Chlordecone: development of a physiologically based pharmacokinetic tool to support human health risks assessments

Abstract

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.

The Pesticide Chlordecone Promotes Parkinsonism-like Neurodegeneration with Tau Lesions in Midbrain Cultures and C. elegans Worms

“…Based on these different observations, we may assume that CLD comes into contact with DA neurons in the head and the body after being absorbed through the mouth and/or the cuticle. This is not surprising in view of the high lipophilicity of this compound, denoted by a log p value of ~5.41 [60].…”

“…The possibility that CLD could become toxic after accumulation in DA neurons through the DA transporter is, however, unlikely for the following reasons: (i) inhibiting this transport system with GBR12909 did not reduce the toxicity of CLD for DA neurons in culture, and (ii) the deficit in the slowing response observed in CLD-treated worms was also detectable in dat-1 (ok157) C. elegans, a deficient mutant lacking the presynaptic DA transporter [64]. We can, therefore, assume that due to its lipophilic character [60], CLD enters DA neurons by passively diffusing through the plasma membrane. This probably also explains why CLD toxicity develops only progressively over time and why this pesticide affects non-DA neurons in midbrain cultures (not shown).…”

“…Such values are very similar to the EC50s reported to be toxic for cultured neurons in this study (7.5-10 µM, i.e., 3.7-4.9 µg/mL). Given that CLD has a good ability to cross the blood-brain barrier [8,60,84], we might assume that extracellular concentrations close to the levels leading to neurodegeneration were present in the brain of intoxicated chemical workers. Blood concentrations of CLD in the general Caribbean population were found, however, at least 50-fold lower than the levels causing neurological symptoms [83,85]; Emeville and colleagues reported highest CLD plasma values of 0.05 µg/mL in their study population [85].…”

Inverse association between plasma chlordecone concentrations and progression of alcoholic liver fibrosis: the role of liver metabolism

“…Chlordecone in the blood is always found as the parent compound, carried by albumin and high-density lipoproteins (HDL) [ 33 ], which are associated with reverse cholesterol transport pathways [ 34 ]. In the liver, chlordecone is firmly bound to cytosolic proteins called chlordecone-binding proteins (CDBPs) [ 35 ], promoting its sequestration or partially reducing it into chlordecone-alcohol by chlordecone reductase, an aldo-keto reductase also named AKR1C4 [ 36 , 37 ] Chlordecone-alcohol and its glucuronide conjugate are then excreted into the bile and eliminated through the feces [ 36 ] However, more than 90% is removed from the bile in the intestine and undergoes enterohepatic recirculation after deconjugation and oxidation in the intestinal lumen [ 10 ] Such enterohepatic recirculation explains the long elimination half-life of chlordecone of 131 days [ 24 ].…”

“…Consequently, it cannot be excluded that liver fibrosis may induce changes in the steady-state plasma concentration of chlordecone and thus alter the surrogate of exposure. We assessed this issue by simulating potential changes in the steady-state blood chlordecone concentration induced by liver fibrosis using a human physiologically based pharmacokinetic (PBPK) model [ 24 ].…”