2. HEALTH EFFECTS

CHROMIUM 14

2. HEALTH EFFECTS

essential nutrient, exposure to high levels via inhalation, ingestion, or dermal contact may cause some

adverse health effects. Most of the studies on health effects discussed below involve exposure to

chromium(0), chromium(III), and chromium(VI) compounds. In addition, chromium(IV) was used in an

inhalation study to determine permissible exposure levels for workers involved in producing magnetic

tape (Lee et al. 1989).

Several factors should be considered when evaluating the toxicity of chromium compounds. The purity

and grade of the reagent used in the testing is an important factor. Both industrial- and reagent-grade

chromium(III) compounds can be contaminated with small amounts of chromium(VI) (Levis and Majone

1979). Thus, interpretation of occupational and animal studies that involve exposure to chromium(III)

compounds is difficult when the purity of the compounds is not known. In addition, it is difficult to

distinguish between the effects caused by chromium(VI) and those caused by chromium(III) since

chromium(VI) is rapidly reduced to chromium(III) after penetration of biological membranes and in the

gastric environment (Petrilli et al. 1986b; Samitz 1970). However, whereas chromium(VI) can readily be

transported into cells, chromium(III) is much less able to cross cell membranes. The reduction of

chromium(VI) to chromium(III) inside of cells may be an important mechanism for the toxicity of

chromium compounds, whereas the reduction of chromium(VI) to chromium(III) outside of cells is a

major mechanism of protection.

To help public health professionals and others address the needs of persons living or working near

hazardous waste sites, the information in this section is organized first by route of exposure (inhalation,

oral, and dermal) and then by health effect (death, systemic, immunological, neurological, reproductive,

developmental, genotoxic, and carcinogenic effects). These data are discussed in terms of three exposure

periods: acute (14 days or less), intermediate (15–364 days), and chronic (365 days or more).

Levels of significant exposure for each route and duration are presented in tables and illustrated in

figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or

lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the

studies. LOAELS have been classified into "less serious" or "serious" effects. "Serious" effects are those

that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory

distress or death). "Less serious" effects are those that are not expected to cause significant dysfunction

or death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a

CHROMIUM 15

2. HEALTH EFFECTS

considerable amount of judgment may be required in establishing whether an end point should be

classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be

insufficient data to decide whether the effect is indicative of significant dysfunction. However, the

Agency has established guidelines and policies that are used to classify these end points. ATSDR

believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between

"less serious" and "serious" effects. The distinction between "less serious" effects and "serious" effects is

considered to be important because it helps the users of the profiles to identify levels of exposure at which

major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not

the effects vary with dose and/or duration, and place into perspective the possible significance of these

effects to human health.

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and

figures may differ depending on the user's perspective. Public health officials and others concerned with

appropriate actions to take at hazardous waste sites may want information on levels of exposure

associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no

adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike.

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of chromium are

indicated in Table 2-1 and Figure 2-1. Because cancer effects could occur at lower exposure levels,

Figure 2-1 also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been

made for chromium. An MRL is defined as an estimate of daily human exposure to a substance that is

likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of

exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of

effect or the most sensitive health effect(s) for a specific duration within a given route of exposure.

MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can

be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes.

Appropriate methodology does not exist to develop MRLs for dermal exposure.

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990a),

uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional

CHROMIUM 16

2. HEALTH EFFECTS

uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an

example, acute inhalation MRLs may not be protective for health effects that are delayed in development

or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic

bronchitis. As these kinds of health effects data become available and methods to assess levels of

significant human exposure improve, these MRLs will be revised.

A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in

the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.

Due to the extremely high boiling point of chromium, gaseous chromium is rarely encountered. Rather,

chromium in the environment occurs as particle-bound chromium or chromium dissolved in droplets. As

discussed in this section, chromium(VI) trioxide (chromic acid) and soluble chromium(VI) salt aerosols

may produce different health effects than insoluble particulate compounds. For example, exposure to

chromium(VI) trioxide results in marked damage to the nasal mucosa and perforation of the nasal septum,

whereas exposure to insoluble(VI) compounds results in damage to the lower respiratory tract.

No studies were located regarding death in humans after acute inhalation of chromium or chromium

compounds. An increased risk of death from noncancer respiratory disease was reported in retrospective

mortality studies of workers in a chrome plating plant (Sorahan et al. 1987) and chromate production

(Davies et al. 1991; Taylor 1966) (see Section 2.2.1.2, Respiratory Effects). However, a number of

methodological deficiencies in these studies prevent the establishment of a definitive cause-effect

relationship. Retrospective mortality studies associating chromium exposure with cancer are discussed in

Section 2.2.1.8.

dichromate, potassium dichromate, and ammonium dichromate) ranged from 29 to 45 mg

rats, respectively (American Chrome and Chemicals 1989). Female rats were more sensitive than males

to the lethal effects of most chromium(VI) compounds except sodium chromate, which was equally toxic

CHROMIUM 17

2. HEALTH EFFECTS

in both sexes. Signs of toxicity included respiratory distress, irritation, and body weight depression (Gad

No studies were located regarding musculoskeletal effects in humans or animals after inhalation exposure

to chromium or its compounds. Respiratory, cardiovascular, gastrointestinal, hematological, hepatic,

renal, endocrine, dermal, ocular, and body weight effects are discussed below. The highest NOAEL

values and all reliable LOAEL values for each systemic effect in each species and duration category are

recorded in Table 2-1 and plotted in Figure 2-1.

chromium compounds. Chromate sensitive workers acutely exposed to chromium(VI) compounds may

develop asthma and other signs of respiratory distress. Five individuals who had a history of contact

dermatitis to chromium were exposed via a nebulizer to an aerosol containing 0.035 mg

chromium(VI)/mL as potassium dichromate. A 20% decrease in the forced expiratory volume of the

lungs was observed and was accompanied by erythema of the face, nasopharyngeal pruritus, nasal

blocking, coughing, and wheezing (Olaguibel and Basomba 1989).

Dyspnea, cough, and wheezing were reported in two cases in which the subjects inhaled "massive

amounts" of chromium(VI) trioxide. Marked hyperemia of the nasal mucosa without nasal septum

perforation was found in both subjects upon physical examination (Meyers 1950). In a chrome plating

plant where poor exhaust resulted in excessively high concentrations of chromium trioxide fumes,

workers experienced symptoms of sneezing, rhinorrhea, labored breathing, and a choking sensation when

they were working over the chromate tanks. All five of the subjects had thick nasal and postnasal

discharge and nasal septum ulceration or perforation after 2–3 months of exposure (Lieberman 1941).

Asthma developed in a man who had been well until one week after beginning employment as an

electroplater. When challenged with an inhalation exposure to a sample of chromium(III) sulfate, he

developed coughing, wheezing, and decreased forced expiratory volume. He also had a strong asthmatic

reaction to nickel sulfate (Novey et al. 1983). Thus, chromium-induced asthma may occur in some

sensitized individuals exposed to elevated concentrations of chromium in air, but the number of sensitized

individuals is low, and the number of potentially confounding variables in the chromium industry is high.

CHROMIUM 32

2. HEALTH EFFECTS

Intermediate- to chronic-duration occupational exposure to chromium(VI) may cause an increased risk of

death due to noncancer respiratory disease. In a retrospective mortality study of 1,288 male and 1,401

female workers employed for at least 6 months in a chrome plating and metal engineering plant in the

United Kingdom between 1946 and 1975, a statistically significant excess of death from diseases of the

respiratory system (noncancer) were obtained for men (observed/expected [O/E]=72/54.8, standard

mortality ratio [SMR]=131, p<0.05) and men and women combined (O/E=97/76.4, SMR=127, p<0.05)

but not for women alone. Exposure was mainly to chromium trioxide, but exposure concentrations were

not precisely known. The contribution of nickel exposure to the effects was found to be unimportant,

while data on smoking habits were not available (Sorahan et al. 1987). Similarly, a high SMR was found

for noncancer respiratory disease among 1,212 male chromate workers who were employed for at least

3 months in 3 chromate plants in the United States during the years 1937–1940 and followed for 24 years

(O/E=19/7.843, SMR=242) (Taylor 1966). The increased risk of death from respiratory effects correlated

with duration of employment in chromate production, but no information on exposure levels, smoking

habits, or exposure to other chemicals was provided. The nature of the respiratory diseases was not

further described in either of these reports. Chromate production workers in the United Kingdom who

were first employed before 1945 had a high risk of death from chronic obstructive airways disease

(O/E=41/28.66, SMR=143, p<0.05) (Davies et al. 1991). Exposure concentrations were not known, and

reliable smoking data were not available.

Occupational exposure to chromium(VI) as chromium trioxide in the electroplating industry caused upper

respiratory problems. A case history of nine men in a chrome plating facility reported seven cases of

nasal septum ulceration. Signs and symptoms included rhinorrhea, nasal itching and soreness, and

epistaxis. The men were exposed from 0.5 to 12 months to chromium trioxide at concentrations ranging

Paulo, Brazil, exposed to chromium trioxide vapors while working with hot chromium trioxide solutions

had frequent incidences of coughing, expectoration, nasal irritation, sneezing, rhinorrhea, and nose-bleed

and developed nasal septum ulceration and perforation. The workers had been employed for <1 year, and

and throat irritation, rhinorrhea, and nose-bleed also occurred at higher incidence in chrome platers in

Singapore than in controls (Lee and Goh 1988).

Numerous studies of workers chronically exposed to chromium(VI) compounds have reported nasal

septum perforation and other respiratory effects. Workers at an electroplating facility exposed to

CHROMIUM 33

2. HEALTH EFFECTS

excessive sneezing, rhinorrhea, and epistaxis. Many of the workers had ulcerations and/or perforations of

the nasal mucosa (Cohen et al. 1974). A study using only questionnaires, which were completed by 997

chrome platers and 1,117 controls, found a statistically significant increase in the incidence of chronic

rhinitis, rhinitis with bronchitis, and nasal ulcers and perforations in workers exposed to chromium(VI) in

the chrome plating industry in 54 plants compared to the control population (Royle 1975b). The workers

had been exposed to chromium(VI) in air and in dust. The air levels were generally <0.03 mg

levels at which effects first occurred could not be determined. A National Institute of Occupational

Safety and Health (NIOSH) Health Hazard Evaluation of an electroplating facility in the United States

reported nasal septum perforation in 4 of 11 workers employed for an average of 7.5 years and exposed to

nasal ulceration (Lucas and Kramkowski 1975). Nasal mucosal changes ranging from irritation to

perforation of the septum were found among 77 employees of 8 chromium electroplating facilities in

Czechoslovakia where the mean level in the breathing zone above the plating baths was 0.414 mg

ulcer, and nasal obstruction were observed in workers at chromium electroplating facilities exposed for a

mean duration of 6.1 years, as compared to workers at zinc electroplating facilities (Kuo et al. 1997a).

The chromium electroplating workers had 31.7 and 43.9 times greater risks of developing nasal septum

ulcers or nasal perforations, respectively, than the zinc workers. A significant relationship between

duration of exposure and the risk of nasal septum ulcers was also found; the chromium electroplating

workers with a work duration of greater than 9 years had a 30.8 times higher risk than those with a work

duration of less than 2 years. Duration did not significantly affect the risk of nasal perforation.

Statistically significant decreases in vital capacity, forced vital capacity, and forced expiratory volume in

one second were also observed in the chromium workers. Alterations in lung function were also reported

in a study of 44 workers at 17 chromium electroplating facilities (Bovet et al. 1977). Statistically

significant decreases in forced expiratory volume in 1 second and forced expiratory flow were observed;

vital capacity was not altered. Lower lung function values were found among workers with high urinary

chromium levels (exposure levels were not reported), and it was determined that cigarette smoking was

not a confounding variable.

A study of respiratory effects, lung function, and changes in the nasal mucosa in 43 chrome plating

workers in Sweden exposed to chromium(VI) as chromium trioxide for 0.2–23.6 years

(median=2.5 years) reported respiratory effects at occupational exposure levels of 0.002 mg

CHROMIUM 34

2. HEALTH EFFECTS

included a smeary and crusty septal mucosa and atrophied mucosa. Nasal mucosal ulceration and septal

mucosal atrophy and irritation occurred in individuals exposed at peak levels of 0.0025–0.011 mg

from exposure levels actually measured, but may have resulted from earlier exposure under unknown

conditions. Furthermore, poor personal hygiene practices resulting in transfer of chromium(VI) in

chrome plating solutions from the hands to the nose could contribute to the development of nasal

ulceration and perforation (Cohen et al. 1974; Lucas and Kramkowski 1975), perhaps leading to an

underestimation of airborne levels of chromium(VI) necessary to cause these effects. Despite these

considerations, the study by Lindberg and Hedenstierna (1983) is useful because it indicates

concentration-responses of chromium(VI) compounds that cause significant nasal and respiratory effects.

as chromium trioxide mists and other dissolved hexavalent chromium aerosols or mists as described in the

footnotes in Table 2-1.

Occupational exposure to chromium(VI) and/or chromium(III) in other chromium-related industries has

also been associated with respiratory effects. These industries include chromate and dichromate

production, stainless steel welding, and possibly ferrochromium production and chromite mining.

In a survey of a facility engaged in chromate production in Italy, where exposure concentrations were

sinusitis, pharyngitis, and bronchitis were found among 65 men who worked in the production of

dichromate and chromium trioxide for at least 1 year (Sassi 1956). In a study of 97 workers from a

chromate plant exposed to a mixture of insoluble chromite ore containing chromium(III) and soluble

chromium(VI) as sodium chromate and dichromate, evaluation for respiratory effects revealed that 63%

CHROMIUM 35

2. HEALTH EFFECTS

had perforations of the nasal septum, 86.6% had chemical rhinitis, 42.3% had chronic chemical

pharyngitis, 10.35% had laryngitis, and 12.1% had sinus, nasal, or laryngeal polyps. The number of

complaints and clinical signs increased as the exposure to respirable chromium(VI) and chromium(III)

compounds increased, but exposure levels at which effects first occurred were not clearly defined

(Mancuso 1951). An extensive survey to determine the health status of chromate workers in seven U.S.

chromate production plants found that effects on the lungs consisted of bilateral hilar enlargement.

Various manufacturing processes in the plants resulted in exposure of workers to chromite ore (mean

(including basic chromium sulfate), which may or may not entirely represent trivalent chromium

processes indicated that the asthma observed in two stainless steel welders was probably caused by

chromium or nickel, rather than by irritant gases (Keskinen et al. 1980). In a report of 10 cases of

pneumoconiosis in underground workers in chromite mines in South Africa, radiographic analysis

revealed fine nodulation and hilar shadows. Chromium in the chromite ore in South Africa was in the

form of chromium(III) oxide. The cause of the pneumoconiosis was considered to be deposition of

insoluble radio-opaque chromite dust in the tissues, rather than fibrosis (Sluis-Cremer and du Toit 1968).

In a case report of a death of a sandblaster in a ferrochromium department of an iron works, the cause of

death was silicosis, but autopsy also revealed diffuse enlargement of alveolar septae and chemical

interstitial and alveolar chronic pneumonia, which were attributed to inhalation of chromium(III) oxide

(Letterer 1939). In an industrial hygiene survey of 60 ferrochromium workers exposed to chromium(III)

of subjective symptoms of coughing, wheezing, and dyspnea were reported compared with controls.

These workers had been employed at the plant for at least 15 years. The control group consisted of

workers employed at the same plant for <5 years. Statistically significant decreased mean forced vital

capacity (p<0.01) and forced expiratory volume in 1 second (p<0.05) were found in the ferrochromium

workers compared with controls. Two of the ferrochromium workers had nasal septum perforations,

which were attributed to previous exposure to hexavalent chromium. A major limitation of this study is

that the control group was significantly younger than the study cohort. In addition, the weekly amount of

tobacco smoked by the control group was slightly greater than that smoked by the study groups, and the

controls began smoking 5 years earlier than the study groups. Therefore, the increase in subjective

respiratory symptoms and decreased pulmonary function parameters cannot unequivocally be attributed to

chromium exposure (Langård 1980). However, no increase in the prevalence of respiratory illness was

found in a study of 128 workers from two factories that produced chromium(III) oxide or chromium(III)

CHROMIUM 36

2. HEALTH EFFECTS

sulfate (Korallus et al. 1974b) or in 106 workers at a factory that produced these chromium(III)

results were reported in a cross sectional study that was conducted to determine whether occupational

exposure to trivalent chromium or hexavalent chromium caused respiratory diseases, decreases in

pulmonary function, or signs of pneumoconiosis in stainless steel production workers (Huvinen et al.

18 years. Spirometry measurements were taken and chest radiographic examinations were conducted.

There were no significant differences in the odds ratios between the exposed workers and the 95 workers

in the control group. The deficits in lung function shown in both populations could be explained by age

and smoking habits.

In many of the studies attributing respiratory effects to chromium exposure, actual levels of

chromium(VI) or chromium(III) to which workers were exposed over time were unknown. Furthermore,

information on the contribution of cigarette smoking, exposure to other hazardous chemicals, and

previous employment histories to the observed effects was often not available. A retrospective mortality

and morbidity study of 398 workers who had worked in a chromate production facility in North Carolina

for at least 1 year from 1971, when the facility began producing chromates, to 1989 was designed to

address these limitations. Personal air monitoring results, which were available for 1974–1989, revealed

8-hour time-weighted average (TWA) concentrations of chromium(VI) ranging from below the detection

Because personal air monitoring data were not available for the years 1971–1973, workroom area levels

were used to estimate the personal air levels for these years, which were included in the analysis of

personal air levels. Levels of chromium(III) or total chromium were not measured. Forty-five workers

also had previous occupational exposure to chromium at other chromate production facilities. Of the 45

workers with previous exposure, 42 had been employed at production facilities either in Painsville, Ohio,

or Kearny, New Jersey (the number from each of these facilities and the location of the plants at which

the other 3 workers had been employed were not reported). Industrial hygiene monitoring at the

facilities were not reported). For statistical comparisons, workers were classified as having high

cumulative exposure and low cumulative exposure. Workers responded to a questionnaire to determine

CHROMIUM 37

2. HEALTH EFFECTS

medical history, smoking history, detailed work history, and exposure to known chemicals and industrial

hazards. Of 289 workers who responded to the questionnaire, 40 reported at least 1 occurrence of nasal

lesions and 12 of nasal perforations. Statistical analysis revealed no increased risk of the nasal effects

associated with high cumulative exposure or duration of previous employment. However, those workers

with longer durations of employment at the facility and those who smoked were more likely to report

these effects. The authors suggested that workers in areas with higher concentrations might be more

likely to apply protective cream to the nasal septum and that smokers might be less likely to wear

respiratory protection and gloves. High cumulative exposure was not associated with increased risk of

chronic bronchitis, emphysema, shortness of breath, or chronic cough (Pastides et al. 1991).

An extensive epidemiological survey was conducted of housewives who lived in an area of Tokyo, Japan,

in which contamination from chromium slag at a construction site was discovered in 1973. The housewives

included in the study were those who lived in the area from 1978 to 1988, and controls included

housewives who lived in uncontaminated areas. Questionnaires, physical examinations, and clinical tests

were conducted annually. Chest x-rays and pulmonary function tests revealed no significant difference

between the exposed and the control populations. The exposed population reported a higher incidence of

subjective complaints of nasal irritation than the control population in the early years of the study, but in

later years the difference between the two groups became progressively less (Greater Tokyo Bureau of

Hygiene 1989).

The respiratory system in animals is also a primary target for inhalation exposure to chromium.

30 minutes revealed sporadic changes in activities of acid phosphatase and alkaline phosphatase in the

concentration. Histological examination revealed alterations representing mild nonspecific irritation but

no morphological damage (Henderson et al. 1979).

Rats exposed to sodium dichromate for 28 or 90 days had increased lung weight but no histopathological

challenge with iron oxide particles when compared to controls. The decreased clearance of iron oxide

CHROMIUM 38

2. HEALTH EFFECTS

correlated with the decrease in macrophage activity (Glaser et al. 1985). In a similar but more extensive

evidence of an irritation effect that was reversible (Glaser et al. 1990). The data from the Glaser et al.

(1990) study was used to develop benchmark concentrations (BMCs) (Malsch et al. 1994). The BMC of

exposure to chromium(VI) as particulate hexavalent compounds as described in the footnote of Table 2-1.

sodium chromate intermittently for 4–6 weeks, changes in the lungs were confined to the macrophage.

Both chromium compounds produced nodular accumulations of macrophages in the lungs. The

morphology of the macrophages of treated rabbits demonstrated black inclusions and large lysosomes.

These changes represent normal physiological responses of the macrophages to the chromium particle.

Phagocytosis and the reduction of nitroblue tetrazolium to formazan was impaired by chromium(III) but

not chromium(VI). These effects represent a decrease in the functional and metabolic activity of the

macrophage (Johansson et al. 1986a, 1986b). Mice exposed to chromium trioxide mist at concentrations

septum, hyperplastic and metaplastic changes in the larynx, trachea, and bronchus, and emphysema

(Adachi 1987; Adachi et al. 1986).

Chronic exposure to chromium(VI) compounds and mixtures of chromium(VI) and chromium(III)

compounds have also resulted in adverse respiratory effects in animals. Experiments in which rats were

exposed to either chromium(VI) alone as sodium dichromate or a 3:2 mixture of chromium(VI) trioxide

and chromium(III) oxide for 18 months showed similar loading of macrophages and increases in lung

together revealed interstitial fibrosis and thickening of the septa of the alveolar lumens due to the large

accumulation of chromium in the lungs, whereas histopathology of the lungs was normal in rats exposed

CHROMIUM 39

2. HEALTH EFFECTS

chromate dust intermittently for 18 months had epithelialization of alveoli. Histopathology revealed

epithelial necrosis and marked hyperplasia of the large and medium bronchi, with numerous openings in

the bronchiolar walls (Nettesheim and Szakal 1972). Significantly increased incidences of pulmonary

lesions (lung abscesses, bronchopneumonia, giant cells, and granulomata) were found in rats exposed

chronically to a finely ground, mixed chromium roast material that resulted in airborne concentrations of

chronically to the chromium roast material along with mists of potassium dichromate or sodium chromate

alveolar and interstitial inflammation, alveolar hyperplasia, and interstitial fibrosis, compared with

controls. Similarly, rabbits were also exposed and also had pulmonary lesions similar to those seen in the

rats and guinea pigs, but the number of rabbits was too small for meaningful statistical analysis (Steffee

and Baetjer 1965).

Therefore, gross and histopathological changes to the respiratory tract resulted from inhalation of

chromium(VI) compounds or a combination of chromium(VI) and chromium(III) compounds, but both

chromium(VI) and chromium(III) altered the function of macrophages.

chromium dioxide dust for 2 years had discolored mediastinal lymph nodes and lungs, and dust laden

(Lee et al. 1989). The increased lung weight and macrophage effects probably represent the increased

lung burden of chromium dioxide dust and normal physiological responses of macrophages to dust.

exposure to chromium and its compounds is limited. In a survey of a facility engaged in chromate

were recorded for 22 of the 65 workers who worked in the production of dichromate and chromium

trioxide for at least 1 year. No abnormalities were found (Sassi 1956). An extensive survey to determine

the health status of chromate workers in seven U.S. chromate production plants found no association

between heart disease or effects on blood pressure and exposure to chromates. Various manufacturing

processes in the plants resulted in exposure of workers to chromite ore (mean time-weighted

CHROMIUM 40

2. HEALTH EFFECTS

1953). No excess deaths were observed from cardiovascular diseases and ischemic heart disease in a

cohort of 4,227 stainless steel production workers from 1968 to 1984 when compared to expected deaths

based on national rates and matched for age, sex, and calender time (Moulin et al. 1993). No measurements

of exposure were provided. In a cohort of 3,408 individuals who had worked in 4 facilities that

produced chromium compounds from chromite ore in northern New Jersey sometime between 1937 and

1971, where the exposure durations of workers ranged from <1 to >20 years, and no increases in

atherosclerotic heart disease were evident (Rosenman and Stanbury 1996). The proportionate mortality

ratios for white and black men were 97 (confidence limits 88–107) and 90 (confidence limits 72–111),

respectively.

Cardiovascular function was studied in 230 middle-aged workers involved in potassium dichromate

production who had clinical manifestations of chromium poisoning (96 with respiratory effects and 134

with gastrointestinal disorders) and in a control group of 70 healthy workers of similar age. Both groups

with clinical manifestations had changes in the bioelectric and mechanical activity of the myocardium as

determined by electrocardiography, kinetocardiography, rheocardiography, and ballistocardiography.

These changes were more pronounced in the workers with respiratory disorders due to chromium

exposure than in the workers with chromium-induced gastrointestinal effects. The changes in the

myocardium could be secondary to pulmonary effects and/or to a direct effect on the blood vessels and

myocardium (Kleiner et al. 1970).

An extensive epidemiological survey was conducted of housewives who lived in an area of Tokyo, Japan,

in which contamination from chromium slag at a construction site was discovered in 1973. The

housewives included in the study were those who lived in the area from 1978 to 1988, and controls

included housewives who lived in uncontaminated areas. Questionnaires, physical examinations, and

clinical tests were conducted annually. Blood pressure determinations revealed no significant difference

between the exposed and the control populations (Greater Tokyo Bureau of Hygiene 1989).

No histopathological lesions were found in the hearts of rats exposed chronically to chromium dioxide at

animals after exposure to chromium or chromium compounds was not located.

CHROMIUM 41

2. HEALTH EFFECTS

of humans to chromium compounds. In a report of two cases of acute exposure to "massive amounts" of

chromium trioxide fumes, the patients complained of abdominal or substernal pain, but further

characterization was not provided (Meyers 1950).

In a NIOSH Health Hazard Evaluation of an electroplating facility in the United States, 5 of 11 workers

reported symptoms of stomach pain, two of duodenal ulcer, one of gastritis, one of stomach cramps, and

one of frequent indigestion. The workers were employed for an average of 7.5 years and were exposed to

not compared to a control group. An otolaryngological examination of 77 employees of 8 chromium

electroplating facilities in Czechoslovakia, where the mean level in the breathing zone above the plating

pharyngitis, and 32 cases of atrophy of the left larynx (Hanslian et al. 1967). In a study of 97 workers

from a chromate plant exposed to a mixture of insoluble chromite ore containing chromium(III) and

soluble chromium(VI) as sodium chromate and dichromate, gastrointestinal radiography revealed that 10

of the workers had ulcer formation, and of these, 6 had hypertrophic gastritis. Nearly all of the workers

breathed through the mouth while at work and swallowed the chromate dust, thereby directly exposing

the gastrointestinal mucosa. Only 2 cases of gastrointestinal ulcer were found in 41 control individuals,

who had the same racial, social, and economic characteristics as the chromium-exposed group (Mancuso

1951). In a survey of a facility engaged in chromate production in Italy where exposure concentrations

and chromium trioxide for at least 1 year had duodenal ulcers and 9.2% had colitis. The ulcers were

considered to be due to exposure to chromium (Sassi 1956). Gastric mucosa irritation leading to

duodenal ulcer was found in 21 of 90 workers engaged in the production of chromium salts. Symptoms

of gastrointestinal pathology appeared about 3–5 years after the workers' initial contact (Sterekhova et al.

1978). Most of these studies reporting gastrointestinal effects did not compare the workers with

appropriate controls. Although the gastrointestinal irritation and ulceration due to exposure to

chromium(VI) in air could be due to a direct action of chromium(VI) on the gastrointestinal mucosa from

swallowing chromium as a result of mouth breathing (or transfer via hand-to-mouth activity), other

factors, such as stress and diet, can also cause gastrointestinal effects. While occupational exposure to

chromium(VI) may result in gastrointestinal effects, a lower than expected incidence of death from

diseases of the digestive tract was found among a cohort of 2,101 employees who had worked for at least

90 days during the years 1945–1959 in a chromium production plant in Baltimore, Maryland, and were

followed until 1977. The rate (O/E=23/36.16, SMR=64) is based on comparison with mortality rates for

CHROMIUM 42

2. HEALTH EFFECTS

Baltimore (Hayes et al. 1979). In contrast to findings with chromium(VI) compounds, no indication was

found that exposure to chromium(III) resulted in stomach disorders in workers employed in two factories

that produced chromium(III) oxide or chromium(III) sulfate (Korallus et al. 1974b).

An extensive epidemiological survey was conducted of housewives who lived in an area of Tokyo, Japan,

in which contamination from chromium slag at a construction site was discovered in 1973. The housewives

included in the study were those who lived in the area from 1978 to 1988, and controls included

housewives who lived in uncontaminated areas. Questionnaires, physical examinations, and clinical tests

were conducted annually. Higher incidences of subjective complaints of diarrhea and constipation were

reported by the exposed population than the control population in the early years of the survey, but in

later years the difference between the two groups became progressively less. Otolaryngological examinations

revealed sporadic significant differences, but the investigators believed that such differences should

be observed more consistently to conclude any association with exposure to chromium slag (Greater

Tokyo Bureau of Hygiene 1989).

Information regarding gastrointestinal effects in animals after inhalation exposure to chromium or its

compounds is limited. Histological examination of the stomachs of rats exposed to sodium dichromate

ulcerations in the stomach and intestinal mucosa were reported to occur occasionally, but the incidence in

the treated mice, in controls, or other details regarding these lesions were not reported (Nettesheim et al.

1971). No treatment-related histopathological lesions were found in the stomach, large intestine,

duodenum, jejunum, or ileum of rats chronically exposed to chromium dioxide at 15.5 mg

compounds have yielded equivocal results. Ninety-seven workers from a chromate plant were exposed to

a mixture of insoluble chromite ore containing chromium(III) and soluble sodium chromate and

dichromate. Hematological evaluations revealed leukocytosis in 14.4% or leukopenia in 19.6% of the

workers. The leukocytosis appeared to be related primarily to monocytosis and eosinophilia, but controls

had slight increases in monocytes and occasional increases in eosinophils without leukocytosis.

Decreases in hemoglobin concentrations and slight increases in bleeding time were also observed

(Mancuso 1951). Whether these hematological findings were significantly different from those seen in

controls was not stated, but the effects were attributed to chromium exposure. In a survey of a facility

CHROMIUM 43

2. HEALTH EFFECTS

chromium trioxide for at least 1 year were unremarkable or inconclusive (Sassi 1956). In an extensive

survey to determine the health status of chromate workers in seven U.S. chromate production plants,

hematological evaluations revealed no effects on red blood cell counts, hemoglobin, hematocrit, or white

blood cell counts. The sedimentation rate of red cells was higher than that of controls, but the difference

was not statistically significant. Various manufacturing processes in the plants resulted in exposure of

chromium compounds (including basic chromium sulfate), which may or may not entirely represent

white blood cell counts, hemoglobin levels, or sedimentation rate were found in a case control study of 17

male manual metal arc stainless steel welders from six industries with mean occupational durations of

20 years (Littorin et al. 1984). No hematological disorders were found among 106 workers in a

chromium(III) oxide and chromium(III) sulfate (Korallus et al. 1974a).

Results from hematological evaluations in rats were also equivocal. Hematological evaluations of rats

mixture of chromium(VI) trioxide and chromium(III) oxide for 18 months had increased red and white

blood cell counts, hemoglobin content, and hematocrit (Glaser et al. 1986, 1988).

chromium dioxide for 2 years (Lee et al. 1989).

animals after inhalation exposure to chromium.

CHROMIUM 44

2. HEALTH EFFECTS

workers exposed to chromium trioxide in the chrome plating industry. Derangement of the cells in the

liver, necrosis, lymphocytic and histiocytic infiltration, and increases in Kupffer cells were reported.

Abnormalities in tests for hepatic dysfunction included increases in sulfobromophthalein retention,

gamma globulin, icterus, cephalin cholesterol flocculation, and thymol turbidity (Pascale et al. 1952). In

a cohort of 4,227 workers involved in production of stainless steel from 1968 to 1984, excess deaths were

observed from cirrhosis of the liver compared to expected deaths (O/E=55/31.6) based on national rates

and matched for age, sex, and calender time having an SMR of 174 with confidence limits of

131–226 (Moulin et al. 1993). No measurements of exposure were provided. Based on limited

information, however, the production of chromium compounds does not appear to be associated with liver

effects. As part of a mortality and morbidity study of workers engaged in the manufacture of

chromium(VI) compounds (84%) and chromium(III) compounds (16%) derived from chromium(VI) in

Japan, 94 workers who had been exposed for 1–28 years were given a complete series of liver function

tests 3 years after exposure ended. All values were within normal limits (Satoh et al. 1981). In a survey

at least 1 year had hepatobiliary disorders. When the workers were given liver function tests, slight

impairment was found in a few cases. These disorders could have been due to a variety of factors,

especially heavy alcohol use (Sassi 1956). No indication was found that exposure to chromium(III)

resulted in liver disorders in workers employed in two factories that produced chromium(III) oxide or

chromium(III) sulfate (Korallus et al. 1974b).

An extensive epidemiological survey was conducted of housewives who lived in an area of Tokyo, Japan,

in which contamination from chromium slag at a construction site was discovered in 1973. The

housewives included in the study were those who lived in the area from 1978 to 1988, and controls

included housewives who lived in uncontaminated areas. Questionnaires, physical examinations, and

clinical tests were conducted annually. Results of clinical chemistry tests for liver function revealed no

significant differences between the exposed and the control populations (Greater Tokyo Bureau of

Hygiene 1989).

The hepatic effects observed in animals after inhalation exposure to chromium or its compounds were

alkaline phosphatase, cholesterol, creatinine, urea, or bilirubin (Glaser et al. 1990). Triglycerides and

CHROMIUM 45

2. HEALTH EFFECTS

examination and liver function tests (Glaser et al. 1986, 1988; Lee et al. 1989).

4 former facilities that produced chromium compounds from chromite ore in northern New Jersey

sometime between 1937 and 1971. The proportionate mortality ratios for white and black men were 71

(40–117) and 47 (15–111), respectively. Exposure durations ranged from less <1 year to >20 years

(Rosenman and Stanbury 1996).

Renal function has been studied in workers engaged in chromate and dichromate production, in chrome

platers, in stainless steel welders, in workers employed in ferrochromium production, in boilermakers,

and in workers in an alloy steel plant. Workers exposed to chromium(VI) compounds in a chromate

production plant were found to have higher levels of a brush border protein antigen and retinol binding

protein in the urine compared with controls (Mutti et al. 1985a). A similar study was conducted in 43

male workers in the chromate and dichromate production industry, where occupational exposures were

7 years. Workers with >15 µg chromium/g creatinine in the urine had increased levels of retinol binding

protein and tubular antigens in the urine (Franchini and Mutti 1988). These investigators believe that the

presence of low molecular weight proteins like retinol binding protein or antigens in the urine are

believed to be early indicators of kidney damage. In an extensive survey to determine the health status of

chromate workers in seven U.S. chromate production plants, analysis of the urine revealed a higher

frequency of white blood cell and red blood cell casts than is usually found in an industrial population

(statistical significance not reported). Various manufacturing processes in the plants resulted in exposure

chromium compounds (including basic chromium sulfate), which may or may not entirely represent

Some studies of renal function in chromate production workers found negative or equivocal results. In a

survey of a facility engaged in chromate production in Italy, where exposure concentrations were

CHROMIUM 46

2. HEALTH EFFECTS

dichromate and chromium trioxide for at least 1 year were generally unremarkable, with the exception of

one case of occasional albuminuria and a few cases of slight urobilinuria (Sassi 1956). As part of a

mortality and morbidity study of workers engaged in the manufacture of chromium(VI) compounds

(84%) and chromium(III) compounds (16%) derived from chromium(VI) in Japan, 94 workers who had

been exposed for 1–28 years were given a complete series of kidney function tests (not further

characterized) 3 years after exposure ended. All values were within normal limits (Satoh et al. 1981).

Studies of renal function in chrome platers, whose exposure is mainly to chromium(VI) compounds, have

ex-chrome platers who had worked for at least one year in an old chrome plating plant from 1940 to 1968,

this effect may be reversible (Lindberg and Vesterberg 1983b). Liu et al. (1998) similarly found

anode-oxidation workers. The prevalence of elevated levels (higher than reference values) was

comparison of results of renal function tests between chrome platers and construction workers revealed

that the chrome platers had significantly (p<0.001) increased levels of urinary chromium and increased

clearance of chromium, but decreased (p<0.05) levels of retinol binding protein. However, no differences

(Verschoor et al. 1988).

Studies of renal function in stainless steel welders, whose exposure is mainly to chromium(VI)

compounds, were negative. Stainless steel welders had significantly increased (p<0.001) levels of urinary

chromium, increased clearance of chromium, and increased serum creatinine compared with controls, but

kidney damage (Verschoor et al. 1988). Similar negative results were found in another group of stainless

steel welders (Littorin et al. 1984).

Occupational exposure to chromium(III) or chromium(0) does not appear to be associated with renal

effects. No renal impairment based on urinary albumin, retinol binding protein, and renal tubular

antigens was found in 236 workers employed in the ferrochromium production industry where

CHROMIUM 47

2. HEALTH EFFECTS

ferrochromite is reduced with coke, bauxite, and quartzite. The mean airborne concentration of

(Triebig et al. 1987). In boilermakers exposed to chromium(0), no increase in urinary levels of

renal toxicity were found (Verschoor et al. 1988).

In a group of 30 men and 25 women who were lifetime residents of an area in northern New Jersey

contaminated with chromium landfill, signs of preclinical renal damage were assessed by examining the

urinary levels of four proteins, intestinal alkaline phophatase, tissue nonspecific alkaline phosphatase,

concentration for the women was 0.2±0.1 µg/g creatinine, and for the men was 0.3 µg/g. None of the four

proteins exceeded normal urinary levels in either men or women. The authors concluded that long-term

environmental exposure to chromium dust did not lead to tubular proteinurea or signs of preclinical renal

damage.

An extensive epidemiological survey was conducted of housewives who lived in an area of Tokyo, Japan,

in which contamination from chromium slag at a construction site was discovered in 1973. The

housewives included in the study were those who lived in the area from 1978 to 1988, and controls

included housewives who lived in uncontaminated areas. Questionnaires, physical examinations, and

clinical tests were conducted annually. Results of urinalysis revealed no significant differences between

the exposed and the control populations (Greater Tokyo Bureau of Hygiene 1989).

abnormalities, as indicated by histopathological examination of the kidneys. Serum levels of creatinine

and urea and urine levels of protein were also normal (Glaser et al. 1985, 1990). Furthermore, no renal

as a 3:2 mixture of chromium(VI) trioxide and chromium(III) oxide for 18 months, based on histological

examination of the kidneys, urinalysis, and blood chemistry (Glaser et al. 1986, 1988). Rats exposed to

CHROMIUM 48

2. HEALTH EFFECTS

damage or impairment of kidney function, as measured by routine urinalysis. Serum levels of blood urea

nitrogen, creatinine, and bilirubin were also normal (Lee et al. 1989).

inhalation exposure to chromium(VI) or (III) compounds. Male rats exposed 22 hours/day for 18 months

chromium(III) oxide did not result in any histopathological changes in adrenal glands (Glaser et al. 1986,

histopathological abnormalities in adrenals, pancreas, and thyroid glands (Lee et al. 1989).

individuals exposed to chromium via inhalation as described in Sections 2.2.3.2 and 2.2.3.3.

No studies were located regarding systemic dermal effects in animals after inhalation exposure to

chromium(VI) or chromium(III) compounds.

aerosols or chromium compounds are described in Section 2.2.3.2. An extensive epidemiological survey

was conducted of housewives who lived in an area of Tokyo, Japan, in which contamination from

chromium slag at a construction site was discovered in 1973. The housewives included in the study were

those who lived in the area from 1978 to 1988, and controls included housewives who lived in

uncontaminated areas. Questionnaires, physical examinations, and clinical tests were conducted annually.

Higher incidences of subjective complaints of eye irritation were reported by the exposed population than

the control population in the early years of the survey, but in later years the difference between the two

groups became progressively less (Greater Tokyo Bureau of Hygiene 1989).

No studies were located regarding systemic ocular effects in animals after inhalation exposure to

chromium(III) compounds.

2 years revealed normal morphology of the ocular tissue (Lee et al. 1989).

CHROMIUM 49

2. HEALTH EFFECTS

trioxide fumes, the patient became anorexic and lost 20–25 pounds during a 3-month period following

exposure (Meyers 1950).

In rats exposed to an aerosol of sodium dichromate for 30 or 90 days or for 90 days followed by an

additional 30 days of nonexposure, body weight gain was significantly decreased at 0.2 and 0.4 mg

18 months (Glaser et al. 1986, 1988). Similarly, there was no effect on body weight gain in rats exposed

Acute reactions have been observed in chromium sensitive individuals exposed to chromium via

inhalation as noted in several individual case reports. A 29-year-old welder exposed to chromium vapors

from chromium trioxide baths and to chromium and nickel fumes from steel welding for 10 years

complained of frequent skin eruptions, dyspnea, and chest tightness. Chromium sensitivity in the

individual was measured by a sequence of exposures, via nebulizer, to chromium(VI) as sodium

chromate. Exposure to 0.029 mg chromium(VI)/mL as sodium chromate caused an anaphylactoid

reaction, characterized by dermatitis, facial angioedema, bronchospasms accompanied by a tripling of

plasma histamine levels, and urticaria (Moller et al. 1986). Similar anaphylactoid reactions were

observed in five individuals who had a history of contact dermatitis to chromium, after exposure, via

nebulizer, to an aerosol containing 0.035 mg chromium(VI)/mL as potassium dichromate. Exposure

resulted in decreased forced expiratory volume, facial erythema, nasopharyngeal pruritus, nasal blocking,

cough, and wheezing (Olaguibel and Basomba 1989). Challenge tests with fumes from various stainless

steel welding processes indicated that the asthma observed in two stainless steel welders was probably

caused by chromium or nickel, rather than by irritant gases produced by the welding process (Keskinen et

al. 1980). A 28-year-old construction worker developed work-related symptoms of asthma which

worsened during periods when he was working with (and sawing) corrugated fiber cement containing

chromium. A skin patch test to chromium was negative. Asthmatic responses were elicited upon

inhalation challenge with fiber cement dust or nebulized potassium chromate (Leroyer et al. 1998).

CHROMIUM 50

2. HEALTH EFFECTS

Chromium-induced asthma may occur in some sensitized individuals exposed to elevated concentrations

of chromium in air, but the number of sensitized individuals is low, and the number of potentially

confounding variables in the chromium industry is high.

Concentrations of some lymphocyte subpopulations (CD4+ helper-inducer, CD5--CD19+ B, CD3--

CD25+ activated B, and CD3--HLA-DR+ activated B and natural killer lymphocytes) were significantly

reduced (about 30–50%) in a group of 15 men occupationally exposed to dust containing several

compounds (including hexavalent chromium as lead chromate) in a plastics factory. Worker blood lead

and urine chromium levels were significantly higher than those of 15 controls not known to be

occupationally exposed to toxic agents. Serum chromium concentrations and serum immunoglobulins

IgA, IgG, and IgM were not significantly different between the two groups (Boscolo et al. 1997). These

results are difficult to interpret due to concomitant exposure to a number of other chemicals.

An animal study was designed to examine the immunotoxic effects of soluble and insoluble hexavalent

chromium agents released during welding (Cohen et al. 1998). Rats exposed to atmospheres containing

had significantly increased levels of neutrophils and monocytes and decreased alveolar macrophages in

bronchoalveolar lavage than air-exposed controls. Significantly increased levels of total recoverable cells

were noted at 2 (but not 4) weeks of exposure. In contrast, no alterations in the types of cells recovered

insoluble barium chromate, as compared to controls. However, the cell types recovered did differ from

those recovered from rats exposed to soluble chromium. Changes seen in pulmonary macrophage

functionality varied between the soluble and insoluble chromium(VI) exposure groups. The production

significantly altered in either group. Barium chromate affected zymosan-inducible reactive oxygen

intermediate formation and nitric oxide production to a greater degree than soluble chromium(VI).

Insoluble chromium(VI) reduced the production of superoxide anion, hydrogen perodise, and nitric oxide;

soluble chromium(VI) only reduced nitric oxide production.

CHROMIUM 51

2. HEALTH EFFECTS

increase in mitogen-stimulated T-cell response in the group exposed for 90 days to 0.2 mg

rats exposed for 90 days had an increased percentage of lymphocytes in the 0.025, 0.05, and 0.2 mg

greater number of macrophages in telophase and an increase in their diameter were observed in the 0.025,

Low-level exposure to sodium dichromate seems to stimulate the humoral immune system (as evidenced

stimulate the humoral immune system (significant decreases in total immunoglobin levels) but still may

have effects on the T lymphocytes. The depression in macrophage cell count and phagocytic activities

correlated with a 4-fold lower rate of lung clearance for inhaled iron oxide in the 0.2 mg

in Table 2-1 and plotted in Figure 2-1.

In a chrome plating plant where poor exhaust resulted in excessively high concentrations of chromium

trioxide fumes, workers experienced symptoms of dizziness, headache, and weakness when they were

working over the chromate tanks (Lieberman 1941). Such poor working conditions are unlikely to still

occur in the United States because improvements in industrial hygiene have been made over the years.

No increases in vascular lesions in the central nervous system were evident in a cohort of 3,408 workers

from 4 former facilities that produced chromium compounds from chromite ore in northern New Jersey

(Rosenman and Stanbury 1996). The proportionate mortality ratios for white and black men were 78

(61–98) and 68 (44–101), respectively. The subjects were known to have worked in the four facilities

sometime between 1937 and 1971 when the last facility closed. Exposure durations ranged from <1 to

>20 years.

CHROMIUM 52

2. HEALTH EFFECTS

An extensive epidemiological survey was conducted of housewives who lived in an area of Tokyo, Japan,

in which contamination from chromium slag at a construction site was discovered in 1973. The

housewives included in the study were those who lived in the area from 1978 to 1988, and controls

included housewives who lived in uncontaminated areas. Questionnaires, physical examinations, and

clinical tests were conducted annually. Higher incidences of subjective complaints of headache,

tiredness, and light headedness were reported by the exposed population than the control population in the

early years of the survey, but in later years the difference between the two groups became progressively

less (Greater Tokyo Bureau of Hygiene 1989).

No information was located regarding neurological effects in humans or animals after inhalation exposure

to chromium(III) compounds or in animals after inhalation exposure to chromium(VI) compounds. No

histopathological lesions were found in the brain, spinal cord, or nerve tissues of rats exposed to 15.5 mg

were conducted.

Information regarding reproductive effects in humans after inhalation to chromium compounds is limited.

The effect of chromium(VI) on the course of pregnancy and childbirth was studied in women employees

at a dichromate manufacturing facility in Russia. Complications during pregnancy and childbirth (not

further described) were reported in 20 of 26 exposed women who had high levels of chromium in blood

and urine, compared with 6 of 20 women in the control group. Toxicosis (not further described) was

reported in 12 exposed women and 4 controls. Postnatal hemorrhage occurred in four exposed and two

control women (Shmitova 1980). Similar results were reported in a more extensive study of 407 women

who worked at a factory producing chromium compounds (not otherwise specified) compared with 323

controls. The frequency of birth complications was 71.4% in a subgroup of highly exposed women,

77.4% in a subgroup of women with a lower level of exposure, and 44.2% in controls. Toxicosis in the

first half of pregnancy occurred in 35.1% of the high exposure group, 33.3% of the low exposure group,

and 13.6% of the controls. The frequency of post-natal hemorrhage was 19.0% for the high exposure

group and 5.2% in controls (Shmitova 1978). Because these studies were generally of poor quality and

results were poorly reported, no conclusions can be made regarding the potential for chromium to

produce reproductive effects in humans.

CHROMIUM 53

2. HEALTH EFFECTS

The occurrence of spontaneous abortion among 2,520 pregnancies of spouses of 1,715 married Danish

metal workers exposed to hexavalent chromium from 1977 through 1987 were examined (Hjollund et al.

1995). Occupational histories were collected from questionnaires and information on spontaneous

abortion, live births, and induced abortion was obtained from national medical registers. The number of

spontaneous abortions was not increased for pregnant women whose spouses worked in the stainless steel

welding industry when compared to controls (odds ratio 0.78, 95% confidence interval 0.55–1.1). The

authors believed the risk estimate was robust enough that factors such as maternal age and parity and

smoking and alcohol consumptions were not confounders. There was no association found in

spontaneous abortions in women whose husbands were in the cohort subpopulations who were mild steel

welders and metal-arc stainless steel welders, which would lead to higher exposures to welding fumes

(workplace chromium exposures not provided). This more recent study does not corroborate earlier

findings (Bonde et al. 1992) which showed wives of stainless steel welders were at higher risk of

spontaneous abortions. The current study was based on abortions recorded in a hospital register, while

the earlier study was based on self-reporting data. The latter study probably included more early

abortions and was biased because the job exposure of male metal workers is apparently modified by the

outcome of their partners’ first pregnancy.

oxide for 18 months (Glaser et al. 1986, 1988) revealed no abnormalities. No effects on reproduction

(Glaser et al. 1984). Similarly, no histopathological lesions were observed in the prostate, seminal

vesicle, testes, or epididymis of male rats or in the uterus, mammary gland, or ovaries of female rats

available that examined reproductive outcome in animals after exposure to chromium(IV).

No studies were located regarding developmental effects in humans after inhalation exposure to

chromium or its compounds.

for three generations (Glaser et al. 1984).

CHROMIUM 54

2. HEALTH EFFECTS

Several studies were located that investigate the genotoxic effects of chromium exposure on workers in

chromium contaminated atmospheres. An epidemiology study of stainless steel welders, with mean

in the number of sister chromatid exchanges in the lymphocytes of exposed workers. The welders were

also exposed to nickel and molybdenum from the welding rods (Littorin et al. 1983). A similar study was

conducted to detect genotoxic effects of chromium(VI) on workers in electroplating factories. Of the 24

workers examined, none showed significant differences in sister chromatid exchange frequency (Nagaya

1986). Similarly, no correlation was found between excretion of chromium in the urine and the frequency

of sister chromatid exchanges in 12 male chromium platers whose mean urinary chromium level was

17.9 µg/g creatinine (Nagaya et al. 1991). No increase in chromosomal aberrations was observed in 17

tannery workers exposed primarily to chromium(III) as compared with 13 controls (Hamamy et al. 1987).

However, parallel measurements in these tannery workers showed that the average chromium levels in

plasma (0.115 µg/L) and in urine (0.14 µg/100 L) did not differ from the nonexposed workers. In

addition, stainless steel welders occupationally exposed to chromium(VI) for a mean of 21 years did not

have any increase in chromosomal aberrations or sister chromatid exchanges compared to a control group.

No actual exposure levels were provided (Husgafvel-Pursiainen et al. 1982). Yet, other studies involving

electroplaters and welders report a higher incidence of chromosomal aberrations or sister chromatid

exchanges in lymphocytes of workers than in controls. In one study, a causal relationship between

chromium exposure and the observed effects could not be established because the exposure was

confounded by co-exposure to nickel and manganese (Elias et al. 1989a). In another study, although

chromium workers were found to have higher rates of sister chromatid exchanges than workers exposed

to nickel-chromium or controls (after adjusting for potential confounding factors), the differences were

not significantly correlated to chromium concentrations in blood or urine (Lai et al. 1998). The frequency

of sister chromatid exchanges in the lymphocytes of 12 workers exposed to chromium(VI) as chromic

acid fumes in a chrome plating industry was significantly increased (Stella et al. 1982). Significantly

increased incidences of chromosomal aberrations in peripheral lymphocytes were found in workers

exposed to chromium(VI) as chromium trioxide in two of four electroplating plants. Of the two plants

where the increases were significant, one was a "bright" plating plant, where exposure involved nickel as

well as chromium, and one was a "hard" plating plant, where exposure involved only chromium.

However, the increase in chromosomal aberrations correlated poorly with urinary chromium levels, and

only the increase in the "bright" platers showed a significant correlation with duration of exposure. A

significantly increased incidence of sister chromatid exchanges was found in "hard" platers compared

CHROMIUM 55

2. HEALTH EFFECTS

with controls (sister chromatid exchange was not evaluated in "bright" platers), and smoking appeared to

enhance the increase (7 of 8 smokers and 7 of 11 nonsmokers had incidences significantly higher than

controls). Moreover, the increased incidence of sister chromatid exchange showed a positive correlation

with urinary chromium levels (Sarto et al. 1982). Repeated cytogenetic analysis of peripheral

lymphocytes for 3 years revealed an increased frequency of chromosomal aberrations and sister

chromatid exchanges in a group of stainless steel welders compared to controls. The workers were

exposed to unreported chromium(VI) concentrations for a mean of 12.1 years, but exposure to ultraviolet

rays and small amounts of manganese, nickel, iron, and magnesium could not be ruled out (Koshi et al.

1984). Compared to 39 controls, significantly elevated sister chromatid exchange values in lymphocytes

and significantly higher rates of DNA single-strand breakages were found in a group of 39 welders

exposed to unreported chromium(VI) and nickel concentrations (Werfel et al. 1998). Only one study was

located regarding the average levels of exposure for electroplating workers: workers exposed to an

chromatid exchanges. However, high levels of nickel as well as chromium were found in hair and stool

samples when compared to controls (Deng et al. 1988). Thus, although most studies gave negative or

equivocal results, chromium and its compounds, particularly chromium(VI), may cause chromosomal

effects in exposed workers, indicating carcinogenic potential because interactions with DNA have been

linked with the mechanism of carcinogenicity.

No elevated levels of DNA strand breaks or hydroxylation of deoxyguanosine in lymphocytes were found

in 10 workers occupationally exposed in the production of bichromate when compared with 10 nonoccupationally-

exposed workers at the same facility Gao et al. (1994). From general background

Information regarding genotoxic effects in animals after inhalation exposure to chromium or its

compounds is limited. Sprague-Dawley rats that inhaled chromium fumes generated from powders of

5 days/week) for 1 week or 2 months, respectively, had increased frequencies of chromosomal aberrations

and sister chromatid exchanges in peripheral lymphocytes, but not in bone marrow cells (Koshi et al.

1987). Some oxidation of metallic chromium may have occurred in the process of generating the

chromium fumes (IARC 1990).

Other genotoxicity studies are discussed in Section 2.5.

CHROMIUM 56

2. HEALTH EFFECTS

Occupational exposure to chromium(VI) compounds in a number of industries has been associated with

increased risk of respiratory system cancers, primarily bronchogenic and nasal. Among the industries

investigated in retrospective mortality studies are chromate production, chromate pigment production and

use, chrome plating, stainless steel welding, ferrochromium alloy production, and leather tanning.

Studies of chromate production workers, who are exposed to a variety of chromium compounds both

hexavalent and trivalent, and chromate pigment industries, where exposure is mainly to chromium(VI),

have consistently demonstrated an association with respiratory system cancer. Studies in chrome platers,

who are exposed to chromium(VI) and other agents, including nickel, generally support the conclusion

that certain chromium(VI) compounds are carcinogenic. Studies in stainless steel welders exposed to

chromium(VI) and other chemicals, and in ferrochromium alloy workers, who are exposed mainly to

chromium(0) and chromium(III), but also to some chromium(VI), were inconclusive. Studies in leather

tanners, who are exposed to chromium(III), were consistently negative.

that demonstrated an association with lung cancer was conducted with 1,445 workers in seven plants

engaged in the extraction of chromates from ore from 1930 to 1947. The mortality rates and causes of

deaths for 193 chromate production workers were compared with 733 deaths in industrial workers not

exposed to chromates. A total of 42 deaths from cancer of the respiratory system was found in the

exposed group, which represented 21.8% of all deaths and 63.6% of all deaths from cancer. In the control

group, 10 deaths from cancer of the respiratory system were found representing 1.4% of all deaths and

8.7% of deaths from all cancers (Machle and Gregorius 1948). Although this study was limited by

inadequate description of the cohort, relatively few deaths, and generally poor reporting, the results

prompted an extensive study of workroom conditions and worker health in the same chromate producing

plants. Various manufacturing processes in the plants resulted in exposure of workers to chromite ore

(including basic chromium sulfate), which may or may not entirely represent chromium(III) (0–0.47 mg

numbers based on the average death rate for the United States for 1940–1948. The SMR for all causes of

death other than cancer was 116, which was not significant. However, for all deaths from cancer of the

respiratory system, exclusive of the larynx, the O/E was 26/0.9, giving an SMR of 2,889 (p<0.001). The

cohort in this study consisted of workers with membership in a sick-benefit association and did not

CHROMIUM 57

2. HEALTH EFFECTS

include terminated employees, retirees, or individuals who died more than 1 year after the diagnosis of

cancer. However, whether these exclusions would result in an overestimation or an underestimation of

the risk is not known. In addition to the cases of lung cancer deaths, 10 cases of bronchogenic carcinoma

were diagnosed among 897 living men who worked in the plants for an average of 22.8 years (PHS

1953). A high rate of respiratory cancer was found in a cohort of 1,212 male workers who were

employed for at least 3 months in any of three chromate plants in the United States during a 4-year period

from 1937 to 1940 and followed until 1960 (O/E=71/8.344, SMR=850.9). The expected death rate was

determined from U.S. male rates. For the period of 1937–1960, the following values were found for

respiratory cancer (Taylor 1966). The increased risk of death from respiratory cancer correlated with

duration of employment in chromate production, but no information on exposure levels, smoking habits,

or exposure to other chemicals was provided. A reanalysis of these data several years later found an even

higher SMR for respiratory cancer (O/E=69/7.3, SMR=942.6) (Enterline 1974).

Examination of records at a hospital in Baltimore, Maryland, revealed that of 290 male lung cancer

patients admitted between 1925 and 1948, 11 had been exposed to chromates and 10 had worked in a

local chromate producing plant. No indication of chromate exposure was found in the referent group of

725 patients admitted for other causes (Baetjer 1950b). In a cohort of 2,101 employees who had worked

for at least 90 days during the years 1945–1959 in the same chromium production plant in Baltimore,

Maryland, and followed until 1977, there were 59 deaths from lung cancer compared with 29.16 expected

based on the mortality rates for Baltimore. The SMR of 202 was significant (p<0.01). Long-term

1979). In a separate analysis by OSHA, concurrent exposure data for the Baltimore plant in this study

were determined from monitoring records for the years of the study (1945–1959), and the usual

were available for later years to estimate usual exposures. However, cumulative exposures were

acknowledged uncertainties in these estimates. Furthermore, reliable smoking data were not available for

the cohort, but it was considered unlikely that cigarette smoking alone could account for the increased

risk, or that the smoking habits of the cohort differed from that of the comparison population (Braver et

al. 1985; Hayes et al. 1979). Using a statistical method called "probability window analysis," a review of

all known cases of lung cancer in the chromium production plant in Baltimore, Maryland during the

period of 1929–1977 revealed a decreasing trend in the incidence of lung cancer that correlated with

CHROMIUM 58

2. HEALTH EFFECTS

major process, and hence exposure, improvements made in the plant in 1951 and 1961 (Hill and Ferguson

1979).

Among 33 deaths of workers at a chromate production plant in Ohio between 1931 and 1949, 6 of the 33

deaths or 18.2% were due to respiratory cancer compared with 1.2% lung cancer deaths among residents

of the county in which the plant was located. For each of the six cases of lung cancer, the concentrations

of chromium(III) from insoluble chromite ore and chromium(VI) from soluble sodium chromate and

were not provided. In a follow-up at this plant, a cohort of 332 men employed for at least 1 year from

1931 to 1937 was followed to 1974. There were 173 deaths, 66 of which were due to cancer of any type.

Of these, 41 cancer deaths were due to lung cancer. Although not compared to a control group, mortality

In an update of this cohort, the 332 employees were followed to 1993 and 283 deaths were identified

(Mancuso 1997a). The present study includes 66 lung cancer deaths, 25 more than in the 1975 study.

The 66 lung cancer deaths constituted 23.3% of all deaths in the cohort and 64.7% of all cancer deaths.

The age-adjusted lung cancer death rates per 100,000 increased with respect to increases in both insoluble

insoluble chromium, the age-adjusted death rate was 187.9/100,000 and 1,045.5/100,000 at insolublechromium

chromium the age-adjusted death rates were 503.7/100,000 and 2,848.3/100,000 at exposure levels of

related to both insoluble and soluble forms of chromium, the study author concluded that increased lung

cancer cannot be contributed solely to one form of chromium compound, but involves both chromium(III)

and (VI). This conclusion has been criticized primarily because the industrial hygiene study conducted in

1949 used measured concentrations of insoluble and soluble chromium compounds as surrogates for

chromium(III) and chromium(VI) compounds, respectively. The use of surrogates introduces the

potential for misclassification of exposure to trivalent or hexavalent chromium (Kimbrough et al. 1999;

Mundt and Dell 1997). Mancuso (1997a) assumed that chromium(III) compounds are insoluble and

chromium(VI) compounds are soluble, but did not consider that there are insoluble chromium(VI)

compounds. Thus, he attributed the increased cancer risk in the insoluble group to exposure to

chromium(III).

CHROMIUM 59

2. HEALTH EFFECTS

A cohort of 3,408 workers from four former facilities that produced chromium compounds from chromite

ore in northern New Jersey was assembled in 1990–1991 using social security records (Rosenman and

Stanbury 1996). The subjects were known to have worked in the four facilities sometime between 1937

and 1971, when the last facility closed. Exposure durations ranged from less than 1 year to greater than

20 years. The overall risk of lung cancer derived from proportionate cancer mortality ratios (PCMR) was

1.51 for white males and 1.34 for black males. The risk increased with duration of employment and

latency since time of first employment. The cancer mortality ratio for greater than 20 years of workplace

exposure and greater than 20 years since first exposure was 194 and 308 for white and black males,

respectively. This study also showed significantly increased risk for nasal cavity/sinus cancer indicated

by a PCMR of 518 which has not been observed in previous studies in the United States. A cluster of

bladder cancer was seen at one facility among black workers with a PCMR of 330.

The risk of lung cancer in chromate production workers has also been studied in the United Kingdom.

The finding of two cases of lung cancer, diagnosed through a radiographic survey, among 786 workers

employed in three chromate producing factories in 1948–1949 (Bidstrup 1951) prompted a follow-up at

these factories in 1955. In this follow-up, 12 of 59 deaths that occurred from 1949–1958 were due to

lung cancer. Comparison with vital statistics from the male population of England and Wales resulted in

O/E=12/3.3, SMR=364 (p<0.005) (Bidstrup and Case 1956). Another follow-up of this study, which

added new employees after 1 year of employment, followed 2,636 workers during the period 1948–1977.

For deaths from all causes, O/E=602/445.3, SMR=135 (p<0.001). Lung cancer was the major

contributory cause of the excess, with O/E=116/47.9, SMR=242 (p<0.001). Nasal cancer was found in

two individuals (O/E=2/0.28, SMR=714, p=0.033). Further analysis of the cohort revealed that the risk

for lung cancer had declined since modifications in the work environment were introduced in 1950

(Alderson et al. 1981). A further follow-up study of the three chromate plants in the United Kingdom

updates the mortality data, paying particular attention to the workers after major industrial hygiene and

process changes were introduced in 1950 and completed during 1958–1960. The analysis covered 2,298

workers in post on January 1, 1950 or who entered employment on or before June 30, 1976, and who

worked for at least 1 year. Mortality was followed to December 31, 1988 (Davies et al. 1991). In

contrast to the previous follow-up by Alderson et al. (1981), the analysis in the present study excluded

office personnel. "Early" workers with long-term service, "prechange" workers, and "postchange"

workers were defined as those workers who began employment prior to 1945, those who began

employment during the years 1945–1960, and those who began employment after improvements were

completed, respectively. At the two larger factories, significant excesses of death from lung cancer

(O/E=175/88.97, SMR=197, p<0.001) and from nasal cancer (O/E=4/0.26, SMR=1,538, p<0.001) were

CHROMIUM 60

2. HEALTH EFFECTS

found among 1,422 "early" and "prechange" workers. No excess of lung cancer deaths was found among

677 "postchange" workers (O/E=14/13.7, SMR 102, not significant), but the possibility of an increased

risk in "postchange" workers cannot be ruled out without further follow-up. In the "early" workers, the

(SMR=225). Men in jobs with the highest exposure to chromate had higher risks (O/E=151/61.73,

SMR=245) than workers with less exposure (O/E=21/19.57, SMR=107) (Davies et al. 1991). In these

reports, reliable smoking data were not available, and exposure concentrations were not reported.

However, an independent analysis of workroom levels of chromium in the three chromate production

factories in the United Kingdom performed around 1950 indicated average levels for various phases in the

(Buckell and Harvey 1951). The importance of further follow-up of the cohort to confirm that the risk

has declined with improvements in the working environment, of simultaneous analysis of such factors as

age, duration of employment, and time since first exposure, and of examining smoking habits was

emphasized (Davies et al. 1991).

The incidence of mortality due to lung cancer in two chromate production plants in the Federal Republic

of Germany was examined in relation to changes in operations and industrial hygiene over the years. The

cohort consisted of 1,140 workers who were employed for at least 1 year from before 1948 to 1979. For

respiratory cancer, O/E=21/10.93, SMR=192 at one plant and O/E=30/13.41, SMR=224 at the other.

Analysis of SMRs over 5-year periods revealed a progressive decline at both plants (Korallus et al. 1982).

Studies of chromate production workers have also been conducted in Japan and Italy. Among

544 workers at a small chromate producing factory in Japan, which had operated from 1936 to 1973,

14 cases of lung cancer were diagnosed or reported on death certificates. An excess risk of 657.9 per

100,000 was calculated and compared with a death rate from bronchial carcinoma of 13.3 per 100,000 in

Japan in 1975 (Ohsaki et al. 1978). In a mortality and morbidity study of 896 men (including 120

deceased previously) engaged in the manufacture of chromium compounds in Japan for at least 1 year

during 1918–1975 and followed until 1978, SMRs were significant only for lung cancer (O/E=26/2.746,

SMR=950). Deaths from all respiratory cancers increased with increased length of engagement in

chromium work. The overall risk for respiratory cancer for the period from 1950–1978 was

O/E=31/3.358 (SMR=923). The 31 cases included 25 cases of lung cancer, 5 cases of maxillary sinus

cancer, and 1 case of nasal cavity cancer. No increased risk of death due to cancer of other organs,

particularly the stomach or liver, was found (Satoh et al. 1981). A survey of 85 men who worked in the

production of dichromate and chromium trioxide for at least 1 year from 1938 to 1953 in a facility in Italy

CHROMIUM 61

2. HEALTH EFFECTS

revealed one case of bronchogenic carcinoma and one case of nasal cancer (Sassi 1956), but further

analysis was not performed.

Among 4 cases of nasal carcinoma in men who worked for 19 and 32 years in a Japanese chromate

factory, 1 patient was diagnosed with squamous cell carcinoma of the left nasal cavity 11 years after

retirement (Satoh et al. 1994). The other three patients underwent lobectomy for lung cancer, and

6–15 years later, all three contracted nasal cancer, two in the nasal cavity and one in the nasopharynx.

The period for the appearance of nasal cancer was about 39 years after first being exposed to chromium.

No mention was made of the possibility of metastasis of lung cancer to the nasal region.

A retrospective mortality and morbidity study of 398 workers who had worked in a chromate production

facility in North Carolina for at least 1 year between 1971 and 1989 was designed to address these

limitations (Pastides et al. 1991, 1994). Personal air monitoring results, which were available for

1974–1989, revealed 8-hour TWA concentrations of chromium(VI) ranging from below the detection

Because personal air monitoring data were not available for the years 1971–1973, workroom area levels

were used to estimate the personal air levels for these years and were included in the analysis of personal

air levels. Levels of chromium(III) or total chromium were not measured. Forty-five workers also had

previous occupational exposure to chromium at other chromate production facilities. Of the 45 workers

with previous exposure, 42 had been employed at production facilities in Painsville, Ohio or Kearny, New

Jersey (the exact number from each of these facilities and the location of the plants at which the other

3 workers had been employed were not reported). Industrial hygiene monitoring at the Painsville, Ohio

not reported). Details of medical history, smoking history, detailed work history, and exposure to known

chemicals and industrial hazards were determined from questionnaires of workers or reconstructed from

personnel records and coworkers' accounts for deceased workers. There were 17 deaths, 6 of which were

due to cancer (2 to lung cancer). One of the deaths from lung cancer occurred in a worker who had

transferred from one of the other plants. Expected rates for cancer of any type were 4.8 using the

statistics for the 8 surrounding counties in North Carolina (SMR=125, not significant) and 4.4 using the

U.S. population vital statistics (SMR=137, not significant). For lung cancer, the observed/expected ratio

was 2/2.1 (SMR=97, not significant) for the eight-county comparison and 2/1.6 (SMR=127, not

CHROMIUM 62

2. HEALTH EFFECTS

significant) for the U.S. population comparison. To address the apparent "healthy worker" effect, the

There was little difference in mortality between the groups and no evidence of an increased risk of cancer

for workers with high cumulative exposure or with longer duration, controlling for age, smoking, and

previous chromium exposure. A significant increased risk of cancer was found for workers who had been

previously employed at the other chromate production facility before transfer to the North Carolina site.

In addition to the cancer deaths, seven living workers had been diagnosed with cancer, three cases of

which were lung cancer. Two of these lung cancers were diagnosed in workers with previous exposure.

The risk of lung cancer was not further analyzed for these cases, but the subgroup with previous exposure

accounted for three of the total five cases of lung cancer (both living and deceased). The authors noted

the limited power of the study for detecting a true cancer risk because of the relatively brief 18-year

history of the facility and small cohort size.

In conclusion, despite limitations of some studies, occupational exposure to chromium(VI) in the

chromate production industry is associated with increased risk of respiratory cancer, but improvements in

the production process and industrial hygiene appear to have reduced the risk over the past 30–40 years.

pigments also have consistently shown an association with increased risk of lung cancer. A study of the

causes of death among 1,296 white and 650 nonwhite males who had worked at some time between 1940

to 1969 at a plant in New Jersey manufacturing lead and zinc chromate pigments showed an SMR for

lung cancer of 160 (O/E=25.5/16.0, p<0.05) for white males compared with U.S. rates. The observed

rates are not expressed as integers because they were adjusted to include the appropriate proportion of

deaths from unknown causes. The cohort included workers with exposures classified as high (continuous

200 for stomach cancer (O/E=6.1/3.0, not significant), 170 for pancreatic cancer (O/E=4.8/2.8, not

significant), and 290 for Hodgkins disease (O/E=2.4/0.8, not significant) were also found. Further

analyses also revealed significant (p<0.05) risk for stomach cancer in white males (O/E=6.1/2.7,

SMR=230) and lung cancer in nonwhite males (O/E=11.2/5.7, SMR=200). Air monitoring at the plant in

the later years (not otherwise specified) indicated exposure concentrations from <0.1 to >2 mg

CHROMIUM 63

2. HEALTH EFFECTS

present in the plant, 98.2% higher concentrations of airborne chromium were present than were

concentrations of airborne nickel. Smoking histories were not available for all workers (Sheffet et al.

1982). A follow-up of this study followed the cohort through 1982. Of the 453 deaths, 41 were due to

lung cancer, compared with 35.3 expected based on the U.S. population rates (SMR=116, not significant).

When analyzed by duration of employment, none of the SMRs were significant, but there was a

significant trend for increased risk with increasing duration of employment (p=0.04). When time since

initial employment was considered in the analysis, a significantly increased risk of lung cancer was found

p=0.02). Of the 41 lung cancer deaths, 24 occurred in those whose jobs involved exposure to chromate

lung cancer deaths by duration of employment and time since initial employment along with duration of

employment were similar to those obtained with the 41 lung cancer deaths. For those employed for

1989).

Another epidemiological study of workers at 3 chromate pigment production plants in the United States

examined the causes of death in 574 male workers with known exposure to lead chromate and who had

been employed for at least 6 months from the mid-1920s to December 31, 1979. At Plant 1, where lead

chromate was the only chromate produced, there were 21 deaths among 246 workers. Four of the deaths

were due to respiratory cancer, compared with 2.4 expected based on U.S. male population rates

(SMR=164.4, not significant), and 2 of the deaths were due to digestive system cancer, compared with 1.7

expected (SMR=120.3, not significant). At least two of the deaths from lung cancer occurred in workers

who smoked. Industrial hygiene monitoring at Plant 1 in 1975 revealed average workroom air

chromate, and barium chromate had also been produced at various times during the facility's operation.

There were 11 deaths among 164 workers, 2 of which were due to respiratory cancer, compared with 1.0

predicted. Both of the workers with respiratory cancer had been smokers. The low number of deaths

from lung cancer precluded meaningful statistical analysis. No death from digestive system cancer

occurred. The industrial hygiene survey of Plant 2 in 1975 found average concentrations of 0.06 mg total

chromate had also been produced. There were 53 deaths among 164 workers, 9 of which were due to

respiratory cancer, compared with 4.1 expected (SMR=218, p<0.05). For cancer of the bronchus, trachea,

and lung, O/E=9/3.9 (SMR=231, p<0.05). At least five of the lung cancer patients had been moderate to

CHROMIUM 64

2. HEALTH EFFECTS

heavy smokers. An increase in deaths from stomach cancer was also observed (O/E=5/0.6; SMR=792,

p<0.01). Average airborne levels of chromium and lead in Plant 3 in 1975 were 0.19 mg total

the co-exposure to other chromates at Plants two and three, no conclusions regarding the risk of lung

cancer in lead chromate-exposed workers can be drawn from this study. Combining the results for lung

cancer from Plants two and three yielded O/E of 11/4.8 (SMR=228, p<0.05), suggesting that exposure to

zinc chromate (and other chromates) is associated with an increased risk of lung cancer (EEH 1976,

1983). Since Plant three was the same facility studied by Sheffet et al. (1982), whose cohort was much

larger because it was not limited to men who worked with chromates, but included personnel with

infrequent exposure (janitors, office workers), and where the investigators already found excess lung and

stomach cancer, this study (EEH 1976, 1983) provides no additional knowledge regarding causative

factors.

Three chromate pigment manufacturing plants in the United Kingdom have been studied. At Factory A,

both lead and zinc chromate were produced from 1932 to 1964, after which lead chromate production

ceased. The main cohort consisted of 411 men first employed between 1932 and 1967. For workers

exposed to "high" and "medium" levels of chromates before 1955, when industrial hygiene improvements

had been introduced, 22 cases of lung cancer death were observed compared with 9.5 expected based on

rates for England and Wales (SMR=232, p<0.01). No excess of lung cancer was found in the group

exposed after 1955 or in workers exposed to "low" levels. At Factory B, both lead and zinc chromate

were produced until 1976, and strontium chromate from 1950 to 1968. The main cohort consisted of 138

men first employed between 1948 and 1967. For lung cancer deaths in workers exposed to "high" and

"medium" levels of chromates before 1961, when industrial hygiene improvements were introduced,

O/E=6/1.61, SMR=373 (p<0.01). For workers exposed to "high" and "medium" levels from 1961 to

1967, the values were O/E=5/0.89, SMR=562 (p<0.01) (Davies 1979, 1984). At Factory C, where only

lead chromate had been produced, no excess death from lung cancer was found (Davies 1979), and

meaningful analysis by subgroups was precluded (Davies 1984). The results suggested that exposure to

both zinc chromate and lead chromate posed more of a risk for lung cancer than exposure to lead

chromate alone. Workroom levels of chromium were not monitored at any of the factories. Although

information regarding smoking habits of the workers was not available, smoking was not permitted

during work, suggesting that the workers smoked no more, or perhaps less, than other members of their

socioeconomic status.

CHROMIUM 65

2. HEALTH EFFECTS

In a study of 133 workers at a chromate pigment producing factories in Norway, three cases of lung

cancer death compared with 0.079 expected based on national rates (SMR=3,797) were found in a

subcohort of 24 workers who had worked for at least 3 years at the factories that had produced zinc and/or

lead chromate from 1948 to 1972. Workroom monitoring revealed air levels ranging from 0.01 to

of this study on the original cohort of 133 workers to 1980 found 4 new cases of lung cancer, 3 of

which were in the subcohort of 24 men (O/E=6/0.135, SMR=4,444) (Langård and Vigander 1983). At

least two of the patients in the original study (Langård and Norseth 1975) and all three of the patients in

the follow-up were smokers or ex-smokers, and one may have been exposed to asbestos. However, the

authors did not consider smoking an important confounding factor, since smoking alone could not

account for the extreme findings (Langård and Vigander 1983).

In a study of workers exposed to lead chromate and zinc chromate at five chromate pigment factories in

Germany and Norway, the cohorts consisted of men employed for >6 months from 1965 to 1976 in any of

the five factories. The cohorts at Factories 1, 2, 3, 4, and 5 consisted of 319, 141, 97, 174, and 247 men,

respectively. Because of differences (not specified) between the factories, a pooled evaluation was

precluded. Cause-specific expected numbers of death were calculated from mortality rates in each of the

districts in Germany or Norway in which the factories were located. An increased risk of lung cancer was

found only at Factory 2. At this factory, there were 9 deaths among 141 men compared with 9.963

expected. Of the nine deaths, two were due to lung cancer, compared with 0.789 expected

(O/Ex100=386, p<0.05). When the cohorts at each factory were categorized by duration of exposure (i.e.,

0–4 years, 5–10 years, or >10 years), a significantly increased risk of lung cancer was found only at

Factory 3. At this factory, two deaths from lung cancer, compared with 0.287 expected (O/Ex100=697,

p<0.01), occurred among 51 workers exposed for 0–4 years, but no increased-risk lung cancer was found

in workers with longer durations. When subcohorts from each factory were subdivided into those with

unambiguous low exposure, medium exposure, and high exposure, no significant increased risk of lung

cancer was found for any of these categories at Factories 1, 4, or 5. At Factory 2, a significantly

increased risk of lung cancer was found only for those categorized with medium exposure (n=36)

(O/Ex100=862, p<0.05). At Factory 3, a significantly increased risk of lung cancer was found only for

those categorized with high exposure (n=46) (O/Ex100=749, p<0.01). An unexplainable, significantly

high risk of death from lung cancer was found in maintenance workers at Factories one and five

(Frentzel-Beyme 1983). While this study suggests that working in a chromate pigment factory was

associated with increased risks of lung cancer, it was unable to resolve the issue regarding the relative

CHROMIUM 66

2. HEALTH EFFECTS

carcinogenicity of lead chromate and zinc chromate because mixed exposure occurred at all of the

factories. Furthermore, exposure levels were not measured, smoking histories were not available for the

entire cohort or for most of the cancer cases, and the individual cohort sizes were relatively small.

Workers exposed to lead and zinc chromate in a chromate pigment manufacturing factory in France have

who were not deceased before 1958. The reference group was the male population of the subdivision in

northern France in which the factory was located. During the 20-year period, 50 deaths occurred among

the workers, but causes of death were known for only 30. Of these 30 deaths, 11 were due to lung cancer

diagnosed in 1978 and 1979. The average latency period was 17.01 years for the 14 total cases of lung

cancer. All but one of the lung cancer cases were smokers or former smokers, but the authors stated that

the workers probably smoked no more than the general population because deaths due to other causes

associated with smoking were not increased (Haguenoer et al. 1981). No exposure data were provided,

and the study could not resolve the issues regarding the relative carcinogenicity of zinc chromate and lead

chromate.

A study was conducted on 977 male painters who had worked for at least 3 months within 10 years prior

to 1959 at two U.S. military aircraft maintenance bases where spray painting utilized zinc chromate

primer paint. They were followed through 1977. There were 21 deaths due to respiratory cancers,

compared with 11.4 expected based on national rates (SMR=184, p<0.01). When compared with national

proportionate cancer mortality rates, however, the excess (SMR=146) was not significant (Dalager et al.

1980).

negative results, but they generally support the conclusion that chromium(VI) is carcinogenic. In an

analysis of the cause of death among 172 white male and 49 white female employees engaged for at least

10 years in die-casting and electroplating at an automobile hardware manufacturing plant in the United

States, statistically significant SMRs were found for all cancers in men (O/E=53/39.39, SMR=135,

p<0.05), for respiratory system cancers in men (O/E=30/15.37, SMR=195, p<0.001) and women

(O/E=10/2.80, SMR=357, p<0.001), and for lung cancer specifically in men (O/E=28/14.68, SMR=191,

p<0.0.001) and women (O/E=10/2.70, SMR=370, p<0.001). The SMR for lung cancer was significant in

matched to a study population of referents of the same sex and race who died of cardiovascular disease,

CHROMIUM 67

2. HEALTH EFFECTS

an association was found between lung cancer and work in certain departments where there were mixed

exposures to die-casting emissions and plating mists (Silverstein et al. 1981). A specific causative agent

could not be identified from this study, and exposure concentrations were not analyzed. Although the

smoking habits of the workers were not assessed, the lack of an increase in other smoking-related

illnesses (emphysema, coronary heart disease, bladder cancer) was considered evidence that the increased

risk of lung cancer was not due to smoking.

A study of 276 male electroplaters who were exposed to chromic acid and had worked for at least

3 months within 10 years prior to 1959 at two U.S. military aircraft maintenance bases and followed

through 1977 found no excess of cancer compared with national rates (Dalager et al. 1980).

Although a significant increase in the incidence of death from all malignant diseases was found, no

significant differences were found for lung cancer or stomach cancer among 1,238 past and current

chrome platers in 54 facilities in Yorkshire, United Kingdom, compared with a control group of

1,099 workers in other departments (Royle 1975a). However, another mortality study of a cohort of

2,689 (1,288 men, 1,401 women) chrome platers employed for at least 6 months in a different plant in the

United Kingdom between 1946 and 1975 found excess risks for several types of cancer, compared with

the mortality rates for England and Wales. Statistically significant excesses among male workers were as

follows: stomach cancer (O/E=21/11.3, SMR=186, p<0.05); primary liver cancer (O/E=4/0.6, SMR=667,

p<0.01); nose and nasal cavity cancer (O/E=2/0.2, SMR=1,000, p<0.05); cancer of the lungs and bronchi

(O/E=63/40.0, SMR=158, p<0.001), and all cancers (O/E=142/96.9, SMR=147, p<0.001). No excesses

were found for women alone. Most of the excesses in men were attributed to working in the chrome bath

works, where exposures were mainly to chromium(VI) as chromic acid. The correlation with duration of

chrome bath work was positive only for cancers of the lung and bronchus. Exact exposure concentrations

were not known, but the contribution of nickel exposure to the effects was found to be unimportant.

While data on smoking habits were not available, the investigators did not believe that duration of chrome

employment would correlate with smoking habits (Sorahan et al. 1987). In a follow-up to this study,

Sorahan et al. (1998) examined mortality rates in this cohort of chrome workers for the period of

1946–1995. The job history data were further refined and workers with presumably no exposure to

chromium were removed from the analyses, resulting in a cohort of 1,762 chrome workers (812 men and

950 women). As with the first study, mortality rates were compared to mortality rates for England and

Wales. Significant excess risks of lung cancer were observed among males and females working in the

chrome bath area for <1 year (SMR=172; 95% confidence interval [CI]=112–277; p<0.05) or greater than

5 years (SMR=320; 95% CI=128–658; p<0.001), females working in the chrome bath area for <1 year

CHROMIUM 68

2. HEALTH EFFECTS

(females: SMR=245; 95% CI=118–451; p<0.5), males starting chrome work in the period of 1951–1955

(SMR=210; 95% CI=132–317; p<0.01), and in male chrome workers 10–19 years after first chrome work

(SMR=203; 95% CI=121–321; p<0.01). A significant (p<0.01) positive trend for lung cancer mortality

and duration of exposure was found for the male chrome bath workers, but not for the female workers.

Lung cancer mortality risks were also examined using an internal standard approach, in which mortality

in chrome workers was compared to mortality in workers without chromium exposure. After adjusting

for sex, age, calendar period, year of starting chrome work, period from first chrome work, and

employment status, a significant positive trend (p<0.05) between duration of chrome bath work and lung

cancer mortality risk was found.

No increase in lung cancer death was found in a cohort of 889 male and 63 female chrome platers in

Japan compared with a control group of 2,514 men and 1,722 women (Okubo and Tsuchiya 1977, 1979)

or in a follow-up cohort of 626 male chrome platers who were employed for at least 6 months in 415

plants in Japan from 1970 to 1976 (Takahashi and Okubo 1990).

However, results of a retrospective cohort study of 178 workers in nine chrome plating plants in Italy

suggested an association between lung cancer and "hard" (thick) chrome plating as opposed to "bright"

(thin) chrome plating. The cohort members had been employed for at least 1 year during 1951–1981.

Death from any cancer was observed in 7 of the 116 hard platers compared with 2.7 expected (SMR=259,

p=0.02). An excess of death from lung cancer was observed only among hard platers (O/E=3/0.7,

SMR=429, p=0.03). Workroom monitoring in 1980 for hard platers, when improvements in industrial

reported (Franchini et al. 1983). However, prior to improvements in industrial hygiene, airborne levels of

bright plating (Guillemin and Berode 1978). Although this study suggests that hard chrome platers may

have an increased risk of lung cancer, the cohort size and the number of lung cancer deaths were small,

precluding definitive conclusions.

In addition to lung, nasal, and possibly stomach cancer, exposure to chromium(VI) in the electroplating

industry may also be associated with oral cavity cancer. In 77 employees of chromium electroplating

factories in Czechoslovakia, 16 growths in the oral cavity were found in 14 individuals. Histological

CHROMIUM 69

2. HEALTH EFFECTS

examination of three of the growths led to the diagnosis of papilloma, which was considered to be a

precancerous lesion. All of the papillomas were found to contain chromium (mean 9.25 mg %), and were

believed to be due to chromium exposure via mouth breathing. Analysis of the breathing zone of the

(Hanslian et al. 1967).

study of 1,221 stainless steel welders in the former Federal Republic of Germany found no increased risk

of lung cancer or any other specific type of malignancy compared with 1,694 workers involved with

mechanical processing (not exposed to airborne welding fumes) or with the general population of the

former Federal Republic of Germany (Becker et al. 1985). A follow-up study (Becker 1999) which

extended the observation period to 1995, found similar results for lung (includes bronchus and trachea)

cancer (SMR=121.5, 95% CI=80.7–175.6). An excess risk of pleura mesothelioma was observed

(SMR=1179.9; 95% CI=473.1–2430.5); however, this was attributed to asbestos exposure. A study of

234 workers from eight companies in Sweden, who had welded stainless steel for at least 5 years during

the period of 1950–1965 and followed until 1984, found five deaths from pulmonary tumors, compared

with two expected (SMR=249), based on the national rates for Sweden. The excess was not statistically

significant. However, when the incidence of lung cancer in the stainless steel welders was compared with

an internal reference group, a significant difference was found after stratification for age. The average

concentration of chromium(VI) in workroom air from stainless steel welding, determined in 1975, was

were also exposed to nickel fumes. Smoking was probably not a confounding factor in the comparisons

with the internal reference group. Further studies of stainless steel welders were recommended.

In a study of the mortality patterns in a cohort of 4,227 workers involved in the production of stainless

steel from 1968 to 1984, information was collected from individual job histories, and smoking habits

were obtained from interviews with workers still active during the data collection (Moulin et al. 1993).

The observed number of deaths was compared to expected deaths based on national rates and matched for

age, sex, and calender time. No significant excess risk of lung cancer was noted among workers

employed in melting and casting stainless steel [SMR=104]. However, there was a significant excess

among stainless steel foundry workers [SMR=229]. The SMR increased for workers with length of

employment over 30 years to 334 (119–705). No measurements of exposure were provided.

CHROMIUM 70

2. HEALTH EFFECTS

No significant increase in the incidence of lung cancer was found among 1,876 employees who worked in

a ferrochromium plant in Sweden for at least 1 year from 1930 to 1975 compared with the expected rates

for the county in which the factory was located. The workers had been exposed mainly to metallic

chromium and chromium(III), but chromium(VI) was also present. The estimated levels ranged from 0 to

An excess of lung cancer was found in a study of 325 male workers employed for >1 year in a

ferrochromium producing factory in Norway between 1928 and 1977, and whose employment began

before 1960. The rates of cancer deaths in the ferrochromium workers were compared with national and

local rates. Seven cases of lung cancer were found in the ferrochromium workers compared with 3.1

expected using the national rate (SMR=226, p=0.08) and 1.8 expected using the local rate (SMR=389,

p=0.06). When the internal reference group of ferrosilicon workers was used, the SMR was 850

(p=0.026). Because the internal reference group was recruited from the same local population as the

ferrochromium group, it was considered to be the most valid basis for comparison. Workroom

monitoring in 1975 indicated that the ferrochromium furnace operators worked in an atmosphere with

1980). Smoking was not believed to be a confounding factor because the percentage of smokers in the

cohort in 1976 was similar to that of the Norwegian population. A follow-up of this study to include

workers whose employment began before 1965 expanded the cohort of ferrochromium workers to 379

and the follow-up period to 1985. Ten cases of lung cancer were found among the 379 ferrochromium

workers (SMR=154, not significant), while 12 cases of prostate cancer (SMR=151) and 5 of kidney

cancer (SMR=273) were found. SMRs were determined by comparison to the national rates. The

statistical significance of the SMRs for prostate and kidney cancer was not reported, but the etiology was

considered to be due to factors (not characterized) other than chromium exposure (Langård et al. 1990).

An internal reference group of ferrosilicon workers was not used in the follow-up study.

concentration specified) (Pippard et al. 1985), and in the Federal Republic of Germany (no concentration

specified) (Korallus et al. 1974a) reported no association between exposure to chromium(III) and excess

risk of cancer.

epidemiology study was conducted of 810 lung cancer deaths in residents of a county in Sweden where

CHROMIUM 71

2. HEALTH EFFECTS

two ferrochromium alloy industries are located. No indication was found that residence near these

industries is associated with an increased risk of lung cancer (Axelsson and Rylander 1980).

A retrospective mortality study conducted on a population who resided in a polluted area near an alloy

plant that smelted chromium in the People's Republic of China found increased incidences of lung and

stomach cancer. The alloy plant began smelting chromium in 1961 and began regular production in 1965,

at which time sewage containing chromium(VI) dramatically increased. The population was followed

from 1970 to 1978. The size of the population was not reported. The adjusted mortality rates of the

exposed population ranged from 71.89 to 92.66 per 100,000, compared with 65.4 per 100,000 in the

general population of the district. The adjusted mortality rates for lung cancer ranged from 13.17 to 21.39

per 100,000 compared with 11.21 per 100,000 in the general population. The adjusted mortality rates for

stomach cancer ranged from 27.67 to 55.17 per 100,000 and were reported to be higher than the average

rate for the whole district (control rates not reported). The higher cancer rates were found for those who

lived closer to the dump site (Zhang and Li 1987). Attempts to abate the pollution from chromium(VI)

introduced in 1967 also resulted in additional pollution from sulfate and chloride compounds. It was not

possible to estimate exposure levels based on the description of the pollution process. The exposed

population was probably exposed by all environmentally relevant routes (i.e., air, drinking water, food,

soil).

A follow-up study reevaluated this cohort; the adjusted total cancer death rates for the six areas analyzed

were 68.8, 68.4, 64.7, 54.3, 57.5, and 45.9 (Zhang and Li 1997) . These rates were comparable to the

overall provincial rate of 66.1 in which the 6 exposed regions were located. When total cancer mortality

rates from five villages of the areas using the contaminated water were combined, a significant increase in

cancer incidence was observed over provincial incidences. However, total cancer incidences, stomach

cancer incidence, or lung cancer incidence did not correlate with the degree of exposure to chromium(VI),

with the villages exposed to the lowest drinking water levels having the higher incidences. The authors

commented that these more recent analyses of the data probably reflect lifestyle or environmental factors

rather than exposure to chromium(VI) being responsible for cancer in these regions.

The studies in workers exposed to chromium compounds clearly indicate that occupational exposure to

chromium(VI) is associated with an increased risk of respiratory cancer. Using data from the Mancuso

(1975) study and a dose-response model that is linear at low doses, EPA (1984a) derived a unit risk

CHROMIUM 72

2. HEALTH EFFECTS

Chronic inhalation studies provide evidence that chromium(VI) is carcinogenic in animals. Mice exposed

compared to controls (Nettesheim et al. 1971). Lung tumors were observed in 3/19 rats exposed to

The tumors included two adenomas and one adenocarcinoma. No lung tumors were observed in 37

incidence of lung tumors in the treated rats was significant by the Fisher Exact Test (p=0.03) performed

by Syracuse Research Corporation.

Several chronic animal studies reported no carcinogenic effects in rats, rabbits, or guinea pigs exposed to

et al. 1959b; Steffee and Baetjer 1965).

significant increased incidence of tumors (Lee et al. 1989).

The Cancer Effect Levels (CELs) are recorded in Table 2-1 and plotted in Figure 2-1.

Cases of accidental or intentional ingestion of chromium that have resulted in death have been reported in

the past and continue to be reported even in more recent literature. In many cases, the amount of ingested

chromium was unknown, but the case reports provide information on the sequelae leading to death. For

example, a 22-month-old boy died 18.5 hours after ingesting an unknown amount of a sodium dichromate

solution despite gastric lavage, continual attempts to resuscitate him from cardiopulmonary arrest, and

other treatments at a hospital. Autopsy revealed generalized edema, pulmonary edema, severe bronchitis,

acute bronchopneumonia, early hypoxic changes in the myocardium, liver congestion, and necrosis of the

liver, renal tubules, and gastrointestinal tract (Ellis et al. 1982). Another case report of a 1-year-old girl

who died after ingesting an unknown amount of ammonium dichromate reported severe dehydration,

CHROMIUM 73

2. HEALTH EFFECTS

caustic burns in the mouth and pharynx, blood in the vomitus, diarrhea, irregular respiration, and labored

breathing. The ultimate cause of death was shock and hemorrhage into the small intestine (Reichelderfer

1968).

Several reports were available in which the amount of ingested chromium compound could be estimated.

A 17-year-old male died after ingesting 29 mg chromium(VI)/kg as potassium dichromate in a suicide.

Despite attempts to save his life, he died 14 hours after ingestion from respiratory distress with severe

hemorrhages. Caustic burns in the stomach and duodenum and gastrointestinal hemorrhage were also

found (Clochesy 1984; Iserson et al. 1983).

A few reports have described death of humans after ingesting lower doses of chromium(VI). In one case,

a 14-year-old boy died 8 days after admission to the hospital following ingestion of 7.5 mg

chromium(VI)/kg as potassium dichromate from his chemistry set. Death was preceded by

gastrointestinal ulceration and severe liver and kidney damage (Kaufman et al. 1970). In another case, a

44-year-old man died of severe gastrointestinal hemorrhage 1 month after ingesting 4.1 mg

chromium(VI)/kg as chromic acid (Saryan and Reedy 1988).

dichromate, potassium dichromate, and ammonium dichromate) range from 13 to 19 mg

chromium(VI)/kg in female rats and from 21 to 28 mg chromium(VI)/kg in male rats (Gad et al. 1986).

chromium(VI)/kg for female and male rats, respectively (American Chrome and Chemicals 1989). An

Pokhodzie 1980). Twenty percent mortality was observed when female Swiss Albino mice were exposed

to potassium dichromate(VI) in drinking water at a dose of 169 mg chromium(VI)/kg/day (Junaid et al.

1996a). Similar exposure to a dose level of 89 mg chromium(VI)/kg/day resulted in 15% mortality

among female rats of the Druckrey strain (Kanojia et al. 1998). The disparity between this dose and the

values in rats of 2,365 mg chromium(III)/kg as chromium acetate (Smyth et al. 1969) and 183 and 200 mg

chromium(III)/kg as chromium nitrate in female and male rats, respectively (Vernot et al. 1977). The

lower toxicity of chromium(III) acetate compared with chromium(III) nitrate may be related to solubility;

CHROMIUM 74

2. HEALTH EFFECTS

chromium(III) acetate is less soluble in water than is chromium(III) nitrate. Signs of toxicity included

chromium(VI) or chromium(III) compounds indicate that female rats are slightly more sensitive to the

Table 2-2 and plotted in Figure 2-2. Mortality was not increased in rats fed 2,040 mg

chromium(III)/kg/day as chromium oxide in the diet 5 days/week for 2 years (Ivankovic and Preussmann

1975).

The systemic effects of oral exposure to chromium(III) and chromium(VI) compounds are discussed

below. The highest NOAEL values and all reliable LOAEL values for each systemic effect in each

species and duration category are recorded in Table 2-2 and plotted in Figure 2-2.

No studies were located regarding musculoskeletal and ocular effects in humans or animals after oral

exposure to chromium or its compounds.

have described respiratory effects as part of the sequelae leading to death. A 22-month-old boy who

ingested an unknown amount of sodium dichromate died of cardiopulmonary arrest. Autopsy revealed

pleural effusion, pulmonary edema, severe bronchitis, and acute bronchopneumonia (Ellis et al. 1982).

Autopsy of a 17-year-old male who committed suicide by ingesting 29 mg chromium(VI)/kg as potassium

dichromate revealed congested lungs with blood-tinged bilateral pleural effusions (Clochesy 1984;

Iserson et al. 1983). Respiratory effects were not reported at nonlethal doses.

No studies were located regarding respiratory effects in animals after oral exposure to chromium(VI)

compounds. Dietary exposure of rats to 2,040 mg chromium(III)/kg/day as chromium oxide 5 days/week

for 2 years did not cause abnormalities, as indicated by histopathological examination of the lungs

(Ivankovic and Preussmann 1975).

have described cardiovascular effects as part of the sequelae leading to death. A 22-month-old boy who

ingested an unknown amount of sodium dichromate died of cardiopulmonary arrest. Autopsy revealed

early hypoxic changes in the myocardium (Ellis et al. 1982). In another case, cardiac output, heart rate,

CHROMIUM 92

2. HEALTH EFFECTS

and blood pressure dropped progressively during treatment in the hospital of a 17-year-old male who had

ingested 29 mg chromium(VI)/kg as potassium dichromate. He died of cardiac arrest. Autopsy revealed

hemorrhages in the anterior papillary muscle of the left ventricle (Clochesy 1984; Iserson et al. 1983).

Cardiovascular effects have not been reported at nonlethal doses.

No reliable studies were located regarding cardiovascular effects in animals after oral exposure to

chromium(VI) compounds. Histological examination revealed no lesions in the hearts of rats exposed to

2,040 mg chromium(III)/kg/day as chromium oxide in the diet 5 days/week for 2 years (Ivankovic and

Preussmann 1975), or in rats exposed to 0.46 mg chromium(III)/kg/day as chromium acetate in drinking

water for 2–3 years (Schroeder et al. 1965). Neither of these studies assessed cardiovascular end points

such as blood pressure or electrocardiograms.

chromium(VI) compounds have been reported. In one study, a 14-year-old boy who died after ingesting

7.5 mg chromium(VI)/kg as potassium dichromate experienced abdominal pain and vomiting before

death. Autopsy revealed gastrointestinal ulceration (Kaufman et al. 1970). In another study, a 44-yearold

man died of gastrointestinal hemorrhage after ingesting 4.1 mg chromium(VI)/kg as chromic acid

solution (Saryan and Reedy 1988). Gastrointestinal burns and hemorrhage have also been described as

contributing to the cause of death of infants who ingested unknown amounts of sodium dichromate (Ellis

chromium(VI)/kg as potassium dichromate (Clochesy 1984; Iserson et al. 1983).

Some chromium(VI) compounds, such as potassium dichromate and chromium trioxide, are caustic and

irritating to mucosal tissue. A 25-year-old woman who drank a solution containing potassium dichromate

experienced abdominal pain and vomited (Goldman and Karotkin 1935). Two people who ate oatmeal

contaminated with potassium dichromate became suddenly ill with severe abdominal pain and vomiting,

followed by diarrhea (Partington 1950). Acute gastritis developed in a chrome plating worker who had

accidentally swallowed an unreported volume of a plating fluid containing 300 g chromium trioxide/L.

He was treated by hemodialysis, which saved his life (Fristedt et al. 1965).

Ingestion of chromium compounds as a result of exposure at the workplace has occasionally produced

gastrointestinal effects. In a chrome plating plant where poor exhaust resulted in excessively high

concentrations of chromium trioxide fumes, in addition to symptoms of labored breathing, dizziness,

headache, and weakness from breathing the fumes during work, workers experienced nausea and

CHROMIUM 93

2. HEALTH EFFECTS

vomiting upon eating on the premises (Lieberman 1941). Gastrointestinal effects were also reported in an

epidemiology study of 97 workers in a chromate plant exposed to dust containing both chromium(III) and

chromium(VI) compounds. Blocked nasal passages, as a result of working in the dust laden atmosphere,

forced the individuals to breathe through their mouths, thereby probably ingesting some of the chromium

dust. A 10.3% incidence of gastric ulcer formation and a 6.1% incidence of hypertrophic gastritis was

reported. Epigastric and substernal pain were also reported in the chromate production workers (Mancuso

1951). Gastric mucosa irritation resulting in duodenal ulcer, possibly as a result of mouth breathing, has

also been reported in other studies of chromate production workers (Sassi 1956; Sterechova et al. 1978).

Subjective symptoms of stomach pain, duodenal ulcers, gastritis, stomach cramps, and indigestion were

facility where zinc, cadmium, nickel, tin, and chromium plating were carried out (Lucas and Kramkowski

1975). An otolaryngological examination of 77 employees of eight chromium electroplating facilities in

Czechoslovakia, where the mean level in the breathing zone above the plating baths was 0.414 mg

atrophic changes in the left larynx (Hanslian et al. 1967). These effects were probably also due to

exposure via mouth breathing.

In a cross sectional study conducted in 1965 of 155 villagers whose well water contained 20 mg

chromium(VI)/L as a result of pollution from an alloy plant in the People's Republic of China,

associations were found between drinking the contaminated water and oral ulcer, diarrhea, abdominal

pain, indigestion, and vomiting. The alloy plant began chromium smelting in 1961 and began regular

production in 1965. Similar results were found in two similar studies in other villages, but further details

were not provided (Zhang and Li 1987). The 20 mg chromium(VI)/L concentration is equivalent to a

dose of 0.57 mg chromium(VI)/kg/day, using a default reference water consumption rate and body weight

value of 2 L/day and 70 kg, respectively (note that these values may not be appropriate for the Chinese

study population).

Gastrointestinal hemorrhage was observed in rats given a lethal gavage dose of potassium dichromate

(130 mg chromium(VI)/kg) (Samitz 1970). No adverse effects were observed in rats fed 2,040 mg

chromium(III)/kg/day as chromium oxide in the diet 5 days/week for 2 years, as indicated by

histopathology of the stomach and small intestine (Ivankovic and Preussmann 1975).

CHROMIUM 94

2. HEALTH EFFECTS

ingestion of lethal or sublethal doses of chromium(VI) compounds. In a case of an 18-year-old woman

who ingested a few grams of potassium dichromate, decreased hemoglobin content and hematocrit, and

increased total white blood cell counts, reticulocyte counts, and plasma hemoglobin were found 4 days

after ingestion. These effects were indicative of intravascular hemolysis (Sharma et al. 1978). A 25-yearold

woman who drank a solution containing potassium dichromate had a clinically significant increase in

leukocytes due to a rise in polymorphonuclear cells (Goldman and Karotkin 1935). In another study, a

44-year-old man had decreased hemoglobin levels 9 days after ingestion of 4.1 mg chromium(VI)/kg as

chromic acid solution that probably resulted from gastrointestinal hemorrhage (Saryan and Reedy 1988).

Inhibition of blood coagulation was described in a case of a 17-year-old male who died after ingesting

following severe hemorrhaging developed in a chrome plating worker who had accidentally swallowed an

unreported volume of a plating fluid containing 300 g chromium trioxide/L. He was treated by

hemodialysis, which saved his life (Fristedt et al. 1965).

In a cross sectional study conducted in 1965 of 155 villagers whose well water contained 20 mg

chromium(VI)/L as a result of pollution from an alloy plant in the People's Republic of China,

associations were found between drinking the contaminated water and leukocytosis and immature

neutrophils. The alloy plant began chromium smelting in 1961 and began regular production in 1965.

Similar results were found in two similar studies in other villages, but further details were not provided

(Zhang and Li 1987). The 20 mg chromium(VI)/L concentration is equivalent to a dose of 0.57 mg

chromium(VI)/kg/day.

Minor hematological effects were observed in animals after oral exposure to chromium(VI), but no

hematological effects were observed in animals after oral exposure to chromium(III) compounds.

Routine hematological examination revealed no changes in rats exposed to 3.6 mg chromium(VI)/kg/day

as potassium chromate in the drinking water for 1 year (MacKenzie et al. 1958). In feeding studies of

potassium dichromate in rats and mice, the only hematological effects consisted of slightly reduced mean

corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) values (NTP 1996a, 1996b, 1997).

In rats and mice fed potassium dichromate for 9 weeks, MCV and MCH values were decreased at the

highest concentration only, which was equivalent to 8.4 and 9.8 mg chromium(VI)/kg/day in male and

female rats, respectively (NTP 1996b) and 32.2 and 48 mg chromium(VI)/kg/day in male and female

mice respectively (NTP 1996a). These effects did not occur at lower dietary concentrations equivalent to

CHROMIUM 95

2. HEALTH EFFECTS

chromium(VI)/day for male and female mice, respectively. In a multigeneration study of mice given

16 and 36.7 mg chromium(VI)/kg/day and decreased MCH values at 36.7 mg chromium(VI)/kg/day

chromium(VI)/kg/day. Since 7.8 mg chromium(VI)/kg/day was the lowest dose in the study, a no effect

level was not identified. Although the statistically significant decreases in MCVs and MCH values were

small and often within normal ranges for these species, the consistent finding of these effects in the three

studies led NTP to conclude that potassium dichromate exposure did result in slight hematopoietic

toxicity.

No hematological abnormalities were found in rats fed diets providing 1,806 mg chromium(III)/kg/day as

chromium oxide 5 days/week for 90 days (Ivankovic and Preussmann 1975), or in rats exposed to 3.6 mg

chromium(III)/kg/day as chromium trichloride in the drinking water for 1 year (MacKenzie et al. 1958).

chromium(VI) compounds. Liver damage, evidenced by the development of jaundice, increased

bilirubin, and increased serum lactic dehydrogenase, was described in a case of a chrome plating worker

who had accidentally swallowed an unreported volume of a plating fluid containing 300 g chromium

trioxide/L (Fristedt et al. 1965). In a 14-year-old boy who died after ingesting 7.5 mg chromium(VI)/kg

as potassium dichromate, high levels of the liver enzymes, glutamic-oxaloacetic transaminase (aspartate

aminotransferase) and glutamic-pyruvic transaminase (alanine aminotransferase), were found in the serum

24 hours after ingestion. Upon postmortem examination, the liver had marked necrosis (Kaufman et al.

1970).

Effects on the liver of rats exposed to chromium compounds have been detected by biochemical and

histochemical techniques. Rats treated by gavage with 13.5 mg chromium(VI)/kg/day as potassium

chromate for 20 days had increased accumulations of lipids (Kumar and Rana 1982) and changes and

relocalization of liver enzymes (alkaline phosphatase, acid phosphatase, glucose-6-phosphatase,

cholinesterase, and lipase) (Kumar et al. 1985), as determined by histochemical means. No

morphological changes, however, were detected in the livers of rats exposed to 3.6 mg

chromium(VI)/kg/day as potassium chromate in the drinking water for 1 year (MacKenzie et al. 1958). In

another study, no treatment-related histological changes in liver cells were observed in groups of

Sprague-Dawley rats containing 24 males and 48 females that were exposed to chromium(VI) as

potassium dichromate in the diet for 9 weeks followed by a recovery period of 8 weeks (NTP 1996b).

CHROMIUM 96

2. HEALTH EFFECTS

Average daily ingestion of chromium(VI) for males was 1, 3, 6, and 24 mg/kg/day and 1, 3, 7, and

28 mg/kg/day for females. Although no indication of hepatic effects was found in mice exposed to

found in a 9-week feeding study in mice exposed to 1.1, 3.5, 7.4, and 32 mg chromium(VI)/kg/day for

males and 1.8, 5.6, 12, and 48 mg chromium(VI)/kg/day for females (NTP 1996a). Hepatocyte

cytoplasmic vacuolization occurred in 1/6 males at 3.5 mg/kg/day, 2/5 males at 7.4 mg/kg/day, and

2/6 males at 32 mg/kg/day, and in 1/12 control females, 0/12 females at 1.8 mg/kg/day, 3/12 females at

5.6 mg/kg/day, 2/12 females at 12 mg/kg/day, and 4/12 females at 48 mg/kg/day. The vacuoles were

small, clear, and well demarcated, which is suggestive of lipid accumulation. The small number of

animals and lack of a clear dose-response preclude a definitive conclusion as to whether this effect was

toxicologically significant. Rats orally exposed to chromium(III) compounds had no evidence of liver

damage. Histological examination revealed no morphological changes in the livers of rats exposed to

2,040 mg chromium(III)/kg/day as chromium oxide in the diet 5 days/week for 2 years (Ivankovic and

Preussmann 1975), of rats exposed to 2.7 mg chromium(III)/kg/day as chromium trichloride in the

drinking water for 1 year (MacKenzie et al. 1958), of rats exposed to 9 mg chromium(III)/kg/day as

chromium chloride or chromium picolinate in the diet for 20 weeks (Anderson et al. 1997b), or of rats

exposed to 0.46 mg chromium(III)/kg/day as chromium acetate in the drinking water for 2–3 years

(Schroeder et al. 1965).

chromium(VI) compounds. Acute renal failure, characterized by proteinuria, hematuria, followed by

anuria, developed in a chrome plating worker who had accidentally swallowed an unreported volume of a

plating fluid containing 300 g chromium trioxide/L. He was treated by hemodialysis (Fristedt et al.

1965). Necrosis of renal tubules was found upon autopsy of a 22-month-old boy who died after ingesting

an unknown amount of sodium dichromate (Ellis et al. 1982) and of a 17-year-old boy who died after

ingesting 29 mg chromium(VI)/kg as potassium dichromate (Clochesy 1984; Iserson et al. 1983). A fatal

ingestion of 4.1 mg chromium(VI)/kg as a chromic acid solution in a 44-year-old man resulted in acute

tubular necrosis and renal failure (Saryan and Reedy 1988). A 14-year-old boy who ingested 7.5 mg

chromium(VI)/kg as potassium dichromate died from renal failure 8 days after he was admitted to the

hospital. Upon postmortem examination, the kidneys were pale, enlarged, and necrotic with tubular

necrosis and edema (Kaufman et al. 1970). Another case study of an 18-year-old woman who ingested a

few grams of potassium dichromate reported proteinuria, oliguria, and destruction of the tubular

epithelium of the kidneys. She regained renal function following dialysis (Sharma et al. 1978).

CHROMIUM 97

2. HEALTH EFFECTS

Proteinuria and oliguria were also observed after ingestion of potassium dichromate by a 25-year-old

woman (Goldman and Karotkin 1935).

Effects on the kidneys of rats exposed to potassium chromate have been detected by biochemical and

histochemical techniques. Rats treated by gavage with 13.5 mg chromium(VI)/kg/day for 20 days had

increased accumulation of lipids and accumulated triglycerides and phospholipids in different regions of

the kidney than controls (Kumar and Rana 1982). Similar treatment of rats also resulted in inhibition of

membrane enzymes (alkaline phosphatase, acid phosphatase, glucose-6-phosphatase, and lipase) in the

kidneys (Kumar and Rana 1984). Oliguria and proteinuria were observed in rats exposed to 100 mg

chromium(VI)/kg/day as sodium chromate in drinking water for 28 days (Diaz-Mayans et al. 1986).

However, histological examination revealed no morphological changes in the kidneys of rats exposed to

3.6 mg chromium(VI)/kg/day as potassium chromate in drinking water for 1 year (MacKenzie et al.

1958). Animals exposed to oral doses of chromium(III) compounds had no evidence of kidney damage.

Histological examination revealed no morphological changes in the kidneys of rats exposed to 2,040 mg

chromium(III)/kg/day as chromium oxide in the diet 5 days/week for 2 years (Ivankovic and Preussmann

1975), of rats exposed to 3.6 mg chromium(III)/kg/day as chromium trichloride in drinking water for

1 year (MacKenzie et al. 1958), of rats exposed to 9 mg chromium(III)/kg/day as chromium chloride or

chromium picolinate in the diet for 20 weeks (Anderson et al. 1997b), or of rats exposed to 0.46 mg

chromium(III)/kg/day as chromium acetate in the drinking water for 2–3 years (Schroeder et al. 1965).

tolerance test exacerbated the dermatitis of a building worker who had a 20-year history of chromium

contact dermatitis. A double dose led to dyshidrotic lesions (vesicular eruptions) on the hands (Goitre et

al. 1982). Dermatitis in 11 of 31 chromium-sensitive individuals worsened after ingestion of 0.036 mg

chromium(VI)/kg as potassium dichromate (Kaaber and Veien 1977). The sensitizing exposures were not

discussed or quantified.

No studies were located regarding dermal effects in animals after oral exposure to chromium or its

compounds.

intermediate-duration potassium dichromate drinking water studies. A 19% decrease in body weight gain

was observed male rats exposed to 42 mg chromium(VI)/kg/day for 12 weeks (Bataineh et al. 1997) and a

10% decrease was reported in male mice exposed to 6 mg chromium(VI)/kg/day for 12 weeks. No

CHROMIUM 98

2. HEALTH EFFECTS

changes in body weight gain were seen in rats or mice exposed to 9.8 or 48 mg chromium(VI)/kg/day,

respectively, as potassium dichromate in the diet for 9 weeks (NTP 1996a, 1996b). In contrast, gavage

administration of 40 or 60 mg chromium(VI)/kg/day as sodium dichromate resulted in a 57 and 59%

decrease in body weight gain, respectively (Chowdhury and Mitra 1995). No alterations in body weight

gain were observed in rats chronically (1 year) exposed to 3.6 mg chromium(VI)/kg/day as potassium

chromate in drinking water (Mackenzie et al. 1958).

Several studies have examined the effect of exposure to potassium dichromate in drinking water on

maternal body weight gain. An acute exposure (9 days) resulted in 8 and 24% decreases in body weight

gain in pregnant mice exposed to 101 or 152 mg chromium(VI)/kg/day, respectively (Junaid et al. 1996b).

Similarly, a decrease in maternal body weight gain was observed in pregnant mice exposed to 98 mg

chromium(VI)/kg/day as potassium dichromate for 19 days (Trivedi et al. 1989). Reduced maternal body

weight gains of 8, 14, and 21% were observed in rats exposed to 37, 70, or 87 mg chromium(VI)/kg/day

for 20 days prior to mating (Kanojia et al. 1996). Similar decreases in body weight gain (18 and 24%)

were observed in rats exposed to 89 or 124 mg chromium(VI)/kg/day, respectively, for 3 months prior to

mating (Kanojia et al. 1998). However, no alterations in maternal body weight gain were observed in a

continuous breeding study in which rats were exposed to 36.7 mg chromium(VI)/kg/day as potassium

dichromate in the diet (NTP 1997).

Dietary exposure to 9 mg chromium(III)/kg/day as chromium chloride or chromium picolinate for

20 weeks (Anderson et al. 1997b) or 3.6 mg chromium(III)/kg/day as chromium chloride (Mackenzie et

al. 1958) did not result in significant alterations in body weight gain. However, exposure to chromium

chloride in drinking water resulted in a 14 and 24% decrease in body weight gain in rats exposed to

40 mg chromium(III)/kg/day for 12 weeks (Bataineh et al. 1997) and mice exposed to 5 mg

chromium(III)/kg/day for 12 weeks (Elbetieha and Al-Hamood 1997), respectively. No alterations in

body weight gain were observed in rats or mice exposed to 0.46 or 0.48 mg chromium(III)/kg/day,

respectively, as chromium acetate for a lifetime (Schroeder et al. 1964, 1965).

The only reported effect of human exposure on the immune system was the exacerbation of chromium

dermatitis in chromium-sensitive individuals as noted for dermal effects in Section 2.2.2.2.

CHROMIUM 99

2. HEALTH EFFECTS

Splenocytes prepared from rats given potassium chromate in their drinking water at 16 mg

chromium(VI)/kg/day for 3 weeks showed an elevated proliferative response of T-and B-lymphocytes to

the mitogens, concanavalin A and liposaccharide, compared with splenocytes from control rats. A 5-fold

enhancement of the proliferative response to mitomycin C was also seen when splenocytes from rats

exposed for 10 weeks were incubated with splenocytes from nonexposed rats and additional chromium

(0.1 mg chromium(VI)/L) was added to the incubation compared to the system without added chromium.

It was suggested that these increased proliferative responses represent chromium-induced sensitization

(Snyder and Valle 1991). The LOAEL values are recorded in Table 2-2 and plotted in Figure 2-2.

The only information regarding neurological effects in humans after oral exposure to chromium(VI) is the

report of an enlarged brain and cerebral edema upon autopsy of a 14-year-old boy who died after

ingesting 7.5 mg chromium(VI)/kg as potassium dichromate (Table 2-2 and Figure 2-2). These effects

may be the result of accompanying renal failure (Kaufman et al. 1970).

A decrease in motor activity and balance was reported in rats given 98 mg chromium(VI)/kg/day as

sodium chromate in drinking water for 28 days (Diaz-Mayans et al. 1986) (Table 2-2 and Figure 2-2).

Histological examination of the brain and nervous system did not reveal abnormalities in rats fed

2,040 mg chromium(III)/kg/day as chromium oxide in the diet 5 days/week for 2 years (Ivankovic and

Preussmann 1975); however, more sensitive neurological, neurochemical, or neurobehavioral tests were

not conducted.

No studies were located regarding reproductive effects in humans after oral exposure to chromium or its

compounds.

A number of studies have reported reproductive effects in rats and mice orally exposed to chromium(VI).

Sodium dichromate(VI) was administered by gastric intubation to groups of 10 mature male Charles

Foster strain rats at levels of 20, 40, and 60 mg chromium(VI)/kg/day for 90 days (Chowdhury and Mitra

1995). Testis weight, population of Leydig cells, seminiferous tubular diameter, testicular protein, DNA,

and RNA were all significantly reduced at 40 and 60 mg chromium(VI)/kg/day. The number of

spermatogonia was not affected by treatment; however, resting spermatocytes (high dose), pachytene

CHROMIUM 100

2. HEALTH EFFECTS

spermatocytes (high dose, intermediate dose) and stage-7 spermatid (high and intermediate doses) counts

were significantly reduced and were treatment related. Testicular activity of succinic dehydrogenase was

significantly lowered in the two high-dose groups, testicular cholesterol concentrations were elevated in

dehydrogenase were significantly lowered. The authors also determined that the total testicular levels of

ascorbic acid in the two higher-dosing groups was about twice that of the control values whereas, in the

highest-treated group the total ascorbic acid levels were about half those of controls. At the low dose

decreased. The authors indicated that chromium enhanced levels of the vitamin, but at the highest dose

testicular levels became exhausted, thus decreasing the ability of the cells to reduce chromium(VI).

Significant alterations in sexual behavior and aggressive behavior were observed in male Sprague-Dawley

rats exposed to 42 mg chromium(VI)/kg/day as potassium dichromate in the drinking water for 12 weeks

(Bataineh et al. 1997). The alterations in sexual behavior included decreased number of mounts, lower

percentage of ejaculating males, and increased ejaculatory latency and post-ejaculatory interval. The

adverse effects on aggressive behavior included significant decreases in the number of lateralizations,

boxing bouts, and fights with the stud male and ventral presenting. No significant alterations in fertility

were observed when the exposed males were mated with unexposed females.

Mice exposed for 7 weeks to 15.2 mg chromium(VI)/kg/day as potassium dichromate in the diet had

reduced sperm count and degeneration of the outer cellular layer of the seminiferous tubules.

Morphologically altered sperm occurred in mice given diets providing 28 mg chromium(VI)/kg/day as

potassium dichromate (Zahid et al. 1990). No effect was found on testis or epididymis weight, and

reproduction function was not assessed. In contrast, an increase in testes weight was observed in mice

exposed to 6 mg chromium(VI)/kg/day as potassium dichromate for 12 weeks. At the next highest dose

(14 mg chromium(VI)/kg/day), decreases in seminal vesicle and preputial gland weights were observed

(Elbetieha and Al-Hamood 1997). In studies designed to confirm or refute the findings of the Zahid et al.

(1990) study, the reproductive effects of different concentrations of chromium(VI) as potassium

dichromate in the diet on BALB/c mice and Sprague-Dawley rats were investigated (NTP 1996a, 1996b).

Groups of 24 males and 48 females of each species were fed potassium dichromate(VI) in their feed

continuously for 9 weeks followed by an 8-week recovery period. For mice, the average daily ingestions

of chromium(VI) were 1.05, 3.5, 7.5, and 32.2 mg/kg/day for males and 1.8, 5.7, 12.0, and 48 mg/kg/day

for females. For rats, the average daily ingestions of chromium(VI) were 0.35, 1.05, 2.1, and

8.4 mg/kg/day for males and 0.35, 1.05, 2.45, and 9.8 mg/kg/day for females (NTP 1996b). Microscopic

CHROMIUM 101

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examinations of the ovaries showed no treatment-related effects, and examination of the testes and

epididymis for Sertoli nuclei and preleptotene spermatocyte counts in stage X or XI tubules did not reveal

any treatment-related effects.

Murthy et al. (1996) reported a number of reproductive effects in female Swiss albino mice exposed to

potassium dichromate in drinking water for 20 days. The observed effects included a significant

cycle duration at 180 mg chromium(VI)/kg/day, and histological alterations in the ovaries (e.g.,

proliferated, dilated, and congested blood vessels, pyknotic nuclei in follicular cells, and atretic follicles)

In an ancillary study, electron microscopy of selected ovarian tissues revealed ultrastructural changes

(disintegrated cell membranes of two-layered follicular cells and altered villiform cristae of mitochondria

and decreased lipid droplets in interstitial cells) in mice exposed to 1.2 mg chromium(VI)/kg/day for

90 days; the toxicological significance of these alterations is not known. The study authors suggest that

the effects observed in the interstitial cells may be due to a reduction in lipid synthesizing ability, which

could lead to decreased steroid hormone production. An increase in relative ovarian weight was observed

in female mice exposed for 12 weeks to 14 mg chromium(VI)/kg/day as potassium dichromate (Elbetieha

and Al-Hamood 1997).

Several studies have reported increases in preimplantation losses and resorptions in rats and mice exposed

to chromium(VI). Exposure of pregnant mice to 46 mg chromium(VI)/kg/day as potassium dichromate in

drinking water during gestation resulted in increased preimplantation and postimplantation loss, and

(Trivedi et al. 1989). In female Swiss albino mice exposed for 20 days prior to mating to potassium

dichromate in drinking water at concentrations that resulted in doses of 0, 52, 98, or 169 mg

chromium(VI)/kg/day and then mated, the number of corpora lutea was decreased at 169 mg/kg/day,

in female Swiss albino rats exposed to 37, 70, or 87 mg chromium(VI)/kg/day (as potassium dichromate

in the drinking water) for 20 days prior to mating (Kanojia et al. 1996). Additional reproductive effects

observed at 70 or 87 mg chromium(VI)/kg/day include decreased number of corpora lutea, decreased

number of implantations, and increased number of pre-implanation losses. A treatment-related increase in

the length of estrus cycle was significantly different from controls only in the 87 mg

CHROMIUM 102

2. HEALTH EFFECTS

chromium(VI)/kg/day group. Decreased mating, decreased fertility, and increased pre- and postimplantation

loss were observed in female Druckrey rats receiving doses of 45, 89, and 124 mg

chromium(VI)/kg/day (as potassium dichromate in the drinking water) for 3 months prior to mating; the

89 and 124 mg chromium(VI)/kg/day groups exhibited increased resorptions as well (Kanojia et al.

1998). A decrease in fertility (decreased number of implantations and viable fetuses) was observed in

male and female mice that were exposed to 6 mg chromium(VI)/kg/day as potassium dichromate for

12 weeks and then were mated with unexposed males and females (Elbetieha and Al-Hamood 1997). An

increase in the number of mice with resorptions was also observed in the exposed females.

In a multigeneration reproductive assessment by continuous breeding study of BALB/c mice were fed a

diet containing potassium dichromate(VI). Males and females were exposed to chromium for 7 days and

the 85-day mating period were examined at postnatal day 1. There were no treatment related changes in

average litters/pair, number of live and dead pups per litter, sex ratios, pup weights, or changes in

had lower mean body weights than control animals by about 7%. There were no effects on sperm number

or motility, nor were there any increases in abnormal sperm morphology. Histopathological examination

produced after 85 days were reared by the dam until weaning on post-natal day 21 then separated and

sex ratios, pup weights, or changes in gestational time between exposed groups and controls. There were

differences in organ to body weight ratios. No histological lesions were observed in liver and kidney

cells that were dose related, nor did chromium(VI) have any effects on estrous cycling.

Chromium(III) as chromium oxide did not cause reproductive effects in rats. Male and female rats fed

1,806 mg chromium(III)/kg/day as chromium oxide 5 days/week for 60 days before gestation and

throughout the gestational period were observed to have normal fertility, gestational length, and litter size

(Ivankovic and Preussmann 1975). A study by Bataineh et al. (1997) found significant alterations in

CHROMIUM 103

2. HEALTH EFFECTS

sexual behavior (reductions in the number of mounts, increased post-ejaculatory interval, and decreased

rates of ejaculation), aggressive behavior toward other males, and significantly lower absolute weight of

testes, seminal vesicles, and preputial glands in male Sprague-Dawley rats exposed to 40 mg

chromium(III)/kg/day as chromium chloride in the drinking water for 12 weeks. Male fertility indices

(assessed by impregnation, number of implantations, and number of viable fetuses) did not appear to be

adversely affected by exposure to chromium chloride, although the untreated females mated to treated

males exhibited an increase in the total number of resorptions (Bataineh et al. 1997). In contrast, a

decrease in the number of pregnant females was observed following the mating of unexposed females to

male mice exposed to 13 mg chromium(III)/kg/day as chromium chloride (Elbetieha and Al-Hamood

1997). Impaired fertility (decreased number of implantations and viable fetuses) was also observed in

females exposed to 5 mg chromium(III)/kg/day mated to unexposed males (Elbetieha and Al-Hamood

1997). This study also found increased testes and ovarian weights and decreased preputial gland and

uterine weights at 5 mg chromium(III)/kg/day. At lower concentrations of chromium chloride (9 mg

chromium(III)/kg/day in the diet for 20 weeks), no alterations in testes or epididymis weights were

observed in rats (Anderson et al. 1997b). A similar exposure to chromium(III) picolinate also did not

result in testes or epididymis weight alterations (Anderson et al. 1997b). This study did not assess

reproductive function. Mice exposed for 7 weeks to 9.1 mg chromium(III)/kg/day as chromium sulfate in

the diet had reduced sperm count and degeneration of the outer cellular layer of the seminiferous tubules.

Morphologically altered sperm occurred in mice given diets providing 42.4 mg chromium(III)/kg/day as

chromium sulfate (Zahid et al. 1990).

As discussed in greater detail in Section 2.2.2.6, the reproductive system is also a target in the developing

organism. Delayed vaginal opening and decreased relative weights of the uterus, ovaries, testis, seminal

vesicle, and preputial glands were observed in mouse offspring exposed to potassium dichromate or

chromium(III) chloride on gestational day 12 through lactation day 20 (Al-Hamood et al. 1998).

Impaired fertility was observed in the chromium(III) chloride-exposed female offspring when they were

mated with unexposed males (Al-Hamood et al. 1998); no effect on fertility was observed in the male

offspring.

The highest NOAEL value and all reliable LOAEL values for reproductive effects in each species and

duration category are recorded in Table 2-2 and plotted in Figure 2-2.

CHROMIUM 104

2. HEALTH EFFECTS

No studies were located regarding developmental effects in humans after oral exposure to chromium or its

compounds.

Several animal studies provide evidence that chromium(VI) is a developmental toxicant in rats and mice.

A series of studies (Junaid et al. 1996a; Kanojia et al. 1996, 1998) was conducted to assess whether premating

exposure to potassium dichromate would result in developmental effects. In the first study,

groups of 15 female Swiss albino mice were exposed to 0, 52, 98, or 169 mg chromium(VI)/kg/day as

potassium dichromate in drinking water for 20 days (Junaid et al. 1996a) and then mated with untreated

males. At 52 mg chromium(VI)/kg/day, there was a 17.5% post-implantation loss over controls and a

30% decrease in fetal weight. At 98 mg/kg/day, there were decreases in the number of implantation sites,

the number of live fetuses, and the fetal weight. There were also increases in the number of resorptions

and the number of pre- and post-implantation losses. At 169 mg chromium(VI)/kg/day, there was 100%

pre-implantation loss. The fetuses in the 98 mg/kg/day group had higher numbers of sub-dermal

hemorrhagic patches and kinky short tails and decreased fetal body weight and crown rump length.

Although there were no major skeletal abnormalities in any other treated animals, there was a significant

reduction in ossification at 52 mg chromium(VI)/kg/day (53% compared to 12% for controls) and

significant reduction in ossification in caudal, parietal and interparietal bones of fetuses at 98 mg

chromium(VI)/kg/day. There were no significant soft tissue deformities in any of the treated fetuses.

Although dosing occurred prior to mating, internal chromium levels remaining in females after mating

may have been toxic to the conceptus that caused adverse developmental effects.

In the second study, female Swiss albino rats were exposed to potassium dichromate concentrations in the

drinking water resulting in doses of 37, 70, or 87 mg chromium(VI)/kg/day for 20 days prior to mating

(Kanojia et al. 1996). Lower gestational weight gain, increased post-implantation loss, and decreased

number of live fetuses were observed in all treatment groups, relative to controls. Increased incidences of

reduced fetal ossification in fetal caudal bones were reported at the 70 and 87 mg chromium(VI)/kg/day

dose levels; additionally, the 87 mg chromium(VI)/kg/day dose group of fetuses exhibited increased

incidences of reduced ossification in parietal and interparietal bones, as well as significant incidences of

subdermal hemorrhagic thoracic and abdominal patches (42%), kinky tails (42%), and short tails (53%),

relative to 0% in controls. No treatment-related gross visceral abnormalities were seen.

CHROMIUM 105

2. HEALTH EFFECTS

In the third study, groups of 10 female Druckrey rats were exposed to potassium dichromate in the

drinking water for 3 months pre-mating at concentrations yielding dose levels of 45, 89, or 124 mg

chromium(VI)/kg/day (Kanojia et al. 1998). Reduced maternal gestational weight gain, increased preand

post-implantation loss, reduced fetal weight, fetal subdermal hemorrhagic thoracic and abdominal

patches, increased chromium levels in maternal blood, placenta, and fetuses, and increased incidences of

reduced ossification in fetal caudal bones were observed in all treatment groups. In addition, the 89 and

124 mg chromium(VI)/kg/day dose groups exhibited increased resorptions, reduced numbers of corpora

lutea and fetuses per litter, reduced implantations, reduced placental weight, increased incidences of

reduced ossification in fetal parietal and interparietal bones, and reduced fetal crown-rump length. No

treatment-related gross visceral abnormalities were seen.

Exposure of pregnant mice to 57 mg chromium(VI)/kg/day as potassium dichromate in drinking water

during gestation resulted in embryo lethal effects (i.e., increased resorptions and increased postimplantation

loss), gross abnormalities (i.e., subdermal hemorrhage, decreased cranial ossification, tail

kinking), decreased crown-rump length, and decreased fetal weight. The incidence and severity of

abnormalities increased at higher doses. Maternal toxicity, evidenced by decreased body weight gain,

234 mg chromium(VI)/kg/day (Trivedi et al. 1989).

Groups of 10 female Swiss albino mice received chromium(VI) as potassium dichromate in drinking

water during organogenesis on days 6–14 at levels that provided 0, 53.2, 101.1, and 152.4 mg

chromium(VI)/kg/day (Junaid et al. 1996b). No notable changes in behavior or clinical signs were

observed in control or treated animals. Reduction of gestational weight gains of 8.2 and 30% were

observed for the animals in the intermediate- and high-dose groups. The number of dead fetuses was

higher in the high-dose group and fetal weight was lower in both intermediate- and high-dose groups

(high dose = 1.06 g, intermediate dose = 1.14 g) as compared to the control value of 1.3 g. The number

of resorption sites were 0.31 for controls, 1.00 for the low dose, 1.70 for the intermediate dose, and 2.30

for the high dose, demonstrating a dose-response relationship. The studies also showed that there was a

significantly greater incidence of post-implantation loss in the two highest-dose groups of 21 and 34.60%

as compared to control value of 4.32%. No significant gross structural abnormalities in any of the treated

dosed groups were observed except for drooping of the wrist (carpal flexure) and subdermal hemorrhagic

patches on the thoracic and abdominal regions in 16% in the offspring of the high-dose group.

Significant reduced ossification in nasal frontal, parietal, interparietal, caudal, and tarsal bones were

observed only in the 152.4 mg chromium(VI)/kg/day-treated animals.

CHROMIUM 106

2. HEALTH EFFECTS

Impaired development of the reproductive system was observed in the offspring of female BALB/c mice

exposed to 66 mg chromium(VI)/kg/day as potassium chromate in the drinking water on gestation day 12

through lactation day 20 (Al-Hamood et al. 1998). A significant delay in vaginal opening was observed.

Significant decreases in the numbers of pregnant animals, of implantations, and of viable fetuses were

also observed when the female offspring were mated at age 60 days with unexposed males. No

developmental effects were observed in the male offspring.

Two studies examined the developmental toxicity of chromium(III) following oral maternal exposure. In

the first study, no developmental effects were observed in offspring of rats fed 1,806 mg

chromium(III)/kg/day as chromium oxide 5 days/week for 60 days before mating and throughout

gestation (Ivankovic and Preussmann 1975). In contrast, reproductive effects have been observed in the

offspring of mice exposed to chromium(III) chloride. Significant decreases in the relative weights of

reproductive tissues (testes, seminal vesicles, and preputial glands in males; ovaries and uterus in females)

were observed in the offspring of BALB/c mice exposed to 74 mg chromium(III)/kg/day as

chromium(III) chloride in the drinking water on gestation day 12 through lactation day 20 (Al-Hamood et

al. 1998). A significant delay in timing of vaginal opening was also noted in the female offspring. At age

60 days, the male and female offspring were mated with unexposed animals. No significant alterations in

fertility (number of pregnant animals, number of implantations, number of viable fetuses, and total

number of resorptions) were observed in the exposed males. A significant decrease in the number of

pregnant females (62.5 versus 100% in controls) was observed among the female offspring mated with

untreated males. The conflicting results between the Ivankovic and Preussman (1975) study and the Al-

Hamood et al. (1998) study may be a reflection on the developmental end points examined or the

differences in the species tested.

The NOAEL and LOAEL values for developmental effects in each species are recorded in Table 2-2 and

plotted in Figure 2-2.

No studies were located regarding genotoxic effects in humans after oral exposure to chromium or its

compounds.

No increased incidence of micronuclei in polychromatic erythrocytes was observed in mice given single

CHROMIUM 107

2. HEALTH EFFECTS

to potassium chromate via drinking water at 1–20 ppm for 48 hours or to bolus doses up to 4 µg/kg for

2 days (Mirsalis et al. 1996). Similarly in rats, no unscheduled DNA synthesis in hepatocytes was found.

However, an increase in DNA-protein crosslinking was found in the livers of rats exposed to potassium

The clastogenic effects of male Swiss albino mice fed chromium(VI) trioxide (20 mg/kg body weight) by

gavage were studied; after 24 hours, bone marrow cells were isolated and 500 metaphase plates were

scored for chromosomal aberrations (Sarkar et al. 1993). The treated cells showed a significant increase

in aberrations per cell over controls by 4.4-fold. When animals were treated simultaneously with

chlorophyllin (1.5 mg/kg), a sodium-copper derivative of chlorophyll and an antioxidant, numbers of

aberrations were reduced to nearly background levels.

Other genotoxicity studies are discussed in Section 2.5.

A retrospective mortality study conducted on a population who resided in a polluted area near an alloy

plant that smelted chromium in the People's Republic of China found increased incidences of lung and

stomach cancer. The alloy plant began smelting chromium in 1961 and began regular production in 1965,

at which time sewage containing chromium(VI) dramatically increased. The population was followed

from 1970 to 1978. The size of the population was not reported. The adjusted mortality rates of the

exposed population ranged from 71.89 to 92.66 per 100,000, compared with 65.4 per 100,000 in the

general population of the district. The adjusted mortality rates for lung cancer ranged from 13.17 to 21.39

per 100,000 compared with 11.21 per 100,000 in the general population. The adjusted mortality rates for

stomach cancer ranged from 27.67 to 55.17 per 100,000, which were reported to be higher than the

average rate for the whole district (control rates not reported). The higher cancer rates were found for

those who lived closer to the dump site (Zhang and Li 1987). No other information was provided, and it

was not possible to estimate exposure levels based on the description of the pollution process. The

exposed population was probably exposed by all environmentally relevant routes (i.e., air drinking water,

food, soil).

A follow-up study reevaluated this cohort; the adjusted total cancer death rates for the six areas analyzed

were 68.8, 68.4, 64.7, 54.3, 57.5, and 45.9 (Zhang and Li 1997). These rates were comparable to the

overall provincial rate of 66.1 in which the six exposed regions were located. When total cancer mortality

CHROMIUM 108

2. HEALTH EFFECTS

rates from five villages of the areas using the contaminated water were combined, a significant increase

in cancer incidence was observed over provincial incidences. However, total cancer incidences, stomach

cancer incidence, or lung cancer incidence did not correlate with the degree of exposure to chromium(VI),

with the villages exposed to the lowest drinking water levels having the higher incidences. The authors

commented that these more recent analyses of the data probably reflect lifestyle or environmental factors

rather than exposure to chromium(VI) being responsible for cancer in these regions.

No evidence of carcinogenicity was found in mice exposed to potassium chromate in drinking water at

9 mg chromium(VI)/kg/day for three generations (880 days). In treated mice, 2 of 66 females developed

forestomach carcinoma and 9 of 66 females and 1 of 35 males developed forestomach papilloma. The

vehicle controls also developed forestomach papilloma (2 of 79 females, 3 of 47 males) but no carcinoma.

The incidence of forestomach tumors in the treated mice was not significantly higher than controls. Coexposure

to both potassium chromate and 3,4-benzpyrene in a similar protocol showed that potassium

chromate did not potentiate the carcinogenicity of 3,4-benzpyrene (Borneff et al. 1968). No evidence of

carcinogenicity was observed in male or female rats fed diets containing chromium oxide at 2,040 mg

chromium(III)/kg/day 5 days/week for 2 years. Moreover, no evidence of carcinogenicity was found in

the offspring of these rats after 600 days of observation (Ivankovic and Preussmann 1975).

Some chromium(VI) compounds, such as, chromium trioxide (chromic acid), potassium dichromate,

potassium chromate, sodium dichromate, and sodium chromate, are very caustic and can cause burns

upon dermal contact. These burns can facilitate the absorption of the compound and lead to systemic

toxicity.

A 49-year-old man with an inoperable carcinoma of the face was treated with chromic acid crystals.

Severe nephritis occurred following the treatment with the chromium(VI) compounds. Death occurred

4 weeks after exposure (Major 1922). Twelve individuals died as a result of infection to necrotic areas of

the skin that were caused by application of a salve made up with potassium chromate used to treat

scabies. Renal failure was observed. Autopsies revealed fatty degeneration of the heart, hyperemia and

necrosis of kidney tubules, and hyperemia of the gastric mucosa (Brieger 1920).

CHROMIUM 109

2. HEALTH EFFECTS

sodium dichromate, potassium dichromate, and ammonium dichromate were determined by Gad et al.

chromium(VI)/kg for males. Signs of toxicity included dermal necrosis, eschar formation, dermal edema

recorded in Table 2-3.

Several reports of health effects in individuals treated with potassium dichromate are discussed below

(Brieger 1920; Major 1922; Smith 1931). The results of these studies should be interpreted cautiously

because pre-existing conditions may have contributed to the observed effects. The highest NOAEL value

and all reliable LOAEL values for dermal effects in each species and duration category are recorded in

Table 2-3.

mucocutaneous tissue, such as nasal and pharyngeal epithelium, due to inhalation of airborne dust and

mists of these compounds. Such exposures have led to nose and throat irritation and nasal septum

perforation. Because exposure is to airborne chromium, studies noting these effects are described in

Section 2.2.1.2.

A case report of a man who was admitted to a hospital with skin ulcers on both hands due to dermal

exposure to ammonium dichromate in a planographic printing establishment where he had worked for a

few months noted that he also had breathing difficulties. However, because he also had many previous

attacks of hay fever and asthma, it was not possible to distinguish whether his breathing difficulties were

caused by or exacerbated by dermal exposure to ammonium dichromate (Smith 1931).

No studies were located regarding respiratory effects in animals after dermal exposure to chromium or its

compounds.

CHROMIUM 115

2. HEALTH EFFECTS

exposure to chromium or its compounds is limited. Weak, thready, and markedly dicrotic pulse

of an unspecified number of individuals. Some of the people died as a result of infection to the exposed

area, and autopsy revealed degeneration of the heart (Brieger 1920).

No studies were located regarding cardiovascular effects in animals after dermal exposure to chromium or

its compounds.

chromate to the skin of an unspecified number of individuals for the treatment of scabies. Some of these

individuals died as a result of infection of the exposed area, and autopsy revealed hyperemia of the gastric

mucosa (Brieger 1920).

Diarrhea was reported in New Zealand rabbits exposed to lethal concentrations of chromium(VI)

compounds (Gad et al. 1986).

cells, myelocytes, and myeloblasts and nucleated red cells and Howell-Jolly bodies, indicative of

hemolytic anemia were observed in individuals after application of a salve that contained potassium

chromate to treat scabies (Brieger 1920). Leukocytosis was also described in a case report of a man who

was admitted to a hospital with skin ulcers on both hands due to dermal exposure to ammonium

dichromate in a planographic printing establishment, where he had worked for a few months (Smith

1931). It should be noted that the man had a history of asthma.

No studies were located regarding hematological effects in animals after dermal exposure to chromium

compounds.

exposure to chromium or its compounds is limited to a case report. A man was admitted to a hospital

with skin ulcers on both hands due to dermal exposure to ammonium dichromate in a planographic

printing establishment, where he had worked for a few months. He also had tenderness and edema of the

muscles of the extremities (Smith 1931).

CHROMIUM 116

2. HEALTH EFFECTS

No studies were located regarding musculoskeletal effects in animals after dermal exposure to chromium

or its compounds.

exposure to chromium compounds.

Information regarding liver effects in animals after dermal exposure to chromium or its compounds is

limited. A single application of 0.5% potassium dichromate (0.175% chromium(VI)) to the shaved skin

of rats resulted in increased levels of serotonin in the liver, decreased activities of acetylcholinesterase

and cholinesterase in the plasma and erythrocytes, increased levels of acetylcholine in the blood, and

increased glycoprotein hexose in the serum. These effects may indicate alterations in carbohydrate

metabolism (Merkur'eva et al. 1982).

observed in individuals after application of a salve that contained potassium chromate. These effects

disappeared in individuals who survived. Autopsy of people who died revealed hyperemia and tubular

necrosis (Brieger 1920). Acute nephritis with polyuria and proteinuria were also described in a man who

was admitted to a hospital with skin ulcers on both hands due to dermal exposure to ammonium

dichromate in a planographic printing establishment where he had worked for a few months (Smith 1931).

A 49-year-old man with an inoperable carcinoma of the face was treated with chromic acid crystals.

Severe nephritis occurred after treatment with the chromium(VI) compound. Urinalysis revealed marked

protein in the urine. Death resulted 4 weeks after exposure. A postmortem examination of the kidneys

revealed extensive destruction of the tubular epithelium (Major 1922).

No studies were located regarding renal effects in animals after dermal exposure to chromium

compounds.

effects on the nasal septum, such as ulceration and perforation. These studies are discussed in

Section 2.2.1.2 on Respiratory Effects. Dermal exposure to chromium compounds can cause contact

allergic dermatitis in sensitive individuals, which is discussed in Section 2.2.3.3. Skin burns, blisters, and

skin ulcers, also known as chrome holes or chrome sores, are more likely associated with direct dermal

contact with solutions of chromium compounds, but exposure of the skin to airborne fumes and mists of

chromium compounds may contribute to these effects.

CHROMIUM 117

2. HEALTH EFFECTS

Acute dermal exposure of humans to chromium(VI) compounds causes skin burns. Necrosis and

sloughing of the skin occurred in individuals at the site of application of a salve containing potassium

chromate. Twelve of 31 people died as a result of infection of these areas (Brieger 1920). In another

case, a man who slipped at work and plunged his arm into a vat of chromic acid had extensive burns and

necrosis on his arm (Cason 1959).

Longer-term occupational exposure to chromium compounds in most chromium-related industries can

cause deep penetrating holes or ulcers on the skin. A man who had worked for a few months in a

planographic printing establishment, where he handled and washed sheets of zinc that had been treated

with a solution of ammonium dichromate, had skin ulceration on both hands (Smith 1931).

In an extensive survey to determine the health status of chromate workers in seven U.S. chromate

production plants, 50% of the chromate workers had skin ulcers or scars. In addition, inflammation of

oral structures, keratosis of the lips, gingiva, and palate, gingivitis, and periodontis due to exposure of

these mucocutaneous tissues to airborne chromium were observed in higher incidence in the chromate

workers than in controls. Various manufacturing processes in the plants resulted in exposure of workers

chromium compounds (including basic chromium sulfate), which may or may not entirely represent

consisting of yellowing and wearing down of the teeth (Gomes 1972). In a retrospective morbidity study

of employees who had worked in a chromate production facility in North Carolina for at least 1 year from

1971, when the facility began producing chromates, to 1989, 156 of 289 workers who responded to a

questionnaire reported at least 1 occurrence of dermal chrome sores. Personal monitoring results, which

were available for 1974–1989, revealed 8-hour TWA concentrations of airborne chromium(VI) ranging

occupational exposure to chromium at other chromate production facilities, where exposure

concentrations were undoubtedly higher. Statistical analysis revealed that the chrome sores were

associated with cumulative chromium exposure, duration of employment at the North Carolina facility,

duration of previous employment at other chromate production facilities, and smoking. It was suggested

that smokers might be less likely to wear protective gloves (Pastides et al. 1991).

CHROMIUM 118

2. HEALTH EFFECTS

Irritation and ulceration of the buccal cavity, as well as chrome holes on the skin, were also observed in

workers in a chrome plating plant where poor exhaust resulted in excessively high concentrations of

chromium trioxide fumes (Lieberman 1941). Electroplaters in Czechoslovakia exposed to an average of

including chronic tonsillitis, pharyngitis, and papilloma (Hanslian et al. 1967). In a study of 303

electroplating workers in Brazil, whose jobs involve working with cold chromium trioxide solutions,

>50% had ulcerous scars on the hands, arms, and feet. Air monitoring revealed that most workers were

lesions (Gomes 1972). Chrome holes were also noted at high incidence in chrome platers in Singapore,

while controls had no skin ulcers (Lee and Goh 1988). The incidence of skin ulcers was significantly

increased in a group of 997 chrome platers compared with 1,117 controls. The workers had been exposed

levels were generally between 0.3 and 97 mg chromium(VI)/g (Royle 1975b). In a NIOSH Health

Hazard Evaluation of an electroplating facility in the United States, seven workers reported past history of

skin sores, and nine had scars characteristic of healed chrome sores. The workers had been employed for

In addition, spot tests showed widespread contamination of almost all workroom surfaces and hands

(Lucas and Kramkowski 1975).

An early report of cases of chrome ulcers in leather tanners noted that the only workmen in tanneries who

suffered chrome holes were those who handled dichromate salts. In one of these cases, the penetration

extended into the joint, requiring amputation of the finger (Da Costa et al. 1916). In a medical survey of a

chemical plant that processed chromite ore, 198 of 285 workers had chrome ulcers or scars on the hands

and arms. These workers had been exposed to one or more chromium(VI) compounds in the form of

chromium trioxide, potassium dichromate, sodium dichromate, potassium chromate, sodium chromate,

and ammonium dichromate (Edmundson 1951).

Similar dermal effects have been observed in animals. Dermal application of chromium(VI) compounds

to the clipped, nonabraded skin of rabbits at 42–55 mg/kg resulted in skin inflammation, edema, and

necrosis. Skin corrosion and eschar formation occurred at lethal doses (see Section 2.2.3.1) (Gad et al.

1986). Application of 0.01 or 0.05 mL of 0.34 molar solution of potassium dichromate (0.35 mg

chromium(VI) or 1.9 mg chromium(VI)/kg) to the abraded skin of guinea pigs resulted in skin ulcers

(Samitz 1970; Samitz and Epstein 1962). Similar application of 0.01 mL of a 1 molar solution of

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chromium sulfate (1 mg chromium(III)/kg) however, did not cause skin ulcers in guinea pigs (Samitz and

Epstein 1962).

Dermal sensitization due to hypersensitivity to chromium is discussed in Section 2.2.3.3.

area of Tokyo, Japan, in which contamination from chromium slag at a construction site was discovered

in 1973. The housewives included in the study were those who lived in the area from 1978 to 1988, and

controls included housewives who lived in uncontaminated areas. Questionnaires, physical examinations,

and clinical tests were conducted annually. Higher incidences of subjective complaints of eye irritation

were reported by the exposed population than by the control population in the early years of the survey,

but in later years the difference between the two groups became progressively less (Greater Tokyo Bureau

of Hygiene 1989).

Direct contact of the eyes with chromium compounds also causes ocular effects. Corneal vesication was

described in a worker who accidentally got a crystal of potassium dichromate or a drop of a potassium

dichromate solution in his eye (Thomson 1903). In an extensive study of chromate workers in seven U.S.

chromate production plants, eyes were examined because accidental splashes of chromium compounds

into the eye had been observed in these plants. Congestion of the conjunctiva was found in 38.7% of the

897 workers, discharge in 3.2%, corneal scaring in 2.3%, any abnormal finding in 40.8%, and burning in

17.0%, compared with respective frequencies of 25.8, 1.3, 2.6, 29.0, and 22.6% in 155 nonchromate

workers. Only the incidences of congestion of the conjunctiva and any abnormal findings were

significantly higher in the exposed workers than in the controls (PHS 1953).

Instillation of 0.1 mL of a 1,000 mg chromium(VI)/L solution of sodium dichromate and sodium

chromate (pH 7.4) was not irritating or corrosive to the eyes of rabbits (Fujii et al. 1976). Histological

no lesions (Lee et al. 1989).

In addition to the irritating and ulcerating effects, direct skin contact with chromium compounds elicits an

allergic response, characterized by eczema or dermatitis, in sensitized individuals. Numerous studies

have investigated the cause of dermatitis in patients and in workers in a variety of occupations and

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industries and have determined that chromium compounds are the sensitizing agents. In these studies,

patch tests were conducted with chromium(VI) or chromium(III) compounds using various concentrations

(see Table 2-3). In one study using 812 healthy volunteers, patch testing with a 0.5% solution of

potassium dichromate chromium(VI) revealed chromium sensitivity in 14 of the volunteers (1.7% of the

test population). Of the 14 positive reactions, 10 occurred in a group of 110 offset printers, lithographers,

and printing plant cleaners with concurrent exposure to chromium (Peltonen and Fraki 1983). Subjects

with a sensitivity to chromium and challenged with a 0.001% solution potassium dichromate had

increased skin thickness and blood flow (Eun and Marks 1990). Studies conducted on chromium(VI)

sensitive printers and lithographers indicate that chromium(VI) compounds elicit reactions more

frequently than do chromium(III) compounds (Levin et al. 1959; Mali et al. 1966; Samitz and Schrager

1966). The authors attributed this to a greater degree of permeation of the hexavalent form than the

trivalent form through the skin (see Section 2.3.1.3). Patch testing of chromium(VI)-sensitive patients

with chromium(III) compounds has revealed that high concentrations of chromium(III) compounds can

elicit an allergic reaction (Fregert and Rorsman 1964, 1966; Mali et al. 1966).

In a study of skin disease among workers at an automobile factory, 230 workers with skin disease and

66 controls were patch tested with potassium dichromate (0.175% chromium(VI)). Sensitivity to

potassium dichromate was seen in 24% of the patients and 1% of the controls. Most of the sensitive

patients were assemblers who handled nuts, bolts, screws, and washers, which were found to have

chromate on the surfaces as a result of a chromate dip used in the engine assembly process.

Discontinuation of use of the chromate dip resulted in a significant decrease in the prevalence of

dermatitis 6 months later (Newhouse 1963). Among 300–400 men directly exposed to cement dust, 8 had

clinical symptoms of cement eczema. All eight tested positive with potassium dichromate, while only

four tested positive with cement (Engebrigsten 1952). Patch testing of employees of the Baltimore and

Ohio Railroad system with a variety of chemicals revealed that in 32 of 98 cases of dermatitis, the antirust

diesel-engine coolant compound, which contained sodium chromate, was the etiological agent (Kaplan

and Zeligman 1962). Among 200 employees who worked in a diesel locomotive repair shop, 6 cases of

chromate dermatitis were diagnosed by positive patch tests to samples of radiator fluid and to 0.25%

sodium dichromate (0.09% chromium(VI)). The radiator fluid to which the workers were occupationally

exposed contained 66% sodium dichromate (Winston and Walsh 1951). A search for the source of

chromium exposure in workers who developed contact dermatitis in wet sandpapering of primer paint on

automobiles revealed that the paint contained zinc chromate (Engel and Calnan 1963).

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In a study of 1,752 patients considered to have occupational dermatoses, contact dermatitis was the main

diagnosis in 1,496 patients (92% women, 83% men). The allergic type, as opposed to the irritant type,

was more prevalent in men (73%) than in women (51%). Positive patch tests to chromium (not otherwise

specified) occurred in 8% of the women and 29% of the men. Among 280 chromium-sensitized men,

50% were employed in building and concrete work, 17% in metal work, and 12% in tanneries. In the

42 chromium-sensitized women, 20% were in cement work, 19% in metal work, 28% in cleaning, and

15% in laboratory work (Fregert 1975).

Chromate sensitivity has also been reported in women who frequently used dichromate-containing

detergent and bleach (Wahba and Cohen 1979).

Other industries and sources of chromium that have resulted in chromium sensitivity include welding,

printing, glues, wood ash, foundry sand, match heads, machine oils, timber preservative, boiler linings,

making of television screens, magnetic tapes, tire fitting, chrome plating, wood and paper industry, and

milk testing (Burrows 1983).

A study was performed on 54 volunteers who were sensitive to chromium-induced allergic contact

dermatitis to determine a dose-response relationship and to determine a minimum-elicitation threshold

concentration (MET) that produces an allergic response in sensitive individuals (Nethercott et al. 1994).

Patch testing was performed on the subjects in which the concentration of potassium chromate(VI) was

retesting was negative. Based on these findings the authors concluded that soil concentrations of

chromium(VI) and chromium(III) of 450 and 165,000 ppm, respectively, should not pose a hazard of

allergic contact dermatitis to 99.99% of people who might be exposed to chromium through soil-skin

contact.

Animals can also be sensitized to chromium compounds. Contact sensitivity was induced in mice by

abdomens. Challenge with potassium dichromate on the ear resulted in significant induction of

sensitivity, measured by ear thickness and histologically observed infiltration of nucleophilic leukocytes

(Mor et al. 1988).

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Guinea pigs can be sensitized to chromium(VI) and chromium(III) compounds by a series of intradermal

injections of 0.009 mg chromium(VI)/kg as potassium dichromate or of 0.004 mg chromium(III)/kg as

chromium trichloride. Regardless of the compound used to sensitize the guinea pigs, subsequent patch

testing with chromium(VI) or chromium(III) yielded the same erythmatic reaction. The response,

however, was greater when chromium(VI) was used as the sensitizer (Gross et al. 1968). Similarly, the

same erythmatic response to chromium(VI) and chromium(III) compounds was noted in guinea pigs

sensitized to 0.04 mg chromium(VI)/kg as potassium dichromate or 0.03 mg chromium(III)/kg as

chromium sulfate (Jansen and Berrens 1968).

No studies were located regarding the following health effects in humans or animals after dermal

exposure to chromium compounds:

Genotoxicity studies are discussed in Section 2.5.

No studies were located regarding cancer in humans or animals after dermal exposure to chromium

compounds.

The toxicokinetics of a given chromium compound depend on the valence state of the chromium atom

and the nature of its ligands. Naturally occurring chromium compounds are generally in the trivalent state

(chromium(III)), while hexavalent chromium compounds (chromium(VI)) are produced industrially by

the oxidation of chromium(III) compounds. Absorption of chromium(VI) compounds is higher than that

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diffusion through non-specific anion channels (similarly to phosphate and sulfate anions). Absorption of

chromium(III) compounds is via passive diffusion and phagocytosis. Absorption of inhaled chromium

compounds takes place in the lung via transfer across cell membranes and in the gastrointestinal tract

from particles cleared from the lungs. Absorption after oral exposure in humans varies from essentially

none for the highly insoluble chromium(III) compound chromic oxide, to 0.5–2.0% for chromium(III)

compounds in the diet, to approximately 2–10% for chromium(VI) as potassium chromate. Dermal

absorption depends on the physical and chemical properties of the compound, the vehicle, and the

integrity of the skin. Concentrated solutions of chromium(VI) compounds such as potassium chromate

can cause chemical burns and facilitate absorption. Once in the blood, chromium compounds are

distributed to all organs of the body. Particles containing chromium can be retained in the lung for years

after occupational exposure. Chromium(VI) is unstable in the body and is reduced to chromium(V),

chromium(IV), and ultimately to chromium(III) by many substances including ascorbate and glutathione.

It is believed that the toxicity of chromium(VI) compounds results from damage to cellular components

chromium(III) can be reduced to chromium(II) and exert toxic effects. Absorbed chromium is excreted

primarily in urine, the half-time for excretion of chromium administered as potassium chromate is

estimated to be 35–40 hours in humans. Hair and nails are minor pathways of excretion.

The absorption of inhaled chromium compounds depends on a number of factors, including physical and

chemical properties of the particles (oxidation state, size, solubility) and the activity of alveolar

macrophages.

The identification of chromium in urine, serum and tissues of humans occupationally exposed to soluble

chromium(III) or chromium(VI) compounds in air indicates that chromium can be absorbed from the

lungs (Cavalleri and Minoia 1985; Gylseth et al. 1977; Kiilunen et al. 1983; Mancuso 1997b; Minoia and

Cavalleri 1988; Randall and Gibson 1987; Tossavainen et al. 1980). In most cases, chromium(VI)

compounds are more readily absorbed from the lungs than chromium(III) compounds, due in part to

differences in the capacity to penetrate biological membranes. Nevertheless, workers exposed to

concentrations of chromium in the urine at the end of their shifts. Based on a one compartment kinetic

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model, the biological half-life of chromium(III) from the lignosulfonate dust was 4–10 hours which is the

same order of magnitude as the half-life for chromium(VI) compounds (Kiilunen et al. 1983).

single inhalation of chromium(VI) trioxide mist from electroplating at a concentration of 3.18 mg

in the lungs declined from 13.0 mg immediately after exposure to 1.1 mg at 4 weeks in a triphasic pattern

with an overall half-life of 5 days (Adachi et al. 1981). In another study in which rats were exposed to

chromium(VI) as potassium dichromate or to chromium(III) as chromium trichloride, the pulmonary

clearance of both valence states was dependent on particle size, but chromium(VI) was more rapidly and

extensively transported to the bloodstream than chromium(III). The rats had been exposed to

or 1.6 µm had a two-compartment pulmonary clearance curve with half-lives of 31.5 hours for the first

phase and 737 hours for the second phase. Chromium(VI) particles of 2 µm had a single component

curve with a half-life between 151 and 175 hours. Following exposure to chromium(VI), the ratio of

blood chromium/lung chromium was 1.44 at 0.5 hours, 0.81 at 18 hours, 0.85 at 48 hours, and 0.96 at

168 hours after exposure. Chromium(III) particles of 1.5–1.8 µm had a single component pulmonary

clearance curve with a half-life of 164 hours. Following exposure to chromium(III), the ratio of blood

chromium/lung chromium was 0.39 at 0.5 hours, 0.24 at 18 hours, 0.22 at 48 hours, and 0.26 at 168 hours

after exposure. Therefore, the amount of chromium(VI) transferred to the blood from the lungs was

always at least three times greater than the amount of chromium(III) transferred (Suzuki et al. 1984).

Other studies reporting absorption from the lungs are intratracheal injection studies (Baetjer et al. 1959b;

Bragt and van Dura 1983; Visek et al. 1953; Wiegand et al. 1984, 1987). These studies indicate that

53–85% of chromium(VI) compounds (particle size <5 µm) are cleared from the lungs by absorption into

the bloodstream or by mucociliary clearance in the pharynx; the rest remain in the lungs. Absorption by

the bloodstream and mucociliary clearance was only 5–30% for chromium(III) compounds.

The kinetics of three chromium(VI) compounds, sodium chromate, zinc chromate, and lead chromate,

were compared in rats in relation to their solubility. The rats received intratracheal injections of the

chromium(VI)/kg as zinc chromate, or 0.21 mg chromium(VI)/kg as lead chromate). Peak blood levels of

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for zinc chromate (0.60 µg chromium/mL) and lead chromate (0.007 µg chromium/mL). At 30 minutes

after administration, the lungs contained 36, 25, and 81% of the respective dose of the sodium, zinc, and

lead chromate. On day 6, >80% of the dose of all three compounds had been cleared from the lungs,

during which time the disappearance from lungs followed linear first-order kinetics. The residual amount

left in the lungs on day 50 or 51 were 3.0, 3.9, and 13.9%, respectively. The results indicate that zinc

lungs, but peak blood levels are higher than sodium chromate. Lead chromate was more poorly and

slowly absorbed, as indicated by very low levels in blood and other tissues, and greater retention in the

lungs (Bragt and van Dura 1983).

The fate of lead chromate(VI), chromium(VI) trioxide, chromium(III) oxide and chromium(III) sulfate

were examined when solutions or suspensions of these chemicals were slowly infused into the tracheal

lobe bronchus of sheep via bronchoscopic catheterization (Perrault et al. 1995). At 2, 3, 5, and 30 days

the samples of bronchoalveolar lavage were taken, and on day 31 the animals were sacrificed and lung

specimens were examined for chromium particulates. There was no difference in lung particle

soluble chromium(III) oxide and chromium sulfate was calculated to be 11 and 80 days, respectively.

The insoluble lead chromate particles appeared to break up, forming isometric particles of lead chromate

as well as lead-containing particulates that may have retarded clearance. Retention of chromium

particulates from exposure to soluble chromium trioxide may have resulted in the formation of a less

soluble hydroxyl complex and/or chemical interaction between chromium and protein that prolongs the

retention of the metal. Analyses of the particulates in lavage samples indicate that these diameters

increase with time for lead chromate, decrease with time for chromium sulfate and chromium trioxide,

and are unchanged for chromium(III) oxide. The authors state that their findings indicate that slightly

soluble chromium(III) oxide and chromium sulfate that are chemically stable can be cleared from lungs at

different rates, depending on the nature and morphology of the compound.

Amounts of total chromium were measured in lymphocytes, blood, and urine after intratracheal administration

of either sodium dichromate(VI) or chromium(III) acetate hydroxide (a water-soluble

chromium(III) compound) to male Wistar rats (Gao et al. 1993). The total amount of chromium

administered was 0.44 mg Cr/kg body weight for each compound. The highest concentrations in tissues

and urine occurred at 6 hours after treatment, the first time point examined. Mean chromium

concentrations (n= 4 rats per time point) from treatment with chromium(III) were 56.3 µg/L in whole

CHROMIUM 126

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treatment with chromium(VI) the levels were 233.2 µg/L for whole blood, 138 µg/L for plasma,

chromium(III) treated animals were no different than in untreated animals. However, for chromium(VI)

the lymphocyte levels were about 6-fold higher than control values. After 72 hours, the chromium levels

were significantly reduced. These results suggest that absorbed chromium(III) compounds may be

excreted more rapidly than absorbed chromium(VI) compounds because of a poorer ability to enter cells.

Chromium(III) is an essential nutrient required for normal energy metabolism. The National Research

Council recommends a dietary intake of 50–200 µg/day (NRC 1989). The biologically active form is an

unidentified organic complex of chromium(III) often referred to as GTF. Chromium(III) picolinate is a

common form of chromium(III) nutritional supplementation.

Approximately 0.5–2.0% of dietary chromium(III) is absorbed via the gastrointestinal tract of humans

(Anderson et al. 1983; Anderson 1986) as inferred from urinary excretion measurements. The absorption

chromium(III) complexes are absorbed at 25%, this has not been corroborated by other studies (Anderson

1981).

The bioavailability of chromium(III) was determined in 8 healthy adults who were administered 400 µg

chromium(III)/day as chromium picolinate for 3 consecutive days by Gargas et al. (1994). The mean

absorption of chromium was 2.8%±1.4 % (standard deviation).

Urinary excretion data from 15 female and 27 male subjects given 200 µg chromium(III) as chromium

trichloride indicated that gastrointestinal absorption was at least 0.4% (Anderson et al. 1983). Net

absorption of chromium(III) by a group of 23 elderly subjects who received an average of 24.5 µg/day

(0.00035 mg chromium(III)/kg/day) from their normal diets was calculated to be 0.6 µg

chromium(III)/day, based on an excretion of 0.4 µg chromium/day in the urine and 23.9 µg chromium/

day in the feces, with a net retention of 0.2 µg/day. Thus about 2.4% was absorbed. The retention was

considered adequate for their requirements (Bunker et al. 1984).

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Studies using both chromium(VI) and chromium(III) indicated that chromium(VI) is better absorbed. The

6-day fecal and 24-hour urinary excretion patterns of radioactivity in groups of 6 volunteers given

indicated that at least 0.5% and 2.1% of the chromium(III) and chromium(VI) compounds, respectively,

were absorbed. After intraduodenal administration, absorption of the chromium(III) compound was not

changed, while at least 10% of the chromium(VI) compound was absorbed. These studies further showed

that chromium(VI) compounds are reduced to chromium(III) compounds in the stomach, thereby

accounting for the relatively poor gastrointestinal absorption of orally administered chromium(VI)

compounds (Donaldson and Barreras 1966). Gastric juices taken from the stomachs of patients

reduction was directly related to the amount of gastric juice. The peak reduction occurred for gastric juice

collected 3–4 hours after the patients were given meals, when gastric secretion is greatly stimulated, and

amounted to tens of µg chromium(VI) reduced per mL gastric juice per hour. It was estimated that total

reduction of chromium(VI) in the gastric environment is on the order of several tens of mg/day (De Flora

et al. 1987a).

Comparative absorption of chromium(III) and chromium(VI) was examined under similar dosing

conditions (Kuykendall et al. 1996). Four male volunteers ingested 5 mg of chromium(VI) as potassium

dichromate in 0.5 L of water with the complete dose swallowed within 2 minutes. In one dosing group,

the chromium(VI) was placed in orange juice to reduce the chromium(VI) to the less absorbed trivalent

state. Based on body weight, the estimated dose was 0.06 mg chromium(VI)/kg in both trials.

Bioavailability based on 14-day urinary excretion was 0.6% (range 0.31–0.82%) for chromium(III) and

6.9% (range 1.2–18%) for chromium(VI). Peak red blood cell levels, plasma levels, and urinary levels

were increased 5.5-, 21-, and 536-fold for those treated with chromium alone but increased only 1.7-,

1.8-, and 62-fold when ingested in orange juice. Peak blood levels were observed at 15–120 minutes.

The amount of absorption of chromium(VI) and chromium(III) was measured in four male and two

female volunteers (ages ranging from 25 to 39 years) treated orally with potassium chromate

(chromium(VI)) or chromic oxide (chromium(III)) in capsules at doses of 0.005 mg/kg/day and

1.0 mg/kg/day, respectively (Finley et al. 1996b). Subjects were exposed to each compound for 3 days.

Based on urinary excretion data, mean absorption of potassium chromate was 3.4% (range 0.69–11.9%).

No statistically significant increase in urinary chromium was observed during chromic oxide dosing,

indicating that little, if any, was absorbed. In a follow-up study by the same group (Finley et al. 1997),

five male volunteers ingested a liter, in three volumes of 333 mL, of deionized water containing

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chromium(VI) concentrations ranging from 0.1 to 10.0 mg/L (approximately 0.001–0.1 mg

chromium(VI)/kg/day) for 3 days. A dose-related increase in urinary chromium was seen in all subjects

and the percent of the dose excreted ranged from <2 to 8%. Dose-related increases in plasma and

erythrocyte chromium levels were also observed.

The absorption of chromium, calculated from urinary excretion, was determined following ingestion of a

single oral dose of 5 mg chromium as either chromium(III) chloride in 0.5 liters of distilled water,

potassium dichromate(VI) in 0.5 liters of orange juice (believed to result in the reduction of the

chromium(VI) to chromium(III) and the formation of chromium-organic complexes), or potassium

dichromate in 0.5 liters of distilled water (Kerger et al. 1996a). Chromium chloride was absorbed in the

lowest amounts (estimated 0.13% bioavailability), whereas the chromium(III)-orange juice was absorbed

more efficiently (0.60% bioavailability), with the chromium(VI) absorbed most efficiently (6.9%

bioavailability). Plasma concentrations generally peaked around 90 minutes following exposure for all

three chromium mixtures tested. All three chromium mixtures caused transient elevations in red blood

cell chromium concentrations, with a trend of chromium(IV)>chromium(III)-orange juice

>chromium(III).

The absorption of a single bolus dose of chromium(VI) as potassium dichromate has been assessed in

male volunteers (Kerger et al. 1997). In this study, 5 volunteers ingested either 2.5 or 5 mg

chromium(VI) as a 10 mg/L solution in a 2 minute period. Based on the volunteer’s weight, the estimated

doses were 0.03 and 0.05 mg chromium(VI)/kg. A peak in plasma and red blood cell chromium was

reached within 90 minutes after dosing for the 4 volunteers ingesting 0.05 mg chromium(VI)/kg (average

plasma concentration 25 µg chromium/L; range 5.1 to 57 µg/L, average RBC concentration 17.6 µg

chromium/L, range 13.5 to 24 µg/L). Peak plasma chromium concentration was 23 µg chromium/L (at

30 minutes after ingestion) for the 1 volunteer at 0.03 mg chromium(VI)/kg. No chromium(VI) was

detected in any of the plasma samples from the 5 volunteers for up to 14 hours post-dosing, indicating

that reduction of chromium(VI) had taken place in the gastrointestinal tract or bloodstream.

Bioavailability, as assessed by urinary excretion for 4 days after dosing, averaged 5.7% but varied

considerably among the volunteers (range 1.1–14.5%). The authors stated that the individual absorbing

14.5% of the dose was an “outlier” compared to other subjects in this and other absorption experiments

performed by this group.

In an experiment using three of the same volunteers, chromium(VI) as potassium chromate was given in

water at 5 mg chromium/day for 3 consecutive days (Kerger et al. 1997). Three divided doses were taken

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at approximately 6 hour intervals over a 5–15 minute period. After at least 2 days without dosing, the

3-day exposure regimen was repeated at 10 mg chromium/day. Estimated doses based on body weight

were 0.05 and 0.1 mg/kg/day, respectively. Bioavailability based on 4-day urinary excretion was 1.7%

(range 0.5–2.7%) at 0.05 mg chromium(VI)/kg/day and 3.4% (range 0.8–8.0%) at 0.1 mg

chromium(VI)/kg/day. Absorption of 0.05 mg chromium(VI)/kg appeared to be somewhat lower when

given as three divided doses rather than when given as a single bolus dose (1.7 vs. 5.7%).

Uptake of potassium dichromate was determined in a man who was given 0.8 mg of chromium(VI) in

drinking water 5 times each day for 17 days (Paustenbach et al. 1996). Steady-state concentrations of

chromium in blood were attained after 7 days. Red blood cell and plasma levels returned to background

levels within a few days after exposure was stopped. The data are consistent with a bioavailability of 2%

and a plasma elimination half-life of 36 hours.

from the gastrointestinal tract after oral exposure. When radioactive sodium chromate (chromium(VI))

was given orally to rats, the amount of chromium in the feces was greater than that found when sodium

chromate was injected directly into the jejunum. Since chromium(III) is absorbed less readily than

chromium(VI) by the gastrointestinal tract, these results are consistent with evidence that the gastric

environment has a capacity to reduce chromium(VI) to chromium(III). Furthermore, the administration of

radioactive chromium(III) or chromium(VI) compounds directly into the jejunum decreased the amount

of chromium recovery in the feces indicating that the jejunum is the absorption site for chromium

dose in rats (Sayato et al. 1980) and hamsters (Henderson et al. 1979). Based on distribution (see

Section 2.3.2.2) and excretion (see Section 2.3.4.2) studies in rats administered chromium by gavage for

2–14 days from various sources, that is, from sodium chromate (chromium(VI)), from calcium chromate

(chromium(VI)), or from soil contaminated with chromium (30% chromium(VI) and 70%

chromium(III)), the low gastrointestinal absorption of chromium from any source was confirmed.

Chromium appeared to be better absorbed from the soil than from chromate salts, but less than 50% of the

administered chromium could be accounted for in these studies, partly because not all tissues were

examined for chromium content and excretion was not followed to completion (Witmer et al. 1989,

1991). Adult and immature rats given chromium(III) chloride absorbed 0.1 and 1.2% of the oral dose,

respectively (Sullivan et al. 1984). This suggests that immature rats may be more susceptible to potential

toxic effects of chromium(III) compounds.

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Although chromium or chromium compounds alone are poorly absorbed from the gastrointestinal tract,

the association of chromium with chelating agents, which may be naturally present in feed, can alter the

chelating agents, either oxalate or phytate, phytate significantly (p<0.05) decreased the levels of

radioactivity in blood, whole body, and urine achieved with chromium trichloride alone. Oxalate,

however, greatly increased the levels in blood, whole body, and urine. The oxalate served as a strong

ligand to protect against the tendency of chromium(III) to form insoluble macromolecular chromium

indicating that the presence of food in the gastrointestinal tract slows the absorption of chromium.

duodenum or ileum and that oxalate significantly (p<0.05) increased, while phytate significantly (p<0.05)

found to have no effect on chromium(III) intestinal transport; therefore, these chelating agents were not

Treatment of rats by gavage with a nonencapsulated lead chromate pigment or with a silica-encapsulated

lead chromate pigment resulted in no measurable blood levels of chromium (detection limit=10 µg/L)

after 2 or 4 weeks of treatment or after a 2-week recovery period. However, kidney levels of chromium

were significantly higher in the rats that received the nonencapsulated pigment than in the rats that

received the encapsulated pigment, indicating that silica encapsulation reduces the gastrointestinal

bioavailability of chromium from lead chromate pigments (Clapp et al. 1991).

Both chromium(III) and chromium(VI) can penetrate human skin to some extent, especially if the skin is

damaged. Systemic toxicity has been observed in humans following dermal exposure to chromium

compounds, indicating significant cutaneous absorption (see Section 2.2.3). Fourteen days after a salve

containing potassium chromate was applied to the skin of an individual to treat scabies, appreciable

amounts of chromium were found in the blood, urine, feces, and stomach contents (Brieger 1920) (see

Section 2.3.2.3). It should be noted that the preexisting condition of scabies or the necrosis caused by the

potassium chromate (see Section 2.2.3) could have facilitated dermal absorption of potassium chromate.

Potassium dichromate (chromium(VI)), but not chromium(III) sulfate, penetrated the excised intact

epidermis of humans (Mali et al. 1963). Dermal absorption by humans of chromium(III) sulfate in

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aqueous solution was negligible, with slightly larger amounts of chromium(III) nitrate in aqueous solution

absorbed. The absorption of chromium(III) chloride was similar to potassium dichromate(VI) (Samitz

and Shrager 1966). Chromium(III) from a concentrated chromium sulfate solution at pH 3 penetrated

sodium chromate and chromium(III) from chromium trichloride penetrated excised human mammary skin

at similar rates, but the rate was generally slightly faster for chromium(VI). Absolute rates of absorption

chromium(III) (Wahlberg 1970). The average rate of systemic uptake of chromium in four volunteers

submersed up to the shoulders in a tub of chlorinated water containing a 22 mg chromium(VI)/L solution

of total chromium (Corbett et al. 1997). The study authors noted that the pattern of blood uptake and

urinary excretion was consistent with chromium(III) absorption, suggesting that chromium(VI) is

converted to chromium(III) prior to absorption.

The influence of solvent on the cutaneous penetration of potassium dichromate by humans has been

studied. The test solutions of potassium dichromate in petrolatum or in water were applied as occluded

circular patches of filter paper to the skin. Results with dichromate in water revealed that chromium(VI)

penetrated beyond the dermis and penetration reached steady state with resorption by the lymph and

blood vessels by 5 hours. About 10 times more chromium penetrated when potassium dichromate was

applied in petrolatum than when applied in water. About 5 times more chromium penetrated when

potassium dichromate was applied than when a chromium trichloride glycine complex was applied (Liden

and Lundberg 1979). The rates of absorption of solutions of sodium chromate from the occluded forearm

skin of volunteers increased with increasing concentration. The rates were 1.1 µg chromium(VI)/

Chromium and its compounds are also absorbed dermally by animals. The dermal absorption of sodium

chromate (chromium(VI)) by guinea pigs was somewhat higher than that of chromium(III) trichloride, but

the difference was not significant. At higher concentrations (0.261–0.398 M), absorption of sodium

chromate was statistically higher than that of chromium trichloride. The peak rates of absorption were

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Examination of tissues from Japanese chrome platers and chromate refining workers at autopsy revealed

higher chromium levels in the hilar lymph node, lung, spleen, liver, kidney, and heart, compared to

normal healthy males (Teraoka 1981). Analysis of the chromium concentrations in organs and tissues at

autopsy of a man who died of lung cancer 10 years after his retirement from working in a chromate

producing plant for 30 years revealed measurable levels in the brain, pharyngeal wall, lung, liver, aorta,

kidney, abdominal rectal muscle, suprarenal gland, sternal bone marrow, and abdominal skin. The levels

were significantly higher than in five controls with no occupational exposure to chromium. The man had

been exposed mainly to chromium(VI), with lesser exposure to chromium(III) as the chromite ore (Hyodo

et al. 1980). The levels of chromium were higher in the lungs, but not in the liver or kidneys, of autopsy

specimens from 21 smeltery and refinery workers in North Sweden compared with that for a control

group of 8 individuals. The amount of enrichment in the lungs decreased as the number of elapsed years

between retirement and death increased (Brune et al. 1980). Tissues from three individuals having lung

cancer who were industrially exposed to chromium were examined by Mancuso (1997b). One was

employed for 15 years as a welder, a second worked for 10.2 years, and a third for 31.8 years in ore

milling and preparations and boiler operations. The three cumulative chromium exposures for the three

analyzed 3.5 years after last exposure, the second worker 18 years after, and the third worker 0.6 years

after last exposure. All tissues from the three workers had elevated levels of chromium with the possible

exception of neural tissues. Levels were orders of magnitude higher in lungs than other tissues. The

highest lung level reported was 456 mg/10 g tissue in the first worker, 178 in the second worker, and

1,920 for the third worker. There were significant chromium levels in the tissue of the second worker

even though he had not been exposed to chromium for 18 years. Chromium concentrations in lung

tissues from autopsy samples were 5 times higher in subjects who originated from the Ruhr and

Dortmund regions of Germany, where emissions of chromium are high, than in subjects from Munster

and vicinity. The lung concentrations of chromium increased with increasing age. Men had twice as high

concentrations of chromium in the lungs than did women, which may reflect the greater potential for

occupational exposure by men, the higher vital capacity of men, and possibly a greater history of smoking

(Kollmeier et al. 1990).

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Chromium may be transferred to fetuses through the placenta and to infants via breast milk. Analysis of

chromium levels in women employees of a dichromate manufacturing facility in Russia during and after

pregnancy revealed that the exposed women had significantly higher levels of chromium in blood and

urine during pregnancy, in umbilical cord blood, placentae, and breast milk at child birth, and in fetuses

aborted at 12 weeks than did nonexposed controls (Shmitova 1980). The reliability of this study is

suspect because the levels of chromium reported in the blood and urine of the control women were much

higher than usual background levels of chromium in these biological fluids (see Section 5.5), perhaps due

to problems with analytical methods. Measurement of the chromium content in 255 samples from

45 lactating American women revealed that most samples contained <0.4 µg/L, and the mean value was

0.3 µg/L (Casey and Hambidge 1984). While these probably represent background levels in women

whose main exposure to chromium is via the diet, the findings indicate that chromium may be transferred

to infants via breast milk.

followed for 40 days by autoradiography and scintillation counting. Three days after the administration

relative concentrations in the tissue was lung > kidney > gastrointestinal tract > erythrocytes > liver >

serum > testis > skin. Twenty-five days after dosing, the tissue distribution was lung > kidney >

erythrocytes > testis > liver > serum > skin > gastrointestinal tract. Kidney, erythrocytes, and testis

maintained their chromium levels for a period of 10–15 days before decreasing (Weber 1983). The

distribution of chromium(VI) compared with chromium(III) was investigated in guinea pigs after

intratracheal instillation of potassium dichromate or chromium trichloride. At 24 hours after instillation,

11% of the original dose of chromium from potassium dichromate remained in the lungs, 8% in the

erythrocytes, 1% in plasma, 3% in the kidney, and 4% in the liver. The muscle, skin, and adrenal glands

contained only a trace. All tissue concentrations of chromium declined to low or nondetectable levels in

140 days with the exception of the lungs and spleen. After chromium trichloride instillation, 69% of the

dose remained in the lungs at 20 minutes, while only 4% was found in the blood and other tissues, with

the remaining 27% cleared from the lungs and swallowed. The only tissue that contained a significant

amount of chromium 2 days after instillation of chromium trichloride was the spleen. After 30 and

60 days, 30 and 12%, respectively, of the chromium(III) was retained in the lungs, while only 2.6 and

1.6%, respectively, of the chromium(VI) dose was retained in the lung (Baetjer et al. 1959a).

CHROMIUM 134

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Autopsy studies in the United States indicate that chromium concentrations in the body are highest in

kidney, liver, lung, aorta, heart, pancreas, and spleen at birth and tend to decrease with age. The levels in

liver and kidney declined after the second decade of life. The aorta, heart, and spleen levels declined

rapidly between the first 45 days of life and 10 years, with low levels persisting throughout life. The

level in the lung declined early, but increased again from mid life to old age (Schroeder et al. 1962).

The distribution of chromium in human body tissue after acute oral exposure was determined in the case

of a 14-year-old boy who ingested 7.5 mg chromium(VI)/kg as potassium dichromate. Despite extensive

treatment by dialysis and the use of the chelating agent British antilewisite, the boy died eight days after

admission to the hospital. Upon autopsy, the chromium concentrations were as follows: liver,

2.94 mg/100 cc (normal, 0.016 mg/100 cc); kidneys, 0.64 and 0.82 mg/100 cc (normal, 0.06 mg/100 cc);

and brain, 0.06 mg/100 cc (normal, 0.002 mg/100 cc) (Kaufman et al. 1970). Although these data were

obtained after extensive treatment to rid the body of excess chromium, the levels of chromium remaining

after the treatment clearly demonstrate that these tissues absorbed at least these concentrations after an

acute, lethal ingestion of a chromium(VI) compound.

Chromium may be transferred to infants via breast milk as indicated by breast milk levels of chromium in

women exposed occupationally (Shmitova 1980) or via normal levels in the diet (Casey and Hambidge

1984). It has been demonstrated that in healthy women, the levels of chromium measured in breast milk

are independent of serum chromium levels, urinary chromium excretion, or dietary intake of chromium

(Anderson et al. 1993, Mohamedshah et al. 1998), but others (Engelhardt et al. 1990) have disputed this

observation.

The tissue distribution of chromium was studied in rats administered chromium from a variety of sources.

In one experiment, sodium chromate in water was administered by gavage for 7 days at 0, 1.2, 2.3, or

5.8 mg chromium(VI)/kg/day. Very little chromium (generally <0.5 µg/organ) was found in the organs

analyzed (liver, spleen, lung, kidney, and blood) after administration of the two lower doses. The levels

were generally comparable to those in controls. After 5.8 mg/kg/day, the largest amount of chromium

tissues represented only 1.7% of the final dose of 5.8 mg/kg/day, but not all organs were analyzed. In the

next experiment, rats were exposed by gavage to 7.0 mg chromium/kg/day for 7 days from various

CHROMIUM 135

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sources: (1) sodium chromate; (2) calcium chromate; (3) soil containing chromium (30% chromium(VI),

70% chromium(III)); or (4) a mixture of calcium chromate and the contaminated soil. The highest levels

of chromium were found in liver, spleen, kidney, lung, blood, brain, and testes after dosing with sodium

chromate, but the relative levels in these tissues after the other treatments followed no consistent pattern.

Rats gavaged for 14 days with 13.9 mg chromium/kg/day from the four different sources had higher

levels of chromium in the tissues after they were dosed with the contaminated soil or the mixture of

calcium chromate and the contaminated soil than with either of the chromate salts alone. Thus, the

relative organ distribution of chromium depends on the source of chromium (Witmer et al. 1989, 1991).

Components in soil may affect the oxidation state and the binding of chromium to soil components, and

pH of the soil may also affect the bioavailability from soil.

The chromium content in major organs of mice receiving drinking water that provided doses of 4.8, 6.1,

or 12.3 mg chromium(III)/kg/day as chromium trichloride or 4.4, 5.0, or 14.2 mg chromium(VI)/kg/day

as potassium dichromate was determined after 1 year of exposure. Chromium was detected only in the

liver in the chromium(III)-treated mice. Mice treated with chromium(VI) compounds had accumulation

in all organs, with the highest levels reported in liver and spleen. Liver accumulation of chromium was

40–90 times higher in the chromium(VI)-treated group than in the chromium(III)-treated group

(Maruyama 1982). Chromium levels in tissue were 9 times higher in rats given chromium(VI) as

potassium chromate in drinking water for 1 year than in rats given the same concentration of

chromium(III) as chromium trichloride (MacKenzie et al. 1958). In rats exposed to potassium chromate

in the drinking water for three or six weeks, a general trend of increasing chromium concentration with

time of exposure was apparent in the liver and kidneys, but only the kidneys showed a difference in the

concentration after exposure to 100 and 200 ppm. Blood concentrations were almost saturated by

3 weeks with little further accumulation by 6 weeks. No chromium was detected in the lungs after

drinking water exposure (Coogan et al. 1991a). After acute oral dosing with radiolabeled chromium

trichloride (1 µCi for immature rats, 10 µCi for adults), adult and neonatal rats accumulated higher levels

of chromium in the kidneys than in the liver. At 7 days after dosing, the liver and kidney contained

0.05% and 0.12% of the dose, respectively, in the neonates and 0.002 and 0.003% of the dose,

respectively, in the adult rats. The carcass contained 0.95% of the dose in the neonates and 0.07% of the

dose in adult rats. The lungs contained 0.0088% of the dose in neonates and 0.0003% of the dose in adult

rats. No chromium(III) was detected in the skeleton or muscle. Approximately 35 and 0.2% of the

administered dose of chromium(III) at day 7 was retained in the gut of neonates and adults, respectively

(Sullivan et al. 1984).

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The distribution of potassium chromate(VI) was compared in male Fisher rats and C57BL/6J mice

exposed either by drinking water (8 mg chromium(VI)/kg/day for 4 and 8 weeks) or by intraperitoneal

injection (0.3 and 0.8 mg chromium(VI)/kg/day for 4 or 14 days) (Kargacin et al. 1993). The

concentrations of chromium (µg/g wet tissue) after drinking water exposures for 8 weeks in mice were:

liver 13.83, kidney 4.72, spleen 10.09, femur 12.55, lung 1.08, heart 1.02, muscle 0.60, and blood 0.42.

These concentrations were not markedly different than for 4-week exposures. For rats, the concentrations

were liver 3.59, kidney 9.49, spleen 4.38, femur 1.78, lung 0.67, heart 1.05, muscle 0.17, and blood 0.58.

These results demonstrate that considerable species differences exist between mice and rats and need to

be factored into any toxicological extrapolations across species even if the routes of administration are the

same. In the drinking water experiments, blood levels in rats and mice were comparable, but in intraperitoneal

injection experiments, rats’ levels were about 8-fold higher than mice after 4 days of exposure.

This difference appeared to be due to increased sequestering by rat red blood cells, since accumulation in

white blood cells was lower in rats than mice. The higher incidence of red cell binding was also

associated with greater binding of chromium to rat hemoglobin.

The feeding of five male Wistar rats at 0.49 mg chromium(III)/kg/day as chromium(III) chloride for

10 weeks resulted in increased chromium levels in liver, kidney, spleen, hair, heart, and red blood cells

(Aguilar et al. 1997). Increases were highest in kidney (0.33 µg/g wet tissue in controls versus 0.83 µg/g

in treated animals) and erythrocytes (1.44 µg/g wet tissue in controls versus 3.16 µg/g in treated animals).

The higher tissue levels of chromium after administration of chromium(VI) than after administration of

chromium(III) (MacKenzie et al. 1958; Maruyama 1982; Witmer et al. 1989, 1991) reflect the greater

tendency of chromium(VI) to traverse plasma membranes and bind to intracellular proteins in the various

tissues, which may explain the greater degree of toxicity associated with chromium(VI). In an

experiment to determine the distribution of chromium in red and white blood cells, rats were exposed

fractionated blood cells was determined either 24 hours or 7 days after exposure. After 24 hours, the

cells was reduced only 2.5-fold, while that of the red blood cells was reduced 10-fold. Thus, white blood

cells preferentially accumulated chromium(VI) and retained the chromium longer than did the red blood

cells. As discussed in Section 2.3.2.4, a small amount of chromium(III) entered red blood cells of rats

cells (Coogan et al. 1991b).

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Twelve pregnant female albino rats (Druckrey strain) and 13 Swiss albino mice were exposed to 500 ppm

potassium dichromate(VI) in their drinking water during pregnancy up to one day before delivery (Saxena

et al. 1990a). The chromium(VI) daily intake was calculated to be 11.9 mg chromium(VI)/day for the rats

and 3.6 mg chromium(VI)/day for mice which were considered to be maximal non-toxic doses for both

species. In rats, concentrations of chromium were 0.067, 0.219, and 0.142 µg/g fresh weight in maternal

blood, placenta, and fetuses respectively, and 0.064, 0.304, and 0.366 µg/g fresh weight in mice,

respectively. In treated rats, chromium levels were 3.2-fold higher in maternal blood, 3-fold higher in

placenta, and 3.1-fold higher in fetal tissue when compared to control values. In treated mice, chromium

levels were 2.5-fold higher in maternal blood, 3.2-fold higher in placenta, and 9.6-fold higher in fetuses

when compared to control values. In treated mice there was a significant elevation in chromium levels in

placental and fetal tissues over maternal blood levels, and a significant increase in chromium levels in

fetal tissue over placental concentrations when compared to controls. These differences were not

observed in rats, indicating that the distribution patterns in mice and rats are different.

A study of transplacental transfer of chromium(III) in different forms indicated that placental transport

varies with the chemical form. Male and female rats were fed either a commercial diet that contained

500 ppb chromium or a 30% Torula yeast diet that contained <100 ppb chromium. They were also given

drinking water with or without 2 ppm chromium(III) added as chromium acetate monohydrate. The rats

were mated and immediately after delivery, the neonates were analyzed for chromium content. The

neonates whose dams were fed the commercial diet contained almost twice as much chromium as those

whose dams were fed the chromium-deficient yeast diet. Addition of chromium(III) acetate to the

drinking water of the yeast-fed rats (2 ppm) did not increase the levels of chromium in the neonates.

Administration of chromium(III) trichloride intravenously or by gavage before mating, during mating, or

during gestation resulted in no or only a small amount of chromium in the neonates. Administration of

chromium(III) in the form of GTF from Brewer's yeast by gavage during gestation resulted in chromium

levels in the litters that were 20–50% of the dams' levels. The results indicate that fetal chromium is

derived from specific chromium complexes in the diet (e.g., GTF) (Mertz et al. 1969).

The findings of toxic effects in the heart, stomach, blood, muscles, and kidneys of humans who were

dermally exposed to chromium compounds is suggestive of distribution to these organs (see

Section 2.2.3.2). Fourteen days after a salve containing potassium chromate(VI) was applied to the skin

of an individual to treat scabies, appreciable amounts of chromium were found in the blood

CHROMIUM 138

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(2–5 mg/100 mL), urine (8 mg/L), feces (0.61 mg/100 g), and stomach contents (0.63 mg/100 mL)

(Brieger 1920). The preexisting condition of scabies or the necrosis caused by the potassium chromate

could have facilitated its absorption. A transient increase in the levels of total chromium in erythrocytes

and plasma was observed in subjects immersed in a tank of chlorinated water containing potassium

dichromate(VI) (Corbett et al. 1997).

Chromium compounds are absorbed after dermal administration by guinea pigs. Measurement of

chromium(III) and chromium(VI) compounds, to the blood, spleen, bone marrow, lymph glands, urine,

and kidneys. Absorption was greater for chromium(VI) than for chromium(III) (see Section 2.3.1.3)

(Wahlberg and Skog 1965).

The distribution of chromium(III) in humans was analyzed using a whole-body scintillation scanner,

whole-body counter, and plasma counting. Six individuals given an intravenous injection of

various body organs within hours of administration. The liver and spleen contained the highest levels.

After 3 months, the liver contained half of the total body burden of chromium. The study results

indicated a three-compartment model for whole-body accumulation and clearance of chromium(III). The

half-lives were 0.5–12 hours for the fast component, 1–14 days for the medium component, and

3–12 months for the slow component (Lim et al. 1983).

(Corbett et al. 1998). The reduction capacity appears to be concentration dependent and is overwhelmed

at spike concentrations between 2,000 and 10,000 µg/L. High chromium(VI) concentrations

(10,000 µg/L spike concentration) resulted in an accumulation of chromium(VI) in the erythrocytes and a

lower plasma:erythrocyte ratio of total chromium. This study also found that the plasma reduction

capacity was enhanced by a recent meal.

CHROMIUM 139

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red blood cells, decreased by approximately 1.7-fold after 7 days. When rats were injected intravenously

with 20 ng of radiolabeled sodium chromate (chromium(VI)) or radiolabeled chromium trichloride

The distribution pattern in rats treated with sodium chromite (chromium(III)) by intravenous injection

revealed that most of the chromium was concentrated in the reticuloendothelial system, which, together

with the liver accumulated 90% of the dose. The accumulation in the reticuloendothelial system was

thought to result from colloid formation by chromite at physiological pH. Organs with detectable

chromium levels 42 days postinjection were: spleen > liver > bone marrow > tibia > epiphysis > lung >

kidney. Chromium trichloride given to rats by intravenous injection also concentrated in the liver, spleen,

and bone marrow (Visek et al. 1953). In rats administered chromium(III) nitrate intraperitoneally for 30

or 60 days, the highest levels of chromium were found in the liver, followed by the kidneys, testes, and

brain. The levels increased with increased doses but not linearly. The levels in the kidneys, but not the

other organs, increased significantly with duration (Tandon et al. 1979).

Whole-body analysis of mice given a single intraperitoneal injection of 3.25 mg chromium(III)/kg as

chromium trichloride showed that chromium trichloride was released very slowly over 21 days: 87% was

retained 3 days after treatment, 73% after 7 days treatment, and 45% after 21 days. In contrast, mice

given a single intraperitoneal injection of 3.23 chromium(VI)/kg as potassium dichromate retained only

31% of the chromium(VI) dose at 3 days, 16% at 7 days, and 7.5% at 21 days. Mice injected weekly with

ability to form coordination complexes with tissue components such a proteins and amino acids (Bryson

and Goodall 1983).

In rats injected intraperitoneally with 2 mg chromium(VI)/kg/day as potassium chromate 6 days/week for

45 days, the mean levels of chromium (µg chromium/g wet weight) were 25.68 in the liver, 40.61 in the

kidney, 7.56 in the heart, and 4.18 in the brain (Behari and Tandon 1980).

CHROMIUM 140

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In rats injected subcutaneously with 5.25 mg chromium(VI)/kg as potassium dichromate, most of the

chromium in the tissues analyzed was found in the red blood cells with a peak level (63 µg chromium/g)

achieved 24 hours after dosing. White blood cells were not analyzed for chromium content. Whole

plasma contained 2.7–35 µg/mL, and the plasma ultrafiltrate contained 0.15–0.79 µg/mL. Tissue

distribution 48 hours after dosing was as follows: 221.2 µg/g in renal cortex, 110.0 µg/g in liver,

103.0 µg/g in spleen, 86.8 µg/g in lung, 58.9 µg/g in renal medulla, and 8.8 µg/g in bone, compared with

2.28–5.98 µg/g in any tissues in controls. When rats were given repeated subcutaneous injections of

1.05 mg chromium(VI)/kg/day, every other day for 2, 4, 8, 10, or 12 weeks, most of the chromium was

again found in the red blood cells. However, while red blood cell levels rose progressively during

treatment, levels as high as those seen after a single dose were never achieved, even when the total dose

exceeded the dose in the single injection experiment 10-fold. The tissue levels of chromium determined

48 hours after the last dose in the rats injected for 12 weeks were of the same order of magnitude as those

seen after a single injection. These results suggest little tendency of soluble chromium(VI) compounds to

accumulate in tissues with repeated exposure (Mutti et al. 1979).

compounds. The results showed a greater level of chromium inside erythrocytes after treatment with

chromium(VI) compounds, compared to chromium(III) compounds. The investigators reported that both

chromium(VI) and chromium(III) compounds permeated the cell membrane, but only chromium(VI)

compounds are taken up by erythrocytes and form complexes with intracellular proteins that could not be

eliminated (Lewalter et al. 1985).

The distribution of radioactivity was compared in mouse dams and fetuses following the intravenous

labelled-chromium(III) trichloride. In the maternal tissues, the highest levels of radioactivity from both

treatments were achieved in the renal cortex, but the concentration of radioactivity in the tissues of dams

given the hexavalent form was much higher than that of the dams given the trivalent form. The patterns

of distribution of radioactivity in other tissues were identical regardless of administered valence state,

with the skeleton, liver, kidneys, and ovaries accumulating the highest levels and the brain and muscle the

lowest. The serum concentration of radioactivity after treatment with chromium(III) was 3 times higher

than that after treatment with chromium(VI). Radioactivity after treatment with both valence forms

crossed the placenta, but the radioactivity from the hexavalent form crossed more readily. For

the dams were administered sodium dichromate in mid-gestation (days 12–15). When the dams were

CHROMIUM 141

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concentration when the dams were injected with radiolabelled chromium trichloride in mid-gestation and

0.8% of the maternal serum radioactivity concentration when injected in late gestation. Radioactivity

from both treatments accumulated in fetal skeletons in calcified areas and in the yolk sac placenta

(Danielsson et al. 1982). Daniellson et al. (1982) noted that the radioactivity after administration of

chromium(VI) may represent chromium(III) after reduction in the tissues. Chromium(III) also crossed the

placenta of mice injected intraperitoneally with chromium trichloride (Iijima et al. 1983). While the

results indicate that both chromium(VI) and chromium(III) may pose developmental hazards, they cannot

be used to indicate that exposure of pregnant animals to chromium(III) by inhalation or oral routes would

result in significant placental transfer because chromium(III) compounds are not well absorbed by these

routes (see Section 2.3.1).

Tissue distribution in rats and mice respectively after 14 days of intraperitoneal injection of 0.8 mg

chromium(VI)/day as potassium chromate were: liver 6.00 µg/g wet weight in rats and 8.89 in mice,

kidney 24.14 and 11.77, spleen 15.26 and 6.92, femur 6.53 and 6.30, lung 3.99 and 2.89, heart 3.13 and

1.75, muscle 1.10 and 0.51, and blood 4.52 and 1.56. (Kargacin et al. 1993). Kidney and blood chromium

concentrations were 2-fold and 4-fold higher, respectively, in rats compared to mice. Red blood cell

concentrations were 3-fold higher in rats than mice and hemoglobin binding of chromium was twice as

high in rats. By contrast, after oral exposure levels, in blood for rats and mice were similar. The authors

ascribed this to faster entry into the blood after intraperitoneal injection and thus a greater likelihood that

chromium(VI) could be sequestered in rat erythrocytes by reduction.

The biologically active chromium(III) molecule often referred to as GTF appears to be a dinicotinatochromium(

III) glutathione-like complex. The molecule has not been fully characterized (Pi-Sunyer and

Offenbacher 1984). This biologically active molecule functions by facilitating interaction of insulin with

its receptor site, thus influencing glucose, protein, and lipid metabolism. Inorganic chromium compounds

do not appear to have insulin-potentiating activity. However, humans and animals are capable of

converting inactive chromium compounds to biologically active forms (Anderson 1986).

Chromium(III) compounds are essential to normal glucose, protein, and fat metabolism. In addition,

chromium(III) is capable of forming complexes with nucleic acids and proteins. Chromium(VI) is

CHROMIUM 142

2. HEALTH EFFECTS

agents. Chromium(V) and chromium(IV) are transient intermediates in this process.

chromium(III) by ascorbate. The reduction of chromium(VI) by ascorbate results in a shorter residence

time of chromium in the lungs and constitutes the first defense against oxidizing reagents in the lungs.

When ascorbate is depleted from the lungs, chromium(VI) can also be reduced by glutathione. The

reduction of chromium(VI) by glutathione is slower and results in greater residence time of chromium in

the lungs, compared to reduction by ascorbate (Suzuki and Fukuda 1990). Other studies reported the

reduction of chromium(VI) to chromium(III) by epithelial lining fluid (ELF) obtained from the lungs of

15 individuals by bronchial lavage. The average reduction accounted for 0.6 µg chromium(VI)/mg of

ELF protein. In addition, cell extracts made from pulmonary alveolar macrophages derived from five

chromium(VI)/mg protein (Petrilli et al. 1986b). Metabolism of the chromium(VI) to chromium(III) by

these cell fractions significantly reduced the mutagenic potency of the chromium when tested in the Ames

reversion assay. Postmitochondrial (S12) preparations of human lung cells (peripheral lung parenchyma

and bronchial preparations) were also able to reduce chromium(VI) to chromium(III) (De Flora et al.

1984). Moreover, large individual differences were observed (De Flora et al. 1984, 1987b), and extracts

from pulmonary alveolar macrophages of smokers reduced significantly more chromium(VI) to

chromium(III) than extracts from cells of nonsmokers. Because chromium(III) does not readily enter

cells, these data suggest that reduction of chromium(VI) by the ELF may constitute the first line of

defense against toxicity of inhaled chromium compounds. Furthermore, uptake and reduction of

chromium compounds by the pulmonary alveolar macrophages may constitute a second line of defense

against pulmonary toxicity of chromium(VI) compounds. Microsomal reduction of chromium(VI) occurs

in the lungs mainly as it does in the liver, as discussed below.

The first defense against chromium(VI) after oral exposure is the reduction of chromium(VI) to

chromium(III) in the gastric environment where gastric juice (De Flora et al. 1987a) and ascorbate

(Samitz 1970) play important roles. Studies using low-frequency electron paramagnetic resonance (EPR)

chromium(V), whereas higher concentrations of ascorbate favor the formation of the reduced oxidation

state, chromium(III) (Liu et al. 1995). EPR spectrometric monitoring also showed that chromium(VI)

was rapidly reduced to chromium(V) on the skin of rats, with a 3-fold greater response when the stratum

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corneum was removed (Liu et al. 1997a). Thus, dermal effects from direct skin contact with

chromium(VI) compounds may be mediated by rapid reduction to chromium(V). In whole blood and

plasma, increasing ascorbate levels led to an increased oxidation of chromium(VI) to chromium(III)

(Capellmann and Bolt 1992).

For humans, the overall chromium(VI)-reducing/sequestering capacities were estimated to be

0.7–2.1 mg/day for saliva, 8.3–12.5 mg/day for gastric juice, 11–24 mg for intestinal bacteria eliminated

daily with feces, 3,300 mg/hour for liver, 234 mg/hour for males and 187 mg/hour for females for whole

blood, 128 mg/hour for males and 93 mg/hour for females for red blood cells, 0.1–1.8 mg/hour for ELF,

136 mg/hour for pulmonary alveolar macrophages, and 260 mg/hour for peripheral lung parenchyma.

Reduction of chromium(VI) in the red blood cell occurs by the action of glutathione. Since the red blood

cell membrane is permeable to chromium(VI) but not chromium(III), the chromium(III) formed by

reduction of chromium(VI) by glutathione is essentially trapped within the red blood cell. Eventually the

diffusion of chromium(VI), the reduction to chromium(III), and complexing to nucleic acids and proteins

within the cell will cause the concentration equilibrium to change so that more chromium(VI) is diffused

through the membrane. Thus, there is a physiological drag so that increased diffusion results in greater

chromium concentrations in the cell (Aaseth et al. 1982). It appears that the rate of uptake of

chromium(VI) by red blood cells may not exceed the rate at which they reduce chromium(VI) to

chromate(VI) (10 mM) decreased glutathione levels to 10% of the original amount (Wiegand et al. 1984).

The effect of glutathione-depleting agents on the amounts of cellular chromium(III) and chromium(V)

was determined in Chinese hamster V-79 cells treated with sodium chromate (Sugiyama and Tsuzuki

1994). Buthionine sulfoximine at 25 µM reduced glutatione levels to about 1% of control values, and

increased chromium(V) levels by about 67%. The total chromium uptake was decreased by about 20%,

and chromium(III) levels were decreased by 20%. Diethylmaleate (1 mM) decreased glutathione levels

less than 1%, decreased chromium(V) levels by 27%, and chromium(III) levels by 31%. However, the

cellular uptake of total chromium was decreased to nearly 46%. The authors explained that the reason

that the diethylmaleate inhibited the reduction of chromium(VI) to both chromium(III) and chromium(V)

was not due to the decreased uptake, but involved the inhibition of the chromate-reducing enzymes in the

cell.

CHROMIUM 144

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demonstrated reduction of chromium(VI) by microsomal enzymes. Hepatic microsomal proteins from

male Sprague-Dawley rats pretreated with chromium(VI) reduced chromium(VI) to chromium(III). The

rate of reduction varied both with the concentration of microsomal protein and the concentration of

nicotinamide adenine dinucleotide phosphate (NADPH). In the absence of NADPH, microsomes did not

reduce significant amounts of Cr(VI) over the 24-hour observation period. Therefore, the reduction of

chromium(VI) in rat hepatic microsomes is NADPH-dependent (Gruber and Jennette 1978). Another

study followed the kinetics of chromium(VI) reduction in hepatic microsomes from rats (Garcia and

Jennette 1981). Induction of cytochrome P448 enzymes had no effect on the kinetics of the reaction,

while induction of cytochrome P450 and NADPH-cytochrome P450 reductase resulted in a decrease in

the apparent chromate-enzyme dissociation constant, and an increase in the apparent second-order rate

constant, and no change in the apparent turnover number. Inhibition of NADPH-cytochrome P450

chromium(VI), as did the addition of specific inhibitors of cytochrome P450. The results demonstrate the

involvement of cytochrome P450, NADPH-dependent-cytochrome P450 reductase, and to a lesser extent

microsomes. The conversion of chromium(VI) to chromium(III) in rats can occur by electron transfer

1989). The assertion that cytochrome P450 is involved in the reduction of chromium(VI) to

chromium(III) has been further strengthened by Petrilli et al. (1985), who demonstrated that inducers of

cytochrome P450 can increase the conversion of chromium(VI) to chromium(III) in S-9 mixtures

prepared from the liver and lungs of exposed rats. Furthermore, it was observed that chromium(VI) can

induce pulmonary cytochrome P450 and thus its own reduction in the lungs (Petrilli et al. 1985).

Chromium(VI) apparently can alter the P450 activity in isolated rat microsomes. Witmer et al. (1994)

demonstrated that hepatic microsomes from male rats treated with chromium(VI) resulted in a significant

which demonstrated that the metabolic effects of chromium differ between males and females.

Two studies have examined possible species differences in the ability of microsomes to reduce

chromium(VI) (Myers and Myers 1998; Pratt and Myers 1993). Chromium(VI) reduction was enzymatic

CHROMIUM 145

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and NADPH-dependent, and the rates were proportional to the amount of microsome added. In humans,

than the rat liver. Also contrary to the rodent data, oxygen and cytochrome P450 inhibitors (carbon

monoxide, piperonyl butoxide, metyrapone, and aminopyrine) did not inhibit chromium(VI) reduction.

These differences indicate that, in humans, cytochrome P450 does not play a significant role in the

reduction process, but that other microsomal flavoproteins are responsible for reducing chromium(VI).

cytochrome c reductase (P450 reductase) by bromo-4'-nitroacetophenone resulted in an 80–85%

inhibition of chromium(VI) reduction. Combined, these observations implicate P450 reductase, working

independently of cytochrome P450, as a major contributor in the reduction of chromium(VI) in human

microsomes. These findings suggest that metabolism of chromium(VI) in rodent systems may not readily

be extrapolated to humans.

Microsomal reduction of chromium(VI) can also result in the formation of chromium(V), which involves

a one-electron transfer from the microsomal electron-transport cytochrome P450 system in rats. The

chromium(V) complexes are characterized as labile and reactive. These chromium(V) intermediates

eventually lead to cancer (Jennette 1982). Because chromium(V) complexes are labile and reactive,

electron paramagnetic resonance (EPR) spectroscopy on whole mice. In mice injected with sodium

dichromate(VI) intravenously into the tail vein, maximum levels of chromium(V) were detected within

levels of chromium(V) decreased in a linear manner as the administered dose levels of sodium dichromate

decreased. The relative tissue distributions of chromium(V) indicated that most was found in the liver

and much lesser amounts in blood. None was detected in kidney, spleen, heart, or lung. When the mice

were pretreated with metal ion chelators, the intensity of the EPR signal decreased demonstrating that the

formation of chromium(V) was inhibited. Reactions of chromium(VI) with glutathione produced two

chromium(V) complexes and a glutathione thiyl radical. Reactions of chromium(VI) with DNA in the

presence of glutathione produced chromium-DNA adducts. The level of chromium-DNA adduct

formation correlated with chromium(V) formation. The reaction of chromium(VI) with hydrogen

peroxide produced hydroxyl radicals. Reactions of chromium(VI) with DNA in the presence of high

CHROMIUM 146

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significant DNA strand breakage and the 8-hydroxy guanosine adduct, which correlated with hydroxyl

radical production (Aiyar et al. 1989, 1991). Very little chromium(V) was generated by this pathway. It

was postulated that the reaction of chromium(VI) with hydrogen peroxide produces tetraperoxochromium(

V) species that act as a catalyst in a Fenton-type reaction producing hydroxyl radicals in which

chromium(V) is continuously being recycled back to chromium(VI). The regeneration of chromium(VI)

through interactions with chromium(V) and hydrogen peroxide is consistent with the findings of

Molyneux and Davies (1995) (see Section 2.4.2). As discussed above, chromium(VI) is ultimately

reduced to chromium(III) within the cell. Chromium(III) can form stable complexes with DNA and

protein (De Flora and Wetterhahn 1989) which is discussed further in Section 2.4.2.

The mechanism for clearance of chromium(VI) once reduced inside the liver cell may involve a

chromium(III)-glutathione complex. The glutathione complex would be soluble through the cell

membrane and capable of entering the bile (Norseth et al. 1982). The complexing of chromium(III) to

other ligands has been shown to make them more permeable to the cell membrane (Warren et al. 1981).

Although chromium(III) complexes are generally considered to be inert, Shi et al. (1993) demonstrated

that free radicals could be generated from extremely high non-physiological concentrations of hydrogen

pH in the presence of chromium(III) chloride. The reduction of peroxides may indicate that

chromium(III) is capable of being reduced to chromium(II) and is consistent with other findings that have

shown that cysteine and NADH are capable of reducing trivalent chromium. Later studies demonstrated

that chromium(III) could enhance the formation of hydroxyl radicals from superoxide, though to a lesser

extent than chromium(VI), suggesting that chromium(III) can act as a catalyst for the Haber-Weiss cycle

(Shi et al. 1998). Therefore, the presence of these naturally occurring substances and cellular lipid

hydroperoxides formed in lipid metabolism may contribute to the generation of free radicals that could be

potentially genotoxic.

Normal urinary levels of chromium in humans have been reported to range from 0.24–1.8 µg/L

(0.00024–0.0018 mg/L) with a median level of 0.4 µg/L (0.0004 mg/L) (Iyengar and Woittiez 1988).

CHROMIUM 147

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from 0.0247 to 0.037 mg chromium(III)/L. Workers exposed mainly to chromium(VI) compounds had

higher urinary chromium levels than workers exposed primarily to chromium(III) compounds. An

analysis of the urine did not detect the hexavalent form of chromium, indicating that chromium(VI) was

rapidly reduced before excretion (Cavalleri and Minoia 1985; Minoia and Cavalleri 1988).

Chromium(III) compounds were excreted rapidly in the urine of workers, following inhalation exposure

urine concentrations of 0.011–0.017 mg chromium(III)/L. The half-time for urinary excretion of

chromium was short, 4–10 hours, based on an open, one-compartment kinetic model (Kiilunen et al.

1983). Tannery workers had higher urinary chromium(III) concentrations in postshift urine samples

taken Friday afternoon and in preshift urine samples taken Monday, compared to controls. These workers

also had hair concentrations of chromium that correlated with urinary levels. Analysis of workroom air

and Gibson 1987). Elimination of chromium(III) from hair, serum, and urine has been studied in a group

of 5 men who had ceased working in a leather tannery 9 months earlier (Simpson and Gibson 1992).

Compared to levels recorded during employment, the mean level of chromium in hair was reduced from

28.5 to 2.9 µmol/g; serum levels were reduced from 9.4 to 3.8 nmol/L. These levels are comparable to

those in the general population. Urine levels were unchanged (13.8 nmol/L while working and

14.4 nmol/L 9 months later); the authors stated that this was probably caused by consumption of beer (a

source of chromium) the night before sampling.

Peak urinary chromium concentrations were observed at 6 hours (the first time point examined) in rats

exposed intratracheally to 0.44 mg/kg chromium(III) as chromium acetate hydroxide or chromium(VI) as

sodium dichromate (Gao et al. 1993). Chromium urinary concentrations decreased rapidly, falling from

4,535 µg chromium/g creatinine at 6 hours to 148 µg chromium/g at 72 hours for the chromium acetate

hydroxide and from 2,947 µg chromium/g creatinine at 6 hours to 339 µg chromium/g at 72 hours for

sodium dichromate.

6 hours/day for 4 days. Urinary levels of chromium remained almost constant for 4 days after exposure

and then decreased, indicating that chromium bound inside the erythrocyte is released slowly (Langård et

al. 1978).

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Given the low absorption of chromium compounds by the oral route, the major pathway of excretion after

oral exposure is through the feces.

An acute, oral dose of radioactive chromium(III) as chromium chloride or chromium(VI) as sodium

chromate was administered to humans after which feces and urine were collected for 24 hours and 6 days,

respectively, and analyzed for chromium. The amount of chromium in the 6-day fecal collection was

99.6 and 89.4% of the dose for chromium(III) and chromium(VI) compounds, respectively. The amount

of chromium in the 24-hour urine collection was 0.5 and 2.1% of the dose for chromium(III) and

chromium(VI) compounds, respectively (Donaldson and Barreras 1966). In subjects drinking

0.001–0.1 mg chromium(VI)/kg/day as potassium chromate in water for 3 days, <2–8% of the dose was

excreted in the urine (Finley et al. 1997). The percentage of the dose excreted appeared to increase with

increasing dose.

Urinary excretion rates have been measured in humans after oral exposure to several chromium

compounds (Finley et al. 1996b). A group of four male and two female volunteers ingested capsules

containing chromium(III) picolinate at a dose of 200 µg/day for 7 days, to ensure that chromium

deficiency was not a confounding factor. They then ingested 0.005 mg/kg/day chromium(VI) as

potassium chromate (3 days), and 1.0 mg/kg/day chromium(III) as chromic oxide (3 days), with 3 days

without dosing between the potassium chromate and chromic oxide doses. Urinary excretion rates of

chromium were significantly elevated compared to post-dosing control levels after seven daily doses of

chromium(III) picolinate (2.4±0.8 µg/day vs 0.75±0.53 µg/day). The excretion rate increased sharply on

the first of 3 days of potassium chromate dosing (11±17 µg/day) and remained steady over the next

2 days (13–14 µg/day). Excretion rates fell to 2.5±0.72 during 2 days without dosing and continued to

fall during the three days of chromic oxide dosing, reaching rates similar to those seen post-dosing. Mean

pooled urinary concentrations during the dosing periods were 2.4 µg chromium/g creatinine from

exposure to chromium(VI) and 0.4 µg chromium/g creatinine from exposure to chromium(III) as

compared to 0.23 µg chromium/g creatinine during the post-dosing time periods. The lower urinary

excretion of chromium(III) after exposure to chromic oxide reflects the poorer absorption of inorganic

chromium(III) compounds compared to inorganic chromium(VI) compounds.

The half-life for chromium urinary excretion after administration in drinking water as potassium

dichromate has been estimated in humans (Kerger et al. 1997). Ingestion of 0.05 mg chromium(VI)/kg

CHROMIUM 149

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resulted in an extended time course of excretion. Approximately 76–82% of the 14-day total amount of

chromium in the urine was excreted within the first 4 days (mean peak concentration 209 µg chromium/g

creatinine; range 29–585 µg chromium/g creatinine). The average urinary excretion half-life for four of

the volunteers was 39 hours at this dose. All subjects had returned to background concentrations

(0.5–2.0 µg chromium/g creatinine) by 14 days post-dosing. About 87% of the total amount of chromium

in the urine measured over 8 days was excreted during the first 4 days for one volunteer ingesting

0.03 mg chromium(VI)/kg (peak 97 µg chromium/g creatinine on day of ingestion). Urinary chromium

concentrations had returned to an average of 2.5 µg chromium/g creatinine within 7 days post-dosing, the

last time point measured. Urinary excretion half-life in this volunteer was 37 hours. Similar time courses

of excretion were observed when volunteers took the same doses as daily doses over 3-day periods. An

earlier study by this group (Kerger et al. 1996a) examined urinary excretion half-lives following a bolus

dose of 10 ppm (approximately 0.06 mg chromium/kg) chromium(III) chloride, potassium dichromate

reduced with orange juice (presumably, the juice reduced the potassium dichromate to chromium(III)-

organic complexes and chromium(III) ions), or potassium dichromate. The calculated urinary excretion

half-lives for the three chromium solutions were 10.3, 15, and 39.3 hours, respectively. The potassium

dichromate half-life is consistent with the results from the Kerger et al. (1997) study.

The urinary excretion kinetics of chromium have also been examined in eight adults that were

administered chromium(III) at 400 µg/day as chromium(III) picolinate for 3 consecutive days (Gargas et

al. 1994). The mean time to peak urinary concentration was 7.18±2.11 hours (range 2.9–13.0 hours), the

mean peak concentration being 7.92±4.24 µg chromium/g creatinine (range 3.58–19.13 µg/g creatinine).

Excretion diminished rapidly after the peak but did not appear to return to background in most of the

volunteers before the next daily dose.

Pharmacokinetic models were used to predict the retention and excretion of ingested chromium(III)

picolinate (Stearns et al. 1995a). A single dose of 5.01 mg (assuming 2.8% or 140 µg of the

chromium(III) picolinate is absorbed) resulted in 11 µg (7.9%) retained after 1 year. The model predicted

that about 1.4 µg would still be present in body tissues 10 years after dosing, and continuous dosing over

a 1-year period would result in 6.2 mg of chromium(III) picolinate being retained, requiring about

20 years to reduce the retained level to 0.046 mg. These projected retention estimates may be two- to

four-fold lower than results obtained from actual clinical findings. The authors caution that accumulative

daily intake of chromium(III) may result in tissue concentrations that could be genotoxic.

CHROMIUM 150

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Daily urinary excretion levels of chromium were nearly identical in men and women (averages of 0.17

chromium(III)/day). When the subjects' normal diets were supplemented with 200 µg chromium(III)/day

rose proportionately to an average of 0.98 µg/L combined. Thus a five-fold increase in oral intake

resulted in about a five-fold increase in excretion, indicating absorption was proportional to the dose

regardless of whether the source was food or supplement (Anderson et al. 1983). A group of 23 elderly

subjects who received an average of 24.5 µg/day (0.00035 mg chromium(III)/kg/day) from their normal

diets excreted 0.4 µg chromium/day in the urine (1.6%) and 23.9 µg chromium/day in the feces (97.6%),

with a net retention of 0.2 µg/day (0.8%). Based on the 1980 daily requirement for absorbable chromium

of 1 µg/day by the National Academy of Science Food and Nutrition Board, the retention was considered

adequate for their requirements (Bunker et al. 1984).

An estimate of the half-life of elimination from plasma has been reported in humans. Uptake of

potassium dichromate was determined in a man who was given 0.8 mg of chromium(VI) in drinking

water 5 times each day for 17 days (Paustenbach et al. 1996). Steady-state concentrations of chromium in

blood were attained after 7 days and a plasma elimination half-life of 36 hours was estimated.

Measurement of the chromium content in 255 milk samples from 45 lactating American women revealed

that most samples contained <0.4 µg/L with a mean value of 0.3 µg/L (Casey and Hambidge 1984).

Another study (Anderson et al. 1993) measured chromium levels in the breast milk of 17 women 60 days

postpartum, and reported mean levels of ~0.2 µg/L. Lactation, therefore, represents a route of excretion

of chromium and a potential route of exposure to the nursing infant. However, the precise relationship

between maternal chromium levels and levels in breast milk is unclear, if such a relationship exists at all

(Anderson et al. 1993; Engelhardt et al. 1990; Mohamedshah et al. 1998).

Chromium can be excreted in hair and fingernails. Mean trace levels of chromium detected in the hair of

individuals from the general population of several countries were as follows: United States, 0.23 ppm;

Canada, 0.35 ppm; Poland, 0.27 ppm; Japan, 0.23 ppm; and India, 1.02 ppm (Takagi et al. 1986). Mean

levels of chromium in the fingernails of these populations were: United States, 0.52 ppm; Canada,

0.82 ppm; Poland, 0.52 ppm; Japan, 1.4 ppm; and India, 1.3 ppm (Takagi et al. 1988).

CHROMIUM 151

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Rats given 18 mg chromium(VI)/kg as potassium dichromate by gavage excreted about 25 µg chromium

1986).

In rats and hamsters fed chromium compounds, fecal excretion of chromium varied slightly from 97 to

99% of the administered dose. Urinary excretion of chromium varied from 0.6 to 1.4% of the dose

administered as either chromium(III) or chromium(VI) compounds (Donaldson and Barreras 1966;

Henderson et al. 1979; Sayato et al. 1980). The urinary and fecal excretion over 2-day periods in rats

treated for 8 days by gavage with 13.92 mg chromium/kg/day in corn oil was higher when soil containing

70% chromium(III) and 30% chromium(VI) was the source of chromium than when chromium(VI) as

calcium chromate was the source (see Section 2.3.2.2). Total urinary and fecal excretion of chromium on

days 1 and 2 of dosing were 1.8 and 19%, respectively, of the dose from soil and <0.5 and 1.8%,

respectively, of the dose from calcium chromate. Total urinary and fecal excretion of chromium on days

seven and eight of dosing were higher than on days one and two. For contaminated soil, urinary excretion

was 1.12% and fecal excretion was 40.6% of the dose. For calcium chromate, urinary excretion was

0.21% and fecal excretion was 12.35% of the dose (Witmer et al. 1991). Whether the higher excretion of

chromium after dosing with soil than with the chromate salt represents greater bioavailability from soil

could not be determined because about 50% of the administered dose could not be accounted for from the

excretion and distribution data (see Section 2.3.2.2). Excretion of chromium(III) in dogs was

approximately equal to the clearance of creatinine, indicating little tubular absorption or reabsorption of

chromium in the kidneys (Donaldson et al. 1984).

Information regarding the excretion of chromium in humans after dermal exposure to chromium or its

compounds is limited. Fourteen days after application of a salve containing potassium chromate(VI),

which resulted in skin necrosis and sloughing at the application site, chromium was found at 8 mg/L in

the urine and 0.61 mg/100 g in the feces of one individual (Brieger 1920). A slight increase (over

background levels) in urinary chromium levels was observed in four subjects submersed in a tub of

chlorinated water containing 22 mg chromium(VI)/L as potassium dichromate(VI) for 3 hours (Corbett et

al. 1997). For three of the four subjects, the increase in urinary chromium excretion was less than

1 µg/day over the 5-day collection period.

CHROMIUM 152

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chromium(III) trichloride solutions were placed over skin depots that were monitored by scintillation

counting to determine the dermal absorption (Wahlberg and Skog 1965).

Elevated levels of chromium in blood, serum, urine, and other tissues and organs have been observed in

patients with cobalt-chromium knee and hip arthroplasts (Michel et al. 1987; Sunderman et al. 1989).

Whether corrosion or wear of the implant can release chromium (or other metal components) into the

systemic circulation depends on the nature of the device. In one study, the mean postoperative blood and

urine levels of chromium of nine patients with total hip replacements made from a cast cobalt-chromiummolybdenum

alloy were 3.9 and 6.2 µg/L, respectively, compared with preoperative blood and urine

levels of 1.4 and 0.4 µg/L, respectively. High blood and urinary levels of chromium persisted when

measured at intervals over a year or more after surgery. These data suggest significant wear or corrosion

of the metal components. No significant difference was found for patients with hip replacements made

from the alloy and articulated with polyethylene (Coleman et al. 1973). Similarly, serum and urinary

levels of chromium in patients with implants made from a porous coated cobalt chromium alloy with

polyethylene components (to prevent metal-to-metal contact) were not significantly different from

patients with implants made without chromium (Sunderman et al. 1989).

A number of factors have been shown to alter the rate of excretion of chromium in humans. Intravenous

injection of calcium EDTA resulted in a rapid increase in the urinary excretion of chromium in metal

workers (Sata et al. 1998). Both acute and chronic exercises have been shown to increase chromium

excretion in the urine, though the increased excretion did not appear to be accompanied with decreased

levels of total native chromium (Rubin et al. 1998). An increased rate of chromium excretion has been

reported in women in the first 26 weeks of pregnancy (Morris et al. 1995b). Chromium supplementation

did not appear to alter the rate of excretion into breast milk in postpartum women (Mohamedshah et al.

1998).

The urinary excretion of chromium after a single or during repeated subcutaneous injections of potassium

dichromate was followed in rats. Following a single dose of 5.35 mg chromium(VI)/kg, chromium was

excreted rapidly in two phases and was essentially complete at 48 hours. The filtered chromium load rose

considerably during the first few hours after dosing and exceeded the tubular reabsorption rate. This

increase was followed by a decrease that paralleled the urinary excretion of chromium. During repeated

CHROMIUM 153

2. HEALTH EFFECTS

injections with 1.05 mg chromium(VI)/kg/day, every other day for 12 weeks, urinary excretion and

diffusible chromium renal clearance rose at relatively high parallel rates, and reached plateaus at

10 ng/min for urinary excretion and 550 µL/min for renal clearance. The filtered load increased slightly.

Since high levels of chromium were found in the renal cortex (see Section 2.3.2.4), the tubular

reabsorption appeared to be limited by the accumulation of chromium in the tubular epithelium (Mutti et

al. 1979).

Rats given a subcutaneous injection of potassium dichromate (chromium(VI)) and chromium nitrate

(chromium(III)) excreted 36% of the chromium(VI) dose in urine and 13.9% in the feces within 7 days;

8% and 24.2% of the chromium(III) was excreted in the urine and feces within the same time period,

chromium(III) chloride at 3 mg/kg chromium, rats excreted 5.23% of the dose in the feces and 16.3% in

the urine (Gregus and Klaassen 1986).

chromium(III) trichloride at 0.0003 or 0.345 mg chromium/kg, the bile contained 2–2.5% of the dose

following chromium(VI) exposure; however, after chromium(III) exposure the concentration in the bile

excreted in the bile as chromium(III), compared to 0.1–0.5% of chromium(III) compounds, after

intravenous injection in rats (Cirkt and Bencko 1979; Norseth et al. 1982). Administration of

diethylmaleate, which depletes glutathione, resulted in only chromium(VI) in the bile after injection of

sodium chromate.

Two hours after dosing rats intravenously with potassium dichromate at 0.45–4.5 mg chromium(VI)/kg,

1.4–2.2% of the chromium was recovered in the bile. Less than 1% of the total measurable chromium in

the bile was identified as chromium(VI) compounds (Cavalleri et al. 1985).

Male Swiss mice exposed to 52 mg chromium(III)/kg as chromium chloride by single intraperitoneal

injection or subcutaneous injection had plasma clearance half-times of 41.2 and 30.6 hours, respectively.

In each case, blood levels reached control levels by 6–10 days (Sipowicz et al. 1997).

CHROMIUM 154

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Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and

disposition of chemical substances to quantitatively describe the relationships among critical biological

processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry

models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of

potentially toxic moieties of a chemical that will be delivered to any given target tissue following various

combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based

pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to

quantitatively describe the relationship between target tissue dose and toxic end points.

PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to

delineate and characterize the relationships between: (1) the external/exposure concentration and target

tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al.

1987; Andersen and Krishnan 1994). These models are biologically and mechanistically based and can

be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from

route to route, between species, and between subpopulations within a species. The biological basis of

PBPK models results in more meaningful extrapolations than those generated with the more conventional

use of uncertainty factors.

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model

representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and

Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of

toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen

1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substancespecific

physicochemical parameters, and species-specific physiological and biological parameters. The

numerical estimates of these model parameters are incorporated within a set of differential and algebraic

equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations

provides the predictions of tissue dose. Computers then provide process simulations based on these

solutions.

The structure and mathematical expressions used in PBPK models significantly simplify the true

complexities of biological systems. If the uptake and disposition of the chemical substance(s) is

adequately described, however, this simplification is desirable because data are often unavailable for

CHROMIUM 155

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many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The

adequacy of the model is, therefore, of great importance, and model validation is essential to the use of

PBPK models in risk assessment.

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the

maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994).

PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in

humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste

sites) based on the results of studies where doses were higher or were administered in different species.

Figure 2-3 shows a conceptualized representation of a PBPK model.

If PBPK models for chromium exist, the overall results and individual models are discussed in this

section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species

extrapolations.

PBPK models for chromium are discussed below.

One PBPK model for chromium has been published. The O’Flaherty model (O’Flaherty 1993a, 1996)

simulates the absorption, distribution, metabolism, elimination, and excretion of chromium(III) and

chromium(VI) compounds in the rat. Two kinetic models describing the distribution and clearance of

chromium(III) compounds in humans are described at the end of this section.

The O’Flaherty model is the only PBPK model available for chromium.

CHROMIUM 156

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Skin

Kidney

Richly

perfused

tissues

Slowly

perfused

tissues

Fat

Liver

Lungs

A

RT

ERIAL

BLOO

D

VEN

O

US

BLOO

D

GI

Tract

Urine

Chemicals in air

contacting skin

Inhaled chemical Exhaled chemical

Ingestion

Feces

Source: adapted from Krishnan et al. 1994

Note: This is a conceptual representation of a physiologically based pharmacokinetic

(PBPK) model for a hypothetical chemical substance. The chemical substance is

shown to be absorbed via the skin, by inhalation, or by ingestion, metabolized in the

liver, and excreted in the urine or by exhalation.

CHROMIUM 157

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chromium(III) absorption and kinetics in the rat, and reduction from the chromium(VI) to the

chromium(III) valence state, but the bioavailability/absorbability of chromium from environmental

sources is mostly unknown, except for bioavailability/absorbability of a few chemically defined salts.

Furthermore, the mechanisms by which chromium reserves from bone tissue are released into plasma as

well as age, physiological conditions and species variations are important considerations in the refinement

of any PBPK model for risk assessment purposes.

lead and contained 10 compartments, alveolar space, well-perfused tissues, poorly-perfused tissues,

kidney, liver, intestine, blood, and intestinal tract contents. The blood compartment was divided into

plasma and red blood cells. Reduction of chromium(VI) to chromium(III) was considered to occur in

every compartment except bone. The refined model (O’Flaherty 1996) replaced the alveolar space

compartment with a two pool lung compartment, Pool A representing bioavailable chromium for entering

either blood or the gastrointestinal tract, and Pool B containing non-bioavailable chromium that only

moves into the gastrointestinal tract. The intestinal tract compartment was modified so that absorbed

chromium entered the liver. A urinary retention compartment was added to better fit the data. The

parameters of the model are given in Table 2-4 and the structure of the model is shown in Figure 2-4.

The model was developed from several data sets in which rats were dosed with chromium(VI) or

chromium(III) intravenously, orally, or by intratracheal instillation, because depending on route of

administration, different distribution and excretion patterns occur. In cases where parameters were not

available (absorption rates, tissue affinity, biotransformation), estimates were obtained by fitting. This

was done by duplicating the initial conditions of published experiments in the model, varying the

unknown parameters and comparing the results of the simulation to the reported results. Tissue affinity

constants were estimated using reported chromium levels in tissues at various times after exposure.

Metabolic rate constants and absorption rate constants were estimated using data for excretion of

chromium in urine and feces. The model includes exchanges of chromium between plasma and bone, and

CHROMIUM 158

2. HEALTH EFFECTS

Absorption

0.2, 2.0 First-order rate constant for absorption from the bioavailable lung pool (pool A)

0.8 First-order rate constant for mucociliary clearance from pool A to the

0.025 First-order rate constant for mucociliary clearance from nonbioavailable lung

Distribution

5.0, 15.0 Relative clearance of chromium into mineralizing bone (liters of blood plasma

cleared per liter of new bone formed)

0.0003, 1.5 Clearance from plasma to red cell (liters/day)

0.007, 1.5 Clearance from plasma to kidney (liters/day)

0.0001, 1.5 Clearance from plasma to liver (liters/day)

0.0001, 1.5 Clearance from plasma to other well-perfused tissues (liters/day)

0.0001, 0.1 Clearance from plasma to poorly-perfused tissues (liters/day)

0.0001, 0.1 Clearance from plasma to bone (liters/day)

0.0003, 10.0 Clearance from red cell to plasma (liters/day)

0.001, 10.0 Clearance from kidney to plasma (liters/day)

0.0003, 10.0 Clearance from liver to plasma (liters/day)

0.001, 10.0 Clearance from other well-perfused tissues to plasma (liters/day)

0.003, 10.0 Clearance from poorly perfused tissues to plasma (liters/day)

0.003, 10.0 Clearance from bone to plasma (liters/day)

Excretion

1.5 First-order rate constant for loss of chromium from intestinal tract contents to the

0.065, 0.065 Excretion clearance from the plasma (urinary clearance) (liters/kg/day)

0.0, 0.0 Fraction of body burden secreted in the bile

0.0, 0.0 Fraction of body burden excreted via the gastrointestinal tract

CHROMIUM 159

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Reduction

0.7 First-order rate constant for reduction of Chromium(VI) to Chromium(III) in the

0.5 First-order rate constant for reduction of Cr(VI) to Cr(III) in all other tissues and

10.0 First-order rate constant for reduction of Cr(VI) to Cr(III) in gastrointestinal tract

Lag time for

excretion of urine

0.7 Fraction of urinary chromium not excreted immediately; that is, temporarily held

in pool

0.10 Fraction of chromium in retained urine that is associated with the kidney

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POOL A

Cr(VI) Cr(III)

WELL PERFUSED

Cr(VI) Cr(III)

POOL B

LUNG INHALATION

EXPOSURE

POORLY PERFUSED

Cr(VI) Cr(III)

BONE

Cr(VI) Cr(III)

LIVER

Cr(VI) Cr(III)

KIDNEY

Cr(VI) Cr(III)

RETAINED

URINE

PLASMA

PLASMA

RED CELLS

Cr(VI) Cr(III)

URINARY

EXCRETION

GI TRACT

Cr(VI) Cr(III)

ORAL

EXPOSURE

FECAL

EXCRETION

*O’Flaherty 1996

CHROMIUM 161

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incorporation of chromium into actively mineralizing bone. It also includes the reductive process for

conversion of chromium(VI) to chromium(III) and takes into account differences in their absorption

through tissues of the body as well as in the lung and gastrointestinal tract. The chromium model needed

to be modified to include two lung compartments. Chromium via inhalation or intratracheal routes enters

the lung in compartment A where it can be systemically absorbed, transferred to the second lung

compartment B, or cleared by mucociliary action and enter the digestive tract. Chromium entering

compartment B can only be cleared by mucociliary action, and no chromium re-enters compartment A

from B. In order to account for the urinary excretion delay observed in the experimental data, a urinary

retention compartment was added. Because the absorption of chromium compounds into the body and

various tissues depends on the type and solubility of the complexes formed with ligands, adjustments to

the model must be made based on physicochemical characteristics of individual chromium compounds.

chromium(VI) as zinc chromate dust in Wistar rats (Langård et al. 1978). This study was chosen for

validation because none of the studies used to develop the model were inhalation studies. Rats were

and after each exposure and 4 times over the next 37 days post-exposure. The model tended to

overpredict chromium blood levels during the 4-day exposure period, but agreement during the postexposure

period was good. The exposure conditions of a drinking water exposure to potassium

chromate(VI) for 1 year at concentrations of 045, 2.2, 4.5, 7.7, 11.2, and 25 ppm in Sprague-Dawley rats

were also simulated (MacKenzie et al. 1958).

The model overestimated final liver chromium concentrations, but bone and kidney concentrations were

well-predicted. This was not a completely independent test of the model’s validity since data from this

study were used to set parameters for fractional uptake of chromium into bone.

and kidney can be predicted by this model.

entirely on data from rat kinetic studies.

CHROMIUM 162

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studies and then refined using data from oral and intratracheal routes. The final model was able to

reasonably predict the results from an inhalation exposure experiment.

Two kinetic models describing distribution and clearance in humans have been developed based on

studies in volunteers. A model for distribution and clearance of chromium(III) as chromium(III)

trichloride was developed by Lim et al. (1983) that has fast, medium, and slow exchange compartments.

The model’s parameters were based on distribution measurements obtained from whole body scintillation

scanning after intravenous injections of radiolabeled chromium into volunteers. Total chromium

remaining in the body as a function of time was determined with a whole-body scanner, plasma clearance

was determined by measurement of radiolabel in the blood. Measurements taken immediately after

injection showed that 96% of the label was bound to plasma proteins while 4% was free, after 24 hours

the label was too low to measure. Whole-body scanning showed labeled chromium primarily in the liver,

spleen, body soft tissues, and bone with highest concentrations in the liver and spleen. Examination of

the scanning images over time revealed three major accumulation and clearance components in each

organ, half-lives were 0.5–12 hours, 1–14 days, and 3–12 months. Each organ exhibited this pattern, i.e.,

each organ has varying proportions of fast, medium, and slow components for chromium clearance. A

model was constructed based on a central compartment of plasma chromium in equilibrium with three

pools defined by clearance rate and elimination from the body taking place at the kidney through filtration

of unbound chromium and loss of bound chromium by shedding of epithelial cells. The model indicates

that in a normal individual in chromium balance, absorbed chromium distributes into three pools, a fast

pool containing approximately 0.13 µg, and a clearance half-time of 5.2 minutes, a medium pool

containing 0.8 µg and a half-time of 2.2 days, and a slow pool containing 24.7 µg and a half-time of

315 days.

Gargas et al. (1994) employed a three compartment model describing the urinary excretion of chromium

(Aitio et al. 1988) to estimate the bioavailability of chromium(III) from chromium(III) picolinate in

volunteers ingesting capsules containing 400 µg. The model contained 3 compartments, a fast-exchange

compartment receiving 40% of absorbed chromium with a half-life of 7 hours, a medium-exchange

compartment receiving 50% of absorbed chromium with a half-life of 15 days, and a slow-exchange

compartment receiving 10% of absorbed calcium with a half-life of 3 years. Estimates of absorbed

chromium were used as inputs to the model and predicted urinary excretion was compared to that

observed. Adjustments to the estimate of absorbed chromium were made until the predictions agreed

CHROMIUM 163

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with the observed data. Bioavailability of chromium(III) as chromium(III) picolinate was estimated as

2.80±1.14% (standard deviation).

Using these models for estimating bioavailability, distribution, and excretion, Stearns et al. (1995a)

predicted that chromium(III) may accumulate in the body of humans ingesting large doses of chromium

picolinate dietary supplements.

Chromium(III) is an essential nutrient required for normal energy metabolism. The biologically active

form is an unidentified organic complex of chromium(III) often referred to as GTF. Chromium is poorly

taken up by cells in any valence state, but chromium(III) is absorbed less efficiently than chromium(VI).

This is believed to be due to the tetrahedral configuration of the chromate anion, which allows it to enter

the cells via facilitated diffusion and through non-specific anion channels. In contrast, chromium(III) is

absorbed via passive diffusion and phagocytosis, resulting in much lower total uptake into cells. Once

absorbed, chromium(VI) is reduced to chromium(III), with chromium(V) and chromium(IV) as

intermediates in the process. Chromium(V) and chromium(IV) are believed to be able to react with

intracellular constituents, resulting in either the formation of free radicals or direct binding to

macromolecules. Most of the effects of chromium(III) are mediated by direct binding to macromolecules,

although there is a slight possibility that it may also contribute to free radical formation. The radical

intermediates and the direct binding to macromolecules, can then result in DNA-protein crosslinks, DNADNA

crosslinks, DNA strand breaks, lipid peroxidation, and alterations in cellular signaling pathways.

All of these may contribute to toxicity and carcinogenicity of chromium compounds.

The absorption of inhaled chromium compounds depends on a number of factors, including physical and

chemical properties of the particles (oxidation state, size, solubility) and the activity of alveolar

macrophages. Chromium has been identified in the tissues of occupationally-exposed humans, suggesting

that chromium can be absorbed from the lungs (Cavalleri and Minoia 1985; Gylseth et al. 1977; Kiilunen

et al. 1983; Mancuso 1997b; Minoia and Cavalleri 1988; Randall and Gibson 1987; Tossavainen et al.

1980). Animal studies have also demonstrated increased amounts of chromium in the blood following

inhalation or intratracheal instillation exposures (Baetjer et al. 1959b; Bragt and van Dura 1983; Langård

et al. 1978; Visek et al. 1953; Wiegand et al. 1984, 1987). Chromium(VI) is more rapidly absorbed into

CHROMIUM 164

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the bloodstream than is chromium(III) (Gao et al. 1993; Suzuki et al. 1984). Chromium that is not

absorbed in the lungs may be cleared via mucociliary clearance and enter the gastrointestinal tract.

Chromium is poorly absorbed from the gastrointestinal tract; the primary site of chromium absorption

appears to be the jejunum (Donaldson and Barreras 1966). The bioavailability of chromium compounds

seems to be most dependant on the oxidation state of the chromium atom. However, other factors,

including dose level and formulation of the chromium, can influence the extent of absorption.

Chromium(III) is very poorly absorbed, with only 0.5–2.8% of dietary chromium absorbed via the

gastrointestinal tract of humans (Anderson 1986; Anderson et al. 1983; Donaldson and Barreras 1966;

Gargas et al. 1994; Kerger et al. 1996a; Kuykendall et al. 1996). Chromium(III) absorption efficiency

appears to be related to dietary intake; the efficiency decreases with increasing dose (Anderson 1986;

Anderson et al. 1983). Human studies demonstrate that chromium(VI) is effectively reduced to

chromium(III) by gastric juices (De Flora et al. 1987a) and in general, chromium(VI) is better absorbed

than chromium(III) following oral exposure in humans (Donaldson and Barreras 1966; Finley et al.

1996b; Kerger et al. 1996a; Kuykendall et al. 1996). Absorption efficiencies ranging from 1.7 to 6.9%

have been estimated in humans (Finley et al. 1996a; Kerger et al. 1996a, 1997; Kuykendall et al. 1996).

Unlike chromium(III), absorption efficiency appears to increase with dose; Kerger et al. (1997) estimated

an efficiency of 1.7% at 0.05 mg chromium(VI)/kg/day and 3.4% at 0.1 mg chromium(VI)/kg/day.

Ingestion of chromium with a meal appears to increase the absorption efficiency (Chen et al. 1973).

Both chromium(III) and chromium(VI) can penetrate human skin to some extent, especially if the skin is

damaged. Following dermal exposure, chromium has been detected in the blood, feces, and urine of

exposed humans (Brieger 1920), though in this study, the skin was damaged, which likely facilitated

absorption. An average rate of systemic uptake of chromium(VI) in humans submersed in chlorinated

Chromium(VI) appears to penetrate the skin faster than chromium(III) (Mali et al. 1963; Spruit and van

Neer 1966; Wahlberg 1970), though many other factors may be involved, including solvent (Liden and

Lundberg 1979) and concentration (Baranowska-Dutkiewicz 1981).

Absorbed chromium is carried throughout the body in the blood, eventually being distributed to all

tissues. Greatest concentrations of chromium are found in the blood, liver, lung, spleen, kidney, and heart

(Kaufman et al. 1970; Schroeder et al. 1962; Teraoka 1981). Because insoluble chromium is not

completely cleared or absorbed following inhalation exposure, greater levels of chromium are often found

in lung tissues following inhalation of chromium compounds than following other methods of exposure.

CHROMIUM 165

2. HEALTH EFFECTS

Tissue levels appeared to be higher after exposure to chromium(VI) than to chromium(III). This may be

due to the greater ability of chromium(VI) to cross cell membranes and may also be a function of

administration of doses high enough to overwhelm the chromium(VI) reduction mechanisms.

De Flora et al. (1997) have demonstrated that liver, erythrocytes, whole blood, lung epithelial fluid,

alveolar macrophages, and peripheral parenchyma cells all have the ability to reduce chromium(VI) to

chromium(III). Chromium has been detected in breast milk (Casey and Hambidge 1984; Schmitova

1980), but the relationship between chromium exposure, dietary or otherwise, and breast milk chromium

levels is inconclusive (Anderson et al. 1993; Engelhardt et al. 1990; Mohamedshah et al. 1998).

Systemic chromium does not appear to be stored for extended periods of time within the tissues of the

body. Single- and multiple-exposure studies in humans have shown a one-compartment clearance halftime

in humans on the order of 36 hours (Kerger et al. 1997; Paustenbach et al. 1996) following oral

exposure. However, this half-time is sufficiently long to allow for accumulation of chromium following

regular repeated exposure. Following inhalation exposure, insoluble chromium that is not cleared from

the lungs may remain for a considerable time. Chromium may also persist within erythrocytes, bound to

intracellular constituents.

Inhaled chromium can be eliminated from the lungs by absorption into the bloodstream, by mucociliary

clearance, and by lymphatic system clearance (Bragt and van Dura 1983; Perrault et al. 1995; Visek et al.

1953; Weigand et al. 1984, 1987). The primary routes of elimination of absorbed chromium is urine and

feces. It can also be eliminated in hair and fingernails (Randall et al. 1992; Stearns et al. 1995a; Takagi et

al. 1986). Chromium, once reduced to chromium(III) in the liver, is then conjugated with glutathione and

enters bile where it is excreted in the feces (Norseth et al. 1982). Because chromium is poorly absorbed

following oral exposure, a large percentage of the amount ingested is excreted in the feces. The half-time

of urinary excretion of chromium is short, 4–10 hours for inhalation exposure (Kiilunen et al. 1983),

10 hours for oral exposure to chromium(III) (Kerger et al. 1996a), and 40 hours for oral exposure to

chromium(VI) (Kerger et al. 1996a, 1997). Following dermal exposure, chromium that is not absorbed

into the bloodstream will remain on the skin until it is eliminated, usually by washing or other physical

processes. Absorbed chromium is primarily eliminated in the urine.

Following inhalation exposure, the majority of chromium-induced effects are seen in the respiratory tract,

with some systemic effects reported at extremely high concentrations, but generally being lesser in

CHROMIUM 166

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prevalence. Following oral exposure, hepatic and renal effects are most prevalent, with effects being

generally lesser in other tissues. Studies of systemic effects following dermal exposure are limited, but

the primary target organ following such exposures seems to be the skin.

The toxicity of chromium is dependent on the oxidation state of the chromium atom, with chromium(VI)

being significantly more toxic than chromium(III). One of the factors believed to contribute to this

increased toxicity is the greater ability of chromium(VI) to enter cells, compared to chromium(III).

Chromium(VI) exists as the tetrahedral chromate anion at physiological pH, and resembles the forms of

other natural anions, such as sulfate and phosphate, which are permeable across nonselective membrane

channels. Chromium(III), however, forms octahedral complexes and cannot easily enter through these

channels. Therefore, the lower toxicity to chromium(III) may be due in part to lack of penetration

through cell membranes. It follows that extracellular reduction of chromium(VI) to chromium(III) may

result in a decreased penetration of chromium into cells, and therefore, a decreased toxicity.

Once it is taken into cells, chromium(VI) has been shown to undergo a reduction to chromium(III), with

chromium(V) and chromium(IV) as intermediates. These reactions commonly involve intracellular

species, such as ascorbate, glutathione, or amino acids (Aiyar et al. 1991; Blankenship et al. 1997;

Capellmann et al. 1995; Hojo and Satomi 1991; Kim and Yurkow 1996; Lin et al. 1992; Liu et al. 1997b;

Mao et al. 1995; Wiegand et al. 1984; Zhitkovich et al. 1996). Chromium(VI), chromium(V), and

chromium(IV) have all been shown to be involved in Fenton-like oxidative cycling, generating oxygen

radical species (Aiyar et al. 1991; Chen et al. 1997; Liu et al. 1997b; Luo et al. 1996; Mao et al. 1995;

Molyneux and Davies 1995; Tsou et al. 1996). Although unlikely to occur under physiological

conditions, chromium(III) may be able to undergo radical-generating cycling, though at lesser levels than

chromium(IV) or chromium(V) (Shi et al. 1993, 1998; Tsou et al. 1996). It is believed that the formation

of these radicals may be responsible for many of the deleterious effects of chromium on cells, including

the formation of DNA strand breaks (Aiyar et al. 1991; Kuykendall et al. 1996b; Manning et al. 1992;

Ueno et al. 1995a), DNA-protein crosslinks (Aiyar et al. 1991; Blankenship et al. 1997; Capellmann et al.

1995; Costa et al. 1996, 1997; Kuykendall et al. 1996b; Lin et al. 1992; Manning et al. 1992;

Mattagajasingh and Misra 1996; Miller et al. 1991; Zhitkovich et al. 1996 ), and alterations in cellular

communication and signaling pathways (Chen et al. 1997; Kim and Yurkow 1996; Mikalsen 1990;

Shumilla et al. 1998; Wang et al. 1996a; Xu et al. 1996; Ye et al. 1995). Cellular damage from exposure

to many chromium compounds can be blocked by radical scavengers, further strengthening the hypothesis

that oxygen radicals play a key role in chromium toxicity (Luo et al. 1996; Tsou et al. 1996; Ueno et al.

1995a).

CHROMIUM 167

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The products of metabolic reduction of chromium(VI) (free radicals and chromium(IV) and (V)) and the

newly generated chromium(III) are thought to be primarily responsible for the carcinogenic effects seen

in human and animal studies. The interaction of free radicals, chromium(V), chromium(IV), and

chromium(III) with DNA can result in structural DNA damage, functional damage, and cellular effects

(Singh et al. 1998a). The types of structural damage include DNA strand breaks (Aiyar et al. 1991;

Manning et al. 1992; Ueno et al. 1995a), DNA-protein crosslinks (Aiyar et al. 1991; Blankenship et al.

1997; Capellmann et al. 1995; Costa et al. 1996, 1997; Kuykendall et al. 1996; Lin et al. 1992; Manning

et al. 1992; Mattagajasingh and Misra 1996; Miller et al. 1991; Zhitkovich et al. 1996 ), DNA-DNA

interstrand crosslinks (Xu et al. 1996), chromium-DNA adducts, and chromosomal aberrations

(Blankenship et al. 1997; Sugiyama et al. 1986; Umeda and Nishmura 1979; Wise et al. 1993).

Functional damage includes DNA polymerase arrest (Bridgewater et al. 1994a, 1994b, 1998), RNA

polymerase arrest, mutagenesis, and altered gene expression. Chromium can also interact with DNA to

form adducts/complexes and DNA-protein crosslinks that interfere with DNA replication and

inhibit regulatory genes such as GRP78 (Chen et al. 1997; Kim and Yurkow 1996; Manning et al. 1992;

Mikalsen 1990; Shumilla et al. 1998; Wang et al. 1996a; Xu et al. 1996; Ye et al. 1995). Disruption of

these pathways by other compounds has been implicated in carcinogenesis. The structural and functional

damage can lead to growth arrest (Xu et al. 1996) and apoptosis (Carlisle et al. 2000; Singh et al. 1999).

As discussed by Singh et al. (1998a), the mechanism by which chromium induces apoptosis is not fully

understood, but is believed to involve oxidative stress and DNA-DNA crosslinks and transcriptional

inhibition.

Species-related differences in chromium pharmacokinetics have been demonstrated, both between rodent

species and between rodents and humans. However, studies directly examining species differences have

been limited. Human microsomal chromium(VI) reduction is different from the P450-mediated

microsomal reduction in rodents; specifically, the human system is much less oxygen-sensitive, has a

much greater affinity for chromate, and is apparently mediated by flavoproteins (Myers and Myers 1998;

Pratt and Myers 1993). Tissue distributions of chromium were found to be different between rats and

mice after administration of bolus amounts of chromium(VI). Rat erythrocytes had a greater capacity to

sequester chromium(VI) and reduce it to chromium(III) than mouse erythrocytes (Coogan et al. 1991b;

Kargacin et al. 1993), thus demonstrating that both physiologic and metabolic differences can exist

among species.

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Issues relevant to children are explicitly discussed in Sections 2.7, Children’s Susceptibility, and 5.6,

Exposures of Children.

Chromium(III) is an essential nutrient required for normal energy metabolism. The National Research

Council (NRC) recommends a dietary intake of 50–200 µg/day (NRC 1989). The biologically active

form of an organic chromium(III) complex, often referred to as GTF, is believed to function by

facilitating the interaction of insulin with its cellular receptor sites. The exact mechanism of this

interaction is not known (Anderson 1981; Evans 1989). Studies have shown that chromium

supplementation in deficient and marginally deficient subjects can result in improved glucose, protein,

and lipid metabolism.

Evidence of overt signs of chromium deficiency in humans is limited to a few case reports. In one such

case report, a woman receiving total parenteral nutrition for 3 years exhibited peripheral neuropathy,

weight loss, and impaired glucose metabolism. Administration of insulin did not improve glucose

tolerance. Administration of 250 µg/day chromium without exogenous insulin resulted in normal glucose

tolerance of an oral load of glucose and the absence of peripheral neuropathy (Jeejeebhuoy et al. 1977).

In animals, severe chromium deficiency has resulted in hyperglycemia, decreased weight gain, elevated

serum cholesterol levels, aortic plaques, corneal opacities, impaired fertility and lethality. Administration

of inorganic trivalent chromium compounds or extracts of brewers' yeast resulted in decreased blood

glucose levels and cholesterol levels and regression of atherosclerotic plaques (Pi-Sunyer and

Offenbacher 1984). Improved insulin sensitivity also resulted in an increased incorporation of amino

acids into proteins and cell transport of amino acid in rats receiving supplemental chromium (Roginski

and Mertz 1969).

Although the incidence of severe chromium deficiency is low, the occurrence of marginal chromium

deficiency may be common. Studies have shown that the daily dietary intake of chromium in the United

States is 25–224 µg/day, with an average of 75 µg/day (Kumpulainen et al. 1979). An average daily

intake of 60 µg has been reported by Bennett (1986). Numerous studies have been designed to determine

the effect of chromium supplementation in individuals exhibiting abnormal glucose tolerance and/or

CHROMIUM 169

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elevated lipid levels. Serum chromium levels before and after supplementation were often not measured

because of limitations in analytical techniques available. Brewer's yeast, extracts of brewer's yeast,

synthetic chromium compounds with biological activity, chromium(III) picolinate, and inorganic trivalent

chromium have been used as chromium supplements (Pi-Sunyer and Offenbacher 1984). In general,

these studies have demonstrated improved glucose tolerance to an oral glucose load in Type II diabetics

(adult onset) and nondiabetic elderly subjects receiving a 4–200 µg/day chromium supplement (Evans

1989; Levine et al. 1968; Liu and Morris 1978; Offenbacher and Pi-Sunyer 1980). The subjects receiving

the daily chromium supplements had significantly lower blood glucose levels than the controls and no

difference in serum insulin levels between the groups. This reduction in blood glucose without a change

in insulin levels provides support that chromium enhances insulin sensitivity. Decreases in total

cholesterol, LDL-cholesterol, and serum lipids and increases in HDL-cholesterol have also been observed

in Type II diabetics and nondiabetics administered chromium supplements (Anderson et al. 1997c; Evans

1989; Lee and Reasner 1994; Offenbacher and Pi-Sunyer 1980; Press et al. 1990). This improvement in

serum lipids and cholesterol levels may be secondary to the decreased serum glucose levels.

In recent years, the use of chromium picolinate as a dietary supplement to aid in weight loss and increase

lean body mass has gained in popularity. As discussed by (Anderson 1998b), the role of chromium in the

regulation of lean body mass, percentage body fat, and weight reduction is highly controversial with

negative and positive results being reported in the literature. Initial studies (Evans 1989; Hasten et al.

1992) on chromium picolinate supplementation during resistance training served as the basis for the

marketing of chromium picolinate to promote muscle growth and fat loss. Evans (1989) found that

administration of 200 µg chromium(III)/day as chromium picolinate for 6 weeks to healthy males

performing daily weight training exercises resulted in an increase in body weight that was mostly due to

an increase in lean body mass. Control subjects undergoing the same exercise regimen but given a

placebo of calcium phosphate gained significantly less lean body mass and lost significantly less body fat

than the subjects receiving the chromium supplement; the weight gain in the controls was mostly due to

increased fat tissue. Hasten et al. (1992) reported an increase in lean body mass in women receiving

200 µg chromium(III)/day as chromium picolinate during 12 weeks of resistance training. Although

some other studies have found increases in lean body mass (Bulbulian et al. 1996; Kaats et al. 1996) in

adults taking 200 or 400 µg chromium(III) as chromium picolinate along with an exercise program, many

studies did not find any alterations in lean body mass (Campbell et al. 1999; Clancy et al. 1994; Hallmark

et al. 1996; Lukaski et al. 1996; Trent and Thieding-Cancel 1995).

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Several studies have also looked at the relationship between weight loss or increases in lean body mass in

sedentary adults and chromium picolinate supplementation. Kaats et al. (1992) reported an improvement

in body composition (loss of body fat without a loss of lean body mass) in obese subjects consuming

400 µg chromium(III)/day as chromium picolinate for 72 days. In contrast to these studies, Grant et al.

(1997) found a significant increase in body weight gain with no change in percent body fat or fat free

mass in sedentary, young, obese women consuming 400 µg chromium(III)/day as chromium picolinate

for 9 weeks. If the women participated in a exercise program, then no significant alterations in body

weight, percent body fat, fat mass, or fat free mass were observed. Proponents of chromium picolinate

supplementation have made numerous claims as to the benefits of chromium picolinate for weight loss

and increasing lean body mass. However, for the most part, clinical studies have not supported these

claims (Campbell et al. 1999; Clancy et al. 1994; Grant et al. 1997; Hallmark et al. 1996; Lukaski et al.

1996; Trent and Thielding-Cancel 1995). The potential toxicity of chromium picolinate has not been

thoroughly investigated. An intermediate-duration rat study did not find any adverse effects in rats

Wasser et al. (1997) reported a case of an individual with chronic renal failure following ingestion of

0.6 mg/day (approximately 0.085 mg/kg/day) of chromium picolinate supplements for 6 weeks. This

dose is 3 times the recommended doses for dietary supplements and 12–45 times the usual intake. Thus,

individuals using these supplements are cautioned to avoid taking more than recommended doses.

The general population is exposed to chromium by inhaling ambient air, ingesting food, and drinking

water containing chromium. Dermal exposure of the general public to chromium can occur from skin

contact with certain consumer products or soils that contain chromium. As discussed in Section 5.4,

ambient air in U.S. urban and nonurban areas typically contains mean total chromium concentrations

30 µg/L, with a median value of 10 µg/L. Typical U.S. drinking water supplies contain total chromium

levels mainly as chromium(III) ranging from 0.4 to 8.0 µg/L, with a mean of 1.8 µg/L. U.S. soil levels of

total chromium range from 1.0 to 2,000 mg/kg, with a mean level of 37 mg/kg. Chromium content in

foods varies greatly and depends on the processing and preparation. In general, most fresh foods

typically contain <50 µg total chromium/kg. Although workers in chromium-related industries in the past

were exposed to much higher levels of chromium than present day workers, present day workers in

chromium-related industries can be exposed to chromium concentrations two orders of magnitude higher

than the general population. Current OSHA TWA standards for an 8-hour workday, 40-hour workweek

CHROMIUM 171

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Chromium(VI) is better absorbed from the lung, gastrointestinal tract, and skin than is chromium(III).

Chromium(VI) is reduced to chromium(III) within the stomach, limiting the bioavailability of chromium

after ingestion and accounting for the relatively low oral toxicity of chromium(VI). Although

chromium(III) occurs naturally in the environment, chromium(VI) in the environment is almost always

related to anthropogenic activity. The presence of chromium compounds at hazardous waste sites can

contribute to the exposure of populations residing or working nearby through exposure to air containing

particulates or mists of chromium(VI) compounds, through drinking water if soluble forms of

chromium(VI) leach into groundwater, or through skin contact with soil at hazardous waste sites. The

potential for exposure to chromium(VI) at hazardous waste sites must be determined on a case-by-case

basis.

Effects in humans exposed occupationally to high levels of chromium or its compounds, primarily

chromium(VI), by inhalation may include nasal septum ulceration and perforation, and other irritating

respiratory effects, possible cardiovascular effects, gastrointestinal and hematological effects, liver and

kidney effects, and increased risks of death from lung cancer. In addition to the respiratory effects,

exposure to chromium(VI) and (III) compounds can be associated with allergic responses (e.g., asthma

and dermatitis) in sensitized individuals. Chromosome aberrations have been observed in some humans

occupationally exposed to chromium(VI) compounds and other substances. Accidental or intentional

ingestion of extremely high doses of chromium(VI) compounds by humans has resulted in severe

respiratory, cardiovascular, gastrointestinal, hematological, hepatic, renal, and neurological effects as part

of the sequelae leading to death or in patients who survived because of medical treatment. Dermal

exposure to chromium(VI) compounds has lead to death of humans that had pre-existing medical

conditions. Severe renal and hematological effects, and effects on the cardiovascular system and gastric

mucosa were observed in people with pre-existing medical conditions who died as a result of dermal

exposure. Occupational exposure by dermal contact can result in deeply penetrating ulcers (known as

chrome sores, chrome holes, or chrome ulcers) on the skin if left untreated. Dermal contact in chromium

sensitized individuals can also lead to an allergic type dermatitis.

Inhalation studies in animals with chromium(VI) and chromium(III) compounds generally support the

respiratory and immunological findings in humans. Inhalation and intratracheal studies with certain

chromium(VI) compounds in animals also support the carcinogenic findings in humans. Oral exposure of

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animals to very high doses of chromium(VI) and chromium(III) compounds has resulted in gastrointestinal,

hepatic, renal, immunological, neurological, developmental, and reproductive effects. Dermal exposure of

animals to chromium(VI) and chromium(III) compounds has resulted in skin ulcers and allergic response.

In general, chromium(VI) compounds are more toxic than chromium(III) compounds. The toxicity of

hexavalent chromium is in part due to the generation of free radicals formed during reduction to

chromium(III) in biological systems.

Chromium(IV) dioxide is a tetravalent chromium compound with limited industrial application. It is used

to make magnetic tape, as a catalyst in chemical reactions, and in ceramics (Hartford 1979). Because of its

limited industrial uses, the potential for human exposure is less for chromium dioxide than for the more

industrially important chromium(VI) and chromium(III) compounds. A single chronic inhalation study in

gastrointestinal, hematological, hepatic, renal, or dermal/ocular effects (Lee et al. 1989).

exposure as chromic acid (chromium trioxide mist) and other dissolved hexavalent chromium aerosols

and mists.

The MRL is derived from the study by Lindberg and Hedenstierna (1983) and is based on nasal irritation,

mucosal atrophy, and ulceration, and decreases in spirometric parameters observed in workers

based on chromic acid will also be health-protective against exposures to less irritating soluble

chromium(VI) compounds.

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The respiratory tract is the major target of inhalation exposures to chromium compounds. Respiratory

effects due to inhalation exposures are likely due to direct action of chromium at the site of contact. Workers

exposed to chromium(VI) compounds for intermediate- and chronic-durations were found to exhibit

epistaxis, chronic rhinorrhea, nasal itching and soreness, nasal mucosal atrophy, perforations and ulcerations

of the nasal septum, bronchitis, pneumonoconiosis, decreased pulmonary function, and pneumonia (Bovet et

al. 1977; Cohen et al. 1974; Davies et al. 1991; Gomes 1972; Greater Tokyo Bureau of Hygiene 1989;

Hanslian et al. 1967; Keskinen et al. 1980; Kleinfeld and Rosso 1965; Lee and Goh 1988; Letterer 1939;

Liebermann 1941; Lindberg and Hedenstierna 1983; Lucas and Kramkowski 1975; Mancuso 1951; Meyers

1950; Novey et al. 1983; Pastides et al. 1991; PHS 1953; Royle 1975b; Sassi 1956; Sluis-Cremer and du Toit

1968; Sorahan et al.1987; Taylor 1966).

The intermediate inhalation MRL derived from the Lindberg and Hedenstierna (1983) study is primarily

based on effects in the nose due to direct contact with irritating properties of soluble chromates. Furthermore,

the likelihood for environmental exposure to chromium trioxide and other soluble chromium(VI) compound

mists is less than the likelihood for environmental exposure to particulate chromium(VI) compounds.

Therefore, it is also appropriate to derive an inhalation MRL for particulate chromium(VI) compounds.

chromium(VI) compounds.

(1994) for alterations in the level of lactate dehydrogenase in bronchoalveolar lavage fluid (Glaser et al.

uncertainty factor of 30 (3 to account for pharmacodynamic differences not addressed by the dose conversion

and 10 for human variability). The MRL is supported by a similar study by Glaser et al. (1985) in which an

increase in the number of bronchoalveolar lavage macrophages in telephase was observed in rats exposed to

tract will be dependent on particle size, this MRL may be not be applicable to particle sizes that differ

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No MRLs were derived for oral exposure to chromium(VI) or chromium(III). The available data on

reproductive and developmental effects are insufficient or too contradictory to establish acute-, intermediate-,

or chronic-duration oral NOAELs or LOAELs which are both used in the uncertainty factor approach to

derive MRL values. However, the upper range of the estimated safe and adequate daily dietary intake

(ESADDI) of 200 µg chromium/day (0.003 mg/kg/day for a 70 kg individual) (NRC 1989) has been adopted

as provisional guidance for oral exposure to chromium(VI) and chromium(III). This guidance is necessary

because of the prevalence of chromium at hazardous waste sites, the fairly complete database, and the fact

that chromium is an essential nutrient.

1982; Iserson et al. 1983; Kaufman et al. 1970; Reichelderfer 1968; Saryan and Reedy 1988) or dermal

(Brieger 1920; Major 1922) exposure to chromium(VI) compounds. Although no studies were located

regarding death in humans after acute inhalation exposure to chromium compounds, occupational exposure

to chromium via inhalation has been associated with increased mortality due to lung cancer and possibly

noncancer respiratory disease; however, methodological deficiencies in the studies reporting increased risk

and from 21 to 811 mg chromium(VI)/kg for male rats (American Chrome and Chemicals 1989; Gad et al.

sodium chromate and dichromate, and ammonium dichromate ranged from 361 to 553 mg chromium(VI)/kg

for female rabbits and from 336 to 763 mg chromium(VI)/kg for male rabbits (Gad et al. 1986). A dermal

chromium acetate (Smyth et al. 1969) and 183 and 200 mg chromium(III)/kg as chromium nitrate for

females and males, respectively (Vernot et al. 1977). Female animals are generally more susceptible to the

lethal effects of chromium compounds, and chromium(VI) compounds are more toxic than chromium(III)

compounds. The environmental or workroom concentrations of chromium(III) or chromium(VI) compounds

are not likely to be high enough to cause death in humans.

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chromium(VI) compounds in humans and animals. Respiratory effects due to inhalation exposure are

probably due to direct action of chromium at the site of contact. Intermediate- and chronic-duration

exposure of workers to chromium(VI) compounds has resulted in epistaxis, chronic rhinorrhea, nasal itching

and soreness, nasal mucosal atrophy, perforations and ulceration of the nasal septum, bronchitis,

pneumonoconiosis, decreased pulmonary function, and pneumonia (Bovet et al. 1977; Cohen et al. 1974;

Davies et al. 1991; Gomes 1972; Greater Tokyo Bureau of Hygiene 1989; Hanslian et al. 1967; Keskinen et

al. 1980; Kleinfeld and Rosso 1965; Kuo et al. 1997a; Lee and Goh 1988; Letterer 1939; Lieberman 1941;

Lindberg and Hedenstierna 1983; Lucas and Kramkowski 1975; Mancuso 1951; Meyers 1950; Novey et al.

1983; Pastides et al. 1991; PHS 1953; Royle 1975b; Sassi 1956; Sluis-Cremer and du Toit 1968; Sorahan et

al. 1987; Taylor 1966). In some chromium-sensitive patients, inhalation of airborne chromium(VI)

compounds in the workplace may result in asthma (Keskinen et al. 1980; Novey et al. 1983; Olaguibel and

Basomba 1989). The chromium-related industries associated with these effects include chrome plating,

chromate and dichromate production, stainless steel welding, and possibly ferrochromium production and

chromite mining. Nasal irritation and mucosal atrophy and decreases in pulmonary function have occurred

exposed 8 hours/day, 5 days/week for <1 to >1 year was used as a basis for an inhalation MRL of

mist and other dissolved hexavalent chromium aerosols and mists. Autopsies of humans who died from

cardiopulmonary arrest after ingesting chromium(VI) compounds have revealed pleural effusion, pulmonary

edema, bronchitis, and acute bronchopneumonia (Clochesy 1984; Ellis et al. 1982; Iserson et al. 1983).

Respiratory effects due to ingestion of nonlethal doses are not likely to occur. It is not certain whether skin

contact with chromium compounds could result in respiratory effects.

Adverse effects on the respiratory system following inhalation exposure to chromium(III) and chromium(VI)

have also been observed in animals. Acute- and intermediate-duration exposure to moderate levels of

chromium(III) and/or chromium(VI) compounds generally caused mild irritation, accumulation of

macrophages, hyperplasia, inflammation, and impaired lung function (Glaser et al. 1985; Henderson et al.

particles for increased percentage of lymphocytes in bronchoalveolar lavage fluid in rats exposes for 28 or

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2. HEALTH EFFECTS

lungs of rats exposed to sodium dichromate for 30 or 90 days. The fibrosis and hyperplasia were reversible

(Glaser et al. 1990). Increases in the levels of total protein, albumin, and activity of lactate dehydrogenase

for exposure to chromium(VI) particulates. Nasal septum perforation, hyperplasia and metaplasia of the

larynx, trachea, and bronchus, and emphysema developed in mice exposed to chromium trioxide mists for

calcium chromate also had epithelial necrosis and hyperplasia of the bronchiolar walls (Nettesheim and

Szakal 1972). Rats, guinea pigs, and rabbits exposed chronically to a dust of mixed chromium roast material

bronchopneumonia, inflammation, or alveolar infiltration and hyperplasia (Steffee and Baetjer 1965).

Chronic exposure of rats to a 3:2 mixture of chromium(VI) trioxide and chromium(III) oxide at 0.1 mg total

weight and loading of macrophages. The reason for the differential response to sodium dichromate and the

mixture of chromium(VI) trioxide and chromium(III) oxide is probably related to solubility differences, with

the less soluble oxides having a longer residence time in the lungs than the more soluble sodium dichromate

(Glaser et al. 1986, 1988). Cytochrome-P450 activity in lungs of rats was significantly increased after

intraperitoneal injections of potassium dichromate(VI) (Witmer et al. 1994). Cytochrome P450 activity was

determined by hydroxylation of testosterone.

Occupational exposure to chromium(VI) primarily as mist/aerosol can result in respiratory effects. Animal

studies have reported respiratory effects following exposure to chromium(VI) or chromium(III) mists and

particulates. Exposure to chromium in ambient air is mainly to chromium(III) adhered to dust particles (see

Section 5.4.1). The possibility that inhalation exposure to chromium in the environment, from industrial

sources, or at hazardous waste sites could result in respiratory effects cannot be ruled out.

of the myocardium, were reported in potassium dichromate production workers in Russia (Kleiner et al.

1970), but studies of chromate workers in Italy (Sassi 1956) and the United States (PHS 1953) found no

electrocardiogram abnormalities or association with heart disease or blood pressure. Likewise, the

examination of mortality records of large cohorts that worked in the production of stainless steel and

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2. HEALTH EFFECTS

chromium mining industries revealed no increases in cardiovascular disease or ischemic heart disease

compared to overall national incidences (Moulin et al. 1993; Rosenman and Stanbury 1996). Case reports of

humans who died after ingesting sodium or potassium dichromate have described such effects as

cardiopulmonary arrest, hypoxic changes in the myocardium, progressive drops in cardiac output, heart rate,

and blood pressure, and hemorrhages in the left ventricle muscle as sequelae leading to death (Ellis et al.

1982; Iserson et al. 1983). Weak pulse was observed in some people after dermal application of a salve

containing potassium chromate to treat scabies, and degeneration of the heart was seen in others who died

after such an exposure (Brieger 1920).

Based on the limited information in humans, cardiovascular effects due to inhalation, oral, and dermal

exposure to chromium compounds in the workplace, in the environment, or at hazardous waste sites does not

seem likely.

No histopathological cardiac lesions were observed in rats exposed chronically to diets containing chromium

oxide at 2,040 mg chromium(III)/kg/day (Ivankovic and Preussmann 1975) or drinking water containing

chromium acetate at 0.46 mg chromium(III)/kg/day (Schroeder et al. 1965). However, degenerative changes

in the myocardium were found in rabbits injected intraperitoneally with 2 mg chromium(VI)/kg as potassium

dichromate or 2 mg chromium(III)/kg as chromium nitrate daily for 6 weeks (Mathur et al. 1977).

Intraperitoneal injection studies may not be predictive of effects or doses by environmentally relevant routes.

atmospheric chromium(III) and chromium(VI) have developed stomach pains and cramps, duodenal ulcers,

gastric ulcers, and gastritis (Lucas and Kramkowski 1975; Mancuso 1951; Sassi 1956; Sterekhova et al.

1978). The gastrointestinal irritation and ulceration could be due to direct action of chromium on gastric

mucosa as a result of mouth breathing or transfer via hand to mouth activity. It should be noted that these

gastrointestinal effects could be caused by other factors, such as stress and diet, and most of the studies did

not include a control group. Higher incidences of complaints of diarrhea and constipation were reported in

housewives who lived in an area contaminated with chromium slag in Japan than in housewives who lived in

an uncontaminated area (Greater Tokyo Bureau of Hygiene 1989). Cases of tonsillitis, chronic pharyngitis,

and atrophy of the larynx have been reported in chromium electroplaters, probably due to mouth breathing of

high levels of chromium(VI) above the plating baths (Hanslian et al. 1967). Abdominal pain, vomiting, and

gastrointestinal burns and hemorrhage have occurred in humans after ingesting lethal doses of chromium(VI)

as potassium dichromate, chromium trioxide, sodium dichromate, or ammonium dichromate (Clochesy 1984;

Ellis et al. 1982; Iserson et al. 1983; Kaufman et al. 1970; Reichelderfer 1968; Saryan and Reedy 1988).

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Nausea and vomiting occurred in some workers upon eating on the premises of a chrome plating plant where

poor exhaust resulted in excessively high concentrations of chromium trioxide (Lieberman 1941), and acute

gastritis occurred in a worker who accidentally swallowed plating fluid containing chromium trioxide

(Fristedt et al. 1965). Ingestion of oatmeal contaminated with potassium dichromate led to abdominal pain,

vomiting, and diarrhea in two people (Partington 1950). Oral ulcer, diarrhea, abdominal pain, indigestion,

and vomiting were found to be associated with drinking well water contaminated with 20 mg

chromium(VI)/L from an alloy plant in China (Zhang and Li 1987). Dermal application of a salv