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Toxicological information

Epidemiological data

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Administrative data

epidemiological data
Type of information:
other: summary of available studies
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Review of studies published in established scientic journals

Data source

Reference Type:
other: summary of epidemiolocigal studies
Epidemiologic data on chromate production workers

Materials and methods

Study type:
other: review of published data
Endpoint addressed:
Test guideline
no guideline required
Principles of method if other than guideline:
Summary of relevant epidemiological studies related to carcinogenicity in chromate production.
GLP compliance:

Test material

Constituent 1
Reference substance name:
Hexavalent chromate
Hexavalent chromate


Type of population:
other: chromate production workers
Ethical approval:
not applicable
Details on study design:
Details on exposure:
Exposure at chromate production work

Results and discussion

Any other information on results incl. tables

Summary of selected epidemiologic studies of lung cancer in workers exposed in chromate production to hexavalent chromium


Study Population

Reference Population

Chromium (VI) Exposure

Lung Cancer Risk

(Hayes, Lilienfeld et al. 1979;Braver, Infante et al. 1985)

1803 male workers initially employed 3 or more months 1945-1974 at old and new Baltimore MD production facility; follow-up through 1977

Baltimore City mortality

Primarily sodium chromate and dichromate production. Avg Cr(VI) of 21 to 413μg/m3 and avg duration 1.6 yr to 13 yr depending on subcohort, plant, and year employed

-O/E of 2.0 (p<0.01) based on 59 lung cancer deaths

-Increased risk with duration of employment

(Gibb, Lees et al. 2000a)

2357 male workers initially employed 1950-1974 only at new,production facility; follow-up through 1992


Primarily sodium chromate and dichromate. Mean cumulative Cr(VI) of 0.070 mg/m3-yr and work duration of 3.1 yr

- O/E of 1.86 (p<0.01) based on 71 lung cancer deaths

- Significant upward mortality trend with cumulative Cr(VI) exposure

(Bourne and Yee 1950;Mancuso and Hueper 1951;Mancuso 1975;Mancuso 1997)

332 male workers employed atfacility 1931–1937; follow-up through 1993

Mortality rate directly calculated using the distribution of person years by age group for the entire exposed population as the standard

Primarily sodium chromate and dichromate production with some calcium chromate as a result of using high lime process.

Most cumulative soluble Cr(VI) between 0.25 and 4.0 mg/m3-yr based on 1949 survey

O/E not calculated but significant increase in age-adjusted lung cancer death rate with cumulative chromium exposure based on 66 deaths

(Luippold, Mundt et al. 2003)

492 male workers employed one year between 1940 and 1972 at,facility; follow-up through 1997

U.S.and Ohio Mortality Rates

Primarily sodium chromate and dichromate production with minor calcium chromate Mean cumulative soluble Cr(VI) of 1.58 mg/m3-yr

- O/E of 2.41 (p<0.01) based onrates and 51 deaths

- Significant upward mortality trend with cumulative Cr(VI) exposure

(Bidstrup and Case 1956;Alderson, Rattan et al. 1981;Davies, Easton et al. 1991)

2298 male chromate production workers employed for one year between 1950 and 1976 at three differentplants; follow-up through 1989

Cancer mortality of England, Wales and Scotland and unexposed local workers

Principally sodium chromate and dichromate production with some calcium chromate before switch from high lime to no lime process. Avg soluble Cr(VI) in early 1950s from 2 to 880μg/m3depending on job.

- O/E of 1.97 (p<0.01) pre-process change based on 175 deaths

- SMR of 1.02 (NS) post-process change based on 14 deaths

- Increased risk for high exposed compared with less exposed

(Korallus, Lange et al. 1982;Korallus, Ulm et al. 1993;Birk, Mundt et al. 2006)

1417 chromate production workers employed for one year between 1948 and 1987 at two different German plants; follow-up through 1988.

901 'post-process change' [to no lime process] workers followed through 1998.

Mortality rates for North Rhine-Westphalia region of Germany where plants located as well as German national rates

Principally sodium chromate and dichromate production with some calcium chromate before switch from high lime to no lime process. Annual mean Cr(VI) between 6.2 and 38μg/m3after 1977. Cr(VI) exposure not reported before 1977.

- O/E of 2.27(p<0.01) pre-process change based on 66 deaths

- O/E of 1.22 (NS) post-process change based on 22 deaths

- O/E of 2.09 (p<0.05) post-process change with

≥200μg urinary Cr/dl-yr based on 12 deaths

(Pastides, Austin et al. 1994a)

398 chromate production workers employed for one year between September 4, 1971 and December 31, 1989 at aplant;follow-up through 1989

Mortality rates for eight N. Carolina counties, state rates (not reported), and U.S.mortality rates

Principally sodium bichromateand chromic acid production with as a result of low lime process. About 50% of personal air monitoring samples <1μg/m3Cr(VI), 75% <3μg/m3, and 96% <25μg/m3.

-O/E of 127 based onrates and 2 deaths

-O/E of 97 based oncounty


Applicant's summary and conclusion

Numerous studies on cancer among chromate production workers constistently show increased cancer mortality. The data makes it evident that hexavalent chromium compounds are carcinogenic in human.
Executive summary:

Numerous studies of cancer mortality among chromate production workers have been reported.

Collectively, these studies provide evidence for associations between lung cancer mortality and employment in chromate production; also with risks declining with improved industrial hygiene. Less consistently, nasal cancers have been observed (Alderson et al. 1981; Rosenman and Stanbury 1996; Sassi 1956; Satoh et al. 1994).

Evidence for associations between exposure to chromium and cancer is strongest for lung cancer mortality. A meta-analysis of 49 epidemiology studies based on 84 papers of cancer outcomes, primarily among chromium workers, found SMRs ranging from 112 to 279 for lung cancer, with and overall SMR of 141 (95% CI 135–147; Cole and Rodu 2005). When limited to high-quality studies controlled for smoking, the overall SMR for lung cancer was 112 (95% CI 104–119). SMRs for other forms of cancer from studies that controlled for confounders were not elevated. Several studies have attempted to derive dose-response relationships for this association (Mancuso 1997;Gibb, Lees et al. 2000a;Crump, Crump et al. 2003;Park, Bena et al. 2004;Park and Stayner 2006).These studies are particularly important because they have included individual exposure estimates to chromium for each member of the cohort based on work place monitoring; dose-response modelling to ascertain the contribution of changing exposures to chromium to risk (in workers who were also exposed to other work-place hazards that could have contributed to cancer risk); and evaluation of the impacts of potential co-variables and confounders (e.g., age, birth cohort, and smoking) on chromium-associated risk.

The term "Luippold cohort" originates from the retrospective cohort study of lung cancer mortality by Luippold et al.(Luippold, Mundt et al. 2003). The cohort members were 493 chromate production workers employed more than one year between 1940 and 1972 in a,, plant. These workers were studied earlier by Mancuso et al.(1975;1997)and several studies have found increased mortality (e.g., SMRs) among workers at the plant(Mancuso 1951;Mancuso 1997;Crump, Crump et al. 2003;Luippold, Mundt et al. 2003). This cohort of Luippold et al.(2003)also provides a strong basis for risk analysis; it has high-quality documentation of worker Cr(VI) exposure and mortality, a long follow-up, and a large proportion of relatively long-term employees (55% were employed for longer than 5 years).

Mancuso(1997)reconstructed cumulative exposure histories of individual members of the Ohio cohort (n=332), hired during the period 1931–1937 and followed through 1993. The exposure estimations were based on historical workplace air monitoring data for soluble and insoluble chromium and job title records. Age-adjusted death rates from lung cancer were estimated for cumulative exposure strata, and increased with increasing cumulative exposure to total chromium, insoluble chromium, and soluble chromium (a dose response model was not reported). The highest rates were observed in soluble chromium strata >4 mg/m3-years (2,848 per 100,000). Death rates were not adjusted for smoking, which would have been a major contributor to lung cancer death rates in the cohort. Although the study discriminated exposures to soluble and insoluble chromium, these classifications are not adequate surrogates for exposures to trivalent or hexavalent chromium (Kimbrough et al. 1999; Mundt and Dell 1997); therefore, the study cannot attribute risk specifically to either species.

More recent studies of this cohort have reconstructed individual exposure histories, based on species-specific air monitoring data, and have attempted to quantify the potential contribution of smoking to lung cancer risk(Crump, Crump et al. 2003;Luippold, Mundt et al. 2003). These studies included workers (n=482) hired after 1940 and followed through 1997. Increasing lung cancer risk was significantly associated with increasing cumulative exposure to CrVI). Relative risk for lung cancer mortality was estimated to be 0.794 per mg/m3year (90% CI 0.518–1.120). The analogous excess risk was 0.00161 per mg/m3-year per person year (90% CI 0.00107–0.00225). These estimates correspond to unit risks (i.e., additional lifetime risk from work exposure to 1μg/m3) of 0.00205 (90% CI 0.00134–0.00291), based on the relative risk Poison model, and 0.00216 (90% CI 0.00143–0.00302), based on the additional risk Poison model. Risk estimates were not appreciably sensitive to birth cohort or to smoking designation (for the 41% of the cohort that could be classified). The latter outcome suggests that smoking did not have a substantial effect on CrVI) associated lung cancer risk (i.e., smoking and chromium appeared to contribute independently to cancer risk).

The study of Luippold et al.(Luippold, Mundt et al. 2003)identified a more recent cohort that did not overlap with the Mancuso et al. cohorts. The workers had not been employed in any of the company’s other facilities that used or produced Cr(VI). Their mortality was followed from 1941 to the end of 1997. More than 800 area samples of airborne Cr(VI) from 21 industrial hygiene surveys were available for formation of a job-exposure matrix. Details about the exposure data are given by Proctor et al.(2003). Insufficient data prevented the evaluation of the effects of smoking.

Cumulative Cr(VI) exposure was divided into five categories: 0.00—0.19, 0.20—0.48, 0.49—1.04, 1.05—2.69, and 2.70—23.0 mg/m3-years. The selection criteria of these categories were not described. Person-years in each category ranged from 2,369 to 3,220 and the number of deaths from trachea, bronchus, or lung cancer ranged from three in the lowest exposure category to 20 in the highest (n=51). The standardized mortality ratios (SMRs) were statistically significant in the two highest cumulative exposure categories (3.65 (95% CI 2.08—5.92) and 4.63 (2.83—7.16), respectively). SMRs were also significantly increased for those who were hired before 1960, >20 years of employment, and >20 years since first exposure. The tests for trend across increasing categories of cumulative exposure, year of hire, and duration of employment were statistically significant (p<0.005). This is also akey studyin the risk assessment of chromates.

Pastides et al.(1994a;1994b)conducted a retrospective cohort study of 398 current and former workers employed for at least one year between 1971 and 1989 was conducted in a large chromate production facility in Castle Hayne,. The plant opened in 1971 and was designed to reduce the high level of chromium exposure found at the former facilities. The aim of the study was to determine if there was early evidence for an increased risk of cancer incidence or mortality and whether any increase was related to the level or duration of exposure to Cr(VI). More than 5,000 personal breathing zone samples collected from 1974 to 1989 were available from company records for 352 of the 398 employees. Concentrations of Cr(VI) ranged from below the limit of detection to 289μg/m3(8-hour TWA), with >99% of the samples less than 50μg/m3. Area samples were used to estimate personal concentrations for 1971—1972. Forty-two of the forty-five workers with previous occupational exposure to chromium had transferred from the older,plant to Castle Hayne. Estimated airborne chromium concentrations at theplant ranged from 0.05–1.45 mg/m3of total chromium for production workers to a maximum of 5.67 mg/m3for maintenance workers.

Mortality of the 311 white male Castle Hayne workers from all causes of death (n=16), cancer (all sites) (n=6), or lung cancer (n=2) did not differ significantly from the mortality experience of eight surrounding counties or thewhite male population. Internal comparisons were used to address an apparent “healthy worker” effect in the cohort. Workers with “high” cumulative Cr(VI) exposure (i.e., ≥ 10μg-years” of Cr(VI)) were compared to workers with “low” exposure (i.e., less than 10μg-years” Cr(VI)). No significant differences in cancer risk were found between the two groups after considering the effects of age, previous chromium exposure, and smoking. There was a significantly increased risk of mortality and cancer, including lung cancer, among a subgroup of employees (11% of the cohort) that transferred from older facilities (odds ratio OR =1.27 for each three years of previous exposure; 90% CI=1.07—1.51; cancer OR=1.22 for each three years of previous exposure; 90% CI=1.03—1.45, controlling for age, years of previous exposure, and smoking status and including malignancies among living and deceased subjects). (Regression analyses that excluded transferred employees were not reported). The results of this study are limited by a small number of deaths and cases and a short follow-up period and the authors stated “only large and early-acting cancer risk would have been identifiable”. The average total years between first employment in any chromate production facility and death was 15.2 years; the maximum was 35.3 years(Pastides, Austin et al. 1994a)

Park and Stayner(2006)deployed the Ohio Gibb cohort to investigate nonlinear features of the exposure response in a cohort of 2,357 chemical workers with 122 lung cancer deaths. In Poisson regression, a simple model representing a two-step carcinogenesis process was evaluated. In a one-stage context, fractional polynomials were investigated. Cumulative exposure dose metrics were examined corresponding to cumulative exposure thresholds, exposure intensity (concentration) thresholds, dose-rate effects, and declining burden of accumulated effect on future risk. A simple two-stage model of carcinogenesis did not improve the fit. The best-fitting one-stage models used simple cumulative exposure with no threshold for exposure intensity and had sufficient power to rule out thresholds as large as 30μg CrO3/m3(16μg/m3as Cr). Slightly better-fitting models were observed with cumulative exposure thresholds of 0.03 and 0.5 mg-yr/m3(as CrO3) with and without an exposure-race interaction term, respectively. With the best model, cumulative exposure thresholds as large as 0.4 mg-yr CrO3/m3were excluded. A small departure from dose-rate linearity corresponding to (intensity) 0.8 was not statistically significant. Models in which risk-inducing damage burdens declined over time, based on half-lives ranging from 0.1 to 40 years, fit less well than assuming a constant burden. A half-life of 8 years or less was excluded (one-sided 95% confidence limit). Examination of nonlinear features of the hexavalent chromium-lung cancer exposure response in a population used in a recent risk assessment supports using the traditional (lagged) cumulative exposure paradigm: no intensity (concentration) threshold, linearity in intensity, and constant increment in risk following exposure.