Article Cite This: Environ. Sci. Technol. XXXX, XXX, XXX−XXX
pubs.acs.org/est
Determinants of Exposure to Pyrethroid Insecticides in the VHEMBE Cohort, South Africa Stephen Rauch,† Asa Bradman,† Eric Coker,† Jonathan Chevrier,‡ Sookee An,† Riana Bornman,§,∥ and Brenda Eskenazi*,†
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Center for Environmental Research and Children’s Health (CERCH), School of Public Health, University of California at Berkeley, Berkeley, California 94720, United States ‡ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal, Quebec H3A 1A2,Canada § Department of Urology, University of Pretoria, Pretoria 0028, South Africa ∥ University of Pretoria Institute for Sustainable Malaria Control and School of Health Systems and Public Health, University of Pretoria, Pretoria 0028, South Africa S Supporting Information *
ABSTRACT: Exposure to pyrethroid insecticides has been linked to adverse health effects, and can originate from several sources, including indoor residual spraying (IRS) for malaria control, home pest control, food contamination, and occupational exposure. We aimed to explore the determinants of urinary pyrethroid metabolite concentrations in a rural population with high pesticide use. The Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) is a birth cohort of 752 mother-child pairs in Limpopo, South Africa. We measured pyrethroid metabolites in maternal urine and collected information on several factors possibly related to pesticide exposure, including IRS, home pesticide use, and maternal factors (e.g., dietary habits and body composition). We performed statistical analysis using both conventional bivariate regressions and Bayesian variable selection methods. Urinary pyrethroid metabolites are consistently associated with pesticide factors around homes, including pesticide application in yards and food stocks, and IRS in the home during pregnancy, while more distant factors such as village spraying are not. High fat intake is associated with higher metabolite concentrations, and women from homes drawing water from wells or springs had marginally higher levels. Home pesticide use is the most consistent correlate of pyrethroid metabolite concentrations, but IRS, dietary habits, and household water source may also be important exposure determinants.
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INTRODUCTION Pyrethroids are synthetic insecticides derived from pyrethrum, a naturally occurring compound found in chrysanthemum flowers.1 They are used for household pest control, to protect agricultural crops, and for disease vector control.2−4 Pyrethroids have become a preferred pesticide with the phasing out of many uses for several classes of pesticides, such as the organochlorine pesticide dichlorodiphenyldichloroethylene (DDT) and organophosphate (OP) pesticides.5 Unlike DDT, which has a half-life of 6 years in humans,6,7 pyrethroids metabolize quickly, with half-lives on the order of hours.8 Pyrethroids are less acutely toxic than OP pesticides,9 but are also neurotoxicants,10−12 acting on voltage-gated sodium channels and cholinergic muscarinic receptors of axons with a mechanism similar to DDT.13 Pyrethroids have been associated with adverse effects on neurodevelopment and growth in animals14−18 and humans,5,19−24 and may also disrupt endocrine systems.15 © XXXX American Chemical Society
Human exposure to pyrethroids likely occurs through several routes and pathways, including inhalation from pesticides applied in homes or fields,25,26 nondietary ingestion from house dust,27,28 and ingestion of food with pyrethroid residues.25,29,30 In the United States, higher pyrethroid metabolite levels have been found in agricultural populations compared with a nationwide sample participating in the NHANES study. 31 Populations living in areas where pyrethroids are used for malaria control may experience additional exposures.32 Malaria continues to pose a serious public health risk, with 216 million cases worldwide in 2016, including 445 000 deaths, mostly in children under 5.33 To combat the spread of malaria, Received: May 23, 2018 Revised: September 27, 2018 Accepted: September 28, 2018
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DOI: 10.1021/acs.est.8b02767 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
Article
Environmental Science & Technology
(QFFQ) developed for the regional diet.39−41 Height and weight were also measured before and after delivery. During the home inspection, staff collected information on housing type and building materials, location of food and water storage, condition of housekeeping, pesticide use in the home and grounds, presence of insecticide stains on the walls, location and contents of pesticide containers (including brand and active ingredients), proximity to nearby agricultural fields, and Global Positioning System (GPS) coordinates of the home. Mothers were also asked about water sources and use, cleaning, and cooking practices including fuel use, and daily activities. Pyrethroid Measurements in Urine. Spot urine samples were collected from 739 women either prior to delivery (n = 456) or postdelivery (n = 283). Urine was collected in a sterilized measuring jug then aliquoted into smaller containers by the staff member performing the sample collection. Specific gravity was measured using an Atago PAL-10S refractometer (Tokyo, Japan) at the time of collection. Samples were stored at −80 °C in the field office before being shipped on dry ice to the School of Public Health Biorepository at the University of California, Berkeley, and then for analysis at the Institut National de Santé Publique du Québec. The urinary pyrethroid metabolites cis-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylicacid (cis-DBCA), cis-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane-1-carboxylicacid (cis-DCCA), trans-DCCA, 3-phenoxybenzoic acid (3-PBA), and 4-fluoro3-phenoxybenzoic acid (4-F-3-PBA) were extracted from 1 mL samples and measured using GC-MS, using an Agilent 6890 Network gas chromatograph equipped with an Agilent 7683B series automatic injector and an Agilent 5975 mass spectrometer (Agilent Technologies; Mississauga, Ontario, Canada).42 cis-DBCA is a metabolite of deltamethrin, while cisDCCA, trans-DCCA, and 3-PBA are nonspecific metabolites of several pyrethroid pesticides, including permethrin, cypermethrin, and/or cyfluthrin.43 Limits of detection (LODs) were determined by first estimating concentrations of analytes yielding a signal-to-noise ratio of 3. A urine sample spiked with analytes in concentrations ranging from 4 to 10 times the estimated LODs was analyzed (10 replicates) and standard deviations were multiplied by three to obtain the LODs. Limits of detection were 0.0025 μg/L cis-DBCA, 0.0045 μg/L for cisDCCA, 0.0038 μg/L for trans-DCCA, 0.0047 μg/L for 3-PBA, and 0.005 μg/L for 4-F-3-PBA; limits of quantification were 0.0082 μg/L cis-DBCA, 0.015 μg/L for cis-DCCA, 0.013 μg/L for trans-DCCA, 0.016 μg/L for 3-PBA, and 0.011 μg/L for 4F-3-PBA. Laboratory-produced reference materials and ClinChek reference materials in urine (RECIPE; Munich, Germany) were used for internal quality control. Quality and accuracy of the laboratory are monitored by twice-annual participation in the German External Quality Assessment Scheme (G-EQUAS; Erlangen, Germany). Recoveries for each analyte ranged from 76% to 86%. The intraday precision (repeatability) of the method was between 2.2% to 5.0%, and the interday precision (reproducibility) was between 3.0% to 7.7%, depending on the analyte. All urine measurements were standardized using specific gravity. Detection was almost universal for all metabolites except 4-F-3-PBA, which was detected in less than 20% of samples and was excluded from further analysis. Statistical Analysis. While 739 of the enrolled women provided urine samples, only those who also completed the 1week home visit (n = 715) were included in the present
many malaria-endemic African countries use Indoor Residual Spraying (IRS), the systematic application of insecticides to the interior walls of homes to kill malaria-infected Anopheles mosquitoes.34 In the 1990s, malaria-prevention programs employing IRS largely shifted from DDT to pyrethroids, including deltamethrin and cypermethrin. In the Limpopo province of South Africa, sprayers typically use DDT on traditional dwellings such as rondavels (a circular home with a thatched roof), and pyrethroids on western-style houses within the same communities.35 Consequently, coexposure to DDT and pyrethroids has been observed in South African populations.36 Thus, in addition to exposure sources seen in higher-income countries, IRS may be another important source of exposure to pyrethroid insecticides in South Africa. The VHEMBE (Venda Health Examination of Mothers, Babies and the Environment) birth cohort study in South Africa’s Limpopo Province is investigating DDT and pyrethroid pesticide exposure of pregnant women and the potential health effects to their children living in the Vhembe district, where IRS is commonly used to prevent malaria.19 To date, we have observed positive associations between DDT or DDE serum concentrations and factors such as IRS in the homes and villages where mothers resided during pregnancy, consumption of meat or dairy produced in the village, and inverse associations with frequency of household wet mopping, and whether water was piped into the home.37 In the present study, we examine determinants of pyrethroid exposure during pregnancy.
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METHODS Study Population. The VHEMBE study is a longitudinal birth cohort examining the effects of in utero exposure to IRS pesticides on children’s health. Details about the study have been published elsewhere.19 Briefly, pregnant women at the early stage of labor were screened and recruited at Tshilizidini Hospital in the Vhembe district of Limpopo Province, South Africa, between August 2012 and December 2013. Eligible women were at least 18 years old, had contractions >5 min apart, spoke primarily TshiVenda at home, lived within 20 km of the hospital and planned to remain in the area, had not been diagnosed with malaria during pregnancy, and delivered a live singleton infant. Among 920 eligible women, 752 completed a baseline questionnaire and 739 provided a urine sample. Of the 752 enrolled mothers, 723 (96.3%) completed a home visit 1 week postpartum. Written informed consent was obtained from the mothers. The study was approved by the Institutional Review Boards at the University of California, Berkeley; McGill University; University of Pretoria; Limpopo Department of Health and Social Development; and the Ethics Committee of Tshilidzini Hospital. Procedures. Women were interviewed in TshiVenda after delivery and before hospital discharge (1.1 ± 1.3 days postpartum). The interview collected information on sociodemographic characteristics, reproductive and medical history, personal habits (smoking and use of alcohol or drugs), household composition, occupational and residential history, and use of pesticides around the home, at work, in agricultural fields, on livestock, and for malaria control, as well as the use of bed nets. Interviews included parts of the South Africa National Income Dynamics Study survey38 and an adapted version of a Quantitative Food Frequency Questionnaire B
DOI: 10.1021/acs.est.8b02767 Environ. Sci. Technol. XXXX, XXX, XXX−XXX
Article
Environmental Science & Technology
can accommodate potential nonlinearity.48 Briefly, BART creates a sum of smaller models (called “trees”) to explain the outcome data, using a back-fitted Markov Chain Monte Carlo (MCMC), and imposing a prior that regularizes the fit by keeping the individual tree effects small.48,49 We used 200 trees in the sum-of-trees model. As a measure of variable importance, BART models produce a variable inclusion proportion: the proportion of how many times that predictor is chosen as a splitting rule relative to the total number of splitting rules included in the model. This can be considered analogous to the PIPs from Bayesian Model Averaging, giving an indication of the relative importance of a variable (although the numeric scales are quite different and not comparable). Finally, due to the short half-life of urinary metabolites, it is possible that measured concentrations for samples taken after delivery partly reflect exposure while in the hospital instead of at home. In sensitivity analyses, we restricted the sample to the 447 mothers who provided urine samples prior to delivery. Data analyses were performed using the Stata version 15.0 (College Station, Texas) and R version 3.4.1. BMA and BART analyses were performed with the R packages BMS and bartMachine, respectively.
analysis. Urinary pyrethroid metabolite concentrations were strongly right-skewed, so urinary concentrations were log10transformed to normalize residuals. Less than 1% of samples were assigned values between the LOD and LOQ; these values were used for the analysis. Candidate covariates for statistical analyses were chosen from past studies, as well as previous analyses of pesticide exposure determinants for DDT or DDE in the VHEMBE cohort.37 These included maternal, household, and village factors. Maternal covariates included age (35 years), education ( high school), marital status (married or living as married vs not married or living as married), postdelivery BMI (75th percentile of the VHEMBE population vs ≤75th percentile), high-protein dietary intake (>75th percentile vs ≤75th percentile), and fruit and vegetable consumption (number of times per day). Because less than 10% of the women used bed nets for sleeping most or all the time, numbers were too small for further analysis. Household factors included poverty status (above vs below the South Africa food poverty level for 2013 of 386 Rands per capita per month44), agricultural workers in the home (yes vs no), IRS in the home during pregnancy (yes vs no), IRS used in village while the woman lived there (during pregnancy or before) (yes vs no), pesticides applied to food stocks (yes vs no), pesticide containers stored in homestead (based on home inspection) (yes vs no), stored pesticides used indoors (yes vs no), stored pesticides used in yard (yes vs no), any interior walls in homestead painted (yes vs no), primary source of drinking water (municipal water supply, public tap, or well or spring), frequency of mopping the home (≥7 vs
