AbstractThe working group “Analyses in Biological Materials” of the Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area verified the present biomonitoring method.The described method allows the simultaneous determination of the metabolites of hexamethylene diisocyanate (HDI), 2,4‐toluenediamine and 2,6‐toluene diisocyanate (TDI), isophorone diisocyanate (IPDI) and methylene diphenyl diisocyanate (MDI) in human urine. After acid hydrolysis the released amines, hexamethylenediamine (HDA), 2,4‐, and 2,6‐toluenediamine (TDA), isophorone diamine (IPDA) and 4,4′‐methylenedianiline (4,4′‐MDA) are extracted from urine, derivatised using heptafluorobutyric anhydride and quantified by NCI‐GC‐MS. The method was extensively validated and the reliability data were confirmed by independent laboratories, which have established and cross‐checked the whole procedure

AbstractThe working group “Analyses in Biological Materials” of the Permanent Senate Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area verified the present biomonitoring method.The described method allows the simultaneous determination of the metabolites of hexamethylene diisocyanate (HDI), 2,4‐toluene diisocyanate and 2,6‐toluene diisocyanate (TDI), isophorone diisocyanate (IPDI) and methylene diphenyl diisocyanate (MDI) in human urine. After acid hydrolysis the released amines, hexamethylenediamine (HDA), 2,4‐toluenediamine, and 2,6‐toluenediamine (TDA), isophorone diamine (IPDA) and 4,4′‐methylenedianiline (4,4′‐MDA) are extracted from urine, derivatised using heptafluorobutyric anhydride and quantified by NCI‐GC‐MS. The method was extensively validated and the reliability data were confirmed by independent laboratories, which have established and cross‐checked the whole procedure.

Acrylamide is classified as a potential human carcinogen and neurotoxicant. Biological monitoring is a useful tool for monitoring worker exposure. However, other sources of exposure to acrylamide (including cigarette smoke and diet) also need to be considered. This study has performed repeat measurements of the urinary mercapturic acids of acrylamide (AAMA) and its metabolite glycidamide (GAMA) and determined globin adducts in 20 production-plant workers at a UK acrylamide production facility. The relationship between biomarker levels and environmental monitoring data (air levels and hand washes) was investigated. Good correlations were found between all of the biomarkers (r(2)=0.86-0.91) and moderate correlations were found between the biomarkers and air levels (r(2) = 0.56-0.65). Our data show that urinary AAMA is a reliable biomarker of acrylamide exposure. Occupational hygiene data showed that acrylamide exposure at the company was well within the current UK Workplace Exposure Limit. The 90th percentile of urinary AAMA in non-smoking production-plant workers (537 μmol/mol creatinine (n = 59 samples)) is proposed as a possible biological monitoring guidance value. This 90th percentile increased to 798 μmol/mol if smokers were included (n = 72 samples). These values would be expected following an airborne exposure of less than 0.07 mg/m(3), well below the current UK workplace exposure limit of 0.3mg/m(3). Comparison of biomarker levels in non-occupationally exposed individuals suggests regional variations (between UK and Germany), possibly due to differences in diet.

Background levels of 38 elements of a UK population are presented here from 137 people. It has been possible to assign 95th percentile data most of these elements. This presentation will summarise the findings of the background level study and show how this compares with biological monitoring data collected from routine occupational monitoring.

Human biomonitoring (HBM) is a widely accepted tool to aid assessment of chemical uptake in risk assessment. However, our understanding of the biological relevance of the results of HBM can be restricted, due in some part to the limited information on background environmental exposures and biomarker concentrations in the general population. The study described here specifically addresses the question of what constitutes normal background levels in the UK population of a number of biomarkers (the chemical itself or one of its stable metabolites) for a variety of environmental chemicals that are frequently encountered because of their widespread use. The environmental chemicals selected for this study were benzene, chlorinated hydrocarbons, dithiocarbamates, cadmium, mercury, naphthalene, diethylhexyl phthalate, synthetic pyrethroids and xylene. Volunteers (n=436) were randomly sought by a postal survey based on the UK Electoral Register. Participants were asked to complete a questionnaire and provide a urine sample. The overall response rate was 7.5%, with volunteers being recruited from all areas of the UK including, England, Scotland, Wales and Northern Ireland. Study participants were adults and comprised 45% male and 55% females. We have conducted a simple, postal-based, cost-effective study and generated similar reference values to very large surveys such as NHANES. This demonstrates that large investigations may not be necessary to get a reasonable idea of environmental exposures, especially in initial 'screening-type' investigations to identify particular exposures of concern or to demonstrate that exposures are reassuring low and that no further survey data needs to be gathered.

This is a follow up survey of exposure to 4,4'-methylene-bis(2-chloroaniline) (MbOCA) and isocyanates in the UK polyurethane industry. Urine samples (n = 446) were collected from 90 different workers. MbOCA levels were below the limit of detection in 170 samples and 26 were above the UK Biological Monitoring Guidance Value (BMGV) of 15 mu mol MbOCA/mol creatinine. Detailed advice and guidance was given to each workplace at the end of the survey in 2008 and the 90% value reduced from 10 to 3 mu mol MbOCA/mol creatinine in samples collected since. There was a positive correlation between glove contamination and urinary MbOCA and levels were dependant upon individual working practices especially how gloves were used.Of the 446 samples analysed for urinary metabolites of toluene diisocyanate 280 were below the detection limit and 126 were above the BMGV (1 mu mol/mol creatinine). Of the 326 urine samples that were analysed for metabolites of methylenediphenyl diisocyanate, 270 were below the detection limit and 13 were above the BMGV for isocyanates. There was no correlation between urinary levels of isocyanates and MbOCA suggesting different routes of absorption, most likely inhalation and dermal respectively. Crown Copyright (C) 2011 Published by Elsevier Ireland Ltd. All rights reserved.

Background Biological monitoring (BM) aids exposure assessment but where this is based on incomplete collections of single urine voiding measurement of creatinine is often used to adjust analyte concentrations for the effects of fluid balance.Aims To provide reference data on creatinine concentrations in urine samples from a population of UK workers.Methods Urine samples sent to the Health and Safety Laboratory were analysed for creatinine by an automated kinetic Jaffe technique using alkaline picric acid and the results stored in a database. Statistical analysis of the data used linear mixed effects models on the natural log-transformed data.Results Between 1996 and 2007, the laboratory analysed 49 506 urine samples from 20 433 UK adult workers. In the 42 817 samples where gender was known, 93% were from men and 7% were from women. The overall mean and median creatinine concentrations were both 12 mmol/l corresponding to 1.36 g/l. The mean (13 mmol/l) and median (12 mmol/l) creatinine concentrations for men were higher than those (9 and 10 mmol/l, respectively) for women.Conclusions Gender differences in creatinine concentrations and the range of 0.3-3.0 g/l (2.653 and 26.53 mmol/l) traditionally used for confirming acceptability of urine samples mean that 2.5% of samples from male and 9% from female workers were flagged as 'low creatinine' and required a repeat sample. In addition, care should be taken interpreting any apparent gender differences in BM results to ensure that they are due to exposure and not an artefact of creatinine adjustment.

There are numerous programs ongoing to analyze environmental exposure of humans to xenobiotic chemicals via biomonitoring measurements (e.g.: EU ESBIO, COPHES; US CDC NHANES; Canadian Health Measures Survey). The goal of these projects is to determine relative trends in exposure to chemicals, across time and subpopulations. Due to the lack of data, there is often little information correlating biomarker concentrations with exposure levels and durations. As a result, it can be difficult to utilize biomonitoring data to evaluate if exposures adhere to or exceed hazard/exposure criteria such as the Derived No-Effect Level values under the EU REACH program, or Reference Dose/Concentration values of the US EPA. A tiered approach of simple, arithmetic pharmacokinetic (PK) models, as well as more standardized mean-value, physiologically-based (PBPK) models, have therefore been developed to estimate exposures from biomonitoring results. Both model types utilize a user-friendly Excel spreadsheet interface. QSPR estimations of chemical-specific parameters have been included, as well as accommodation of variations in urine production. Validation of each model's structure by simulations of published datasets and the impact of assumptions of major model parameters will be presented.

Methods: An occupational hygienist and a field scientist visited the two UK suppliers and 20 out of the 25 workplaces known to be using MbOCA in the UK during 2005 and 2006. They collected air samples, surface wipes, gloves, and urine samples and made observations to assess exposure and the adequacy of controls. All samples were analysed for MbOCA and urine samples were additionally analysed for isocyanate metabolites. A statistical analysis was made of the results.Results: Only 2.5% of the 80 personal inhalation exposures to MbOCA exceeded the workplace exposure limit of 5 mu g m(-3) 8-h time-weighted average and 84% were below the limit of detection (LOD). Surface samples (n = 334) were collected from MbOCA users and suppliers and 60% had detectable levels of MbOCA ranging from 0.019 to 400 mu g cm(-2). The highest levels were around a hopper, ovens, and the weighing and pouring areas. MbOCA was also detected in 8 of the 75 samples collected from areas not likely to be in contact with MbOCA. At the two suppliers, samples (n = 28) were collected from the outside surfaces of recently imported kegs, pallets, and the floor around kegs. Six samples had detectable levels and four of these (0.2, 0.8, 1, and 6 mu g cm(-2)) were from the floor and pallets in both suppliers. The other two positive results were found on the outside rim (18 mu g cm(-2)) and side (23 mu g cm(-2)) of a keg at one supplier indicating contamination by the manufacturer. Urine samples (n = 79) were collected and 49% were below the LOD for MbOCA and only three samples had levels of MbOCA that exceeded the biological monitoring guidance value (BMGV) of 15 mu mol mol(-1) creatinine. The highest urinary MbOCA concentrations were in samples from workers casting and moulding. The 90th percentile of the urine MbOCA results was 8.6 mu mol MbOCA per mol creatinine. Urine samples were also analysed for the diamine metabolites of toluene diisocyanate and hexamethylene diisocyanate and 33% had detectable levels with 22 and 13% of results, respectively, above the BMGV for isocyanates (1 mu mol isocyanate-derived diamine per mol creatinine). The maximum urinary concentration of toluene diamine and hexane diamine were 15.6 and 10.1 mu mol mol(-1) creatinine, respectively.Conclusions: The survey found that the measures used to control exposure to MbOCA could be improved. Although air levels of MbOCA were generally low, there was evidence of spread of surface contamination and poor maintenance of controls such as local exhaust ventilation. A BMGV based on the 90th percentile of data from workplaces with good control would be less than the 90% value of 8.6 mu mol mol(-1) creatinine found in this study and suggests that the current BMGV of 15 mu mol mol(-1) creatinine is no longer acting as a stimulus to reduce exposure. The metabolites of isocyanates found in urine samples in this study could arise from inhalation exposure to isocyanates or from dermal exposure to either isocyanates or their diamine breakdown product and need further investigation.

The use of biomarkers is now an accepted measure of chemical uptake (possibly exposure) in risk assessment. However, information on background exposures and biomarker concentrations of many environmental chemicals in the general UK population is limited. This study aims to determine reference ranges for eleven biomarkers of chemical exposure, measurable in urine, within the general adult UK population. The study will involve 400 volunteers throughout the UK and is currently underway. Described here is a pilot study, carried out during August and September 2005 to test the study methodology. The initial results of the postal survey and urinary concentrations for cadmium (UCd) and mercury (UHg) are reported. A total of 78 individuals were recruited by post from the UK Electoral Register, to take part in the pilot study. Participants were asked to complete a questionnaire and provide a urine sample. The overall response rate was 16%, of which 60.3% were female and 39.7% male. Those living in suburban areas accounted for 60% of respondents, current smokers 12.8% and vegetarians 1.3%. Levels of UCd were higher in females compared to males and smoking status influenced levels; smokers displayed higher levels of UCd than individuals who had previously smoked or who had never smoked. The mean, median and range of UHg was 1.12, 0.55 (<limit of detection (LD)-13.46) mu g/g creatinine, respectively. This pilot study shows that postal sampling may be a useful and cost effective method for carrying out biomonitoring studies using urine as the matrix. (C) 2007 Elsevier GmbH. All rights reserved.

The UK Health and Safety Laboratory (HSL) provides research and analytical support to the Health and Safety Executive, other Government Departments and employers. In the area of biomonitoring HSL conducts research studies and provides an analytical service for regular surveillance of worker exposure to hazardous substances. This paper gives brief examples of how data from such studies can be used to develop biological monitoring guidance values for isocyanates, polycyclic aromatic hydrocarbons and hexavalent chromium. In addition, a study of occupational exposure to copper chrome arsenic wood preservatives is briefly described to show how biological monitoring can be used for post-approval surveillance of a biocide.

Isocyanates are reactive chemicals and thousands of workers may be exposed to them during their manufacture and use in a wide range of products. They are classed as sensitizers and are a major cause of occupational asthma in the UK. Workplace exposure limits are low and control of exposure often depends on personal respiratory protection. Biological monitoring is increasingly used to assess exposure and the efficacy of control measures, including the behavioural aspects of controls. Biological monitoring methods are available for the most common isocyanates hexamethylene diisocyanate, toluene diisocyanate, isophorone diisocyanate, and methylenediphenyl diisocyanate. They are based on the analysis of hexamethylene diamine, toluene diamine, isopherone diamine, and methylenediamine released after hydrolysis of isocyanate-protein adducts in urine or blood. Volunteer and occupational studies show good correlations between inhalation exposure to isocyanate monomers and isocyanate-derived diamines in urine or blood. However, occupational exposure to isocyanates is often to a mixture of monomers and oligomers so there is some uncertainty comparing biological monitoring results with airborne exposure to 'total NCO'. Nevertheless, there is a substantial body of work demonstrating the utility of biological monitoring as a tool to assess exposure and the efficacy of controls, including how they are used in practice. Non-health-based biological monitoring guidance values are available to help target when and where further action is required. Occupational hygienists will need to use their knowledge and experience to determine the relative contributions of different routes of exposure and how controls can be improved to reduced the risk of ill health.

This study reports a survey of occupational exposure to copper chrome arsenic (CCA) based wood preservatives during vacuum pressure timber impregnation. The survey involved biological monitoring based on analysis of chromium and arsenic in urine samples collected from UK workers. The aim of the study was to determine the extent of occupational exposure to arsenic and chromium in the UK timber treatment industry. The objectives were to collect and analyse urine samples from as many workers as possible, where CCA wood preservatives might be used, at 6 monthly intervals for 2 years. In addition, to investigate day-to-day variations in urinary excretion of chrome and arsenic by collecting and analysing three samples a week for 3 weeks in subsets of workers and controls (people not occupationally exposed). All urine samples were analysed for chromium and inorganic arsenic. To investigate any residual interference every sample was accompanied by a short questionnaire about recent consumption of seafood and smoking. The analytical methods for arsenic used a hydride generation technique to reduce interference from dietary sources of arsenic and also a technique that would measure total arsenic concentration in urine. The main findings show that workers exposed to CCA wood preservatives have concentrations of inorganic arsenic and chromium in urine that are significantly higher than those from non-occupationally exposed people but below biological monitoring guidance values that would indicate inhalation exposure at UK occupational exposure limits for chromium and arsenic. The effects of consumption of seafood on urinary arsenic were not significant using the hydride generation method for inorganic arsenic but were significant if 'total' arsenic was measured. The 'total' arsenic method could not distinguish CCA workers from controls and is clearly unsuitable for assessment of occupational exposure to arsenic. There was a significant increase in the urinary concentration of chromium in workers over the four sample collection rounds indicating increasing exposure to chromium during the 2 years of the study. This unexpected finding may be worth further investigation. Overall, the study demonstrated the utility of biological monitoring for assessment of occupational exposure to chromium and arsenic.

A physiologically based pharmacokinetic (PBPK) model describing the disposition of 2-butoxyethanol (2-BE) was developed in order to predict the urinary concentration of its major metabolite, butoxyacetic acid (BAA) under a range of exposure scenarios. Based on Corley et al. [Corley, R.A., Bormett, G.A., Ghanayem, B.I., 1994. Physiologically based pharmacokinetics of 2-butoxyethanol and its major metabolite, 2-butoxyacetic acid, in rats and humans. Toxicol. Appl. Pharmacol. 129, 61-79], the model included such features as multiple entry routes into the body, varying workload conditions, metabolism in the liver and elimination of free BAA in urine by glomerular filtration and acid transport. A bladder compartment simulating the fluctuations in metabolite concentration in urine caused by micturition formed a novel aspect of the model. Good agreement between model predictions and existing experimental data of total BAA levels in the blood and urine over various exposure conditions were observed. The mechanistically based PBPK model allowed comparison of disparate studies and also enabled the prediction of urinary concentrations of BAA post-shift. By calculating the total amount of BAA, any inter-individual variability in conjugation is taken into account. This led us to conclude that a biological monitoring guidance value should be proposed for total rather than free BAA with a value of 250 mmol/mol of creatinine (post-shift), based on an 8h exposure to 25 ppm 2-BE at resting working conditions.