Use of benchmark dose and meta-analysis to determine the most sensitive endpoint for risk assessment for dimethoate

Abstract

A meta-analysis of several rat toxicity studies for dimethoate was conducted to determine the most sensitive endpoint for use in risk assessment. The analysis was motivated by a recent developmental neurotoxicity (DNT) study, which identified the same no observed adverse effect level (NOAEL) for pup mortality and cholinesterase inhibition. The pup mortality NOAEL was lower than that determined in a range-finding study for the DNT and other reproduction studies, and was highly influenced by a single total litter loss in the middle dose group, which made interpretation difficult. First, a meta-analysis was conducted of four recent studies by gavage dosing with very similar designs, including the DNT. Benchmark dose (BMD) modeling was used to determine the appropriate point of departure for regulatory purposes, the lower limit of the BMD for a 5% incidence for pup mortality (BMDL 5) and the lower limit of a 10% inhibition of brain cholinesterase ( BMDL 10 ∗ ) , the asterisk denotes that the BMD is based on continuous response variable as opposed to an incidence level. For pup mortality, the BMDL 5 for post-natal days (PND) 1–4 was 0.64 mg/kg/day. For cholinesterase inhibition, the lowest BMDL 10 ∗ was 0.19 mg/kg/day for the dams at gestation day 20. These results show that the regulatory point-of-departure for cholinesterase inhibition is more than threefold lower than pup mortality. Thus, risk assessments protecting against cholinesterase inhibition are likely to also be protective of pup mortality. In addition, cholinesterase inhibition and pup mortality were evaluated in two 2-generation reproduction studies by dietary exposure. Also, cholinesterase inhibition was evaluated in a 28-day dietary study. Dietary exposure is more relevant than gavage exposures for many human risk assessment scenarios. There was no consistent pup mortality at the highest doses of the two 2-generation dietary studies (6.0 and 6.5 mg/kg/day). The average BMD 10s for brain cholinesterase inhibition for the 2-generation studies was 0.65 mg/kg/day, with a range of 0.49–0.96 mg/kg/day. This suggests that cholinesterase inhibition is at least a 10-fold more sensitive endpoint than pup mortality for dietary exposures. For the 28-day dietary study, the BMD 10 for brain cholinesterase inhibition was 1.1 mg/kg/day for males and 0.70 mg/kg/day for females. The exposure duration in the 28-day dietary study is closest to the durations in the gavage studies. Compared to the dams in the gavage studies, which had a BMDL 10 of 0.19 mg/kg/day, the animals were more than threefold more sensitive to cholinesterase inhibition by gavage compared to dietary exposure.