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Chlordecone (CD; Kepone™) is a carcinogenic organochlorine insecticide with neurological, reproductive, and developmental toxicity that was widely used in the French West Indies (FWI) from 1973 to 1993 to fight banana weevils. Although CD has not been used there for more than 25 years, it still persists in the environment and has polluted the waterways and soil of current and older banana fields. Today, human exposure to CD in the FWI mainly arises from consuming contaminated foodstuffs. The aims of this study were to develop a physiologically based pharmacokinetic (PBPK) model in the rat and extrapolate it to humans based on available pharmacokinetic data in the literature. A comparison of simulations using the rat model with published experimental datasets showed reasonable predictability for single and repetitive doses, and, thus, it was extrapolated to humans. The human PBPK model, which has seven compartments, is able to simulate the blood concentrations of CD in human populations and estimate the corresponding external dose using the reverse dosimetry approach. The human PBPK model will make it possible to improve quantitative health risk assessments for CD contamination and reassess the current chronic toxicological reference values to protect the FWI population.

Background Attrition in cohort studies challenges causal inference. Although inverse probability weighting (IPW) has been proposed to handle attrition in association analyses, its relevance has been little studied in this context. We aimed to investigate its ability to correct for selection bias in exposure-outcome estimation by addressing an important methodological issue: the specification of the response model. Methods A simulation study compared the IPW method with complete-case analysis (CCA) for nine response-mechanism scenarios (3 missing at random – MAR and 6 missing not at random - MNAR). Eighteen response models differing by the type of variables included were assessed. Results The IPW method was equivalent to CCA in terms of bias and consistently less efficient in all scenarios, regardless of the response model tested. The most effective response model included only the confounding factors of the association model. Conclusion Our study questions the ability of the IPW method to correct for selection bias in situations of attrition leading to missing outcomes. If the method is to be used, we encourage including only the confounding variables of the association of interest in the response model.

Chronic epididymitis and varicocele are frequently observed genital disorders in men consulting for couple infertility, but their impact on semen characteristics at the time of infertility consultation is still a matter of debate. We investigated 652 male partners of couples who had their first infertility consultation between 1999 and 2015 in Argentina. Men with chronic epididymitis (n = 253), Grade III varicocele (n = 106), and both conditions (n = 125) were compared with a control group (n = 168) composed of men without these disorders or any other recognized causes of male infertility. We showed that men who presented isolated chronic epididymitis were more likely to have high percentages of low sperm motility and abnormal sperm morphology as well as a high number of white blood cells. Men with isolated Grade III varicocele had low sperm production and motility and an increased percentage of abnormal sperm morphology. Finally, men who simultaneously presented chronic epididymitis with Grade III varicocele had a low sperm motility and increased percentage of abnormal sperm morphology as well as a high number of white blood cells. Physical examination of the genital organs may identify common disorders, potentially involved as causal factors of patient's infertility. These disorders are associated with specific seminal profiles that should help in identifying the best treatment from the available therapeutic options, effectiveness, safety, and allowing as much as possible natural conception.

Background Chlordecone is a persistent organochlorine insecticide that was widely used to control banana root borer in the French West Indies until 1993. Animal studies have reported an impact of chlordecone exposure on female fertility, but no data are available for humans. Here, we investigated the association between chlordecone exposure in women and time to pregnancy (TTP). Methods We included 668 pregnant women from the Timoun mother-child cohort study performed in Guadeloupe between 2004 and 2007. TTP was measured with a questionnaire at the inclusion visit. Chlordecone concentrations in maternal blood samples were determined at the time of delivery. A discrete-time Cox model was used to estimate fecundability odds ratios (fOR) and their 95% confidence intervals (95% CIs), with adjustment for potential confounders. Sensitivity analyses were performed by modifying the study population and censoring criteria. Results Chlordecone was detected in 91% of the study population, with a median concentration of 0.3 µg/L (IQR: 0.1–0.7). The third and fourth quartiles of chlordecone exposure were associated with significantly lower fecundability (fORa [95% CI] = 0.76 [0.58, 0.99]; fORa [95% CI] = 0.72 [0.55, 0.95], respectively). A significant dose-dependent relationship was observed between chlordecone exposure and TTP ( p -trend = 0.01). Similar results were observed in all sensitivity analyses except that for primiparous women. Conclusion Our study supports the hypothesis that chlordecone affects the fertility of women and is therefore a public health concern in widely contaminated areas, such as the French West Indies. Highlights • Chlordecone is an organochlorine pesticide used in the French West Indies until 1993. • Chlordecone affects female fertility in animals, but this has not yet been studied in humans. • Chlordecone was detected in 91% of blood samples from pregnant women in the Timoun cohort. • Chlordecone exposure is associated with a dose-response trend towards longer time to pregnancy in women.

Chlordecone is an organochlorine pesticide that was extensively used to control the banana root borer population in the French West Indies until 1993. Its persistence in soil has led to widespread pollution of the environment, and human beings, including pregnant women, are still exposed to this chemical. High levels of exposure to chlordecone during gestation have been shown to cause congenital anomalies, including undescended testes in rodents. We assessed the associations between chlordecone concentrations in maternal and cord plasma and the risk of congenital anomalies in the Timoun Mother-Child Cohort Study (2004–2007) that included 1068 pregnant women in Guadeloupe. Odds ratios were estimated using unconditional logistic regression analysis, controlling for confounding factors. The median plasma concentrations in maternal and cord plasma were 0.39 μg/L and 0.20 μg/L, respectively. Thirty-six children were diagnosed with malformations according to the European Registration of Congenital Anomalies guidelines and 25 with undescended testes. There was no association between maternal or cord plasma concentration of chlordecone and the risk of overall malformations nor undescended testes. These results suggest that prenatal exposure to the currently observed environmental levels of chlordecone in French West Indies does not increase the risk of birth defects.

Background Chlordecone is a highly persistent organochlorine insecticide that was intensively used in banana fields in the French West Indies, resulting in a widespread contamination. Neurotoxicity of acute exposures in adults is well recognized, and empirical data suggests that prenatal exposure affects visual and fine motor developments during infancy and childhood, with greater susceptibility in boys. Objective To assess the associations between pre- and postnatal exposures to chlordecone and cognitive and behavioral functions in school-aged children from Guadeloupe. Methods We examined 576 children from the TIMOUN mother–child cohort in Guadeloupe at 7 years of age. Concentrations of chlordecone and other environmental contaminants were measured in cord- and children’s blood at age 7 years. Cognitive abilities of children were assessed with the Wechsler Intelligence Scale for Children-IV (WISC-IV), and externalizing and internalizing problem behaviors documented with the Strengths and Difficulties Questionnaire (SDQ) completed by the child’s mother. We estimated covariate-adjusted associations between cord- and 7-years chlordecone concentrations and child outcomes using structural equations modeling, and tested effect modification by sex. Results Geometric means of blood chlordecone concentrations were 0.13 µg/L in cord blood and 0.06 µg/L in children’s blood at age 7 years. A twofold increase in cord blood concentrations was associated with 0.05 standard deviation (SD) (95% Confidence Interval [CI]: 0.0, 0.10) higher internalizing problem scores, whereas 7-years chlordecone concentrations were associated with lower Full-Scale IQ scores (FSIQ) and greater externalized behavioral problem scores. A twofold increase in 7-year chlordecone concentrations was associated with a decrease of 0.67 point (95% CI: -1.13, -0.22) on FSIQ and an increase of 0.04 SD (95% CI: 0.0, 0.07) on externalizing problems. These associations with Cognitive abilities were driven by decreases in perceptive reasoning, working memory and verbal comprehension. Associations between 7-year exposure and perceptive reasoning, working memory, and the FSIQ were stronger in boys, whereas cord blood and child blood associations with internalizing problems were stronger in girls. Conclusions These results suggests that cognitive abilities and externalizing behavior problems at school age are impaired by childhood, but not in utero, exposure to chlordecone, and that prenatal exposure is related to greater internalizing behavioral problems.

Chlordecone, an organochlorine insecticide, was widely used in the French West Indies banana plantations. We set up a cohort of banana plantation workers who worked between 1973 and 1993, the period of authorized use of chlordecone. Vital status and causes of death were collected from French national registries. Workers were followed up from 1 January 2000 to 31 December 2015. Cause-specific mortality in the cohort was compared to that of the general population of the French West Indies by computing standardized mortality ratios (SMRs). A total of 11,112 workers (149,526 person-years, 77% men) were included in the mortality analysis, and 3647 deaths occurred over the study period. There was a slight deficit in all-cause mortality, which was statistically significant in men (SMR = 0.93, 95% CI 0.89–0.96), but not in women (SMR = 0.96, 95% CI 0.89–1.04). All-cancer mortality did not differ significantly from that of the general population (men: SMR = 0.96, 95% CI 0.90–1.03; women: SMR = 1.04, 95% CI 0.89–1.21). Significant excesses of deaths were observed for stomach cancer in women (SMR = 1.94, 95% CI 1.24–2.89) and pancreatic cancer in women farm owners (SMR = 2.31, 95% CI 1.06–4.39). Mortality from prostate cancer was similar to that of the general population in the whole cohort (SMR = 1.00; 95% CI 0.89–1.13) and non-significantly elevated among farm workers (SMR = 1.10, 95% CI 0.87–1.36). Non-significant increases in mortality were also observed for lung cancer in women, leukemia in men, and non-Hodgkin lymphoma in both genders.

Background and Aims Chlordecone is a persistent organochlorinated insecticide, extensively used in the French West Indies and has been contaminating the population for more than thirty years. Its potentiation effect on hepatotoxic agents has been demonstrated in animal models. We investigated the relationship between environmental exposure to chlordecone and the progression of liver fibrosis. Methods This study included 182 consecutive patients with chronic alcoholic hepatitis whose liver fibrosis was assessed using non-invasive methods. Measured plasma chlordecone concentrations at inclusion were used as surrogate of long-term exposure under steady-state conditions. As the pharmacokinetic processing of chlordecone is largely determined by the liver, we used a human physiologically based pharmacokinetic model to predict plausible changes in the steady-state blood chlordecone concentrations induced by liver fibrosis. Results With a median follow-up of 27.1 years after the onset of alcohol consumption, we found a significant decrease in the risk of advanced liver fibrosis with increasing plasma chlordecone concentration (adjusted hazard ratio = 0.56; 95% confidence interval: 0.34–0.95 for the highest vs. lowest tertile, p  = 0.04). Changes induced by liver fibrosis influenced the pharmacokinetic processing of chlordecone, resulting in substantial modifications in its steady-state blood concentrations. Conclusion According to this human model of coexposure to alcohol, reverse causality is the most plausible explanation of this inverse association between plasma chlordecone concentrations and progression of liver fibrosis. This study underlines the importance of considering the pharmacokinetic of environmental contaminants in epidemiological studies when biomarkers of exposure are used to investigate their own impact on the liver. Trial registration ClinicalTrials.gov Identifier: NCT03373396.

Background Exposure to persistent environmental organic pollutants may contribute to the development of obesity among children. Chlordecone is a persistent organochlorine insecticide with estrogenic properties that was used in the French West Indies (1973–1993) and is still present in the soil and the water and food consumed by the local population. We studied the association between prenatal and childhood exposure to chlordecone and the adiposity of prepubertal children. Methods Within the Timoun Mother–Child Cohort Study in Guadeloupe (French West Indies), 575 children had a medical examination at seven years of age, including adiposity measurements. A Structural Equation Modeling approach was used to create a global adiposity score from four adiposity indicators: the BMI z-score, percentage of fat mass, sum of the tricipital and subscapular skinfold thickness, and waist-to-height ratio. Chlordecone concentrations were measured in cord blood at birth and in the children’s blood at seven years of age. Models were adjusted for prenatal and postnatal covariates. Sensitivity analyses accounted for co-exposure to PCB-153 and pp’-DDE. Mediation analyses, including intermediate birth outcomes, were conducted. Results Prenatal chlordecone exposure tended to be associated with increased adiposity at seven years of age, particularly in boys. However, statistical significance was only reached in the third quartile of exposure and neither linear nor non-linear trends could be formally identified. Consideration of preterm birth or birth weight in mediation analyses did not modify the results, as adjustment for PCB-153 and pp’-DDE co-exposures. Conclusion Globally, we found little evidence of an association between chlordecone exposure during the critical in utero or childhood periods of development and altered body-weight homeostasis in childhood. Nevertheless, some associations we observed at seven years of age, although non-significant, were consistent with those observed at earlier ages and would be worth investing during further follow-ups of children of the Timoun Mother–Child Cohort Study when they reach puberty.

The seasonal patterns of conceptions and births differ between geographic areas. Several potential determinants of this variation have been identified, including biological, environmental and behavioral elements, but festive events are rarely mentioned. We investigated the possible association between the carnival and seasonal fertility variations in the French West Indies. We ran a retrospective registry-based study. The data were extracted from the registry of all births on Guadeloupe between 2000 and 2011 (n = 74,412), and from the Maternity Birth Register of the University Hospital, for all pregnancies of at least 14 completed weeks of gestation (observable conceptions) with an outcome recorded between 2007 and 2010 (n = 8,425). We compared data during and outside the carnival period for each year, including 2009, when there was no carnival due to a 44-day general strike. In all years other than 2009, the weekly number of births was higher for pregnancies initiated during the carnival period than for pregnancies initiated at other times, and the weekly number of observable conceptions was higher during the carnival period than at other times. Our findings support the hypothesis that carnivals in the French West Indies are associated with an increase in the number of conceptions and subsequent births.