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.

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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).

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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.


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