Chlorpyrifos metabolites

Drevenkar V, Vasilic Z, Stengl B, et al. 1993. Chlorpyrifos metabolites in serum and urine of poisoned persons. Chem Biol Interactions 87 315-322. 

Chlorpyrifos metabolite Polychlorobiphenyls Comparison with subcritical water extraction [157]... 

An important caveat in interpreting chlorpyrifos metabolite concentrations in urine is that this metabolite (TCP) is widespread in the environment and thus can appear in urine as a result of direct intake as well as from conversion from a parent chemical (Lu et al. 2005 Wilson et al. 2003). For example, the concentration of TCP in foods can be greater than that of chlorypyrifos, and concentrations in house dust can be generally comparable (Morgan et al. 2005). Direct intake of TCP from environmental media makes extrapolation of urinary biomarker concentration to chlorpyrifos exposure dose uncertain. 

The USEPA reviewed a number of registrant-submitted studies to assess exposure to handlers applying chlorpyrifos in agricultural and residential settings (USEPA, 2001). The biomonitoring studies measured urinary concentrations of the primary chlorpyrifos metabolite and back-calculated these to the absorbed dose of the parent. The passive dosimetry study results were corrected for 3 % dermal absorption from a human dosing study (Nolan et al 1984). The results of the studies are reported in Table 1.4 and demonstrate fairly close concordance between the two methodologies. 

We developed a magnetic beads-based detection system for competitive assay of metabolites from OPs (Figure 3) (4J). This method employed a sequentially injecting washing buffer, a mixture of TCP (chlorpyrifos metabolite) containing sample,... 

It is important to emphasize that the initial metabolites after hydrolysis may be both toxic and sometimes resistant to further degradation. Examples include nitrophenols, whose degradation is discussed in Chapter 9, Part 5 and 3,5,6-trichloropyridin-2-ol (Feng et al. 1997), which is produced by the hydrolysis of chlorpyrifos (0,0-diethyl-0-[3,5,6-trichlo-2-pyridyl]phosphorothioate). 

The urine samples were analyzed using a modified version of a published method.8 The method involved fortification of the urine samples with an internal standard 3,4,5-trichloro-2-pyridinyl, which is a structural isomer of the 3,5,6-TCP metabolite of chlorpyrifos hydrolysis of labile acid conjugates to 3,5,6-TCP solvent extraction derivitization to the f-butyl-dimethylsilyl ester of 3,5,6-TCP and subsequent negative-ion chemical ionization gas chromatography/mass spectrometry (GC/MS) analysis. Creatinine was determined in urine using a modification of a method of Fabiny and Erting-shausen.9... 

To monitor the absorbed chlorpyrifos doses in human volunteers, urine was collected before and following a 4-hr activity period on the treated grass surface(re-entry). The urine was analyzed for 3,5,6-trichloropyridinol (3,5,6-TCP), the urinary metabolite of chlorpyrifos, and creatinine, which was determined to verify completeness of urine collection by each volunteer. 

Estimation of dose from urinary metabolite analysis From the analysis of volunteer s urine for 3,5,6-TCP, the amount of absorbed chlorpyrifos was determined for each individual volunteer. Table 5 summarizes the calculated chlorpyrifos dose based on analysis of urine samples. The average chlorpyrifos dose was estimated to be 7.07 pg/kg, 182% of the dose estimated using physical techniques. 

Chemicals degraded by WRF include pesticides such as organochlorines DDT and its very toxic metabolite DDE [8, 9] and organophosphate pesticides such as chlorpyrifos, fonofos and terbufos [10] polychlorinated biphenyls (PCBs) of different degrees of chlorine substitution [11-13], some even to mineralization [14, 15] diverse polycyclic aromatic hydrocarbons (PAHs) in liquid media and from contaminated soils or in complex mixtures such as creosote [16-18] components of munition wastes including TNT and its metabolites DNT [19-23], nitroglycerin [24] and RDX [25]. 

A report entitled Chemical Trespass was issued in May 2004 by the Pesticide Action Network (Schafer et al., 2006). It contained detailed analysis of 2000/01 National Health and Nutrition Examination Survey (NHANES) OP urinary metabolite data and used published methods to estimate exposure levels to parent compounds from creatinine corrected urinary metabolite levels. They focused on chlorpyrifos and its metabolite 3,4,6-trichloro-2-pyridinol (TCP), and found that chlorpyrifos exposures for children ages 6-11 and 12-19 exceeded EPA s chronic population-adjusted dose (cPAD) by surprisingly wide margins. Geometric mean TCP levels were 3 to 4.6 times higher than the EPA-estimated safe dose, as shown in Fig. 14.2. The more heavily exposed children received daily doses more than ten times the safe level. 

Figure 14.1 Structures of chlorpyrifos and some of its metabolites. (Modified from Barron, M.G., S.M. Plakas, and PC. Wilga. 1991. Chlorpyrifos pharmacokinetics and metabolism following intravascular and dietary administration in channel catfish. Toxicol. Appl. Pharmacol. 108 474-482.)...

Human subjects who ingested chlorpyrifos once daily for 4 weeks showed depression of plasma cholinesterase but were symptomless at a dose of 0.1 mg/kg. When four repeated doses were applied to the skin of human volunteers for 12 hours each, doses of 25 mg/kg depressed plasma cholinesterase but caused no symptoms. Chlorpyrifos and its principal metabolite, 3,5,6-trichloro-2-pyridinol, are rapidly eliminated, predominantly in the urine. ... 

R Serrano, FJ Lopez, A Roig-Navarro, F Hernandez. Automated sample clean-up and fractionation of chlorpyrifos, chlorpyrifos-methyl and metabolites in mussels using normal-phase liquid chromatography. J Chromatogr A 778 151-160, 1997. 

G. Jeanty, Ch. Ghommidh and J.L. Marty, Automated detection of chlorpyrifos and its metabolites by a continuous flow system-based enzyme sensor, Anal. Chim. Acta, 436(1) (2001) 119-128. 

Biocides are known to be tracked into the homes after a certain outdoor application (Lewis and Nishioka, 1999 Nishioka et al., 2001). Furthermore transport routes, that is, transfer from the workplace to the home (para-occupational or take-home exposure) may be relevant. Household dust concentrations of azino-phosmethyl, chlorpyrifos, parathion and phosmet were significantly lower in reference homes when compared with farmer/farmworker homes (Simcox et al., 1995). Dialkyl phosphate metabolites measured in children s urine were elevated for agrarian children compared with children whose parents did not work in agriculture (Fenske et al., 2000). 

The chlorpyrifos example described in Appendix B illustrates another caveat related to biomarkers that are urinary metabolites. A metabolite can sometimes appear in urine not only as a result of parent-chemical uptake and metabolism but also as a result of uptake of the metabolite from environmental media (Tu et al. 2005 Wilson et al. 2003). Thus, the biomarker for chlorpyrifos, 3,5,6-trichloro-2-pyridinol (TCP), occurs in a wide variety of environmental media, and the concentration in foods surpasses that of the parent chemical (Morgan et al. 2005). If the intake of the metabolite from environmental sources is substantial in comparison with that of the parent chemical, as in the case of chlorpyrifos and TCP, the extrapolation of urinary biomarker concentration to parent-chemical exposure dose is uncertain. 

The chlorpyrifos and phthalate examples demonstrate that urinary biomarker data can be used within the context of pharmacokinetic modeling to interpret human exposure and risk. For a number of workplace urinary biomarkers, simple approaches have been used to relate biomarker concentration to exposure dose. A prime example is styrene an empirically derived relationship between urinary concentration of the metabolite, man-... 

Chlorpyrifos provides an example of the utility of human pharmacokinetic models to estimate daily dose from biomonitoring data for a rapidly cleared pesticide. The urinary metabolite trichloro-2-pyridinol (TCP) is used in the NHANES study to monitor population exposure to chlorpyrifos (CDC 2005). Several epidemiologic studies have linked chlorpyrifos exposure to adverse birth outcomes through associations between urinary and blood biomarkers and have demonstrated maternal exposure and physiologic measurements in the neonate (Berkowitz et al. 2003, 2004 Whyatt et al. 2004 Needham 2005). 

Alachlor, benzene hexachloride, cycloodines, aldrin, chlordane, dieldrin, endrin, endosulfan, heptachlor, isodrin, telodrin and toxaphene, DDT and metabolites, dicofol, dimethoate, lindane, methoxychlor, mirex, pentachlorophenol, perthane Azinphosmethyl, bromophos ethyl, chlorpyrifos, crotoxyphos, demeton, diazinon, dichlorvos, ethion, fenitrothion, fensulfothin, fenthion, flusulfothin, methamidophos, mevinphos monocrotophos and dichrotophos, oxamyl, phorate, parathion (ethyl), parathion (methyl), phosphomidon, quinolphos temephos Aldicarb, benomyl, carbaryl, chlorpropham, fenvalerate, methomyl... 

Urinary Metabolite Monitoring 28 Salivary Monitoring 29 VALIDATION OF PASSIVE DOSIMETRY 30 Atrazine 30 Chlorpyrifos 31... 

J.V. Sancho, O.J. Pozo, F. Hernandez, Direct determination of chlorpyrifos and its main metabolite 3,5,6-trichloro-2-pyridinol in human serum and urine by coupled-column LC-ESI-MS-MS, Rapid Commun. Mass Spectrom., 14 (2000) 1485. 

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