Cholinesterase inhibition in chlorpyrifos workers: Characterization of biomarkers of exposure and response in relation to urinary TCPy

Abstract

The objective of this study was to evaluate the quantitative relation between measured red blood cell acetylcholinesterase (RBC AChE) and plasma butyrylcholinesterase (BuChE) activities with exposure to chlorpyrifos (CPF) as assessed by measurement of urinary 3,5,6-trichloro-2-pyridinol (TCPy) in a study group of workers occupationally exposed in the manufacture of CPF and a referent group of chemical manufacturing workers. Measures of plasma BuChE and RBC AChE activity and urinary TCPy concentration collected over a year-long study (1999)(2000) in CPF-exposed workers (n ¼ 53) and referents (n ¼ 60) were analyzed using linear mixed models to characterize exposure-response relationships. Intraindividual variability in cholinesterase measures was compared between CPF-exposed workers and referents. Urinary TCPy concentrations in CPF workers were substantially elevated compared to referents, with median and 95th percentile concentrations during typical employment conditions 10-fold and more than 30-fold higher, respectively, than corresponding measures in the referents. Intraindividual variability in cholinesterase activities was substantial, with 17% of unexposed referents experiencing one or more plasma BuChE measures more than 20% below baseline over a year of repeated, periodic measurements. RBC AChE activity, an early biomarker of effect, was unrelated to urinary TCPy concentration over the entire range of exposure, up to 1000 mg TCPy/g creatinine (Cr). Plasma BuChE activity, a non-adverse biomarker of exposure, was negatively related to urinary TCPy concentrations above approximately 110 mg TCPy/g Cr. No-effect levels for inhibition of plasma BuChE and RBC AChE corresponding to absorbed doses of CPF of approximately 5 and greater than 50 mg/kg/day, respectively, were identified. These findings are consistent with previous no-effect level determinations for ChE inhibition in humans and suggest that general population CPF exposure levels are substantially below the identified no-effect levels. The doseresponse relationships observed in this study are consistent with predictions from the previously published physiologically based pharmacokinetic/ pharmacodynamic model for CPF. Intraindividual variability in measured cholinesterase activities in referents was substantial, suggesting that ongoing monitoring programs may have a substantial rate of false positives.

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers

“…Although the chlorpyrifos exposure causes rapid inhibition of BuChE activity, the average BuChE inhibition in relation to the average TCP/Cr correctly reflects this relationship, assuming that the measures are a random sample of both distributions. In support of our methodology, we have previously reported additional analyses in which we identified all BuChE and TCP/Cr measurements taken within 7 days of each other for a given subject (Garabrant et al, 2009). Using this subset of the data, we analyzed the relationship between TCP/Cr and BuChE activity using linear mixed models, which correctly account for both intra-subject and inter-subject variation, while controlling for covariates.…”

Assessment of Health Risk in Human Populations Due to Chlorpyrifos

“…The impact of occupational chlorpyrifos exposure on the urinary TCP levels and blood ChE levels of the workers in a chlorpyrifos manufacturing plant in USA was reported by Garabrant et al [4]. The ChE levels were analysed in blood together with the TCP levels in urine, obtained on four occasions, with 50 to 53 individuals, during 1999 and 2000.…”

“…Based on the half life of excretion of TCP in humans [23] it is assumed that a continuous daily exposure to chlorpyrifos results in a steady state for the TCP levels in urine [4,22]. However it has been suggested by Eaton et al [17] that levels of TCP present in the food and other sources can lead to estimations of higher concentrations values for chlorpyrifos than actually occur.…”

“…Results from these samples can be compared to the Guideline Values for chronic exposure in Table 1, eg CRfD. The method used to estimate the daily dose developed by Garabrant et al [4] was modified to convert TCP levels (ng/g creatinine) in urine into Equivalent Chlorpyrifos Ingested Dose (ECID in ng/kg body weight/day) as expressed by the following equation…”

“…The major metabolite in biological systems is 3,5,6-trichloro-2 pyridinol (TCP) which is passed in the urine of mammals as shown in Figure 1. Its insecticide properties (or its metabolites) are related to its ability to inhibit cholinesterase (AChE) [3] which affects nervous function and leads to severe and often lethal biological damage in organisms [4]. In humans, chlorpyrifos can inhibit the AChE enzyme in the central and peripheral nervous systems, causing adverse effects within hours of exposure [5,6].…”