Search

Large quantities of chlordecone-based insecticides were produced and used throughout the world. One of its most important uses was to control the damage caused by Cosmopolites sordidus in banana-growing regions. In the islands of Martinique and Guadeloupe, 18,000 ha of farmland are potentially contaminated. Despite the key role played by soil macrofauna in agroecosystems, there are currently no data on their contamination. The aim of this study was to explore the fate of chlordecone (CLD) and its transfer to different organisms of the soil food web. Seven species of invertebrates representing different taxonomic groups and trophic levels of the soil communities of Martinique were targeted and collected in six experimental banana fields, with a level of contamination within a range of values classically observed. Soil samples and macrofauna from the study sites were analysed for CLD and chlordecol (CLDOH) its main transformation product. The contamination of the soil fauna were related to δ 15 N (trophic level), proportion of soil ingestion (diet) and types of epidermis (mucus or exoskeleton) in order to study the different mechanisms of macrofauna contamination. Presence of CLD and CLDOH could be quantified in all the soil organisms from contaminated fields. Results showed a significant relationship between the CLD contamination of detritivorous and the ash content of their faeces, suggesting that soil ingestion was the main contamination pathway. In contrast, the exoskeleton-bearing diplopod Trigoniulus coralinus and the soft-bodied earthworm Eudrilus eugeniae, both detritivores with a comparable diet, had similar contamination levels, suggesting that the type of tegument has little influence on bioaccumulation. At the scale of the entire trophic network, a significant relationship was uncovered between δ 15 N values and CLD contamination of the fauna, therefore providing some in situ evidence for a bioamplification process along the soil food chain., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Mathieu coulis reports financial support was provided by the BANABIO project funding obtained under DEPHY EXPE program of the Ecophyto II plan. Julien PARINET reports financial support was provided by French National Research Agency (ANR-19-CE21-0002). Lai Ting pak reports financial support was provided by The French Ministry of the Overseas for this study that was part of the Territoires Durables project carried out in Martinique. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A Physiology Based Pharmacokinetic (PBPK) model has been developed to predict the kinetics of Persistent Organic Pollutants (POPs) in laying hens. Different datasets have enabled the calibration of the model for chlordecone (CLD), an organochlorine pesticide used in the French West Indies between 1972 and 1993, as well as for chlorinated paraffins (CPs), widely used for various industrial applications worldwide. For this purpose, the sensitivity analysis showed that intake parameters, laying rate, partition coefficients of yolk, hepatic clearance, percentage of metabolism and age were key parameters. Applied to CLD and CPs, this model shows a good capacity for prediction, with 88 % of the experimental values ranging within 1.5-fold of the predicted value at steady state for CPs and 100 % for CLD. The fine modelling of the physiology and the laying process contributes to precision of the model and gives genericity, enabling the switch from one bird species to another. The model can be implemented with other POPs if the clearance and partition coefficient are known., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Chlordecone (CLD) is an organochlorine pesticide (OCP) that is currently banned but still contaminates ecosystems in the French Caribbean. Because OCPs are known to increase the risk of Parkinson's disease (PD), we tested whether chronic low-level intoxication with CLD could reproduce certain key characteristics of Parkinsonism-like neurodegeneration. For that, we used culture systems of mouse midbrain dopamine (DA) neurons and glial cells, together with the nematode C. elegans as an in vivo model organism. We established that CLD kills cultured DA neurons in a concentration- and time-dependent manner while exerting no direct proinflammatory effects on glial cells. DA cell loss was not impacted by the degree of maturation of the culture. The use of fluorogenic probes revealed that CLD neurotoxicity was the consequence of oxidative stress-mediated insults and mitochondrial disturbances. In C. elegans worms, CLD exposure caused a progressive loss of DA neurons associated with locomotor deficits secondary to alterations in food perception. L-DOPA, a molecule used for PD treatment, corrected these deficits. Cholinergic and serotoninergic neuronal cells were also affected by CLD in C. elegans , although to a lesser extent than DA neurons. Noticeably, CLD also promoted the phosphorylation of the aggregation-prone protein tau (but not of α-synuclein) both in midbrain cell cultures and in a transgenic C. elegans strain expressing a human form of tau in neurons. In summary, our data suggest that CLD is more likely to promote atypical forms of Parkinsonism characterized by tau pathology than classical synucleinopathy-associated PD.

Recently, Comte et al. (2022) re-examined the natural degradation of chlordecone (CLD) in the soils of the French West Indies (FWI) by introducing an additional 'dissipation parameter' into the WISORCH model developed by Cabidoche et al. (2009). Recent data sets of CLD concentrations in FWI soils obtained by Comte et al. enabled them optimizing the model parameters, resulting in significantly shorter estimates of pollution persistence than in the original model. Their conclusions jeopardize the paradigm of a very limited degradation of CLD in FWI soils, which may lead to an entire revision of the management of CLD contamination. However, we believe that their study is questionable on several important aspects. This includes potential biases in the data sets and in the modeling approach. It results in an inconsistency between the estimated dissipation half-life time (DT50) of five years that the authors determined for CLD and the fate of CLD in soil from the application period 1972-1993 until nowadays. Most importantly, a rapid dissipation of CLD in the field as proposed by Comte et al. is not sufficiently supported by data and estimates. Hence, the paradigm of long-term persistence of CLD in FWI soils is still to be considered., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Chlordecone (CLD) is a chlorinated persistent organic pollutant (POP) whose presence despite the 1993 ban in agriculture areas has caused numerous public health concerns. CLD accumulates in the liver, and the CLD metabolite, chlordecol (CLD-OH) is found in bile, an important site of excretion for cholesterol transported to the liver via lipoproteins. Here, we studied the real-time molecular interaction between CLD and CLD-OH with human serum lipoproteins, LDL and HDL. While no interaction was detected between CLD and HDL, or between CLD-OH and LDL, relatively high specific affinities were observed between CLD and CLD-OH for LDL and HDL, respectively., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Ingested soil is a major vector of organic contaminants from environment to free-ranged animals, particularly for grazing herbivores. Therefore, a better understanding of processes driving soil intake may provide new insights to limit animal exposure to contaminants and ensure safety of animal products. To maintain the supply service of livestock farming activities in contaminated areas, it is necessary to design adapted farming practices aiming at controlling the risk for human health. This study was conducted in the French West Indies, where chlordecone, an organochlorine insecticide previously used to protect banana plantation against the black weevil and banned since 1993, has polluted nearly 20% of agricultural surfaces since the 1970s. A crossover study design was performed to estimate soil intake by twelve tethered Creole young bulls according to different grazing practices. The objectives were to characterize the influence of (i) daily herbage allowance (LOW, HIGH, ADLIB: 100, 150, 300 g DM/kg BW 0.75 respectively); (ii) and soil surface moisture (SSM) testing grazing on a water-saturated (HUM) vs dried (DRY) ground. The herbage offer was managed via the allocated surfaces varying the chain length as animal holders commonly do in informal Caribbean systems. The results evidenced an increase in soil intake with DHA reduction (2.1 to 3.8% of DM intake; P < 0.05) and with SSM increase (2.4 to 3.6% of DM intake; P < 0.05). Herbage offer reduction involved a closer-to-the-ground grazing with shorter post-grazing sward surface height (82.2 to 63.3 mm; P < 0.001), and both herbage offer reduction and SSM increase amplified sward soiling (measured from titanium content in unwashed herbage and image analysis). This work showed that soil intake is unavoidable even when herbage offer is very generous. The animals will significantly increase soil intake when herbage offer would be at 150 g DM/kg BW 0.75 or less, especially when the grazed surface is humid., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In the French West Indies (Caribbean), the insecticide Chlordecone (CLD) has been extensively used to reduce banana weevil (Cosmopolites sordidus) infestations in banana plantations. Previous studies have shown high CLD concentrations in freshwater and coastal communities of the region. CLD concentrations, however, have not yet been assessed in marine top predators. We investigated CLD concentrations in cetacean blubber tissues from Guadeloupe, including Physeter macrocephalus, Lagenodelphis hosei, Stenella attenuata and Pseudorca crassidens. Chlordecone was detected in all blubber samples analysed, with the exception of four P. macrocephalus. Concentrations (range: 1 to 329 ng·g -1 of lipid weight) were, however, lower than those found in species from fresh and brackish water. Ecological factors (open ocean habitat), CLD kinetics, and cetacean metabolism (high or specific enzymatic activity) might explain low concentrations found in cetacean blubber. Future analyses that include internal organ sampling would help to confirm CLD levels observed in this study., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Chlordecone (CLD) is a Persistent Organic Pollutant used between 1972 until 1993 in the French West Indies (FWI). Due to its persistence and extensive application, a quarter of the total local agricultural acreage is still moderate to heavily polluted. In consequence, livestock may be contaminated at various levels. This is a major public health concern, particularly for local consumers. In order to better understand the fate of CLD in livestock organisms, in vivo studies are required. There is no information available about its metabolism and elimination in ruminants, common livestock in the FWI. To be able to monitor the fate of chlordecone and its metabolites in livestock and to assess if the compounds could be released in the environment, urinary and fecal samples were logically targeted. In order to reach this goal, robust and validated analytical methods are required. For this purpose, Quick, Easy, Cheap, Effective, Rugged, and Safe (QuEChERS) extraction methods were validated to analyze CLD and its metabolites in the urine and feces. The analysis was carried using liquid phase chromatography with tandem mass spectrometry and validated according to French standard NF V03-110 and SANTE guidelines. Matrix effect, Accuracy, within-laboratory repeatability, specificity, Q/q relative ion intensities and uncertainty were reported. Recoveries between 70% and 120% were obtained from urine and feces. The limits of quantification (LOQ) in urine samples were 0.1 μg CLD L -1 , 0.1 μg total CLD (CLD and its conjugates)·L -1 , 1.3 μg CLDOH L -1 and 2.4 μg total CLD (chlordecol and its conjugates) L -1 of urine. LOQ in fresh feces were 3.2 μg CLD kg -1 and 5.8 μg CLDOH kg -1 . Contaminated urinary and fecal samples from ewes were analyzed to confirm the relevance of the methods. In urine, CLD and conjugated CLDOH could be quantified whereas only free CLD and free CLDOH were found in feces. These methods are essential for future toxicokinetic studies and also to estimate the environmental contamination., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Because of its high persistence in soils, t 1/2 =30years, chlordecone (CLD) was classified as a persistent organic pollutant (POP) by the Stockholm Convention in 2009.The distribution of CLD over time has been heterogeneous, ranging from banana plantations to watersheds, and contaminating all environmental compartments. The aims of this study were to (i) evaluate the potential of Miscanthus species to extract chlordecone from contaminated soils, (ii) identify the growth parameters that influence the transfer of CLD from the soil to aboveground plant parts. CLD uptake was investigated in two species of Miscanthus, C4 plants adapted to tropical climates. M. sinensis and M.×giganteus were transplanted in a soil spiked with [ 14 C]CLD at environmental concentrations (1mgkg -1 ) under controlled conditions. Root-shoot transfer of CLD was compared in the two species after two growing periods (2 then 6months) after transplantation. CLD was found in all plant organs, roots, rhizomes, stems, leaves, and even flower spikes. The highest concentration of CLD was in the roots, 5398±1636 (M.×giganteus) and 14842±3210ngg -1 DW (M. sinensis), whereas the concentration in shoots was lower, 152±28 (M.×giganteus) and 266±70ngg -1 DW (M. sinensis) in soil contaminated at 1mgkg -1 . CLD translocation led to an acropetal gradient from the bottom to the top of the plants. CLD concentrations were also monitored over two complete growing periods (10months) in M. sinensis grown in 8.05mgkg -1 CLD contaminated soils. Concentrations decreased in M. sinensis shoots after the second growth period due to the increase in organic matters in the vicinity of the roots. Results showed that, owing to their respective biomass production, the two species were equally efficient at phytoextraction of CLD., (Copyright © 2017. Published by Elsevier B.V.)

Sixteen weaned male Alpine kids (Capra hircus) were subjected to a 21-day oral daily exposure of 0.05 mg kg -1 BW. d -1 of chlordecone (CLD) and 0.30 μg kg -1 BW. d -1 of each non-dioxin-like polychlorinated biphenyls (NDL-PCBs, congeners 28, 52, 101, 138, 153 and 180). Four kids, identified as the CONTA group, were slaughtered at the end of the exposure, while the remaining animals (n = 12) were fed with specific diets for an additional 21-day decontamination period before slaughtering. Kids from the DECONTA (n = 4) group were fed a control diet, while those from the AC10% and PO8% group received pellets supplemented with 10% activated carbon (AC) and 8% paraffin oil (PO), respectively. CLD and NDL-PCB levels in blood, liver, peri-renal fat and muscles from different groups were analysed to compare the decontamination dynamics of the pollutants and to determine the efficiency of AC and PO to decrease the body levels of pollutants. After the decontamination period, the CLD levels considerably decreased (more than 60%) in blood, liver, muscles and fat. Concerning NDL-PCBs, the decontamination process was much lower. Overall, CLD appeared to be less retained in kids' organism compared with NDL-PCBs, and the decontamination dynamics of these pollutants appeared to be different because of their specific physicochemical properties and lipophilicity. Furthermore, the dietary supplementation with AC or PO did not significantly affect the decontamination dynamics., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Chlordecone is a persistent organochlorine pesticide that has been widely used in Guadeloupe (French West Indies) to control the banana weevil Cosmopolites sordidus from 1972 to 1993. A few years after its introduction, widespread contamination of soils, rivers, wild animals and aquatic organisms was reported. Although high chlordecone concentrations have been reported in several crustacean species, its uptake, internal distribution, and elimination in aquatic species have never been described. This study aimed at investigating the accumulation and tissue distribution of chlordecone in the giant freshwater prawn Macrobrachium rosenbergii, using both laboratory (30 days exposure) and field (8 months exposure) approaches. In addition, depuration in chlordecone-free water was studied. Results showed that chlordecone bioconcentration in prawns was dose-dependent and time-dependent. Moreover, females appeared to be less contaminated than males after 5 and 7 months of exposure, probably due to successive spawning leading in the elimination of chlordecone through the eggs. Chlordecone distribution in tissues of exposed prawns showed that cephalothorax organs, mainly represented by the hepatopancreas, was the most contaminated. Results also showed that chlordecone was accumulated in cuticle, up to levels of 40% of the chlordecone body burden, which could be considered as a depuration mechanism since chlordecone is eliminated with the exuviae during successive moults. Finally, this study underlined the similarity of results obtained in laboratory and field approaches, which highlights their complementarities in the chlordecone behaviour understanding in M. rosenbergii., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Understanding how persistent organic pollutants (POPs) are released from adipose tissue (AT) to blood is a critical step in proposing rearing strategies hastening the removal of POPs from contaminated livestock. The current study aimed to determine in nonlactating ewes whether polychlorinated biphenyls (PCBs) and chlordecone are released from AT to blood along with lipids during body fat mobilization achieved through β-agonist challenges or undernutrition. β-Agonist challenges did not affect serum POP concentrations, whereas serum PCBs 138, 153, and 180 were readily increased in response to undernutrition. After 21 days of depuration in undernutrition, AT PCB 153 and 180 concentrations were increased concomitantly with a decrease in adipocyte volume, whereas AT chlordecone concentration was not different from that observed at the end of the well-fed contamination period. Thus, undernutrition may be of practical relevance for accelerating POP depuration unless it is combined with a strategy increasing their excretion pool.

Chlordecone (CLD) is an organochlorine pesticide whose extended use led to the contamination of at least 20% of agricultural soils from the French West Indies. Livestock reared on polluted areas are involuntary contaminated by CLD and their level of contamination may exceed the threshold values set by the European Union. Thus, characterizing the CLD behaviour in farm animals appear as a real issue in terms of food safety for local populations. The aim of this experiment was (i) to characterize the CLD disappearance in various tissues after exposure cessation and (ii) to evaluate the potential effect of body fatness on this process. Two groups of eight growing goats were submitted to either a basal diet or a high energy diet for 50 days before being intravenously contaminated with 1 mg CLD kg(-1) body weight. Two days after CLD contamination, half of the kids of each experimental group were slaughtered in order to determine pollutant levels in the serum, liver, adipose tissues, and empty carcass. The remaining animals were submitted to a 30-day decontamination period before slaughtering and measurements as described above. The implemented nutritional plan resulted in both groups of kids with significant differences in terms of body fatness. CLD was mainly concentrated in the liver of animals as described in the literature. It was found also in kids' empty carcass and adipose tissues; however its levels in the empty carcass (muscles and bones) were unexpected since they were higher than in fat. These results indicate that the lipophilic pollutant CLD is found mainly in liver but also in muscles and fat. Concerning the animals' depuration, a 30-d decontamination period was sufficient to observe a decrease of CLD levels by more than 75% in both experimental groups and neither CLD concentrations nor CLD amounts were significantly affected by kids' body fatness.

Chlordecone (CLD) is a persistent organic pollutant (POP) that was mainly used as an insecticide against banana weevils in the French West Indies (1972-1993). Transfer of CLD via the food chain is now the major mechanism for exposure of the population to CLD. The uptake and the transfer of CLD were investigated in shoots of maize, a C4 model plant growing under tropical climates, to estimate the exposure of livestock via feed. Maize plants were grown on soils contaminated with [(14)C]CLD under controlled conditions. The greatest part of the radioactivity was associated with roots, nearly 95%, but CLD was detected in whole shoots, concentrations in old leaves being higher than those in young ones. CLD was thus transferred from the base toward the plant top, forming an acropetal gradient of contaminant. In contrast, results evidenced the existence of a basipetal gradient of CLD concentration within leaves whose extremities accumulated larger amounts of CLD because of evapotranspiration localization. Extractable residues accounted for two-thirds of total residues both in roots and in shoots. This study highlighted the fact that the distribution of CLD contamination within grasses resulted from a conjunction between the age and evapotranspiration rate of tissues. CLD accumulation in fodder may be the main route of exposure for livestock.

Chlordecone (CLD) was an organochlorine insecticide whose previous use resulted in an extensive pollution of the environment with severe health effects and social consequences. A closely related compound, 5b-hydrochlordecone (5b-hydroCLD), has been searched for and often detected in environmental matrices from the geographical area where CLD was applied. The current consensus considered that its presence was not the result of a biotic or abiotic dechlorination of CLD in these matrices but rather the consequence of its presence as impurity (synthesis by-product) in the CLD released into the environment. The aim of the present study was to determine if and to what extent degradation of CLD into 5b-hydroCLD occurred in the field. To test this hypothesis, the ratios of 5b-hydroCLD and CLD concentrations in a dataset of 810 soils collected between 2006 and 2012 in Martinique were compared to the ratios measured in 3 samples of the CLD dust commercial formulations applied in the banana fields of French West Indies (FWI) and 1 sample of the technical-grade CLD corresponding to the active ingredient used in such formulations. Soil data were processed with a hierarchical Bayesian model to account for random measurement errors and data censoring. Any pathway of CLD transformation into 5b-hydroCLD occurring over the long term in FWI soils would indeed change the ratio of 5b-hydroCLD/CLD compared to what it was in the initially applied formulations. Results showed a significant increase of the 5b-hydroCLD/CLD ratio in the soils-25 times greater in soil than in commercial formulations-which suggested that natural CLD transformation into 5b-hydroCLD over the long term occurred in these soils. Results from this study may impact future decisions for the remediation of the polluted areas.

Background: Perinatal exposure to endocrine-disrupting chemicals may affect thyroid hormones homeostasis and impair brain development. Chlordecone, an organochlorine insecticide widely used in the French West Indies has known estrogenic and progestin properties, but no data is available, human or animal, on its action on thyroid hormone system., Objectives: Our aim was to evaluate the impact of perinatal exposure to chlordecone on the thyroid hormone system of a sample of infants from the Timoun mother-child cohort in Guadeloupe and their further neurodevelopment., Methods: Chlordecone was measured in cord blood and breast milk samples. Thyroid stimulating hormone (TSH), free tri-iodothyronine (FT3), free thyroxine (FT4) were determined in child blood at 3 months (n=111). Toddlers were further assessed at 18 months using an adapted version of the Ages and Stages Questionnaire (ASQ)., Results: Cord chlordecone was associated with an increase in TSH in boys, whereas postnatal exposure was associated with a decrease in FT3 overall, and in FT4 among girls. Higher TSH level at 3 months was positively associated with the ASQ score of fine motor development at 18 months among boys, but TSH did not modify the association between prenatal chlordecone exposure and poorer ASQ fine motor score., Conclusions: Perinatal exposure to chlordecone may affect TSH and thyroid hormone levels at 3 months, differently according to the sex of the infant. This disruption however did not appear to intervene in the pathway between prenatal chlordecone exposure and fine motor child development., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Chlordecone (CLD) was an organochlorine insecticide mainly used to struggle against banana weevils in the French West Indies. Forbidden since 1993, it has been a long-term contaminant of soils and aquatic environments. Crops growing in contaminated soils lead to human exposure by food consumption. We used radiolabeled [(14)C]-CLD to investigate the contamination ways into radish, a model of edible roots. Radish plants were able to accumulate CLD in both roots (RCF35d 647) and tubers (edible parts, CF35d 6.3). CLD was also translocated to leaves (CF35d 1.7). The contamination of tuber was mainly due to peridermic adsorption or CLD systemic translocation to the pith. TSCF was 3.44×10(-)(3). CLD diffused across periderm to internal tissues. We calculated a mean flux of diffusion J through periderm about 5.71×10(-)(14)gcm(-)(2)s(-)(1). We highlighted different contamination routes of the tuber, (i) adsorption on periderm followed by diffusion of CLD towards underlying tissues, cortex, xylem, and pith (ii) adsorption by roots and translocation by the transpiration stream followed by diffusion from xylem vessels towards inner tissues, pith, and peripheral tissues, cortex and periderm. Concerning chemical risk assessment for other tubers, contamination would depend on various parameters, the thickness of periderm and CLD periderm permeance, the origin of secondary tissues - from cortex and/or pith - , the importance of xylem flow in tuber, and the lipid amount within tuber., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The former use of chlordecone (CLD) in the French West Indies has resulted in long-term pollution of soils. In this area, CLD may be transferred into eggs of hens reared outdoors, through soil ingestion. In order to assess this risk, a kinetic study involving the contamination of laying hens (22 weeks of age) with a diet containing 500 μg CLD kg(-1) during 42 d, followed by a depuration period of 35 d was carried out. Forty-four hens were sequentially slaughtered all over the experimental period and their liver, egg, abdominal fat and serum were collected. Two additional edible tissues, pectoral and leg muscles, were collected in hens slaughtered at the end of the contamination period. The depuration half-life of CLD in liver, egg, abdominal fat and serum was estimated at 5.0 ± 0.38 (mean ± SE), 5.5 ± 0.29, 5.3 ± 0.37 and 5.1 ± 0.66 d, respectively. CLD concentration at the end of the contamination period reached 1640 ± 274, 460 ± 41, 331 ± 23, and 213 ± 8.5 μg kg(-1) fresh matter (FM), respectively. The corresponding concentrations in pectoral and leg muscles were 119 ± 8.4, 127 ± 11 μg kg(-1) FM, respectively. The steady state carry over rate of CLD in eggs reached 43 ± 7.6%. This experiment demonstrates the preferential accumulation of CLD in liver, its significant transfer to eggs and its quite short half-life. It is concluded that raising hens on even mildly contaminated areas would lead to products exceeding the regulatory maximum residue limit of 20 μg CLD kg(-1)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The pollution of soil with the pesticide chlordecone (CLD) is a problem for the use of agricultural surfaces even years after its use has been forbidden. Therefore, the exposure of free-ranged animals such as ruminants needs to be investigated in order to assess the risk of contamination of the food chain. Indeed, measured concentrations could be integrated in a lowered extent if the soil binding would reduce the bioavailability of the pesticide. This bioavailability of soil-bound CLD in a heavily polluted andosol has been investigated relatively of CLD given via spiked oil. Twenty-four weaned lambs were exposed to graded doses of 2, 4 or 6 μg CLD/kg body weight during 15 days via the contaminated soil in comparison to spiked oil. The concentration of this pesticide has been determined in two target tissues: blood serum and kidney fat. The relative bioavailability (RBA) corresponds to the slope ratio between the test matrix-contaminated soil- in comparison to the reference matrix oil. The RBA of the soil-bound CLD was not found to significantly differ from the reference matrix oil in lambs meaning that the pesticide ingested by grazing ruminants would not be sequestered by soil binding. Therefore, CLD from soil gets bioavailable within the intestinal level and exposure to contaminated soil has to be integrated in risk assessments.

The former use of chlordecone (CLD) in the French West Indies has resulted in long-term pollution of soils and subsequently of food chains. In contaminated areas, free-range ducks used to control weeds in orchards may be exposed to CLD through polluted soil ingestion. The question arises whether they may be consumed. Muscovy ducks were raised on a guava orchard planted on a soil moderately contaminated (410 μg CLD/kg dry matter). Ducks were raised indoor up to 6 weeks of age and allowed to range freely outdoors thereafter. Twenty-nine females were sequentially slaughtered by groups of 2 to 5 ducks, after 4, 16, 19, 22 or 26 weeks spent in the orchard or after 16-17 weeks in the orchard followed by 3, 6 or 9 weeks in a closed shelter for depuration. CLD concentration increased from 258 to 1051, 96 to 278, 60 to 169 and 48 to 145 μg/kg fresh matter (FM) as the exposure through grazing increased from 4 to 22 weeks, in liver, abdominal fat and leg with and without skin, respectively. Eggs collected in the orchard contained up to 1001 μg CLD/kg FM. All these values exceeded the Maximum Residue Limit (MRL) of 20 μg/kg FM. CLD concentration in all tissues was divided by around 10 within the 9-week confinement period. Despite this quite rapid decontamination, it is estimated that 12-13 weeks would be required to achieve the MRL in liver and in eggs, and 5-6 weeks in leg muscle. Such durations would be too long in practice. Thus, the consumption of products from free-range ducks should be avoided, even in areas mildly contaminated with CLD., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The application of chlordecone (CLD), a chlorinated polycyclic ketone pesticide, until 1993 in the French West Indies has resulted in long-term pollution of agricultural soils (10% of them exceed 1 mg kg(-1)). The aim of this study was to assess the impact of two tropical volcanic soils, an andosol and a nitisol, on CLD availability in piglets, using the relative bioavailability (RBA) approach. For both soils and relative to an oil matrix, RBA was close to 100%, indicating that CLD was not retained in the soil matrices during the piglet digestive process. Additionally, after a 14 day exposure period, liver and subcutaneous fat CLD concentrations exceeded the maximum residue limit (10 μg kg(-1) of fresh matter and 100 μg kg(-1) of fat for liver and subcutaneous fat, respectively) beyond a CLD ingestion of 2.1 and 6.8 μg CLD kg(-1) of body weight per day, respectively. Thus, rearing practices in CLD-contaminated areas should avoid involuntary soil ingestion by farm animals.

The former use of chlordecone (CLD) in the French West Indies has resulted in long-term pollution of soils and of food chains. CLD may be transferred into eggs of hens reared outdoors, through polluted soil ingestion. Tropical volcanic soils display variable capacities of pollutant retention: CLD is less available and more persistent in andosol than in nitisol. The impact of soil type on CLD bioavailability to hens was tested through a relative bioavailability study. The deposition of CLD in egg yolk and in abdominal fat was measured in 42 individually housed laying hens fed with diets containing graded levels of CLD from polluted andosol, nitisol, or spiked oil during 23 days. Within each ingested matrix, the concentration of CLD in yolk and in abdominal fat linearly increased with the amount of ingested CLD (P < 0.001). However, the response to andosol diets and to nitisol diets was not different from the response to oil diets (P > 0.1), indicating that CLD was equally bioavailable to laying hens, irrespective of the matrix. This suggests that the hen's gastrointestinal tract efficiently extracts CLD from the two tropical volcanic soils, regardless of their retention capacity. Thus, hens reared on polluted soils with CLD may lay contaminated eggs.

Concentrations of organochlorine pesticides and stable isotope ratios of nitrogen and carbon were measured in a tropical freshwater ecosystem to evaluate the contamination level of biota and examine the bioaccumulation patterns of pollutants through the food web. Chemical analyses showed a general and heavy contamination of the entire food web. They revealed the strong accumulation of pollutants by juveniles of diadromous fishes and shrimps, as they re-enter the river. The role of ecological factors in the bioaccumulation of pesticides was evaluated. Whereas the most persistent pollutants (chlordecone and monohydro-chlordecone) were related to the organisms diet and habitat, bioaccumulation of β-HCH was only influenced by animal lipid content. The biomagnification potential of chlordecone through the food chain has been demonstrated. It highlighted the importance of trophic transfer in this compound bioaccumulation process. In contrast, bioconcentration by passive diffusion from water seemed to be the main exposure route of biota to β-HCH., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

17beta-Estradiol (E2) activates non-genomic pathways in MCF-7 cells, and this study investigates the effects of structurally-diverse estrogenic compounds on activation of mitogen-activated protein kinase (MAPK), phosphatidylinositol-3-kinase (PI3-K), protein kinase C (PKC), PKA, and calcium calmodulin-dependent kinase IV (CaMKIV). Activation of kinases was determined by specific substrate phosphorylation and transactivation assays that were diagnostic for individual kinases. The compounds investigated in this study include E2, diethylstilbestrol (DES), the phytoestrogen resveratrol, and the following synthetic xenoestrogens, bisphenol-A (BPA), nonylphenol, octylphenol, endosulfan, kepone, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), and 2',3',4',5'-tetrachloro-4-biphenylol (HO-PCB-Cl(4)). With the exception of resveratrol, all the compounds activated PI3-K and MAPK. Activation of PKC by the xenoestrogens was structure-dependent since resveratrol, kepone and HO-PCB-Cl(4) were inactive and only minimal activation of PKA was observed. CaMKIV was activated only by E2 and DES, and HO-PCB-Cl(4) was a potent inhibitor of CaMKIV-dependent activity. These results demonstrate that activation of estrogen receptor-alpha-mediated non-genomic pathways by estrogenic compounds in MCF-7 cells is structure-dependent and can result in activation or inhibition of kinase activities.

Although many environmental contaminants disrupt endocrine function by binding to nuclear steroid receptors, it is not known whether they are capable of binding to steroid membrane receptors and interfering with nongenomic actions of steroids. The binding of several organochlorine pesticides to the plasma membrane receptor for the maturation-inducing steroid, 17,20beta,21-trihydroxy-4-pregnen-3-one (20beta-S), in the ovaries of spotted seatrout (Cynoscion nebulosus) was investigated in in vitro competition assays. Kepone and o,p'-DDD were competitive inhibitors of 20beta-S binding and caused concentration-dependent displacement of [3H]-20beta-S from its receptor site over the range of 10(-4) to 10(-6) or 10(-7) M, whereas several other pesticides had lower affinities for the receptor. Interference with the nongenomic actions of 20beta-S on final meiotic maturation of spotted seatrout oocytes (final oocyte maturation, FOM) was examined in an in vitro bioassay. A concentration-dependent inhibition of FOM in response to 20beta-S was observed after 5 min and 12 h exposure to the same range of Kepone and o,p'-DDD concentrations (10(-4) to 10(-6) or 10(-7) M). The close correspondence between competitive binding of the two pesticides to the 20beta-S membrane receptor and their inhibition of 20beta-S induced FOM suggests a mechanism of endocrine disruption mediated by binding to a steroid membrane receptor and antagonism of a nongenomic steroid action.

Previous studies from our laboratory have indicated that chlordecone (Kepone CD), an organochlorine insecticide, inhibited cardiac sodium pump activity and catecholamine uptake suggesting that CD may interfere with cardiac function. Sarcoplasmic reticulum (SR) calcium pump has an important role in myocardial contraction and relaxation, besides Na+ transport. Since CD interferes with cardiac Na+ ion translocases, we have studied CD effects on cardiac SR calcium pump activity. Experiments were carried out both in vitro and in vivo. SR was isolated from heart ventricles of male Sprague-Dawley rats. Cardiac SR Ca2(+)-ATPase. 45Ca-uptake and cAMP as well as calmodulin (CaM) dependent protein phosphorylation were measured. Ca2(+)-ATPase was differentiated into low affinity and high affinity forms by measuring the activity using 50 and 0.7 microM free Ca2(+)-respectively. CD in vitro inhibited 45Ca-uptake by SR in a concentration dependent manner with an IC50 value of 7 microM and SR 45Ca-uptake was totally inhibited at 20-30 microM CD. In agreement with this, both high affinity and low affinity Ca2(+)-ATPases, which are involved in Ca2+ transport across membranes, were also inhibited by CD in a concentration dependent manner with IC50 values of 0.7 and 3.2 microM respectively. Both Ca2(+)-ATPase and 45Ca-uptake by cardiac SR were significantly lower in rats treated with CD (25, 50 or 75 mg/kg) when compared to control rats. cAMP as well as CaM significantly elevated the 32P-binding to SR proteins in vitro to about 70-80%. In the presence of CD, this 32P-binding was reduced, however, not concentration dependent.(ABSTRACT TRUNCATED AT 250 WORDS)

Freshwater fish (larval lampreys Petromyzon marinus) occupied plastic tubes and ventilated aqueous solutions (around 1.0 mg/L) of the organochlorine pesticide Kepone at 13 degrees C. The efficiency with which Kepone was extracted from solution during a single pass through the pharynx, and the effect of Kepone on fluxes of Na+ and Cl- across the gills were measured. The efficiency with which lampreys extracted Kepone from local tap water averaged 55-66%, confirmed by measuring Kepone accumulation within the lampreys (as 14C-equivalents), using a mass-balance approach. The extraction efficiency matches predictions based on studies using teleosts. Extraction efficiencies declined slowly throughout the exposure period and related inversely to ventilatory rates. In ion-flux measurements, Kepone produced a 40% decline in the rate of influx of Cl- across the pharynx. Effluxes of Na+ and Cl- were not affected, nor was influx of Na+. These latter findings are difficult to reconciliate with accepted theories of Kepone's toxic action; they may relate to the fact that lampreys are unusually tolerant to Kepone poisoning.

The effects of organochlorine (O.C.) compounds, such as aldrin, dieldrin, endrin, isodrin, chlordecone and mirex, on calmodulin (CaM) activity were investigated. Changes induced by O.C. compounds on biological and physical properties of CaM were monitored in terms of phosphodiesterase stimulation and tyrosine fluorescence, respectively. None of the O.C. compounds altered tyrosine fluorescence of CaM in the presence of Ca2+. Except for chlordecone, none of the O.C. compounds inhibited CaM-activated phosphodiesterase (PDE). Chlordecone significantly decreased (P less than 0.05) CaM-activated PDE in a concentration-dependent manner without affecting the basal enzyme. Combination of chlordecone with W-7 (CaM antagonist) increased the inhibitory effect of W-7 on CaM activity. These results suggest that O.C. compounds may not be changing the tyrosine fluorescence of CaM. Among the O.C. compounds tested, chlordecone is a specific inhibitor of CaM-activated PDE.

Chlordecone (CD) is an organochlorine pesticide associated with albumin and high-density lipoproteins (HDL) in the plasma. It is found in higher concentrations in the liver than in other tissues and is excreted in the bile. The influence of plasma HDL on the biliary excretion of CD was studied using isolated pig liver perfused with a Krebs-Ringer bicarbonate solution containing albumin, dextrose, and pig red blood cells. Within 5 min after administration into the perfusion medium of [14C]CD bound to albumin or to HDL, only 13% of the [14C]CD dose remained in the perfusate, showing that CD is rapidly taken up by the liver. After 60 min the plasma concentration was constant at 0.008% dose/ml when [14C]CD was administered bound to albumin in the absence of HDL and at 0.004% dose/ml when administered bound to HDL. The mean concentration of CD in the bile was higher when CD was administered bound to albumin in the absence of HDL (0.039% dose/ml) than when it was administered bound to HDL (0.010% dose/ml). The elimination rate constant of CD from the liver into the bile was 0.007/min whether CD was administered bound to albumin or to HDL. The addition of HDL to the perfusion system after the administration of albumin-bound CD resulted in lower biliary CD concentrations. The results suggest that HDL affects the distribution of CD between the perfusate and liver and between liver and bile. In both cases, distribution toward the liver is favored.

Adult male rats were fed diets containing 0, 5, 15, and 30 ppm chlordecone for 90 d and then either bred to untreated females or sacrificed for terminal studies. Chlordecone residues in liver, fat, and serum were determined in the treated males. Reproductive performance was unaffected, and no histologic changes in the male sex organs could be attributed to chlordecone treatment. Reversible decreases in the motility and viability of epididymal spermatozoa and decreased sperm reserves in the cauda epididymidis were observed in rats fed 15 or 30 ppm. No effect on sperm morphology or on sperm concentration in epididymal fluid was detected. Chlordecone accumulation in tissues was linearly related to dietary levels, with the highest chlordecone concentration occurring in the liver.

Due to lack of adequate industrial safety measures, workers in a small factory that manufactured the organochlorine pesticide chlordecone were exposed to large amounts of this toxic material for many months. High concentrations of chlordecone were present in samples of blood, liver, and fat from these workers. Toxic manifestations prominently involved the nervous system, liver and testes. Although a plasmaphoresis experiment indicated that chlordecone is rapidly transferred from tissues to blood, attempts to employ hemoperfusion as a means for removing chlordecone from the body were unsuccessful because chlordecone is avidly bound by plasma proteins and was not extracted by the hemoperfusion sorbents. An alternative approach to therapy was based on the observations that stool contains only a small fraction of the substantial amounts of chlordecone excreted in bile. Oral administration of cholestyramine, a nonabsorbable resin that binds chlordecone in vitro, increased fecal excretion of chlordecone and accelerated its disappearance from the body. This treatment was accompanied by amelioration of the clinical manifestations of toxicity, indicating that the subacute toxic effects of chlordecone are reversible. Studies of chlordecone excretion in one patient with a surgically created bile fistula disclosed the existence of the novel, nonbiliary mechanism for excretion of chlordecone in the stool. Further physiological studies are needed to explore the possible role of the gut in the excretion of many kinds of slowly eliminated lipophilic toxins.

Chlordecone (Kepone) is a decachloroketone analog of the dodecachlorohydrocarbon mirex and is used as a stomach poison insecticide. Despite the structural similarity to mirex, chlordecone is unlike mirex in general organ-specific toxic properties. Chlordecone is primarily accumulated in the liver, where it causes a variety of morphological and biochemical alterations. Although less effective than mirex as a hepatotoxin, it causes liver enlargement, focal necrosis, mitochondrial changes, fatty infiltration of hepatocytes, and proliferation of endoplasmic reticulum. Chlordecone accumulation and morphological alterations in the liver were also observed in occupationally exposed human patients. Induction of hepatic microsomal mixed-function oxidases (MFOs) and impaired production and utilization of hepatocellular energy are the principal biochemical aberrations produced by chlordecone. Chronic exposure causes carcinogenesis in mice and rats. Hyperplastic nodules, which progress to hepatocellular carcinomas, are the principal pathological lesions. Acute and chronic exposures to chlordecone result in hepatobiliary dysfunction manifested as impaired excretion of anionic compounds accompanied by choleresis. Exposure to chlordecone results of greatly potentiated haloalkane hepatotoxicity, representing a most potent toxic interaction at otherwise individually nontoxic levels. In view of the demonstrated carcinogenic effect of chlordecone, such interactions at very low levels assume extraordinary significance in terms of chronic toxicological and pathological manifestations induced by combinations of toxic chemicals.

The biotransformation of chlordecone (CD) to chlordecone alcohol (CDOH) occurs in man and gerbils but not in rats, guinea pigs and hamsters [1, 2]. Because of the species differences in CDOH formation and the need for a suitable animal model, pigs were administered CD by intraperitoneal (i.p.) injection. Plasma, gallbladder bile, hepatic bile, liver and feces were collected and analyzed by gas chromatography for CD metabolites. CDOH was present in bile and feces with up to 85% conjugated in the bile but only 15% was conjugated in the feces. Up to 20% of the CD in plasma and bile and less than 3% in feces was in the conjugated form. Both reduction and conjugation of CD in the pig are similar to those in man.

In rats, as reported in humans, chlordecone (Kepone) is excreted predominantly in the feces. Cholestyramine, an anion exchange resin, binds chlordecone in rat intestine, increases its excretion into the feces, and decreases its content in the tissues. The resin appears to offer a practical method for treating chronic poisoning with this and possibly with other lipophilic toxins.

Workers in a small factory that manufactured the organochlorine pesticide chlordecone were exposed to large amounts of this toxic material for many months. Toxic manifestations prominently involved the nervous system, liver and testes. Chlordecone was present in high concentrations in samples of blood, liver, and fat from these workers. A plasmaphoresis experiment indicated that chlordecone is rapidly transferred from tissues to blood. However, hemoperfusion was unsuccessful for removing chlordecone from the body because chlordecone is avidly bound by plasma proteins. Based on the observation that stool contains only a small fraction of the substantial amounts of chlordecone excreted in bile, we administered orally cholestyramine, a nonabsorbable resin that binds chlordecone in vitro. Cholestyramine increased fecal excretion of chlordecone and accelerated the rate of disappearance of the pesticide from the body. This was accompanied by amelioration of the clinical manifestations of toxicity, indicating that the subacute toxic effects of chlordecone are reversible. We conclude that therapy with binding agents taken orally provide a safe and effective means for treatment of humans poisoned with chlordecone and, possibly with other organochlorine pesticides.

It has been established that the major metabolic pathway for chlordecone (CD) (Kepone) both in humans and in the Mongolian gerbil is bioreduction of this organochlorine pesticide to chlordecone alcohol (CDOH) in the liver. In the present study we developed a gas-liquid chromatography assay to measure the enzymatic reduction of CD to CDOH in vitro and characterized "CD reductase" activity in gerbil liver cytosol. CD reductase is a cytosolic enzyme readily detectable in liver samples prepared from humans, rabbits, and gerbils, the only species of many tested that convert CD to CDOH in vivo. Gerbil CD reductase exhibited a Km of 2.6 microM, a Vmax of 0.14 nmol/min, and a pH optimum of 6.5. The enzyme activity required NADPH, was sensitive to thiol reagents, and was distributed in all tissues with the highest activities found in the liver, intestine, and kidneys. These results are consistent with CD reductase belonging to the family of enzymes referred to as the "aldo-keto reductases." However, unlike previously described reductases, CD reductase was undetectable in rats, mice, hamsters, or guinea pigs and was insensitive to the model aldehyde and ketone reductase inhibitors, phenobarbital and quercetin, respectively. In addition, CD reductase activity in liver was increased by 38% (p less than 0.01) following treatment of gerbils with CD. We conclude that CD reductase is a novel aldo-keto reductase that is uniquely inducible by its substrate.

It has previously been shown that oral administration to rats of sucrose polyester (SPE4), a nonabsorbable lipophilic binding agent, greatly stimulates the fecal excretion of coorally administered DDT5 (R.J. Jandacek, 1982, Drug Metab. Rev., 13, 695-714). To determine whether this agent would stimulate the excretion of persistent metabolites of DDT stored in body tissues, we treated a group of gerbils with [14C]-DDT and monitored the fecal excretion of radioactivity for several months until a terminal, log-linear phase of excretion was observed. At this point, when greater than 75% of the fecal radioactivity was identified as [14C]DDE, we fed the animals diets containing up to 10% sucrose polyester and found that the rate of excretion of radioactivity in the stool promptly increased two to three times as compared to the rate in the preceding control period. Some rats were subjected to a 25-50% restriction in total food allotment, but this produced no significant change in fecal excretion of total radioactivity. However, when food restriction was combined with administration of sucrose polyester, there was a dramatic, eightfold average increase in excretion of fecal radioactivity. This synergistic effect was reversed (within 24 hr) when the animals were transferred to a normal diet. Measurement of total body radioactivity confirmed that food restriction plus sucrose polyester treatment reduced the body content of the pesticide. We conclude that stimulation of intestinal excretion may offer a new approach to treatment of patients exposed to lipophilic environmental contaminants.

The hypothesis that liver is the site of the previously demonstrated chlordecone alcohol formation in man was tested. Human bile obtained from chlordecone-poisoned factory workers contained substantial amounts of free chlordecone, but little free chlordecone alcohol. However, when the same bile specimens were pretreated with beta-glucuronidase before analysis by gas-liquid chromatography, large amounts of chlordecone alcohol appeared, accounting for 75% of total organochlorine compounds. Confirmation of the identity of chlordecone and chlordecone alcohol was made by using gas liquid chromatography-mass spectrometry. Whereas biliary chlordecone alcohol was present predominantly as its glucuronide conjugate (93%), chlordecone was excreted primarily as the unaltered compound (72%) with only a small portion conjugated with glucuronic acid (9%). The remaining fraction of the total chlordecone measured in bile appeared to be a stable polar metabolite resistant to beta-glucuronidase. This unidentified metabolite could be converted to free chlordecone only by acid hydrolysis under harsh conditions. In contrast to human bile, rat bile contained only trace amounts of chlordecone alcohol (less than 0.5% of total chlordecone), thus indicating that hepatic metabolism of chlordecone is species-specific. We conclude that in man, the major metabolic route for chlordecone is its reduction in the liver followed by glucuronidation.

The uptake, distribution, and exchange of chlorinated hydrocarbon insecticides (dieldrin and chlordecone) and biphenyls (2,4,5-2',4',5'-hexachlorobiphenyl and 3-chlorobiphenyl) among human lipoproteins was examined by fluorescence quenching, gel filtration, and ultrafiltration. The chlorinated hydrocarbons were rapidly taken up from solution or silica particles by lipoproteins. The distribution of chlorinated hydrocarbons among the lipoproteins was independent of the amount taken up by the lipoproteins. The partition coefficient for each lipoprotein and the serum concentration of individual lipoproteins determined the distribution pattern of chlorinated hydrocarbons among lipoproteins. The chlorinated hydrocarbons attached to albumin or one of the lipoproteins were rapidly transferred to all other lipoproteins. The exchange was complete in less than one minute. The role of rapid exchange of chlorinated hydrocarbons among lipoproteins in removal of these chemicals from blood and distribution to other tissues is discussed.

This overview summarizes the available data concerning the neurotoxic effects of chlordecone on the basal ganglia in mice. Included are the effects of chlordecone on motor coordination, levels of biogenic amines, uptake of catecholamines and GABA, release of 3H-dopamine from striatal slices, newly synthesized dopamine, levels of dopamine metabolites in striatum, total and protein-bound Ca++ in discrete areas of brain, and distribution of chlordecone in discrete areas of brain. These data suggest that the basal ganglia may be the brain site at which chlordecone acts to produce its neurotoxic effects.

The possibility that pesticides are secreted in the saliva and that this secretion can be used to assess exposure to pesticides is discussed. Both Kepone and carbaryl were tested through a series of in vitro studies and in vivo experiments including both acute and subchronic studies. In the in vivo studies, both Kepone and carbaryl were detected in the saliva in the first twenty-four hours, but seldom thereafter. Analysis of urinary samples indicated a rapid clearance of the substances from the animals. In vitro uptake and efflux studies suggested that movement of both substances was by passive diffusion and reached a plateau after 60 minutes of incubation. Efflux rates were unaffected by experimental conditions, but were ten times faster for carbaryl.

The toxic organochlorine pesticide, chlordecone (Kepone), is excreted in human bile primarily as a stable, reduced monoalcohol metabolite. This bioreduction is catalyzed by a hepatic cytosolic enzyme activity termed chlordecone reductase. We purified this enzyme from human liver and found that chlordecone reductase resembles the family of xenobiotic metabolizing enzymes referred to as the aldo-keto reductases based on its biochemical characteristics, including its ability to catalyze the reduction of a carbonyl-containing substrate. However, analyses of liver cytosolic samples on immunoblots developed with anti-chlordecone reductase antibodies revealed that immunoreactive proteins were present only in those mammalian species that convert chlordecone to chlordecone alcohol in vivo (man, gerbil, and rabbit) and not in those species unable to reduce chlordecone (rat, mouse, and hamster). Hence, chlordecone reductase is unique among aldo-keto reductases in being species-specific. Quantitative immunoblot analyses of seven human liver specimens disclosed two immunoreactive proteins whose total concentration varied over a 6-fold range. Moreover, the amount of immunoreactive protein was directly proportional to chlordecone reductase activity in each sample. We conclude that chlordecone reductase is a unique aldo-keto reductase of potential clinical importance whose expression varies markedly among individuals.

Pharmacokinetic modeling is being applied to chemicals posing health hazards because of their presence as contaminants in our environment. This paper presents a rationale for constructing mathematical models based on anatomic and physiological principles. Pharmacokinetic investigations incorporating such models are illustrated for two halogenated hydrocarbons that exhibit different patterns of disposition in the rat: 2,2',4,4',5,5'-hexachlorobiphenyl and Kepone. The models permit interspecies comparison and prediction of normal pharmacokinetic behavior and alterations induced by intervention measures. As an example a theoretical limit is predicted in the case of a treatment for Kepone poisoning involving oral administration of adsorbents.

Rats received a single, oral, 40-mg/kg dose of 14C-labeled chlordecone in a corn-oil solution. Initially the highest levels of radioactivity were found in the adrenal gland, liver, lung, and fat. While levels declined steadily in all tissues during the course of the study (182 days), the ratio of liver content to that of other tissues increased considerably. The blood half-life was 8.5 days for the first 4 weeks, 24 days for the next 8 weeks, and 45 days for the final 14 weeks, The amount excreted in the feces was 12.7% for the first 24 hr, 2.9% for the second, and 3.3% during the third 24-hr period. By 84 days 65.5% of the dose had been excreted by this route. Total urinary excretion of radioactivity for 84 days was 1.6%. These results indicate that chlordecone is well absorbed and distributed throughout the body, has a long half-life, and disappears more slowly from the liver than from other tissues. The majority of a dose is eliminated slowly in the feces with very little appearing in the urine. The findings are consistent with the expected pharmacokinetics of a chlorinated hydrocarbon, although there was less of a tendency to localize in fat than anticipated.