Ruth Bevan

Occupation and cancer in Britain.

Background:Prioritising control measures for occupationally related cancers should be evidence based. We estimated the current burden of cancer in Britain attributable to past occupational exposures for International Agency for Research on Cancer (IARC) group 1 (established) and 2A (probable) carcinogens.Methods:We calculated attributable fractions and numbers for cancer mortality and incidence using risk estimates from the literature and national data sources to estimate proportions exposed.Results:5.3% (8019) cancer deaths were attributable to occupation in 2005 (men, 8.2% (6362); women, 2.3% (1657)). Attributable incidence estimates are 13 679 (4.0%) cancer registrations (men, 10 063 (5.7%); women, 3616 (2.2%)). Occupational attributable fractions are over 2% for mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma, larynx and stomach cancers. Asbestos, shift work, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, occupation as a painter or welder, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists each contribute 100 or more registrations. Industries and occupations with high cancer registrations include construction, metal working, personal and household services, mining, land transport, printing/publishing, retail/hotels/restaurants, public administration/defence, farming and several manufacturing sectors. 56% of cancer registrations in men are attributable to work in the construction industry (mainly mesotheliomas, lung, stomach, bladder and non-melanoma skin cancers) and 54% of cancer registrations in women are attributable to shift work (breast cancer).Conclusion:This project is the first to quantify in detail the burden of cancer and mortality due to occupation specifically for Britain. It highlights the impact of occupational exposures, together with the occupational circumstances and industrial areas where exposures to carcinogenic agents occurred in the past, on population cancer morbidity and mortality; this can be compared with the impact of other causes of cancer. Risk reduction strategies should focus on those workplaces where such exposures are still occurring.

Occupational cancer burden in Great Britain

A sound knowledge base is required to target resources to reduce workplace exposure to carcinogens. This project aimed to provide an objective estimate of the burden of cancer in Britain due to occupation. This volume presents extensive analyses for all carcinogens and occupational circumstances defined as definite or probable human occupational carcinogens by the International Agency for Research on Cancer. This article outlines the structure of the supplement – two methodological papers (statistical approach and exposure assessment), eight papers presenting the cancer-specific results grouped by broad anatomical site, a paper giving industry sector results and one discussing work-related cancer-prevention strategies. A brief summary of the methods and an overview of the updated overall results are given in this introductory paper. A general discussion of the overall strengths and limitations of the study is also presented. Overall, 8010 (5.3%) total cancer deaths in Britain and 13, 598 cancer registrations were attributable to occupation in 2005 and 2004, respectively. The importance of cancer sites such as mesothelioma, sinonasal, lung, nasopharynx, breast, non-melanoma skin cancer, bladder, oesophagus, soft tissue sarcoma and stomach cancers are highlighted, as are carcinogens such as asbestos, mineral oils, solar radiation, silica, diesel engine exhaust, coal tars and pitches, dioxins, environmental tobacco smoke, radon, tetrachloroethylene, arsenic and strong inorganic mists, as well as occupational circumstances such as shift work and occupation as a painter or welder. The methods developed for this project are being adapted by other countries and extended to include social and economic impact evaluation.

Sources of Variability in Biomarker Concentrations

Human biomonitoring has become a primary tool for chemical exposure characterization in a wide variety of contexts: population monitoring and characterization at a national level, assessment and description of cohort exposures, and individual exposure assessments in the context of epidemiological research into potential adverse health effects of chemical exposures. The accurate use of biomonitoring as an exposure characterization tool requires understanding of factors, apart from external exposure level, that influence variation in biomarker concentrations. This review provides an overview of factors that might influence inter- and intraindividual variation in biomarker concentrations apart from external exposure magnitude. These factors include characteristics of the specific chemical of interest, characteristics of the likely route(s) and frequency of exposure, and physiological characteristics of the biomonitoring matrix (typically, blood or urine). Intraindividual variation in biomarker concentrations may be markedly affected by the relationship between the elimination half-life and the intervals between exposure events, as well as by variation in characteristics of the biomonitored media such as blood lipid content or urinary flow rate. Variation across individuals may occur due to differences in time of sampling relative to exposure events, physiological differences influencing urinary flow or creatinine excretion rates or blood characteristics, and interindividual differences in metabolic rate or other factors influencing the absorption or excretion rate of a compound. Awareness of these factors can assist researchers in improving the design and interpretation of biomonitoring studies.

Inter- and intra-individual variation in urinary biomarker concentrations over a 6-day sampling period. Part 1: Metals

The aim of the current HBM-study is to further the understanding of the impact of inter- and intra-individual variability in HBM surveys as it may have implications for the design and interpretation of the study outcomes. As spot samples only provide a snapshot in time of the concentrations of chemicals in an individual, it remains unclear to what extent intra-individual variability plays a role in the overall variability of population-wide HBM surveys. The current paper describes the results of an intensive biomonitoring study, in which all individual urine samples of 8 individuals were collected over a 6-day sampling period (a total of 352 unique samples). By analyzing different metals (As, Cd, Mn, Ni) in each individual sample, inter- and intra-individual variability for these four metals could be determined, and the relationships between exposure, internal dose, and sampling protocol assessed. Although the range of biomarker values for different metals was well within the normal range reported in large-scale population surveys, large intra-individual differences over a 6-day period could also be observed. Typically, measured biomarker values span at least an order of magnitude within an individual, and more if specific exposure episodes could be identified. Fish consumption for example caused a twenty- to thirty-fold increase in urinary As-levels over a period of 2-6h. Intra-class correlation coefficients (ICC) were typically low for uncorrected biomarker values (between 0.104 and 0.460 for the 4 metals), but improved when corrected for creatinine or specific gravity (SG). The results show that even though urine is a preferred matrix for HBM studies, there are certain methodological issues that need to be taken into account in the interpretation of urinary biomarker data, related to the intrinsic variability of the urination process itself, the relationship between exposure events and biomarker quantification, and the timing of sampling. When setting up HBM-projects, this expected relationship between individual exposure episode and urinary biomarker concentration needs to be taken into account.

Framework for the development and application of environmental biological monitoring guidance values

Human biomonitoring (HBM) is widely recognised as a useful tool to aid assessment of exposure to chemical substances, but our ability to detect hazardous substances (or their metabolites and health effects) often exceeds our understanding of their biological relevance. There are only a few established frameworks for developing and using occupational and environmental biological guidance values (BGVs), mostly for data-rich substances that have been in use for some time. BGVs for new substances and those with unknown dose-response relationships are difficult to derive. An accepted framework based on current scientific knowledge and best practice is therefore urgently needed to help scientists, regulators, and stakeholders to design appropriate HBM studies, interpret HBM data (both for groups and individuals) understand the limitations and to take appropriate action when required. The development and application of such a tool is described here. We derived a conceptual framework that was refined by consultation with an advisory group and workshop. The resulting framework comprised four levels defined by increasing data, with increasing confidence for human health risk assessment. Available data were used for 12 chemicals with expert judgement to illustrate the utility of the framework.

Determination of ethylenethiourea in urine by liquid chromatography-atmospheric pressure chemical ionisation-mass spectrometry for monitoring background levels in the general population

This study reports a sensitive analytical method suitable for the quantitative analysis of ethylenethiourea (ETU) in human urine and its application to samples from the general population. Sample preparation involved the use of diatomaceous earth extraction columns to remove matrix interferences. Quantification was achieved by liquid chromatography-mass spectrometry using positive ion atmospheric pressure chemical ionisation. Within-day and between-day variability of 14% (n=10) and 11% (n=6), respectively, were obtained at 98 nmol/l (10 μg l(-1)). The assay was linear over the investigated range 2.5-245 nmol/l, with a limit of detection of 2.5 nmol/l. The method was applied to monitoring background levels of ETU in urine samples from the general population in the UK. Results obtained from 361 spot samples contained ETU levels ranging from less than the detection limit (54% of samples) to a maximum of 15.8 μmol/mol creatinine (14.3 μg/g creatinine). The 95th percentile was 5.7 μmol/mol creatinine (5.2 μg/g creatinine).

An assessment of potential cancer risk following occupational exposure to ethanol.

Recognition of the carcinogenic properties of ethanol has resulted from comprehensive evidence regarding the effect of consumption of alcohol; indeed, ethanol in alcoholic beverages is now considered a Group 1 carcinogen by the International Agency for Research on Cancer. However, there is little information on the effects of ethanol following exposure via the occupationally relevant routes of inhalation and dermal exposure. This review therefore focuses on these exposure routes, to assess potential carcinogenic risk associated with occupational exposure to ethanol. Inhalatory exposure at the current occupational exposure limit (OEL) for the United Kingdom (1000 ppm ethanol over an 8-h shift) was estimated to be equivalent to ingestion of 10 g ethanol (approximately 1 glass of alcohol) per day. However, in the occupational setting the dose-rate delivery of this amount of ethanol is low, allowing for its rapid and effective elimination, for the majority of individuals. Similarly, while dermal absorption in an occupational setting could potentially add to overall body ethanol burden, additional carcinogenic risk of such exposure is considered negligible. Thus, on balance, there appears little cause to suppose occupational exposure at or below the current OEL associates with any appreciable increase in risk of cancer. However, available occupational exposure data to confirm this view are currently limited. It is also suggested that adoption of a more flexible classification regime, considering risk in the context of hazard and exposure (such as that adopted by the German MAK commission), would represent an improvement over traditional occupational risk assessment practices.

Setting evidence-based occupational exposure limits for manganese

HighlightsOELs for Mn are based on subtle neurological changes as the key toxicity endpoint.These changes are limited in particular by unreliable exposure estimates.Clinical significance of subclinical cognitive or neuromotor changes is unknown.8‐h TWAs for respirable and inhalable fractions are recommended by the SCOEL.These are considered the most methodologically‐sound of those currently proposed. Abstract In 2004, a review by the Institute of Environment and Health (IEH) made recommendations on occupational exposure limits (OELs) for manganese and its inorganic compounds for inhalable and respirable fractions respectively. These OELs were based on a detailed comprehensive evaluation of all the scientific data available at that time. Since then, more published studies have become available and a number of occupational standard‐setting committees (EU SCOEL, US ACGIH‐TLV, and German MAK) have proposed OEL’s for manganese and its inorganic compounds that are somewhat lower that those proposed in the 2004 review. Based on current understanding, the key toxicological and human health issues that are likely to influence a health‐based recommendation relate to: neurotoxicology; reproductive and developmental toxicology; and mutagenicity/carcinogenicity. Of these, it is generally considered that neurotoxicity presents the most sensitive endpoint. As such, many of the studies that have been reported since the IEH review have sought to use those neurofunctional tests that appear to be particularly sensitive at identifying the subtle neurological changes thought to associate with manganese toxicity. These recent studies have, however, continued to be limited to a significant extent by reliance on cross‐sectional designs and also by use of unreliable exposure estimation methods. Consequently the strength of the potential association between manganese exposure and these subtle subclinical cognitive or neuromotor changes is still poorly characterised and the relevance of these minor differences in terms of either their clinical or quality of life consequences remains unknown. Based upon the overall evidence, it is concluded that the 8‐h time weighted averages (TWA) for respirable (0.05 mg/m3 as Mn) and inhalable (0.2 mg/m3 as Mn) fractions as recommended by the SCOEL in 2011 are the most methodologically‐sound, as they are based on the best available studies, most suited to the development of health‐based OELs for both respirable and inhalable fractions. The dose‐response characterisation informed by the examined studies used can be considered to establish a true human NOAEL for all the neurofunctional endpoints examined within the selected studies.

Multicenter study to assess potential hazards from exposure to lipid peroxidation products in soya bean oil from Trilucent™ breast implants

In response to a Hazard Notice by the Medical Devices Agency of the UK in 2000 regarding the Trilucent breast implant (TBI), an expert panel was convened to implement a research program to determine whether genotoxic compounds were formed in the soybean oil filler (SOF) of TBIs and whether these could be released to produce local or systemic genotoxicity. The panel established a research program involving six laboratories. The program recruited 47 patients who had received TBIs (9 patients had received silicone implants previously). A reference group (REBI) of 34 patients who had exchanged either silicone (17 patients) implants (REBI-E) or patients (17) who were to receive primary implantation augmentation with silicone (REBI-PIA), and who were included as needed to increase either the pre- or post-explantation sample number. Of the 17 REBI-E patients, 5 had silicone implants and 12 had saline implants previously (prior to the last exchange). Investigation was undertaken before and after replacement surgery in the TBI patients and before and after replacement or augmentation surgery in the REBI patients. The pre- to post-operative sample interval was 8-12 weeks. Pre-operative samples were collected within 7 days prior to the operation. Information on a variety of demographic and behavioral features was collected. Biochemical and biological endpoints relating to genotoxic lipid peroxidation (LPO) products potentially formed in the SOF, and released locally or distributed systemically, were measured. The SOF of explanted TBIs was found to have substantial levels of LPO products, particularly malondialdehyde (MDA), and low levels of trans-4-hydroxy-2-nonenal (HNE) not found in unused implants. Mutagenicity of the SOF was related to the levels of MDA. Capsules that formed around TBIs were microscopically similar to those of reference implants, but MDA-DNA adducts were observed in capsular macrophages and fibroblasts of only TBI capsules. These cell types are not progenitors of breast carcinoma (BCa) and the location of the implants precludes LPO products reaching the mammary epithelial cells which are progenitors of BCa. Blood levels of LPO products were not increased in TBI patients compared to REBI patients and did not change with explantation. In TBI patients, white blood cells did not show evidence of increased levels of LPO-related aldehyde DNA adducts. In conclusion, based on a number of measured parameters, there was no evident effect that would contribute to breast or systemic cancer risk in the TBI patients, and the recommended treatment of TBI patients involving explantation was judged appropriate.

Toxicity testing of poorly soluble particles, lung overload and lung cancer

ABSTRACT In 2013, an ECETOC Task Force evaluated scientific understanding of the ‘lung overload’ hypothesis. As there is no evidence that humans develop lung tumours following exposure to poorly soluble particles (PSPs), emphasis was given to the observed higher sensitivity and specificity of rat lung responses and potential impacts of this on human risk assessment. Key arguments and outcomes are summarised here, together with discussion of additional findings published since 2013. Inhalation exposure to PSPs in all species is associated with localised pulmonary toxicity initiated by a persistent pro‐inflammatory response to particle deposition. Events in the rat indicate a plausible adverse outcome pathway for lung tumour development following exposure to PSPs under overload conditions. A different particle lung translocation pattern compared to rats make humans less sensitive to developing comparable lung overload conditions and appears to also preclude tumour formation, even under severe and prolonged exposure conditions. Evidence continues to suggest that the rat lung model is unreliable as a predictor for human lung cancer risk. However, it is a sensitive model for detecting various thresholded inflammatory markers, with utility for non‐neoplastic risk assessment purposes. It is noteworthy that preventing inflammatory rat lung responses will also inhibit development of neoplastic outcomes. HIGHLIGHTSInhalation of high concentrations of PSPs leads to pro‐inflammatory responses and pulmonary toxicity in all species.In humans, inhalation exposure to PSPs is not associated with development of lung tumours.Interstitialisation of PSPs in humans is a key factor in the difference in pathological response between rats and humans.The rat model is sensitive and valuable for detecting early and thresholded responses of inflammatory markers.