Registration Dossier

Administrative data

Endpoint:
epidemiological data
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: The EU RAR summarises a number of epidemiological studies of workers occupationally exposed to Cr (VI) compounds.

Data source

Reference
Reference Type:
review article or handbook
Title:
European Union Risk Assessment Report: chromium trioxide, sodium chromate, sodium dichromate, ammonium dichromate, potassium dichromate
Author:
European Chemicals Bureau
Year:
2005
Bibliographic source:
3rd Priority List; Volume 53

Materials and methods

Study type:
other: various
Endpoint addressed:
carcinogenicity
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Epidemiological studies investigating cancer incidence in workers occupationally exposed to various forms of chromium
GLP compliance:
no
Remarks:
not relevant for this study type

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The EU RAR summarises several studies relating to occupational exposure to various chromium compounds.

Method

Details on study design:
Various studies are summarised.
Exposure assessment:
not specified

Results and discussion

Results:
The EU RAR discusses the findings of the epidemiological studies of cancer incidence reviewed previously by the UK Health & Safety Executive (HSE, 1989) and the UK Institute of Health (IOH, 1997). These studies investigated cancer risks among workers exposed to various forms of Cr (III) and Cr (VI). Unfortunately, detailed analysis of smoking habits is almost invariably absent. In chromate production, workers are exposed to Cr (III) during the production of Cr (VI) in water-soluble form e.g. sodium chromate. Although studies of chromate production have clearly established that there is an increase in lung cancer mortality, it is not clear precisely which Cr (VI) compound(s) produced the effect. An excess risk of lung cancer mortality has also been reported for workers in the chromate pigment production industry. However, this industry involves exposure to sparingly soluble or poorly soluble zinc or lead chromates as well as the more water-soluble Cr (VI) compounds covered by the various reviews. Chromium plating workers are exposed to aqueous chromium (VI) trioxide. One study provides clear evidence of an association between chromium plating work and increased lung cancer risk. It is not possible to relate in any reliable manner, the excess lung cancer mortality seen to particular levels of Cr (VI) in the atmosphere. Overall, it was concluded by the HSE and IOH reviews that chromium (VI) trioxide in solution ('chromic acid') is a human carcinogen. However only limited information is available for the other Cr (VI) compounds in this group.

A number of additional studies were included in the EU RAR. Two more recently published studies have significant methodological weaknesses but were included in the RAR because they extended earlier studies which are found in the IOH and HSE reviews:

An epidemiology study of mortality among chromate production workers showed a statistically significant increase in proportional mortality for death from all cancers (PCMR 1.37, 95% CI 1.23-1.51), digestive tract cancer (PCMR 1.33, CI 1.08-1.61), stomach cancer (PCMR 2.05, CI 1.38-2.92), nasal cancer (PCMR 5.18, CI 2.18- 11.30) and lung cancer (PCMR 1.51, CI 1.29-1.75) in white men. For black men, a statistically significant increase in proportional mortality for death from all cancer, lung cancer, bladder cancer and diseases of the digestive system was found among a total of 394 deaths. In black men, the proportion of deaths from lung cancer was slightly increased (PCMR 1.34 CI 1.00-1.75) while the proportion of bladder cancer deaths was statistically significantly higher; PCMR 3.30 (CI 1.42-6.51). Proportional mortality for lung cancer increased with increasing time employed and with latency since first employed.

An additional follow-up study looked at a cohort of 332 males working in a chromate plant between 1931-1937 and were followed through to 1993. Of 283 deaths identified, lung cancer deaths accounted for about 23% (66 deaths). Cumulative exposures to Cr (III) or Cr (VI) were calculated; age-adjusted mortality rates for lung cancer increased with increasing cumulative exposure. The authors claim that there is an association between Cr (III) and increased lung cancer mortality but the EU RAR considers this association to be 'probably spurious', and likely to be the indirect consequence of a correlation between Cr (III) and Cr (VI) exposures.

A follow-on study, concentrating on lung cancer deaths was conducted, extending the period of follow-up on chromium platers in the Midlands, UK, to 1995 (Sorahan et al., 1998). A reliable, statistically significant excess mortality from cancer of the lung was found in the earlier study. There was a positive association between increased incidence of lung cancer and duration of chrome bath work in male workers. In the 1998 study, For those workers with no exposure to chrome bath work, no excess in lung cancer mortality was found, whereas a higher SMR was calculated from the statistics for men exposed to chrome bath work. A statistically significant increased lung cancer SMR was calculated for all male chrome workers 10-19 years after first working with Cr(VI) but other periods of follow-up did not show a statistically significant excess. A significant positive statistical trend was observed for lung cancer mortality in men and cumulative duration of chrome bath work. In the case of men employed for 5 years or more in chrome bath work, the SMR for lung cancer mortality was 375 (10 observed, 2.7 expected, 95% CI 180-689). A raised SMR was also found for women workers with any chrome bath work (observed 15, expected 8.6, SMR 175, 95% CI 98-289). This study confirms the earlier findings that exposure to Cr (VI) in chrome plating work causes a significant increase in the risk of death from lung cancer. It remains impossible to establish a clear dose-response relationship for this excess risk of lung cancer.
Confounding factors:
See discussion below.
Strengths and weaknesses:
See discussion below.

Any other information on results incl. tables

The EU RAR discusses the findings of the epidemiological studies of cancer incidence reviewed previously by the UK Health & Safety Executive (HSE, 1989) and the UK Institute of Health (IOH, 1997). These studies investigated cancer risks among workers exposed to various forms of Cr (III) and Cr (VI). Unfortunately, detailed analysis of smoking habits is almost invariably absent. In chromate production, workers are exposed to Cr (III) during the production of Cr (VI) in water-soluble form e.g. sodium chromate. Although studies of chromate production have clearly established that there is an increase in lung cancer mortality, it is not clear precisely which Cr (VI) compound(s) produced the effect. An excess risk of lung cancer mortality has also been reported for workers in the chromate pigment production industry. However, this industry involves exposure to sparingly soluble or poorly soluble zinc or lead chromates as well as the more water-soluble Cr (VI) compounds covered by the various reviews. Chromium plating workers are exposed to aqueous chromium (VI) trioxide. One study provides clear evidence of an association between chromium plating work and increased lung cancer risk. It is not possible to relate in any reliable manner, the excess lung cancer mortality seen to particular levels of Cr (VI) in the atmosphere. Overall, it was concluded by the HSE and IOH reviews that chromium (VI) trioxide in solution ('chromic acid') is a human carcinogen. However only limited information is available for the other Cr (VI) compounds in this group.

A number of additional studies were included in the EU RAR. Two more recently published studies have significant methodological weaknesses but were included in the RAR because they extended earlier studies which are found in the IOH and HSE reviews:

An epidemiology study of mortality among chromate production workers showed a statistically significant increase in proportional mortality for death from all cancers (PCMR 1.37, 95% CI 1.23-1.51), digestive tract cancer (PCMR 1.33, CI 1.08-1.61), stomach cancer (PCMR 2.05, CI 1.38-2.92), nasal cancer (PCMR 5.18, CI 2.18- 11.30) and lung cancer (PCMR 1.51, CI 1.29-1.75) in white men. For black men, a statistically significant increase in proportional mortality for death from all cancer, lung cancer, bladder cancer and diseases of the digestive system was found among a total of 394 deaths. In black men, the proportion of deaths from lung cancer was slightly increased (PCMR 1.34 CI 1.00-1.75) while the proportion of bladder cancer deaths was statistically significantly higher; PCMR 3.30 (CI 1.42-6.51). Proportional mortality for lung cancer increased with increasing time employed and with latency since first employed.

An additional follow-up study looked at a cohort of 332 males working in a chromate plant between 1931-1937 and were followed through to 1993. Of 283 deaths identified, lung cancer deaths accounted for about 23% (66 deaths). Cumulative exposures to Cr (III) or Cr (VI) were calculated; age-adjusted mortality rates for lung cancer increased with increasing cumulative exposure. The authors claim that there is an association between Cr (III) and increased lung cancer mortality but the EU RAR considers this association to be 'probably spurious', and likely to be the indirect consequence of a correlation between Cr (III) and Cr (VI) exposures.

A follow-on study, concentrating on lung cancer deaths was conducted, extending the period of follow-up on chromium platers in the Midlands, UK, to 1995 (Sorahan et al., 1998). A reliable, statistically significant excess mortality from cancer of the lung was found in the earlier study. There was a positive association between increased incidence of lung cancer and duration of chrome bath work in male workers. In the 1998 study, For those workers with no exposure to chrome bath work, no excess in lung cancer mortality was found, whereas a higher SMR was calculated from the statistics for men exposed to chrome bath work. A statistically significant increased lung cancer SMR was calculated for all male chrome workers 10-19 years after first working with Cr (VI) but other periods of follow-up did not show a statistically significant excess. A significant positive statistical trend was observed for lung cancer mortality in men and cumulative duration of chrome bath work. In the case of men employed for 5 years or more in chrome bath work, the SMR for lung cancer mortality was 375 (10 observed, 2.7 expected, 95% CI 180-689). A raised SMR was also found for women workers with any chrome bath work (observed 15, expected 8.6, SMR 175, 95% CI 98-289). This study confirms the earlier findings that exposure to Cr (VI) in chrome plating work causes a significant increase in the risk of death from lung cancer. It remains impossible to establish a clear dose-response relationship for this excess risk of lung cancer.

Applicant's summary and conclusion

Conclusions:
The studies reviewed in the EU RAR (including those previously summarised in the UK HSE and IOH reviews) demonstrate an association between occupational exposure to chromic acid mist (aqueous chromium (VI) trioxide) and lung cancer. While the acidic and corrosive nature of this compound may play a significant role in the development of lung cancer, it is considered likley that the toxic moeity is the Cr (VI) ion. Therefore concerns are raised regarding the human carcinogenicity of the other Cr (VI) compounds in this group.
Executive summary:

The EU RAR summarises the results of a number of epidemiological studies investigating the association between occupational exposure to Cr (VI) compounds and cancer mortality. Studies of chrome plating workers (specifically exposed to chromic acid mists) in the US and UK show a clear association between exposure and increased mortality form lung cancer. Studies of occupational exposure to other Cr (VI) compounds have not shown a similar association. The EU RAR notes that the acidic and corrosive nature of chromium trioxide may be a significant contributory factor in the carcinogenesis of chromic acid (aqueous chromium (VI) trioxide), but that the Cr (VI) ion is likely to be the toxic moiety. It is considered that there is concern for the human carciogenicity of the other water-soluble Cr (VI) compounds in this group.