A physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) model for the insecticide dimethoate.

1. Dimethoate is an organophosphate insecticide that is converted in vivo to omethoate, the active toxic moiety. Omethoate inhibits acetylcholinesterase (AChE) in the brain and red blood cells (RBCs). This paper describes the development of rat and human physiologically-based pharmacokinetic/pharmacodynamic (PBPK/PD) models for dimethoate.2. The model simulates the absorption and distribution of dimethoate and omethoate, the conversion of dimethoate to omethoate and to other metabolites, the metabolism and excretion of omethoate, and the inhibition of RBC and brain AChE. An extensive data collection program to estimate metabolism and inhibition parameters is described.3. The suite of models includes an adult rat, post-natal rat, and human model. The rat models were evaluated by comparing model predictions of dimethoate and omethoate to measured blood time course data, and with RBC and brain AChE inhibition estimates from an extensive database of in vivo AChE measurements.4. After the demonstration of adequately fitted rat models that were robust to sensitivity analysis, the human model was applied for estimation of points-of-departure (PODs) for risk assessment using the human-specific parameters in the human PBPK/PD model. Thus, the standard interspecies uncertainty factor can be reduced from 10X to 1X.

Determination of enzymatic kinetics of metabolism of dimethoate and omethoate in rats and humans.

1. Dimethoate is an organophosphate insecticide. The objective of this work was to determine the enzymatic kinetics of metabolism of dimethoate and its active metabolite omethoate in rats and humans and obtain key input parameters for physiologically based pharmacokinetic (PBPK) model.2. First, the intrinsic clearance of dimethoate expressed as formation rate of omethoate was determined to be ∼42-fold lower in human liver microsomes (HLM) (0.39 µL/min/mg) than in rat liver microsomes (RLM) (16.6 µL/min/mg) by an LC/MS/MS method. Next, dimethoate clearance in liver microsomes was determined using parent depletion and total [14C]-metabolite formation methods. Results from both approaches showed slower clearance of dimethoate in HLM (1.1-3.3 µL/min/mg) than in RLM (12.7-17.4 µL/min/mg).3. Investigation of in vitro enzymatic kinetics of omethoate demonstrated that the intrinsic clearance rates for omethoate in adult and juvenile RLM and HLM were similar. No significant turnover of dimethoate was apparent in rat cytosol or plasma. In contrast, degradation of omethoate in human plasma was slightly higher than in rat plasma.4. Finally, toxicokinetics of dimethoate were determined in adult and juvenile rats. In both age groups, following oral dosing, absorption of dimethoate was rapid with formation of significant amounts of omethoate.

Evaluation of Watershed-Scale Simulations of In-Stream Pesticide Concentrations from Off-Target Spray Drift.

The estimation of pesticide concentrations in surface water bodies is a critical component of the environmental risk assessment process required by regulatory agencies in North America, the European Union, and elsewhere. Pesticide transport to surface waters via deposition from off-field spray drift can be an important route of potential contamination. The spatial orientation of treated fields relative to receiving water bodies make prediction of off-target pesticide spray drift deposition and resulting aquatic estimated environmental concentrations (EECs) challenging at the watershed scale. The variability in wind conditions further complicates the simulation of the environmental processes leading to pesticide spray drift contributions to surface water. This study investigates the use of the Soil Water Assessment Tool (SWAT) for predicting concentrations of malathion (O,O-deimethyl thiophosphate of diethyl mercaptosuccinate) in a flowing water body when exposure is a result of off-target spray drift, and assesses the model's performance using a parameterization typical of a screening-level regulatory assessment. Six SWAT parameterizations, each including incrementally more site-specific data, are then evaluated to quantify changes in model performance. Results indicate that the SWAT model is an appropriate tool for simulating watershed scale concentrations of pesticides resulting from off-target spray drift deposition. The model predictions are significantly more accurate when the inputs and assumptions accurately reflect application practices and environmental conditions. Inclusion of detailed wind data had the most significant impact on improving model-predicted EECs in comparison to observed concentrations.

Evaluation of an acute oral gavage method for assessment of pesticide toxicity in terrestrial amphibians.

Development of an acute oral toxicity test with a terrestrial-phase amphibian was considered necessary to remove the uncertainty within the field of agrochemical risk assessments. The bullfrog (Lithobates catesbeianus) was selected for use as it is a representative of the family Ranidae and historically this species has been used as an amphibian test model species. Prior to definitive study, oral gavage methods were developed with fenthion and tetraethyl pyrophosphate. Dimethoate and malathion were subsequently tested with both male and female juvenile bullfrogs in comprehensive acute oral median lethal dose (LD50) studies. Juvenile bullfrogs were administered a single dose of the test article via oral gavage of a single gelatin capsule of dimethoate technical (dimethoate) or neat liquid Fyfanon® Technical (synonym malathion), returned to their respective aquaria, and monitored for survival for 14 d. The primary endpoint was mortality, whereas behavioral responses, food consumption, body weight, and snout-vent length (SVL) were used to evaluate indications of sublethal toxicity (secondary endpoints). Acute oral LD50 values (95% fiducial interval) for dimethoate were 1459 (1176-1810, males) and 1528 (1275-1831, females), and for malathion they were 1829 (1480-2259, males) and 1672 (1280-2183, females) mg active substance/kg body weight, respectively. Based on the results of these studies, the methodology for the acute oral gavage administration of test items to terrestrial-phase amphibians was demonstrated as being a practical method of providing data for risk assessments. Environ Toxicol Chem 2018;37:436-450. © 2017 SETAC.

A refined ecological risk assessment for California red-legged frog, Delta smelt, and California tiger salamander exposed to malathion.

The California red-legged frog (CRLF), Delta smelt (DS), and California tiger salamander (CTS) are 3 species listed under the United States Federal Endangered Species Act (ESA), all of which inhabit aquatic ecosystems in California. The US Environmental Protection Agency (USEPA) has conducted deterministic screening-level risk assessments for these species potentially exposed to malathion, an organophosphorus insecticide and acaricide. Results from our screening-level analyses identified potential risk of direct effects to DS as well as indirect effects to all 3 species via reduction in prey. Accordingly, for those species and scenarios in which risk was identified at the screening level, we conducted a refined probabilistic risk assessment for CRLF, DS, and CTS. The refined ecological risk assessment (ERA) was conducted using best available data and approaches, as recommended by the 2013 National Research Council (NRC) report "Assessing Risks to Endangered and Threatened Species from Pesticides." Refined aquatic exposure models including the Pesticide Root Zone Model (PRZM), the Vegetative Filter Strip Modeling System (VFSMOD), the Variable Volume Water Model (VVWM), the Exposure Analysis Modeling System (EXAMS), and the Soil and Water Assessment Tool (SWAT) were used to generate estimated exposure concentrations (EECs) for malathion based on worst-case scenarios in California. Refined effects analyses involved developing concentration-response curves for fish and species sensitivity distributions (SSDs) for fish and aquatic invertebrates. Quantitative risk curves, field and mesocosm studies, surface-water monitoring data, and incident reports were considered in a weight-of-evidence approach. Currently, labeled uses of malathion are not expected to result in direct effects to CRLF, DS or CTS, or indirect effects due to effects on fish and invertebrate prey. Integr Environ Assess Manag 2018;14:224-239. © 2017 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC).

Ecological risk assessment for Pacific salmon exposed to dimethoate in California.

A probabilistic risk assessment of the potential direct and indirect effects of acute dimethoate exposure to salmon populations of concern was conducted for 3 evolutionarily significant units (ESUs) of Pacific salmon in California. These ESUs were the Sacramento River winter-run chinook, the California Central Valley spring-run chinook, and the California Central Valley steelhead. Refined acute exposures were estimated using the Soil and Water Assessment Tool, a river basin-scale model developed to quantify the impact of land-management practices in large, complex watersheds. Both direct effects (i.e., inhibition of brain acetylcholinesterase activity) and indirect effects (i.e., altered availability of aquatic invertebrate prey) were assessed. Risk to salmon and their aquatic invertebrate prey items was determined to be de minimis. Therefore, dimethoate is not expected to have direct or indirect adverse effects on Pacific salmon in these 3 ESUs. Environ Toxicol Chem 2017;36:532-543. © 2016 SETAC.