Occupational Disease Panel
Report No. 19
July, 1997

Occupational Disease Panel

In 1985, the Ontario legislature established the Industrial Disease Standards Panel to investigate and identify diseases related to work. The Panel is independent of both the Ministry of Labour and the Workers' Compensation Board. At the end of each fiscal year the WCB reimburses the Ministry for the Panel's expenditures. In 1995, the name was changed to the Occupational Disease Panel (ODP).

The Panel's authority flows from section 95 of the Workers' Compensation Act and its functions are set out as follows:

95(8) (a) to investigate possible industrial diseases;

(b) to make findings as to whether a probable connection exists
between a disease and an industrial process, trade or occupation in Ontario;

(c) to create, develop and revise criteria for the evaluation of claims respecting industrial diseases; and

(d) to advise on eligibility rules regarding compensation for claims.

Decisions of the Panel are made by its members who represent labour, management, scientific, medical and community interests. Once the Panel makes a finding, the WCB is required to publish the Panel's report in the Ontario Gazette and solicit comments from interested parties. After considering the submissions the WCB Board of Directors decide if the Panel's recommendations are to be implemented, amended or rejected.

To assist with its work, the Panel has a small staff of researchers, analysts and support people. In addition to its own staff, the Panel relies heavily on the advice of outside experts in science, medicine and law, as well as input from parties of interest.

Additional copies of this publication are available by writing:
Occupational Disease Panel
69 Yonge Street, Suite 1004
Toronto, Ontario M5E 1K3
(416) 327-4156

Panel Membership

Panel Staff

TABLE OF CONTENTS

Letter of Transmittal
Panel Members
Panel Staff

Chapter 1. The Panel's investigation

The issue and how it arose
The ODP mandate
Scope of the investigation
Consultation with the stakeholders

Chapter 2. The evidence and conclusions relevant to nickel and nickel production

Cancer of the larynx
WCB policy on respiratory cancer associated with nickel exposures
Ontario's WCB policy on laryngeal cancer
Epidemiological factors to consider

A. Nickel production

B. International Agency for Research on Cancer (IARC) evaluation of nickel and its compounds

C. Mining

i) Epidemiological Evidence
ii) Potential Causative Agents in Nickel Mining
iii) Conclusions

D. Milling

i) Epidemiological Evidence
ii) Potential Causative Agents in Nickel Milling
iii) Conclusions

E. Smelting and sintering

i) Epidemiological Evidence
ii) Potential Causative Agents in Nickel Smelting and Sintering
iii) Conclusions

F. Refining

i) Epidemiological Evidence
ii) Potential Causative Agents in Nickel Refining
iii) Conclusions

Chapter 3. Other possible causes of laryngeal cancer

Chapter 4. Conclusions, findings and recommendations

A. Mining
B. Milling
C. Smelting and sintering
D. Refining

References

APPENDICES

Appendix A: The Bradford Hill considerations for evaluating whether a probable connection to work exists

Appendix B: WCB policy

Appendix C: Glossary of some epidemiological terms

Appendix D: Epidemiological studies

Appendix E: IARC evaluation of evidence for carcinogenicity

Appendix F: Statistical appendix

FIGURES, DIAGRAMS AND TABLES

Figure 1. Dose/Response. Mining (never sinter).
from Julian & Muir, 1996. 15 years after first exposure

Figure 2. Dose/Response. Milling (never sinter).
from Julian & Muir, 1996. 15 years after first exposure

Figure 3. Laryngeal Cancer in Nickel Smelting

Figure 4. Laryngeal Cancer in Nickel Refining

Figure 5. Lung Cancer SIRs by Age Group & Duration of Employment

Figure 6 Larynx and Lung Cancer Incidence All UG Production Mining (never sinter) Smoothed Data

Diagram 1. Nickel mining, milling, smelting, sintering and refining

Diagram 2. Flowsheet of Port Colborne nickel anode electrolysis

Diagram 3. Flowsheet of nickel anode production at Port Colborne

Table 1. Selected points in history of the INCO Process at Port Colborne

WORKING DEFINITIONS

Cancer of the larynx: (ICD 161) Malignant neoplasm of the larynx includes neoplasm affecting the glottis, supra glottis (excluding the anterior aspect of the epiglottis and folds touching on the pharynx), subglottis, laryngeal cartilages and neoplasm of contiguous or overlapping sites of the larynx of undetermined origin.

An aerosol is a dispersion in air of liquid droplets or solid particles fine enough to remain dispersed for a period of time, (e.g., an atomized mist or dust cloud).

The nickel industry, in this Report, includes primary extracting, processing and refining, briefly identified as the following operations:

1. Nickel mining
2. Nickel milling, including crushing, grinding and concentrating
3. Nickel smelting and sintering
4. Nickel refining

The Panel's investigation does not include secondary processing and uses of nickel and nickel products in other industries as, for example, the use of nickel in the making of stainless steel or in electroplating.

CHAPTER ONE
THE PANEL'S INVESTIGATION

The issue and how it arose

The issue of laryngeal cancer in the nickel industry was first brought to the Ontario Workers' Compensation Board (WCB) in 1977 on the basis of a Norwegian study of nickel refinery workers conducted by Pedersen et al. [67]. The authors reported an excess of laryngeal cancer amongst workers in the roasting and smelting processes.

In 1974, Dr. A.C. Ritchie, a pathologist at the Toronto Hospital conducted a literature review on asbestos exposure and lung cancer. His research identified laryngeal cancer and asbestos exposure as a subject that warranted additional investigation. On the basis of this work the Workers' Compensation Board contracted with Dr. A. B. Miller, Director of the Epidemiology Unit of the National Cancer Institute of Canada, to conduct a case control study and report on the relationship between occupational exposures of asbestos and nickel in Ontario and cancer of the larynx. In April 1978, Dr. Miller reported his preliminary findings to the WCB. In his opinion the data did not permit a final conclusion on the role of either asbestos and/or nickel and elevated rates of laryngeal cancer. However, Dr. Miller also reported that if there was an urgent basis for the development of a policy he would recognize that occupational exposure to both nickel and asbestos were causal factors in the development of laryngeal cancer [16].

The WCB developed a policy authorizing the payment of compensation to workers who contracted cancer of larynx and who were exposed to asbestos fibre and/or nickel aerosol in their work environment. The policy was adopted on May 4, 1978.

Dr. Miller and colleagues completed the case control study in 1981 and added additional cases of laryngeal cancer to their analyses [7]. In the report that was published in the Journal of the National Cancer Institute the researchers did not find an elevated rate of cancer of the larynx among nickel exposed workers.

Dr. J. Stuart Warner, Vice-President, INCO Limited, in a letter dated December 8, 1986 [82], noted that the WCB had known since 1982 that any link between nickel and laryngeal cancer had yet to be established and that, furthermore, lifestyle factors were clearly linked to the incidence of laryngeal cancer. Dr. Warner asked the WCB to refer the matter to the Occupational Disease Panel (ODP)¹.

Subsequently, in September 1988, Dr. Robert Elgie, Chairman of the WCB at that time, wrote to the ODP, asking the Panel to review the Board's policy guidelines on the adjudication of laryngeal cancer claims in the nickel industry.

The ODP was asked to provide advice on the issue and, in particular, on the following questions:

1) Is there a causal relationship between occupational exposure to nickel and the development of laryngeal cancer?

2) If yes, what should be the criteria and eligibility rules for evaluation of claims respecting laryngeal cancer among nickel-exposed workers?

The WCB's request was discussed at the ODP meeting in October 1988 and the ODP reviewed the results of a mortality study of the INCO workforce conducted by McMaster University. That mortality study failed to show evidence of excess deaths for laryngeal cancer. However, in its deliberations the Panel acknowledged that mortality studies might not have been an appropriate tool to evaluate the risk of laryngeal cancer because the survival rate for this type of cancer is quite high. It therefore decided to arrange for a cancer incidence study of the primary nickel industry in Ontario. That incidence study has now been completed and in this document the ODP will be reporting its conclusions and addressing the questions raised by the WCB.

In this report, the ODP has limited its investigation and findings to the primary nickel industry as defined in the Working Definitions section. Because of budgetary and time limitations the ODP deferred the investigation of the relationship between nickel exposures and welding and electroplating to its ongoing investigation of welding. Additional investigations concerning other occupationally exposed nickel workers will also be deferred.

The ODP mandate

Section 95 of the Workers' Compensation Act (the Act) requires the ODP to investigate possible occupational diseases and when appropriate make findings of "probable connection" between disease and work.

The ODP weighs both scientific and medical evidence in order to determine probable connection. Specifically, the ODP will consider epidemiological studies, industrial hygiene studies and toxicological evidence about the identified contaminants and alternative causes of disease.

In its evaluation of the evidence, the Panel is aided by the work of Sir Austin Bradford Hill [26]. Bradford Hill argued that to infer causality, consideration should be given to the following factors:²

After weighing all of the evidence, the Panel decides what, if any, connection exists between occupation and disease. If the investigation fails to indicate the existence of a probable connection, the Panel will also report this finding.

If a probable connection is identified, and depending on the strength of association, the Panel may recommend that the WCB establish guidelines for adjudication of claims on a class or case-by-case basis; or it may recommend the disease and relevant exposures be added to Schedule 3 or 4 of the Act.

Evidence to support a schedule entry must be either strong or very strong because Schedules 3 and 4 carry a presumption of work-relatedness for listed diseases. A worker who has a Schedule 3 disease and has worked in a listed industrial process may be compensated pursuant to Section 134 of the Act, which states that the disease "shall be deemed to have been due to the nature of that employment unless the contrary is proved" [emphasis added]. A conclusive presumption applies to claims for diseases in Schedule 4 and a worker who has the listed disease and has worked in the listed process shall be compensated without further proof.

Scope of the investigation

When the WCB referred the matter to the ODP, included was a review of the literature conducted by L. Elinson, a staff epidemiologist, dated May 30, 1988 [16]. Ms. Elinson reported some mixed findings in the case control studies. She also reported that the data from Falconbridge showed elevated rates of laryngeal cancer among some groups of the work force.

The ODP decided to pursue an incidence study - a study that would examine the cases of cancer of the larynx regardless if it was the cause of death or not. It was decided that such a study would best be conducted by McMaster University which had knowledge of the INCO cohort. Additional discussions took place with management from Falconbridge (the other large Ontario nickel mining company) and Mine Mill and Smelter Workers and the United Steelworkers of America (USWA), the unions that represented those workers. Ultimately it was decided to join both company workforces for study purposes.

The ODP requested permission from the Labour/Management Joint Health and Safety Committee of INCO to use the data collected on the INCO workforce. In 1989, the Panel then solicited a proposal for such a study from Dr. David F. Muir of the McMaster University Occupational Health Programme. The proposal, submitted by James Julian as principal author with Dr. Muir, was reviewed and accepted in May 1990 and was to be completed in 1993.

One difficulty that delayed the final report was the time taken in following the mortality cases Canada-wide. The follow-up of morbidity cases, however, was limited to Ontario.

Another difficulty arose from defining and amalgamating the data from the two different companies to create one cohort. Because few reliable exposure estimates were available, INCO cohort members were classified into sub-groups by process and/or location based on their hierarchial job codes. These classifications were originally designed for payroll and accounting purposes. Falconbridge, on the other hand, assigned workers as exposed or unexposed based on hygiene assessments of areas defined by department codes.

Following a preliminary presentation of the study results to the ODP, Panel members expressed concern that the development of the INCO cohort using job classifications intended for accounting and payroll needs may have diluted the cohort by including large numbers of unexposed and out-of-province nickel workers. It was agreed by the researchers to:

• exclude person years at risk from the INCO data for those employees who worked in INCO's nickel operation in Manitoba or at the Shebanowan mine or mill and,
• separate all salaried personnel, other than immediate supervisors, from all production departments and calculate their incidence of cancer separately.

Seven linkages involving three agencies were further supplemented by additional diligent effort on the part of the McMaster team to resolve conflicts and questionable links. This cohort should now reflect the best ascertainment to date with the longest period of follow-up of nickel workers in Ontario. It is hoped that the great efforts of the McMaster team have resulted in what is now the most accurate analysis to date of cancer in this large working population.

A draft report was submitted by the authors to the ODP in late 1995. Following a peer review process the final report, herein referred to as the Julian and Muir report, was made available to workplace parties in meetings held in Sudbury in January 1996 [45].

During the time needed to complete the protocol for the Julian and Muir study, two renowned international scientific bodies released work on the carcinogenicity of nickel. Specifically, the International Agency for Research on Cancer (IARC) published its conclusions on the carcinogenicity of nickel in 1989. In February 1990, the International Committee on Nickel Carcinogenesis in Man, chaired by Sir Richard Doll, was published.

The Panel also had completed some independent work on laryngeal cancer and work exposures. In April 1990, the ODP published its Report No. 7 entitled the Second Report to the Workers' Compensation Board on certain issues arising from the Report of the Royal Commission on Asbestos. The Panel recommended that asbestos-related laryngeal cancer be added to Schedule 3. The WCB has as yet made no policy changes or schedule additions as a result of the Panel's Report. In June 1995, the ODP published its Report No. 15 entitled Report to the Workers' Compensation Board on the health effects of occupational exposure to petroleum-based fluids used for machining and lubricating metal in manufacturing: Cancer of the larynx . In that report, the Panel found a probable connection between laryngeal cancer and oil mists and recommended that this association be recognized in Schedule 3. The WCB has also not addressed this recommendation.

With respect to its evaluation of the incidence of laryngeal cancer among workers in the primary nickel industry the Panel conducted its own literature searches through Medline, NIOSH and Biosis databases, using appropriate keywords; all relevant studies are capsulized in Appendix D.

In deciding which studies to evaluate, the Panel excluded any study without 80% power to detect a two-fold risk. The ODP, like the WCB, found shortcomings with the Miller case control study. The case control study by Dr. A. Miller [7] in its final form looked at 204 new laryngeal cancer cases, regardless of exposure, in the cities of Toronto, Hamilton, Sudbury and North Bay matched to 204 controls by age, sex, residence, smoking and alcohol use. The study ultimately identified only 11 nickel exposed cases that were matched to 13 controls. The RR for nickel exposure was 0.9 after controlling for smoking and alcohol use. In this study, no attempt was made to determine the speciation, solubility or extent of occupational nickel exposure. The authors noted:

In contrast [to the asbestos findings] the RR observed in the present study for nickel exposure is not elevated. A study [Pedersen] that suggested an increased cancer risk for nickel workers did not indicate that a specific group of workers was affected. Nevertheless, any risk could possibly be restricted to a limited number of specific occupations in the nickel processing industry. Under the circumstances cohort studies on the basis of accurate occupational exposures may be of more value than the case control approach [7].

What the authors meant by "specific group of workers" is unknown because the Pedersen study [67] did identify specific groups of workers affected, namely, those in roasting and smelting operations, which is why these operations are noted in the WCB policy.

The Miller study also found elevated risks for moulders or coremakers, plumbers, pipe fitters and metal processors. These findings concerning metal processing and metal dusts are consistent with the evidence in the Panel's report on metal-working fluids and laryngeal cancer. It was not possible, however, to identify which of the 11 nickel exposed workers in this study were miners, millers, smelter or refinery workers. Thus, the Miller study was of little help in the Panel's investigation and is not included in the evidentiary base for its findings.

In its search the Panel also identified a case-control study published by Olsen & Sabroe [65]. In this study the authors identified an increased RR of 1.7 (95% CI 1.2-2.5) for laryngeal cancer among nickel exposed workers. As in the Miller study, the Olsen & Sabroe study did not confine their research to workers in the primary nickel industry and therefore for the purposes of this paper that research was not included.

Finally, the ODP was assisted by advice from both management and labour, particularly Dr. B. Conard of INCO and D. Deluca of the USWA who helped the Panel understand the complex process involved in the refining of nickel.

Consultation with the stakeholders

As discussed above much of the research necessary to complete this project was viable because of the cooperation of workplace parties with the researchers. Most of the data was collected by the nickel producers in Canada. The data was refined with the assistance of labour and management.

When the Nickel Morbidity Study was presented to the Panel the workplace parties were given an opportunity to discuss the results of the findings with Julian and Muir. The Panel also provided the comments of the peer reviewers to the workplace parties.

During its deliberations the Panel was aware of the concerns of the workplace parties about potential confounders and have addressed these issues wherever possible.

CHAPTER TWO
THE EVIDENCE AND CONCLUSIONS RELEVANT TO NICKEL AND NICKEL PRODUCTION

Cancer of the Larynx

The larynx is the organ of voice production. It is a part of the respiratory tract that lies between the pharynx and the trachea [9]. It consists of a framework of cartilages and elastic membranes housing the vocal folds and the muscles which control the position and tension of these elements.

Cancer of the larynx is a relatively rare disease with prolonged survival. The latest incidence rate (published 1996) among men in Ontario was seven per 100,000 population; the corresponding incidence for lung cancer was 81 per 100,000. Laryngeal cancer mortality in 1992 among men in Ontario was estimated to be three per 100,000 compared with 67 per 100,000 for lung cancer mortality [58].

The National Cancer Institute of Canada reported that laryngeal cancer had a 5-year survival rate of 62% for males of all ages in Quebec between 1984 and 1986 [57]. A substantial proportion of affected persons will not die of the disease because curative treatment is available. The larynx can be removed, or the tumour treated with radiation.

Occupation and lifestyle are known to contribute to laryngeal cancer. Smoking and alcohol consumption are established contributors to higher rates of laryngeal cancer [72]. Most authors of studies on laryngeal cancer take smoking and alcohol use into account [1, 7, 8, 12, 18, 19, 20, 27, 51, 56, 65, 84, 95, 96].

WCB policy on respiratory cancers associated with nickel exposures

The Ontario WCB has policies in force dealing with respiratory cancers and nickel exposure. They include laryngeal, nasal/sinus and lung cancers. The evidence for nasal/sinus cancers is so compelling that they have been included in Schedule 4, as well as Schedule 3. These policies are summarized in Appendix B for the reader's reference. Also in Appendix B is a review of policies in other jurisdictions on entitlement to benefits on laryngeal cancer. These are not of significant assistance in evaluating the current issue.

Ontario's WCB policy on laryngeal cancer

The policy guideline for laryngeal cancer and asbestos/nickel exposure identifies exposure and latency periods. Policy 04-04-13 states that workers with claims for laryngeal cancer are entitled to benefits if these criteria are met:

- 15 years exposure to nickel aerosols through any process in the nickel industry which produces nickel in aerosol dispersion, in combined or elemental form, including:

• roasting
• smelting
• refining
• welding
• electroplating

with 20 years latency, OR;

- 10 years exposure to asbestos dust with 20 years latency, OR;

- 7.5 years nickel aerosol and 5 years asbestos dust exposure with 15 years latency.

The policy identifies as compensable laryngeal cancer relatable to "any process" [emphasis added], including the named processes, in the nickel industry, that produces nickel in aerosol dispersion in combined or elemental form. If the exposure and diagnosis criteria are met, a claim will be adjudicated as an occupational disease. If the criteria are not met, the guideline has an exception clause that states:

Claims which do not meet the criteria will be individually judged on their own merit, having regard for the intensity of exposure and other factors peculiar to the individual case.

Epidemiological factors to consider

Definitions and abbreviations of commonly used epidemiological terms are available in Appendix C. When evaluating the epidemiological evidence the Panel suggests that the reader consider some factors which may affect the data. Those factors include:

The Healthy Worker Effect

Many epidemiological studies compare workers to the general population. Since the general population includes people who do not or cannot work due to illness or disability, including work-related disability, a working population is usually healthier overall and usually has a lower rate of mortality from most causes. The influence of this factor on the results of epidemiological studies is known as the healthy worker effect. This effect results in lower SMRs, RRs and SIRs than would occur if comparisons had been made with a working population.

The influence of the healthy worker effect on findings for cancer, however, is somewhat controversial.

There is no screening test for susceptibility to cancer, but there is a belief that workers who are selected for being at low risk for cardiovascular and respiratory disease are healthier overall and are therefore less likely to develop cancer [39]. A review of 10 different studies concluded that the healthy worker effect had little or no effect on cancer mortality [39], while another study concluded that a healthy worker effect amounting to 20% to 40% reduced mortality was shown to persist over the entire age range for various causes including cancers [39].

The ODP, in its Report Number 3 (July, 1988), "Report to the Workers' Compensation Board on the Healthy Worker Effect" concluded that the healthy worker effect must be taken into account when interpreting epidemiological studies of mortality or morbidity from any cause, including cancer. No uniform correction factor should be used because each study requires individual interpretation.

Choice of Reference Population

When an SMR is computed, the general population, on which the expected number of deaths is based, includes the observed number of deaths from the study population. This is because these deaths contribute to both populations: that is, the deaths are counted in both the observed and the expected groups. For example, deaths due to nasal cancer are almost always caused by occupational factors. As a result, an SMR for nasal cancer will thus be underestimated. This is true for all rare diseases, and laryngeal cancer is a rare disease, in comparison to lung cancer, for example.

The Healthy Worker Survivor Effect

The healthy worker survivor effect (HWSE) refers to the observation that long-term workers experience lower mortality than would be expected because they are less susceptible to hazards in the workplace, and that short-term workers experience higher mortality than would be expected because they are more susceptible to hazards in the workplace, all other things being equal. If there is an association between length of employment and mortality, the healthy worker survivor effect would thus tend to obscure it.

In the following pages data relevant to all aspects of primary nickel production are set out. For each process within the continuum the Panel has reviewed the available epidemiological and hygiene data. A summary of all of the studies considered is available in Appendix D.

A: NICKEL PRODUCTION

In this Report, the nickel industry includes primary extracting, processing and refining. Occupational exposures to airborne nickel and other carcinogenic agents in the primary industry (diagram below) are briefly identified as the following operations [30]:

1. Nickel mining;
2. Nickel milling, including crushing, grinding and concentrating;
3. Nickel smelting and sintering;
4. Nickel refining.

The following diagram simplifies the operations and processes found in the production of nickel from extraction to preparation to processing and refining. The refining stage is the processing of smelted product into pure nickel form. Various forms of pure nickel are sold to other industries to use in the manufacture of other products (e.g., stainless steel).

B: INTERNATIONAL AGENCY FOR THE RESEARCH ON CANCER (IARC) EVALUATION OF NICKEL AND ITS COMPOUNDS

IARC has reported on the carcinogenicity of nickel and its compounds. The analysis used and standards employed by IARC are set out in Appendix E. The ODP relies on IARC as the preeminent international scientific body for determination of carcinogenicity.

Because nickel and its compounds are found in every aspect of primary nickel production, IARC's conclusions are relevant to each process.

IARC and the American Conference of Governmental Industrial Hygienists (ACGIH) have classified nickel compounds as carcinogenic in humans (Group 1), on the basis of both epidemiological evidence and experimental data [33,3].

IARC has found:

a) Sufficient evidence for the carcinogenicity in humans of nickel sulphate and of the combinations of nickel sulphides and oxides encountered in the nickel refining industry [Group 1];

b) Inadequate evidence of human carcinogenicity for metallic nickel and nickel alloys, but sufficient or limited evidence for carcinogenicity in experimental animals [Group 2A];

c) Only limited or inadequate evidence of carcinogenicity in experimental animals for compounds such as nickel carbonyl, nickel salts and other nickel compounds such as nickel arsenides, nickel antimonies, nickel selenides and nickel tellurides [Group 2B].

IARC has further concluded that:

Epidemiological studies conclusively demonstrate an excess risk of cancer of the nasal cavity and lung in workers in nickel refineries. It is likely that nickel in some form(s) is carcinogenic to man [33].

C: MINING

Mining operations involve drilling, primary and secondary blasting, mucking, slushing, crushing, hauling and hoisting.

i) Epidemiological Evidence

1. Julian & Muir (1996):

The most recent data come from the Julian and Muir cancer morbidity study, which includes both fatal and non-fatal cases [45].³

The value of a morbidity study in contrast to a mortality study is highlighted in Ms. Elinson's memo to the WCB. She wrote:

It is also possible that Inco workers with laryngeal cancer, which has a low fatality rate may have been missed in this study because they survived, and, did not appear in the National Mortality Data Base. As illustration of this possibility, in 1984 the age adjusted incidence rate of laryngeal cancer in males was 6.7 per 100,000. The age adjusted mortality rate in males that same year was 2.2 per 100,00 [16].

Julian and Muir reported in Table 19 of their report the following data:

INCO-Falconbridge Mining:
hourly, foremen and exposed (never sinter)

Julian and Muir found [Figure 1] that the rate of laryngeal cancer increased with exposure and wrote:

The ODP conducted additional analysis using the Julian and Muir data to determine the rate of cancer for miners with 25 or more years of exposure⁴. The Panel calculated an SIR of 174 (95% CI 111-259) for these miners.

2. Report of the International Committee on Nickel Carcinogenesis in Man (1990)

Chaired by Sir Richard Doll, this committee studied nickel processes the world over, reviewed the extant literature on the subject of nickel exposure and cancer and examined the mortality data of ten cohorts [14]. The committee reported elevated rates of laryngeal cancer among Canadian nickel miners. The authors did not draw any specific conclusions based on these findings.

3. Shannon, Julian & Roberts (1983 & 1984):

Shannon examined the cancer mortality among nickel workers over the period of 1950-1976 using a cohort of 11,500 Falconbridge employees located at Sudbury, Ontario with at least six months employment in the industry [73, 74]. The overall SMR for laryngeal cancer is 261 (95% CI 84 - 608).

By occupational subgroup, however, there is a statistically significant SMR of 400 (95%CI 109-1024) for miners. The authors interpret the data for laryngeal (and lung) cancer in the following way:

The results for laryngeal cancer showed that all cases occurred at least 20 years after first exposure, although the lengths of exposure involved were variable. ...

... The laryngeal cancer excess appeared to be restricted to miners, although the higher risk in men with shorter exposure weighs against the risk being occupational [73].

These conclusions were drawn before information from later reviews of the Mining Master File (MMF) became available. Subsequent analysis by ODP staff of patterns of work among miners listed in the MMF has revealed that 51% of person-years for miners who worked in nickel were nickel only. For nickel miners with less than 5 years of experience, only 21% were nickel only. Effectively, this means the SMRs for the short term nickel exposed groups reflect rates for miners with multi-ore experience. The multi-ore exposure is greater than nickel only experience. Thus, under estimation of total mining exposures could undermine the potential dose response trend.

4. Roberts, Julian et al (1983):

This study of cancer mortality among workers over the period of 1950-1976 examined a cohort of 54,000 INCO employees located at Sudbury and Port Colborne, Ontario, with six months or more employment in the industry [70]. The findings are divided between non-sinter and sinter plant workers at Sudbury and Port Colborne.

The SMR of 118 (95% CI 61-206) for laryngeal cancer among non-sinter workers at Sudbury did not reach statistical significance. Non-sinter workers included miners, millers, transportation and maintenance workers, and non-exposed administrative staff⁵.

ii) Potential Causative Agents in Nickel Mining

The concentration of nickel in igneous rock is about 0.01% and between 1 to 2% in most sulphide ores (the concentration in pentlandite, the major nickel mineral of importance, may be as high as 35% by weight) [83]. Although little exposure data is available, the exposure of miners to nickel is probably low. From the 1970's, when systematic gravimetric dust sampling examined the nickel content of airborne dust, there is no record of findings exceeding the Ontario exposure guideline of 0.1 mg/m³ for soluble nickel. The exposure guideline for airborne insoluble nickel is 1 mg/m³ [64], and estimates of historical exposures showed that respirable nickel concentrations in Ontario mines rarely exceeded this guideline [33, 83].

2. Oil Mists

IARC has classified oil mist (airborne particulates generated from oil used to lubricate drills and other equipment) into two groups: Untreated and mildly treated oils (Group 1) and highly refined oils (Group 3) [31].

The Panel has recently found a strong probable connection between metalworking fluids (MWFs) and primary cancer of the larynx. This conclusion was based largely on evidence showing significantly increased rates of laryngeal cancer in exposed workers (especially amongst those with long-term exposures to straight oils) and on the recognition that components of MWFs are known carcinogens [61].

Historical records from INCO show that there was some use of MWFs (mostly for cutting and quenching) in machine shops, but the predominant lubricants used in the past were hydraulic and compressor oils for pneumatic equipment such as drills, pumps and hoists [17]. There is little record of the composition of these lubricants; however, the oil would likely have been of the straight oil type.

The introduction of diesel equipment into the mining environment in the 1960s complicates the measuring of oil mists. Any dust sample could contain both diesel soot and oil mist [20]. A study of Finnish sulphide ore miners reported that the average airborne concentration of oil mist during drilling was as high as 3 mg/m³ in the 1970s, ranging from 0.1 to 17 mg/m³. The authors estimated that underground mining exposure to oil mist between 1950 and 1960 could have been double that of the 1970s [2].

The Ontario Ministry of Labour's bipartite Occupational Exposure Limits Task Force conducted a review recently of the current exposure limits for 101 substances and recommended lowering the current time-weighted average exposure value (TWAEV) for mineral oil mist from 5 mg/m³ to 1 mg/m³, and the current short term exposure value (STEV) from 10 mg/m³ to 3 mg/m³. The lowering of the TWAEV to 1 mg/m³ was agreed upon as part of the negotiated collective agreements between the Canadian Auto Workers (CAW) and the three auto manufacturers (General Motors, Ford and Chrysler).

Some of the other Task Force recommendations have been implemented, but those pertaining to mineral oil mist have not. In their 1993 presentation to the Task Force, INCO stressed that compliance to the lower oil mist standard would cause the company undue economic hardship [36]. The members of the Task Force eventually agreed to maintain the current guidelines due to the potential economic impact of reducing them [63].

3. Diesel Emission and Sulphuric Acid

Diesel equipment was first introduced to Ontario underground mining in the early 1960's, and its use underground has been a continuous health concern among mine workers, their union and management. Some diesel equipment was gradually replaced in some mines by electric machinery during the late 1970's and 1980's. Many Ontario nickel mines are still using diesel equipment underground today. IARC has found that "diesel engine exhaust is probably carcinogenic to humans" (Group 2A) [32]. This emission is a complex mixture of particulates, gases and vapours that include polycyclic aromatic hydrocarbons (PAHs), sulphuric acid and other potential carcinogens.

Sulphuric acid mist has been evaluated as a Group 1 carcinogen by IARC. Studies of exposed workers have shown a statistically significant increase in upper-respiratory cancer risk, including laryngeal carcinoma [77, 78]

According to the Ontario Regulation respecting Control of Exposure to Biological or Chemical Agents - made under the Occupational Health and Safety Act 654/86, the TWAEV for sulphuric acid mist is 1 mg/m³ [64]. In a survey of 24 US mines, as cited by IARC, mean sulphuric acid concentrations of 12.8 mg/m³ (ranging less than 0.2 to 46 mg/m³) from diesel emission sources and of 0.3 mg/m³ (ranging less than 0.004 to 2 mg/m³) were measured from personal and area samples [32]. The Panel was not aware of similar studies for Ontario nickel mines.

4. Asbestos

IARC has designated asbestos as a Group 1 human carcinogen for various sites in the respiratory tract including the larynx [30].

Asbestos may be present in the mining environment both intrinsically and extrinsically. Appreciable levels (0.1 to 0.22 fibre/cc) have been measured by the Ontario Ministry of Labour in underground nickel mines [16]. Its presence in the natural state may not be much of a danger to nickel miners; however, once disturbed and made airborne, asbestos dust can be an inhalation hazard.

Asbestos is also brought into the mining environment in its processed form. It is used in the brakes of motorized mining equipment and insulating materials around pipes.

5. Other Respiratory Tract Carcinogens

Nickel miners are also exposed to other airborne carcinogens (radon, PAHs, cobalt, cadmium, chromium, arsenic and silica) in the underground environment. Several of them (radon, arsenic, cobalt, PAHs and silica) have been identified by IARC as known or suspected respiratory tract carcinogens in humans [30]. None of these agents have been found to be positively associated with cancer of the larynx, although exposure to either silica [6] or arsenic [60] has been suggested as a risk factor for respiratory tract cancers. The inhalation exposure to airborne radon and silica was low in nickel miners [50], as was exposure to airborne arsenic because its concentration in the Sudbury ore is less than 0.1% [83].

Formaldehyde is classified by IARC as a Group 2B carcinogen with inadequate evidence in humans [29]. This agent has not been shown to be a respiratory tract carcinogen in humans but has been found to cause nasal cancers in experimental animals (rats). IARC cited from the survey of 24 US mines a mean formaldehyde concentration of 7 mg/m³ (range from less than 0 to 42 mg/m³) from diesel emission sources [32]. A mean concentration of 0.8 mg/m³ (range from less than 0 to 8 mg/m³) was measured from personal and area samples.

Cobalt is found in nickel bearing ores in small but commercially valuable amounts. It has been recognized by IARC as a possible carcinogen in humans (Group 2B). Evidence of elevated lung cancer rates in humans has been confounded by concomitant exposures to other metals (e.g. nickel and arsenic) [34]. In one animal study, inhalation exposure of rats and mice to aerosols of cobalt sulphate heptahydrate resulted in various injuries including metaplastic lesions of the respiratory tract. The larynx of the animals tested appeared to be the most sensitive tissue affected [59].

iii) Conclusions

• Data from Julian and Muir calculated by ODP staff show a statistically significant elevated SIR of 174 (95% CI 111-259) for miners with more than 25 years exposure.
• Shannon and Roberts, on an examination of fatal laryngeal cases only, found a statistically significant SMR of 400 (95% CI 109-1024) for miners;
• A clear dose-response relationship for laryngeal cancer among miners was found (Fig.1); Julian and Muir state:

In underground miners, an increasing trend, beginning in the 15-24 year DOE category, was apparent and statistically significant [chi square analysis], even though the individual relative risks were not[45].

• Miners are exposed to IARC Group 1 carcinogens including, nickel aerosols, PAHs and sulphuric acid from diesel emission, asbestos, radon and oil mists.
• Miners are exposed to other agents which are suspected to be respiratory carcinogens including arsenic, cobalt, cadmium, chromium, and silica.

D. MILLING

I) Epidemiological Evidence

The SIRs from this table are shown in Figure 2 and illustrate that incidence rises with duration of exposure. Julian and Muir determined that statistically significant elevated incidence of laryngeal cancer is observed among mill workers with more than 25 years exposure: SIR = 400 (95% CI 147-871), and more than 30 years exposure, SIR = 500 (95% CI 136-1280).⁶

Based on this data Julian and Muir concluded that:

a four-fold risk in millers with more than 25 years of exposure was identified and is likely to be work related.

Although the rates of cancer increased with duration of exposure as is evident from the data, this trend was not statistically significant according to the analysis conducted by the authors. Given the very high rates of cancer for the longest serving mill workers the Panel asked for additional analysis of the possible dose/response trend.

When they conducted the analysis for trend in the milling sub-cohort, Julian and Muir excluded the first category of mill workers - those with less than 15 years of exposure. This step was taken because the authors were of the opinion that there was a significant under ascertainment bias operating among the workers with the least exposure which resulted in an artificially low rate. This same process for excluding the least exposed workers was used when evaluating the mining sub-cohort.

Following another careful look at the data, the ODP staff found that PcMR, MOR and SIR are in concordance for mill workers with less than 15 years of exposure.⁷ There is not the same degree of concordance in the <15 years of exposure in the mining sub-cohort. In simple terms that means that any possible bias caused by under ascertainment was not important for mill workers. Therefore, the rationale given by Julian and Muir for excluding the mill workers with the least exposure is less compelling than in the mining group. Furthermore there is a monotonically increasing pattern of risk for the other duration categories.

When the data was recalculated including the mill workers with less that 15 years exposure, the dose response trend was statistically significant (X² = 12.7 and p. = 0.0004).

2. Shannon, Julian & Roberts (1983 & 1984):

This is a study of cancer mortality among nickel workers over the period of 1950-1976 [73, 74]. By occupational subgroup, the SMR 507 (95%CI 12-2785) for millers is not statistically significant, but this number represents one death. This case is likely to have been captured in the Julian and Muir later study.

ii) Potential Causative Agents in Nickel Milling

By far, the predominant exposure of Ontario nickel mill workers has been to nickel sulphides. IARC has classified nickel compounds including nickel sulphides, oxides and sulphate as Group 1 carcinogens. The concentration of nickel in the ore during milling processes (9-12%) is typically much higher than concentration in the ore from underground mining (0.5-2.0%). Therefore, it is likely that Ontario mill workers would have also been significantly exposed to airborne nickel particulates from the various milling operations. High-volume samples taken in the milling and ore-separating areas showed airborne nickel concentrations range from less than 0.1 to 2.8 mg/m³ [56].

Moreover, flotation reagents (predominantly pine oil, xanthates and Downfroth) used in the concentrating process create surface bubbles which when burst can generate a mist and release airborne nickel particulates. Spillage is a common occurrence in flotation and as these spills dry, further dust may be released into the air from the floor.

2. Other Respiratory Tract Carcinogens

Little exposure data is available for mill workers just as for nickel miners. Surveys from the mid 1970s showed airborne dust levels from nickel crushing, grinding and milling activities (140 - 280 particulates/cc) comparable to levels measured underground [24]. Since the chemical composition of the ore is not altered by these activities, nickel mill workers involved in these processes were exposed to a similar mixture of airborne contaminants and carcinogens as experienced by underground nickel miners. Besides nickel sulphides, they include other nickel species, cobalt, arsenic, silica, cadmium, chromium, asbestos and radon, the important difference being the absence of a significant amount of oil mist or diesel emission in milling.

iii) Conclusions

• Data from Julian and Muir show a statistically significant SIR of 400 (95% CI 147-871) for all mill workers with more than 25 years exposure.
• Julian and Muir found:

A four-fold risk in millers with more than 25 years of exposure was identified and is likely to be work-related [45].

• The rates of laryngeal cancer for mill workers increase with duration of exposure. When all four exposure categories are used in the calculations there is a statistically significant dose/response trend.
• Mill workers are exposed to IARC Group 1 carcinogens including nickel aerosols and asbestos.
• Mill workers are exposed to other agents which are suspected to be respiratory carcinogens including arsenic, cobalt, cadmium, chromium, and silica.

E. SMELTING AND SINTERING

Smelting involves melting roasted charge in one of several types of furnaces (e.g., blast, reverberatory, flash or electric furnaces) to separate out the lighter liquid iron oxides (slag) and other ore materials (gangue) from the heavier molten sulphides. The resultant product is a molten mixture of mostly nickel, copper, iron and sulphur, with small amounts of base elements and precious metals [5].

Converters are used to melt this product, and any iron and sulphur content is changed into iron oxide and sulphur dioxide for further elimination. The end product is a nickel matte for subsequent processing which contains almost no iron sulphides and a specific sulphur content.

I) Epidemiological Evidence

In this study of nickel workers located at Sudbury and Port Colborne [45], workers overall were separated on the basis of experience in sinter smelting and identified as never sinter or sinter. Non-sinter smelter and refinery workers were therefore classed as never sinter (Fig. 3). An elevated rate of laryngeal cancer was not observed for never sinter(smelter) or sinter plant workers. However, sinter workers showed very high, statistically significant elevated rates of other respiratory cancer including lung and nasal.

2. Shannon, Julian & Roberts (1983 & 1984):

This is one study of cancer mortality among nickel workers over the period of 1950-1976 using a cohort of 11,500 Falconbridge employees located at Sudbury [73,74].

By occupational sub-group, the SMR is 169 (95% CI 4-944) for smelter workers and is not statistically significant and represents only one case.⁸

3. Roberts, Julianet al (1983):

This is a study of cancer mortality among nickel workers over the period of 1950-1976 using a cohort of 54,000 INCO employees located at Sudbury and Port Colborne, Ontario with six months or more employment in the industry. No laryngeal cancers were observed among sinter workers [70].

ii) Potential Causative Agents in Nickel Smelting and Sintering

The sintering process used at the various smelters was quite similar, resulting in a large amount of airborne dust. A single high-volume sample from Copper Cliff in 1960 showed an airborne total dust concentration 46 mg/m³ [60]. Similar samples from Coniston also showed high airborne total dust concentrations (5 - 125 mg/m³) even after improvements in ventilation and processes were installed in 1968 - 69.

Subsequent dust sample analysis revealed a composition consisting of nickel (62%), sulphur (12.6%), copper (3%), and much lower concentrations (>1%) of cobalt, arsenic and other elements. INCO speculated that the airborne concentrations of trace elements such as arsenic may be higher - since the high temperatures used for sintering may revolatilize these elements so that smaller airborne particles would tend to contain a greater amount of these elements than larger particles [60].

Estimates of airborne nickel, both soluble and insoluble, were extrapolated from total dust. Between 1948-1963 the airborne concentration for total nickel was estimated to be 8 - 100 mg/m³ (as Ni) at Copper Cliff. Estimates of airborne nickel sulphide and oxide concentrations (as Ni) at the Copper Cliff sintering plant between 1948 and 1954 ranged from 25-60 mg/m³ and 15-35 mg/m³, respectively [14]. The Ontario time-weighted average exposure value (TWAEV) for nickel sulphides and oxides (as Ni) (insoluble) is 1 mg/m³.

In the sintering plant, levels of nickel sulphates were as high as twenty times (up to 2 mg/m³ as Ni) the TWAEV of 0.1 mg/m³ for water soluble nickel, and the concentration for metallic nickel was negligible.

Recent measurements taken by INCO between 1988 and 1992 showed that mean airborne nickel concentrations (as Ni) at the Copper Cliff smelter seldom exceeded 0.5 mg/m³ but could be as high as 1 mg/m³ [83, 33, 14]. The average concentrations of airborne nickel were higher in the roaster areas (0.048 mg/m³) than in the converter areas (0.033 mg/m³), because the handling of fine solids is a greater source of dust than the handling of molten materials. Airborne levels as high as 79 mg/m³ have also been recorded in some area samples [36]. In one report, samples showing the highest airborne nickel concentration were those from the matte separation areas (0.17-15.3 mg/m³), while samples from the converters, roasters and reverbratory furnaces showed much lower levels (0.03-3.3 mg/m³) [56]. Nickel-bearing dust from the converters contain mainly nickel subsulphides (a subgroup of nickel sulphides). Arsenic, silica, copper, cobalt and other metal compounds may also occur in workplace air [33].

2. Asbestos

IARC has designated asbestos as a Group 1 human carcinogen of various sites in the respiratory tract, including the larynx [30].

Nickel smelter workers may be potentially exposed to airborne asbestos fibres as a result of the installation, maintenance and repair of furnace and pipe insulation. Friable asbestos fibres could also be made airborne in the smelter as a result of disturbance or during repair or replacement of damaged asbestos building material.

3. Other Respiratory Tract Carcinogens

As noted above, nickel smelter workers were also exposed to airborne elements such as arsenic, copper, cobalt and silica. Some of these (arsenic, cobalt and crystalline silica) have been identified by IARC as known or suspected respiratory tract carcinogens in humans [30]. None of the elements identified are known to be associated with laryngeal cancer in humans.

Cobalt is found in nickel bearing ores in small but commercially valuable amounts. It has been recognized by IARC as a possible carcinogen in humans (Group 2B). Evidence of elevated lung cancer rates in humans has been confounded by concomitant exposures to other metals (e.g. nickel and arsenic) [34]. In one animal study, inhalation exposure of rats and mice to aerosols of cobalt sulphate heptahydrate resulted in various injuries including metaplastic lesions of the respiratory tract. The larynx of the animals tested appeared to be the most sensitive tissue affected [59].

iii) Conclusions

F. REFINING

The refining practice among nickel producers varies depending on economic and technical considerations (e.g., the type of energy source available)[5] and may include the following operations:

Crushing and grinding

Leaching

Calcining

Roasting

Smelting

Electrolytic separation

Reduction and packaging

Carbonyl processing.

Many of these operations were typical of the ones used at INCO's Port Colborne refinery in Ontario and at Falconbridge's Kristiansand refinery in Norway. Flowsheets of the Port Colborne refining process after 1965 are shown in Diagrams 2 and 3. Operations such as high temperature calcining, roasting and open sintering were eliminated from this refinery in 1963 [50]. Other notable changes since this refinery opened in 1918 are listed in Table A. After 1984, the nickel refining portion of the operation at Port Colborne was closed and the facility was converted to a cobalt only refinery [5].

Nickel oxide was also refined (after roasting and leaching) in a rotary kiln and at atmospheric pressure to produce nickel carbonyl.⁹. This "carbonyl process" was used at the Clydach refinery in Wales and has been employed at INCO's Copper Cliff plant in Ontario since 1972 [5].

In the past, nickel refining was commonly performed using pyrometallurgic methods (roasting, calcining and smelting). After crushing and size reduction, the finely ground matte material from the smelter would undergo one or more of these pyrometallurgic operations and be leached with sulphuric acid to remove the copper and cobalt. At Port Colborne there were seven acres of large, open tanks of sulphuric acid/nickel solution covering a twelve acre facility which utilized an electrolysis process to produce nearly pure nickel [5].

Nickel refining can also be done without pyrometallurgy by leaching the smelter matte directly with ammonia in autoclaves (hydrometallurgy). This method, which was also used at the Clydach refinery, can be carried out in combination with electrolysis. The resultant solution is clarified and purified to selectively precipitate out other metals such as cobalt and copper. Any nickel remaining in the precipitate is further separated out and later reduced along with nickel in the purified solution (and in the presence of hydrogen and ammonia) to form nickel metal powder [5].

I) Epidemiological Evidence

1. Julian & Muir (1996):

For non-sintering exposed refinery workers there are nine reported cases of laryngeal cancer identified in this study period. There is a statistically non-significant SIR of 171 (95% CI 78-325) overall. These cases occurred predominantly in the electrolytic department. Specific subgroups reveal an SIR of 206 (95% CI 89-406) in the electrolytic department and an SIR of 111 (95% CI 13-401) in the nickel and anode furnace department. This data is shown in Fig. 4.

The authors show an overall SIR of 96 (95%CI 26-247) for workers at the Port Colborne leaching, calcining and sintering departments. Table 17 from their report is included on the next page. More detailed data provided to the ODP by the authors revealed that all four cases in this department occurred with less than one year of exposure [55]. Although these cases do not appear to be work-related, previous exposures in other refining activities cannot be ruled out.

Additional data provided by Julian and Muir shows that five of the eight cases in the electrolytic department occurred with less than ten years duration of exposure.

Port Colborne Nickel Refinery Electrolytic Department and foremen (never sinter)
DOE	OBS	EXP	SIR	95% CI
<15	5	2.35	213	69-497
15+	3	1.53	196	40-573

The authors stated that "the uniform relative risks over DOE, [i.e., less than 15 and greater than 15 years], suggested a high baseline risk unrelated to exposure" [45]. In other words no dose/response trend has been identified.

Two separate facts, however, must be considered when examining this data for a dose/response trend. Firstly, the small number of expected cases in each exposure category means there is very little power to detect a statistically significant trend even if present [79]. That is, the absence of a statistically significant dose/ response is not an instructive finding [80].

Secondly, it is known that closures of other operations at the Port Colborne refinery at various times led to an influx of workers from other departments into the electrolytic department. Workers with the greatest seniority would be more likely to win new assignments in the electrolytic department. Workers with lower seniority in the electrolytic department could have significant exposure in other parts of the refinery. Therefore, duration of exposure in the electrolytic department may not reflect a worker's true refinery exposure and could mask a dose/response trend.

2. Roberts, Julian et al (1983):

This is a study of cancer mortality among nickel workers over the period of 1950-1976 using a cohort of 54,000 INCO employees located at Sudbury and Port Colborne, Ontario with six months or more employment in the industry. The elevated SMR of 243 (95% CI 24-878) for laryngeal cancer for non-sinter workers at the Port Colborne refinery is not statistically significant .

3. Pedersen et al (1973):

This is a study of all cancer mortality among 1,916 nickel workers who began work prior to 1961 and were employed at the refinery in Kristiansand, Norway (a non-sinter process) for at least 3 years. The workers were followed for 19 years from 1953 until 1971 [67].

The authors found increased mortality from all cancers, especially respiratory cancers. For the five cases of laryngeal cancer the overall SMR of 357 (95% CI 116-834) is statistically significant. For roasting/smelting workers, the greater SMR of 1000 (95% CI 272-2560) is statistically significant and definitely points to an occupational link for laryngeal cancer.

In 1982, Magnus et al produced additional data on the cancer mortality among the Norwegian workers after following the workers for an additional 8 years ( until 1979)[51]. No new deaths from laryngeal cancer were reported; however, the SMR for roasting/smelting fell to 670 (95% CI 182-1706).

ii) Potential Causative Agents in Nickel Refining

Epidemiological evidence on the carcinogenicity of nickel has centered largely on refinery workers exposed to a complex mixture of airborne agents. The nickel species include metallic nickel and its compounds such as nickel carbonyl, nickel sulphides, nickel subsulphides and nickel oxides [83]

Average concentrations of airborne nickel in refining operations can be considerably higher than those encountered in mining (but comparable to levels in smelting) because of the higher nickel content of the materials being handled in the refining processes [33]. The nickel species consist of mostly sulphidic and oxidic nickel and to a lesser extent, "soluble nickels" such as nickel sulphates and nickel chlorides [14]. Nickel sulphides and subsulphides are both intermediates in many of the nickel refining processes [5].

While no specific agents have been singled out, nickel and its compounds have been linked to the excess rate of lung, nasal and laryngeal cancers observed in nickel workers. Other airborne carcinogens which have been identified as respiratory tract carcinogens encountered in nickel refineries include sulphuric acid, arsenic and asbestos.

1. Nickel and its compounds

Sintering Areas

Large amounts of airborne dust were generated from various operations associated with nickel sintering (e.g. sizing, transporting, discharging, recycling and blending with coke and fine nickel sinter). According to NIOSH, INCO reported that convection currents created by hot sintering machines and recirculating sinter were sufficient to suspend many particles with diameters less than 25 microns and keep them airborne for a long time [60]. In calcining, many workers were exposed to high concentrations of calcine dust during the manual handling and feeding of the calcined product.

As in the Copper Cliff smelter, airborne nickel concentrations at Port Colborne have also been estimated on the basis of nickel content in total dust. These estimates (made by either the Ontario Ministry of Health, Industrial Hygiene Division or by INCO) showed that airborne nickel concentrations in the sintering areas were comparable to levels at Copper Cliff (20-100 mg/m³) after 1950 [14]. The composition of nickel species in the dust was also similar between the two plants, consisting of mostly insoluble nickel sulphides and nickel oxides. Their concentrations (as Ni) in the sintering department at Port Colborne (between 1926 and 1958) ranged from 10-20 mg/m³ and 20-40 mg/m³ , respectively. The Ontario time-weighted average exposure value (TWAEV) for nickel sulphides and oxides (as Ni) is 1 mg/m³. The airborne concentration for total nickel was estimated to be 5 - 80 mg/m³ (as Ni). Levels for water soluble nickel (e.g. nickel sulphates) were as high as 30 times (3 mg/m³) the TWAEV of 0.1 mg/m³ and concentration for metallic nickel was negligible.

Similarly, highest sulphidic and oxidic nickel levels were also estimated for calcining and furnace areas at the Clydach, U.K. (2.6 - 18.8 mg/m³) and Kristiansand, Norway (5.0 - 10.0 mg/m³) refineries. The Clydach estimates also included milling and grinding. The estimates, however, were higher for soluble nickel (1.3 - 5 mg/m³) than for nickel sulphides or oxides (<1.3 mg/m³) - both for the hydrometallurgic operations in the Clydach refinery and the electrolysis area in the Norwegian refinery.

Non-Sintering Areas

The process used to refine nickel electrolytically at Port Colborne had not changed significantly since the refinery began operation in 1918, but only a limited amount of data on nickel exposures is available for electrolysis workers [60]. Most of these data were available only for periods after the 1960's. Estimates made by the Ontario Ministry of Health and INCO indicated that the average nickel concentrations (as Ni) in the electrolytic department after 1960 were generally below 0.5 mg/m3. Pre-1977 measurements of high-volume samples in tankhouses showed an average airborne nickel concentration of 0.11 (range 0.022-0.254) mg/m³. Similar personal sample measurements were also found for operators, pressman and tank cleaners.

2. Sulphuric Acid

Occupational exposure to sulphuric acid mist has recently been evaluated as a Group 1 carcinogen by IARC. Studies on exposed workers have shown a statistically significant increase in upper-respiratory cancer risk, including laryngeal carcinoma [78, 77].

Large volumes of sulphuric acid were used in the various leaching and electrolytic operations to purify and extract nickel in solutions. In Port Colborne, sulphuric acid solutions were found in various vessels such as electrolytic, storage, acid, pH correction, copper pachuca and cobalt tanks, many of which were open to the atmosphere. Many of the operations were also performed at elevated temperature and pressure [71], allowing the sulphuric acid solution to aerosolize. Therefore, the airborne concentrations of sulphuric acid in the electrolytic areas of the nickel refinery, where a large proportion of the Port Colborne workers were employed [13] could have been significant.

IARC has designated asbestos as a Group 1 human carcinogen of various sites in the respiratory tract, including the larynx [30].

As in the smelter, nickel refinery workers may have been exposed to airborne asbestos fibres as a result of the installation, maintenance and repair of furnace and pipe insulation. Friable asbestos fibres could also be made airborne in the refinery as a result of disturbance or during repair or replacement of damaged asbestos containing building material.

4. Other Respiratory Tract Carcinogens

Nickel refinery workers were also exposed to other airborne contaminants such as arsenic, cobalt, boric acid, silica, hydrogen sulphide, ammonia, chlorine and sulphur dioxide [83, 33]. Some of these agents (arsenic, cobalt, and crystalline silica) have been identified by IARC as known or suspected respiratory tract carcinogens in humans [30]. None of these agents, however, has yet been positively associated with cancer of the larynx in humans.

Cobalt, in particular, is an important by-product of nickel refining and since 1984 is the primary product of the Port Colborne refinery. It has been recognized by IARC as a possible carcinogen in humans (Group 2B). Evidence of elevated lung cancer rates in humans has been confounded by concomitant exposures to other metals (e.g. nickel and arsenic) [34]. In one animal study, inhalation exposure of rats and mice to aerosols of cobalt sulphate heptahydrate resulted in various injuries including metaplastic lesions of the respiratory tract. The larynx of the animals tested appeared to be the most sensitive tissue affected [59].

iii) Conclusions

• In Norway, workers in refining operations have a statistically significant elevated rate for laryngeal cancer. The highest elevation is found among refinery workers in the roasting and smelting operations.
• In Ontario, the workers in the nickel refinery without sintering experience had an elevated overall SIR for laryngeal cancer of 171 (95%CI 78-325). For sintering workers the rate approximated the expected, at an SIR of 96 (95%CI 26-247).
• Workers in the refinery would have been exposed to known respiratory carcinogens including nickel aerosols, asbestos and sulphuric acid. They would also have been exposed to suspected respiratory carcinogens including cobalt and arsenic.

CHAPTER THREE
OTHER POSSIBLE CAUSES OF LARYNGEAL CANCER

Smoking and alcohol consumption

Smoking and alcohol use are known causes of laryngeal cancer and case control studies will normally control for these confounders.¹⁰ The Panel's internal consultant on occupational medicine reports that the literature has established in both prospective and retrospective studies a linear dose-response relationship for tobacco use and cancer of the larynx [9]. In addition, the Reports of the US Surgeon General show an increasing risk for this cancer of 10 to 20 times for smokers versus non-smokers, and a less elevated risk of five to 12 times for ex-smokers [9].

Alcohol use has also revealed a consistent relationship with laryngeal cancer, and the effect appears to be multiplicative with tobacco use [9]. Separating the effects of smoking from those of alcohol use is difficult because smoking and drinking are often related activities. The pathology of the effect of alcohol on the larynx is unclear. Alcohol, however, acts as a promoting agent for different environmental carcinogens, without itself being carcinogenic [9]. This might explain the association with alcohol use in laryngeal cancer cases. Alcohol use is also associated with esophageal and oropharyngeal cancer [9].

Ontario miners' mortality from cirrhosis of the liver has shown a statistically significant deficit (SMR=77, 95% CI=66-88) from this cause, which suggests that alcohol consumption in Ontario miners in general is less than that of other men in Ontario [48]. Julian and Muir [45] also observed that the SIRs for cirrhosis of the liver were less than expected in the nickel cohort, and the authors conclude that "based on the cirrhosis of the liver relative risks in the four sub-cohorts, the findings suggest little or no positive confounding related to alcohol consumption."

Because there are no reliable data on tobacco use for the Ontario nickel cohort, Julian and Muir acknowledge the potential for bias in their results since smoking, as well as alcohol, could not be controlled for in their study.

Julian and Muir noted consistently elevated rates of lung cancer in workers with less than 15 years since first exposure. For this reason the authors concluded that there may have been a positive effect from confounding due to smoking on their data.

As mentioned previously in this report, elevated lung cancer risks in shorter duration workers may be partly due to the combination of nickel mining experience and experience in other ores. The distribution of person years in nickel only miners indicates it may be a mistake to infer confounding from smoking. As well, Dr. A.B. Miller in his review of the Julian and Muir study, dated February 1996, considers the question of confounding and concludes its effect may be negligible:[52]

... empirical studies have suggested that the difference between a study cohort's smoking rates and those in the general population has to be quite large to result in SIRs that approach 150 due to such confounding. Further, for a spurious dose-response relationship to be produced, the degree of confounding has to increase with increasing exposure to the factor of interest, generally considered to be somewhat improbable.

... For smoking Julian and Muir do suggest positive confounding [for the combined cohort], largely because of "excesses" of lung cancer in workers under 15 years from first exposure... Apart from the fact that these "excesses" are not statistically significant, there is no corresponding excess of respiratory disease in any of the sub-cohorts in either of the two time periods. This suggests that there is no positive confounding by smoking...

Another disease potentially affected by smoking is cardiovascular disease... However, the excesses noted in circulatory disease are not for 1950-63, but for 1964-89, a period when for much of North America, including Ontario as a whole, mortality from cardiovascular disease was falling. It is possible that at the time the fall was less in Northern Ontario than in the rest of the province. Be that as it may, this pattern (coupled with the lack of a similar effect for respiratory disease), does not suggest that confounding by smoking is a major concern.

Furthermore, in their presentation to stakeholders in September 1995, Julian and Muir showed data that effectively addressed the rather improbable scenario of a spurious dose response mentioned above. The researchers examined the effect of duration of exposure on lung cancer risk among workers of various ages. Figure 5 depicts the results for miners of similar age groupings and shows the same pattern of increasing lung cancer risk with increasing exposure. If smoking were the most significant cause of the excess lung cancer in this cohort, one would expect to see a flat line with duration of exposure for any particular age group. The assumption is that workers of the same age, living in the same locale, and working in the same industry would have similar smoking histories. As lung cancer is even more strongly associated with smoking than laryngeal cancer, it would appear reasonable to conclude that these findings are relevant for laryngeal cancer as well.

In addition, the authors attempted to adjust for smoking and other confounders by an internal comparison between exposed and non-exposed workers in the whole cohort. The opinion of the authors regarding the possibility of confounding due to smoking must also be weighed against the information, described as smoothed data, that they presented in response to peer review criticisms of insufficient analysis of confounding.

Figure 6, taken from the final text of the Julian and Muir report, shows an internal comparison of laryngeal cancer rates for miners compared with other non-mining workers. The miners show elevated rates of laryngeal cancer which increase with duration of exposure. However, the value of internal comparisons with respect to laryngeal cancer is limited for two reasons. In the first instance, the number of cases of laryngeal cancer is small. Therefore, the rates for the reference groups, like never-mining (hourly and foremen) and the resulting SIRs, are based on small numbers and are accordingly unstable. This instability diminishes the probability of an accurate comparison. Secondly, the never mining (hourly and foreman) comparison is known to include workers in the mill who have statistically significant elevated rates of cancer of the larynx. Also included in this group are refinery and Iron Ore Recovery Plant workers who also have elevated, although not statistically significant, rates of cancer. Therefore this would be a comparison of exposed mining to exposed never mining workers.

The internal comparison conducted for lung cancer is a better method of evaluating the potential confounding by smoking. (There were approximately six times more cases of lung cancer than laryngeal cancer which would significantly improve the stability of the rates). The lung cancer rates increase with workplace exposure regardless of the comparison group. Since it can be reasonably assumed that the smoking habits of all miners are similar to their work peers, the rates of lung cancer which exceed the rates of their peers, are most probably explained by work exposures rather than lifestyle factors.

CHAPTER FOUR
CONCLUSIONS, FINDINGS AND RECOMMENDATIONS

In the following pages the Panel bases its findings on the subcohorts of mining, milling, smelting and refining in terms of the Bradford Hill criteria. Since all of the cases of laryngeal cancer occurred following the onset of exposures, temporality has been met in all cases and will not be dealt with individually.

In dealing with the Hill criteria of specificity the Panel noted that workplace exposures for nickel production workers include many carcinogenic agents for respiratory tract cancers. This fact makes it very difficult to single out one specific workplace carcinogen for laryngeal cancer. Accordingly the test for specificity has not been met; however as Bradford Hill warned, there may be over-reliance on the specificity criterion.

Finally, with respect to the issue of biological plausibility, all workers in the primary nickel industry could be exposed to respirable dusts, mists and fumes. Since these dusts, mists and fumes contain known respiratory carcinogens, it is therefore, biologically plausible that laryngeal cancer is occupationally related in these workers.

A. MINING

Conclusions

• Data from Julian and Muir calculated by ODP staff show a statistically significant elevated SIR of 174 (95% CI 111-259) for miners with more than 25 years exposure.
• Shannon and Roberts, on an examination of fatal laryngeal cases only, found a statistically significant SMR of 400 (95% CI 109-1024) for miners;
• A clear dose-response relationship for laryngeal cancer among miners was found; Julian and Muir state:

In underground miners, an increasing trend, beginning in the 15-24 year DOE category, was apparent and statistically significant [chi square analysis], even though the individual relative risks were not [45].

• Miners are exposed to IARC Group 1 carcinogens including, nickel aerosols, PAHs and sulphuric acid from diesel emission, asbestos, radon and oil mists.
• Miners are exposed to other agents which are suspected to be respiratory carcinogens including arsenic, cobalt, cadmium, chromium, and silica.

Analysis of the data

Strength of Association

There is a strong association between the incidence of laryngeal cancer and mining experience for those workers with the longest service [ SIR 174 (95%CI 111-259)]. Such a finding is supported by the Shannon data which showed an SMR of 400 for the Falconbridge mining population. An earlier mortality study of the INCO cohort by Roberts et al. showed an overall excess laryngeal cancer SMR of 118 which was not statistically significant. These earliest data were not reported in such a way as to examine the potential for a dose response. In addition this early study was of the entire cohort which may dilute findings in the mining, milling and refinery portions of the cohort. There were no other studies available to the Panel that examined the rates of laryngeal cancer among miners specifically.

Consistency

Since there is no evidence concerning miners outside the Sudbury area with nickel experience and laryngeal cancer, it is impossible to assess the consistency of the data studied. However in the Sudbury area the findings for workers at the separate complexes at Falconbridge and INCO show consistently elevated rates as reported previously.

Dose/Response

The most recent data by Julian and Muir show a clear dose/ response between duration of employment as an underground miner and the incidence of laryngeal cancer. The authors confirmed the dose/response trend to be statistically significant.

Biological Plausibility and Experimental Evidence

The research analyzed by IARC confirms that exposures experienced by underground miners, including exposure to nickel, asbestos, PAHs and oil mists, have been shown in animal experiments to cause respiratory cancers including cancer of the larynx.

Coherence

Closely aligned with plausibility, coherence implies that an observed association being considered as possibly causal should not conflict with what is known about the natural history and biology of the disease. There is no conflict between what is known about the natural history of laryngeal cancer and a possible occupational connection. In the mining environment, workers are potentially exposed to substances which have been shown to cause cancer in histologically similar parts of the upper respiratory tract, including the larynx.

Analogy

Workers exposed to similar substances, including Norwegian nickel refinery workers and workers in the manufacturing sector exposed to oil mists, have also experienced elevated rates of laryngeal cancer.

In summary, the evidence shows that nickel miners exposed to Group 1 carcinogens have elevated rates of laryngeal cancer and those rates increase with duration of exposure. Other available evidence about the mining cohort, specifically the absence of elevated rates of non-malignant respiratory illness, cardiovascular disease and cirrhosis of the liver, dispels the argument that elevated rates of laryngeal cancer are attributable to non-work related factors.

The Panel's Findings and Recommendations

• The Panel finds that there is a strong probable connection between nickel mining and laryngeal cancer.
• Accordingly, the Panel recommends that nickel mining and laryngeal cancer should be added to Schedule 3 of the Workers' Compensation Act.

B. MILLING

Conclusions

• Data from Julian and Muir show a statistically significant SIR of 400 (95% CI 147-871) for all mill workers with more than 25 years exposure.
• Julian and Muir found:

A four-fold risk in millers with more than 25 years of exposure was identified and is likely to be work-related [45].

• The rates of laryngeal cancer for mill workers increase with duration of exposure. When all four exposure categories are used in the calculations there is a statistically significant dose/response trend.
• Mill workers are exposed to IARC Group 1 carcinogens including nickel aerosols and asbestos.
• Mill workers are exposed to other agents which are suspected to be respiratory carcinogens including arsenic, cobalt, cadmium, chromium, and silica.

Analysis of the data

Strength of Association

The only research with sufficient power to allow for a complete analysis of the nickel milling experience comes from Julian and Muir. Their data reveal elevated rates of laryngeal cancer among mill workers. The overall SIR for all mill workers with more than 15 years experience is 400 (CI 95% 147-871). The data show a five-fold increase of risk at SIR 500(CI 95% 136-1280) for mill workers with 30 or more years of exposure.

Consistency

Although there are no studies of mill workers outside the Sudbury basin, there have been two studies of mill workers at 6 different mills at 2 different companies. These findings for mill workers are consistent.

Dose/Response

Julian and Muir conclude that their data show that the rate of laryngeal cancer among long-term mill workers is likely to be work related. This opinion is based on the evidence of increasing rates of laryngeal cancer with increasing duration of employment. When all of the data is evaluated there is a statistically significant dose/response trend.

Biological Plausibility and Experimental Evidence

The available evidence on exposures shows that mill workers are exposed to more nickel dust than miners and that this dust is also more concentrated. IARC has identified animal studies which have shown elevated rates of respiratory cancer among animals exposed to nickel aerosols.

Coherence

Closely aligned with plausibility, coherence implies that an observed association being considered as possibly causal should not conflict with what is the natural history and biology of the disease. There is no conflict between what is known about the natural history of laryngeal cancer and a possible occupational connection. In the milling environment, workers are exposed to substances, such as concentrated nickel dust, which have been shown to cause cancer in histologically similar parts of the upper respiratory tract, including the larynx.

A greater than four-fold statistically significant elevation of laryngeal cancer rising with duration of exposure establishes a strong association between nickel milling and this cancer. The absence of a rise in other non-malignant respiratory diseases, cardiovascular disease and cirrhosis of the liver makes it unlikely that lifestyle factors can offset the workplace association. The exposure of these workers to respiratory carcinogens, which include nickel and its compounds, satisfies the Panel that there is a biologically plausible explanation for the elevated rates of laryngeal cancer.

Panel's Findings and Recommendations

• The Panel finds a strong probable connection between nickel milling and laryngeal cancer.
• Accordingly, the Panel recommends that nickel milling and laryngeal cancer be included in Schedule 3 of the Workers Compensation Act.

C. SMELTING AND SINTERING

Conclusions

• Workers employed in nickel smelting and in the sintering process are exposed to known respiratory carcinogens.
• In the Sudbury sintering operation there were no elevated rates of laryngeal cancer.
• The data from Ontario studies show very high statistically significant rates of lung and nasal cancers for sinter workers but not for nickel smelter workers with no sinter experience. Lung and nasal cancers have a low survival rate, which fact may mask the true incidence of laryngeal cancer for sinter workers.

Analysis of the data

Strength of Association

There is no reliable data available to the Panel to establish that workers in the smelting and sintering processes have elevated rates of laryngeal cancer. An association, therefore, cannot be established on this Bradford Hill criterion which requires evidence of a strong statistical association.

Dose/Response

There is no evidence of a dose/response relationship.

Biological Plausibility and Experimental Evidence

It is known and not disputed that workers engaged in sintering and smelting are exposed to Group 1 carcinogens, including nickel and asbestos. It is also known that this group of workers has documented rates of other respiratory cancers well in excess of the expected.

Analogy

An analogous situation usually describes similar patterns of disease among workers in different work environments. In this case because of the very high rates of other respiratory cancers including nasal and lung one would expect to see potentially elevated rates at other histologically similar sites in the respiratory tract such as the larynx. The fact that these are not seen is probably explained by the rapid mortality of lung and nasal cancers superseding the development and diagnosis of laryngeal cancer.

In this case, the Panel does not believe that the evidence is sufficiently complete to recommend that a legal presumption in favour of compensation be implemented. The Panel feels, however, that it is reasonable to look at the total work experience of smelter and sinter workers, together with known exposures, to determine if cases of laryngeal cancer among these workers merit compensation.

The Panel's Findings and Recommendations

• The Panel finds that a probable connection between laryngeal cancer and nickel exposures in the smelting and sintering processes has not been established. However, the high incidence of lung and nasal cancers among these workers suggests that laryngeal cancer, also a respiratory cancer, could possibly be work-related.
• In light of this finding, the Panel recommends that cases of laryngeal cancer among smelter and sinter workers be given case by case consideration.

D. REFINING

Conclusions

• In Norway, workers in refining operations have a statistically significant elevated rate for laryngeal cancer. The highest elevation is found among refinery workers in the roasting and smelting operations.
• In Ontario, the workers in the nickel refinery without sintering experience had an elevated overall SIR for laryngeal cancer of 171 (95%CI 78-325). For sintering workers the rate approximated the expected, at an SIR of 96(95%CI 26-247).
• Workers in the refinery would have been exposed to known respiratory carcinogens including nickel aerosols, asbestos and sulphuric acid. They would also have been exposed to suspected respiratory carcinogens including cobalt and arsenic.

Analysis of the data

Strength of Association

The international evidence shows very high rates of laryngeal cancer among nickel refinery workers. These very high rates are not apparent in Ontario; however, there are high but not statistically elevated rates among the workers in the electrolytic department at Port Colborne. These high rates are in keeping with the known exposures of these workers.

Consistency

The rates for all nickel refinery workers for cancer of the larynx are elevated indicating a consistent finding across different cohorts. However, it must be noted that the Ontario rates are not statistically significant.

Dose/Response

Julian and Muir argued against an association between laryngeal cancer and Ontario refinery work because they were unable to find a dose/response relationship. Two separate facts, however, must be considered when examining this data for a dose response trend. Firstly, the small number of expected cases in each exposure category means there is very little power to detect a statistically significant trend even if present [79]. That is, the absence of a statistically significant dose/ response is not an instructive finding. [80].

Secondly, it is known that closures of other operations at the Port Colborne refinery at various times led to an influx of workers from other departments into the electrolytic department. Workers with the greatest seniority would be more likely to win new assignments in the electrolytic department. Workers with lower seniority in the electrolytic department could have significant exposure in other parts of the refinery. Therefore, duration of exposure in the electrolytic department may not reflect a worker's true refinery exposure and could mask a dose/response trend.

Biological Plausibility and Experimental Evidence

Workers in Ontario refineries are exposed to concentrated nickel aerosols and significant amounts of sulphuric acid mist, both of which are established causes of laryngeal cancer. The most recent animal studies show elevated rates of laryngeal cancer among rats exposed to cobalt.

Analogy

While laryngeal cancer is not seen to be elevated among sinter workers it is important to note that other respiratory cancers are highly elevated including nasal and lung.

It would have been interesting to evaluate the difference, if any, between exposures in the Norwegian and Ontario refineries. This is, however, not possible since the Ontario nickel refinery operation has been closed for more than a decade.

In the Panel's opinion the most recent evidence, albeit lacking in power, does not rebut the possibility that workers at Port Colborne may have experienced work-related laryngeal cancers as defined in the Workers' Compensation Board's current policy. Since the workers are known to be exposed to carcinogens at work some of which are known to cause laryngeal cancer and some groups of workers experienced elevated rates of such cancers, the Panel believes that the current policy should stand.

Panel's Findings and Recommendations

• The Panel finds that there is no evidence to dispute the probable connection between work in Ontario nickel refineries and elevated rates of laryngeal cancer established by the WCB in Policy 04-04-13.
• The Panel recommends that WCB adjudicators continue to rely on the current policy when evaluating laryngeal cancer claims from nickel refinery workers.

Concerns

1. In contrast to the individual findings for workers in mining, milling, smelting and refining, this Report has not specifically dealt with the findings related to workers in the Iron Ore Recovery Plant (IORP). Among the IORP workers the overall rate for cancer of the larynx is elevated but not statistically significant, SIR 174 (CI 95% 65-383). For the IORP workers with 15 or more years of exposure the SIR is 345 (CI 95% 42-1246).
   The Panel suggests that these rates warrant attention and monitoring by the INCO/USWA Joint Occupational Health Committee and the Workers' Compensation Board.
2. While the focus of this report has been on the health of workers engaged in the primary production of nickel, the Panel believes that it would be remiss in not commenting on the need to also monitor the health of workers at the Port Colborne refinery who may have been employed in nickel refining but continue to be employed in the refining of cobalt. Potential adverse health effects have been raised by IARC and more recently by the work of the National Toxicology Program.
   The Panel suggests that the health of these workers continue to be monitored by the WCB and JOHC.

REFERENCES

1. Ahrens, W.; Jöckel, K.-H.; Patzak, W.; Eisner, G. Alcohol, smoking, and occupational factors in cancer of the larynx: a case-control study. American Journal of Industrial Medicine. Vol. 20(1991). p.477-493.
   
2. Ahlman, K.; Koskela, R-S.; et al. Mortality among Sulphide Ore Miners. American Journal of Industrial Medicine. Vol. 19(1991). p.603-17.
   
3. American Conference of Governmental Industrial Hygienists. 1992-1993. Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati: ACGIH, 1992.
   
4. Bieber, O. [Letter to Hon. Joe Dear, Assistant Secretary of Labour for OSHA, requesting a change in the PEL limit for machining fluids]. December 9, 1993.
   
5. Boldt, J.; Queneau, P. The Winning of Nickel. The Hunter Rose Co. Toronto. 1967.
   
6. Bravo, M.P.; Espinosa, J.; Calero, J.D.R. Occpuational Risks Factors for Cancer of the Larynx in Spain. Neoplasma. 37(4), 1990. p. 477-481.
   
7. Burch, J.D.; Howe, G.R.; Miller, A.B.; Semenciw, R. Tobacco, alcohol, asbestos, and nickel in the etiology of cancer of the larynx: A case-control study. Journal of the National Cancer Institute. Vol. 67, no. 6(1981). p.1219-1224.
   
8. Cauvin, J.M.; Guénel, P.; et al. Occupational exposure and head and neck carcinoma. Clinical Otolaryngology. Vol. 15(1990). p.439-445.
   
9. Chase, R. Laryngeal cancer and nickel workers. ODP internal memo. May 27, 1996.
   
10. Chovil, A.; Sutherland, R.B.; Halliday, M. Respiratory cancer in a cohort of nickel sinter plant workers. British Journal of Industrial Medicine. Vol.38(1981). p.327-333.
    
11. Clarke, E.A.; Marrett, L.D.; Kreiger, N. Twenty years of cancer incidence 1964-1983. In: Cancer in Ontario, 1985. The Ontario Cancer Treatment and Research Foundation. 1985.
    
12. Coggon, D.; Pannett, B.; et al. A survey of cancer and occupation in young and middle aged men. I: Cancers of the respiratory tract. British Journal of Industrial Medicine. Vol. 43(1986). p.332-338.
    
13. Deluca, D. [Personal Communication to ODP, on Nickel Smelting and Refining]. 1997.
    
14. Doll, R. et al. Report of the International Committee on Nickel Carcinogenesis in Man. Scandinavian Journal of Work, Environment & Health. Vol. 18, no. 1 (special issue) (1990).
    
15. Dupré J.S. Report of Commission on Matters of Health and Safety Arising from the Use of Asbestos in Ontario. Vol. 2. Toronto: Ministry of the Attorney General, 1984.
    
16. Elinson, L. Review of the literature on laryngeal cancer and occupational nickel exposure. Toronto, Ontario: WCB Occupational Disease Department. May 30, 1988.
    
17. Elliott, W. Personal communication [to ODP] regarding underground mining lubrication requirements. 1996.
    
18. Flanders, W.D.; Cann, C.I.; Rothman, K.J.; Fried, M.P. Work-related risk factors for laryngeal cancer. American Journal of Epidemiology. Vol. 119, no.1(1984). p.23-32.
    
19. Flanders, W.D.; Rothman, K.J. Occupational risk for laryngeal cancer. American Journal of Public Health. Vol. 72, no. 4(1982). p.369-372.
    
20. French, Ian W & Associates. Health Implications of Exposure of Underground Mine Workers to Diesel Exhaust Emissions: An Update. Markham: Ian W. French and Associates Ltd. April 1984.
    
21. Grandjean, P. Health effects of nickel. Submitted to Ontario Ministry of Labour. Odense, Denmark: Department Of Environmental Medicine, 1986.
    
22. Guenel, P.; Engholm, G.; Lynge, E. Laryngeal cancer in Denmark: a nationwide longitudinal study based on register linkage data. British Journal of Industrial Medicine. Vol. 47(1990). p.473-479.
    
23. Haguenoer, J.M.; Cordier, S.; Morel, C.; Lefebvre, J.L.; Hemon, D. Occupational risk factors for upper respiratory tract and upper digestive tract cancers. British Journal of Industrial Medicine. Vol. 47(1990). p.380-383.
    
24. Ham, J. Report of the Royal Commission on the Health & Safety of Workers in Mines. Toronto: Ministry of the Attorney General, 1976.
    
25. Hammond, E.C.; Selikoff, I.J.; et al. Asbestos exposure, cigarette smoking and death rates. Annals of the New York Academy of Sciences. Vol. 330(1979). p.473-490.
    
26. Hill, A.B. The environment and disease: Association or causation? Proceedings of the Royal Society, Section of Occupational Medicine. Vol. 58(1965). p.295-300.
    
27. Hinds, M.W.; Thomas, D.B.; O'Reilly, H.P. Asbestos, dental x-rays, tobacco, and alcohol in the epidemiology of laryngeal cancer. Cancer. Vol. 44(1979). p.1114-1120.
    
28. IARC. Cadmium, Nickel, Some Epoxides, Miscellaneous Industrial Chemicals and General Consideration on Volatile Anaesthetics. Vol. 11. Lyon, France: International Agency for Research on Cancer, 1976.
    
29. IARC. Monographs on the evaluation of carcinogenic risks of chemicals to humans. suppl. 4. Lyon, France: International Agency for Research on Cancer, 1982.
    
30. IARC. Monographs on the evaluation of carcinogenic risks of chemicals to humans. suppl. 7. Lyon, France: International Agency for Research on Cancer, 1987.
    
31. IARC. Polynuclear Aromatic Compounds, Part 2 , Carbon Blacks, Mineral Oils and Some Nitroarenes. (Vol 33). Lyon: International Agency for Research on Cancer, 1984.
    
32. IARC. Diesel and Gasoline Engine Exhaust and Some Nitroarenes. Vol. 46. Lyon, France: International Agency for Research on Cancer, 1989.
    
33. IARC. Chromium, Nickel and Welding. Vol. 49. Lyon, France: International Agency for Research on Cancer, 1990.
    
34. IARC. Chlorinated Drinking Water; Chlorination By-products; Some other Halogenated Compounds; Cobalt and Cobalt Compounds. Vol. 52. Lyon, France: International Agency for Research on Cancer, 1991.
    
35. IARC. Occupational Exposures to Mists and Vapours from Strong Inorganic Acids; and Other Industrial Chemicals. Vol. 54. Lyon, France: International Agency for Research on Cancer, 1992.
    
36. INCO Submission to the Occupational Exposure Limits Task Force. INCO. 1993.
    
37. Industrial Disease Standards Panel. Report to the Workers' Compensation Board on the Ontario Gold Mining Industry. (IDSP Report No. 1). Toronto: Industrial Disease Standards Panel, April, 1987.
    
38. Industrial Disease Standards Panel. Second report to the Workers' Compensation Board on certain issues arising from the report of the Royal Commission on Asbestos. (IDSP Report No. 7). Toronto: Industrial Disease Standards Panel, April, 1990.
    
39. Industrial Disease Standards Panel. Report to the Workers' Compensation Board on lung cancer in the hardrock mining industry. (IDSP Report No. 12). Toronto: Industrial Disease Standards Panel, March, 1994.
    
40. Industrial Disease Standards Panel. Report to the Workers' Compensation Board on cardiovascular disease and cancer among firefighters. (IDSP Report No.13). Toronto: Industrial Disease Standards Panel, September, 1994.
    
41. International Labour Organization (ILO). Encyclopaedia of Occupational Health and Safety, 3rd ed. Parmeggiani, L., ed. Geneva: Vol.2(1983). p.1753-1759.
    
42. International Labour Office (ILO). Revisions of the ILO list of occupational diseases appended to Convention No. 121. Working document. Dr. M. Lesage. Geneva (1991).
    
43. International Social Security Association. Occupational diseases & possibilities of preventing them. Geneva: Report IV(1993). p.73-83.
    
44. Jackson, J.F. The Evolution of the Falconbridge Smelter. Falconbridge Ltd, Sudbury Division. December 1990.
    
45. Julian, J.A.; Muir, D.C.F. A Study of Cancer Incidence in Ontario Nickel Workers. Final report. Toronto: Occupational Disease Panel, January, 1996.
    
46. Kennaway, N.M.; Kennaway, E.L. A further study of the incidence of cancer of the lung and larynx. British Journal of Cancer. Vol. 1(1947). p.260-298.
    
47. Kusiak, R.A.; Ritchie, A.C.; et al. Mortality from lung cancer in Ontario uranium miners. British Journal of Industrial Medicine. Vol.50 (1993). p.920-928.
    
48. Kusiak, R.A. Does occupational exposure to dust prevent colorectal cancer? [Letter to the Editor]. Occupational and Environmental Medicine. Vol.52 (1995). p.699.
    
49. Liddell, F.D.K. Laryngeal Cancer and Asbestos. British Journal of Industrial Medicine. Vol. 47(1990). p.289-291.
    
50. Mastromatteo, E. Nickel and its compounds. In : Zenz, Dickerson, Horvath, eds. Occupational Medicine, 3rd ed. St. Louis : Mosby, 1994. p.558-571.
    
51. Magnus, K.; Andersen, A.; Hogetveit, A.C. Cancer of respiratory organs among workers at a nickel refinery in Norway. 2nd Report. International Journal of Cancer. Vol. 30(1982). p. 681-685.
    
52. Miller, A. B. [Review of Julian and Muir for the ODP]. Jan 15, 1996.
    
53. Morgan, L.G.; Usher, V. Health problems associated with nickel refining and use. Annals of Occupational Hygiene Vol. 38. no.2(1994). p.189-198.
    
54. Muir, D.C.F.; Jadon, N.; Julian, J.A.; Roberts, R.S. Cancer of the respiratory tract in nickel sinter plant workers: effect of removal from sinter plant exposure. Occupational and Environmental Medicine. Vol. 51(1994). p.19-22.
    
55. Muir, D.C.F. [Memorandum to N. Carlan]. November 12, 1996.
    
56. Muscat J.E.; Wynder E.L. Tobacco, alcohol, asbestos, and occupational risk factors for laryngeal cancer. Cancer. Vol. 69 (1992). p.2244-2251.
    
57. National Cancer Institute of Canada: Canadian Cancer Statistics 1995. Toronto, Canada, 1995.
    
58. National Cancer Institute of Canada: Canadian Cancer Statistics 1996. Toronto, Canada, 1996.
    
59. National Toxicology Program (NTP). Report on the Toxicity Studies of Cobalt Sulfate Heptahydrate in F344/N Rats and B6C3F1 Mice (inhalation studies). NTP Tox.5, Pub. No. 91-3124, Research Triangle Park, N.C., 1991.
    
60. NIOSH. Criteria for a recommended standard. Occupational Exposure to Inorganic Nickel. NIOSH Pub. No. 77-164. US Gov. Printing Office, Washington, DC. (May 1977).
    
61. Occupational Disease Panel. Report to the Workers' Compensation Board on the health effects of occupational exposure to petroleum-based fluids used for machining and lubricating metal in manufacturing: Cancer of the larynx.