The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for CHROMIUM

NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.

EXECUTIVE SUMMARY
1. INTRODUCTION
2. METABOLISM AND DISPOSITION: 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
3. NONCARCINOGENIC HEALTH EFFECTS: 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
4. CARCINOGENICITY: 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
5. REFERENCES

September 1992

Prepared by: Mary Lou Daugherty, M.S., Chemical Hazard Evaluation and Communication Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division*, , Oak Ridge, Tennessee.

Prepared for: OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM.

*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.

EXECUTIVE SUMMARY

Elemental chromium (Cr) does not occur in nature, but is present in ores, primarily chromite (FeOCr₂O₃) (Hamilton and Wetterhahn, 1988). Only two of the several oxidation states of chromium, Cr(III) and Cr(VI), are reviewed in this report based on their predominance and stability in the ambient environment and their toxicity in humans and animals.

Chromium plays a role in glucose and cholesterol metabolism and is thus an essential element to man and animals (Schroeder et al., 1962). Non-occupational exposure to the metal occurs via the ingestion of chromium-containing food and water, whereas occupational exposure occurs via inhalation (Langard, 1982; Pedersen, 1982). Workers in the chromate industry have been exposed to estimated chromium levels of 10-50 µg/m³ for Cr(III) and 5-1000 µg/m³ for Cr(VI); however, improvements in the newer chrome-plating plants have reduced the Cr(VI) concentrations 10- to 40-fold (Stern, 1982).

Chromium(III) is poorly absorbed, regardless of the route of exposure, whereas chromium(VI) is more readily absorbed (Hamilton and Wetterhahn, 1988). Humans and animals localize chromium in the lung, liver, kidney, spleen, adrenals, plasma, bone marrow, and red blood cells (RBC) (Langard, 1982; ATSDR, 1989; Bragt and van Dura, 1983; Hamilton and Wetterhahn, 1988). There is no evidence that chromium is biotransformed, but Cr(VI) does undergo enzymatic reduction, resulting in the formation of reactive intermediates and Cr(III) (Hamilton and Wetterhahn, 1988). The main routes for the excretion of chromium are via the kidneys/urine and the bile/feces (Guthrie, 1982; Langard, 1982).

Animal studies show that Cr(VI) is generally more toxic than Cr(III), but neither oxidation state is very toxic by the oral route. In long-term studies, rats were not adversely affected by ~1.9 g/kg/day of chromic oxide [Cr(III)] (diet), 2.4 mg/kg/day of Cr(III) as chromic chloride (drinking water), or 2.4 mg/kg/day of Cr(VI) as potassium dichromate (drinking water) (Ivankovic and Preussmann, 1975; MacKenzie et al., 1958).

The respiratory and dermal toxicity of chromium are well-documented. Workers exposed to chromium have developed nasal irritation (at <0.01 mg/m³, acute exposure), nasal ulcers, perforation of the nasal septum (at ~2 µg/m³, subchronic or chronic exposure) (Hamilton and Wetterhahn, 1988; ATSDR, 1989; Lindberg and Hedenstierna, 1983) and hypersensitivity reactions and "chrome holes" of the skin (Pedersen, 1982; Burrows, 1983; U.S Air Force, 1990). Among the general population, contact dermatitis has been associated with the use of bleaches and detergents (Love, 1983).

Compounds of both Cr(VI) and Cr(III) have induced developmental effects in experimental animals that include neural tube defects, malformations, and fetal deaths (Iijima et al., 1983; Danielsson et al., 1982; Matsumoto et al., 1976).

The subchronic and chronic oral RfD value is 1 mg/kg/day for Cr(III). The subchronic and chronic oral RfD for Cr (VI) are 0.02 and 0.005 mg/kg/day, respectively (U.S. EPA, 1991a,b; 1992). The subchronic and chronic oral RfD values for Cr(VI) and Cr(III) are derived from no-observed-adverse-effect levels (NOAELs) of 1.47 g/kg Cr(III)/day and 25 ppm of potassium dichromate (Cr[VI]) in drinking water, respectively (Ivankovic and Preussmann, 1975; MacKenzie et al., 1958). The inhalation RfC values for both Cr(III) and Cr(VI) are currently under review by an EPA workgroup.

The inhalation of chromium compounds has been associated with the development of cancer in workers in the chromate industry. The relative risk for developing lung cancer has been calculated to be as much as 30 times that of controls (Hayes, 1982; Leonard and Lauwerys, 1980; Langard, 1983). There is also evidence for an increased risk of developing nasal, pharyngeal, and gastrointestinal carcinomas (Hamilton and Wetterhahn, 1988). Quantitative epidemiological data were obtained by Mancuso and Hueper (1951), who observed an increase in deaths (18.2%; p<0.01) from respiratory cancer among chromate workers compared with 1.2% deaths among controls. In a follow-up study, conducted when more than 50% of the cohort had died, the observed incidence for lung cancer deaths had increased to approximately 60% (Mancuso, 1975). The workers were exposed to 1-8 mg/m³/year total chromium. Mancuso (1975) observed a dose response for total chromium exposure and attributed the lung cancer deaths to exposure to insoluble [Cr(III)], soluble [Cr(VI)], and total chromium. The results of inhalation studies in animals have been equivocal or negative (Nettesheim et al., 1971; Glaser et al, 1986; Baetjer et al., 1959; Steffee and Baetjer, 1965).

Based on sufficient evidence for humans and animals, Cr(VI) has been placed in the EPA weight-of-evidence classification A, human carcinogen (U.S. EPA, 1991a). For inhalation exposure, the unit risk value is 1.2E-2 (µg/m³)^-1 and the slope factor is 4.1E+01 (mg/kg/day)^-1 (U.S. EPA, 1991a).

1. INTRODUCTION

Elemental chromium (Cr) (CAS No. 7440-47-3) has an atomic weight of 51.996, a density of 7.2 g/mL at 28C, a melting point of 1857 20C, a vapor pressure of 1 mm Hg at 1610C, and is insoluble in water (Weast et al., 1988-1989). Elemental chromium does not occur in nature, but is present in ores, primarily chromite (FeOCr₂O₃) (Hamilton and Wetterhahn, 1988). Chromium can exist in several oxidation states, but only two of them, Cr(III) and Cr(VI), are considered in this report because of their predominance and stability in the ambient environment and their toxicological characteristics. Cr(III) results from the weathering of minerals and is the most stable state of environmental chromium. Cr(VI) in the environment is man-made, the result of contamination by industrial emissions (WHO, 1984; Hertel, 1986), and is the more toxic (U.S. EPA, 1984b). Examples of Cr(III) compounds include chromium acetate, chromium chloride, chromic oxide, and chromium sulfate; examples of Cr(VI) compounds include ammonium chromate, calcium chromate, potassium chromate, potassium dichromate, and sodium chromate (U.S. Air Force, 1990).

Chromium plays a role in glucose and cholesterol metabolism and is thus essential to man and animals (Schroeder et al., 1962). Reference values for chromium vary, but one source estimates a level of 70 ng/dL for whole blood [this includes Cr(VI) bound to red blood cells] and 14 ng/dL for serum (Tietz, 1986). The major non-occupational source of chromium for animals and humans is food, such as vegetables, meat, unrefined sugar, fish, vegetable oil, and fruits (Hertel, 1986; U.S. Air Force, 1990; U.S. EPA, 1984b). Other potential non-occupational sources include urban air, hip or knee prostheses, and cigarettes (U.S. EPA, 1984b).

Workers are exposed to chromium during its use in (1) the production of dichromate, (2) the chemical, stainless-steel, refractory and chromium-plating industries, and (3) the production and use of alloys (Langard and Norseth, 1986). Workers in the chromate industry encounter both Cr(III) and Cr(VI) (U.S. EPA, 1984). Chromium (III) concentrations in tanning facilities have been estimated at 10-50 µg/m³; the average concentration of Cr(VI) in fumes and dust of the various industries ranged from 5 to 1000 µg/m³ (Stern, 1982). Ten- to forty-fold reductions in Cr(VI) concentrations have been reported in modern chrome plating plants (Stern, 1982).

Chromium enters the body through the lungs, gastrointestinal tract and, to a lesser extent, the skin (Hamilton and Wetterhahn, 1988). Inhalation is the most important route for occupational exposure (Hertel, 1986). Although overt signs of chromium toxicity (e.g. perforation of the nasal septum, skin ulcers, and liver and kidney damage) are rarely seen today, some workers are still exposed to toxic concentrations of the metal (Hamilton and Wetterhahn, 1988). Non-occupational exposure occurs via the ingestion of chromium-containing food and water (Langard, 1982; Pedersen, 1982).

In the environment, Cr(III) is generally immobile in soil and is not very toxic to plants and animals (Kabata-Pendias and Pendias, 1984), whereas Cr(VI) is both mobile and toxic. Chromium (VI) in solution exists as hydrochromate (HCrO₄^-), chromate (CrO₄^2-), and dichromate (Cr₂O₇^2-) ionic species (U.S. EPA, 1984a) and reacts over time to form Cr(III) (U.S. EPA, 1984b).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

Chromium(III) and chromium(VI) exhibit different absorption characteristics. Chromium(III) is poorly absorbed, regardless of route of exposure, whereas chromium(VI) is more readily absorbed (Hamilton and Wetterhahn, 1988). In one study, for example, animals absorbed approximately 10% of an orally administered dose of Cr(VI), but less than 0.5% of the orally administered Cr(III) (Langard, 1982); therefore, the reduction of Cr(VI) to Cr(III) (which can occur in the stomach) may result in decreased absorption. In another study, humans and rats absorbed approximately 2% of the chromium that was administered orally as Na₂⁵¹CrO₄ and measured in the urine (humans) and feces (rat) as ⁵¹Cr (Donaldson and Barreras 1966). However, when Na₂⁵¹CrO₄ was administered intraduodenally and intrajejunally, absorption of the administered dose was 50% in humans and 25% in animals.

The detection of chromium in the urine, serum, and red blood cells (RBC) of humans exposed in the workplace suggests that the metal is absorbed following inhalation exposure. Limited experimental data indicate that water-soluble inhaled Cr(VI) is absorbed rapidly (Langard et al., 1978). Rats exposed to 7.35 mg/m³ of zinc chromate dust for 1, 100, 250 and 350 minutes had chromium levels in the blood of 0.007, 0.024, 0.22, and 0.31 µg/mL, respectively. Animals were also exposed to the same concentration of zinc chromate 6 hours/day for 4 days and blood levels were measured at the end of each day. Blood chromium levels peaked at the end of the second exposure and began to decline at the end of the third exposure.

Both Cr(VI) and Cr(III) compounds can be absorbed by the skin, but the degree of absorption is apparently determined by valence state, anionic form and concentration and pH of the solution (U.S. EPA, 1984c).

2.2. DISTRIBUTION

Humans and animals exhibit similar patterns of distribution for chromium. Workers exposed to chromium by inhalation had levels of the metal in the lung, liver, kidney, and adrenals that were 300-fold, 2- to 4-fold, 10-fold, and 10- to 50-fold higher, respectively, than those in of controls (Langard, 1982). Workers also exhibit elevated chromium levels in the urine, serum [Cr(III) and Cr(VI)] and RBC [Cr(VI) only] (ATSDR, 1989). Animals exposed by intratracheal or intravenous injection distributed both Cr(III) and Cr(VI) throughout the body, but mainly to the lungs, spleen, bone marrow, liver, and kidney (Bragt and van Dura, 1983; Hamilton and Wetterhahn, 1988).

Chromium (given in drinking water to rats for one year as potassium chromate or chromic chloride and to dogs for 4 years as potassium chromate) was distributed to the bone (rat only), liver, kidney, and spleen (MacKenzie et al. 1958; Anwar et al., 1961). Other studies have demonstrated higher tissue levels in animals receiving Cr(VI) in the drinking water than those receiving Cr(III) (ATSDR, 1989).

2.3. METABOLISM

Chromium is not biotransformed, but Cr(VI) undergoes enzymatic reduction, resulting in the formation of reactive intermediates and Cr(III) (Hamilton and Wetterhahn, 1988). In vitro and under physiologic conditions, ascorbic acid, the thiols, glutathione, cysteine, cysteamine, lipoic acid, coenzyme A, and coenzyme M reduce Cr(VI) at a significant rate (Hamilton and Wetterhahn, 1988). The in vitro reaction of Cr(VI) with glutathione results in the formation of a Cr(V) intermediate that is possibly the form that interacts with cellular macromolecules (Jennette, 1982). DT-diaphorase is a major cytosolic enzyme involved in Cr(VI) reduction (DeFlora et al., 1985). The NADPH-dependent Cr(VI) reductase activity of rat liver microsomes has been attributed to cytochrome P-450, whereas the Cr(VI) reductase activity of rat liver mitochondria is attributed to NADH-ubiquinone oxidoreductase (complex I) (Hamilton and Wetterhahn, 1988).

2.4. EXCRETION

The main routes for the excretion of chromium are via the kidneys/urine and the bile/feces; minor routes include milk, sweat, hair, and nails (Guthrie, 1982; Langard, 1982). Studies in humans and/or animals have shown that chromium administered orally or intravenously is excreted principally in the urine, whereas chromium administered by inhalation or intratracheal injection is excreted in both the urine and the feces (Love 1983; Hamilton and Wetterhahn, 1988).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1. ORAL EXPOSURES

3.1.1. Acute Toxicity

3.1.1.1. Human

For humans, the estimated lowest lethal dose is 71 mg/kg for chromium (oxidation state not identified) (Sax and Lewis, 1989) and 1-5 g for unspecified Cr(VI) compounds (Leonard and Lauwerys, 1980; Langard and Norseth, 1986).

3.1.1.2. Animal

Oral LD₅₀ values for Cr(VI) compounds range from 54 mg/kg for ammonium dichromate in the rat (Gad et al., 1986) to 300 mg/kg for potassium chromate in the mouse (Shindo et al., 1989). Oral LD₅₀ values for Cr(III) and Cr(II) compounds in the rat are 11.26 g/kg (chromic acetate) and 1.87 mg/kg (chromous chloride), respectively (Smyth et al., 1969). Animals given lethal doses of sodium chromates, potassium dichromate, or ammonium dichromate exhibited hypoactivity, lacrimation, mydriasis, diarrhea, changes in body weight, pulmonary congestion, fluid in the stomach and intestine, and erosion and discoloration of the gastrointestinal mucosa (Gad et al., 1986). Lethal doses of chromium trioxide produce cyanosis, tail necrosis, diarrhea, and gastric ulcers (Kobayashi, 1976). Because the gastrointestinal absorption of chromium is poor, the oral toxicity of the metal has been attributed to other than systemic poisoning, e.g. gastrointestinal bleeding (Hamilton and Wetterhahn, 1988).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Information on the subchronic toxicity of chromium following oral exposure in humans was unavailable.

3.1.2.2. Animal

In one study, BD rats received 2 or 5% chromic oxide [Cr(III)] in the diet for 90 days (total doses, 72-75 g/kg or 160-170 g/kg) (Ivankovic and Preussmann, 1975). Food consumption and body weight were monitored and serum protein, bilirubin, hematology, urinalysis, organ weights, and histopathology were evaluated. Other than 12-37% reductions in the absolute weights of the livers and spleens at the higher dose, no adverse effects were observed.

In another study, MacKenzie et al. (1958) administered 0-25 ppm of Cr(III) (as chromic chloride) or Cr(VI) (as potassium dichromate) in drinking water to groups of male and female rats for one year, and saw no effect on body weight, gross external condition, histopathology, and blood chemistry at any dose. Microscopic examination revealed accumulations of chromium in the liver, kidneys, bone, and spleen (MacKenzie et al., 1958). The No Adverse Effect Level (NOAEL) of 25 ppm was used to calculate the chronic and subchronic oral RfD values for Cr(VI) (U.S. EPA, 1991a).

3.1.3. Chronic Toxicity

3.1.3.1. Human

Information on the chronic toxicity of chromium following oral exposure in humans was unavailable.

3.1.3.2. Animal

Animals appear to tolerate long-term oral treatment with chromium. Ivankovic and Preussmann (1975) conducted a feeding study in which male and female rats were fed chromic oxide [Cr(III)] baked in bread at levels of 0, 1, 2, or 5%, 5 days/week for 600 feedings (over 840 days). The total doses given were 360, 720, and 1800 g/kg body weight. After termination of exposure, animals that died or were killed when moribund were examined for microscopic lesions. The investigators did not mention other specific toxicologic parameters, but did report that adverse effects were not observed in any of the groups. The U.S. EPA (1991b) selected the 5% level as the no-observed-effect level (NOEL) to be used in the derivation of a chronic oral RfD.

Dogs (2/group) were not adversely affected by exposure to 0, 0.45, 2.25, 4.5, 6.75, and 11.2 ppm potassium chromate in the drinking water for 4 years (Anwar et al., 1961). The toxicologic evaluation consisted of gross and microscopic analysis of all major organs, urinalysis, and weights of spleen, liver and kidney. Assuming an average water consumption for the dog of 0.0275 L/kg/day, the U.S. EPA (1984a) converted the highest dose tested, 11.2 ppm, to the NOEL of 0.31 mg potassium chromate/kg/day [0.089 mg Cr(VI)/kg/day].

3.1.4. Developmental and Reproductive Toxicity

3.1.4.1. Human

Information on the developmental or reproductive toxicity of chromium following oral exposure in humans was unavailable.

3.1.4.2. Animal

As part of a 90-day feeding study, male and female BD rats received 2% or 5% chromium oxide 5 days/week (Ivankovic and Preussmann, 1975). During the last 30 days of treatment, males and females from each treatment group were paired for a developmental toxicity assay. All females became pregnant, the gestation period was normal, and the young had no malformations or other adverse effects. One group of progeny, observed for 600 days, developed no tumors. The investigators concluded that no toxic or teratogenic effects resulted from treatment of both males and females with chromium oxide prior to and throughout the gestation period. No other information on the developmental or reproductive toxicity of chromium following oral exposure in animals was available.

3.1.5. Reference Dose

3.1.5.1. Subchronic

3.1.5.1.1. Chromium(III)

ORAL RfD: 1.0 mg/kg/day (as an insoluble salt) (U.S. EPA, 1991b)
UNCERTAINTY FACTOR: 100
NOAEL: 5% Cr₂O₃ in diet 5 days/week for 90 days (1468 mg/kg Cr(III)/day)
COMMENT: The principal study (Ivankovic and Preussmann, 1975) is the same for the subchronic and chronic RfD and is described in section 3.1.3.2.

3.1.5.1.2. Chromium(VI)

ORAL RfD: 0.02 mg/kg/day (U.S. EPA, 1991b)
UNCERTAINTY FACTOR: 100
NOAEL: 25 ppm (mg/L) of chromium as K₂CrO₄ converted to 2.4 mg of Cr(VI)/kg/day.
COMMENT: The principal study (MacKenzie et al., 1958) is the same for the subchronic and chronic RfD and is described in section 3.1.2.2.

3.1.5.2. Chronic

3.1.5.2.1. Chromium(III)

ORAL RfD: 1.0 mg/kg/day (as an insoluble salt) (U.S. EPA, 1991c)
UNCERTAINTY FACTOR: 1000
NOEL: 5% Cr₂O₃ in diet 5 days/week for 600 feedings (1800 g/kg b.w. average total dose; 1468 mg/kg Cr(III)/day)
CONFIDENCE: Study: Low Data Base: Low RfD: Low
VERIFICATION DATE: 11/21/85
PRINCIPAL STUDY: Ivankovic and Preussmann, 1975
COMMENTS: The NOEL was based on no effects reported at the highest dose tested in a one year feeding study in rats. The RfD is limited to metallic Cr(III) of soluble salts (U.S. EPA, 1991c). The uncertainty factor of 1000 reflects a factor of 10 to account for interspecies variability, a factor of 10 for interhuman variability in the toxicity of the chemical in lieu of specific data, and an additional modifying factor of 10 for uncertainty in the NOEL.

3.1.5.2.2. Chromium(VI)

ORAL RfD: 0.005 mg/kg/day (U.S. EPA, 1991a)
UNCERTAINTY FACTOR: 500
NOAEL: 25 mg/L of chromium as K₂CrO₄ for one year, converted to 2.4 mg of Cr(VI)/kg/day.
CONFIDENCE: Study: Low Data Base: Low RfD: Low
VERIFICATION DATE: 02/05/86
PRINCIPAL STUDY: MacKenzie et al., 1958
COMMENTS: The NOAEL was based on no effects reported at the highest dose tested in a one year drinking water study in rats. The RfD is limited to metallic Cr(VI) of soluble salts (U.S. EPA, 1991). The calculation assumed drinking water consumption of 0.097 L/kg/day. The uncertainty factor of 500 reflects a factor of 10 to account for interspecies variability and a factor of 10 for interhuman 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 study (U.S. EPA, 1991a).

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

Estimated LC₅₀ values for humans range from 5 mg/m³ for zinc chromate [Cr(VI)] (Sax and Lewis, 1989) to 94 mg/m³ for potassium dichromate [Cr(VI)] (Gad et al., 1986). The inhalation of chromium can cause nasal ulcers and perforation of the nasal septum (Hamilton and Wetterhahn, 1988). The perforation lesions do not disappear when exposure ceases. Nasal irritation has been observed following short-term exposure to chromium levels of <0.01 mg/m³ (ATSDR, 1989).

3.2.1.2. Animal

The estimated LC₅₀ values (mg/m³) in the Sprague Dawley rat (males and females combined) exposed to Cr(VI) compounds are: 158 for ammonium dichromate, 104 for sodium chromate, 124 for sodium dichromate, and 94 for potassium dichromate (Gad et al., 1986). Clinical signs of toxicity include respiratory distress and irritation and body weight loss (Gad et al., 1986). Lethality data were not found for Cr(III) compounds.

3.2.2. Subchronic Toxicity

3.2.2.1. Human

The respiratory tract is the target of subchronic inhalation exposure to chromium compounds. In one study, chromeplaters exposed to hot chromic acid concentrations <1.4 mg/m³ for less than one year exhibited various symptoms including simple scarring and perforation of the nasal septum, dental lesions, coughing and expectoration, sneezing, and nasal irritation (Gomes, 1972).

3.2.2.2. Animal

Johansson et al. (1986a, 1986b) exposed rabbits to aerosols of sodium chromate [0.9 mg of Cr(VI)/m³] or chromium nitrate [0.6 mg of Cr(III)/m³], 6 hours/day, 5 days/week for 4-6 weeks and examined the lungs and pulmonary macrophages for adverse effects. Neither compound affected lung morphology, but macrophages in both groups were enlarged, multinucleated, or vacuolated, and accumulated in intraalveolar or intrabronchiolar spaces as nodules ("naked" granulomas). In addition to producing morphological changes, the chromium nitrate also reduced the phagocytic activity of the cells.

Immunological effects have been noted following subchronic exposure to chromium compounds. In rats, 0.2 mg/m³ Cr(VI) (90-days continuous exposure) depressed the activity of alveolar macrophages and the humoral immune response, whereas <=0.1 mg/m³ Cr(VI) stimulated phagocytic activity of the alveolar macrophages and increased the humoral immune response (Glaser et al., 1985).

Nettesheim et al. (1971) reported rapid weight loss, fatty liver, distended and atrophic intestines, and early death in C57Bl/6 mice exposed to calcium chromate concentrations of 30 mg/m³. The study was preliminary and exposure duration was described only as "subchronic".

3.2.3. Chronic Toxicity

3.2.3.1. Human

Long-term exposure to chromium produced various effects in workers in the chromium industry. For example, nine chromeplaters exposed to chromic acid concentrations of 0.18 to 1.4 mg/m³ for 0.5-12 months, had upper respiratory tract lesions that ranged from nasal itching and soreness to septal ulcerations and perforations (Kleinfeld and Rosso, 1965). Thirty-five of thirty-seven chromeplaters, engaged in using the hot chromic acid process for 0.3 months to 11 years and exposed to air concentrations of 7.1 µg total Cr/m³ and 2.9 µg Cr(VI)/m³, developed nasal lesions that ranged from shallow erosions to frank perforations (Cohen et al., 1974). Forty-three Swedish chrome-plating workers, exposed to chromic acid [Cr(VI)] for a median of 2.5 years, were examined for respiratory symptoms (Lindberg and Hedenstierna, 1983). A dose-response was observed for nasal symptoms. Workers exposed to concentrations of <1-2 µg/m³ (8-hour mean) complained of runny nose and stuffy nose (p<0.05); workers exposed to >2 µg/m³ suffered ulceration and perforation of the nasal mucosa.

3.2.3.2. Animal

Nettesheim et al. (1971) exposed C57Bl/6 mice to calcium chromate dust concentrations of 13 mg/m³ [4.33 mg Cr(VI)/m³, as calculated by U.S. EPA (1984)] 5 hours/day, 5 days/week for the lifetime of the animals. Sizes of 99% of the calcium chromate particles averaged <=1.0 micron. Toxicity in the animals, as evidenced by decreased body weight gain, was observed after 6 months of exposure. Other non-carcinogenic effects observed in animals exposed for 6 months or longer included marked hyperplasia, necrosis, and atrophy of the bronchial epithelium; bronchiolization of alveoli (growth of the bronchial epithelium into alveoli); proteinosis of terminal bronchioli and alveoli (emphysema-like changes); extreme dilation of alveolar ducts and disruption of alveolar membranes; atrophy of spleen and liver; and enlargement, followed by atrophy of the lymph nodes (particularly tracheal and submandibular).

In other studies: (1) rats and rabbits exposed to 3 to 4 mg/m³ of potassium dichromate [Cr(VI)] and sodium chromate [Cr(VI)] 4 hours/day, 5 days/week for life developed nasal perforations and foreign-body type inflammation of the lung, but did not develop systemic effects (Stefee and Baetjer, 1965); (2) Wistar rats, exposed continuously to 100 µg Cr/m³ [Cr(III) and Cr(VI)] as chromium oxide for 18 months, exhibited a slight increase in white blood cells, and significant increases in red blood cell, hemoglobin and hematocrit values (Glaser et al., 1986); and (3) rats and hamsters exposed to calcium chromate aerosol levels of 2 mg/m³ (0.67 mg Cr(VI)/m³) for 589 days over a period of 891 days had laryngeal hyperplasias and metaplasias (Laskin et al., 1972). Non-specific effects of inhalation exposure to Cr(III) and Cr(VI) included pneumonia in mice and "nuisance dust reaction" in rats (Baetjer et al., 1959; Lee et al. 1988).

3.2.4. Developmental and Reproductive Toxicity

Information on the developmental or reproductive toxicity of chromium following inhalation exposure in humans and animals was unavailable.

3.2.5. Reference Concentration

The inhalation RfC values for both Cr(III) and Cr(VI) are currently under review by an EPA workgroup.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Dermal exposure to chromium compounds can induce contact dermatitis or the formation of lesions that, without treatment, can develop into deep ulcers or "chrome holes". The chrome holes usually heal when exposure ceases (Pedersen, 1982; Burrows, 1983).

3.3.1.2. Animal

LD₅₀ values (mg/kg) for chromium compounds applied to the skin of New Zealand rabbits (male and female combined) are 1.64 for ammonium dichromate, 1.6 for sodium chromate, 1.00 for sodium dichromate, and 1.7 for potassium dichromate (Gad et al., 1986). Lethal doses of these chemicals produced dermal necrosis, corrosion, edema and erythema; eschar formation; diarrhea; and hypoactivity. Non-lethal doses of the dichromates were also tested for corrosion and irritation potential. Based on a four-hour exposure time and a 48-hour observation period, the chemicals, in the dry solid form, were not corrosive, but sodium dichromate and ammonium dichromate caused erythema in some animals. When moistened with saline, the chemicals were not corrosive but all were irritating.

Dermal hypersensitivity reactions are elicited by both Cr(III) and Cr(VI) compounds (U.S. Air Force, 1990). For example, Schwarz-Speck and Grundmann (1972) induced hypersensitivity in the guinea pig with chromium sulfate ([Cr(III)] dissolved in Triton X-100 and with potassium dichromate [Cr(VI)] in an aqueous solution and in the BALB/c and ICR mice with potassium dichromate in dimethyl sulfoxide (Mor et al., 1988). BALB/c mice treated with potassium dichromate in Triton X-100 or methanol did not develop hypersensitivity (Mor et al., 1988).

For injected trivalent and hexavalent chromium compounds, the kidney is the main target for toxicity (U.S. EPA, 1984b). Gumbleton and Nicholls (1988) examined the effect of single subcutaneous doses of potassium dichromate on the release of tissue enzymes into the urine, an early and sensitive indicator of renal toxicity. The enzyme assays were conducted 52-727 hours after injection. There was no effect on the enzymes at 6 mg/kg. At doses of 10, 15, and 20 mg/kg, excretion rates for the cytosolic and lysosomal enzymes (aspartate aminotransferase and lactate dehydrogenase) and the lysosomal enzyme (N-acetyl-ß-D-glucosamidase) were increased while brush border enzymes (-glutamyl transferase, alkaline phosphatase, and leucine aminopeptidase) were unchanged. The enzyme changes were accompanied by dose-related necrosis of the proximal tubules in the outer cortex of the kidney and loss of alkaline phosphatase from the outer cortex of the kidney. Necrosis of the inner cortex of the kidney and loss of alkaline phosphatase from that tissue were observed at the highest dose. The effects appeared to be transient.

3.3.2. Subchronic Toxicity

Information on the subchronic toxicity of chromium by other routes of exposure in humans and animals was unavailable.

3.3.3. Chronic Toxicity

Information on the chronic toxicity of chromium by other routes of exposure in humans and animals was unavailable.

3.3.4. Developmental and Reproductive Toxicity

3.3.4.1. Human

Information on the developmental or reproductive toxicity of chromium by other routes of exposure in humans was unavailable.

3.3.4.2. Animal

Danielsson et al. (1982) reported that radioactive sodium dichromate [Cr(VI)], injected into pregnant mice was more efficiently taken up by the fetus than radioactive chromic chloride [Cr(III)]. Nevertheless, compounds of both Cr(VI) and Cr(III) have induced developmental effects in experimental animals. In one study, for example, one noninbred and two inbred strains of hamsters injected intravenously with 5 mg/kg of chromium trioxide [Cr(VI)] on day 8 of gestation and sacrificed on day 15 exhibited cleft palate and external malformations that included edema, omphalocele, tail bud abnormalities and encephalocele. The noninbred strain also had increased resorptions and hydrocephalus.

In another study, Matsumoto et al. (1976) administered 19.5 mg Cr/kg as chromic chloride [Cr(III)] to pregnant mice by subcutaneous injection on days 7, 8, or 9 of gestation and examined the fetuses on day 18. The highest frequency of fetal deaths occurred with the day 9 injection and the highest number of malformations (exencephaly, open eyelids, cleft palate, and fused ribs) occurred with the day 8 injection. Further studies (injection on day 8 of gestation) demonstrated a dose response for the effects. No significant fetal effects were noted with 9.76 mg Cr/kg administered as chromic chloride every other day from day 0 to day 16 of gestation.

Iijima et al. (1983) administered 19.5 mg Cr/kg as chromic chloride [Cr(III)] to pregnant mice by intraperitoneal injection on day 8 of gestation and observed pyknosis within the neuroepithelium and defects in the neural tube 8 and 24 hours, respectively, after injection.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

3.4.1.1. Primary Target Organs

The poor gastrointestinal absorption of chromium and its low oral toxicity preclude the identification of primary target organs/critical effects.

3.4.1.2. Secondary Target Organs

Gastrointestinal system: Animals exposed to very high doses acute of chromium exhibit diarrhea, gastric ulcers, and discoloration and erosion of the gastric mucosa, most likely local, rather than systemic effects.

3.4.2. Inhalation Exposures

3.4.2.1. Primary Target Organs

The primary target organ for the subchronic/chronic toxicity of chromium is the respiratory system as evidenced by various symptoms in humans that range from irritation of the respiratory tract to perforation of the nasal septum and symptoms in animals that include severe bronchiolar and alveolar damage.

3.4.2.2. Other Target Organs

Immune system: In rats, accumulations of alveolar macrophages formed "naked granulomas" in the bronchioles and alveoli of rabbits. In rats the activity of alveolar macrophages and the humoral immune response were depressed, whereas phagocytic activity of the alveolar macrophages and the humoral immune response were increased.
Spleen and liver: Mice exhibited atrophy of the spleen and liver.

3.4.3. Other Routes of Exposure

3.4.3.1. Primary Target Organs

Skin: Acute dermal toxicity is characterized by dermatitis and the formation of "chrome holes" in humans and by dermatitis and dermal hypersensitivity in animals.
Fetus: Compounds of both Cr(III) and Cr(VI), injected into pregnant animals, induced fetal toxicity and fetal malformations.

3.4.3.2. Other Target Organs

Kidney: Injection of Cr(VI) caused renal enzyme changes and necrosis.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Information on the carcinogenicity of chromium by oral exposure in humans was unavailable.

4.1.2. Animal

Chromium was not carcinogenic in Sprague-Dawley rats exposed to 25 ppm of potassium chromate [Cr(VI)] and chromic chloride [Cr(III)] in their drinking water for one year (MacKenzie et al., 1958), or in male or female BD rats exposed to 5% chromic oxide [Cr(III)] in food 5 days/week for over 2 years (total dose, 1800 g/kg body weight) (Ivankovic and Preussmann, 1975).

4.2. INHALATION EXPOSURES

4.2.1. Human

Workers occupationally exposed to chromium are considered to be at risk for developing lung cancer (Hayes, 1982; Leonard and Lauwerys, 1980; Langard, 1983; Mackison et al. 1981; Mancuso and Hueper, 1951; Mancuso, 1975; Sano and Mitohara, 1978). The relative risk for developing lung cancer has been calculated to be up to 30 times that of controls (Hayes, 1982; Leonard and Lauwerys, 1980; Langard, 1983). There is also evidence for an increased risk of developing nasal, pharyngeal, and gastrointestinal carcinomas (Hamilton and Wetterhahn, 1988). Many of the early epidemiology studies failed to identify the specific etiologic agent [i.e. Cr(III) or Cr(VI)] (U.S. EPA, 1984b).

Mancuso and Hueper (1951) investigated lung cancer incidence in a cohort of workers employed for more than one year (from 1931-1949) in a chromate production plant. In the county where the plant was located, 34 of 2931 deaths (1.2%) of control males were due to respiratory cancer, whereas among the chromate workers, 6 of 33 deaths (18.2%; p<0.01) were due to respiratory cancer. Mancuso (1975) then followed 332 workers (employed from 1931-1951) until 1974, when more than 50% of the cohort had died. The workers were exposed to 1-8 mg/m³/year total chromium. Incidences for cancer deaths were 63.6% for men employed from 1931-1932, 62.5% for men employed from 1933-1934, and 58.3% for those employed from 1935-1937. Mancuso (1975) observed a dose response for total chromium exposure and attributed the lung cancer deaths to exposure to insoluble [Cr(III)], soluble [Cr(VI)], and total chromium. However, the U.S. EPA (1984b) questioned the correlation because of small sample number.

Studies of workers in the chrome pigment industry revealed a correlation between exposure to Cr(VI) and lung cancer (Langard and Norseth, 1975; Davies, 1978, 1979; Frentzel-Beyme, 1983). Studies from the chrome-plating industry either showed a correlation (Royle, 1975; U.S. EPA, 1984a) or were inconclusive (Silverstein et al., 1981; Okubo and Tsuchiya, 1979; U.S. EPA, 1984a) regarding lung cancer and exposure to chromium compounds. Studies of ferrochromium workers were also inconclusive regarding lung cancer risk (Pokrovskaya and Shabynina, 1973; Langard et al., 1980, 1990; Axelsson et al., 1980).

4.2.2. Animal

The results of inhalation studies in animals are equivocal regarding the carcinogenicity of chromium.

Nettesheim et al. (1971) observed an increase in the incidence of pulmonary adenomas and decreased tumor latency in C57Bl/6 mice exposed to 13 mg/m³ calcium chromate dust [4.33 mg Cr(VI)/m³, as calculated by U.S. EPA (1984)] 5 hours/day, 5 days/week for life. Ninety-nine percent of the calcium chromate particles were <=1.0 micron. Early mortality among the unexposed controls may have affected cumulative tumor incidence, but examination of groups of animals dying of lung tumors at subsequent 10-week periods revealed that at 60-70 and 70-80 weeks (approximately 30 animals/group), none of the unexposed mice died with lung tumors, whereas 5 and >6%, respectively, of the exposed mice died with lung tumors (animal numbers not clear). The significance of the study was questioned because statistical analysis was not performed (U.S. EPA, 1984a). IARC (1980) concluded that the study did not show a significant increase in treatment-related tumors.

Glaser et al. (1986) observed "weak" tumor responses in groups of 20 rats exposed for 18 months to 100 µg/m³ sodium dichromate dust (3 lung tumors) or to the slightly soluble chromium oxide containing both Cr(VI) and Cr(III) in a ratio of 3:2 (1 lung tumor). Lee et al. (1988) described a unique tumor in the lungs of rats exposed to 0.54-22 mg/m³ of chromium dioxide [Cr(IV)] 6 hours/day, 5 days/week for 2 years. The tumor (in 2/108 females, but not in males) was described as a cystic keratinizing squamous cell carcinoma. The investigators indicated that the tumors were devoid of characteristics of true malignancy and have negligible relevance to man.

In other studies, mice and rats exposed to mixed chromate dust (~1 mg/m³) containing both Cr(III) and Cr(VI) did not develop tumors (Baetjer et al., 1959); and neither did rabbits, guinea pigs or rats exposed, 4-5 hours/day, 1 to 2 times/week for life, to various mixes of chromate dust either with or without chromate mist (Steffee and Baetjer, 1965).

4.3. OTHER ROUTES OF EXPOSURE

Chromium(VI) induces cancer in experimental animals at some sites of exposure, whereas chromium(III) does not. Chromium(VI) induced tumors (1) at the site of intrapleural implantation as calcium chromate (Hueper and Payne, 1962), (2) at the site of intrabronchial implantation as strontium, calcium, or zinc chromate (Levy and Martin, 1983), and (3) in the rat lung following intratracheal injection of sodium chromate and calcium chromate (Steinhoff et al., 1983). However, there is no evidence in humans and little evidence in animals that skin cancer is induced by topical application of chromium (Hayes, 1982; Leonard and Lauwerys, 1980; Langard, 1983).

4.4. EPA WEIGHT-OF-EVIDENCE

4.4.1. Chromium(III)

Chromium(III) has not been evaluated by the U.S. EPA for evidence of human carcinogenic potential (U.S. EPA, 1991b).

4.4.2. Chromium(VI)

4.4.2.1. Oral

Not assigned.

4.4.2.2. Inhalation

Classification -- A; human carcinogen
Basis -- Sufficient evidence for humans and animals (U.S. EPA, 1991a). "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 chromium III and chromium VI compounds. However, because only chromium VI has been found to be carcinogenic in animals studies, it was concluded that only chromium(VI) should be classified as a human carcinogen" (U.S. EPA, 1991a).

4.5. CARCINOGENICITY SLOPE FACTORS [Chromium(VI)]

4.5.1. Oral

Not available.

4.5.2. Inhalation

SLOPE FACTOR: 4.1E+01 (mg/kg/day)^-1
INHALATION UNIT RISK: 1.2E-2 (µg/m³)^-1
PRINCIPAL STUDY: Mancuso, 1975
VERIFICATION DATE: 06/26/86, (U.S. EPA, 1991a)
COMMENT: Extrapolation method, multistage, extra risk (U.S. EPA, 1991a). Based on dose response data for inhalation carcinogenicity in humans (Mancuso, 1975).

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Last Updated 8/29/97