Comparison of aldicarb and methamidophos neurotoxicity at different ages in the rat: behavioral and biochemical parameters.
Young organisms are often more sensitive to the toxic effects of pesticides, and this finding has spurred research on further characterization of this susceptibility. The neurotoxic effects of cholinesterase (ChE)-inhibiting pesticides are of particular concern for human health risk assessment due to the widespread exposure potential in children. This study evaluated age-related differences in susceptibility for a carbamate (aldicarb) and an organophosphorus pesticide (methamidophos). Comparisons were made between preweanling (Postnatal Day 17, PND17), postweanling (PND27), and adult (approximately PND70) male and female rats. All were acute studies using oral administration. Sensitivity was quantified by (1) determination of maximally-tolerated doses (MTDs); (2) measurement of brain and blood ChE inhibition; and (3) neurobehavioral evaluation using end points known to be sensitive indicators of exposure to anticholinesterases. MTD data showed that preweanling rats were twice as sensitive as adults to aldicarb, but there was no differential sensitivity to methamidophos. The dose-response data for brain ChE inhibition followed a similar pattern of age-related differences, and similar levels of inhibition were measured at the MTD regardless of age. Dose-response and time course studies of neurobehavioral end points indicated that differential effects due to age depend on the behavioral end point examined. Following aldicarb administration, the dose-response curves for a few end points overlapped; however, the young rats otherwise showed fewer signs of toxicity than did the adults despite similar levels of brain ChE inhibition. Motor activity assessment showed that aldicarb did not produce any activity depression in PND17 rats, whereas the data for the PND27 and adult rats overlapped. With methamidophos, the dose-response curves for most end points for preweanling and adult rats were quite similar. Aldicarb-induced ChE inhibition was readily reversible in all age groups, whereas with methamidophos, enzyme activity recovered more rapidly in the young. Most behavioral alterations had recovered by 24 h with either pesticide. The results of these studies indicate that (1) ChE-inhibiting pesticides are not all the same regarding relative sensitivity of the young; (2) age-related differences were reflected in both the MTDs and degree of ChE inhibition; and (3) age-related differences in neurobehavioral measures depended on the pesticide and on the end points examined.
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National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711, USA.
D000375:Aging; D000448:Aldicarb / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001522:Behavior, Animal / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D002802:Cholinesterases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005684:Gait / Q000187:drug effects; D007306:Insecticides / Q000633:toxicity*; D007928:Lethal Dose 50; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009420:Nervous System / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D013997:Time Factors; D014202:Tremor / Q000139:chemically induced
D002800:Cholinesterase Inhibitors; D007306:Insecticides; D009946:Organothiophosphorus Compounds; D000448:Aldicarb; C014655:methamidophos; D002802:Cholinesterases