title: Thermoregulatory response to an organophosphate and carbamate insecticide mixture: testing the assumption of dose-additivity.
abstract: Most toxicity data are based on studies using single compounds. This study assessed if there is an interaction between mixtures of the anticholinesterase insecticides chlorpyrifos (CHP) and carbaryl (CAR) using hypothermia and cholinesterase (ChE) inhibition as toxicological endpoints. Core temperature (T(c)) was continuously monitored by radiotelemetry in adult Long-Evans rats administered CHP at doses ranging from 0 to 50mg/kg and CAR doses of 0-150 mg/kg. The temperature index (TI), an integration of the change in T(c) over a 12h period, was quantified. Effects of mixtures of CHP and CAR in 2:1 and 1:1 ratios on the TI were examined and the data analyzed using a statistical model designed to assess significant departures from additivity for chemical mixtures. CHP and CAR elicited a marked hypothermia and dose-related decrease in the TI. The TI response to a 2:1 ratio of CHP:CAR was significantly less than that predicted by additivity. The TI response to a 1:1 ratio of CHP and CAR was not significantly different from the predicted additivity. Plasma and brain ChE activity were measured 4h after dosing with CHP, CAR, and mixtures in separate groups of rats. There was a dose-additive interaction for the inhibition of brain ChE for the 2:1 ratio, but an antagonistic effect for the 1:1 ratio. The 2:1 and 1:1 mixtures had an antagonistic interaction on plasma ChE. Overall, the departures from additivity for the physiological (i.e., temperature) and biochemical (i.e., ChE inhibition) endpoints for the 2:1 and 1:1 mixtures studies did not coincide as expected. An interaction between CHP and CAR appears to depend on the ratio of compounds in the mixture as well as the biological endpoint.
authors.affiliation: Neurotoxicology Division, National Health and Environmental Effects Research Laboratory, B105-04, U.S. Environmental Protection Agency, 109 S.T.W. Alexander Drive, Research Triangle Park, NC 27711, USA. gordon.christopher@epa.gov
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Gordon
authors.forename: David W
authors.initials: DW
authors.lastname: Herr
authors.forename: Chris
authors.initials: C
authors.lastname: Gennings
authors.forename: Jaimie E
authors.initials: JE
authors.lastname: Graff
authors.forename: Matthew
authors.initials: M
authors.lastname: McMurray
authors.forename: LeAnna
authors.initials: L
authors.lastname: Stork
authors.forename: Todd
authors.initials: T
authors.lastname: Coffey
authors.forename: Adam
authors.initials: A
authors.lastname: Hamm
authors.forename: Cina M
authors.initials: CM
authors.lastname: Mack
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001833:Body Temperature Regulation / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D012721:Carbaryl / Q000008:administration & dosage / Q000633:toxicity*; D004390:Chlorpyrifos / Q000008:administration & dosage / Q000633:toxicity; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000633:toxicity; D002802:Cholinesterases / Q000378:metabolism; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D007306:Insecticides / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D008409:Mastication / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018908:Muscle Weakness / Q000139:chemically induced; D010755:Organophosphates / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D012798:Sialorrhea / Q000139:chemically induced; D013666:Tears / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
chemical_list: D002800:Cholinesterase Inhibitors; D007306:Insecticides; D010755:Organophosphates; D002802:Cholinesterases; D004390:Chlorpyrifos; D012721:Carbaryl