Naphthenic acids, cobalt salts

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

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

Rationale for reliability incl. deficiencies:

other: Reasonably well-documented survey

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:

Scan j work environ health, 6 (1): 1-49

Reference 2

Reference Type:

publication

Title:

Cobalt asthma - acase series from a cobalt plant

Author:

Sauni, R. et al.

Year:

2010

Bibliographic source:

Occupational Medicine (Lond), 60 (4), 301-306.

Materials and methods

Study type:

cross sectional study

Endpoint addressed:

repeated dose toxicity: inhalation

Test guideline

Qualifier:

no guideline followed

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 at Outokumpu Kokkola Works. This study was conducted to analyse all 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:

not specified

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: Cobalt, cobalt sulphate, cobalt carbonates, cobalt oxides, and cobalt hydroxides

Method

Type of population:

occupational

Ethical approval:

not specified

Details on study design:

STUDY 1 (Roto, P. (1980)):METHOD OF DATA COLLECTIONThe 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 characteristics of flow volume curves have been described by Cotes (Cotes J.E. Lung function assessment and application in medicine. Blackwell scientific publications, Oxford 1975, pp 101-108). The indices of the analyzed expiratory flow volumes were the following: forced expiratory volume in 1 s (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 three tracings were recorded for the analyses. The interval between tracings was 30-60 s.Screening for chronic bronchitis was conducted following Hall and Gandevia (Hall GJL, Gandevia B. Relationship of the loose cough sign to daily sputum volume: Observer variation in its detection. Br j prev soc med 25 (1971) 109-113.).STUDY PERIOD: 1 February and 1 November 1977SETTING: 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.STUDY POPULATION- Selection criteria: Those workers who had worked for more than 1 a in the Company and had spent at least two-thirds 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 six months or more. Two hundred and forty-three cobalt workers satisfied these criteria. Two hundred and nine workers who had been employed for more than 1 a in the Company were the eligible referents.- Exclusion criteria: Women, maintenance workers, and men who had worked less than 1 a in the Company before 1 February 1977 were excluded.Fifty 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)COMPARISON POPULATION- Type: Reference group (161 subjects; laboratory, office and power plant workers)- Smoker/nonsmoker: smokers: 48 subjects (30 %); exsmokers: 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)STUDY 2 (Sauni, R. et al. (2010)):SETTING: Kokkola cobalt plant in Finland. METHOD OF DATA COLLECTIONThe 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). Fourteen 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 min in both the referent and in the active test. In the active test, CoCl (0.1–1 ml/l) was used in 15 cases and CoSO4 powder in 2 cases. In nine cases, the reaction was confirmed with a provocation test with cobalt powder dust or with the dust from sulphatizing roasting process. In five cases, only cobalt powder or dust from sulphatizing 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 h 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.Twenty common environmental allergens were scratch chamber tested until 1978 (Bencard, UL and Dome, Division of Miles Laboratories Ltd, Buckinghamshire, UK) and were skin prick tested from 1979. Skin prick tests for cobalt and common environmental allergens (ALK-Abello A/S, Copenhagen, Denmark) 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.].

Exposure assessment:

measured

Details on exposure:

STUDY 1 (Roto, P. (1980)):TYPE OF EXPOSURE: The studied cobalt plant comprised a cobalt roasting building (pyrometallurgic stage of the process) and solution purification/leaching and reduction buildings (hydrometallurgic stage). The annual mean concentration of the total dust in the roasting building varied between 8 and 19 mg/m³ and that of sulfur dioxide between 1 and 2.5 ppm (cm³/m³). The dust contained 0.5- 1.0 % water-soluble cobalt and nickel sulfates. It did not contain measurable amounts of other forms of cobalt. The content of water-soluble cobalt in the air of the roasting building varied between 0.05 and 0.1 mg/m³ (Finnish TLV = 0.1 mg/m³).The main impurities in the cobalt leaching building were ammonia and hydrogen sulfide. Their annual geometric mean varied between 1 and 4 ppm (cm³/m³) at a height of 1.5 m above the floor of the process areas. Total dust concentration in the leaching building ranged between 0.1 and 0.5 mg/m³ and consisted of sulfides and sulfates. It contained 3.5-5 % cobalt sulfate (CoS04). In a limited cobalt packing area metallic cobalt dust in the air ranged between 0.01 and 0.1 mg/ma during the operations.TYPE OF EXPOSURE MEASUREMENT: Quantitatively, the most important impurities found in roasting buildings of the cobalt plant were aerosols containing metals, sulfur, and surfur dioxide.Regular monitoring of the total dust and sulfur dioxide concentration was started in the cobalt plant in 1970.Stationary samples were collected on Millipore® filters placed in different work areas of the plant. The sampling procedure was the same as that later adopted by the Finnish Standardization Association (Suomen Standardisoimisliitto. SFS 3860 Työpaikan ilman pölypitoisuuden mittaus suodatinmenetelmällä. 1st. ed. Helsinki 1976, pp 1- 6.) as the recommended dust sampling technique.The dust samples were analyzed gravimetrically in the laboratory of the Company. About 25 % of the dust from all the areas monitored contained particles of a diameter of less than 3µ. The analyses to determine particle size were carried out in 1977, also in the laboratory of the Company with a celloscope after ultrasound dispersion.The monitoring of gases was conducted with Drager® ampuls. Sulfur dioxide, ammonia (NRJ), and hydrogen sulfide were monitored in the process areas where they occur.The geometric mean concentration was used in the description of the exposure level of the ambient air. This model provides a better reflection of the real exposure level than does the arithmetic mean, on which momentary peaks of high gas or dust concentrations have a greater effect (Leidel NA, Busch KA. Statistical methods for the determination of noncompliance with occupational health standards. US Department of Health Education and Welfare, Cincinnati, OH 1975. (HEW publication no (NIOSH) 75-159).STUDY 2 (Sauni, R. et al. (2010)):Between 1966 and 1987, cobalt powder was produced from pyrite ore concentrate. After 1987, cobalt powder, inorganic cobalt and nickel compounds were produced using by-products of metallurgic industry as raw material.In the sulphatizing roasting, dust in the ambient air was shown to contain 15–20% iron, 1% zinc, 0.4% cobalt and 0.2%nickel,whereas in the leaching building, the dust consisted of metal sulphides and sulphates. Cobalt and nickel were present as water-soluble sulphates. In the reduction plant and powder production facility, cobalt was mainly in the formof cobalt powder and fine powder. In the chemical department, the cobalt and nickel compounds were mainly sulphates, carbonates, oxides and hydroxides.Total exposure to dust, cobalt, nickel, sulphur dioxide, hydrogen sulphide and ammonia were regularly monitored several times a year since 1966 both as static measurements and with personal sampling. The mean exposure level of total dust was high in the sulphatizing roasting department, 8.5 mg/m³.According to biological monitoring surveillance, exposure to cobalt was highest in the reduction and powder production department. The highest urinary content of cobalt was 16 000 nmol/l (level of unexposed persons being ,40 nmol/l). In the solution purification and chemical departments, the urinary cobalt levels were between 200 and 2000 nmol/l.

Statistical methods:

The chi-square test was applied in the evaluation of the statistical significance of the differences in the frequencies of respiratory symptoms between the exposed and nonexposed groups. In the significance testing of the results of the ventilatory capacity measurements the t-test was used. A stepwise multiple linear regression analysis was used in the determination of possible effects of various industrial exposures upon the ventilatory capacity ofcobalt workers. An IBM application of the step-up multiple regression was used (International Business Machines (IBM). Stat. basic manual. New York, NY 1973.(No. SH 20-1069-2: 79-90).

Results and discussion

Results:

STUDY 1 (Roto, P. (1980)):The population of 224 cobalt workers exposed to cobalt metal, oxides and salts at concentrations in the range from 10 to about 50 µg Co/m³ showed significantly more wheezing than in the reference population of 161 non-exposed subjects, as assessed with a questionnaire (Roto 1980). These findings were predominantly observed in the presence of irritant gases. 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 reference group. 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. The author concluded that workers exposed to air containing cobalt sulfate at concentrations below 100 µg Co/m³ for 6 to 8 years did not show any increased risk of developing chronic bronchitis. However, smoking highly significantly decreased the FEV1 of cobalt workers.Study 2 (Sauni, R. et al. (2010)):Between 1967 and 2003, a total of 22 cases of cobalt asthma about 700 cobalt-exposed workers were diagnosed in the cobalt plant that started operating in 1966. All patients except 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 a non-immunologic mechanism of asthma. The incidence 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 sulfatising 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 sulfatising roasting department, where the total dust concentration and the sulfur dioxide level were high (mean exposure to dust of 8.5 mg/m³ and to sulfur dioxide of 1.4 ppm, cf. Linna et al., 2003). All cases of cobalt asthma were encountered in those departments where additional irritant gases like sulfur dioxide, hydrogen sulfide 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 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. In conclusion, the current evidence indicates that as the mean exposure levels to cobalt increase, the risk of occupational asthma induced by cobalt also increases and irritant gases contribute to the risk. When exposure to the causative agent ceases, the symptoms and bronchial hyper-reactivity persisted in some cases.

Applicant's summary and conclusion

Conclusions:

STUDY 1 (Roto, P. (1980)):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 reference group. 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. The author concluded that workers exposed to air containing cobalt sulfate at concentrations below 100 µg Co/m³ for 6 to 8 years did not show any increased risk of developing chronic bronchitis. However, smoking highly significantly decreased the FEV1 of cobalt workers.STUDY 2 (Sauni, R. et al. (2010)):In conclusion, the current evidence indicates that as the mean exposure levels to cobalt increase, the risk of occupational asthma induced by cobalt also increases and irritant gases contribute to the risk. When exposure to the causative agent ceases, the symptoms and bronchial hyper-reactivity persisted in some cases.