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Investigation of a cluster of leukaemia in the Illawarra region of New South Wales, 1989-1996

Victoria J Westley-Wise, Bernard W Stewart, Irene Kreis, Paolo F Ricci, Anthony Hogan, Chris Darling, Steve Corbett, John Kaldor, Neill H Stacey and Pauline Warburton
Med J Aust 1999; 171 (4): 178-183.
Published online: 16 August 1999
Research

Investigation of a cluster of leukaemia in the Illawarra region of New South Wales, 1989-1996

Victoria J Westley-Wise, Bernard W Stewart, Irene Kreis, Paolo F Ricci, Anthony Hogan, Chris Darling, Steve Corbett, John Kaldor, Neill H Stacey, and Pauline Warburton

MJA 1999; 171: 178-183
For editorial comment, see Cartwright

Abstract - Introduction - Methods - Results - Discussion - Conclusions - Follow-up - Acknowledgements - References - Authors' details
- - More articles on Haematology


Abstract Objectives: To investigate a cluster of leukaemia among young people and assess the plausibility of a disease-exposure relationship.
Design: Descriptive analysis of population-based leukaemia incidence data, review of evidence related to the causation of leukaemia, assessment of environmental exposures to known leukaemogens, and resulting risks of leukaemia.
Setting: Illawarra region of New South Wales, Australia, focusing on suburbs between the Port Kembla industrial complex and Lake Illawarra (the Warrawong area).
Main outcome measures: Standardised incidence ratios (SIRs) for leukaemia; current measured and past estimated ambient air benzene concentrations; and expected leukaemia cases attributable to estimates of ambient air benzene concentrations.
Results: In 1989-1996, 12 leukaemia cases among Warrawong residents aged less than 50 years were observed, more than the 3.49 cases expected from the rate in the rest of the Illawarra region (SIR, 343.8; 99% CI, 141.6-691.7). These people lived in suburbs immediately to the south-southwest of a coke byproducts plant (a major industrial source of benzene, one of the few known leukaemogens). The greatest excess was among 15-24-year-olds (SIR, 1085.6; 99% CI, 234.1-3072.4). In 1996, ambient air concentrations of benzene averaged less than 1 part per billion (ppb). Since 1970, ambient air concentrations of benzene were estimated to have averaged up to 3 ppb, about one-thousandth of the level at which leukaemia risk has been identified in occupational epidemiological studies. Using the risk assessment model developed by the US Environmental Protection Agency, we estimate that past benzene levels in the Warrawong area could have resulted in 0.4 additional cases of leukaemia in 1989-1996.
Conclusions: The excess occurrence of leukaemia in the Warrawong area in 1989-1996 is highly unusual. Current environmental benzene exposure and the reconstructed past environmental benzene exposure level are too low to explain the large excess of leukaemia. The cause of the cluster is uncertain.


Introduction In July 1996 the Illawarra Public Health Unit (located in the Wollongong/Port Kembla region, New South Wales) was notified that four former students of a local high school had been diagnosed with leukaemia since 1989. Preliminary investigations established that a cluster of at least 11 people aged less than 40 years who had lived in suburbs near the school had been diagnosed with leukaemia since 1989. On the basis of New South Wales cancer registration data, only about 2 to 3 cases would have been expected.

Established causes of leukaemia include occupational benzene exposure, ionising radiation, chemotherapeutic agents, and some inherited and congenital conditions.1-5 Coke byproduct plants are a recognised source of occupational, and potentially of environmental, benzene exposures.1,6,7 The people in the cluster lived in suburbs adjacent to the Port Kembla industrial complex, which includes coke ovens and an associated byproducts plant.

We report the investigation of the Illawarra region leukaemia cluster and discuss the plausibility of a disease-exposure relationship.


Methods Our investigation followed published guidelines for cancer cluster investigations.8-10 The main components were evaluations of:

  • the pattern of leukaemia incidence in the Illawarra region, with specific attention to residential areas near the Port Kembla industrial complex;

  • environmental exposure to known and putative leukaemogens; and

  • the plausibility of a disease-exposure relationship (whether past environmental exposures to known leukaemogens could explain the excess leukaemia occurrence).

The NSW Cancer Council Ethics Committee approved the study.

Case finding and investigation
Active and passive case-finding methods were used to identify all people resident in the Illawarra region (Wollongong, Shellharbour and Kiama Local Government Areas) aged less than 50 years who had been diagnosed with leukaemia in 1989-1996. The cut-off at age 50 years was chosen as the index cases were young and the age interval 40-50 years represents a natural change in leukaemia occurrence, when the leukaemia risk begins to rise steeply.

We actively identified cases from bone marrow aspirate reports, hospital discharge and day-only admission data, and discussions with clinicians in Sydney and Wollongong, community members and organisations. The population-based New South Wales Central Cancer Registry provided the passive case-finding data.

For each leukaemia case, we sought to review the medical record and interview the patient and/or a relative to obtain or confirm information about dates of birth and diagnosis, leukaemia cell-type, genetic and medical risk factors, residential and school histories, and personal and/or parental occupational histories.

Occurrence evaluation
Leukaemia incidence was analysed in eight areas within the Illawarra region with a similar population size (about 20 000-30 000 in 1986), including the area close to the Port Kembla industrial complex (Area 1) (Figure 1).

Leukaemia incidence rates in the whole Illawarra region, and each of the eight areas within it, were compared with rates in a reference population by calculating standardised incidence ratios (SIRs) as a means of indirect age standardisation.11 The reference population used was "Urban NSW" (Sydney, Wentworth, Central Coast, Hunter and Illawarra administrative health areas). The calculation of rates was based on place of residence at diagnosis.

Using Central Cancer Registry data, we calculated leukaemia SIRs for males and females and for people aged less than 50 years for four five-year periods which had Census years as their mid-points: 1974-1978, 1979-1983, 1984-1988 and 1989-1993.

The SIR is the ratio of the number of cancer cases in a study population to the number of cases expected according to the age-specific rate in the reference population (multiplied by 100).

For the Illawarra region, leukaemia rates could be calculated to 1996. Thus, for 1989-1996, leukaemia SIRs were calculated for each of the Illawarra areas. In Area 1, they were also classified by age group and cell-type (according to ICD-9),12 using the rest of the Illawarra region as the reference population.

Australian Bureau of Statistics (ABS) census data for 30 June 1976, 1981, 1986 and 1991 were used for urban NSW reference populations.13 For the Illawarra region, the ABS provided population data by postcode.

Exact Poisson confidence intervals (CI) around the SIRs were estimated.14 CIs were set at 99%, rather than 95%, to reduce the possibility of identifying a chance excess of cancer as statistically significant. SIRs and CIs were calculated with SAS for Windows version 6.11. NSW Central Cancer Registry data and urban NSW population data were accessed from NSW Health's Health Outcomes Information and Statistical Toolbox, a repository of health-related databases for New South Wales.

Environmental monitoring and historical exposure reconstruction
We undertook an extensive review of the literature on risk factors for and causes of leukaemia, and on carcinogenic effects of occupational and environmental exposures.

The environmental assessment focused on exposure to known leukaemogens from the 1970s to 1996. It involved interviewing representatives from industry, government agencies, local residents and workers; inspecting relevant sites; reviewing government, industry and press reports; and collecting and reviewing information on environmental and occupational exposure for residents and workers.

The NSW Environment Protection Authority (EPA) and BHP Steel began daily ambient air benzene monitoring in September 1996 in the residential areas nearest the plant (Figure 2). Monitoring was also conducted at three control sites. The EPA used the standard protocol developed by the US Environmental Protection Agency (US EPA) for assessing toxic organic compounds in ambient air.15 BHP used personal samplers, adapted to a stationary role, which collected organic vapours onto an active adsorbent medium by drawing air through the sampler. Both the EPA and BHP analysed the samples with gas chromatography at laboratories registered with the National Association of Testing Authorities.

We estimated environmental benzene exposure from the main local sources before September 1996. Using methods developed by the US EPA,16 we estimated levels of emissions from the coke production facilities for each year since 1970 (based on levels in 1996, adjusted for changes in plant equipment and processes and changes in coke and benzene production). Information related to benzene emissions from motor vehicles and other petroleum sources, including Roads and Traffic Authority data on local traffic volumes, was used to provide an upper estimate of the extent to which emissions from these other major local sources may have differed in previous years relative to 1996.

Risk estimation The US EPA's benzene risk assessment model of dose-response17 was used to estimate the number of excess leukaemia cases expected in Area 1 between 1989-1996. It was assumed that the Area 1 population had breathed ambient air (70 kg person breathing 20 m3 of air daily) with benzene concentrations equivalent to the estimated maximum annual average concentration since 1970 for the maximally exposed site, continuously over a lifetime (24 hours per day for 70 years).


Results

Case finding and investigation
The same cases were identified by both active and passive case-finding methods. We identified 44 Illawarra residents aged less than 50 years who were diagnosed with leukaemia in 1989-1996. These included 12 people resident in Area 1 at diagnosis, and a 13th person who had moved out of Area 1 a few months before diagnosis (Table 1).

None of these 13 people from Area 1 were found to have genetic or medical risk factors for leukaemia. Nor had they ever worked in the production of coke or its byproducts. Six were diagnosed with acute lymphoblastic leukaemia (ALL), four with chronic myeloid leukaemia (CML), and three with acute myeloid leukaemia (AML). Immunophenotypic features and leukaemic classifications revealed no unusual patterns. Six people have died.

Of the nine people from Area 1 aged 20 years or less, seven had lived there all their lives, and two for about 11 years. Four attended the same high school in the late 1980s, with three being in the same school year; these three people had leukaemia of different cell-types.

Occurrence evaluation
For the four five-year periods between 1974-1993, leukaemia incidence in the Illawarra region, and each of its areas, was not significantly different to that throughout urban New South Wales.18 The incidence of total cancers and other specific cancers (including lymphoma and multiple myeloma) was also not significantly higher in Area 1.18

However, leukaemia incidence among Area 1 residents aged less than 50 years in 1989-1996 was more than three times higher than in the rest of the Illawarra region (12 cases observed, versus 3.49 expected; SIR, 344; P = 0.0003) (Table 2). The SIR was more than 200 for all leukaemia cell-types, and was significantly increased for ALL (Table 3).

The greatest excess of leukaemia was among teenagers and young adults. Among 15-24-year-olds, five cases were observed, versus 0.46 expected (SIR, 1086; 99% CI, 234.1-3072; P = 0.0001).

Environmental monitoring and reconstruction of historical exposure
The Port Kembla industrial complex contains heavy industries such as copper smelting, sulphuric acid and superphosphate manufacture, petroleum depots, and Australia's largest steelworks, which includes coke ovens and their byproducts plant. In spring and summer, the predominant wind direction is from the northeast; hence, the residential area where the people with leukaemia lived received the greatest exposure from industrial emissions in the region.

Benzene was the only known leukaemogen for which local environmental exposures may have been relevant. While ionising radiation is also an established leukaemogen, and there is evidence that exposure to occupational ethylene oxide or 1,3-butadiene can cause leukaemia,3-5 no specific local environmental sources of these agents were identified.

At the byproducts plant, coke oven gases are distilled into a benzene- toluene-xylene commercial product (which is 80% benzene), while past practices (until 1977) separated them. The closest residences are more than 1 km from the plant, with all but two Area 1 cases residing 1-3 km from the plant. The other major benzene sources in Area 1 are motor vehicles and petroleum storage tanks.

Both EPA and BHP monitoring found that ambient air benzene concentrations in Area 1 averaged less than one part per billion (ppb) in 1996 (Table 4), typical of urban sites in Sydney.19 Analysis of benzene, toluene and xylene ratios in the EPA's samples indicated that about 50% of the benzene was from petroleum.

Annual average ambient air benzene concentrations at the most exposed site within Area 1, since 1970, are estimated to have been up to about 3 ppb.

Roads and Traffic Authority data showed that traffic volumes in Area 1 have not changed appreciably since the 1970s.20 Local petroleum storage tanks had a greater storage capacity in previous years, which may have been associated with higher emissions.20

Risk estimation The estimated maximum annual average ambient air benzene concentration in Area 1 of 3 ppb is only about one-thousandth of concentrations at which leukaemia risk has been detected in occupational studies.1 The World Health Organization (WHO) has concluded that occupational exposure to an average of 1 part per million (1 ppm, ie 1000 ppb) over a working lifetime has been associated with no statistical increase in leukaemia deaths.1

Using the US EPA benzene risk assessment model,17 if a population of 17 500 people (the number of people in Area 1 aged less than 50 years in 1991) had all breathed air with an average benzene concentration of 3 ppb over a lifetime, at the most 0.2 excess leukaemia deaths (or 0.4 cases) would have been expected in 1989-1996.


Discussion This investigation into the reported cluster found a highly significant excess leukaemia occurrence in the Warrawong area, particularly among teenagers, in 1989-1996. Estimated past environmental benzene levels are too low to explain this excess.

Cluster studies Cancer cluster studies have rarely provided insights into aetiology.3,8-10,21,22 Studies of very rare diseases with well-defined, high exposures are the most likely to yield conclusive results.22 However, these circumstances, in the context of geographic (spatial or spatiotemporal) clusters, are uncommon.10,22 Disease clusters occur continually in any population, and as such represent "expectedly unexpected" events.9,22

Drawing boundaries tightly around people observed in clusters inadvertently identifies and overestimates disease excesses.21,22 However, in this study, the geographic, age and time criteria setting the boundaries were not defined or varied to influence the magnitude of the observed excess. Area 1 was a natural geographic grouping of postcodes bounded by industrial zones, Lake Illawarra and the Pacific Ocean. It included suburbs and a postcode area in which no cases were resident. The age range 0-49 years was broad given that the reported cluster was among teenagers. On the other hand, the most recent period analysed (1989-1996) was preceded by a period in which few leukaemia cases were diagnosed.18

Possible leukaemogens
Several known leukaemia causes and risk factors were excluded as explanations for the cluster: ionising radiation, ethylene oxide, 1,3-butadiene, and genetic and medical risk factors. For other agents considered, such as dioxins, pesticides, and heavy metals, evidence is lacking of a causal relationship between these agents and leukaemia, despite numerous studies conducted worldwide.5 Although benzene is structurally related to carcinogenic polycyclic hydrocarbons, these agents are generally associated with lung and some other cancers, but not leukaemia.23 Similarly, the influence of genetic polymorphisms, specifically within the cytochrome P450 family, has been associated with lung cancer rather than leukaemia.24

Viruses have been causally associated with the rare hairy cell leukaemia and adult T-cell leukaemia.4,5 They have also been suspected to cause leukaemia in childhood and adolescence, but there is still little convincing evidence that they play an important role.4,5,25 Several studies have associated parental smoking with childhood leukaemia.3,26 While many other parental occupational and/or personal exposures (including pesticides, benzene, solvents, petroleum products, and spray paints) have also been implicated in childhood leukaemia, most relevant studies have used poor exposure measures, with inconsistent results.2,3

To our knowledge no leukaemia "clusters" have been reported and investigated in close proximity to industrial facilities similar to those in the Warrawong area. Occupational exposure during steel and coke production has been causally associated with an increased risk of lung and certain other cancers, but not leukaemia.23,27-29

Benzene Benzene was the only known human leukaemogen to which people in Area 1 had potentially significant environmental exposures. Despite the inevitable focus on the steelworks and coke byproducts plant as a benzene source, petrol exhaust and tobacco smoke (the primary source of benzene for smokers, and relevant to non-smokers through passive smoking) are the most significant sources in urbanised populations.1 Food and water are not major sources of benzene exposure,30 and the possibility of contamination of the water supply in Area 1 with benzene from local sources was examined and excluded.20

While other haematological malignancies have been associated with occupational benzene exposure,31-36 the evidence has been considered strongest for AML,1 which affected only three people in this cluster. However, a recent review concluded that the few available studies of leukaemia cell-types do not indicate larger or more consistent elevations in risk for AML than for other cell-types.36

Study strengths and limitations
Studies of geographic cancer clusters must typically deal with poor information about environmental exposures.22 In this study we had to rely on estimates of past environmental benzene exposure, but several factors suggest that the emission estimates for the coke production facilities are accurate. An independent audit of the emissions estimates concluded that the underlying assumptions were robust and that the emissions inventory was calculated as accurately as possible without an onsite testing program.37 The estimated past annual average ambient air benzene concentration in the maximally exposed part of the Warrawong area, 3 ppb, was similar to concentrations measured38-40 and modelled41 at similar distances from byproducts plants overseas. Measured occupational benzene exposures for Port Kembla byproducts plant workers between 1979 and 199642 were similar to occupational monitoring results for byproducts plant workers from the United States43 and Britain in the 1980s.29,44

Using the US EPA benzene risk assessment model,17 even if we assume that average ambient air benzene concentration in Area 1 was 30 ppb (rather than the estimated 3 ppb), this level of exposure would still only explain up to four excess leukaemia cases. Given that the observed leukaemia excess was primarily among young people, the default assumption of 70 kg adults used in our risk estimate is also likely to have slightly overestimated the risk, and hence the number of expected cases.

Consistent with public health principles, the US EPA benzene risk assessment model, which uses data from studies of US rubber and chemical workers,36,45,46 is itself based on assumptions that would exaggerate rather than minimise risk, including a linear relationship between exposure to genotoxic carcinogens and leukaemia risk. However, results from some animal studies suggest that a non-linear response may be more biologically plausible.47,48 If this applies to benzene-induced human leukaemia, application of the US EPA model may considerably overestimate risks in the low exposure range.

More plausible are biologically based multistage stochastic models for chemical carcinogenesis, which account for cellular birth, death, initiation, promotion and other biological processes, each stage being linked by a stochastic transition probability that accounts for exposure (or dose).47,48 Such models are likely to produce lower estimates of leukaemia risk for low levels of environmental exposure.

However, large uncertainties are inherent in any conversion of risk estimates from animal studies or occupational studies to risk estimates for benzene exposure in the general community. Many people -- children, people of reproductive age, those with other risk factors -- may have susceptibilities to leukaemia quite different from those of the male workers studied in occupational studies. Animal and human studies have begun to clarify the potential risk associated with relatively high transient and/or intermittent benzene exposure49 versus cumulative exposure, but the relationship is still poorly understood for low dose extrapolations. In addition, people in the community are exposed to a variety of agents, which may have as yet unidentified additive and possibly synergistic effects.


Conclusions On current knowledge, the recent ambient air benzene concentrations in the Warrawong area represent a negligible leukaemia risk, and the estimated past benzene concentrations are too low to explain the large excess of leukaemia cases that occurred in 1989-1996. However, factors such as variation in susceptibilities of individuals and population groups such as children, the possible effects of intermittent and high transient benzene exposures, and interactions between different agents, mean that we cannot exclude a causal association between leukaemia occurrence among young people in the Warrawong area and chemical exposures.


Follow-up A feasibility study is being undertaken to examine the potential for relating disease to chemical exposures through a case-control study. Broadly, chemical exposures of interest are personal exposures (environmental and individual, to benzene and industrial emissions in general) and parental exposures (focusing on those with prior evidence of an association with leukaemia).

In addition, routine surveillance of leukaemia and lymphoma is continuing, as is ambient air monitoring for benzene and other hazardous pollutants in the Warrawong area.



Acknowledgements
We gratefully acknowledge the assistance given by the individuals with leukaemia and their relatives, and other community members who participated in the investigation's Community Reference Group. We give special thanks to members of the Illawarra Leukaemia Investigation Steering Committee for their commitment and contributions: Giovanna Crocco and David Gilmour (Community Reference Group), Richard Willison and Trevor Dunn (Illawarra Public Health Unit), Joe Woodward and Craig Lamberton (NSW Environmental Protection Authority), Ron Hales (Wollongong City Council), and Christine Ewan (University of Wollongong). Many individuals and organisations assisted in and supported the study, but we would particularly like to thank the following organisations: NSW Health; Illawarra Area Health Service; New South Wales Cancer Council; BHP Port Kembla; NSW Environmental Protection Authority; and the University of Wollongong. We also thank John Marthick (University of Wollongong) and Paddy Ranasinghe (Illawarra Public Health Unit) for preparing the maps.


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(Received 2 July 1998, accepted 18 May 1999)


Authors' details Illawarra Public Health Unit, Illawarra Area Health Service, Wollongong, NSW.
Victoria J Westley-Wise, MPH, FAFPHM, Director;
Anthony Hogan, MSc(Hons), PhD, Public Health Officer.

Children's Cancer Research Institute, Sydney Children's Hospital, Sydney, NSW.
Bernard W Stewart, PhD, FRACI, Research Director; now Head of Cancer Control Program, South Eastern Sydney Area Health Service.

University of Wollongong, Wollongong, NSW.
Irene Kreis, PhD, FAFPHM, Senior Lecturer;
Paolo F Ricci, MSc, PhD, Professorial Fellow.

BHP Steel Flat Products Division, Wollongong, NSW.
Chris Darling, MSc(Occup Med), FAFOM, Occupational Health Advisor.

NSW Health Department, Sydney, NSW.
Steve Corbett, MPH, FAFPHM, Manager.

National Centre for HIV Epidemiology and Clinical Research, University of New South Wales, Sydney, NSW.
John Kaldor, PhD, Deputy Director, and Professor of Epidemiology.

University of Sydney, Sydney, NSW.
Neill H Stacey, BSc(Hons), PhD, Associate Professor.

Illawarra Regional Hospital, Illawarra Area Health Service, Wollongong, NSW.
Pauline Warburton, MB BS, FRACP, Director.

Reprints: Dr V J Westley-Wise, Illawarra Public Health Unit, PO Box 66, Keiraville, NSW 2500.
Email: vwestATdoh.health.nsw.gov.au






Figure 1 (above): Map of the Illawarra region, showing areas used for comparing leukamia incidence.
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Figure 2 (below): Map of the Warrawong area (central portion of area 1), showing the location of the four ambient air monitoring stations.
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Received 26 September 2018, accepted 26 September 2018

  • Victoria J Westley-Wise
  • Bernard W Stewart
  • Irene Kreis
  • Paolo F Ricci
  • Anthony Hogan
  • Chris Darling
  • Steve Corbett
  • John Kaldor
  • Neill H Stacey
  • Pauline Warburton


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