An assessment of the developmental, reproductive, and neurotoxicity of endosulfan

Abstract

BACKGROUND: Endosulfan has been used for over 50 years. Although most analogs have been discontinued, endosulfan has less environmental persistence. Nevertheless, pressure groups are lobbying for a worldwide ban. The reasons are: possible rodent male reproductive toxicity, other endocrine effects and cancer; human epidemiology, and exposure studies; residues appearing in remote areas of the world, e.g., the Arctic. METHODS: The endosulfan toxicology database is described and risks of its use assessed. RESULTS: Endosulfan is an antagonist at the GABA A receptor Cl À ionophore in mammalian CNS. Rat acute toxicity is moderate, LD 50 5 48 (M) or 10 mg/kg/d (F), oral gavage; 130 (M), 70 mg/kg/d (F) dermal; LC 50 5 34.5 mg/L (M), 12.6 mg/L (F), inhalation. Critical NOELs for risk assessment: acute oral (gavage) 5 0.7 mg/kg/d (rabbit developmental); Subchronic oral (diet) 5 1.2 mg/kg/d (rat reproduction); Chronic oral (diet) 5 0.6 mg/kg/d. There were no acceptable dermal toxicity studies. The critical acute and subchronic inhalation NOELs 5 0.001 mg/L, chronic inhalation 5 0.0001 mg/L (estimated). Toxicity to rat sperm occurred at doses causing neurotoxicity. Endocrine effects, resulting from P450 oxygenase(s) induction, were reversible. Increased cancer, genotoxicity, or histopathology in rodents was not observed in any organ. Possible effects on brain biogenic amine levels were probably secondary. CONCLUSIONS: Epidemiology and rodent studies suggesting autism and male reproductive toxicity are open to other interpretations. Developmental/ reproductive toxicity or endocrine disruption occurs only at doses causing neurotoxicity. Toxicity to the fetus or young animals is not more severe than that shown by adults.

Pesticide Exposure in Children

“…Other herbicides (atrazine, 2,4-D, and glyphosate) and fungicides (vinclozolin) also have some endocrine activity. [156][157][158][159] The associations are very complex and are primarily based on in vitro and animal studies. Estrogenmimicking properties tend to be the most commonly reported, although effects on androgen and thyroid hormones, among others, are also reported.…”

Neonatal exposure to low doses of endosulfan induces implantation failure and disrupts uterine functional differentiation at the pre-implantation period in rats

“…Many experimental studies performed in rodents have associated early exposure to endosulfan during development with male reproductive toxicity (Dalsenter et al, 1999;Silva and Gammon, 2009;Sinha et al, 2001). In another study, Saiyed et al (2003) associated developmental exposure to endosulfan with reproductive Abbreviations: Endo6, female rat group treated with 6 μg/kg/d of endosulfan; Endo600, female rat group treated with 600 μg/kg/d of endosulfan; E2, 17β-estradiol; DES, diethylstilbestrol; MXC, methoxychlor; EDCs, endocrine-disrupting chemicals; P, progesterone; ERα, estrogen receptor alpha; PR, progesterone receptor; SRC-1, steroid receptor coactivator 1; SRC-3, steroid receptor coactivator 3; SMRT, silencing mediator for retinoic acid and thyroid hormone receptor; α-SMA, alpha smooth muscle actin; BrdU, bromodeoxyuridine; CKIs, cyclin-dependent kinase inhibitors; CLs, corpora lutea; PND, postnatal day; GD, gestational day; RfD, reference dose; NOEL, no observed effect level; IOD, integral optical density.…”

Prediction of embryotoxic potential using the ReProGlo stem cell-based Wnt reporter assay

“…Concerning the 23 test compound in question, we searched the available literature and found evidence for teratogenic effects occurring at the level of maternal toxicity only for the following compounds: monobutyltin trichloride, dibutyltin dichloride and tributyltin chloride [42], fenoxycarb [43], benomyl and carbendazim [44], endosulfan [45], glycolic acid [46], pentachlorophenol [47].…”