for 14 days or less. The
second column, long-term, represents health effects for exposures
lasting more than 14 days. The levels marked on the graphs as
anticipated to be associated with minimal risk for health effects other
than cancer are based on information that is currently available, but
some uncertainty still exists. Based on data from humans exposed to
hexavalent chromium compounds at work, estimates by EPA (1984a) indicate
lifetime exposure to 1 microgram chromium(VI) per cubic meter of air
(Mg/m3) would result in 120 or 120,000 additional cases of cancer in a
population of 10,000 or 10,000,000 people, respectively. It should be
noted that these risk values are plausible upper-limit estimates. Actual
risk levels are unlikely to be higher and may be lower.
Figure 1.2 represents the known health effects from eating or
drinking foods containing chromium. Exposure is measured in milligrams
of chromium per kilogram of body weight per day. These units, mg/kg/day,
are common units for expressing this kind of exposure. As indicated on
the short-term graph, a single dose of a chromium(VI) compound is more
toxic (causes death at a lower exposure level) than a single dose of a
chromium(III) compound. Long-term exposure of animals to chromium
compounds [particularly chromium(III) compounds] in the drinking water
or in the diet has not resulted in any adverse effects. The chromium
doses used in the long-term experiments with animals are much higher
than chromium levels considered safe and adequate (see Fig. 1.2) to
prevent chromium deficiency in humans.
Figure 1.3 represents the known health effects from absorbing
chromium through the skin. As indicated in the figure, not much
information on skin absorption is available. The most common effect of
skin exposure to chromium is skin allergy in sensitive individuals. The
exposures that result in this effect have not been adequately measured.
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Public Health Statement 5
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
EFFECTS CONG IN EFFECTS
IN AIR IN
ANIMALS (mg/m3) HUMANS
DEATH•
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS CONG IN EFFECTS
IN AIR
ANIMALS (mg/m3)
IN
HUMANS
50
\ IRRITATION OF
0 002 NASAL MUCOSA NASAL
00018
00016
00014
00012
00010
OOOOS
00006
00004
00002
PERFORATION
-i
005
004
003
002^
I
001
NASAL
"PERFORATION
0008
0006
0004
0002_
0 00002
NASAL
IRRITATION.
MILD LUNG
.EFFECTS
MINIMAL RISK
FOR EFFECTS
OTHER THAN CANCER
Fig. 1.1. Health effects from breathing chromium [primarily chromium(VI)).
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Seccion 1
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS
IN
ANIMALS
DEATH (Cr(lll).
ONE DOSE] '
DOSE
(mg/kg/day)
2500
"2000
1500
1000
NERVOUS
SYSTEM
EFFECTS
[Cr(VI). 7 DAYS
IN DRINKING
WATER]
EFFECTS
IN
HUMANS
QUANTITATIVE
DATA WERE
NOT
AVAILABLE
EFFECTS
IN
ANIMALS
DOSE
(mg/kg/day)
0006
EFFECTS
IN
HUMANS
0004
500
100
0002
80
SAFE AND ADEQUATE
LEVELS FOR
HUMAN NUTRITION
(Cr(lll)]
60
DEATH (Cr(VI)].
ONE DOSE
PLACED
DIRECTLY
IN ANIMAL'S
STOMACH
(VI)].
H
40
i
10
NO EFFECT ON —i
NERVOUS
SYSTEM [Cr(VI). '
7 DAYS IN
DRINKING WATER]
Fig. 1.2. Health effects from ingesting chromium [primarily chromiumdll) and chromiumfVI)].
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Public Health Scacemenc
SHORT-TERM EXPOSURE
(LESS THAN OR EQUAL TO 14 DAYS)
LONG-TERM EXPOSURE
(GREATER THAN 14 DAYS)
EFFECTS EFFECTS EFFECTS EFFECTS
IN DOSE IN IN DOSE IN
ANIMALS (mg/kg/day) HUMANS ANIMALS (mg/kg/day) HUMANS
DEATH <
7(
s-
6!
6C
5f
5C
4!
4(
3J
3(
30 QUANTITATIVE QUANTITATIVE
DATA WERE DATA WERE
NOT NOT
iO AVAILABLE AVAILABLE
10
0
IO
0
0
0
10
QUANTITATIVE
DATA WERE
NOT
AVAILABLE
Fig. 1.3. Health effects from skin contact with chromium [primarily chromium(VI)].
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8 Section 1
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
HUMAN HEALTH?
The current national interim primary drinking water regulation for
hexavalent chromium proposed by the U.S. Environmental Protection Agency
(EPA) is 0.05 milligram per liter (mg/L). The EPA advises that for
exposure via drinking water, the following concentrations of hexavalent
chromium are levels at which adverse effects would not be anticipated to
occur: 1.4 mg chromium(VI) per liter of water for 10 days for exposure
of children, 0.24 mg chromium(VI) per liter of water for longer-term
exposure for children, 0.84 mg chromium(VI) per liter of water for
longer-term exposure for adults, and 0.120 mg per liter of water for
lifetime exposure for adults.
Chromium levels in the workplace are regulated by the Occupational
Safety and Health Administration (OSHA). The occupational exposure
limits for an 8-hour workday, 40-hour workweek are 0.5 mg/m^ chromium
for soluble chromic [chromium(III)] or chromous (chromium(II)] salts,
1 mg/m^ chromium as insoluble salts or chromium metal, and 0.1 mg/m-* as
a ceiling for chromic acid [chromium(VI)] and chromates [chromium(VI)].
The National Institute for Occupational Safety and Health (NIOSH)
recommends an exposure limit of 0.05 mg/m-* chromic acid for an 8-hour
workday, 40-hour workweek. Chromic acid concentrations should not exceed
0.2 mg/ar in any 15-minute period. NIOSH recommends an exposure limit of
25'Mg/m^ chromium(VI) for chromium(VI) compounds that NIOSH considers to
be noncarcinogenie (chromates and dichromates of hydrogen, lithium,
sodium, potassium, rubidium, cesium, and ammonium and chromic acid
anhydride) for a 10-hour workday, 40-hour workweek. During any 15-minut
period, NIOSH recommends that the occupational exposure level to
chromium(VI) from the noncarcinogenic compounds should not exceed
50 /ig/m^. NIOSH also recommends that carcinogenic chromium(VI) compounds
[any and all chromium(VI) materials not included in the noncarcinogenic
group above] not exceed 1 pg/m^ chromium(VI).
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2. HEALTH EFFECTS SUMHARY
2.1 INTRODUCTION
This section summarizes and graphs data on the health effects
concerning exposure to chromium. The purpose of this section is to
present levels of significant exposure for chromium based on key
toxicological studies, epidemiological investigations, and environmental
exposure data. The information presented in this section is critically
evaluated and discussed in Sect. 4, Toxicological Data, and Sect. 7,
Potential for Human Exposure.
This Health Effects Summary section comprises two major parts.
Levels of Significant Exposure (Sect. 2.2) presents brief narratives and
graphics for key studies in a manner that provides public health
officials, physicians, and other interested individuals and groups with
(1) an overall perspective of the toxicology of chromium and (2) a
summarized depiction of significant exposure levels associated with
various adverse health effects. This section also includes information
on the levels of chromium that have been monitored in human fluids and
tissues and information about levels of chromium found in environmental
media and their association with human exposures.
The significance of the exposure levels shown on the graphs may
differ depending on the user's perspective. For example, physicians
concerned with the interpretation of overt clinical findings in exposed
persons or with the identification of persons with the potential to
develop such disease may be interested in levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health officials
and project managers concerned with response actions at Superfund sites
may want information on levels of exposure associated with more subtle
effects in humans or animals (Lowest-Observed-Adverse-Effect Level,
LOAEL) or exposure levels below which no adverse effects (No-Observed-
Adverse-Effect Level, NOAEL) have been observed. Estimates of levels
posing minimal risk to humans (Minimal Risk Levels) are of interest to
health professionals and citizens alike.
Adequacy of Database (Sect. 2.3) highlights the availability of key
studies on exposure to chromium in the scientific literature and
displays these data in three-dimensional graphs consistent with the
format in Sect. 2.2. The purpose of this section is to suggest where
there might be insufficient information to establish levels of
significant human exposure. These areas will be considered by the Agency
for Toxic Substances and Disease Registry (ATSDR), EPA, and the National
Toxicology Program (NTP) of the U.S. Public Health Service in order to
develop a research agenda for chromium.
-------
10 Section 2
2.2 LEVELS OF SIGNIFICANT EXPOSURE
To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route of exposure--
inhalation, ingestion, and dermal--and then by toxicological end points
that are categorized into six general areas — lethality, systemic/target
organ toxicity, developmental toxicity, reproductive toxicity, genetic
toxicity, and carcinogenicity. The data are discussed in terms of three
exposure periods--acute, intermediate, and chronic.
Two kinds of graphs are used to depict the data. The first type is
a "thermometer" graph. It provides a graphical summary of the human and
animal toxicological end points (and levels of exposure) for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing NOAELs and
LOAELs reflect the actual doses (levels of exposure) used in the key
studies. No adjustments for exposure duration or intermittent exposure
protocol were made.
Adjustments reflecting the uncertainty of extrapolating animal data
to man, intraspecies variations, and differences between experimental
versus actual human exposure conditions were considered when estimates
of levels posing minimal risk to human health were made for noncancer
end points. These minimal risk levels were derived for the most
sensitive noncancer end point for each exposure duration by applying
uncertainty factors. These levels are shown on the graphs as a broken
line starting from the actual dose (level of exposure) and ending with a
concave-curved line at its terminus. Although methods have been
established to derive these minimal risk levels (Barnes et al. 1987),
shortcomings exist in the techniques that reduce the confidence in the
projected estimates. Also shown on the graphs under the cancer end point
are low-level risks (10'4 to 10~7) reported by EPA. In addition, the
actual dose (level of exposure) associated with the tumor incidence is
plotted.
2.2.1 Key Studies and Graphical Presentations
2.2.1.1 Inhalation
As indicated in Figs. 2.1 and 2.2, respiratory tract effects,
including irritation of the nasal mucosa, transient decreases in lung
function, and induction of lung cancer, seem to be the key end points
for inhalation exposure to chromium. These effects can occur in humans
occupationally exposed to chromium(VI) compounds. Nasal irritation has
also been observed in humans who inhaled chromium(VI) aerosols for short
periods in an experimental study.
Lethality. For four soluble chromium(VI) compounds, 4-h rat LC5Q
values range from 33 to 65 mg/m3 chromium(VI) (Gad et al. 1986). The
33-mg/m^ level is plotted on Figs. 2.1 and 2.2 for acute exposure.
-------
Health Effects Summary 11
ANIMALS
(fngvm1)
100 r
HUMANS
10
0 1
001
• RAT LCg,. 4 HOURS
• MOUSE RESPIRATORY TOXICITY AND CANCER 6 MONTHS TO LIFE
INTERMITTENT
I • RABBIT RESPIRATORY TOXICITY SO MONTHS INTERMITTENT
I • RAT GUINEA PIG RESPIRATORY TOXICITY LIFETIME INTERMITTENT
• RABBIT IMMUNOTOXICITY 4-6 WEEKS.
INTERMITTENT [Cr(lll)|
• RAT IMMUNOTOXICITY 90 DAYS CONTINUOUS
.JO RAT IMMUNE SYSTEM 90 DAYS. CONTINUOUS
» RAT CANCER LIFETIME CONTINUOUS
0 1
001
0001 I- A
NASAL MUCOSA
PERFORATION AND
ULCERATION OCCUPATIONAL
ATROPHY OF NASAL MUCOSA
AND IRRITATION
OCCUPATIONAL
NASAL IRRITATION
DECREASED LUNG FUNCTION
OCCUPATIONAL SHORT T=qw
EXPERIMENTAL EXPOSURE
NASAL EFFECTS (LISTED ABOVE)
OCCUPATIONAL
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
A LOAEL FOR HUMANS
A NOAEL FOR HUMANS
Fig. 2.1. Effects of chromium—inhalation exposure (primarily chromium(VI) unless
otherwise specified].
-------
12 Section 2
ACUTE
(S 14 DAYS)
(mg/m3)
100 r
10
LETHALITY TARGET ORGAN
INTERMEDIATE
(15-364 DAYS)
TARGET ORGAN
CHRONIC
(> 365 DAYS)
TARGET ORGAN
CANCER
01
001
0001
00001
000001
0000001
0 0000001
000000001
n (IMMUNE
SYSTEM) (Cr(lll)]
r (IMMUNE
SYSTEM)
m m (RESPIRATORY _m
TRACT)
• r rt g
(RESPIRATORY)
TRACT)
• r
A (NASAL
IRRITATION) f ("ESPIRATORY
1 TRACT)
(RESPIRATORY
TRACT)
10-*
10-5
lO"6
-1 10-'
ESTIMATED
UPPER-BOUND
HUMAN
CANCER
RISK LEVELS
' MINIMAL RISK LEVEL r RAT
| FOR EFFECTS OTHER m MOUSE
u/ THAN CANCER g GUINEA PIG
h RABBIT
A LOAEL FOR HUMANS
A NOAEL FOR HUMANS
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
LOAEL AND
NOAEL IN
SAME SPECIES
I
LOAELAND
NOAEL IN
HUMANS
Fig. 2.2. Levcb of significant exposure for chromium—inhalation [primarily chromium(VI)
unless otherwise specified].
-------
Health Effects Summary 13
Systemic/target organ toxicity. Exposure of normal individuals to
chromium(VI) aerosols for shore periods of time produced nasal
irritation at concentrations of 0.01-0.024 mg/m3, with the most
sensitive individual responding at 0.0025-0.004 mg/m3 (Kuperman 1964)
(LOAEL plotted on Figs. 2.1 and 2.2). In animals, respiratory distress
and irritation have been reported in LC50 studies (Gad et al. 1986), but
without any indication of exposure-effect relationships.
The respiratory tract is a target of intermediate and chronic
inhalation exposure to chromium(VI). Many cases of nasal mucosal
ulceration and nasal septal perforation have been reported in persons
occupationally exposed to chromium(VI). Lindberg and Hedenstierna (1983)
reported that subjective and objective evidence of adverse nasal effects
were found at mean exposure levels of 0.002-0.20 mg/m3 chromium(VI), but
not at <0.001 mg/m3 chromium(VI). The effects noted at <0.002 mg/m-5 were
a smeary and crusty septal mucosa in 11/19 workers and atrophied mucosa
in 4/19. Severity of effect correlated better with highest (peak)
exposure levels than with mean exposure levels. Nasal mucosal ulceration
and septal perforation occurred in individuals exposed at peak levels of
0.02-0.046 mg/m3 chromium(VI), nasal mucosal atrophy and irritation
occurred at peak exposures of 0.0025-0.011 mg/m3, and no significant
nasal effects were seen at peak exposures of 0.0002-0.0012 mg/m3. The
effects observed in this study may not have been a result of exposure
levels actually measured, but may have been a result of earlier exposure
under unknown conditions. Despite this limitation, the study provides
useful data to indicate concentrations of chromium that may result in
effects and concentrations that cause minimal or no effects. This study
indicates that effects on the nasal mucosa (irritation, atrophy) may
occur at chromium(VI) concentrations at 0.002 mg/m3 and greater. That a
concentration of about 0.002 mg/m3 (LOAEL on Figs. 2.1 and 2.2) is an
effect level is supported by the experimental exposure study by Kuperman
(1964), which reported nasal irritation in sensitive individuals at a
chromium(VI) concentration of 0.0025-0.004 mg/m3. Because the nasal
effects observed in the Lindberg and Hedenstierna (1983) study at
concentrations <0.0002 mg/m3 were mild and no effects were observed at
concentrations <0.001 mg/m3 or peak concentrations of 0.0002-0.0012
mg/m3, a concentration of 0.001 mg/m3 is considered a NOAEL for nasal
effects.
In addition, slight effects on lung function have been observed in
workers exposed to chromium(VI). Lindberg and Hedenstierna (1983) found
that workers exposed to mean concentrations of 0.002-0.020 mg/m3
chromium(VI) for a median duration of 2.5 years had slight, transient
decreases in forced vital capacity (FVC), forced expired volume in 1 s
(FEV1), and forced mid-expiratory flow (FEF25-75) during the workday. No
permanent changes were seen in this group (after 2 days without
exposure) in comparison with unexposed controls. Workers exposed to
<0.002 mg/m3 chromium(VI) showed no effect on lung function. The
chromium(VI) concentrations at which minor lung function changes were
observed (0.002-0.02 mg/m3) and those at which no changes were observed
(<0.002 mg/m3) are similar to those for nasal irritation, so the NOAEL
of 0.001 mg/m3 chromium(VI) for nasal mucosal irritation should also
prevent changes in lung function. Because occupational exposures involve
both intermediate and chronic durations, the LOAEL and NOAEL from the
-------
14 Section 2
Lindberg and Hedenstierna (1983) study are plotted on Fig. 2.1 for
effects in humans and on Fig. 2.2 under intermediate and chronic
exposure for respiratory tract toxicity and serve as the basis of the
minimal risk levels for both intermediate and chronic inhalation
exposure to chromium(VI).
In animals, immune system reactions were depressed in rats exposed
to 0.2 mg/m3 chromium(VI) virtually continuously for 90 days (LOAEL,
intermediate exposure on Figs. 2.1 and 2.2). while the immune system was
stimulated at concentrations <0.1 mg/m3 chromium(VI) (NOAEL,
intermediate exposure on Figs. 2.1 and 2.2) (Glaser et al. 1985).
Johansson et al. (1986) found changes in macrophages from rabbits
exposed 6 h/day, 5 days/week for 4-6 weeks to chromium(VI) (Na2Cr04) or
chromium(III) [Cr(N03)3] at chromium concentrations of 0.9 and
0.6 mg/m3, respectively. A decrease in phagocytic activity was observed
in macrophages from chromium(III)- but not chromium(VI)-exposed rabbits
Therefore, the 0.6 mg/m3 concentration can be considered a LOAEL for
chromium(III) exposure and is presented on Figs. 2.1 and 2.2 for
intermediate exposure.
Respiratory tract effects, including nasal mucosa perforation and
granulomata of the lungs, were observed in rabbits exposed for 50 months
and in rats and guinea pigs exposed for their lifetime to chromium(VI)
as mixed chromate dust at 3-4 mg/m3 CrO3 [1.6-2.1 mg/m3 chromium(VI)]
5 h/day, 4 days/week (LOAEL for several species, chronic exposure on
Figs. 2.1 and 2.2) (Steffee and Baetjer 1965). Nettesheim et al. (1971)
observed necrosis, atrophy and hyperplasia of the bronchial epithelium,
and alveolar proteinosis in mice exposed to chromium(VI) as calcium
chromate dust at 13 mg/m3 CaCr04 [4.3 mg/m3 chromium(VI)], 5 h/day,
5 days/week for 6 months to life (LOAEL for mice, chronic exposure on
Figs. 2.1 and 2.2).
Developmental tozicity. Pertinent data regarding developmental
toxicity of inhalation exposure to chromium were not located in the
available literature. Parenteral administration of chromium(III) or
chromium(VI) resulted in adverse developmental effects in animals.
Reproductive tozicity. Pertinent data regarding the reproductive
toxicity of inhalation exposure to chromium were not located in the
available literature. Parenteral administration of chromium(III) or
chromium(VI) resulted in adverse reproductive effects' in animals.
Genotozicity. Studies of chromosome effects in lymphocytes of
workers exposed to chromium(VI) have given mixed results. Bigaliev
et al. (1977) reported an increase in chromosomal aberrations in
lymphocytes of workers exposed to soluble chromium(VI) compounds.
Studies of chromosomal aberrations (Sarto et al. 1982) or sister
chromatid exchange (SCE) (Stella et al. 1982, Nagaya 1986) in chromium-
plating workers [exposed to soluble chromium(VI)J showed significant
increases in these chromosomal effects only in young workers (Sarto et
al. 1982, Stella et al. 1982).
In vivo assays of the genotoxicity of chromium(VI) in nonhuman
systems have given positive results for somatic mutations in Drosophila
melanogaster (Rasmuson 1985), spot test in the mouse (Knudson 1980), a
dominant lethal assay in the mouse (Paschin et al. 1982), a study of
-------
Healch Effects Summary 15
chromosome aberrations in rats (Newton and Lilly 1986), and a
micronucleus assay in mice (Wild 1978). The only in vivo assay of the
genotoxicity of chromium(III) in nonhuman systems, a micronucleus assay
in mice, gave negative results (Wild 1978).
In vitro assays for gene mutations, chromosome effects, and cell
transformation have consistently given positive results for chromium(VI)
(Bianchi and Levis 1985, EPA 1984a). Positive results have been obtained
for chromium(III) only in cells with phagocytic activity or at very high
concentrations of chromium (Bianchi and Levis 1985).
In general, the genotoxicity data support the carcinogenicity
results in animal studies: chromium(VI) is a more active genotoxin than
chromium(III). The positive dominant lethal study taken together with
positive results in human somatic cells raises concern that chromium(VI)
may be a potential human germ-cell mutagen.
Carcinogenicity. Case studies and epidemiological studies indicate
that occupational exposure to chromium compounds is associated with
respiratory cancer. Although these studies do not clearly implicate
specific compounds, they do implicate chromium(VI), and the results of
animal testing also implicate chromium(VI). The key epidemiological
study used for quantitative risk assessment is by Mancuso (1975), who
found a dose-related increase in lung cancer death rates in chromate
production workers exposed to chromium at 1-8 mg/m3-year total chromium.
Using these data and a dose-response model which is linear at low doses,
EPA (1984a, 1986c) has derived a unit risk estimate of 1.2 x 10'2 for
exposure to air containing 1 j*g/m3 chromium(VI) [or potency of 1.2 x
10"2 (/jg/m3)*!]. The exposure levels associated with increased lifetime
upperbound cancer risks of 1 x 10'^ to 1 x 10"7 are 8.3 x 10"6 to 8.3 x
10'9 mg/m3 and are indicated in Fig. 2.2.
Chronic inhalation studies of chromium(VI) in animals provide
sufficient evidence that certain chromium(VI) compounds are carcinogenic
to animals. Nettesheim et al. (1971) reported a statistically
significant increase in lung tumors in mice exposed to calcium chromate
at 13 mg/m3 [4.3 mg/m3 chromium(VI)] 5 h/day, 5 days/week for life. In a
review of the study, the International Agency for Research on Cancer
(IARC 1980) stated that an excess tumor incidence was not observed.
Glaser et al. (1986) found lung tumors in 3/19 rats exposed to sodium
dichromate at 0.1 mg/m3 chromium(VI) virtually continuously for
18 months (followed by 12 months of observation) versus 0/37 in
controls. Statistical analysis at Syracuse Research Corporation
indicates that the tumor incidence is statistically significant
(P - 0.03, Fisher Exact test). The concentrations of chromium(VI)
resulting in a carcinogenic effect in mice and rats are plotted on
Fig. 2.2.
Studies in which chromium compounds were instilled or implanted
into the lungs or injected into sites other than the lungs have given
positive results for some chromium(VI) compounds and negative results
for chromium(III) compounds and chromium metal.
After reviewing all available data, the EPA Carcinogen Assessment
Group (CAG) (EPA 1984a) stated that the level of evidence for combined
animal and human data would place hexavalent chromium [chromium(VI)]
-------
16 Section 2
compounds Into Group A, meaning chat there is decisive evidence for the
carcinogenicity of those compounds in humans. The EPA (1986c) applies
the classification of Group A to inhaled chromium(VI) (see Sect. 9.2.3
on data analysis in Regulatory and Advisory Status).
2.2.1.2 Oral
For adults, the estimated safe and adequate daily dietary
recommendation of chromium, considered to be an essential nutrient, is
50-200 us/day (0.0007-0.003 mg/kg/day) (Danford and Anderson 1985).
As indicated in Figs. 2.3, 2.4, 2.5, and 2.6. effects observed
after chromium(VI) and chromium(III) oral exposure have not been well
defined. The safe and adequate level for human nutrition is shown on
Figs. 2.5 and 2.6 for ingestion of chromium(III).
Lethality. Oral rat LD50 values for soluble chromium(VI) compounds
(sodium chromate; sodium, potassium, and ammonium dichrornate) of
16.7-22.5 mgAg chromium(VI) have been reported (Gad et al. 1986). The
lowest LD50 of 16.7 mgAg chromium(VI) is indicated on Figs. 2.3 and 2.4
for acute exposure. Smyth et al. (1969) demonstrated rat oral LDSQs for
chromium(III) compounds of 3.25 g/kg of chromic nitrate (nonahydrate)
[Cr(N03)3-9H20) [422 mgAg chromium(III) ] and 11.26 gAg of chromic
acetate (monohydrate) [Cr(CH3COO)3'H20] [2,369 mgAg chromium(III) ] .
Both doses are indicated on Fig. -2.5 and the lower dose is plotted on
Fig. 2.6 for acute lethality for chromium(III) .
Although some data on the lethality of chromium(VI) to humans are
available (Langard and Norseth 1986, NIOSH 1979), the data are
inadequate to characterize a lethal dose for humans.
Systemic/target organ toxicity. Diaz-Mayans et al. (1986) observed
hypoactivity in rats provided with sodium chromate(VI) in their drinking
water for 28 days at a dose of 0.7 g/L chromium (98 mgAg/day, LOAEL,
acute and intermediate exposure on Figs. 2.3 and 2.4). The decrease in
activity was noted after 7 days of treatment. No effects on activity
were noted at 0.07 g/L (9.8 mgAg/day, NOAEL) throughout the 28-day
treatment period. Doses were calculated from drinking water
concentrations using EPA (1986a) methods. Minimal risk levels for acute
and intermediate oral exposure were not derived from the NOAEL, because
adequate data are not available for other possibly more sensitive end
points.
Chronic oral studies of chromium compounds in rats, mice, and dogs
have not identified any adverse effects on toxicological end points
including body and organ weights, clinical chemistry values,
hematological values, and histological appearance of tissue. The highest
NOAEL for chromium(VI), 25 ppm in drinking water, equivalent to
2.4 mgAg/day chromium (EPA 1980, 1984b; EPA 1986c) in rats, was
. identified by MacKenzie et al. (1958). In this study, rats were dosed
with potassium chromate in the drinking water for 1 year and examined
for body weights, clinical blood chemistry, and gross and microscopic
pathology. The 2.4-mgAg/day dose is plotted on Figs. 2.3 and 2.4 and is
the basis for the minimal risk level for chronic oral exposure to
chromium(VI) as calculated by EPA (1986c).
-------
Health Effects Summary 17
ANIMALS
(mg/Xg/day)
100 i- • RAT NERVOUS SYSTEM. 7-28 DAYS CONTINUOUS (DRINKING WATER)
HUMANS
10
01 l-
• RAT. LDW. 1 DOSE (GAVAGE)
- O RAT, NERVOUS SYSTEM. 7-28 DAYS. CONTINUOUS (DRINKING WATER)
O RAT. NO EFFECTS. 1 YEAR. CONTINUOUS (DRINKING WATER)
QUANTITATIVE DATA
WERE NOT AVAILABLE
• LOAEL
O NOAEL
Fig. 2.3. Effects of chromium(VI)—oral exposure.
-------
18 Section 2
ACUTE
(< 14 DAYS)
LETHALITY TARGET ORGAN
(mg/kg/day)
100 i- 9 r (NERVOUS
SYSTEM)
10
0.1
0.01
0.001 I-
INTERMEDIATE CHRONIC
(15-364 DAYS) {> 365 DAYS)
TARGET ORGAN TARGET ORGAN
f r (NERVOUS
SYSTEM)
O r (NO EFFECTS
1 ON ANY
ORGAN)
i MINIMAL RISK LEVEL
| FOR EFFECTS OTHER
vi, THAN CANCER
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
r RAT
LOAEL AND NOAEL
IN SAME SPECIES
Fig. 2.4. Leveb of significant exposure for chromimnCVI)—oraL
-------
Health Effects Summary 19
ANIMALS
(mg/Kg/day)
10000 i-
1000
100
10 •-
HUMANS
(mg/kg/day)
01 r-
• RAT La,,. 1 DOSE (GAVAGE) (CHROMIC ACETATE)
O RAT. NO EFFECTS. 2 YEARS. INTERMITTENT (IN DIET) (CHROMIC OXIDE)
RAT.
. 1 DOSE (GAVAGE) (CHROMIC ACETATE)
001
0001
00001
O
> RANGE OF
JSAFE ANO ADEQUATE
LEVELS FOR HUMAN
NUTRITION
LOAEL FOR ANIMALS O NOAEL FOR ANIMALS
Fig. 2.5. Effects of chromium(IID—oral exposure.
-------
20 Section 2
ACUTE
(< 14 DAYS)
LETHALITY
INTERMEDIATE
(15-364 DAYS)
QUANTITATIVE DATA
WERE NOT AVAILABLE
CHRONIC
(> 365 DAYS)
TARGET ORGAN
(mg/kg/day)
10000 i—
1000
10
01
001
0001
0 0001 >—
r(no eftects
on any organ)
i MINIMAL RISK LEVEL
! FOR EFFECTS OTHER
* THAN CANCER
• LOAEL FOR ANIMALS
O NOAEL FOR ANIMALS
r RAT
I
RANGE OF SAFE AND
ADEQUATE LEVELS FOR
HUMAN NUTRITION
Fig. 2.6. Leveb of significant exposure for chromiunXIII)—oral.
-------
Health Effects Summary 21
Ivankovic and Preussmann (1975) found that rats tolerated a dosage
of 1,468 mg/kg/day chromiua(III) for 2 years (as chromic oxide in bread
at 5%) with no effects on survival, body weight, blood and urine
clinical chemistry values, or gross and microscopic appearance of organs
and tissues. This dosage, calculated by EPA (1985d) (Sect. 9.2.3 on data
analysis in Regulatory and Advisory Status) from data provided by the
investigators, is higher than the oral LD50 found for the chromium(III)
tested as chromic nitrate but not higher than chromium(III) tested as
chromic acetate. The discrepancy in dose may be due to the use of
different compounds and different methods of administration. In the LDso
study (Smyth et al. 1969), the compounds were given by gavage in one
bolus dose, while in the long-term study, rats consumed smaller amounts
(as chromic oxide) with food throughout the dosing days. The dosage of
1,468 mgAg/day chromium(III) is plotted as a NOAEL on Figs. 2.5 and 2.6
and is the basis of the minimal risk level for chronic oral exposure to
chromium(III) as calculated by EPA (1985d).
Developmental tozicity. Pertinent data regarding developmental
toxicity of oral exposure to chromium were not located in the available
literature. Parenteral administration of chromium(III) or chromium(VI)
to animals produced adverse developmental effects.
Reproductive tozicity. The study by Gross and Heller (1946)
provides some data that indicate that oral chromium(VI) may result in
reproductive toxicity. Because data concerning the length of the study,
the number of rats used, and the method of sterility ascertainment were
not available, the study is not adequate for use in the determination of
levels of significant exposure. Similarly, the study by Ivankovic and
Preussmann (1975) on chromium(III), in which only a few rats were mated
and no reproductive effects were observed, is not adequate for
assessment of reproductive toxicity. Parenteral administration of
chromium(III) or chromium(VI) to animals resulted in adverse
reproductive effects.
Genotozicity. See Sect. 2.2.1.1, genotoxicity subsection in Health
Effects Summary, for a summary of the available data.
Carcinogenicity. Chronic oral administration of chromium(III)
compounds to rats and mice (Schroeder et al. 1964, Schroeder et al.
1965, Ivankovic and Preussman 1975, Borneff et al. 1968) has not
resulted in significantly increased tumor incidences. Oral studies of
chromium(VI) compounds are not of adequate duration for evaluation of
carcinogenic potential in animals. Signs of toxicity included dermal
edema, erythema, necrosis, eschar formation and corrosion, and diarrhea
and hypoactivity. The cause of death was not specified.
2.2.1.3 Dermal
The only dose-response dermal data are rabbit LD50 values for
chromium(VI) compounds determined by Gad et al. (1986). These values
ranged from 1,000 mg/kg for sodium dichromate (397 mg/kg chromium) to
1,640 mg/kg f°r ammonium dichromate (677 mg/kg chromium) (Fig. 2.7). The
lover value is displayed on Fig. 2.8. Necrosis of the skin, kidney
damage, and death have been reported in humans following acute dermal
exposure to high levels of chromium(VI) compounds (Brieger 1920, Major
1922, Fritz et al. 1959). Skin sensitivity (dermatitis with eczema) is
-------
22 Section 2
ANIMALS
(mg/kg/day)
HUMANS
1000
too
10 I-
• RABBIT. LOge 1 DOSE (AMMONIUM OCHROMATE)
• RABBIT. LOW 1 DOSE (SOOIUM OCHROMATE)
QUANTITATIVE DATA
WERE NOT AVAILABLE
• LOAEL
Fig. 2.7. Effects of chromiuin(VT>—dermal exposure.
-------
Health Effects Summary 23
ACUTE
(< 14 DAYS)
LETHALITY
INTERMEDIATE
(15-364 DAYS)
QUANTITATIVE DATA
WERE NOT AVAILABLE
CHRONIC
(> 365 DAYS)
(mg/kg/day)
1000 i-
QUANTITATIVE DATA
WERE NOT AVAILABLE
100
10 "-
• LOAEL h RABBIT
Fig. 2.8. Levels of significant exposure for chromium(VI)—dermal.
-------
24 Section 2
the most common effect in humans following exposure to chromium
compounds [especially chromium(VI) compounds] at concentrations below
those resulting in irritation. Skin sensitivity is more common among men
as a result of.occupational exposure to chromium(VI) compounds. The
types of workers in which the effect has been reported includes
printers, cement workers, metal factory workers, painters, and leather
tanners. Doses of chromium resulting in sensitization were not
available.
2.2.2 Biological Monitoring as a Measure of Exposure and Effects
Normal chromium levels in human fluid and tissues should be
interpreted with caution. Low sensitivities of most commonly used
methods and the ubiquitous presence of chromium in laboratories make
detection of low levels of chromium in blood and urine difficult. Normal
endogenous levels listed by Danford and Anderson (1985) are: tissues,
0.02-0.04 Mg/g; serum/plasma, <0.05 ng/mL (not in equilibrium with body
stores); 24-h urine, <0.05 A»g/day (correlates with dietary intake >40 ng
chromium, but not <40 pg chromium); and hair, 50-1,000 ppm (measurement
methodology not reliable). See Versieck (1985) for additional
information concerning the evaluation of data for chromium in biological
samples.
Biological monitoring of human fluids and tissues has not been used
to associate chromium levels with specific effects, other than a
positive association between urine chromium levels and chromosome
aberrations in peripheral lymphocytes of workers exposed to soluble
chromium(VI) compounds (Sect. 4.3.5 on genotoxicity in the Toxicologi
Data section). Biological monitoring has been used to relate serum am.
urine chromium levels to occupational exposure levels. Gylseth et al.
(1977) studied five welders exposed to chromium(VI) and observed a
statistically significant (r - 0.95, P < 0.001) relationship between
total chromium exposure and urinary chromium concentrations at the end
of the workday. The investigators state that urinary chromium
concentrations of 40-50 Mg/L immediately after work would reflect
exposure to levels corresponding to the American Conference of
Governmental Industrial Hygienists (ACGIH 1986) Threshold Limit Value
(TLV) of 0.05 mg/m3 chromium for soluble chromium(VI) compounds (a
concentration associated with nasal perforations in some studies). The
investigators caution that individual variations in habits make it
difficult to state an exact biological threshold, but that urinary
concentrations of 40-50 pg/L should be used to indicate the need for air
monitoring in the workplace.
Mutti et al. (1985) examined end-of-shift chromium levels and
related them to chromium(VI) and/or chromium(III) exposure. Their
results indicated that urinary chromium levels correlated with exposure
to soluble chromium(VI) but not insoluble chrornates or chromium(III)
compounds. Figure 2.9 shows the relationship between workroom air
concentrations of water-soluble chromium(VI) compounds and daily
increase in urinary chromium (pre-exposure values subtracted from end-
of -shift values). A urinary chromium increase of 12.2 pg/g creatinine or
a total concentration of 29.8 pg/g creatinine corresponded to an air
concentration of 50 pg/m3 chromium(VI) from welding fumes.
-------
Health Effects Summary 25
30
25
e»
o
a
x
20
15
10
I
ACrU - 3 88 + 0.167 CrA
n-8 r-0.883 P<0.01
WELDING FUMES
CrO3 OUSTS
K2Cr207 DUSTS
I i
0 20 40 60 80 100
CrA. 8-h-TWA BREATHING-ZONE CHROMIUM(VI)
Fig. 2.9. Relationship between water-soluble chromimnCVI) concentratioa
in the workroom air (CrA) and daily increase in urinary chromium levels (CrU)
(pre-«xposure values were subtracted from eod-of-shift values). Source: Mutti
etal. (1985).
-------
26 Seccion 2
In an examination of Che distribution of chromium in serum, red
blood cells (RBC), and urine in workers exposed to chromium(III) and
chromium(VI), Cavalleri and Minoia (1985) also concluded that the
determination of chromium in the urine at the end of the workday is a
good indicator of" exposure to chromium(VI) but not chromium(III).
Following exposure to chromium(III), a significant (P < 0.01) increase
in serum chromium was observed compared to controls and individuals
exposed to chromium(VI). RBC chromium was significantly higher
(P < 0.001) in chromium(VI)-exposed individuals compared to controls and
chromium(III)-exposed groups.
Randall and Gibson (1987) found that serum and urine concentrations
of chromium were significantly elevated in a group of 72 tannery workers
as compared with a group of 52 control subjects at the end of the
workweek on Friday and before exposure began on Monday. Serum and urine
chromium levels did not correlate with length of employment in the
tanning industry, but did correlate with work area of the tannery, wich
workers who handled wet hides in the chrome tan and wringing departments
having the highest chromium levels in these body fluids. The tanning
compounds contained chromium primarily as chromium(III). The time-
weighted average (TWA) level of total chromium in tannery air was
1.7 Aig/m-* and did not vary significantly among the various tanneries
involved in the study or among various work areas of each tannery.
Chromium(VI) could not be detected in tannery air. The investigators
concluded that significant absorption of chromium(III) had occurred and
that serum and urine levels of chromium may be useful indices of
chromium exposure. The finding of higher serum and urine chromium levels
in workers having the greatest opportunity for skin contact with the
tanning compounds indicates that dermal absorption may have contributed
to the results, but the investigators did not address this issue.
In an attempt to determine a urine concentration of chromium to
screen for levels of occupational exposure to chromic acid that may
cause nasal ulcerations and impairment of lung function, Lindberg and
Vesterberg (1983a) studied exposure levels and postshift urinary
chromium in 91 workers exposed to chromic acid in the chrome-plating
industry. After excluding workers with obvious contamination of the
skin, the authors found a correlation between air chromium concentration
and urinary chromium concentration (r - 0.71) and determined that a
urinary chromium level of slOO nmol/L (5.2 /ig/L) would reflect TWA
exposure to £2 Mg/m^ chromium(VI) from chromic acid. (Inclusion of
workers with skin contamination weakened the association between air
chromium and urinary chromium concentrations, presumably because of
dermal absorption.) A related study (Lindberg and Hedenstierna 1983) had
determined that exposure to chromic acid at TWA levels below 2 Mg/°>
chromium(VI) did not produce severe damage to the nasal septum or affect
lung function.
Lewalter et al. (19B5) stated that following exposure to soluble
chromium(VI) compounds, the chromium is reduced in the plasma to form
chromium protein complexes, which can be eliminated by the kidneys. In
contrast, exposure to soluble chromium(III) compounds, mainly in the
form of hydrate complexes, does not result in the formation of chromium
protein complexes. The inability of "native" chromium(III) to form
-------
Health Effects Summary 27
excretable chromium protein complexes may account for the lack of
correlation between chromium(III) exposure and urinary chromium levels.
Korallus (1986) further examined the use of RBC chromium levels as
an indication of chromium(VI) exposure. When chromium(VI) plasma levels
exceed the plasma reduction capacity (PRC), chromium(VI) enters
erythrocytes, is reduced, and becomes bound to hemoglobin. The bond
persists for the lifetime of the erythrocytes (120 days), so that a
single determination allows a longitudinal evaluation of exposure for an
extended period in the past. Low chromium concentrations in the
erythrocytes indicate that the amount of chromium(VI) uptake did not
exceed the PRC. The capacity of human plasma to reduce chromium(VI) to
chromium(III) varies, with slow and fast reducers recognized. It is not
clear what is responsible for individual differences in PRC, although
the difference in magnitude of PRC has been shown to correlate with the
levels of ascorbic acid in plasma. The relationship between blood and
urine chromium levels and air Cr03 concentrations in slow and fast
reducers at the end of a 5-day shift at a dichromate plant is shown in
Fig. 2.10. The figure indicates that individuals who reduce chromium(VI)
slowly have much higher blood chromium levels, while fast reducers have
higher urinary chromium levels.
The occupational data indicate a correlation between urine and
blood chromium levels at relatively high air chromium(VI)
concentrations. Because of variable background urine and blood chromium
levels, a correlation between exposure at low concentrations found in
the environment and urine and blood chromium levels is not possible.
2.2.3 Environmental Levels as Indicators of Exposure and Effects
2.2.3.1 Levels found in the environment
Except for the correlation of occupational exposure and blood and
urine chromium levels, no data are available that correlate
environmental levels of chromium and adverse effects.
2.2.3.2 Human exposure potential
Absorption studies of chromium compounds in humans and animals
indicate that chromium(VI) compounds are more readily absorbed from all
routes of exposure than are chromium(III) compounds (Sect. 4.2.1 on
absorption in the Toxicological Data section). This is consistent with
the water solubilities of these compounds. Ogawa (1976) found that the
absorption of orally administered chromium increased in rats fasted for
48 h. The soluble organic complex GTF, which contains chromium(III), is
more readily absorbed from the gastrointestinal tract than is inorganic
chromium (Hertz, 1969).
In addition, the bioavailabilty of chromium from soil has been
studied. Factors that may increase the mobility of chromium in soils
include the speculated conversion of chromium(III) to chromium(VI),
increases in pH, and the complexation of chromium(III) with organic
matter to form water-soluble complexes. Hexavalent chromium is
relatively stable and mobile in sandy soils or soils that contain low
concentrations of organic matter. Although chromium is found primarily
-------
28 Section 2
0
C
'c
£3
CO
0)
o
CD
O)
O
QC
I
O
UJ
80
70
60
50
40
30
20
10
A: SLOW REDUCER
B: FAST REDUCER
A-BLOOD
B-URINE
0 50 100 150
AIRBORNE CHROMIUM (^gCrO3/m3)
80
70
60
50
40
30
20
10
0
O)
O
QC
O
0
GO
FTf. 110. Linear rriitiOMUp betweo the airborne hydrooofaiMe chromium concentration and the
chromium concentration in blood and urine at (he end of i 5-day shift in workers of a dichromate
plait Source: Korallus 1986.
-------
Health Effects Summary 29
as chromium(III) in nature, Carey (1982) has speculated that weathering
of rocks under extreme conditions or the elevated temperatures produced
during brush fires in the presence of Mn02, present in some soil, may
oxidize chromium(III) to chromium(VI). Increasing pH will help mobilize
chromium(VI) from soils. Part of the chromium(VI) in soil will be
sorbed, some will be reduced, and some may leach into groundwater and
may be available for plant uptake. This distribution will depend on soil
pH, organic matter content, presence of reducing agent, and the texture
of soil. Formation of soluble organic complexes of chromium(III) will
also increase its mobility in soils. The complexes are probably formed
more readily as chromium(VI) is reduced to chromium(III) by organic
matter in soil than by interaction of already present chromium(III) with
organic matters present in soils (Carey 1982). No information is
available regarding the effect of pH on these complexes formed in soils.
Similarly, very little is known about the effect of increased organic
carbon content on the mobility of the complexes. In certain soils,
increases in organic carbon content may increase the mobility of the
complexes as a result of enhanced complexation, while in other soils
increases in organic matter may decrease the mobility because of
increased sorption.
2.3 ADEQUACY OF DATABASE
2.3.1 Introduction
Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
"(A) An examination, summary, and interpretation of available
toxicological information and epidemiologic evaluations on a
hazardous substance in order to ascertain the levels of
significant human exposure for the substance and the
associated acute, subacute, and chronic health effects.
(B) A determination of whether adequate information on the health
effects of each substance is available or in the process of
development to determine levels of exposure which present a
significant risk to human health of acute, subacute, and
chronic health effects.
(C) Where appropriate, an identification of toxicological testing
needed to identify the types or levels of exposure that may
present significant risk of adverse health effects in humans."
This section identifies gaps in current knowledge relevant to
developing levels of significant exposure for chromium. Such gaps are
identified for certain health effects end points (lethality,
systemic/target organ toxicity, developmental toxicity, reproductive
toxicity, and carcinogenicity) reviewed in Sect. 2.2 of this profile in
developing levels of significant exposure for chromium and for other
areas such as human biological monitoring and mechanisms of toxicity.
The present section briefly summarizes the availability of existing
human and animal data, identifies data gaps, and summarizes research in
progress that may fill such gaps.
-------
30 Section 2
Specific research programs for obtaining data needed to develop
levels of significant exposure for chromium will be developed by ATSDR
NTP, and EPA in the future.
2.3.2 Health Effect End Points
2.3.2.1 Introduction and graphic summary
The availability of data for health effects in humans and animals
is depicted on bar graphs in Figs. 2.11, 2.12, and 2.13.
The bars of full height indicate that there are data to meet at
least one of the following criteria:
1. For noncancer health end points, one or more studies are available
that meet current scientific standards and are sufficient to define
a range of toxicity from no effect levels (NOAELs) to levels that
cause effects (LOAELs or FELs).
2. For human carcinogenicity, a substance is classified as either a
"known human carcinogen" or "probable human carcinogen" by both EPA
and IARC (qualitative), and the data are sufficient to derive a
cancer potency factor (quantitative).
3. For animal carcinogenicity, a substance causes a statistically
significant number of tumors in at least one species, and the data
are sufficient to derive a cancer potency factor.
4. There are studies which show that the chemical does not cause this
health effect via this exposure route.
Bars of half height indicate that "some" information for the end
point exists, but does not meet any of these criteria.
The absence of a column indicates that no information exists for
that end point and route.
2.3.2.2 Description of highlights of graphs
As indicated in Fig. 2.11, very few human effect/route/duration
data are available. Adequate data are available from occupational
exposure studies showing nasal mucosal and lung function effects
attributed to chromium(VI). Because these effects can occur following
intermediate or long-term exposure, the data are considered for both
exposure durations. Numerous epidemiological studies associate
occupational chromium exposure with respiratory cancer and constitute
adequate evidence of carcinogenicity. Although the studies do not
clearly implicate specific chromium compounds, they do implicate
chromium(VI). The EPA (1984b, 1986c) concludes that chromium(VI) is the
fora responsible for the carcinogenic effect because of the evidence in
humans and the results of animal studies, including implantation and
injection studies.
Acute oral and dermal exposure of humans to chromium(VI) compounds
has resulted in liver and kidney effects and death. Chromium(VI)
compounds are powerful skin irritants, and at lower concentrations they
are sensitizers. Following acute inhalation exposure, chromium(VI)
-------
HUMAN DATA
SUFFICIENT
INFORMATION*
V SOME
'INFORMATION
J
NO
INFORMATION
ORAL
INHALATION
I
DERMAL
LETHALITV ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CARCINOOENICITT
Z / TOXICITY TOXICITY
SYSTEMIC TOXICITV
o
£
00
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
Fig. 2.11. Availability of information on health effects of chromium(VI) and (111) (human data).
-------
ANIMAL DATA
LETHALITY
V SUFFICIENT
'INFORMATION*
J
J
SOME
INFORMATION
NO
INFORMATION
ORAL
INHALATION
DERMAL
ACUTE INTERMEDIATE CHRONIC DEVELOPMENTAL REPRODUCTIVE CAHCINOGENICITY
. _____ / TOXICITY TOXICITY
SYSTEMIC TOXICIT*
'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.
Fig. 2.12. Availability of information on b«- -"h effects of chromium( VI) (animal data).
-------
LETHALITY
ANIMAL DATA
O II N I U W (i S 9 C 13435
ACUTE INTERMEDIATE
CHRONIC DEVELOPMENTAL REPRODUCTIVE CAHCINOOENICITY
/ TOXICITY TOXICITY
SUFFICIENT
INFORMATION*
J
SOME
INFORMATION
NO
INFORMATION
ORAL
INHALATION
DERMAL
r
>-
3-
a
SYSTEMIC TOXICITY
'Sufficient information exists to meet at least one ol the criteria for cancer or noncancer end points.
Fig. 2.13. Availability of information on health effects of chromium(lll) (animal data).
-------
34 Section 2
compounds are respiratory tract irritants. Because adequate dose-
response data for lethality and acute exposure to chromium compounds at
not available, the bars for systemic toxicity for inhalation, oral, and
dermal exposure-and-for lethality following oral and dermal exposure
indicate that some data exist.
Figures 2.12 and 2.13 indicate that there are many gaps in the
animal effect/route/duration data. Except for dermal LD50 values for
chroraium(VI) compounds, dermal data are lacking. Inhalation studies
indicate effects on the respiratory tract and immune system, but NOAELs
are not clearly defined. Although LOAELs and NOAELs for nervous system
toxicity were available for acute and intermediate oral exposure to
chromium(VI), other perhaps more sensitive end points for systemic
toxicity were not examined. Thus the bars for systemic toxicity due to
acute and intermediate oral exposure to chromium(VI) in Fig. 2.12
indicate that only some data exist. As shown in Fig. 2.13, some data are
available for intermediate oral exposure to chromium(III) compounds.
Developmental and reproductive toxicity studies conducted by parenteral
routes have shown adverse effects with both chromium(III) and
chromium(VI), but no adequate experiments have been conducted by
inhalation, oral, or dermal routes. Results of inhalation cancer studies
with chromium(VI) are suggestive but not definitive. Chronic oral
studies of chromium(VI) and (III) toxicity do not identify effect levels
for systemic toxicity and are not entirely adequate for investigating
carcinogenicity.
2.3.2.3 Summary of relevant ongoing research
IARC (1987a) provides an extensive listing of ongoing research in
cancer epidemiology. Included on this list are numerous ongoing studies
of chromium-exposed populations. Primary investigators and populations
under study in representative studies include studies of stainless steel
welders in Denmark (S. K. Hansen) and in Sweden (B. Sjogren), studies of
auto workers in France (S. Schraub) and the United States (A. H. Okun),
a study of plating workers in Japan (K. Tsuchiya), a study of persons
exposed to chromium(VI) compounds in chemical plants in Rumania
(M. Eftimescu), a study of workers in the dichromate-producing industry
in England (J. M. Davis), and a study of workers exposed to lead
chromate paints in the United States (J. Walker).
EPA is sponsoring a study on the feasibility of determining the
relative contributions of chromium(III) and chromium(VI) to total
chromium exposure in Allied Chemical workers in Baltimore, Maryland, in
order to study the relative carcinogenic potential of chromium(III) vs
chromium(vT) (Gibb 1987; EPA 1986d, 1987c). The ongoing research will
also attempt to refine the dose-response for carcinogenicity of
chromium(VI) with the intention of replacing the Mancuso (1975)
epidemiological study as the basis of the potency factor for
chromium(VI).
The Metal Oxides and Ceramic Colors Committee of the Dry Color
Manufacturers' Association (DMCA) is currently collecting toxicological
data on chromium pigments (Robinson 1988) . The data will be forwarded to
ATSDR when it is available.
-------
Health Effaces Summary 35
2.3.3 Other Information Needed for Human Health Assessment
2.3.3.1 Pharmacokinetics and mechanisms of action
Chromium (IIIK.an essential nutrient, plays a role in glucose,
fat, and protein metabolism by potentiating insulin action. Because the
potentiation of insulin action results in an improvement in glucose
tolerance, the form of chromium(III) that is biologically active is
called glucose tolerance factor (GIF). The structure of GIF has not been
characterized fully, but GTF is known to consist of chromium(III)
complexed with nicotinic acid, and possibly glycine, glutamic acid, and
cysteine (Anderson 1981, Mertz 1975). Estimated safe and adequate daily
dietary recommendations of chromium for adults are 50-200 ng/day based
on the absence of signs of chromium deficiency in the U.S. population
consuming 60 /ig/day (Danford and Anderson 1985) .
It is not yet clear which valence state of chromium is the ultimate
carcinogen. In vitro studies of genotoxicity have found that
chromium(VI) but not chromium(III) is genotoxic to intact cells, while
chromium(III) but not chromium(VI) can react with isolated nuclei and
purified DNA. After reviewing all the available data, Norseth (1986)
states that genotoxic action of chromium(VI) in cells and animals may be
dependent on the reduction of chromium(VI) inside the cell to generate
reactive chromium species that form complexes with DNA. The reactive
intermediate may be chromium(V) (Jennette 1982, Norseth 1986, Anderson
1981). Until the mechanism of action of chromium is clarified, Norseth
(1986) believes that all chromium compounds [soluble, slightly soluble,
and insoluble chromium(VI) compounds; particles of slightly soluble
chromium(VI) and soluble chromium(III); and soluble chromium(III) bound
to ligands] should be regarded as having a potential carcinogenic
effect, with the differences in activity related to their biological
availability.
Petrilli and DeFlora (1987) and Levy et al. (1987) disagree with
Norseth (1987). Petrilli and DeFlora (1987) suggest that because some
forms of chromium compounds are essential and because there are
mechanisms that limit the bioavailability and attenuate the potential
effects of chromium compounds in vivo, "chromium should not be regarded
as a 'universal' carcinogen." Levy et al. (1987) believe that there is
sufficient experimental evidence suggesting that chromium(III) compounds
are not carcinogenic and good evidence to indicate that a limited number
of chromium(VI) compounds (sparingly soluble) "represent a real
carcinogenic risk to man."
The pharmacokinetics of chromium at the whole-animal level is
relatively well studied. More work should be completed on how chromium
compounds cross cell membranes so that toxicity of individual chromium
compounds could be predicted by chemical properties.
There are several studies in the areas of chromium essentiality and
absorption in progress. R. A. Anderson of Agricultural Research Service
is conducting a study sponsored by the U.S. Department of Agriculture to
more clearly define the nutritional and biochemical roles of chromium in
humans (NTIS 1987). H. M. Goff of the University of Iowa is working on
the chemical structure and biological activity of GTF under the
sponsorship of the U.S. Department of Agriculture, Competitive Research
-------
36 Section 2
Grant Office. Gastrointestinal tract absorption of chromium is under
study by P. E. Johnson at Agricultural Research Service and by F. X.
Pi-Sunyer at St. Luke's Roosevelt Hospital Center; both of these studi
are also sponsored by the U.S. Department of Agriculture (NTIS 1987).
• -
2.3.3.2 Monitoring of human biological samples
Measurements of chromium in urine and blood are useful methods for
monitoring human occupational exposure to chromium compounds. Serum
levels reflect exposures to chromium(III), chromium(VI), and chromium
metal, while urine and RBC chromium levels reflect exposure to
chromium(VI). In contrast to monitoring human biological samples for
occupational exposure, the monitoring of human biological samples for
low-level environmental exposure may not be useful because serum
chromium levels change only in cases of extreme exposure or deficiency.
The measurement of low levels of chromium in blood and urine is
difficult; using "normal" levels of chromium to assess deficiency is not
yet possible (Danford and Anderson 1985).
No ongoing studies concerning monitoring of human biological
samples were located, although the monitoring of human body fluids to
assess mobilization of chromium from orthopedic prostheses appears to be
a subject of current research and publication (Sunderman et al. 1987).
2.3.3.3 Environmental considerations
There is no major gap in the understanding of the different routes
of exposure of chromium into human bodies from environmental media
(Sect. 7 on Potential for Human Exposure).
In one ongoing study by C. Blincoe of the University of Nevada, the
bioavailability of chromium from various foods is being studied under
the sponsorship of the U.S. Department of Agriculture (NTIS 1987).
Although limited data regarding the physical fate processes of
chromium in different environmental media and its transport from one
media to another are available, data on its chemical fate are almost
nonexistent (Sect. 6.3, Releases to the Environment). Even the nature of
chemical species present in a medium is not known with certainty.
Therefore, significant uncertainties are expected in the estimated data
on its fate and transport. In an ongoing research program conducted by
North Texas State University under the sponsorship of the Industrial
Health Foundation, the fate of both chromium(III) and chromium(VI) in
aquatic surface and subsurface conditions is being studied. The effect
of Eh (electrode potential or redox potential) and pH on the fate of
chromiun(III) and chromium(VI) is being studied in this yet unpublished
study (Loewengast 1988).
Limited speculative data exist on the interactions of chromium in
the environment (Sect. 6.3, Releases to the Environment). As a result,
data gaps exist in this area.
-------
37
3. CHEMICAL AND PHYSICAL INFORMATION
3.1 CHEMICAL IDENTITY
The synonyms, trade name, chemical formula, Wiswesser Line
Notation, and identification numbers of chromium are given in Table 3.1
3.2 PHYSICAL AND CHEMICAL PROPERTIES
Chromium is found in nature as ores only in the combined oxidation
states, but not in the zero valence state (IARC 1980). Of the three
common valence states of chromium, only chromium(III) occurs naturally;
both chromium(VI) and chromium(O) are produced through industrial
processes.
The physical properties, chemical formulas, and synonyms of
chromium and a few of its trivalent and hexavalent salts are given in
Tables 3.2 and 3.3.
The ammonium and alkali metal salts of hexavalent chromium are
generally water soluble, whereas the alkaline metal salts (e.g.,
calcium, strontium) are less soluble in water (Table 3.3). Hexavalent
chromium rarely occurs in nature apart from anthropogenic sources
because it is readily reduced in the presence of oxidizable organic
matter; however, hexavalent chromium compounds that occur most commonly
in the form of chromate and dichromate are stable in many natural waters
because of the low concentration of reducing matter (EPA 1984a). With
the exception of a few compounds, hexavalent chromium exists only as oxo
species that are strong oxidizing agents. The oxidizing potential of
chromate ions depends on the pH of the media. These ions are much more
powerful oxidizing agents in acid solutions than in basic solutions
(ORNL/EPA 1978).
With the exception of acetate and nitrate salts, the trivalent
chromium compounds are generally insoluble in water (Table 3.2). In most
biological systems, chromium is present in the trivalent form (Anderson
1981). The physical or chemical forms and the mode by which
chromium(III) compounds are incorporated into biological systems are
poorly characterized. Inorganic chromium(III) compounds display little
or no in vitro insulin-potentiating activity, but upon chelation with
certain organic compounds acquire significant insulin-potentiating
activity. Although the structure is not known, GTF, an insulin-
potentiating factor present in normal humans, was identified as a
chromium complex of nicotinic acid. A biologically active form of
chromium isolated from brewer's yeast was found to contain
chromium(III), nicotinic acid, and possibly the amino acids glycine,
cysteine, and glutamic acid (Anderson 1981).
-------
38 Section 3
Table 3.1. Chemical identity of chromium metal [chromium(0)]
Chemical name
Synonyms
Trade name
Chemical formula
Wiswesser Line Notation
Chemical structure
Identification numbers
CAS Registry No.
NIOSH RTECS No.
EPA Hazardous Waste No.
OHM-TADS No.
DOT/UN/NA/IMCO Shipping No.
STCC No.
Hazardous Substances Data Bank No.
National Cancer Institute No.
Chromium
Chrome
Chrom (German)
Chrome (French)
Chrome
Cr
CR
Cr
HSDB 1987
HSDB 1987
I ARC 1980
HSDB 1987
7440-47-3
GB4200000
D007
7216647
Not assigned
Not assigned
910
Not assigned
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
HSDB 1987
SANSS 1987
-------
Table 3.2. Physical properties of chromium and selected Iritakol compounds
Properly
Atomic/molecular weight
Chemical formula
Synonyms
Chemical Abstracts Registry No.
Color
Physical slate
Odor
Melting point
Boiling point
Autoignilion temperature
Solubility
Water
Organic solvents
Density, g/cm'
Partition coefficients
Vapor pressure
Henry's law constant
Refractive index
Flashpoint
Flammability limits
Chromium
SI 996
Sec Table 3.1
See Table 3 1
See Table 3 1
Steel gray
Solid
NRfl
I.857°C
2.672°C
NR
Insoluble
Insoluble
7 20 (28°C)*
NAa
1 mmHgal I.6I6°C
NA
1 64-3 28 (a-form)
NR
NR
Chromium(lll)
acetate, monohydrale
247 IS
CrtCH.COOJ.-HjO
Chromic acetate, monohydrale
1066-30-4
Gray-green or bluish green
Solid
NR
NR
NR
NR
Soluble
Insoluble in ethanol
NR
NA
NR
NA
NR
NR
NR
Chromium(lll)
nitrate
400 IS
Cr(NO,)J9H]O
Chromic nitrate
7789-02-8
Purple or violet
Solid
NR
60°C
Decomposes at IOO°C
NR
Soluble
Soluble in elhanol
and acetone
NR
NA
NR
NA
NR
NR
NR
Chromium(lll)
chloride
IS836
CrCI,
Chromic chloride
10025-73-7
Violet or purple
Solid
NR
-i.iso-c
Sublimes at I.300°C
NR
Slightly soluble in
hot water
Insoluble
276(I5°C)
NA
NR
NA
NR
NR
NR
Ferrochromite
22384
FeCr,O,
Ferrous chromile
12068-77-8
Brown-black
Solid
NR
NR
NR
NR
Insoluble
NR
497(20°C)
NA
NR
NA
NR
NR
NR
o
'heaical
fi
Q.
3
in
n
Di
H
O
ft
h-
O
a
OJ
vO
-------
-c*
o
Table 3.2 (cootlaued)
Property
Atomic/molecular weight
Chemical formula
Synonyms
Chemical Abstracts Registry No
Color
Physical slate
Odor
Melting point
Boiling point
Auloignition temperature
Solubility
Water
Organic solvents
Density, g/cm'
Partition coefficients
Vapor pressure
Henry's law constant
Refractive indei
Flashpoint
Flammabdity limits
Chromium(lll) oxide
15199
CrA
Chromium sesquioxide
1308-38-9
Green
Solid
NR
2.266'C
4.000'C
NR
Insoluble
Insoluble in elhanol
521
NA
NR
' NA
2.551
NR
NR
Cbromium(lll)
phosphate
14697
CrPO,
Chromic phosphate
27096-04-4
Green
Solid
NR
NR
NR
NR
NR
NR
NR
NA
NR
NA
NR
NR
NR
Chrommm(lll)
sulfate
39216
Cr,(S04),
Chromic sulfale
IOIOI-S3-8
Violet or red
Solid
NR
NR
NR
NR
Insoluble
Slightly soluble in elhanol
3012
NA
NR
NA
NR
NR
NR
Sodium chromilc
10698
NaCrO,
Same
12314-42-0
NR
NR
NR
NR
NR
NR
NR
NR
NR
NA
NR
NA
NR
NR
NR
°NA - Not applicable. NR - not reported
Temperature at which the densities were measured
Sourcei Weasl 1985, Weslbrook 1979. Hartford 1979
0»
ft
o
rt
K-.
§
U
-------
Table 3.3. Physkml properties of selected heunleol chromium compounds
Properly
Atomic/molecular weight
Chemical formula
Synonyms
Chemical Abstracts Registry No.
Color
Physical state
Odor
Melting point
Boiling point
Auloigmtion temperature
Solubility
Water
Organic solvents
Density, g/cm1
Partition coefficients
Vapor pressure
Henry's law constant
Refractive index
Flashpoint
Flammabilily limits
Ammonium
dichromale
252.06
(NH4)1Cr20,
Ammonium bichromate
7789-09-5
Orange
Solid
NRfl
Decomposes at I70°C
NAa
NR
Soluble
Soluble in ethanol
2I5(25°C)*
NA
NR
NA
NR
NR
NR
Calcium
chromate
15607
CaCrO.
Same
13765-19-0
Yellow
Solid
NR
NR
NR
NR
2 23% at 20°C
NR
NR
NA
NR
NA
NR
NR
NR
Chromium(VI)
Inoxide
9999
CrO,
Chromic acid
1333-82-0
Red
Solid
NR
I96°C
Decomposes
NR
Soluble
Soluble in ethanol
and ether
2 70 (25°C)
NA
NR
NA
NR
NR
NR
Lead
chromate
323.18
PbCrO,
Same
7758-97-6
Yellow
Solid
NR
844°C
Decomposes
NR
Insoluble
Insoluble in acelyl
acetone
6I2(I5°C)
NA
NR
NA
231
NR
NR
Potassium
chromale
19420
KjCrO,
Natural larapacaile
7789-00-6
Yellow
Solid
NR
968 3°C
NR
NR
Soluble
Insoluble in ethanol
2732(I8°C)
NA
NR
NA
1 74 (0-form)
NR
NR
5
n
a
h"
n
DI
§
a
'B
a-
t—
n
ft>
^
a
n
0
3
-------
Table 3.3 (coottmned)
Property
Atomic/molecular weight
Chemical formula
Synonyms
Chemical Abstracts Registry No
Color
Physical state
Odor
Melting point
Boiling point
Autoigmtion temperature
Solubility
Water
Organic solvents
Density, g/cm'
Partition coefficients
Vapor pressure
Henry's law constant
Refractive index
Flashpoint
Flammabilily limits
Potassium
dichromale
294.18
K,Cr,0,
Potassium bichromate
7778-50-9
Red
Solid
NR
398°C
Decomposes at 500°C
NR
Soluble
Insoluble in ethanol
2 676 (25°C)
NA
NR
-NA
1738
NR
NR
Sodium
chromate
161.97
Na,CrO4
Same
7775-11-3
Yellow
Solid
NR
792'C
NR
NR
Soluble
Soluble in methanol
2710-2736
NA
NR
NA
NR
NR
NR
Sodium dichromale.
dihydralc
29800
Na2Cr]O,. 2H2O
Sodium bichromate.
dihydralc
7789-12-0
Red
Solid
NR
356 7°C
Decomposes at 400°C
NR
Soluble
Insoluble in ethanol
252(l3eC)
NA
NR
NA
1661
NR
NR
Strontium
chromate
20361
SrCrO4
Same
7789-06-2
Yellow
Solid
NR
NR
NR
NR
Slightly soluble
Soluble in acetyl
acetone
3895(I5"C)
NA
NR
NA
NR
NR
NR
Zinc
chromate
18137
ZnCrO«
Same
13530-65-9
Lemon yellow
Solid
NR
NR
NR
NR
Insoluble
Insoluble in acetone
340
NA
NR
NA
NR
NR
NR
Section
Ul
°NA - Not applicable. NR - Not reported
^Temperature at which the densities were measured
Sources Weasi I98S. Hartford 1979
-------
Chemical and Physical Information 43
In aqueous solutions, chromium(III) forms a hexaaquo complex
[Cr(H )6P+ of reasonable stability. In alkaline solutions or when
heated, the hexaaquo chromium(III) readily undergoes the following
polymerization through the formation of hydroxy- or oxo-bridged
compounds (EPA 1984a) :
Cr(N03)3 -. [Cr(H20)6]3+-e,-> [Cr(OH) (H^),.] 2+
(in solution) i heat and standing
/OH\
[(H20)5-Cr-0-Cr(H 0) ]*+ _ [(H 0)4 C/ XCr(H,0), ]*+ .
NOHX ^
(oxolation) (olation)
Such ions may cross-link protein fibers and may play an important part
in the chemistry of tanning (EPA 1984a) . Hexaaquo chromium(III) complex
does not exist in biological systems because it undergoes olation and
polymerization. Once the chromium(III) compounds undergo olation and
polymerization, they are rendered biologically inactive. Only chelated
chromium(III) compounds that remain in solution are bioavailable (Hertel
1986). Some organic and inorganic ligands present in physiological
systems can keep chromium(III) in solution by preventing the olation and
polymerization process through chelation, thereby allowing chromium(III)
to perform its physiological functions (Anderson 1981).
-------
4. TOXICOLOGICAL DATA
4.1 OVERVIEW
Chromium can enter the body via oral, inhalation, and dermal
exposure. For the general population, the gastrointestinal (GI) tract is
the primary route of entry, although entry through the airways can be
significant near industrial sources. Following occupational exposure,
the airways and skin are the primary routes of uptake. Rates of uptake
in the GI tract are relatively low and depend on the valence state of
chromium [chromium(VI) is more readily absorbed than is chromium(III)],
the water solubility of the compound, and gastrointestinal transit time.
Uptake in the airways is also influenced by particle size of aerosols
and by factors that govern clearance time in the lungs.
Studies of chromium distribution in animals following inhalation
exposure have found high levels in the kidneys, lungs, and spleen.
Higher tissue chromium levels have been found in animals receiving
chromium(VI) in drinking water compared with animals receiving
chromium(III) in drinking water.
Once absorbed, chromium(VI) is reduced to chromium(III). During
reduction of chromium(VI) in the plasma, chromium protein complexes are
formed; these complexes are excreted by the kidneys. In addition,
chromium(VI) crosses cell membranes easily and is reduced inside cells,
forming chromium protein complexes during reduction. Once complexed with
protein, chromium cannot leave the cell. Chromium(III) crosses cell
membranes less readily, does not readily bind to intracellular protein,
and can diffuse out. Chromium(VI) can be reduced to chromium(III) in
vitro by gastric juice, but whether intragastric reduction occurs in
vivo is not known. Chromium(III) is not oxidized to a higher state in
biological systems.
Absorbed chromium is excreted from the body in a rapid phase
representing clearance from the blood and in at least two slower phases
representing clearance from tissues. Urinary excretion is the primary
route of elimination.
Chromium(III) is considered to be an essential nutrient. The intake
of chromium that is recommended for good health is much lower than
levels of ingested chromium that have been associated with toxic
effects.
Acute lethality data indicate that chromium(VI) compounds are more
toxic by the oral route of exposure than are chromium(III) compounds. No
acute lethality data are available for chromium(III) compounds by the
inhalation and dermal routes of exposure. Chronic studies of oral
administration of chromium(VI) or (III) compounds to rats or mice do not
clearly indicate doses that result in decreased longevity.
-------
46 Section 4
Evaluation of Che toxicological database for chromium compounds
suggests that the effects of chromium(VI) on the nasal mucosa and on
lung function in humans may be the most sensitive noncancer end points
for inhalation exposure to chromium(VI) compounds.
Long-term oral exposure of animals to relatively low levels of
chromium compounds has not resulted in systemic toxic effects. Acute
high doses of chromium(VI) compounds by oral, dermal, or parenteral
routes can result in kidney effects. Other effects observed following
chromium(VI) exposure include effects on the immune system, nervous
system, and the liver. Dermal exposure to both chromium(III) and
chromium(VI) can result in chromium sensitivity.
Limited parenteral studies in animals indicate that chromium
exposure can result in developmental effects.
Data regarding the reproductive toxicity of chromium are not
sufficient to conclude whether chromium is a hazard to human
reproduction.
Tests of chromium compounds for mutations and genotoxicity in
various in vitro test systems indicate that effects in whole cells can
be induced by chromium(VI) compounds but not by chromium(lll) compounds
In isolated nuclei and purified DNA, interactions are observed with
chromium(III) but not chromium(VI). In vivo induction of chromosome
aberrations by chromium(VI) has'been observed, while chromium(III)
compounds have not been well tested.
Human epidemiology studies provide adequate evidence to indicate
that in some form chromium is a respiratory tract carcinogen. The date
do not clearly implicate specific compounds, but do implicate
chromium(VI). Animal studies have shown some positive results for
several chromium(VI) compounds; chromium(III) compounds and chromium(O)
(metallic chromium powder) have not been as well studied.
4.2 TOXICOKINETICS
4.2.1 Absorption
4.2.1.1 Inhalation
Human. The identification of chromium in the urine, serum, and RBC
following occupational exposure to compounds of chromium(VI) and
chromium(III) indicates that chromium can be absorbed via inhalation
exposure (Gylseth et al. 1977, Cavalleri and Minoia 1985, Randall and
Gibson 1987). Exposure to chromium(VI) resulted in increased serum and
RBC chromium levels, while chromium(III) exposure resulted in elevated
serum chromium concentrations (Cavalleri and Minoia 1985, Randall and
Gibson 1987).
Animal. Blood chromium concentrations of rats increased after
inhalation exposure to zinc chromate [chromium(VI)] dust at 7.35 mg/m3
(Langard et al. 1978). The only other studies noting absorption from the
lungs are intratracheal injection studies (Baetjer et al. 1959, Visek ec
al. 1953, Wiegand et al. 1984), which indicated that 53 to -85% of the
chromium from chromium(VI) compounds is cleared from the lungs compar'
to 5 to 30% of the chromium from chromium(III) compounds. Baetjer et
-------
lexicological Data Ul
(1959) postulated that chromium(III) may be absorbed more slowly from
the lungs as a result of precipitation as hydrous chromic oxide or with
proteins. Additional data from the study by Wiegand et al. (1984)
indicate that chromium(VI) is absorbed through the lung without
reduction to chromium(III) (Sunderman 1986).
4.2.1.2 Oral
Human. Based on fecal excretion. Donaldson and Barreras
found that, in humans, -0.4% of the 5^-Cr from an oral dose of
[chromium(III)] and -10.6% of the 51Cr from an oral dose of 51CrNa2Cr04
[chromium(VI)] were absorbed. After intraduodenal administration,
absorption of chromium(III) was not changed, while 50% of the
chromium(VI) was absorbed.
Using urinary excretion data from 15 female and 27 male subjects,
Anderson et al. (1983) estimated that the minimum gastrointestinal
absorption of dietary and supplemental chromium was -0.4%. The
supplemental chromium was provided as a tablet containing 200 Mg
chromium(III) as chromic chloride.
Animal. Based on whole-body counting of rats given a single gavage
dose of 51CrCl3 [chromium(III)], Mertz et al. (1965) found that,
regardless of the dose (0.15-10 /*g per 100 g body weight), -2 to 3% of
the dose was absorbed. In contrast to inorganic chromium(III) compounds,
Mertz (1969) found the organic GIF, which contains chromium(III), is
more readily absorbed (10 to 15%). Animal experiments also indicate that
10 to 25% of the chromium in brewer's yeast (which is a source of GIF)
is absorbed by rats (WHO 1973, Hertel 1986).
Based on fecal excretion. Donaldson and Barreras (1966) estimated
that rats absorbed 2% of the 51Cr from intragastric doses of 51CrCl3
[chromium(III)] and Na251Cr04 [chromium(IV)]. When the compounds were
given by jejunal administration, absorption increased to 8 and 25% for
CrCl3 and Na2Cr04, respectively.
Ogawa (1976) noted that gastrointestinal absorption of chromium
from CrCl3 [chromium(III)] in rats was -1.4%, with absorption of
chromium from Na2Cr04 [chromium(IV)] at -2.4%. Absorption of chromium
from both salts increased to 11% when rats were fasted for 48 h.
Sullivan et al. (1984) found that 51Cr from 51CrCl3 was absorbed from
the gastrointestinal tract of 2-day-old rats at levels 10 times higher
than in adults. Absorption of 5^-Cr by adult rats was <0.5% of the
administered dose.
4.2.1.3 Dermal
Human. Using volunteers, Mali (1963) found that potassium
dichromate(VI) but not chromic(III) sulfate penetrated intact epidermis.
Samitz and Shrager (1966) found that absorption of chromic sulfate was
negligible, with slightly larger amounts of chromium(III) nitrate
absorbed. The absorption of chromic(III) chloride was similar to
potassium dichromate.
In addition, indirect evidence from occupational studies (Randall
and Gibson 1987, Lindberg and Vesterberg 1983a) indicates some
absorption of chromium(III) and (VI) through the skin. These studies are
-------
48 Section 6
discussed in Sect. 2.2.2 on biological monitoring in Health Effects
Summary.
Animal. Wahlberg and Skog (1965) noted that at low concentrations
(0.017-0.239 rt) , the dermal absorption of sodium chromate(VI) by guinea
pigs was somewhat higher than chromic(III) chloride, but the difference
was not significant. At higher concentrations (0.261-0.398 M) ,
absorption of sodium chromate was statistically higher than chromic
chloride. The peak rates of absorption were 690-725 and 315-330 m/j
mol/h/cm2 for sodium chromate at 0.261-0.398 M and chromic chloride ac
0.239-261 M. respectively. Wahlberg and Skog (1965) also found that
percutaneous absorption of sodium chromate was higher at pH >6.5
compared with pH £5.6.
4.2.2 Distribution
Distribution of chromium to the fetus following administration to
pregnant rodents by gavage or parenteral routes is discussed in Sect.
4.3.3 on developmental toxicity in the Toxicological Data section.
4.2.2.1 Inhalation
Human. Examination of tissues from chromate workers at autopsy
found the highest chromium levels in the lungs, lymph nodes, kidney,
liver, bladder, and bone (IARC 1980). An autopsy study of West German
people who may have been exposed to chromium in the workplace and also
through industrial pollution of the environment revealed higher
concentrations of chromium in lung than in spleen, liver, or kidney;
levels in lung, but not other tissues, increased significantly with ag.
(Kollmeier et al. 1985). (See oral exposure for distribution of chromium
absorbed from all routes of exposure in individuals not occupationally
exposed to chromium.)
Animal. The highest chromium levels were in the kidneys followed
by the lungs, spleen, liver, and blood in rats exposed to chromite(III)
dust for 28 days (Kamiya et al. 1981). Chromium levels in the lungs were
10 times higher in rats exposed to a pyrolyzed chromium oxide mixture
[Cr50i2, 3:2 chromium(VI)/chromium(III)] aerosol at 100 pg/m3 chromium
for 18 months, followed by 12 months of observation, compared to rats
exposed to Na2Cr20y at 100 /ig/m3 chromium(VI) (Glaser et al. 1986).
4.2.2.2 Oral
Human. Analysis at autopsy of tissue samples from Japanese people
not exposed to chromium in their occupations indicated that the greatest
chromium concentrations were in the hilar lymph nodes and lungs followed
by spleen, liver, kidney, and heart (Teraoka 1981). The National Academy
of Sciences (NAS 1974) states that autopsy studies in the United States
indicate that chromium concentrations in lung are among the highest in
the body and tend to increase with age, while chromium levels in most
other tissues appear to decline with increasing age. A recent West
German autopsy study of people with no occupational exposure to
chromium, however, found that chromium levels in lung and kidney were
not correlated with age (Zober et al. 1984). Levels in lung were
consistently higher than levels in kidney, in agreement with results
cited by Teraoka (1981) and NAS (1974).
-------
lexicological Data 49
Animal. Tissue chromium levels were 9 times higher in rats given
K2Cr04 (chromium(VI)] than rats given CrCl3 [chromium(III)] in drinking
water for 1 year (HacKenzie et al. 1958). The results were interpreted
to indicate a greater gastrointestinal absorption of the chromium(VI)
salt. The role of possible differences in excretion was not discussed.
Maruyama (1982) examined the chromium content of major organs in
mice provided with K2Cr20? (chromium(VI)] or CrCl3 [chromium(III)] in
the drinking water at 25-100 mg/L chromium for up to 1 year. In
chromium(III)-treated mice, chromium was detected only in the liver. In
chromium(VI)-treated mice, chromium accumulated in all organs, with the
greatest concentrations in the spleen and liver. Liver chromium
concentrations were 40 to 90 times greater in mice treated with
chromium(VI) than those treated with chromium(III), with the greater
discrepancy noted at the 100 mg/L treatment levels.
4.2.2.3 Dermal
Data concerning the distribution of chromium in humans and animals
following dermal exposure were not located.
4.2.2.4 Other routes of exposure
Human. Lim et al. (1983) found that in six patients given an
intravenous injection of ^Cr(III), >50% of the blood plasma chromium
was distributed into various body organs within hours of administration,
with the liver and spleen containing the highest levels. After 3 months,
the liver contained half of the total body burden of chromium. The study
results indicated three major accumulation and clearance components. The
fast component had a half-life of 0.5-12 h, the medium component, 1-14
days, and the slow component, 3-12 months.
As reviewed by Sunderman et al. (1987), studies of patients who
received surgical implantations of chromium alloy prostheses have given
conflicting results regarding mobilization of chromium from these
devices. The discrepancies in results may have been due not only to
differences among alloys and coating of the prostheses, but also to
analytical "inaccuracies," including metal contamination during specimen
collection. In their .own study of serum and urine from 44 patients from
day 1 through 2.5 years after implantation of Co-Cr and/or Ti-Al-V alloy
prostheses, Sunderman et al. (1987) detected elevated'levels of chromium
only in the urine of three patients at day 1-2 after surgery. These
increased urinary chromium concentrations were thought to be due to the
trauma of surgery rather than to mobilization from the prosthesis.
Duckett (1986) studied abnormal brain deposits of chromium in three
patients with encephalopathies. The author suggested that the source of
chromium was radiological contrast substance injected before the
patients' deaths and that chromium may have contributed to the deaths.
He hypothesized that chromium was able to enter the brain because all
three patients had vascular siderosis, a condition found in the brains
of a majority of middle-aged and elderly humans.
In an in vitro study (Lewalter et al. 1985), whole blood samples
were spiked with water-soluble chromium(VI) or chromium(III) compounds.
After a 10-min incubation period, the cells were dialyzed five times and
-------
SO Section 4
the amount of chromium inside the erythrocytes was determined. The
results showed a greater level of chromium inside erythrocytes follow!
treatment with chromium(VI) compared to chromium(III) compounds.
Erythrocyte chromium levels remained stable during the five dialysis
steps following chromium(VI) treatment, while dialysis of
chromium(III)-treated cells resulted in decreasing erythrocyte chromium
levels. The investigators stated that under the experimental conditions
both chromium(VI) and chromium(III) permeated the cell membrane, buc
only chromium from chromium(VT) compounds became bound to intracellular
proteins so that it could not be eliminated.
Animal. Weber (1983) treated rats by intratracheal injection with
51Cr-sodium dichromate dihydrate [chromium(VI)] and determined the
distribution of radioactivity for various periods up to 40 days.
Throughout the study, concentrations of radioactivity in the lungs and
kidneys were about 60 to 80 and 3.5 to 7 times higher compared to
concentrations in the whole body. Radioactivity concentrations in
erythrocytes, serum, liver, testis, skin and gastrointestinal tract were
generally similar to or lower than radioactivity concentrations in the
whole body. Tissue and organ elimination half-lives ranged from 14 to
50 days. Autoradiographs of the kidney and bone revealed that the
radioactivity was distributed unequally. In the kidney, radioactivity
localized predominantly in the cortex, while in bone, radioactivity was
located mainly in the region of the bone epiphyses. Microautoradiographs
of lung parenchyma indicated that radioactivity was preferentially
located in a specific type of alveolar cells. The investigators
suggested that the cells were type II alveolar cells, but stated that
further investigation was required before the cell type could be state.
definitively.
Visek et al. (1953) treated rats with sodium chromite(III) by
intravenous injection and found that large quantities of chromium were
concentrated in the reticuloendothelial system, which in combination
with the liver accumulated 90% of the dose. The accumulation in the
reticulendothelial system was thought to result from colloid formation
by chromite at physiological pH. Organs with detectable chromium levels
42 days postinjection were: spleen > liver > bone marrow > tibia
epiphysis > lung > kidney. Chromic(III) chloride given to rats by
intravenous injection also concentrated in the liver,, spleen, and bone
marrow (Visek et al. 1953). Four days postexposure, chromium levels were
lower in liver, spleen, and bone marrow of CrCl3-treated rats than in
NaCr02-treated rats, although more chromium accumulated in the kidneys
from CrCl3 than from NaCr02-treated rats.
Bryson and Goodall (1983) injected mice intraperitoneally with
chromic(III) chloride at 3.25 Mg/g chromium or potassium dichromate(VI)
at 3.23 pg/g chromium. Whole-body analysis of mice showed that
chromium(III) was released very slowly over 21 days; 87% was retained
3 days after treatment, 73% after 7 days, and 45% after 21 days. In
contrast, mice retained only 31% of the chromium(VI) at 3 days, 16% at
7 days, and 7.5% at 21 days. Mice injected with chromium(III) weekly at
1/6 the LD50 retained -6 times the amount of chromium as mice injected
with chromium(VI) at 1/6 the LD50- The authors attributed the retention
of chromium(III) to its ability to form coordination complexes with
proteins and amino acids.
-------
Toxicologies! Data 51
4.2.3 Metabolism
In vitro studies indicate that chromium(VI) is readily reduced to
chromium(III) (Kitagawa et al. 1982, Levis et al. 1978). Jennette (1982)
provided evidence that a chromium(V) intermediate was formed during in
vicro reduction of chromium(VI) to chromium(III) in rat liver microsomes
and suggested that the intermediate may be the form of chromium that
interacts with cellular macromolecules. Chromium(VI) is readily reduced
to chromium(lll) in the presence of glutathione (GSH). Uiegand et al.
(1984) incubated human RBC with an excess of chromium(VI) (Na2Cr04)
(10 mtf) and found that the GSH content of the cells was depleted to 10%
of the original amount. Chromium(VI) incubated alone with GSH was
reduced to chromium(III). The reaction required 3 GSH molecules to
reduce 1 molecule of chromate and was faster at pH values
-------
52 Section 4
form of hydrate complexes, does not result in the formation of chromii'-
protein complexes. The inability of "native" chromiun(III) to form
excretable chromium protein complexes may account for the lower urinar,
chromium concentrations observed in the Cavalleri and Minoia (1985)
study following exposure to chromium(III) compared to chromium(VI)
compounds.
Randall and Gibson (1987) reported that chromium concentrations in
postshift urine samples taken Friday afternoon and in preshift urine
samples taken Monday morning were significantly elevated in tannery
workers as compared with control subjects. Analysis of workroom air
revealed no detectable chromium(VI) and 1.7 Mg/n3 total chromium
[presumably chromium(III)] as a time-weighted average.
Animal. Pertinent data regarding the excretion of chromium
following inhalation exposure of animals were not located in the
available literature.
4.2.4.2 Oral
Human. Anderson et al. (1983) found that the daily urinary
excretion of chromium in 15 female subjects was 0.20 ± 0.03 Mg/L and in
27 male subjects was virtually the same, 0.17 ± 0.02 /Jg/L. When chromium
intake was supplemented fivefold with CrCl3, urinary excretion also
increased about fivefold.
Animal. Donaldson et al. (1984) found that renal clearance of
ultrafilterable 51Cr in dogs was about equal to the clearance of
endogenous creatinine following gavage (50 Mg) or intravenous
(1.6-7.6 pg) administration of 5lCr(III) chloride. The ratio of
clearance by both routes was independent of plasma chromium
concentration and urinary flow rate.
Sayato et al. (1980) treated rats with 51Cr-labeled Na2Cr04
[chromium(VI)] or CrCl3 [chromium(III)] by gavage or intravenous
injection and found that, regardless of the route, 51Cr from
chromium(VI) was excreted more rapidly through the urine and feces than
was 51Cr from chromium(III). Following oral administration, the biologic
half-life was 22.24 days for Na2Cr04 and 91.79 days for CrCl3.
4.2.4.3 Dermal
Quantitative data regarding excretion of chromium following dermal
exposure were not located in the available literature. Following an
accident in which a man was burned extensively with chromic acid
[chromium(VI)] and treated with ascorbic acid, chromium (valence not
determined) was excreted in the urine (Korallus et al. 1984).
4.2.4.4 Other routes of exposure
Human. Pertinent data regarding excretion of chromium following
other routes of administration in humans were not located in the
available literature.
Animal. Hertz et al. (1965) observed a three-compartment
elimination process in rats given a single intravenous dose of
-------
Toxicological Data 53
chromic(III) chloride. The half-lives of clearance for the three
compartments were estimated to be 0.5, 5.9, and 83.4 days.
Yamaguchi et al. (1983) found that within 7 days of a subcutaneous
injection of K2Cr20? (chromium(VI)] or Cr(N03)3 [chromium(III)], rats
excreted 36% of the chromium from the chromium(VI) salt in the urine and
13.9% in the feces; 8 and 24.2% of the chromium from the chromium(III)
salt was excreted in the urine and feces, respectively. Four days after
an intravenous dose of ^^CrCl3 at 3 mg/kg chromium, rats excreted 10 5%
of the dose in the feces and 32.6% in the urine (Gregus and Klaassen
1986).
In rats treated by intravenous injection with ^^-Cr-labeled sodium
chromate(VI) or chromic(III) chloride at 0.1 or 100 /*g chromium per rat,
2 to 2.5% of the administered chromium was recovered in the bile
following chromium(VI) exposure, while the excretion of chromium into
the bile following chromium(III) exposure was -50 times lower (Manzo et
al. 1983). Similar results were reported by Cirkt and Bencko (1979) and
Norseth et al. (1982), with 3.5 to 8.4% of the administered chromium
excreted in the bile following intravenous chromium(VI) injection and
-0.1 to 0.5% of the administered chromium excreted in the bile after
intravenous chromium(III) injection into rats.
Cavalleri et al. (1985) found that 2 h after an intravenous dose of
potassium dichromate(VI) at 0.1-1 mg chromium per rat, 1.35 to 2.23% of
the injected chromium was recovered in the bile. Less than 1% of the
total measurable chromium in the bile was identified as chromium(VI);
the remainder was thought to be chromium(III).
4.3 TOXICITY
Chromium(III) is considered to be an essential nutrient for
maintenance of normal glucose, cholesterol, and fat metabolism.
Chromium(III) functions biologically by potentiating the action of
insulin. Hence, the improvement of glucose tolerance is an indicator of
chromium activity (Mertz 1975, Anderson 1981, Danford and Anderson
1985). Inorganic chromium has little or no insulin potentiating
activity, but can be converted by animals and humans to an organic form
that is biologically active (Mertz 1975, Anderson 1981). This organic
form, glucose tolerance factor (GTF), is not fully characterized. The
active component has been identified as chromium(III), which may be
complexed with nicotinic acid, and possibly also with glycine, glutamic
acid, and cysteine (Mertz 1975, Anderson 1981). The estimated safe and
adequate daily dietary recommendation for intake of chromium in adults
is 50-200 pg/day based on the absence of signs of chromium deficiency in
the U.S. population consuming 60 jig/day (Danford and Anderson 1985).
Brewer's yeast and fresh or unprocessed foods are good sources of
chromium. Signs of chromium deficiency in humans include weight loss,
impaired glucose tolerance, fasting hyperglycemia, increased serum
cholesterol and triglycerides, and relative unresponsiveness to
administered insulin (Anderson 1981, Danford and Anderson 1985).
Soluble chromium(VI) compounds tend to be oxidizing agents (Sect.
3.2 on physical and chemical properties in Chemical and Physical
Information) and are irritating and corrosive. Many of the toxic effects
of these compounds stem from these properties (NAS 1974, IARC 1980).
-------
54 Section 4
4.3.1 Lethality and Decreased Longevity
4.3.1.1 Inhalation
Human. Decreased longevity from effects other than cancer has not
been reported in humans exposed by inhalation to chromium compounds.
Animal. Four-hour inhalation LCSQs for sodium chromate, sodium
dichromate, potassium dichromate, and ammonium dichromate in F344 rats
were determined by Gad et al. (1986). The LCSQs for these chromium(VI)
compounds range from 33 to 65 mg/m^ chromium for both sexes combined
(Table 4.1). Sex-specific LCSQs not reported in Table 4.1 indicate that
females were more sensitive than males for all the compounds but sodium
chromate, which was equally toxic for both sexes. Signs of toxicity
produced by exposure to all four chromates included respiratory distress
and irritation; exposure-effect data for these signs were not reported.
4.3.1.2 Oral
Human. Langard and Norseth (1986) reviewed a number of case that
indicate that doses of 2-5 g of unspecified chromate compounds
[chromium(VI)] are fatal to humans. Doses as milligrams of chromium were
not given. In humans who ingested >5 g of chromate compounds, the
symptoms included gastrointestinal bleeding, massive fluid loss, and
death in some individuals following a clinical picture of cardiovascular
shock. These effects tended to occur within 12 h of ingestion. When the
ingested chromate dose was <2 g, tubular renal necrosis and diffuse
liver necrosis developed and contributed to the cause of death in fatal
cases. Effects on the liver and kidney developed 1 to 4 days after
ingestion. The National Institute for Occupational Safety and Health
(NIOSH 1979) reported a human oral LDLo for sodium dichromate of 50
mg/kg; however, NIOSH no longer reports this value in the on-line
version of this database, which indicates that the value is
questionable.
Animal. Single-dose oral LDSQs for chromium(VI) and chromium(III)
compounds are summarized in Table 4.1. The LDSQs for chromium(VI) ranged
from 16.7 to 22.5 mg/kg chromium for sodium chromate, sodium dichromate,
potassium dichromate, and ammonium dichromate in rats (Gad et al. 1986);
70 to 92 mg/kg chromium for chromium trioxide in mice (Kobayashi 1976);
and 42 to 59 mg/kg chromium for chromium trioxide in mice (Kobayashi
1976). Chromium(III) compounds are less toxic than chromium(VI)
compounds, as U>50 values for chromium acetate and chromium nitrate in
rats were 2,369 and 422 mgAg chromium, respectively (Smyth et al.
1969). Toxic effects in rats that were administered lethal doses of
chromium(VI) compounds by Gad et al. (1986) included pulmonary
congestion, fluid distention of the gastrointestinal tract, and erosion
and discoloration of the gastrointestinal mucosa. Rats and mice that
died from treatment with chromium(VI) trioxide had diarrhea, cyanosis,
tail necrosis, and gastric ulcers (Kobayashi 1976).
Sex-specific LDSQs reported for sodium chromate, sodium dichromate.
potassium dichromate, and ammonium dichromate by Gad et al. (1986) show
that female F344 rats were more sensitive than males. Gad et al. (1986)
also found that, as the concentration of sodium dichromate increased,
-------
Table 4.1. Acute lethality of chromium compounds
Route Compound
Inhalation ( LC»)a Sodium chromate( VI )
Sodium dichromate(VI)
Potassium dichromale(VI)
Ammonium dichromaie(VI)
Oral (LD,o)* Sodium chromate(VI)r
Sodium dichromate(VI)r
Potassium dichromate(VI)r
Ammonium dichromalc(VI)r
Chromium(VI) trioxide
Chromium(VI) trioxide
Chromium(lll) acetate
Chromium(lll) nitrate
Dermal (LDM)d Sodium chroma te( VI)
Sodium dichromatc(Vl)
Potassium dichromate(VI)
Ammonium dichromale(VI)
Species/strain
Ral/F344
Rat/FJ44
Ral/F344
Ral/F344
Rat/F344
Rat/F344
Rdl/F344
Rat/F344
Ral/NR
Mouse/NR
Rat/Carworth-Wistar
Rat/Carworlh-Wislar
Rabbit/New Zealand
Rabbit/ New Zealand
Rabbit/New Zealand
Rabbit/ New Zealand
mg compound/in' (LCM)
or
Sex/age ing compound/kg (LD*,)
Combmed/NR
Combmed/NR
Combmed/NR
Combmed/NR
Combmed/NR
Combmed/NR
Combmed/NR
Combmed/NR
NR/NR
NR/NR
Male/NR
Male/NR
Combmed/NR
Combmed/NR
Combmed/NR
Combmed/NR
10414
12442
9365
15817
SI 91
SI 10
S7I8
5375
135-177
80-114
11.260
3.250
1.600
1.000
1.170
1.640
LCj,, (mg/m1 Cr)
or
LDy, (mg/kg Cr) References
33
49
37
65
167
203
225
222
70-92
42-59
2.369
422
SI4
397
461
677
Gadeial 1986
Gad el al 1986
Gadeial 1986
Gadeial 1986
Gadeial 1986
Gad el al 1986
Gad el al 1986
Gadeial 1986
Kobayashi 1976
Kobayashi 1976
Smyth el al 1969
Smyth el al 1969
Gadeial 1986
Gad el al 1986
Gad el al 1986
Gad el al 1986
a4-h exposure lo aerosol of aqueous solutions.
Oral administration was conducted by gavage
'S% (w/v) solution in water
d24-h exposure to clipped back and side skin Skin was wet with an equal volume of saline following compound application
NR - not reported
n
o
n
o>
O
n>
r»
Pi
-------
56 Section 4
the LD50 (as milligrams of compound) for F344 rats decreased (e.g., LT
in females - 57.13 mg/kg for a 0.5% aqueous solution versus 34.17 mg/i
for a 10% solution).
Without providing any details, Steven et al. (1976) reported that
Brard (1935) found that dogs given oral doses of potassium chromate(VI)
at 0.1-0.2 g/day for 3 months died.
4.3.1.3 Dermal
Human. Brieger (1920) reported the deaths of 12 patients following
application to the skin of antiscabies ointment containing chromium(VI)
Necrosis at the sites of application and nausea, vomiting, shock, and
coma occurred. Albumin and blood were found in the urine; autopsies
revealed tubular necrosis and hyperemia of the kidneys. Similarly, Major
(1922) reported severe nephritis and death of a patient after
cauterization of a wound with chromium(VI) oxide. Fritz et al. (1959)
reported necrotic glomerulonephrosis and the death of a worker following
an industrial accident in which the worker was burned with hot potassium
dichromate over his arms and body. It should be noted that these cases
involved damaged rather than intact skin.
Animal. Single-dose dermal LD5Qs for sodium chromate, sodium
dichromate, potassium dichromate, and ammonium dichromate in New Zealand
rabbits were determined by Gad et al. (1986). As detailed in Table 4.1,
L050s for these chromium(VI) compounds in F344 rats ranged from 397 to
677 mg/kg chromium. Signs of toxicity included dermal necrosis, eschar
formation, dermal corrosion, diarrhea, hypoactivity, and dermal edema
and erythema. The cause of death was not specified.
4.3.2 Systemic/Target Organ Toxicity
4.3.2.1 Respiratory tract effects
Inhalation, human. In a Russian study (Kuperman 1964) , 10 normal
individuals were exposed to chromium(VI) aerosols of unspecified
composition at 0.0015 to 0.04 mg/m3. Concentrations of 0.01-0.024 mg/m3
chromium(VI) sharply irritated the nose when inhaled for short periods.
The most sensitive individual responded at a concentration of 0.0025 to
0.004 mg/m3 chromium(VI) . It was not known if this was a reaction to
chromium(VI) or to the acidity of the aerosol.
Many cases of nasal mucosa injury (inflamed mucosa, ulcerated
septum, perforated septum) in workers exposed to Cr03 have been reported
(Bloomfield and Blum 1928, Gresh 1944, Zvaifler 1944, Klienfeld and
Russo 1965, Vigliani and Zurlo 1955). These effects occurred at
chromium(VI) concentrations ranging from 0.06 to 0.72 mg/m3. The length
of exposure in these cases was highly variable. Cohen and Kramkowski
(1973) and Cohen et al . (1974) found that 12/37 workers employed by a
chrome-plating plant developed nasal ulceration or perforation within 1
year of being employed. Airborne chromium(VI) concentrations ranged from
<0.71 to 9.12
Otolaryngolic examinations of 77 workers exposed to chromic (VI)
acid aerosols during chrome plating revealed nasal perforation in 19%,
with nasal mucosal irritation in 48% (Hanslian et al. 1967). The worke
-------
Toxicologies! Data 57
examined averaged 6.6 years of exposure to a chromium concentration of
0.4 mg/m3. Papillomas of the oral cavity and larynx, confirmed by
histologic examination, were observed in 14 workers. No signs of
atypical growth or malignant degeneration were noted.
No ulcerated nasal mucosa or perforated nasal septa were observed
in 32 employees at a chrome-plating plant where the maximum airborne
chromium(VI) concentration was 3 ^g/m3 (Markel and Lucas 1973). Sixteen
employees had varying degrees of mucosal irritation, but the
investigators did not consider this to be significant because the survey
was carried out at the peak of an influenza epidemic. The length of
employment ranged from <1 year to >8 years.
Lindberg and Hedenstierna (1983) examined respiratory symptoms,
lung function, and changes in the nasal mucosa in 43 chrome-plating
workers in Sweden, exposed almost exclusively to chromic(VI) acid, with
19 persons exposed to chromic acid at an 8-h mean below 2 /ig/m3 and
24 persons exposed at an 8-h mean of 2 /ig/m3 or greater. Exposure
durations ranged from 0.2 to 23.6 years (median - 2.5 years). The
reference group for lung function tests was a group of 119 auto
mechanics, while 19 office employees were used as controls for changes
in the nasal mucosa. Exposure measurements were made with stationary
samplers placed close to the chromic acid baths and with personal
samplers. The personal samplers were used on a total of 84 subjects on
13 different days. Data were collected with the use of interviews, based
on a standardized questionnaire for the assessment of respiratory
symptoms, an inspection of the nose, forced expiratory studies with a
spirometer, and single-breath nitrogen washouts.
The results of interviews indicated that at mean air chromium(VI)
concentrations of >2 jig/m3 about half of the workers complained of
"constantly running nose" or "stuffy nose." Within this higher exposure
group, subjective symptoms did not correlate with exposure
concentration. At mean chromium(VI) concentrations of <2 ^g/m3, 4/19
complained of nasal symptoms, while at <1 ^g/m3 0/9 complained of
symptoms. Results of nasal examinations are presented in Table 4.2. The
examinations revealed a dose-response relationship especially with
highest exposure value rather than mean value of exposure. The number of
workers with a smeary and crusty septal nasal mucosa in workers exposed
to mean chromium(VI) concentrations of <2 A»g/m3 were significantly
higher than controls (11/19 exposed versus 5/19 controls, P < 0.05).
Atrophy of the nasal mucosa was observed in four workers exposed at
<2 Mg/m • Ulcerations and perforations were confined to the group
exposed to a mean concentration of 2-20 /*g/m3. Among the high group,
ulcerations and perforations did not correlate with mean exposure
concentrations. All workers with ulceration and/or perforation were
temporarily exposed to at least 20 /*g/m3 when working near the baths.
The period of exposure for individuals experiencing ulceration varied
from 5 months to >10 years. Examination of the ulcers indicated that
they were clearly active. None of the controls showed signs of atrophy,
ulceration, or perforation.
Results of lung function tests showed that workers exposed to mean
concentrations of 2-20 /ig/m3 chromium(VI) had slight, transient
decreases in forced vital capacity (FVC), forced expired volume in
-------
58 Section
Table 4.2. Condition of the nose and subjective symptoms
in groups with different mean values of exposure and
with different highest exposure values"
Exposure to chromium(VI) Ug/m3)
8-h Mean
Number exposed
Subjective irritation
Atrophy
Ulceration
Perforation
«1.9
19
4
4
0
0
2-20
24
11
8
8*
3
Highest value
0.2-1.2
10
0
1
0
0
2.5-11
12
8
8
0
0
20-46
14
4
0
7f
3
"Measured near the baths where the exposed worker had
worked during some part of the day.
*Two of 8 also had a perforation.
Two of 7 also had a perforation.
Source: Lindberg and Hedenstierna 1983.
-------
lexicological Data 59
1 s (FEV1), and forced mid-expiratory flow (FEF25-75) during the workday
(measurements were different on Thursday afternoon compared to Thursday
morning or Monday morning). Effects were greater in nonsmokers compared
to smokers. No permanent effects were seen in workers exposed at
2-20 jig/m3 chromium(VI) (after 2 days without exposure) compared with
unexposed controls when values were adjusted for age and height. Workers
exposed to <2 pg/m3 chromium(VI) showed no effects on lung function.
Although the Lindberg and Hedenstiema (1983) study contains the
best available data relating chromium(VI) exposure concentration to lung
and nasal effects, the study does have limitations. The effects observed
may not have been a result of exposure levels actually measured but may
have been a result of earlier exposure under unknown conditions. In
addition, varying personal hygiene practices may have contributed to the
observed nasal mucosal effects.
A wide range of other respiratory effects have also been reported
in workers exposed to chromium compounds. German investigators (Alwens
and Jonas 1938, Fischer-Wasels 1938, Koelsch 1938, Lehmann 1932, Mancuso
1951) have reported that prolonged inhalation of chromate(VI) dust
resulted in chronic irritation of the respiratory tract, as well 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 perivascular lung markings. X-ray observations included enlargement
of the hilar region and lymph nodes, increase in peribronchial and
perivascular lung markings, and adhesions of the diaphragm.
Inhalation, animal. Steffee and Baetjer (1965) exposed 8 rabbits
for 50 months and 50 guinea pigs and 78 rats for their lifetime to mixed
chromate(VI) dust via inhalation at 3-4 mg/m3 Cr03, 5 h/day,
4 days/week, or via intratracheal injection. The average weekly
exposures were -53, 44, and 49 mg/h for rabbits, guinea pigs, and rats,
respectively. The results indicated that -25% of the rabbits and rats
had nasal perforations (guinea pigs were not examined).
Histopathological examinations of the lungs revealed that 15% of rabbits
and rats exposed by inhalation, and 15% of rabbits and guinea pigs
exposed by intratracheal injection, exhibited granulomata. This lesion
was observed in one control rat and none of the control rabbits or
guinea pigs. The incidence of alveolar and interstitial, inflammation was
also greater than controls in guinea pigs exposed by both routes. No
compound-related histopathological effects were noted in the liver,
kidney, and spleen.
Nettesheim et al. (1971) exposed at least 136 C57BL/6 mice of each
sex to calcium chromate(VI) dust at 13 mg/m3 CaCr04, 5 h/day,
5 days/week for 6 months to life. After 6 months of exposure, marked
alteration of the bronchial epithelium (necrosis, atrophy, and
hyperplasia), bronchiolization of alveoli, and alveolar proteinosis were
observed. Changes in the tracheal and submandibular lymph nodes included
enlargement and hyperplasia during the first 6 to 8 months of exposure,
followed by cortical atrophy and extensive histiocytosis. After 2 years,
marked atrophy of the spleen and liver were noted, and ulcerations in
the stomach and intestinal mucosa were occasionally observed. Body
-------
60 Section 4
weights were lower In- the treated groups of male and female mice than
controls throughout the study.
Oral. Lung effects have not been reported in humans or animals
following oral exposure to chromium compounds regardless of valence
state.
Dermal. Lung effects have not been reported in humans or animals
following dermal exposure to chromium compounds.
General discussion. Human occupational experience clearly
indicates that by inhalation, chromium(VI) is a respiratory tract
irritant. Concentrations of 0.2-1.2 A*g/n3 seem to be a NOAEL, with nasal
irritation and slight, transient effects on pulmonary function occurring
at levels £2 A»g/m3. At concentrations of 20-46 /*g/m3 (PEL), ulceration
and perforation have been observed. Limited animal studies using
inhalation exposure also indicate that chromium(VI) is a respiratory
tract irritant, but the studies do not define NOAELs.
In a study by Steinhoff et al. (1986a) (also reported in Steinhoff
et al. 1986b), groups of 40 male and 40 female rats were treated by
intratracheal instillation of sodium dichromate [chromium(VI)] at doses
of 0.05, 0.25, or 1.25 mg/kg once Per week or at doses of 0.01, 0.05. or
0.25 mg/kg five times per week for 30 months. Similar groups of rats
were treated with calcium chromate [chromium(VI)] at 0.25 mg/kg five
times per week or at 1.25 mg/kg o«ce per week. Control rats were left
untreated or were treated with a 0.9% NaCl solution at 1 mL/kg once or
five times per week. Rats treated with sodium dichromate once per week
at 1.25 mgAg had difficulties in breathing after treatment, and body
weights were significantly reduced in males, with a nonsignificant
reduction of body weights in females. Nonsignificant reduction in body
weight was also observed in male rats treated with calcium chromate once
per week at 1.25 mg/kg. Lung weights were significantly increased in
high-dose sodium dichromate and calcium chromate rats following both
treatment regimens. Changes in lung weights were greater in sodium
dichromate treated rats compared to calcium chromate treated rats. No
chromate-related changes in routine hematology and clinical chemistry
parameters were noted. Results of microscopic examinations were reported
by Mohr et al. (1986-) and Steinhoff et al. (1986b). Minor changes in the
lungs, described as clusters of peribronchiolar alveoli filled with
macrophages, were observed in a dose-related manner in rats treated with
sodium dichromate one or five times per week at doses of 0.25 mg/kg and
below. The lungs of rats treated with sodium dichromate once per week at
1.25 mgAg were moderately to severely damaged. Effects that occurred at
1.25 mg/kg included peribronchiolar fibrosis accompanied by alveolar
atelectasis or emphysematous enlargement and distortion of air spaces,
hyperplasia of smooth muscle, and the presence of prominent mast cells
Changes in the lungs of rats treated with calcium chromate were similar
to those observed in rats treated with an equivalent dose of sodium
dichromate, except fibrosis and emphysema in rats treated with calcium
chromate at 1.25 mg/kg were less severe than in rats treated with the
same amount of sodium dichromate. Macroscopic and microscopic
examinations did not reveal chromate-related effects in any other
organs.
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Toxicological Data 61
4.3.2.2 Immune system' effects excluding hypersensltivlty
Inhalation, human. Except for hypersensitivity reactions
[discussed in the next section (Sect. 4.3.2.3)], immune system effects
have not been reported in humans following inhalation exposure to
chromium compounds.
Animal. Glaser et al. (1985) exposed groups of 20 Vistar rats to
aerosols of sodium dichromate at concentrations of 0, 25, 50, 100, or
200 Mg/m3 chromium(VI) for 22 h/day, 7 days/week for 28 or 90 days, and
examined effects on alveolar macrophages and immune function. At
25-100 Mg/m3 for both exposure periods, increased phagocytic activity of
macrophages was observed, and total serum immunoglobin levels and
antibody response to injected sheep red blood cells (SRBC) were
significantly increased. At 200 Mg/n3 phagocytic activity of macrophages
was inhibited, and serum immunoglobin levels and response to SRBC were
decreased, indicating an effect on the immune function.
Johansson et al. (1986) examined changes in macrophages after
rabbits (8 per dose group) were exposed to aerosols of Na2Cr04 at
0.9 mg/m3 chromium(VI) or Cr(N03)3 at 0.6 mg/m3 chromium(III) for
6 h/day, 5 days/week for 4 to 6 weeks. A significant increase in the
number of macrophages occurred in chromium(VI)- but not chromium(III)-
exposed rabbits. Examination of macrophages with an electron microscope
revealed more conspicuous changes in macrophages from chromium(III)-
exposed rabbits. A decrease in phagocytic activity was observed in
macrophages from chromium(III)- but not chromium(VI)-exposed rabbits.
Oral. Immune system effects have not been reported in humans or
animals following oral exposure to chromium compounds.
Dermal. With the exception of hypersensitivity reactions, immune
system effects have not been reported in humans or animals following
dermal exposure to chromium compounds.
General discussion. Inhalation exposure to chromium(VI) and
chromium(III) compounds at concentrations of 0.2-0.9 mg/m3 chromium
results in depression of some indices of immune system function in
animals, whereas chromium(VI) at concentrations £0.1 mg/m3 chromium
results in stimulation. In vitro studies reviewed by Steven et al.
(1976) indicate that chromium can affect macrophage activity. Camner et
al. (1974) found that chromium metal coating on teflon particles
stimulated phagocytic activity of macrophages, while Waters et al.
(1975) observed that the viability of rabbit macrophages was reduced at
chromium(III) concentrations >52 ppm (in the medium).
4.3.2.3 Chromium hypersensitivity and skin effects
Inhalation, human. Holler et al. (1986) reported a case of delayed
anaphylactoid reaction in a male worker occupationally exposed to
chromium vapors from chromium(VI) trioxide baths and chromium fumes from
steel welding. Exposure levels were not reported. An inhalation
challenge with sodium chromate at 1.2 j*g/m3 for 5 min did not result in
a reaction, while a challenge at 29 Mg/m3 for 25 min resulted in a
reaction (late onset uticaria, angioedema, and bronchospasm accompanied
by a tripling of plasma histamine levels).
-------
62 Section 4
As reviewed by EPA (1984c), a number of studies have attributed
asthma to occupational exposure to chromium, but the etiological
relation to chromium exposure is unclear because of the presence of
other chemicals in the work environment.
Inhalation, animal. No data were available.
Oral, human. In a study by Kaaber and Veien (1977), the dermatitis
of 11/31 chromium sensitive individuals became worse after a single oral
ingestion of 7.1 mg potassium dichromate [chromium(VI)] in a tablet. The
sensitizing exposures were not discussed or quantified.
Oral, animal. No data were available.
Dermal, human. Chromic acid, dichromate compounds, and other
chromium(VI) compounds are not only powerful skin irritants but can also
be corrosive. When these compounds are deposited on broken skin, a
penetrating round ulcer may develop. Common sites for ulcer development
include the nail root areas, over the knuckles and finger webs, the back
of the hands, and the forearms (Maloof 1955). These ulcers are usually
painless, but may persist for months.
At lower concentrations, chromium compounds [especially
chromium(VI) compounds] are sensitizers rather than irritants (NAS
1974). In a case reported by Milner (1980), dermal application of a 10%
solution of ascorbic acid, a reducing agent, greatly reduced the
chromium sensitivity of a worker exposed to chromium(VI) in inks,
indicating that in this case, exposure to chromium(VI) and not
chromium(III) caused the adverse reaction. EPA (1984a) reported a numb'
of cases of chromium sensitization resulting in allergic dermatitis wi
eczema. The majority of cases were in men as a result of occupational
exposure. The types of workers in which the effect was reported included
printers, cement workers, metal factory workers, painters, and leather
tanners. Avnstorp and Henne (1982) reported that cement eczema,
attributed to the chromium(VI) content, is one of the commonest
occupational diseases among men.
In a patch test study of nonoccupationally exposed patients in
Scotland, Husain (1977) found that among the 1,312 patients examined,
11.58% were sensitive to 0.5% potassium dichromate. The reaction rate
was higher in males (15.19%) than in females (8.18%).
Dermal, animal. EPA (1984a) reviewed a number of studies that
indicate that chromium hypersensitivity can develop in guinea pigs
following acute dermal or subcutaneous administration of chromium(III)
or chromium(VI) compounds (Gross et al. 1968, Schwartz-Speck and
Grundsman 1972, Jansen and Berrens 1968, Siegenthaler et al. 1983).
Exposure doses were not provided.
General discussion. Dermal chromium exposure of humans and guinea
pigs can result in sensitization. Although reactions to chromium(VI) are
more common, reactions to chromium(III) can also occur. According to
Steven et al. (1976), data from several studies indicate that complexes
of chromium(III) with proteins and amino acids cause the allergic
reaction. Inhalation exposure of workers to chromium compounds may also
result in sensitization. Because the development of hypersensitivity i
-------
Toxicological Data 63
highly variable between individuals, it is not possible to develop a
dose-response relationship.
4.3.2.4 Nervous system effects
Inhalation. Nervous system effects have not been reported in
animals or humans following inhalation exposure to chromium compounds.
Oral, human. No data were available.
Oral, animal. In a study examining the effects of chromium(VI) on
motor activity (Diaz-Mayans et al. 1986), no effects were noted in six
rats provided with drinking water containing sodium chromate at 0.07 g/L
chromium(VI) for 28 days. A significant decrease in motor activity was
noted 7 days after six rats were provided with drinking water containing
sodium chromate at 0.7 g/L chromium(VI) (P < 0.02) and 1 day after six
rats were given a single intraperitoneal injection of sodium chromate at
2 mgAg body weight chromium(VI) (F < 0.01).
Dermal. Nervous system effects have not been reported in humans or
animals following dermal exposure to chromium compounds.
General discussion. The study by Diaz-Mayans et al. (1986), which
found hypoactivity in rats provided with drinking water containing
0.7 g/L chromium(VI) for 28 days, indicates that chromium may have some
central nervous system effects. This is further supported by the study
by Mathur et al. (1977) in which changes in brains of rabbits given
daily intraperitoneal doses of chromium(III) nitrate or potassium
dichromate(VI) at 2 mg/kg chromium for 3 or 6 weeks were reported. The
changes observed included neuronal degeneration in the cerebral cortex,
marked chromatolysis, nuclear changes in the neurones, neuronal
degeneration in the cerebral cortex accompanied by neuronophagia,
neuroglial proliferation, and meningeal congestion. Abnormal deposits of
chromium in the brains of patients with encephalopathies treated with
radiological contrast substances containing chromium (Duckett 1986) (see
Sect. 4.2.2.4 on distribution in humans after parenteral exposure)
provide limited evidence that the brain may also be a target organ for
chromium toxicity in humans.
4.3.2.5 Kidney effects
Inhalation, human. Mutti et al. (1979) examined welders and
chromium platers and found that workers with higher levels of chromium
exposure showed a pattern of nephrotoxicity as indicated by an increase
in indices for renal tubular damage. Lengths of exposure and chromium
concentrations were not reported.
Lindberg and Vesterberg (1983b) studied the urinary excretion of
02-microglobulin and albumin in 24 male chromium platers, in 27 former
chrome platers, and in 27 controls (similar ages to subjects). Mean 8-h
exposures of current workers, measured with personal air samplers,
ranged between 2 and 20 pg chromium(VI)/m3, with an average of 6 pg/m3
for the group. The duration of exposure for current workers ranged from
0.1 to 26 years, with an average of 5.3 years and a median of 4 years.
Most of the current workers had irritation symptoms of the airways, two
had ulcerated nasal septum, and two had complete perforation of the
septum. Exposure concentrations were not available for the former
-------
64 Section 4
placers, but because 7 of the 27 former workers had a permanent
perforation of the nasal septum, the investigators concluded that
exposure concentrations were probably similar or higher than for current
workers. Duration of exposure for the former workers ranged from 1 to
22 years, with an average and median of 4 years. Urinary albumin levels
were not significantly affected compared to controls in either current
or former chromium platers. Urinary 02 microglobulin levels were
significantly (P - 0.045) higher in current platers compared to
controls, with higher levels observed in younger individuals exposed to
higher chromium(VI) concentrations. Increased urinary levels of 02-
microglobulin are an indicator of renal tubular damage. Determination of
urinary cadmium levels did not reveal elevated concentrations, excluding
cadmium as a cause of elevated 02-microglobulin. A correlation between
total exposure time and 02-nicroglobulin levels was not observed. Among
former platers, 02-microglobulin levels did not differ from controls.
The investigators suggested that chromium(VI) exposure concentrations
that can cause effects on the airways (>2 pg chromium(VI)/m^) can result
in a temporary increase in the urinary excretion of 02-microglobulins.
Because of the small number of subjects examined in this study and
because there are many other causes of increased urinary levels of
02-microglobulin (e.g., infections, analgesics), the association between
increased urinary 02-microglobulin and chromium(VI) exposure found in
this study is not conclusive.
Saner et al. (1984) studied urinary chromium and 02-microglobulin
levels in 18 tannery workers, in 16 tannery controls employed in offices
and the kitchen of the same factory, and in 12 normal adults (staff an'
medical students from an undisclosed institution). The levels of
chromium or chromate in factory air were not monitored, but may have
been high, according to the authors, since the factory lacked special
ventilation facilities. Duration of employment of tannery workers and
tannery controls ranged from 1 month to 30 years. Urinary chromium
levels were 6.6, 2.3, and 0.22 pg/L for the tannery workers, tannery
controls, and normal adults, respectively. These values indicate that
the tannery controls were exposed to chromium at levels greater than the
general population. Urinary ft2-microglobulin levels in all three groups
were within normal limits, but the 02-microglobulin/creatinine ratios of
both tannery workers and tannery controls were significantly lower than
those of normal adults and correlated inversely with urinary
chromium/creatinine ratios. (Urine volumes and creatinine values did not
differ among the three groups.) The authors speculated that impaired
synthesis and/or decreased turnover of 02-microglobulin might account
for these findings.
Inhalation, animal. Kidney effects in animals have not been
reported following inhalation exposure to chromium compounds.
Oral, human. Langard and Norseth (1986) reported that tubular
renal necrosis developed in humans ingesting chromate compounds at <2 g
and contributed to the cause of death in fatal cases (Sect. 4.3.1.2 on
lethality and decreased longevity after oral exposure).
Oral, animal. Kidney effects in animals have not been reported
following oral exposure to chromium compounds.
-------
ToxicologiesL Daca 65
Dermal, human. Korallus et al. (1984) states that the most
frequent effect of acute dermal absorption of large amounts of
chromium(VI) compounds is uremia due to tubular necrosis. Kidney damage
and death have been reported following the treatment of patients with an
antiscabies ointment containing chromium(VI) (Brieger 1920), following
cauterization of a wound with chromium(VI) oxide, and following an
industrial accident involving skin exposure to hot potassium dichromate
(Fritz et al. 1959) (Sect. 4.3.1.3 on lethality and decreased longevity
after dermal exposure). Schiffl et al. (1982) reported a case of anuria
in a worker who fell in a vat of hot chromic acid, burning about 20% of
his body. There were no lesions in the mouth or throat. Aggressive
peritoneal dialysis resulted in complete recovery after 35 days. Kidney
damage was prevented by intravenous treatment with ascorbic acid shortly
after a person was extensively burned with chromic acid in an industrial
accident (Korallus et al. 1984). These cases involved damaged rather
than intact skin.
Dermal, animal. Kidney effects in animals have not been reported
following dermal exposure to chromium compounds.
General discussion. Chromium is a nephrotoxin that produces tubular
necrosis, with low doses acting specifically at the proximal convoluted
tubule. Unfortunately, human and animal studies do not clearly define
FELs and NOAELs by inhalation, oral, and dermal routes of exposure. In
studies reviewed by EPA (1984a) (Kirschbaum et al. 1981, Baines 1965.
Evan and Dail 1974), kidney effects have been observed in laboratory
animals following parenteral administration. Powers et al. (1986)
reported marked acute proteinuria, glycosuria, phosphaturia, enzymuria,
severe electrolytic imbalance, increased kidney weight, and
morphological changes in the kidneys of rats given a single subcutaneous
injection of sodium dichromate (chromium(VI)] at a dose of 20 mg/kg.
Concurrent treatment with an intramuscular injection of ascorbic acid
(150 mg/kg) greatly reduced the nephrotoxicity of sodium dichromate. In
a study by Laborda et al (1986), rats treated intraperitoneally with
chromic(III) chloride or sodium chromate(VI) at 2 mg/kg chromium 3 times
a week for up to 60 days developed kidney damage. Chromium(VI) caused
somewhat more severe damage than did chromium(III).
Berndt (1976) examined chromium(VI) uptake in rat and rabbit renal
slices. The results indicated that chromium ion was accumulated by the
slices by mechanisms other than simple, passive binding. Treatment of
rat kidney slices with chromate or dichromate ion interfered with the
transport of organic compounds and the maintenance of normal
electrolytic gradients. In rabbit kidney slices, dichromate was more
effective than chromate at inhibiting transport.
Srivastava et al. (1985) treated rats with chromic(III) nitrate or
potassium chromate(VI) by intraperitoneal injection at 4 mg/kg/day
chromium for up to 14 days. The results indicated a significant decrease
(P < 0.05) in renal glutamic oxalacetic transaminase, acid phosphatase,
and lactic dehydrogenase activities following treatment with
chromium(III) but not chromium(VI).
-------
66 Section 4
4.3.2.6 Liver effects
Inhalation, human. Pascale et al. (1952) reported a case of
hepatic injury in a woman who had been employed for 5 years at a
chromium-plating factory. She was hospitalized with jaundice and was
found to be excreting large amounts of chromium in the urine. A liver
biopsy revealed microscopic changes. Examination of eight coworkers
revealed that four were excreting significant amounts of urinary
chromium. Liver biopsies and hepatic function tests of three workers who
had been exposed to chromic acid mists for 1-4 years revealed mild to
moderate abnormalities.
Inhalation, animal. In addition to respiratory tract effects
(Sect. 4.3.2.1 on respiratory tract effects in animals after inhalation
exposure), atrophy of the liver was observed in mice exposed to calcium
chromate dust at 13 mg/m3 CaCrO^ 5 h/day, 5 days/week for 6 months to
life (Nettesheim et al. 1971).
Oral, human. Reviews of effects following acute oral exposure to
chromium(VI) compounds (Langard and Norseth 1986, Hathaway 1986) report
that liver effects have been observed in persons dying from the
ingestion of chromate(VI) compounds.
Oral, animal. Hepatic changes have not been reported in animals
following oral exposure to chromium compounds.
Dermal. Hepatic changes have not been reported in humans or
animals following dermal exposure to chromium compounds.
General discussion. In addition to reports of liver effects in
humans following fatal oral exposure to chromium(VI) compounds, limited
data indicate that inhalation exposure to chromium compounds can result
in hepatic effects in humans and animals. Hepatic effects have also been
observed in animals following parenteral exposure. Hepatic changes were
observed in rabbits exposed daily to chromium at 2 mg/kg as chromic(III)
nitrate or potassium dichromate(VI) via intraperitoneal injection for
3-6 weeks (Tandon et al. 1978). The effects observed included congestion
and dilation of the central veins and sinusoids, discrete foci of
necrosis and hemorrhage in liver parenchyma, nuclear pleomorphism,
multinucleated cells in the lobules, and bile duct proliferation. In a
study by Laborda et al. (1986), rats treated intraperitoneally with
chromic(III) chloride or sodium chromate(VI) at 2 mg/kg chromium 3 times
per week for up to 60 days developed liver damage. Chromium(VI) caused
more damage than did chromium(III).
Srivastava et al. (1985) found a decrease in the activity of
hepatic aniline hydroxylase following treatment of rats with
chromic(III) nitrate or potassium chromate(VI) by intraperitoneal
injection at 4 mg/kg/day chromium for up to 14 days. A decrease in
hepatic glutathione S-transferase activity was also seen; the decrease
occurred sooner and was more pronounced with chromium(VI) than with
chromium(III) treatment.
4.3.2.7 General tozicity not discussed in other sections
Overview. A number of animal studies of the toxicity of chromium
compounds have not identified any adverse effects. These studies are
-------
Toxicological Data 67
presented below. A human oral study In which gastrointestinal irritation
was observed following chromium(VI) intake is also presented.
Inhalation, human. No additional human inhalation data are
available.
Inhalation, animal. Akatsuka and Fairhall (1934) exposed two cats
to chromic oxydicarbonate [Cr20(C03)2] at an average concentration of
58.3 mg/m^ chromium(III) for 86 sessions, resulting in an average of
28 min for one cat and 52 min for the second cat. No changes in gross
and microscopic pathology were noted.
Oral, human. In an experiment reported by McKee and Wolf (1963),
three periods of nausea were noted in a volunteer who drank a 10-ppm
solution of chromium(VI) as his only fluid for 15 days. A total of
235 mg chromium(VI) was ingested. The study was continued for 14 more
days at chromium(VI) concentrations of 2.5-5 ppm. Mild nausea occurred
when the subject drank a 5-ppm solution on an empty stomach; this did
not occur at 2.5-3.5 ppm.
Oral, animal. In a Japanese study (Maruyama 1982), groups of at
least 40 male ddY mice were provided with drinking water containing
CrCl3 [chromium(III)] or K2Cr20? [chromium (VI)] at 0, 25, 50, or 100
mg/L chromium for up to 1 year. Body weight and food and water intake
were measured weekly, and every month five mice were sacrificed. At
sacrifice, blood was collected for hematological examination, and the
concentrations of chromium, iron, copper, and zinc in the organs were
determined. The results showed no consistent changes in body weight.
Hematological examination indicated a decrease in hemoglobin and
hematocrit that was greater in chromium(III)- than in chromium(VI)-
treated mice. This effect did not show a dose-response relationship
Analysis of organs for iron revealed a decrease in iron in all organs,
especially the liver, spleen, and testes. Levels of copper and zinc in
organs were not affected.
In a study by Akatsuka and Fairhall (1934), 10 cats were provided
with chromic(III) oxydicarbonate [Cr20(C03)2] or chromic(III) phosphate
(CrP04) in the diet at doses of 50-1,000 mg per cat per day for 1 to
3 months. No effects on organ weights or macroscopic and microscopic
pathology of major organs were noted.
No effects were observed in groups of 9-12 male and female rats
provided with K2Cr04 in the drinking water at 0, 0.45, 2.2, 4.5, 7.7,
11, or 25 ppm chromium(VI) or CrCl3 at 0 or 25 ppm chromium(III) for
12 months (MacKenzie et al. 1958). The parameters examined included
clinical blood chemistry, body weight, and gross and microscopic
pathology.
Ivankovic and Preussmann (1975) fed groups of up to 60 rats
chromic(III) oxide (Cr203) in bread at 2 or 5%, 5 days/week for 90 days,
or at 1, 2, or 5%, 5 days/week for 2 years. At the 5% level in the
2-year study, the total dose of Cr203 consumed on 600 feeding days was
1,800 gAg body weight, according to the investigators. No changes in
survival or body weight and no histopathologic changes of major organs
were noted, and no effects on urinary protein, sugar, bilirubin, and
blood, or on blood sugar, serum protein, serum bilirubin, and hemoglobin
-------
68 Section 4
were observed. The only effect observed was a depression of spleen and
liver weight (statistical analyses were not reported) in rats fed for
90 days.
Chronic ora-1 studies of chromium(III) were conducted in mice
(Schroeder et al. 1964) and rats (Schroeder et al. 1965). In these
studies. 54 Swiss mice of each sex and at least 46 Long-Evans rats of
each sex were provided with drinking water containing chromium acetate
at 5 ppm chromium throughout their lifetime. The diets fed these animals
were low in metals, including chromium. No adverse effects on growth,
mortality, or tumor incidences occurred in either rats or mice exposed
to chromium(III).
Anwar et al. (1961) observed no effects in 5 groups of two dogs
provided with drinking water containing K2Cr04 at 0.45-11.2 ppm
chromium(VI) for 4 years. The parameters examined included urinalysis,
hematological values, organ weights, and gross and microscopic
appearance of major organs.
Dermal. No additional effects have been reported in animals or
humans following dermal exposure to chromium compounds.
General discussion. The report by McKee and Wolf (1963) indicates
that chromium(VI) solutions >5 ppm are irritating to the GI tract of
humans. Long-term oral studies of chromium compounds in animals have not
clearly defined effect levels. The highest NOAEL for chromium(III) was
1,468 mg/kg/day found in the Ivankovic and Preussmann (1975) study. The
dose level was calculated in EPA (1985d) from data provided by the
authors. The highest NOAEL for chromium(VI) was 2.4 mg/kg/day found in
the MacKenzie et al. (1958) study. The dose was calculated by EPA
(1984b) by multiplying the 25-ppm water concentration by the average rac
water consumption (0.035 L/day) and dividing by the average rat body
weight (0.35 kg).
4.3.3 Developmental Toxicity
There are no human or animal studies of developmental toxicity
following inhalation, oral, or dermal exposure to chromium.
A number of studies, reviewed by EPA (1984a), have shown that only
a small fraction (usually 31.5%) of a dose of chromium given to pregnant
rodents by gavage or parenteral routes is transported"to the fetus.
Mertz et al. (1969) found that exposure of pregnant rats to 51Cr as
chromium(III) acetate in drinking water at 2 mg/L did not result in
transfer of 51Cr to the litters.
Parenteral studies reviewed by EPA (1984a) indicate that exposure
to chromium(III) or chromium(VI) compounds may result in developmental
effects. In studies by Gale (1978) and Gale and Bunch (1979), increased
fetal death and an increase in external abnormalities were observed in
hamsters treated by intravenous injection with Cr03 [chromium(VI)] on a
single day of gestation. The effects occurred near levels that resulted
in maternal effects (depressed weight gain and kidney tubular necrosis)
Gale (1982) found that the teratogenic effects following injection with
Cr03 intravenously were strain dependent in hamsters. Matsumoto et al.
(1976) observed fetal weight depression and an increase in external
abnormalities in mice treated intraperitoneally with CrCl3 at
-------
Toxicological Data 69
14.64-24.4 mg/kg chromium(III) on gestation day 8. No effects were
observed at 9.76 mg/kg.
4.3.4 Reproductive Toxicity
4.3.4.1 Inhalation
There are no human or animal studies of reproductive toxicity
following inhalation exposure to chromium compounds.
4.3.4.2 Oral
Human. There are no human data indicating reproductive toxicity
following oral exposure to chromium compounds.
Animal. In an early feeding and drinking water study with rats and
mice. Gross and Heller (1946) reported that there were no effects in
rats on general condition or reproduction at 0.125%, "subnormal" young
at 0.25%. and sterility at 0.5 or 1.0% K2Cr04 in the diet. Sterility and
poor general condition were seen in rats at >0.125% ZnCr04 in the diet
No effects on general condition or reproduction were noted in mice
or rats provided with drinking water containing K2Cr04 at levels up to
500 ppm or mice fed diets containing 1% ZnCr04. Group sizes, duration of
treatment, and criteria for determining sterility were not stated.
No effects on reproduction were reported in nine pairs of rats fed
up to 5% Cr203 in a supplemented bread, 5 days/week for 60 days before
mating and throughout gestation (Ivankovic and Preussmann 1975). No
grossly observable malformations or adverse effects occurred in the
pups.
4.3.4.3 Dermal
No adequate data describing reproductive toxicity in humans or
animals following dermal exposure were found in the literature.
4.3.4.4 General discussion
Data concerning reproductive effects of chromium compounds
administered by natural routes of exposure are limited to the poorly
described study by Gross and Heller (1946), in which sterility was
noted, and the study by Ivankovic and Preussmann (1975), in which no
effects on reproduction were noted.
Additional studies by parenteral routes indicate that chromium(III)
and chromium(VI) compounds may affect reproduction. In a dominant lethal
study in mice, Paschin et al. (1982) found a significant decrease
(P < 0.05) in the survival of embryos from cells treated as early
spermatids and late spermatocytes from males given a single
intraperitoneal injection of potassium dichromate(VI) at 20 mg/kg or 21
daily injections at 2.0 mg/kg- Behari et al. (1978) observed testicular
effects in rabbits injected intraperitoneally with chromium(III) nitrate
or potassium dichromate(VI) at 2 mg/kg/day for 3 or 6 weeks. Exposure co
both compounds resulted in a decrease in testicular succinic
dehydrogenase and a decrease in adenosine triphosphatase activity, which
was more severe in chromium(III)-treated rabbits. Only chromium(III)
-------
70 Section 4
resulted in a depression of acid phosphatase. Microscopic examination oe
the testes showed thickening of the tunis albuginea, congestion of bio
vessels, and degenerative changes of the seminiferous epithelium in
chromium(III)-treated rats. Chromium(VI) treatment resulted in mild
edema of the interstitial tissue and congestion of the blood vessels,
and at 6 weeks the tubules were devoid of spermatocytes.
4.3.5 Genotoxicity
4.3.5.1 Human
Chromosome aberration and SCE tests of chromium(VI) compounds in
cultured mammalian cells, including human cells, consistently gave
positive results (Table 4.3). Negative results are observed with
chromium(III) except at high concentrations or in cells with phagocycic
activity.
Results of in vivo studies are not conclusive (Table 4.4). Bigaliev
et al. (1977) found an increase in chromosomal aberrations in peripheral
blood lymphocytes of workers exposed to soluble chromium(VI) compounds
(3.6 to 9.4% cells with aberrations, exposed, versus 1.9% in controls).
Studies of chromium-plating workers, exposed to airborne soluble
chromium(VI), have given mixed results. Sarto et al. (1982) found that
young workers at a hard chromium-plating plant had significantly
elevated numbers of chromosomal aberrations while the number was not
significantly elevated from control levels in older workers. A positive
association between urinary chromium levels and the number of
chromosomal aberrations was noted. No significant difference in the
incidence of SCE was noted in lymphocytes from 12 chromium-plating
workers and 10 controls (Stella et al. 1982). A significant increase was
noted in the 7 youngest workers. Results in control subjects indicated
an age-associated increase in SCE, while the level in the exposed
population appeared constant. Nagaya (1986) examined the frequency of
SCE in lymphocytes of 24 chromium platers and 24 office workers matched
in terms of sex, age, and smoking habits. The chromium platers had
worked for an average of 11.6 ± 7.5 years. The results indicated no
significant differences in SCE frequencies between the two groups.
Urinary chromium levels of chromium platers averaged 13.1 ftg/L; chromium
was not detected in the urine of controls. A correlation between urinary
chromium concentrations and SCE frequency in chromium'platers was not
observed.
4.3.5.2 Nonhuman
Studies of the in vitro genotoxicity of chromium compounds are
presented in Table 4.3. As reviewed by Bianchi and Levis (1985), tests
of chromium(VI) for gene mutation, chromosome aberrations, and cell
transformation have been consistently positive for all cell types.
Results in whole cells are consistently negative for chromium(III)
compounds except at very high concentrations or in cells with phagocycic
activity. Chromium(III) has also been shown to interact with isolated
nuclei and purified DNA. Bianchi and Levi (1985) noted that several
studies that found positive mutagenicity results for industrial
chromium(III) compounds have demonstrated that the effect was due to
contamination by chromium(VI).
-------
Table 4.3. Ccnoloxlcily of chromium compounds in vitro
End point
Reverse mutation
Valence slate
of chromium
VI
Species
(lest system)
Escherichia coll.
Result
with/withoul activation Re
Forward mutation
Point mutation
Chromosomal aberrations
Sister chromalid exchange
Cell transformation
Salmonella lyphimurium
III £ coli. S lyphimurium
VI Schizosaccharomyces pombe.
Saccharomyces cerevisiae
VI Hamster cells
III Hamster cells
VI Mammalian cell lines
III Mammalian cell lines
VI Mammalian cell lines
III Mammalian cell lines
VI Mammalian cell lines
III Mammalian cell lines
-/-, except when chromium(lll) is
complexed with organic ligands able to
enter the cells or when premcubated
at a slightly alkaline pH
Not tested/ +
+ . presence of metabolic activation not
slated
-.presence of metabolic activation not
staled
+ , presence of metabolic activation not
staled
t. presence of metabolic activation not
staled, -t- results at concentrations
2-3 orders of magnitude higher than
active chromium(VI) concentrations
+ , presence of metabolic activation not
staled
-, except + in cells with phagocytic
activity, presence of metabolic activa-
tion not staled
+. presence of metabolic activation not
stated
-, except I- in cells with phagocylic
activity, presence of metabolic activa-
tion not stated
References
Many studies reviewed in
Bianchi and Lcvis 1985,
EPA I984a
Many studies reviewed in
Bianchi and Lcvis 1985.
EPA I984a
Bonali el al 1976.
Singh I98J
Studies reviewed in
Bianchi and Levis 1985
Studies reviewed in
Bianchi and Lcvis 1985
Many studies reviewed in
Bianchi and Levis 1985
Many studies reviewed in
Bianchi and Levis 1985
Many studies reviewed in
Bianchi and Levis 1985
Many studies reviewed in
Bianchi and Levis 1985
Many studies reviewed in
Bianchi and Levis 1985
Many studies reviewed in
Bianchi and Levis 1985
o1
X
t-.
n
o
K-
O
to
rt
D>
-------
72
Section 4
TaMe 4.4. Gcnotoxkity of chromium compounds in wo
Valence state Species
End point of chromium (test system)
Somatic mutations
Gene mutation — spot test
Dominant lethal
Chromosomal aberrations
Micronucleus test
Cell transformation
in embryo
Chromosomal aberrations
Sister chromatid exchange
VI
VI
VI
VI
VI
III
VI
VI
VI
Drosophila melanogasier
Mouse dp)
Mouse (ip)
Rat (ip)
Mouse (ip)
Mouse dp)
Hamster, assay of embryo
after intrapentoneal
administration to dam
Human
Human
Result References
-t- Rasmuson 1985
+ Knudsen 1980
+ Paschm et al 1982
+ Newton and Lilly 1986.
Bigahev et al. 1978
+ Wild 1978
Wild 1978
+ DiPaolo and Casto 1979
+ Bigaliev et al 1977.
Sartoet al. 1982
Stella etal 1982.
Nagaya et al 1986
-------
ToxicoLogical Data 73
Studies of in vivo genotoxicity of chromium compounds are presented
in Table 4.4. Chromium(VI) has tested consistently positive in
Drosophila melanogaster and in a mammalian spot test, dominant lethal
assay, micronucleus test, and transplacental cell transformation study
Chromium(III) tested negative in a micronucleus test and has not been
examined in any other studies.
4.3.5.3 General discussion
Results of mutagenicity studies have consistently shown positive
results for chromium(VI) compounds and negative results for
chromium(III) in standard tests. These results support the
carcinogenicity findings in animal studies. Chromium(III) has tested
positive in only isolated nuclei and purified DNA, in studies at high
concentrations, and in cells with phagocytic activity. The difference in
activity of the two valence states of chromium is a result of
differences in ability to permeate cell membranes. Beyersmann et al.
(1985) found that human RBC, Chinese hamster ovary (CHO) cells, and S.
typhimirLum rapidly took up chromates [chromium(VI)] while chromium(III)
was not taken up.
According to Beyersman et al. (1985), possible mechanisms of
genotoxicity of chromium(VI) are direct oxidation of DNA bases by
chromium(VI); reaction of chromium intermediate oxidation states with
DNA; indirect genotoxicity via reactive metabolites (e.g., hydroxyl
radical); interaction of intracellularly produced chromium(III) with DNA
or DNA replicating enzymes; or reaction of intracellular chromium(III)
complexes with DNA. Jennette (1982) reported evidence of a relatively
stable reactive intermediate, chromium(V), formed from chromium(VI) by
rat liver microsomes in the presence of NADPH. Jennette (1982), Norseth
(1986), and Anderson (1981) suggest that chromium(V) may be the reactive
intermediate that reacts with DNA to produce genotoxic or carcinogenic
effect. Alternatively, a recent study by Kawanishi et al. (1986)
provides support for the production of hydroxyl radicals as a mechanism
of chromium(VI) genotoxicity. Their study indicates that sodium chromate
reacts with hydrogen peroxide to form tetraperoxochromate, which leads
to the production of hydroxyl radicals. Hydroxyl radicals cause base
alterations and deoxyribosephosphate backbone breakage.
4.3.6 Carcinogenicity
4.3.6.1 Inhalation
Human. Occupational exposure to chromium compounds has long been
associated with respiratory cancer. Baetjer (1950) reviewed 122 cases of
respiratory cancer that occurred between 1890 and 1950 in chromium
compound-related industry workers. The cases were predominantly in the
United States and Germany. The workers were exposed to chromite(III)
ore, sodium chromate(VI), sodium bichromate(VI), chromic(VI) acid,
calcium chromate(VI), and the "liming process."
Numerous epidemiological studies concerning the relationship
between respiratory cancer and occupational exposure to chromium have
been reviewed by IARC (1980, 1982, 1987b) and EPA (1984a, 1986c). An
association between occupational chromium exposure and respiratory
-------
74 Section U
cancer has been established for chromate production workers in studies
such as those by Alderson et al. (1981), Hayes et al. (1979), Machle ar
Gregorius (1948), Mancuso and Heuper (1951), Mancuso (1975), Ohsaki et
al. (1978), and Taylor (1966), and is suggested for chrome pigment
workers in studies such as those by Langard and Norseth (1975) and
Davies (1984). Two studies of chrome platers (Franchini et al. 1983.
Sorahan et al. 1987) reported an association of chromium exposure with
lung cancer, but results of other studies of chrome platers (Royle 1975,
Silverstein et al. 1981) were inconclusive, as were results of studies
of ferrochromium workers (e.g., Langard et al. 1980).
The key epidemiological study that has been used for quantitative
risk assessment is the study by Mancuso (1975). The Mancuso (1975) study
is a follow-up study of chromate production workers examined in Mancuso
and Hueper (1951). Mancuso and Hueper (1951) investigated lung cancer
associated with chromate production using vital statistics for employees
who worked for >1 year at the Painesville, Ohio, chromate plane during
1931-1949. The percentage of deaths due to lung cancer among chromate
workers (18.2%) was significantly different (P < 0.01) from deaths due
to lung cancer among the males in the county where the plant was located
(1.2%). The workers were exposed to insoluble [primarily chromium(III)]
and soluble [primarily chromium(VI)] compounds. Analysis of lung tissue
from a chromate worker who had died of lung cancer and one who had died
of bladder cancer revealed chromium levels in the lung of 390 and 250 pg
per 10 g tissue, respectively. The individual who died of lung cancer
had not been exposed to chromium for 3.4 years. In contrast, chromium
levels in the lung were reported to be between 0 and 3 Mg per 10 g of
tissue in nonexposed individuals.
In Mancuso (1975), the vital status of 322 Painesville chromate
workers who had worked at least 1 year between 1931 and 1937 was studied
until 1974. The workers studied were divided into three groups, those
first employed during 1931-1932, 1933-1934, and 1935-37. The percentage
of cancer deaths due to lung cancer in the three groups were 63.6%,
62.5%, and 58.3%, respectively. The latency period clustered around
27-36 years. Using data from an industrial hygiene survey of the plant
conducted in 1949 (Bourne and Yee 1950), Mancuso (1975) found that lung
cancer mortality was dose-related to total chromium exposure. These data
are shown in Table 4.5. This study did not discriminate between
chromium(VI) and chromium(III) as the carcinogenic species.
Animal. Studies by Baetjer et al. (1959) and Steffee and Baetjer
(1965) did not result in significant carcinogenic effects in mice, rats,
rabbits, or guinea pigs exposed to chromium dust containing 13.7% Cr03
(VI). 6.9% Cr203, and 1% K2Cr207 at -1-1.5 mg/m3 chromium for 4 h/day,
5 days/week for long-term exposures.
Nettesheim et al. (1971) exposed 136 C57BL/6 mice of each sex
5 h/day, 5 days/week throughout their lifetime to an atmosphere
containing calcium chromate(VI) at 13 mg/m3 (95% of particles <0.6 \a&) .
At 6, 12, and 18 months, 7 or 8 mice were removed for interim sacrifice;
the sex distribution and number removed at each period were not stated
Lung tumors developed in 6 male and 8 females, compared to 3 male and 2
females in the control group. The tumors were described as alveologenic
adenomas and adenocarcinomas; the numbers of each tumor type were not
-------
ToxLeo logical Data 75
Table 4.5. Age-specific lung cancer deaths and gradient exposures
to total chromium
Deaths
Person-years
Deaths
Person-years
Deaths
Person-years
<1.00
1
886
1
707
1
235
Exposure to total chromium
1.0-199 2.0-3.99 40-5.99
Age 45-54
224
459 583 348
Age 55-64
3 1 4
356 462 250
Age 65-74
1 2 1
166 182 80
(mg/m3/year)
60-6.99
3
159
2
113
1
42
7.0-7 99
3
140
3
98
0
41
8 + fl
0
262
1
203
3
81
"Data in the last column are not used in the CAG's 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.
Source: Mancuso 1975.
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76 Section 4
pr-.vided. The authors stated that calcium chrornate exposure resulted in
a significant increase in lung tumors, but statistical analysis was no
reported. IARC (1980) reviewed the study and stated that no excess in
treatment-related tumors was observed. Because it is not clear how many
mice were killed at interim sacrifices, it is impossible to perform
independent statistical analysis of the data.
Glaser et al. (1986) exposed groups of 20 male Wistar rats to
submicron-sized aerosols of sodium dichromate(VI) at 25, 50, or
100 /fg/m^ chromium or to a pyrolyzed chromium oxide mixture [(Cr50l2,
3:2 chromium(VI)/chromium(III)] at 100 Mg/m3 chromium, 22-23 h/day,
7 days/week for 18 months, followed by a 12-month observation period. A
group of 40 rats were maintained as controls. No lung tumors were
observed in rats exposed at chromium levels <50 jag/m-* chromium (37 rats
in the control group and 18 rats in each of the treatment groups
survived 2 years). At 100 /ig/m3 chromium, two adenomas and one
adenocarcinoma of the lung and a malignant tumor of the pharynx were
observed in 19 sodium dichromate-exposed rats, and one primary adenoma
of the lung was observed in 18 chromium oxide-exposed rats surviving at
least 2 years. Without conducting statistical analysis of the data, the
authors concluded that the results indicate a weak carcinogenicity at
100 A»g/n3 chromium, but that the results need to be confirmed with
larger animal populations (see Sect. 4.3.6.4, General discussion, for
intratracheal injection and implantation studies resulting in lung
cancer).
4.3.6.2 Oral
Human. No data describing carcinogenic effects in humans followir
oral exposure to chromium were found in the literature.
Animal. Chronic oral studies of chromium(III) compounds have not
resulted in increased tumor incidences in rats or mice (Schroeder et al
1964, Schroeder et al. 1965, Ivankovic and Preussmann 1975). These
studies were not conducted at maximum tolerated doses.
In a study by Borneff et al. (1968), a nonsignificant increase in
stomach tumors was observed in NMRI mice provided with drinking water
(3% Tenside solution) containing potassium chrornate (chromium(VI)] at
500 ppm for up to 880 days, compared to vehicle treated controls. At
500 ppm potassium chromate, drinking water intake was^ reduced compared
to controls. Potassium chromate treatment (500 ppm) did not increase the
incidence of stomach tumors induced by 3,4-benzpyrene in the drinking
water (10 pg/mL). A conclusion about the carcinogenic potential of
potassium chromate cannot be made from this study, which is limited by
the use of only one concentration. The results of the study were also
confounded by an ectromelia epidemic, which began during the eighth
month of the study, resulting in the deaths of 512 of 971 mice. The
epidemic was ended through the use of vaccinations, which were
administered during the ninth month of the study.
Additional oral studies of chromium(VI) compounds are not of
adequate duration for evaluation of carcinogenic potential.
-------
Toxicological Data 77
4.3.6.3 Dermal
No studies concerning the carcinogenicity of chromium compounds in
humans or animals following dermal exposure were available.
4.3.6.4 General discussion
Epidemiological studies reviewed in IARC (1980, 1982, 1987b) and
EPA (1984a, 1986c) clearly indicate an increased respiratory cancer risk
in chromate production workers. Increased risks of respiratory cancer
have also been found in some studies of chrome pigment workers, chrome-
plating workers, and ferrochromium workers, but these studies were
considered to be flawed by inadequate reporting or small study
populations. The epidemiology studies do not clearly implicate specific
compounds, but do implicate chromium(VI). Based on the epidemiological
evidence, the EPA (1986c) and IARC (1987b) have concluded that exposure
to chromium(VI) compounds is carcinogenic for humans. The potential
contributions of chromium(III) and chromium(O) to carcinogenesis during
occupational exposure cannot be evaluated on the basis of the available
data.
Animal studies tend to implicate chromium(VI) compounds as
carcinogens, although the data available are more limited for
chromium(III) than for chromium(VI) compounds. By inhalation, calcium
chromate and sodium dichromate may be weak carcinogens; chromium(III)
compounds have not been tested by inhalation. IARC (1980) concluded that
"calcium chromate(VI) is carcinogenic in rats when given by several
routes, producing tumors at the sites of administration." This
conclusion was based on 10 rat studies using intramuscular implantation,
subcutaneous injection, and bronchial and intrapleural implantation
routes of exposure, but did not include the Steinhoff et al. (1986a,b)
study or those performed by Levy and Martin (1983) or Levy et al.
(1986).
In a study by Steinhoff et al. (1986a,b), groups of 40 male and
40 female Sprague-Dawley rats were treated by intratracheal instillation
with sodium dichromate (chromium(VI)] at doses of 0.05, 0.25, or
1.25 mg/kg once per week or at doses of 0.01, 0.05, or 0.25 mgAg five
times per week for 30 months. Similar groups of rats were treated with
calcium chromate (chromium(VI)] at 0.25 mg/kg five times per week or at
1.25 mgAg once per week. Control rats were left untreated or were
treated with a 0.9% NaCl solution at 1 mLAg once or five times per
week. No lung tumors were observed in control rats or in rats treated
with sodium dichromate five times per week at 0.01, 0.05, or 0.25 mgAg,
or once per week at 0.05 mgAg. Only 1/80 (1%) rats treated with sodium
dichromate at 0.25 mgAg once per week developed lung tumors
(malignant), while 14/80 (17.5%) rats treated at 1.25 mgAg once per
week had lung tumors (8 malignant. 12 benign). In rats treated with
calcium chromate, 6/80 rats treated at 0.25 mgAg five times per week
(7.5%) developed lung tumors (1 malignant, 5 benign), while 13/80 (16%)
treated once per week at 1.25 mgAg developed lung tumors (3 malignant,
11 benign). Steinhoff et al. (1986a) stated that this study provides
evidence that sodium dichromate is a weak carcinogen because the tumors
appeared only after a toxic dose (see Sect. 4.3.2.1, Respiratory tract
effects, for noncarcinogenic effects), the tumors were small and did not
-------
78 Section 4
contribute to the deaths of the animals, the tumors appeared near the
end of the study, and 50% of rats with tumors had benign tumors.
Although treatment of rats with calcium chromate (Steinhoff et al.
1986b) was not as extensive, similar effects were noted, providing
evidence that calcium chromate may also be a weak carcinogen.
Laskin et al. (1970) studied the carcinogenic effects of chromium
compounds [chromic chromate, chromic(III) oxide, chromic(VI) trioxide,
calcium chromate(VI), and process residue] by implanting cholesterol
pellets containing the compounds in bronchia of rats. After
implantation, the rats were observed for up to 136 weeks. The only
compound resulting in a significant carcinogenic effect was calcium
chromate; six squamous cell carcinomas and two adenocarcinomas developed
in 100 rats, and no tumors developed in 24 controls.
Levy and associates (Levy and Martin 1983, Levy et al. 1986, Levy
and Venitt 1975) conducted an extensive investigation of the
carcinogenicity of -20 chromium(VI)-containing materials intra-
bronchially implanted in rats. In the more recent and comprehensive
studies (Levy and Martin 1983, Levy et al. 1986), a 0.5-g cholesterol
pellet containing -0.25 g of test compound was surgically implanted into
the lower left bronchus of 8-week-old rats. The rats were maintained for
2 years. The results, shown in Table 4.6, indicate that bronchial
carcinomas were statistically significant in comparison with controls in
the groups given strontium chromate. zinc chromate, and calcium
chromate. [Similar results were obtained in the earlier study by Levy
and Venitt (1975).] The investigators concluded that the carcinogenicir
of chromium(VI) compounds was dependent on their solubility, with only
sparingly soluble compounds found to be carcinogenic. Insoluble and
highly soluble chromium(VI) compounds were not carcinogenic in these
studies. Because highly soluble chromium compounds may readily leach
from cholesterol pellets, surgical implantation of pellets containing
soluble chromium compounds may not be an appropriate design to study the
carcinogenicity of these compounds. In contrast to the implantation
study, the studies of Glaser et al. (1986) and Steinhoff et al.
(1986a,b) (reported previously in this profile) provide some evidence
that the highly soluble sodium dichromate may be carcinogenic.
Many studies concerning the carcinogenicity of chromium compounds
are injection studies at sites other than the lungs. These studies are
reviewed in IARC (1980) and EPA (1984a), and several will be presented
briefly.
In studies using intrapleural injection in rodents, no positive
results were observed for metallic chromium powder or for chromium(III)
compounds (EPA 1984c). Positive results were noted for intrapleural
injection of calcium chromate(VI) (Hueper and Payne 1962), but small
numbers of rats were used, so the study does not provide conclusive
evidence of carcinogenicity.
Metallic chromium powder tested negative when injected into the
marrow of the femur of rats, rabbits, and dogs (Hueper 1955). Roe and
Carter (1969) reported injection site tumors in rats injected with
calcium chromate. Injection site tumors were found in rats given an
intramuscular injection of particles of a cobalt-chromium alloy (65%
cobalt, 27% chromium) obtained from prostheses (Heath et al. 1971). The
-------
Table 4.6. Incidence of lung lumora in rate following intrabronchkl ImpluUlloa
of various chromium compounds
Group
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
IS
16
Test material
Lead chromatc
Primrose chrome
yellow
Strontium
chromate
Barium chromate
Molybdate
chromate orange
Zinc chromatc
(low sol )
Zinc
tetroxychromate
Cholesterol
(negative
control)
Light chrome
yellow
LD chrome
yellow
Calcium chromale
(positive control)
Chromic acid
Medium chrome
yellow
Zinc chromate
(Norge)
Sodium
dichromaie
High lime
residue
Number of
rats"
100
100
100
101
100
100
100
100
100
100
100
100
100
100
100
100
Number of lungs
examined
98
100
99
101
100
100
100
100
100
100
100
100
100
100
99
99
Number of bronchial
carcinomas
1
1
43
0
0
5
1
0
0
1
25
2
1
3
1
1
Probability
02-0 IS
02-0 15
<0 00005
0015-0010
02-015
02-015
<0.00005
008 007
02-015
005-004
015-010
015-010
Significance
NS
NS
S
S
NS
NS
S
NS
NS
S
NS
NS
Valence of
chromium
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6 f 3
I
n
o
to
it
ft)
\0
-------
oo
O
Table 4.6 (condoned)
Group
No.
17
18
19
20
21
22
23
Number of Number of lungs
Test material rats' examined
Vanadium 100 100
solids
High silica 101 99
chrome ore
Kiln frit 100 100
(2% limestone)
Recycled residue 100 100
(2% limestone)
Silica encaps 100 100
medium chrome
yellow
Strontium 100 99
chromate
20-Mclhyl- 48 48
cholanthrcne
(positive control)
Number of bronchial Valence of
carcinomas Probability Significance* chromium
1 02-015 NS 6
0 3
2 008-007 NS 6 + 3
0 6+3
0 6
62 <0 00005 S 6
22 <0 00005 S 6
"For groups 1-22. 52 females and 48 males were used For group 23, 24 females and 24 males were used
*NS - Not statistically significant. S - statistically significant at the 5% level
Source Levy and Martin 1983. Levy el al 1986, EPA I984a
C/J
n>
n
a
-------
Toxicological Data 81
contribution of the individual metals to the observed effect is not
known. Intramuscular implantation studies have resulted in positive
results with hexavalent compounds [lead chromate, calcium chromate
(Furst et al. 1976)) and negative results with trivalent compounds and
metallic chromium powder [chromic acetate (Hueper and Payne 1962);
metallic chromium (Sunderman et al. 1974, 1980)].
NTP (1985) states that "if any chromium compounds are carcinogenic,
then all compounds containing chromium are potentially carcinogenic
This also applies to the elemental metal, given the property of most
tissues of being able to solubilize most metals to some degree."
After reviewing the available data, Norseth (1986) stated that the
genotoxic action of chromium(VI) in cells and animals may be dependent
on the reduction of chromium(VI) inside the cell to generate highly
reactive chromium species that form complexes with DNA. The highly
reactive intermediate is probably pentavalent chromium. Norseth (1986)
believes that all chromium compounds [soluble, slightly soluble, and
so-called insoluble chromium(VI) compounds; particles of slightly
soluble chromium(VI) and soluble chromium(III); and soluble
chromium(III) bound to ligands] should be regarded as having a
carcinogenic effect, with the differences in activity related to their
biological availability.
Petrilli ard DeFlora (1987)-disagree with Norseth (1986). They
suggest that because some forms of chromium compounds are essential and
because there are mechanisms that limit the bioavailability and
attenuate the potential effects of chromium compounds in vivo, "chromium
should not be regarded as 'universal' carcinogen." Levy et al. (1987)
also disagree with Norseth (1986). They believe that there is sufficient
experimental evidence to suggest that chromium(III) compounds are not
carcinogenic and good evidence to indicate that a limited number of
chromium(VI) compounds (sparingly soluble) "represent a real
carcinogenic risk to man."
4.4 INTERACTIONS WITH OTHER CHEMICALS
doggett (1986) found that treatment of rats with potassium
dichromate [chromium(VI)] by subcutaneous injection potentiated the
effects of the nephrotoxins mercuric chloride, citrinin, and
hexachloro-1,3-butadiene. Effects on renal function included changes in
urine volume, osmolality, electrolyte and glucose excretion, and a
reduction in renal cortical slice organic ion [p-amino(14C)hippurate
(PAH) and (^C)tetraethyl ammonium (TEA)] transport. Treatment of rats
with chromium(III) nitrate and mercuric chloride potentiated the effect
on TEA but not PAH uptake. Additional parameters were not examined in
chromium(III) nitrate and mercuric chloride treated rats.
Bianchi and Levis (198S) reviewed a number of studies that indicate
that chromium(VI) can interact with other genotoxic agents. A positive
synergism has been observed between chromium(VI) and oncogenic viruses,
zinc, and benz[a]pyrene in inducing cell transformation. A decrease in
activity is observed with agents that reduce chromium(VI) to
chromium(III).
-------
83
5. MANUFACTURE, IMPORT, USE, AND DISPOSAL
5.1 OVERVIEW
Apparent consumption of chromium and chromium-containing materials
in the United States in 1987 was 56,400 short tons of chromite ore and
concentrate and 376,400 short tons of metals and alloys. Chromite ore
has not been mined in the United States for domestic consumption since
1961. In 1985, the United States was completely dependent on importation
for primary chromium supply; however, about 25% of the apparent
consumption was supplied by secondary production. From 1981 to 1984, the
primary United States import sources for chromium contained in chromite
ore and ferrochromium were the Republic of South Africa (about 56%),
Zimbabwe (about 11%), Yugoslavia (about 6%), Turkey (about 5%), and
others (about 22%). Chromate and dichromates are the highest volume
chromium compounds produced in the United States. Most other chromium
compounds are produced from these two chemicals. Of the total reported
chromite ore consumed in the United States in 1985, 48.7% was used in
the metallurgical industry, 11.6% was used in the refractory industry,
and 39.7% was used for the chemical industry. On a gross weight basis,
metallurgical industry consumption was mainly for making steel and other
alloys; refractory industry for bricks and coating; and chemical
industry for pigments, metal finishing, leather tanning, and wood
treatment.
5.2 PRODUCTION
Ferrochromium, chromium metal and its compounds, and chromium
refractories are commercially produced in the United States.
Ferrochromium is produced by reducing chromite ore in an electronic arc
furnace with carbon to make high-carbon ferrochromium, or with silicon
to make low-carbon ferrochromium. The metal is produced by
aluminothermic reduction of chromium(III) oxide or by the
electrodeposition of chromium from dissolved ferrochromium. Sodium
chromates and dichromates are produced by roasting chromite ore with
soda ash and lime. Most other chromium compounds are produced from
sodium chromate and dichromates (EPA 1984a, Westbrook 1979).
In 1985, the combined production of chromium ferroalloys and
chromium metal in the United States was 109,563 short tons. The U.S.
annual production capacities for chromium(VI) oxide (chromic acid) and
sodium dichromate as of January 1986 were 47.4 and 165.3 thousand short
tons, respectively (SRI 1986, U.S.D.I. 1986). The following U.S.
companies were the major metallurgical, refractory, and chemical
industry consumers of chromium in 1985 (U.S.D.I. 1986, Blanchard 1987).
-------
84 Section 5
Metallurgical:
Elkem Metals Co., Marietta, Ohio, and Alloy, West Virginia
Macalloy Inc., Charleston, South Carolina
Shieldalloy Corp. , Newfield, New Jersey
SKW Alloys Inc.. Calvert City, Kentucky, and Niagara Falls, New York
Refractory:
Basic Inc., Maple Grove, Ohio
Corhart Refractories Inc., Pascagoula, Mississippi
Davis Refractories Inc., Jackson, Ohio
General Refractories Co., Lehi, Utah
Dresser Industries Inc., Hammond, Indiana, and Baltimore, Maryland
Kaiser Aluminum and Mineral Corp., Plymouth Meeting, Pennsylvania
National Refractories and Mineral Corp., Moss Landing, California, and
Columbiana, Ohio
North American Refractories Co. Ltd., Uomelsdorf, Pennsylvania
Chemicals:
American Chrome and Chemical Inc., Corpus Christi, Texas
Occidental Chemical Corp., Castle Hayne. North Carolina
5.3 IMPORT
Chromite ore has not been mined in the United States for domestic
consumption since 1961. In 1985, the United States was completely
dependent on importation for primary chromium supply; however, about
of apparent consumption was supplied by secondary production. From 19b.
to 1984, the primary United States import sources for chromium contained
in chromite ore and ferrochromium were the Republic of South Africa
(about 56%), Zimbabwe (about 11%), Yugoslavia (about 6%), Turkey (about
5%). and others (about 22%) (U.S.D.I. 1986, 1988; EPA 1984a).
According to the U.S. Department of the Interior (U.S.D.I. 1986),
the following amounts of chromium materials (short tons) were imported
into the United States in 1985: gross weight of chromite ore, 414,000;
metal and alloys, 339,000; chemicals, 16,500; and pigments, 8,300.
5.4 USE
The three basic industries that use chromium are metallurgical,
refractory, and chemical. In the metallurgical industry, chromium is
used in making stainless steels, alloy cast irons, nonferrous alloys,
and other miscellaneous materials. Of the total chromite ore consumed in
the United States in 1985, 48.7% was used in the metallurgical industry
In the refractory industry, chromium is used in chrome and chrome-
magnesite, magnesite-chrome brick, granular chrome-bearing and granular
chromite. In 1985, 11.6% of total consumed chromite was used by the
refractory industry. In the chemical industry, chromium is used
primarily in pigments 'both chromium(VI) and mixed metal, Cr(III) and
Cr(VI), oxides], metal finishing (chromium(VI)], leather tanning
[chromium(III)], and wood treatment [chromium(VI)]. Smaller amounts are
used in drilling muds, water treatment, chemical manufacture, textile
catalysts, toners for copying machines, and magnetic tapes. Chromite
-------
Manufacture, Import, Use, and Disposal 85
consumption in the U.S. chemical industry in 1985 was 39.7% of the total
domestic consumption (Bond 1987, DCMA 1982, U.S.D.I. 1986, EPA 1984a
CMR 1985). A large fraction of chromium demand by metallurgical industry
is supplied by chromium ferroalloys. Metal joint prostheses with
chromium alloys are used widely in clinical orthopedics (Sunderman et
al. 1987).
5. 5 DISPOSAL
Information on the disposal of finished products and wastes
(produced during the manufacture of consumable items) containing
chromium is limited. About 20% of chromium demand in the United States
is supplied by recycled stainless steel scrap. Although much of the
chromium wastes from plating operations are also recovered, relatively
large amounts of chromium-containing wastewaters from plating,
finishing, and textile industries are discharged into surface'waters
Very little is known about the method of disposal of waste refractory
materials used as lining for metallurgical furnaces. Although the
process wastes from several chromium chemical industries are designated
ff ™Zo^SoWaSCSS (45 ^ 4617'4618. January 6, 1981, as amended in
46 FR 27476-27477, May 20, 1981) and hence their disposal is regulated
by EPA, very little is known about the disposal methods for the finished
products, such as chromium-containing pigments (Westbrook 1979, Fishbein
1981, U.S.D.I., 1988). A substantial amount of the total toner powders
containing both chromium(III) and chromium(VI), used in copying machines
is disposed of as ordinary trash (Bond 1987).
-------
87
6. ENVIRONMENTAL FATE
6.1 OVERVIEW
Chromium occurs naturally in the earth's crust. Continental dust is
the main source of natural chromium present in the environment; however
chromium is released to the environment in much larger amounts as a
result of human activities. Of the total atmospheric chromium emissions
in the United States, approximately 64.1% is due to chromium(III) from
coal and oil combustion and steel production, and 31.6% is due to
chromium(VI) from chemical manufacture, primary metal production, chrome
plating, and cooling towers. Wastewaters from electroplating, leather
tanning, and textile industries release relatively large amounts of
chromium in surface waters. Solid wastes produced during roasting and
leaching processes of chromate manufacture, when disposed of improperly
in landfill sites, can be sources of chromium emission. Copying machine
toner powder waste, when disposed of without containment, can be a
source of chromium emission. Chromium released to the environment from
combustion processes and metallurgical industries is probably present
mainly as Cr203. On the other hand, chromium released to the environment
from chromate manufacturing and user sites largely contains bioavailable
chromium(VI). Chromium is primarily removed from the atmosphere by
fallout and precipitation. The residence time of chromium in the
atmosphere is expected to be <10 days. The residence times of chromium
in water and soil may be several years.
6.2 RELEASES TO THE ENVIRONMENT
Chromium is released into the atmosphere mainly by stationary point
sources. Stationary point sources that release chromium in the
atmosphere are industrial, commercial, and residential fuel combustion
primarily the combustion of natural gas, oil, and coalv Other important
stationary point sources of chromium emission to the atmosphere are
metal industries. It has been estimated that -12,000 to 18,000 tons of
chromium was emitted in the atmosphere from U.S. sources in 1970 These
older estimates indicated that emission from the metal industry ranges
from 35 to 86% of the total and emission from fuel combustion ranges
from 11 to 65% of the total. More recent estimates (1976 and 1980) of
atmospheric chromium emission in the Los Angeles, California, and
Houston, Texas, areas indicated that emission from stationary fuel
combustion ranges from 46 to 47% of the total and emission from the
metal industry ranges from 26 to 45% of the total. The primary
stationary nonpoint source of chromium emission in the atmosphere is
fugitive emission from road dusts. Other potentially small sources of
atmospheric chromium emission are cement-producing plants (cement
contains chromium). the wearing of asbestos brake linings containing
chromium, incineration of municipal refuse and sewage sludge and
-------
88 Section 6
emission from chromium-based automotive catalytic converters. Emission-
from cooling towers that use chromate chemicals as rust inhibitors an
also sources of atmospheric chromium (Cass and McRae 1986, EPA 1984a,
Fishbein 1981). The estimated atmospheric chromium emission factors for
almost all sources are given in an EPA report (EPA 1984c). Given the
chromium consumption or production volumes for each of these sources, it
is possible to estimate the total atmospheric chromium emission from
these individual sources. A recent EPA report (EPA 1987) estimates that
-2,840 metric tons of total chromium is emitted per year in the
atmosphere in the United States. Table 6.1 shows the sources, estimates
of yearly emissions, and percentage of hexavalent chromium in the total
atmospheric chromium emissions in the United States as reported by EPA
(1987a). Another potential source of chromium emission is the very fine
powders used as toners in copying machines. The powders may be emitted
in offices during copying machine maintenance and servicing or during
disposal without containment both in offices and garbage dumps. It is
reported that toner powder may contain more than 0.1% total chromium and
about 0.003% chromium(VI). The reported average particle size of the
toner powders of 10 pm indicates that at least part of these particles
are respirable (Bond 1987).
Surface waters and groundwaters contaminated with wastewaters from
electroplating operations, leather tanning, and textile manufacturing or
through deposition of airborne chromium may also be nonpoint sources of
chromium exposure. Similarly, solid wastes resulting from the roasting
and leaching steps of chromate manufacture or from municipal
incineration, when disposed of improperly in landfill sites, may be
sources of nonpoint chromium exposure (EPA 1984a).
6 . 3 ENVIRONMENTAL FATE
Chromium is primarily removed from the atmosphere by fallout and
precipitation. Atmospheric chromium removed by physical processes
predominantly enters surface water or soil; however, prior to their
removal, chromium particles of aerodynamic diameter <20 urn may remain
airborne for long periods and may be transported long distances. Roughly
half of the total chromium in the ferrochrome smelter dust may be
bioavailable. About 40% of the bioavailable part may exist as
chromium(VI), mostly in the form of Cr207"2 or Cr04:2. About 75% of the
total chromiuni(VI) particles have diameters <10 urn. The remainder of
chromium particles are primarily present as insoluble Cr203 particles of
diameter >10 /im. There is no evidence in the literature to indicate that
chromium particles are transported from the troposphere to the
stratosphere. This is not surprising since, by analogy with the
residence time of atmospheric copper, the residence time of atmospheric
chromium is expected to be <10 days (Nriagu 1979, EPA 1984a, Pacyna and
Ottar 1985, Cox et al. 1985). In the atmosphere, chromium(VI) may be
reduced to chromium(III) at a significant rate by vanadium (V2+, V3+,
and V02+), Fe2+. HS03'. and As3* (EPA 1987a).
Because there are no known chromium compounds that can volatilize
from water, transport of chromium from water to the atmosphere is not
likely other than by transport by windblown sea sprays. Most of the
chromium(III) is eventually expected to precipitate in sediments. Sm.-
amounts of chromium(III) may remain in solution as soluble complexes.
-------
Environmental Face
89
Table 6.1. Sources and estimates of U.S. atmospheric chromium emissions
Source category
Combustion of coal and oil
Chromium chemical manufacturing
Chemical manufacturing cooling towers
Petroleum refining cooling towers
Speciality/steel production
Primary metal cooling towers
Chrome plating
Comfort cooling towers
Textile manufacturing cooling
towers
Refractory production
Ferrochromium production
Sewage sludge incineration
Tobacco cooling towers
Utility industry cooling towers
Chrome ore refining
Tire and rubber cooling towers
Glass manufacturing cooling
towers
Cement production
Municipal refuse incineration
NATIONWIDE TOTAL
Number of
sources
Many
2
2,039
475
18
224
4,000
38,000
SI
10
2
133
16
6
6
40
3
145
95
Estimated
chromium emissions
(metric tons/year)
1.723
18
43
32
103
8
700
7.2-206
0.1
24
16
13
0.2
1.0
4.8
0.2
0.0 1
3
2.5
2,700-2,900
Estimated
chromium(VI)
(%)
02
67
100
100
2.2
100
= 100
too
100
1 3
5.4
-------
90 Section 6
Chromium(VI) will predominantly be present in soluble form. These
soluble forms of chromium may be stable enough to undergo intramedia
transport; however, chromium(VI) will eventually be reduced to
chromium(III) by organic matters present in water. It has been estimated
that the residence time of chromium in lake water is in the range of 4 6
to 18 years. The oxidation of chromium(III) to chromium(VI) by solid
Mn02 in water remained unaffected by dissolved oxygen, and the process
was very slow in slightly acidic (pH 6) and basic solutions (pH 11)
because of the low solubility of the Cr(OH)3 that is formed at these pHs
(Eary and Rai 1987). Therefore, this oxidation process would not be
significant in most natural water where the pH range is usually between
6 and 9. Similar oxidation of chromium(III) to chromium(VI) in the
atmosphere is unlikely (EPA 1987a).
It was reported that only small amounts of chromium(III) in
leachates from some coal fly ash disposal sites having pH <6 would be
converted to chromium(VI) by reaction with solid Mn02 because of the
short residence time in soil. The converted chromium(VI) in the leachate
would encounter reducing conditions in the underlying soil where
chromium(VI) would be reduced to chromium(III) and possibly precipitate
as Cr(OH)2 (Eary and Rai 1987). The oxidation of chromium(III) to
chromium(VI) during chlorination of water was highest in the pH range
5.5 to 6.0. However, the process would occur rarely during chlorination
of drinking water because of low concentrations of chromium(III) in
these waters and the presence of naturally occurring organics that may
protect chromium(III) from oxidation, either by forming strong complexes
with chromium(III) or by acting as a reducing agent to free available
chlorine. In chromium(III)-contaminated wastewaters having pH ranges o
5 to 7, chlorination may readily convert chromium(III) to chromiura(VI)
in the absence of chromium(III) complexing and free chlorine reducing
agents (EPA 1988a). The bioconcentration factor for chromium(VI) in
rainbow trout (Salmo gairdneri) is -1. In bottom-feeder species, such as
the oyster (Crassostrea virginica), blue mussel (Mytilus edulis), and
soft shell clam (Mya arenaria). the BCF values for chromium(III) and
chromium(VT) may range from 86 to 192 (EPA 1980, 1984a; Schmidt and
Andren 1984; Fishbein 1981).
Chromium probably occurs as insoluble Cr203-nH20 in soil, since the
organic matter in soil is expected to convert soluble chromate
[chromium(VI] to insoluble Cr2<>3. Chromium in soil may be transported to
the atmosphere in the form of aerosol, while runoff and leaching may
transport chromium from soil to surface waters and groundwaters. Runoff
could remove both soluble and bulk precipitate with final deposition on
either a different land area or a water body. Flooding of soils and the
subsequent anaerobic decomposition of plant matters may increase
mobilization of chromium in soils due to formation of soluble complexes
The half-life of chromium in soils may be several years (EPA 1984a,
1985c).
-------
91
7. POTENTIAL FOR HUMAN EXPOSURE
7.1 OVERVIEW
The general population can be exposed to chromium by inhalation of
air and ingestion of drinking water and food. Chromium has been found in
at least 386 of 1,177 sites on the National Priorities List (View 1989)
The mean daily dietary intake of chromium from air, water, and food has
been estimated to be 0.3, 4.0, and 280 ng, respectively. A recent study
estimated a median value of 240 ^g as the daily dietary intake of
chromium from foods in Belgium; however, inhalation intake in
occupationally exposed people and cigarette smokers may far exceed the
inhalation intake in the general population.
7.2 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT
7.2.1 Air
The atmospheric chromium concentration in the United States is
typically <0.01 Mg/m3 in rural areas and 0.01-0.03 /ig/m3 in urban areas
(Fishbein 1984). The levels of total chromium in the ambient air in the
U.S. urban and nonurban areas during 1977-1980 are available from the
EPA's National Aerometric Data Bank maintained by the Agency's
Monitoring and Data Analysis Division at Research Triangle Park, North
Carolina (EPA 1984c). The arithmetic mean of chromium concentrations
ranged from 0.0052 to 0.1568 jig/m3 in all samples. The highest chromium
concentrations were observed in 1977 samples collected from Baltimore,
Maryland (2.487 pg/m3), and Steubenville, Ohio (0.684 Mg/m3), both sites
where chromates were manufactured. The atmospheric chromium levels in
samples from Castle Hayne, North Carolina, another site for chromate
manufacture, were not available in this data bank, and the maximum level
of chromium in 1977 samples from Corpus Christi, Texas, was 0.04 /ig/m3
The company that currently manufactures chromates in Corpus Christi was
not in operation there in 1977. The concentrations of atmospheric
chromium range from 0.0012 to 0.0026 Mg/m3 in the Norwegian arctic and
0.00006 to 0.00041 pg/m3 in the Canadian arctic (Barrie and Hoff 1985).
Saltzman et al. (1985) compared the levels of atmospheric chromium at 59
sites in U.S. cities during 1968-1971 with data from EPA's National
Aerometric Data Bank file for the period 1975-1983 and concluded that
atmospheric chromium levels may have declined in recent years.
7.2.2 Water
The concentration of chromium in the U.S. river waters usually
ranges between 1 and 30 j*g/L (EPA 1984a). The higher levels of chromium
can be related to source(s) of anthropogenic pollution. The chromium
levels in drinking water determined in earlier studies (1962-1967
survey) may be erroneous because of questionable sampling and analytical
-------
92 Section 7
methods. A more recent survey (1974-1975) that had a detection limit of
0.1 A»g/L and surveyed 3,834 U.S. tap waters probably provides better
estimates of chromium concentrations in U.S. drinking waters. The surv..
reported the concentrations of chromium to range from 0.4 to 8.0 ng/L
The reported chromium concentrations in this study may be a little
higher than the actual values because of inadequate flushing of tap
water before collection of samples (EPA 1984a). This indicates that the
concentration of chromium in household tap water may increase because of
plumbing materials. In a survey of drinking waters from 115 Canadian
municipalities (1976-1977), the concentration range of chromium was <2.0
to 4.1 ng/L. In ocean water, the mean chromium concentration is lower
than in river water, and its value is 0.3 /ig/L, with a range of 0.2 to
50 /*g/L (Carey 1982).
7.2.3 Soil
The level of chromium in soils varies greatly depending on the
composition of parent rock from which they are formed. Chromium
concentrations in soils are reported to range from 5 to 1,500 mg/kg
(Carey 1982). The mean concentration of chromium in Canadian soils was
43 mg/kg (Carey 1982). In a recent study with different kinds of soils
from 20 sites in Maryland, Pennsylvania, and Virginia, the chromium
concentration was reported to range from 4.9 to 71 mg/kg (Beyer and
Cromartie 1987).
7.2.4 Foodstuffs
The typical chromium levels in most fresh foods are extremely low
[vegetables (20-50 pgAg), fruits (20 jig/kg). and grains and cereals
(40 MgAg)l (Fishbein 1984). The chromium levels of a variety of foods
are given in Table 7.1. The chromium contents of acidic foods that come
in contact with stainless steel surfaces during harvesting, processing,
or preparation for market are sometimes higher because of better
leaching conditions. On the other hand, processing removes a large
percentage of chromium from foods; e.g., whole-grain bread contains
1-7 A»g/g chromium, but processed white bread contains only 0.14 /*g/g;
molasses contains 0.26 jig/g chromium, whereas refined sugar contains
0.02 /ig/g chromium (Anderson 1981, EPA 1984a).
7.2.5 Other Media
The chromium concentration in 261 samples of breast milk randomly
collected from 45 American women had a mean concentration of 0.30 ng/L
with a range of 0.06 to 1.56 ng/L (Casey and Hambidge 1984). The mean
concentration of chromium in human hair from randomly selected people in
the United States was 0.23 mg/kg (Takagi et al. 1986). The concentration
range of chromium in the particulate portion of melted snow collected
from two urban areas (Toronto and Montreal) of Canada was 100 to
3,500 mg/kg (Landsberger et al. 1983). In suspended materials and
sediments of water bodies, the level of chromium ranges from 1 to 500
mg/kg- The concentration of chromium in incinerated sewage sludge ash
may be as high as 5,280 mg/kg (EPA 1984a). Cigarettes have been reported
to contain 0.24-14.6 mg/kg of chromium, but no estimates of the amount
inhaled were available (Langard and Norseth 1986) . Cigarette tobacco
grown in the United States contains up to 6.3 mg/kg of chromium (IARC
-------
Potential for Human Exposure 93
Table 7.1. Chromium content in various U.S. foods
Sample
Fresh vegetables
Fresh vegetables
Fresh vegetables
Frozen vegetables
Canned vegetables
Fresh fruits
Fresh fruits
Fruits
Canned fruits
Chicken eggs
Dairy products
Chicken eggs"
Whole fish
Edible portion of fresh
finfish
Meat and fish
Meat and fish
Seafoods
Seafoods
Fish and shellfish*
Grains and cereals
Grains and cereals
Fruit juices
Mean concentration
(ppm)
0.14
0.03-0.05
0.14
0.23
0.23
0.09
0.19
0.02
0.51
006
0.10
0.16-0.52
0.05-0.08
<0.3-0.16
0.23
0.11
0.12
0.47
<0.3-1.2
0.04
0.22
0.09
References
EPA 1984a
EPA 1984a
EPA 1984a
EPA 1984a
EPA 1984a
EPA 1984a
EPA 1984a
EPA 1984a
EPA 1984a
Kirkpatrick and Coffin 1975
EPA I984a
Kirkpatrick and Coffin 1975
EPA 1984a
Eisenberg and Topping 1986
EPA 1984a
EPA 1984a
EPA 1984a
EPA 1984a
Greig and Jones. 1976
EPA 1984a
EPA 1984a
EPA 1984a
"These values reported by authors are from the results of other
investigators.
*The samples were collected from ocean dump sites of the middle
eastern United States.
-------
94 Section 7
1980). Cement-producing plants are a potential source of atmospheric
chromium. Portland cement contains 41.2 mg/kg chromium (range 27.5 to
60 mg/kg> of which 2.9 mg/kg (range 0.03 to 7.8 mgAg) is chromium(VI)
and 4.1 mg/kg (range. 1.6 to 8.8 mg/kg) is soluble chromium. The wearing
of vehicular brake linings containing asbestos represents another source
of atmospheric chromium, since asbestos can contain -1,500 mg/kg of
chromium. The introduction of catalytic converters on automobiles
produced since 1975 in the United States is an additional source of
atmospheric chromium. Catalysts such as copper chromite have been found
to emit <106 metal-containing condensation nuclei per cubic centimeter
in the exhaust emitted under different vehicular operating conditions
(Ftshbein 1981).
7.3 OCCUPATIONAL EXPOSURE
Occupational exposure to chromium occurs mainly from stainless
steel production and welding, chromate production, chrome plating,
ferrochrome alloys, chrome pigment, and tanning industries. For most
occupations, the exposure is due to both chromium(III) and chromium(VI)
states present as soluble and insoluble fractions. However, exceptions
are the tanning industry, where exposure is almost exclusively to
soluble chromium(lll); the plating industry, where it is due to soluble
chromium(VI); and the pigment industry handling lead chromate, where the
exposure is due to insoluble chromium(VI). The typical concentration
ranges (/*g/m3) of airborne chromium(VI) to which workers in these
industries were exposed during an average 5 to 20 years of employment
were: stainless steel welding, 50 to 400; chromate production, 100 to
500; chrome plating, 5 to 25; ferrochrome alloys, 10 to 140; and chrom
pigment, 60 to 600. In the tanning industry, except for two bath
processes, the typical range of exposure level due to chromium(III) was
10 to 50 Mg/ro3- Because of better emission control measures,
occupational airborne chromium concentrations have declined
significantly during the past decades (Stern 1982). Since, as described
in Sect. 6.2 on Releases to the Environment, some toner powders used in
copying machines contain inhalable chromium, occupational exposure to
chromium is likely for machine operators, service technicians, and
persons employed in the disposal of garbage containing discarded toner
powders (Bond 1987). It is estimated that 175,000 persons in the United
States may be occupationally exposed to chromium(VI) (IARC 1980).
7.4 POPULATIONS AT HIGH RISK
One segment of the population that is especially at high risk to
chromium exposure are workers in industries that use chromium.
Occupational exposure from stainless steel welding, chromate production,
chrome plating, ferrochrome, and chrome pigment industries is especially
significant since the exposure from these industries is to chromium(VI)
Occupational exposure to chromium(III) compounds may not be as great a
concern; pulmonary cancer was not observed in chrome ore miners exposed
to large amounts of chromite dust (Baetjer 1959). Among populations at
large, residents living near chromate production sites may be
susceptible to higher levels of chromium(VI) exposure because ambient
concentrations as high as 2.5 Mg/ni3 chromium were detected in a 1977
sample from Baltimore, Maryland (EPA 1984a). Tobacco grown in the Unit
-------
Potential for Human Exposure 95
States has been reported to contain 0.24 to 6.3 mg/kg of chromium (IARC
1980), but neither the chemical form nor the amount of chromium in
tobacco smoke is known.
EPA (1980) stated that no special groups at risk have been
identified outside the occupational environment. EPA (1984a) also did
not identify any groups with a higher risk of exposure or with greater
susceptibility.
As discussed in Sect. 2.2.2 on biological monitoring as a measure
of exposure and effects in Health Effects Summary, individuals who
reduce chromium(VI) slowly have much higher blood chromium levels, while
fast reducers have higher urinary chromium levels. The connection
between variations in ability to reduce chromium(VI) and chromium
toxicity is not clear. Plasma reduction of chromium(VI) would probably
have no effect on changes at the site of contact (e.g., nasal mucosa
damage or the induction of lung cancer). Slow reducers may have
increased susceptibility to kidney and liver toxicity of chromium, but
clinical evidence is not available.
-------
97
8. ANALYTICAL METHODS
8.1 ENVIRONMENTAL AND BIOMEDICAL SAMPLES
Several methods are available for the analysis of chromium in
different environmental and biological media. Some of the more recent
methods for the determination of chromium are given in Table 8.1. EPA
Methods 200.7, 218.2, and 218.1 are required by the EPA Contract
Laboratory Program for analysis of chromium in water, soil, and
sediment. Several other reviews on the subject give a more detailed
description of the available analytical methods (Torgrimsen 1982, EPA
1984a, Fishbein 1984).
The determination of trace quantities of chromium requires special
precautionary measures, from the initial sample collection process to
the final analytical manipulations of the samples. Contaminations or
losses of the samples during collection, transportation, and storage
should be avoided. For example, biological samples collected with
stainless steel scalpels, trays, and utensils are unacceptable for
chromium analysis. Similarly, contamination or loss arising from sample
containers should be avoided. Reagents of highest purity should be used
to avoid contamination. The use of chromium-containing grinding and
homogenizing equipment will produce unacceptable results. The possible
loss of chromium because of volatilization during wet and dry ashing
should be minimized (EPA 1984a). Excellent reviews discussing these
problems and their resolution are given by Thiers (1955) and Thiers and
Bringham (1957).
The problem of developing accurate data for chromium in biological
samples is further complicated by the lack of standard reference
materials (SRM). Only recently, chromium 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), have been issued by the National Bureau of
Standards (now National Institute for Standards and Technology). SRMs
are still not available for several biological tissues and body fluids.
In view of the lack of standard reference materials, the older data
should be interpreted with caution (EPA 1984a). Although it is not
suitable for routine analysis, the isotope distribution-mass
spectrometric method (Kumpulainen 1984) is an excellent reference method
for the verification of ultratrace chromium levels in samples.
Another difficulty in the determination of chromium is the ability
of the applied analytical method to distinguish between chromium(III)
and chromium(VI). This is particularly important since chromium(VI) has
been associated with health hazards, while chromium(III) is of far less
concern. In foods, sediments, soils, and biological samples where
chromium is generally present in the III state, only chromium(III) is
-------
Sample matrix
Air
Air
Occupational air
(total chromium)
Occupational air
(total chromium)
Occupational air
|Cr(VI)J
Occupational air
(welding fumes)
Welding fuma
| total chromium(VI)]
Drinking water, surface
water, and certain
domestic and industrial
effluent* (dissolved
chromium(VI)]
Water and aqueous extract
from soil and biological
(whole scallop) sample;
simultaneous determina-
tion of soluble
chromium(lll) and
chromium(VI)
Table 8.1. Analytical methods for <
Sample preparation
Air paniculate mailer collected
on filler is cut out and irradiated
with X-ray photons
The collected particulatea in Tiller
dissolved in HNO,. dried and
•MMfiamllMwl ••• BMlillMwl HfAl^r
rcQiiaoivoii in •cuiiieii waicr
Collect air paniculate on cellulose
ester membrane filler, extract filter
with HCI/HNO, on hoi plate
Collect air paniculate on cellulose
ester membrane Tiller, wet ash with
HNO,/HCIO«
Filler air through PVC membrane
filter, extract with 0 S NH^O, or
2% NaOH-3% Na,CO, and complex with
diphenyl carbazide
The paniculate mailer on filter
wci ashed with HjSO, and chromium(lll)
Air paniculate collected on PVC filler
is extracted with hot 3% Na,CO,.
2% NaOH in the presence of MgCI,;
extract acidified with H,SO, and
complexed with diphenylcarbazide
Complex chromium(VI) in water
with APDC at pH 2.4 and
extracted with methyl
isobutyl keione (MIBK)
No pretreatmenl
Analytical method'
XRF
ICP-AES
AAS-flame
ICP/AES
Visible speclro-
photomelry
HPLC-UV
Speclropholomelry at
540 nm
Furnace AAS
HPLC with counter-ion
solution as eluent
and DCP-emission-
speclromelnc deter-
mination
irloH ausple autrlces
Detection limit Accuracy
OOI7pg/m' Not given
0.05-0 2 ng/m1 Not given
0 6 pg/samplc 98% at 45- 1 90
Mg Cr/sample
1 fig/samplc 98-106% at
2.5-100 M8 Cr/
sample
005/ig/sample 94 5% at
OS-IOfig/m1
10 pg Not given
0.05 pg/rn1 >95%
2 3 jig/L Not given
5-10 jig/L (for 106% at 30 Mg/L
both species)
References
Wicrsema
el al 1984
Barrie and
Hoff 1985
NIOSH I984a
(NIOSH method
7024)
NIOSH I984b
(NIOSH method
7300)
NIOSH I984c
(NIOSH method
7600)
Maili and
Desai 1986
NIOSH 1980.
Zatka 1985
EPA 1983
(method 218 5)
Krull
el al 1983
SO
oo
n
rt
H.
§
-------
Table 8.1 (continued)
Sample malru
Water, ml. and tcdimenl
Wei atmospheric deposi-
tion (mow), delermma-
lioo in soluble and in
paniculate pan
Sample preparation
Digestion with HNO,/ HA
The melted snow filtered through
Nucleoporc filter, the filtrate
acidified with HNO, and dried
by freeze-drier; residue dis-
Analytical method
ICP (method 200 7
CLP-M)
AAS-furnace (method
218 2 CLP-M)
AAS-flame (method
218 1 CLP-M)
PIXE
Detection limit
7 Mg/L
IPS/I-
SO Mg/L
2 Mg/L (soluble
portion)
26 pg/L (snow
panicle)
Accuracy
Not given
Not given
0.5-10 mg/L
Not given
References
EPA I987d
Jems el al
1983.
Landsberger
elal 1983
Waslcwaler and industrial
effluent for chromium(VI)
only
Simultaneous determina-
tion of chromium(lll) and
chromium(VI) in water
extract from metal fumes
Wastewater
Sludge or soil
(lolal chromium)
solved in HNO,, this preconcen-
trated solution placed in plastic
lubes, both plastic lube and
Nuclcoporc filter irradiated
with protons
Either the above Nucleoporc
filler or preconcenlraled liquid
placed in plastic vial is irradi-
ated by thermal neutron
Buffered sample mixed with AICI,
and the precipitate separated by
cenlnfugation or filtration
Sample solution at pH S reacted
with disodium ethylenediamine
lelraacetic acid at 50° C for I h
Sample mixed with a masking agent
and cetyllnmethylammonium bromide
solution al pH 4 7-6 6. healed
in water balh al 50°C for 10 mm
Dried and pulverized sample digested
with HNO,/H,O,. refluxed with MCI
or UNO,
INAA
DPPAatpH 10-12
HPLC on amon
exchange column with
Na,CO, elutmg
solution and simul-
taneous UV and AAS
detection
Spcclropholomctry
al 582 nm
AAS-flame or EAAS
5 Mg/L (soluble
portion)
11 5 Pg/g (snow
panicle)
95-105% al
002-20 us
Lower than
diphenylcar-
bazonc method
005 mg/L or
I Mg/L for the
digested sample
Not given
90% at 0 2 mg/L
0 2 ng by UV
for chromium(VI)
5 0 ng by AAS
for chromium(VI)
2 ng by UV
for chromium(lll)
5 ng by AAS
for chromium(lll)
Not given
Not given
Jems el al
1983.
Landsberger
clal 1983
Haudorf and
Janser 1984
Suzuki and
Serila 1985
Qiand Zhu
1986
LPA I982a
(EPA methods
7190 and 7191)
to
K»
SJ
O
to
-
o
ex
In
vO
vD
-------
Table 8.1 (comlMMd)
Sample matrix
Plasma
Serum
Blood, serum, orchard
leave*
Serum and urine
Unne
Unnc
Urine
Body fluid*
(c g . milk, urine)
Sample preparation
Analytical method
Detection limit
Accuracy
References
Sludge or soil [Cr(VI)|
Dried and pulverized sample digested
with hot 3% Na,CO,-2% NaOH and
complex with diphenylcarbazide at
pH 2 or chelate with ammonium pyrro-
lidinc duhwcarbamale (APCD) at
pH 2.4 and extract with methyl
isobutyl ketone (MIBK)
Visible speclro-
pholometry or
AAS-flame
0 5 mg/L or Not given
1 jig/L for
the digested
sample
EPA I982a
(EPA methods
7196 and 7197)
O
O
A
O
rt
»-•
O
a
Wet ashing with H NO,/HCIO,/11,80.,
residue completed with APDC and
extracted with MIBK. evaporated
residue dissolved in HNO,/HCI.
and solution deposited on a poly-
carbonate foil
Mg(NO,), added to serum, dried
by lyophilizaiion, ashed, and
dissolved in 0 IN HCI
Sample after wet digestion converted
to a volatile chelate usually
with fluorinatcd aoetylacetone
None
Not given
No sample preparation other lhan
addition of yttrium internal standard
None
Dried sample ashed by oxygen
plasma, H,O, addition, drying.
dilution in IN HCI
PIXE
EAAS
GC/EC
GC-MS
GC-AAS
EAAS with pyrolytic
graphite lubco and
Zeeman background
correction •
Electrothermal AAS
with CEWM background
correction and WM-AES
ICP-AES
EAAS
EAAS with tungsten
iodide or deuterium arc
or CliWM background
03«ig/L
OOSpg/L
003pg
OSpg
lOng
002M8/L
(serum)
0 I «/L
(urine)
87% at 4 5 kg/g Simonoff
etal 1984
103% at 0 30 «ig/L Randall and
Gibson 1987
0.09
(CEWM-AAS)
0.02 jig/L
(WM-AES)
Not given
Not given
Not given
Fuhbem 1984
Sunderman el
al 1987
Harnly et i
1983
OOSMg/L
<0 25
77%all3ng/L Kimberlyand
Paschal I98S
91% at 0 22 *ig/L Randall and
Gibton 1987
91% al 0 55
Kumpulamen
1984
-------
Table 8.1 (coBtbucd)
Sample matrix
Sample preparation
Analytical method
Detection limit
Accuracy
References
Hair
Washed and dried sample wet
ashed with HNOj/HCIO.. residue
dissolved in dilute HCI
oxidized to chronuum(VI) by addition
of Na,O,, the ccnlrifuged solution
was acidified with HCI and re-
duced to chromium(lll) by SO,, the
solution was completed with 0-iso-
propyhropolone in CHCI,
ICP-AES
Not given
Not given
Takagi cl al
1986
"AAS - atomic absorption spectrometry.
CEWM - continuum source echclle monochromaior wavelength-modulated.
DCP - direct current plasma.
OPPA - differential-pulse polarographic analysis,
EAAS - electrothermal atomic absorption speclromeiry.
HPLC - high pressure liquid chromatography.
ICP-AES - inductively coupled plasma-atomic emission spectromelry,
INAA - instrumental neutron activation analysis.
IPAA - instrumental photon activator analysis.
MS - mass speclromeiry.
PIXE - proton-induced X-ray emission spectrometry.
XRF - X-ray fluorescence analysis.
ft
n>
a-
o
-------
102 Section 8
quantified. However, .chromium may be present in both oxidation states 1-
most ambient environmental and occupational samples, and sometimes the
distinction between soluble and insoluble forms of chromium(VI) becomes
necessary. A few methods that distinguish the two chromium states are
given in Table 8.1. There is no known analytical method that can
distinguish the different valence states of chromium when it is present
as insoluble chelates.
The choice of a particular method is dictated by several factors
including the type of sample, its chromium level, and the scope of the
analysis. These factors, in combination with the desired precision and
accuracy and the cost of analysis, should be considered in selecting a
particular analytical method. Although the methods given in Table 8.1
are some of the more recent methods, they are not necessarily the most
commonly used ones. Atomic absorption spectrometry and spectrophotometry
still are the two most commonly used methods for the quantification of
chromium. A comparison of the various commonly used methods and the
methods for the avoidance of contamination during sampling, sample
handling, and analysis are provided by Kumpulainen (1984).
-------
103
9. REGULATORY AND ADVISORY STATUS
9.1 INTERNATIONAL
WHO (1970) recommends a European standard of 0.05 mg/L for
chromium(VI) in drinking water.
9.2 NATIONAL
9.2.1 Regulations
9.2.1.1 Air
AGENCY
OSHA
9.2.1.2 Vater
AGENCY
EPA
EPA
VALUE
Permissible Exposure Limit (PEL) for soluble chromic
[chromium (III)] or chromous [chromium (II)] salts--
0.5 mg/m3 chromium (OSHA 1985)
PEL for insoluble salts or chromium metal--! mg/m3
(OSHA 1985)
Acceptable Ceiling Concentration (ACC) for chromic
acid [chromium(VI)] and chromates [chromium(VI)] - -
1 mg/10 m3 (OSHA 1985)
VALUE
Maximum Contaminant Level (MCL) for total chromium in
drinking water--0.05 mg/L (EPA 1975}
Chromium is regulated by the Clean Water Act Effluent
Guidelines for the following industrial point sources:
textiles, electroplating, organic chemicals, inorganic
chemicals, petroleum refining, iron and steel
manufacturing, nonferrous metals, steam electric,
ferroalloy, leather tanning and finishing, asbestos,
rubber, timber products processing, metal finishing,
mineral mining, paving and roofing, paint formulating,
ink formulating, gum and wood, carbon black, batter
manufacturing, coil coating, porcelain enameling,
aluminum forming, copper forming, electrical and
electronic components, nonferrous metals forming (EPA
1988b).
-------
104 Section 9
9.2.1.3 Non-media-specific
AGENCY VALUE
EPA Federal law (CERCLA 103a and b) requires that the
National Response Center be notified when there is a
release of a hazardous substance in excess of the
reportable quantity (RQ). The RQ for metallic chromium
(diameter <100 pm) is 1 Ib; the RQs for ammonium
dichromate, chromic acid, calcium chromate, potassium
dichromate, potassium chromate, sodium dichromate,
sodium chromate and strontium chromate are 1,000 Ib.
These RQs are subject to change when the assessment of
potential carcinogenicity and/or chronic toxicity is
complete. The RQs for chromic acetate, chromic
sulfate, and chromous chloride are 1,000 Ib (EPA
1985b).
EPA Federal law (section 302 of SARA) requires any
facility where an extremely hazardous substance is
present in excess of che threshold planning quantity
(TPQ) to notify the state emergency planning
commission. The TPQ for chromic chloride is 10,000 Ib,
except if it exists in a powdered form with a particle
size of less than 100 fim, is handled in solution or
molten form, or has a National Fire Protection
Association rating of 2, 3, or 4 for reactivity. Und<
these conditions the TPA for chromic chloride is 1 It
Federal law (section 304 of SARA) also requires
immediate reporting of releases of hazardous
substances to local emergency planning committees and
the state emergency planning commission. Releases of
1 Ib of chromic chloride must be reported (EPA 1987b)
9.2.2 Advisory Guidance
9.2.2.1 Air
AGENCY VALUE
ACGIH TLV-TWA values for the metal and inorganic compounds
as milligrams chromium per cubic meter:
Chromium metal--0.5 mg/m3
Chromium(II) and chromium(III) compounds--0.5 mg/m3
Water-soluble chromium(VI) compounds--0.05 mg/m3
Certain water-insoluble chromium(VI) compounds--0.05
mg/m3 [Appendix Ala, Recognized Human Carcinogen
(ACGIH 1986)]
Chromite ore processing (chromate) for an 8-h workday
40-h workweek--0.05 mg/m3 [Appendix Ala, Recognized
Human Carcinogen (ACGIH 1986)]
-------
NIOSH
Regulatory and Advisory Status 105
Chromic acid: TWA criterion for an 8-h workday 40-h
workweek--0.05 mg/m3 Cr03; ceiling limit (15 min)- -
0.2 mg/m3 Cr03 (NIOSH 1973)
Noncarcinogenic chromium(VI) compounds (chromates and
dichromates of hydrogen, lithium, sodium, potassium,
rubidium, cesium, and ammonium and chromic acid
anhydride) TWA criterion for a 10-h workday, 40-h
workweek--25 ^g/m3 chromium(VI) ceiling limit
(15-min)--50 /ig/n>3 chromium (VI) (NIOSH 1975)
Carcinogenic chromium(VI) compounds [any and all
chromium(VI) materials not included in the
noncarcinogenic group above]--! /*g/m3 chromium(VI)
(NIOSH 1975)
9.2.2.2 Vater
AGENCT
U.S. Public
Health Service
EPA
EPA
EPA
VALUE
Drinking water criterion for chromium(VI)--0.05 mg/L
(U.S. Public Health Service 1962)
Proposed Recommended Maximum Contaminant Levels (RMCL)
[now called Maximum Contaminant Level Goals (MCLG))
for total chromium(VI) and chromium(III) in drinking
water--0.12 mg/L (EPA 1985a)
Ambient water quality criteria: chromium(III)--
59 mg/L; chromium(VI)--50 /i/L (EPA 1980, 1982b)
One-day HA for chromium(VI)--not available, use 10-day
value
10-day HA (child) for chromium(VI)--1.4mg/L
Longer-term HA for chromium(VI)--0.24 mg/L for a 10-kg
child; 0.84 mg/L for a 70-kg adult
Lifetime HA for chromium(VI)--0.120 mg/L for a 70-kg
adult
Drinking water equivalent level (DWEL) for chromium
(VI)--0.170 mg/L (EPA 1986c)
9.2.3 Data Analysis
9.2.3.1 Reference doses
EPA (1985d) presents an oral RfD (Reference Dose) of 1 mg/kg/day
for metallic chromium(III) (insoluble salts) based on a free-standing
NOAEL from the study by Ivankovic and Preussmann (1975). The RfD,
verified by the EPA, was calculated according to the methods of Barnes
et al. (1987) as follows:
RfD - (1,468 mgAg/day)/(100)(10) - 1 mg/kg/day
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106 Section 9
Where: 1,468 mg/kg/day - NOAEL, dose calculated with data provided by
the authors. Dose conversion: 1,800 g Cr203
per kilogram body weight per 600 feeding days
x 1,000 mgAg x 0.6849 g chromium per gram
Cr203 x 5 feeding days/7 days - 1,468
mg/kg/day
100 - uncertainty factor to account for interspecies and
intraspecies variability
10 - modifying factor to reflect uncertainty around the NOAEL:
effects observed in the 90-day study were not addressed in
the 2-year study, absorption of chromium is low and is
influenced by a number of factors so that considerable
variation is possible, and histology was performed in rats
after they died naturally and feeding was stopped after
2 years.
EPA (1986c) presents a chronic oral RfD of 0.005 mg/kg/day for
chromium(VI) (soluble salts) based on the study by MacKenzie et al.
(1958), in which no adverse effects were observed in rats provided with
drinking water containing potassium chromate at a concentration of
25 mg/L chromium(VI) for 1 year. The RfD, verified by the EPA, was
calculated according to the methods of Barnes et al. (1987) as follows:
RfD - (2.4 mg/kg/day chromium(VI)/(100) (5) - 0.005 mgAg/day
Where: 2.4 mg/kg/day - NOAEL, dose calculated with drinking water
consumption and body weight data provided by ti
investigators. Dose conversion: 25 mg/L x 0.097
L/kg/day - 2.4 mg/kg/day.
100 - Uncertainty factor appropriate for use with an animal
NOAEL for interspecies and intraspecies extrapolation
5 - Uncertainty factor for less-than-lifetime exposure
duration.
9.2.3.2 Carcinogenic potency
EPA (1984a) calculated a unit risk of 1.2 x 10'2 for lifetime
inhalation exposure to 1 pg/m-* of hexavalent chromium compounds [or
potency of 1.2 x 10"? (jig/m3)'*] based on the epidemiology study by
Mancuso 1975). This unit risk has been verified by the EPA (EPA 1986c).
Doses associated with increased upper-bound lifetime cancer risk levels
of 1 x 10'4, 10'5, 10'6, and 10'7 are 8 x 10'3, 8 x 10'4, 8 x 10'5, and
8 x 10*6 pg/m3, respectively. Inhaled chromium (VI) has been assigned an
EPA classification of A--human carcinogen--by the inhalation route (EPA
1984b, EPA 1986c) based on sufficient evidence from epidemiology studies
showing increased lung cancer incidences in chromate production workers
and possibly in chrome pigment workers and chrome platers (EPA, 1986c).
EPA (1986c) also concluded that the evidence of careinogenieity of
chromium(VI) compounds to animals was sufficient, based on implantation
and injection studies in which tumors were produced at the site of
administration.
-------
Regulatory and Advisory Status 107
The scientific data are Inadequate to evaluate whether chromium(VI)
is carcinogenic via Ingestion.
Based on the earlier IARC (1980) review and an evaluation of more
recent data, lARCT (1987b) classified chromium(VI) compounds in IARC
Group 1 (carcinogenic to humans). IARC (1987b) concluded that the
evidence for carcinogenicity of chromium(VI) compounds to humans is
sufficient and consists of increased lung cancer incidences in
dichromate production workers and chromate-pigment manufacturing
workers, and possibly among chrome platers and chromium alloy workers.
IARC (1982, 1987b) concluded that evidence for carcingenicity of
chromium(VI) compounds to animals is also sufficient: Calcium chromate
is carcinogenic to rats by several routes of administration, including
intrabronchial implantation; chromium chromate, strontium chromate, and
zinc chromate cause local sarcomas at the sites of application. IARC
(1987b) classified chromium(III) compounds and chromium(O) in IARC Group
3 (cannot be classified as to its carcinogenicity) based on inadequate
evidence in both humans and animals (IARC 1980, 1987b).
9.3 STATE
Regulations and advisory guidance from the states were not
available.
-------
109
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131
11. GLOSSARY
Acute Exposure--Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.
Bioconcentration Factor (BCF)--The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surroundine
water at the same time or during the same time period.
Carcinogen--A chemical capable of inducing cancer.
Ceiling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously.
Chronic Exposure--Exposure to a chemical for 365 days or more as
specified in the Toxicological Profiles.
Developmental Toxicity--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.
Embryotoxicity and Fetotoxicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.
Frank Effect Level (FEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.
EPA Health Advisory--An estimate of acceptable drinking water levels for
a chemical substance based on health effects information. A health
advisory is not a legally enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.
Immediately Dangerous to Life or Health (IDLH)--The maximum
environmental concentration of a contaminant from which one could escape
within 30 min without any escape-impairing symptoms or Irreversible
health effects.
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132 Section 11
Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.
Immunologic Toxicity--The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.
In vitro-- Isolated from the living organism and artificially maintained,
as in a test tube.
In vivo--Occurring within the living organism.
Key Study--An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.
Lethal Concentration(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.
Lethal Concentration(SQ) (LCso)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.
Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.
Lethal Dose(50) (LDSO)--The dose of a chemical which has been calculated
to cause death in 50% of a defined experimental animal population.
Lowest-Observed-Adverse-Effect Level (LOAEL)--The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases in frequency or severity of adverse
effects between the exposed population and its appropriate control.
Lowest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.
Malformations--Permanent structural changes that may adversely affect
survival, development, or function.
Minimal Risk Level--An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.
Mutagen--A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages, or cancer.
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Glossary L33
Neurotoxtcity--The occurrence of adverse effects on the nervous system
following exposure to 'a chemical.
No -Observed- Adverse -Effect Level (NOAEL)--That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.
No-Observed-Effect Level (NOEL) --That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.
Permissible Exposure Limit (PEL) --An allowable exposure level in
workplace air averaged over an 8-h shift.
ql*--The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The ql* can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually Mg/L for water, mg/kg/day for
food, and Mg/n^ for air) .
Reference Dose (RfD)--An estimate (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population to a
potential hazard that is likely to be without risk of deleterious
effects during a lifetime. The RfD is operationally derived from the
NOAEL (from animal and human studies) by a consistent application of
uncertainty factors that reflect various types of data used to estimate
RfDs and an additional modifying factor, which is based on a
professional Judgment of the entire database on the chemical. The RfDs
are not applicable to nonthreshold effects such as cancer.
Reportable Quantity (RQ)--The quantity of a hazardous substance that is
considered repor table under CERCLA. Reportable quantities are: (1) 1 Ib
or greater or (2) for selected substances, an amount established by
regulation either under CERCLA or under Sect. 311 of the Clean Water
Act. Quantities are measured over a 24 -h period.
Reproductive Toxicity--The occurrence of adverse effects on the
reproductive system that may result from exposure to a chemical . The
toxic ity may be directed to the reproductive organs and/or the related
endocrine system. The manifestation of such toxicity may be noted as
alterations in sexual behavior, fertility, pregnancy outcomes, or
modifications in other functions that are dependent on the integrity of
this system.
Short-Term Exposure Limit (STEL)--The maximum concentration to which
workers can be exposed for up to 15 min continually. No more than four
excursions are allowed per day, and there must be at least 60 min
between exposure periods. The daily TLV-TWA may not be exceeded.
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134 Section 11
Target Organ Toxicity--This term covers a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from those arising through a single limited exposure to those
assumed over a lifetime of exposure to a chemical.
Teratogen--A chemical that causes structural defects that affect the
development of an organism.
Threshold Limit Value (TLV)--A concentration of a substance to which
most workers can be exposed without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.
Time-weighted Average (TWA)--An allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.
Uncertainty Factor (UF)--A factor used in operationally deriving the RfD
from experimental data. UFs are intended to account for (1) the
variation in sensitivity among the members of the human population,
(2) the uncertainty in extrapolating animal data to the case of humans,
(3) the uncertainty in extrapolating from data obtained in a study that
is of less than lifetime exposure, and (4) the uncertainty in using
LOAEL data rather than NOAEL data. Usually each of these factors is set
equal to 10.
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135
APPENDIX: PEER REVIEW
A peer review panel was assembled for chromium. The panel
consisted of Che following members: Dr. Rolf Hartung, Chairman
Toxicology Program, University of Michigan; Dr. Derek Hodgson,'Vice
Chairman, Department of Chemistry, University of North Carolina; and
Dr. F. William Sunderman, Jr., Chair of Toxicology, University of
Connecticut Medical School. These experts collectively have knowledge of
chromium's physical and chemical properties, toxicokinetics, key health
end points, mechanisms of action, human and animal exposure, and
quantification of risk to humans. All reviewers were selected in
conformity with the conditions for peer review specified in the
Superfund Amendments and Reauthorization Act of 1986, Section 110.
A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.
The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.
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