Impact of chemical proportions on the acute neurotoxicity of a mixture of seven carbamates in preweanling and adult rats.
Statistical design and environmental relevance are important aspects of studies of chemical mixtures, such as pesticides. We used a dose-additivity model to test experimentally the default assumptions of dose additivity for two mixtures of seven N-methylcarbamates (carbaryl, carbofuran, formetanate, methomyl, methiocarb, oxamyl, and propoxur). The best-fitting models were selected for the single-chemical dose-response data and used to develop a combined prediction model, which was then compared with the experimental mixture data. We evaluated behavioral (motor activity) and cholinesterase (ChE)-inhibitory (brain, red blood cells) outcomes at the time of peak acute effects following oral gavage in adult and preweanling (17 days old) Long-Evans male rats. The mixtures varied only in their mixing ratios. In the relative potency mixture, proportions of each carbamate were set at equitoxic component doses. A California environmental mixture was based on the 2005 sales of each carbamate in California. In adult rats, the relative potency mixture showed dose additivity for red blood cell ChE and motor activity, and brain ChE inhibition showed a modest greater-than additive (synergistic) response, but only at a middle dose. In rat pups, the relative potency mixture was either dose-additive (brain ChE inhibition, motor activity) or slightly less-than additive (red blood cell ChE inhibition). On the other hand, at both ages, the environmental mixture showed greater-than additive responses on all three endpoints, with significant deviations from predicted at most to all doses tested. Thus, we observed different interactive properties for different mixing ratios of these chemicals. These approaches for studying pesticide mixtures can improve evaluations of potential toxicity under varying experimental conditions that may mimic human exposures.
Toxicity Assessment Division, US EPA, Research Triangle Park, North Carolina 27711, USA. Moser.ginger@epa.gov
Virginia C
VC
Moser
Stephanie
S
Padilla
Jane Ellen
JE
Simmons
Lynne T
LT
Haber
Richard C
RC
Hertzberg
D000375:Aging; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002219:Carbamates / Q000737:chemistry / Q000633:toxicity*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000633:toxicity*; D002802:Cholinesterases / Q000097:blood / Q000378:metabolism; D045424:Complex Mixtures; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D020318:Rats, Long-Evans
D002219:Carbamates; D002800:Cholinesterase Inhibitors; D045424:Complex Mixtures; D002802:Cholinesterases