John Cocker - Academia.edu (original) (raw)

Papers by John Cocker

International Journal of Workplace Health Management, 2015

Frontiers in pharmacology, 2015

Global sensitivity analysis (SA) was used during the development phase of a binary chemical physi... more 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 ...

J Mass Spectrometry, 1988

ABSTRACT

Toxicology Letters, Apr 10, 2006

A physiologically based pharmacokinetic (PBPK) model describing the disposition of 2-butoxyethano... more 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 8 h exposure to 25 ppm 2-BE at resting working conditions.

Toxicology Letters, Oct 5, 2010

Journal of Exposure Science and Environmental Epidemiology, 2015

There is limited information on the exposure to pesticides experienced by UK residents living nea... more 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.Journal of Exposure Science and Environmental Epidemiology advance online publication, 16 September 2015; doi:10.1038/jes.2015.54.

Regulatory Toxicology and Pharmacology, 2015

The UK regulatory methods currently used for estimating residents&amp... more 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.

PloS one, 2015

A major challenge in biomonitoring studies with members of the general public is ensuring their c... more 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.

Toxicology letters, Jan 13, 2012

This is a follow up survey of exposure to 4,4'-methylene-bis(2-chloroaniline) (MbOCA) and iso... more 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 μmol 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 μmol MbOCA/mol creatinine in samples collected since. There was a positive correlation between glove contamination and urinary MbOCA and levels were dependent 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 μmol/mol creatinine). Of the 326 urine samples that were analysed for metabolites of methylenediphenyl diisocyanate, 270 were below t...

Environmental mutagenesis, 1985

4,4'-Methylene-bis-(2-chlorobenzeneamine) (MbOCA) is a commercially important industrial chem... more 4,4'-Methylene-bis-(2-chlorobenzeneamine) (MbOCA) is a commercially important industrial chemical that is carcinogenic in three animal species and mutagenic in the Ames test. The ability of hepatic postmitochondrial supernatant from humans, dogs, mice, and rats to activate MbOCA to a bacterial mutagen has been investigated using the Ames plate incorporation test and a bacterial fluctuation test. In the Ames plate test, hepatic S9 preparations from mice and Aroclor 1254-induced rats only were sufficiently active to produce a significant mutagenic response. Preincubation of MbOCA with S9 from human liver produced a slight increase in the number of revertants but not a doubling as compared to controls. However, using the more sensitive bacterial fluctuation test, liver S9 from all species activated MbOCA to a bacterial mutagen. The responses produced were dose-related and, for at least part of the dose range, were double the background levels observed in controls. The increases in ...

Occupational and environmental medicine, 2010

This study evaluated blood lead data (including zinc protoporphyrin (ZPP) and haemoglobin levels)... more 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. 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. 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 ...

Toxicology Letters, 2002

Organophosphates (OPs) are readily absorbed through the skin and biological monitoring is an esse... more Organophosphates (OPs) are readily absorbed through the skin and biological monitoring is an essential component of any comprehensive assessment of exposure. This paper presents a summary of our experience in a wide range of occupational studies. Additionally, we have conducted studies of non-occupational exposure and human volunteer studies looking at the kinetics of chlorpyrifos, propetamphos, diazinon and malathion. In non-occupationally exposed people, 95% of urinary alkyl phosphates do not exceed 72 mmol/mol creatinine. In occupationally exposed people, the corresponding 95th percentile of total urinary alkyl phosphates is 122 mmol/mol creatinine. In volunteer studies with 1 mg oral doses of chlorpyifos, diazinon and propetamphos the mean peak values were 160, 750 and 404 mmol/mol creatinine, respectively, and were not associated with any reduction in blood cholinesterase activity. The levels of OP metabolites seen in urine from workers potentially exposed to OPs are generally low and unlikely to cause significant reduction in blood cholinesterase activity. Crown

Toxicology letters, Jan 5, 2002

N-methyl pyrrolidone (NMP) is a substance widely used for its strong and selective solvent capaci... more 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.

Journal of toxicology, 2012

There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exp... more There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals. Due to the lack of exposure and kinetic data, the correlation of biomarker levels with exposure concentrations leads to difficulty in utilizing biomonitoring data for biological guidance values. Exposure reconstruction or reverse dosimetry is the retrospective interpretation of external exposure consistent with biomonitoring data. We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene. We used exhaled breath and venous blood mxylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures. We also investigated the importance of model structure and dimensionality with respect to its ability to reconstruct exposure.

Toxicology Letters, 2006

This paper reports an occupational hygiene survey of exposure to acrylamide comparing acrylamide ... more 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.

Toxicology Letters, 2004

The enzyme kinetics of the initial hydroxylation of ethylbenzene to form 1-phenylethanol were det... more 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.

Toxicology Letters, 2002

Historically biological monitoring to assess exposure has been difficult due to the rapid half-li... more 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.

International Journal of Workplace Health Management, 2015

Frontiers in pharmacology, 2015

Global sensitivity analysis (SA) was used during the development phase of a binary chemical physi... more 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 ...

J Mass Spectrometry, 1988

ABSTRACT

Toxicology Letters, Apr 10, 2006

A physiologically based pharmacokinetic (PBPK) model describing the disposition of 2-butoxyethano... more 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 8 h exposure to 25 ppm 2-BE at resting working conditions.

Toxicology Letters, Oct 5, 2010

Journal of Exposure Science and Environmental Epidemiology, 2015

There is limited information on the exposure to pesticides experienced by UK residents living nea... more 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.Journal of Exposure Science and Environmental Epidemiology advance online publication, 16 September 2015; doi:10.1038/jes.2015.54.

Regulatory Toxicology and Pharmacology, 2015

The UK regulatory methods currently used for estimating residents&amp... more 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.

PloS one, 2015

A major challenge in biomonitoring studies with members of the general public is ensuring their c... more 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.

Toxicology letters, Jan 13, 2012

This is a follow up survey of exposure to 4,4'-methylene-bis(2-chloroaniline) (MbOCA) and iso... more 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 μmol 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 μmol MbOCA/mol creatinine in samples collected since. There was a positive correlation between glove contamination and urinary MbOCA and levels were dependent 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 μmol/mol creatinine). Of the 326 urine samples that were analysed for metabolites of methylenediphenyl diisocyanate, 270 were below t...

Environmental mutagenesis, 1985

4,4'-Methylene-bis-(2-chlorobenzeneamine) (MbOCA) is a commercially important industrial chem... more 4,4'-Methylene-bis-(2-chlorobenzeneamine) (MbOCA) is a commercially important industrial chemical that is carcinogenic in three animal species and mutagenic in the Ames test. The ability of hepatic postmitochondrial supernatant from humans, dogs, mice, and rats to activate MbOCA to a bacterial mutagen has been investigated using the Ames plate incorporation test and a bacterial fluctuation test. In the Ames plate test, hepatic S9 preparations from mice and Aroclor 1254-induced rats only were sufficiently active to produce a significant mutagenic response. Preincubation of MbOCA with S9 from human liver produced a slight increase in the number of revertants but not a doubling as compared to controls. However, using the more sensitive bacterial fluctuation test, liver S9 from all species activated MbOCA to a bacterial mutagen. The responses produced were dose-related and, for at least part of the dose range, were double the background levels observed in controls. The increases in ...

Occupational and environmental medicine, 2010

This study evaluated blood lead data (including zinc protoporphyrin (ZPP) and haemoglobin levels)... more 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. 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. 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 ...

Toxicology Letters, 2002

Organophosphates (OPs) are readily absorbed through the skin and biological monitoring is an esse... more Organophosphates (OPs) are readily absorbed through the skin and biological monitoring is an essential component of any comprehensive assessment of exposure. This paper presents a summary of our experience in a wide range of occupational studies. Additionally, we have conducted studies of non-occupational exposure and human volunteer studies looking at the kinetics of chlorpyrifos, propetamphos, diazinon and malathion. In non-occupationally exposed people, 95% of urinary alkyl phosphates do not exceed 72 mmol/mol creatinine. In occupationally exposed people, the corresponding 95th percentile of total urinary alkyl phosphates is 122 mmol/mol creatinine. In volunteer studies with 1 mg oral doses of chlorpyifos, diazinon and propetamphos the mean peak values were 160, 750 and 404 mmol/mol creatinine, respectively, and were not associated with any reduction in blood cholinesterase activity. The levels of OP metabolites seen in urine from workers potentially exposed to OPs are generally low and unlikely to cause significant reduction in blood cholinesterase activity. Crown

Toxicology letters, Jan 5, 2002

N-methyl pyrrolidone (NMP) is a substance widely used for its strong and selective solvent capaci... more 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.

Journal of toxicology, 2012

There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exp... more There are numerous biomonitoring programs, both recent and ongoing, to evaluate environmental exposure of humans to chemicals. Due to the lack of exposure and kinetic data, the correlation of biomarker levels with exposure concentrations leads to difficulty in utilizing biomonitoring data for biological guidance values. Exposure reconstruction or reverse dosimetry is the retrospective interpretation of external exposure consistent with biomonitoring data. We investigated the integration of physiologically based pharmacokinetic modelling, global sensitivity analysis, Bayesian inference, and Markov chain Monte Carlo simulation to obtain a population estimate of inhalation exposure to m-xylene. We used exhaled breath and venous blood mxylene and urinary 3-methylhippuric acid measurements from a controlled human volunteer study in order to evaluate the ability of our computational framework to predict known inhalation exposures. We also investigated the importance of model structure and dimensionality with respect to its ability to reconstruct exposure.

Toxicology Letters, 2006

This paper reports an occupational hygiene survey of exposure to acrylamide comparing acrylamide ... more 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.

Toxicology Letters, 2004

The enzyme kinetics of the initial hydroxylation of ethylbenzene to form 1-phenylethanol were det... more 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.

Toxicology Letters, 2002

Historically biological monitoring to assess exposure has been difficult due to the rapid half-li... more 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.