Cobalt dinitrate

Sensitisation data (human)

Administrative data

Endpoint:

sensitisation data (humans)

Type of information:

other: human data

Adequacy of study:

key study

Reliability:

other: not rated acc. to Klimisch

Rationale for reliability incl. deficiencies:

other: Any kind of reliability rating is not considered to be applicable, since human studies/reports are not conducted/reported according to standardised guidelines.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Asthma, symptoms of chronic bronchitis and ventilatory capacity among cobalt and zinc production workers

Author:

Roto, P.

Year:

1980

Bibliographic source:

Scand. J. Work Environ. Health 6, 1-49

Reference 2

Reference Type:

publication

Title:

Cobalt asthma - a case series from a cobalt plant

Author:

Sauni, R. et al.

Year:

2010

Bibliographic source:

Occupational Medicine (Lond), 60, 301-306.

Materials and methods

Type of sensitisation studied:

respiratory

Study type:

survey

Principles of method if other than guideline:

The purpose of the cross-sectional study was to determine whether cobalt-containing aerosols increase the occurence of symptoms of chronic bronchitis or decrease ventilatory capacity. The study was carried out in the Outokumpu Kokkola Works ((Roto, P. (1980); Study 1).
A second study was conducted to re-evaluate the cases of cobalt asthma encountered in the Kokkola cobalt plant and diagnosed in the Finnish Institute of Occupational Health with specific inhalation provocation tests. Clinical data was gathered at the time of diagnosis and during a follow-up visit 6 months later in the patient files. Also, the significance of exposure to cobalt and to irritant gases in workplace air in relation to the risk of cobalt asthma was evaluated ((Sauni, R. et al. (2010); Study 2)

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

cobalt and cobalt compounds

IUPAC Name:

cobalt and cobalt compounds

Details on test material:

- Name of test material (as cited in study report): Cobalt, cobalt sulphate, cobalt carbonates, cobalt oxides, and cobalt hydroxides
- Physical state: solids

Method

Type of population:

occupational

Ethical approval:

confirmed, but no further information available

Subjects:

Study 1 (Roto, 1980):
STUDY POPULATION
- Selection criteria: Those workers who had worked for more than 1 year in the Company and had spent at least 2/3 of their employment in the cobalt plant were included as eligible subjects. Workers who were employed for a year or less were included if they had been in the plants for 6 months or more. 243 cobalt workers satisfied these criteria. 209 workers who had been employed for more than 1 year in the Company were the eligible referents.
- Exclusion criteria: Women, maintenance workers, and men who had worked less than 1 year in the Company before 1 February 1977 were excluded.
50 workers who had changed from one process plant to another were also excluded because of their heterogeneous exposure history. Asthmatic persons were excluded because the results of their ventilatory capacity measurements would reflect more status of the disease than the effect of exposure. Unsatisfactory performance in the ventilatory capacity measurements led to exclusion.
- Total number of subjects participating in study: 224 cobalt workers
- Sex: Males
- Smoker/nonsmoker: smokers: 77 subjects (32 %); exsmokers: 101 subjects (45 %); nonsmokers: 52 subjects (23 %)
- Age: 33.6 +/- 6.6 years (mean)
- Height: 175.2 +/- 5.4 cm (mean)
- Length of exposure: 7.3 +/- 3.4 years (mean)

Study 2 (Sauni, 2010):
The cases were identified in the cobalt plant’s occupational health care registers, and the patient files were retrospectively reviewed.

Clinical history:

No details given here.

Controls:

Study 1 (Roto, 1980):
COMPARISON POPULATION
- Type: Reference group (161 subjects; laboratory, office and power plant workers)
- Smoker/nonsmoker: smokers: 48 subjects (30 %); ex-smokers: 52 subjects (32 %); nonsmokers: 61subjects (38 %)
- Age: 33.7 +/- 7.7 years (mean)
- Height: 175.5 +/- 5.6 cm (mean)
- Length of exposure: 8.7 +/- 3.9 years (mean)

Route of administration:

inhalation

Details on study design:

Study 1 (Roto, 1980):
The study was carried out in the Outokumpu Kokkola Works located on the Ykspihlaja peninsula, 4 km to the west of the city of Kokkola. The Works consists of separate sulfur, cobalt and zinc plants. The cobalt plant uses pyrite ore concentrate, which contains 0.5 % cobalt. From this raw material the plant produces metallic cobalt, hematite, ammonium sulfate, copper sulfide and nickel ammonium sulfate and sulfur dioxide.

The frequency of respiratory symptoms was obtained from a Finnish translation of a Harvard questionnaire for respiratory symptoms, which was based on the British medical Research Council's questionnaire (Medical Research Council. Committee on research into chronic bronchitis: Questionnaire on respiratory symptoms and instructions for its use. London 1966.)
Ventilatory capacity measurements: The maximal expiratory flow volume (MEFV) loop was the main index of ventilatory capacity. The indices of the analysed expiratory flow volumes were the following: forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), (FEV1/FVC) X 100 (FEV %), and the instantaneous flow rate at 50 % of FVC (Vmax50).
Before the measurements were made the eligibility of each subject was determined in a brief interview and examination. The subject's weight, height without shoes, and blood pressure were recorded. The MEFV curves were recorded from the subject as he stood wearing a nose clip. Each subject practiced one or more times, and then 3 tracings were recorded for the analyses. The interval between tracings was 30-60 seconds.
Screening for chronic bronchitis was conducted.

Study 2 (Sauni, 2010):
The cases were identified in the cobalt plant’s occupational health care registers, and the patient files were retrospectively reviewed. The diagnosis was confirmed in clinical examinations with specific inhalation challenge tests performed at the Finnish Institute of Occupational Health in Helsinki (FIOH). 14 patients participated in the follow-up examinations in the FIOH 6 months after diagnosis. The follow-up data were completed from the records of the occupational health care unit of the cobalt plant.
Data from spirometry was obtained. In addition, data from histamine challenge test were collected. Also, specific bronchial provocation test were performed in an 8-m³ challenge chamber according to international guidelines (Allergy Practice Forum. Guidelines for the diagnosis of occupational asthma. Clin Exp Allergy 1992;22:103–108.). The exposure time was 30 minutes in both the referent and in the active test. In the active test, CoCl2 (0.1–1 ml/L) was used in 15 cases and CoSO4 powder in 2 cases. In 9 cases, the reaction was confirmed with a provocation test with cobalt powder dust or with the dust from sulphatising roasting process. In 5 cases, only cobalt powder or dust from sulphatising roasting was used. In the referent test, lactose powder was used in 17 cases, and the dilution fluid was used in 5 cases as a placebo. Patients were monitored for 24 hours after each challenge. A portable, pocket-size spirometer was used to record peak expiratory flow (PEF) measurements and, after 1993, also FEV1 measurements. The clinical symptoms and lung auscultation were recorded as well.
20 common environmental allergens were scratch chamber tested until 1978 and were skin prick tested from 1979. Skin prick tests for cobalt and common environmental allergens were performed as described by Kanerva et al. [Kanerva L, Estlander T, Jolanki T. Skin testing for immediate hypersensitivity in occupational allergology. In: Menne T, Maibach H, eds. Exogenous Dermatoses: Environmental Dermatitis. Boca Raton, FL: CRC Press, 1991; 103–126.].

Results and discussion

Results of examinations:

Study 1 (Roto, 1980):
The population of 224 cobalt workers exposed to cobalt metal, oxides and salts at concentrations less than 50 µg Co/m³ showed significantly more wheezing than in the referent population. The chronic production of phlegm and wheezing were clearly associated with smoking among the cobalt workers. The prevalence of chronic bronchitis was 2% in the cobalt exposed workers and 0% among the referents. Multiple regression analyses indicated that exposure to the air of the cobalt plant did not significantly decrease the FEV1 or FVC of workers when the exposure level was below 100 µg Co/m³. However, smoking highly significantly decreased the FEV1 of cobalt workers. The author concluded that workers exposed to air containing cobalt sulphate at concentrations below 100 µg Co/m³ for 6 to 8 years did not show any increased risk of developing chronic bronchitis.

Study 2 (Sauni, 2010):
Between 1967 and 2003, a total of 22 cases of cobalt asthma were diagnosed in the cobalt plant that started operating in 1966. All patients bar one were male. None of them had positive reactions against cobalt in skin prick tests, indicating a non-immunologic mechanism. The mean duration of symptoms was 7.4 years on average before diagnosis of occupational asthma. Mostly late or dual asthmatic reactions were observed in specific bronchial challenge tests with cobalt which may also suggest rather a non-immunologic mechanism of asthma.
The incidences of cobalt asthma correlated with the exposure levels of cobalt in the corresponding departments of the plant during 1967-1987. The incidence density of cobalt asthma (number of new cases per person-year) was highest in the reduction and powder production department (0.02), where the cobalt exposure levels were highest (median 150 µg/m³, min to max 100-400 µg/m³). The incidence density in the sulphatising roasting department and leaching and solution purification department was 0.006 and 0.005, respectively, with median exposure levels to cobalt of 100 µg/m³ (min to max 6-1000 µg/m³) and 30 µg/m³ (min to max 10-100 µg/m³), respectively. There was significant individual variation in the working time before the onset of symptoms (0.1-17 years). The shortest latencies were in the sulphatising roasting department, where the total dust concentration and the SO2 level were high. All cases of cobalt asthma were encountered in those departments where additional irritant gases like SO2, hydrogen sulphide or ammonia were present in the ambient air in addition to cobalt. No cases of cobalt asthma were reported in the chemical department with a cobalt exposure level of 120 µg/m³ (median, min to max 20-300 µg/m³) where co-exposure to additional irritant gases was not present. At the time of the follow-up examination 6 months later, non-specific bronchial hyper-reactivity had mostly remained at the same level or increased.

Applicant's summary and conclusion

Conclusions:

Roto (1980) and a follow-up analysis by Sauni et al. (2010) published a detailed survey of lung effects in workers of a Finnish cobalt metallurgical plant in Kokkola. In a cross-sectional part of the study, the occurrence of symptoms of chronic bronchitis and an eventual decrease of ventilatory capacity in workers exposed to cobalt-containing aerosols was determined. The incidence density of cobalt asthma correlated with cobalt exposure levels. However, all diagnosed cases of asthma occurred only under workplace conditions with co-exposures to irritant gases such as sulfur dioxide, hydrogen sulfide or ammonia, whereas in the absence of such irritants in the workplace atmosphere, exposure to cobalt alone at levels of 0.12 mg/m³ (median, min to max 0.02-0.3 g/m³) did not elicit any asthma-like conditions (Sauni et al., 2010).