Analysis and integration of developmental neurotoxicity and ancillary data into risk assessment: a case study of dimethoate.
Dimethoate is an organophosphate (OP) pesticide used to control a wide variety of insects on agricultural crops and ornamentals. To ensure that dimethoate is used safely, it is important to determine exposure levels that protect against adverse effects at all life stages, including the developing fetus, infant, and child. Based on an analysis of a developmental neurotoxicity (DNT) study, a cholinesterase (ChE) sensitivity study, a cross-fostering study, and several single- and multigenerational reproductive toxicity studies, two potential critical endpoints for dimethoate were identified: brain ChE inhibition (ChEI) in adult females, and pup mortality. An initial evaluation concluded that pup mortality was a preferable endpoint, based on an increased number of pup deaths born to dams dosed with > or =3 mg/kg dimethoate via oral gavage. Closer examination, however, revealed that the pup deaths were clustered in a small number of litters in which the dams providing postnatal care exhibited maternal care deficits. When the data were analyzed using the dam as the unit of statistical significance, a significant increase in the average litter proportion of pup deaths was observed only when the dams were dosed postnatally with 6 mg/kg dimethoate while they were raising the pups. Gestational exposure (i.e., during pregnancy only) to 6 mg/kg dimethoate exerted no effect on pup survival. This leads to the conclusion that it is postnatal exposure of the nursing dams that is associated with pup mortality. Furthermore, a previous benchmark dose (BMD) meta-analysis approach revealed that BMDL(10) for adult females (the lower 95% bound of the dose resulting in a 10% reduction in the parameter of interest) for ChEI was > 3-fold lower than the BMDL(10) for pup mortality (0.19 and 0.68 mg/kg, respectively). Overall, this study underscores the importance of using the dam as the unit of statistical significance when assessing data collected in the perinatal period, and it is concluded that adult brain ChEI is the correct critical endpoint for assessing risk of dimethoate toxicity.
DeSesso
John M
JM
Noblis, Falls Church, Virginia 22042, USA. jdesesso@noblis.org
Watson
Rebecca E
RE
Keen
Carl L
CL
Hazelden
Keith P
KP
Haws
Laurie C
LC
Li
Abby A
AA
D000818:Animals; D000831:Animals, Newborn; D002800:Cholinesterase Inhibitors / Q000032:analysis / Q000633:toxicity*; D004117:Dimethoate / Q000008:administration & dosage / Q000633:toxicity*; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D007441:Intubation, Gastrointestinal; D008098:Litter Size; D020258:Neurotoxicity Syndromes / Q000209:etiology* / Q000401:mortality; D019055:No-Observed-Adverse-Effect Level; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D012098:Reproduction / Q000187:drug effects; D018570:Risk Assessment; D013997:Time Factors
D002800:Cholinesterase Inhibitors; D004117:Dimethoate