Urinary Pyrethroid and Chlorpyrifos Metabolite Concentrations in

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Urinary Pyrethroid and Chlorpyrifos Metabolite Concentrations in Northern California Families and Their Relationship to Indoor Residential Insecticide Levels, Part of the Study of Use of Products and Exposure Related Behavior (SUPERB) Kelly J. Trunnelle,*,† Deborah H. Bennett,‡ Nicolle S. Tulve,§ Matthew Scott Clifton,§ Mark D. Davis,∥ Antonia M. Calafat,∥ Rebecca Moran,‡ Daniel J. Tancredi,⊥ and Irva Hertz-Picciotto‡ †

Agricultural and Environmental Chemistry, ‡Public Health Sciences, University of California, Davis, California 95616, United States Human Exposure and Atmospheric Sciences, National Exposure Research Laboratory, Office of Research and Development, U.S. EPA, Research Triangle Park, North Carolina 27711, United States ∥ Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control, Atlanta, Georgia 30341, United States ⊥ Department of Pediatrics, University of California, Davis, School of Medicine, Sacramento, California 95817, United States §

S Supporting Information *

ABSTRACT: Since the 2001 U.S. federally mandated phase-out of residential uses of organophosphates (OPs), use of and potential for human exposure to pyrethroids in the indoor residential environment has increased. We report concentrations of common pyrethroids, pyrethroid metabolites, and chlorpyrifos in floor wipes, and urinary concentrations of pyrethroid metabolites and 3,5,6-trichloro-2-pyridinol (TCPy) in samples collected in 2007−2009 from 90 northern California families as part of the Study of Use of Products and Exposure Related Behavior (SUPERB). Correlation and regression analyses examined associations between floor wipe and urine sample concentrations. The most frequently detected urinary metabolites were TCPy (64.7%, median concentration of 1.47 ng/mL) and 3-phenoxybenzoic acid (3PBA) (62.4%, 0.79 ng/mL). Compared to the National Health and Nutrition Examination Survey (NHANES) 2001−2002 general U.S. population, this population had substantially higher pyrethroid metabolite and lower TCPy urinary concentrations. This may be related to the increased residential use of pyrethroids after the phase-out of OPs. Chlorpyrifos (98.7%), cis- and trans-permethrin (97.5%), bifenthrin (59.3%), and 3PBA (98.7%) were frequently detected in the floor wipes. Floor wipe concentrations for pyrethroid insecticides were found to be significant predictors of child creatinine-adjusted urinary metabolite concentrations (log−log regression coefficients ranging from 0.26 to 0.29; p < 0.05) suggesting that indoor residential exposure to pyrethroid insecticides is an important exposure route for children.

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INTRODUCTION Insecticides are commonly used both in and around residential homes in the United States. Exposure to insecticides may result from ingestion of food or drinking water or from inhalation, dermal contact, or nondietary ingestion resulting from residential applications. Once insecticides have entered the home, carpets and cushioned furniture can act as repositories for the parent compounds and their metabolites.1 Children have an increased risk of exposure to environmental contaminants partly because of behaviors leading to higher nondietary ingestion than adults.2 Thus, indoor sources pose a special risk to children.3,4 The indoor residential environment is a more important route of exposure to pyrethroids than dietary ingestion, unlike organophosphate (OP) insecticides.5−9 Adding to the importance of this route of exposure is the increased indoor usage of synthetic pyrethroids since the 2001 U.S. © 2014 American Chemical Society

federally mandated phase-out of residential uses of the OP insecticides chlorpyrifos and diazinon.10−13 Although pyrethroids have relatively low mammalian toxicity, there is still caution with regard to human exposure. Studies have shown that exposure to high levels of pyrethroids may cause significant toxicity and health effects, including acute neurotoxic effects,14 immunotoxic effects,15 and endocrine disruption which can adversely affect mammalian reproduction.16,17 Pyrethroids are possible human carcinogens,18 with associations seen between exposure and cutaneous melanoma,19 as well as childhood leukemia.20 The impact of chronic Received: Revised: Accepted: Published: 1931

August 16, 2013 January 6, 2014 January 14, 2014 January 14, 2014 dx.doi.org/10.1021/es403661a | Environ. Sci. Technol. 2014, 48, 1931−1939

Environmental Science & Technology

Article

Informed consent for participation was obtained before data or specimen collection. Sample Collection. Samples were collected December 2007−November 2009. An end-of-day spot urine sample was collected from 90 adults and 83 children. Participants were provided specimen collection “hats” (Commode Specimen Collector, Fisher Scientific P/N 22-363-149) to be placed under the toilet seat21 and standard plastic urine cups to store the collected sample overnight in the refrigerator. Adult participants were instructed to record the volume and time of both the collected and previous void for themselves and their child. Samples were transported on ice packs to UC Davis the following day, and were frozen and stored at −80 °C until shipment to the CDC facility in Atlanta, GA for analysis. On the day urine samples were retrieved, UC Davis staff also collected floor wipe samples from 930 cm2 of the kitchen floors in 88 out of the 90 homes using two 4 in. × 4 in. precleaned cotton Twillwipe cloths (M.G. Chemicals, P/N 829-50) dampened with 6 mL of isopropanol (pesticide residue analysis grade, Fisher Scientific, Fair Lawn, NJ). Wipes were precleaned via Soxhlet extraction with isopropanol, followed by extraction with hexane, dried in a vacuum oven, and ultimately placed in a sealed clean glass jar until use.30 The floor was marked with painter’s masking tape, wiped uniformly in one direction, then wiped again perpendicular to the first direction. The procedure was repeated on the same section of floor with the second wipe. Immediately after use, each wipe was placed in a single precleaned 60-mL amber jar. These samples were transported back to UC Davis on ice packs, frozen and stored at −20 °C until shipment to the U.S. EPA (Research Triangle Park, NC), where they were stored at −20 °C until extraction. Sample Analysis. Urine samples were analyzed at CDC following a modification of a previously reported method.31 Briefly, 1 mL of urine was fortified with a standard solution of isotopically labeled 3PBA, 4F3PBA, cis-DBCA, and TCPy, and incubated with β-glucuronidase/sulfatase (Sigma-Aldrich, Co., St. Louis, MO) to hydrolyze conjugated metabolites. Metabolites were extracted using the Quadra 3 (Tomtec Inc. Hamden, CT) 96-well plate technology with an OASIS HLB mixed-mode solid-phase extraction 96-well plate (Waters Corp., Milford, MA). The plate was washed with a 25% methanol in 0.1% acetic acid solution, and metabolites were eluted with acetone. Target insecticide metabolites in the eluates were separated and quantified using high-performance liquid chromatography (Agilent Technologies, Santa Clara, CA) coupled with heated electrospray ionization tandem mass spectrometry (Thermo Scientific, West Palm Beach, FL) operating in the negative ion mode. 3PBA, 4F3PBA, cisDBCA, and TCPy were quantified using isotope dilution calibration; trans-DCCA was quantified using the labeled 3PBA as the internal standard. Because calibrators were prepared in diluted urine, corrections were made to account for these endogenous compounds in the calibrator matrix. Positive and negative control samples represented 10% of the samples analyzed and were used as laboratory controls to ensure proper method operation. Due to the potential presence of analytes in the laboratory background, a blank sample was prepared with every analytical run and monitored throughout the study for possible contamination. If blank values were unacceptable (above three times the limit of detection (LOD)), the analytical run would be considered out of control and all of the samples in the batch would be reanalyzed. For 3PBA, trans-DCCA, cisDBCA, and TCP, the LODs were set to the lowest detectable

low or moderate level exposures in general, and on the developing fetus or child, has not been well studied. Pyrethroids metabolize quickly in the body and most also degrade rapidly in sunlight. 3-Phenoxybenzoic acid (3PBA) is a nonspecific metabolite of multiple pyrethroids including cyhalothrin, cypermethrin, deltamethrin, esfenvalerate, permethrin, and sumithrin. The metabolite 4-fluoro-3-phenoxybenzoic acid (4F3PBA) is specifically produced from cyfluthrin. 3(2,2-Dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (DCCA) is a metabolite of cyfluthrin, cypermethrin, and permethrin, while 3-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylic acid (DBCA) is a specific metabolite of deltamethrin (Supporting Information (SI), Table S1). 3PBA has been commonly used as a nonspecific biomarker for evaluating human exposure to multiple pyrethroid insecticides,21 and has also been measured in the indoor environment.1 Chlorpyrifos, an OP insecticide, was frequently used indoors until being banned for residential use in 2001. 22 Its nonresidential uses include application on a variety of food and feed crops (but these uses have also decreased over the past decade), as well as golf courses and nonstructural wood.22 Exposure to chlorpyrifos has been found to disrupt endocrine regulation in ewes,23 has been associate with negative impacts of the neurodevelopment of children,24,25 and can cause cholinesterase inhibition in humans.22 Chlorpyrifos metabolizes rapidly in the body, occurring predominantly in the liver, with 3,5,6-trichloro-2-pyridinol (TCPy) being the principal metabolite.26 We report results from 83 child and 90 adult northern California residents, a subcohort of participants taking part in the Study of Use of Products and Exposure Related Behavior (SUPERB). Specifically, we report urinary concentrations of 3PBA, trans-DCCA, cis-DBCA, 4F3PBA, and TCPy. We report the indoor environmental concentrations (as measured from floor wipe samples of 81 of the participating households) of allethrin, bifenthrin, cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, λ-cyhalothrin, cis-permethrin, trans-permethrin, sumithrin, tetramethrin, chlorpyrifos, 3PBA, 4F3PBA, DCCA, and DBCA. We make the assumption that floor wipes are a better proxy for exposure than self-reported use information as they reflect current concentrations to which children are exposed and because previous studies27,28 have not found use data to effectively reflect exposure levels. Finally, we evaluate whether urinary concentrations of metabolites are associated with measurements in floor wipe samples.

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MATERIALS AND METHODS Study Population. SUPERB investigated human behaviors that could influence exposure to environmental pollutants by studying food consumption patterns, household product use, and daily activities. Northern California families (one parent and one child, n = 499), with children born between 2000 and 2005, were identified and randomly selected through birth certificate records, with details previously published.29 Ninety households were enrolled in this substudy to collect environmental and biological samples, and this paper reports results for indoor residential and urinary pyrethroid and OP insecticides. At the time of enrollment to this substudy all children were aged two through eight years. All recruitment and data collection protocols were approved by the Institutional Review Boards at the University of California, Davis (UC Davis) and the Centers for Disease Control and Prevention (CDC). 1932

dx.doi.org/10.1021/es403661a | Environ. Sci. Technol. 2014, 48, 1931−1939


Article

compounds for which at least 60% of the floor-wipe samples were detectable. In these analyses the log-transformed volumebased adult or child urinary metabolite concentrations were regressed on log-transformed creatinine concentrations and log-transformed individual or combined floor wipe levels of insecticides or metabolites. A combined variable was created which summed the concentrations of the parent pyrethroids permethrin, cypermethrin, deltamethrin, esfenvalerate, and λcyhalothrin found in the floor wipe samples was entitled “Pyrethroid Total”, a second variable called “Pyrethroid total plus 3PBA” was computed by summing the 3PBA floor wipe concentrations to the “Pyrethroid total” variable, and a third variable, “Metabolite Total”, was computed by summing concentrations of the pyrethroid metabolites cis-DBCA, transDCCA, 3PBA, and 4F3PBA found in the floor wipe samples. Three general linear models were fit,33 one with the data from both the adults and the children, one with data from only the children, and one with data from only the adults. To express associations on the original scale of measurement for the outcome, point estimates and confidence intervals for these log−log regression coefficients were inverse log-transformed and reported as adjusted geometric mean ratios (AGMR’s). The AGMR describes the relative increase in the conditional geometric mean level of the outcome associated with a 1-unit change in the log-transformed exposure. Statistical significance was set at p < 0.05. Analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC).

standard in each analytical run. The LOD for 4F3PBA was calculated as three times the standard deviation (SD) of the blank concentration measurements.32 Urinary creatinine concentrations were determined21 and used to correct urinary metabolite concentrations for variable urine dilutions in the “spot” samples. Wipe samples were analyzed by U.S. EPA and details of the analysis and laboratory QA/QC procedures can be found in the previously published method.30 Briefly, after being spiked with 50 μL of the surrogate recovery solution (SRS) of the insecticide surrogates diazinon-d10 and trans-permethrin-13C6 (Cambridge Isotope Laboratories), which were prepared together at 2.4 μg/mL in hexane, the wipes were extracted with an acetone/hexane solution (1:1 by volume) in an ultrasonic cleaner for 30 min. Extracts were solvent-exchanged into hexane and partitioned with aqueous NaOH with a total of three portions of hexane. The hexane layers containing the insecticides were passed through ∼10 g of Na2SO4 before being volume-reduced and purified using Bond Elut NH2 SPE cartridges (Agilent Technologies, Palo Alto, CA). The cartridges were washed with 25% acetone in hexane followed by hexane, and the pyrethroids were eluted using hexane followed by a 25% acetone in hexane solution. Eluates were concentrated, an internal standard (IS) solution of phenanthrene-d10 and cis-permethrin-13C6 was added, and samples were analyzed using electron impact gas chromatography−mass spectrometry. The NaOH layer, which still contained the metabolites, was acidified using 2N HCl. This layer was partitioned three times with dichloromethane, passing through Na2SO4 prior to volume reduction, and solvent-exchanged into ethyl acetate. An IS containing 3PBA-13C6 was added before extracts were transferred to auto sampler vials and silylation with Sylon BFT (Supelco, Bellefonte, PA, USA) at 70 °C for 10 min. The silylated extracts were analyzed by EI GC/MS in selected ion monitoring mode. Method detection limits (MDLs) were determined using the guidelines from 40 CFR Part 136, Appendix B, and were calculated based on a standard 930 cm2 sampling area.30 Statistical Analysis. Descriptive statistics summarized distributions of insecticide and metabolite concentrations in floor wipes and urine. U.S. EPA reported all detectable floor wipe concentrations. In correlation and regression analyses, nondetectable floor wipe concentrations were recoded to a small nonzero value. CDC reported only urinary metabolite concentrations above the LOD. Concentrations below the LOD were set equal to LOD/√2. Visual analysis of normal quantile−quantile plots revealed substantial departures from normality for urinary concentrations and floor wipe levels. Spearman rank-order correlation coefficients (rs ) were calculated to determine intrahousehold correlations between parent and child urinary concentrations. Confidence intervals (CI) for correlation coefficients were computed using Fisher’s z-transformation. Separately for children and for adults, multivariate regression analyses were used to estimate associations between urinary insecticide metabolite concentrations (dependent variable) and floor wipe concentrations of individual insecticide and metabolite concentrations (independent variable) when statistically adjusting for urinary creatinine concentrations (independent variable). The multivariate regression analyses conducted to estimate associations between urinary metabolite concentrations and floor wipe concentrations are only reported for

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RESULTS Population Demographics. Demographic information is presented in Table 1. Participating adults were 90% female (mean age = 36 years; 91% having at least some college education). The proportions of stay-at-home (48%) and employed (42%) parents were almost equal, and 22% of participants were foreign born. With approximately 60% of this population having a bachelor’s degree or higher compared to 30% of adults aged 25 or older in the U.S.,34 this population is not representative of the general U.S. population. Urinary Concentrations. Urinary concentrations of pyrethroid metabolites were detected in 63% of samples with a detectable range of 0.67−89.7 ng/mL 3PBA, 4.92−121 ng/ mL trans-DCCA, 1.09−1.48 ng/mL cis-DBCA, and 0.43−0.77 ng/mL 4F3PBA. 3PBA was the most frequently detected pyrethroid metabolite with 50 (60.2%) children and 58 (64.4%) adult samples having detectable concentrations, corresponding to 39 (48.2%) households with detectable urinary concentrations in both the adult and child. Urinary concentrations of 3PBA between adults and children within a household were positively correlated for both volume-based (n = 83, rs = 0.43, 95% CI: 0.23−0.59, p < 0.0001) and creatinine-adjusted concentrations (n = 83, rs = 0.46, 95% CI: 0.27−0.62, p < 0.0001). Summary statistics are presented in Table 2. The urinary pyrethroid metabolites trans-DCCA, cis-DBCA, and 4F3PBA were detected less frequently. More details on their detection frequencies and concentration ranges are reported in the SI. Urinary concentrations of the chlorpyrifos metabolite TCPy were detected in 64.7% of samples, with 61 children and 51 adult samples having concentrations ranging from 0.74−18.9 ng/mL, corresponding to 40 households with detectable levels in both the adult and child. Urinary concentrations of TCPy within a household were positively correlated for both volumebased (n = 83, rs = 0.32, 95% CI: 0.11−0.50, p = 0.003) and 1933



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Floor Wipe Concentrations. Measurements were available from 81 out of 88 household samples; and the distribution of pyrethroids and metabolites along with MDL values (0.0012− 0.0038 ng/cm2 for parent pyrethroids and 0.0059−0.011 ng/ cm2 for metabolites) are presented in Table 3. Chlorpyrifos (99%), cis- and trans-permethrin (97.5%), and bifenthrin (59.3%) were frequently detected, with the remaining compounds only detected in 2.5−14.8% of samples. Although chlorpyrifos was the most frequently detected, the mean concentration (0.0014 ng/cm2) was over an order of magnitude lower than either cis- or trans-permethrin. 3PBA was the most frequently detected pyrethroid metabolite (98.7%). 4F3PBA was also detected with moderate frequency (34.2%). DCCA was detected in only 2.5% of samples, and DBCA was not detected in any samples. Floor Wipe vs Urine Concentrations. In children, floor wipe concentrations of cis-permethrin and of trans-permethrin were highly significant predictors of urinary concentrations of 3PBA (Table 4). The summed total of pyrethroid concentrations and the summed total of parent pyrethroids plus 3PBA concentrations found in the floor wipes were also strongly significant predictors of urinary concentrations of 3PBA in children. As a sensitivity analysis, the child with the highest concentration of 3PBA (89.7 ng/mL, almost 20 times higher than the 95th percentile for the SUPERB population) was removed and regression models refit: the relationships with parent compounds cis-permethrin (adjusted geometric mean ratio (agmr) = 1.30, 95% CI: 1.09−1.55, p = 0.004), transpermethrin (agmr = 1.32, 95% CI: 1.10−1.60, p = 0.004), and the total summed concentrations of pyrethroids that metabolize to 3PBA (agmr = 1.26, 95% CI: 1.06−1.50, p = 0.01) remained significant. In contrast, concentrations of chlorpyrifos in the floor wipes were not significant predictors of urinary concentrations of TCPy for children (agmr = −0.13, 95% CI: −0.46−0.21, p = 0.47). None of the parent pyrethroids detected in at least 60% of floor wipes were significant predictors of urinary concentrations of 3PBA in adult participants. Only 4F3PBA in floor wipe samples had a marginal effect on adult urinary concentrations of 3PBA (agmr = 1.13, 95% CI: 0.99−1.28, p = 0.07). Concentrations of chlorpyrifos in floor wipes were also not significant predictors of urinary concentrations of TCPy for adults (agmr = −0.03, 95% CI: −0.37−0.31, p = 0.87). Because of low detection frequencies of trans-DCCA, cisDBCA, and 4F3PBA in urine samples, we did not report the full results of regression analyses comparing these concentrations to floor wipe levels. In the homes of the 8 adults with detectable levels of trans-DCCA, a metabolite of permethrin, cypermethrin, and cyfluthrin, two homes had detectable levels of cypermethrin and 7 homes had detectable levels of permethrin in the floor wipes. Creatinine-adjusted geometric mean concentrations of trans-DCCA were marginally (but not statistically significantly) higher in adults whose homes had detectable levels of cypermethrin (agmr = 1.15, 95% CI: 0.99− 1.32, p = 0.06) in the floor wipes and in adults whose homes had detectable levels of permethrin (agmr = 1.14, 95% CI: 0.94−1.37, p = 0.18) in the floor wipes. The child with the highest urinary concentration of trans-DCCA (111.3 ng/mL) lived in the home with the highest floor wipe concentration of total permethrin (2.7 ng/cm2), suggesting the possibility that this child’s exposure came from the home. However, the parent of this child showed no detectable levels of trans-DCCA.

Table 1. Socio-Demographic Characteristics of Participants, SUPERB 2007−2009 Adult Characteristics (N = 90)

N (%)

Sex female male

81 (90) 9 (10)

Age Group 18−34 years 26 (29) 35−54 years 62 (69) 55+ years 2 (2) mean age of primary adult participant 36.6 Education Level 0−11 years 0 (0) 12 years 8 (9) 13−15 years 27 (30) 16 years 31 (34.4) >16 years 23 (26) missing 1 (1) Employment Status employed 38 (43) stay at home parent 43 (48) unemployed 1 (1) other 6 (7) missing 1 (1) Race/Ethnicity non-Latino white 60 (67) Latino (of any race) 13 (14) African American 2 (2) Asian 7 (8) other 4 (4) multiple 3 (3) missing 1 (1) Foreign Born yes 20 (22) no 69 (77) missing 1 (1) Marital Status married/living together 89 (99) widowed/divorced/separated/single 0 (0) missing 1 (1) Homeowner yes 71 (79) no 18 (20) missing 1 (1) Number of Children in the Family/Living in Home 1−2 67 (74) 3−4 20 (22) 5−6 2 (2) missing 1 (1) Child Characteristics (N = 90) N (%) Sex female male

45 (50) 45 (50)

Age Group 2−3.9 years 4−5.9 years 6−7.9 years 8−8.1 years mean age of child participant (years)

18 (20) 38 (42) 31 (34) 3 (3) 5.5

creatinine-adjusted concentrations (n = 83, rs = 0.34, 95% CI: 0.13−0.52, p = 0.001). 1934



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Table 2. Volume-Based (ng/mL) and Creatinine-Adjusted (μg/g) 3PBA and TCPy Urinary Concentrations from SUPERB (2009) and NHANES (2001−2002) 3PBA

TCPy selected percentiles

n

% detection frequency

50th

75th

selected percentiles n

95th

% detection frequency

50th

75th

95th

Total Population SUPERBa volume-based creatinine-adjusted NHANESb volume- based creatinine adjusted SUPERBa , aged 2−8 volume-based creatinine-adjusted NHANESb, aged 6−11 volume-based creatinine-adjusted SUPERBa, aged 18−57 volume-based creatinine-adjusted NHANESb, aged 20−59 volume- based creatinine-adjusted

173

62

0.79 0.76

1.56 1.77

5.34 9.04

173

65

1.47 1.51

2.88 2.96

5.86 5.92

1,994

75

0.27 0.29

0.70 0.60 Children

2.54 3.35

1,994

91

1.70 1.47

3.50 2.85

9.90 5.43

83

60

0.75 0.80

1.56 2.34

4.69 6.26

83

74

1.70 2.53

3.19 4.81

5.70 7.72

580

75

0.30 0.33

0.76 0.66 Adults

3.38 3.04

481

97

2.70 3.20

6.90 6.37

90

64

0.82 0.61

1.58 1.39

9.44 12.61

90

57

1.22 0.88

2.57 2.34

6.08 3.63

1,128

76

0.27 0.30

0.67 0.60

3.25 3.43

832

89

1.50 1.33

2.80 2.37

8.60 6.40

16.0 14.0

a

SUPERB limits of detection (LODs) were 0.58−0.75 ng/mL (3PBA), and 0.62−1.17 ng/mL (TCPy). bNHANES LODs were 0.1 ng/mL (3PBA), and 0.4 ng/mL (TCPy).

Table 3. Floor Wipe Insecticide and Metabolite Concentrations (ng/cm2), SUPERB 2009a compound

a

N

MDL

chlorpyrifos

81

0.000087

cis-permethrin trans-permethrin bifenthrin cypermethrin tetramethrin allethrin sumithrin cyfluthrin deltamethrin esfenvalerate λ-cyhalothrin

81 81 81 81 81 81 81 81 81 81 81

0.0016 0.002 0.0012 0.0038 0.0012 0.0034 0.0012 0.0021 0.0029 0.0028 0.0031

3PBA 4F3PBA DCCA DBCA

79 79 79 79

0.0059 0.0068 0.0085 0.011

%D

mean

median

Organophosphate Pesticides 98.7 0.0014 0.00048 Pyrethroid Pesticides 97.5 0.048 0.0074 97.5 0.072 0.01 59.3 0.0068 0.00058 14.8 ND 9.9 ND 7.4 ND 6.2 ND 3.7 ND 2.5 ND 2.5 ND 2.5 ND Pyrethroid Pesticide Metabolites 98.7 0.0014 34.2 ND 2.5 ND 0

75th

95th

max

0.00088

0.0038

0.033

0.024 0.041 0.0029 ND ND ND ND ND ND ND

0.21 0.3 0.035 0.14 0.0029 0.0093 0.004 ND ND ND ND

0.8 1.95 0.15 0.54 0.018 0.29 0.19 0.13 0.043 0.0081 0.062

0.0025 0.00033 ND

0.0047 0.00066 ND

0.0076 0.0017 0.0055

N = Number; MDL = method detection limit; %D = detection frequency; max = maximum; ND = nondetect.

The metabolite cis-DBCA, specific to deltamethrin, was detected in the urine of only three participants, one adult and child from the same home, and one child from a separate home. However, neither deltamethrin nor cis-DBCA was detected in the floor wipe samples from these households, suggesting that exposure came from other sources. 4F3PBA, the specific metabolite of cyfluthrin, was detected in the urine of 11 participants (8 adults, 3 children) and the floor wipes of 27 homes. There was only one home that had

detectable levels of 4F3PBA in the adult and child urine samples, as well as the floor wipe sample. Four of the remaining adult participants and one of the remaining child participants with detectable urinary levels resided separately in homes with detectable levels in the floor wipes. Creatinine-adjusted geometric mean concentrations of 4F3PBA, were higher, but not significantly higher in adults (agmr = 1.07, 95% CI: 0.99− 1.15, p = 0.0996) and children (agmr = 1.03, 95% CI: 0.99− 1.07, p = 0.17) whose homes had detectable levels of 4F3PBA. 1935



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multiethnic urban cohort in New York City from 1998 to 200133 reported higher levels. However, it was suspected that sumithrin was sprayed aerially in New York City during sampling, which may have contributed to these findings. We saw similar creatinine-adjusted urinary TCPy concentrations in SUPERB adults (median, 75th and 95th percentiles = 0.88, 2.34, and 3.63 μg/g, respectively) as in adult NHANES participants in 2001−2002 (1.33, 2.37, 6.42 μg/g, respectively).35 OP insecticide use is still present in agriculture, thus exposure to these insecticides through the food pathway continues. The creatinine-adjusted urinary TCPy concentrations in SUPERB children were lower (median, 75th, and 95th percentiles = 2.53, 4.81, 7.72 μg/g, respectively) than in children from NHANES in 2001−2002 (3.20, 6.37, 14.0 μg/g, respectively).36 The levels in children could have decreased over time due to reduced agricultural use for foods highly consumed by children,13 and through the gradual reduction of OP products in homes since the ban on production of residential OP insecticides. This coincides with the almost 10fold difference of the mean concentration of chlorpyrifos in floor wipes collected from SUPERB homes of 0.0014 ng/cm2, than that measured in the American Healthy Homes Survey’s national study of residential pesticides, measured from floor wipes from 1131 homes in 2005−2006, of 0.01 ng/cm2.37 Other factors, such as differences in insecticide use practices between the populations, may have also contributed to the lower concentrations found in SUPERB homes. Still, chlorpyrifos was detected in nearly 100% of SUPERB homes, indicating that residential exposure to this insecticide that persists in the indoor environment will continue.38 Urinary concentrations of 3PBA from adults and children within a household were positively correlated, and overlap for the less commonly detected metabolites (see SI). These data suggest that parents and children in these households are likely being exposed to common sources of pyrethroids, either from the home or a common diet, although discrepancies in other homes may point to additional sources of exposure, or differences in diet or activities. Floor wipe pyrethroid concentrations were correlated with urinary concentrations of 3PBA in children, but not adults. This finding suggests that children may be receiving a higher portion of their exposure to pyrethroids from their home environment than adults, most likely due to a child’s increased exposure to pollutants through dermal and nondietary ingestion routes.2 Urinary concentrations of TCPy from adults and children within a household were positively correlated. In contrast to pyrethroids, floor wipe OP concentrations were not correlated with urinary concentrations of TCPy for children. These data suggest that at the current time, parents and children in these households are likely being exposed to common sources of chlorpyrifos which are not from the home environment, most likely a common diet.39 Although many studies have measured both indoor environmental concentrations of insecticides and urinary concentrations of metabolites, only a few have looked at correlations between those measurements, and those have focused on OP insecticides with studies conducted both when OPs were still applied indoors,4,40 and after the federally mandated phase-out of residential OP use.41 The total urinary concentrations of diethyl phosphate metabolites (nmol/L), the common metabolite of OP insecticides, measured in overnight urine collected from diapers of 20 farm-worker children aged 5−27 months in Salinas Valley, CA from June to September, 2002,

Table 4. Estimated Coefficients from Multiple Linear Model Analyses Showing the Relationship between Child LogTransformed Volume-Based Urinary Concentrations of 3PBA (Dependent Variable) and Log-Transformed Floor Wipe Concentrationsa floor wipe compound cis-permethrin trans-permethrin pyrethroid totalb pyrethroid total plus 3PBAc trans-DCCA 3PBA 4F3PBA metabolite totald

N

estimate

standard error

t value

Pr > |t|

76 76 76 75

0.32 0.34 0.29 0.26

0.09 0.09 0.09 0.10

3.71 3.79 3.34 2.70

0.0004 0.0003 0.001 0.009

75 75 75 75

0.30 0.17 0.13 0.26

0.37 0.21 0.07 0.20

0.80 0.83 2.00 1.29

0.43 0.41 0.0495 0.20

Separate linear regression models were fit for each of the listed compounds, each contained two independent variables: log-transformed creatinine and the listed log-transformed compound. b Pyrethroid total computed as sum of permethrin, cypermethrin, deltamethrin, esfenvalerate, and λ-cyhalothrin. cPyrethroid total plus 3PBA computed by adding 3PBA floor wipe concentration to pyrethroid total. dMetabolite total computed as sum of cis-DBCA, trans-DCCA, 3PBA, and 4F3PBA. a

Cyfluthrin was detected in only three homes, one of which had a child with detectable urinary 4F3PBA and a floor wipe with detectable 4F3PBA. Creatinine-adjusted geometric mean concentrations of 4F3PBA were significantly higher in children (agmr = 1.10, 95% CI: 1.03−1.17, p = 0.006) whose homes had detectable levels of cyfluthrin. These data suggest that some, but not all, of the participants with evidence of cyfluthrin exposure may have been exposed to it and/or its metabolite in their home environment.

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DISCUSSION Measurements from the 90 northern California households highlighted in this paper show pyrethroid exposure occurs commonly, based on the frequent detection of several pyrethroid metabolites in participants’ urine and frequent detection of both insecticides and their metabolites in the floor wipe samples. The median creatinine-adjusted urinary concentrations of 3PBA in the 2001−2002 National Health and Nutrition Examination Survey (NHANES), a population based sample, were 0.33 and 0.30 μg/g for children (aged 6−11 years) and adults (aged 20−59 years), respectively (Table 2).21 The median creatinine-adjusted urinary 3PBA concentrations in the SUPERB participants, recruited in 2007−2009, were over twice as high at 0.80 and 0.61 μg/g creatinine for children and adults, respectively. Similarly, the SUPERB population has higher 75th and 95th percentiles urinary concentrations of 3PBA than the 2001−2002 NHANES population (Table 2). The higher urinary concentrations of 3PBA in SUPERB participants are potentially due to the well-documented increased use of pyrethroids for indoor and outdoor residential applications since the 2001 federally mandated phase-out of residential uses of the OP insecticides chlorpyrifos and diazinon.10−13 Although SUPERB participants show increased levels of 3PBA as compared to NHANES, they are still lower than those of other populations reported in the literature. Both a 2001 biomonitoring study in Jacksonville, FL, a city previously determined to have elevated rates of pesticide use,9 and a 1936



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degree or higher), making them less than representative with regard to education level, although it is true of virtually all research studies that participants tend to be more educated than the general population. We did have a sizable majority of Hispanic and non-white non-Hispanic participants, as well as families of immigrant parents, reflecting these aspects of the California population. It has been shown that the detoxification of organophosphate insecticides may vary within and between different ethnic groups,44,45 but genetic variability in the metabolism of pyrethroids has not yet been determined. As such, we did not think there was an effective way to integrate this into our analysis. Despite its limitations, this study contributes to existing research in multiple ways. To our knowledge this is the first study evaluating correlations between floor wipe and urinary metabolite levels for pyrethroids, and it demonstrates the usefulness of floor wipe samples as indicators of pyrethroid exposure for children. The resulting correlation provides evidence that children are being exposed to pyrethroid insecticides in their home, and thus indoor use is an important contributor to exposure. Additionally, a comparison of measured levels in this study vs those reported for samples collected in 2001−2002 is consistent with increased use of pyrethroids and decreased use of OPs for residential applications since the 2001 Federally mandated phase-out of residential uses of chlorpyrifos and diazinon. Further research is warranted to investigate the specific sources of these exposures to pyrethroid insecticides and to understand whether these compounds have long-term effects on child health or development.

were significantly correlated with diazinon (p < 0.05) measured in house dust and chlorpyrifos (p < 0.05) measured in toy wipe samples.4 A study looking at OP insecticide exposure among 93 Hispanic workers in the agricultural community of Hood River, Oregon in the summer and fall of 1999 reported a moderate but significant correlation between methyl OP insecticides measured in house dust and their urinary metabolites.40 In contrast the OP insecticides chlorpyrifos and diazinon levels measured in the house dust of 40 urban (Oakland, CA) and farm worker (Salinas, CA) homes from July to September of 2006 were not significantly correlated to urinary concentrations of the metabolites in children aged 3−6 years in a study looking at OP breakdown products in house dust and children’s urine.41 Levels of OP insecticides are expected to be higher in the dust of farm worker homes than in homes of the general population due to drift from agricultural applications.42 As OPs are applied agriculturally in large quantities, there is exposure through dietary ingestion as well. In comparison with the general population, the drift indoors from agricultural applications and possible residues on clothing brought into the home after work in the fields may lead to a greater proportion of exposure from the indoor environment, potentially explaining why previous reports of correlations between indoor OP levels and urinary concentrations of OP metabolites were limited to agricultural regions. As compared with chlorpyrifos, we expect higher and more consistent correlations between levels of pyrethroids measured in California homes and the corresponding urinary pyrethroid metabolites of the residents because of their lower use in agriculture in California,43 lessening the contribution to exposure from dietary ingestion. Results from the present study and multiple other reports for a wide range of communities support this hypothesis: data on indoor levels of pyrethroid insecticides and urinary concentrations of metabolites indicate residential insecticide use to be one of the most important contributors to pyrethroid exposures.6−9 There were several limitations to this study involving our sample size and sample collection methods. We had relatively low detection frequencies of several target analytes (allethrin, cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, λ-cyhalothrin, sumithrin, tetramethrin, DCCA, and DBCA in the floor wipes; and trans-DCCA, cis-DBCA, and 4F3PBA in urine samples), making it difficult to achieve precise estimates of correlation parameters, hence our sample size may have been underpowered to detect exposure−outcome associations that may still be clinically significant. A small sample size may have also contributed to the lack of association between chlorpyrifos and urinary concentrations of TCPy in both adults and children. Without obtaining data from all possible exposure routes, including dietary and those found outside the home, it is difficult to ascertain the sources of exposure to insecticides in this population. Although self-reported food consumption on the day of sample collection was available for most participants, diets were varied and there was not a good way to integrate this information into the analysis. Differences in household cleanliness at the time of sample collection may have resulted in variation among the floor wipe concentrations. Also, there is often variability in urinary concentrations of metabolites of nonpersistent compounds such as pyrethroids when only single spot urine samples are collected. Additional limitations of this study were associated with the demographics of our sample population. This population was highly educated (90% of the adults reported having a high school diploma, and 60% reported having a 4-year college

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ASSOCIATED CONTENT

S Supporting Information *

Uurinary concentrations of trans-DCCA, cis-DBCA, and 4F3PBA. This information is available free of charge via the Internet at http://pubs.acs.org/.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; Cell: 925-408-5177; mail: Department of Environmental Toxicology, 1 Shields Avenue, University of California, Davis, CA 95616 USA. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The U.S. EPA through its Office of Research and Development funded this research through a Science to Achieve Results (STAR) grant RD-83154001. The U.S. EPA provided in-kind support for analysis of wipe samples. Analysis of urinary metabolites was provided through in-kind support by CDC. This study would not have been possible without the participants who patiently gave their time. We acknowledge the technical assistance of C. Chambers, P. Olive, P. Restrepo, W. Roman, and E. Wade in measuring the urinary concentrations. The U.S. EPA through its Office of Research and Development partially funded and managed the research described here. It has been subjected to Agency administrative review and approved for publication. The use of trade names is for identification only and does not constitute endorsement by the U.S. Department of Health and Human Services or the CDC. The findings and conclusions in this report are those of 1937



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(16) Ji, G.; Xia, Y.; Gu, A.; Shi, X.; Long, Y.; Song, L.; Wang, S.; Wang, X. Effects of non-occupational environmental exposure to pyrethroids on semen quality and sperm DNA integrity in Chinese men. Reprod. Toxicol. 2011, 31 (2), 171−176. (17) Kim, S. S.; Lee, R. D.; Lim, K. J.; Kwack, S. J.; Rhee, G. S.; Seok, J. H.; Lee, G. S.; An, B. S.; Jeung, E. B.; Park, K. L. Potential estrogenic and antiandrogenic effects of permethrin in rats. J. Reprod. Dev. 2005, 51 (2), 201−210. (18) USEPA. Permethrin Facts (Reregistration Eligibility Decision (RED) Fact Sheet). http://www.epa.gov/oppsrrd1/REDs/factsheets/ permethrin_fs.htm#health (October 8, 2011). (19) Fortes, C.; Mastroeni, S.; Melchi, F.; Pilla, M. A.; Alotto, M.; Antonelli, G.; Camaione, D.; Bolli, S.; Luchetti, E.; Pasquini, P. The association between residential pesticide use and cutaneous melanoma. Eur. J. Cancer. 2007, 43 (6), 1066−1075. (20) Ding, G.; Shi, R.; Gao, Y.; Zhang, Y.; Kamijima, M.; Sakai, K.; Wang, G.; Feng, C.; Tian, Y. Pyrethroid pesticide exposure and risk of childhood acute lymphocytic leukemia in Shanghai. Environ. Sci. Technol. 2012, 46 (24), 13480−13487. (21) Barr, D. B.; Olsson, A. O.; Wong, L.-Y.; Udunka, S.; Baker, S. E.; Whitehead, R. D., Jr.; Magsumbol, M. S.; Williams, B. L.; Needham, L. L. Urinary concentrations of metabolites of pyrethroid insecticides in the general U.S. population: National health and nutrition examination survey 1999−2002. Environ. Health Perspect. 2010, 118 (6), 742−748. (22) USEPA. Pesticides: Reregistration - Chlorpyrifos Facts. http:// www.epa.gov/oppsrrd1/REDs/factsheets/chlorpyrifos_fs.htm (November 1, 2013). (23) Rawlings, N. C.; Cook, S. J.; Waldbillig, D. Effects of the pesticides carbofuran, chlorpyrifos, dimethoate, lindane, triallate, trifluralin, 2,4-D, and pentachlorophenol on the metabolic endocrine and reproductive endocrine system in ewes. J. Toxicol. Environ. Health, A 1998, 54 (1), 21−36. (24) Rauh, V. A.; Garfinkel, R.; Perera, F. P.; Andrews, H. F.; Hoepner, L. A.; Barr, D. B.; Whitehead, R. D. J.; Tang, D.; Whyatt, R. W. Impact of prenatal chlorpyrifos exposure on neurodevelopment in the first 3 years of life among inner-city children. Pediatrics 2006, 118 (6), 1845−1859. (25) Eskenazi, B.; Marks, A. R.; Bradman, A.; Harley, K.; Barr, D. B.; Johnson, C.; Morga, N.; Jewell, N. P. Organophosphate pesticide exposure and neurodevelopment in young Mexican-American children. Environ. Health Perspect. 2007, 115 (5), 792−798. (26) Olsson, A. O.; Baker, S. E.; Nguyen, J. V.; Romanoff, L. C.; Udunka, S. O.; Walker, R. D.; Flemmen, K. L.; Barr, D. B. A liquid chromatography−tandem mass spectrometry multiresidue method for quantification of specific metabolites of organophosphorus pesticides, synthetic pyrethroids, selected herbicides, and DEET in human urine. Anal. Chem. 2004, 76 (9), 2453−2461. (27) Sexton, K.; Adgate, J. L.; Eberly, L. E.; Clayton, C. A.; Whitmore, R. W.; Pellizzari, E. D.; Lioy, P. J.; Quackenboss, J. J. Predicting children’s short-term exposure to pesticides: Results of a questionnaire screening approach. Environ. Health Perspect. 2003, 111 (1), 123−128. (28) Trunnelle, K. J.; Bennett, D. H.; Tancredi, D. J.; Gee, S. J.; Stoecklin-Marois, M. T.; Hennessy-Burt, T. E.; Hammock, B. D.; Schenker, M. B. Pyrethroids in house dust from the homes of farm worker families in the MICASA study. Environ. Int. 2013, 61, 57−63. (29) Hertz-Picciotto, I.; Cassady, D.; Lee, K.; Bennett, D.; Ritz, B.; Vogt, R. Study of Use of Products and Exposure-Related Behaviors (SUPERB): Study design, methods, and demographic characteristics of cohorts. Environ. Health 2010, 9 (54), 1−14. (30) Clifton, M. S.; Wargo, J. P.; Weathers, W. S.; Colon, M.; Bennett, D. H.; Tulve, N. S. Quantitative analysis of organophosphate and pyrethroid insecticides, pyrethroid transformation products, polybrominated diphenyl ethers and bisphenol A in residential surface wipe samples. J. Chromatogr. A 2013, 1273, 1−11. (31) Davis, M. D.; Wade, E. L.; Restrepo, P. R.; Roman-Esteva, W.; Bravo, R.; Kuklenyik, P.; Calafat, A. M. Semi-automated solid phase extraction method for the mass spectrometric quantification of 12 specific metabolites of organophosphorus pesticides, synthetic

the authors and do not necessarily represent the official position of the CDC.

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Urinary Pyrethroid and Chlorpyrifos Metabolite Concentrations in

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