Exposure assessment using human biomonitoring for glyphosate and fluroxypyr users in amenity horticulture.

BACKGROUND: Pesticides and their potential adverse health effects are of great concern and there is a dearth of knowledge regarding occupational exposure to pesticides among amenity horticulturalists. OBJECTIVE: This study aims to measure occupational exposures to amenity horticuturalists using pesticides containing the active ingredients, glyphosate and fluroxypyr by urinary biomonitoring. METHODS: A total of 40 work tasks involving glyphosate and fluroxypyr were surveyed over the period of June - October 2015. Workers used a variety of pesticide application methods; manual knapsack sprayers, controlled droplet applicators, pressurised lance applicators and boom sprayers. Pesticide concentrations were measured in urine samples collected pre and post work tasks using liquid chromatography tandem mass spectrometry (LC-MS/MS). Differences in pesticide urinary concentrations pre and post work task, and across applications methods were analysed using paired t-tests and linear regression. RESULTS: Pesticide urinary concentrations were higher than those reported for environmental exposures and comparable to those reported in some agricultural studies. Log-transformed pesticide concentrations were statistically significantly higher in post-work samples compared to those in pre-work samples (paired t-test, p<0.001; for both µgL-1 and µmol/mol creatinine). Urinary pesticide concentrations in post-work samples had a geometric mean (geometric standard deviation) of 0.66 (1.11) µgL-1 for glyphosate and 0.29 (1.69) µgL-1 for fluroxypyr. Linear regression revealed a statistically significant positive association to exist between the time-interval between samples and the log-transformed adjusted (i.e. post- minus pre-task) pesticide urinary concentrations (ß=0.0039; p<0.0001). CONCLUSION: Amenity horticulturists can be exposed to pesticides during tasks involving these products. Further research is required to evaluate routes of exposure among this occupational group.

Application of an assay for 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) in urine for the assessment of tobacco-related harm.

BACKGROUND: The tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is formed from nicotine and related compounds during tobacco curing and is classified as a human carcinogen. Its major metabolite, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), is thought to be useful in the assessment of cigarette smoking harm minimisation strategies. METHODOLOGY: Urine samples were collected from 24 current Caucasian smokers participating in a smoking cessation study; before and four weeks after a quit attempt. Samples were spiked with NNAL-d3 internal standard, extracted with ethyl acetate using liquid-liquid extraction, reconstituted with deionised water and analysed using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS). Both free (unconjugated) and total NNAL was measured, with totals determined by cleavage of NNAL-glucuronide using standard enzymatic hydrolysis methods. RESULTS: Free NNAL levels (193.5±158.2pg/mL [mean±standard deviation]) measured in urine samples obtained at baseline (during ad lib smoking) were indicative of biological exposure to NNK. Free NNAL levels were significantly reduced four weeks after the quit attempt (64.5±77.6pg/mL; p<0.002). Assay performance met acceptance criteria with mean recovery of 59±23%, intra-day accuracy was 3.7%, 3.7 and 3.6% and precision was 11.3%, 5.1% and 5.3% at 5pg/mL, 20pg/mL and 100pg/mL levels respectively. Enzymatic hydrolysis of NNAL-glucuronide proved unreliable with complete loss of NNAL aglycone in some subject samples following the hydrolysis procedure. CONCLUSION: Liquid-liquid extraction with UPLC-MS/MS is a convenient approach to measure low levels of NNAL in urine as a marker of biological NNK exposure, which can be used to assess the effectiveness of smoking reduction harm minimisation strategies. Enzymatic hydrolysis of NNAL-glucuronide and measuring the aglycone is not recommended.

Characterization of the disposition of fostamatinib in Japanese subjects including pharmacokinetic assessment in dry blood spots: results from two phase I clinical studies.

PURPOSE: The aims of the present study were to characterize the pharmacokinetics of fostamatinib in two phase I studies in healthy Japanese subjects after single- and multiple-dose administration, and to evaluate the utility of dried blood spot (DBS) sampling. METHODS: In study A, 40 Japanese and 16 white subjects were randomized in a double-blind parallel group study consisting of seven cohorts, which received either placebo or a fostamatinib dose between 50 and 200 mg after single and multiple dosing. Pharmacokinetics of R406 (active metabolite of fostamatinib) in plasma and urine was assessed, and safety was intensively monitored. Study B was an open-label study that assessed fostamatinib 100 and 200 mg in 24 Japanese subjects. In addition to plasma and urine sampling (as for study A), pharmacokinetics was also assessed in blood. RESULTS: Mean maximum plasma concentration (C max) and area under total plasma concentration­time curve (AUC) increased with increasing dose in Japanese subjects. Steady state was achieved in 5­7 days for all doses. C max and AUC were both higher in Japanese subjects administered a 150-mg single dose than in white subjects. This difference was maintained for steady state exposure by day 10. Overall, R406 blood concentrations were consistent and ∼2.5-fold higher than in plasma. Minimal (<0.1 %) R406 was excreted in urine. Fostamatinib was well tolerated at all doses. CONCLUSIONS: Fostamatinib pharmacokinetics following single- and multiple-dose administration was approximately dose proportional at all doses ≤150 mg and greater than dose proportional at 200 mg in Japanese subjects. Japanese subjects administered fostamatinib 150 mg had higher exposure than white subjects. R406 could be measured in DBS samples and distributed into red blood cells, and DBS sampling was a useful method for assessing R406 pharmacokinetics.

Proposed cutoff for identifying adult smokeless tobacco users with urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanonol: an aggregated analysis of NHANES 2007-2010 data.

INTRODUCTION: NNAL [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanonol] is a valid biomarker of tobacco use. However; no study has assessed its use in distinguishing current smokeless tobacco (SLT) users from nonusers. Therefore, this study used aggregated data from the 2007-2008 and 2009-2010 waves of the National Health and Nutrition Examination Survey to determine an optimal threshold for identifying SLT users with NNAL. METHODS: Optimal urinary total NNAL concentrations for discriminating SLT-only users from nonusers of any tobacco were determined using receiver operating characteristic analysis. Percentage agreement between self-reported SLT use status and NNAL levels was calculated overall and by sociodemographic characteristics. All analyses were weighted and performed with Stata, Version 11, and MedCalc for Windows, Version 9.5.0.0. RESULTS: In total, 264 individuals reported exclusively using SLT (and no other combustible tobacco product) within the past 5 days, whereas 14,824 were self-reported nonusers of any combustible or smokeless tobacco product. The optimal NNAL cutoff point was 34.0 pg/ml, which was associated with a high sensitivity (95.2%), specificity (93.4%), and overall correct classification rate (93.5%). The area under the curve was 98.3% and the corresponding Youden's Index was 88.7%. There was high agreement between the proposed NNAL cutoff point and self-reported SLT-only use (95.6%) and self-reported SLT nonuse (93.9%). CONCLUSION: The proposed cutoff point of 34.0 pg/ml had high sensitivity and specificity and may be used by clinicians and researchers to verify or detect recent SLT use. This study also indicated that self-reported SLT use among adults is a reliable measure and has high agreement with biochemical assessment.

Assessment of DNA damage in WBCs of workers occupationally exposed to fumes and aerosols of bitumen.

We conducted a cross-shift study with 66 bitumen-exposed mastic asphalt workers and 49 construction workers without exposure to bitumen. Exposure was assessed using personal monitoring of airborne bitumen exposure, urinary 1-hydroxypyrene (1-OHP), and the sum of 1-, 2 + 9-,3-,4-hydroxyphenanthrene (OHPH). Genotoxic effects in WBC were determined with nonspecific DNA adduct levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and the formation of DNA strand breaks and alkali-labile sites. Concentration of fumes and aerosols of bitumen correlated significantly with the concentrations of 1-OHP and OHPH after shift (r(s) = 0.27; P = 0.03 and r(s) = 0.55; P < 0.0001, respectively). Bitumen-exposed workers had more DNA strand breaks than the reference group (P < 0.0001) at both time points and a significant correlation with 1-OHP and OHPH in the postshift urines (r(s) = 0.32; P = 0.001 and r(s) = 0.27; P = 0.004, respectively). Paradoxically, we measured higher levels of DNA strand breaks, although not significant, in both study groups before shift. 8-OxodGuo adduct levels did not correlate with DNA strand breaks. Further, 8-oxodGuo levels were associated neither with personal exposure to bitumen nor with urinary metabolite concentrations. Significantly more DNA adducts were observed after shift not only in bitumen-exposed workers but also in the reference group. Only low-exposed workers had significantly elevated 8-oxodGuo adduct levels before as well as after shift (P = 0.0002 and P = 0.02, respectively). Our results show that exposure to fumes and aerosols of bitumen may contribute to an increased DNA damage assessed with strand breaks.

Assessment of potential (inhalation and dermal) and actual exposure to acetamiprid by greenhouse applicators using liquid chromatography-tandem mass spectrometry.

New analytical methods based on liquid chromatography with electrospray tandem mass spectrometry (LC-MS/MS) have been developed and validated for assessing the exposure of greenhouse workers to acetamiprid. Both ambient (potential inhalation and dermal exposure) and internal dose (biological monitoring of urine samples) measurements were carried out. Potential inhalation exposure was assessed using Chromosorb 102 cartridges connected to air personal samplers. Potential dermal exposure was estimated by using whole body dosimetry. The measurement of actual exposure was done by analyzing the parent compound in urine samples of the applicators, after a solid-phase extraction (SPE) step. The methods showed a good accuracy (72-92%), precision (2-13%) and lower limits (few microg l(-1)). The validated approaches have been applied to assess potential and actual exposure of agricultural workers spraying acetamiprid in greenhouses. The results shown the need to wear personal protective equipment (suits) in order to reduce the absorbed dose of acetamiprid.

Assessment of urinary hydroxypyridinium cross-links measurement in osteoarthritis.

The aim of this study is to re-evaluate urinary collagen cross-links, previously proposed as markers of osteoarthritis (OA). The urinary excretion of collagen cross-links, pyridinoline (PYD) and deoxypyridinoline (DPD), was measured using high-performance liquid chromatography (HPLC) in 114 patients with OA, 19 patients with rheumatoid arthritis (RA) and 40 healthy subjects. An increase in PYD and DPD, expressed per millimole of creatinine, was confirmed in RA. However, PYD and DPD in patients with hip OA, knee OA and polyOA were similar, and did not differ from controls. In patients with radiographic end-stage OA, PYD and DPD were significantly higher than in patients with an early OA, but not significantly higher than in controls. The PYD/DPD ratio did not vary with the OA stage. Thus, urinary collagen cross-links are not elevated in OA, but could reflect bone sclerosis and/or erosion in late OA.