Diiron trioxide

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: well documented and scientifically acceptable cohort study on iron oxide exposure and lung cancer risk among workers employed in a French carbon steel-producing factory

Data source

Reference

Reference Type:

publication

Title:

Lung cancer mortality and iron oxide exposure in a French steel-producing factory

Author:

Bourgkard E, Wild P, Courcot B, Diss M, Ettlinger J, Goutet P, Hemon D, Marquis N, Mur JM, Rigal C, Rohn-Janssens MP, Moulin JJ

Year:

2008

Bibliographic source:

Occup Environ Med published online doi:10.1136/oem.2007.038299

Report date:

2008

Materials and methods

Study type:

cohort study (retrospective)

Endpoint addressed:

carcinogenicity

Principles of method if other than guideline:

Objective: To study the possible association between iron oxide exposures and lung cancer risk among workers employed in a French carbon steel-producing factory.
Methods: A historical cohort was set up of all workers ever employed for at least one year between 1959 and 1997. The cohort was followed up for mortality from January 1968 to December 1998. Causes of death were ascertained from death certificates. Job histories in the factory and smoking
habits were available for 99.7% and 72.3% respectively. Occupational exposures were assessed by a factory-specific job-exposure matrix (JEM) developed by a panel of 8 experts and validated with atmospheric measurements. Standardized Mortality Ratios (SMRs) were computed using local
death rates (external references). Poisson regressions were used to estimate the Relative Risks (RRs) for occupational exposures (internal references), adjusted on potential confounding factors.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Triiron tetraoxide

EC Number:

215-277-5

EC Name:

Triiron tetraoxide

Cas Number:

1317-61-9

Molecular formula:

Fe3O4

IUPAC Name:

Iron oxide

Constituent 2

Reference substance name:

Iron oxide

EC Number:

215-721-8

EC Name:

Iron oxide

Cas Number:

1345-25-1

IUPAC Name:

oxoiron

Details on test material:

iron oxides (not further specified)

Method

Details on study design:

Study population and follow up
The historical cohort was set up of all workers, men and women, ever employed in a French carbon steel-producing factory for at least one year between 1 January 1959, date of the factory opening, and 30 June 1997, date of data collection.
The data related to civil status (name, sex, birth date, birth place) and to work history were abstracted from the administrative records (date of hire and a list of successive jobs held in the factory with dates of beginning and end). Data on smoking habits were abstracted from the medical records of the factory. This information had been collected by the occupational physician during the yearly clinical examinations of workers.
The cohort was followed up for mortality from 1 January 1968 to 31 December 1998. The vital status for all subjects was assessed (1) by searching in the national computerized database listing all deceased subjects in France since 1978, (2) by contacting the registry offices of the birth places for
people born in France, (3) by contacting the registry office devoted to foreign born French people.
The cause of death was determined by matching the file of the deceased subjects with the French national file of causes of death, which was set up in 1968. As this file is anonymous, the matching was done using sex, date of birth, date of death, and place of death. Causes of death were
ascertained from death certificates coded using the International Classification of Disease (WHO): 8th revision for the deaths occurring between 1968 and 1978,18 and 9th revision for deaths occurring after 1979.

Exposure assessment
Present and past occupational exposures were assessed by a specific job-exposure matrix (JEM) through job histories of the subjects. The JEM was developed by a group of 8 experts comprising two epidemiologists, two occupational hygienists, and four occupational physicians from the
factory.
It was elaborated in four stages :
(1) Collection of information on exposures and working conditions
Visits of the factory workplaces gave information about present processes, working conditions, ventilation system. Interviews of former workers and assessments of historical documents allowed the comparison of present and past workplaces.
(2) Definition of rows and columns of the matrix
The individual work histories contained the successive job titles, dates, and departments (coke-oven plant, sinter plant, blast furnace plant, steel making plant, hot rolling mill, heavy plate mill, stocks and warehouses, maintenance, transport, research, support). Job titles were regrouped into 264 similar exposure groups based on the location of the workshop and/or the tasks of the workers. These job groups were separated into different
time periods according to the historical evolution of exposure. A total of 390 jobs-periods representing JEM rows were thus defined.
All known potential carcinogens were coded in the matrix (JEM columns) : iron oxides, polycyclic aromatic hydrocarbons (PAHs), silica, asbestos and oil mist, as well as total dust .
(3) Definition of the coding procedure
An exposure intensity code on a 0 to 5 scale was defined for total dust and a 0 to 3 scale for iron oxides, asbestos, PAHs, silica, and oil mist. For each of these agents, the experts identified typical jobs corresponding to each level of the intensity codes. These job-groups were used as
reference groups throughout the coding procedure. However, in the course of the coding procedure, the experts added another intensity code for low exposure of iron oxides, asbestos, PAHs, and silica. Thus, they introduced an additional category coded ¿e¿ between the intensity codes 0 and 1, corresponding to a very low exposure. Furthermore, the exposure frequency was coded according to the percentage of working
time, in following categories : 1%, 1-10%, 10-30%, 30-50%, >50%.
Finally, the experts coded the reliability of the assigned intensity and frequency codes in: disagreement between experts, some doubt as to the code, consensus among the experts.
(4) Coding
For each substance, codes were assigned to each job-period group, based on the collected information, in successive plenary meetings of the experts. The coding decisions were reached by consensus. When the experts disagreed, a minimum-coding consensus was agreed on and the disagreement was coded in the reliability code.
In order to correct a possible drift in coding, the job-groups were grouped into the final assigned exposure levels and the homogeneity of the coding was critically re-examined by the group of experts.
Exposures to iron oxides, asbestos, PAHs, and silica were expressed in different ways: ever exposed, highest exposure level in the work history, duration of exposure at a level=2, frequency weighted cumulative index defined as the sum of level x duration of exposure x percentage of
working time (frequency).
As the experts coding the exposure levels were blind to results of exposure measurements, the JEM could be validated by comparing the assigned exposure levels and the historical exposure measurements. Only total dust and Benzo[a]Pyrene (B[a]P) measurements were in sufficient
numbers, although only from 1980 on, to allow such a validation. Correlations between intensity codes of the JEM and total dust or B[a]P measurements were assessed by regressing the matched corresponding intensity codes on the log-transformed measurements.
In order to put our results in a more quantitative perspective, both cumulative and mean exposure levels over the job-history were computed for each study-subject for total dust and B[a]P based on all the available evidence i.e. the individual job history and the quantitative concentration estimates
for each JEM code based on the regression predictions on the available historic atmospheric measurements. Moreover, approximate mean exposure levels of total iron were estimated based on some sporadic percentages of total iron in total dust available for four departments of the factory.

Exposure assessment:

measured

Results and discussion

Results:

The cohort comprised 17,701 subjects (16,742 men, 959 women), corresponding to 400,218 person-years. The mean follow-up length was 22.7 years for men and 21.8 years for women. A total of 1,086 subjects, mainly foreign-born workers, were considered as lost of follow-up. Most of the subjects (86.2%) had been hired between 1959 and 1980. The total number of deaths was 2,367 for which 96.5 % of the causes could be found. Information on smoking was gathered for 12,797 subjects (72.3%).
Among men, the overall observed mortality was markedly lower than expected when compared to the local population (Obs=2,338, SMR=0.81, 95%CI 0.78-0.85) and higher than expected when compared to the French population (SMR=1.10, 95%CI 1.06-1.15). For lung cancer, the SMR was 0.89 (Obs=233, 95%CI 0.78-1.01 - local rates) and 1.30 (95%CI 1.15-1.48 - French rates). No trend was observed according to period of death, age at death, time since first employment, duration of employment, period of first employment and age at first employment.
Among women, mortality from all causes was lower than expected when compared to the local population (Obs=29, SMR=0.57, 95%CI 0.38-0.82) and to the French population (SMR=0.75, 95%CI 0.50-1.08).

Exposure assessment
For each exposure, typical workshops corresponding to each level of the intensity codes were used as reference in the coding procedure. For iron oxides, the highest exposures corresponded to the floor of the steel making plant or of the blast furnace before the installation of a ventilation
system. The non-exposed code related to the coke oven plant. For asbestos, the ore stockyard was considered as non-exposed and soaking pits were the place of the highest exposure although probably much lower than in the asbestos-industries. The highest PAH exposures were coded for
the top of the coke ovens, whereas no exposure to PAH was assigned to the ore stockyard. For silica, the maximal exposure was linked to the bricklayer tasks whereas blast furnace hands were coded non-exposed to silica. The highest oil mist exposure levels were for machine-tools and no
exposure was coded in sinter plant and blast furnace plant.
The experts reached a consensus for most codings: for the intensity code, the percentages of job groups with a disagreement between experts were 4.6% (iron oxides), 5.6% (asbestos), 9.2% (PAHs), 13.0% (silica), and 2.8% (oil mist). The corresponding percentages for frequency codes
were respectively 4.1%, 4.9%, 8.2%, 8.7%, and 2.8%.
A total of 973 measurements of atmospheric total dust (412 individual and 561 area samples) and 372 B[a]P measurements (177 individual and 195 area samples) could be identified. The geometric and arithmetic means show an increasing trend according to the JEM codes except level
5 for individual and area measurements of total dust (see also21) and level 1 for the arithmetic mean of B[a]P area measurements. The high arithmetic mean observed for B[a]P area measurements in job codes coded as level 1 is due to two quite high measurements corresponding to an occasional
activity in the blast furnace area. Ignoring these two values, the arithmetic mean for this group is below the exposure in level 2 job codes (B[a]P arithmetic mean: 1.03 µg/m3). Linear regressions of the log-transformed atmospheric measurements by intensity codes assigned in the JEM showed
significantly increasing trends for total dust (p<0.0001) and for B[a]P (p<0.0001).
The total dust atmospheric measurements in the factory showed a large exposure gradient: 10% of the individual measurements and 30% of the area measurements were above 10 mg/m3. Among cohort subjects, 59% were exposed to total dust at an intensity level=3 where mean measurements
exceeded 2.5 mg/m3 and 48.3% were exposed at a level=4 among which 39.1% at a level=5 where mean measurements exceeded 5 mg/m3.
The median of the total dust cumulative exposure index estimated for each subject was 41.2 mg/m3.years and 90% of the exposed subjects were below 203.6 mg/m3.years. The quartiles of the total dust concentrations were 1.78, 3.22 and 8.48 mg/m3 respectively. The percentage of total
iron in total dust ranged from 10% to 50% according to the factory's departments (data not shown). The quartiles of the total iron concentrations ranged thus from 0.18, 0.32 and 0.85 mg/m3 for a 10% total iron content to 0.89, 1.61, 4.24 mg/m3 for a 50% total iron content.
The median of the B[a]P cumulative exposure index was 3.61 µg/m3.years and 90% of the exposed subjects were below 20.1 µg/m3.years. The quartiles of the B[a]P concentrations calculated for each subject were 0.14, 0.34, 0.56 µg/m3 respectively.

Confounding factors:

confounding factors (smoking, exposure to asbestos, silica) were considered

Any other information on results incl. tables

The cohort comprised 16,742 males and 959 females. Among males, the observed mortality was lower than expected for lung cancer when compared to the local population (233 deaths, SMR 0.89, 95%CI 0.78-1.01) and higher than expected when compared to the French population (SMR 1.30, 95%CI 1.15-1.48) No lung cancer excess was observed for exposure to iron oxides (RR 0.80, 95%CI 0.55-1.17) and we found no dose-response relationship with intensity, duration of exposure, and cumulative index.

Applicant's summary and conclusion

Executive summary:

Objective:

To study the possible association between iron oxide exposures and lung cancer risk among workers employed in a French carbon steel-producing factory.

Methods:

A historical cohort was set up of all workers ever employed for at least one year between 1959 and 1997. The cohort was followed up for mortality from January 1968 to December 1998. Causes of death were ascertained from death certificates. Job histories in the factory and smoking habits were available for 99.7% and 72.3% respectively. Occupational exposures were assessed by a factory-specific job-exposure matrix (JEM) developed by a panel of 8 experts and validated with atmospheric measurements. Standardized Mortality Ratios (SMRs) were computed using local death rates (external references). Poisson regressions were used to estimate the Relative Risks (RRs) for occupational exposures (internal references), adjusted on potential confounding factors. Results:

The cohort comprised 16,742 males and 959 females. Among males, the observed mortality was lower than expected for lung cancer when compared to the local population (233 deaths, SMR 0.89, 95%CI 0.78-1.01) and higher than expected when compared to the French population (SMR 1.30, 95%CI 1.15-1.48) No lung cancer excess was observed for exposure to iron oxides (RR 0.80, 95%CI 0.55-1.17) and we found no dose-response relationship with intensity, duration of exposure, and cumulative index. A significant bladder cancer excess was observed among workers exposed to oil mist (RR 2.44, 95%CI 1.06-5.60), increasing significantly with intensity, duration of exposure, and cumulative index.

Conclusion: This study did not detect any relationship between exposure to iron oxides and lung cancer mortality.