HEALTH HAZARD
ASSESSMENT SUMMARY:
STEEL MILL EMISSIONS
Work Assignment 07
RADIAN
CORPORATION
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DCN No. 89-239-009-07-02
EPA Contract No. 68-09-0011
HEALTH HAZARD
ASSESSMENT SUMMARY:
STEEL HILL EMISSIONS
Work Assignment 07
Prepared for:
U. S. Environmental Protection Agency
Emissions Standards Division
Pollutant Assessment Branch
Research Triangle Park, North Carolina 27711
Prepared by:
Radian Corporation
3200 E. Chapel Hill Road
Research Triangle Park, North Carolina 27709
September 29, 1989
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DCN No. 89-239-009-07-02
EPA Contract No. 68-D9-0011
HEALTH HAZARD
ASSESSMENT SUMMARY:
STEEL MILL EMISSIONS
Work Assignment 07
Prepared for:
Dr. Nancy B. Pate
U. S. Environmental Protection Agency
Emissions Standards Division
Pollutant Assessment Branch
Research Triangle Park, North Carolina 27711
Prepared by:
Radian Corporation
3200 E. Chapel Hill Road
Research Triangle Park, North Carolina 27709
September 29, 1989
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DISCLAIMER
This document is a preliminary draft for review purposes only and does
not constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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TABLE OF CONTENTS
Section Page
1.0 INTRODUCTION 1
2.0 HEALTH EFFECTS OF METALS EMITTED FROM STEEL MILLS 4
2.1 Chromium 4
2.1.1 Noncancer Health Effects 4
2.1.2 Carcinogenicity of Chromium 5
2.1.2 Interaction with Other Compounds 6
2.2 Manganese 6
2.2.1 Noncancer Health Effects 6
2.2.2 Carcinogenicity of Manganese 9
2.2.3 Interaction with Other Compounds 9
2.3 Zinc 9
2.3.1 Noncancer Health Effects 9
2.3.2 Carcinogenicity of Zinc 10
2.3.3 Interaction with Other Compounds 10
2.4 Copper 11
2.4.1 Noncancer Health Effects 11
2.4.2 Carcinogenicity of Copper 12
2.5 Nickel 12
2.5.1 Noncancer Health Effects 12
2.5.2 Carcinogenicity of Nickel 13
2.5.3 Interaction with Other Compounds 14
2.5.4 Populations at Risk 14
2.6 Cadmium 14
2.6.1 Noncancer Health Effects 14
2.6.2 Carcinogenicity of Cadmium 15
2.6.3 Interaction with Other Compounds 16
2.6.4 Populations at Risk 16
2.7 Vanadium 16
2.7.1 Noncancer Health Effects 17
2.7.2 Carcinogenicity of Vanadium 18
2.7.3 Interaction with Other Compounds 18
3.0 HEALTH EFFECTS OF OTHER COMPOUNDS EMITTED FROM STEEL MILLS 19
3.1 Ammonia and Ammonium sulfate 19
3.1.1 Noncancer Health Effects 19
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Table of Contents Continued
Section Page
3.1.2 Carcinogenicity of Ammonia and Ammonium sulfate 20
3.1.3 Interaction with Other Compounds 20
3.2 Hydrogen chloride 21
3.2.1 Noncancer Health Effects 21
3.2.2 Carcinogenicity of Hydrogen chloride 21
3.3 Tol uene 22
3.3.1 Noncancer Heal th Effects 22
3.3.2 Carcinogenicity of Toluene 23
3.4 Benzene 23
3.4.1 Noncancer Heal th Effects 23
3.4.2 Carcinogenicity of Benzene 24
3.4.3 Interaction with Other Compounds 24
3.5 Naphthalene 24
3.5.1 Noncancer Health Effects 24
3.5.2 Carcinogenicity of Naphthalene 25
4.0 HEALTH EFFECTS OF COMPLEX MIXTURES 26
4.1 Polycyclic Organic Matter 26
4.1.1 Noncancer Health Effects 26
4.1.2 Carcinogenicity of Polycyclic Organic Matter 27
4.2 Coke Oven Emissions 28
4.2.1 Noncancer Health Effects 28
4.2.2 Carcinogenicity of Coke Oven Emissions 29
5.0 REFERENCES 30
APPENDIX A: Glossary of Health, Exposure, and Risk Assessment Terms A-l
APPENDIX B: Available Integrated Risk Information System (IRIS)
Files for Pollutants Emitted From Steel Mills B-l
LIST OF TABLES
Table Page
1. Substances of Concern Potentially Emitted from Steel Mills 2
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1.0 INTRODUCTION
The U. S. Environmental Protection Agency's (EPA) Air Risk Information
Support Center (Air RISC) was developed and is maintained by the Pollutant
Assessment Branch of the Office of Air Quality Planning and Standards
(PAB/OAQPS) and the Environmental Criteria and Assessment Office of the Office
of Health and Environmental Assessment (ECAO/OHEA) to assist State and local
air pollution control agencies and EPA regional offices on technical matters
pertaining to toxic air pollutants. In response to an Air RISC request on the
public health hazards associated with steel mill emissions, this document was
prepared to assist State and local air pollution control officials in the
identification of possible health hazards, and can be used with its companion
document, "Emission Factors For Iron and Steel Sources/Criteria and Toxic
Pollutants" (Barnard, 1989) to quantify steel mill emissions and assess the
health impacts on affected populations.
The majority of the information presented in this assessment is derived
from summary documents prepared by the U. S. Environmental Protection Agency
for the specific compounds shown in Table 1. When information was available
for a mixture of compounds known to be emitted during steel production, the
discussion considers the mixture as a whole rather than the individual
chemicals. This is the case for polycyclic organic matter and coke oven
emissions (see Section 4).
One of the objectives of this document is to present the Lowest Observed
Effect Levels (or Lowest Observed Adverse Effect Levels) and the No Observed
Effect Levels (or the No Observed Adverse Effect Levels) for the noncancer
health effects associated with exposure to steel mill emissions. The Lowest
Observed Effect Levels (LOELs) and the No Observed Effect Levels (NOELs)
presented here are derived from the EPA's reviews of animal toxicity and human
epidemiology studies, and it is possible that further research may find a
lower or alternate NOEL or LOEL.
For some pollutants, the "critical" study or effect for a NOEL or a LOEL
has been identified by the U. S. EPA and adjusted to represent a concentration
level to which humans can be exposed constantly throughout their lifetimes
without an adverse effect. This concentration level is called an Inhalation
Reference Dose (RfDi), and can be found in the EPA's Integrated Risk
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Table 1. Substances of Concern Potentially Emitted from Steel Mills
Chromium
Manganese
Zinc
Copper
Nickel
Cadmium
Vanadium
Ammonia/Ammonium sulfate
Hydrogen chloride
Toluene
Benzene
Naphthalene
Polycyclic organic matter
Coke oven emissions
Information System (IRIS), a computer-based compilation of pollutant health
effect information.
Information is also presented here on the carcinogenic potential of
steel mill emissions. This information was also derived from EPA documents
and IRIS. The EPA's Human Health Assessment Group has calculated unit risk
estimates for several of the compounds discussed in this document. The
incremental unit risk estimate for an air pollutant is defined as the
additional lifetime cancer risk for a given population exposed continuously
for their lifetimes (70 years) to a concentration of 1 ug/m3 of an airborne
pollutant (U. S. EPA, 1986a). These unit risk estimates are then used to
compare the carcinogenic potency between air pollutants and to give an
estimate of the population risk that might be associated with exposures to air
or water that contains the carcinogenic substance. The data used to calculate
these unit risk numbers come either from lifetime animal studies or human
epidemiology studies. The EPA also assigns a weight-of-evidence judgment of
the likelihood that an agent is a human carcinogen (IRIS, 1989).
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The Integrated Risk Information System also includes an estimation of the air
concentrations expected to result in 1 in 10,000; 1 in 100,000; and 1 in
1,000,000 excess cases of cancer.
Finally, it should be noted that, for some of the compounds discussed in
this document, little or no information is available concerning their effects
from chronic inhalation exposure. For these compounds, acute inhalation
studies are summarized to provide some indication of their potential toxicity.
Oral exposures may also be discussed, but it must be kept in mind that route-
to-route extrapolation for some effects may be inappropriate.
Appendix A contains a glossary of health, exposure, and risk terms
prepared by the Air Risk Information Support Center to describe commonly used
risk assessment terms. The reader is also referred to Appendix B for a copy
of the EPA's Integrated Risk Information System's files for those pollutants
discussed in this report that have been included in IRIS. In addition, the
references listed in Section 5 may be consulted for further information.
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2.0 HEALTH EFFECTS OF METALS EMITTED FROM STEEL MILLS
2.1 CHROMIUM
Chromium is a naturally occurring essential element that can also be
carcinogenic (U. S. EPA, 1984a). Chromium can be present in the atmosphere in
several valence states, but this discussion will center on the two valence
states that humans are most likely to encounter. Trivalent chromium [Cr
(III)] and hexavalent chromium [Cr (VI)] are the two most stable forms of
chromium (U. S. EPA, 1984a). Chromium (III) is emitted naturally from the
earth's crust. Chromium (VI) is readily reduced to Cr (III) in the presence
of organic matter, but is emitted from anthropogenic sources such as steel
mills (U. S. EPA, 1984a). Steel mills are one source category thought to emit
both Cr (III) and Cr (VI) but the relative proportions are unknown (U. S. EPA,
1984a).
Because the mineral chromite occurs naturally, chromium can be taken
into the body through air, food, and water exposures. All of these exposure
routes must be taken into consideration in making an estimate of total
chromium uptake.
2.1.1 Noncancer Health Effects
Epidemiologic studies by Bloomfield and Blum (1928), Langard and Norseth
(1979), Seeber et al. (1976), Lindberg and Hedenstierna (1983), and others
reviewed by the World Health Organization (WHO, 1988) and the Agency for Toxic
Substances and Disease Registry (ATSDR, 1989) indicate that perforation of the
nasal septum is the critical noncancer health effect associated with chronic,
low-level exposure to chromium (VI). Lindberg and Hedenstierna (1983) studied
workers in the chrome plating industry who were exposed to "low" chromic acid
concentrations (8-hour mean below 2 ug/m3) and "high" chromic acid
concentrations (above 2 ug/m3) for an average exposure time of 2.5 years.
Lindberg and Hedenstierna (1983) also studied lung function in chrome plating
workers, and reported that an 8-hour mean exposure level of more than 2 ug/m3
might cause a transient decrease in lung function (WHO, 1988).
On the basis of this study, the World Health Organization (1988)
concluded that long term exposure to doses greater than 1 ug chromium (VI) can
cause nasal irritation, atrophy of the nasal mucosa, and ulceration or
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perforation of the nasal septum. This concentration can be considered to be
the unadjusted NOEL for exposure to chromium, and 2 ug/m3 can be considered
the LOEL.
The effects of chromium have been studied in animal experiments, with
the chronic studies primarily evaluating chromium's carcinogenic potential.
These experiments are discussed below, and support the finding of
carcinogenicity seen in human occupational studies.
2.1.2 Carcinoqenicitv of Chromium
Animal studies have not shown lung cancer resulting from chromium
inhalation exposures, but epidemiologic studies of several chromate production
facilities have shown an association between chromium exposure among workers
and lung cancer. Epidemiology studies conducted in the chrome pigment
industry and the chromium plating industry also have shown an association
between lung cancer and exposure to chromium (IRIS, 1989). These exposures
have been to both Cr (III) and Cr (VI), but animal studies indicate that Cr
(VI) rather than Cr (III) causes cancer following exposure via other routes
(IRIS, 1989), thus implicating Cr (VI) as the carcinogenic form of chromium.
Research is currently underway to elucidate the issue. Because of the excess
cancers seen in chromate production facilities, chromium (VI) is considered by
the EPA's Human Health Assessment Group (HHAG) to have sufficient evidence for
designation as a human carcinogen. Epidemiologic evidence has been derived
from studies in the United States, Great Britain, Japan, and West Germany
(IRIS, 1989).
The HHAG estimated a unit risk number based on the epidemiologic studies
of Mancuso (1975), Langard et al. (1980), Axelsson et al. (1980), and
Pokrovskaya and Shabynina (1973). The Human Health Assessment Group thus
calculated a unit risk number of 1.2 x 10~2/ug/m3. This means that if a
person continuously breathes 1 ug/m3 of Cr (VI) for 70 years, the probability
of getting lung cancer would not exceed 1.2 chances in 100. The Integrated
Risk Information System (IRIS, 1989) presents the carcinogenic risk levels for
chromium (VI), showing a conservative estimate of lung cancer risk of 1 in
10,000 for a population exposed continuously to 0.008 ug/m3 Cr(VI) for 70
years.
As mentioned previously, lung cancer has not been observed in animal
assays with Cr (VI). The HHAG's review of the supporting data for
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carcinogenicity comes from animal assays in which intramuscular injection site
tumors were seen (Furst et al, 1976; Maltoni, 1974, 1976; Payne, 1960; Hueper
and Payne, 1959), as cited in IRIS (1989). In addition, intrapleural implant
site tumors, intrabronchial implantation site tumors, and subcutaneous
injection site sarcomas have been seen in rats in several studies (IRIS,
1989).
On the basis of the human and animal studies, chromium (VI) is
considered by the EPA to be a Group A carcinogen, with sufficient evidence as
a human carcinogen and sufficient evidence as an animal carcinogen (IRIS,
1989).
2.1.3 Interaction with Other Compounds
Chromium's carcinogenicity has been tested in laboratory animals
preexposed with virus infections, ionizing radiation, and 20-methyl-
cholanthrene, another known carcinogen (Nettesheim et al., 1970, 1971; Steffee
and Baetjer, 1965; Shimkin and Leiter, 1940). No synergism was detected in
any of the experiments (WHO, 1988).
2.2 MANGANESE
Manganese, like chromium, is present in the earth's crust and is
released to the atmosphere through entrainment of road dusts, wind erosion,
soil disturbances through farming and construction activities, combustion, and
the manufacture of ferroalloys, iron and steel, batteries, and chemical
products (U. S. EPA, 1984b). Exposure can occur from contact with food,
water, and air that contains either naturally occurring or anthropogenically
released manganese. Manganese-containing particles released during the steel
manufacturing process are submicron in size, ranging from 0.5 to 5.0 urn mass
median diameter (U. S. EPA, 1971). Manganese is emitted in the form of the
metal, as trimanganese tetraoxide (Mn3OJ, and as manganese oxide (MnO) during
steel manufacture (U. S. EPA, 1971).
2.2.1 Noncancer Health Effects
Following exposure to manganese particles, deposition is dependent upon
the mass median diameter of the inhaled particles. According to the
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Environmental Protection Agency (1984b), 25 to 65% of the particles between 2
and 4 urn are deposited in the alveoli of the lungs, with the remainder
deposited in the tracheobronchial region. Nearly all of the particles smaller
than 2 urn reach the alveoli. Particles less than 1 urn are likely.to be
adsorbed directly into the blood (Task Group on Metal Accumulation, 1973), and
the GI tract is the portal of entry for the larger particles (Mena et al.,
1969).
Although manganese has been shown to be necessary for normal growth and
reproduction in laboratory animals, there is no minimum daily requirement for
humans, and no human studies have demonstrated a manganese deficiency.
Chronic occupational exposures to manganese concentrations above
300 ug/m3 often result in manganism, which predominantly affects the central
nervous system. The symptoms of manganism range from anorexia, insomnia, and
abnormal behavior to severe rigidity, tremors, and autonomic dysfunction
(U. S. EPA, 1984b).
The U.S. Environmental Protection Agency (1984b) examined over ten
epidemiologic studies of workers exposed to several chemical forms of
manganese and particle sizes to determine a NOEL for manganism (Flinn et al.,
1941; Ansola et al., 1944a,b; Rodier, 1955; Schuler et al., 1957; Tanaka and
Lieben, 1969; Emara et al., 1971; Smyth et al., 1973; Suzuki et al., 1973a,b;
Saric et al., 1977; Chandra et al., 1981). The occupations examined were ore
crushing, mining, general industrial, dry-cell battery production,
ferromanganese production, and welding. From review of these studies, the EPA
concluded that the dose-response information was insufficient to establish the
NOEL, but that enough information was available to estimate a LOEL.
Ansola et al. (1944b) and Rodier (1955) concluded that manganism can
develop after a few months of occupational exposure, but most cases are seen
following several years of exposure. The EPA found that the data identifying
a LOEL below 0.3 mg/m3 (300 ug/m3) were equivocal or inadequate, but exact the
duration of exposure to this level was not stated, and the chemical form and
the particle sizes of the manganese were not reported in the original studies.
However, the study by Saric et al. (1977) of ferromanganese plant dust and
fumes estimated the duration of exposure to be less than 4 years for 27% of
the study population. A NOEL could not be established because of an inability
to evaluate the early stages of the disease (U. S. EPA, 1984b).
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Bronchitis and pneumonitis are the primary pulmonary effects of
manganese, but these effects are thought to be due to particulate matter in
general, rather than manganese specifically (U. S. EPA, 1984b). Pulmonary
effects below 1 mg/m3 are generally reversible. Several reports suggested a
relationship between manganese levels and the rate of pneumonia and other
respiratory ailments in populations living near sources of manganese. The
lowest exposure level where pulmonary effects occurred was reported in a study
of junior high school students exposed to emissions from a ferromanganese
plant in Japan. Nogawa et. al. (1973) studied school children who lived from
50 to 1500 meters from the plant and attended a school that was 100 meters
from the plant. They found a relationship between the distance of the
children's homes and the plant, with those closest to the plant showing a
higher number of cases of "throat swelling and soreness in summer" and a "past
history of pneumonia" (Nogawa et al., 1973). They estimated that more than
1500 meters from the plant, manganese concentrations were negligible, and 300
meters from the plant suspended dust and manganese concentrations were 160
ug/m3 and 6.7 ug/m3, respectively (Nogawa et al., 1973). Other measurements
100 meters from the plant indicated dust levels of 299 ug/m3 and manganese
levels of 4 ug/m3. The U. S. Environmental Protection Agency (1984b)
concluded on the basis of this study that the LOAEL for pulmonary effects for
exposure to manganese-containing particulate matter is 3-11 ug/m3.
Based on the high incidence of pneumonia or other acute respiratory
diseases in many occupational studies (Heine, 1943; Rodier, 1955; Cauvin,
1943; Lloyd-Davies, 1946), the EPA (1984b) concluded that manganese-containing
particulate matter may disturb normal lung clearance mechanisms, thus
increasing susceptibility. Animal studies have been undertaken to investigate
this possibility. Several investigators found that manganese had an effect on
the number and phagocytic activity of alveolar macrophages. Ulrich et al.
(1979a,b,c) found no pulmonary effects, however, in rats and monkeys exposed
to 0.113 mg/m3 (113 ug/m3) Mn304 for 24 hours/day for 9 months, and the EPA
concluded that this level was the highest available animal NOEL. Suzuki et
al. (1978) found positive radiologic findings in monkeys exposed for 10 months
(22 hours/day) to 0.7 mg/m3 Mn02, and the EPA considers this to be the animal
LOAEL.
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2.2.2 Carcinogenicitv of Manganese
The U. S. EPA's review of manganese carcinogenicity studies is presented
in IRIS (1989). No evidence exists in the epidemiology studies to support a
claim that manganese is carcinogenic, and the animal data are considered to be
inadequate by the EPA's HHAG. The weight-of-evidence classification for
manganese is that it is a group D compound, not classifiable as to human
carcinogenicity.
2.2.3 Interaction with Other Compounds
Populations at risk for manganese exposure are those with iron
deficiencies, as an iron deficiency may exacerbate manganese toxicity (Thomson
et al., 1971). Manganese has also been shown to inhibit local sarcoma
induction by benzo(a)pyrene (U. S. EPA, 1984b).
2.3 ZINC
Zinc is found in nature in its salt or oxide form and does not occur
naturally in its elemental form (U. S. EPA, 1987a). Elemental zinc is,
however, used extensively in the galvanizing of iron and steel. Exposure to
zinc may occur via inhalation and ingestion of food and water.
2.3.1 Noncancer Health Effects
The form in which zinc is emitted from steel mills is not known,
therefore the health effects presented here pertain to elemental zinc and zinc
oxide. The primary health effect observed in the occupational settings is
"metal fume fever." It has been reported that this condition exists at zinc
oxide concentrations greater than 15 mg/m3 (Batchelor et al., 1926; Kemper and
Troutman, 1972; Hammond, 1944). Symptoms associated with metal fume fever are
headache, fever, hyperpnea, nausea, sweating, and muscle pain. Metal fume
fever symptoms tend to recur at the beginning of the work week (U. S. EPA,
1987a).
One epidemiologic study has shown that exposure to zinc oxide (0.2 to
5.1 mg/m3) over a 5 year period resulted in increased respiratory effects
(Bobrishchev-Pushkin et al., 1977). These effects included chronic bronchitis
and diffuse pneumosclerosis. In another epidemiologic study, Batchelor et al.
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(1926) found slight leukocytosis in 14 of 24 workers at a zinc smelter in New
Jersey. The smelter workers were exposed to elemental zinc in concentrations
ranging from 35 to 130 mg/m3.
The effects of zinc have been studied in animals to determine its
subchronic toxicity. Pistorius (1976) investigated the effects of inhalation
of zinc oxide particles (less than 1 micron in size) on rat lungs. The only
differences noted in lung function between the controls and exposed animals
were a decrease in specific conductance and difference volume in the exposed
group given 15 mg/m3 zinc oxide for 1, 4, or 8 hours/day for 84 days. In
another study Pistorius et al. (1976) examined the effect of zinc oxide dust
administered to rats for 4 hours/day, 5 days/week for 1, 14, 28, and 56 days.
Histological examination showed leukocytic inflammatory changes and fluid in
the alveolar region. These inflammatory changes decreased by days 28 and 56.
On the basis of the above epidemiologic and animal studies, the
unadjusted LOEL for zinc oxide is 0.2 mg/m3 for humans and 15 mg/m3 in
laboratory animals. No data were found from which a NOEL could be determined.
2.3.2 Carcinoqenicitv of Zinc
No evidence was found in the literature reviewed to indicate that
inhalation, ingestion, or parenteral administration of zinc induces the
formation of tumors. Based on the EPA carcinogenic classification system,
zinc has a group D weight-of evidence, not classifiable as to human
carcinogenicity. However, information does not exist indicating that zinc is
indirectly involved in tumor formation as a growth promoter or inhibitor.
Wallenius et al. (1979) found that 4-nitro-quinoline-n-oxide-induced cancer of
the oral cavity in female rats appeared earlier in animals ingesting a diet
containing 200 mg/kg zinc than animals fed 15 or 50 mg/kg zinc. Another
researcher discovered that a zinc-deficient diet (7 mg/kg) promoted the
formation of methyl benzylnitrosamine-induced esophageal tumors (Fong et al.,
1978).
2.3.3 Interaction with Other Compounds
Zinc oxide fumes have been reported to cause hypocalcemia in workers
exposed at a zinc oxide factory (Klucik and Koprda, 1979). The range of
employee exposure was 0.5 to 7.15 mg/m3. Mulhern and co-workers (1986)
reported that excess dietary zinc (2000 ppm zinc/day) produced copper
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deficiency in the offspring of C57 BL/GJ mice. The development of alopecia
was also noted in the offspring by five weeks of age.
2.4 COPPER
Copper (Cu) is an essential element that occurs naturally in the +1 and
+2 valence states. The biological availability and toxicity of copper are
thought to be related to free Cu*2 ion activity (U. S. EPA, 1987b). Emissions
of copper occur from natural (windblown dust, volcanoes, vegetation, forest
fires, and sea spray) and anthropogenic sources (Nriagu, 1979). The valence
state of copper emissions from iron and steel production is not known.
2.4.1 Noncancer Health Effects
The primary manifestations of exposure to copper fumes, dusts, or mists
are dermatologic and respiratory symptoms (U. S. EPA, 1987b). "Metal fume
fever" has been reported to occur following exposure to fine copper dusts
(Gleason, 1968), copper fumes (Armstrong et al., 1983), and copper oxide and
copper acetate dusts (Stokinger, 1981; Cohen, 1974). Copper concentrations as
low as 0.1 mg/m3 are reported to cause this disease (Gleason, 1968).
Human studies have been conducted to determine the chronic effects of
copper exposure. Chronic effects observed for occupational exposure to copper
include contact dermatitis (Stokinger, 1981; Cohen, 1974; Williams, 1982) and
leukocytosis (Armstrong et al., 1983). Mild anemia was reported by Finelli et
al. (1984) in workers exposed to 0.6 to 1.0 mg/m3 copper. Enterline and co-
workers (1986) examined the overall mortality of 14,562 workers from the
copper and zinc smelting industries and found no increased mortality.
Plamenac et al. (1985) found that copper sulfate affected the respiratory
epithelium and the pulmonary parenchyma.
In an animal study conducted Johansson et al. (1984), 0.6 mg/m3 copper
chloride administered to rabbits 6 hours/day, 5 days/week for 4 to 6 weeks
showed no significant changes in phospholipid content or histological lesions
in the lungs of exposed rabbits. The only significant change observed was an
increase in the number of alveolar type II cells. Another study, conducted by
Lundberg and Camner (1984) and using the same concentrations and exposure
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times listed above, resulted in no observed changes in the number of alveolar
macrophages or the lysozyme concentration in lavage fluid.
These data indicate that the unadjusted LOEL for humans exposed to
copper and laboratory animals exposed to copper chloride is 0.6 mg/m3. The
investigations presented do not allow the estimation of a NOEL in either
humans or laboratory animals.
2.4.2 Carcinogenicitv of Copper
There is no available evidence to indicate that copper exposure can
cause cancer (U. S. EPA, 1987b). Studies concerning the carcinogenicity,
mutagenicity, and teratogenicity of inhaled copper or copper compounds could
not be located in the available literature. As a result, the U. S.
Environmental Protection Agency has assigned copper to Group D, not
classifiable as to human carcinogenicity.
2.5 NICKEL
Nickel emitted from steel mills is thought to be in the form of complex
oxides of nickel and other metals (Page, 1983; Koponen et al., 1981). The
following discussion includes any specific information found in the literature
on chronic inhalation studies with nickel oxide. Where these data are
lacking, the general effects of the nickel ion and other nickel compounds are
presented.
2.5.1 Noncancer Health Effects
The direct respiratory effects of nickel compounds include asthma, nasal
septal perforations, chronic rhinitis, and sinusitis (U. S. EPA, 1986a).
Human exposure information for nickel is derived from occupational studies,
and the literature reviewed contained no specific human data on the
respiratory effects of nickel oxide. Asthma has been seen following working
exposure to nickel carbonyl (Sunderman and Sunderman, 1961), and nickel
sulfate exposure has resulted in septal perforation, chronic rhinitis, and
sinusitis (Kucharin, 1970).
Respiratory effects studies of animals indicate that the nickel ion
affects the viability and phagocytic activity of alveolar macrophages, and
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thus may affect resistance to respiratory infection (Graham et al., 1975a,b).
Rabbits exposed to 1 mg/m3 of metallic nickel dust for 3 and 6 months showed
changes in the number and volume of alveolar epithelial cells, and the 6-month
exposure group showed pneumonia (Johansson et al., 1981). Adult Wistar rats
exposed to 25 ug Ni/m3 for 4 months showed a significant increase in the size
and number of polynucleated macrophages and a 130% increase in phagocytic
activity (Spiegelberg et al., 1984).
Studies of nickel effects on other systems are not well documented.
Animal studies indicate that the nickel ion may affect carbohydrate metabolism
(U. S. EPA, 1986a). Nickel has been shown to have low neurotoxic potential
(NIOSH, 1977).
On the basis of the studies reviewed by the U. S. EPA (1986a), the
increase in the size and number of polynucleated macrophages and increase in
phagocytic activity in rats following 4 months of exposure to 25 ug/m3 is
estimated to represent the LOEL for exposure to nickel.
2.5.2 Carcinoqenicitv of Nickel
None of the three carcinogenic nickel compounds are known to be emitted
from steel mills. These compounds are nickel refinery dust (Group A), nickel
subsulfide (also Group A because it is the major species in refinery dust),
and nickel carbonyl (Group B2, probable human carcinogen). The incremental
unit risk due to lifetime exposure to 1 ug/m3 is 2.4 x 10"* for nickel
refinery dust and twice that for nickel subsulfide (U. S. EPA, 1986a). The
human evidence for nickel carbonyl's carcinogenicity is equivocal, but the
presence of distal site tumors in animal studies implicate it as a Group B2
carcinogen (U. S. EPA, 1986a). No incremental unit risk has been calculated
for nickel carbonyl.
Some studies indicate that the nickel ion may be the carcinogenic form,
thus implicating all forms of nickel as potential carcinogens. Inhalation
studies of nickel metal do not show the development of respiratory tract
tumors, but one investigation found adenomatoid lung lesions in rats,
bronchial adenomatoid lesions in guinea pigs, an alveolar anaplastic carcinoma
in one guinea pig lung, and a "metastatic lesion" in another animal (Hueper,
1958). This information (aside from the lack of controls in the guinea pig
study), together with a strong tumor response from intramuscular injection (at
the injection site), lends credence to the possibility that metallic nickel
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has limited evidence of carcinogenicity in animals (U. S. EPA, 1986a). Human
epidemiologic studies of workers exposed to nickel metal are confounded by the
presence of other possible carcinogens (U. S. EPA, 1986a).
2.5.3 Interaction with Other Compounds
Waalkes and co-workers (1985) reported that the injection of zinc offset
renal damage and hyperglycemia seen in animals exposed to nickel.
Pretreatment with nickel was shown to offset the effects of cadmium exposure
in rats (Tandon et al., 1984).
2.5.4 Populations at Risk
Populations at special risk to adverse effects from nickel exposure are
those with nickel hypersensitivity, generally from dermal exposures. While
there is no information that nickel exposure of pregnant women leads to
adverse effects, it has been shown that nickel can cross the placental barrier
in animals (Stack et al., 1976).
2.6 CADMIUM
The toxicologic effects of cadmium exposure are important because the
metal tends to accumulate and be retained in soft body tissues (especially in
the kidneys); exposure occurs from ambient air, food, water, and from
cigarette smoking; and the adverse health effects which occur following
exposure are generally irreversible (U. S. EPA, 1981). In addition, cadmium
has been classified as a probable human carcinogen.
2.6.1 Noncancer Health Effects
Deposition following inhalation of cadmium is higher for smaller
particles, and the absorbed cadmium is incorporated into metallothionein and
deposited in the kidney (Task Group on Lung Dynamics, 1966). Chronic cadmium
exposures thus typically result in renal dysfunction, which is the "critical"
noncancer effect following cadmium exposure (Nordberg, 1976).
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Animal studies indicate a dose-related progression of kidney damage from
early degenerative proximal tubule changes to interstitial edema and basement
membrane fibrosis (U. S. EPA, 1981). Proteinuria is the biochemical index of
renal dysfunction (U. S. EPA, 1981), and Kjellstrom (1976) estimated that
workplace cadmium levels of 50 ug/m3 increased the incidence of proteinuria in
workers exposed for 10 to 20 years. The EPA (1981) estimated that industrial
exposure for 10 years to cadmium levels of 23 to 25 ug/m3 would result in
renal cadmium levels sufficient to induce proteinuria.
The chief chronic pulmonary effect of cadmium exposure is centrilobular
emphysema and bronchitis (U. S. EPA, 1981). These effects have been found
following occupational exposure to cadmium-oxide fumes, cadmium-oxide dust,
and cadmium-pigment dust (Friberg et al., 1974). Lung impairment has been
seen in workers exposed to cadmium oxide levels below 100 ug/m3, depending on
exposure length (Lauwerys et al., 1974).
Several investigators have found that cadmium exerts immunosuppressive
effects in animal studies (Koller et al. 1975, Cook et al., 1975a,b; Exon et
al., 1975), but these effects have not been demonstrated in humans.
In order to estimate a NOEL and a LOEL for cadmium inhalation exposure,
exposure from other routes must also be considered because of cadmium's
accumulation and retention within the body. The U. S. EPA (1981) specified a
critical cadmium renal cortex concentration for renal dysfunction, and
assessed the impact of ambient air cadmium exposures taking into account
differing dietary intake levels and smoking status. In general, the EPA
(1981) concluded that ambient levels below 10 ng/m3 do not significantly
increase kidney cortex concentrations of cadmium, but above 100 ng/m3 renal
accumulation begins to occur and 1,000 ng/m3 approaches the critical level for
renal dysfunction. Thus, 10 ng/m3 can be considered the NOEL for cadmium
inhalation exposure, and 100 ng/m3 the LOEL.
2.6.2 Carcinoqenicitv of Cadmium
Cadmium is listed by the EPA's HHAG as a Bl carcinogen (probable human
carcinogen by inhalation). The basis for this classification is limited
evidence from epidemiologic studies and sufficient evidence of carcinogenicity
in two animal species (IRIS, 1989).
Thun and co-workers (1985) studied the incidence of lung cancer among
cadmium smelter workers, and reported a 2-fold excess risk of lung cancer.
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Like the other epidemiologic studies of cadmium-exposed workers (Varner, 1983;
Sorahan and Waterhouse, 1983; Armstrong and Kazantzis, 1983), however, the
presence of other carcinogens may have confounded the results. The U. S. EPA
thus considers cadmium to have only limited evidence of human carcinogenicity
(IRIS, 1989).
Evidence of cadmium's carcinogenic potential in animal studies is based
on increased lung tumors in rats exposed to cadmium and cadmium oxide via
inhalation (Takenaka et al., 1983), and injection site tumors in rats and mice
following intramuscular and subcutaneous injection (IRIS, 1989).
On the basis of these results, the EPA calculated a unit risk number of
1.8 x 10~3/ug/m3 for cadmium exposure. Thus, a person exposed continuously to
1 ug/m3 of cadmium for life has a probability of getting lung cancer of not
more than 1.8 chances in 1000. A conservative estimate is that a lung cancer
risk of 1 in 10,000 would occur at a concentration of 0.06 ug/m3 cadmium
(IRIS, 1989).
2.6.3 Interaction with Other Compounds
Cadmium is affected by or can affect levels of other metals in the body.
A deficiency of zinc increases the toxicity of cadmium, and increased zinc
levels offset cadmium's toxic effects (Choudhury et al., 1977; Pond and
Walker, 1975). Individuals with low iron levels may have a four-fold increase
in cadmium absorption.
2.6.4 Populations at Risk
Populations especially at risk to cadmium exposure are the elderly (due
to its long retention in the body), cigarette smokers, and those whose diets
add high amounts of the metal. The reader should refer to the U. S. EPA
(1981) document for detailed information on the estimated relative
contribution of cadmium through diet, smoking, and ambient air exposures.
2.7 VANADIUM
Vanadium is a naturally occurring metal that is widely distributed in
small amounts in the earth's crust. It is also found in trace amounts in
fossil fuels (U. S. EPA, 1987c). Vanadium in the air is believed to be solely
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a result of industrial processes. The oxidation states of vanadium are +2,
+3, +4 and +5 (NLM, 1986). It could not be determined which species of
vanadium are emitted from steel mills. The following discussion is focused
primarily on the effects of vanadium pentoxide exposure because the literature
contains little to no other information concerning inhalation exposures to
vanadium or its salts.
2.7.1 Noncancer Health Effects
The chronic effects of various vanadium compounds have been studied in
man with most reporting only minor irritations of the respiratory tract.
Sjoberg (1950) evaluated 36 workers exposed to vanadium pentoxide (0.05-5.58
mg/m3) at a vanadium processing plant in Sweden. Severe respiratory
irritation was the most common manifestation found in the workers, whom the
study followed for a two year period. In a study by Lewis (1959), 24 men
exposed vanadium pentoxide concentrations ranging from 0.018 to 0.38 mg/m3 had
an increased incidence of respiratory distress (cough, bronchospasm, pulmonary
congestion). The average duration of worker exposure was 2.5 years and the
author concluded that there were no permanent effects from chronic vanadium
exposure. Other chronic manifestations reported in the literature include
conjunctivitis, tracheobronchitis, and contact dermatitis (Tebrock and Machle,
1968; Symanski, 1939).
Subchronic effects resulting from relatively high concentrations of
vanadium have also been reported. A number of studies have documented the
development of respiratory symptoms (wheezing, coughing, dyspnea) after
exposure to high concentrations of vanadium over short time periods (Musk and
Tees, 1982; Zenz et al., 1962; McTurk et al., 1956). Zenz and Berg (1967)
exposed 2 volunteers to 1 mg/m3 vanadium pentoxide for 8 hours and reported
the presence of persistent cough in both. These investigators also exposed 5
other volunteers to 0.2 mg/m3 of vanadium pentoxide for 8 hours and reported
the development of a cough that lasted from 7 to 10 days. The unadjusted LOEL
based upon the above human studies would be 0.018 mg/m3 for vanadium
pentoxide. A NOEL could not be determined from the data.
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2.7.2 Carcinoqenicitv of Vanadium
The available literature on vanadium is not sufficient to evaluate its
carcinogenicity in laboratory animals or man. As a result, EPA has classified
vanadium a Group D carcinogen, not classifiable as to carcinogenic potential.
2.7.3 Interaction with Other Compounds
Vanadyl sulfate (25 ppm) has been found to inhibit the carcinogenic
effects of 1-methyl-l-nitrosourea in rats (Dimond et al., 1963). In terms of
antidotes, ascorbic acid and ethylenediaminetetraacetate were effective in
sequestering vanadium poisoning in mice, rats and dogs (Mitchell and Floyd,
1954).
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3.0 HEALTH EFFECTS OF OTHER COMPOUNDS EMITTED FROM STEEL MILLS
3.1 AMMONIA AND AMMONIUM SULFATE
This section discusses the health effects associated with exposure to
ammonia and ammonium sulfate. Both of these compounds are known to be emitted
from steel mill operations (Barnard, 1989).
3.1.1 Noncancer Health Effects
Exposure to ammonia will cause rapid increases in blood ammonia concen-
trations, as it is readily absorbed through the lungs (U. S. EPA, 1988). The
U. S. Environmental Protection Agency (1986b) reported that no adequate animal
studies with chronic exposures were found in the literature. Similarly, the
available human chronic exposure information is limited. The available
subchronic animal information and the human exposure information as presented
by the EPA (1988) are summarized below.
The National Research Council (1977) reported the average odor threshold
for ammonia to be 5 ppm (3.5 mg/m3). Continuous exposure to ammonia may cause
an increase in the occurrence or severity of respiratory tract infections
(National Research Council, 1977). Retention of ammonia in the respiratory
tract is about 80 percent for humans (not dose-related) (Silverman et al.,
1949).
No clinically significant effects were seen in one study of rats, guinea
pigs, rabbits, dogs, or monkeys exposed continuously to 57 ppm (40 mg/m3)
ammonia for 114 days (Coon et al., 1970). Mice and guinea pigs exposed to 20
ppm (14 mg/m3) for 28 days also showed no effect (Anderson et al., 1964), but
no averaging time was given. However, when exposure duration was increased to
42 days or concentration was increased to 50 ppm (35 mg/m3), pulmonary edema,
congestion, and hemorrhage occurred (Anderson et al., 1964). These studies
considered the lowest observed effect levels (14 mg/m3 for 42 days and 35
mg/m3 for 28 days) and the no observed effect level (14 mg/m3 for 28 days) as
presented by the U. S. EPA (1986b). The limited data available and the fact
that these studies are based on subchronic rather than chronic exposures make
it difficult to conclude that these are the true NOELs and LOELs.
Chronic exposure to humans at 30 mg/m3 ammonia caused headaches, nausea,
and reduced appetite (National Research Council, 1977), but again no averaging
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time was reported. Repeated exposure to 17, 35, or 69 mg/m3 for 6 hours per
day per week, for 6 weeks showed no changes in respiratory rate, blood
pressure, pulse, or forced vital capacity, but mild eye irritation occurred in
the early sessions (Ferguson et al., 1977).
In its review of the health effects of acid aerosol exposure, EPA found
that most of the studies of acid aerosols involve sulfuric acid, but some
effects of ammonium sulfate [(NHJ2SOJ can be inferred from these studies
(U.S. EPA, 1988). Most of the studies of acid aerosol exposure to humans do
not involve ammonium sulfate, and the only studies described by the
Environmental Protection Agency (1988) involved short exposure durations. One
study showed no effects in asthmatic and normal human subjects exposed to up
to 1.0 mg/m3 (0.5-1.0 mass median aerodynamic diameter, MMAD) for 16 minutes
(Utell et al., 1982).
The LOAEL based on animal studies reviewed by the Environmental
Protection Agency (1988) was determined from a study by Godleski et al. (1984)
in which emphysemic lesions were seen in hamsters exposed to 187 ug/m3 (0.187
mg/m3) (NHJ2S04 (0.3 MMAD) for 6 hours per day, 5 days per week, for 15 weeks.
Busch et al. (1984) found interstitial thickening in rats and guinea pigs
exposed to 1.03 mg/m3 (NHJ2S04 (0.42 MMAD) for 6 hours/day, 5 days/week, for
20 days. Other studies of ammonium sulfate exposure were based on short term
exposures (usually 1 hour) to 0.4 to 9.54 mg/m3 (Amdur et al., 1978; Loscutoff
et al., 1985; Schlesinger et al, 1978).
3.1.2 Carcinoqenicitv of Ammonia and Ammonium sulfate
No inhalation information is available to assess the carcinogenicity of
ammonia, but it has been shown to be noncarcinogenic in mice following oral
administration (Toth, 1972; Uzvolgi and Bojan, 1980). The EPA's HHAG
considers ammonia a group D compound, with insufficient evidence to judge its
carcinogenic potential in humans. No discussion of ammonium sulfate's
carcinogenic potential is provided by the Environmental Protection Agency
(1988), and this pollutant is not currently included in the IRIS data base.
3.1.3 Interaction with Other Compounds
The effect of ammonium sulfate exposure in conjunction with exposure to
other pollutants has been examined. Exposure to 2.6 mg/m3 S02 and 528 ug/m3
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(NHJ2S04 in human subjects for 4 hours showed upper airway irritation in 9 of
20 subjects, as compared to 4 of 20 subjects receiving S02 exposure only
(Kulle et al., 1984). Acid aerosols have also been shown to provide short-
term protection (up to 6 months) against benzo(a)pyrene-induced tumors
(Godleski et al., 1984).
3.2 HYDROGEN CHLORIDE
Hydrogen chloride (hydrochloric acid) is an acutely toxic gas because it
is highly soluble in water, and the resulting hydronium ion is reactive with
organic molecules and causes cellular injury and necrosis (U. S. EPA, 1987d).
The World Health Organization (WHO, 1982) reports a threshold for odor
perception of 0.2 ppm (0.3 mg/m3), but other reports range from 0.1 to 459
mg/m3 (U. S. EPA, 1987d).
3.2.1 Noncancer Health Effects
There are little chronic or subchronic inhalation data available for
hydrogen chloride in the literature. One subchronic study of guinea pigs
exposed to 0.15 mg/m3 hydrogen chloride for 2 hours/day for 28 days showed no
effect (Kirch and Drabke, 1982). Guinea pigs exposed to 15 mg/m3 for 2
hours/day, 5 days/week for 49 days showed no differences in lung function
compared to controls (Oddoy et al., 1982).
The only chronic study of hydrogen chloride exposure evaluated the
effects of inhalation of 15 mg/m3 on Sprague-Dawley rats exposed for 6
hours/day, 5 days/week for life (Albert et al., 1982). Nasal mucosa lesions
found at autopsy included rhinitis, epithelial or squamous hyperplasia, and
squamous metaplasia. Because of the limited data available, 15 mg/m3 hydrogen
chloride can be considered the LOAEL, and a NOAEL of 0.15 mg/m3 can be
estimated from the subchronic hamster study of Kirche and Drabke (1982).
3.2.2 Carcinoqenicitv of Hydrogen chloride
There are no adequate epidemiologic or animal carcinogenicity studies of
hydrogen chloride, thus it is classified as a Group D carcinogen.
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3.3 TOLUENE
Toluene, another compound that may be emitted during the steel -
manufacturing process, has its primary effects on the central nervous system,
with occupational studies reporting symptoms of headache, dizziness, fatigue
and feelings of intoxication among those exposed. Gusev (1965) estimated the
minimum toluene odor threshold to be 0.40 to 0.85 ppm (1.5 to 3.2 mg/m3). May
(1966), however, found the minimum odor threshold to be 37 ppm (140 mg/m3).
3.3.1 Noncancer Health Effects
Several investigators (Anderson et al., 1983; Baelum et al., 1985; Ogato
et al., 1970; von Oettingen et al., 1942) evaluated the effects of toluene in
workers exposed for 1 day to concentrations of 0, 10, 40, 100, and 200 parts
per million (ppm). At 100 ppm (377 mg/m3), nasal and eye irritation,
headache, dizziness, and intoxication were reported among those exposed for 6
hours (Andersen et al., 1983). Groups exposed for 6 hours to 10 and 40 ppm
(38 and 151 mg/m3) reported no effects. Baelum and co-workers (1985) also
found neurotoxic effects in workers (with a history of toluene exposure)
exposed to 100 ppm for 6.5 hours.
Ogata and co-workers (1970) examined subjects exposed to 200 ppm (754
mg/m3) for 7 hours and found prolongation of reaction time and decreased pulse
rate, von Oettingen et al. (1942) reported that muscular weakness, confusion,
and impaired coordination occurred following exposure to 200 ppm for 8 hours,
and at 100 ppm moderate fatigue and headache occurred. Wilson (1943) reported
headaches and lassitude among humans exposed for 1 to 3 weeks to 50 and
100 ppm toluene.
On the basis of these 1-day occupational studies, it can be concluded
that the LOAEL for toluene exposure is 100 ppm (377 mg/m3) and the NOAEL is 40
ppm (151 mg/m3). This information has strong support even though the studies
are based on one-day exposure periods. This support includes longer-term
animal studies such as those of the American Petroleum Institute (1980),
Gibson and Hardisty (1983), Kyrklund et al. (1987), and Okeda et al. (1986).
The American Petroleum Institute (1980) conducted a chronic rat study for 26
weeks with exposure levels of 0, 100, and 1500 ppm for 6 hr/day, 5 days/week.
The LOAEL for this study was 100 ppm. Gibson and Hardisty (1983) exposed rats
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to 0, 30, 100 and 300 ppm for 6 hr/day, 5 days/week for up to 24 months, and
reported a LOEL of 100 ppm.
3.3.2 Carcinogenicitv of Toluene
Toluene's carcinogenic potential has been evaluated by the National
Toxicology Program (U. S. DHHS, 1989). Toxicology and carcinogenesis studies
in rats and mice exposed to toluene by inhalation for 15 or 24 months (0, 600,
and 1200 ppm) indicated no evidence of carcinogenicity (U. S. DHHS, 1989).
The Chemical Industry Institute of Toxicology (1980) also concluded that
exposure to toluene levels of 30, 100 and 300 ppm for 24 months did not
implicate toluene as a carcinogen.
3.4 BENZENE
Benzene is an aromatic hydrogen that is slightly soluble in water. Once
a widely used solvent, benzene can produce narcotic effects similar to those
of toluene. Of most concern, however, are the hematotoxic effects of benzene.
3.4.1 Noncancer Health Effects
Deichmann and co-workers (1963) studied the effects of subchronic
benzene inhalation exposure in rats at concentrations ranging from 15 to 83
ppm (48 to 2600 mg/m3). Groups exposed to 47 and 44 ppm (150 and 140 mg/m3)
for 7 hours/day, 5 days/week for 8 weeks or more showed slight or moderate
leukopenia. Groups exposed to < 31 ppm (99 mg/m3) showed no effects, and this
level is reported by the EPA (1984c) to be the NOEL for leukopenia in rats.
Chronic mouse inhalation studies conducted by Snyder et al. (1980)
revealed marked lymphocytopenia, slight anemia, and bone marrow hypoplasia in
mice exposed to 100 ppm (320 mg/m3) benzene for 6 hours/day, 5 days/week for
life. Chronic human exposure to benzene may cause pancytopenia (a reduction
in blood erythrocytes, leucocytes, and thrombocytes)(U. S. EPA, 1984c). Mild
cases of anemia, leukopenia, and thrombocytopenia are generally reversible if
exposure is ceased. Studies by NIOSH (1974) indicate that the lowest limit of
hematologic effects in humans is less than 100 ppm (Hardy and Elkins, 1948;
Pagnotto et al., 1961). Elkins (1976) and Pagnotto et al. (1977) conclude
that a benzene level of 25 ppm (80 mg/m3) is safe for most workers.
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3.4.2 Carcinoqenicitv of Benzene
There is substantial evidence from epidemiologic studies that benzene
causes leukemia (U. S. EPA, 1985). Benzene is thus a Group A known human
carcinogen. Animal studies have not demonstrated this effect, however.
Epidemiologic studies by Pinsky et al. (1981), Ott et al. (1978), and Wong et
al. (1983) were reviewed by the U. S. EPA (1985) in order to prepare an
inhalation unit risk estimate of 8.3 x 10~6/iig/m3 for benzene. This can be
translated to indicate that a person's risk of getting lung cancer, following
continuous lifetime (70 years) exposure to 1 ug/m3 of benzene will not exceed
8.3 chances in one million.
3.4.3 Interaction with Other Compounds
The metabolism and toxicity of benzene can be affected by the presence
of other solvents that are oxidized by the same hepatic enzymes (Ikeda et al.,
1972). These solvents include xylene and toluene. The inability of benzene
alone to induce leukemia in experimental animals has lead some researchers to
hypothesize that the hematotoxic effects seen in humans are actually the
result of exposure to benzene along with other solvents. (Andrews et al.,
1977; U. S. EPA, 1980).
3.5 NAPHTHALENE
Naphthalene is an aromatic hydrocarbon that can be released to the
ambient environment either in a gaseous or particulate form. While airborne,
naphthalene will undergo photochemical degradation and has a half-life of
eight hours during sunlight hours. At night, it has been estimated that
naphthalene has a half-life of 15 hours as a result of reaction with nitrate
radicals (U. S. EPA, 1987e).
3.5.1 Noncancer Health Effects
The health effects associated with inhalation exposure to naphthalene
have not been well documented in either humans or laboratory animals (U. S.
EPA, 1987e). Cataracts have been found to develop in individuals exposed to
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naphthalene by the oral, dermal, and inhalation routes (U. S. EPA, 1980).
Naphthalene exposure in the occupational setting also has resulted in cataract
development (Ghetti and Mariani, 1956; Hollowich et al., 1975). Acute effects
of naphthalene exposure have been reported in humans, the most common
manifestation being acute hemolytic anemia. Investigators have described
incidences where acute hemolytic anemia has developed after combined dermal
absorption and inhalation of naphthalene vapors by neonates (Grigor et al.,
1966) and adults (Younis et al., 1957), and inhalation of naphthalene vapors
alone by neonates (Hanssler, 1964) and adults (Linick, 1983). The
concentration of the naphthalene in the above cases was not reported in the
literature due to the poorly defined nature of the exposure.
Few studies have been conducted on laboratory animals to determine the
effect of naphthalene exposure. An 8-hour Median Lethal Concentration (LC50)
value of 180 ppm (940 mg/m3) for naphthalene in laboratory animals was
reported by Union Carbide (1968). However, Buckpitt (1985) suggests that this
value may be too low based on the oral and intraperitoneal Median Lethal Dose
(LD50) values. Male and female Wistar rats exposed to 78 ppm (408 mg/m3)
naphthalene for 4 hours resulted in no mortalities, nor any lung, liver,
kidney or nasal passage abnormalities (Fait and Nachreiner, 1985). This
value, 78 ppm naphthalene, could be considered the unadjusted NOEL in
laboratory animals. In an unpublished inhalation study by Buckpitt (1985),
male Swiss-Webster mice were exposed to 90 ppm (470 mg/m3) naphthalene for 4
hours without any resulting mortalities. The researcher did note the
development of prominent lesions in the lungs of the exposed mice, however.
This value reported by Buckpitt, 90 ppm naphthalene, is the unadjusted LOEL in
laboratory animals.
3.5.2 Carcinoqenicitv of Naphthalene
Because of the lack of definitive data, naphthalene is classified as a
Group D carcinogen. The available evidence is inadequate to evaluate the
carcinogenic potential of naphthalene in man.
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4.0 HEALTH EFFECTS OF COMPLEX MIXTURES
Sections 2.0 and 3.0 of this report presented health effects information
for individual pollutants that comprise steel mill emissions. This section
discusses the effects of mixtures known to be emitted during steel
manufacture. Polycyclic organic matter is one such mixture, and denotes many
chemical groups, including polycyclic aromatic hydrocarbons, aza-, imino-, and
carbonyl-arenes, and polychloro compounds, among others.
The coke oven emission mixture includes not only polycyclic organic
matter, but also includes many of the individual pollutants discussed in
Sections 2.0 and 3.0. These pollutants include cadmium, chromium, nickel,
ammonia, toluene, and benzene.
4.1 POLYCYCLIC ORGANIC MATTER
Polycyclic organic matter (POM) is a mixture of many groups of compounds
commonly formed in combustion or high temperature processes involving carbon
and hydrogen (Santodonato et al., 1979). The two POM groups most commonly
detected in ambient air are polycyclic aromatic hydrocarbons (PAH) and PAH
nitrogen analogs (aza- and imino- arenes). Polycyclic organic matter is
generally present in the atmosphere as particulate matter or attached to
particulate matter.
4.1.1 Noncancer Health Effects
Benzo(a)pyrene (BaP) is the best known and most studied PAH, and much of
the POM health effects knowledge is derived from BaP studies. The major
health-related effects of POM inhalation involve local lesions of the
respiratory tract (Santodonato et al., 1979). Particle size of the POM or POM
carrier is very important in determining deposition, cellular reactions, and
clearance of inhaled POM. Mucociliary clearance plays an important role in
the reactivity and clearance of POM. Scala (1975) has shown that irritants
that inhibit ciliary activity can increase the length of time POM is present
in the tracheobronchial tract, thus increasing the potential to form reactive
electrophiles. These reactive electrophiles are capable of interacting with
cellular constituents such as RNA, DMA, and proteins, which can lead to the
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formation of tumors (Lehr et al., 1978). This process will be covered in more
detail in Section 4.1.2. Tumor formation is also possible due to particles
that are cleared via mucociliary activity, swallowed, and absorbed through the
gastrointestinal tract (Santodonato et al., 1979)
There is little information in the literature on the noncancer health
effects of POM. Several POM are known to be noncarcinogens (i.e.,
benzo(e)pyrene, anthracene). Several POM have been shown to be
immunosuppressives (Malmgren et al., 1952), but immunosuppression is thought
to be correlated with carcinogenic potency (Baldwin, 1973). Benzo(e)pyrene
and anthracene show no immunosuppression.
Other noncancer effects occur because a threshold exists for exposure to
carcinogenic POM below which tumor formation will not be induced. Gross and
co-workers (1965) administered 100 ug of 7-12 dimethylbenz(a)anthracene (DMBA)
or BaP via intratracheal application to hamsters for 4 to 16 months that
resulted in acute pneumonia and chronic pneumonitis.
Because of the complexity of the POM mixture and the lack of noncancer
data in the literature, it is not possible to delineate NOEL or LOEL values.
It is thought, however, that the noncarcinogenic effects of POM will occur at
the same dose levels that induce tumor formation.
4.1.2 Carcinoaenicitv of Polvcvclic Organic Matter
There is little quantitative cancer data available for POM. Most of the
information available concerns PAH compounds. Benzo(a)pyrene,
benz(a)anthracene, dibenzo(a,h)pyrene, dibenz(a,h)anthracene, and
dibenzo(a,i)pyrene are considered animal carcinogens. Benzo(a)pyrene and
dibenz(a,h)anthracene are complete carcinogens (capable of initiation and
promotion), and have similar carcinogenic potency (Santodonato et al., 1979).
Benz(a)anthracene, dibenzo(a,i)pyrene, and dibenzo(a,h)pyrene are weaker
carcinogens (Santodonato et al., 1979).
Benzo(a)pyrene is the only POM included in IRIS with quantitative
carcinogenic information, and it is classified as a Bl probable human
carcinogen (IRIS, 1989). The human data are inadequate to judge BaP's ability
to induce cancer because BaP cannot be delineated as the cancer causing agent
in studies of cigarette smoke, roofing tar, and coke oven emission exposures.
Benzo(a)pyrene has sufficient evidence as an animal carcinogen, with
subcutaneous, intramuscular, intratracheal, and oral administration resulting
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in tumors in mice, rats, rabbits, and hamsters (IRIS, 1989). Inhalation of
BaP at concentrations of 2.2, 9.5, and 45 mg/m3 for up to 24 months in
hamsters resulted in respiratory tract tumors in the groups exposed to 9.5 and
45 mg/m3 (Thyssen et al., 1981). According to the U. S. EPA, the unit risk
number for BaP is calculated to be 3.3 x 10~3/ug/m3.
4.2 COKE OVEN EMISSIONS
Coke is used primarily in the steel industry's blast furnaces to
generate iron which is subsequently refined into steel (U. S. EPA, 1984d).
During the production of coke, chemically-complex emissions are released which
consist of gases and respirable particulate matter. An extensive list of
these emissions can be found in the EPA document "Carcinogen Assessment of
Coke Oven Emissions" (U. S. EPA, 1984d).
4.2.1 Noncancer Health Effects
The available literature on the effects of coke oven emissions focuses
on coal tar, which results from the condensation of coke oven emissions.
Kinkead (1973) exposed Sprague-Dawley yearling rats, Sprague-Dawley weanling
rats, ICR mice, and CAF-1 mice to an aerosol of coal tar continuously for 90
days at concentrations of 0.2, 2.0, and 10 mg/m3. The result was a high
degree of mortality among the exposed animals attributable to general
debilitation resulting in greater chance of infection. A high incidence of
chronic murine pneumonia was observed in all species studied (Kinkead, 1973).
In another study, MacEwen and co-workers (1976) investigated the effect
of a coal tar mixture collected from multiple coke ovens in the greater
Pittsburgh area. ICR-CF-1 mice, CAF-1-JAX mice, weanling Sprague-Dawley rats,
New Zealand white rabbits, and Macaca mullata monkeys were exposed to a coal
tar aerosol at 10 mg/m3, 6 hour/day, 5 days/week, for 18 months.
The investigators reported a significant inhibition of body growth rate in the
rabbits after 1 month and in the rats after 4 months. None of the monkeys
showed significant inhibition of growth (MacEwen et al., 1976).
On the basis of these animal studies, an unadjusted LOAEL of 0.2 mg/m3
can be estimated for exposure to coke oven emissions (coal tar).
stllmll 28
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4.2.2 Carcinoqenicitv of Coke Oven Emissions
A large body of literature exists concerning the carcinogenic activity
of coke oven emissions in humans. In a review of the available epidemiologic
literature by the U. S. EPA (1984d), it was concluded that exposure to coke
oven emissions increases the risk of lung, tracheal, bronchial, kidney, and
prostrate cancer, as well as cancer at all sites combined. Redmond et al.
(1972, 1976, 1979) conducted a number of epidemiologic studies to determine if
coke oven emissions result in increased cancer risk. In the 1979 study this
group found a significant excess of lung, trachea, and bronchus cancer
mortality in coke oven workers. The investigation also showed an increase in
prostate and kidney cancer (Redmond et al., 1979). Lloyd (1971) found an
increase in death from respiratory neoplasms and an increase in mortality from
all causes in steel workers employed in 1953 in the coke plants of two
Allegheny County, Pennylvania steel mills.
Animal models have also been used to assess the carcinogenic potential
of coal tar. C3H mice were exposed to 0.30 mg/Titer coal tar aerosol for 2-
hour periods, 3 times a week for up to 36 weeks (Morton et al., 1963). Six of
the 33 mice tested developed squamous cell tumors in the periphery of the
lung. Tye and Stemmer (1967) studied the carcinogenic effects of different
fractions of coal tar in male C3H/HeJ mice. The mice were exposed to 0.20
mg/liter for 2 hours every 3 weeks during the first 8 weeks, but, because so
many mice died during this time period, the concentration was reduced to 0.12
mg/liter for the remainder of the experiment (55 weeks). Upon histological
examination, adenomas and adenocarcinomas of the lung were observed in 60 to
100% of the mice inhaling aerosols of coal tars while control mice developed
no observable tumors.
The available epidemiologic and animal data overwhelmingly prove that
coke oven emissions are carcinogenic in man and experimental animals. Three
separate organizations have classified the coke oven emission mixture as a
known human carcinogen. The U. S. EPA lists coke oven emissions as a Group A
carcinogen; the International Agency for Cancer Research groups coke oven
emissions into category 1; and the National Toxicology Program also classifies
coke oven emissions as a known human carcinogen. The EPA's unit risk number
for coke oven emissions, based on lifetime continuous exposure to 1 ug/m3, is
6.2 x 10"4/ug/m3, based on epidemiologic studies of steelworkers exposed to
coke oven emissions for up to 15 years.
stllmll 29
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43
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APPENDIX A
GLOSSARY OF HEALTH, EXPOSURE, AND RISK ASSESSMENT TERMS*
*Source: U. S. Environmental Protection Agency (1989). Glossary of Terms
Related to Health, Exosure, and Risk Assessment. Air Risk Information Support
Center; EPA/450/3-88/016.
A-l
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Glossary of Health, Exposure, and Risk Assessment Terms
This section provides brief definitions of terms that
are frequently encountered in discussions of health,
exposure, and risk assessments for toxic air
pollutants.
Absorbed dose. The amount of a substance
penetrating across the exchange boundaries of
an organism, via either physical or biological
processes, after contact (exposure).
Absorption. To take in a substance through a
body surface such as the lungs,
gastrointestinal tract, or skin and, ultimately
into body fluids and tissues.
Acute exposure. One or a series of short-
term exposures generally lasting less than 24
hours.
Administered dose. The amount of a
substance given to a human or test animal in
determining dose-response relationships,
especially through ingestion or inhalation (see
applied dose). Even though this term is
frequently encountered in the literature,
administered dose is actually a measure of
exposure, because even though the substance
is "inside" the organism once ingested or
inhaled, administered dose does not account
for absorption (see absorbed dose).
Adverse effect. A biochemical change,
functional impairment, or pathological lesion
that either singly or in combination adversely
affects the performance of the whole organism,
or reduces an organism's ability to respond to
an additional environmental challenge.
Adenoma. A benign tumor originating in the
covering tissue (epithelium) of a gland.
Additivity. A pharmacologic or toxicologic
interaction in which the combined effect of two
or more chemicals is approximately equal to
the sum of the effect of each chemical alone.
(Compare with: antagonism, synergism.)
Aerodynamic diameter. A measurement of
the diameter of a particle expressed as the
diameter of a unit density sphere with identical
inertial properties.
Aerosol. A suspension of liquid or solid
particles in a gaseous medium.
Aggregate risk. The sum of individual
increased risks of an adverse health effect in
an exposed population.
Airway. Any conducting segment of the
respiratory tract through which air passes
during breathing. The bronchial tubes are
examples of airways.
Airway resistance (Raw). The functional
resistance to air flow afforded by the airways
between the mouth and the alveoli.
Alkylation. The substitution of an alkyl radical
for a hydrogen atom in a chemical molecule.
An alkyl radical follows the general formula
CnH2n +1. Alkylation is viewed as an event that
may lead to toxicity.
Allergen. An antigenic substance capable of
eliciting an allergic response.
Altered growth. A change in offspring, organ,
or body weight or size. Altered growth can be
induced at any stage of development, may be
reversible, or may result in a permanent
change.
Alveolar. Pertaining to the air sacs (alveoli) of
the lung where gas exchange occurs.
Alveolar macrophage. A cell within the lung
that contributes to immunological activities of
the lung by phagocytosing (engulfing) and
killing microbes, phagocytosing inhaled
particles, secreting/excreting antimicrobial
substances, and performing other activities.
Under some conditions, it also can secrete/
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excrete enzymes capable of digesting lung
tissue.
Alveolar ventilation. The volume of air
entering the alveoli each minute.
Ambient. Encompassing or surrounding area.
Ames test. An in vitro bacterial test for
detecting point mutations in a group of
histidine-requiring strains of Salmonella
typhimurium. An Ames test is usually
conducted with an exogenous source of
metabolic activation by adding, for example,
enzymes obtained from mammalian liver cells
(S9 liver fraction), to the S. typhimurium assay
system.
Anaphylaxis. An exaggerated reaction to an
antigen to which an organism has been
previously sensitized.
Anemia. A condition characterized by a
reduction in the number of circulating red blood
cells and/or the number of hemoglobin
molecules in red blood cells.
Anergy. Diminished reactivity to specific
antigens.
Aneuploidy. A condition in which the
chromosome number is not an exact multiple
of the usual number of chromosomes for that
species. For example, a "normal" human has
46 chromosomes; an individual with 47
chromosomes would be described as
aneuploid.
Annual incidence. The number of new cases
of a disease occurring or predicted to occur in
a population over a year.
Anoxia. Absence/lack of or significant
reduction in oxygen.
Antagonism. A pharmacologic or toxicologic
interaction in which the combined effect of two
chemicals is less than the sum of the effect of
each chemical alone; the chemicals either
interfere with each other's actions, or one
interferes with the action of the other.
(Compare with: additivity, synergism.)
Antibody. A protein substance developed in
response to, and interacting specifically with,
an antigen. The antibody-antigen reaction
forms a major basis for immunity.
Antigen. A substance that induces the
formation of antibodies and interacts with its
specific antibody. Antigens may be introduced
into the body or may be formed within the
body. The antigen-antibody reaction forms a
basis for immunity.
Apnea. Temporary cessation of breathing.
Applied Dose. The amount of a substance
given to a human or test animal in determining
dose-response relationships, esp. through
dermal contact (see administered dose). Even
though this term is encountered in the
literature, applied dose is actually a measure of
exposure, since it does not take absorption into
account.
Arrhythmia. Any variation from the normal
rhythm of the heartbeat.
Asthma. A condition marked by recurrent
attacks of difficult or labored breathing and
wheezing resulting from spasmodic contraction
and hypersecretion of the bronchi resulting
from exposure to allergens such as drugs,
foods, environmental pollutants, or intrinsic
factors.
Atmospheric half-life. The time required for
one-half of the quantity of an air pollutant to
react and/or break down in the atmosphere.
Atmospheric residence time. The time
required for removal of a substance from the
atmosphere to the extent that l/e
(approximately 37%) of the original material
remains.
Atrophy. Reduction in the size of a structure
or organ resulting from lack of nourishment or
functional activity, death and reabsorption of
cells, diminished cellular proliferation, pressure,
ischemia or hormone changes.
Averaging time. The time period over which a
function (e.g., average concentration of an air
pollutant) is measured, yielding a time-
weighted average.
Benign. A condition of a neoplasm (tumor) in
which the morphological and behavioral
characteristics of the tumor differ minimally
from the tissue from which it originates. A
benign neoplasm (as distinct from malignant)
may expand, but remains encapsulated, and
has limited potential to invade local structure
and proliferate.
Bioaccumulation. Progressive increase in
amount of a chemical in an organism or part of
an organism that occurs because the rate of
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intake exceeds the organism's ability to
remove the substance from the body.
region of the lungs. Bronchial airways provide a
passageway for air movement.
Bioassay. A test conducted in living organisms
to determine the hazard or potency of a
chemical by its effect on animals, isolated
tissues, or microorganisms.
Bioavailability. A measure of the degree to
which a dose of a substance becomes
physiologically available to the body tissues
depending upon absorption, distribution,
metabolism and excretion rates.
Bioconcentration. Same as bioaccumulation;
refers to the increase in concentration of a
chemical in an organism.
Biological half-life. The time required for the
concentration of a chemical present in the
body or in a particular body compartment to
decrease by one-half through biological
processes such as metabolism and excretion.
Biological markers/monitoring. Measuring
chemicals or their metabolites in biological
materials (e.g., blood, urine, breath) to estimate
exposure, or to detect biochemical changes in
the exposed subject before or during the onset
of adverse health effects. Sometimes refers to
a specific indicator for a particular
disease/functional disturbance.
Biologically significant effect. A response in
an organism or other biological system that is
considered to have a substantial or noteworthy
effect (positive or negative) on the well-being
of the biological system. Used to distinguish
statistically significant effects or changes,
which may or may not be meaningful to the
general state of health of the system.
Biotransformation. An enzymatic chemical
alteration of a substance within the body that
generally leads to a more excretable
metabolite, sometimes producing a more toxic
form of the substance.
Block group/enumeration district (BG/ED).
The smallest geographic areas used by the
Bureau of Census in conducting the population
census. Block groups are designated for urban
areas, while enumeration districts are
designated for rural areas. BG/EDs data are
frequently incorporated into exposure models
to estimate population exposure to
environmental pollutants.
Bronchial. Pertaining to the airways of the
lung below the larynx that lead to the alveolar
Bronchiectasis. Pathological dilation of a
bronchus or of the bronchial tubes.
Bronchitis. Inflammation of the mucous
membrane of the bronchial tubes.
Cancer. A malignant new growth. Cancers are
divided into two broad categories: carcinoma
and sarcoma.
Carcinogenic. Able to produce malignant
tumor growth. Operationally most benign
tumors are usually included also.
Carcinogenic process. A series of stages at
the cellular level after whichcancer will develop
in an organism. Some believe there are at least
3 stages: initiation, promotion, and
progression.While hypothesized as staged
process, little is known about specific
mechanisms of action.
Carcinoma. A malignant tumor of epithelial cell
origin (e.g., skin, lung, breast), tending to
infiltrate the surrounding tissue and give rise to
metastases.
Case-ccntro/ study. A retrospective
epidemiologic study in which individuals with
the disease under study (cases) are compared
with individuals without the disease (controls)
in order to contrast the extent of exposure in
the diseased group with the extent of exposure
in the controls.
Ceiling limit. A concentration limit in the work
place that should not be exceeded, even for a
short time, to protect workers against frank
health effects.
Central nervous system. The portion of the
nervous system that includes the brain and
spinal cord, and their connecting nerves.
Chemical mixture. Any combination of two or
more substances regardless of source or of
spatial or temporal proximity.
Chromosome. A very long molecule of ONA
complexed with protein, containing genetic
information arranged in a linear sequence.
Chromosome abnormality. A group of
conditions associated with abnormalities in the
number or structure of chromosomes. These
can be produced by insertion, deletion, or
rearrangement of chromosomal segments.
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Chronic exposure. Long-term exposure
usually lasting six months to a lifetime.
Chronic obstructive pulmonary disease
(COPD). A disease of the lung, involving
increased resistance to air flow in the bronchial
airways and loss of tissue elasticity, that leads
to decreased ability of the lungs to perform
ventilation. The pathological changes that lead
to COPD can be caused by chronic bronchitis,
pulmonary emphysema, chronic asthma, and
chronic bronchiolitis.
Cirrhosis. A liver disease characterized by
increased fibrous tissue, accompanied by other
abnormal physiological changes. Clinical signs
of cirrhosis include the loss of functional liver
cells and increased resistance to blood flow
through the liver.
Ciliated epithelial cell. A cell with cilia that
lines the tracheobronchial region of the lung.
The beating of the cilia moves mucus and
substances (such as inhaled particles trapped
on/in the mucus) upwards and out of the lung,
thereby contributing significantly to lung
clearance.
Clastogenic. Able to break chromosomes and
thereby produce chromosome abnormalities, a
form of genotoxicity. This results in the gain,
loss, or rearrangement of pieces of
chromosomes.
Clearance. The disappearance of a compound
from a specific organ or body compartment or
the whole body. In pulmonary toxicology,
clearance refers specifically to removal of an
inhaled substance that deposits on the lung
surface.
Cohort study. A study of a group of persons
sharing a common experience (e.g., exposure
to a substance) within a defined time period;
this experiment is used to determine if an
increased risk of a health effect (disease) is
associated with that exposure.
Complete carcinogen. Chemicals that are
capable of inducing tumors in animals or
humans without supplemental exposure to
other agents. Complete refers to the three
stages of carcinogenesis, initiation, promotion,
and progression which need to be present in
order to induce a cancer.
Compliance. Pulmonary compliance. The
volume change per unit of pressure change for
the lungs, the thorax, or the lungs-thorax
system. The distensibility of the lungs or
thorax.
Confidence limit. The confidence interval is a
range of values that has a specified probability
(e.g., 95 percent) of containing a given
parameter or characteristic. The confidence
limit refers to the upper value of the range (e.g.
upper confidence limit).
Control group. A group of subjects observed
in the absence of the exposure agent for
comparison with exposed groups.
Critical Endpoint. A chemical may elicit more
than one toxic effect (endpoint), even in one
test animal, in tests of the same or different
duration (acute, subchronic, and chronic
exposure studies). The doses that cause these
effects may differ. The critical endpoint used in
the dose-response assessment is the one
that occurs at the lowest dose. In the event
that data from multiple species are available, it
is often the most sensitive species that
determines the critical endpoint. This term is
applied in the derivation of risk reference
doses.
Cross-sectional study. An epidemiologic
study assessing the prevalence of a disease in
a population. These studies are most useful for
conditions or diseases that are not expected to
have a long latent period and do not cause
death or withdrawal from the study population.
Potential bias in case ascertainment and
exposure duration must be addressed when
considering cross-sectional studies.
Cyanosis. Bluish discoloration, especially of
the skin and mucous membranes and fingernail
beds caused by deficient oxygenation of the
blood.
Cytochrome P-448 and P-450. Enzymes
which are important in the detoxification by
biotransformation of many chemical
substances. Cytochrome P-448 and P-450
enzymes, integral in the metabolic activation
and detoxification of many compounds, are
found primarily in the liver and, to a lesser
extent, in the lung and other tissues.
Cytotox/cfty. Producing a specific toxic action
upon cells.
ON A. Deoxyribonucleic acid. The nucleic acid
molecule in chromosomes that contains the
genetic information. The molecule is double
stranded, with a "backbone" of phosphate and
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sugar (deoxyribose) to which the nucleotide
bases are attached. The nucleotides form a
ladder-like structure by hydrogen bonds such
that adenine (A) pairs with thymine (T) and
guanine (G) pairs with cytosine (C). The
specific sequence of nucleotide bases defines
the gene.
DNA adduct. A lesion in the DNA formed by
the covalent binding of an exogenous chemical
to one of the nucleotide bases. DNA adducts
are frequently the precursors to changes in the
sequence of nucleotides (mutations).
DNA crosslink. A lesion in the DNA formed by
the covalent binding of an exogenous chemical
to two nucleotide bases, one each on opposing
strands of the DNA. DNA crosslinks usually
prevent DNA replication and are lethal to cells
attempting to divide.
Deposition. Specific to air toxics, the
adsorption on the respiratory tract surface of
inhaled, gaseous, or particulate pollutants.
Also, adsorption of a gaseous or particulate air
pollutant at the surface of the ground,
vegetation, or water.
Dermatitis. Inflammation of the skin.
Detoxification. Reduction of a chemical's toxic
properties by means of biotransformation
processes, to form a more readily excreted, or
a less toxic chemical than the parent
compound.
Developmental toxicity. Adverse effects on
the developing organism that may result from
exposure 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. Major
manifestations of developmental toxicity
include: death of the developing organism;
induction of structural abnormalities
(teratogenicity); altered growth; and functional
deficiency.
Diffusion. Movement of a chemical substance
from areas of high concentration to areas of
low concentration. Biologically, diffusion is an
important means for toxicant deposition for
gases and very small particles in the
pulmonary region of the lungs.
Diploid. The chromosome state in which each
homologous chromosome is present in pairs.
Normal human somatic (non-reproductive)
cells are diploid (i.e., they have 46
chromosomes), whereas reproductive cells.
with 23 chromosomes are haploid.
Dispersion model. A mathematical model or
computer simulation used to predict the
movement of airborne pollution. Models take
into account a variety of mixing mechanisms
which dilute effluents and transport them away
from the point of emission.
Disposition. The movement and fate of
chemicals in the body, including absorption,
distribution, biotransformation, and excretion.
Distribution. Transport of a substance through
the body by physical means (e.g., active
transport or diffusion). Distribution is dependent
on the chemical properties of the toxicant or its
metabolites and, to some extent, the route of
exposure as well as physiologic variables.
Diuresis. Increased production of urine.
Dose-response relationship. A relationship
between: (1) the dose, often actually based on
"administered dose" (i.e., exposure) rather
than absorbed dose, and (2) the extent of toxic
injury produced by that chemical. Response
can be expressed either as the severity of
injury or proportion of exposed subjects
affected. A dose-response assessment is one
of the four steps in a risk assessment.
Dosimetry. In general, the measurement or
modeling of the amount, rate, and distribution
of a drug or toxicant especially as it pertains to
producing a particular biological effect.
Dyspnea. Difficult or labored breathing.
Edema. An accumulation of an excessive
amount of fluid in cells, tissues, or serous
cavity. Lung edema is the accumulation of fluid
in the lung.
Embryo. In mammals, the stage in the
developing organism at which organs and
organ systems are developing. For humans,
this involves the stage of development
between the second through eighth weeks
(inclusive) post conception.
Embryotoxicity. Any toxic effect on the
conceptus as a result of prenatal exposure
during the embryonic stages of development.
These effects may include malformations and
variations, altered growth, in utero death, and
altered postnatal function.
Emphysema. Chronic pulmonary disease
characterized by loss of lung function due to
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destruction of many of the alveolar walls with
resulting enlargement of the air spaces. The
total epithelial area for gas exchange in the
lungs is reduced in emphysema patients.
Endemic. Present in a community or among a
group of people; said of a disease prevailing
continually in a region.
Endocrine. Pertaining to hormones or to the
glands that secrete hormones into the blood.
Endothelial. Pertaining to the layer of flat cells
lining the inner surface of blood and lymphatic
blood vessels, and the surface lining of serosa
and synovia! membranes.
Endpoint. An observable or measurable
biological or chemical event used an an index
of the effect of a chemical on a cell, tissue,
organ, organism, etc.
Environmental Fate. The destiny of a
chemical or biological pollutant after release
into the environment. Environmental fate
involves temporal and spatial considerations of
transport, transfer, storage, and transformation.
Epidemiology. The study of the occurrence
and distribution of a disease or physiological
condition in human populations and of the
factors that influence this distribution.
Epigenetic. Alterations in the expression of
genes by mechanisms other than changes in
the nucleotide sequence of DMA. The term has
historically been used in the area of embryonic
differentiation, but more recently has been
used in describing a component of the
formation of cancer.
Epithelial. Pertaining to the cell layer that
covers all internal and external surfaces of the
body, including the gastrointestinal, respiratory,
and urinary tracts.
Equilibrium. The state in which opposing
forces are exactly counteracted or balanced.
Types of equilibrium include acid-base,
colloid, dynamic, homeostatic, and chemical.
Used in risk assessment of toxic air pollutants
to generally describe the chemical equilibrium
between a pollutant in the inhaled air and the
level in the body.
Excess risk. An increased risk of disease
above the normal background rate.
Excretion. Elimination or discharge of excess
and waste chemicals from the body. Chemicals
may be excreted through feces, urine, exhaled
breath, etc..
Exposure. Contact of an organism with a
chemical, physical, or biological agent.
Exposure is quantified as the amount of the
agent available at the exchange boundaries of
the organism (e.g., skin, lungs, digestive tract)
and available for absorption.
Exposure assessment. Measurement or
estimation of the magnitude, frequency,
duration and route of exposure of animals or
ecological components to substances in the
environment. The exposure assessment also
describes the nature of exposure and the size
and nature of the exposed populations, and is
one of four steps in risk assessment.
Extrapolation. An estimate of response or
quantity at a point outside the range of the
experimental data. Also refers to the estimation
of a measured response in a different species
or by a different route than that used in the
experimental study of interest (i.e., species-
to-species, route-to-route, acute-to-
chronic, high-to-low).
Extrathoracic. Situated or occurring outside
the thorax (the part of the respiratory tract
above the trachea).
Fence Line Concentration. Modeled or
measured concentrations of air pollutants found
at the boundaries of a property on which a
pollution source is located. Usually assumed to
be the nearest location at which an exposure
of the general population could occur.
Fertility. The ability to achieve conception and
to produce offspring. For litter-bearing
species, the number of offspring per litter is
also used as a measure of fertility. Reduced
fertility is sometimes referred to as subfertility.
Fetus. The post-embryonic stage of the
developing young. In humans, from the end of
the second month of pregnancy up to birth.
Fibrosis. Formation of scar tissue in the lung
or other tissues, usually as a result of
inflammation occurring over a long period of
time.
First pass effect. Reduction in a substance's
systemic availability resulting from metabolism
or excretion by the first major organ of contact
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with such capability after the absorption
process. This phenomenon of removing
chemicals after absorption before entering the
general systemic circulation can occur in the
lung or liver.
Flash point. The lowest temperature at which
a chemical will ignite.
Forced expiratory volume (FEV). The amount
of air that can be forcefully exhaled in a
specified time, usually one second (FEVi). A
forced expiratory volume test provides an index
of lung function.
Forced vital capacity (FVC). The greatest
amount of air that can be forcefully exhaled
following maximum inhalation.
Frank effect level (FEL). Related to biological
responses to chemical exposures (compare
with NOAEL and LOEL); the exposure level
that produces an unmistakable adverse health
effect (such as inflammation, severe
convulsions, or death).
Gamma muni-hit model. A dose-response
model that can be derived under the
assumption that the response is induced if the
target site has undergone some number of
independent biological events (hits).
Functional developmental toxicity. The study
of the causes, mechanisms, and manifestations
of alterations or delays in functional
competence of the organism or organ system
following exposure to an agent during critical
periods of development pre- and/or
postnatally. This is a subset of development
toxicity.
Gamete. A mature male or female germ cell
[sperm or ovum (egg)] usually possessing a
haploid chromosome set and capable of
initiating formation of a new diploid individual
by fusion with a gamete from the opposite sex.
Gastrointestinal. Pertaining to the intestines
and stomach.
Gavage. Experimental exposure regimen in
which a substance is administered to an animal
into the stomach via a tube.
Gene. The simplest complete functional unit in
a DMA molecule. A linear sequence of
nucleotides in DNA that is needed to
synthesize a protein and/or regulate cell
function. A mutation in one or more of the
nucleotides in a genemay lead to abnormalities
in the structure of the gene product or in the
amount of gene product synthesized.
Genome. A term used to refer to all the
genetic material carried by a single gamete.
Genotoxic. A broad term that usually refers to
a chemical which has the ability to damage
DNA or the chromosomes. This can be
determined directly by measuring mutations or
chromosome abnormalities or indirectly by
measuring DNA repair, sister-chromated
exchange, etc. Mutagenicity is a subset of
genotoxicity.
GEMS (Graphical Exposure Modeling
System). An interactive computerized
management tool developed by the U.S. EPA
that ties together several previously discrete
tools into a coordinated system, allowing for
multiple types of analyses. These tools include
environmental fate and transport models.
chemical property estimation techniques,
statistical analysis, and graphical and modeling
programs.
Germ cell. A cell capable of developing into a
gamete [ovum (egg) or sperm).
Glomerulus. Part of the nephron, the basic
structure of the kidney.
Half-life. See atmospheric half-life and
biological half-life. Also, the period of time
characteristic of a radionuclide in which one-
half of the activity has decayed.
Haploid. Containing a single set of unpaired
chromosomes. Gametes (specialized
reproductive cells) are characterized as
haploid. (Compare with: diploid.)
Hazard identification. The process of
determining whether exposure to a substance
is causally related to the incidence and/or
severity of an adverse health effect (e.g.,
cancer, birth defects, etc.). Hazard
identification involves gathering and evaluating
data on the types of health injury or disease
that may be produced by a chemical and on
the conditions of exposure under which injury
or disease is produced. It may also involve
characterization of the behavior of a chemical
within the body and the interactions it
undergoes within organs, cells, or even parts
of cells. Hazard identification is the first step in
the risk assessment process.
Hemangiosarcoma. A malignant neoplasm
characterized by rapidly' proliferating,
extensively infiltrating, anaplastic cells derived
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from blood vessels and lining blood-filled
spaces.
Hema or Memo. Prefix, pertaining to blood.
Hemoglobin. The oxygen-carrying protein in
red blood cells.
Hepato. Prefix, pertaining to the liver.
Histology. The discipline that deals with the
structure of cells, tissues, and organs in
relation to their function.
Homeostasis. Maintenance of normal, internal
stability in an organism by coordinated
responses of the organ systems.
Hormone. A chemical substance, formed in
one organ or part of the body and carried in
the blood to another organ or part where it
alters the functional activity, and sometimes
the structure, of one or more organs by its
specific chemical activity.
Host defense(s)/systems. A complex system
that defends the body against biological or
chemical agents. Often referred to with respect
to the lungs where the system clears the lungs
of microbes and particulate pollutants. Also
refers to chemical defenses such as
antioxidant substances that defend against
oxidants such as ozone or nitrogen dioxide.
Human equivalent dose. The human dose of
an agent expected to induce the same type
and severity of toxic effect that an animal dose
has induced.
Human Exposure Model (HEM). A
mathematical model used in exposure
assessments for toxic air pollutants to quantify
the number of people exposed to pollutants
emitted by stationary sources and the pollutant
concentrations they are exposed to. Input data
include plant characteristics such as location,
emission, parameters, etc. as well as Bureau
of Census data used in the estimation of
persons exposed and appropriate
meteorological data.
Hygroscopic. Absorbing moisture from the air.
Hyper. Prefix, pertaining to a higher than
normal value.
Hyperplasia. The abnormal multiplication or
increase in the number of normal cells in
normal arrangement in a tissue.
Hypersensitivity. Exaggerated response by
the immune system to an allergen. Sometimes
used incorrectly in a non-immune sense to
indicate increased susceptibility to the effects
of a pollutant.
Hypertension. Abnormally elevated arterial
blood pressure.
Hypertrophy. Enlargement of an organ due to
increase in cell size with no change in the cell
number. For example, liver hypertrophy occurs
in mice exposed to chlorinated hydrocarbons
or to phenobarbital.
Hyperventilation. Overventilation; increased
rate of air exchange relative to metabolic
carbon dioxide production so that alveolar
carbon dioxide pressure tends to fall below
normal.
Hypo. Prefix, pertaining to a less than normal
value.
Hypoxia. Low oxygen content in a body
tissue(s); below physiologic levels.
Immediately dangerous to life and health
(IDLH). A concentration representing the
maximum level of a pollutant from which an
individual could escape within 30 minutes
without escape-impairing symptoms, or
irreversible health effects.
Immune system. All internal structures and
processes providing defense against disease
causing organisms (viruses, bacteria, fungi,
parasites).-Includes nonspecific defense
mechanisms, such as interferon production,
epithelialmembranes and phagocytic cells, as
well as specific immune responses of cells
producing antibodies in response to antigens
entering the body.
Immunodeficiency. A condition resulting from
ineffective functioning of the immunological
system. Immunodeficiency may be primary
(due to a defect in the immune mechanism per
se) or secondary (dependent upon another
disease process or toxicant exposure).
Immunosuppression. Decrease of
immunologic response, usually resulting from
exposure to chemical, pharmacologic, physical,
or immunologic agents.
Incidence. The number of new cases of a
disease within a specified time period. It is
frequently presented as the number of new
cases per 1,000, 10,000, or 100,000. The
incidence rate is a direct estimate of the
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probability or risk of developing a disease
during a specified time period.
Individual risk. The increased risk for a
person exposed to a specific concentration of a
toxicant.
Indoor/outdoor ratio. The ratio of the indoor
concentration of an air pollutant to the outdoor
concentration of that pollutant.
Industrial Source Complex (ISC) model. A
Gaussian dispersion model used to predict the
movement of a plume of air pollution and
concentrations the general population may be
exposed to near a facility. There are two
versions of the ISC model, short-term and
long-term. This is a standard model used by
the U.S.EPA and incorporates detailed source
and emissions characteristics and appropriate
meteorological data.
Infertile. Lacking fertility, inability to conceive
offspring. Infertility may be temporary or
permanent; permanent infertility is termed
sterility.
Inflammation. A protective tissue response to
injury that serves to destroy, dilute, or wall off
both the injurious agent and the injured tissue.
It is characterized by symptoms such as pain,
heat, redness, swelling and loss of function.
Under some circumstances, it can be a toxic
response due to local accumulations of cells
and mediators.
Initiator. An agent capable of starting but not
necessarily completing the process of
producing an abnormal, uncontrolled growth of
tissue usually by altering a cell's genetic
material. Initiated cells may or may not be
transformed into tumors.
Interspecies. Between different species.
Interspecies scaling factors. Numerical
values used in the determination of the
equivalent doses between species, (e.g.
frequently a known animal dose is scaled to
estimate an equivalent human dose.) The U.S.
EPA's cancer risk assessment guidelines (50
FR 33992) note that commonly used dosage
scales include milligram per kilogram body
weight per day, parts per million in soil or water
or air, milligram per square meter body surface
area per day, and milligram per kilogram body
weight per lifetime. The guidelines for
carcinogen assessment generally recommend
using the surface area approach unless there
is evidence to the contrary. The dose as mg/kg
of body weight/day is generally used to scale
between species for non-cancer effects of
chemicals after dermal, oral, or parenteral
exposure.
Intramuscular. Within the muscle; refers to
injection.
Intraperitoneal. Within the membrane
surrounding the organs of the abdominal
cavity; refers to injection.
Intraspecies. Within a particular species.
Intravascular. Within the blood vessels; refers
to injection, usually into the veins (intravenous
or i.v.).
in vitro. Tests conducted outside the whole
body in an artificially maintained environment,
as in a test tube, culture dish, or bottle.
in vivo. Tests conducted within the whole
living body.
Lacrimation. Secretion and discharge of tears.
Larynx. The enlarged upper end of the
trachea, below the root of the tongue
commonly referred to as the voice box.
Latency. The period of time between exposure
to an injurious agent and the manifestation of a
response.
Lavage. A technique used to wash out a cavity
such as the stomach or a portion of the lungs
via a tube. This technique is commonly used
clinically to remove toxic substances from the
stomach. This procedure may also be used to
obtain cell populations and fluids from the lung
for experimental manipulation.
Lesion. A pathologic or traumatic discontinuity
of tissue or loss of function.
Lethal. Deadly; fatal.
(Lethal Concentration Low). The
lowest concentration of a chemical required to
cause death in some of the population after
exposure for a specified period of time and
observed for a specified period of time after
exposure. Refers to inhalation time exposure in
the context of air toxics (may refer to water
concentration for tests of aquatic organisms or
systems).
(Median Lethal Concentration). The
concentration of a chemical required to cause
death in 50% of the exposed population when
exposed for a specified time period, and
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observed for a specified period of time after
exposure. Refers to inhalation exposure
concentration in the context of air toxics (may
refer to water concentration for tests of aquatic
organisms or systems).
LDio (Lethal Dose Low). The lowest dose of
a chemical required to cause death in some of
the population after noninhalation exposure,
e.g., injection, ingestion, for a specified
observation period after exposure.
LDso (Median Lethal Dose). The dose of a
chemical required to cause death in 50% of
the exposed population after noninhalation
exposure, e.g., injection, ingestion, for a
specified observation period after exposure.
Leukemia. A progressive, malignant disease of
the blood-forming tissues, marked by an
excessive number of white blood cells and
their precursors.
Lifetime. Covering the lifespan of an organism
(generally considered 70 years for humans).
Limited evidence. According to the U.S. EPA
carcinogen risk assessment guidelines, limited
evidence is a collection of facts and accepted
scientific inferences that suggests the agent
may be causing an effect but the suggestion is
not strong enough to be an established fact.
Local effect. A biological response occurring
at the site of first contact between the toxic
substance and the organism.
Log/t model. A dose-response model that
can be derived under the assumption that the
individual tolerance level is a random variable
following the logit distribution.
Lower respiratory tract. That part of the
respiratory tract below the larynx.
Lowest-observed-adverse-effect level
(LOAEL). The lowest dose or exposure level of
a chemical in a study at which there is a
statistically or biologically significant increase in
the frequency or severity of an adverse effect
in the exposed population as compared with an
appropriate, unexposed control group.
Lowest-observed effect level (LOEL). In a
study, the lowest dose or exposure level at
which a statistically or biologically significant
effect is observed in the exposed population
compared with an appropriate unexposed
control group.
Lymphoma. Any abnormal growth (neoplasm)
of the lymphoid tissues. Lymphoma usually
refers to a malignant growth and thus is a
cancer.
Macrophage. A specialized cell of the immune
system capable of engulfing and digesting
foreign particles.
Male reproductive toxicity. The occurrence
of adverse effects on the male reproductive
system, which may result from exposure to
environmental agents. The toxicity may be
expressed as alterations to the male
reproductive organs and/or the related
endocrine system. The manifestation of such
toxicity may include alteration in sexual
behavior, fertility, pregnancy outcomes, or
modifications in other functions that are
dependent on the integrity of the male
reproductive system.
Malformation. A permanent structural change
in a developing organism that may adversely
affect survival, development, or function.
Compare with variation.
Malignant. A condition of a neoplasm (tumor)
in which it has escaped normal growth
regulation and has demonstrated the ability to
invade local or distant structures, thereby
disrupting the normal architecture or functional
relationships of the tissue system.
Margin of exposure (MOE). The ratio of the
no-observed-adverse-effect level (NOAEL)
to the estimated human exposure. The MOE
was formerly referred to asthe margin of safety
(MOS).
Margin of safety (MOS). The term formerly
applied to the margin of exposure concept.
Mass median aerodynamic diameter
(MMAD). Median of the distribution of mass
with respect to the aerodynamic diameter of a
particle.
Maximum individual risk (MIR). The
increased risk for a person exposed to the
highest measured or predicted concentration of
a toxicant.
Maximum likelihood estimate (MLE). A
statistical best estimate of the value of a
parameter from a given data set.
Maximum tolerated dose (MTD). The highest
dose of a toxicant that causes toxic effects
without causing death during a chronic
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exposure and that does not decrease the body
weight by more than 10%.
Meiosis. Cell and nuclear division in which the
number of chromosomes is reduced from
diploid (2n) to haploid (n). This process is
characteristic of germ cells (spermatocyte or
oocyte) division in which two successive
divisions of the nucleus produce four cells that
contain half the number of chromosomes
present in the somatic cells. Each of the four
daughter cells obtain, at random, any one of
the two copies of each chromosome from
parent cell. These cells may mature to sperm
or egg cells.
Metabolism. The biochemical reactions by
which energy is made available for the use of
an organism. Metabolism includes all chemical
transformations occurring in an organism from
the time a nutrient substance enters, until it
has been utilized and the waste products
eliminated. In toxicology, metabolism of a
toxicant consists of a series of chemical
transformations that take place within an
organism. A wide range of enzymes act on
toxicants, that may increase water solubility,
and facilitate elimination from the organism. In
some cases, however, metabolites may be
more toxic than their parent compound.
Metaplasia. The abnormal transformation of an
adult, fully differentiated tissue of one kind into
a differentiated tissue of another kind.
Metastasis. The transfer of a disease, or its
local manifestations, from one part of the body
to another. In cancer, this relates to the
appearance of neoplasms in parts of the body
remote from the site of the primary tumor. This
is a characteristic of malignancy.
Microbe/microorganism. A single-cell
organism such as a virus or a bacterium.
Microenvironment. The immediate local
environment of an organism.
Minute volume. Volume of air breathed per
minute, usually liters/minute. The product of
the tidal volume (the normal volume of air
moved into and out of the lungs with each
breath) and the respiratory rate.
Mitosis. Cellular and nuclear division that
involves duplication of the chromosomes of a
parent cell, and formation of two daughter
cells. This type of cell division occurs in most
somatic cells.
MLE. See maximum likelihood estimate.
Model. A mathematical representation of a
natural system intended to mimic the behavior
of the real system, allowing description of
empirical data, and predictions about untested
states of the system.
Modifying factor (MF). A factor that is greater
than zero and less than or equal to 10; used in
the operational derivation of a reference dose.
Its magnitude depends upon an assessment of
the scientific uncertainties of the lexicological
data base not explicitly treated with standard
uncertainty factors (e.g., number of animals
tested). The default value for the MF is 1.
Morbidity. The number of sick individuals or
cases of disease in a population.
Morphology. Study of the form or structure of
cells, tissues, organs, or organisms.
Morphometry. Quantitative measure of
morphology.
Mortality. The number of individual deaths in a
population.
Multistage model. A mathematical function
used to extrapolate the probability of incidence
of disease from a bioassay in animals using
high doses, to that expected to be observed at
the low doses that are likely to be found in
chronic human exposure. This model is
commonly used in quantitative carcinogenic
risk assessments where the chemical agent is
assumed to be a complete carcinogen and the
risk is assumed to be proportional to the dose
in the low region.
Mutagenic. Ability to cause a permanent
change in the structure of ONA. More specific
than, but often used interchangeably with,
genotoxic.
Mutation. Changes in the composition of DNA,
generally divided according to size into "gene
mutations" (changes within a single gene) and
"chromosome mutations" (affecting larger
portions of the chromosome, or the loss or
addition of an entire chromosome). A "heritable
mutation" is a mutation that is passed from
parent to offspring and therefore was present
in the germ cell of one of the parents. Somatic
cell mutations may result in cancer.
Narcosis. A disorder characterized by
drowsiness or unconsciousness, caused by the
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action of a toxicant on the central nervous
system.
Nasopharyngeal region. The area including
the nasopharynx, oropharynx, and nose. The
pharynx is the cavity situated between the
nasal cavities, mouth, and larynx, where it
divides to form the trachea and esophagus,
which accept air and food, respectively.
Necrosis. Death of areas of tissue or bone,
usually as individual cells, as groups of cells,
or in localized areas. Necrosis can be caused
by cessation of blood supply, physical agents
such as radiation, or chemical agents.
Neonatal. Newly born; in humans, up to 6
weeks of age.
Neoplasia. The pathologic process that results
in the formation and growth of a tumor, i.e., a
neoplasm.
V
Neoplasm. A new and abnormal growth of
tissue, such as a tumor.
Nephritis. Inflammation of the kidney.
Nephron. The structural and functional unit of
the kidney, consisting of capillaries and tubes
that adjust the composition of blood and form
urine.
Nephro-. Prefix, pertaining to the kidney.
Neuropathy. Functional disturbances and/or
pathological changes in the peripheral nervous
system.
Neurotoxicity. Ability to damage nervous
tissue.
Nonthreshold toxicant. An agent considered
to produce a toxic effect from any dose; any
level of exposure is deemed to involve some
risk. Usually used only in regard to
carcinogenesis.
No-observed-adverse-effect level
(NOAEL). The highest experimental dose at
which there is no statistically or biologically
significant increases in frequency or severity of
adverse health effects, as seen in the exposed
population compared with an appropriate,
unexposed population. Effects may be
produced at this level, but they are not
considered to be adverse.
No-observed-effect level (NOEL). The
highest experimental dose at which there is no
statistically or biologically significant increases
in frequency or severity of toxic effects seen in
the exposed compared with an appropriate,
unexposed population.
Nucleus. The structure within the cell that
contains the chromosomes and the nucleolus.
The nucleus controls cellular function, both
chemical reactions that occur in the cell, and
reproduction of the cell. Also, the part of an
atom containing protons and neutrons.
Obligate nose breathers. Animals that must
breathe through the nose rather than through
the mouth. Beyond the infant stage, humans
may breathe either through the nose or mouth
but this difference is significant when
comparing effects between obligate nose
breathers (e.g., rats, mice) and humans as the
nasopharyngeal region can remove a
proportion (often significant) of inhaled
toxicants before they reach the lungs. When
humans breathe through the mouth, this early
removal does not occur. Infant humans are
obligate nose breathers.
Occupational exposure limit (OEL). A
generic term denoting a variety of values and
standards, generally time-weighted average
concentrations of airborne substances to which
a worker can be exposed during defined work
periods.
Oocyte. The immature ovum.
Oncogene. A naturally occurring gene that
specifies the synthesis of a protein which is
involved in normal cellular processes.
Alterations in the structure or function of
oncogenes are associated with the
development of some cancers.
Oncogenesis. The origin and growth of a
neoplasm.
One-hit model. A mathematical model that
assumes a single biological event can initiate a
response.
Organogenesis. The development of specific
body structures or organs from undifferentiated
tissue. In humans, this relates primarily to
weeks 2 through 8 (inclusive) post conception.
Organoleptic. Affecting or involving an organ,
especially a sense organ as of taste, smell, or
sight.
Ovum. The female sex cell or gamete (egg).
Peripheral nervous system. The portion of
the nervous system outside of the brain and
-------
spinal cord, which includes sense organs and
the nerves controlling the body.
Pharmacokinetics. The field of study
concerned with defining, through measurement
or modeling, the absorption, distribution,
metabolism, and excretion of drugs or
chemicals in a biological system as a function
of time.
Pharynx. Passageway for air from the nasal
cavity to the larynx and for food from the
mouth to the esophagus.
Physiologically based pharmacokinetics.
Pharmacokinetics (see above) based on
measured physiological variables such as blood
flows through organs, etc.
Population variability. The concept of
differences in susceptibility of individuals
within a population to toxicants due to
variations such as genetic differences in
metabolism and response of biological tissue to
chemicals.
Portal of entry effects. Biological response at
the site of entry (e.g., the lungs, stomach) of a
toxicant into the body.
Potency. A comparative expression of
chemical or drug activity measured in terms of
the relationship between the incidence or
intensity of a particular effect and the
associated dose of a chemical, to a given or
implied standard or reference.
Prevalence. The percentage of a population
that is affected with a particular disease at a
given time.
Probit model. A dose-response model that
can be derived under the assumption that
individual tolerance is a random variable
following log normal distribution.
Promotion. The second hypothesized stage in
a multistage process of cancer development.
The conversion of initiated cells into
tumorigenic cells.
Proteinuria. An excess of serum proteins in
the urine.
Pulmonary region. The area of the respiratory
system consisting of respiratory bronchioles
and alveoli where gas exchange occurs.
<7»* The symbol used to denote the 95% upper
bound estimate of the linearized slope of the
dose-response curve in the low dose region
as determined by the multistage model.
Reactivity. Tendency of a substance to
undergo chemical change.
Reference dose (BID). An estimate (with
uncertainty spanning perhaps an order of
magnitude) of the daily exposure to the human
population (including sensitive subpopulations)
that is likely to be without deleterious effects
during a lifetime. The RfD is reported in units
of mg of substance/kg body weight/day for oral
exposures, or mg of substance/m3 of air
breathed for inhalation exposures.
Renal toxicity. Ability to damage kidney cells;
kidney toxicity.
Reportable quantity. The quantity of a
hazardous substance that is considered
reportable under CERCLA. Reportable
quantities are: (1) one pound, or (2) for
selected substances, an amount established by
regulation either under CERCLA or under
Section 311 of the Clean Water Act.
Reportable quantities are measured over a
24-hour period.
Reproductive toxicity. Harmful effects on
fertility, gestation, or offspring, caused by
exposure of either parent to a substance.
Residual volume. The volume of air remaining
in the lungs after a maximal forceful exhalation.
Respiratory rate. The frequency of a
complete cycle of a breath (inhalation and
exhalation).
Restrictive lung disease Lung disease in
which the expansion of the lung is restricted
either because of alterations in the supportive
structures of the lung (parenchyma) or
because of disease of the pleura, the chest
wall, or the neuromuscular apparatus. An
example is fibrosis.
Retention. The state of being held in a
specific location. Used to refer to the amount
of an inhaled material that remains in the lung
(pulmonary retention) or to the amount of a
toxicant dose that remains in the body or body
compartment for a specified period of time.
RfD. See reference dose.
Risk. The probability of injury, disease, or
death under specific circumstances. In
quantitative terms, risk is expressed in values
ranging from zero (representing the certainty
-------
that harm will not occur) to one (representing
the certainty that harm will occur).
Risk assessment. The scientific activity of
evaluating the toxic properties of a chemical
and the conditions of human exposure to it in
order both to ascertain the likelihood that
exposed humans will be adversely affected,
and to characterize the nature of the effects
they may experience. May contain some or all
of the following four steps:
Hazard identification The determination
of whether a particular chemical is or is not
causally linked to particular health effect(s).
Dose-response assessment The
determination of the relation between the
magnitude of exposure and the probability
of occurrence of the health effects in
question.
Exposure assessment The
determination of the extent of human
exposure.
Risk characterization - The description
of the nature and often the magnitude of
human risk, including attendant uncertainty.
Risk characterization. The final step of a risk
assessment, which is a description of the
nature and often the magnitude of human risk,
including attendant uncertainty.
Risk management. The decision-making
process that uses the results of risk
assessment to produce a decision about
environmental action. Risk management
includes consideration of technical, scientific,
social, economic, and political information.
Risk-specific dose. The dose corresponding
to a specified level of risk.
Route of exposure. The means by which
toxic agents gain access to an organism (e.g.,
ingestion, inhalation, dermal exposure,
intravenous, subcutaneous, intramuscular,
intraperitoneal administration).
Sarcoma. A malignant tumor arising in
connective tissue and composed primarily of
anaplastic cells resembling supportive tissue.
SCE. See sister chromatid exchange.
Sedimentation. Deposition of particles in the
small airways of the lungs which occurs as
gravity acts on particles in a downward
direction and buoyancy and air resistance act
in an upward direction. Also, the settling out of
particles in the atmosphere due to their
gravitational fall.
Sensitization. An allergic condition that usually
effects the skin or lungs. Once exposure to a
substance has caused a reaction, the individual
may be sensitized to that substance and
further exposure even at low levels may elicit
an adverse reaction.
Serosa. A membrane producing a serous
secretion, or containing serum or a serumlike
substance.
Short-term exposure limit (STEL). A time-
we-jhted average OEL that the American
Conference of Government and Industrial
Hygienists (ACGIH) indicates should not be
exceeded any time during the work day.
Exposures at the STEL should not be longer
than 15 minutes and should not be repeated
more than 4 times per day. There should be at
least 60 minutes between successive exposure
at the STEL
Sister chromatid exchange (SCE). The
reciprocal exchange of chromosomal material
between two chromatids (longitudinal subunits
of a replicated chromosome). Increased SCE is
indicative of genotoxic effects.
Somatic cells. All cells other than germ cells
or gametes.
Spermatozoan. Sperm. The male sex cell or
gamete.
Spirometry. The measurement of air volumes
of the lungs. (Example, tidal volume, reserve
volume, etc.).
Squamous cell carcinoma. A malignant
neoplasm derived from squamous epithelium.
Standardized Mortality Ratio. The number of
deaths, either total or cause-specific, in a
given group expressed as a percentage of the
number of deaths that could have been
expected if the group has the same age and
sex specific rates as the general population.
Used in epidemiologic studies to adjust
mortality rates to a common standard so that
comparisons can be made among groups.
Statistically significant effect. In statistical
analysis of data, a health effect that exhibits
differences between a study population and a
control group that are unlikely to have arisen
by chance alone.
-------
STEL. See short-term exposure limit.
Structure-activity relationship. Relationships
of biological activity or toxicity of a chemical to
its chemical structure or substructure.
Subcutaneous. A method of exposure where
the substance is injected beneath the skin.
Subchronic exposure. Exposure to a
substance spanning approximately 10% of the
lifetime of an organism.
Surface area scaling factor. The intra- and
interspecies scaling factor most commonly
used for cancer risk assessment by the U.S.
EPA to convert an animal dose to a human
equivalent dose; milligrams per square meter
surface area per day. Body surface area is
proportional to basal metabolic rate; the ratio of
surface area to metabolic rate tends to be
constant from one species to another. Since
body surface area is approximately proportional
to an animal's body weight to the 2/3 power,
the scaling factor can be reduced to milligrams
per (body weight)2/3.
Synergism. A pharmacologic or toxicologic
interaction in which the combined effect of two
or more chemicals is greater than the sum of
the effect of each chemical alone. (Compare
with: additivity, antagonism.)
Systemic. Pertaining to or affecting the body
as a whole or acting in a portion of the body
other than the site of entry. Used to refer
generally to non-cancer effects. (Compare
with portal-of -entry effects.)
Target organ/system. An organ or functional
system (e.g., respiratory, immune, excretory,
reproductive systems) which demonstrates
toxicity to a specific chemical; not necessarily
the organ/system with the highest
accumulation of the chemical, but rather that
which elicits a toxic response(s) of concern.
(Toxic dose low). The lowest dose of a
substance required to cause a toxic-effect in
some of the exposed population.
Teratogenicity. The property of a chemical to
cause structural or functional defects during
the development of an organism.
Threshold Limit Value (TLV). The
concentration of a substance below which no
adverse health effects are expected to occur
for workers assuming exposure for 8 hours per
day, 40 hours per week. TLVs are published by
the American Conference of Governmental
Industrial Hygienists (ACGIH). This listing may
be useful in identifying substances used in the
workplace and having the potential to be
emitted into the ambient air.
Threshold toxicant. A substance showing an
apparent level of effect that is a minimally
effective dose, above which a response
occurs; below that dose no response is
expected.
Tidal volume. The amount of air that is inhaled
or exhaled during one breath; in humans,
approximately 0.5 liter.
Time-weighted average (TWA). An
approach to calculating the average exposure
over a specified time period.
Toxicology. The multidisciplinary study of
toxicants, their harmful effects on biological
systems and the conditions under which these
harmful effects occur. The mechanisms of
action, detection, and treatment of the
conditions produced by toxicants are studied.
Tracheobronchial region. The area of the
lungs including the trachea (windpipe) and
conducting airways (bronchi, bronchioles, and
terminal bronchioles).
Tumor. An abnormal growth of tissue; a
neoplasm.
Uncertainty. In the conduct of risk assessment
(hazard identification, dose-response
assessment, exposure assessment, risk
characterization) the need to make
assumptions or best judgments in the absence
of precise scientific data creates uncertainties.
These uncertainties, expressed qualitatively
and sometimes quantitatively, attempt to define
the usefulness of a particular evaluation in
making a decision based upon the available
data.
Uncertainty factor (UF). One of several,
generally 10-fold factors, applied to a NOAEL
or a LOAEL to derive a reference dose (RfD)
from experimental data. UFs are intended to
account for (a) the variation in the sensitivity
among the members of the human population;
(b) the uncertainty in extrapolating animal data
to humans; (c) the uncertainty in extrapolating
from data obtained in a less-than-lifetime
exposure study to chronic exposure; and (d)
the uncertainty in using a LOAEL rather than a
NOAEL for estimating the threshold region.
Unit cancer risk. A measure of the probability
of an individual's developing cancer as a result
-------
of exposure to a specified unit ambient
concentration. For example, an inhalation unit
cancer risk of 3.0 x 10'4 near a point source
implies that if 10,000 people breathe a given
concentration of a carcinogenic agent (e.g., u.1
g/m3) for 70 years, three of the 10,000 will
develop cancer as a result of this exposure. In
water the exposure unit is usually 1 ug/l, while
in air it is 1 ug/m3.
Upper Bound Cancer Risk-assessment. A
qualifying statement indicating that the cancer
risk estimate is not a true value in that the
dose-response modeling used provides a
value which is not likely to be an underestimate
of the true value. The true value may be lower
than the upper bound cancer risk estimate and
it may even be close to zero. This results from
the use of a statistical upper confidence limit
and from the use of conservative assumptions
in deriving the cancer risk estimate.
Upper respiratory tract. The structures that
conduct air into the lungs, including the nasal
cavity, mouth, pharynx, and larynx.
Variation. A divergency in the developing
organism beyond the usual range of structural
constitution that may not adversely affect
survival or health. A specific category in the
evaluation of developmental effects. (Compare
with malformation.)
Vasoconstriction. Narrowing of a blood vessel
resulting in decreased blood flow.
Ventilation. The movement of air between the
lungs and the ambient air.
Vital capacity. The maximal volume of air
exhaled after the deepest inspiration without
forced or rapid effort. In adult humans,
generally 5 liters.
Weibull model. A dose-response model of
the form:
P(d) = 1 -
where P(d) is the probability of
cancer due to a continuous
dose rate d, and b and m are
constants.
Weight-of-evidence. The extent to which
the available biomedical data support the
hypothesis that a substance causes an effect
in humans. For example, the following factors
increase the weight-of-evidence that a
chemical poses a hazard to humans; an
increase in the number of tissue sites affected
by the agent; an increase in the number of
animal species, strains, sexes, and number of
experiments and doses showing a response;
the occurrence of a clear-cut dose-response
relationship as well as a high level of statistical
significance in the occurrence of the adverse
effect in treated subjects compared with
untreated controls; a dose related shortening of
thetime of occurrence of the adverse effect;
etc.
Xenobiotlc. A substance not normally present
in the environment, such as a pesticide or
pollutant.
-------
APPENDIX B
AVAILABLE INTEGRATED RISK INFORMATION SYSTEM (IRIS)
FILES FOR POLLUTANTS EMITTED FROM STEEL MILLS*
"Source: U. S. Environmental Protection Agency (1989). Integrated Risk
Information System; PB 88-215884; Washington, D. C.
B-l
-------
Chromium(III); CASRN 16065-83-1 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. Th<
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Chromium(III)
File On-Line 01/31/87
Category (section)
Status
Last Revised
Oral RfD Assessment (I.A.)
Inhalation RfD Assessment (I.B.)
Carcinogenicity Assessment (II.)
Drinking Water Health Advisories (III.A.)
U.S. EPA Regulatory Actions (IV.)
Supplementary Data (V.)
on-line
no data
no data
on-line
on-line
no data
03/01/88
03/01/88
03/01/88
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGENIC EFFECTS
Substance Name Chromium(III)
CASRN 16065-83-1
Last Revised ~ 03/01/88
The Reference Dose (RfD) is based on the assumption that thresholds exist for
certain toxic effects such as cellular necrosis, but may not exist for other
toxic effects such as carcinogenicity. In general, the RfD is an estimate
(with uncertainty spanning perhaps an order of magnitude) of a daily exposure
to the human population (including sensitive subgroups) that is likely to be
without an appreciable risk of deleterious effects during a lifetime. Please
-------
refer to Background Document 1 in Service Code 5 for an elaboration of these
concepts. RfDs can also be derived for the noncarcinogenic health effects of
compounds which are also carcinogens. Therefore, it is essential to refer to
other sources of information concerning the carcinogenicity of this substance
If the U.S. EPA has evaluated this substance for potential human carcinogen-
icity, a summary of that evaluation will be contained in Section II of this
file when a review of that evaluation is completed.
<« Chromium(III) »>
I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfDo)
_I.A.l. ORAL RfD SUMMARY
Critical Effect Experimental Doses*
UF
MF
RfD
No effects observed
Rat Chronic Feeding
Study
Ivankovic and
Preussmann, 1975
NOEL: 5% Cr203 in
diet 5 days/week for
600 feedings (1800
g/kg bw average total
dose)
LOAEL: none
100 10 1E+0
mg/kg/day
(as an
insoluble
salt)
*Dose Conversion Factors & Assumptions: 1800 g Cr203/kg bw x 1000 mg/g x
0.6849 Cr/g Cr203 / 600 feeding days x 5 feeding days/7 days = 1468
mg/kg/day
_I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Ivankovic, S. and R. Preussmann. 1975. Absence of toxic and carcinogenic
effects after administration of high doses of chromic oxide pigment in sub-
acute and long-term feeding experiments in rats. Food Cosmet. Toxicol. 13:
347-351.
Groups of 60 male and female rats were fed chromic oxide (Cr203) baked in
bread at dietary levels of 0, 1, 2, or 5%, 5 days/week for 600 feedings (840
total days). The primary purpose of this study was to assess the carcino-
-------
genie potential of Cr203. Body weight and food consumption were monitored.
The average total amounts of ingested Cr203 were given as 360, 720, and 1800
g/kg bw for the 1, 2, and 5% treatment groups, respectively. The animals were
maintained on control diets following 'termination of exposure until they
became moribund or died. All major organs were examined histologically.
Other toxicologic parameters were not mentioned explicitly, but may have
included some or all of those described for the accompanying subchronic study
(see below). No effects due to Cr203 treatment were observed at any dose
level.
Ivankovic and Preussmann (1975) also treated rats (both sexes, 12-19
rats/group) at dietary levels of 0, 2, or 5% Cr203 in bread, 5 days/week for
90 days. Food consumption and body weight were monitored. Toxicologic
parameters included serum protein, bilirubin, hematology, urinalysis, organ
weights, and histopathology. The only effects observed were reductions (12-
37%) in the absolute weights of .the livers and spleens of animals in the high-
dose group. Organ weights relative to body weight were not reported. The
high doae is equivalent to 1400 mg/kg/day (dose converted using reported
data).
Other subchronic oral studies show no indication of adverse effects
attributable to trivalent chromium compounds, but dose levels were consider-
ably lower.
<« Chromium(III) >»
_I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF = 100. The factor of 100 represents two 10-fold decreases in mg/kg bw/day
dose that account for both the expected interhuman and interspecies
variability to the toxicity of the chemical in lieu of specific data.
MF = 10. The additional modifying factor of 10 ia adopted to reflect
uncertainty in the NOEL because: 1) the effects observed in the 90-day study
were not explicitly addressed in the 2-year study and, thus, the highest NOAEL
in the 2-year study may be a LOAEL; 2) the absorption of chromium is low
(<1%) and is influenced by a number of factors; thus, a considerable potential
variation in absorption exists; and 3) animals were allowed to die naturally
after feeding stopped (2 years) and only then was histology performed.
_I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
This RfD is limited to metallic chromium (III) of insoluble salts.
Examples of insoluble salts include chromic III oxide (Cr203) and chromium III
sulfate [Cr2(804)3].
Very limited data suggest that Cr III may have respiratory effects on
humans. No data on chronic or subchronic effects of inhaled Cr III in ani-
mals can be found. Adequate teratology data do not exist, but reproductive
effects are not seen at dietary levels of 5% Cr203.
_I.A.5. CONFIDENCE IN THE ORAL RfD
-------
Study: Low
Data Base: Low
RfD: Low
The principal study is rated low because of the lack of explicit detail on
study protocol and results. Low confidence in the data base reflects the lack
of high-dose supporting data. The low confidence in the RfD reflects the
foregoing, but also reflects the lack of an observed effect level. Thus, the
RfD, as given, should be considered conservative, since the MF addresses only
those factors which might lower the RfD.
^
_I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
U.S. EPA. 1984. Health Effects Assessment for Trivalent Chromium. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid Waste and
Emergency Response.
The ADI in the 1984 Health Effects Assessment document received an Agency
review with the help of two external scientists.
Agency RfD Work Group Review: 11/21/85, 02/05/86
Verification Date: 11/21/85
_I.A.7. EPA CONTACTS (ORAL RfD)
Michael L. Dourson / ORD ~ (513)569-7544 / FTS 684-7544
Christopher T. DeRosa / ORD (513)569-7534 / FTS 684-7534
<« Chromium(III) >»
I.E. REFERENCE DOSE FOR CHRONIC INHALATION EXPOSURE (RfDi)
Not available at this time
LII- CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name Chromium(III)
CASRN 16065-83-1
This chemical has not been evaluated by the U.S. EPA for evidence of
human carcinogenic potential.
-------
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Chromium(III)
CASRN ~ 16065-83-1
Last Revised 03/01/88
III.A. DRINKING WATER HEALTH ADVISORIES
The Office of Drinking Water provides Drinking Water Health Advisories (HAs)
as technical guidance for the protection of public health. HAs are not
enforceable Federal standards. HAs are concentrations of a substance in
drinking water estimated to have negligible deleterious effects in humans,
when ingested, for a specified period of time. Exposure to the substance from
other media is considered only in the derivation of the lifetime HA. Given
the absence of chemical-specific data, the assumed fraction of total intake
from drinking water is 10% for inorganic contaminants and 20% for organic
contaminants. The lifetime HA is calculated from the Drinking Water Equiv-
alent Level (DWEL) which, in turn, is based on the Oral Chronic Reference
Dose. Lifetime HAs are not derived for compounds which are potentially
carcinogenic for humans because of the difference in assumptions concerning
toxic threshold for carcinogenic and noncarcinogenic effects. A more detailed
description of the assumptions and methods used in the derivation of HAs is
provided in Background Document 3 in Service Code 5.
<« Chromium(III) >»
An HA has been developed for total chromium and applies to chromium(III).
Please refer to Section III in the file on chromium(VI) for the total chromium
HA.
<« Chromium(III) >»-
III.E. OTHER ASSESSMENTS
Content to be determined
l_IV. U.S. EPA REGULATORY ACTIONS
Substance Name -- Chromium(III)
CASRN 16065-83-1
Last Revised 03/01/88
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
-------
updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in sections
I and II, as this may explain inconsistencies. Also note that some regulatory
actions consider factors not related to health risk, such as technical or
economic feasibility. Such considerations are indicated for each action. In
addition, not all of the regulatory actions listed in this section involve
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background inform-
ation on each regulatory action in Background Document 4 in Service Code 5.
IV.A. CLEAN AIR ACT (CAA)
No data available
<« Chromium(III) >»
IV.B. SAFE DRINKING WATER ACT (SDWA)
_IV.B.l. MAXIMUM CONTAMINANT LEVEL GOAL (MCLG) for Drinking Water
Value (status) 0.12 mg/L [total chromium] (Proposed, 1985)
Considers technological or economic .feasibility? NO
Discussion An MCLG of 0.12 mg/L for total chromium (Cr III and Cr VI) is
proposed based on a provisional DWEL of 0.17 mg/L with data on human exposure
factored in (0.10 mg/day in the diet and 0 mg/day by air). A DWEL of 0.17
mg/L was calculated from a NOAEL of 2.41 mg/kg/day in rats [1-year drinking
water study (Cr VI)], with an uncertainty factor of 500 applied and
consumption of 2 L of water/day assumed.
Reference 50 FR 46936 Part IV (11/13/85)
EPA Contact Kenneth Bailey / Criteria and Standards Division, ODW /
(202)382-7571 / FTS 382-7571; or Drinking Water Hotline / (800)426-4791
_IV.B.2. MAXIMUM CONTAMINANT LEVEL (MCL) for Drinking Water
Value (status) 0.05 mg/L [total chromium] (Interim, 1980)
Considers technological or economic feasibility? NO
Discussion
Reference 45 FR 57332
EPA Contact Kenneth Bailey / Criteria and Standards Division, ODW /
(202)382-7571 / FTS 382-7571; or Drinking Water Hotline / (800)426-4791
-------
<« Chromium(III) >»
IV.C. CLEAN WATER ACT (CWA)
_IV.C.l. AMBIENT WATER QUALITY CRITERIA, Human Health
Water and Fish Consumption: 1.7E+5 ug/L
Fish Consumption Only: 3.433E+6 ug/L
Considers technological or economic feasibility? NO
Discussion The WQC of 1.7E+5 ug/L is based on consumption of contaminated
aquatic organisms and water. A WQC of 3.433E+6 ug/L has also been established
based on consumption of contaminated aquatic organisms alone.
Reference 45 FR 79318 (11/28/80)
EPA Contact Criteria and Standards Division, OWRS
(202)475-7315 / FTS 475-7315
_IV.C.2. AMBIENT WATER QUALITY CRITERIA, Aquatic Organisms
Freshwater:
Acute 9.8E+2 ug/L (hardness dependent)
Chronic 1.2E+2 ug/L (hardness dependent)
Marine: None
Considers technological or economic feasibility? NO
Discussion For freshwater aquatic life the concentration (in ug/L) of
total recoverable trivalent chromium should not exceed the numerical value
given by the equations "e**(0.8190 [In (hardness)]+3.688)" for acute exposure
and "e**(0.8190 [In (hardness)3+1.561)" for chronic exposure (** indicates
exponentiation; hardness is in mg/L). For example, at a hardness of 50 mg/L,
the acute and chronic WQC would be 980 and 120 ug/L, respectively.
Reference 50 FR 30784 (07/29/85)
EPA Contact Criteria and Standards Division, OWRS
(202)475-7315 / FTS 475-7315
-<« Chromium(III) »>-
IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
No data available
-------
<« Chromium(III) >»-
IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA)
No data available
<« Chromium(III) >»
IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA)
_IV.F.I. RCRA APPENDIX IX, for Ground Water Monitoring
Status Listed
Reference 52 FR 25942 (07/09/87)
EPA Contact Jerry Garman / OSW / (202)382-4658 / FTS 382-4658
<« Chromium(III) >»
IV.G. SUPERFUND (CERCLA)
_IV.G.l. REPORTABLE QUANTITY (RQ) for Release into the Environment
Value (status) See discussion (Final, 1985)
Considers technological or economic feasibility? NO
Discussion Though "Chromium (III), insoluble salts" is not specifically
designated as a CERCLA hazardous substance, insoluble chromium (III) salts
would be considered hazardous substances under the CERCLA broad generic
listing for "Chromium and Compounds." There is no corresponding reportable
quantity (RQ) for this generic class of compounds. However, the releaser is
still liable for cleanup costs if the designated Federal On-Scene Coordinator
(OSC) decides to take response action with respect to the release of an
insoluble chromium (III) salt that is not otherwise specifically listed as a
CERCLA hazardous substance. There are two chromium (III) salts which are
specifically listed as CERCLA hazardous substances, chromic acetate and
chromic sulfate. Both have been assigned final RQs of 1000 pounds based on
aquatic toxicity (as established under section 311(b)(4) of the Clean Water
Act).
Reference 51 FR 34534 (09/29/86)
EPA Contact RCRA/Superfund Hotline
(800)424-9346 / (202)382-3000 / FTS 382-3000
-------
_V. SUPPLEMENTARY DATA
Substance Name Chromium(III)
CASRN ~ 16065-83-1
Not available at this time
_VI . REFERENCES
HI
Not available at this time
SYNONYMS
16065-83-1
CHROMIC ION
CHROMIUM
Chromium(III)
CHROMIUM (III) ION
CHROMIUM, ION
-------
Chromium(VI); CASRN 7440-47-3 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Chromium(VI)
File On-Line 03/31/87
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) on-line 03/01/88
Inhalation RfD Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 03/01/88
Drinking Water Health Advisories (III.A.) on-line 03/01/88
U.S. EPA Regulatory Actions (IV.) on-line 03/01/88
Supplementary Data (V.) no data
-------
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGENIC EFFECTS
Substance Name Chromium(VI)
CASRN 7440-47-3
Last Revised -- 03/01/88
The Reference Dose (RfD) is based on the assumption that thresholds exist for
certain toxic effects such as cellular necrosis, but may not exist for other
toxic effects such as carcinogenicity. In general, the RfD is an estimate
(with uncertainty spanning perhaps an order of magnitude) of a daily exposure
to the human population (including sensitive subgroups) that is likely to be
without an appreciable risk of deleterious effects during a lifetime. Please
refer to Background Document 1 in Service Code 5 for an elaboration of these
concepts. RfDs can also be derived for the noncarcinogenic health effects of
compounds which are also carcinogens. Therefore, it is essential to refer to
other sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogen-
icity, a summary of that evaluation will be contained in Section II of this
file when a review of that evaluation is completed.
<« Chromium(VI) >»
I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfDo)
_I.A.l. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
No effects reported NOAEL: 25 mg/L of 500 1 5E-3
chromium as K2Cr04 mg/kg/day
Rat, 1-Year Drinking (converted to 2.4 mg
Study of chromium(VI)/kg/day)
MacKenzie et al., LOAEL: none
1958
-------
*Dose Conversion Factors & Assumptions: Drinking water consumption =
0.097 L/kg/day (reported)
_I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
MacKenzie, R.D., R.U. Byerrum, C.F. Decker, C.A. Hoppert and R.F. Langham.
1958. Chronic toxicity studies. II. Hexavalent and trivalent chromium
administered in drinking water to rats. Am. Med. Assoc. Arch. Ind. Health.
18: 232-234.
Groups of eight male and eight female Sprague-Dawley rats were supplied
with drinking water containing 0-11 ppm (0-11 mg/L) hexavalent chromium (as
K2Cr04) for 1 year. The control group (10/sex) received distilled water. A
second experiment involved three groups of 12 males and 9 female rats. One
group was given 25 ppm (25 mg/L) chromium (as K2Cr04); a second received 25
ppm chromium in the form of chromic chloride; and the controls again received
distilled water. No significant adverse effects were seen on appearance,
weight gain, or food consumption, and there were no pathologic changes in the
blood or other tissues in any treatment group. The rats receiving 25 ppm of
chromium (as K2Cr04) showed an approximate 20% reduction in water consumption.
This dose corresponds to 2.4 mg chromium(VI)/kg/day based on actual body
weight and water consumption data.
For rats treated with 0-11 ppm (in the diet), blood was examined monthly,
and tissues (livers, kidneys and femurs) were examined at 6 months and 1 year.
Spleens were also examined at 1 year. The 25 ppm groups (and corresponding
controls) were examined similarly, except that no animals were killed at 6
months. An abrupt rise in tissue chromium concentrations was noted in rats
treated with greater than 5 ppm. The authors stated that "apparently, tissues
can accumulate considerable quantities of chromium before pathological changes
result." In the 25 ppm treatment groups, tissue concentrations of chromium
were approximately 9 times higher for those treated with hexavalent chromium
than for the trivalent group.
Similar no-effect levels have been observed in dogs and humans. Anwar et
al. (1961) observed no significant effects in female dogs (2/dose group) giver
up to 11.2 ppm chromium(VI) (as K2Cr04) in drinking water for 4 years. The
calculated doses were 0.012-0.30 mg/kg of chromium(VI). In humans, no adverse
health effects were detected (by physical examination) in a family of four
persons who drank for 3 years from a private well containing chromium(VI) at
approximately 1 mg/L (0.03 mg/kg/day for a 70-kg human).
<« Chromium(VI) >»
_I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF = 500. The uncertainty factor of 500 represents two 10-fold decreases in
-------
dose to account for both the expected interhuman and interspeciea variability
in the toxicity of the chemical in lieu of specific data, and an additional
factor of 5 to compensate for the less-than-lifetime exposure duration of the
principal study.
MF = 1
_I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
This RfD is limited to metallic chromium(VI) of soluble salts. Examples
of soluble salts include potassium dichromate (K2CR207), sodium dichromate
(Na2Cr207), potassium chromate (K2Cr04) and sodium chromate (Na2Cr04).
Trivalent chromium is an essential nutrient. There is some evidence to
indicate that hexavalent chromium is reduced in part to trivalent chromium in
vivo (Petrilli and DeFlora, 1977, 1978; Gruber and Jennette, 1978).
The literature available on possible fetal damage caused by chromium
compounds is limited. No studies were located on teratogenic effects
resulting from ingestion of chromium.
_I.A.5. CONFIDENCE IN THE ORAL RfD
Study: Low
Data Base: Low
RfD: Low
Confidence in the chosen study is low because of the small number of
animals tested, the small number of parameters measured and the lack of toxic
effect at the highest dose tested. Confidence in the data base is low because
the supporting studies are of equally low quality, and teratogenic and
reproductive endpoints are not well studied. Low confidence in the RfD
follows.
<« Chromium(VI) >»
_I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
U.S. EPA. 1984. Health Effects Assessment for Hexavalent Chromium. Pre-
pared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC.
-------
U.S. EPA. 1985. Drinking Water Health Advisory for Chromium. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC. (Draft)
Agency RfD Work Group Review: 11/21/85, 02/05/86
Verification Date: 02/05/86
_I.A.7. EPA CONTACTS (ORAL RfD)
Kenneth L. Bailey / ODW ~ (202)382-5535 / FTS 382-5535
Christopher T. DeRosa / ORD ~ (513)569-7534 / FTS 684-7534
<« Chromium(VI) >»
I.E. REFERENCE DOSE FOR CHRONIC INHALATION EXPOSURE (RfDi)
Not available at this time
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name Chromium(VI)
CASRN 7440-47-3
Last Revised 03/01/88
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
-------
ia presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
<« Chromium(VI) >»
II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
_II.A.l. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification A; human carcinogen by the inhalation route
Basis Results of epidemiologic studies are consistent across investigators
and locations. Dose-response relationships for lung tumors have been
established.
_II.A.2. HUMAN CARCINOGENICITY DATA
Sufficient. Epidemiologic studies of chromate production facilities in
the United States (Machle and Gregorius, 1948; Brinton et al., 1952; Mancuso
and Hueper, 1951, Mancuso, 1975; Baetjer, 1950; Taylor, 1966; Enterline, 1974;
Hayes et al., 1979; Hill and Ferguson, 1979), Great Britain (Bidstrup, 1951;
Bidstrup and Case, 1956; Alderson et al., 1981), Japan (Watanabe and Fukuchi,
1975; Ohsaki et al., 1978; Sano and Mitohara, 1978; Satoh et al., 1981) and
West Germany (Korallus et al., 1982; Bittersohl, 1971) have established an
association between chromium (Cr) exposure and lung cancer. Most of these
studies did not attempt to determine whether Cr III or Cr VI compounds were
the etiologic agents.
Three studies of the chrome pigment industry, one in Norway (Langard and
Norseth, 1975), one in England (Davies, 1978, 1979), and the third in the
Netherlands and Germany (Frentzel-Beyme, 1983) also found an association
between occupational chromium exposure (predominantly to Cr VI) and lung
cancer.
Results of two studies of the chromium plating industry (Royle, 1975;
Silverstein et al., 1981) were inconclusive, while the findings of a Japanese
study of chrome platers were negative (Okubo and Tsuchiya, 1979). The results
of studies of ferrochromium workers (Pokrovskaya and Shabynina, 1973; Langard
et al., 1980; Axelsson et al., 1980) were inconclusive as to lung cancer risk.
_II.A.3. ANIMAL CARCINOGENICITY DATA
-------
Sufficient. Hexavalent chromium compounds were carcinogenic in animal
assays producing the following tumor types: intramuscular injection site
tumors in Fischer 344 and Bethesda Black rats and in C57BL mice (Furst et
al.f 1976; Maltoni, 1974, 1976; Payne, 1960; Heuper and Payne, 1959); intra-
plural implant site tumors for various chromium VI compounds in Sprague-
Dawley and Bethesda Black rats (Payne, 1960; Heuper 1961; Heuper and Payne,
1962); intrabronchial implantation site tumors for various Cr VI compounds
in Wistar rats (Levy and Martin, 1983; Laskin et al., 1970; Levy as quoted
in NIOSH, 1975); and subcutaneous injection site sarcomas in Sprague-Dawley
rats (Maltoni, 1974, 1976).
_II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
A large number of chromium compounds have been assayed in in vitro
genetic toxicology assays. In general, hexavalent chromium is mutagenic in
bacterial assays whereas trivalent chromium is not (Lofroth, 1978; Petrellie
and Flora, 1977, 1978). Likewise Cr VI but not Cr III was mutagenic in yeasts
(Bonatti et al., 1976) and in V79 cells (Newbold et al., 1979). Chromium III
and VI compounds decrease the fidelity of DNA synthesis in vitro (Loeb et al.,
1977), while Cr VI compounds inhibit replicative DNA synthesis in mammalian
cells (Levis et al., 1978) and produce unscheduled DNA synthesis, presumably
repair synthesis, as a consequence of DNA damage (Raffetto, 1977). Chromate
has been shown to transform both primary cells and cell lines (Fradkin et al.,
1975; Tsuda and Kato, 1977; Casto et al., 1979). Chromosomal effects produced
by treatment with chromium compounds have been reported by a number of
authors; for example, both Cr VI and Cr III salts were clastogenic for
cultured human leukocytes (Nakamuro et al., 1978).
<« Chromium(VI) >»
II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
There are no studies indicating that Cr VI is carcinogenic by oral
administration. Because there appears to be significant in vivo conversion
of Cr VI to Cr III and III to VI, exposure to one form of chromium involves
exposure to all forms of chromium. Cr III is an essential trace element.
<« Chromium(VI) >»
II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
_II.C.l. SUMMARY OF RISK ESTIMATES
-------
Inhalation Slope Factor 4.lE+1/mg/kg/day
Inhalation Unit Risk 1.2E-2/ug/cu.m
Extrapolation Method Multistage, extra risk
Air Concentrations at Specified Risk Levels:
Risk Level
Concentration
E-4 (1 in 10,000)
E-5 (1 in 100,000)
E-6 (1 in 1,000,000)
8E-3 ug/cu.m
8E-4 ug/cu.m
8E-5 ug/cu.m
_II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Species/Strain
Tumor Type
Dose
Tumor
Incidence
Reference
human
Route: Occupational exposure
(inhalation)
Age
(years)
50
60
70
Midrange
( ug/cu . m )
5.68
25.27
46.83
4.68
20.79
39.08
4.41
21.29
Deaths from
Lung Cancer
3
6
6
4
5
5
2
4
Person
Years
1345 Mancuso ,
931 1975
299
1063
712
211
401
345
<« Chromium(VI) >»
_II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
The cancer mortality in Mancuso (1975) was assumed to be due to Cr VI,
which was further assumed to be no less than one-seventh of total chromium.
-------
It was also assumed that the smoking habits of chromate workers were similar
to those of the U.S. white male population. Slope factors based on Langard et
al. (1980), Axelsson et al. (1980), and Pokrovskaya and Shabynina (1973)
result in air unit risk estimates of 1.3E-1, 3.5E-2 and 9.2E-2 ug/cu.m,
respectively.
Hexavalent chromium compounds have not produced lung tumors in animals
by inhalation. Trivalent chromium compounds have not been reported as car-
cinogenic by any route of administration.
The unit risk should not be used if the air concentration exceeds 8E-1
ug/cu.m, since above this concentration the slope factor may differ from
that stated.
_II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
Results of studies of chromium exposure are consistent across investi-
gators and countries. A dose-relationship for lung tumors has been estab-
lished. The assumption that the ratio of Cr III to Cr VI is 8:1 may lead to
a 7-fold underestimation of risk. The use of 1949 hygiene data, which may
underestimate worker exposure, may result in an overestimation of risk.
Further overestimation of risk may be due to the implicit assumption that
the smoking habits of chromate workers were similar to those of the general
white male population, since it is generally accepted that the proportion of
smokers is higher for industrial workers than for the general population.
<« Chromium(VI) >»
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
_II.D.l. EPA DOCUMENTATION
Mancuso, T.F. 1975. International Conference on Heavy Metals in the Envi-
ronment. Toronto, Ontario, Canada.
U.S. EPA. 1984. Health Assessment Document for Chromium. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH. EPA 600/8-83-014F.
_II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The quantification of cancer risk in the 1984 Health Assessment Document
has received peer review in public sessions of the Environmental Health Com-
-------
mittee of the U.S. EPA'a Science Advisory Board.
Agency Work Group Review: 06/26/88
Verification Date: 06/26/86
_II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Herman J. Gibb / ORD -- (202)382-5898 / FTS 382-5898
Chao W. Chen / ORD ~ (202)382-5719 / FTS 382-5719
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Chromium(VI)
CASRN ~ 7440-47-3
Last Revised 03/01/88
III.A. DRINKING WATER HEALTH ADVISORIES
The Office of Drinking Water provides Drinking Water Health Advisories (HAs)
as technical guidance for the protection of public health. HAs are not
enforceable Federal standards. HAs are concentrations of a substance in
drinking water estimated to have negligible deleterious effects in humans,
when ingested, for a specified period of time. Exposure to the substance from
other media is considered only in the derivation of the lifetime HA. Given
the absence of chemical-specific data, the assumed fraction of total intake
from drinking water is 10% for inorganic contaminants and 20% for organic
contaminants. The lifetime HA is calculated from the Drinking Water Equiv-
alent Level (DWEL) which, in turn, is based on the Oral Chronic Reference
Dose. Lifetime HAs are not derived for compounds which are potentially
carcinogenic for humans because of the difference in assumptions concerning
toxic threshold for carcinogenic and noncarcinogenic effects. A more detailed
description of the assumptions and methods used in the derivation of HAs is
provided in Background Document 3 in Service Code 5.
«< Chromium(VI) >»
NOTE: All chromium HAs are based on total chromium (III and VI).
-------
_III.A.l. ONE-DAY HEALTH ADVISORY FOR A CHILD
Appropriate data for calculating a One-day HA are not available. It is
recommended that the Ten-day HA of 1.4 mg/L be used as the One-day HA.
_III.A.2. TEN-DAY HEALTH ADVISORY FOR A CHILD
Ten-day HA 1.4E+0 mg/L
NOAEL 14.4 mg/kg/day
UF 100 (allows for interspecies and intrahuman variability with the use of
a NOAEL from an animal study)
Assumptions 1 L/day water consumption for a 10-kg child
Principal Study Gross and Heller, 1946
Rats were exposed to drinking water containing Cr(VI) (K2Cr04) at levels
of 80 or 134 mg Cr(VI)/L for 60 days (8.3 or 14.4 mg Cr(VI)/kg/day,
respectively) without adverse effects. Therefore, a NOAEL of 14.4 mg/kg/day
is identified.
_III.A.3. LONGER-TERM HEALTH ADVISORY FOR A CHILD
Longer-term (Child) HA 2.4E-1 mg/L
NOAEL 2.4 mg/kg/day
UF 100 (allows for interspecies and intrahuman variability with the use of
a NOAEL from an animal study)
Assumptions 1 L/day water consumption for a 10-kg child
Principal study MacKenzie et al., 1958
In a 1-year drinking water study, consumption of water containing either
Cr(III) (CrC13) or Cr(VI) (K2Cr04) (0 to 1.87 mgAg/day for male rats and 0 to
2.41 mg/kg/day for female rats) produced no significant differences in weight
gain, appearance, or pathological changes in the blood or other tissue.
Therefore, a NOAEL of 2.41 mgAg/day is identified.
_III.A.4. LONGER-TERM HEALTH ADVISORY FOR AN ADULT
Longer-term (Adult) HA 8.4E-1 mg/L
-------
NOAEL 2.4 mg/kg/day
UF 100 (allows for interspecies and intrahuman variability with the use of
a NOAEL from an animal study)
Assumptions 2 L/day water consumption for a 70-kg adult
Principal study MacKenzie et al., 1958 (study described in III.A.3.)
<« Chromium(VI) >»
_III.A.5. DRINKING WATER EQUIVALENT LEVEL / LIFETIME HEALTH ADVISORY
DWEL -- 1.7E-1 mg/L
Assumptions 2 L/day water consumption for a 70-kg adult
RfD Verification Date = 02/05/88 (see Section I.A. of this file)
Lifetime HA -- 1.2E-1 mg/L
Assumptions 71% exposure by drinking water
Principal study MacKenzie et al., 1958 (This study was used in the
derivation of the chronic oral RfD; see Section I.A.2.)
_III.A.6. ORGANOLEPTIC PROPERTIES
No data available
_III.A.7. ANALYTICAL METHODS FOR DETECTION IN DRINKING WATER
Determination of chromium is by an atomic absorption technique using
either direct aspiration into a flame or a furnace.
_III.A.8. WATER TREATMENT
The treatment technologies that are available to remove chromium from
water include coagulation/filtration, lime softening, ion exchange, and
reverse osmosis.
-------
<« Chromium(VI) >»
_III.A.9. DOCUMENTATION AND REVIEW OF HAs
Gross, W.G., and V.G. Heller. 1946. Chromates in animal nutrition. J. Ind.
Hyg. Toxicol. 28: 52-56.
MacKenzie, R.D., R.U. Byerrum, C.F. Decker, C.A. Hoppert and R.F. Langham.
1958. Chronic toxicity studies. II. Hexavalent and trivalent chromium
administered in drinking water to rats. Am. Med. Assoc. Arch. Ind. Health.
18: 232-234.
U.S. EPA. 1985. Draft of the Drinking Water Criteria Document on Chromium.
Office of Drinking Water, Washington, DC.
EPA review of HAs in 1985.
Public review of HAs following notification of availability in October, 1985.
Scientific Advisory Panel review of HAs in January, 1986.
Preparation date of this IRIS summary 06/22/87
_III.A.10. EPA CONTACTS
Kenneth Bailey / ODW ~ (202)382-5535 / FTS 382-5535
Edward V. Ohanian / ODW (202)382-7571 / FTS 382-7571
<« Chromium(VI) »>-
III.E. OTHER ASSESSMENTS
Content to be determined
-------
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Chromium(VI)
CASRN 7440-47-3
Last Revised 03/01/88
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in sections
I and II, as this may explain inconsistencies. Also note that some regulatory
actions consider factors not related to health risk, such as technical or
economic feasibility. Such considerations are indicated for each action. In
addition, not all of the regulatory actions listed in this section involve
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background inform-
ation on each regulatory action in Background Document 4 in Service Code 5.
<« Chromium(VI) >»
IV.A. CLEAN AIR ACT (CAA)
_IV.A.l. CAA REGULATORY DECISION
Action Intent to list under Section 112
Considers technological or economic feasibility? NO
Discussion Chromium VI is considered a human carcinogen (IARC Group I),
and according to EPA's preliminary risk assessment from ambient air exposures,
public health risks are significant. There is considerable uncertainty as to
the carcinogenicity of other valence states of chromium and the proportion of
chromium VI in emission or ambient air samples. The EPA indicated that it
intends to add total chromium or chromium VI to the list of hazardous air
pollutants for which it intends to establish emission standards under section
112(b)(l)(A) of the Clean Air Act. The EPA will decide whether to add total
chromium or chromium VI to the list only after studying possible techniques
that might be used to control emissions and further assessing the public
health risks. The EPA will add total chromium or chromium VI to the list if
emission standards are warranted.
Reference 50 FR 24317 (06/10/85)
-------
EPA Contact Emissions Standards Division, OAQPS
(917)541-5571 / FTS 629-5571
<« Chromium(VI) >»
IV.B. SAFE DRINKING WATER ACT (SDWA)
_IV.B.l. MAXIMUM CONTAMINANT LEVEL GOAL (MCLG) for Drinking Water
Value (status) 0.12 mg/L [total chromium] (Proposed, 1985)
Considers technological or economic feasibility? NO
Discussion ~ An MCLG of 0.12 mg/L for total chromium (Cr III and Cr VI) is
proposed based on a provisional DWEL of 0.17 mg/L with data on human exposure
factored in (O.]0 mg/day in the diet and 0 mg/day by air). A DWEL of 0.17
mg/L was calculated from a NOAEL of 2.41 mg/kg/day in rats [1-year drinking
water study (Cr VI)], with an uncertainty factor of 500 applied and
consumption of 2 L of water/day assumed.
Reference ~ 50 FR 46936 Part IV (11/13/85)
EPA Contact Kenneth Bailey / Criteria and Standards Division, ODW /
(202)382-7571 / FTS 382-7571; or Drinking Water Hotline / (800)426-4791
_IV.B.2. MAXIMUM CONTAMINANT LEVEL (MCL) for Drinking Water
Value (status) 0.05 mg/L [total chromium] (Interim, 1980)
Considers technological or economic feasibility? NO
Discussion
Reference 45 FR 57332
EPA Contact Kenneth Bailey / Criteria and Standards Division, ODW /
(202)382-7571 / FTS 382-7571; or Drinking Water Hotline / (800)426-4791
-------
<« Chromium(VI) >»
IV.C. CLEAN WATER ACT (CWA)
_IV.C.l. AMBIENT WATER QUALITY CRITERIA, Human Health
Water and Fish Consumption 5.0E+1 ug/L
Fish Consumption Only None
Considers technological or economic feasibility? NO
Discussion
Reference 45 FR 79318 (11/28/80)
EPA Contact Criteria and Standards Division, OWRS
(202)475-7315 / FTS 475-7315
_IV.C.2. AMBIENT WATER QUALITY CRITERIA, Aquatic Organisms
Freshwater:
Acute 1.6E+1 ug/L (1-hour average)
Chronic 1.1E+1 ug/L (4-day average)
Marine:
Acute 1.1E+3 ug/L (1-hour average)
Chronic 5.0E+1 ug/L (4-day average)
Considers technological or economic feasibility? NO
Discussion
Reference 50 FR 30784 (07/28/85)
EPA Contact Criteria and Standards Division, OWRS
-------
(202)475-7315 / FTS 475-7315
<« Chromium(VI) >»
IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
No data available
<« Chromium(VI) >»
IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA)
No data available
«< Chromium(VI) >»
IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA)
_IV.F.l. RCRA APPENDIX IX, for Ground Water Monitoring
Status Listed
Reference 52 FR 25942 (07/09/87)
EPA Contact Jerry Garman / OSW / (202)382-4658 / FTS 382-4658
<« Chromium (VI) >»
IV.G. SUPERFUND (CERCLA)
_IV.G.l. REPORTABLE QUANTITY (RQ) for Release into the Environment
Value (status) 1 pound (Proposed, 1987)
-------
Considers technological or economic feasibility? NO
Discussion The proposed RQ for chromium is based on potential
carcinogenicity. Available epidemiological data on inhalation of hexavalent
chromium indicate a hazard ranking of high based on a potency factor of
388.99/mg/kg/day and assignment to weight-of-evidence group A. This
corresponds to an RQ of 1 pound.
Reference ~ 52 FR 8140 (03/16/87)
EPA Contact RCRA/Superfund Hotline
(800)424-9346 / (202)382-3000 / FTS 382-3000
_V. SUPPLEMENTARY DATA
Substance Name Chromium(VI)
CASRN ~ 7440-47-3
Not available at this time
_VI. REFERENCES
Substance Name Chromium(VI)
CASRN 7440-47-3
Not available at this time
SYNONYMS
-------
7440-47-3
CHROMIC ION
CHROMIUM
CHROMIUM, ION
Chromium(VI)
CHROMIUM (VI) ION
-------
Manganese; CASRN 7439-96-5 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Manganese
File On-Line 09/26/88
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) no data
Inhalation RfD Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 09/26/88
Drinking Water Health Advisories (III.A.) no data
U.S. EPA Regulatory Actions (IV.) no data
Supplementary Data (V.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGENIC EFFECTS
Substance Name Manganese
CASRN 7439-96-5
Not available at this time
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
-------
Substance Name Manganese
CASRN 7439-96-5
Last Revised -- 09/26/88
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
is presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
<« Manganese >»
Substance Name Manganese
CASRN 7439-96-5
Preparation Date 08/31/88
II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
_II.A.l. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification D; not classifiable as to human carcinogenicity
Basis Existing studies are inadequate to assess the carcinogenicity of
manganese.
_II.A.2. HUMAN CARCINOGENICITY DATA
None.
_II.A.3. ANIMAL CARCINOGENICITY DATA - Inadequate
DiPaolo (1964) subcutaneously or intraperitoneally injected DBA/1 mice
with 0.1 mL of an aqueous of solution 1% manganese chloride twice weekly for 6
months. A larger percentage of the mice exposed subcutaneously (24/36; 67%)
and intraperitoneally (16/39; 41%) to manganese developed lymphosarcomas
compared with controls injected with water (16/66; 24%). In addition, tumors
appeared earlier in the exposed groups than in the control group. The
incidence of tumors other than lymphosarcomas, (i.e., mammary adenocarcinomas,
leukemias, injection site tumors) did not differ significantly between the
exposed groups and controls. A thorough evaluation of the results of this
study was not possible because the results were published in abstract form.
-------
Stoner et al. (1976) tested manganous sulfate in a mouse lung adenoma
screening bioassay. Groups of strain A/Strong mice (10/sex), 6-8 weeks old,
were exposed by intraperitoneal injection to 0, 6, 15 or 30 mg/kg manganous
sulfate 3 times per week for 7 weeks (a total of 22 injections). The
animals were observed for an additional 22 weeks after the dosing period,
before sacrifice at 30 weeks. There was an apparent increase in the average
number of pulmonary adenomas per mouse both at the mid and high doses, as
compared with the vehicle controls 10 mice/sex, but the increase was
significant only at the high dose (Student's t-test, p<0.05). Lung tumors
were observed in 12/20, 7/20 and 7/20 animals in the high, medium and low
dosage groups, respectively. The percentage of mice with tumors was
elevated slightly, but not significantly, at the highest dose level (Fisher
Exact test) compared with that observed in the vehicle controls. In the
mouse lung adenoma bioassay, certain specific criteria should be met in
order for a response to be considered positive (Shimkin and Stoner, 1975).
Among these criteria are an increase in the mean number of tumors per mouse
and an evident dose-response relationship. While the results of this study
are suggestive of carcinogenicity, the data cannot be considered conclusive
since the mean number of tumors per mouse was significantly increased at
only one dose, and the evidence for a dose-response relationship was
marginal.
Furst (1978) exposed groups of F344 rats (25/sex) intramuscularly or by
gavage to manganese powder, manganese dioxide and manganese (II)
acetylacetonate (MAA). Treatment consisted of either 9 i.m. doses of 10 mg
each of manganese powder or manganese dioxide, six i.m. doses of 50 mg of MAA
or 24 doses of 10 mg manganese powder by gavage. Female swiss mice (25/group)
were exposed intramuscularly to manganese powder (single 10 mg dose) and
manganese dioxide (six doses of 3 or 5 mg each). There was an increased
incidence of fibrosarcomas at the injection site in male (40%) and female
(24%) rats exposed intramuscularly to MAA compared with vehicle controls (4%
male, 4% female). EPA (1984) determined that these increases were
statistically significant. No difference in tumor incidence was found between
rats and mice exposed to manganese powder and manganese oxide and controls.
The U.S. EPA (1984) noted that the study results regarding MAA, an organic
manganese compound, cannot necessarily be extrapolated to pure manganese or
other inorganic manganese compounds.
Sunderman et al. (1974, 1976) exposed male 344 rats to 0.5 to 4.4 mg
manganese dust intramuscularly and found that no tumors were induced at the
injection site. It was further observed that co-administration of manganese
with nickel subsulfide resulted in decreased sarcoma production by comparison
to nickel subsulfide alone. Subsequent studies by Sunderman et al. (1980)
suggest that manganese dust may inhibit local sarcoma induction by
benzo(a)pyrene.
Witschi et al. (1981) exposed female A/J mice intraperitoneally to 80
mg/kg methylcyclopentadienyl manganese tricarbonyl (MMT) and found that
although cell proliferation was produced in the lungs, lung tumor incidence
did not increase.
<« Manganese >»
-------
.II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
None.
Note: Manganese is an element considered essential to human health.
.II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
_II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
_II.D.l. EPA DOCUMENTATION
U.S. EPA. 1984. Health Assessment Document for Manganese. Office of
Research and Development, Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 600/8-83-
013F.
U.S. EPA. 1988. Drinking Water Criteria Document for Manganese. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC. ECAO-CIN-D008. (External Review Draft).
DiPaolo, J.A. 1964. The potentiation of lymphosarcomas in mice by manganous
chloride. Fed. Proc. 23: 393. (Abstract).
Furst, A. 1978. Tumorigenic effect of an organomanganese compound on F344
rats and Swiss albino mice: brief communication. J. Natl. Cancer Inst.
60(5): 1171-1173.
Shimkin, M.B. and G.D. Stoner. 1975. Lung tumors in mice: Application to
carcinogenesis bioassay. Adv. Cancer Res. 21: 1-58.
Stoner, G.D., M.B. Shimkin, M.C. Troxell, T.L. Thompson and L.S. Terry.
1976. Test for carcinogenicity of metallic compounds by the pulmonary tumor
response in strain A mice. Cancer Res. 36: 1744-1747.
-------
Sunderman, F.W., Jr., K.S. Kasprzak, P.P. Minghetti, R.M. Maenza, N. Becker,
C. Onkelinx and P.J. Goldblatt. 1976. Effects of manganese on
carcinogenicity and metabolism of nickel subsulfide. Cancer Res. 36:
1790-1800.
Sunderman, F.W., Jr., T.J. Lau and L.J. Cralley. 1974. Inhibitory effect of
manganese upon muscle tumorigenesis by nickel subsulfide. Cancer Res. 34:
92-95.
Sunderman, F.W., Jr., M.C. Reid, P.R. Allpass and S.B. Taubman. 1980.
Manganese inhibition of sarcoma induction by benzo(a)pyrene in Fischer rats.
Proc. Am. Assoc. Cancer Res. 21: 72. (Abstract)
Witschi, H.P., P.J. Hakkinen and J.P. Kehrer. 1981. Modification of lung
tumor development in A/J mice. Toxicology. 21: 37-45. II.D.I.
<« Manganese >»
_II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The Drinking Water Criteria Document for Manganese has received OHEA
review.
Agency Work Group Review: 05/25/88
Verification Date: 05/25/88
_II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Cynthia Sonich-Mullin / ORD (513)569-7523 / FTS 684-7523
Julie Du / ODW -- (202)382-7583 / FTS 382-7583
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Manganese
CASRN 7439-96-5
Not available at this time
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Manganese
CASRN 7439-96-5
-------
Not available at this time
_V. SUPPLEMENTARY DATA
Substance Name Manganese
CASRN 7439-96-5
Not available at this time
_VI. REFERENCES
Substance Name Manganese
CASRN 7439-96-5
Not available at this time
SYNONYMS
7439-96-5
COLLOIDAL MANGANESE
MAGNACAT
MANGAN
Manganese
MANGAN NITRIDOVANY
TRONAMANG
-------
Copper; CASRN 7440-50-8 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Copper
File On-Line 09/07/88
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) no data
Inhalation RfD Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 09/07/88
Drinking Water Health Advisories (III.A.) no data
U.S. EPA Regulatory Actions (IV.) no data
Supplementary Data (V.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGENIC EFFECTS
Substance Name Copper
CASRN 7440-50-8
Not available at this time
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
-------
Substance Name Copper
CASRN ~ 7440-50-8
Last Revised 09/07/88
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
is presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
<« Copper >»
Substance Name Copper
CASRN 7440-50-8
Preparation Date 09/01/87
II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
_II.A.l. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification D; not classified
Basis There are no human data, inadequate animal data from assays of
copper compounds, and equivocal mutagenicity data.
_II.A.2. HUMAN CARCINOGENICITY DATA
None.
_II.A.3. ANIMAL CARCINOGENICITY DATA
Inadequate. Bionetics Research Labs (1968) studied the carcinogenicity of
a copper-containing compound, copper hydroxyquincline, in two strains of mice
(-B6C3F1 and B6AKF1). Groups of 18 male and 18 female 7-day-old mice were
administered 1000 mg copper hydroxyquinoline/kg bw (180.6 mg Cu/kg) suspended
in 0.5% gelatin daily until they were 28 days old, after which they were
administered 2800 ppm (505.6 ppm Cu) in the feed for 50 additional weeks. No
statistically significant increases in tumor incidence were observed in the
treated 78-week-old animals.
In the same study, Bionetics Research Labs (1968) administered a single
-------
subcutaneous injection of gelatin (control) or 1000 mg of copper
hydroxyquinoline/kg bw (180.6 mg Cu/kg) suspended in 0.5% gelatin to groups of
28-day-old mice of both strains. After 50 days of observation, the male
B6C3F1 had an increased incidence of reticulum cell sarcomas compared with
controls. No tumors were observed in the treated male B6AKF1 mice, and a low
incidence of reticulum cell sarcomas was observed in the treated female mice
of both strains.
Oilman (1962) administered intramuscular injections containing 20 mg of
cupric oxide (16 mg Cu), cupric sulfide (13.3 mg Cu), and cuprous sulfide (16
mg Cu) into the left and right thighs of 2- to 3-month-old Wistar rats.
After 20 months of observations, no injection-site tumors were observed in
any animals, but other tumors were observed at very low incidence in the
animals receiving cupric sulfide (2/30) and cuprous sulfide (1/30). As the
relevance of the organic copper compound to the observation of sarcoma
induction is uncertain and the incidence of tumors in rats treated i.m. with
inorganic copper was very low, data are considered inadequate for
classification.
<« Copper >»
_II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Moriya et al. (1983) reported no increase in mutations in E. coli and S.
typhimurium strains TA98, TA1535, TA1537 and TA1538 incubated with up to 5 mg
copper quinolinolate/plate and in S. typhimurium TA98 and TA100 incubated
with up to 5 mg copper sulfate/plate. Demerec et al. (1951) reported
dose-related mutagenic effects in E. coli with 2 to 10 ppm copper sulfate in
a reverse mutation assay. Negative results were obtained with copper sulfate
or copper chloride in assays using S. cerevisiae (Singh, 1983) and Bacillus
subtilis (Nishioka, 1975, Matsui, 1980, Kanematsu et al., 1980). Errors in
DNA synthesis from poly(c)templates have been induced in viruses incubated
with copper chloride or copper acetate (Sirover and Loeb, 1976). Chromosomal
aberrations were induced in isolated rat hepatocytes when incubated with
copper sulfate (Sina et al., 1983). Casto et al. (1979) showed enhanced cell
transformation in Syrian hamster embryo cells infected with simian adenovirus
with the addition of cuprous sulfide and copper sulfate. High concentrations
of copper compounds have been reported to induce mitosis in rat ascites cells
and recessive lethals in Drosophila melanogaster. Law (1983) reported
increases in the percent lethals observed in Drosophila larvae and eggs when
exposed to copper by microinjection (0.1% copper sulfate) or immersion
(concentrated aqueous copper sulfate), respectively.
II.E. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
-------
II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
«< Copper >»
_II.D.l. EPA DOCUMENTATION
U.S. EPA. 1987. Drinking Water Criteria Document for Copper. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC. ECAO-CIN 417.
Bionetics Research Labs. 1968. Evaluation of carcinogenic, teratogenic and
mutagenic activities of selected pesticides and industrial chemicals. Vol.
I. Carcinogenic study prepared for National Cancer Institute.
NCI-DCCP-CG-1973-1-1.
Castro, B.C., J. Meyers and J.A. DiPaolo. 1979. Enhancement of viral
transformation for evaluation of the carcinogenic or mutagenic potential of
inorganic metal salts. Cancer Res. 30: 193.
Demerec, M., G. Bertani and J. Flint. 1951. A survey of chemicals for
mutagenic action on E. coli. Am. Natur. 85: 119.
Oilman, J.P.W. 1962. Metal carcinogenesis. II. A study on the carcinogenic
activity of cobalt, copper, iron and nickel compounds. Cancer Res. 22:
158-166.
Kanematsu, N., M. Hara and T. Kada. 1980. Rec assay and mutagenicity
studies on metal compounds. Mutat. Res. 77: 109-116.
Matsui, S. 1980. Evaluation of a Bacillus subtilis rec-assay for the
detection of mutagens which may occur in water environments. Water Res.
14(11): 1613-1619.
Moriya, M., T. Ohta, K. Watanabe, T. Miyazawa, K. Kato and Y. Shirasu.
1983. Further mutagenicity studies on pesticides in bacterial reversion
assay systems. Mutat. Res. 116(3-4): 185-216.
Nishioka, H. 1975. Mutagenic activities of metal compounds in bacteria.
Mutat. Res. 31: 185-189.
Sina, J.F., C.L. Bean, G.R. Dysart, V.I. Taylor and M.O. Bradley. 1983.
Evaluation of the alkaline elution/rat hepatocyte assay as a predictor of
carcinogenic/mutagenic potential. Mutat. Res. 113(5): 357-391.
Singh, I. 1983. Induction of reverse mutation and mitotic gene conversion
-------
by some metal compounds in Saccharomyces cerevisiae. Mutat. Res. 117(1-2)
149-152.
Sirover, M.A. and L.A. Loeb. 1976. Infidelity of DNA synthesis in vitro:
Screening for potential metal mutagens or carcinogens. Science. 194:
1434-1436.
«< Copper >»
_II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The values in the 1987 Drinking Water Criteria Document for Copper have
received peer and administrative review.
Agency Work Group Review: 09/15/87
Verification Date: 09/15/87
_II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
David J. Reisman / ORD (513)569-7588 / FTS 684-7588
W. Bruce Peirano / ORD (513)569-7540 / FTS 684-7540
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Copper
CASRN 7440-50-8
Not available at this time
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Copper
CASRN 7440-50-8
Not available at this time
_V. SUPPLEMENTARY DATA
-------
Substance Name Copper
CASRN 7440-50-8
Not available at this time
_VI. REFERENCES
Substance Name Copper
CASRN 7440-50-8
Not available at this time
SYNONYMS
7440-50-8
Copper
-------
Nickel, soluble salts; CASRN 7440-02-0 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Nickel, soluble salts
File On-Line 09/30/87
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) on-line 03/01/88
Inhalation RfD Assessment (I.B.) no data
Carcinogenicity Assessment (II.) message only
Drinking Water Health Advisories (III.A.) no data
U.S. EPA Regulatory Actions (IV.) on-line 03/01/88
Supplementary Data (V.) on-line 09/30/87
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGEN1C EFFECTS
Substance Name Nickel, soluble salts
CASRN ~ 7440-02-0
Last Revised 03/01/88
The Reference Dose (RfD) is based on the assumption that thresholds exist for
certain toxic effects such as cellular necrosis, but may not exist for other
toxic effects such as Carcinogenicity. In general, the RfD is an estimate
(with uncertainty spanning perhaps an order of magnitude) of a daily exposure
to the human population (including sensitive subgroups) that is likely to be
without an appreciable risk of deleterious effects during a lifetime. Please
-------
refer to Background Document 1 in Service Code 5 for an elaboration of these
concepts. RfDs can also be derived for the noncarcinogenic health effects of
compounds which are also carcinogens. Therefore, it is essential to refer to
other sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogen-
icity, a summary of that evaluation will be contained in Section II of this
file when a review of that evaluation is completed.
<« Nickel, soluble salts >»
I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfDo)
_I.A.l. ORAL RfD SUMMARY
Critical Effect Experimental Doses*
UF
MF
RfD
Decreased body and
organ weights
Chronic Rat Feeding
Study
Ambrose et al., 1976
NOAEL: 100 ppm diet
(5 mg/kg/day)
LOAEL: 1000 ppm diet
(50 mg/kg/day)
100
2E-2
mg/kg/day
*Dose Conversion Factors & Assumptions:
food consumption)
1 ppm = 0.05 mg/kg/day (assumed rat
_I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Ambrose, A.M., D.S. Larson, J.R. Borzelleca and G.R. Hennigar, Jr. 1976.
Long-term toxicologic assessment of nickel in rats and dogs. J. Food Sci.
Technol. 13: 181-187.
Ambrose et al. (1976) reported the results of a 2-year feeding study using
rats given nickel sulfate hexahydrate in concentrations of 0, 100, 1000 or
2500 ppm as nickel (Ni) (estimated as 0, 5, 50, and 125 mg Ni/kg bw) in the
diet. Body weights in the high-dose male and female rats were significantly
decreased compared with controls. Body weight was also reduced at 1000 ppm;
-------
this reduction was significant for females at week 6 and from week 26 through
104, whereas males showed body weight reductions only at 52 weeks. Groups of
female rats on the 1000 or 2500 ppm nickel diets (50 and 125 mg Ni/kg bw) had
significantly higher heart-to-body weight ratios and lower liver-to-body
weight ratios than controls. No significant effects were reported at 100 ppm
(5 mg Ni/kg bw). The dose of 1000 ppm (50 mg Ni/kg bw) represents a LOAEL for
this study, while the 100 ppm (5 mg Ni/kg bw) dose is a NOAEL. In this study,
2-year survival was poor, particularly in control rats of both sexes (death:
44/50); this raised some concern about the interpretation of the results of
this study.
A subchronic study conducted by American Biogenics Corp. (ABC, 1986) also
found 5 mg/kg/day to be a NOAEL, which supports the Ambrose et al. (1976)
chronic NOAEL of 5 mg/kg/day. ABC (1986) conducted the 90-day study with
nickel chloride in water (0, 5, 35, and 100 mg/kg/day) administered by gavage
to both male and female CD rats (30 animals/sex/group). The data generated in
this study included clinical pathology, ophthalmologic evaluations, serum
biochemistry, body and organ weight changes, and histopathologic evaluations
of selected organs (heart, kidney, liver). The body weight and food
consumption values were consistently lower than controls for the 35 and 100
mg/kg/day dosed males. Female rats in both high-dose groups had lower body
weights than controls, but food consumption was unaffected by the chemical.
Clinical signs of toxicity, such as lethargy, ataxia, irregular breathing,
cool body temperature, salivation, and discolored extremities, were seen
primarily in the 100 mg/kg/day group; these signs were less severe in the 35
mg/kg/day group. The 5 mg/kg/day group did not show any significant clinical
signs of toxicity. There was 100% mortality in the high-dose group; 6/30
males and 8/30 females died in the mid-dose group (35 mg/kg/day). Histopatho-
logic evaluation indicated that the deaths of 3/6 males and 5/8 females in the
mid-dose group were due to gavage errors. At sacrifice, kidney, liver, and
spleen weights for males treated at the 35 mg/kg/day dose level and right
kidney weights for females treated at the 35 mg/kg/day dose level were
significantly lower than controls. Based on the results obtained in this
study, the 5 mg/kg/day nickel dose was a NOAEL, whereas the 35 mg/kg/day was a
LOAEL for decreased body and organ weights.
<« Nickel, soluble salts >»
_I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF = 100. An uncertainty factor of 100 is used: 10 for interspecies
extrapolation and 10 to protect sensitive populations. The nickel dietary
study by Ambrose et al. (1976) identifying a NOAEL of 100 ppm (5 mg/kg/day) is
supported by the subchronic gavage study in water (ABC, 1986), which indicated
the same NOAEL (5 mg/kg/day). The uncertainty factor of 100 is therefore
appropriate, since two studies support the NOAEL of 5 mg/kg/day.
MF = 3. A modifying factor of 3 is used because of inadequacies in the
reproductive studies (RTI, 1987; Ambrose et al., 1976, see Additional Comments
section). During the gestation and postnatal development of Fib litters in
the RTI (1987) study, temperatures were about 10F higher than normal at
certain times, which makes evaluation of this part of the reproductive study
impossible. In the Ambrose et al. (1976) study there were some statistical
-------
design limitations, such as small sample size and use of pups rather than
litters as the unit for comparison.
_I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Ambrose et al. (1976) also reported reproductive toxicity of nickel, but
the study had some statistical design limitations, such as small sample size
and use of pups rather than litters as the unit for comparison. Furthermore,
the results were equivocal and did not clearly define a NOAEL or LOAEL. The
fact that nickel was administered in a laboratory chow diet containing milk
powder, rather than in drinking water, in this study caused problems in
quantification of nickel exposure when applying these data to drinking water
situations.
In a 2-generation study (RTI, 1987), nickel chloride was administered in
drinking water to male and female CD rats (30/sex/group) at dose levels of 0,
50, 250, and 500 ppm (0, 7.3, 30.8, and 51.6 mg/kg/day, estimated) for 90 days
prior to breeding (10 rats/sex/group comprised a satellite subchronic
nonbreeder group). At the 500 ppm dose level there was a significant decrease
in the P-zero maternal body weights, along with absolute and relative liver
weights. Thus, 250 ppm (30.8 mg/kg/day) was a NOAEL for P-zero breeders.
Histopathology was performed for liver, kidney, lungs, heart, pituitary,
adrenals, and reproductive organs to make this assessment. This NOAEL is
higher than the NOAEL derived from the chronic Ambrose et al. (1976) and
subchronic gavage (ABC, 1986) assays.
The number of live pups/litter was significantly decreased, pup mortality
was significantly increased, and average pup body weight was significantly
decreased in comparison with controls for the Fla generation (postnatal days
1-4) at the 500 ppm dose level (RTI, 1987). Similar effects were seen with
Fib litters of P-zero dams exposed to 500 ppm nickel. In the 50 and 250 ppm
dose group, increased pup mortality and decreased live litter size were
observed in the Fib litters. However, these effects seen with Fib litters are
questionable because the room temperature tended to be 10F higher than normal
at certain times (gestation-postnatal days) along with much lower levels of
humidity. As evidenced in the literature, temperatures that are 10F above
normal during fetal development cause adverse effects (Edwards, 1986).
Therefore, the above results seen at the 50 and 250 dose levels cannot be
considered as genuine adverse effects.
Fib males and females of the RTI (1987) study were randomly mated on
postnatal day 70 and their offspring (F2a and F2b) were evaluated through
postnatal day 21. This phase included teratologic evaluations of F2b
fetuses. Evaluation of the data indicated that the 500 ppm dose caused
significant body weight depression of both mothers and pups, and increased
neonatal mortality during the postnatal development period. The intermediate
dose, 250 ppm nickel, produced transient depression of maternal weight gain
and water intake during gestation of the F2b litters. The 50 ppm nickel
exposure caused a significant increase in short ribs (11%). However, since
this effect was not seen in both of the higher dose groups, the reported
incidence of short ribs in the 50 ppm group is not considered to be of
biological significance.
Schroeder and Mitchener (1971) conducted a 3-generation study in which
-------
five mating pairs of rats were provided drinking water containing 5 mg Ni/L
(estimated as 0.43 mg/kg bw). Results of this study indicated significant
increases in neonatal mortality and number of runts born to exposed rats
compared with controls. The major weakness of this study, however, is that
the end result is based on a total of five matings. The matings were not
randomized and the males were not rotated. The Schroeder and Mitchener (1971)
study was conducted in an environmentally controlled facility where rats had
access to food and water containing minimal levels of essential trace metals.
Because of the interaction of nickel with other trace metals, the restricted
exposure to trace metals (chromium was estimated as inadequate) may have
contributed to the toxicity of nickel.
<« Nickel, soluble salts >»
_I.A.5. CONFIDENCE IN THE ORAL RfD
Study: Low
Data Base: Medium
RfD: Medium
The chronic study (Ambrose et al., 1976) was properly designed and
provided adequate toxicologic endpoints; however, there was high mortality
in the controls (44/50). Therefore, a low confidence is recommended for the
study. The data base provided adequate supporting subchronic studies, one by
gavage and the other in drinking water [P-zero animals of the RTI (1986)
subchronic study]. A medium confidence level in the data base is recommended
because there are inadequacies in the remaining reproductive study data. The
RfD is adequately supported by the oral subchronic and reproductive studies,
and until additional reproductive studies are available a medium confidence in
the RfD is recommended.
_I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
U.S. EPA. 1983. Health Assessment Document for Nickel. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Research Triangle Park, NC. External Review Draft.
U.S. EPA. 1985. Drinking Water Criteria Document for Nickel - Quantification
of Toxicological Effects Chapter Only. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Drinking Water, Washington, DC. EPA 600/x-
84-193-1.
Extensive Agency-wide Review, 1987
Agency RfD Work Group Review: 04/16/87, 05/20/87, 07/16/87
Verification Date: 07/16/87
_I.A.7. EPA CONTACTS (ORAL RfD)
Harlal Choudhury / ORD (513)569-7536 / FTS 684-7536
-------
Christopher T. DeRosa / ORD (513)569-7534 / FTS 684-7534
<« Nickel, soluble salts >»
I.E. REFERENCE DOSE FOR CHRONIC INHALATION EXPOSURE (RfDi)
Not available at this time
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name Nickel, soluble salts
CASRN 7440-02-0
The U.S. EPA has not evaluated soluble salts of nickel, as a class of
compounds, for potential human carcinogenicity. However, nickel refinery dust
and specific nickel compounds - nickel carbonyl and nickel subsulfide - have
been evaluated. Summaries of these evaluations are on IRIS.
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Nickel, soluble salts
CASRN 7440-02-0
Not available at this time
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Nickel, soluble salts
CASRN 7440-02-0
Last Revised 03/01/88
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in sections
I and II, as this may explain inconsistencies. Also note that some regulatory
actions consider factors not related to health risk, such as technical or
economic feasibility. Such considerations are indicated for each action. In
addition, not all of the regulatory actions listed in this section involve
-------
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background inform-
ation on each regulatory action in Background Document 4 in Service Code 5.
IV.A. CLEAN AIR ACT (CAA)
No data available
-«< Nickel, soluble salts >»-
IV.B. SAFE DRINKING WATER ACT (SDWA)
No data available
-<« Nickel, soluble salts >»-
IV.C. CLEAN WATER ACT (CWA)
No data available
-<« Nickel, soluble salts >»-
IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
No data available
-<« Nickel, soluble salts >»-
IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA)
No data available
<« Nickel, soluble salts >»
IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA)
_IV.F.I. RCRA APPENDIX IX, for Ground Water Monitoring
Status Listed
Reference 52 FR 25942 (07/09/87)
-------
EPA Contact Jerry Garman / OSW / (202)382-4658 / FTS 382-4658
<« Nickel, soluble salts >»
IV.G. SUPERFUND (CERCLA)
No data available
_V. SUPPLEMENTARY DATA
Substance Name Nickel, soluble salts
CASRN 7440-02-0
Last Revised 09/30/87
The information contained in this section (subsections A and B) has been
extracted from the EPA Chemical Profiles Database, which has been compiled
from a number of secondary sources and has not undergone formal Agency review.
The complete reference listings for the citations in this section are provided
in Service Code 5. The user is urged to read Background Document 5 in Service
Code 5 for further information on the sources and limitations of the data
presented here.
«< Nickel, soluble salts >»
V.A. ACUTE HEALTH HAZARD INFORMATION
Toxicity Numerous cases of dermatitis have been reported (Clayton and
Clayton, 1981-82).
Medical Conditions Generally Aggravated by Exposure Not Found
Signs and Symptoms of Exposure -- Symptoms include nausea, vomiting, diarrhea,
central nervous system depression (Weiss, 1980, p. 1105), coughing, shortness
of breath, chest pain, fever and weakness upon inhalation (Rumack, 1975 to
Present).
-«< Nickel, soluble salts >»-
V.B. PHYSICAL-CHEMICAL PROPERTIES
Chemical Formula Ni
Molecular Weight 58.70
Boiling Point 5139F, 2837C (Merck, 1983)
-------
Specific Gravity (H20=l) 8.90 (Sax, 1979)
Vapor Pressure (mmHg) 1 at 1810C (Sax, 1979)
Melting Point 2831F, 1555C (Merck, 1983)
Vapor Density (AIR=1) Not Found
Evaporation Rate (Butyl acetate=l) Not Found
Solubility in Water Insoluble (Weast, 1979)
Flash Point (Method Used) Not Found
Flammable Limits Not Found
Appearance and Odor Silvery metal (Weast, 1979); lustrous white metal
(Merck, 1983)
Conditions or Materials to Avoid Finely divided nickel (e.g. Raney nickel
catalysts) may become hot enough to ignite if exposed to air or moisture
(Student, 1981, p. 363). Materials containing potassium perchlorate with
nickel and titanium powders and infusional earth give severe explosions during
a friction test. Dioxane reacts explosively with hydrogen and Raney nickel
above 210C (NFPA, 1978). Also, aluminum; aluminum trichloride; ethylene;
hydrogen; methanol; non-metals; oxidants; sulfur compounds (Sax, 1984, p.
1990), and selenium metal (Weiss, 1980, p. 1105) are incompatible with nickel.
Use Nickel is used in nickel-plating; for various alloys such as new
silver, Chinese silver, and German silver; for coins, electrotypes,
lighting-rod tips, electrical contacts and electrodes, spark plugs, machinery
parts; as a catalyst for hydrogenation of organic substances; in manufacturing
of Monel metal, stainless steels, and nickel-chrome resistance wire; and in
alloys for electronic and space applications (Merck, 1983).
_VI. REFERENCES
Substance Name Nickel, soluble salts
CASRN 7440-02-0
Not available at this time
SYNONYMS
7440-02-0
C.I. 77775
NICKEL
-------
Nickel
Nickel, soluble salts
-------
Nickel Refinery Dust; CASRN (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Nickel Refinery Dust
File On-Line 09/30/87
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) no data
Inhalation RfD Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 09/30/87
Drinking Water Health Advisories (III.A.) no data
U.S. EPA Regulatory Actions (IV.) no data
Supplementary Data (V.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGENIC EFFECTS
Substance Name Nickel Refinery Dust
CASRN
Not available at this time
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
-------
Substance Name Nickel Refinery Dust
CASRN
Last Revised ~ 09/30/87
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
is presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
<« Nickel Refinery Dust >»
II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
_II.A.l. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification A; human carcinogen
Basis Human data in which exposure to nickel refinery dust caused
lung and nasal tumors in sulfide nickel matte refinery workers in several
epidemiologic studies in different countries, and on animal data in which
carcinomas were produced in rats by inhalation and injection
_II.A.2. HUMAN CARCINOGENICITY DATA
Sufficient. Nickel refinery dust from pyrometallurgical sulfide nickel
matte refineries is considered a human carcinogen when inhaled. Evidence of
carcinogenicity includes a consistency of findings across different countries
(Clydach, Wales; Copper Cliff, Ontario; Port Colborne, Ontario; Kristiansand,
Norway; and Huntington, WV) in several epidemiologic studies, specificity of
tumor site (lung and nose), high relative risks, particularly for nasal
cancer, and a dose-response relationship by length of exposure. Excess risks
are greatest in the dustier areas of the respective refineries. At Port
Colborne, Roberts et al. (1983) reported high risks of lung (SMR = 298) and
nasal (SMR = 9412) cancer among men "ever exposed" to calcining, leaching, and
sintering, the dustier areas of the refinery. Similar exposures and high
risks of lung and nasal cancer were observed in the calcining sheds at Clydach
(lung SMR = 510, nasal SMR = 26,667) (Peto et al., 1984), the sintering
furnaces at Copper Cliff (lung SMR = 424, nasal SMR = 1583) (Roberts and
Julian, 1982), and the roasting/smelting (lung SMR = 360, nasal SMR = 4000)
and electrolysis (lung SMR = 550, nasal SMR = 2700) furnaces at Kristiansand,
Norway (Magnus et al., 1982). In the study of refinery and nonrefinery
-------
workers at a nickel refinery in West Virginia, nasal cancer was exclusive to
the refinery workers, with an SMR of 2443 (Enterline and Marsh, 1982). No
large excess of lung cancer was observed in either refinery (SMR = 118) or
nonrefinery (SMR = 107.6) employees. The data do show a dose-response
relationship between cumulative nickel exposure and lung cancer response
(allowing for a 20-year latent period). The dose-response relationship is
consistent with findings at nickel refineries in Clydach, Wales (Peto et al.,
1984) and Copper Cliff, Ontario (Chovil et al., 1981). While the dust levels
and lung cancer relative risks were much higher in the two latter refineries,
all dose-response relationships appear linear, and the tumor type and sites
are the same, indicating that the functional relationship spans a broad range
of nickel exposures.
«< Nickel Refinery Dust >»
_II.A.3. ANIMAL CARCINOGENICITY DATA
Animal studies indicate that some nickel refinery dusts are potentially
carcinogenic. Nickel refinery flue dust (20% nickel sulfate, 59% nickel
subsulfide, and 6.3% nickel oxide) from Port Colborne, Canada was tested for
carcinogenic potential (Gilman and Ruckerbauer, 1962) by intramuscular
injection. It was found to be a strong inducer of injection-site sarcomas in
Hooded (52/66) and Wistar (8/20) rats after injection of 20 or 30 mg in one or
both thighs and in mice (23/40) after injection of 10 mg/thigh. Fisher et al.
(1971), as reviewed by Rigaut (1983), tested nickel refinery dust (20% nickel
sulfate, 59% nickel subsulfide, and 6.3% nickel oxide) by inhalation. The
refinery dust was one of six types of dust exposures administered to 348 rats
at 5 to 15 mg/cu.m. The combined tumor incidence for refinery dust, synthetic
dust, nickel subsulfide, and iron sulfide was 11 pulmonary tumors in the 348
rats. When Wistar rats were exposed to a combination of nickel and iron dust
at concentrations of 2.1 +/- 0.2 mg Ni/cu.m. and 1.9 +/- 0.2 mg Fe/cu.m (Kim
et al., 1976), one of the 60 surviving rats developed lung cancer.
An intermediate of nickel refinery dust which contains nickel subsulfide,
nickel oxide, and metallic nickel (Feinstein dust) was tested in albino
(nonpedigree) rats at 70 mg dust/cu.m, 5 hours/day for 6 months (Saknyn and
Blohkin, 1978, as reviewed by Sunderman, 1981). Squamous-cell carcinomas were
found in two of the five surviving treated rats. Saknyn and Blohkin (1978)
also treated the Albino rats by intraperitoneal injection of Feinstein dust at
90 to 150 mg/rat. Six of the 39 survivors developed injection-site sarcomas.
Nickel dust from roasting (31% nickel subsulfide and 33.4% nickel oxide +
silicon oxide and oxides of iron and aluminum) was tested for carcinogenicity
in rats by inhalation (Belobragina and Saknyn, 1964, as reviewed by Rigaut,
1983). After exposure to 80 to 100 mg/cu.m, 5 hours/day for 12 months, no
tumors were found.
Three carcinogenicity studies (Schroeder and Mitchener, 1975; Schroeder et
al., 1964, 1974) of nickel acetate and an unspecified nickel salt using doses
of 5 ppm of nickel in the drinking water of Long-Evans rats and Swiss mice
produced negative results. Ambrose et al. (1976) administered nickel sulfate
hexahydrate in the diet of Wistar-derived rats and beagle dogs for 2 years at
nickel concentrations of 100 to 2500 ppm. A lack of carcinogenic response was
-------
observed in both studies. The dog study may have been inadequate to detect a
carcinogenic response, since the duration was relatively short.
_II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Nickel refinery dust has not been studied using in vitro short-term test
systems or tests for macromolecular interactions.
-<« Nickel Refinery Dust >»-
II.E. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
«< Nickel Refinery Dust »>
II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
_II.C.l. SUMMARY OF RISK ESTIMATES
Inhalation Slope Factor 8.4E-l/mg/kg/day
Inhalation Unit Risk 2.4E-4/ug/cu.m
Extrapolation Method Additive and multiplicative
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
E-4 (1 in 10,000) 4E-1 ug/cu.m
E-5 (1 in 100,000) 4E-2 ug/cu.m
E-6 (1 in 1,000,000) 4E-3 ug/cu.m
_II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Estimates of Incremental Unit Risks for Lung Cancer due to Exposure to 1 ug
Ni/cu.m for a Lifetime Based on Extrapolations from Epidemiologic Data Sets
Study Relative Risk Model
Huntington, WV (Enterline and Marsh, 1982)
(maximum likelihood estimates only)
Refinery workers 1.5E-5 - 3.1E-5
Nonrefinery workers 9.5E-6 - 2.1E-5
-------
Copper Cliff, Ontario (Chovil et al., 1981) 1.1E-5 - 8.9E-5
Clydach, Wales (Peto et al., 1984) 8.1E-5 - 4.6E-4
Kristiansand, Norway (Magnus et al., 1982) 1.9E-5 - 1.9E-4
Midpoint of range for refinery
workers 2.4E-4
<« Nickel Refinery Dust >»
_II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
Nickel refinery dust is a mixture of many nickel moieties, and it is not
certain what the carcinogenic nickel species is in the refinery dust.
Data sets from nickel refineries in Huntington, WV (Enterline and Marsh,
1982), Copper Cliff, Ontario (Chovil et al., 1981), Clydach, Wales (Peto et
al., 1984), and Kristiansand, Norway (Magnus et al., 1982) provide information
available for choice of model or for separation of risk by the type of nickel
exposure. The dose-response curves for nasal cancer were not used for risk
estimation because nasal cancer risk from nickel is thought to be an
occupational hazard associated only with the pyrometallurgical process, and
these tumors are not found in the general public to the same extent as lung
tumors. The same lung tumor type was found in all epidemiologic studies of
occupational exposure to nickel refinery dust. The average relative risk
model was applied to the Huntington, WV and Copper Cliff, Ontario data sets.
For the four data sets analyzed, both the additive and multiplicative
excess risk models were fitted whenever possible. The relative risk or
multiplicative model follows the assumption that the background cause-age-
specific rate at any time is increased by an amount proportional to the
cumulative dose up to that time. The model assumes the standardized mortality
ratio (SMR) is linearly related to dose and is constant for a set cumulative
exposure. Excess mortality for a set cumulative exposure is constant over
time, and excess risk remains constant once exposure ceases. The relative
risk model differs from the additive risk model in that the latter model
assumes that the excess cause-age-specific rate is increased by an amount
proportional to the cumulative exposure up to that time.
The unit risk estimates ranged from 1.1E-5 to 4.6E-4/ug/cu.m. The
estimates from the Huntington refinery were somewhat lower, but this may be a
result of only the small sample size. If the nasal cancer deaths are added to
the eight lung cancer deaths, the unit risk estimate becomes 1.3E-4/ug/cu.m,
well within the range of the other estimates. As the best estimate, the
midpoint of the range, 2.4E-4/ug/cu.m, is taken as the incremental unit risk
due to a lifetime exposure to nickel matte refinery dust. When the additive
risk model is applied to the data for Huntington, WV, the estimates (2.8E-4
and 1.8E-4 for refinery and nonrefinery workers, respectively) are close to
those derived by the relative risk model.
The above unit risk should not be used if the air concentration exceeds
40 ug/cu.m, since above this concentration the slope factor may differ from
that stated.
-------
_II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
Four data sets, all from humans, offer a range of incremental unit risk
estimates which are consistent with each other.
<« Nickel Refinery Dust >»
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
_II.D.l. EPA DOCUMENTATION
U.S. EPA. 1986. Health Assessment Document for Nickel and Nickel Compounds.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-
83/0 12FF.
Chovil, A., R.B. Sutherland and M. Halliday. 1981. Respiratory cancer in a
cohort of sinter plant workers. Br. J. Ind. Med. 38: 327-333.
Enterline, P.E. and G.M. Marsh. 1982. Mortality among workers in a nickel
refinery and alloy manufacturing plant in West Virginia. J. Natl. Cancer
Inst. 68: 925-933.
Magnus, K., A. Andersen and A. Hogetveit. 1982. Cancer of respiratory
organs among workers at a nickel refinery in Norway. Int. J. Cancer.
30: 681-685.
Peto, J., H. Cuckle, R. Doll, C. Hermon and L.G. Morgan. 1984. Respiratory
cancer mortality of Welsh nickel refinery workers. In: Nickel in the Human
Environment: Proceedings of a Joint Symposium, March, 1983. IARC Scientific
Publ. No. 53. International Agency for Research on Cancer, Lyon, France,
p. 36-46.
_II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The 1986 Health Assessment Document has received both Agency and
external review.
Agency Work Group Review: 04/01/87
Verification Date: 04/01/87
^II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Steven P. Bayard / ORD (202)382-5722 / FTS 382-5722
Herman J. Gibb / ORD (202)382-5898 / FTS 382-5898
-------
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Nickel Refinery Dust
CASRN
Not available at this time
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Nickel Refinery Dust
CASRN --
Not available at this time
_V. SUPPLEMENTARY DATA
Substance Name Nickel Refinery Dust
CASRN
Not available at this time
_VI. REFERENCES
Substance Name Nickel Refinery Dust
CASRN ~
Not available at this time
SYNONYMS
7440-02-0
NICKEL DUST
NICKEL PARTICLES
Nickel Refinery Dust
-------
Nickel Subsulfide; CASRN 12035-72-2 (04/01/89)
Health risk assessment information on a che.mical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Nickel Subsulfide
File On-Line 09/30/87
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) no data
Inhalation RfD Assessment (I.E.) no data
Carcinogenicity Assessment (II.) on-line 03/01/88
Drinking Water Health Advisories (III.A.) no data
U.S. EPA Regulatory Actions (IV.) on-line 03/01/88
Supplementary Data (V.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGEN1C EFFECTS
Substance Name Nickel Subsulfide
CASRN 12035-72-2
Not available at this time
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
-------
Substance Name Nickel Subsulfide
CASRN 12035-72-2
Last Revised 03/01/88
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
is presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
<« Nickel Subsulfide >»
II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
_II.A.l. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification A; human carcinogen
Basis Increased risks of lung and nasal cancer in humans exposed
to nickel refinery dust, most of which was believed to have been nickel
subsulfide; increased tumor incidences in animals by several routes of
administration in several animal species and strains; and positive results in
genotoxicity assays form the basis for this classification.
_II.A.2. HUMAN CARCINOGENICITY DATA
Sufficient. The lung and nasal cancer risk seen for nickel subsulfide, a
major constituent of nickel refinery dust, is attributable to the formerly
high dust and nickel subsulfide levels at sulfide nickel matte refineries. At
Copper Cliff and Port Colborne, Ontario, populations showing elevated lung and
nasal cancer worked in what were considered the dustier areas of the
refineries. Greatest exposures were to nickel subsulfide, nickel sulfide,
nickel oxide, coke particles, and polycyclic aromatic hydrocarbons at Copper
Cliff (INCO, Ltd., 1976) and nickel subsulfide, nickel sulfate, and nickel
oxide at Port Colborne (Roberts et al., 1982).
Roberts et al. (1982) reported that the calcining/sintering process at
Port Colborne was dusty (SMR for lung cancer = 298 and for nasal cancer =
9412) and caused similar exposures to those at the Clydach, Wales calcining
sheds (SMR for lung cancer = 510 and for nasal cancer = 26,667) (Peto et al.,
1984). Roasting/smelting workers at Kristiansand, Norway were exposed to "dry
dust" containing nickel subsulfide and nickel oxide and had the highest risk
-------
of nasal cancer (SMR = 4000) and an elevated risk of lung cancer (SMR = 360)
(Magnus et al., 1982). The high cancer response in the electrolytic tankhouse
workers of this plant (SMR for lung and nasal cancer are 550 and 2600,
respectively) is the one apparent contradiction to the hypothesis that the
pyrometallurgical process and nickel subsulfide exposures are responsible for
the observed cancer increases. In the electrolytic tankhouse, workers are
exposed primarily to nickel sulfate, nickel metal, copper and nickel oxides,
and nickel chloride. These increases were not observed in the electrolysis
operations at Port Colborne (Roberts et al., 1984). In the study of refinery
and nonrefinery workers at a nickel refinery in West Virginia, nasal cancer
was exclusive to the refinery workers, with an SMR of 2443 (Enterline and
Marsh, 1982). No large excess of lung cancer was observed in either refinery
(SMR = 118) or nonrefinery (SMR = 107.6) employees. The data do show a dose-
response relationship between cumulative nickel exposure and lung cancer
response (allowing for a 20-year latent period).
<« Nickel Subsulfide >»
_II.A.3. ANIMAL CARCINOGENICITY DATA
Although nickel subsulfide is the most studied nickel compound, only one
study has used inhalation as the route of exposure. Ottolenghi et al. (1974)
exposed Fischer 344 rats to an airborne nickel subsulfide concentration. The
design of the experiment included two subtreatments in a 2**4 factorial
arrangement: a total of 467 rats of both sexes (factor 1) were preexposed to
nickel subsulfide, 0.97 mg Ni/cu.m, 6 hours/day, 5 days/week, for 1 month
(factor 2), and then followed by a second treatment of an intraveous injection
with hexachlorotetrafluorobutane (HTFB), an agent used to induce pulmonary
infarction (factor 3). The fourth factor was the actual treatment (after the
injection factor) with nickel subsulfide for 78 to 80 weeks, followed by 30
weeks of observation before terminal sacrifice. Fewer than 5% of the nickel
subsulfide group were alive at the end of 108 weeks, as compared with 31% of
the controls. The lungs were the major organ affected by the nickel
subsulfide treatment. No differences in response were attributed to sex
differences or the injections of HTFB. The lung effects included hyperplasia,
metaplasia, adenomas, and adenocarcinomas equally in both males and females.
These changes and tumors occurred in both the bronchiolar and alveolar regions
of the lung.
Studies comparing species and strain, route of administration, organ
sensitivity, and dose-response characteristics of nickel subsulfide
carcinogenesis have been performed and reviewed by Sunderman (1983) and Oilman
and Yamashiro (1985). While there are definite differences in tumor response
between species/strain and route of administration, different experimental
conditions among laboratories make cross-comparison difficult. Sunderman
(.1983) reported a dose-response relationship for tumor induction by nickel
subsulfide following intrarenal and intramuscular injections. Numerous
studies have shown nickel subsulfide to be a potent carcinogen by injection.
All routes of administration have led to positive tumor induction except
three: buccal brushing of Syrian golden hamsters, submaxillary implantation
into Fischer 344 rats (Sunderman et al., 1978), and intrahepatic injection of
Sprague-Dawley rats (Jasmin and Solymoss, 1978) and Fischer 344 rats
(Sunderman et al., 1978). Although Kasprzak et al. (1973) reported no
-------
pulmonary tumors in Wistar rats given 5 mg nickel subsulfide intratracheally,
bronchial metaplasia was increased from 31% to 62% when 5 mg nickel subsulfide
was administered with benzpyrene (2 mg). Nickel subsulfide pellets implanted
into heterotopic tracheas which were grafted in Fischer 344 rats produced
mainly sarcomas with a low yield of carcinomas (Yarita and Nettesheim, 1978).
_II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Nickel subsulfide induces morphologic transformation in Syrian hamster
embryo (Casto et al., 1979) and baby hamster kidney (BHK-21) cell cultures
(Hansen and Stern, 1983), sister chromatid exchange in human lymphocytes
(Saxholm et al., 1981), and DNA strand breaks (Robison and Costa, 1982).
Nickel as nickel subsulfide has been observed to concentrate in the cell
nucleus in in vitro assays (Sunderman, 1983).
-<« Nickel Subsulfide »>-
II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
<« Nickel Subsulfide >»
II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
_II.C.l. SUMMARY OF RISK ESTIMATES
Inhalation Slope Factor 1.7E+0/mg/kg/day
Inhalation Unit Risk 4.8E-4/ug/cu.m
Extrapolation Method Additive and multiplicative
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
E-4 (1 in 10,000) 2E-1 ug/cu.m
E-5 (1 in 100,000) 2E-2 ug/cu.m
E-6 (1 in 1,000,000) 2E-3 ug/cu.m
_II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Estimates of Incremental Unit Risks for Lung Cancer due to Exposure to 1 ug
Ni/cu.m for a Lifetime Based on Extrapolations from Epidemiologic Data Sets
-------
Study Relative Risk Model
Huntington, WV (Enterline and Marsh, 1982)
(maximum likelihood estimates only)
Refinery workers 1.5E-5 - 3.1E-5
Nonrefinery workers 9.5E-6 - 2.1E-5
Copper Cliff, Ontario (Chovil et al., 1981) 1.1E-5 - 8.9E-5
Clydach, Wales (Peto et al., 1984) 8.1E-5 - 4.6E-4
Kristiansand, Norway (Magnus et al., 1982) 1.9E-5 - 1.9E-4
Midpoint of range for refinery
workers 2.4E-4
<« Nickel Subsulfide >»
_II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
Since nickel subsulfide is a major component of nickel refinery dust and
has been shown to produce the highest incidence of tumors for nickel compounds
in animals (supported by in vitro studies), the incremental unit risk estimate
of nickel refinery dust (2.4E-4/ug/cu.m) may be used with a multiplication
factor of 2 to account for the roughly 50% nickel subsulfide composition. If
the two observed nasal cancer deaths and expected nasal cancer deaths are
included for refinery workers in Huntington, WV, the incremental unit risk
increases to 1.3E-4. The average relative risk model was applied to the
Huntington, WV and Copper Cliff, Ontario data sets. Data sets from nickel
refineries in Huntington, WV (Enterline and Marsh, 1982); Copper Cliff,
Ontario (Chovil et al., 1981); Clydach, Wales (Peto et al., 1984); and
Kristiansand, Norway (Magnus et al., 1982) provide information available
either for choice of model or for separation of risk by the type of nickel
exposure. The dose-response data for nasal cancer were not used for risk
estimation since nasal cancer risk from nickel is thought to be an
occupational hazard associated only with the pyrometallurgical process and is
not found in the general public to the same extent as lung tumors.
For the four data sets analyzed, both the additive and multiplicative
excess risk models were fitted whenever possible. The relative risk or
multiplicative model follows the assumption that the background cause-age-
specific rate at any time is increased by an amount proportional to the
cumulative dose up to that time. The model assumes the SMR is linearly
related to dose and is constant for a set cumulative exposure. Excess
mortality for a set cumulative exposure is constant over time, and excess risk
remains constant once exposure ceases. The relative risk model differs from
the additive risk model in that the latter model assumes that the excess
cause-age-specific rate is increased by an amount proportional to the
cumulative exposure up to that time.
The unit risk estimates ranged from 2.2E-5 to 9.2E-4/ug/cu.m. This is
2 times the incremental unit risk for nickel refinery dust: 1.1E-5 to
4.6E-4/ug/cu.m. The midpoint of the range, 4.8E-4/ug/cu.m, is taken as the
incremental unit risk due to a lifetime exposure to nickel subsulfide.
-------
The unit risk should not be used if the air concentration exceeds 20
ug/cu.m, since above this concentration the slope factor may differ from that
stated.
_II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
Four data sets, all from human exposure, offer a range of incremental unit
risk estimates that are consistent with each other. Upper-limit incremental
unit risks for nickel subsulfide exposure have been estimated from a rat
inhalation study (Ottolenghi et al., 1974). They range from 2.7E-3 to
6.lE-3/ug/cu.m, with the maximum likelihood estimates ranging from 1.8E-3 to
4.lE-3/ug/cu.m. This range is the consequence of a variety of assumptions for
species differences using pooled treated animals vs. pooled controls. These
estimates are approximately one order of magnitude greater than those obtained
from the human studies.
.-<« Nickel Subsulfide >»
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
_II.D.l. EPA DOCUMENTATION
U.S. EPA. 1986. Health Assessment Document for Nickel and Nickel Compounds.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-
83/012FF.
Chovil, A., R.B. Sutherland and M. Halliday. 1981. Respiratory cancer in a
cohort of sinter plant workers. Br. J. Ind. Med. 38: 327-333.
Enterline, P.E. and G.M. Marsh. 1982. Mortality among workers in a nickel
refinery and alloy manufacturing plant in West Virginia. J. Natl. Cancer
Inst. 68: 925-933.
Magnus, K. A. Andersen and A. Hogetveit. 1984. Cancer of respiratory
organs among workers at a nickel refinery in Norway. Int. J. Cancer.
30: 681-685.
Peto, J. H. Cuckle, R. Doll, C. Hermon and L.G. Morgan. 1984. Respiratory
cancer mortality of Welsh nickel refinery workers. In: Nickel in the Human
Environment: Proceedings of a Joint Symposium, March, 1983. IARC Scientific
Publ. No. 53. International Agency for Research on Cancer, Lyon, France,
p. 36-46.
_II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The 1986 Health Assessment Document has received both Agency and
external review.
Agency Work Group Review: 04/01/87
-------
Verification Date: 04/01/87
_II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Steven P. Bayard / ORD (202)382-5722 / FTS 382-5722
Herman J. Gibb / ORD (202)382-5898 / FTS 382-5898
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Nickel Subsulfide
CASRN 12035-72-2
Not available at this time
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Nickel Subsulfide
CASRN ~ 12035-72-2
Last Revised 03/01/88
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in sections
I and II, as this may explain inconsistencies. Also note that some regulatory
actions consider factors not related to health risk, such as technical or
economic feasibility. Such considerations are indicated for each action. In
addition, not all of the regulatory actions listed in this section involve
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background inform-
ation on each regulatory action in Background Document 4 in Service Code 5.
IV.A. CLEAN AIR ACT (CAA)
_'lV.A.I. CAA REGULATORY DECISION
Action Decision not to regulate
Considers technological or economic feasibility? NO
Discussion Nickel subsulfide is considered a known human carcinogen (Group
-------
A under EPA's classification scheme). EPA's assessment of nickel subsulfide
as a potential candidate for regulation under the Clean Air Act (CAA) as a
toxic air pollutant indicated that there are few, if any, emissions of nickel
subsulfide in the U.S. and that even under a worst-case scenario, the risks
are very small. Consequently, EPA concluded that regulation under the CAA was
not warranted.
Reference 51 FR 34135
EPA Contact Emissions Standards Division, OAQPS
(917)541-5571 / FTS 629-5571
<« Nickel Subsulfide >»
IV.B. SAFE DRINKING WATER ACT (SDWA)
No data available
«< Nickel Subsulfide »>
IV.C. CLEAN WATER ACT (CWA)
No data available
-<« Nickel Subsulfide >»-
IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
No data available
-<« Nickel Subsulfide >»-
IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA)
No data available
-<« Nickel Subsulfide >»-
IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA)
No data available
-<« Nickel Subsulfide >»-
-------
IV.G. SUPERFUND (CERCLA)
No data available
_V. SUPPLEMENTARY DATA
Substance Name Nickel Subsulfide
CASRN 12035-72-2
Not available at this time
_VI. REFERENCES
Substance Name Nickel Subsulfide
CASRN 12035^-72-2
Not available at this time
SYNONYMS
12035-72-2
HEAZLEWOODITE
Nickel Subsulfide
NICKEL SUBSULPHIDE
NICKEL SULFIDE
alpha-NICKEL SULFIDE (3:2) CRYSTALLINE
NICKEL SULPHIDE
NICKEL TRITADISULPHIDE
-------
Nickel Carbonyl; CASRN 13463-39-3 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Nickel Carbonyl
File On-Line 09/30/87
Category (section)
Status
Last Revised
Oral RfD Assessment (I.A.)
Inhalation RfD Assessment (I.B.)
Carcinogenicity Assessment (II.)
Drinking Water Health Advisories (III.A.)
U.S. EPA Regulatory Actions (IV.)
Supplementary Data (V.)
no data
no data
on-line
no data
on-line
on-line
09/30/87
03/01/88
09/30/87
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGENIC EFFECTS
Substance Name Nickel Carbonyl
CASRN ~ 13463-39-3
Not available at this time
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
-------
Substance Name Nickel Carbonyl
CASRN 13463-39-3
Last Revised 09/30/87
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
is presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
<« Nickel Carbonyl >»
II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
_II.A.l. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification B2; probable human carcinogen
Basis The observation of pulmonary carcinomas and malignant tumors at
various sites in rats by inhalation and intravenous injection, respectively,
forms the basis for this classification. Nickel administered as nickel
carbonyl binds to DNA.
_II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. Nickel carbonyl was the first nickel compound suspected of
causing cancer in humans in a detailed analysis of epidemiologic data from a
study of workers at a sulfide nickel matte refinery at Clydach, Wales. No
excess risk of cancer, however, was reported in the workers in the reduction
area where nickel carbonyl exposure was present (Peto et al., 1984).
_II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. Nickel carbonyl administered by inhalation has been found to
be carcinogenic in animals in the lung (Sunderman et al., 1959, Sunderman and
Donnelly, 1965). Sunderman et al. (1959) exposed male Wistar rats to nickel
carbonyl; 64 rats were exposed to 0.03 mg/L three times weekly for 1 year, 32
rats were exposed to 0.06 mg/L three times weekly for 1 year, and 80 rats were
exposed once to 0.25 mg/L. In each case, exposure was for 30-minute periods.
Of the nine animals exposed to nickel carbonyl and surviving 2 or more years,
four were reported to have tumors. One animal with repeated exposure to 0.03
-------
mg/L had a squamous-cell carcinoma; one animal with repeated exposure to 0.06
mg/L showed masses of clear-cell carcinoma having an adenocarcinomatous
pattern; and of two animals from a single heavy exposure, one exhibited masses
of clear-cell carcinoma having the adenocarcinomatous pattern, and the other
had two small papillary bronchial adenomas. No pulmonary tumors were seen in
the three surviving controls.
Sunderman and Donnelly (1965) treated male Wistar rats in six groups
(three were controls). The exposure groups consisted of the following:
(a) 285 animals exposed to 0.6 mg/L of carbonyl for 30 minutes and followed
for their lifetimes; (b) 60 animals exposed as in (a), but receiving an
injection of "dithiocarb" nickel chelate 15 minutes after exposure; and (c) 64
animals exposed for 30 minutes three times weekly to 0.03 mg/L carbonyl for
the remainder of their lifetimes. In the chronic and acute nickel carbonyl
exposure groups, three animals of the 80 surviving the 2-year exposure and/or
observation period showed pulmonary carcinomas and metastases: one with
pulmonary adenocarcinoma, one with anaplastic carcinoma, and one with
adenocarcinoma. No pulmonary neoplasms were observed in any of the 44
surviving controls.
Intravenous injection of Sprague-Dawley rats produced malignant tumors at
various sites (Lau et al., 1972).
_II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Hui and Sunderman (1980) found that after exposure of rats to radioactive
nickel carbonyl, nickel was bound to the liver and kidney DNA.
-<« Nickel Carbonyl >»-
II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
The low survival rate for both control and treated animals in the
studies of Sunderman and coworkers and the intravenous route of exposure in
the study by Lau et al. (1972) preclude a quantitative risk estimate.
-<« Nickel Carbonyl >»-
II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
None.
<« Nickel Carbonyl »>
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
_II.D.l. EPA DOCUMENTATION
-------
U.S. EPA. 1986. Health Assessment Document for Nickel and Nickel Compounds.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Research Triangle Park, NC. EPA/600/8-83/012FF.
_II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The 1986 Health Assessment Document has received both Agency and
external review.
Agency Work Group Review: 04/01/87
Verification Date: 04/01/87
_II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Steven P. Bayard / ORD ~ (202)382-5722 / FTS 382-5722
Herman J. Gibb / ORD (202)382-5898 / FTS 382-5898
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Nickel Carbonyl
CASRN 13463-39-3
Not available at this time
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Nickel Carbonyl
CASRN 13463-39-3
Last Revised 03/01/88
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in sections
I and II, as this may explain inconsistencies. Also note that some regulatory
actions consider factors not related to health risk, such as technical or
economic feasibility. Such considerations are indicated for each action. In
addition, not all of the regulatory actions listed in this section involve
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background inform-
ation on each regulatory action in Background Document 4 in Service Code 5.
-------
IV.A. CLEAN AIR ACT (CAA)
_IV.A.I. CAA REGULATORY DECISION
Action Decision not to regulate
Considers technological or economic feasibility? NO
Discussion Nickel carbonyl is considered a probable human carcinogen
(Group B2 under EPA's classificiation scheme). EPA's assessment of nickel
carbonyl as a potential candidate for regulation under the Clean Air Act (CAA)
as a toxic air pollutant indicated that nickel carbonyl is no longer produced
in this country and is only used in very small amounts (100 g lots) from
existing inventories. Consequently, EPA concluded that regulation under the
CAA was not warranted.
Reference 51 FR 34135
EPA Contact Emissions Standards Division, OAQPS
(917)541-5571 / FTS 629-5571
-<« Nickel Carbonyl >»-
IV.B. SAFE DRINKING WATER ACT (SDWA)
No data available
<« Nickel Carbonyl >»
IV.C. CLEAN WATER ACT (CWA)
No data available
<« Nickel Carbonyl >»-
IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
No data available
-<« Nickel Carbonyl >»-
IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA)
No data available
-------
-<« Nickel Carbonyl >»-
IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA)
No data available
<« Nickel Carbonyl >»
IV.G. SUPERFUND (CERCLA)
No data available
_V. SUPPLEMENTARY DATA
Substance Name Nickel Carbonyl
CASRN 13463-39-3
Last Revised 09/30/87
The information contained in this section (subsections A and B) has been
extracted from the EPA Chemical Profiles Database, which has been compiled
from a number of secondary sources and has not undergone formal Agency review.
The complete reference listings for the citations in this section are provided
in Service Code 5. The user is urged to read Background Document 5 in Service
Code 5 for further information on the sources and limitations of the data
presented here.
<« Nickel Carbonyl >»
V.A. ACUTE HEALTH HAZARD INFORMATION
Toxicity The probable oral lethal dose of nickel carbonyl for a human is
between 50 and 500 mg/kg, between 1 teaspoon and 1 ounce/150 Ib. person
(Gosselin et al., 1976). Nickel carbonyl has also been estimated to be lethal
in humans at atmospheric exposures of 30 ppm for 20 minutes (Doull et al.,
1980). Autopsies show congestion, collapse, and tissue destruction, as well
as hemorrhage in the brain (Hamilton and Hardy, 1974). Dermatitis, recurrent
asthmatic attacks, and increased number of white blood cells (eosinophils) in
respiratory tract are acute health hazards (DOT, 1984). Nickel carbonyl is
poisonous. It can be fatal if inhaled, swallowed, or absorbed through skin.
Vapors may cause irritation, congestion, and edema of lungs (Merck, 1983).
Medical Conditions Generally Aggravated by Exposure Not Found
Signs and Symptoms of Exposure Symptoms include frontal headache, vertigo,
chest tightness, weakness, sweating, cough, vomiting, and difficulty in
breathing (Hamilton and Hardy, 1974).
-------
-«< Nickel Carbonyl »>-
V.B. PHYSICAL-CHEMICAL PROPERTIES
Chemical Formula C4Ni04
Molecular Weight 170.75
Boiling Point -- 109F, 43C (Merck, 1983)
Specific Gravity (H20=l) ~ 1.318 at 17C (Merck, 1983)
Vapor Pressure (mmHg) 400 at 25.8C .(Hawley, 1981)
Melting Point 2.2F, -19.3C (Merck, 1983)
Vapor Density (AIR=1) 5.89 (NFPA, 1984, p. 325M-74)
Evaporation Rate (Butyl acetate=l) Not Found
Solubility in Water Soluble in about 5000 parts water free from air (Merck,
1983)
Flash Point (Method Used) Less than -18C (no method given) (NFPA, 1978)
Flammable Limits Flammable and burns with a yellow flame (Clayton and
Clayton, 1982)
LEL -- 2% (NIOSH/OSHA, 1978, p. 138)
UEL Not Found
Appearance and Odor Nickel carbonyl exists as a gas or as a colorless
liquid (Merck, 1983; Hamilton and Hardy, 1974). It has a peculiar sooty odor
(Clayton and Clayton, 1982).
Conditions or Materials to Avoid Contact with air (Clayton and Clayton,
1981-82). Contact with heat, acid, or acid fumes (Sax, 1979). Ignition
sources and vapors entering a confined space (NIOSH/OSHA, 1981).
Hazardous Decomposition or Byproducts Nickel carbonyl may explode at 68F
(20C) in presence of air or oxygen (Clayton and Clayton, 1981-82). Nickel
carbonyl emits highly toxic fumes when heated or on contact with acid or acid
fumes (Sax, 1979).
Use Nickel carbonyl is used to nickel-coat steel and other metals (Student,
1981, p. 363). It is also used in the electronics industry (Doull et al.,
1980).
_VI. REFERENCES
-------
Substance Name Nickel Carbonyl
CASRN 13463-39-3
Not available at this time
SYNONYMS
13463-39-3
NICKEL TETRACARBONILE
Nickel carbonyl
NICKEL CARBONYLE
NICKEL TETRACARBONYL
NICKEL TETRACARBONYLE
NIKKELTETRACARBONYL
RCRA WASTE NUMBER P073
UN 1259
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Cadmium; CASRN 7440-43-9 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Cadmium
File On-Line 03/31/87
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) pending
Inhalation RfD Assessment (I.E.) no data
Carcinogenicity Assessment (II.) on-line 03/01/88
Drinking Water Health Advisories (III.A.) no data
U.S. EPA Regulatory Actions (IV.) on-line 01/01/89
Supplementary Data (V.) no data
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_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGEN1C EFFECTS
Substance Name Cadmium
CASRN 7440-43-9
A risk assessment for this chemical is under review by an EPA work group.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name Cadmium
CASRN 7440-43-9
Last Revised 03/01/88
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
is presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
<« Cadmium >»
II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
_II.A.l. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification Bl; probable human carcinogen by inhalation
Basis Limited evidence from epidemiologic studies and sufficient evidence
-------
of carcinogenicity in rats and mice by two routes
_II.A.2. HUMAN CARCINOGENICITY DATA
Limited. A 2-fold excess risk of lung cancer was observed in cadmium
smelter workers. The cohort consisted of 602 white males who had been
employed in production work a minimum of 6 months during the years 1940-1969.
The population was followed to the end of 1978. Urine cadmium data available
for 261 workers employed after 1960 suggested a highly exposed population.
The authors were able to ascertain that of these possible confounding factors
the increased lung cancer risk was probably not due to the presence of arsenic
or to smoking (Thun et al., 1985). An evaluation by the Carcinogen Assessment
Group of these possible confounding factors has indicated that the assumptions
and methods used in accounting for them may not be valid. As the SMRs
observed were low and there is a lack of clear cut evidence of a causal
relationship of the cadmium exposure only, this study is considered to supply
only limited evidence of human carcinogenicity.
An excess lung cancer risk was also observed in three other studies which
were, however, compromised by the presence of other carcinogens (arsenic,
smoking) in the exposure or by a small population (Varner, 1983; Sorahan and
Waterhouse, 1983; Armstrong and Kazantzis, 1983).
Four studies of workers exposed to cadmium dust or fumes provided evidence
of a statistically significant positive association with prostate cancer
(Kipling and Waterhouse, 1967; Lemen et al., 1976; Holden, 1980; Sorahan and
Waterhouse, 1983), but the total number of cases was small in each study. The
Thun et al. (1985) study is an update of an earlier study (Lemen et al., 1976)
and does not show excess prostate cancer risk in these workers. Studies of
human ingestion of cadmium are inadequate to assess carcinogenicity.
_II.A.3. ANIMAL CARCINOGENICITY DATA
Exposure of Wistar rats to cadmium as cadmium chloride at concentrations
of 12.5, 25 and 50 ug/cu.m for 18 months, with an additional 13-month obser-
vation period, resulted in significant increases in lung tumors (Takenaka et
al., 1983). Intratracheal instillation of cadmium oxide did not produce lung
tumors in Fischer 344 rats but rather mammary tumors in females and tumors at
multiple sites in males (Sanders and Mahaffey, 1984). Injection site tumors
and distant site tumors (for example, testicular) have been reported by a
number of authors as a consequence of intramuscular or subcutaneous
administration of cadmium metal and chloride, sulfate, oxide and sulfide
compounds of cadmium to rats and mice (U.S. EPA, 1985). Seven studies in rats
and mice where cadmium salts (acetate, sulfate, chloride) were administered
orally have shown no evidence of a carcinogenic response.
_II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
-------
Results of mutagenicity tests in bacteria and yeast have been inconclu-
sive. Positive responses have been obtained in mutation assays in Chinese
hamster cells (Dom and V79 lines) and in mouse lymphoma cells (Casto, 1976;
Ochi and Ohsawa, 1983; Oberly et al., 1982).
Conflicting results have been obtained in assays of chromosomal aberra-
tions in human lymphocytes treated in vitro or obtained from exposed workers.
Cadmium treatment in vivo or in vitro appears to interfere with spindle
formation and to result in aneuploidy in germ cells of mice and hamsters
(Shimada et al., 1976; Watanabe et al., 1979; Gilliavod and Leonard, 1975).
«< Cadmium >»
II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Insufficient data exist to classify cadmium as carcinogenic to humans by
the oral route.
«< Cadmium >»
II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
_II.C.l. SUMMARY OF RISK ESTIMATES
Inhalation Slope Factor 6. lE+0/mg/kg/day
Inhalation Unit Risk 1.8E-3/ug/cu.m
Extrapolation Method Two stage; only first affected by exposure; extra risk
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
E-4 (1 in 10,000) 6E-2 ug/cu.m
E-5 (1 in 100,000) 6E-3 ug/cu.m
E-6 (1 in 1,000,000) 6E-4 ug/cu.m
_II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
-------
Species/Strain
Tumor Type
Doae Tumor Reference
Administered Human Equivalent Incidence
Human/white male;
lung, trachea,
bronchus cancer
deaths
Route: Inhalation exposure
in the workplace
Thun
et al.,
1985
Cumulative
Exposure
(mg/day/cu.m)
Median
Observation
24 hour/
ug/cu.m
Equivalent
No. of Expected
Lung, Trachea and
Bronchus Cancers
Assuming No
Cadmium Effect
Observed No.
of Deaths
(lung, trachea,
bronchus
cancers)
less than or
equal to 584 280
585-2920 1210
168 3.77
727 4.61
2
7
greater than
or equal to
2921
4200
2522
2.50
The 24-hour equivalent = median observation x 10E-3 x 8/24 x 1/365 x 240/365.
<« Cadmium >»
_II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
The unit risk should not be used if the air concentration exceeds 6
ug/cu.m, since above this concentration the slope factor may differ from that
stated.
_II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
v
The data were derived from a relatively large cohort. Effects of arsenic
and smoking were accounted for in the quantitative analysis for cadmium
effects.
A slope factor derived from cadmium chloride inhalation assay data in rats
-------
(Takenaka et al., 1983) equals 3.4E-l/ug/kg/day for elemental cadmium or
2.lE-1/ug/kg/day for cadmium chloride. An inhalation unit risk for cadmium
based on this analysis is 9.2E-2/ug/cu.m. While this estimate is higher than
that derived from human data (1.8E-3/ug/cu.m) and thus more conservative, it
was felt that the use of available human data was more reliable because of
species variations in response and the type of exposure (cadmium salt vs.
cadmium fume and cadmium oxide).
<« Cadmium >»
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
_II.D.l. EPA DOCUMENTATION
U.S. EPA. 1985. Updated Mutagenicity and Carcinogenicity Assessment of
Cadmium: Addendum to the Health Assessment Document for Cadmium (May 1981,
EPA 600/B-B1-023). EPA 600/B-83-025F.
Thun, M.J., T.M. Schnorr, A.B. Smith and W.E. Halperin. 1985. Mortality
among a cohort of U.S. cadmium production workers: An update. J. Natl.
Cancer Inst. 74(2): 325-333.
_II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The Addendum to the Cadmium Health Assessment has received both Agency
and external review.
Agency Work Group Review: 11/12/86
Verification Date: 11/12/86
_II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
William E. Pepelko / ORD (202)382-5904 / FTS 382-5904
David Bayliss / ORD (202)382-5726 / FTS 382-5726
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_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Cadmium
CASRN 7440-43-9
Not available at this time
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Cadmium
CASRN 7440-43-9
Last Revised 01/01/89
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in sections
I and II, as this may explain inconsistencies. Also note that some regulatory
actions consider factors not related to health risk, such as technical or
economic feasibility. Such considerations are indicated for each action. In
addition, not all of the regulatory actions listed in this section involve
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background inform-
ation on each regulatory action in Background Document 4 in Service Code 5.
IV.A. CLEAN AIR ACT (CAA)
_IV.A.l. CAA REGULATORY DECISION
Action Intent to list under Section 112
Considers technological or economic feasibility? NO
Discussion Cadmium is a probable human caracinogen (IARC category 2A) and
according to EPA's preliminary risk assessment from ambient air exposures,
public health risks are significant (3-7 cancer cases/year and maximum
-------
lifetime individual risks of 0.003. Thus, EPA indicated that it intends to
add cadmium to the list of hazardous air pollutants for which it intends to
establish emission standards under section 112(b)(l)(A) of the Clean Air Act.
The EPA will decide whether to add cadmium to the list only after studying
possible techniques that might be used to control emissions and further
assessing the public health risks. The EPA will add cadmium to the list if
emission standards are warranted.
Reference 50 FR 42000 (10/16/85)
EPA Contact Emissions Standards Division, OAQPS
(917)541-5571 / FTS 629-5571
<« Cadmium >»
IV.B. SAFE DRINKING WATER ACT (SDWA)
_IV.B.l. MAXIMUM CONTAMINANT LEVEL GOAL (MCLG) for Drinking Water
Value (status) 0.005 mg/L (Proposed, 1985)
Considers technological or economic feasibility? NO
Discussion An MCLG of 0.005 mg/L for cadmium is proposed based on a
provisional DWEL of 0.018 mg/L and drinking water contribution (plus aquatic
organism) of 25%. A DWEL of 0.018 mg/L was calculated from a LOAEL of 0.352
mg/day for renal toxicity in humans (calculated), with an uncertainty factor
of 10 applied and consumption of 2 L of water/day assumed.
Reference 50 FR 46936 Part IV (11/13/85)
EPA Contact Criteria and Standards Division, ODW /
(202)382-7571 / FTS 382-7571; or Drinking Water Hotline / (800)426-4791
_IV.B.2. MAXIMUM CONTAMINANT LEVEL (MCL) for Drinking Water
Value (status) 0.01 mg/L (Interim, 1980)
Considers technological or economic feasibility? YES
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Discussion
Reference 45 FR 57332
EPA Contact Kenneth Bailey / Criteria and Standards Division, ODW /
(202)382-7571 / FTS 382-7571; or Drinking Water Hotline / (800)426-4791
-<« Cadmium >»-
IV.C. CLEAN WATER ACT (CWA)
_IV.C.l. AMBIENT WATER QUALITY CRITERIA, Human Health
Water and Fish Consumption: 1E+1 ug/L
Fish Consumption Only: None
Considers technological or economic feasibility? NO
Discussion The criteria is the same as the existing standard for drinking
water.
Reference 45 FR 79318 (11/28/80)
EPA Contact Criteria and Standards Division, OWRS
(202)475-7315 / FTS 475-7315
_IV.C.2. AMBIENT WATER QUALITY CRITERIA, Aquatic Organisms
Freshwater:
Acute 3.9E+0 ug/L (1-hour average)
Chronic 1.1E+0 ug/L (4-day average)
Marine:
Acute 4.3E+1 ug/L (1-hour average)
Chronic 9.3E+0 ug/L (4-day average)
-------
Considers technological or economic feasibility? NO
Discussion The freshwater criteria are hardness dependent. Values given
here are calculated at a hardness of 100 mg/L CaCOS. A complete discussion
can be found in the referenced notice.
, Reference ~ 50 FR 30784 (07/29/85)
EPA Contact Criteria and Standards Division, OWRS
(202)475-7315 / FTS 475-7315
<« Cadmium >»
IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
_IV.D.l. PESTICIDE ACTIVE INGREDIENT, Registration Standard
None
_IV.D.2. PESTICIDE ACTIVE INGREDIENT, Special Review
Action Final regulatory action - PD4 (1987)
Considers technological or economic feasibility? YES
Summary of regulatory action The basis for selection of the final
regulatory option is presented in Position Document 4.
Reference 52 FR 31076 (08/19/87)
EPA Contact Special Review Branch, OPP / (703)557-7400 / FTS 557-7400
<« Cadmium >»
IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA)
No data available
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«< Cadmium >»
IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA)
_IV.F.l. RCRA APPENDIX IX, for Ground Water Monitoring
Status Listed
Reference 52 FR 25942 (07/09/87)
EPA Contact Jerry Garman / OSW / (202)382-4658 / FTS 382-4658
<« Cadmium »>
IV.G. SUPERFUND (CERCLA)
_IV.G.l. REPORTABLE QUANTITY (RQ) for Release into the Environment
Value (status) 10 pounds (Proposed, 1987)
Considers technological or economic feasibility? NO
Discussion The proposed RQ for cadmium is 10 pounds, based on potential
carcinogenicity. Available data indicate a hazard ranking of medium, based on
a potency factor of 57.87/mg/kg/day and weight-of-evidence group Bl, which
corresponds to an RQ of 10 pounds. Cadmium has also been found to
bioaccumulate in the tissues of aquatic and marine organisms, and has the
potential to concentrate in the food chain.
Reference 52 FR 8140 (03/16/87)
EPA Contact RCRA/Superfund Hotline
(800)424-9346 / (202)382-3000 / FTS 382-3000
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_V. SUPPLEMENTARY DATA
Substance Name Cadmium
CASRN 7440-43-9
Not available at this time
_VI. REFERENCES
Substance Name Cadmium
CASRN 7440-43-9
Not available at this time
SYNONYMS
7440-43-9
C.I. 77180
Cadmium
KADMIUM
-------
Vanadium Pentoxide; CASRN 1314-62-1 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Vanadium Pentoxide
File On-Line 01/31/87
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) on-line 03/01/88
Inhalation RfD Assessment (I.B.) no data
Carcinogenicity Assessment (II.) no data
Drinking Water Health Advisories (III.A.) no data
U.S. EPA Regulatory Actions (IV.) on-line 03/01/88
Supplementary Data (V.) on-line 01/31/87
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGENIC EFFECTS
Substance Name Vanadium Pentoxide
CASRN 1314-62-1
Last Revised 03/01/88
The Reference Dose (RfD) is based on the assumption that thresholds exist for
certain toxic effects such as cellular necrosis, but may not exist for other
toxic effects such as carcinogenicity. In general, the RfD is an estimate
(with uncertainty spanning perhaps an order of magnitude) of a daily exposure
to the human population (including sensitive subgroups) that is likely to be
without an appreciable risk of deleterious effects during a lifetime. Please
-------
refer to Background Document 1 in Service Code 5 for an elaboration of these
concepts. RfDs can also be derived for the noncarcinogenic health effects of
compounds which are also carcinogens. Therefore, it is essential to refer to
other sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogen-
icity, a summary of that evaluation will be contained in Section II of this
file when a review of that evaluation is completed.
<« Vanadium Pentoxide >»
I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfDo)
_I.A.l. ORAL RfD SUMMARY
Critical Effect Experimental Doses*
UF
MF
RfD
Decreased hair
cystine
Rat Chronic Oral
Study
Stokinger et al., 1953
NOAEL: 17.85 ppm
converted to 0.89
mg/kg/day
LOAEL: none
100
9E-3
mg/kg/day
*Dose Conversion Factors & Assumptions:
to be 5% bw/day.
Adult rat food consumption assumed
_I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Stokinger, H.E., W.D. Wagner, J.T. Mountain, F.R. Stacksill, O.J. Dobrogorski
and R.G. Keenan. 1953. Unpublished results. Division of Occupational
Health, Cincinnati, OH. (Cited in Patty's Industrial Hygiene and Toxicology,
3rd ed., 1981)
In this chronic study, an unspecified number of rats were exposed to
dietary levels of 10 or 100 ppm vanadium (about 17.9 or 179 ppm vanadium
pentoxide) for 2.5 years. The results of this unpublished study were sum-
marized by Stokinger et al. (1981). The criteria used to evaluate vanadium
-------
toxicity were growth rate, survival, and hair cyatine content. The only sig-
nificant change reported was a decrease in the amount of cystine in the hair
of animals ingesting vanadium.
Of the subchronic and chronic animal studies available, the lower dose
level (17.9 ppm vanadium pentoxide) reported in the Stokinger et al. (1953)
study is the highest oral NOAEL upon which an RfD can be derived. An oral
RfD of 0.009 mg/kg/day (0.62 mg/day for a 70-kg person) can be calculated by
assuming that rats eat food equivalent to 5% of their body weight and by
applying an uncertainty factor of 100.
_I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF = 100. An uncertainty factor of 100 was applied, 10 for interspecies
extrapolation and a factor of 10 to provide added protection for unusually
sensitive individuals.
MF = 1
<« Vanadium Pentoxide >»
_I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
In a subchronic feeding study (Mountain et al., 1953), groups of five male
Wistar rats were fed vanadium pentoxide at levels of 0, 25, or 50 ppm for 35
days, after which dietary levels of vanadium were increased to 100 and 150
ppm and continued for 68 days. There was a decrease in the amount of cystine
in the hair of the high-dosed (50-150 ppm or 2.5-7.5 mg/kg/day, based on food
consumption of 5% bw) rats. A significant decrease was also reported in
erythrocyte and hemoglobin levels of the high-dosed rats. In an abstract of a
subchronic inhalation study (Suguira, 1978), mice and rats exposed to 1 to 3
mg/cu.m vanadium pentoxide for 3 months, 6 hours/day developed histopatho-
logic changes in their lungs and had a decrease in growth rate. Adverse
effects were not detected in either species similarly exposed at 0.1 to 0.4
mg/cu.m.
Although several epidemiologic studies have been conducted on factory
workers exposed to vanadium pentoxide for several years, the air concentra-
tion levels of vanadium pentoxide were measured only at scattered intervals,
making it impossible to determine a minimum effective dose. Also, in cases of
humans exposed to relatively high atmospheric concentrations of vanadium
pentoxide for short periods of time, all individuals developed respiratory
symptoms that usually subsided within 7-14 days.
^I.A.5. CONFIDENCE IN THE ORAL RfD
Study: Low
Data Base: Low
RfD: Low
Because of the lack of details in the reference study and the scarcity of
data available on vanadium pentoxide, low confidence is assigned to both the
-------
study and the data base. Low confidence in the RfD follows.
_I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
The only U.S. EPA documentation at present is on IRIS.
Agency RfD Work Group Review: 02/26/86
Verification Date: 02/26/86
_I.A.7. EPA CONTACTS (ORAL RfD)
Christopher T. DeRosa / ORD (513)569-7534 / FTS 684-7534
Michael L. Dourson / ORD (513)569-7544 / FTS 684-7544
<« Vanadium Pentoxide >»
I.E. REFERENCE DOSE FOR CHRONIC INHALATION EXPOSURE (RfDi)
Not available at this time
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name Vanadium Pentoxide
CASRN 1314-62-1
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
is presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
<« Vanadium Pentoxide >»
The NTP (1985) has approved vanadium pentoxide for carcinogenicity test-
ing; however, the route of administration has not been determined (i.e., oral,
-------
inhalation).
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Vanadium Pentoxide
CASRN 1314-62-1
Not available at this time
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Vanadium Pentoxide
CASRN 1314-62-1
Last Revised 03/01/88
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in sections
I and II, as this may explain inconsistencies. Also note that some regulatory
actions consider factors not related to health risk, such as technical or
economic feasibility. Such considerations are indicated for each action. In
addition, not all of the regulatory actions listed in this section involve
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background inform-
ation on each regulatory action in Background Document 4 in Service Code 5.
IV.A. CLEAN AIR ACT (CAA)
No data available
-<« Vanadium Pentoxide >»-
IV.B. SAFE DRINKING WATER ACT (SDWA)
No data available
<« Vanadium Pentoxide >»-
IV.C. CLEAN WATER ACT (CWA)
-------
No data available
<« Vanadium Pentoxide >»-
IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
No data available
-<« Vanadium Pentoxide >»-
IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA)
No data available
<« Vanadium Pentoxide »>
IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA)
_IV.F.l. RCRA APPENDIX IX, for Ground Water Monitoring
Status Listed
Reference 52 FR 25942 (07/09/87)
EPA Contact Jerry Carman / OSW / (202)382-4658 / FTS 382-4658
<« Vanadium Pentoxide »>
IV.G. SUPERFUND (CERCLA)
_IV.G.l. REPORTABLE QUANTITY (RQ) for Release into the Environment
Value (status) 1000 pounds (Final, 1986)
Considers technological or economic feasibility? NO
Discussion The final RQ is based on aquatic toxicity (as established under
Section 311(b)(4) of the Clean Water Act), chronic toxicity and acute
toxicity. The available data indicate that the aquatic 96-hour Median
Threshold Limit for vanadium pentoxide is between 10 and 100 ppm. RQ
assignments based on chronic toxicity reflect two primary attributes of the
hazardous substance, the minimum effective dose (MED) levels for chronic
exposure (mg/day for 70-kg man) and the type of effect (liver necrosis,
teratogenicity, etc. The composite score of these two attributes for vanadium
pentoxide is between 6 and 20, corresponding to a chronic toxicity RQ of 1000
-------
pounds. In addition, the oral LD50 for rats is between 10 and 100 mg/kg and
the inhalation LC10 for rats is between 40 and 400 ppm, also a 1000-pound RQ.
Reference 51 FR 34534 (09/29/86)
EPA Contact RCRA/Superfund Hotline
(800)424-9346 / (202)382-3000 / FTS 382-3000
_V. SUPPLEMENTARY DATA
Substance Name Vanadium Pentoxide
CASRN 1314-62-1
Last Revised 01/31/87
The information contained in this section (subsections A and B) has been
extracted from the EPA Chemical Profiles Database, which has been compiled
from a number of secondary sources and has not undergone formal Agency review.
The complete reference listings for the citations in this section are provided
in Service Code 5. The user is urged to read Background Document 5 in Service
Code 5 for further information on the sources and limitations of the data
presented here.
<« Vanadium Pentoxide >»
V.A. ACUTE HEALTH HAZARD INFORMATION
Toxicity Probable oral lethal dose of vanadium pentoxide for humans is
between 5 and 50 mg/kg or between 7 drops and 1 teaspoonful for a 70-kg
(150-lb.) person (Gosselin et al., 1984). Toxicity is about the same
magnitude as pentavalent arsenic (Gosselin et al., 1984, p. 11-148).
Medical Conditions Generally Aggravated by Exposure Chronic respiratory
disease (Encyc. Occupat. Health and Safety, 1983).
Signs and Symptoms of Exposure Can cause death by pulmonary edema. Contact
with eyes and skin causes irritation and redness. Ingestion causes irritation
of mouth and stomach, vomiting, abdominal spasms, and a green discoloration of
the tongue. Inhalation of dust initially irritates the nose and throat,
causing coughing and shortness of breath followed by headaches, a greenish
discoloration of the tongue, blood in sputum, bronchospasm and pulmonary
edema. Chronic inhalation may cause bronchitis, emphysema, and bronchial
pneumonia (Weiss, 1980, p. 909; DASE, 1980, p. 950; ACGIH, 1980; Gosselin et
al., 1976; Clayton and Clayton, 1981-1982).
<« Vanadium Pentoxide >»-
V.B. PHYSICAL-CHEMICAL PROPERTIES
-------
Chemical Formula V205
Molecular Weight ~ 181.90
Boiling Point 3182F, 1750C (decomposition)
Specific Gravity (H20=l) ~ 3.357 at 18C
Vapor Pressure (mmHg) Approximately 0 at 20C, 68F
Melting Point 1274F, 690C
Vapor Density (AIR=1) Not Found
Evaporation Rate (Butyl acetate=l) Not Found
Solubility in Water 1 g in 125 mL
Flash Point [Method Used] Not Found
Flammable Limits Not Flammable
Appearance and Odor Vanadium pentoxide exists as a yellow-orange powder,
dark gray flakes, or yellow to rust brown crystals (NIOSH/OSHA, 1981; Merck,
1983). It is odorless (CHRIS, 1978)
Conditions or Materials to Avoid Avoid chlorine trifluoride; lithium;
peroxyformic acid; and calcium, sulfur, water complexes (Sax, 1984, p. 2718)
Hazardous Decomposition or Byproducts When heated to decomposition, it
emits acrid smoke and fumes of vanadium oxides (Sax, 1984, p. 2718).
Use Vanadium pentoxide is used as a catalyst in the oxidation of sulfur
dioxide to sulfur trioxide, alcohol to acetaldehyde, etc.; for the manufacture
of yellow glass; inhibiting ultraviolet light transmission in glass; as a
depolarizer; as a developer in photography; in form of ammonium vanadate as
mordant in dyeing and printing fabrics and in manufacture of aniline black
(Merck, 1983, p. 1418).
_VI. REFERENCES
Substance Name Vanadium Pentoxide
CASRN 1314-62-1
Not available at this time
SYNONYMS
-------
1314-62-1
CI 77938
Divanadium Pentaoxide
Divanadium Pentoxide
Vanadic Anhydride
Vanadium Oxide
Vanadium Pentaoxide
Vanadium Pentoxide
-------
Toluene; CASRN 108-88-3 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Toluene
File On-Line 01/31/87
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) on-line 03/01/88
Inhalation RfD Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 02/01/89
Drinking Water Health Advisories (III.A.) no data
U.S. EPA Regulatory Actions (IV.) on-line 03/01/88
Supplementary Data (V.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGENIC EFFECTS
Substance Name Toluene
CASRN 108-88-3
Last Revised 03/01/88
The Reference Dose (RfD) is based on the assumption that thresholds exist for
certain toxic effects such as cellular necrosis, but may not exist for other
toxic effects such as carcinogenicity. In general, the RfD is an estimate
(with uncertainty spanning perhaps an order of magnitude) of a daily exposure
to the human population (including sensitive subgroups) that is likely to be
without an appreciable risk of deleterious effects during a lifetime. Please
-------
refer to Background Document 1 in Service Code 5 for an elaboration of these
concepts. RfDs can also be derived for the noncarcinogenic health effects of
compounds which are also carcinogens. Therefore, it is essential to refer to
other sources of information concerning the carcinogenicity of this substance.
If the U.S. EPA has evaluated this substance for potential human carcinogen-
icity, a summary of that evaluation will be contained in Section II of this
file when a review of that evaluation is completed.
<« Toluene >»
I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfDo)
NOTE: The Oral RfD for Toluene may change in the near future pending the
outcome of a further review now being conducted by the Oral RfD Workgroup.
_I.A.l. ORAL RfD SUMMARY
Critical Effect Experimental Doses*
UF
MF
RfD
Clinical chemistry NOAEL: 300 ppm (1130 100 1 3E-1
and hematological MG/CU.m) converted to mg/kg/day
parameters
Rat Chronic Inha-
lation Study
CITT, 1980
NOAEL: 300 ppm (1130
MG/CU.m) converted to
29 mg/kg/day
LOAEL: none
*Dose Conversion Factors & Assumptions: 5 days/7 days, 6 hour/24 hour;
0.5 absorption factor, 20 cu.m human breathing rate; 70 kg; thus, 1130
mg/cu.m x 5 day/7 days x 6 hours/24 hours x 0.5 x 20 cu.m/day / 70 kg =
28.8 mg/kg/day
_I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
CUT (Chemical Industry Institute of Toxicology). 1980. A 24-month
inhalation toxicology study in Fischer-344 rats exposed to atmospheric
-------
toluene. CUT, Research Triangle Park, NC.
Toluene is most likely a potential source of respiratory hazard. The only
chronic toxicity study on toluene was conducted for 24 months in male and
female F344 rats (CUT, 1980). Toluene was administered by inhalation at 30,
100, or 300 ppm (113, 377, or 1130 mg/cu.m) to 120 male and 120 female F344
rats for 6 hours/day, 5 days/week. The same number of animals (120 males and
120 females) was used as a control. Clinical chemistry, hematology and
urinalysis testing was conducted at 18 and 24 months. All parameters measured
at the termination of the study were normal except for a dose-related
reduction in hematocrit values in females exposed to 100 and 300 ppm toluene.
Based on these findings, a NOAEL of 300 ppm or 1130 mg/cu.m was derived.
An oral RfD of 20 mg/day can be derived using route-to-route extrapolation.
This was done by expanding the exposure from 6 hours/day, 5 days/week to con-
tinuous exposure and multiplying by 20 cu.m/day and 0.5 to reflect a 50%
absorption factor.
<« Toluene »>
_I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF = 100. An uncertainty factor of 100 (10 for sensitive individuals and 10
for intraspecies extrapolation) was also applied.
MF = 1
_I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Subchronic inhalation and subchronic oral studies in both mice and rats
support the chosen NOAEL (NTP, 1981, 1982). Furthermore, an oral study (Wolf
et al., 1956) contains subchronic data in which no adverse effects of toluene
were reported at the highest dose tested (590 mg/kg/day).
_I.A.5. CONFIDENCE IN THE ORAL RfD
Study: High
Data Base: Medium
RfD: Medium
Confidence in the principal study is high because a large number of
animals/sex were tested in each of three dose groups and many parameters were
studied. Interim kills were performed. The data base is rated medium because
several studies support the chosen effect level. The confidence of the RfD is
not higher than medium because the critical study was by the inhalation route.
_I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Limited Peer Review and Agency-wide Internal Review, 1984.
U.S. EPA. 1985. Drinking Water Criteria Document for Toluene. Prepared by
-------
the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC.
Agency RfD Work Group Review: 05/20/85, 08/05/85, 08/05/86
Verification Date: 05/20/85
_I.A.7. EPA CONTACTS (ORAL RfD)
Christopher T. DeRosa / ORD (513)569-7534 / FTS 684-7534
Michael L. Dourson / ORD (513)569-7544 / FTS 684-7544
<« Toluene >»
I.E. REFERENCE DOSE FOR CHRONIC INHALATION EXPOSURE (RfDi)
Not available at this time
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name Toluene
CASRN 108-88-3
Last Revised 02/01/89
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
is presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
<« Toluene >»
Substance Name Toluene
CASRN 108-88-3
Preparation Date 08/14/88
-------
II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
_II.A.l. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification D; not classified
Basis -- No human data and inadequate animal data. Toluene did not produce
positive results in the majority of genotoxic assays.
_II.A.2. HUMAN CARCINOGENICITY DATA
None.
_II.A.3. ANIMAL CARCINOGENICITY DATA
A chronic (106-week) bioassay of toluene in F344 rats of both sexes
reported no carcinogenic responses (CUT, 1980). A total of 960 rats were
exposed by inhalation for 6 hours/day, 5 days/week to toluene at 0, 30, 100,
or 300 ppm. Groups of 20/sex/dose were sacrificed at 18 months. Gross and
microscopic examination of tissues and organs identified no increase in
neoplastic tissue or tumor masses among treated rats when compared with
controls. The study is considered inadequate because the highest dose
administered was well below the MTD for toluene and because of the high
incidence of lesions and pathological changes in the control animals.
Several studies have examined the carcinogenicity of toluene following
repeated dermal applications. Toluene (dose not reported) applied to shaved
interscapular skin of 54 male mice (strains A/He, CSHeB, SWR) throughout their
lifetime (3 times weekly) produced no carcinogenic response (Poel, 1963). One
drop of toluene (about 6 mL) applied to the dorsal skin of 20 random-bred
albino mice twice weekly for 50 weeks caused no skin papillomas or carcinomas
after a 1-year latency period was allowed (Coombs et al., 1973). No increase
in the incidence of skin or systemic tumors was demonstrated in male or female
mice of three strains (CF, C3H, or CBaH) when toluene was applied to the back
of 25 mice of each sex of each strain at 0.05-0.1 mL/mouse, twice weekly for
56 weeks (Doak et al., 1976). One skin papilloma and a single skin carcinoma
were reported among a group of 30 mice treated dermally with one drop of 0.2%
(w/v) solution toluene twice weekly, administered from droppers delivering 16-
20 uL per drop for 72 weeks (Lijinsky and Garcia, 1972). It is not reported
whether evaporation of toluene from the skin was prevented during these
studies.
<« Toluene >»
_II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Toluene was found to be nonmutagenic in reverse mutation assays with S.
typhimurium (Mortelmans and Riccio, 1980; Nestman et al., 1980; Bos et al.,
1981; Litton Bionetics, Inc., 1981; Snow et al., 1981) and E. coli (Mortelmans
and Riccio, 1980), with and without metabolic activation. Toluene did not
induce mitotic gene conversion (Litton Bionetics, Inc., 1981; Mortelmans and
-------
Riccio, 1980) or mitotic crossing over (Mortelmans and Riccio, 1980) in S.
cerevisiae. Although Litton Bionetics, Inc. (1981) reported that toluene did
not cause increased chromosomal aberrations in bone marrow cells, several
Russian studies (Dobrokhotov, 1972; Lyapkalo, 1973) report toluene as
effective in causing chromosal damage in bone marrow cells of rats. There was
no evidence of chromosomal aberrations in blood lymphocytes of workers exposed
to toluene only (Maki-Paakkanen et al., 1980; Forni et al., 1971), although a
slight increase was noted in workers exposed to toluene and benzene (Forni et
al., 1971; Funes-Craviota et al., 1977). This is supported by studies of
cultured human lymphocytes exposed to toluene in vitro. No elevation of
chromosomal aberrations or sister chromatid exchanges was observed (Gerner-
Smidt and Friedrich, 1978).
II.E. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
«< Toluene >»
_II.D.1. EPA DOCUMENTATION
U.S. EPA. 1987. Drinking Water Criteria Document for Toluene. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC. ECAO-CIN-408.
Bos, R.P., R.M.E. Brouns, R. van Doom, J.L.G. Theuws and P.Th. Henderson.
1981. Non-mutagenicity of toluene, o-, m- and p-xylene, o-methylbenzylalcohol
and o-methylbenzylsulfate in the Ames assay. Mutat. Res. 88(3): 273-279.
CUT (Chemical Industry Institute of Toxicology). 1980. A twenty-four month
inhalation toxicology study in Fischer-344 rats exposed to atmospheric
toluene. Executive Summary and Data Tables. October 15.
Coombs, M.M., T.S. Bhatt and C.J. Croft. 1973. Correlation between
carcinogenicity response in mice to the topical application of propane sultone
-------
to the skin. Toxicology. 6: 139-154.
Doak, S.M.A., B.J.E. Simpson, P.F. Hunt and D.E. Stevenson. 1976. The
carcinogenic response in mice to the topical application of propane sultone
to the skin. Toxicology. 6: 139-154.
Dobrokhotov, V.B. 1972. The mutagenic influence of benzene and toluene
under experimental conditions. Gig. Sanit. 37: 36-39. (Rus.) (Evaluation
based on an English translation provided by the U.S. EPA.)
Forni, A., E. Pacifico and A. Limonta. 1971. Chromosome studies in workers
exposed to benzene or toluene or both. Arch. Environ. Health. 22(3):
373-378.
Funes-Cravioto, F., B. Kolmodin-hedman, J. Lindsten, et al. 1977. Chromosome
aberrations and sister-chromatid exchange in workers in chemical laboratories
and a rotoprinting factory and in children of women laboratory workers.
Lancet. 2: 322-325.
Gerner-Smidt, P. and U. Friedrich. 1978. The mutagenic effect of benzene,
toluene and xylene studied by the SCE technique. Mutat. Res. 58(2-3):
313-316.
Lijinsky, W. and H. Garcia. 1972. Skin carcinogenesis tests of hydrogenated
derivatives of anthanthrene and other polynuclear hydrocarbons. Z.
Krebsforsch. Klin. Onkol. 77: 226-230.
Litton Bionetics, Inc. 1981. Mutagenicity Evaluation of Toluene. Final
Report. Submitted to the American Petroleum Institute, Washington, DC in
January, 1981. LBI Project No. 21141-05. Litton Bionetics, Inc., Kansington,
MD. p. 58.
Lyapkalo, A.A. 1973. Genetic activity of benzene and toluene. Gig. Tr.
Prof. Zabol. 17(3): 24-28. (Rus.) (Evaluation based on an English
translation provided by the U.S. EPA.)
Maki-Paakkanen, J., K. Husgafvel-Pursiainen, P.L. Kalliomaki, J. Tuominen and
M. Sorsa. 1980. Toluene-exposed workers and chromosome aberrations. J.
Toxicol. Environ. Health. 6: 775-781.
Mortelmans, K.E. and E.S. Riccio. 1980. In vitro microbiological
genotoxicity assays of toluene. Prepared by SRI International, Menlo Park,
CA, under Contract No. 68-02-2947 for the U.S. EPA, Research Triangle Park,
NC. p. 25.
Nestmann, E.R., E.G.H. Lee, T.I. Matula, G.R. Douglas and J.C. Mueller.
1980. Mutagenicity of constituents identified in pulp and paper mill
effluents using the Salmonella/mammalian-microsome assay. Mutat. Res. 79:
203-212.
Poel, W.E. 1963. Skin as a test site for the bioassay of carcinogens and
carcinogen precursors. Natl. Cancer Inst. Monogr. 10: 611-625.
Snow, L., P. MacNair and B.C. Casto. 1981. Mutagenesis testing of toluene
in Salmonella strains TA100 and TA98. Report prepared for the U.S. EPA by
-------
Northrup Services, Inc., Research Triangle park, NC.
<« Toluene >»
_II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The values in the 1987 Drinking Water Criteria Document for Toluene have
received peer and administrative review.
Agency Work Group Review: 09/15/87
Verification Date: 09/15/87
_II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Dharm V. Singh / ORD (202)382-5958 / FTS 382-5958
Robert E. McGaughy / ORD (202)382-5898 / FTS 382-5898
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Toluene
CASRN 108-88-3
Not available at this time
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Toluene
CASRN 108-88-3
Last Revised 03/01/88
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in sections
I and II, as this may explain inconsistencies. Also note that some regulatory
actions consider factors not related to health risk, such as technical or
economic feasibility. Such considerations are indicated for each action. In
addition, not all of the regulatory actions listed in this section involve
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background inform-
ation on each regulatory action in Background Document 4 in Service Code 5.
-------
IV.A. CLEAN AIR ACT (CAA)
_IV.A.I. CAA REGULATORY DECISION
Action Decision not to regulate
Considers technological or economic feasibility? NO
Discussion The U.S. EPA concluded that current information does not
indicate that toluene endangers public health at ambient concentrations
(excluding emergency releases), and thus no regulation directed specifically
at toluene is necessary at this time under the CAA.
Reference 45 FR 22195 (05/25/84)
EPA Contact Emissions Standards Division, OAQPS
(917)541-5571 / FTS 629-5571
<« Toluene >»
IV.B. SAFE DRINKING WATER ACT (SDWA)
_IV.B.I. MAXIMUM CONTAMINANT LEVEL GOAL (MCLG) for Drinking Water
Value (status) 2.0 mg/L (Proposed, 1985)
Considers technological or economic feasibility? NO
Discussion An MCLG of 2.0 mg/L for toluene is proposed based on a DWEL of
10.1 mg/L and an assumed contribution of 20% from drinking water. A DWEL of
10.1 mg/L was calculated from a NOAEL of 1130 mg/cu.m (highest dose tested) foi
lung effects in rats (2-year inhalation study), with an uncertainty factor of
100 applied and an assumed 50% pulmonary absorption rate.
Reference 50 FR 46936 Part IV (11/13/85)
EPA Contact Krishan Khanna / Criteria and Standards Division, ODW /
(202)382-7571 / FTS 382-7571; or Drinking Water Hotline / (800)426-4791
<« Toluene >»
IV.C. CLEAN WATER ACT (CWA)
_IV.C.l. AMBIENT WATER QUALITY CRITERIA, Human Health
Water and Fish Consumption: 14.3 mg/L
Fish Consumption Only: 424 mg/L
Considers technological or economic feasibility? NO
-------
Discussion The WQC of 14.3 mg/L is based on consumption of contaminated
aquatic organisms and water. A WQC of 424 mg/L has also been established
based on consumption of contaminated aquatic organisms alone.
Reference 45 FR 79318 (11/28/80)
EPA Contact Criteria and Standards Division / OWRS /
(202)475-7315 / FTS 475-7315
_IV.C.2. AMBIENT WATER QUALITY CRITERIA, Aquatic Organisms
Freshwater:
Acute 17,500 ug/L (LEL)
Chronic None
Marine:
Acute 6300 ug/L (LEL)
Chronic 5000 ug/L (LEL)
Considers technological or economic feasibility? NO
Discussion Water quality criteria for the protection of aquatic life are
derived from a minimum data base of acute and chronic tests on a variety of
aquatic organisms. The "(LEL)" after the value indicates that the minimum
data were not available and the concentration given is not a criteria value
but the lowest effect level found in the literature.
Reference 45 FR 79318 (11/28/80)
EPA Contact Criteria and Standards Division / OWRS /
(202)475-7315 / FTS 475-7315
-<« Toluene >»-
IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
No data available
-<« Toluene »>-
IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA)
No data available
-<« Toluene >»-
-------
IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA)
_IV.F.I. RCRA APPENDIX IX, for Ground Water Monitoring
Status Listed
Reference 52 FR 25942 (07/09/87)
EPA Contact Jerry Garman / OSW / (202)382-4658 / FTS 382-4658
<« Toluene »>
IV.G. SUPERFUND (CERCLA)
_IV.G.l. REPORTABLE QUANTITY (RQ) for Release into the Environment
Value (status) 1000 pounds (Final, 1985)
Considers technological or economic feasibility? NO
Discussion The final RQ is based on aquatic toxicity, as established under
Section 311(b)(4) of the Clean Water Act, ignitability, and chronic toxicity.
Available data indicate that the aquatic 96-Hour Median Threshold Limit for
Toluene is between 10 and 100 ppm. Its closed-cup flash point is less than
100F and its boiling point is >100F. RQ assignments based on chronic toxicity
reflect two primary attributes of the hazardous substance, the minimum
effective dose (MED) levels for chronic exposure (mg/day for a 70-kg person)
and the type of effect (liver necrosis, teratogenicity, etc). A composite
score is determined from an evaluation of these two attributes. Toluene was
determined to have a composite score between 6 and 20, corresponding to a
chronic toxicity RQ of 1000 pounds.
Reference 50 FR 13456 (04/04/85)
EPA Contact RCRA/Superfund Hotline
(800)424-9346 / (202)382-3000 / FTS 382-3000
_V. SUPPLEMENTARY DATA
Substance Name Toluene
CASRN 108-88-3
Not available at this time
-------
_VI. REFERENCES
Substance Name Toluene
CASRN 108-88-3
Not available at this time
SYNONYMS
108-88-3
ANTISAL la
BENZENE, METHYL
METHACIDE
METHYL-BENZENE
METHYLBENZOL
NCI-C07272
PHENYL-METHANE
RCRA WASTE NUMBER U220
TOLUEEN
TOLUEN
Toluene
TOLUOL
TOLUOLO
TOLU-SOL
UN 1294
-------
Benzene; CASRN 71-43-2 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the most recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Benzene
File On-Line 03/01/88
Category (section)
Status
Last Revised
Oral RfD Assessment (I.A.)
Inhalation RfD Assessment (I.E.)
Carcinogenicity Assessment (II.)
Drinking Water Health Advisories (III.A.)
U.S. EPA Regulatory Actions (IV.)
Supplementary Data (V.)
pending
no data
on-line
on-line
on-line
no data
12/01/88
03/01/88
03/01/88
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGENIC EFFECTS
Substance Name -- Benzene
CASRN 71-43-2
A risk assessment for this chemical will be reviewed by an EPA work group.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
-------
Substance Name Benzene
CASRN 71-43-2
Last Revised 12/01/88
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
is presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
<« Benzene >»
II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
_II.A.l. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification A; human carcinogen
Basis Several studies of increased incidence of nonlymphocytic leukemia
from occupational exposure, increased incidence of neoplasia in rats and mice
exposed by inhalation and gavage, and some supporting data form the basis for
this classification.
_II.A.2. HUMAN CARCINOGENICITY DATA
Aksoy et al. (1974) reported effects of benzene exposure among 28,500
Turkish workers employed in the shoe industry. Mean duration of employment
was 9.7 years (1-15 year range) and mean age was 34.2 years. Peak exposure
was reported to be 210-650 ppm. Twenty-six cases of leukemia and a total of
34 leukemias or preleukemias were observed, corresponding to an incidence of
13/100,000 (by comparison to 6/100,000 for the general population). A follow-
up paper (Aksoy, 1980) reported eight additional cases of leukemia as well as
evidence suggestive of increases in other malignancies.
In a retrospective cohort mortality study Infante (1977a,b) examined
leukemogenic effects of benzene exposure in 748 white males exposed while
employed in the manufacturing of rubber products. Exposure occurred from
1940-1949, and vital statistics were obtained through 1975. A statistically
significant increase (p less than or equal to 0.002) of leukemias was found by
comparison to the general U.S. population. There was no evidence of solvent
exposure other than benzene. Air concentrations were generally found to be
below the recommended limits in effect during the study period.
-------
In a subsequent retrospective cohort mortality study Rinsky (1981)
observed seven deaths from leukemia among 748 workers exposed to benzene and
followed for at least 24 years (17,020 person-years). This increased
incidence was statistically significant; standard mortality ratio (SMR) was
560. For the five leukemia deaths that occurred among workers with more than
5 years exposure, the SMR was 2100. Exposures (which ranged from 10-100 ppm
8-hour TWA) were described as less than the recommended standards for the time
period of 1941-1969.
In an updated version of the Rinsky et al. (1981) study, the authors
followed the same cohort to 12/31/81 (Rinsky et al., 1987). An in his earlier
study, cumulative exposure was derived from historic air-sampling data or
interpolated estimates based on exisitng data. Standardized mortality rates
ranged from 109 at cumulative benzene exposures under 40 ppm-years and
increased montonically to 6637 (6 cases) at 400 ppm-years or more. The
authors found significantly elevated risks of leukemia at cumulative exposures
less than the equivalent current standard for occupational exposure which is
10 ppm over a 40-year working lifetime.
Ott (1978) observed three deaths from leukemia among 594 workers followed
for at least 23 years in a retrospective cohort mortality study, but the
increase was not statistically significant. Exposures ranged from <2 to >25
ppm 8-hour TWA.
Wong et al. (1983) reported on the mortality of male chemical workers who
had been exposed to benzene for at least 6 months during the years 1946-1975.
The study population of 4062 persons was drawn from seven chemical plants, and
jobs were categorized as to peak exposure. Those with at least 3 days/week
exposure (3036 subjects) were further categorizeed on the basis of an 8-hour
TWA. The control subjects held jobs at the same plants for at least 6 months
but were never subject to benzene exposure. Dose-dependent increases were
seen in leukemia and lymphatic and hematopoietic cancer. The incidence of
leukemia was responsible for the majority of the increase. It was noted that
the significance of the increase is due largely to a less than expected
incidence of neoplasia in the unexposed subjects.
Numerous other epidemiologic and case studies have reported an increased
incidence or a causal relationship between leukemia and exposure to benzene
(IARC, 1982).
<« Benzene »>
_II.A.3. ANIMAL CARCINOGENICITY DATA
Both gavage and inhalation exposure of rodents to benzene have resulted in
development of neoplasia. Maltoni (1979, 1983) administered benzene by gavage
at dose levels of 0, 50, 250, and 500 mg/kg bw to 30-40 Sprague-Dawley
rats/sex for life. Dose-related increased incidences of mammary tumors were
seen in females and of Zymbal gland carcinomas, oral cavity carcinomas and
leukemias/lymphomas in both sexes.
In an NTP (1986) study, benzene was administered by gavage doses of 0, 50,
100, or 200 mg/kg bw to 50 F344/N rats/sex or 0, 25, 50, or 100 mg/kg bw to 50
-------
B6C3F1 mice/sex. Treatment was 5 times/week for 103 weeks. Significantly
increased incidences (p<0.05) of various neoplasic growths were seen in both
sexes of both species. Both male and female rats and mice had increased
incidence of carcinomas of the Zymbal gland. Male and female rats had oral
cavity tumors, and males showed increased incidences of skin tumors. Mice of
both sexes had increased incidence of lymphomas and lung tumors. Males were
observed to have harderian and preputial gland tumors and females had tumors
of mammary gland and ovary. In general, the increased incidence was dose-
related.
Slightly increased incidences of hematopoietic neoplasms were reported for
male C57B1 mice exposed by inhalation to 300 ppm benzene 6 hours/day, 5 days/
week for 488 days. There was no increase in tumor incidence in male AKR or
CD-I mice similarly exposed to 100 ppm or 100 or 300 ppm benzene, respec-
tively. Likewise male Sprague-Dawley rats exposed by inhalation to 300 ppm
benzene were not observed to have increased incidence of neoplasia (Snyder et
al., 1980).
Maltoni et al. (1983) treated male and female Sprague-Dawley rats in the
following manner. Starting at 13 weeks of age rats were exposed to 200 ppm
benzene 4 hours/day, 5 days/week for 7 weeks; 200 ppm 7 hours/day, 5 days/week
for 12 weeks; 300 ppm 7 hours/day, 5 days/week for 85 weeks. An 8-hour/day
TWA for 5 days/week was calculated to be 241 ppm. A statistically significant
increase was noted in hepatomas and carcinomas of the Zymbal gland.
_II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Numerous investigators have found significant increases in chromosomal
aberrations of bone marrow cells and peripheral lymphocytes from workers with
exposure to benzene (IARC, 1982). Benzene also induced chromosomal aberra-
tions in bone marrow cells from rabbits (Kissling and Speck, 1973), mice
(Meyne and Legator, 1980) and rats (Anderson and Richardson, 1979). Several
investigators have reported positive results for benzene in mouse micronucleus
assays (Meyne and Legator, 1980). Benzene was not mutagenic in several
bacterial and yeast systems, in the sex-linked recessive lethal mutation assay
with Drosophila melanogaster or in mouse lymphoma cell forward mutation assay.
<« Benzene »>
II.E. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
_II.B.l. SUMMARY OF RISK ESTIMATES
Oral Slope Factor 2.9E-2/mg/kg/day
Drinking Water Unit Risk 8.3E-7/ug/L
Extrapolation Method One-hit (pooled data)
Drinking Water Concentrations at Specified Risk Levels:
-------
Risk Level Concentration
E-4 (1 in 10,000) 1E+2 ug/L
E-5 (1 in 100,000) 1E+1 ug/L
E-6 (1 in 1,000,000) 1E+0 ug/L
_II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
See table in Section II.C.2.
The slope factor was derived from human data for inhalation exposure as
described in section II.C.2. The human respiratory rate was assumed to be 20
cu.m/day, inhalation absorption was taken as 100% and an air concentration of
benzene of 1 ppm was taken to equal 3.25 mg/cu.m. The water unit risk was
calculated on the assumption that an adult human consumes 2 L water/day.
_II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
The unit risk estimate is the geometric mean of four ML point estimates
using pooled data from the Rinsky (1981) and Ott (1978) studies, which was
then adjusted for the results of the Wong (1983) study as described in the
additional comments section for inhalation data.
The unit risk should not be used if the water concentration exceeds 1E+4
ug/L, as above this concentration the slope factor may differ from that
stated.
_II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
The pooled cohorts were sufficiently large and were followed for an
adequate time period. The increases in leukemias were statistically
significant and dose-related in one of the studies. Wong (1983) disagrees
that exposures reported in Rinsky (1981) were within the recommended
standards. For the five leukemia deaths in persons with 5 or more years
exposure, the author notes that mean exposure levels (range 15-70 ppm)
exceeded the recommended standard (25 ppm) in 75% of the work locations
sampled. A total of 21 unit risk estimates were prepared using 6 models and
various combinations of the epidemiologic data. These range over slightly
more than one order of magnitude. A geometric mean of these estimates is
2.7E-2. Regression models give an estimate similar to the geometric mean.
The risk estimate above based on reconsideration of the Rinsky (1981) and
Ott (1978) studies is very similar to that of 2.4E-2/ppm (cited in U.S. EPA,
1980) based on Infante (1977a,b), Ott (1978) and Aksoy (1974). It was felt by
the authors of U.S. EPA (1985) that the exposure assessment provided by Aksoy
was too imprecise to warrant inclusion in the current risk estimate.
Risk estimates based on animal gavage studies are about 5 times higher
than those derived from human data. Pharmacokinetic data which could impact
the risk assessment are currently being evaluated.
-------
<« Benzene >»
II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
_II.C.l. SUMMARY OF RISK ESTIMATES
Inhalation Slope Factor 2.9E-2/mg/kg/day
Inhalation Unit Risk 8.3E-6/ug/cu.m
Extrapolation Method One-hit (pooled data)
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
E-4 (1 in 10,000) 1E+1 ug/cu.m
E-5 (1 in 100,000) 1E+0 ug/cu.m
E-6 (1 in 1,000,000) 1E-1 ug/cu.m
.II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Species/Strain Reference
Tumor Type
<« Benzene >»
Human/leukemia Route: Occupational, inhalation Rinsky, 1981;
Ott, 1978;
Wong, 1983
_II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
The unit risk estimate is the geometric mean of four ML point estimates
using pooled data from the Rinsky (1981) and Ott (1978) studies, which was
then adjusted for the results of the Wong (1983) study. The Rinsky data used
were from an updated tape which reports one more case of leukemia than was
published in 1981. Equal weight was given to cumulative dose and weighted
cumulative dose exposure categories as well as to relative and absolute risk
model forms. The results of the Wong (1983) study were incorporated by
assuming that the ratio of the Rinsky-Ott-Wong studies to the Rinsky-Ott
studies for the relative risk cumulative dose model was the same as for other
model-exposure category combinations and multiplying this ratio by the Rinsky-
Ott geometric mean. The age-specific U.S. death rates for 1978 (the most
current year available) were used for background leukemia and total death
rates. It should be noted that Rinsky has recently published (1987) a paper
reporting yet another case of leukemia from the study population.
The unit risk should not be used if the air concentration exceeds 100
ug/cu.m, since above this concentration the slope factor may differ from that
-------
stated.
_II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
The pooled cohorts were sufficiently large and were followed for an ade
quate time period. The increases in leukemias were statistically significant
and dose-related in one of the studies. Wong (1983) disagrees that exposures
reported in Rinsky (1981) were within the recommended standards. For the five
leukemia deaths in persons with 5 or more years exposure, the author notes
that mean exposure levels (range 15-70 ppm) exceeded the recommended standard
(25 ppm) in 75% of the work locations sampled. The risk estimate above based
on reconsideration of the Rinsky (1981) and Ott (1978) studies is very similar
to that of 2.4E-2/ppm (cited in U.S. EPA, 1980) based on Infante (1977a,b),
Ott (1978) and Aksoy (1974). It was felt by the authors of U.S. EPA (1985)
that the exposure assessment provided by Aksoy was too imprecise to warrant
inclusion in the current risk estimate. A total of 21 unit risk estimates
were prepared using 6 models and various combinations of the epidemiologic
data. These range over slightly more than one order of magnitude. A
geometric mean of these estimates is 2.7E-2/ppm. Regression models give an
estimate similar to the geometric mean.
<« Benzene >»
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
_II.D.l. EPA DOCUMENTATION
U.S. EPA. 1985. Interim Quantitative Cancer Unit Risk Estimates Due to
Inhalation of Benzene. Prepared by the Office of Health and Environmental
Assessment, Carcinogen Assessment Group, Washington, DC for the Office of Air
Quality Planning and Standards, Washington, DC.
Memorandum from J. Orme HEB, CSD/ODW to C. Vogt, Criteria and Standards
Division, ODW, June, 1987.
Ott, M.G., J.C. Townsend, W.A. Fishbeck and R.A. Langner. 1978. Mortality
among individuals occupationally exposed to benzene. Arch. Environ. Health.
33: 3-10.
Rinsky, R.A., R.J. Young and A.B. Smith. 1981. Leukemia in benzene workers.
Am. J. Ind. Med. 2: 217-245.
Wong, 0., R.W. Morgan and M.D. Whorton. 1983. Comments on the NIOSH study of
leukemia in benzene workers. Technical report submitted to Gulf Canada, Ltd.,
by Environmental Health Associates.
_II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The 1985 Interim Evaluation was reviewed by the Carcinogen Assessment Group.
The 1987 memorandum is an internal document.
-------
Agency Work Group Review: 03/05/87, 10/09/87
Verification Date: 10/09/87
_II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
D.L. Bayliss / ORD (202)382-5726 / FTS 382-5726
R. McGaughy / ORD (202)382-5898 / FTS 382-5898
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Benzene
CASRN 71-43-2
Last Revised ~ 03/01/88
III.A. DRINKING WATER HEALTH ADVISORIES
The Office of Drinking Water provides Drinking Water Health Advisories (HAs)
as technical guidance for the protection of public health. HAs are not
enforceable Federal standards. HAs are concentrations of a substance in
drinking water estimated to have negligible deleterious effects in humans,
when ingested, for a specified period of time. Exposure to the substance from
other media is considered only in the derivation of the lifetime HA. Given
the absence of chemical-specific data, the assumed fraction of total intake
from drinking water is 10% for inorganic contaminants and 20% for organic
contaminants. The lifetime HA is calculated from the Drinking Water Equiv-
alent Level (DWEL) which, in turn, is based on the Oral Chronic Reference
Dose. Lifetime HAs are not derived for compounds which are potentially
carcinogenic for humans because of the difference in assumptions concerning
toxic threshold for carcinogenic and noncarcinogenic effects. A more detailed
description of the assumptions and methods used in the derivation of HAs is
provided in Background Document 3 in Service Code 5.
<« Benzene >»
_III.A.l. ONE-DAY HEALTH ADVISORY FOR A CHILD
Appropriate data for calculating a One-day HA are not available. It is
recommended that the Ten-day HA of 0.235 mg/L used as the One-day HA.
_III.A.2. TEN-DAY HEALTH ADVISORY FOR A CHILD
Ten-day HA 2.35E-1 mg/L
NOAEL 2.35 mg/kg/day
-------
UF 100 (allows for interspecies and intrahuman variability with the use of
a NOAEL from an animal study)
Assumptions 1 L/day water consumption for a 10-kg child
Principal Study Deichman et al., 1963
Rats were exposed to benzene for 6 hours/day, 4 days/week by inhalation
and their hematology was monitored weekly. By the second week of treatment,
hematological impairment was observed at the 2659 mg/cu.m exposure concentra-
tion and there was some indication, especially in females, that white blood
cells were depressed at the 103 mg/cu.m exposure concentration. No effect was
seen when animals were exposed to 96 mg/cu.m for up to 4 months. Based on the
conditions of exposure and an assumed absorption factor of 50%, a NOAEL of
2.35 mg/kg/day can be calculated.
_III.A.3. LONGER-TERM HEALTH ADVISORY FOR A CHILD
A Longer-term HA has not been calculated for benzene because of its potent
carcinogenicity.
_III.A.4. LONGER-TERM HEALTH ADVISORY FOR AN ADULT
A Longer-term HA has not been calculated for benzene because of its potent
carcinogenicity.
_III.A.5. DRINKING WATER EQUIVALENT LEVEL / LIFETIME HEALTH ADVISORY
DWEL None
Lifetime HA None
Benzene is classified in Group A: Human carcinogen. Neither a DWEL nor a
Lifetime HA have been calculated for benzene. Refer to Section II of this
file for information on the carcinogenicity of this substance.
<« Benzene >»
_III.A.6. ORGANOLEPTIC PROPERTIES
Odor perception threshold (air) 4.9 mg/cu.m.
Odor perception threshold (water) 2.0 mg/L.
llII.A.7. ANALYTICAL METHODS FOR DETECTION IN DRINKING WATER
Analysis of benzene is by a purge-and-trap gas chromatographic procedure
used for the determination of volatile aromatic and unsaturated organic
compounds in water.
-------
_III.A.8. WATER TREATMENT
Treatment technologies which will remove benzene from water include
granular activated carbon adsorption and air stripping.
_III.A.9. DOCUMENTATION AND REVIEW OF HAs
Deichman, W.B., W.E. MacDonald and E. Bernal. 1963. The hemopoietic toxicity
of benzene vapors. Toxicol. Appl. Pharmacol. 5: 201-224.
U.S. EPA. 1985. Final Draft of the Drinking Water Criteria Document on
Benzene. Office of Drinking Water, Washington, DC.
EPA review of HAs in 1985.
Public review of HAs following notification of availability in October, 1985.
Scientific Advisory Panel review of HAs in January, 1986.
Preparation date of this IRIS summary 06/19/87
/
_III.A.10. EPA CONTACTS
William Marcus / ODW (202)382-7580 / FTS 382-7580
Edward V. Ohanian / ODW (202)382-7571 / FTS 382-7571
«< Benzene >»
III.E. OTHER ASSESSMENTS
Content to be determined
_IV. U.S. EPA REGULATORY ACTIONS
Substance Name Benzene
CASRN 71-43-2
Last Revised 03/01/88
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in sections
I and II, as this may explain inconsistencies. Also note that some regulatory
actions consider factors not related to health risk, such as technical or
economic feasibility. Such considerations are indicated for each action. In
-------
addition, not all of the regulatory actions listed in this section involve
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background inform-
ation on each regulatory action in Background Document 4 in Service Code 5.
IV.A. CLEAN AIR ACT (CAA)
_IV.A.l. NATIONAL EMISSIONS STANDARDS FOR HAZARDOUS AIR POLLUTANTS (NESHAP)
Considers technological or economic feasibility? YES
Discussion -- Benzene has been listed as a hazardous air pollutant under
Section 112 of the Clean Air Act. EPA promulgated NESHAP for benzene from
equipment leaks on June 6, 1984 (49 FR 23498) and proposed regulations for
coke oven by-product plants.
Reference 40 CFR Part 61, Subpart J
EPA Contact Emissions Standards Division, OAQPS
(917)541-5571 / FTS 629-5571
<« Benzene »>
IV.B. SAFE DRINKING WATER ACT (SDWA)
_IV.B.l. MAXIMUM CONTAMINANT LEVEL GOAL (MCLG) for Drinking Water
Value (status) 0 mg/L (Final, 1985)
Considers technological or economic feasibility? NO
Discussion An MCLG of zero mg/L for benzene is proposed based on
carcinogenic effects. In humans, exposure to benzene is associated with
myelocytic anemia, thrombocytopenia and leukemia (acute myelogenous and
monocytic leukemia). In animals, an increase in tumors and leukemia have been
reported. EPA has classified benzene in Group A: sufficient evidence from
epidemiological studies.
Reference 50 FR 46880 Part III (11/13/85)
EPA Contact Criteria and Standards Division, ODW /
(202)382-7571 / FTS 382-7571; or Drinking Water Hotline / (800)426-4791
_IV.B.2. MAXIMUM CONTAMINANT LEVEL (MCL) for Drinking Water
Value (status) 5 ug/L (Final, 1987)
Considers technological or economic feasibility? YES
-------
Discussion The MCL is based on technology and cost factors.
Reference 52 FR 25690 (07/08/87)
EPA Contact Criteria and Standards Division, ODW /
(202)382-7571 / FTS 382-7571; or Drinking Water Hotline / (800)426-4791
<« Benzene >»
IV.C. CLEAN WATER ACT (CWA)
_IV.C.l. AMBIENT WATER QUALITY CRITERIA, Human Health
Water and Fish Consumption 6.6E-1 ug/L
Fish Consumption Only 4.0E+1 ug/L
Considers technological or economic feasibility? NO
Discussion For the maximum protection from the potential carcinogenic
properties of this chemical, the ambient water concentration should be zero.
However, zero may not be attainable at this time, so the recommended criteria
represents a E-6 estimated incremental increase of cancer risk over a
lifetime.
Reference ~ 45 FR 79318 (11/28/80)
EPA Contact Criteria and Standards Division, OWRS
(202)475-7315 / FTS 475-7315
_IV.C.2. AMBIENT WATER QUALITY CRITERIA, Aquatic Organisms
Freshwater:
Acute LEG 5.3E+3 ug/L
Chronic LEG -- None
Marine:
Acute LEG 5.1E-I-3 ug/L
Chronic LEG 7.OE+2 ug/L
Considers technological or economic feasibility? NO
Discussion The values that are indicated as "LEG" are not criteria, but
are the lowest effect levels found in the literature. LECs are given when the
minimum data required to derive water quality criteria are not available.
Reference 45 FR 79318 (11/28/80)
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EPA Contact Criteria and Standards Division, OWRS
(202)475-7315 / FTS 475-7315
-<« Benzene >»-
IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
No data available
-<« Benzene >»-
IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA)
No data available
<« Benzene >»
IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA)
_IV.F.l. RCRA APPENDIX IX, for Ground Water Monitoring
Status Listed
Reference -- 52 FR 25942 (07/09/87)
EPA Contact Jerry Garman / OSW / (202)382-4658 / FTS 382-4658
«< Benzene >»
IV.G. SUPERFUND (CERCLA)
_IV.G.l. REPORTABLE QUANTITY (RQ) for Release into the Environment
Value (status) -- 10 pounds (Proposed, 1987)
Considers technological or economic feasibility? NO
Discussion The proposed RQ for benzene is 10 pounds, based on its
potential carcinogenicity. The available data indicate a hazard ranking of
medium based on a potency factor of 0.27/mg/kg/day and a weight-of-evidence
group A, which corresponds to an RQ of 10 pounds.
Reference 52 FR 8140 (03/16/87)
EPA Contact RCRA/Superfund Hotline
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(800)424-9346 / (202)382-3000 / FTS 382-3000
_V. SUPPLEMENTARY DATA
Substance Name Benzene
CASRN 71-43-2
Not available at this time
_VI. REFERENCES
Substance Name Benzene
CASRN 71-43-2
Not available at this time
SYNONYMS
71-43-2
Benzene
benzol
coal naphtha
cyclohexatriene
phene
phenyl hydride
polystream
pyrobenzol
-------
Benzo[a]pyrene (BaP); CASRN 50-32-8 (04/01/89)
Health risk assessment information on a chemical is included in IRIS only
after a comprehensive review of chronic toxicity data by work groups composed
of U.S. EPA scientists from several Program Offices. The summaries presented
in Sections I and II represent a consensus reached in the review process. The
other sections contain U.S. EPA information which is specific to a particular
EPA program and has been subject to review procedures prescribed by that
Program Office. The regulatory actions in Section IV may not be based on the
most current risk assessment, or may be based on a current, but unreviewed,
risk assessment, and may take into account factors other than health effects
(e.g., treatment technology). When considering the use of regulatory action
data for a particular situation, note the date of the regulatory action, the
date of the moat recent risk assessment relating to that action, and whether
technological factors were considered. Background information and explan-
ations of the methods used to derive the values given in IRIS are provided in
the five Background Documents in Service Code 5, which correspond to Sections
I through V of the chemical files.
STATUS OF DATA FOR Benzo[a]pyrene (BaP)
File On-Line 03/31/87
Category (section) Status Last Revised
Oral RfD Assessment (I.A.) no data
Inhalation RfD Assessment (I.B.) no data
Careinogenicity Assessment (II.) on-line 03/31/87
Drinking Water Health Advisories (III.A.) no data
U.S. EPA Regulatory Actions (IV.) on-line 03/01/88
Supplementary Data (V.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENT FOR NONCARCINOGENIC EFFECTS
Substance Name Benzo[a]pyrene (BaP)
CASRN 50-32-8
Not available at this time
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
-------
Substance Name Benzo[a]pyrene (BaP)
CASRN ~ 50-32-8
Last Revised 03/31/87
Section II provides information on three aspects of the carcinogenic risk
assessment for the agent in question; the U.S. EPA classification, and quant-
itative estimates of risk from oral exposure and from inhalation exposure.
The classification reflects a weight-of-evidence judgment of the likelihood
that the agent is a human carcinogen. The quantitative risk estimates are
presented in three ways. The slope factor is the result of application of a
low-dose extrapolation procedure and is presented as the risk per mg/kg/day.
The unit risk is the quantitative estimate in terms of either risk per ug/L
drinking water or risk per ug/cu.m air breathed. The third form in which risk
is presented is a drinking water or air concentration providing cancer risks
of 1 in 10,000, 1 in 100,000 or 1 in 1,000,000. Background Document 2
(Service Code 5) provides details on the rationale and methods used to derive
the carcinogenicity values found in IRIS. Users are referred to Section I for
information on long-term toxic effects other than carcinogenicity.
«< BaP >»
II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
_II.A.l. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification B2; probable human carcinogen
Basis Human data specifically linking BaP to a carcinogenic effect are
lacking. There are, however, multiple animal studies in rodent and nonrodent
species demonstrating BaP to be carcinogenic following administration by oral,
intratracheal, inhalation and dermal routes. BaP has produced positive
results in several in vitro bacterial and mammalian genetic toxicology assays.
_II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. Lung cancer has been shown to be induced in humans by
various mixtures of polycyclic aromatic hydrocarbons known to contain BaP,
including cigarette smoke, roofing tar and coke oven emissions. It is not
possible, however, to conclude from this information that BaP is the
responsible agent.
_II.A.3. ANIMAL CARCINOGENICITY DATA
BaP is well known as a complete carcinogen when applied to the skin of
mice, rats, and rabbits (IARC, 1973). Subcutaneous or intramuscular BaP
injection has been shown to result in local tumors in mice, rats, guinea pigs,
monkeys and hamsters (IARC, 1973). Intratracheal instillation of BaP produced
increased incidences of respiratory tract neoplasms in both male and female
Syrian hamsters (Feron et al., 1973; Kobayashi, 1975).
-------
BaP administered orally to rats and hamsters produces stomach tumors.
Neal and Rigdon (1967) administered dietary BaP at concentrations of 0, 1, 10,
20, 30, 40, 45, 50, 100, and 250 ppm to male and female CFW-Swiss mice. The
control group numbered 289; treatment groups varied in number from 9 to 73
animals and treatment time from 1 to 197 days. Stomach tumors were observed
in mice consuming 20 or more ppm BaP. Incidence was apparently related both
to the dose and the number of administered doses. Apparent increased inci-
dences of leukemia and lung adenomas were reported in the mice on high BaP
diets (250 and 1000 ppm) (Rigdon and Neal, 1966, 1969).
Thyssen et al. (1981) exposed groups of 24 hamsters by inhalation of BaP
at concentrations of 2.2, 9.5, or 45 mg/cu.m for 4.5 hours/day for 10 weeks
followed by 3 hours/day (7 days/week) for up to 675 days. No animals in the
lowest treatment group developed respiratory tumors. Those hamsters exposed
to 9.5 mg/cu.m developed tumors of the nasal cavity, larynx, trachea, and
pharynx. In addition to respiratory tract tumors, animals in the highest dose
group were seen to have neoplasms of the upper digestive tract.
_II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
BaP is among the best-studied agents producing genetic toxicological
effects. It is metabolized to reactive electrophiles capable of binding to
DNA. In vitro assays in which BaP has produced positive results include the
following: bacterial DNA repair, bacteriophage induction, point mutations
at multiple loci in several bacterial species and strains, mutations in
Drosophila melanogaster, sister-chromatid-exchange, chromosomal aberrations
and mutation and transformation of cultured mammalian cells. In vivo expo-
sure of mammalian species to BaP has produced the following results:
sister-chromatid-exchange, chromosomal aberrations, sperm abnormalities, and
positive results in the mouse specific locus (spot) test (IARC, 1973, 1983;
Santodonato et al., 1981).
-«< BaP >»-
II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
-«< BaP >»-
II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
<« BaP >»
II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
-------
_II.D.l. EPA DOCUMENTATION
U.S. EPA. 1980. Ambient Water Quality Criteria Document for Polynuclear
Aromatic Hydrocarbons. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Water Regulations and Standards, Washington, DC. EPA
440/5-80-069. NTIS PB 81 117806.
U.S. EPA. 1984. Health Effects Assessment for Benzo[a]pyrene. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Emergency and
Remedial Response, Washington, DC. EPA 540/1-86-022.
_II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
The risk assessment in the 1984 Health Effects Assessment for Benzo[a]-
pyrene has received an Agency review. The 1980 Ambient Water Quality Cri-
teria Document for Polynuclear Aromatic Hydrocarbons has received both
Agency and public review.
Agency Work Group Review: 01/07/87
Verification Date: 01/07/87
_II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Robert E. McGaughy / ORD (202)382-5898 / FTS 382-5898
Herman J. Gibb / ORD (202)382-5720 / FTS 382-5720
_III. HEALTH HAZARD ASSESSMENTS FOR VARIED EXPOSURE DURATIONS
Substance Name Benzo[a]pyrene (BaP)
CASRN 50-32-8
Not available at this time
._IV. U.S. EPA REGULATORY ACTIONS
Substance Name Benzo[a]pyrene (BaP)
CASRN 50-32-8
Last Revised 03/01/88
EPA risk assessments may be updated as new data are published and as
assessment methodologies evolve. Regulatory actions are frequently not
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updated at the same time. Compare the dates for the regulatory actions in
this section with the verification dates for the risk assessments in sections
I and II, as this may explain inconsistencies. Also note that some regulatory
actions consider factors not related to health risk, such aa technical or
economic feasibility. Such considerations are indicated for each action. In
addition, not all of the regulatory actions listed in this section involve
enforceable federal standards. Please direct any questions you may have
concerning these regulatory actions to the U.S. EPA contact listed for that
particular action. Users are strongly urged to read the background inform-
ation on each regulatory action in Background Document 4 in Service Code 5.
IV.A. CLEAN AIR ACT (CAA)
No data available
<« BaP >»
IV.B. SAFE DRINKING WATER ACT (SDWA)
No data available
-<« BaP >»-
IV.G. CLEAN WATER ACT (CWA)
No data available
-<« BaP >»-
IV.D. FEDERAL INSECTICIDE, FUNGICIDE, AND RODENTICIDE ACT (FIFRA)
No data available
-<« BaP »>-
IV.E. TOXIC SUBSTANCES CONTROL ACT (TSCA)
No data available
-<« BaP >»-
IV.F. RESOURCE CONSERVATION AND RECOVERY ACT (RCRA)
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_IV.F.l. RCRA APPENDIX IX, for Ground Water Monitoring
Status Listed
Reference 52 FR 25942 (07/09/87)
EPA Contact Jerry Garman / OSW / (202)382-4658 / FTS 382-4658
-<« BaP >»-
IV.G. SUPERFUND (CERCLA)
No data available
_V. SUPPLEMENTARY DATA
Substance Name Benzo[a]pyrene (BaP)
CASRN ~ 50-32-8
Not available at this time
_VI. REFERENCES
Substance Name Benzo[a]pyrene (BaP)
CASRN 50-32-8
Not available at this time
SYNONYMS
50-32-8
BaP
Benzo[a]pyrene
BENZO(d,e,f)CHRYSENE
3,4-BENZOPIRENE
3,4-BENZOPYRENE
6,7-BENZOPYRENE
BENZO(a)PYRENE
3,4-BENZPYREN
3,4-BENZPYRENE
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3,4-BENZ(a)PYRENE
BENZ(a)PYRENE
3,4-BENZYPYRENE
BP
3,4-BP
B(a)P
RCRA WASTE NUMBER U022
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