EPIDEMIOLOGICAL STUDY

Transcription

1 IP THE INSTITUTE OF PETROLEUM EPIDEMIOLOGICAL STUDY EXECUTIVE SUMMARIES

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3 IP THE INSTITUTE OF PETROLEUM 61 NEW CAVENDISH STREET, LONDON, W1M 8AR SWITCHBOARD : FAX : DIRECT LINE INSTITUTE OF PETROLEUM BENZENE STUDY RESULTS A major UK epidemiological study sponsored by the Institute of Petroleum (IP), and published on September 1st, 1995, found no consistent association between low-level benzene exposure ( ppm exposure levels over a 45-year working career) and any type of leukaemia. The results offer reassurance for those working in the oil industry and form a valuable contribution to the development of scientifically-based benzene-related regulations, both occupational and environmental. BACKGROUND The Institute of Petroleum, the leading UK scientific body specialising in the petroleum industry, has sponsored major epidemiological studies in UK oil refinery and distribution centres over the last 16 years. Reports have already been published in 1980 and The earlier two studies showed a lower than average incidence of mortality from leukaemia amongst refinery employees than in the general population, and a slightly raised incidence for distribution employees. Although the marginally higher incidence for distribution employees was not statistically significant, the IP decided that further study would be of value. The third study was carried out over 2%2 years from December 1992 to August This was based on over 23,000 oil distribution employees who had worked in the oil industry for at least one year between 1950 and 1975, and were employed at 750 UK distribution centres run by BP, Esso, Fina, and Shell. Amongst these employees, 91 cases of leukaemia had occurred. The employees included drivers, technical, and administrative ("white collar") staff. Dr Lesley Rushton, a Senior Lecturer in Medical Statistics at the University of Nottingham who had been involved in the earlier work, designed and conducted the third study. Dr Rushton worked independently with specialist technical input from a Scientific Advisory Board consisting of epidemiologists, recognised experts in their field. On its completion the study was additionally reviewed by four external independent experts in the field of epidemiology. The study is the largest yet undertaken on low levels of benzene exposure and oil industry employees. It covers a larger population of individuals than any other study. RESULTS Dr Rushton concludes that "there is no significant increase in the overall risk of all leukaemias with, cumulative exposure to benzene, or with intensity of exposure". A CHARITABLE COMPANY LIMITED BY GUARANTEE (REGISTERED OFFICE) REGISTERED NO ENGLAND

4 On both acute and chronic lymphatic leukaemias, she states that "there is little evidence in this study of an association between exposure to benzene and lymphatic leukaemia, either acute or chronic". She also finds that "the risk of chronic lymphatic leukaemia appeared to be related most closely to duration of employment and the highest risk occurred in white collar workers with long service". This finding, amongst administrative staff, indicates risk levels bearing no relationship whatsoever to occupational benzene exposure. For chronic myeloid leukaemia at low benzene exposures, Dr Rushton found no evidence of an increased risk. For lymphatic leukaemias and chronic myeloid leukaemias, Dr Rushton's work thus confirms previous study findings which indicate that the disease is not related to benzene exposure. For acute myeloid leukaemias, the type most noted as bearing an association with high levels of benzene exposure in the past, Dr Rushton's team analysed the data using both the continuous variable statistical method and analysis by discrete ranges. She found for acute myeloid leukaemias that the risk when treated as a continuous variable "did not increase with cumulative exposure, maximum intensity, or average intensity of exposure". Analysis by discrete ranges suggested a possible increase in risk at cumulative exposures in the higher range of ppm years, compared to less than 0.45 ppm years. However Dr Rushton found these results to be statistically insignificant. She states that "these results should be considered within the study's limitations", which for example included incomplete information about smoking habits and some weaker documentation of work histories. Dr Rushton's team therefore conducted supplementary analyses using the same methodology and excluding the data associated with poorly-documented work histories, and found that when the best quality work histories were used, there was no observed excess risk of acute myeloid leukaemias due to benzene exposure. In conclusion, Dr Rushton doubted whether "the risk of acute myeloid leukaemia is increased by cumulative exposure (to benzene) of less than 45 ppm years". This equates to exposure to 1.0 ppm daily over a 45 year working career. INDEPENDENT REVIEW and CONCLUSION The study results were reviewed by four independent experts. The independent review of the results provided a consensus that the weight of evidence indicated no association between low-level benzene exposure and leukaemia. Dr Julian Peto, Professor of Epidemiology at the Institute of Cancer Research states : "there is no clear evidence of any effect of benzene". This third Institute of Petroleum study found no link to leukaemia for workers exposed to the typical low levels of benzene which existed over the period studied, or to the even lower levels currently found in the petroleum industry. REGULATORY VALUE The study contributes significant new information to the assessment of benzene leukaemia risk at low levels of exposure. These assessments had previously relied upon extrapolation from much higher levels of exposure of up to 400 ppm years. The Institute of Petroleum data covers benzene exposures of up to 45 ppm years (equating to 1.0 ppm exposure levels daily over a 45 year working career). Such comprehensive data have not previously been available.

5 NEXT STEPS The new IP data will now be included in risk assessments aimed at providing a sound scientific bases for regulatory decision-making about benzene. For example, the European Union (EU) requires a formal risk assessment on substances which it classifies as "high priority". The German government has been assigned responsibility for overseeing the development of the assessment for benzene. Exxon Biomedical Sciences Inc. (EBSI) has been selected by the German Industry Advisory Group to provide the assessment for submission to the German authorities. This has utilised the new IP data, and is now well under way with plans for completion by the end of Other activities include participation in an important World Health Organisation workshop on air quality standards for benzene, and active dialogue with the occupational exposure advisory group of the American Conference of Government Industrial Hygienists. This latter group provides important input to the setting of international occupational standards. The Institute of Petroleum intends to continue wider epidemiology studies in the future as part of its ongoing role in monitoring and safeguarding the health of workers in the industry. Institute of Petroleum September 1995

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7 THE UNIVERSITY OF NOTTINGHAM Faculty of Medicine Department of Public Health Medicine and Epidemiology THE INSTITUTE OF PETROLEUM EPIDEMIOLOGICAL STUDY RESULTS OF A CASE-CONTROL STUDY TO INVESTIGATE THE RISK OF LEUKAEMIA ASSOCIATED WITH EXPOSURE TO BENZENE IN PETROLEUM MARKETING AND DISTRIBUTION WORKERS IN THE UNITED KINGDOM Dr Lesley Rushton Ms Helena Romaniuk University of Nottingham August 1995

8 EXECUTIVE SUMMARY A previous cohort study of workers in UK oil distribution centres, funded by the Institute of Petroleum, found raised mortality from leukaemia, in particular among drivers and from acute myeloid leukaemia. Mortality from all leukaemias in the total distribution worker cohort was slightly higher than that expected in the national population (Standardised Mortality Ratio (SMR) = 108, 95% Confidence Interval (CI) ), but for drivers was 125 (95 % CI ) and for acute myeloid leukaemia in drivers was 155 (95 % CI ). Similar elevation of mortality has been found in three other studies of distribution workers. A nested case-control study has been carried out to investigate this finding further and to evaluate the risk of leukaemia associated with exposure to benzene. From the distribution worker cohort, 91 cases were identified with a diagnosis of leukaemia on either a death certificate or a cancer registration. These cases were compared to controls (4 per case) randomly selected from the cohort. The controls were from the same Company as the respective case, matched on age, and alive and under follow-up at the time of the case occurrence. Work histories were collected for the cases and controls, together with information about the terminals at which they had worked, including fuel compositions, and occupational hygiene measurements of benzene. These data were used to derive quantitative estimates of personal exposure to benzene. The exposure estimation methodology is described in detail in a separate summary. A representative set of documented benzene measurements was assembled for selected tasks in the distribution centres, such as road tanker loading. The exposures associated with jobs carried out by the cases and controls were then estimated from these measurements with appropriate adjustments. The factors taken into account in the adjustment were job activity (to allow for known differences in tasks), number of loads handled, loading technology, percentage benzene in the fuel, product mix, and air temperature. An estimate of benzene exposure was made for each job in a work history and these were then totalled to give an estimate of cumulative exposure. Exposures were further classified according to whether they were likely to have occurred in intermittent peaks. The potential for skin exposure to benzene was estimated qualitatively. Data on other variables which might influence risk of leukaemia, such as smoking habits were sought but were incomplete and could not be used in the analysis. The main comparison variable in all analyses was case/control status. Odds ratios (OR) (the odds, or risk, of disease in higher versus low exposure groups) were calculated, conditional on the matching, to identify those variables in the study which were associated with risk for leukaemia. An odds ratio greater than 1 indicates an increased risk. For each OR a 95% confidence interval was calculated. Examination of the potential effects of confounding and other variables was carried out using conditional logistic regression, a method which enables the risk of disease to be related to several risk factors in a mathematical model, and provides ORs for exposure variables which are adjusted for the effect of confounding or other variables.

9 The 91 cases included 7 cases of acute lymphatic leukaemia (ALL), 31 cases of chronic lymphatic leukaemia (CLL), 32 cases of acute myeloid and monocytic leukaemia (AMML), 11 cases of chronic myeloid leukaemia (CML), and 10 'other' leukaemias. Analyses were carried out for all leukaemia and separately for the four main subtypes. Cumulative exposures ranged from close to 0 to over 200 ppm years, although 81 % were under 5 ppm years. Overall, there were slightly more cases than controls with a cumulative exposure above 1 ppm years, and cases had a higher mean cumulative exposure than controls. There was no significant increase in the overall risk of all leukaemias with higher cumulative exposure to benzene or with intensity of exposure, but risk was consistently doubled in subjects employed in the industry for more than 10 years. Acute lymphatic leukaemia tended to occur in workers employed after 1950, starting work after age 30 years, who worked for a short duration and who experienced low cumulative exposure with few peaks. The ORs did not increase with increasing cumulative exposure. These findings accord with those of previous studies which have shown no consistent relation between benzene and ALL. The risk of CLL appeared to be related most closely to duration of employment and the highest risk occurred in white collar workers with long service. These workers had only background levels of benzene exposure. There was little evidence for an association of risk with any exposure variables, and no evidence of an increasing risk with increasing cumulative exposure, average intensity or maximum intensity of exposure. The ORs for all categories of peak exposure were less than 1. These findings are consistent with earlier studies which have shown little evidence of a relationship between benzene exposure and CLL. Acute myeloid leukaemia is the type of leukaemia that has been most frequently reported as being associated with exposure to benzene. In the current study 94% of cases of acute myeloid and monocytic leukaemia (AMML) occurred in blue collar workers (in contrast to the CLL). The patterns of risk for this disease subgroup were different from those of the lymphatic subgroups, in which duration of employment was the variable most closely related to risk. Risk did not increase with cumulative exposure, maximum intensity or average intensity of exposure when treated as continuous variables. When they were categorised into discrete ranges, risk was increased to an odds ratio of 2.8 (95 % CI ) for a cumulative exposure between 4.5 and 45 ppm years as compared with < 0.45 ppm years. In addition, for average intensity between 0.2 and 0.4 an odds ratio of 2.8 (95% CI ) was found. However, these results were statistically unstable, with wide confidence intervals and relatively poor goodness-of-fit statistics. Cases of AMML were more often classified as having peaked exposures than controls, and when variables characterising peaks, particularly daily and weekly peaks, were included in the analysis these tended to dominate the other exposure variables. However, because of the small numbers it is not possible to distinguish the relative influence of peaked and unpeaked exposures on risk of AMML. For the 11 cases of CML there was no evidence for an increased risk as cumulative exposure, maximum intensity, average intensity and duration of employment increased, either as continuous or categorical variables. Most were blue collar workers with long service.

10 Similar patterns off peak exposure were found in CML as AMML. In summary, this study provides a valuable contribution to the assessment of the risk of leukaemia associated with exposure to low levels of benzene. The importance of recognising that the separate leukaemia subtypes may have different aetiologies has been substantiated in the varying patterns of risk shown in these results, particularly between the lymphatic and myeloid groups. There is little evidence in this study of an association between exposure to benzene and lymphatic leukaemia, either acute or chronic. There is some suggestion of a relationship between benzene exposure and myeloid leukaemia, in particular for acute myeloid and monocytic leukaemia. However, these results should be considered within the context of the study's limitations. These include uncertainties and gaps in the information collected, and small numbers in subcategories of exposure which can lead to wide confidence intervals around the risk estimates and poor fit of the mathematical models. Also there were some inconsistencies between the results obtained when the measures of exposure. were treated as continuous rather than categorical variables. In view of these limitations, doubt remains as to whether the risk of AMML is increased by cumulative exposures less than 45 ppm years. This study estimated ORs for cases relative to controls in a group of oil distribution workers in the UK. It was limited in the range of exposures experienced by the study sample. Future work currently underway includes a risk assessment for the European Union which involves combining these data with data from similar studies so that a dose response relationship over a wider range of exposures can be estimated. A tendency for risk of AMML to be associated with peaked exposure has been demonstrated but further work is needed to confirm this relation epidemiologically and to explore possible toxicological mechanisms that would explain it.

11 IP THE INSTITUTE OF PETROLEUM EPIDEMIOLOGICAL STUDY RETROSPECTIVE ESTIMATION OF EXPOSURE TO BENZENE IN A LEUKAEMIA CASE-CONTROL STUDY OF PETROLEUM MARKETING AND DISTRIBUTION WORKERS IN THE UNITED KINGDOM August 1995

12 EXECUTIVE SUMMARY BACKGROUND During 1993, the findings of the follow-up epidemiology study, funded by the Institute of Petroleum (IP), on the mortality of the workers in a United Kingdom (UK) oil distribution centre cohort, were published. These suggested raised mortality patterns, particularly for drivers and for acute myeloid leukaemia. As a result, a nested case-control study has been conducted to examine whether there is a relationship between the risk of leukaemia and exposure to low levels of benzene. The study comprised 91 leukaemia cases and 364 controls, covering the period At the outset it was recognised that reliable quantitative estimates of exposure to benzene were vital in order to achieve the overall objective. It was known that some quantitative benzene exposure data were available for a number of job titles in oil distribution operations, but the data were limited in both quantity and quality, with high quality data only being available since the late 1970s. Nevertheless, in recent years the retrospective estimation of exposures to a variety of substances in a wide range of industries has been developing with a number of approaches available. METHODOLOGY A review of possible approaches to the retrospective estimation of exposures to benzene for the cases and controls in the present study concluded that a multiplicative model should be selected. The basis of the particular model chosen had been developed and used successfully in another recent epidemiology study carried out on petroleum marketing and distribution workers in Canada. It was subsequently subjected to critical evaluation in order to confirm its general applicability to the IP study population. The model utilises well-characterised exposure data, termed Base Estimates, for the wide range of job titles involved. Modifying factors are applied to these estimates to account for differences between the conditions pertaining to the Base Estimates and those conditions relating to the work histories for the cases and controls. Thirty Base Estimates were generated by an Exposure Assessment Task Force for the IP Study. Some were derived from full shift exposure data, whilst other Base Estimates, because of the limited number of full shift data for some job titles, were synthesised from shorter term exposure measurements obtained during specific tasks and exposure situations. A wide range of potential modifying factors were initially considered. These were originally discussed at an International Workshop on Benzene Exposure Estimating, held at the University of Nottingham in February 1993, and were classified as associated with the job, product, process technology, meteorology, geographic location and topography. However, a number of the factors were subsequently eliminated for one or more of the following reasons ; they were unlikely to have had a significant effect on exposure ; insufficient data were available to quantify and apply

13 in a predictive manner ; or the modifying effect was essentially short term and likely to prove irrelevant over long term periods. Six modifying factors were ultimately utilised, relating to the job activities, the number of loads handled, the percentage benzene in the gasolines, the product mixes involved, air temperature (as a surrogate for product temperature) and the loading technology. The values for each factor were determined from scientific considerations and on the basis of objective data obtained by the University of Nottingham research team that included questionnaires, interviews, personnel records and company publications. Since the historical percentage of benzene in fuel was considered to be a very important factor, the IP undertook a comprehensive investigation to provide estimates of the average benzene content in gasolines from individual refinery sources for the period The information was supplemented by a similar investigation related to benzene-enriched fuels and gasolines. Each case and control was described by individual lines of work history and a Base Estimate exposure assigned to each job title. The Base Estimate was then adjusted by applying the modifying factors, as appropriate, to generate a Workplace Exposure Estimate (in ppm) for each work history line. These Workplace Exposure Estimates were multiplied by the number of years involved to generate a dose estimate expressed in parts per million years, i.e. ppm.years. The dose estimates for individual work history lines were then summed to give the estimated working lifetime dose for each person. All the exposure estimates were conducted blind to the case/control status. Semi-quantitative estimates of "peak" exposures were also assigned to individual lines of work history for each job title, to facilitate some subsequent analysis designed to identify if such events were likely to be of biological importance. Similarly, the potential dermal exposure to gasoline for each work history line was assessed judgmentally and assigned to one of four simple qualitative exposure categories, ranging from none to high. Each facet of the work undertaken by the IP Exposure Assessment Task Force included a quality assurance phase and all decisions, judgements and important actions have been documented. The data used for the Base Estimates and the logic relevant to the application of the modifying factors were tested and shown to be satisfactory by comparison against other real exposure data. RESULTS The Base Estimates, expressed as mean eight hour time-weighted average concentrations, were in the range ppm. The estimates of cumulative benzene exposures for the cases and controls show that 92% were below 10 ppm.years, 81% below 5 ppm years, 1.1% exceed 50 ppm.years and 0.7% exceed 100 ppm.years. The highest estimated dose was in excess of 200 ppm.years.

14 Although it is often assumed that the benzene content of UK gasolines was higher in the past than the present, this is not in accord with the findings. The IP investigation indicated that the benzene content was approximately 1 % from , about 2% from and had means in the range 1-6% for the period , depending on the refinery and period involved. The benzene content exceeded 5% for only 57 of the 1616 lines in the work histories. A particularly important factor to emerge from this work was the influence of product mix on the Workplace Exposure Estimates. Prior to 1960, many terminals were small and the percentage of gasolines handled in the product mix was relatively low. Hence, although splash loading occurred prior to the 1960s, the combination of relatively low benzene content and low gasoline in the product mix, strongly mitigated against high daily exposures to benzene vapour. Overall, about 42% of the work history lines corresponded to "background exposures" to benzene for which the two relevant Base Estimates are both below 0.02 ppm. A further 34% of work history lines corresponded to drivers, for which the Base Estimate is 0.40 ppm. Hence for the majority of the lines of work history, the Base Estimates are well below 1 ppm and given that the mean duration of employment for all of the cases and controls is just over 21 years, the retrospectively estimated cumulative dose exposures for the vast majority of persons are relatively low, i.e. less than 10 ppm.years.