Maternal exposure to DDT, DDE, and pyrethroid insecticides for malaria vector control and hypospadias in the VHEMBE birth cohort study, Limpopo, South Africa.

Hypospadias is the ectopic opening of the urethra on the penis or scrotum. Exposure to estrogenic and/or anti-androgenic chemicals in utero may play an etiologic role. DDT and the pyrethroids cypermethrin and deltamethrin, are used to control malaria. DDT is estrogenic and its breakdown product DDE is anti-androgenic; cypermethrin and deltamethrin can also disrupt androgen pathways. We examined the relationship between maternal exposure to these insecticides during pregnancy and hypospadias among boys participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) in Limpopo Province, South Africa. We measured peripartum levels of p,p'-DDT and p,p'-DDE in maternal serum and urinary pyrethroid metabolites. We conducted urogenital examination on 359 one-year-old boys. A total of 291 (81.0 %) had phimosis, which prevented full urogenital examination, leaving a final sample of 68 boys for determination of the presence of hypospadias. Diagnosis was based on concordance of two independent physicians. We identified hypospadias in 23 of the 68 boys (34 %). Maternal urinary concentrations of cis-DCCA and trans-DCCA metabolites of cypermethrin and other pyrethroids, were associated with an increased risk for hypospadias, but the other metabolite 3-PBA was not (adjusted relative risk per 10-fold increase = 1.58, 95 % CI 1.07-2.34; 1.61, 95 % CI 1.09-2.36; and 1.48, 95 % CI 0.78-2.78, respectively). No associations were found between p,p'-DDT, p,p'-DDE, 3-PBA or cis-DBCA and hypospadias. We observed a high prevalence of hypospadias among boys without phymosis. Boys with higher prenatal exposure to pyrethroid insecticides were at higher risk of hypospadias. Our findings may have global implications given that pyrethroid insecticides are widely used for malaria control, in agriculture and for home use.

Assessment of the safety, pharmacokinetics and pharmacodynamics of GSK3335065, an inhibitor of kynurenine monooxygenase, in a randomised placebo-controlled first-in-human study in healthy volunteers.

GSK3335065 is an inhibitor of kynurenine monooxygenase (KMO) being developed for the treatment of acute pancreatitis. Healthy male volunteers were administered ascending doses of GSK3335065 or matched placebo as a single intravenous bolus injection to assess safety, tolerability, pharmacokinetics and pharmacodynamics. GSK3335065 displayed an apparent volume of distribution between 20.6 L and 44.6 L, a clearance between 0.462 L/h and 0.805 L/hr and a terminal half-life between 31.3 and 34.5 hr. In the single subject who received 1.3 mg GSK3335065, changes in tryptophan pathway metabolites were observed consistent with the changes seen in preclinical species suggesting that KMO enzyme activity was partially inhibited. However, a broad complex ventricular tachycardia was observed in this subject, which was judged to be a Serious Adverse Event (SAE) and resulted in early termination of the study. While development of GSK3335065 was subsequently discontinued, significant confounding factors hinder a clear interpretation that the tachycardia was directly related to administration of the compound.

Seasonality of antenatal care attendance, maternal dietary intake, and fetal growth in the VHEMBE birth cohort, South Africa.

BACKGROUND: Seasonality of food availability, physical activity, and infections commonly occurs within rural communities in low and middle-income countries with distinct rainy seasons. To better understand the implications of these regularly occurring environmental stressors for maternal and child health, this study examined seasonal variation in nutrition and health care access of pregnant women and infants in rural South Africa. METHODS: We analyzed data from the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) birth cohort study of 752 mother-infant pairs recruited at delivery from August 2012 to December 2013 in the Vhembe District of Limpopo Province, the northernmost region of South Africa. We used truncated Fourier series regression to assess seasonality of antenatal care (ANC) attendance, dietary intake, and birth size. We additionally regressed ANC attendance on daily rainfall values. Models included adjustment for sociodemographic characteristics. RESULTS: Maternal ANC attendance, dietary composition, and infant birth size exhibited significant seasonal variation in both unadjusted and adjusted analyses. Adequate frequency of ANC attendance during pregnancy (≥ 4 visits) was highest among women delivering during the gardening season and lowest during the lean (rainy) season. High rainfall during the third trimester was also negatively associated with adequate ANC attendance (adjusted OR = 0.59, 95% CI: 0.40, 0.86). Carbohydrate intake declined during the harvest season and increased during the vegetable gardening and lean seasons, while fat intake followed the opposite trend. Infant birth weight, length, and head circumference z-scores peaked following the gardening season and were lowest after the harvest season. Maternal protein intake and ANC ≤ 12 weeks did not significantly vary by season or rainfall. CONCLUSIONS: Seasonal patterns were apparent in ANC utilization, dietary intake, and fetal growth in rural South Africa. Interventions to promote maternal and child health in similar settings should consider seasonal factors.

Sex and poverty modify associations between maternal peripartum concentrations of DDT/E and pyrethroid metabolites and thyroid hormone levels in neonates participating in the VHEMBE study, South Africa.

Indoor Residual Spraying (IRS), the application of insecticides on the inside walls of dwellings, is used by 84 countries for malaria control. Although effective in preventing malaria, this practice results in elevated insecticide exposure to >100 million people, most of whom are Africans. Pyrethroid insecticides and dichlorodiphenyl trichloroethane (DDT) are currently used for IRS. Animal and in vitro studies suggest that pyrethroids and DDT interfere with thyroid hormone homeostasis but human studies are inconsistent and no prior study has investigated this question in a population residing in an area where IRS is conducted. Our objective was thus to evaluate whether prenatal exposure to pyrethroids, DDT or DDT's breakdown product dichlorodiphenyl dichloroethylene (DDE) is associated with altered thyroid hormone levels among neonates from Limpopo, South Africa, where pyrethroids and DDT are used annually to control malaria. We measured serum DDT/E and urinary pyrethroid metabolite concentrations in maternal peripartum samples from 717 women participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE), a birth cohort study conducted in Limpopo's Vhembe district. We measured total thyroxine (T4) and thyroid-stimulating hormone (TSH) in dried blood spots collected via heel stick. We found that all pyrethroid metabolites were positively associated with TSH; trans-DCCA and 3-PBA showed the strongest associations with a 12.3% (95%CI = 3.0, 22.3) and 14.0% (95%CI = 0.5, 30.2) change for each 10-fold increase in biomarker concentration, respectively. These associations were substantially stronger among children from households below the South African food poverty line. DDT and DDE were associated with lower total T4 among boys only (ß = -0.27 µg/dL per 10-fold increase; 95%CI = -0.47, -0.04). Results suggest that prenatal exposure to DDT, DDE and pyrethroid insecticides is associated with changes in neonatal thyroid hormones consistent with hypothyroidism/hypothyroxinemia and that sex and poverty modify associations. Further research is needed to confirm these findings and examine whether they have implications for child development.

A community-based education programme to reduce insecticide exposure from indoor residual spraying in Limpopo, South Africa.

BACKGROUND: Indoor residual spraying (IRS), the coating of interior walls of houses with insecticides, is common in malaria-endemic areas. While important in malaria control, IRS potentially exposes residents to harmful insecticides. The World Health Organization recommends steps to minimize exposure; however, no programme has focused on educating populations. METHODS: A dramatic presentation and song were developed by study personnel and performed by lay performers in order to spread awareness of the importance of IRS and to minimize insecticide exposure. Performances were staged at 16 sprayed villages in the Vhembe District of Limpopo, South Africa, at which 592 attendees completed short questionnaires before and after the performance about behaviors that might limit insecticide exposure. Overall indices of the attendees' change in knowledge of precautions to take prior to and after spraying to prevent insecticide exposure were analyzed using hierarchical mixed models to assess the effect of the performance on change in participants' knowledge. RESULTS: Approximately half of attendees lived in homes that had been sprayed for malaria and 62% were female. Over 90% thought it better to allow IRS prior to the presentation, but knowledge of proper precautions to prevent exposure was low. The proportion answering correctly about proper distance from home during spraying increased from 49.4% pre-performance to 62.0% post-performance (RR = 1.26, 95% CI = 1.13, 1.41), and the proportion reporting correctly about home re-entry interval after spraying increased from 58.5 to 91.1% (RR = 1.54, 95% CI 1.35, 1.77). Attendees improved in their knowledge about precautions to take prior to and after spraying from mean of 57.9% correct to a mean of 69.7% (ß = 12.1%, 95% CI 10.9, 13.4). Specifically, increased knowledge in closing cupboards, removing food and bedding from the home, covering immoveable items with plastic, and leading animals away from the home prior to spraying were observed, as was increased knowledge in sweeping the floors, proper disposal of dead insects, and discarding dirty washrags after spraying. CONCLUSIONS: A dramatic presentation and song were able to increase the attendees' knowledge of precautions to take prior to and after spraying in order to limit their insecticide exposure resulting from IRS. This approach to community education is promising and deserves additional study.

Associations of Maternal Exposure to Dichlorodiphenyltrichloroethane and Pyrethroids With Birth Outcomes Among Participants in the Venda Health Examination of Mothers, Babies and Their Environment Residing in an Area Sprayed for Malaria Control.

Although effective in controlling malaria, indoor residual spraying results in elevated exposure to insecticides such as dichlorodiphenyltrichloroethane (DDT) and pyrethroids. These chemicals cross the placenta, but no studies have examined their associations with birth outcomes in populations residing in indoor residual spraying areas. We investigated this question in the Venda Health Examination of Mothers, Babies and Their Environment (VHEMBE), a birth cohort study of 751 South African children born between 2012 and 2013. We measured maternal peripartum serum DDT and urine pyrethroid metabolite concentrations and collected data on birth weight, length, head circumference, and duration of gestation. We analyzed the data using marginal structural models with inverse-probability-of-treatment weights, generalized propensity scores, and standard conditional linear regression. Using all 3 analytical methods, p,p'-DDT, o,p'-DDT, and to a lesser extent p,p'-dichlorodiphenyldichloroethylene were related to elevated birth weight, birth length, and head circumference among girls. Changes in gestational duration did not mediate this relationship, suggesting that these exposures accelerate fetal growth, which is consistent with the known estrogenic properties of o,p'-DDT and p,p'-DDT. No associations with pyrethroid metabolites were found. Results suggest that prenatal exposure to DDT is related to elevated birth size. Further studies are needed to elucidate the implications of these findings.

Prenatal Exposure to DDT and Pyrethroids for Malaria Control and Child Neurodevelopment: The VHEMBE Cohort, South Africa.

BACKGROUND: Although indoor residual spraying (IRS) with dichlorodiphenyltrichloroethane (DDT) and pyrethroids effectively controls malaria, it potentially increases human exposure to these insecticides. Previous studies suggest that prenatal exposure to these insecticides may impact human neurodevelopment. OBJECTIVES: We aimed to estimate the effects of maternal insecticide exposure and neurodevelopment of toddlers living in a malaria-endemic region currently using IRS. METHODS: 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 maternal exposure to DDT and its breakdown product, dichlorodiphenyldichloroethylene (DDE), in maternal serum, and measured pyrethroid metabolites in maternal urine. We assessed children's neurodevelopment at 1 and 2 y of age using the Bayley Scales of Infant Development, third edition (BSID-III), and examined associations with maternal exposure. RESULTS: DDT and DDE were not associated with significantly lower scores for any BSID-III scale. In contrast, each 10-fold increase in cis-DCCA, trans-DCCA, and 3-phenoxybenzoic acid were associated, respectively, with a -0.63 (95% CI: -1.14, -0.12), -0.48 (95% CI: -0.92, -0.05), and -0.58 (-1.11, -0.06) decrement in Social-Emotional scores at 1 y of age. In addition, each 10-fold increase in maternal cis-DBCA levels was associated with significant decrements at 2 y of age in Language Composite scores and Expressive Communication scores [ß=-1.74 (95% CI: -3.34, -0.13) and ß=-0.40 (95% CI: -0.77, -0.04), respectively, for a 10-fold increase]. Significant differences by sex were estimated for pyrethroid metabolites and motor function scores at 2 y of age, with higher scores for boys and lower scores for girls. CONCLUSIONS: Prenatal exposure to pyrethroids may be associated at 1 y of age with poorer social-emotional development. At 2 y of age, poorer language development was observed with higher prenatal pyrethroid levels. Considering the widespread use of pyrethroids, these findings deserve further investigation. https://doi.org/10.1289/EHP2129.

Association between prenatal exposure to multiple insecticides and child body weight and body composition in the VHEMBE South African birth cohort.

BACKGROUND: Pregnant women may be co-exposed to multiple insecticides in regions where both pyrethroids and dichlorodiphenyltrichloroethane (DDT) are used for indoor residual spraying (IRS) for malaria control. Despite the potential for adverse effects on offspring, there are few studies in areas where IRS is currently used and little is known about the effects of pyrethroids on children's health. METHODS: We investigated the relationship between concentrations of four urinary pyrethroid metabolites in urine and organochlorine pesticide concentrations in maternal blood collected near delivery on body weight and body composition among children ≤2 years old participating in the prospective South Africa VHEMBE birth cohort (N = 708). We used measurements of length/height and weight collected at 1 and 2 years of age to calculate body mass index (BMI)-for-age, weight-for-age, and weight-for-height z-scores based on World Health Organization standards. We fit separate single-pollutant mixed effects models for each exposure of interest and also stratified by sex. We also fit all analyte concentrations jointly by using a Bayesian kernel machine regression (BKMR) statistical method to assess variable importance of each analyte and to explore the potential for joint effects of the multiple exposures. RESULTS: Single-pollutant linear mixed effects models showed that, among girls only, p,p'-DDT was associated with higher BMI-for-age (adjusted [a]ß = 0.22 [95% CI: 0.10, 0.35]; sex interaction p-value = 0.001), weight-for-height (aß = 0.22 [95% CI: 0.09, 0.34]; sex interaction p-value = 0.002), and weight-for-age (aß = 0.17 [95% CI: 0.05, 0.29], sex interaction p-value = 0.01). Although single-pollutant models suggested that p,p'-DDT and dichlorodiphenyldichloroethylene (p,p'-DDE) were also associated with these outcomes in girls, p,p'-DDE was no longer associated in multi-pollutant models with BKMR. The pyrethroid metabolites cis-(2,2-dibromovinyl)-2,2-dimethylcyclopropane-1-carboxylicacid (cis-DBCA) and trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropane carboxylic acid (trans-DCCA) were inversely related to BMI-for-age and weight-for-height overall; however, results suggested that weight-for-age and weight-for-height associations for trans-DCCA (sex interaction p-valueweight-for-age = 0.02; p-valueweight-for-height = 0.13) and cis-DCCA (sex interaction p-valueweight-for-age = 0.02; p-valueweight-for-height = 0.08) were strongest and most consistent in boys relative to girls. BKMR also revealed joint effects from the chemical mixture. For instance, with increased concentrations of p,p'-DDE, the negative exposure-response relationship for cis-DBCA on BMI-for-age became steeper. CONCLUSIONS: Our single-pollutant and multi-pollutant model results show that maternal serum p,p'-DDT concentration was consistently and positively associated with body composition and body weight in young girls and that maternal urinary pyrethroid metabolite concentrations (particularly cis-DBCA and trans-DCCA) were negatively associated with body weight and body composition in young boys. Joint effects of the insecticide exposure mixture were also apparent, underscoring the importance of using advanced statistical methods to examine the health effects of chemical mixtures.

Exposure to DDT and hypertensive disorders of pregnancy among South African women from an indoor residual spraying region: The VHEMBE study.

Indoor Residual Spraying (IRS), the use of insecticides inside residences for malaria control, may cause elevated exposure to insecticides such as dichlorodiphenyl trichloroethane (DDT). Evidence suggests that DDT exposure may increase blood pressure but no study has investigated associations with hypertensive disorders of pregnancy (HDP) in an IRS area. We measured the serum concentration of DDT and its breakdown product dichlorodiphenyl trichloroethylene (DDE) at the time of delivery among 733 rural South African women participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE). We also collected data on HDP diagnosis through questionnaires administered to participants and medical record abstraction. We used multiple logistic regression models to examine the relation between DDT/E and HDP. p,p'-DDT and p,p'-DDE serum concentrations were associated with HDP based on self-report (OR = 1.50; 95%CI = 1.10, 2.03 for p,p'-DDT and OR = 1.58; 95%CI = 1.09, 2.28 for p,p'-DDE) and medical records (OR = 1.32; 95%CI = 0.99, 1.75 for p,p'-DDT and OR = 1.47; 95%CI = 1.03, 2.09 for p,p'-DDE). p,p'-DDE was also associated with gestational hypertension (OR = 1.44; 95% CI = 1.00, 2.07). Exposure to DDT and DDE may be associated with elevated risks of HDP in South African women residing in an area sprayed for malaria control.

Corrigendum to "Undisturbed dust as a metric of long-term indoor insecticide exposure: Residential DDT contamination from indoor residual spraying and its association with serum levels in the VHEMBE cohort" [Environ. Int. 85C (2015) 163-167].

Although approximately 123 million people may be exposed to high levels of insecticides through the use of indoor residual spraying (IRS) for malaria control, few studies exist on indoor insecticide contamination due to IRS and its relationship with human exposure. In the present study, we developed a sampling method to collect undisturbed dust from 50 homes in Limpopo, South Africa, a region where dichlorodiphenyltrichloroethane (DDT) has been used in IRS programs to prevent malaria for ~70years. We quantified DDT and its degradation products, dichlorodiphenyldichloroethylene (DDE), and dichlorodiphenyldichloroethane (DDD) in dust samples to determine dust loading levels and compared these levels to paired serum concentrations of p,p'-DDT and p,p'-DDE in women residents. p,p'-DDT and p,p'-DDE had the highest detection frequencies in both dust (58% and 34% detection, respectively) and serum samples (100% detection). Significantly higher detection frequencies for o,p'-DDT, p,p'-DDE, and p,p'-DDD were observed in dust samples collected in buildings that had been previously sprayed for malaria control. We also observed a significant, positive association between dust loading and serum concentrations of p,p'-DDT and p,p'-DDE (Spearman's rho=0.68 and 0.54, respectively). Despite the low detection frequency in dust, our results indicate that undisturbed dust may be a good metric to quantify long-term home exposure to DDT-related compounds and that contamination of the home environment may be an important determinant/source of DDT and DDE exposure.

Undisturbed dust as a metric of long-term indoor insecticide exposure: Residential DDT contamination from indoor residual spraying and its association with serum levels in the VHEMBE cohort.

Although approximately 123 million people may be exposed to high levels of insecticides through the use of indoor residual spraying (IRS) for malaria control, few studies exist on indoor insecticide contamination due to IRS and its relationship with human exposure. In the present study, we developed a sampling method to collect undisturbed dust from 50 homes in Limpopo, South Africa, a region where dichlorodiphenyltrichloroethane (DDT) has been used in IRS programs to prevent malaria for ~70years. We quantified DDT and its degradation products, dichlorodiphenyldichloroethylene (DDE), and dichlorodiphenyldichloroethane (DDD) in dust samples to determine dust loading levels and compared these levels to paired serum concentrations of p,p'-DDT and p,p'-DDE in women residents. p,p'-DDT and p,p'-DDE had the highest detection frequencies in both dust (58% and 34% detection, respectively) and serum samples (98% and 100% detection, respectively). Significantly higher detection frequencies for o,p'-DDT, p,p'-DDE, and p,p'-DDD were observed in dust samples collected in buildings that had been previously sprayed for malaria control. We also observed a significant, positive association between dust loading and serum concentrations of p,p'-DDT and p,p'-DDE (Spearman's rho=0.68 and 0.54, respectively). Despite the low detection frequency in dust, our results indicate that undisturbed dust may be a good metric to quantify long-term home exposure to DDT-related compounds and that contamination of the home environment may be an important determinant/source of DDT and DDE exposure.