3055 Major benzene study results

The Institute of Petroleum
Epidemiological Study

Executive Summaries

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 (0.1- 1.0 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 1991. 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 1995. 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".

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 4.5-45 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.

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 1995.

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

The Institute of Petroleum
Epidemiological Study

Restrospective Estimation of Exposure to Benzene in a Leukaemia Case-Control Study of Petroleum Marketing and Distribution Workers in the United Kingdom

August 1995

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 1909-1992.

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 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 1920-1980. 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 0.003 - 8.20 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.

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 1920-1930, about 2% from 1931-1949 and had means in the range 1-6% for the period 1950-1980, 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.