Volume 171 Issue 4

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 1.18However, 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.1Using 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.9,22Drawing 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.24Viruses 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.20While 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.29,44Using 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. References World Health Organization. Benzene (Environmental Health Criteria No. 150). Geneva: International Programme on Chemical Safety, 1993. Ross JA, Davies SM, Potter JD, Robison LL. Epidemiology of childhood leukaemia, with a focus on infants. Epidemiol Rev 1994; 16: 243-272. Cartwright RA, Staines A. Acute leukaemias. Clin Haematol 1992; 5: 1-26. Finch SC, Linet MS. Chronic leukaemias. Clin Haematol 1992; 5: 27-56. Tomatis L, editor. Cancer: causes, occurrence and control (IARC Scientific Publications No. 100). Lyon: International Agency for Research on Cancer, 1990. Fishbein L, O'Neill IK, editors. Benzene and alkylated benzenes. Environmental carcinogens: methods of analysis and exposure measurement, vol. 10 (IARC Scientific Publications No. 85). Lyon: International Agency for Research on Cancer, 1988. 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Australian Bureau of Statistics. Estimated resident populations by age and sex in statistical local areas, New South Wales (Catalogue. No. 3209.1, 30 June 1976, 1981, 1986, 1991). Canberra: ABS, 1978, 1983, 1988, 1993. Daly L. Simple SAS macros for the calculation of exact binomial and Poisson confidence limits. Comput Biol Med 1992; 22: 351-361. United States Environmental Protection Agency. Compendium of methods for the determination of toxic organic compounds in ambient air. 2nd edition. Compendium method TO-14A. Determination of volatile organic compounds (VOCs) in ambient air using specially prepared canisters with subsequent analysis by gas chromatography (EPA/625/R-96/010b). Cincinnati, OH: Center for Environmental Research Information, 1999. <http://www.epa.gov/ttn/amtic/files/ambient/airtox/to-14ar.pdf> Accessed 5 July 1999. United States Environmental Protection Agency. AP-42, 5th ed., vol. I. Chapter 12: metallurgical industry. 12.2 Coke production [draft]. Research Triangle Park, NC: Emission Factor And Inventory Group, US EPA, 1995. <http://www.epa.gov/ttn/chief/ap42pdf/c12s02.pdf>. Accessed 5 July 1999. [No longer available, but see final version at <http://www.epa.gov/ttn/chief/ap42/ch12/final/c12s02.pdf> Accessed 10 May 2001. United States Environmental Protection Agency. Integrated risk information system (IRIS). Benzene (CASRN 71-43-2). 16 October 1998. Cincinnati, OH: Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, Cincinnati, 1996. <http://www.epa.gov/ngispgm3/iris/subst/0276.htm> Accessed 5 July 1999. Westley-Wise V, Hogan A. Report on the occurrence of leukaemia (1974-96) and other cancers (1974-93) in the Illawarra. Illawarra Area Health Service. Wollongong 1997. Wadge A, Salisbury J. Benzene. National Environmental Health Forum Monographs, Air Series 2. National Environmental Health Forum, South Australian Health Commission, Adelaide,1997. Kreis I, Willison R. Environmental assessment related to a leukaemia cluster. University of Wollongong. Wollongong 1997. Olsen SF, Martuzzi M, Elliott P. Cluster analysis and disease mapping -- why, when and how? A step by step guide. BMJ 1996; 313: 863-866. Rothman KJ. A sobering start for the cluster busters' conference. Am J Epidemiol 1990; 132 Suppl 1: S6-S13. International Agency for Research on Cancer. Polynuclear aromatic compounds. Part 3, Industrial exposures in aluminium production, coal gasification, coke production, and iron and steel founding. IARC Monographs on the evaluation of the carcinogenic risk of chemicals to humans, vol. 34. Lyon: IARC, 1984. Wormhoudt LW, Commandeur JNM, Vermeulen NPE. Genetic polymorphisms of human N-acetyltransferase, cytochrome P450, glutathione-S-transferase, and epoxide hydrolase enzymes: relevance to xenobiotic metabolism and toxicity. Crit Rev Toxicol 1999; 29: 59-124. Alexander FE. Viruses, clusters and clustering in childhood leukaemia: a new perspective? Eur J Cancer 1993; 29A: 1424-1443. Sorahan T, Lancashire RJ, Hulten MA, Stewart AM. Childhood cancer and parental use of tobacco: Deaths from 1953 to 1955. Br J Cancer 1997; 75: 134-138. Redmond CKA, Strobino BR, Cypress RH. Cancer experience among coke byproduct workers. Ann N Y Acad Sci 1976; 217: 102-115. Swaen GM, Slanged JAM, Volovics A, et al. Mortality of coke plant workers in the Netherlands. Br J Indust Med 1991; 48: 130-135. Hurley JF, Cherrie JW, Maclaren W. Exposure to benzene and mortality from leukaemia: results from coke oven and other coal product workers. Br J Indust Med 1991; 48: 502-504. Wallace L. Environmental exposure to benzene: an update. Environ Health Perspect 1997; 104: 1129-1136. Yin SN, Hayes RB, Linet MS, Li GL, et al. A cohort study of cancer among benzene-exposed workers in China: overall results. Am J Indust Med 1996; 29: 227-235. Hayes RB, Yin S-N, Dosemeci M, Li G-L, et al. Benzene and the dose-related incidence of hematologic neoplasms in China. J Natl Cancer Inst 1997; 89: 1065-1071. Rinsky RA, Alexander B, Smith MD, Hornung R, et al. Benzene and leukaemia: an epidemiological risk assessment. N Engl J Med 1987; 136: 1044-1050. Christie D, Robinson K, Gordon I, Bisby J. A prospective study in the Australian petroleum industry. I. Mortality. Br J Indust Med 1991; 48: 507-510. Wong O. An industry wide mortality study of chemical workers occupationally exposed to benzene. II. Dose response analyses. Br J Indust Med 1987; 44: 382-395. Savitz DA, Andrews KW. Review of epidemiologic evidence on benzene and lymphatic and hematopoietic cancers. Am J Indust Med 1997; 31: 287-295. Holmes Air Sciences 1997. Air quality report: review of BHP report to the Illawarra Area Health Service Leukaemia Task Force. Report prepared for the NSW Environment Protection Authority. Sydney: Holmes Air Sciences, 1997. Harkov R, Olsakovsky AC, Fillo JP. Determining the ambient impacts of coke and coke by-products manufacturing on selected pollutant levels in neighboring communities: I -- results from a six-month ambient air benzene monitoring study. Air toxics and volatile organic compounds: papers from the 84th Annual Meeting and Exhibition of the Air and Waste Management Association, Vancouver, 1991. Vol 6. Pittsburgh: Air and Waste Management Association, 1991. GDCh (Society of German Chemists) Advisory Committee on Existing Chemicals of Environmental Relevance. Benzene. Weinhmam, VCH Verlagsgesellschaft, 1988. In: World Health Organization. Benzene (Environmental Health Criteria No. 150). Geneva: WHO, 1993: 36. Fentiman AF, Neher MB, Kinzer GW, et al. Environmental monitoring benzene (PB-295 641). Prepared for US EPA. Springfield, VA: Battelle Columbus Laboratories, National Technical Information Service, 1979. In: IARC. Some industrial chemicals and dyestuffs (IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans, vol. 29). Lyon: IARC, 1982. United States Environment Protection Agency. Benzene emissions from coke byproduct recovery plants -- background information for proposed standards (EPA-450/3-83-016a). Research Triangle Park, NC: Office of Air Quality Planning and Standards, 1984. BHP Flat Products Division. Report to the Illawarra Area Health Service. Port Kembla: BHP Flat Products Division, 1997. Runion HE, Scott LM. Benzene exposure in the United States, 1978-1983: an overview. Am J Indust Med 1985; 7: 385-393. Drummond L, Luck R, Afacan AS, Wilson HK. Biological monitoring of workers exposed to benzene in the coke oven industry. Br J Indust Med 1988; 45: 256-261. Rinsky RA, Young RJ, Smith AB. Leukemia in benzene workers. Am J Indust Med 1981; 2: 217-245. Ott MG, Townsend DT, Fishbeck WA, Langner RA. Mortality among workers occupationally exposed to benzene. Arch Environ Health 1978; 33: 3-10. Cox LA Jr, Ricci PF. Reassessing benzene cancer risks using internal doses. Risk Analysis 1992; 12: 401-409. Cox LA Jr, Ricci PF. Dose-response non-linearities for benzene revisited: A reply to C Crump. Risk Analysis 1993; 14: 485-486. (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. Back to textFigure 2 (below): Map of the Warrawong area (central portion of area 1), showing the location of the four ambient air monitoring stations. Back to textBack to textBack to textBack to textBack to text

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

Healthcare Hepatitis C: an economic evaluation of extended treatment with interferon Alan Shiell, Sue Brown and Geoff C Farrell MJA 1999; 171: 189-193 Abstract - Introduction - Methods - Results - Discussion - References - Authors' details Abstract Objectives: To re-evaluate the cost effectiveness of treating hepatitis C virus (HCV) infection with interferon alfa (IFα) in Australia, taking into account changes in clinical practice. Design: A decision-analytic method (Markov model) was used to simulate the costs and effects of 6 months and 12 months of treatment with IFα versus no treatment (conventional management). Both costs and effects were modelled over 30 years. Data sources: Published meta-analysis of the effectiveness of treatment, professional judgement about treatment protocols, scheduled medical fees, diagnosis-related costs for hospital admission, and a literature search for quality-of-life weights. Patients: A hypothetical cohort of 1000 patients with chronic HCV infection aged 40 years at the start of treatment. Main outcome measures: Incremental costs per life-year gained and per quality-adjusted life-year (QALY) gained. Results: Compared with no treatment, IFα treatment for 6 months results in an extra 94.2 life-years or 320.1 QALYs at an extra cost of $1.8 million (after discounting at 3%) in a cohort of 1000 patients. Discounted cost per life-year gained is $19 110, which is about a quarter of the cost reported in 1994. The discounted cost per QALY gained is $5625. Extended treatment for another 6 months results in an additional 89.0 life-years saved or 170.8 QALYs gained at an incremental discounted cost of $15 835 per life-year gained and $8250 per QALY gained. Conclusions: The cost effectiveness of IFα treatment for HCV infection has improved as a result of better patient selection, cost reductions and enhanced effectiveness of extended treatment. The results are sensitive to assumptions made about quality of life and the discount rate. Introduction Infection with the hepatitis C virus (HCV) is an important public health problem in Australia. It is estimated that there are at least 100 000 people carrying the virus and that up to 10 000 new cases are diagnosed each year.1 As many as 85% of those with acute HCV infection will develop chronic infection, and, of these, a significant proportion will develop cirrhosis and hepatocellular carcinoma (HCC). The only approved treatment for chronic HCV infection, interferon alfa (IFα), is expensive, has significant adverse effects and is effective in only 10%-35% of patients. The cost effectiveness of treatment is uncertain. Decision-analytic techniques have been used to simulate the expected costs and effects of treatment, and several economic evaluations of IFα have been published.2-7 The only Australian study (published in 1994)3 estimated the cost per life-year gained by treatment with IFα to be $33 000 in patients with cirrhosis at the start of treatment and $71 000 for patients without cirrhosis. These figures are substantially higher than those reported elsewhere, reflecting a more cautious view of the long term effectiveness of IFα and the exclusion of the broader benefits of therapy, such as its assumed effects on employment and production capacity. The impact that IFα has on the natural history of HCV infection is now better known. Treatment is discontinued in patients who fail to show a response after 12 weeks, with no reduction in effectiveness but with substantial cost savings. Further, several studies have shown benefits of extended treatment over 12 months rather than 6 months, and this has become the recommended treatment period in most countries including Australia. The effect that this has on cost effectiveness is not clear, as both costs and benefits are likely to increase. Our aim is to update our previous estimate of the cost effectiveness of IFα in the treatment of chronic HCV infection.3 Under section 100 of the Health Act 1953 (Cwlth) (Highly Specialised Drugs Program), subsidised treatment is restricted to patients with no signs of cirrhosis at start of treatment and we have restricted our analysis to such patients. Methods The costs and effects of IFα treatment were simulated by a decision-analytic method (the Markov model) in a hypothetical cohort of 1000 patients with chronic HCV infection aged 40 years at start of treatment (the mean age at diagnosis is 42 years). Both costs and effects were modelled over 30 years. The cost effectiveness of treatment with IFα over 6 months versus no treatment (ie, conventional management only) was re-evaluated, incorporating changes in clinical practice, treatment costs and the price of IFα. The incremental costs and effects of moving from 6 months to 12 months' treatment were then estimated. The software used was Microsoft Excel 97. The assumptions and methods for the decision analytic technique are shown in the Box. Results The net cost of 6 months' treatment with IFα for chronic HCV infection (ie, the cost of treatment minus the cost of conventional management of the disease) was estimated to be $1800 per patient after discounting at 3%. Treatment with IFα results in an extra 94.2 discounted life-years saved or 320.1 additional (discounted) QALYs (Table 2). The incremental cost per life-year saved was $19 110, which is about a quarter of the cost reported in our previous study.3 The incremental cost per QALY gained was $5625. Extending treatment from 6 to 12 months results in an additional 89.0 discounted life-years gained or 170.8 discounted QALYs at incremental costs of $15 835 per life-year gained and $8250 per QALY gained. Average cost per unit of outcome increases as the duration of the model is reduced. As duration of the model acts as a proxy for age at the start of treatment, this finding suggests that treatment is less cost effective in older age groups. The sensitivity analysis (Table 3) suggests that the results for 6 months' treatment are robust with respect to assumptions made about rates of disease progression, the long term effectiveness of IFα, the price of IFα and the exclusion of patients not responding after 12 weeks. The most important variables are the choice of discount rate and the adjustment for quality of life (Table 3). Relatively minor adjustments to the quality-of-life weight for treatment have a large effect on cost per QALY gained. In the extreme, the adverse effects of treatment offset any gains in quality of life brought about by disease resolution. The effect of 12 months' treatment over 6 months' treatment is also sensitive to changes in the discount rate and the duration of the model and, in addition, is more sensitive to assumptions made about disease progression and treatment effectiveness. Discussion Our results suggest that the cost per life-year gained from 6 months' treatment with IFα is lower than when it was first evaluated in an Australian context in 1994.3 This change is attributable to three main factors: a reduction in the cost of treating people with IFα; a reduction in the price of IFα itself; and cessation of treatment at 12 weeks in those who fail to show a reduction in serum alanine aminotransferase levels. The latter has been clinical policy in Australia since IFα was first listed for public subsidy in 1994, but our initial evaluation preceded this.3Quality adjustment of the outcomes also has a substantial effect on the cost-effectiveness ratios, suggesting that the major impact of IFα treatment is on improving quality of life rather than increasing life expectancy through the prevention of cirrhosis. There is also the relief offered to those in whom the infection is resolved. However, the sensitivity of the results to changing assumptions about the effect of the disease and its treatment on quality of life reinforces the need for further research into the subjective impact of HCV infection. Only one other study has considered the cost effectiveness of 12 months' versus 6 months' therapy.7 Consistent with our results, it concluded that treatment over 12 months may be cost effective, except in patients older than 60 years of age. The cost-effectiveness ratios reported here compare favourably with many other public health interventions, such as screening for breast and cervical cancer.20,21 However, there are problems in comparing the results of economic evaluations, particularly when different methods have been used.22 Furthermore, if the benefits of extended treatment with IFα are to be realised within a limited healthcare budget, then some other program or activity must be dropped or reduced in scale to accommodate the increase in expenditure. Thus, before drawing conclusions about cost effectiveness, one should compare the benefits of IFα treatment with the benefits of the other program or activity affected.23 See Box for summary points. Caution is especially warranted when, as in this case, a decision-analytic model has been employed, as it is often difficult to assess the validity of the assumptions made. The protracted nature of HCV infection, however, makes it difficult to assess the cost effectiveness of treatment by another means.24,25 Decisions on when and how to use IFα have to be made with available data. However, our comprehensive sensitivity analysis showed that, for most of the assumptions made, the results appear to be robust. The exceptions are the two subjective variables -- the utility attached to different disease endpoints and the rate at which future costs and benefits are discounted. HCV infection is not the benign disease it was once believed to be, but little is known about the impact it has on people's lives or the lengths to which they might go for relief. Our results are particularly sensitive to assumptions made about the relative effect of living with chronic infection, and its associated risks of long term sequelae versus the known risks and the uncertain effectiveness of treatment. Individual attitudes to risk and time preference will affect the perceived cost effectiveness of treatment. Further research is needed to examine the personal and social impact of HCV infection and the utility of its treatment.26 References Australian Health Ministers' Advisory Council. National Hepatitis C Action Plan, October 1994. Canberra; AGPS, 1994. 2. Garcia de Ancos JL, Roberts JA, Dusheiko GM. An economic evaluation of the costs of a-interferon treatment for chronic active hepatitis due to hepatitis B or C virus. J Hepatol 1990; 11: S11-S18. Shiell A, Briggs A, Farrell G. The cost-effectiveness of alpha interferon in the treatment of chronic active hepatitis C. Med J Aust 1994; 160: 268-272. Dusheiko GM, Roberts JA. Treatment of chronic type B and C hepatitis with interferon alfa: an economic appraisal. Hepatology 1995; 22: 1863-1873. Joliet E, Vanlemmens C, Kerleau M, et al. Cost-effectiveness analysis of the treatment of chronic hepatitis C. Gastroenterol Clin Biol 1997; 21: 336-338. Bennet WG, Inoue Y, Beck R, et al. Estimates of the cost-effectiveness of a single course of interferon-a 2b in patients with histologically mild hepatitis C. Ann Intern Med 1997; 127: 855-865. Kim WR, Poterucha JJ, Hermans JE, et al. Cost-effectiveness of 6 and 12 months of interferon-a therapy for chronic hepatitis C. Ann Intern Med 1997; 127: 866-874. National Institutes of Health Consensus Development Panel statement: management of hepatitis C. Hepatology 1997; 26(3 Suppl 1): 2S-10S. Fattovitch G, Giustina G, Degos F, et al. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 1997; 112: 463-472. Australian Bureau of Statistics. Deaths: Australia 1994. Canberra: ABS, 1994. (Catalogue No. 3302.0.) Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration. Hepatology 1996; 24: 778-789. Carithers RL Jr, Sugano D, Bayliss M. Health assessment for chronic HCV infection: results of quality of life. Dig Dis Sci 1996; 41: 75S-80S. Davis GL, Balart LA, Schiff ER, et al. Assessing health-related quality of life in chronic hepatitis C using the Sickness Impact Profile. Clin Ther 1994; 16: 334-343. Foster GR, Goldin RD, Thomas HC. Chronic hepatitis C virus infection causes a significant reduction in quality of life in the absence of cirrhosis. Hepatology 1998; 27: 209-212. National Health and Medical Research Council. A strategy for the detection and management of hepatitis C in Australia. Canberra: NHMRC/AGPS, 1997. Commonwealth Department of Health and Family Services. Medical Benefits Schedule. Nov 1996. Canberra; AGPS, 1996. Commonwealth Department of Health, Housing, Local Government and Community Services. Manual of Resource Items and their Associated Costs. Canberra: AGPS, November 1993. Drummond MF, Brandt A, Luce B, Rovira J. Standardising methodologies for economic evaluation in health care. Int J Technol Assess Health Care 1993; 9: 26-36. Gold MR, Siegel JE, Russell LB, Weinstein MC, editors. Cost-effectiveness in health and medicine. New York: Oxford University Press, 1996: 230. AHMAC Breast Cancer Screening Evaluation Committee. Breast screening in Australia: future directions. Canberra: Australian Institute of Health and Welfare, 1990. AHMAC Cervical Cancer Screening Evaluation Committee. Cervical Screening in Australia: options for change. Canberra: Australian Institute of Health and Welfare, 1991. Salkeld G, Davey PD, Arnolda G. A critical review of health-related economic evaluations in Australia: implications for health policy. Health Policy 1995; 31: 111-125. Birch S, Donaldson C. Cost-benefit analysis: dealing with the problems of indivisible projects and fixed budgets. Health Policy 1987; 7: 61-72. Bennet WG, Pauker SG, Davis GL, Wong JB. Modeling therapeutic benefit in the midst of uncertainty: therapy for hepatitis C. Dig Dis Sci 1996; 41: 56S-62S. Koff RS, Seeff LB. Economic modeling of treatment of chronic hepatitis B and chronic hepatitis C: promises and limitations. Hepatology 1995; 22: 1880-1885. Owens DK. In the eye of the beholder: assessment of health-related quality of life. Hepatology 1998; 27: 292-293. (Received 20 Nov 1998, accepted 3 May 1999) Authors' details Social and Public Health Economics Research Group (SPHERe), Department of Public Health and Community Medicine, University of Sydney, Sydney, NSW. Alan Shiell, MSc(Econ), Honorary Research Associate. Medical Benefits Fund of Australia, Sydney, NSW. Sue Brown, MPH, BPharm, Pharmacy Manager, Provider Relations. Department of Medicine, Westmead Hospital, University of Sydney, NSW. Geoff C Farrell, MD, FRACP, Storr Professor of Medicine. Reprints will not be available from the authors. Correspondence: Mr A Shiell, Social and Public Health Economics Research Group (SPHERe), Department of Public Health and Community Medicine, University of Sydney (A27), NSW 2006. Email: alansATpub.health.usyd.edu.au Assumptions and methods for the decision analytic technique Natural history of hepatitis C (HCV) Chronic HCV infection to cirrhosis: The rate of progression was assumed to be 20% at 20 years,8 consistent with experience in patients attending liver clinics, but is higher than in a community sample. Cirrhosis to hepatocellular carcinoma (HCC): Rates of progression range from 1% to 4% per year and are higher in older age groups.8 We have assumed an annual rate of 1.4% (14% over 10 years), which is the lowest rate from more than 10 published studies from Europe and Japan.9 The small chance of HCC developing in patients without cirrhosis (< 0.25% per year)8 was ignored. Cirrhosis to advanced liver failure: We assumed that 20% of the cohort would progress to advanced liver failure over 10 years from the onset of cirrhosis.8 Death: All patients developing HCC or advanced liver failure were assumed to die within 2 years of diagnosis. Deaths from other causes were estimated from Australian life tables.10 Effectiveness of IFα treatment Previous evaluation: In our previous evaluation,3 we assumed that 6 months' treatment with IFα would be effective in 20% of cases overall and 26% of cases without cirrhosis at the start of treatment. A recent meta-analysis by Poynard et al11 suggests that a sustained response is achieved in 14%-22% of cases treated with 3 million international units (miu) of IFα over 6 months, and in 28%-38% of patients treated with the same dose for 12 months or longer. Our estimates of the effectiveness of treatment were based on the assumption of an 18% sustained response rate after IFα treatment for 6 months and a 35% sustained response rate after 12 months' treatment, with both rates subject to sensitivity analysis. Quality of life Chronic HCV infection has been described as largely asymptomatic, with less than 20% of patients developing non-specific symptoms such as fatigue.8 However, recent studies suggest that it has an impact on quality of life.12-14 People with chronic HCV infection scored significantly lower than a comparable but healthy population on various generic health measures, such as the 36-item short-form health survey (SF-36).12 Side effects of treatment: Mild side effects of IFα are common and most patients will experience flu-like symptoms which diminish over time. Less transient effects -- fatigue, irritability, depression, thyroid disease and skin disorders -- are more troublesome and cause some patients to discontinue treatment. Less than 2% of patients will experience severe side effects.8 Quality-adjusted life-years (QALYs): The impact of the disease (including its sequelae and treatment with IFα) on quality of life can be incorporated into the analysis by weighting the life-years gained according to their quality, thus generating an estimate of quality-adjusted life-years, or QALYs. These weights are usually calibrated on a scale of 0 to 1, where 0 is equivalent to death and 1 to a year of life in full health. Subjective impact of the disease: A major shortcoming is a lack of understanding of the subjective impact of the disease. In the absence of patient-generated weights, other authors have used quality-of-life weights based on clinical judgement or small scale surveys.4,6,7 The weights are 0.8-0.95 for chronic hepatitis, 0.7-0.8 for compensated cirrhosis, 0.28-0.5 for decompensated cirrhosis, and 0.1-0.25 for hepatocellular carcinoma. The weights we used were adapted from those derived by Kim et al,7 as these were the only ones based on patient judgement (Table 1). In the baseline case, it was assumed that treatment had no additional adverse effect on quality of life -- an assumption relaxed in the sensitivity analysis. Costs of treatment Estimates of the treatment costs for each of the main clinical endpoints were based on clinical protocols as specified by the National Health and Medical Research Council (NHMRC)15 and the clinical opinion of one of the authors (G C F). The protocols were costed using the Medicare Benefits Schedule for medical services,16 and Australian national diagnosis-related groups (AN-DRG-3.1) for hospital admissions (Table 1).17 See Appendix for details. All costs are in Australian dollars at 1996 prices. Cirrhosis: A weighted cost was computed on the basis of specified treatment protocols for each of the main clinical manifestations of cirrhosis. The weights reflect the estimated proportion of patients likely to experience each state.6 It was further assumed that 2% of patients experiencing cirrhosis would undergo a liver transplant each year and that 25% of cirrhotic patients would experience at least one episode of septicaemia requiring hospital admission. IFα: The unit cost of IFα reflected its price to the healthcare system. It was assumed that treatment would be given at a rate of 3 miu three times a week for either 24 or 48 weeks and would be discontinued in people who did not show a reduction in serum alanine aminotransferase (ALT) levels after 12 weeks. Experience in Australia suggests that 26% of people will fail to respond in this period and will discontinue treatment (R G Batey, Deputy Dean, and Professor of Gastroenterology, Faculty of Medicine and Health Sciences, University of Newcastle, Newcastle, NSW, personal communication). Other costs: Lost production capacity caused by morbidity and premature mortality associated with HCV infection was not considered.18 Other patient costs, such as the use of community services and alternative medicine, were also omitted. This biases the findings against treatment with IFα. Cost effectiveness of IFα treatment The cost effectiveness of treatment for 6 months is expressed as the additional cost per QALY gained over and above no treatment (conventional management). The incremental cost effectiveness of 12 months' treatment over 6 months' treatment is also reported. Future costs and outcomes were discounted at both 3% and 5% (as recommended by Gold et al19). Undiscounted results are also presented and the effect of using a higher discount rate is assessed in the sensitivity analysis. (Discounting is the process whereby costs and benefits occurring at different points in time are made commensurate with each other.) Sensitivity analysis The robustness of the results was examined by sensitivity analysis (given the uncertainties inherent in the modelling approach). Key variables included in the sensitivity analysis were response rates, rates of disease progression, time to develop sequelae, costs of treatment, percentage of patients excluded at 12 weeks, age groups, the discount rate, and the adjustment for quality of life. Back to text 1: Baseline assumptions: values and costs used in the Markov modelValueRangeDisease transition probabilities From chronic infection to cirrhosis20%10%-30% From cirrhosis to advanced liver failure20%10%-30% From cirrhosis to hepatocellular carcinoma14%7%-21%Effectiveness of treatment Long term response after 6 months18%14%-24% Long term response after 12 months35%26%-38% Discontinue treatment after 12 weeks because of lack of response26%13%-39%Health state (quality of life) weights Chronic infection0.950.80-1.00 Cirrhosis0.750.50-0.90 Advanced liver failure0.250.10-0.40 Hepatocellular carcinoma0.250.10-0.40 Treatment with interferon alfa (IFα)0.950.80-0.95 Resolved infection1.001.00-1.00Treatment episode costs*$$Medical management of chronic infection405200-600Treatment with IFα 6 months' treatment including discontinuing treatment2 8001 975-3 630 12 months' treatment including discontinuing treatment5 1503 620-6 670Cirrhosis (weighted average)2 8251 400-4 200 Management of compensated cirrhosis660330-990 Diuretic-sensitive ascites1 880940-2 820 Refractory ascites13 6406 820-20 460 Variceal haemorrhage (Year 1)5 8502 925-8 775 Hepatic encephalopathy (Year 1) 6 3753 190-9 565 Hepatocellular carcinoma (Year 1)8 8654 435-13 290 Liver transplant (Year 1)92 52546 265-138 790 Septicaemia5 3002 650-7 950Terminal care28 40014 200-42 600Back to text 2: Summary of costs and outcomes of interferon treatment for chronic hepatitis C infection in a hypothetical cohort of 1000 patients Treatment durationNet costs ($)Lives saved Life-years savedQALYs gainedUndiscounted(a) 6 months1 185 55512.0176.3 531.4(b) 12 months2 013 84523.4 342.7830.7(c) Increment828 290 11.3166.5299.3Discounted (3%)(a) 6 months1 800 3807.694.2320.1(b) 12 months3 209 34514.7183.2490.9(c) Increment1 408 9657.189.0170.8Discounted (5%)(a) 6 months2 049 6455.763.9237.7(b) 12 months3 694 02011.1124.2359.5(c) Increment1 644 3755.460.3121.8Treatment DurationCost/life saved ($)Cost/ life-year saved ($)Cost/ QALY gained ($)Undiscounted(a) 6 months98 7106 7202 230(b) 12 months86 2355 875 2 425(c) Increment73 0204 9752 765Discounted (3%)(a) 6 months238 52519 1105 625(b) 12 months218 67017 520 6 540(c) Increment197 64515 835 8 250Discounted (5%)(a) 6 months360 37032 095 8 620(b) 12 months334 02029 750 10 275(c) Increment306 120 27 265 13 505 Incremental cost and outcomes (a) 6 months' treatment with interferon v. no treatment; (b) 12 months' treatment with interferon v. no treatment; (c) 12 months' treatment with interferon v. 6 months' treatment. Net costs = costs of treatment minus costs of conventional management of the disease. QALY = quality-adjusted life-year. Back to text 3: Discounted costs of interferon treatment for chronic hepatitis C infection per life-year and per quality-adjusted life-year (QALY) gained under best and worst case scenarios (sensitivity analysis)Treatment for 6 months v. no treatmentCosts ($) per QALY (Baseline = $5 625)Costs ($) per life-year (Baseline = $19 110)VariableRangeBest caseWorst caseBest caseWorst caseRate of cirrhosis10%-30% 3 2409 6459 20548 820Time to cirrhosis (years)10-304 09010 29011 64537 470Rate of sequelaeComposite*5 1156 26512 95037 590 Liver failure10%-30% Hepatocellular carcinoma7%-21%Time to sequelae (years)5-155 4955 77516 21522 970Long term response rateComposite3 3908 26511 68027 600 6 months14%-24% 12 months26%-38%Cost of interferon per dose$13-$393 0358 12010 31027 595Cost of health service useComposite4 0657 18513 81024 410 Chronic infection50%-150% Cirrhosis50%-150% Terminal care50%-150%Discontinue treatment at 12 weeks13%-33%5 2406 01017 81020 415Duration of model (years)20-404 30512 95012 89049 090Discount rate0-10%2 23018 6206 72589 900Quality-of-life weightsComposite (See Table 1)2 08028 03019 110† 19 110†Treatment for 12 months v. 6 months Costs ($) per QALY (Baseline = $8 250)Costs ($) per life-year (Baseline = $15 835)VariableBest caseWorst caseBest caseWorst caseRate of cirrhosis3 80019 8257 02542 270Time to cirrhosis (years)5 21012 6859 32026 455Rate of sequelae6 98010 16510 76531 040 Liver failure Hepatocellular carcinomaTime to sequelae (years)7 8358 72513 49518 970Long term response rate 4 36063 1758 125214 105 6 months 12 monthsCost of interferon per dose 4 15512 3407 91023 475Cost of health service use 5 48511 01010 53521 135 Chronic infection Cirrhosis Terminal care at 12 weeks 6 8109 58513 07518 595Duration of model (years) 7 20017 3009 75541 910Discount rate2 76533 4754 97578 310Quality-of-life weights 7 5309 81015 835†15 835† * Composite refers to the aggregate effect on cost per unit of outcome of changing all subsidiary variables simultaneously. †Quality adjustment has no effect on the number of life-years saved. Back to text Summary points Costs and benefits of healthcare interventions have to be considered in the context of a limited healthcare budget. The cost effectiveness of interferon alfa (IFα) treatment of chronic hepatitis C infection in Australia has improved since it was first evaluated in 1994. The major effect of IFα therapy is on improving quality of life, not life expectancy. More research is required on the impact of chronic hepatitis C infection and IFα treatment on quality of life. Back to text APPENDIX 1 Treatment episode costs Back to article 1: Medical management of chronic infection Resource categoryNumberUnit costTotal Cost Specialist visits2112.65225.30 Pathology Liver function test219.8039.60 Alfa fetoprotein219.9039.80 Ultrasound1101.70101.70 Total 406.40 2: Treatment with interferon (6 months) including workup Resource categoryNumberUnit costTotal Cost Specialist review initial consultation194.1594.15 subsequent consultation647.15282.90 Interferon (allowing for drop out)0.871889.281643.67 Pathology Full blood count717.20120.40 Liver biopsy1130.35130.35 Liver function test719.80138.60 International normalisation ratio112.4012.40 Thyroid function test341.00123.00 PCR380.00240.00 Anti-HCV113.7013.70 Total2799.17 3: Treatment with interferon (12 months) including workup Resource categoryNumberUnit costTotal Cost Specialist review initial consultation194.1594.15 subsequent consultation1447.15660.10 Interferon (allowing for drop out)0.813 755.253 041.74 Pathology FBC1517.20258.00 Liver biopsy1130.35130.35 LFT1519.80297.00 International normalisation ratio112.4012.40 Thyroid function test441.00164.00 PCR680.00480.00 Anti-HCV113.7013.70 Total5151.44 4: Management of compensated cirrhosis Resource categoryNumberUnit costTotal Cost GP visits424.5098.00 Specialist visits initial1110.75110.75 subsequent355.45166.35 Pathology LFT219.8029.60 AFP419.9079.60 Ultrasound283.95167.90 Total662.20 5: Management of diuretic-sensitive ascites Resource categoryNumberUnit costTotal Cost Inpatient admissions0.331980.00653.40 Day-only admissions1455.00455.00 Specialist review initial visit1110.75110.75 subsequent visit555.45277.25 Pathology LFT419.8079.20 Creatinine417.7571.00 AFP219.9039.80 FBC217.2034.40 Prothrombin time212.4024.80 Medication Aldactone 200 mg/day199.0699.06 Procedures Paracentesis138.2038.20 Total1882.86 6: Management of refractory ascites Resource categoryNumberUnit costTotal Cost Day-only admissions26455.0011 830.00 Specialist review initial visit1110.75110.75 subsequent visit555.45277.25 Pathology LFT419.8079.20 Creatinine417.7571.00 AFP219.9039.80 FBC217.2034.40 Prothrombin time212.4024.80 Medication Norfloxacillin 200 mg/tds0.33545.15179.90 Procedures Paracentesis2638.20993.20 13,640.30 7: Management of variceal haemorrhage - Year 1 Resource categoryNumberUnit costTotal Cost Hospital admission11980.001980.00 Day-only admissions5455.002275.00 Specialist review initial visit1110.75110.75 subsequent visit555.45277.25 Pathology LFT419.8079.20 Creatinine417.7571.00 AFP219.9039.80 FBC217.2034.40 Prothrombin time212.4024.80 Medication Propanolol182.4982.49 Procedures Oesophagoscopy (+ anaesthetic)3291.95875.85 Total5850.40 8: Management of hepatic encephalopathy - Year 1 Resource categoryNumberUnit costTotal Cost Hospital admission2.41980.004752.00 Specialist review initial visit1110.75110.75 subsequent visit555.45277.25 Pathology LFT419.8079.20 Creatinine417.7571.00 AFP219.9039.80 FBC217.2034.40 Prothrombin time212.4024.80 Medication Lactulose 60 mls1734.96734.96 Procedures Diagnostic endoscopy (+ anaesthetic)1213.75213.75 Paracentesis138.2038.20 Total6376.11 9: Management of hepatocellular carcinoma - Year 1 Resource categoryNumberUnit costTotal Cost Hospital admission (diagnosis)16947.006947.00 Inpatient admission17846.907846.90 Specialist visits initial visit1110.75110.75 subsequent visits955.4555.45 Pathology LFT419.8079.20 Creatinine417.7571.00 AFP219.9039.80 FBC217.2034.40 Prothrombin time212.4024.80 Procedures Paracentesis138.2038.20 Total8866.60 10: Other hospital admissions Reason for admission/treatmentRateUnit cost ($) Liver transplant (+ associated admissions)0.0292,527 Major infection (septicaemia)0.255,300 Terminal care - Advanced liver failure28,400 - hepatocellular carcinoma28,400 Back to text

Alan Shiell · Sue Brown · Geoff C Farrell

Sports Medicine Ethics of prescribing drugs to enhance sporting performance Crossing the line between good medicine and cooperating with unhealthy or illegal behaviour Michael C Kennedy and Judith R Kennedy MJA 1999; 171: 204-205 See also Corrigan Introduction - What should be done for athletes - Patient autonomy - Harm minimisation - Acknowledgements - References - Authors' details - - More articles on Sports medicine Introduction There are two groups of people who undertake sporting activity while taking drugs. The first are those who require medication for chronic conditions such as hypertension and hyperlipidaemia, in specific circumstances such as paraplegia or organ transplant, or for acute intermittent conditions such as inflamed joints, infections and injuries. The second group comprises healthy people who take drugs to enhance sporting performance. We include bodybuilders in this category. Doctors are always the prescribers for the first group and are often the prescribers for the second.1 In this article, we provide an overview of ethical practice when consulted by individuals in this second category. The use of drugs for enhancing sporting performance is widespread and has been documented in Europe, North America and Australia.2-5 Some drugs seem to have enduring appeal, while others come and go in fashion. Anabolic/androgenic steroids (AAS) have been popular for over four decades; in 1990, an estimated one million people in the United States were either current or former users of AAS.6 Over the past 15 years there has also been a steady increase in the use of growth hormone,7 erythropoietin8 and insulin.9 The use of stimulants is still common, although the popularity of amphetamines has decreased since the 1960s. The media's focus on high-profile athletes who test positive for a banned substance overshadows the pattern of use: most non-therapeutic drug use is at the non-competitive, non-elite level of sport where there is no drug testing.6 Particularly troubling is the use of AAS on and by adolescents2,3 and the known connection between some of the drugs and myocardial infarction, stroke and psychiatric episodes in apparently healthy athletes.10,11 It is therefore important that doctors carefully consider their actions before prescribing drugs to those who wish to enhance their sporting performance. The doctor's purpose should be no more than assessment of the clinical state and the management of this as best suits the patient within prevailing social and ethical constraints. There is no authority for either the patient or the doctor to widen the purview to include the creation of social rights, coaching in how to cheat, or violating regulations.12 What should be done for athletes It is important to incorporate questions about sporting activities into clinical history-taking. Before prescribing to athletes, the following points should be routinely addressed: Banned drugs: If the athlete is competing at competition level it is essential that care be taken to avoid a drug on the banned list. Mistakes can be easily avoided by checking the drug details in publications such as MIMS or the Drugs in sport handbook2 (published by the Australian Sports Drug Agency [ASDA], or by contacting the ASDA hotline on 1800 020 506). Exposure conditions: Doctors should be aware that athletes will often expose themselves to extremes of endurance, so care is needed when using agents such as non-steroidal anti-inflammatory drugs, prochlorperazine and pseudoephedrine, which can affect heat regulation or cardiac rhythm. Patients should also be informed of the effects a drug may have on their sporting performance per se. For example, if β-blockers are medically indicated, the trade-off will be a decrease in aerobic performance. Professional competence: It is the responsibility of each prescriber to know the pharmacological facts about a drug and the medical facts about the patient. For example, AAS are not only widely abused, but also are a drug group about which there is much published information. A healthy athlete has no medical condition that will require prescribing of AAS, which will worsen, not improve, tendon and muscle injuries.13 There are no studies showing that AAS enhance skilled performance. There are data showing AAS increase muscle size and strength,14 although these data need to be interpreted conservatively.15 There are also a number of predictable adverse reactions that occur with their use, such as acne and gynaecomastia.10In the absence of a clinical reason for prescribing drugs, and in the presence of good clinical reason for not doing so, any case for prescribing a drug must then rely on over-riding, non-medical considerations. The patient-autonomy and harm-minimisation arguments are the most ethically powerful of these. Patient autonomy Patient autonomy is the right to self-determination. Starting with this notion, it is argued that non-medical use of drugs is simply a matter of personal liberty and individual experimentation: if athletes are aware of possible adverse reactions and are willing to accept the risks in the hope of other rewards, there should be no prohibition on doctors' prescribing. It follows that the doctor's task is merely to ensure informed consent. Clearly, society does not agree with this argument. Prescribing is restricted to those with both clinical and pharmacological knowledge for good reason -- the expectation is that there will be a causal link between specific drug use and clinical benefit. Predictable negative effects -- and, for athletes, this may be exclusion from competition -- are traded off against the required medical outcome. There is no suggestion that medical practitioners should do whatever the patient asks. We are not obliged to prescribe a drug simply because it has been asked of us. Another important issue needs to be considered in relation to autonomy: athletes are in an environment where competition is fierce and selection is never assured. Therefore, they may be in no position to object to proposed medical interventions and sports-health supervision by doctors who are not their usual practitioner. An extreme example of the type of abuse possible under these circumstances occurred in the former German Democratic Republic.16 One lesson from this is that it may be difficult for an athlete to refuse even seemingly innocuous procedures such as vitamin injections or the taking of supplements to "boost the immune system" when suggested by those in official positions. Respect for the athlete's autonomy requires that administration of substances occurs only when the athlete is fully informed and truly free to refuse. Harm minimisation The harm-minimisation argument is that some athletes will take drugs irrespective of whether supervised or not, and that giving drugs under medical supervision potentially results in less harm as there is control over the quality of the drugs supplied and early detection and treatment of adverse reactions. The controlled use of heroin in registered addicts is one example of the application of the harm-minimisation argument in medicine.17 However, this model is not applicable to drugs in sport. Both types of drug-taking may involve unfortunate victims and major criminal and financial enterprises,18 but there the similarity ends. In contrast to heroin, little is known of the pharmacokinetics and pharmacodynamics of high doses of AAS taken as single agents. There is even less knowledge of their pharmacokinetics and pharmacodynamics when taken in various multiple doses ("stacking") or in increasing doses ("pyramiding"). In addition, experience has shown that when a doctor prescribes low doses of AAS, this may lead to the prescriber's being used as one of a number of sources of supply.19 Under these circumstances, the doctor faces a new dilemma when an adverse reaction follows: to cease prescribing the offending agent or to prescribe yet another drug (for example, tamoxifen when oestrogenic side effects occur). The absurdity of this argument becomes evident when extended to justify prescribing insulin, erythropoietin or amphetamines. Respect for the general principle of autonomy and individual freedom means an acceptance that individuals -- both doctors and patients -- "own" their actions and are responsible for what they do. Athletes can request what they like, but doctors need not comply. Non-maleficence means that medical actions must cause as little harm as possible, not that medical skills should be used to fine-tune enterprises of harm. If approached about prescribing drugs to enhance sporting performance, the proper medical response is to provide accurate information and advice in a non-judgemental manner. If the patient has been or is exposed to a known health risk it is reasonable to diagnose and treat any ill-effects. This applies to drug use as much as it does to smoking, and does not require crossing the line between good medicine and cooperating with behaviour that is unhealthy, illegal or just plain wrong. If requested to prescribe drugs to enhance sporting performance the proper response is to refuse. Saying "no" to unreasonable requests is not always easy, but to do otherwise is to miss the point of what practising medicine is all about. Acknowledgements Ms Dianne James, Librarian, Manly Hospital, Manly, NSW. References Copeland J, Peters R, Dillon P. A study of 100 anabolic-androgenic steroid users [letter]. Med J Aust 1998; 168: 311-312. Nilsson S. Androgenic anabolic steroid use among male adolescents in Falkenberg. Eur J Clin Pharmacol 1995; 48: 9-11. Korkia P, Stimson GV. Indications of prevalence, practice and effects of anabolic steroid use in Great Britain. Int J Sports Med 1997; 18: 557-562. Yesalis CE, Barsukiewicz CK, Kopstein AN, Bahrke MS. Trends in anabolic-androgenic steroid use among adolescents. Arch Pediatr Adolesc Med 1997; 151: 1197-1206. Australian Sports Medicine Federation. Survey or drug use in Australian sport. Sports Coach 1988: 9-10. Medical and nonmedical uses of anabolic-androgenic steroids. Council on Scientific Affairs. JAMA 1990; 264: 2923-2927. Wu Z, Bidlingmaier M, Dall R, Strasburger CJ. Detection of doping with human growth hormone. Lancet 1999; 353: 895. Sawka MN, Joyner MJ, Miles DS, et al. American College of Sports Medicine position stand. The use of blood doping as an ergogenic aid. Med Sci Sports Exerc 1996; 28: i-viii. Willey J. Insulin as an anabolic aid? The Physician and Sports Medicine 1997; 25: 103-104. Kennedy MC. Anabolic steroid abuse and toxicology. Aust N Z J Med 1992; 22: 374-381. Corrigan B. Anabolic steroids and the mind. Med J Aust 1996; 165: 222-226. Gillon R. Medical ethics: four principles plus attention to scope. BMJ 1994; 309: 184-188. Laseter JT, Russell JA. Anabolic steroid-induced tendon pathology: a review of the literature. Med Sci Sports Exerc 1991; 23: 1-3. Bhasin S, Storer TW, Berman N, et al. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996; 335: 1-7. Kennedy MC, O'Sullivan AJ. Do anabolic-androgenic steroids enhance sporting performance? [editorial]. Med J Aust 1997; 166: 60-61. Franke WW, Berendonk B. Hormonal doping and androgenization of athletes: a secret program of the German Democratic Republic government. Clin Chem 1997; 43: 1262-1279. Farrell M, Hall W. The Swiss heroin trials: testing alternative approaches [editorial]. BMJ 1998; 316: 639. Fleming C. Abuse and trafficking in anabolic steroids -- United States and Canada. A report to the Sir Winston Churchill Memorial Trust. Australia 1997. Duda M. Do anabolic steroids pose an ethical dilemma for US physicians? Phys Sports Med 1986; 14: 173-175. Authors' details St Vincent's Hospital, Sydney, NSW. Michael C Kennedy, MD(UNSW), FRACP, Research Associate, Department of Clinical Pharmacology and Toxicology, and Consultant Physician, Manly. Manly, NSW. Judith R Kennedy, MA(ACU), MAPS, Psychologist. Reprints: Dr M C Kennedy, Manly Non-Invasive Cardiac Laboratory, Level 4, 22 Darley Road, Manly, NSW 2095. Email: drmkennATozemail.com.au

Michael C Kennedy · Judith R Kennedy

Sports Medicine Dehydroepiandrosterone and sport Dehydroepiandrosterone (DHEA) is a weak androgen, but is one of the main precursors of testosterone. Athletes use it for its androgenic and anticatabolic effects and it has been described as a "wonder drug", although there is little evidence to support these claims. There are no published studies of the long term effects of taking DHEA, particularly in the large doses used by athletes, or of its possible interactions with other agents. A Brian Corrigan MJA 1999; 171: 206-208 See also Kennedy Introduction - Physiology - DHEA and exercise - Medical use - Use by athletes - Screening for DHEA use - Long term effects - Acknowledgements - References - Authors' details - - More articles on Sports medicine Introduction In Australia, considerable interest in the use of dehydroepiandrosterone (DHEA) in sports has followed the positive drug tests of two sportsmen, one for DHEA and one for its metabolite, androstenediol. DHEA is a 19-carbon steroid, classified as an androgen,1 albeit a weak one. It is the major steroid hormone secreted by the adrenal glands2,3 and circulates in two forms. One is unconjugated DHEA; the other, present in a much higher concentration, is conjugated as its sulfate, DHEAS. The two are readily interconvertible.4-6DHEA is one of the main precursors in the biosynthesis of the male and female sex hormones.1 It is formed from the metabolism of cholesterol to pregnenolone and then to DHEA or DHEAS, and can be converted in the tissues to the far more potent androgens testosterone and dihydrotestosterone (Box 1).7 DHEA first burst into prominence nearly 20 years ago when, following animal experiments, it was described as a "wonder drug"8 and "the fountain of youth", with claims that it was an anti-aging, anti-obesity, and anticancer drug. At that time it was available in the United States only on prescription, but in 1985 the Food and Drug Administration (FDA) ordered manufacturers to stop marketing DHEA as a weight-loss product. In 1994, following intense lobbying by the healthfood industry, an Act of Congress allowed DHEA to be sold in the US as an over-the-counter dietary nutritional supplement.9 The effect of this Act was to shift the burden of proof onto the FDA to prove that a nutritional substance was harmful. The Act also stated that labelling was not to make any unsubstantiated health claims, but this failed to stop the profusion of advertisements on the Internet.10 The fond belief that, if labelled as having "no drug intent", DHEA would be used only as a food supplement, or that it would be used only in small doses, turned out to be just that -- a fond belief. The FDA still does not approve it for any medical indication.9,11 In Australia, DHEA is a banned drug, and a prohibited import under the Customs (Prohibited Imports) Regulations (Cwlth). It has no listed medical uses, and cannot be marketed. Physiology Circulating levels of DHEA and DHEAS peak in early adulthood, then progressively decline with age.6,12 DHEA has a short half-life of 25 minutes; DHEAS has a half-life of some 10 hours. Most DHEA circulates bound to albumin,13,14 with only minimal binding to sex hormone binding globulin (SHBG) and a smaller amount being free. In contrast, DHEAS is more strongly bound to albumin, only a small amount is free, and none appears bound to SHBG.13 Secretion of DHEA, but not of DHEAS, has a circadian rhythm.1,15,16 DHEAS is present at a plasma concentration much higher than any other adrenal steroid. Despite its abundance and rapid turnover rate, DHEA's physiological role remains uncertain.14,17,18 A DHEA deficiency state has never been described.19 For men or women who have either adrenal insufficiency or hypopituitarism, although gluco- and mineralocorticosteroid replacement is needed, 50 mg a day of DHEA is sufficient for replacement.12,20 DHEA and exercise Four studies have been published concerning the effect of physical exercise on DHEA levels. Two of these, involving trained sportsmen, found exercise produced a significant rise in DHEA levels.21,22 The third, with patients in a cardiac rehabilitation program,23 reported no effect. In the other,24 middle-aged women using a treadmill had raised serum DHEA and DHEAS levels. Medical use DHEA has been described in the treatment of many disorders, including cardiovascular disease,25 breast cancer,26 obesity,27 and as replacement therapy to improve the fall in DHEA levels that occurs in aging men and women.6,28,29 These are all controversial. DHEA is usually available in 25 mg or 50 mg tablets, which have an average absorption of 50% from the gut.28 It has also been used in an injectable ester form, intramuscular prasterone enanthate 200 mg (Gynodian Depot, Schering), and it has been given as a vaginal pessary. As with other sports drugs, such as steroids, tablets can be readily bought on the black market or on the Internet, but may prove to be counterfeit.30 Use by athletes The number of athletes who use DHEA as a supplement is unknown (Box 2).31 Athletes use DHEA for several reasons: as an anabolic agent to increase levels of androgens such as androstenediol and testosterone. Its effectiveness as an anabolic or energy-producing agent remains unproven. Nevertheless, an anabolic effect was supported in one study,18 when DHEA was given to healthy young men in a dose of 1600 mg a day orally for four weeks. Fat levels decreased and fat-free body mass increased by an average of 4.5 kg. However, in another study using better technology,32 a ninefold increase in DHEAS levels was induced in eight healthy young men given 1600 mg a day for four weeks in a double-blind crossover study. No effect on bodyweight, lean mass or cholesterol resulted; the authors concluded that "DHEA is not an important regulator of energy or protein metabolism in humans".32 There are no published data on what happens when athletes take long term supraphysiological doses of these agents, nor what might happen if older athletes, such as participants in the Master's Games, used DHEA to achieve the levels found in younger people. as an anticatabolic agent.33 One major proposed mechanism of DHEA's mode of action is to counteract the catabolic effect of corticosteroids, which may be elevated following stress and exhaustion due to sporting events or heavy training schedules.3 DHEA is a powerful antiglucocorticoid33-36 and could accelerate recovery from the stress. as a difficult-to-detect means to increase steroid levels. A positive drug test for anabolic steroids is based on the testosterone (T) to epitestosterone (E) ratio (epitestosterone is an inactive isomer of testosterone produced in the testes). The T/E ratio is around 1:1 in normal individuals, and it rises with exogenous steroid administration. The International Olympic Committee (IOC) uses a cut-off of 6:1 for drug testing; any test result above that is considered to be a positive that requires further investigation. As DHEA is a precursor in testosterone formation, it would increase the concentrations of both T and E, so that the T/E ratio would remain within the normal range. Although the T/E ratio does rise with DHEA use, it usually does so to only a modest degree, usually remaining below the IOC cut-off level.37 However, this is also obviously dependent on the dose and length of time of administration, so that, with a high enough dose, the ratio can be increased.38 Cases of a high T/E ratio have been known after excessive intake, but such an increase in the ratio is more likely to occur with androstenediol than with DHEA. as with most other steroids, DHEA is a neurosteroid39-41 capable of producing marked psychological effects,28,42-44 such as euphoria or anxiety.45 Screening for DHEA use In Australia, DHEA is an illegal drug that may not be imported, prescribed or administered. However, it is still possible to order it from the Internet. In early 1997, the IOC specifically added it to the list of drugs proscribed because of its androgenic effects. Previously, it would have been banned as "a related substance". Few technical difficulties are associated with detecting DHEA in the urine, but its normal range and a legal level for detection purposes need to be established. In one report, the authors recommend a urinary concentration threshold of 300 mg per litre of DHEA glucuronide for drug-screening purposes.3 Similar figures have been obtained in Australia (Dr R Kazlauskas, Director, Australian Sports Drug Testing Laboratory, personal communication). A screening test might need to rely on urinary ratios between DHEA and other steroids, or else some form of carbon isotope ratio measurement might be developed.46 Long term effects The long term effects of DHEA are not known, although it does seem to be capable of interfering with many basic hormonal and endocrine systems, including breast, uterine and prostate tumours.47,48 Most of the theories concerning its anticipated effects have been extrapolated from epidemiological or animal studies. There have never been any properly conducted long term clinical trials of its efficacy or side effects in humans, and nothing is known about its interactions with other compounds. For these reasons, it should never be used as a long term treatment in young people such as athletes. Acknowledgements I would like to thank Dr John Carter and Dr Michael Kennedy; the Australian Sports Drug Agency, and the librarians at Concord Hospital, for all their help. References Williams JD. Textbook of endocrinology. Williams JD, Foster DW, editors. 8th ed. Philadelphia: WB Saunders, 1992; 579-581. Greenspan FS. Basic and clinical endocrinology. 3rd ed. New Jersey: Prentice-Hall, 1991; 469-471. Dehennin L, Ferry M, Lafarge P, et al. Oral administration of dehydroepiandrosterone to healthy men: alteration of the urinary androgen profile and consequences for the detection of abuse in sport by gas chromatography-mass spectrometry. Steroids 1998; 63: 80-87. Bird CE, Masters V, Clark AF. Dehydroepiandrosterone sulfate: kinetics of metabolism in normal young men and women. Clin Invest Med 1984; 7: 119-122. Haning RV Jr, Carlson IH, Flood CA, et al. Metabolism of dehydroepiandrosterone sulfate (DS) in normal women and women with high DS concentrations. J Clin Endocrinol Metab 1991; 73: 1210-1215. Herbert J. The age of dehydroepiandrosterone [editorial]. Lancet 1995; 345: 1193-1194. Labrie F, Belanger A, Simard J, et al. DHEA and peripheral androgen and estrogen formation: intracrinology. Ann N Y Acad Sci 1995; 774: 16-28. Kent S. DHEA: "miracle" drug? Geriatrics 1982; 37: 157-161. Skolnick AA. Scientific verdict still out on DHEA. JAMA 1996; 276: 1365-1367. Kreeger KY. Researchers ponder the benefits of DHEA on many fronts. The Scientist 1997; 11(9): 11,14. Dehydroepiandrosterone (DHEA). Med Lett Drugs Ther 1996; 38: 91-92. Young J, Couzinet B, Nahoul K, et al. Panhypopituitarism as a model to study the metabolism of dehydroepiandrosterone (DHEA) in humans. J Clin Endocrinol Metab 1997; 82: 2578-2585. Longcope C. Dehydroepiandrosterone metabolism. J Endocrinol 1996; 150 Suppl: S125-S127. Ebeling P, Koivisto VA. Physiological importance of dehydroepiandrosterone. Lancet 1994; 343: 1479-1481. Liu CH, Laughlin G, Fischer U, et al. Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17,20-desmolase enzymatic activity. J Clin Endocrinol Metab 1990; 71: 900-906. Baulieu EE. Dehydroepiandrosterone (DHEA): a fountain of youth? J Clin Endocrinol Metab 1996; 81: 3147-3151. Nestler JE, Kahwash Z. Sex-specific action of insulin to acutely increase the metabolic clearance rate of dehydroepiandrosterone in humans. J Clin Invest 1994; 94: 1484-1489. Nestler JE, Barlascini CO, Clore JN, et al. Dehydroepiandrosterone reduces serum low density lipoprotein levels and body fat but does not alter insulin sensitivity in normal men. J Clin Endocrinol Metab 1988; 66: 57-61. Regelson W, Loria R, Kalimi M. Dehydroepiandrosterone (DHEA) -- the "mother steroid". I. Immunologic action. Ann N Y Acad Sci 1994; 719: 553-563. Arlt W, Justl H-G, Callies F, et al. Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression. J Clin Endocrinol Metab 1998; 83: 1928-1932. Keizer H, Janssen GM, Menheere P, Kranenburg G. Changes in basal plasma testosterone, cortisol, and dehydroepiandrosterone sulfate in previously untrained males and females preparing for a marathon. Int J Sports Med 1989; 10 Suppl 3: S139-S145. Velardo A, Pantaleoni M, Valerio L, et al. Influence of exercise on dehydroepiandrosterone sulphate and delta 4-androstenedione plasma levels in man. Exp Clin Endocrinol 1991; 97: 99-101. Milani RV, Lavie CJ, Barbee RW, Littman AB. Lack of effect of exercise training on dehydroepiandrosterone-sulfate. Am J Med Sci 1995; 310: 242-246. Johnson LG, Kraemer RR, Haltom R, et al. Effects of estrogen replacement therapy on dehydroepiandrosterone, dehydroepiandrosterone sulfate, and cortisol responses to exercise in postmenopausal women. Fertil Steril 1997; 68: 836-843. Barrett-Connor E, Goodman-Gruen D. The epidemiology of DHEAS and cardiovascular disease. Ann N Y Acad Sci 1995; 774: 259-270. Bulbrook RD, Hayward JL, Spicer CC, et al. Relation between urinary androgen and corticoid excretion and subsequent breast cancer. Lancet 1971; 2: 395-398. Clore JN. Dehydroepiandrosterone and body fat. Obes Res 1995; 3 Suppl 4: 613S-616S. Morales AJ, Nolan JJ, Nelson JC, et al. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994; 78: 1360-1367. Yen SSC, Morales AJ, Khorram O. Replacement of DHEA in aging men and women. Ann N Y Acad Sci 1995; 774: 128-142. Lifrak ET, Parker LN. Analysis of nonprescription capsules purported to contain an adrenal androgen. Am J Hosp Pharm 1985; 42: 587-589. Sturmi JE, Diorio DJ. Anabolic agents. Clin Sports Med 1998; 17: 261-282. Welle S, Jozefowicz R, Statt M. Failure of dehydroepiandrosterone to influence energy and protein metabolism in humans. J Clin Endocrinol Metab 1990; 71: 1259-1264. Loria RM. Antiglucocorticoid function of androstenetriol. Psychoneuroendocrinology 1997; 22 Suppl 1: S103-S108. Kalimi M, Shafagoj Y, Loria R, et al. Anti-glucocorticoid effects of dehydroepiandrosterone (DHEA). Mol Cell Biochem 1994; 131: 99-104. Regelson W, Kalimi M. Dehydroepiandrosterone (DHEA) -- the multifunctional steroid. II. Effects on the CNS, cell proliferation, metabolic and vascular, clinical and other effects. Mechanism of action? Ann N Y Acad Sci 1994; 719: 564-575. Fleshner M, Pugh CR, Tremblay D, et al. DHEA-S selectively impairs contextual-fear conditioning: support for the antiglucocorticoid hypothesis. Behav Neurosci 1997; 111: 512-527. Bosy TZ, Moore KA, Poklis A. The effect of oral dehydroepiandrosterone (DHEA) on the urine testosterone/epitestosterone (T/E) ratio in human male volunteers. J Anal Toxicol 1998; 22: 455-459. Bowers LD. Oral dehydroepiandrosterone supplementation can increase the testosterone/epitestosterone ratio. Clin Chem 1999; 45: 295-297. Baulieu EE. Neurosteroids of the nervous system, by the nervous system, for the nervous system. Recent Prog Horm Res 1997; 52: 1-32. Khorram O. DHEA: a hormone with multiple effects. Curr Opin Obstet Gynecol 1996; 8: 351-354. Dubrovsky B. Natural steroids counteracting some actions of putative depressogenic steroids on the central nervous system: potential therapeutic benefits. Med Hypotheses 1997; 49: 51-55. Corrigan AB. Anabolic steroids and the mind. Med J Aust 1996; 165: 222-226. Miller RA. DHEA -- brass ring or red herring? [editorial]. J Am Ger Soc 1977; 45: 1402-1403. Wang C, Alexander G, Berman N, et al. Testosterone replacement therapy improves mood in hypogonadal men -- a clinical research center study. J Clin Endocrinol Metab 1996; 81: 3578-3583. Imamura M, Prasad C. Modulation of GABA-gated chloride ion influx in the brain by dehydroepiandrosterone and its metabolites. Biochem Biophys Res Commun 1998; 243: 771-775. Magnay J. Days numbered for testosterone cheats. Sydney Morning Herald 1999; 16 July: 12. Armsey TD, Green GA. Nutrition supplements: science vs hype. Phys Sportsmed 1997; 25: 77-92. Dorgan JF, Stanczyk FZ, Longcope C, et al. Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate and 5-androstene-3b,17b-diol to risk of breast cancer in postmenopausal women. Cancer Epidemiol Biomarkers Prev 1997; 6: 177-181. Authors' details Institute of Sports Medicine, Concord Hospital, Sydney, NSW. A Brian Corrigan, AM, FRACP, FRCP, Consultant Reprints will not be available from the author. Correspondence: Dr A B Corrigan, Lookout Avenue, Dee Why, NSW 2099. Email: abcATsouthernx.com.au Back to text2: DHEA use by Australian athletes In Australia, there have been two recent instances involving footballers. In the first, a player was given DHEA for presumed chronic fatigue syndrome, although there is no medical evidence that DHEA is of benefit in this condition. At the tribunal hearing, a complicated set of legal arguments resulted in the player being let off without any penalty. However, he was only to play again if he ceased his medication,which he has done, seemingly without any problems. In the second instance, a footballer used 50mg androstenediol capsules, allegedly because he believed that it was only a food supplement. On testing, a very high testosterone/epitestosterone ratio of 14.5 was found, and he was found guilty, and the maximum penalty imposed.