Nickel(III) oxy hydroxide

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

Not Reported

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study was based on a large cohort and a comprehensive evaluation of many endpoints; however, exposure information was very limited and was not appropriately classified for the test susbstance. A detailed description of the scoring criteria and results can be found in the attached scoring document.

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Exposure to nickel compounds and smoking in relation to incidence of lung and nasal cancer among nickel refinery workers

Author:

Andersen AA, Berge SR, Engeland A, Norseth T

Year:

1996

Bibliographic source:

Occup Environ Med. 53: 708-713

Materials and methods

Study type:

cohort study (retrospective)

Endpoint addressed:

carcinogenicity

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Investigated the relationship between exposure to various forms of nickel and cancer incidence in workers from a nickel refinery; included evaluation of the interaction between smoking and total exposure to nickel.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Nickel dihydroxide

EC Number:

235-008-5

EC Name:

Nickel dihydroxide

Cas Number:

12054-48-7

IUPAC Name:

nickel(2+) dihydroxide

Details on test material:

Epidemiological exposure assessment was based on work area sampling; samples were collected and analyzed for total nickel four times (it was assumed that the nickel species occurred in respirable dust in the same proportion as the material being handled in various work areas). The authors divided nickel species into four categories for assessment: metallic nickel, oxidic nickel, soluble nickel and sulphidic nickel. Soluble nickel was considered to consist primarily of nickel sulphate and nickel chloride, and also of nickel carbonate and nickel hydroxide.

Method

Type of population:

occupational

Ethical approval:

other: Not Reported

Details on study design:

HYPOTHESIS TESTED (if cohort or case control study): to investigate changes in the occupational risk of lung and nasal cancer over time, dose-exposure relations between different forms of nickel, and to evaluate the interactions between smoking and exposure to nickel.


METHOD OF DATA COLLECTION
- Type: Interview / Questionnaire / Record review / Work history / Clinical tests / other: Record review , work history, questionnaries
- Details: For the study population, data were obtained via files with the following information: name, date of birth, dates of beginning and final end of employment, working areas. Data on smoking habits were collected by the medical department at the refinery from medical records for 4605 workers and from colleagues for 159 workers (smoking data were divided into never smoked and past/present smokers).


STUDY PERIOD: The study population was followed for cancer incidence, date of emigration and death from the beginning of 1953 to the end of 1993. Follow up started after three years of total employment for those with first entry 1916-1940, or if first entry was in 1946 or later then follow up started after one year of employment. People who died or emigrated were followed up to the time of event.


SETTING: Falconbridge nickel refinery, Norway


STUDY POPULATION
- Total population (Total no. of persons in cohort from which the subjects were drawn): 4764
CANCER: The study population consisted of: (1) 379 workers that started work during 1916-1940 and worked 3+ years, (2) all 4385 workers who started work in the period 1946-83 and worked 1+ years. The study was confined to employees alive at the beginnign of the follow up period on 1 Jan 1953.
SMOKING: The interaction between smoking in the general population and smoking and exposrue to nickel was restricted to nickel refinery workers with the same birth cohort as the general population (1983-1927) and the same follow-up period (1966-1972). Only workers first employed before 1966 and with a cumulative exposure of >1 mg/m3/yr of total nickel were included 1337 workers).
- Selection criteria: male employees working at a nickel refinery during the period of 1916-1983
- Sex/age/race: male
- Smoker/nonsmoker: Data were available for almost 95% of the workers; 76% had smoked at some time (this was higher than the percentage in the same age group in the general male population)


COMPARISON POPULATION
- Type: State registry / Regional registry / National registry / Control or reference group / Other comparison group: National Registry, questionnaire
- Details: Comparative cancer incidence data were obtained from the Cancer Registry of Norway (data collection began in 1953). Smoking data for the general population were based on a questionnaire on smoking habits conducted in 1964-5 in a 0.5-1.0% sample of the Norwegian male population born 1983-1927.


HEALTH EFFECTS STUDIED
- Disease(s): All cancer and selected types of cancer ((primarily focus was on lung and nasal, though stomach, colon/rectum, larynx, pleura, prostate, testis, kidney, bladder, malignant melanoma, brain, haemopoetic tissues, other specific sites, and unspecified sites were also evaluated.
- ICD No.: 151, 153-154, 160, 161, 162,162.2, 177, 178, 180, 181, 190, 193, 200, 207, 199, 140-207
- Year of ICD revision: ICD-7

Exposure assessment:

estimated

Details on exposure:

TYPE OF EXPOSURE: Occupational exposure via the air, based on exposure to different forms of nickel on the Hybinetic process (used at the refinery between 1910 until 1978).


TYPE OF EXPOSURE MEASUREMENT: Area air sampling / Personal sampling / Exposure pads / Biomonitoring (urine) / Biomonitoring blood / other: Air concentrations estimated based on atmospheric nickel measurements from 1973 (several process areas), some measurements in 1964, and some measurements from the roasting and smelting areas in 1952-3.


EXPOSURE LEVELS/EXPOSURE GROUPS: The concentrations of airborne nickel and the different forms present in all periods were estimated by a group of engineers, medical personnel with experience in occupational medicine, and others with long experience at the refinery and researchers from the Institute of Occupational Health and the Cancer Registry. This expert group estimated exposure for 82 different work areas. TWA concentrations were estimated to be: low (0.1 - 0.4 mg/m3/yr), medium (0.5-1.9 mg/m3/yr), high (2.0-8.0 mg/m3/yr), and very high (>8 mg/m3/yr). The mean concentration for each category was taken to be the average of the extremes of the range, except in the highest category in which 10 mg/m3/yr was taken as the mean concentration. Cumulative nickel estimates were calculated in mg/m3/yr and presented as mg/m3 for the various species of nickel. Estimates were calculated for various work areas/departments.


EXPOSURE PERIOD: Estimates were based on four technological periods corresponding to improvements in worker conditions: (1) 1946-55, (2) 1956-67, (3) 1968-77, and (4) 1978-84.

Statistical methods:

The study population consisted of: (1) 379 workers that started work during 1916-1940 and worked 3+ years, (2) all 4385 workers who started work in the period 1946-83 and worked 1+ years. The study was confined to employees alive at the beginning of the follow up period on 1 Jan 1953.
The interaction between smoking in the general population and smoking and exposure to nickel was restricted to nickel refinery workers with the same birth cohort as the general population (1983-1927) and the same follow-up period (1966-1972). Only workers first employed before 1966 and with a cumulative exposure of >1 mg/m3/yr of total nickel were included (1337 workers).

Results and discussion

Results:

FINDINGS
Based on exposure to total nickel, workers had increased risk of cancers of the nose and nasal cavities, lung and prostate. Excess risk was observed for workers with first employment in 1968 or later, and increasing risk with increasing exposure was noted. Evaluation based on the four groups of nickel species assessed in this study suggested strong evidence of a relationship between exposure to soluble nickel compounds and lung cancer. Evidence was not as strong for oxidic nickel, though some evidence suggested that oxidic nickel was a stronger hazard for nasal cancer than soluble nickel.
Study findings also indicated a multiplicative effect of the risk of lung cancer from smoking and total exposure to nickel.



Based on TOTAL NICKEL (see Table 1 in study):

INCIDENCE / CASES
- Incidence/ Number of cases for each disease / parameter under consideration:
Nose and nasal cavity: 32 observed, 1.8 expected
Lung: 203 observed, 68.3 expected
Prostate: 129 observed, 91.1 expected
No increased risk observed for other cancer types evaluated

STATISTICAL RESULTS:
SIR (Standardized Incidence Ratio) and 95% CIs (Confidence intervals)
Nose and nasal cavity: 18 (12.3-25.4) - note that all cases of nasal cancer occurred in workers first employed before 1956
Lung: 3.0 (2.6 - 3.4)
Prostate: 1.4 (1.2-1.7)
No increased risk observed for other cancer types evaluated

Evaluation of lung cancer based on cumulative exposure to nickel (see Table 4 in study): [data presented as amount of nickel: SIR (95% CI)]
0.1-0.9 mg/m3: 1.4 (0.5-3.0)
1-4 mg/m3: 1.9 (1.2-2.8)
5-14 mg/m3: 2.6 (1.9-3.6)
>15 mg/m3: 4.6 (3.8-5.6)

Confounding factors:

Group of smokers not exposed to nickel had a RR of 6.1 (95% CI 3.0-12.4). RR for workers that never smokeed was 3.6 (95% CI 1.1 - 12), and for workers that smoked, a RR of 23 (95%CI 11-48) was observed. The authors suggested that results indicated a multiplicative effect of smoking and nickel exposure.

Strengths and weaknesses:

No strengths were identified by the study authors.

Weaknesses:
1) Exposure estimates were based on a job exposure matrix and measurements of total nickel, thus exposure to specific nickel species was not well defined. Futhermore, because the refinery process is complex, it was difficult to identify working areas where exposure was exclusively to soluble or insoluble nickel compounds.
(2) The smoking analysis was based on a relatively small "n" for non-smokers.

Additional considerations regarding study strengths and weaknesses (not noted as such by the study authors):
(1) Some workers (particularly those that worked in maintenance shops) were likely exposed to asbestos; the authors state that it is unlikely that exposure to asbestos could expain the overall increased risk of lung cancer at the refinery.

Any other information on results incl. tables

The authors note that a dose-response relationship was observed for exposure to soluble nickel and nasal cancer (see Table 2 in original publication) (note a similar relationship was noted for nickel oxide):

Cum soluble Nickel (mg/m3)	Observed	SIR	95% CI
<1	14	13.7	7.5 -23.0
1 -4	2	5.1	0.6 -18.5
5 -14	1	5.5	0.1 -30.5
>15	15	81.7	45 -135

The relative risk (RR) of lung cancer by cumulative exposure to soluble nickel and nickel oxide was evaluated using a multivariate Poisson regression analysis which considered the two variables simultaneously (see Table 5 in original publication); workers with the highest cumulataive soluble nickel exposures had a threefold increase in RR as compared to the reference population (test for linear trend, p = <0.001).

Cum soluble nickel (mg/m3)	Mean exposure (mg/m3)	Cases (n)	RR	CI
<1	0.1	86	1.0	Referent
1 -4	2.3	36	1.2	0.8 -1.9
5 -14	8.8	23	1.6	1.0 -2.8
>15	28.9	55	3.1	2.1 -4.8

Applicant's summary and conclusion

Conclusions:

The authors concluded that the study confirms results of previous studies on cancer risk associated with exposure to soluble forms of nickel and indicates risks also in working areas with exposure to soluble nickel and exposure to other forms of nickel. It is not possible to state with certainty which specific nickel compounds are carcinogenic, but a significant excess risk was found for workers exposed to soluble nickel alone or in the combination with other forms of nickel. The study also suggests a multiplicative effect between smoking and exposure to nickel.

Executive summary:

An occupational cohort from a nickel refinery in Norway was investigated to determine the relationship between exposure to different forms of nickel over time and cancer incidence, as well as to investigate the interaction between smoking and total exposure to nickel with respect to cancer. Exposure to nickel compounds was estimated using a job exposure matrix that relied on limited measurements of total nickel compounds in the air at the refinery and expert judgment. Assessments were based on cumulative exposure to total nickel or to one of four groups of nickel based on speciation (one of which was soluble nickel that was assumed to contain nickel hydroxide). Cancer incidence was evaluated in over 4000 male workers based on comparison to information collected from a national registry and a smoking questionnaire administered to the general population. Results indicated that of all cancer types evaluated, workers had increased risk of cancers of the nose and nasal cavities, lung and prostate based on exposure to total nickel; increasing risk with increasing exposure was noted. Evaluation based on the four groups of nickel species assessed in this study suggested strong evidence of a relationship between exposure to soluble nickel compounds and lung cancer, and specifically noted that a dose-response relationship was observed for exposure to soluble nickel and nasal cancer. Evidence was not as strong for oxidic nickel, though some evidence suggested that oxidic nickel was a stronger hazard for nasal cancer than soluble nickel. Study findings also indicated a multiplicative effect of the risk of lung cancer from smoking and total exposure to nickel. The authors concluded that the study confirms results of previous studies on cancer risk associated with exposure to soluble forms of nickel and indicates risks also in working areas with exposure to soluble nickel and exposure to other forms of nickel. The authors indicate that it is not possible to state with certainty which specific nickel compounds are carcinogenic, but a significant excess risk was found for workers exposed to soluble nickel alone or in the combination with other forms of nickel.