EPA-540/1-86-019 Office of Emergency and Remedial Response Washington DC 20460 Off'ce of Research and Development Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Cincinnati OH 45268 Superfund xvEPA HEALTH EFFECTS ASSESSMENT FOR HEXAVALENT CHROMIUM ------- EPA/540/1-86-019 September 1984 f HEALTH EFFECTS ASSESSMENT FOR HEXAVALENT CHROMIUM VJ U.S. Environmental Protection Agency Office of Research and Development Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Cincinnati, OH 45268 U.S. Environmental Protection Agency Office of Emergency and Remedial Response Office of Solid Waste and Emergency Response Washington, DC 20460 U.S. Environmental Protection Agency Region 5, Library (PL-12J) 77 West Jackson Boulevard, 12th Floor Chicago, IL 60604-3590 ------- DISCLAIMER This report has been funded wholly or 1n part by the United States Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse Research Corporation. It has been subject to the Agency's peer and adminis- trative review, and 1t has been approved for publication as an EPA document. Mention of trade names or commercial products does not constitute endorse- ment or recommendation for use. 11 ------- PREFACE This report summarizes and evaluates Information relevant to a prelimi- nary Interim assessment of adverse health effects associated with hexavalent chromium. All estimates of acceptable Intakes and carcinogenic potency presented In this document should be considered as preliminary and reflect limited resources allocated to this project. Pertinent toxlcologlc and environmental data were located through on-Hne literature searches of the Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic literature searched supporting this document 1s current up to September, 1984. Secondary sources of Information have also been relied upon 1n the preparation of this report and represent large-scale health assessment efforts that entail extensive peer and Agency review. The following Office of Health and Environmental Assessment (OHEA) sources have been extensively utilized: U.S. EPA. 1980b. Ambient Water Quality Criteria for Chromium. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-035. NTIS PB 81-117467. U.S. EPA. 1983a. Reportable Quantity Document for Chromium (and Compounds). Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1984. Health Assessment Document for Chromium. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA 600/8-83-014F. NTIS PB 85-115905. The Intent 1n these assessments 1s to suggest acceptable exposure levels whenever sufficient data were available. Values were not derived or larger uncertainty factors were employed when the variable data were limited 1n scope tending to generate conservative (I.e., protective) estimates. Never- theless, the Interim values presented reflect the relative degree of hazard associated with exposure or risk to the chemlcal(s) addressed. Whenever possible, two categories of values have been estimated for sys- temic toxicants (toxicants for which cancer 1s not the endpolnt of concern). The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs during a limited time Interval (I.e., for an Interval that does not constitute a significant portion of the Hfespan). This type of exposure estimate has not been extensively used or rigorously defined, as previous risk assessment efforts have been primarily directed towards exposures from toxicants 1n ambient air or water where lifetime exposure 1s assumed. Animal data used for AIS estimates generally Include exposures with durations of 30-90 days. Subchronlc human data are rarely available. Reported exposures are usually from chronic occupational exposure situations or from reports of acute accidental exposure. 111 ------- The AIC, acceptable Intake chronic, 1s similar in concept to the ADI (acceptable daily intake). It is an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs for a significant portion of the lifespan [see U.S. EPA (1980a) for a discussion of this concept]. The AIC 1s route specific and estimates acceptable exposure for a given route with the Implicit assumption that exposure by other routes is insignificant. Composite scores (CSs) for noncardnogens have also been calculated where data permitted. These values are used for ranking reportable quanti- ties; the methodology for their development is explained in U.S. EPA (1983). For compounds for which there is sufficient evidence of carclnogenlclty, AIS and AIC values are not derived. For a discussion of risk assessment methodology for carcinogens refer to U.S. EPA (1980a). Since cancer is a process that is not characterized by a threshold, any exposure contributes an increment of risk. Consequently, derivation of AIS and AIC values would be inappropriate. For carcinogens, q-|*s have been computed based on oral and inhalation data if available. 1v ------- ABSTRACT In order to place the risk assessment evaluation 1n proper context, refer to the preface of this document. The preface outlines limitations applicable to all documents of this series as well as the appropriate Inter- pretation and use of the quantitative estimates presented. Chromium exposure has been shown to contribute to Increased Incidence of respiratory cancers 1n occupatlonally exposed workers. The particular form(s) of chromium responsible 1s not clear. Increases In cancer Incidence 1n experimental animals following chromium Inhalation has not been demon- strated. However, Intrapleural and Intrabronchlal Implantation of hexava- lent chromium compounds has resulted 1n tumors at the site of Implantation. Hexavalent chromium has been shown to be mutagenlc 1n bacterial systems. Using human ep1dem1olog1cal data, a unit risk of 41 (mg/kg/day)"1 has been estimated for Inhalation exposure. Data are not available to assess the potential cardnogenlcHy of hexavalent chromium following oral exposure. Data are Inadequate to consider chromium as a carcinogen by the oral route. Using data from a 1-year rat drinking water exposure study, an oral AIC of 0.35 mg/day 1s estimated. ------- ACKNOWLEDGEMENTS The Initial draft of this report was prepared by Syracuse Research Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen Blackburn were the Technical Project Monitors and Helen Ball was^the Project Officer. The final documents 1n this series were prepared for the Office of Emergency and Remedial Response, Washington, DC. Scientists from the following U.S. EPA offices provided review comments for this document series: Environmental Criteria and Assessment Office, Cincinnati, OH Carcinogen Assessment Group Office of A1r Quality Planning and Standards Office of Solid Waste Office of Toxic Substances Office of Drinking Water Editorial review for the document series was provided by: Judith Olsen and Erma Durden Environmental Criteria and Assessment Office Cincinnati, OH Technical support services for the document series was provided by: Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon Environmental Criteria and Assessment Office Cincinnati, OH vl ------- TABLE OF CONTENTS 1. ENVIRONMENTAL CHEMISTRY AND FATE 2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . . 2.1. 2.2. ORAL INHALATION 3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. 3.2. 3.3. 3.4. SUBCHRONIC 3.1.1. Oral , 3.1.2. Inhalation , CHRONIC 3.2.1. Oral 3.2.2. Inhalation , TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . . , 3.3.1. Oral , 3.3.2. Inhalation TOXICANT INTERACTIONS 4. CARCINOGENICITY 4.1. 4.2. 4.3. 4.4. 5. REGUL HUMAN DATA 4.1.1. Oral 4.1.2. Inhalation BIOASSAYS 4.2.1. Oral 4.2.2. Inhalation OTHER RELEVANT DATA WEIGHT OF EVIDENCE ATORY STANDARDS AND CRITERIA Page 1 4 , . . 4 4 , , 5 5 . . . 5 5 , , , 12 . . . 12 12 14 . . . 14 14 14 15 15 . . . 15 15 16 . . . 16 16 . . . 18 . . . 18 . . . 19 V11 ------- TABLE OF CONTENTS (cont.) Page 6. RISK ASSESSMENT 21 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 21 6.1.1. Oral 21 6.1.2. Inhalation 21 6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 21 6.2.1. Oral 21 6.2.2. Inhalation 21 6.3. CARCINOGENIC POTENCY (q-|*) 21 6.3.1. Oral 21 6.3.2. Inhalation 21 7. REFERENCES 23 APPENDIX: Summary Table for Hexavalent Chromium 37 V111 ------- LIST OF TABLES No. Title Page 1-1 CAS Numbers and Aqueous Solubilities of Selected Hexavalent Chromium Compounds 2 3-1 Subchronlc Oral Toxldty of Hexavalent Chromium 1n Rats ... 6 3-2 Perforation of Nasal Septum 1n Chromate Workers 8 3-3 Nasal Lesions 1n a Chromium-Plating Plant 9 3-4 Chronic Toxldty of Hexavalent Chromium to Animals Exposed by Inhalation 13 5-1 Standards for Occupational Exposure to Cr(VI) 20 1x ------- LIST OF ABBREVIATIONS ADI Acceptable dally Intake AIC Acceptable Intake chronic AIS Acceptable Intake subchronlc BCF B1oconcentrat1on factor CAS Chemical Abstract Service CS Composite score LOAEL Lowest-observed-adverse-effect level LOEL Lowest-observed-effect level MED Minimum effective dose NOAEL No-observed-adverse-effect level NOEL No-observed-effect level ppm Parts per million RVj Dose-rating value RVe Effect-rating value TWA Time-weighted average ------- 1. ENVIRONMENTAL CHEMISTRY AND FATE In the hexavalent state, chromium exists as oxo species (such as Cr03> ~ and Cr02Cl2) that are strongly oxidizing (Cotton and Wilkin- son, 1980). The CAS Registry numbers and the solubilities of a few Important hexavalent chromium compounds are given 1n Table 1-1. In solution, hexavalent chromium exists as hydrochromate (HCrO^), 2 2- chromate (CrO' ) and dlchromate (Cr^O-, ) 1on1c species. The proportion of each 1on 1n solution 1s pH dependent. In basic and neutral pH, the chromate form predominates. As the pH 1s lowered (6.0 to 6.2), the hydrochromate concentration Increases. At very low pH, the dlchromate species predominate (U.S. EPA, 1984). The primary sources of hexavalent chromium 1n the atmosphere probably are chromate chemicals used as rust Inhibitors 1n cooling towers and emitted as mists, partlculate matter emitted during manufacture and use of metal chromates, and chromic add mist from the plating Industry. Hexavalent chromium 1n air could eventually react with dust particles or other pollu- tants to form trlvalent chromium (NAS, 1974); however, the exact nature of such atmospheric reactions has not been studied extensively. Both hexava- lent and trlvalent chromium are removed from air by atmospheric fallout and precipitation (Flshbein, 1981). The atmospheric half-life for the physical removal mechanism 1s expected to depend on the particle size and particle density. Chromium particles of small aerodynamic diameter (<10 pm) may remain airborne for a long period (U.S. EPA, 1984). Hexavalent chromium may exist In aquatic media as water soluble complex anlons and may persist 1n water for a long time. Hexavalent chromium is a moderately strong oxidizing agent and may react with organic matter or other -1- ------- TABLE 1-1 CAS Numbers and Aqueous Solubilities of Selected Hexavalent Chromium Compounds* Compound CAS No. Water Solubility Ammonium chromate 7788-98-9 40.5 g/100 ma at 30°C (NH4)2 Cr04 Calcium chromate 13765-19-0 2.23 g/100 mil at 20°C Potassium K2Cr04 Potassium K2Cr207 chromate dichromate Sodium chromate Na2Cr04 Chromic acid Cr03 7789-00-6 7789-50-9 7775-11-3 1333-82-0 62. 4.9 87. 61. 9 g/100 g/100 3 g/100 7 g/100 ma ma ma ma at at 0 at at 20 o C 30 0 0 °C °C C *Sources: Weast, 1980; Hartford, 1979 -2- ------- reducing agents to form trlvalent chromium. The trlvalent chromium will eventually be precipitated as Cr(L'xH_0. Therefore, 1n surface water I- O (L rich 1n organic content, hexavalent chromium will exhibit a much shorter lifetime (Callahan et al., 1979). Any hexavalent chromium 1n soil 1s expected to be reduced to trlvalent chromium by the organic matter 1n soil. The primary processes by which the converted trlvalent chromium 1s lost from soil are aerial transport through aerosol formation and surface water transport through runoff (U.S. EPA, 1984). Very little chromium Is leached from soil because 1t 1s present as Insoluble CrO,,.xH00 (Flshbeln, 1981). t « £• The BCF for hexavalent chromium In fish muscle appears to be <1.0 (U.S. EPA, 1980b), but values of 125 and 192 were obtained for oyster and blue mussel, respectively (U.S. EPA, 1980b). -3- ------- 2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 2.1. ORAL Absorption of Ingested hexavalent chromium 1s estimated to be <5%. Donaldson and Barreras (1966) fed Na2slCrO. to rats and humans. Based on mean urinary excretion of 51Cr, absorption was estimated to be 2.1% 1n humans. In rats, -2% of the administered dose was absorbed based on fecal excretion of 51Cr. When Na.51CrO. was administered Intraduodenaly (1n humans) or Intrajejunally (1n rats), however, absorption was estimated to -50 and -25%, respectively. MacKenzle et al. (1959) administered Na251CrO. to rats by gavage. Based on urinary excretion, absorption was estimated to be 6% 1n fasted rats and 3% 1n nonfasted rats. 2.2. INHALATION A study by Langard et al. (1978) Indicates that water-soluble hexavalent chromium 1s. absorbed rapidly by Inhalation. Rats were exposed to zinc chromate dust at a level of 7.35 mg/m3. After 0, 100, 250 and 350 minutes of exposure, the concentrations of chromium 1n the blood (yg/ms,) were 0.007, 0.024, 0.22 and 0.31, respectively. In the second part of this study, rats were exposed to the same level for 6 hours on 4 consecutive days. Blood concentrations appeared to peak at the end of the second exposure and then began to decline slowly. Mean blood chromium values measured at the end of each exposure period averaged 0.03, 0.56, 0.46 and 0.34 yg/ma, for exposures 1-4, respectively. No signifi- cant differences 1n absorption as reflected by blood chromium levels were noted between the sexes or between day and night exposures. -4- ------- 3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. SUBCHRONIC 3.1.1. Oral. Data from two subchronlc studies Involving oral exposure to hexavalent chromium are summarized 1n Table 3-1. MacKenzle et al. (1958) exposed groups of rats, both male and female, to potassium dlchromate (0-25 ppm of hexavalent chromium) 1n drinking water for 1 year. Since no effects were observed at any level of treatment, a NOEL can be established based on body weight, gross external condition, hlsto- pathologlcal analysis and blood chemistry. Converting 25 ppm to mg/kg/day, 25 ppm (mg/a, water) 1s multiplied by the average water consumption/day for a rat (0.035 8,/day), and divided by the weight of an average rat (0.35 g), to give a value of 2.50 mg/kg/day. The study by Gross and Heller (1946), lacking detailed pathological analysis and sufficiently large sample sizes (two animals/treatment level), cannot be used for quantitative risk assessment. 3.1.2. Inhalation. Pertinent data regarding subchronlc exposure of animals to hexavalent chromium by Inhalation could not be located 1n the available literature; however, there are many studies regarding occupational exposure of humans to hexavalent chromium. Bloomfleld and Blum (1928) examined 23 men from 6 chromium plating plants 1n the United States. Fourteen of these workers typically spent 2-7 hours/day over vats of chromic add, which generated airborne hexavalent chromium ranging from 0.12-5.6 mg/m3. These men experienced nasal tissue damage. Including perforated septum (2), ulcerated septum (3), chrome holes (6), nosebleed (9) and Inflamed mucosa (9). In general, the 9 remaining workers examined, not directly exposed to chromium vapors, had only Inflamed mucosae. -5- ------- TABLE 3-1 Subchronic Oral Toxlclty of Hexavalent Chromium In Rats Number of Animals Dose and Compound Period of Exposure Endpolnts Monitored and Effect Reference 9 females, 12 males at 25 ppm 10 males, 10 females at 0 ppm 8 males, 8 females at other treatment levels 1 male, 1 female per level of treatment 0, 0.45, 2.2, 4.5, 7.7, 11, 25 ppm as potassium dlchromate In drinking water 0, 0.036, 0.072, 0.143, 0.2854 Cr(VI) as zinc chromate or 0, 0.033, 0.067, 0.134 or 0.268% Cr(VI) as potassium chromate In feed 1 year No effect based on body weight, gross external condition, hlsto- pathologlcal analysis and blood chemistry. 2-3 months Animals were "subnormal" and sterile at all doses of zinc chromate and at 0.134 and 0.268% potassium chromate. MacKenzle et al., 1958 Gross and Heller, 1946 ------- Several other studies report nasal tissue destruction resulting from hexavalent chromium. The United States Health Public Service conducted a study of workers 1n seven chromate-produdng plants 1n the early 1950s. The results Indicated severe nasal tissue destruction but exposure levels were not measured; hence, the data are of limited usefulness (Federal Security Agency, 1953). Mancuso (1951) reported on physical examinations of a random sample of 97 workers from a chromate-chemlcal plant. The results, presented in Table 3-2, Indicated that 61 of the 97 workers (63%) had septal perforation. The data suggested to the author that Cr(III) may be partly responsible for the perforations; however, later studies have not provided support for this theory. The results of examinations of nine workers In a chrome-plating plant are shown 1n Table 3-3. Analyses of air samples showed chromium concentra- tions of 0.18-1.4 mg/m3. Some degree of nasal septal ulceratlon was seen 1n 7 of the 9 men, with 4 of 7 demonstrating frank perforations (Kleinfeld and Russo, 1965). The effects of chromium exposure for a specific length of time at a fixed concentration were not studied. Vigllani and Zurlo (1955) reported nasal septal perforation 1n workers exposed to chromic acid and chromates In concentrations of 0.11-0.15 mg/m3. The lengths of exposure were not known. Otolaryngologic examina- tions of 77 persons exposed to chromic add aerosol during chrome plating revealed 19% to have septal perforation and 48% to have nasal mucosal irritation. These people averaged 6.6 years of exposure to an air chromium concentration of 0.4 mg/m3. In 14 persons, paplllomas of the oral cavity and larynx were found. The diagnosis of papilloma was confirmed by hlsto- loglc examination. There were no signs of atypical growth or malignant degeneration (Hanslian et al., 1967). -7- ------- TABLE 3-2 Perforation of Nasal Septum 1n Chromate Workers* Ratio of Insol Cr+3 Chromium concentration, No. Workers to sol Cr+6 yg/fn3 (as Cr) Examined Workers 1n plant <1.0:1 1.1 to 4.9:1 >5.0:1 TOTAL Office workers <0.25 0.26 - 0.51 <0.52 <0.25 0.26 - 0.51 >0.52 <0.25 0.26 - 0.51 >0.52 0.06 4 7 8 9 32 15 7 2 13 97 4 Workers with Septal Perforation No. 2 3 4 7 20 11 2 1 11 61 0 % 50 43 50 78 63 73 29 50 85 63 0 *Source: Mancuso, 1951 Insol = Insoluble; sol = soluble -8- ------- TABLE 3-3 Nasal Lesions In a Chromium-Plating Plant* Case Age (yrs) 1 30 2 19 3 19 4 18 5 47 6 45 7 23 8 20 9 48 Duration of Exposure (mos) 6 2 12 9 10 6 1 0.5 9 Findings perforated septum perforated septum perforated septum perforated septum ulcerated septum ulcerated septum ulcerated septum moderate Injection of septum and turblnates moderate Injection of septum *Source: Klelnfeld and Russo, 1965 -9- ------- The literature suggests that chromium compounds are also responsible for a wide variety of other respiratory effects. German studies demonstrating mixed results from exposure to chromium compounds were reviewed by the U.S. EPA (1984). Because In all of these studies no correlation between symptom- atology, physical signs, length of exposure and dose of chromium compounds was available, they are not useful for risk assessment and are not reviewed here. In the United States, 897 workers In chromate-produclng plants had a higher Incidence of severely red throats and pneumonia, but did not show any Increase 1n the Incidence of other respiratory diseases when compared with control groups. Although bilateral hllar enlargement was observed, there was no evidence of excessive pulmonary flbrosls 1n these workers (Federal Security Agency, 1953). The various lung changes described 1n these workers may represent a nonspecific reaction to Irritating material or a specific reaction to chromium compunds. Many of the conditions mentioned occur widely In the general population (NAS, 1974). Gomes (1972) examined 303 employees who worked 1n 81 electroplating operations 1n Sao Paulo, Brazil. Over two-thirds of the workers had mucous membrane or cutaneous lesions, with many of them having ulcerated or perforated nasal septa. The duration of exposure was not stated, but the author mentioned that the harmful effects were noted 1n <1 year. A direct correlation between workers exposed to a given airborne concentration of chromium (VI) and the development of harmful effects could not be made. Cohen and Kramkowskl (1973) and Cohen et al. (1974) examined 37 workers employed by a chromium-plating plant. Within 1 year of employment, 12 workers experienced nasal ulceratlon or perforation. The airborne chromium (VI) concentrations ranged from <0.71-9.12 -10- ------- In a chromium plating plant where the maximum airborne chromium (VI) concentration was 3 yg/m3, no ulcerated nasal mucosa or perforated nasal septa were found; however, half of the 32 employees had varying degrees of mucosal Irritation (Markel and Lucas, 1973). The authors did not consider this to be significant, because the survey was carried out at the peak of the 1972-1973 Influenza epidemic. Machle and Gregorlus (1948) reported an Incidence of nasal septa! perforation of 43.5% In 354 employees who worked 1n a chromate-produdng plant that manufactured sodium chromate and bichromate. At the time of the study, airborne chromate concentrations ranged from 10 to 2800 yg/m3. The plant had been 1n operation for at least 17 years, and some employees probably worked 1n the plant when reverberatory furnaces, a prominent source of high chromate exposure, were used. In a more recent study, lung function, the condition of the nasal septum and subjective symptoms related to respiratory health (data obtained by questionnaire) were compared In unexposed controls (119) and workers (43) exposed to chromic add 1n chrome plating operations (Undberg and Hedenstlerna, 1983). Workers were further divided Into low (<2) and high (>2 yg Cr* /m3) exposure groups. Complaints of diffuse nasal symptoms ("constantly running nose," "stuffy nose" or "a lot to blow out") were registered by 4/19 workers 1n the low group and half of the 24 workers 1n the high group. Complaints were not registered by workers exposed to <1 yg/m3. The frequency of throat and chest symptoms did not appear to be related to treatment. Examination of the nasal septum revealed that damage was significantly greater 1n exposed workers than 1n unexposed controls and appeared to be somewhat more severe 1n the high group than the low group. Measurements of -11- ------- lung function revealed a detrimental effect due to exposure to chromic add fumes, but significant differences between low and high groups were not observed. There was a tendency for lung function parameters to return to normal over a 2-day weekend. Various other disease states have been attributed to chromium, but, In most cases, the etlologlc relation to chromium 1s doubtful because of the presence of other chemicals (NAS, 1974). These studies, reviewed by the U.S. EPA (1984), will not be reviewed here. 3.2. CHRONIC 3.2.1. Oral. Only one chronic study pertaining to the oral toxldty of hexavalent chromium was located 1n the available literature. Anwar et al. (1961) exposed dogs orally to potassium chromate 1n drinking water for 4 years. Treatment levels were 0, 0.45, 2.25, 4.5, 6.75 and 11.2 ppm potas- sium chromate; there were two dogs/group. No effects were observed with regard to gross and microscopic analysis of all major organs, urlnalysls, and weights of spleen, liver and kidney. The exposure of 11.2 ppm can be converted to units of mg/kg/day by multiplying 11.2 ppm by the average dally water consumption for a dog of average weight (0.0275 i/kg/day) to produce a NOEL of 0.31 mg potassium chromate/kg/day. This 1s equivalent to 0.089 mg Cr(VI)/kg/day. 3.2.2. Inhalation. Data regarding the chronic toxldty of hexavalent chromium administered by Inhalation are summarized 1n Table 3-4. Netteshelm et al. (1971) exposed mice to an aerosol of calcium chromate at levels of either 10 mg/m3 (4.33 mg Cr(VI)/m3) or 30 mg/m3 (10 mg Cr(VI)/m3) for 5 hours/day, 5 days/week for life. Based on epithelial necrosis, marked hyperplasla and atrophy of the pulmonary bronchi, emphysema-like changes, and atrophy of the spleen and liver, a LOAEL can be -12- ------- TABLE 3-4 Chronic Toxlclty of Hexavalent Chromium to Animals Exposed by Inhalation Species Nice Number of Animals 136 total (male and female); unspecified number of controls Dose and Compound 13 or 30 mg calcium chromate aerosol/m3 [4.33 or 10 mg Cr(Vl)/m», respectively] Period of Exposure 5 hours/day, 5 days/week for life Endpolnts Monitored and Effect At 6-month Intervals, bacteriological. parasltologlcal, vlrologlcal and htsto- pathologlcal analyses were performed. Reference Netteshelm et al.. 1971 oo I Rats 100 2 mg calcium chromate S89/B91 days aerosol/m» [0.67 Cr(Vl)/m»] Hamsters 100 10 mg/m» level: 4.33 mg/m' level: early death, rapid weight loss, fatty liver, distended and atrophlc Intestines epithelial necro- sis, marked hyper- plasla and atrophy of pulmonary bronchi, alveolar scarring after 6 months; after 2 years, atrophy of spleen and liver Laryngeal hyperplasla (2) and laryn- geal metaplasia (3) were found upon examination Immediately after treat- ment was stopped. Squamous metaplasia (8) and laryngeal hyperplastas (8) were found Immedi- ately after treatment was stopped. No other details were provided. Laskln. 1972 ------- established at 4.33 mg Cr(VI)/m3. Adjusting to units of mg/kg/day, 4.33 mg/m3 is multiplied by the product of 5 hours/24 hour day times 5 days of exposure/week times the average Inhalation rate/day for a mouse (0.05 mVday). This value 1s subsequently divided by the average body weight of a mouse (0.03 kg) to yield a value of 1.07 mg CR(VI)/kg/day. Laskin (1972) exposed rats and hamsters to calcium chromate aerosol at a level of 2 mg/m3 (0.67 mg Cr(VI)/m3) for 589 of 891 days. Although some laryngeal hyperplaslas and metaplasias were observed 1n both species tested, details pertaining to controls were not given 1n the available review. 3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 3.3.1. Oral. Pertinent data regarding the teratogenidty of orally administered hexavalent chromium could not be located in the available literature. 3.3.2. Inhalation. Pertinent data regarding the teratogenicity of inhaled hexavalent chromium could not be located in the available literature. 3.4'. TOXICANT INTERACTIONS Pertinent data regarding the toxicant Interactions of hexavalent chro- mium with other compounds could not be located in the available literature. -14- ------- 4. CARCINOGENICITY 4.1. HUMAN DATA 4.1.1. Oral. Pertinent human data regarding' the cardnogenlcHy of Ingested hexavalent chromium could not be located 1n the available litera- ture. 4.1.2. Inhalation. Occupational exposure to chromium compounds via Inhalation has been studied 1n the chromate, chrome-plating and chrome pigment Industries. Workers In the chromate Industry are exposed to both tMvalent and hexa- valent compounds of chromium. Ep1dem1olog1cal studies of chromate produc- tion plants 1n Japan, Great Britain, West Germany and the United States have revealed a correlation between occupational exposure to chromium and lung cancer, but the specific etlologlcal agent was not Identified (Machle and GregoMus, 1948; Brlnton et al., 1952; Baetjer, 1950a,b; Mancuso and Hueper, 1951; Mancuso, 1975; Taylor, 1966; Enterllne, 1974; Hayes et al., 1979; H111 and Ferguson, 1979; Bldstrup, 1951; Bldstrup and Case, 1956; Alderson et al., 1981; Todd, 1962; Watanabe and Fukuchi, 1975; Ohsakl et al., 1978; Sano and MHohara, 1978; Satoh et al., 1981; Korallus et al., 1982). Of these, the studies by Mancuso and Hueper (1951) and Mancuso (1975) are of Interest, since they were used by the Carcinogen Assessment Group to derive a cancer- based criterion for lifetime exposure to chromium (U.S. EPA, 1984). Mancuso and Hueper (1951) analysed the vital statistics of a cohort of chromate workers (employed for >1 year from 1931-1949 1n a Pa1nesv1lle, OH chromate plant) In order to Investigate lung cancer associated with chromate production. Of the 2931 deaths of males 1n the county where the plant was located, 34 (1.2%) were due to respiratory cancer. Of the 33 deaths among the chromate workers, however, 6 (18.2%) were due to respiratory cancer. -15- ------- The difference between these groups 1s significant at p<0.01. Furthermore, two of these workers exposed primarily to Insoluble chromlte had -390 and 250 yg chromium/10 g of lung tissue, respectively. By contrast, chromium levels 1n the lungs of nonexposed Individuals were nearly zero. In an update of the Mancuso and Hueper (1951) study, Mancuso (1975) followed 332 of the workers employed from 1931-1951 until 1974. By 1974, >50% of this cohort had died. Of these men, 63.6, 62.5 and 58.3% of the cancer deaths for men employed from 1931-1932, 1933-1934 and 1935-1937, respectively, were due to lung cancer. Mancuso (1975) reported that these lung cancer deaths were related to Insoluble (tMvalent), soluble (hexava- lent) and total chromium exposure, but the small numbers involved make this relationship questionable (U.S. EPA, 1984). In two studies derived from the chrome pigment industry, workers were exposed only to hexavalent chromium. In both studies, exposure to chromium was correlated with lung cancer (Langard and Norseth, 1975; Davies, 1978, 1979). Studies from the chrome-plating industry either demonstrated a correla- tion between lung cancer and exposure to chromium compounds (Royle, 1975), or were inconclusive (Silversteln et al., 1981; Okubo and Tsuchlya, 1979). 4.2. BIOASSAYS 4.2.1. Oral. Pertinent data regarding the carclnogenlcity of orally administered hexavalent chromium in animal systems could not be located in the available literature. 4.2.2. Inhalation. To date, It has not been possible to Induce tumors in laboratory animals by exposing them to chromium (either tMvalent or hexa- valent) via inhalation. -16- ------- Baltjer et al. (1959) chronically exposed three strains of mice (Strain A, Swiss, C57B1) and mixed-breed rats to ~1 mg chromium dust/m3, and reported no Increase In the Incidence of lung tumors with respect to untreated controls. Similar results were obtained by Steffee and Baetjer (1965) for Wlstar rats, rabbits and guinea pigs exposed to chromium dust. Netteshelm et al. (1971) exposed C57B1 mice to 4.33 mg calcium chromate dust/m3, 5 hours/day, 5 days/week for life, and reported an Increase 1n the number of lung tumors with respect to controls. Since statistical analysis was not performed, however, the significance of these results 1s unclear. In a review of this study, IARC (1980) concluded that a signifi- cant excess of treatment-related tumors was not observed. There 1s some evidence that hexavalent chromium may be carcinogenic following Intrapleural Implantation of calcium chromate (Hueper and Payne, 1962) or 1ntrabronch1al Implantation of strontium chromate, calcium chromate or zinc chromate (Levy and Martin, 1983). These tumors, however, were observed at the site of Implantation. In addition, Stelnhoff et al. (1983) have shown that Intratracheal administration to rats both Na?Cr?07 and CaCrO. produced Increased Incidences of lung tumors following 30 months of administration. In contrast, zinc chromate was not carcinogenic following Intratracheal Implantation (Steffee and Baetjer, 1965; Baetjer et al., 1959), nor were barium chromate, chromium dust, lead chromate, chromlte ore, powdered chro- mium metal, potassium chromate and sodium dlchromate following 1ntra- bronchlal, Intrapleural or Intratracheal Implantation (Steffee and Baetjer, 1965; Baetjer et al.. 1959; Hueper, 1955, 1958; Payne, 1960; Hueper and Payne, 1962; Levy and Venltt, 1975). -17- ------- 4.3. OTHER RELEVANT DATA Hexavalent chromium has been shown to be mutagenlc 1n bacterial systems 1n the absence of a mammalian activating system (VenHt and Levy, 1974; N1sh1oka, 1975; Nakamuro et a!., 1978; Green et al., 1976; Kanematsu et al., 1980; Lofroth and Ames, 1978; Newbold et al., 1979; Bonattl et al., 1976; Fukanaga et al., 1982), and not mutagenlc when a mammalian activating system 1s present (Lofroth, 1978; PetrllH and Deflora, 1977, 1978a,b). Hexavalent chromium 1s also mutagenlc 1n eucaryotlc test systems (Bonattl et al., 1976; Newbold et al., 1979; Fukanaga et al., 1982) and clastogenlc In cultured mammalian cells (Raffetto, 1977; Levls and Majone, 1979; Umeda and N1shi- mura, 1979; Tsuda and Kato, 1977; Newbold et al., 1979; Nakamuro et al., 1978; Stella et al., 1982; Ohno et al., 1982; Gomez-Arroyo et al., 1981; Wild, 1978; Sarto et al., 1982). 4.4. WEIGHT OF EVIDENCE IARC (1980) has concluded that there 1s sufficient evidence of respira- tory cardnogenlcHy 1n men occupatlonally exposed during chromate produc- tion; however, the ep1dem1olog1cal data do not allow elucidation of the relative contributions to carcinogenic risk of metallic chromium, tMvalent chromium, hexavalent chromium, or of soluble versus Insoluble chromium compounds. Furthermore, the animal studies using non-natural routes of administration have provided sufficient evidence that certain compounds of hexavalent chromium (sintered calcium chromate, lead chromate, strontium chromate, sintered chromium trioxlde and zinc chromate) are carcinogenic. Therefore, IARC (1982) classified chromium and chromium compounds as Group I chemicals. Applying the criteria proposed by the Carcinogen Assessment Group of the U.S. EPA for evaluating the overall weight of evidence for cardnogenlcHy to humans (Federal Register, 1984), hexavalent chromium 1s most appropriately designated a Group A - Human Carcinogen. -18- ------- 5. REGULATORY STANDARDS AND CRITERIA Recommended standards for occupational exposure to hexavalent chromium compounds are summarized 1n Table 5-1. The U.S. EPA (19805) has recommended a criterion of 0.05 mg/8. for the concentration of hexavalent chromium 1n water. They also established an Interim ADI of 0.175 mg/man/day for chronic 1ngest1on of hexavalent chromium based on the study of MacKenzle et al. (1958). These levels are not Intended to protect against potential carcinogenic effects of chromium VI compounds. The considered opinion when these levels were suggested was that Cr(VI) would potentially be reduced In the gastrointestinal tract to Cr(III). Although this 1s a plausible assumption, conclusive data are not available. -19- ------- TABLE 5-1 Standards for Occupational Exposure to Cr(VI) Compound Standard (mg/m3) Reference Noncardnogenlc chromium VI* Carcinogenic chromium Soluble chromic or chromous salt Insoluble salts Water soluble compounds of chromium (VI) (noncarclnogenlc) Insoluble compounds of chromium (VI) (carcinogenic potential) 0.025 TWA 0.050 ceiling 0.001 TWA 0.500 TWA 1.000 TWA 0.05 TWA 0.05 TWA NIOSH, 1975 NIOSH, 1975 OSHA, 1978 OSHA, 1978 ACGIH, 1983 ACHIH, 1983 *Monochromates and dichromates of hydrogen, lithium, potassium, rubidium, cesium, ammonium and chromic oxide -20- ------- 6. RISK ASSESSMENT 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 6.1.1. Oral. A 1-year oral study has established a NOEL for hexavalent chromium in rats of 2.5 mg/kg/day (MacKenzle et al., 1958) (see Section 3.1.1.). Applying an uncertainty factor of 100 (10 for Interspedes extrapolation and 10 for 1nter1nd1v1dual variability) and assuming a 70 kg body weight results 1n an estimated oral AIS of 1.75 mg/day. 6.1.2. Inhalation. Hexavalent chromium has been shown to be a human carcinogen by the Inhalation route for which data are sufficient for computation of a q,*. It 1s Inappropriate, therefore, to calculate an Inhalation AIS for hexavalent chromium. 6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 6.2.1. Oral. Using the oral AIS of 1.75 mg/day and applying an addi- tional uncertainty factor of 5 to adjust for a study which 1s of Inter- mediate duration between subchronlc and chronic results in an .estimated oral AIC of 0.35 mg/day. This 1s the approach recommended by U.S. EPA (1985). 6.2.2. Inhalation. Hexavalent chromium has been shown to be a human carcinogen for which data are sufficient for computation of a q *. It is inappropriate, therefore, to calculate an Inhalation AIC for hexavalent chromium. 6.3. CARCINOGENIC POTENCY (q^) 6.3.1. Oral. The lack of data regarding the carcinogeniclty of orally administered hexavalent chromium precludes assessment of carcinogenic risk. 6.3.2. Inhalation. Based on the epidem1olog1cal study of Mancuso (1975), the Carcinogen Assessment Group has derived a cancer-based criterion for exposure to chromium by Inhalation (U.S. EPA, 1984). Assuming a lifetime -21- ------- exposure to 1 yg elemental chrom1um/m3, the upper limit unit carcino- genic risk was estimated to be 1.16xlO~2 (yg/m3)"1 1n units of lifetime risk per 1 yg/m3 exposure for humans. This unit risk may be transformed to units of (mg/kg/day}"1 as follows: the concentration of 1 yg/m3 Is equivalent to 20 yg/day or 0.02 mg/day assuming a human respiratory rate of 20 mVday. Assuming an average human weighs 70 kg, the dosage becomes 2.857xlO~4 mg/kg/day. The unit risk of 1.16xlO"2 (yg/m3)"1 * 2.857xlO~4 mg/kg/day results 1n an expression of unit risk of 41 (mg/kg/day)'1. -22- ------- 7. 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Lowney, H. Steffee and V. Budacz. 1959. Effect of chromium on Incidence of lung tumors In mice and rats. Arch. Ind. Health. 20: 124-135. (Cited in IARC, 1980; U.S. EPA, 1984) -23- ------- Bldstrup, P.L. 1951. Carcinoma of the lung In chromate workers. Br. J. Med. 8: 302-305. (Cited In U.S. EPA, 1984) Bldstrup, P.L. and R.A.M. Case. 1956. Carcinoma of the lung 1n workmen 1n the bichromates-producing Industry 1n Great Britain. Br. J. Ind. Med. 13: 260-264. (Cited In U.S. EPA, 1984) Bloomfleld, O.J. and W. Blum. 1928. Health hazards 1n chromium plating. Public Health Rep. 43: 2330-2351. (Cited 1n U.S. EPA, 1984) Bonatti, S., M. Melnl and A. Abbondandolo. 1976. Genetic effects of potas- sium dlchromate 1n Schlzosaccharomyces pombe. Mutat. Res. 38: 147-150. (Cited 1n U.S. EPA, 1984) BMnton, H..P., E.S. Rasler and A.L. Koven. 1952. Morbidity and mortality experience among chromate workers. Public Health Rep. 67: 835-847. (CHed In U.S. EPA, 1984) Callahan, M.A., M.W. Sllmak and N.W. 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Chromium Compounds. .In.: K1rk-0thmer Encyclopedia of Chemical Technology, 3rd ed., Vol. 6, M. Grayson and D. Eckroth, Ed. John Wiley and Sons, Inc., NY. p. 82-120. Hayes, R.B., A.M. L1l1enf1eld and L.M. Snell. 1979. Mortality 1n chromium chemical production workers: A prospective study. Internat. J. Ep1dem1ol. 8: 365-374. H111, W.J. and W.S. Ferguson. 1979. Statistical analysis of ep1dem1olog1- cal data from chromium chemical manufacturing plant. J. Occup. Med. 21: 103-106. (Cited 1n U.S. EPA, 1984) Hueper, W.C. 1955. Experimental studies 1n metal cardnogenesls. VII. Tissue reactions to parenterally Introduced powdered metallic chromium and chromlte ore. J. Natl. Cancer Inst. 16(2): 447-469. (Cited 1n U.S. EPA, 1984) Hueper, W.C. 1958. Experimental studies 1n metal cancerogenesls. X. Cancerogenlc effects of chromlte ore roast deposited 1n muscle tissue and pleural cavity of rats. Am. Med. Assoc. Arch. Ind. Health. 18: 284-291. (Cited 1n U.S. EPA, 1984) Hueper, W.C. and W.W. Payne. 1962. Experimental studies 1n metal cardno- genesls — Chromium, nickel Iron arsenic. Arch. Environ. Health. 5: 445-462. (Cited In IARC, 1980; U.S. EPA, 1984) -27- ------- IARC (International Agency for Research on Cancer). 1980. Chromium and Chromium Compounds. In: Some Metals and Metallic Compounds. IARC Mono- graphs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. IARC, WHO, Lyon, France. 23: 205-323. IARC (International Agency for Research on Cancer). 1982. Results and Conclusions. Ln: Chemicals, Industrial Processes and Industries Associated with Cancer 1n Humans. IARC Monographs on the Evaluation of the Carcino- genic Risk of Chemicals to Humans. IARC, WHO, Lyon, France. 1-29 (Suppl. 4): 18. Kanematsu, N., M. Hara and T. Kada. 1980. Rec assay and mutagenldty studies on metal compounds. Mutat. Res. 77: 109-116. (Cited 1n U.S. EPA, 1984) Klelnfeld, M. and A. Russo. 1965^ Ulceratlons of the nasal septum due to Inhalation of chromic acid mist. Ind. Med. 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Cancer of the respiratory system 1n the United States chromate-produdng Industry. Public Health Rep. 63(35): 1114-1127. (Cited In U.S. EPA, 1984) MacKenzle, R.D., R.U. Byerrum, C.F. Decker, C.A. Hoppert and F.L. Langham. 1958. Chronic toxldty studies. II. Hexavalent and trlvalent chromium administered 1n drinking water to rats. Am. Med. Assoc. Arch. Ind. Health. 18: 232-234. (Cited In U.S. EPA, 1984) MacKenzle, R.D., R.A. Anwar, R.U. .Byerrum and C.A. Hoppert. 1959. Absorp- tion and distribution of 51Cr 1n the albino rat. Arch. Blochem. Blophys. 79: 200-250. (Cited 1n U.S. EPA, 1984) Mancuso, T.F. 1951. Occupational cancer and other health hazards 1n a chromate plant: A mdelcal appraisal. I. Lung cancer 1n chromate workers. Ind. Med. S1ng. 20: 358-363. (Cited 1n U.S. EPA, 1984) Mancuso, T.F. 1975. International Conference on Heavy Metals 1n the Environment, loronto, Canada, Oct. 27-31. (Cited 1n Towlll et al., 1978; U.S. EPA, 1984) -30- ------- Mancuso, T.F. and W.C. Hueper. 1951. 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Effect of calcium chromate dust, Influenza vlrum, and 100 R whole- body X-rad1at1on on lung tumor Incidence 1n mice. J. Natl. Cancer Inst. 47: 1129-1144. (Cited 1n IARC, 1980; U.S. EPA, 1984) Newbold, R.F., J. Amos and J.R. Connell. 1979. The cytotoxlc, mutagenlc and clastogenlc effects of chromium-containing compounds on mammalian cells 1n culture. Mutat. Res. 67: 55-63. (Cited 1n U.S. EPA, 1984) N1sh1oka, H. 1975. Mutagenlc activities of metal compounds 1n bacteria. Mutat. Res. 31: 185-189. (Cited 1n U.S. EPA, 1984) -31- ------- NIOSH (National Institute for Occupational Safety and Health). 1975. Cri- teria for a Recommended Standard...Occupational Exposure to Chromium (VI). U.S. DHEW, PHS, CDC, Rockvllle, MD. Ohno, H., F. Hanaoka and M. Yanada. 1982. IndudbllHy of slster-chromatid exchanges by heavy-metal Ions. Mutat. Res. 104: 141-145. (Cited 1n U.S. EPA, 1984) Ohsakl, Y., S. Abe, K. Klmura, Y. Tsunlta, H. M1kam1 and M. Murao. 1978. Lung cancer In Japanese chromate workers. 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(Cited 1n U.S. EPA, 1984) -36- ------- APPENDIX Summary Table for Hexavalent Chromium Carcinogenic Potency Species Experimental Dose/Exposure Effect Reference Inhalation Oral human Carclnogenlclty lung tumors 41 (mg/kg/day) ND U.S. EPA, 1984; Mancuso, 1975 CO ~J I Route Species Experimental Dose/Exposure Effect Acceptable Intake (AIS or AIC) Reference Inhalation AIS AIC Oral AIS AIC rat rat Systemic Toxiclty 0-25 ppm In none drinking water for 1 year (2.5 mg/kg) 0-25 ppm In none drinking water for 1 year (2.5 mg/kg) ND ND 1.75 mg/day 0.35 mg/day HacKenzle et al.. 1958 HacKenzle et al., 1958 ND = Not derivable ------- |