An assessment of the developmental, reproductive, and neurotoxicity of endosulfan.
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(-) ionophore in mammalian CNS. Rat acute toxicity is moderate, LD(50)=48 (M) or 10 mg/kg/d (F), oral gavage; 130 (M), 70 mg/kg/d (F) dermal; LC(50)=34.5 microg/L (M), 12.6 microg/L (F), inhalation. Critical NOELs for risk assessment: acute oral (gavage)=0.7 mg/kg/d (rabbit developmental); Subchronic oral (diet)=1.2 mg/kg/d (rat reproduction); Chronic oral (diet)=0.6 mg/kg/d. There were no acceptable dermal toxicity studies. The critical acute and subchronic inhalation NOELs=0.001 mg/L, chronic inhalation=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.
Silva
Marilyn H
MH
Department of Pesticide Regulation, California Environmental Protection Agency, 1001 I Street, Sacramento, CA 95812, USA. msilva@cdpr.ca.gov
Gammon
Derek
D
D000328:Adult; D000818:Animals; D001321:Autistic Disorder / Q000453:epidemiology / Q000209:etiology; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000196:embryology*; D052244:Endocrine Disruptors / Q000145:classification / Q000633:toxicity; D004726:Endosulfan / Q000145:classification / Q000633:toxicity*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007248:Infertility, Male / Q000453:epidemiology / Q000209:etiology*; D019570:Inhalation Exposure; D007306:Insecticides / Q000145:classification / Q000633:toxicity*; D008297:Male; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000453:epidemiology; D019055:No-Observed-Adverse-Effect Level; D010573:Pesticide Residues / Q000633:toxicity; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D012098:Reproduction / Q000187:drug effects*; D018570:Risk Assessment; D013094:Spermatozoa / Q000187:drug effects; D013723:Teratogens / Q000145:classification / Q000633:toxicity; D055815:Young Adult
D052244:Endocrine Disruptors; D007306:Insecticides; D010573:Pesticide Residues; D013723:Teratogens; D004726:Endosulfan