Peter Ritchie

Tools for regulatory assessment of occupational exposure: development and challenges

REACH (Registration, Evaluation and Authorization of CHemicals) requires improved exposure models that can be incorporated into screening tools and refined assessment tools. These are referred to as tier 1 and 2 models, respectively. There are a number of candidate in tier 1 models that could be used with REACH. Tier 2 models, producing robust and realistic exposure assessments, are currently not available. A research programme is proposed in this paper that will result in a new, advanced exposure assessment tool for REACH. In addition, issues related to variability and uncertainty are discussed briefly, and some examples of tier 1 screening tools are presented. The proposed framework for the tier 2 tool is based on a Bayesian approach, and makes full use of mechanistically modelled estimates and any relevant measurements of exposure. The new approach will preclude the necessity to conduct of case-by-case exposure measurements for each chemical and scenario, since the system will allow for the use of analogous exposure data from relatively comparable scenarios. The development of the new approach requires substantial effort in the area of mechanistic modelling, database development and Bayesian statistical techniques. In this paper, the data gaps and areas for future research are identified to help realise and further improve this type of approach within REACH. A structured data collection and storage system is a central element of the research programme and the availability of this type of tool may also facilitate the sharing of exposure data down and up the supply chain. In addition, new data that are stored according to the proposed structure could enable the validation of any exposure model and thus this programme enhances the exposure assessment field as a whole.

Advanced REACH Tool (ART): Overview of Version 1.0 and Research Needs

This paper provides an outline of the Advanced REACH Tool (ART) version 1.0 and a discussion of how it could be further developed. ART is a higher tier exposure assessment tool that combines mechanistically modelled inhalation exposure predictions with available exposure data using a Bayesian approach. ART assesses exposure for scenarios across different plants and sites. Estimates are provided for different percentiles of the exposure distribution and confidence intervals around the estimate. It also produces exposure estimates in the absence of data, but uncertainty of the estimates will decrease when results of exposure measurements are included. The tool has been calibrated using a broad range of exposure data and provides estimates for exposure to vapours, mists, and dusts. ART has a robust and stable conceptual basis but will be refined in the future and should therefore be considered an evolving system. High-priority areas for future research are identified in this paper and include the integration of partially analogous measurement series, inclusion of company and site-specific assessments, user decision strategies linked to ART predictions, evaluation of validity and reliability of ART, exploring the possibilities for incorporating the dermal route and integration of ART predictions with tools for modelling internal dose. ART is initially developed in the scope of REACH but is equally useful for exposure assessment in other areas.

Development of a Task-Exposure Matrix (TEM) for pesticide use (TEMPEST).

INTRODUCTION Pesticides have been associated with increased risks for a range of conditions including Parkinsons disease, but identifying the agents responsible has proven challenging. Improved pesticide exposure estimates would increase the power of epidemiological studies to detect such an association if one exists. METHODS Categories of pesticide use were identified from the tasks reported in a previous community-based case-control study in Scotland. Typical pesticides used in each task in each decade were identified from published scientific and grey literature and from expert interviews, with the number of potential agents collapsed into 10 groups of pesticides. A pesticide usage database was then created, using the task list and the typical pesticide groups employed in those tasks across seven decades spanning the period 1945-2005. Information about the method of application and concentration of pesticides used in these tasks was then incorporated into the database. RESULTS A list was generated of 81 tasks involving pesticide exposure in Scotland covering seven decades producing a total of 846 task per pesticide per decade combinations. A Task-Exposure Matrix for PESTicides (TEMPEST) was produced by two occupational hygienists who quantified the likely probability and intensity of inhalation and dermal exposures for each pesticide group for a given use during each decade. CONCLUSIONS TEMPEST provides a basis for assessing exposures to specific pesticide groups in Scotland covering the period 1945-2005. The methods used to develop TEMPEST could be used in a retrospective assessment of occupational exposure to pesticides for Scottish epidemiological studies or adapted for use in other countries.

The Advanced REACH Tool (ART): Incorporation of an Exposure Measurement Database

This article describes the structure, functionalities, and content of the Advanced REACH Tool (ART) exposure database (version 1.5). The incorporation of the exposure database into ART allows users who do not have their own measurement data for their exposure scenario, to update the exposure estimates produced by the mechanistic model using analogous measurement series selected from the ART exposure measurement database. Depending on user input for substance category and activity (sub)classes, the system selects exposure measurement series from the exposure database. The comprehensive scenario descriptions and summary statistics assist the user in deciding if the measurement series are indeed fully analogous. After selecting one or more analogous data sets, the data are used by the Bayesian module of the ART system to update the mechanistically modeled exposure estimates. The 1944 exposure measurements currently stored in the ART exposure measurement database cover 9 exposure situations for handling solid objects (n = 65), 42 situations for handling powders, granules, or pelletized material (n = 488), 5 situations for handling low-volatility liquids (n = 88), 35 situations for handling volatile liquids (n = 870), and 26 situations for handling liquids in which powders are dissolved or dispersed (resulting in exposure to mist) (n = 433). These 117 measurement series form a good basis for supporting user exposure estimates. However, by increasing the diversity of exposure situations and the number of measurement series in the database, the usefulness of the ART system will be further improved. Suggestions to stimulate the process of sharing exposure measurement data both to increase the available data in the ART and for other purposes are made.

Retrospective Collection of Exposure Data from Industry: Results from a Feasibility Study in the United Kingdom

In the United Kingdom the Health and Safety Executive for some years has stored chemical exposure data in their National Exposure Database. However, it has been difficult to persuade industry and other organizations to contribute to this resource. The aim of this project was to devise a cost-effective method of obtaining occupational exposure data on chemicals from U.K. industry and other sources. Five strategies were used to identify data for three different substances: toluene, acrylonitrile, and ethylene oxide. In total, 810 organizations were contacted and over 45 percent responded. However, only 40 had relevant exposure data. Almost equal numbers of acceptable measurements were identified for toluene and acrylonitrile (2,770 and 2,000 respectively) with lesser ethylene oxide data (800). These measurements were drawn from a wide range of industries and are probably representative of measurements made by U.K. industry, although most of the data were from companies employing more than 100 people. During the second phase of the project, more than 3,000 measurements and associated contextual information were collected (499 for toluene, 1,516 for acrylonitrile, and 17 for ethylene oxide, with a further 1,004 measurements for 1 of 27 substances collected simultaneously with one of the above). The costs of identifying and collecting exposure data ranged from ł7 to ł380 per valid measurement, depending on the source of the data. We suggest that, rather than trying to retrospectively collect data, it is likely to be more cost-effective to enlist a number of occupational hygiene consults and industrial organizations to prospectively provide anonymized exposure measurements for inclusion in the Health and Safety Executives National Exposure Database.

The Development of a Prototype Database for the Voluntary Reporting of Occupational Exposure Data on Chemicals

A prototype occupational exposure database was developed as part of a study to retrospectively collect chemical exposure data from U.K. industry. The data dictionary for the database was constructed using existing recommendations on core data elements developed by working groups from the ACGIH and the European Union. The study also made use of existing job and workplace coding schemes. The practicalities of gathering the data by voluntary donation, its storage in a database, and the transfer of suitably anonymised data to the U.K. Health and Safety Executives National Exposure Database system were investigated and assessed. Prior to the development, several existing exposure database systems were evaluated for their suitability to store the data from the study. Though of high quality, these were found to be insufficiently flexible for the diversity of datasets encountered and so the prototype exposure database was constructed using a leading database development package. The database was successfully used to gather data and forward it in a suitable format to the U.K. Health and Safety Executive. The published recommendations on occupational exposure databases and the associated coding schemes provided a very useful foundation for designing and implementing the prototype database. However, as data collection proceeded it became clear that the existing recommendations often were poorly understood and misinterpreted, or at least interpreted differently, by different database designers, data collectors, and other users of occupational exposure data. It is suggested that several items in the ACGIH and European Union core recommendations are ambiguous and need to be clarified. Once agreed, the improved database design criteria need to be widely promoted to foster a common understanding and to encourage their use by all those involved in collecting occupational exposure data. Beyond this, recommendations for exposure databases should be augmented to facilitate easy exchange of data between organizations.

British rubber and cable industry cohort: 49-year mortality follow-up

Background The International Agency for Research on Cancer (IARC) has determined there is sufficient evidence that working in the rubber manufacturing industry increases the risk of cancers of the stomach, lung, bladder and leukaemia and lymphoma. Objectives To examine mortality patterns of a prospective cohort of men from the rubber and cable manufacturing industries in Great Britain. Methods SMRs were calculated for males aged 35+ years at start of follow-up in 1967–2015 using the population of England and Wales as the external comparator. Tests for homogeneity and trends in SMRs were also completed. Results For all causes, all malignant neoplasms, non-malignant respiratory diseases and circulatory diseases, SMRs were significantly elevated, and also particularly for cancers of the stomach (SMR=1.26,95% CI 1.18 to 1.36), lung (1.25,95% CI 1.21 to 1.29) and bladder (1.16,95% CI 1.05 to 1.28). However, the observed deaths for leukaemia, non-Hodgkin’s lymphoma (NHL) and multiple myeloma were as expected. Bladder cancer risks were elevated only in workers exposed to antioxidants containing 1-naphthylamine and 2-naphthylamine. Conclusions This study provides evidence of excess risks in the rubber industry for some non-cancer diseases and supports IARC’s conclusions in relation to risks for cancers of the bladder, lung and stomach, but not for leukaemia, NHL or multiple myeloma.

0361 A 49 year follow-up of mortality in the british rubber industry

Rubber workers in Great Britain were historically exposed to various carcinogenic substances, including β-naphthylamine, which was removed from industrial processes in 1949. The Health and Safety Executive (HSE) initiated in 1967 a prospective occupational cohort study of British rubber industry workers, including men 35 years of age and older, to examine cancer mortality (n=40 867, representing 381 factories). Findings from a 10 year follow-up of that cohort suggested excess mortality from cancers of the bladder, lung, and stomach, which differed by exposure to naphthylamines, as well as by industry sector and job code. The purpose of this analysis is to extend mortality follow-up through to 2015, allowing an assessment of cancers in older ages and with longer latency periods. As well as headline Standardised Mortality Ratios (SMRs) for the cancer subtypes previously investigated, we will present mortality risks for a range of causes including leukaemia, multiple myeloma, circulatory and respiratory diseases. We will use England and Wales reference rates to compare mortality by employment duration and sector in the rubber industry. Preliminary analysis of a majority subset of the cohort (n=34,595) to 2015 identified an elevated all cause SMR of 1.11 (95%CI 1.10–1.12). More detailed results from this multi-decade follow-up of workers from rubber manufacturing will provide valuable insights into cancer mortality risks for exposed occupational populations, both in the UK and elsewhere.

0249 Job-exposure matrix for historical exposure to rubber dust, rubber fumes, and n-nitrosamines in the british rubber industry

In 1982 IARC concluded that there was sufficient evidence for a causal association between occupational exposures in the rubber manufacturing industry and urinary bladder cancer and leukaemia. To enable evaluations of exposure-response associations in a cohort of men age 35+ employed in the British rubber industry in 1967 with a 49 year mortality followup (n=40,867), we created a quantitative historical job-exposure matrix (JEM) covering the period 1915–2000 based on personal and area measurements previously collated within the EU-EXASRUB project for rubber dust (n=4,187), rubber fumes (n=3,852), and n-Nitrosamines (n=10,215). These data were modelled by job function using linear mixed-effects models with sample year and industry sector as explanatory factors and a random factory intercept. Variations in exposure levels over time between compounds and department were observed. For example, rubber dust exposures ranged from −8.8%/yr (crude materials and mixing, p<0.001) to +0.5%/yr (curing, p=0.01) while rubber fumes exposures declined between −8.3%/yr (crude materials and mixing, p<0.001) and −0.2%/yr (finishing, assembly, and miscellaneous, p=0.218). JEM-estimates were linked to all cohort members for each year worked to calculate average annual and lifetime cumulative exposures (AAE, LCE), thereby allowing quantitative evaluation of exposure-response associations between 50 year occupational exposure and cancer mortality. AAE rubber dust exposures ranged between 0.3 mg/m3 (curing) and 36.3 mg/m3 (crude materials and mixing). Rubber fumes exposures range between 0.3 mg/m3 (finishing, assembly, and miscellaneous) and 5.4 mg/m3 (crude materials and mixing). LCE trends mirrored AAE results. JEM-estimates will allow for quantitative exposure-response association assessments between long-term occupational exposure and cancer mortality.