Chromium (VI) (CASRN 18540-29-9)
view QuickView
You will need Adobe Reader to view some of the files on this page. See EPA's PDF page to learn more.
Note: A TOXICOLOGICAL REVIEW is available for this chemical in Adobe PDF Format (70 Pages,189 Kbytes). Similar documents can be found in the List of Available IRIS Toxicological Reviews.
Links to specific pages in the toxicological review are available throughout this summary. To utilize this feature, your Web browser and Adobe program must be configured properly so the PDF displays within the browser window. If your browser and Adobe program need configuration, please go to EPA's PDF page for instructions.
0144
Chromium (VI)
; CASRN 18540-29-9; 09/03/1998
Health assessment information on a chemical substance is included in IRIS
only after a comprehensive review of chronic toxicity data by U.S. EPA
health scientists from several Program Offices and the Office of Research
and Development. The summaries presented in Sections I and II represent
a consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Chromium (VI)
File First On-Line 03/31/1987
Category (section) |
Status |
Last Revised |
---|---|---|
Oral RfD Assessment (I.A.) | on-line | 09/03/1998 |
Inhalation RfC Assessment (I.B.) | on-line | 09/03/1998 |
Carcinogenicity Assessment (II.) | on-line | 09/03/1998 |
_I. Chronic Health Hazard Assessments for Noncarcinogenic Effects
_I.A. Reference Dose for Chronic Oral Exposure (RfD)
Substance Name — Chromium (VI)
CASRN — 18540-29-9
Last Revised — 09/03/1998
The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is expressed
in units of mg/kg-day. 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 the Background Document for an elaboration of these concepts. RfDs
can also be derived for the noncarcinogenic health effects of substances
that 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 carcinogenicity,
a summary of that evaluation will be contained in Section II of this file.
__I.A.1. Oral RfD Summary
Critical Effect |
Experimental Doses* |
UF
|
MF
|
RfD
|
---|---|---|---|---|
None Reported Rat, 1-year drinking MacKenzie et al., 1958 |
NOAEL: 25 mg/L of chromium LOAEL: None |
300
|
3
|
3E-3
mg/kg-day |
*Conversion Factors and Assumptions — Drinking water consumption = 0.1 L/kg-day (reported).
__I.A.2. Principal and Supporting Studies (Oral RfD)
MacKenzie, RD; Byerrum, RU; Decker, CF, et al. (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 0.45-11.2 ppm (0.45-11.2 mg/L) hexavalent
chromium (as K2CrO4) for 1 year. The control group (10/sex) received distilled water.
A second experiment involved three groups of 12 male and 9 female rats.
One group was given 25 ppm (25 mg/L) chromium (as K2CrO4), 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 in 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 K2CrO4) showed an approximate 20% reduction in water consumption. Based
on the body weight of the rat (0.35 kg) and the average daily drinking
water consumption for the rat (0.035 l/day), this dose can be converted
to give an adjusted NOAEL of 2.5 mg/kg-day chromium(VI).
For rats treated with 0-11 ppm (in drinking water), blood was examined
monthly, and tissues (livers, kidneys, and femurs) were examined at 6
mo 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 mo. An abrupt rise in tissue chromium concentrations
was noted in rats treated with more 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. Anwar et al. (1961) observed
no significant effects in female dogs (2/dose group) given up to 11.2
ppm chromium(VI) (as K2CrO4) in drinking water for 4 years. The calculated doses were 0.012-0.30
mg/kg of chromium(VI).
__I.A.3. Uncertainty and Modifying Factors (Oral RfD)
UF = 300.
The uncertainty factor of 300 represents two 10-fold decreases in dose
to account for both the expected interhuman and interspecies variability
in the toxicity of the chemical in lieu of specific data, and an additional
factor of 3 to compensate for the less-than-lifetime exposure duration
of the principal study.
MF = 3.
The modifying factor of 3 is to account for concerns raised by the study
of Zhang and Li (1987).
__I.A.4. Additional Studies/Comments (Oral RfD)
This RfD is limited to soluble salts of hexavalent chromium.
Examples of soluble salts include potassium dichromate (K2Cr2O7), sodium dichromate (Na2Cr2O7), potassium chromate (K2Cr2O4), and sodium chromate (Na2CrO4). Trivalent chromium is an essential nutrient. There is evidence
to indicate that hexavalent chromium is reduced in part to trivalent chromium
in vivo (Petrilli and DeFlora, 1977, 1978; Gruber and Jennette, 1978).
In 1965, a study of 155 subjects exposed to drinking water at concentrations
of approximately 20 mg/L was conducted outside Jinzhou, China. Subjects
were observed to have sores in the mouth, diarrhea, stomachache, indigestion,
vomiting, elevated white blood cell counts with respect to controls, and
a higher per capita rate of cancers, including lung cancer and stomach
cancer. Precise exposure concentrations, exposure durations, and confounding
factors were not discussed, and this study does not provide a NOAEL for
the observed effects. However, the study suggests that gastrointestinal
effects may occur in humans following exposures to hexavalent chromium
at levels of 20 ppm in drinking water (Zhang and Li, 1987).
Zahid et al. (1990) fed BALB/C albino Swiss mice trivalent (chromium disulfate)
and hexavalent (potassium dichromate) chromium at concentrations of 100,
200, and 400 ppm for 35 days in the diet. The author concluded that a
small but significant increase of hexavalent chromium in the testes of
fed animals induced significant degeneration. The National Toxicology
Program (1996a,b, 1997) recently conducted a three-part study to investigate
the potential reproductive toxicity of hexavalent chromium in rats and
mice. The study included oral administration of potassium dichromate in
Sprague-Dawley rats, a repeat of the study of Zahid et al. (1990) using
BALB/C mice, and a reproductive assessment by continuous breeding study
in BALB/C mice. The reproductive assessment indicated that potassium dichromate
administered at 15-400 ppm in the diet is not a reproductive toxicant
in either sex of BALB/C mice or Sprague-Dawley rats.
Several reports of possible fetal damage caused by chromium compounds
were located in the literature. High doses (250-1,000 ppm) of orally administered
chromium (VI) compounds have been reported to cause developmental toxicity
in mice (Trivedi et al., 1989). The authors observed significant increases
in preimplantation and postimplantation losses and dose-dependent reductions
in total weight and crown-rump length in the lower dose groups. Additional
effects included treatment-related increases in abnormalities in the tail
and wrist forelimbs, and subdermal hemorrhagic patches in the offspring.
Junaid et al. (1996) and Kanojia et al. (1996) exposed female Swiss albino
mice and female Swiss albino rats, respectively, to 250, 500, or 750 ppm
potassium dichromate in drinking water to determine the potential embryotoxicity
of hexavalent chromium during days 6-14 of gestation. The authors reported
retarded fetal development and embryo- and fetotoxic effects including
reduced fetal weight, reduced number of fetuses (live and dead) per dam,
and higher incidences of stillbirths and post-implantation loss in the
500 and 750 ppm dosed mothers. Significantly reduced ossification in bones
was also observed in the medium- and high-dose groups. Based on the body
weight and the drinking water ingested by the animals in the 250 ppm dose
group, the exposure levels in the 250 ppm groups can be identified as
67 mg/kg-day and 37 mg/kg-day in mice and rats, respectively.
The Junaid et al. (1996) and Kanojia et al. (1996) studies utilized doses
approximately 10-fold higher than those used in Mackenzie et al (1958),
but neither of the reproductive studies identified a clear NOAEL for the
embryotoxic effects of hexavalent chromium. On the basis of the body weight
and the drinking water ingested by the animals in the low-dose groups
(250 ppm), the LOAELs of 67 mg/kg-day and 37 mg/kg-day can be identified
from Junaid et al. (1996) and Kanojia et al. (1996) in mice and rats,
respectively. Application of 10-fold uncertainty factor to extrapolate
from LOAELs to NOAELs in these studies would generate NOAELs of 6.7 mg/kg-day
and 3.7 mg/kg-day, respectively. These extrapolated NOAEL values are similar
to, and support the use of, the NOAEL of 2.5 mg/kg-day identified from
the study of MacKenzie et al. (1958) for development of the reference
dose.
Elbetieha and Al-Hamood (1997) reported impacts on fertility following
potassium dichromate exposures in mice; however, many of the observed
effects did not occur in a clear dose-dependent fashion. The authors did
not indicate the amount of water ingested by the animals, and stated only
that water ingestion was reduced in the treatment groups relative to the
controls.
Chromium is one of the most common contact sensitizers in males in industrialized
countries and is associated with occupational exposures to numerous materials
and processes, including chrome plating baths, chrome colors and dyes,
cement, tanning agents, wood preservatives, anticorrosive agents, welding
fumes, lubricating oils and greases, cleaning materials, and textiles
and furs (Burrows and Adams, 1990; Polak et al., 1973). Solubility and
pH appear to be the primary determinants of the capacity of individual
chromium compounds to elicit an allergic response (Fregert, 1981; Polak
et al., 1973). The low solubility chromium (III) compounds are much less
efficient contact allergens than chromium (VI) (Spruit and van Neer, 1966).
Dermal exposure to chromium has been demonstrated to produce irritant
and allergic contact dermatitis (Bruynzeel et al., 1988; Polak, 1983;
Cronin, 1980; Hunter, 1974). Primary irritant dermatitis is related to
the direct cytotoxic properties of chromium, while allergic contact dermatitis
is an inflammatory response mediated by the immune system. Allergic contact
dermatitis is a cell-mediated immune response that occurs in a two-step
process. In the first step (induction), chromium is absorbed into the
skin and triggers an immune response (sensitization). Sensitized individuals
will exhibit an allergic dermatitis response when exposed to chromium
above a threshold level (Polak, 1983). Induction is generally considered
to be irreversible. Concentrations of hexavalent chromium in environmental
media that are protective of carcinogenic and noncarcinogenic effects
are likely to be lower than the concentrations required to cause induction
of allergic contact dermatitis. However, these concentrations may not
be lower than concentrations required to elicit an allergic response in
individuals who have been induced.
The RfD was updated in 1998. The RfD is similar to the previous value
on IRIS but now incorporates a threefold uncertainty factor to account
for the less-than-lifetime exposure in the principal study and a threefold
modifying factor to account for uncertainties related to reports of gastrointestinal
effects following drinking water exposures in a residential population
in China.
For more detail on other Hazard Identification Issues,
exit to the toxicological
review, Section 4.7 (PDF).
__I.A.5. Confidence in the Oral RfD
Study — Low
Database — Low
RfD — Low
The overall confidence in this RfD assessment is 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 database is low because the supporting studies are of
equally low quality and the developmental toxicity endpoints are not well
studied.
For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF).
__I.A.6. EPA Documentation and Review of the Oral RfD
Source Document — U.S. EPA, 1998
This assessment was peer reviewed by external scientists. Their comments
have been evaluated carefully and incorporated in finalization of this
IRIS Summary. A record of these comments is included as an appendix to
the Toxicological Review of Acetonitrile in Support of Summary Information
(a PDF document) on the Integrated Risk Information System (IRIS) (U.S.
EPA, 1998). To review
this appendix, exit to the toxicological review, Appendix A, External
Peer Review -- Summary of Comments and Disposition (PDF).
Other EPA Documentation —
U.S. EPA. (1984) Health effects assessment for hexavalent chromium. Prepared
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 consensus date -- 04/28/1998
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfD for Chromium (VI) conducted in August 2003 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 202-566-1676.
__I.A.7. EPA Contacts (Oral RfD)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (fax), or hotline.iris@epa.gov (Internet address).
_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)
Chromium (VI)
CASRN — 18540-29-9
Last Revised — 09/03/1998
The inhalation reference concentration (RfC) is analogous to the oral RfD and is likewise based on the assumption that thresholds exist for certain toxic effects such as cellular necrosis. The inhalation RfC considers toxic effects for both the respiratory system (portal-of-entry) and for effects peripheral to the respiratory system (extrarespiratory effects). It is generally expressed in units of mg/m3. In general, the RfC is an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily inhalation exposure of the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs were derived according to the Interim Methods for Development of Inhalation Reference Doses (U.S. EPA, 1989) and subsequently, according to Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry (U.S. EPA, 1994). RfCs can also be derived for the noncarcinogenic health effects of substances that are 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 carcinogenicity, a summary of that evaluation will be contained in Section II of this file.
__I.B.1. Inhalation RfC Summary
Critical Effect | Experimental Doses* |
UF
|
MF
|
RfC |
---|---|---|---|---|
(1) Chromic acid mists and dissolved Cr (VI)
aerosols: |
||||
Nasal septum atrophy Human subchronic occupational study Lindberg and Hedenstierna, 1983 |
NOAEL: none
LOAEL: 2E-3 mg/m3 |
90
|
1
|
8E-6
mg/m3 |
(2) Cr(VI) particulates: |
||||
Lactate dehydrogenase in bronchioalveolar lavage fluid Rat subchronic study Glaser et al., 1990 Malsch et al., 1994 |
BMD: 0.016 mg/m3 0.034 mg/m3 (adj.) |
300
|
1
|
1E-4
mg/m3 |
*Conversion Factors and Assumptions — Breathing rate for 8-hour occupational exposure = 10 m3; breathing rate for 24-hour continuous exposure = 20 m3; occupational exposure = 5 days/week; continuous exposure = 7 days/week. RDDR (regional deposited dose ratio for particulates to account for differences between rats and humans) = 2.16
Nasal mucosal irritation, atrophy, and perforation have been widely reported following occupational exposures to chromic acid mists and dissolved hexavalent chromium aerosols. However, there is uncertainty regarding the relevance of occupational exposures to chromic acid mists and dissolved hexavalent chromium aerosols to exposures to Cr(VI) dusts in the environment. Lower respiratory effects have been reported in laboratory animals following exposures to Cr(VI) dusts. However, these studies have not reported on nasal mucosal effects following the exposures. The uncertainties in the database have been addressed through the development of two RfCs; one based on nasal mucosal atrophy following occupational exposures to chromic acid mists and dissolved hexavalent chromium aerosols, and a second based on lower respiratory effects following inhalation of Cr(VI) particulates in rats.
__I.B.2. Principal and Supporting Studies (Inhalation RfC)
(1) Chromic acid mists and dissolved Cr (VI) aerosols
Three studies have focused on nasal mucosal irritation, atrophy, and perforation
following occupational exposures to chromic acid mists (Cohen et al.,
1974; Lucas and Kramkowski, 1975; Lindberg and Hedenstierna, 1983). Of
these, the study of Lindberg and Hedenstierna provides the most information
on exposure levels and symptoms reported by exposed workers. Respiratory
symptoms, lung function, and changes in nasal septum were studied in 104
workers (85 males, 19 females) exposed in chrome plating plants. Workers
were interviewed using a standard questionnaire for the assessment of
nose, throat, and chest symptoms. Nasal inspections and pulmonary function
testing were performed as part of the study.
The median exposure time for the entire group of exposed subjects (104)
in the study was 4.5 years (0.1-36 years). A total of 43 subjects exposed
almost exclusively to chromic acid experienced a mean exposure time of
2.5 years (0.2-23.6 years). The subjects exposed almost exclusively to
chromic acid were divided into a low-exposure group (8-hr TWA below 0.002
mg/m3, N=19) and a high-exposure group (8-hr TWA above 0.002 mg/m3,
N=24). Exposure measurements using personal air samplers were performed
for 84 subjects in the study on 13 different days. Exposure for the remaining
20 workers was assumed to be similar to that measured for workers in the
same area. Nineteen office employees were used as controls for nose and
throat symptoms. A group of 119 auto mechanics whose lung function had
been evaluated by similar techniques was selected as controls for lung
functionmeasurements. Smoking habits of workers were evaluated as part
of the study.
At mean exposures below 0.002 mg/m3, 4/19 workers from the
low-exposure group of subjective nasal symptoms. Atrophied nasal mucosa
were reported in 4/19 subjects from this group and 11/19 had smeary and
crusty septal mucosa, which was statistically higher than controls. No
one exposed to levels below 0.001 mg/m3 complained of subjective symptoms. At mean concentrations of 0.002
mg/m3 or above, approximately one-third of the subjects had
reddened, smeary, or crusty nasal mucosa. Atrophy was seen in 8/24 workers,
which was significantly different from controls. Eight subjects had ulcerations
in the nasal mucosa and five had perforations of the nasal septum. Atrophied
nasal mucosa was not observed in any of the 19 controls, but smeary and
crusty septal mucosa occurred in 5/19 controls.
Short-term effects on pulmonary function were evaluated by comparing results
of tests taken on Monday and Thursday among exposed groups and controls.
No significant changes were seen in the low-exposure group or the control
group. Nonsmokers in the high-exposure group experienced significant differences
in pulmonary function measurements from the controls, but the results
were within normal limits.
The authors concluded that 8-hour mean exposures to chromic acid above
0.002 mg/m3 may cause a transient decrease in lung function, and that short-term
exposures to greater than 0.02 mg/m3 may cause septal ulceration and perforation. Based on the results
of this study, a LOAEL of 0.002 mg/m3 can be identified for incidence of nasal septum atrophy following
exposure to chromic acid mists in chromeplating facilities. At TWA exposures
greater than 0.002 mg/m3, nasal septum ulceration and perforations occurred in addition
to the atrophy reported at lower concentrations. The LOAEL is based on
an 8-hour TWA occupational exposure. The LOAEL is adjusted to account
for continuous exposure according to the following equation:
LOAELc = 0.002 mg/m3 x (MVho/MVh)
x 5 days/7 days
where:
LOAELc is the LOAEL for continuous exposure
MVho is the breathing volume for an 8 hour occupational exposure (10 m3)
MVh is the breathing volume for a 24 hour continuous exposure (20 m3)
The LOAEL of 0.002 mg/m3 based on a TWA exposure to chromic
acid is converted to a LOAEL for continuous exposure of 7.14 E-4 mg/m3.
An uncertainty factor of 3 is applied to the LOAEL to extrapolate from
a subchronic to a chronic exposure, an uncertainty factor of 3 is applied
to account for extrapolation from a LOAEL to a NOAEL, and an uncertainty
factor of 10 is applied to the LOAEL to account for interhuman variation.
The total uncertainty factor applied to the LOAEL is 90. Application of
the uncertainty factor of 90 to the LOAEL of 7.14E-4 mg/m3 generates an RfC of 8 E-6 mg/m3 for upper respiratory effects caused by chromic acid mists and
dissolved hexavalent chromium aerosols.
(2) Cr (VI) Particulates:
Two studies provide high-quality data on lower respiratory effects following
exposures to chromium particulates (Glaser et al., 1985, 1990). Glaser
et al. (1990) exposed 8-week-old male Wistar rats to sodium dichromate
at 0.05 - 0.4 mg Cr(VI)/m3 22 hr/day, 7 days/wk for 30-90 days.
Chromium-induced effects occurred in a strong dose-dependent manner. The
authors observed obstructive respiratory dyspnea and reduced body weight
following subacute exposure at the higher dose levels. The mean white
blood cell count was increased at all doses (p < 0.05) and was related
to significant dose-dependent leukocytosis following subacute exposures.
Mean lung weights were significantly increased at exposure levels of 0.1
mg/m3 following both the subacute and subchronic exposures. Accumulation
of macrophages was seen in all of the exposure groups and was postulated
to be a chromium-specific irritation effect that accounted for the observed
increases in lung weights. Focal inflammation was observed in the upper
airways following the subchronic exposure, and albumin and lactate dehydrogenase
(LDH) in bronchioalveolar lavage fluid (BALF) were increased following
the exposure. The authors concluded that chromium inhalation induced pneumocyte
toxicity and suggested that inflammation is essential for the induction
of most chromium inhalation effects and may influence the carcinogenicity
of Cr(VI) compounds.
Glaser et al. (1985) exposed 5-week-old male Wistar rats to aerosols of
sodium dichromate at concentrations ranging from 0.025 to 0.2 mg Cr(VI)/m3,
22 hr/day in subacute (28 day) or subchronic (90 day) protocols. Chromium-induced
effects occurred in a dose-dependent manner. Lung and spleen weights were
significantly increased (p < 0.005) after both subacute and subchronic
exposures at concentrations greater than 0.025 mg/m3. Differences in the mean total serum immunoglobulin were also significant
at exposures above 0.025 mg/m3, while exposures to aerosol concentrations greater than 0.1 mg/m3
resulted in depression of the immune system stimulation. The immune stimulating
effect of subchronic exposure was not reversed after 2 mo of fresh air
regeneration. Bronchoalveolar lavage (BAL) cell counts were significantly
decreased following subchronic exposure to levels above 0.025 mg/m3
chromium. The number of lymphocytes and granulocytes showed a slight but
significant increase in the lavage fluids of the subacute and subchronically
exposed groups. At subacute exposure concentrations up to 0.05 mg/m3 the phagocytic activity of the alveolar macrophages increased;
however, subchronic exposure at 0.2 mg/m3 decreased this function
significantly. The spleen T-lymphocyte subpopulation was stimulated by
subchronic exposure to 0.2 mg/m3 chromium, and serum contents
of triglycerides and phospholipids differed significantly from controls
(p < 0.05) at this concentration.
Together, these studies provide useful information on chromium exposure-related
impacts including lung and spleen weight, LDH in BALF, protein in BALF,
and albumin in BALF. The cellular content of BALF is considered representative
of initial pulmonary injury and chronic lung inflammation, which may lead
to the onset of pulmonary fibrosis (Henderson, 1988). While these studies
present dose-dependent results on sensitive indicators of lower respiratory
toxicity, potential upper respiratory impacts resulting from the exposures
were not addressed. Glaser et al. (1990) state that the upper respiratory
tract was examined, but these data were not reported.
One approach for development of an RfC using the data of Glaser et al.
(1985, 1990) was offered by Malsch et al. (1994), who generated an inhalation
RfC for chromium dusts using a benchmark concentration (BMC) approach.
The Agency developed its RfC for particulates based on this approach.
After excluding exposures for periods of less than 90 days from the BMC
analysis, Malsch et al. (1994) developed BMCs for lung weight, LDH in
BALF, protein in BALF, albumin in BALF, and spleen weight. The Malsch
et al. (1994) analysis defined the benchmark concentration as the 95%
lower confidence limit on the dose corresponding to a 10% relative change
in the endpoint compared to the control. Dose-effect data were adjusted
to account for discontinuous exposure (22 hr/day) and the maximum likelihood
model was used to fit continuous data to a polynomial mean response regression,
yielding maximum likelihood estimates of 0.036 - 0.078 mg/m3
and BMCs of 0.016 - 0.067 mg/m3. Malsch et al. (1994) applied
dosimetric adjustments and uncertainty factors to determine a RfC based
on the following equation:
where:
- RfC is the inhalation reference concentration
- BMC is the benchmark concentration (lower 95% confidence limit on thedose corresponding to a 10% relative change in the endpoint compared to the control)
- RDDR is the regional deposited dose ratio to account for pharmacokineticdifferences between species
- UFA is a threefold uncertainty factor to account for pharmacodynamicdifferences not addressed by the RDDR
- UFF is a threefold uncertainty factor to account for extrapolating from subchronic to chronic exposures; and
- UFH is a 10-fold uncertainty factor to account for the variation in sensitivity among members of the human population
The RDDR factor is incorporated to account for differences
in the deposition pattern of inhaled hexavalent chromium dusts in the
respiratory tract of humans and the Wistar rat test animals (Jarabek et
al., 1990). The RDDR of 2.1576 was determined based on the mass median
aerodynamic diameter (0.28 µm for dose levels of 0.05-0.1 mg/m3
and 0.39 for dose levels of 0.1-0.4 mg/m3) and the geometric
standard deviation (1.63 for dose levels of 0.05-0.1 mg/m3
and 1.72 for dose levels of 0.1-0.4 mg/m3) of the particulates
reported in Glaser et al. (1990). A 3.16-fold uncertainty factor (midpoint
between 1 and 10 on a log scale) was incorporated to account for the pharmacodynamic
differences not accounted for by the RDDR. An additional 3.16-fold uncertainty
factor was incorporated to account for the less-than-lifetime exposure
in Glaser et al. (1990), and a 10-fold uncertainty factor was applied
to account for variation in the human population. A total uncertainty
factor of 100 was applied to the BMC in addition to the RDDR.
Glaser et al. (1990) reported that LDH in BALF increased in a dose-dependent
fashion from 0.05 to 0.4 mg/m3 sodium dichromate, and this
endpoint generated the lowest BMC (0.016 mg/m3) and RfC (3.4 E-4 mg/m3). LDH in BALF is considered the among the most sensitive indicators
of potential lung toxicity (Henderson, 1984, 1985, 1988; Beck et al.,
1982; Venet et al., 1985), as LDH is found extracellularly after cell
damage and BALF is the closest site to the original lung injury. LDH in
BALF may also reflect chronic lung inflammation, which may lead to pulmonary
fibrosis through prevention of the normal repair of lung tissue (Henderson,
1988).
Several uncertainties must be addressed with regard to the BMC and RfC
developed by Malsch et al. (1994). Potentially important endpoints, including
upper airway effects and potential renal or immunological toxicity, were
not addressed in the Glaser et al. (1985, 1990) studies and could not
be included in the BMC analysis. While LDH in BALF resulted in the lowest
BMC and RfC, all of the effects noted in Glaser et al. (1985, 1990) can
be considered indicative of an inflammatory response, and might be equally
suited to development of the RfC. LDH in BALF did not generate the best
fit on the regression curve of the endpoints considered in the BMC analysis.
In addition, the threefold uncertainty factor accounting for the use of
a subchronic study may not be sufficiently protective for long-term effects.
While the analysis acknowledged the importance of particle size and airway
deposition in the development of the RDDR, the potential impact of different
particle sizes in respiratory toxicity by hexavalent chromium particulates
was not addressed.
Several of these uncertainties were conservatively addressed in the analysis
of Malsch et al. (1994). LDH in BALF generated the lowest estimate of
the BMC from the effects noted by Glaser et al. (1985, 1990). This effect
can be considered to be indicative of cell damage that occurs prior to
fibrosis, as LDH appears in BALF following cell lysis. While the Malsch
et al. (1994) analysis demonstrated a relatively poor curve fit for this
endpoint, the model generated a conservative fit in the data that is unlikely
to overestimate the BMC. LDH in BALF as reported in Glaser et al. (1990)
is considered to be an acceptable endpoint for development of an RfC for
inhalation of hexavalent chromium particulates, and Malsch et al. (1994)
used a reasonable approach for development of a BMC based on this endpoint.
The threefold uncertainty factor used by Malsch et al. (1994) to account
for the subchronic study is insufficient for development of the RfC for
inhalation of chromium particulates. Glaser et al. (1985) demonstrated
that at the end of the 90-day exposure period, chromium was still accumulating
in the lung tissue of the test animals, suggesting that lower long-term
exposures might lead to accumulation of a critical concentration in the
lung. Subchronic studies also may not adequately predict the presence
of inflammatory effects from lower long-term exposures. The Agency has
therefore determined that a 10-fold uncertainty factor accounting for
the use of a subchronic study is more appropriate in this case for the
development of an RfC for inhalation of chromium particulates.
Selection of a threefold uncertainty factor to account for the pharmacodynamic
differences not accounted for by the RDDR, an additional 10-fold uncertainty
factor to account for the less-than-lifetime exposure in Glaser et al.
(1990), and a 10-fold uncertainty factor to account for variation in the
human population generates a total uncertainty factor of 300. Application
of the total uncertainty factor of 300 and the RDDR of 2.1576 to the BMC
generated by Malsch et al. (1994) based on LDH in BALF (Glaser et al.,
1990) results in an RfC of 1 E-4 mg/m3 for inhalation of hexavalent chromium particulates.
__I.B.3. Uncertainty and Modifying Factors (Inhalation RfC)
See discussion above.
(1) Chromic acid mists and dissolved Cr (VI) aerosols:
UF = 90.
MF = 1.
(2) Chromium (VI) particulates:
UF = 300.
MF = 1
__I.B.4. Additional Studies/Comments (Inhalation RfC)
There is considerable uncertainty with regard to the relevance
of the nasal septum atrophy endpoint observed in the chromeplating industry
to exposure to hexavalent chromium in the environment. The effects were
observed in chromeplaters who were exposed to chromic acid mists near
the plating baths. Environmental exposures would most likely occur through
contact with hexavalent chromium dusts, and exposures to chromic acid
mists in the environment is considered to be unlikely. An additional uncertainty
is related to the determination of dose in the Lindberg and Hedenstierna
study. Nasal septum atrophy in this study was related to TWA exposures
to chromic acid. The most significant effects (nasal septum perforation)
were observed in workers who experienced peak excursions to levels considerably
greater than the TWA. It is uncertain whether the peak excursion data
or the TWAs are more appropriate for the determination of dose in this
study. The RfC based on the data of Lindberg and Hedenstierna (1983) should
only be used to address exposures to chromic acid and dissolved hexavalent
chromium aerosols.
Nasal mucosal irritation, atrophy, and perforation have been widely reported
following occupational exposures to chromic acid mists and dissolved hexavalent
chromium aerosols. Glaser et al. (1990) did not report on upper respiratory
effects following exposure of rats to sodium dichromate. The RfC based
on the data of Glaser et al. should only be used to address inhalation
of Cr(VI) particulates.
The RfCs in this IRIS Summary were added in 1998. The previous RfC section
for hexavalent chromium in IRIS was empty.
For more detail on other Hazard Identification Issues, exit to the toxicological review, Section 4.7 (PDF).
__I.B.5. Confidence in the Inhalation RfC
(1) Chromic acid mists and dissolved Cr (VI) aerosols:
Study — Low
Database — Low
RfC -- Low
The overall confidence in this RfC assessment is low. Confidence in the
chosen study is low because of uncertainties regarding the exposure characterization
and the role of direct contact for the critical effect. Confidence in
the database is low because the supporting studies are equally uncertain
regarding the exposure characterization.
(2) Chromium (VI) particulates:
Study — Medium
RfC — Medium
The overall confidence in this RfC assessment is medium. Confidence in
the chosen study is medium because of uncertainties regarding upper respiratory,
reproductive, and renal effects resulting from the exposures.
For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF).
__I.B.6. EPA Documentation and Review of the Inhalation RfC
Source Document — U.S. EPA, 1998
This assessment was peer reviewed by external scientists. Their comments
have been evaluated carefully and incorporated in finalization of this
IRIS Summary. A record of these comments is included as an appendix to
the Toxicological Review of Acetonitrile in Support of Summary Information
(a PDF document) on the Integrated Risk Information System (IRIS) (U.S.
EPA, 1998). To review
this appendix, exit to the toxicological review, Appendix A, External
Peer Review -- Summary of Comments and Disposition (PDF).
Agency Consensus Date — 04/28/1998
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the RfC for Chromium (VI) conducted in August 2003 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 202-566-1676.
__I.B.7. EPA Contacts (Inhalation RfC)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (fax), or hotline.iris@epa.gov (Internet address).
_II. Carcinogenicity Assessment for Lifetime Exposure
Substance Name: Chromium (VI)
CASRN: 18540-29-9
Last Revised — 09/03/1998
Section II provides information on three aspects of the carcinogenic assessment
for the substance in question; the weight-of-evidence judgment of the
likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. 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 µg/L drinking water or risk per µg/m3
air breathed. The third form in which risk is presented is a concentration
of the chemical in drinking water or air associated with cancer risks
of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000. The rationale and methods
used to develop the carcinogenicity information in IRIS are described
in The Risk Assessment Guidelines of 1986 (EPA/600/8-87/045) and in the
IRIS Background Document. IRIS summaries developed since the publication
of EPA's more recent Proposed Guidelines for Carcinogen Risk Assessment
also utilize those Guidelines where indicated (Federal Register 61(79):17960-18011,
April 23, 1996). Users are referred to Section I of this IRIS file for
information on long-term toxic effects other than carcinogenicity.
_II.A. Evidence for Human Carcinogenicity
__II.A.1. Weight-of-Evidence Characterization
Under the current guidelines (EPA, 1986), Cr(VI) is classified
as Group A - known human carcinogen by the inhalation route of exposure.
Carcinogenicity by the oral route of exposure cannot be determined and
is classified as Group D.
Under the proposed guidelines (EPA, 1996), Cr(VI) would be characterized
as a known human carcinogen by the inhalation route of exposure on the
following basis.
Hexavalent chromium is known to be carcinogenic in humans by the inhalation
route of exposure. Results of occupational epidemiologic studies of chromium-exposed
workers are consistent across investigators and study populations. Dose-response
relationships have been established for chromium exposure and lung cancer.
Chromium-exposed workers are exposed to both Cr(III) and Cr(VI) compounds.
Because only Cr(VI) has been found to be carcinogenic in animal studies,
however, it was concluded that only Cr(VI) should be classified as a human
carcinogen.
Animal data are consistent with the human carcinogenicity data on hexavalent
chromium. Hexavalent chromium compounds are carcinogenic in animal bioassays,
producing the following tumor types: intramuscular injection site tumors
in rats and mice, intrapleural implant site tumors for various Cr(VI)
compounds in rats, intrabronchial implantation site tumors for various
Cr(VI) compounds in rats, and subcutaneous injection site sarcomas in
rats.
In vitro data are suggestive of a potential mode of action for hexavalent
chromium carcinogenesis. Hexavalent chromium carcinogenesis may result
from the formation of mutagenic oxidatitive DNA lesions following intracellular
reduction to the trivalent form. Cr(VI) readily passes through cell membranes
and is rapidly reduced intracellularly to generate reactive Cr(V) and
Cr(IV) intermediates and reactive oxygen species. A number of potentially
mutagenic DNA lesions are formed during the reduction of Cr(VI). Hexavalent
chromium is mutagenic in bacterial assays, yeasts, and V79 cells, and
Cr(VI) compounds decrease the fidelity of DNA synthesis in vitro and produce
unscheduled DNA synthesis as a consequence of DNA damage. Chromate has
been shown to transform both primary cells and cell lines.
For more detail on Characterization of Hazard and Dose Response, exit to the toxicological review, Section 6 (PDF).
For more detail on other Hazard Identification Issues, exit to the toxicological review, Section 4.7 (PDF).
__II.A.2. Human Carcinogenicity Data
Occupational exposure to chromium compounds has been studied
in the chromate production, chromeplating and chrome pigment, ferrochromium
production, gold mining, leather tanning, and chrome alloy production
industries.
Workers in the chromate industry are exposed to both trivalent and hexavalent
compounds of chromium. Epidemiological studies of chromate production
plants in Japan, Great Britain, West Germany, and the United States have
revealed a correlation between occupational exposure to chromium and lung
cancer, but the specific form of chromium responsible for the induction
of cancer was not identified (Machle and Gregorius, 1948; Baejter, 1950a,b;
Bidstrup, 1951; Mancuso and Hueper, 1951; Brinton et al., 1952; Bidstrup
and Case, 1956; Todd, 1962; Taylor, 1966; Enterline, 1974; Mancuso, 1975;
Ohsaki et al., 1978; Sano and Mitohara, 1978; Hayes et al., 1979; Hill
and Ferguson, 1979; Alderson et al., 1981; Haguenor et al., 1981; Satoh
et al., 1981; Korallus et al., 1982; Frentzel-Beyme, 1983; Langard and
Vigander, 1983; Watanabe and Fukuchi, 1984; Davies, 1984; Mancuso, 1997).
Mancuso and Hueper (1951) conducted a proportional mortality study of
a cohort of chromate workers (employed for > l year from 1931-1949
in a Painesville, OH chromate plant) in order to investigate lung cancer
associated with chromate production. Of the 2,931 deaths of males in the
county where the plant is located, 34 (1.2%) were due to respiratory cancer.
Of the 33 deaths among the chromate workers, however, 6 (18.2%) were due
to respiratory cancer. Within the limitations of the study design, this
report strongly suggested an increased incidence of respiratory cancer
in the chromate-production plant.
In an update of the Mancuso and Hueper (1951) study, Mancuso (1975) followed
332 of the workers employed from 1931-1951 until 1974. By 1974, > 50%
of this cohort had died. Of these men, 63.6%, 62.5%, and 58.3% of the
cancer deaths for men employed from 1931-1932, 1933-1934, and 1935-1937,
respectively, were due to lung cancer. Lung cancer death rates increased
by gradient of exposure to total chromium, and significant deposition
of chromium was found in the lungs of workers long after the exposure
ceased. Mancuso (1975) reported that these lung cancer deaths were related
to insoluble (trivalent), soluble (hexavalent), and total chromium exposure,
but the small numbers involved make identification of the specific form
of chromium responsible for the lung cancer uncertain.
Mancuso (1997) recently updated this study, following the combined cohort
of 332 workers until 1993. Of 283 deaths (85% of the cohort identified),
66 lung cancers were found (23.3% of all deaths and 64.7% of all cancers).
Lung cancer rates clearly increased by gradient level of exposure to total
chromium. The relationship between gradient level of exposure and lung
cancer rates is less clear for trivalent and hexavalent chromium. The
rates of lung cancer within the cohort are consistent with those reported
in Mancuso (1975), and provide further support for the cancer risk assessment
based on those data.
Studies of chrome pigment workers in the United States (Hayes et al.,
1989), England (Davies, 1984, 1979, 1978), Norway (Langard and Vigander,
1983; Langard and Norseth, 1975), and in the Netherlands and Germany (Frentzel-Beyme,
1983) have consistently demonstrated an association between occupational
chromium exposure (predominantly to Cr [VI]) and lung cancer.
Several studies of the chromeplating industry have demonstrated a positive
relationship between cancer and exposure to chromium compounds (Royle,
1975;
Franchini et al., 1983; Sorahan et al., 1987).
__II.A.3. Animal Carcinogenicity Data
Animal data are consistent with the findings of human epidemiological studies of hexavalent chromium. Hexavalent chromium compounds were carcinogenic in animal assays producing the following tumor types: lung tumors following inhalation of aerosols of sodium chromate and pyrolized Cr(VI)/Cr(III) oxide mixtures in rats (Glaser et al., 1986), lung tumors following intratracheal administration of sodium dichromate in rats (Steinhoff et al., 1983), intramuscular injection site tumors in Fischer 344 and Bethesda Black rats and in C57BL mice (Furst et al., 1976; Maltoni, 1974, 1976; Payne, 1960a; Hueper and Payne, 1959); intrapleural implant site tumors for various Cr(VI) compounds in Sprague-Dawley and Bethesda Black rats (Payne, 1960b; Hueper 1961; Hueper 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). Inflammation is considered to be essential for the induction of most chromium respiratory effects and may influence the carcinogenicity of Cr(VI) compounds (Glaser et al., 1985).
__II.A.4. Supporting Data for Carcinogenicity
Metabolism and genotoxicity. Hexavalent chromium is rapidly
taken up by cells through the sulfate transport system (Sugiyama, 1992).
Once inside the cell, Cr(VI) is quickly reduced to the trivalent form
by cellular reductants, including ascorbic acid, glutathione and flavoenzymes
(cytochrome P-450 and glutathione reductase), and riboflavin (De Flora
et al., 1989; De Flora et al., 1990; Sugiyama, 1992). The intracellular
reduction of Cr(VI) generates reactive Cr(V) and Cr(IV) intermediates
as well as hydroxyl free radicals (OH) and singlet oxygen (1O2)
(Kawanishi et al., 1986). A variety of DNA lesions are formed during the
reduction of Cr(VI) to Cr(III), including DNA strand breaks, alkali-labile
sites, DNA-protein and DNA-DNA crosslinks, and oxidative DNA damage, such
as 8-oxo-deoxyguanosine (Klein et al., 1992; Klein et al., 1991; De Flora
et al., 1990). The relative importance of the different chromium complexes
and oxidative DNA damage in the toxicity of Cr(VI) is unknown.
A large number of chromium compounds have been assayed with in vitro genetic
toxicology assays. In general, hexavalent chromium is mutagenic in bacterial
assays whereas trivalent chromium is not (Lofroth, 1978; Petrilli and
DeFlora, 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).
Cr(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).
In dogs (2/group) exposed to potassium dichromate in drinking water at
concentrations up to 11.2 ppm for 4 years, gross and microscopic examination
of all major organs revealed no treatment-related lesions (Anwar et al.,
1961). The small number of animals and the relatively short exposure duration
relative to the lifespan of the dog precludes a conclusion regarding a
possible carcinogenic response. There are no other long-term studies of
ingested Cr(VI). Cr(VI) is readily converted to Cr(III) in vivo, but there
is no evidence that Cr(III) is oxidized to Cr(VI) in vivo. Cr(III) is
an essential trace element.
_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure
The oral carcinogenicity of Cr(VI) cannot be determined. No data were located in the available literature that suggested that Cr(VI) is carcinogenic by the oral route of exposure.
_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure
__II.C.1. Summary of Risk Estimates
___ II.C.1.1. Air Unit Risk — 1.2E-2 per (µ/cu.m)
Source: Mancuso, 1975
___ II.C.1.2. Extrapolation Method — Multistage, extra risk
Air Concentrations at Specified Risk Levels:
Risk Level
|
Concentration
|
---|---|
E-4 (1 in 10,000)
|
8E-3 (µg/m3)
|
E-5 (1 in 100,000)
|
8E-4 (µg/m3)
|
E-6 (1 in 1,000,000)
|
8E-5 (µg/m3)
|
__II.C.2. Dose-Response Data for Carcinogenicity, Inhalation Exposure
Tumor type -- lung cancer
Test animals — human
Route — inhalation, occupational exposure
Source -- Mancuso, 1975
Subject age (years)
|
Exposure Level
midrange (µg/m3) |
Deaths From Lung Cancer
|
Person-Years
|
---|---|---|---|
50
|
5.66
25.27 46.83 |
3
6 6 |
1,345
931 299 |
60
|
4.68
20.79 39.08 |
4
5 5 |
1,063
712 211 |
70
|
4.41
21.29 |
2
4 |
401
345 |
__II.C.3. Additional Comments (Carcinogenicity, Inhalation Exposure)
Mancuso (1997) recently updated the study of Mancuso (1975),
following the combined cohort of 332 workers until 1993. Of 283 deaths
(85% of the cohort identified), 66 lung cancers were found (23.3% of all
deaths and 64.7% of all cancers). Lung cancer rates clearly increased
by gradient level of exposure to total chromium. The relationship between
gradient level of exposure and lung cancer rates is less clear for trivalent
and hexavalent chromium. The rates of lung cancer within the cohort are
consistent with those reported in Mancuso (1975), and provide further
support for the cancer risk assessment based on those data.
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.
Trivalent chromium compounds have not been reported as carcinogenic by
any route of administration.
The unit risk should not be used if the air concentration exceeds 8E-1
µg/m3, since above this concentration the unit risk may not be appropriate.
The carcinogenicity section of this IRIS Summary was updated in 1998;
however, the quantitative results have not been modified.
__II.C.4. Discussion of Confidence (Carcinogenicity, Inhalation Exposure)
Results of studies of chromium exposure are consistent across investigators and countries. A dose relationship for lung tumors has been established. Theassumption that the ratio of Cr(III) to Cr(VI) is 6:1 may lead to a sevenfold underestimation of risk. The use of 1949 hygiene data (Bourne and Yee, 1950), 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.
_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity Assessment)
__II.D.1. EPA Documentation
Source Document — U.S. EPA, 1998
This assessment was peer reviewed by external scientists. Their comments
have been evaluated carefully and incorporated in finalization of this
IRIS Summary. A record of these comments is included as
an appendix to the Toxicological Review of Acetonitrile in Support of
Summary Information (a PDF document) on the Integrated Risk Information
System (IRIS) (U.S. EPA, 1998). To
review this appendix, exit to the toxicological review, Appendix A, External
Peer Review -- Summary of Comments and Disposition (PDF).
Other EPA Documentation — 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. EPA Review (Carcinogenicity Assessment)
Agency consensus date -- 04/28/1998
Screening-Level Literature Review Findings — A screening-level review conducted by an EPA contractor of the more recent toxicology literature pertinent to the cancer assessment for Chromium (VI) conducted in August 2003 did not identify any critical new studies. IRIS users who know of important new studies may provide that information to the IRIS Hotline at hotline.iris@epa.gov or 202-566-1676.
__II.D.3. EPA Contacts (Carcinogenicity Assessment)
Please contact the IRIS Hotline for all questions concerning this assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749 (fax), or hotline.iris@epa.gov (Internet address).
_III.
[reserved]
_IV. [reserved]
_V. [reserved]
_VI. Bibliography
Chromium (VI)
CASRN — 18540-29-9
Last Revised — 09/03/1998
_VI.A. Oral RfD References
Anwar, RA; Langham, FF; Hoppert, CA; et al. (1961) Chronic toxicity studies.
III. Chronic toxicity of cadmium and chromium in dogs. Arch Environ 3:456-460.
Bruynzeel, DP; Hennipman, G; van Ketel, WG. (1988) Irritant contact dermatitis
and chromium-passivated metal. Contact Derm 19:175-179.
Burrows, D; Adams, RM. (1990) In: Occupational skin disease, 2nd ed.,
Adams, RM, d. Philadelphia: W.B. Saunders, pp. 349-386.
Cronin, E. (1980) Contact dermatitis. New York: Churchill Livingstone,
pp. 287-390.
Elbetieha, A; Al-Hamood, MH. (1997) Long-term exposure of male and female
mice to trivalent and hexavalent chromium compounds: effect on fertility.
Toxicology 116:19-47.
Fregert, S. (1981) Chromium valencies and cement dermatitis. Br J Dermatol
105 (suppl. 21):7-9.
Gruber, JE; Jennette, KW. (1978) Metabolism of the carcinogen chromate
by rat liver
microsomes. Biochem Biophys Res Commun 82(2):700-706.
Hunter, D. (1974) The diseases of occupations, 5th ed. Boston: Little,
Brown.
Junaid, M; Murthy, RC; Saxena, DK. (1996) Embryotoxicity of orally administered
chromium in mice: exposure during the period of organogenesis. Toxicol
Lett 84:143-148.
Kanojia, RK; Junaid, M; Murthy, RC. (1996) Chromium induced teratogenicity
in female rat. Toxicol Lett 89:207-213.
MacKenzie, RD; Byerrum, RU; Decker, CF; et al. (1958) Chronic toxicity
studies. II. Hexavalent and trivalent chromium administered in drinking
water to rats. Am Med Assoc Arch Ind Health 18:232-234.
National Toxicology Program (NTP). (1996a) Final Report. Potassium dichromate
(hexavalent): The effects of potassium dichromate on Sprague-Dawley rats
when administered in the diet. December 13, 1996.
National Toxicology Program (NTP). (1996b) Final Report. Potassium dichromate
(hexavalent): The effects of potassium dichromate in BALB/c mice when
administered in the diet. November 27, 1996.
National Toxicology Program (NTP). (1997) Final Report. Potassium dichromate
(hexavalent): Reproductive assessment by continuous breeding when administered
to BALB/c mice in the diet. February 18, 1997.
Petrilli, FL; DeFlora, S. (1977) Toxicity and mutagencity of hexavalent
chromium on Salmonella typhimurium. Appl Environ Microbiol 33(4):805-809.
Petrilli, FL; DeFlora, S. (1978) Oxidation of inactive trivalent chromium
to the mutagenic hexavalent form. Mutat Res 58(2-3):167-178.
Polak, L. (1983) Immunology of chromium. In: Chromium: metabolism and
toxicity. Burrows, D, ed. Boca Raton, FL: CRC Press, pp. 51-135.
Polak, L; Turk, JL; Frey, FR. (1973) Studies on contact hypersensitivity
to chromium compounds. Progr Allergy 17:145-219.
Spruit, D; van Neer, FCJ. (1966) Penetration rate of Cr(III) and Cr(VI).
Dermatological 132:179-182.
U.S. Environmental Protection Agency (U.S. EPA). (1984) Health effects
assessment for hexavalent chromium. Prepared 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.
U.S. EPA. (1998) Toxicological review of hexavalent chromium. Available
online at http://www.epa.gov/ncea/iris.
Zhang, J; Li, X. (1987) Chromium pollution of soil and water in Jinzhou.
J of Chinese Preventive Med 21:262-264.
_VI.B. Inhalation RfC References
Beck, BD; Brain, JD; Bohannon, DE. (1982) An in vivo hamster bioassay to
assess the toxicity of particles for the lungs. Toxicol Appl Pharmacol
66:9-29.
Cohen, SR; Davis, DM; Kramkowski, RS. (1974) Clinical manifestations of
chronic acid toxicity--Nasal lesions in electroplate workers. Cutis 13:558-568.
Glaser, U; Hochrainer, D; Kloppe, H; et al. (1985) Low level chromium
(VI) inhalation effects on alveolar macrophages and immune function in
Wistar rats. Arch Toxicol 57(4):250-256.
Glaser, U; Hochrainer, D; Steinhoff, D. (1990) Investigation of irritating
properties of inhaled Cr(VI) with possible influence on its carcinogenic
action. In: Environmental Hygiene II. Seemayer, NO; Hadnagy, W, eds. Berlin/New
York: Springer-Verlag.
Henderson, RF. (1984) Use of bronchoalveolar lavage to detect lung damage.
Environ Health Perspect 56:115-129.
Henderson, RF. (1988) Use of bronchoalveolar lavage to detect lung damage.
In: Toxicology of the lung. Gardner, DE; Crapo, JD; Masaro, EJ, eds.,
New York: Raven Press.
Henderson, RF; Benson, JM; Hahn, FF. (1985) New approaches for the evaluation
of pulmonary toxicity: bronchoalveolar lavage fluid analysis. Fundam Appl
Toxicol 5:451-458.
Lees, PSJ; Gibb, HJ; Rooney, BC. (1995) Derivation of exposure-response
relationship for chromium from historic exposure data. 11th International
Symposium of Epidemiology in Occupational Health, the Netherlands, September
1995.
Lindberg, E; Hedensteirna, G. (1983) Chrome plating: Symptoms, finding
in the upper airways and effects on lung function. Arch Environ Health
38:367-374.
Lucas, JB; Kramkowski, RS. (1975) Health Hazard Evaluation Report No.
74-87-221. Cincinnati, OH. Health Hazard Evaluation Branch, U.S. Department
of Health, Education, and Welfare, Public Health Service, Center for Disease
Control. National Institute for Occupational Safety and Health.
Malsch, PA; Proctor, DM; Finley, BL. (1994) Estimation of a chromium inhalation
reference concentration using the benchmark dose method: a case study.
Regul Toxicol Pharmacol 20:58-82.
U.S. EPA. (1998) Toxicological review of hexavalent chromium. Available
online at http://www.epa.gov/ncea/iris.
Venet, A; Clavel, F; Israel-Biet, D; et al. (1985) Lung in acquired immune
deficiency syndrome: Infectious and immunological status assessed by bronchioalveolar
lavage. Bull Eur Physiopathol Respir 21:535-543.
_VI.C. Carcinogenicity Assessment References
Alderson, MR; Rattan, NS; Bidstrup, L. (1981) Health of workmen in the
chromate-producing industry in Britain. Br J Ind Med 38:117-124.
Baetjer, AM. (1950a) Pulmonary carcinoma in chromate workers. In: A review
of the literature and report of cases. Arch Ind Hyg Occup Med 2(5):487-504.
Baetjer, AM. (1950b) Pulmonary carcinoma in chromate workers. II. Incidence
on basis of hospital records. Arch Ind Hyg Occup Med 2(5):505-516.
Bidstrup, PL. (1951) Carcinoma of the lung in chromate workers. Br J Med
8:302-305.
Bidstrup, PL; Case, RAM. (1956) Carcinoma of the lung in workmen in the
bichromates-producing industry in Great Britain. Br J Ind Med 13:260-264.
Bonatti, S; Meini, M; Abbondandolo, A. (1976) Genetic effects of potassium
dichromate in Schizosaccharomyces pombe. Mutat Res 38:147-150.
Bourne, HG, Jr; Yee, HT. (1950) Occupational cancer in a chromate plant
- an environmental appraisal. Ind Med Surg 19(12):563-567.
Brinton, HP; Frasier, ES; Koven AL. (1952) Morbidity and mortality experience
among chromate workers. Public Health Rep 67(9):835-847.
Casto, BC; Meyers, J; DiPaolo, JA. (1979) Enhancement of viral transformation
for evaluation of the carcinogenic or mutagenic potential of inorganic
metal salts. Cancer Res 39:193-198.
Davies, JM. (1978) Lung-cancer mortality in workers making chrome pigments.
Lancet 1:384.
Davies, JM. (1979) Lung cancer mortality of workers in chromate pigment
manufacture: An epidemiological survey. J Oil Chem Assoc 62:157-163.
Davies, JM. (1984) Lung cancer mortality among workers making lead chromate
and zinc chromate pigments at three English factories. Br J Ind Med 41:158-169.
De Flora, S; Wetterhahn, KE. (1989) Mechanisms of chromium metabolism
and genotoxicity. Life Chem Rep 7:169-244.
De Flora, S; Bagnasco, M; Serra, D; et al. (1990) Genotoxicity of chromium
compounds: a review. Mutat Res 238:99-172.
Enterline, PE. (1974) Respiratory cancer among chromate workers. J Occup
Med 16:523-526.
Fradkin, A; Janoff, A; Lane, BP; et al. (1975) In vitro transformation
of BHK21 cells grown in the presence of calcium chromate. Cancer Res 35:1058-1063.
Frentzel-Beyme, R. (1983) Lung cancer mortality of workers employed in
chromate pigment factories. A multicentric European epidemiological study.
J Cancer Res Clin Oncol 105:183-188.
Furst, A; Schlauder, M; Sasmore, DP. (1976) Tumorigenic activity of lead
chromate. Cancer Res 36:1779-1783.
Glaser, U; Hochrainer, D; Kloppel, H; et al. (1986) Carcinogenicity of
sodium dichromate and chromium(VI/III) oxide aerosols inhaled by male
Wistar rats. Toxicology 42:219-232.
Haguenor, JM; Dubois, G; Frimat, P; et al. (1981) Mortality due to bronch-pulmonary
>cancer in a factory producing pigments based on lead and zinc chromates.
In: Prevention of occupational cancer - International symposium, occupational
safety and health series 46. Geneva, Switzerland: International Labour
Office, pp. 168-176. (French).
Hayes, RB; Lilienfeld, AM; Snell, LM. (1979) Mortality in chromium chemical
production workers: a prospective study. Int J Epidemiol 8(4):365-374.
Hayes, RB; Sheffet, A; Spirtas, R. (1989) Cancer mortality among a cohort
of chromium pigment workers. Am J Ind Med 16:127-133.
Hill, WJ; Ferguson, WS. (1979) Statistical analysis of epidemiological
data from chromium chemical manufacturing plant. J Occup Med 21:103-106.
Hueper, WC. (1961) Environmental carcinogenesis and cancers. Cancer Res
21:842-857.
Hueper, WC; Payne, WW. (1962) Experimental studies in metal carcinogenesis:
Chromium, nickel, iron, and arsenic. Arch Environ Health 5:445-462.
Hill, WJ; Ferguson, WS. (1979) Statistical analysis of epidemiological
data from a chromium chemical manufacturing plant. J Occup Med 21(2):103-106.
Kawanishi, S; Inoue, S; Sano, S. (1986) Mechanism of DNA cleavage induced
by sodium chromate (VI) in the presence of hydrogen peroxide. J Biol Chem
261:5952-5958.
Klein, CB; Frenkel, K; Costa, M. (1992) Chromium mutagenesis in transgenic
gpt+ Chinese hamster cell lines. Environ Mol Mutagen 19:29a.
Klein, CB; Frenkel, K; Costa, M. (1991) The role of oxidative processes
in metal Carcinogenesis. Chem Res Toxicol 4:592-604.
Korallus, U; Lange H; Ness, A; et al. (1982) Relationships between precautionary
measures and bronchial carcinoma mortality in the chromate-producing industry.
Arbeitsmedizin, Socialmedizin, Preventivmedizin. 17(7):159-167. (German
- Eng. summary)
Langard, S; Norseth, T. (1975) A cohort study of bronchial carcinomas
in workers producing chromate pigments. Br J Ind Med 32:62-65.
Langard, S; Vigander, T. (1983) Occurrence of lung cancer in workers in
producing chromium pigments. Br J Ind Med 40:71-74.
Laskin, S; Kuschner, M; Drew, RT. (1970) Studies in pulmonary carcinogenesis.
In: Hanna, Jr., MG;, Nettesheim, P; and Gilbert, JR, eds.
Levis, AG; Buttignol, M; Bianchi, V; et al. (1978) Effects of potassium
dichromate on nucleic acid and protein syntheses and on precursor uptake
in BHK fibroblasts.
Cancer Res 38:110-116.
Levy, LS; Martin, PA. (1983) The effects of a range of chromium-containing
materials on rat lung. Sponsored by Dry Color Manufacturers' Association
and others. (Unpublished)
Loeb, LA; Sirover, MA; Agarwal, SS. (1977) Infidelity of DNA synthesis
as related to mutagenesis and carcinogenesis. Adv Exp Biol Med 91:103-115.
Lofroth, G. (1978) The mutagenicity of hexavalent chromium is decreased
by microsomal metabolism. Naturvissenschaften 65:207-208.
Machle, W; Gregorius, F. (1948) Cancer of the respiratory system in the
United States chromate-producing industry. Public Health Rep 63(35):1114-1127.
Maltoni, C. (1974) Occupational carcinogenesis. Excerpta Med Int Congr
Ser 322:19-26.
Maltoni, C. (1976) Predictive value of carcinogenesis bioassays. Ann NY
Acad Sci 271:431-443.
Mancuso, TF. (1975) Consideration of chromium as an industrial carcinogen.
International Conference on Heavy Metals in the Environment, Toronto,
Ontario, Canada, October 27-31. pp. 343-356.
Mancuso, TF. (1997) Chromium as an industrial carcinogen: Part 1. Am J
Ind Med 31:129-139.
Mancuso, TF; Hueper, WC. (1951) Occupational cancer and other health Hazards
in a chromate plant: A medical appraisal. In: Lung cancers in chromate
workers. Ind Med Surg 20(8):358-363.
Nakamuro, K; Yoshikawa, K; Sayato, Y; et al. (1978) Comparative studies
of chromosomal aberration and mutagenicity of trivalent and hexavalent
chromium. Mutat Res 58:175-181.
Newbold, RF; Amos, J; Connell, JR. (1979) The cytotoxic, mutagenic and
clastogenic effects of chromium-containing compounds on mammalian cells
in culture. Mutat Res
67:55-63.
National Institute for Occupational Safety and Health (NIOSH). (1975)
Criteria for a recommended standard occupational exposure to chromium
(VI). U.S. Department of Health, Education, and Welfare, Washington, DC.
Ohsaki, Y; Abe, S; Kimura, K; et al. (1978) Lung cancer in Japanese chromate
workers. Thorax 33:372-374.
Payne, WW. (1960a) The role of roasted chromite ore in the production
of cancer. Arch Environ Health 1:20-26.
Payne, WW. (1960b) Production of cancers in mice and rats by chromium
compounds. Arch Ind Health 21:530-535.
Petrilli, FL; DeFlora, S. (1977) Toxicity and mutagenicity of hexavalent
chromium on Salmonella typhimurium. Appl Environ Microbiol 33(4):805-809.
Petrilli, FL; DeFlora, S. (1978) Oxidation of inactive trivalent chromium
to the mutagenic hexavalent form. Mutat Res 58:167-178.
Raffetto, G; Parodi, S; Parodi, C; et al. (1977) Direct interaction with
cellular targets as the mechanism for chromium carcinogenesis. Tumori
63:503-512.
Royle, H. (1975) Toxicity of chromic acid in the chromium plating industry.
Environ Res 10:141-163.
Sano, T; Mitohara, I. (1978) Occupational cancer among chromium workers.
Jpn J Chest Dis 37(2):90-101.
Satoh, K; Fukuda, Y; Torii, K; et al. (1981) Epidemiologic study of workers
engaged in the manufacture of chromium compounds. J Occup Med 23(12):835-838.
Sorahan, T; Burgess, DC; Waterhouse, JA. (1987) A mortality study of nickel/chromium
platers. Br J Ind Med 44:250-258.
Steinhoff, S; Gad, SC; Hatfield, GK; et al. (1983) Listing sodium dichromate
and soluble calcium chromate for carcinogenicity in rats. Bayer AG Institute
of Toxicology. (Unpublished)
Sugiyama, M. (1992) Role of physiological antioxidants in chromium (VI)-induced
cellular injury. Free Rad Biol Med 12:397-407.
Taylor, FH. (1966) The relationship of mortality and duration of employment
as reflected by a cohort of chromate workers. Am J Public Health 56(2):218-229.
Todd, GE. (1962) Tobacco manufacturer's standing committee research papers.
No. 1. Statistics of Smoking in the United Kingdom, 3rd ed. Tobacco Research
Council, London.
Tsuda, H; Kato, K. (1977) Chromosomal aberrations and morphological transformation
in hamster embryonic cells treated with potassium dichromate in vitro.
Mutat Res 46:87-94.
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.
U.S. EPA. (1998) Toxicological review of hexavalent chromium. Available
online at http://www.epa.gov/ncea/iris.
Watanabe, S; Fukuchi, Y. (1975) An epidemiological survey on lung cancer
in workers of a chromate-producing industry in Hokkaido, Japan. Presented
at International Congress on Occupational Health.
_VII. Revision History
Chromium (VI)
CASRN —18540-29-9
Date
|
Section | Description |
---|---|---|
09/30/1987 | II.A.1. | Citation corrected |
03/01/1988 | II.C.4. | Confidence statement revised |
03/01/1988 | II.D.3. | Contacts switched |
03/01/1988 | III.A. | Health Advisory added |
12/01/1989 | I.B. | Inhalation RfD now under review |
06/01/1990 | II.A.1. | Basis - Text revised |
06/01/1990 | II.B. | Text revised |
06/01/1990 | IV.A.1. | Area code for EPA contact corrected |
06/01/1990 | IV.F.1. | EPA contact changed |
06/01/1990 | VI. | Bibliography on-line |
01/01/1991 | II. | Text edited |
01/01/1991 | II.C.1. | Inhalation slope factor removed (global change) |
03/01/1991 | II.A.1 | Text revised |
03/01/1991 | II.A.4. | Text revised |
03/01/1991 | II.B. | Text revised |
01/01/1992 | I.A.7. | Secondary contact change |
01/01/1992 | IV. | Regulatory actions updated |
04/01/1992 | IV.A.1. | CAA regulatory action withdrawn |
06/01/1992 | All | CASRN corrected from 7440-47-3 to 18540-29-9 |
09/01/1994 | I.A.6. | Work group review date added |
02/01/1995 | I.A. | RfD noted as pending change: Work Grp Mtg on 08/03/1994 |
08/01/1995 | I.A., I.A.6., I.B. | EPA's RfD/RfC and CRAVE workgroups were discontinued in May 1995. Chemical substance reviews that were not completed by September 1995 were taken out of IRIS review. The IRIS Pilot Program replaced the workgroup functions beginning in September, 1995. |
04/01/1997 | III., IV., V. | Drinking Water Health Advisories, EPA Regulatory Actions, and Supplementary Data were removed from IRIS on or before April 1997. IRIS users were directed to the appropriate EPA Program Offices for this information. |
12/01/1996 | I.A.7. | Secondary contact removed |
09/03/1998 | I., II., VI. | Revised RfD, RfC, carcinogenicity assessment, refs. |
10/28/2003 | I.A.6., I.B.6., II.D.2. | Screening-Level Literature Review Findings message has been added. |
_VIII. Synonyms
Chromium (VI)
CASRN —18540-29-9
Last Revised — 03/31/1987
- 18540-29-9
- 7440-47-3
- Chromic ion
- Chromium
- Chromium, ion
- Chromium (VI)
- Chromium (VI) ion