Comparison of residents' pesticide exposure with predictions obtained using the UK regulatory exposure assessment approach.

The UK regulatory methods currently used for estimating residents' potential pesticide exposure were assessed to determine whether they provide sufficiently conservative estimates. A non-random sample of 149 residents living within 100 m of fields where pesticides were sprayed provided first morning void urine samples one and/or two days after spraying. Using farmers' spray information, regulatory exposure assessment (REA) models were applied to estimate potential pesticide intake among residents, with a toxicokinetic (TK) model used to estimate urinary biomarker concentrations in the mornings of the two days following the spray. These were compared with actual measured urinary biomarker concentrations obtained following the spray applications. The study focused on five pesticides (cypermethrin, penconazole, captan, chlorpyrifos and chlormequat). All measured cypermethrin urinary biomarker levels were lower than the REA-predicted concentrations. Over 98% and 97% of the measured urinary biomarker concentrations for penconazole and captan respectively were lower than the REA-predicted exposures. Although a number of the chlorpyrifos and chlormequat spray-related urinary biomarker concentrations were greater than the predictions, investigation of the background urinary biomarker concentrations suggests these were not significantly different from the levels expected had no pesticide spraying occurred. The majority of measured concentrations being well below the REA-predicted concentrations indicate that, in these cases, the REA is sufficiently conservative.

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.

Validation of trichloroacetic acid exposure via drinking water during pregnancy using a urinary TCAA biomarker.

Disinfection by-product (DBP) exposure during pregnancy may be related to reduced fetal growth, but the evidence is inconclusive and improved DBP exposure assessment is required. The authors conducted a nested exposure study on a subset (n=39) of pregnant women in the Born in Bradford cohort to assess validity of TCAA exposure assessment based on tap water sampling and self-reported water-use; water-use questionnaire validity; and use of a one-time urinary TCAA biomarker. TCAA levels in urine and home tap water supply were quantified, and water use was measured via a questionnaire and 7-day diary, at 28 weeks gestation. Diary and urine measures were repeated later in pregnancy (n=14). TCAA level in home tap water supply was not correlated with urinary TCAA (0.18, P=0.29). Cold unfiltered tap water intake at home measured by questionnaire was correlated with urinary TCAA (0.44, P=0.007), but correlation was stronger still for cold unfiltered tap water intake reported over the 3 days prior to urine sampling (0.60, P<0.001). For unemployed women TCAA ingestion at home, derived from tap water sampling and self-reported water-use, correlated strongly with urinary TCAA (0.78, P<0.001), but for employed women the correlation was weak (0.31, P=0.20). Results suggest individual tap water intake is most influential in determining TCAA exposure variability in this cohort, and that TCAA ingestion at home is a valid proxy for TCAA exposure for unemployed women but less satisfactory for employed women.

Isocyanate exposure control in motor vehicle paint spraying: evidence from biological monitoring.

AIMS: The purpose of this work was to assess the changes in control of exposure to hexamethylene diisocyanate based paints used in vehicle spraying after a Health & Safety Executive (HSE) national project. METHODS: Paint sprayers and managers from motor vehicle repair (MVR) bodyshops across the UK, were invited to one of 32 Safety and Health Awareness Days (SHADs) to increase their understanding of the hazards, and practical ways of controlling of exposure to isocyanate based paints. Exposure measurement based on biological monitoring was offered, free of charge, to each of the roughly 4000 participants and used to assess the effectiveness of controls and methods of working. Results are compared with pre and post SHAD measurements. RESULTS: Urine samples were received from 995 paint sprayers. Hexamethylene diamine (HDA) levels in urine, indicative of exposure to hexamethylene diisocyanate (HDI), were significantly lower (Mann-Whitney, p<0.0001) than had been seen in a wider population from previous HSE inspections and routine sampling. Where a sprayer's urinary HDA was above the quantification limit they were asked to send another sample after reviewing and improving exposure control measures. The results from these repeat samples were significantly lower than the original results. There was no difference in the exposures of sprayers using air-fed half-mask face-pieces compared with visor type air-fed breathing apparatus, or between spray booths and rooms. CONCLUSIONS: The analysis of HDA in urine is a useful technique for assessing exposure to isocyanates in paint sprayers. The simplicity of this approach has allowed wide-scale use of biological monitoring in an industry dominated by small and micro businesses. Biological monitoring of exposure has enabled individual companies, and sprayers, to check that their control measures are working. This study showed overall lower levels of HDA in paint sprayers following SHADs. These lower levels have been maintained across a wider population of UK paint sprayers over the succeeding years. Whilst there may be many reasons for the reduction in exposure, the weight of evidence suggests that the key messages about exposure control measures, delivered through the SHADs and other means, were influential.

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.

Biological monitoring for isocyanates.

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.

Beryllium in urine by ICP-MS: a comparison of low level exposed workers and unexposed persons.

PURPOSE: To develop a sensitive and reproducible method for urinary beryllium and to use this method to establish levels in workers at an aluminium smelter and in unexposed persons. METHODS: A method was developed for urinary beryllium using a Thermo ICP-MS Series 1, which was used to determine beryllium concentrations in urine from 62 people with no known occupational exposure to beryllium and 167 workers with potential exposure to beryllium at an aluminium smelter, where beryllium exists as an impurity in the bauxite ore. RESULTS: The analytical method has a detection limit (based on three times the background equivalent concentration of the blank) for beryllium in urine of 6 ng/L. The mean and 90th percentiles of urinary beryllium for workers were 19.5 and 42.0 ng/L and compared with 11.6 and 20.0 ng/L in people not occupationally exposed to beryllium. Statistical analysis using mixed effects models showed that workers had 47% (in 135 paired samples) higher levels of urinary beryllium at the end of the working week compared to the start of week and that the workers who smoked also had significantly higher levels of urinary beryllium compared to those that did not smoke. There was also a statistically significant difference between workers and controls in urinary beryllium concentrations not corrected for creatinine. CONCLUSIONS: A sensitive and reliable analytical method was developed for urinary beryllium by ICP-MS. The workers in this study were exposed to beryllium at very low levels.

Biological monitoring of pesticide exposures in residents living near agricultural land.

BACKGROUND: There is currently a lack of reliable information on the exposures of residents and bystanders to pesticides in the UK. Previous research has shown that the methods currently used for assessing pesticide exposure for regulatory purposes are appropriate for farm workers 1. However, there were indications that the exposures of bystanders may sometimes be underestimated. The previous study did not collect data for residents. Therefore, this study aims to collect measurements to determine if the current methods and tools are appropriate for assessing pesticide exposure for residents living near agricultural fields. METHODS/DESIGN: The study will recruit owners of farms and orchards (hereafter both will be referred to as farms) that spray their agricultural crops with certain specified pesticides, and which have residential areas in close proximity to these fields. Recruited farms will be asked to provide details of their pesticide usage throughout the spray season. Informed consenting residents (adults (18 years and over) and children (aged 4-12 years)) will be asked to provide urine samples and accompanying activity diaries during the spraying season and in addition for a limited number of weeks before/after the spray season to allow background pesticide metabolite levels to be determined. Selected urine samples will be analysed for the pesticide metabolites of interest. Statistical analysis and mathematical modelling will use the laboratory results, along with the additional data collected from the farmers and residents, to determine systemic exposure levels amongst residents. Surveys will be carried out in selected areas of the United Kingdom over two years (2011 and 2012), covering two spraying seasons and the time between the spraying seasons. DISCUSSION: The described study protocol was implemented for the sample and data collection procedures carried out in 2011. Based on experience to date, no major changes to the protocol are anticipated for the 2012 spray season although the pesticides and regional areas for inclusion in 2012 are still to be confirmed.

Trends in blood lead levels in UK workers, 1995-2007.

OBJECTIVES: This study evaluated blood lead data (including zinc protoporphyrin (ZPP) and haemoglobin levels) collected at the UK's Health and Safety Laboratory (HSL) in order to determine temporal changes in occupational exposure to lead between 1995 and 2007. METHODS: A total of 20,889 blood lead measurements and accompanying ZPP and haemoglobin results from 8810 workers at 972 companies from routine samples received by HSL over the period 1995-2007 were analysed. Time trends in blood lead levels for each industry sector were estimated using Bayesian mixed effects modelling. RESULTS: Reductions in median blood levels over the period 1995-2007 were seen in every sector except for those samples forwarded by occupational health providers, and range from 1.6% per year for workers in the smelting industry to 12% per year for workers in pottery and glazing industries. An overall reduction of 3.1% per year across all industries was determined. The percentage of results above the current UK suspension limit of 60 microg/dl fell from 4.8% in 1995 to 0.6% in 2007. ZPP and blood lead exhibited a strong association, but no significant correlation was found between blood lead and haemoglobin. CONCLUSIONS: Occupational exposure to lead has fallen across UK industries in recent years, although it remains substantially above background levels. There is evidence that many workers are exposed to elevated lead levels over a long period of time and this deserves renewed consideration now that inorganic lead has been reclassified as a probable human carcinogen.

Exposure to Diisocyanates and Their Corresponding Diamines in Seven Different Workplaces.

Biological monitoring to assess exposure to diisocyanates in the workplace is becoming increasingly widespread due to its relative ease of use and ability to look at all exposure routes. Currently, biological monitoring measures the corresponding isocyanate-derived diamine in urine, after hydrolysis. Because of this, any exposure to the diamines themselves released during the industrial process could confound the assessment of diisocyanate exposure. This paper reports an initial assessment of the extent of diamine formation and exposure during different processes involving diisocyanates including casting, grouting, core making, spray painting, foam blowing, and floor screeding. Air monitoring and glove analysis were conducted for both the relevant diisocyanate (measured as total NCO) and its corresponding diamine; urine samples were analysed (after hydrolysis) for the isocyanate-derived diamine. Processes that generated aerosols (as demonstrated by impinger analysis) such as spray painting and foam blowing were associated with the detection of diamines. Those processes that did not generate aerosols (casting, grouting, core making, and screeding) had no diamines detected, either in air or on gloves. In spray-painting tasks, diamines were a minor component (<15%) of the ambient concentration whereas in the foam blowing processes, where water is added to the process, diamine generation is more marked (up to eight times the airborne NCO concentration). Some non-aerosol processes gave rise to substantial diamine levels in urine (in exceedance of international guidance values, >5 µmol mol-1 creatinine) despite airborne levels being well within occupational exposure limits (20 µg m-3 total NCO in Great Britain); measurement data and statistical modelling indicated that skin absorption was the most likely exposure route. Foam blowing exposures were more complex, but urinary levels were greater than those expected from diisocyanate inhalation alone (measured as total NCO). This study provides evidence that biological monitoring for diisocyanates based on measuring the corresponding diamine in urine is valid, although any co-exposure to diamines themselves should be considered when interpreting results. It also demonstrates the potential for substantial skin absorption of diisocyanates in certain processes such as floor screeding and foam production.

Correlation of haemoglobin-acrylamide adducts with airborne exposure: an occupational survey.

This paper reports an occupational hygiene survey of exposure to acrylamide comparing acrylamide haemoglobin adduct measurements with personal air monitoring and glove liner analysis. The air monitoring data showed that exposure to acrylamide was well-controlled with all samples below the UK maximum exposure limit (MEL) of 300 microg/m(3) with mean exposure about one tenth of the MEL. Each worker provided two blood samples approximately 3 months apart. These samples were well correlated (r=0.61) with a slope of 0.74, indicating that exposure was reasonably constant. Mean personal airborne acrylamide levels and mean acrylamide haemoglobin adduct levels were well correlated (r=0.72, N=46) and using the calculated linear correlation, exposure at the MEL would be expected to give rise to a haemoglobin adduct level of 1,550 pmol/g globin. Smoking status did not affect the correlation. There was also a correlation between levels of acrylamide detected on gloves and haemoglobin adduct levels. A combined regression model between haemoglobin adducts, airborne acrylamide and acrylamide glove contamination was significant for both airborne acrylamide and gloves with a regression coefficient of 0.89. The study showed that haemoglobin adduct level was a good biomarker of acrylamide exposure which correlated to both inhaled and potentially skin absorbed acrylamide estimates. There was excellent discrimination between well-controlled occupational levels and environmental levels from diet and smoking, allowing haemoglobin adduct measurement to be used to determine even low level exposures. Due to the complexity of the current methodology, new techniques would be useful in making haemoglobin adducts more widely applicable.

Development of a Biomarker for Penconazole: A Human Oral Dosing Study and a Survey of UK Residents' Exposure.

Penconazole is a widely used fungicide in the UK; however, to date, there have been no peer-reviewed publications reporting human metabolism, excretion or biological monitoring data. The objectives of this study were to i) develop a robust analytical method, ii) determine biomarker levels in volunteers exposed to penconazole, and, finally, to iii) measure the metabolites in samples collected as part of a large investigation of rural residents' exposure. An LC-MS/MS method was developed for penconazole and two oxidative metabolites. Three volunteers received a single oral dose of 0.03 mg/kg body weight and timed urine samples were collected and analysed. The volunteer study demonstrated that both penconazole-OH and penconazole-COOH are excreted in humans following an oral dose and are viable biomarkers. Excretion is rapid with a half-life of less than four hours. Mean recovery of the administered dose was 47% (range 33%-54%) in urine treated with glucuronidase to hydrolyse any conjugates. The results from the residents' study showed that levels of penconazole-COOH in this population were low with >80% below the limit of detection. Future sampling strategies that include both end of exposure and next day urine samples, as well as contextual data about the route and time of exposure, are recommended.

The application of global sensitivity analysis in the development of a physiologically based pharmacokinetic model for m-xylene and ethanol co-exposure in humans.

Global sensitivity analysis (SA) was used during the development phase of a binary chemical physiologically based pharmacokinetic (PBPK) model used for the analysis of m-xylene and ethanol co-exposure in humans. SA was used to identify those parameters which had the most significant impact on variability of venous blood and exhaled m-xylene and urinary excretion of the major metabolite of m-xylene metabolism, 3-methyl hippuric acid. This analysis informed the selection of parameters for estimation/calibration by fitting to measured biological monitoring (BM) data in a Bayesian framework using Markov chain Monte Carlo (MCMC) simulation. Data generated in controlled human studies were shown to be useful for investigating the structure and quantitative outputs of PBPK models as well as the biological plausibility and variability of parameters for which measured values were not available. This approach ensured that a priori knowledge in the form of prior distributions was ascribed only to those parameters that were identified as having the greatest impact on variability. This is an efficient approach which helps reduce computational cost.

Variance components of short-term biomarkers of manganese exposure in an inception cohort of welding trainees.

Various biomarkers of exposure have been explored as a way to quantitatively estimate an internal dose of manganese (Mn) exposure, but given the tight regulation of Mn in the body, inter-individual variability in baseline Mn levels, and variability in timing between exposure and uptake into various biological tissues, identification of a valuable and useful biomarker for Mn exposure has been elusive. Thus, a mixed model estimating variance components using restricted maximum likelihood was used to assess the within- and between-subject variance components in whole blood, plasma, and urine (MnB, MnP, and MnU, respectively) in a group of nine newly-exposed apprentice welders, on whom baseline and subsequent longitudinal samples were taken over a three month period. In MnB, the majority of variance was found to be between subjects (94%), while in MnP and MnU the majority of variance was found to be within subjects (79% and 99%, respectively), even when controlling for timing of sample. While blood seemed to exhibit a homeostatic control of Mn, plasma and urine, with the majority of the variance within subjects, did not. Results presented here demonstrate the importance of repeat measure or longitudinal study designs when assessing biomarkers of Mn, and the spurious associations that could result from cross-sectional analyses.

Engaging with Community Researchers for Exposure Science: Lessons Learned from a Pesticide Biomonitoring Study.

A major challenge in biomonitoring studies with members of the general public is ensuring their continued involvement throughout the necessary length of the research. The paper presents evidence on the use of community researchers, recruited from local study areas, as a mechanism for ensuring effective recruitment and retention of farmer and resident participants for a pesticides biomonitoring study. The evidence presented suggests that community researchers' abilities to build and sustain trusting relationships with participants enhanced the rigour of the study as a result of their on-the-ground responsiveness and flexibility resulting in data collection beyond targets expected.

Urinary biomarker concentrations of captan, chlormequat, chlorpyrifos and cypermethrin in UK adults and children living near agricultural land.

There is limited information on the exposure to pesticides experienced by UK residents living near agricultural land. This study aimed to investigate their pesticide exposure in relation to spray events. Farmers treating crops with captan, chlormequat, chlorpyrifos or cypermethrin provided spray event information. Adults and children residing ≤100 m from sprayed fields provided first-morning void urine samples during and outwith the spray season. Selected samples (1-2 days after a spray event and at other times (background samples)) were analysed and creatinine adjusted. Generalised Linear Mixed Models were used to investigate if urinary biomarkers of these pesticides were elevated after spray events. The final data set for statistical analysis contained 1518 urine samples from 140 participants, consisting of 523 spray event and 995 background samples which were analysed for pesticide urinary biomarkers. For captan and cypermethrin, the proportion of values below the limit of detection was greater than 80%, with no difference between spray event and background samples. For chlormequat and chlorpyrifos, the geometric mean urinary biomarker concentrations following spray events were 15.4 µg/g creatinine and 2.5 µg/g creatinine, respectively, compared with 16.5 µg/g creatinine and 3.0 µg/g creatinine for background samples within the spraying season. Outwith the spraying season, concentrations for chlorpyrifos were the same as those within spraying season backgrounds, but for chlormequat, lower concentrations were observed outwith the spraying season (12.3 µg/g creatinine). Overall, we observed no evidence indicative of additional urinary pesticide biomarker excretion as a result of spray events, suggesting that sources other than local spraying are responsible for the relatively low urinary pesticide biomarkers detected in the study population.

Determination of nitroglycerin and its dinitrate metabolites in urine by gas chromatography-mass spectrometry as potential biomarkers for occupational exposure.

This paper describes a method for the quantitative analysis of nitroglycerin and its dinitrate metabolites (1,2- and 1,3-glycerol dinitrate) in urine. After liquid-liquid extraction the analytes were separated and quantified using gas chromatography-mass spectrometry with negative ion chemical ionisation. The method can detect above 0.3 nmol/l for all analytes and is linear over the range of at least 0-44 nmol/l. The method was then used to determine metabolite levels in a subject using nitroglycerin therapeutically for the treatment of angina. Metabolites were stable in urine for at least 6 days at room temperature, approximately 4 degrees C and -20 degrees C.

Dermal exposure to aqueous solutions of N-methyl pyrrolidone.

N-methyl pyrrolidone (NMP) is a substance widely used for its strong and selective solvent capacity. The strong potential NMP has for skin absorption makes biological monitoring ideal for exposure assessment. This study looked at brief exposures to NMP in aqueous solutions over a range of concentrations. Two volunteers placed one hand in NMP solutions ranging from 5 to 25% for as long as 15 min followed by urine collection for 48 h. The analyte of interest (analysed by GC-MS) was the NMP metabolite 5-hydroxy-N-methyl pyrrolidone (5-HNMP). Excretion of 5-HNMP was plotted against time and this showed that urine concentrations were at a maximum after about 10 h and 5-HNMP excretion continued for 48 h after exposure. The half-life of excretion was found to be approximately 11 h. The mean correlation between exposure (as a measure of exposure duration and solution concentration) and total 5-HNMP excreted was 0.9297.

Biological monitoring of nitroglycerin exposure by urine analysis.

Historically biological monitoring to assess exposure has been difficult due to the rapid half-life of NG. However, the recent development of a method to assess NG and its metabolites (glycerol dinitrates, GDNs) in urine has made biological monitoring more feasible. The data reported here result from samples taken from three sites using NG. Two of the sites are munitions manufacturing sites and the other site is a pharmaceutical manufacturing site. The range of urinary GDN concentrations found in the samples at the two munitions sites were 0.9-18, and 0-4.7 micromol/mol creatinine, and at the pharmaceutical site were 0-0.9 micromol/mol creatinine). The presence of nitroglycols in the urine of workers despite the use of personal protective equipment and local exhaust ventilation shows the usefulness of biological monitoring to assess the efficacy of any controls in place and the potential of dermal absorption of NG.

Metabolism of ethylbenzene by human liver microsomes and recombinant human cytochrome P450s (CYP).

The enzyme kinetics of the initial hydroxylation of ethylbenzene to form 1-phenylethanol were determined in human liver microsomes. The individual cytochrome P450 (CYP) forms catalysing this reaction were identified using selective inhibitors and recombinant preparations of hepatic CYPs. Production of 1-phenylethanol in hepatic microsomes exhibited biphasic kinetics with a high affinity, low Km, component (mean Km = 8 microM; V(max) = 689 pmol/min/mg protein; n = 6 livers) and a low affinity, high Km, component (Km = 391 microM; V(max) = 3039 pmol/min/mg protein; n = 6). The high-affinity component was inhibited 79%-95% (mean 86%) by diethyldithiocarbamate, and recombinant CYP2E1 was shown to metabolise ethylbenzene with low Km (35 microM), but also low (max) (7 pmol/min/pmol P450), indicating that this isoform catalysed the high-affinity component. Recombinant CYP1A2 and CYP2B6 exhibited high V(max) (88 and 71 pmol/min/pmol P450, respectively) and high Km (502 and 219 microM, respectively), suggesting their involvement in catalysing the low-affinity component. This study has demonstrated that CYP2E1 is the major enzyme responsible for high-affinity side chain hydroxylation of ethylbenzene in human liver microsomes. Activity of this enzyme in the population is highly variable due to induction or inhibition by physiological factors, chemicals in the diet or some pharmaceuticals. This variability can be incorporated into the risk assessment process to improve the setting of occupational exposure limits and guidance values for biological monitoring.