Age- and gender-related differences in the time course of behavioral and biochemical effects produced by oral chlorpyrifos in rats.

It is well known that young animals are generally more sensitive to lethal effects of cholinesterase-inhibiting pesticides, but there are sparse data comparing less-than-lethal effects. We compared the behavioral and biochemical toxicity of chlorpyrifos in young (postnatal Day 17; PND17) and adult (about 70 days old) rats. First, we established that the magnitude of the age-related differences decreased as the rat matures. Next, we evaluated the time course of a single oral dose of chlorpyrifos in adult and PND17 male and female rats. Behavioral changes were assessed using a functional observational battery (with age-appropriate modifications for pre-weanling rats) and an evaluation of motor activity. Cholinesterase (ChE) activity was measured in brain and peripheral tissues and muscarinic receptor binding assays were conducted on selected tissues. Rats received either vehicle (corn oil) or chlorpyrifos (adult dose: 80 mg/kg; PND17 dose: 15 mg/kg); these doses were equally effective in inhibiting ChE. The rats were tested, and tissues were then taken at 1, 2, 3.5, 6.5, 24, 72, 168, or 336 h after dosing. In adult rats, peak behavioral changes and ChE inhibition occurred in males at 3.5 h after dosing, while in females the onset of functional changes was sooner, the time course was more protracted and recovery was slower. In PND17 rats, maximal behavioral effects and ChE inhibition occurred at 6.5 h after dosing, and there were no gender-related differences. Behavioral changes showed partial to full recovery at 24 to 72 h, whereas ChE inhibition recovered markedly slower. Blood and brain ChE activity in young rats had nearly recovered by 1 week after dosing, whereas brain ChE in adults had not recovered at 2 weeks. Muscarinic-receptor binding assays revealed apparent down-regulation in some brain areas, mostly at 24 and 72 h. PND17 rats generally showed more receptor down-regulation than adults, whereas only adult female rats showed receptor changes in striatal tissue that persisted for 2 weeks. Thus, compared to adults (1) PND17 rats show similar behavioral changes and ChE inhibition although at a five-fold lower dose; (2) the onset of maximal effects is somewhat delayed in the young rats; (3) ChE activity tended to recover more quickly in the young rats; (4) young rats appear to have more extensive muscarinic receptor down-regulation, and (5) young rats show no gender-related differences.

[1]  V. Moser,et al.  The Relationship of Oral Chlorpyrifos Effects on Behavior, Cholinesterase Inhibition, and Muscarinic Receptor Density in Rat , 1997, Pharmacology Biochemistry and Behavior.

[2]  V. Moser,et al.  Tissue-specific effects of chlorpyrifos on carboxylesterase and cholinesterase activity in adult rats: an in vitro and in vivo comparison. , 1997, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[3]  C. Disteche,et al.  Paraoxonase (PON1) gene in mice: sequencing, chromosomal localization and developmental expression. , 1997, Pharmacogenetics.

[4]  S. Padilla,et al.  Automated Instrument Analysis of Cholinesterase Activity in Tissues From Carbamate-Treated Animals: A Cautionary Note , 1997 .

[5]  S. Padilla,et al.  Validation of the use of 6,6'-dithiodinicotinic acid as a chromogen in the Ellman method for cholinesterase determinations. , 1996, Veterinary and human toxicology.

[6]  E. Chautard-Freire-Maia,et al.  Butyrylcholinesterase variants (BCHE and CHE2 Loci) associated with erythrocyte acetylcholinesterase inhibition in farmers exposed to pesticides. , 1996, Human heredity.

[7]  J. Crissman,et al.  Single-dose and 13-week repeated-dose neurotoxicity screening studies of chlorpyrifos insecticide. , 1996, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[8]  M. Hooper,et al.  Maturational differences in chlorpyrifos-oxonase activity may contribute to age-related sensitivity to chlorpyrifos. , 1996, Journal of biochemical toxicology.

[9]  V. Moser.  Comparisons of the acute effects of cholinesterase inhibitors using a neurobehavioral screening battery in rats. , 1995, Neurotoxicology and teratology.

[10]  T. Slotkin,et al.  Developmental neurotoxicity of chlorpyrifos: cellular mechanisms. , 1995, Toxicology and Applied Pharmacology.

[11]  J. Chambers,et al.  Organophosphate detoxication potential of various rat tissues via A-esterase and aliesterase activities. , 1995, Toxicology letters.

[12]  W. C. Carr,et al.  Chlorpyrifos: hazard assessment based on a review of the effects of short-term and long-term exposure in animals and humans. , 1995, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[13]  R. Richardson,et al.  Assessment of the neurotoxic potential of chlorpyrifos relative to other organophosphorus compounds: a critical review of the literature. , 1995, Journal of toxicology and environmental health.

[14]  B. Yan,et al.  Regulation of two rat liver microsomal carboxylesterase isozymes: species differences, tissue distribution, and the effects of age, sex, and xenobiotic treatment of rats. , 1994, Archives of biochemistry and biophysics.

[15]  J. Chambers,et al.  Kinetic parameters of desulfuration and dearylation of parathion and chlorpyrifos by rat liver microsomes. , 1994, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[16]  C. Pope,et al.  Comparative neurochemical and neurobehavioral effects of repeated chlorpyrifos exposures in young and adult rats , 1993, Pharmacology Biochemistry and Behavior.

[17]  S. Padilla,et al.  A modified spectrophotometric method appropriate for measuring cholinesterase activity in tissue from carbaryl-treated animals. , 1993, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[18]  P. Bushnell,et al.  Behavioral and neurochemical effects of acute chlorpyrifos in rats: tolerance to prolonged inhibition of cholinesterase. , 1993, The Journal of pharmacology and experimental therapeutics.

[19]  R. Carr,et al.  Inhibition Patterns of Brain Acetylcholinesterase and Hepatic and Plasma Aliesterases Following Exposures to Three Phosphorothionate Insecticides and Their Oxons in Rats , 1993 .

[20]  K. McDaniel,et al.  Utility of a neurobehavioral screening battery for differentiating the effects of two pyrethroids, permethrin and cypermethrin. , 1993, Neurotoxicology and teratology.

[21]  Children.  Pesticides in the Diets of Infants and Children , 1993 .

[22]  D. M. Maxwell,et al.  The specificity of carboxylesterase protection against the toxicity of organophosphorus compounds. , 1992, Toxicology and applied pharmacology.

[23]  C. Pope,et al.  Long-term neurochemical and behavioral effects induced by acute chlorpyrifos treatment , 1992, Pharmacology Biochemistry and Behavior.

[24]  Janice E. Chambers,et al.  Organophosphates : chemistry, fate, and effects , 1992 .

[25]  D. M. Maxwell.  9 – Detoxication of Organophosphorus Compounds by Carboxylesterase , 1992 .

[26]  L. Costa.  14 – Role of Second-Messenger Systems In Response to Organophosphorus Compounds , 1992 .

[27]  R. Carr,et al.  Acute effects of the organophosphate paraoxon on schedule-controlled behavior and esterase activity in rats: Dose-response relationships , 1991, Pharmacology Biochemistry and Behavior.

[28]  C. Pope,et al.  Comparison of in vivo cholinesterase inhibition in neonatal and adult rats by three organophosphorothioate insecticides. , 1991, Toxicology.

[29]  G. Omenn,et al.  Serum paraoxonase and its influence on paraoxon and chlorpyrifos-oxon toxicity in rats. , 1990, Toxicology and applied pharmacology.

[30]  A. Motulsky,et al.  Spectrophotometric assays for the enzymatic hydrolysis of the active metabolites of chlorpyrifos and parathion by plasma paraoxonase/arylesterase. , 1989, Analytical biochemistry.

[31]  John P. Creason,et al.  Data Evaluation and Statistical Analysis of Functional Observational Battery Data Using a Linear Models Approach , 1989 .

[32]  L. Sultatos.  Factors affecting the hepatic biotransformation of the phosphorothioate pesticide chlorpyrifos. , 1988, Toxicology.

[33]  R C MacPhail,et al.  Comparison of chlordimeform and carbaryl using a functional observational battery. , 1988, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[34]  T B Gaines,et al.  Acute toxicity of pesticides in adult and weanling rats. , 1986, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[35]  S. D. Murphy,et al.  The role of hepatic biotransformation in mediating the acute toxicity of the phosphorothionate insecticide chlorpyrifos. , 1984, Toxicology and applied pharmacology.

[36]  L. Reiter,et al.  Acute behavioral toxicity of carbaryl and propoxur in adults rats , 1983, Pharmacology Biochemistry and Behavior.

[37]  Reiter Lw.  Chemical exposures and animal activity: utility of the figure-eight maze. , 1983 .

[38]  A. Lajtha,et al.  Turnover of protein in the nervous system. , 1981, Life sciences.

[39]  W. Dettbarn,et al.  Central cholinergic mechanisms underlying adaptation to reduced cholinesterase activity. , 1977, Biochemical pharmacology.

[40]  R. Harbison.  Comparative toxicity of some selected pesticides in neonatal and adult rats. , 1975, Toxicology and applied pharmacology.

[41]  R. L. Russell,et al.  A rapid, simple radiometric assay for cholinesterase, suitable for multiple determinations. , 1975, Analytical biochemistry.

[42]  S. D. Murphy,et al.  The influence of age on the toxicity and metabolism of methyl parathion and parathion in male and female rats. , 1975, Toxicology and applied pharmacology.

[43]  N. Rosić,et al.  Behavioral Toxicity of Anticholinesterase Agents: Methodological, Neurochemical, and Neuropsychological Aspects , 1975 .

[44]  S. Snyder,et al.  Muscarinic cholinergic binding in rat brain. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[45]  D. D. McCollister,et al.  Studies on the acute and long-term oral toxicity fo chlorpyrifos (0,0-diethyl-0(3,5,6-trichloro-2-pyridyl) phosphorothioate). , 1974, Food and cosmetics toxicology.

[46]  L. Reiter,et al.  Acute and subacute parathion treatment: effects on cholinesterase activities and learning in mice. , 1973, Toxicology and applied pharmacology.

[47]  E. Goldenthal,et al.  A compilation of LD50 values in newborn and adult animals. , 1971, Toxicology and applied pharmacology.

[48]  T B Gaines,et al.  Acute toxicity of pesticides. , 1969, Toxicology and applied pharmacology.

[49]  J. Brodeur,et al.  Studies on factors influencing the acute toxicity of malathion and malaoxon in rats. , 1967, Canadian journal of physiology and pharmacology.

[50]  F. Lu,et al.  Toxicity of pesticides in young versus adult rats. , 1965, Food and cosmetics toxicology.

[51]  J. Brodeur,et al.  Comparison of Acute Toxicity of Anticholinesterase Insecticides to Weanling and Adult Male Rats.∗ , 1963 .

[52]  Thomas B. Gaines,et al.  The acute toxicity of pesticides to rats , 1960 .

[53]  S. D. Murphy,et al.  The influence of various factors on the enzymatic conversion of organic thiophosphates to anticholinesterase agents. , 1958, The Journal of pharmacology and experimental therapeutics.