Dietary Exposure to Pyrethroids in the U.S. Population Rogelio Tornero-Velez1, Jianping Xue2, Edward Scollon3, James Starr2, Peter Egeghy2, Dana Barr4, Mike DeVito3 and Curtis Dary1 O X National Exposure Research Laboratory, U.S. Environmental Protection Agency EPA, Las Vegas, NV;2 Research Triangle Park, NC, 'National Health and Environmental Effects Research Laboratory, Research Triangle Park, NC, 4National Center for Environmental Health, U.S. Centers for Disease Control and Prevention, Atlanta, GA. Introduction Method Pyrethroids are a group of synthetic insecticides similar in structure to the pyrethrins, natural extracts of Chrysanthemum cinerariaefolium. In both insects and mammals pyrethroids target the nervous system, acting directly on voltage-gated sodium channels to modulate nerve firing. Because of their potency, pyrethroids are widely used in agriculture, commercial facilities, and in residential homes to control insect pests. As a consequence, pyrethroid residues present in foods or on treated surfaces may serve as sources of human exposure. However, the importance of individual routes of exposure (e.g.. dietary, non-dietary ingestion, and dermal) remain unclear. We examined the contribution of pyrethroid residues in food as a potential driver of exposure. The levels of urinary metabolites of pyrethroids reported through the 2001-2002 U.S. National Health and Nutrition Examination Survey (NHANES) were used as a general estimate of population exposure to pyrethroids. Dietary exposure to these pyrethroids was estimated using U.S. Department of Agriculture's Continuing Survey of Food Intakes by Individual (CSFII) and Pesticide Data Program (PDP). A pharmacokinetic model of permethrin was used to account for absorption and excretion of urinary DCCA. Comparison of the predicted metabolites levels with values reported in NHANES suggests that dietary permethrin is a minor source of urinary DCCA. I. NHANES provides an ongoing assessment of the U.S. population's exposure to environmental chemicals using biomonitoring. The Third Report (1) provides data on five urinary metabolites of pyrethroids. The findings suggest widespread exposure to pyrethroid insecticides because 3-PBA, a common metabolite of several pyrethroid insecticides was found in much of the U.S. population (Table I). The ratio of trans-DCVA to cis-DCVA (—2.5) suggests oral exposure. In an observational study of 1171 residents of Frankfurt, Germany, Schettgen et al. (2) found this ratio at ~2, citing the work of Woollen et al (3) as evidence of oral exposure since that study deduced a ratio of ~2 following oral exposure and unity following dermal exposure. At the higher percentiles of the distribution of metabolites, 3-PBA levels were comparable to the sum of trans- DCVA and cis- DCVAl, suggesting that exposure in this realm is comprised primarily of permethrin, cypermethrin, and cyfluthrin. The percentiles for FPBA, specific to cyfluthrin, were all below 0.1 micro-g/1, suggesting exposure is more likely attributable to permethrin or cypermethrin, or both. A?-"5- "T" T x ~"XCO Nt«i« ret RI RS 174 CvpenrsBinn a u CM H i=ermemnn: u u H H C.IIuOir a a CN F (H. H H m •JH, Utl H cyiafcthm a U"0 CM H Defewvthrin Or fr Osl H hjmlrolytic products 1, oxidation product Figure 1. Metabolism of pyrethroids by (A) hydrolysis and (B) oxidation. The metabolites resulting from (A) are excreted in urine (five are reported in NHANES). DCVA (see Table I) is specific to cypermethrin, cyfluthrin and permethrin. Table I. Geometric mean and selected percentiles of urine concentration (JAg/L) for the U.S. Population aged 6-59 years, National Health and Nutrition Examination Survey, 2001-2002. (Abstracted from The Third Report, CDC) a on n^iin Sn® on"1 3-Phenoxybenzoic acid (3-PBA) 6 and older .280 .690 1.69 3.32 2539 6-11 .300 .750 1.81 3.28 580 CM-3-(2,2-Dichlorovinyl)-2,2-dim ethyl cyclopropane carboxylic acid (c-DCVA) 6 and older CLOD .160 .490 .890 2539 6-11 CLOD .110 .360 .730 580 /ra«4-3-(2,2-Dichloroviiiyl)-2,2-dim ethylcvclopropai 6 and older CLOD .410 1.2( } carboxylic acid (t-DCVA) 2.50 2525 2.50 576 cis'-3-(2,2-Dibromovinyl)-2,2-dimethylcycloprop ane carboxylic acid (DBVA) 6 and older CLOD CLOD CLOD CLOD 2539 4-Fluoro-3-Phenoxybenzoic Acid 6 and older CLOD CLOD CLOD CLOD 2539 6-11 CLOD CLOD CLOD CLOD 580 Method II. Dietary Model. To estimate the daily dietary intake of the pyrethroids specific to DCVA (cypemethrin, cyfluthrin, and permethrin) we used CPA's Stochastic Human Exposure and Dose Simulation (SHEDS) model. The SHEDS dietary module samples the 40.000 person-days of data from the USDA's 1994^1996 Continuing Survey of Food Intake by Individuals (CSFII) and residues from the FDA's Total Dietary Survey (TDS). Pyrethroid residues and food intake data were matched by food commodities using recipe files (US EPA Office of Pesticide Programs). ~ i jf i 3-r X 3 1 Distribution fitting I j I E. 1 No detected values ;1 IVMcljetl T, I Food Make Calculation Dietary intake of total permethrin by SHEDS-dietary module Figure 2. Dietary intake of total permethrin by SHEDS- dietary module. The 98th percentile for the distribution of cypermethrin was <0.005, and <0.01 for cyfluthrin. III.Pharmacokinetic Model, a provisional model of permethrin disposition in humans was developed based on a physiologically-based pharmacokinetic model of deltamethrin disposition in the rat (4; Fig 3). To derive a human model of permethrin disposition, we updated the physiological and chemical-specific data. We used the P3M software (5), which randomly samples from 30,000 physiological records in NFIANES III (with specification of constraints on age, sex, and ethnicity) and employs algorithms to derive organ volumes and flows. The records of 10,000 children aged 6-11 were randomly sampled to obtain mean physiological constants. Clearance of permethrin was estimated using pooled human hepatic microsomes. A mixture of permethrin (40% eis, 60% trans) exhibited NADPH-dependent clearance of 122.5 i 31.6 ml/min/kg BW and non-NADPH dependent clearance of 132 H 18.1 ml/min/kg BW, suggesting predominant clearance by the esterase pathway in humans. The major products of hydrolysis, 3-PBA and DCCA were assumed to enter a central compartment and clear at a rate equal to CL rt=£yf, where A'=ln(2)/t;/2 and Vis the volume of distribution at steady state. The half-life (til) was estimated at 13 hrs for each metabolite (3). Using the methodology of Poulin and Theil (6), (F) =T (tissue volume) x (tissue:plasma) + plasma volume, F was estimated at 4.60 L/Kg for PBA and 3.971 L/Kg for DCCA. v dosing urinary elimination <=[ diffusion limitation in fat, slowly perfused, RBC Fig. 3. PBPK model of permethrin was described by both flow-limited (brain, gastrointestinal [GI] tract, liver, and rapid-perfused tissues) and diffusion-limited (fat, blood/ plasma, and slowly perfused tissues) rate equations. Simulation: We tested dietary bolus intakes representing the 75 , 90th, and 95th percentiles of the dietary intake distributions permethrin, cypermethrin, and cyfluthrin) . Permethrin represented 100% of these mixtures (0.0041. 0.024, 0.021 micro-g/Kg/day). A 12 hour simulation, representing a nominal morning void time (assumed volume of 600 ml) was conducted, and predicted DCVA was compared to NHANES data. Results Conclusions References Simulations conducted with 75th, 90th, and 95th percentile of dietary intake accounted for only about 1%, 2°%a and 2% of the respective percentiles of excreted DCVA reported in NHANES. Thus, dietary intake of these pyrethroids does not appear to be an important determinant of overall exposure in the general population. Figure 2. Dietary simulation of an oral bolus 0.021 micro-gram/day/kg exposure (951,1 percentile), showing DCVA production versus time. The red dots represent the sum of trans-DCVA and cis-DCVA from the 75th, 90th, and 95th percentiles of the NHANES data. Distribution of urinary markers (1) suggest that higher exposures in the population are attributable primarily to permethrin and cypermethrin. We investigated whether exposure to these DCVA-related pyrethroids could be attributed to dietary exposure. A PBPK model was used to estimate urinary metabolites based on estimated (modeled) dietary exposure to permethrin, but these account for only 1-2% of urinary markers. The findings suggest that non-dietary source (e.g., residential application) of permethrin or cypermethrin. or both account for higher exposure to pyrethroids in the population The United States Environmental Protection Agency through its Office of Research and Development funded and managed the research described here. It has been subjected to Agency review and approved for publication (1) Third National Report on Human Exposure to Environmental Chemicals. CDC/NCEH Pub 05-0570 (2) Schettgen T, Heudorf U, Drexler H, Angerer J. Pyrethroid exposure of the general population-is this due to diet. Toxicol Lett. 2002 Aug 5;134(1-3): 141-5. (3) Woollen BH, Marsh JR, Laird WJ, Lesser JE. The metabolism of cypermethrin in man: differences in urinary metaboliteprofiles following oral and dermal administration. Xenobiotica. 1992 Aug;22(8):983-91 (4) Mirfazaelian A, Kim KB, Anand SS, Kim HJ, Tornero- Velez R, Bruckner JV, Fisher JW. Development of a Physiologically Based Pharmacokinetic Model for Deltamethrin in the Adult Male Sprague-Dawley Rat. Toxicol Sci. 2006 (5) Price, P. S., R.B. Conolly, C.F. Chaisson, E.A. Gross, J.S. Young, E.T. Mathis, D.T. Tedder. Modeling Inter-individual Variation in Physiological Factors Used in PBPK Models of Humans, Critical Reviews in Toxicology Vol. 33 (5): 469- 503, (2003). (6) Poulin P, Theil FP. Prediction of pharmacokinetics prior to in vivo studies. 1. Mechanism-based prediction of volume of distribution. JPharm Sci. 2002 Jan;91(l):129-56. ------- |