Curt Lunchick

Bayesian Calibration of a Physiologically Based Pharmacokinetic/Pharmacodynamic Model of Carbaryl Cholinesterase Inhibition

Carbaryl, an N-methyl carbamate (NMC), is a common insecticide that reversibly inhibits neuronal cholinesterase activity. The objective of this work was to use a hierarchical Bayesian approach to estimate the parameters in a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model from experimental measurements of carbaryl in rats. A PBPK/PD model was developed to describe the tissue dosimetry of carbaryl and its metabolites (1-naphthol and “other hydroxylated metabolites”) and subsequently to predict the carbaryl-induced inhibition of cholinesterase activity, in particular in the brain and blood. In support of the model parameterization, kinetic tracer studies were undertaken to determine total radioactive tissue levels of carbaryl and metabolites in rats exposed by oral or intravenous routes at doses ranging from 0.8 to 9.2 mg/kg body weight. Inhibition of cholinesterase activity in blood and brain was also measured from the exposed rats. Markov Chain Monte Carlo (MCMC) calibration of the rat model parameters was implemented using prior information from literature for physiological parameter distributions together with kinetic and inhibition data on carbaryl. The posterior estimates of the parameters displayed at most a twofold deviation from the mean. Monte Carlo simulations of the PBPK/PD model with the posterior distribution estimates predicted a 95% credible interval of tissue doses for carbaryl and 1-naphthol within the range of observed data. Similar prediction results were achieved for cholinesterase inhibition by carbaryl. This initial model will be used to determine the experimental studies that may provide the highest added value for model refinement. The Bayesian PBPK/PD modeling approach developed here will serve as a prototype for developing mechanism-based risk models for the other NMCs.

Comparative evaluation of absorbed dose estimates derived from passive dosimetry measurements to those derived from biological monitoring: validation of exposure monitoring methodologies.

Passive dosimetry (PD) methods for measuring and estimating exposure to agricultural workers (i.e., persons handling agricultural chemicals and working in treated crops) have been in use since the 1950s. A large number of studies were conducted in the 1950s through 1970s to characterize exposure. Since the 1980s quantitative dermal PD methods are used in conjunction with inhalation PD methods to measure whole-body exposure. These exposure or absorbed dose estimates are then compared to “no effect” exposure levels for hazards identified in toxicology studies, and have become the standard for risk assessment for regulatory agencies. The PD methods used have never been validated. Validation in the context of human exposure monitoring methods means that a method has been shown to measure accurately a delivered dose in humans. The most practical alternative to isolating parts of the body for validating recovery methods is to utilize field exposure studies in which concurrent or consecutive measurements of exposure and absorbed dose have been made with PD and biomonitoring in the same cohorts of individuals. This ensures that a direct comparison can be made between the two estimates of absorbed dose, one derived from PD and the other from biomonitoring. There are several studies available (published and proprietary) employing both of these approaches. Reports involving 14 concurrent or consecutive PD-biomonitoring studies were quantitatively evaluated with 18 different methods of application or reentry scenarios for eight different active ingredients for which measured human kinetics and dermal absorption data existed. This evaluation demonstrated that the total absorbed dose estimated using PD for important handler and reentry scenarios is generally similar to the measurements for those same scenarios made using human urinary biomonitoring methods. The statistical analysis of individual worker PD:biomonitoring ratios showed them to be significantly correlated in these studies. The PD techniques currently employed yield a reproducible, standard methodology that is valid and reliably quantifies exposure.

Comparison of four probabilistic models (CARES ® , Calendex™, ConsExpo, and SHEDS) to estimate aggregate residential exposures to pesticides

Two deterministic models (US EPAs Office of Pesticide Programs Residential Standard Operating Procedures (OPP Residential SOPs) and Draft Protocol for Measuring Childrens Non-Occupational Exposure to Pesticides by all Relevant Pathways (Draft Protocol)) and four probabilistic models (CARES®, Calendex™, ConsExpo, and SHEDS) were used to estimate aggregate residential exposures to pesticides. The route-specific exposure estimates for young children (2–5 years) generated by each model were compared to evaluate data inputs, algorithms, and underlying assumptions. Three indoor exposure scenarios were considered: crack and crevice, fogger, and flying insect killer. Dermal exposure estimates from the OPP Residential SOPs and the Draft Protocol were 4.75 and 2.37 mg/kg/day (crack and crevice scenario) and 0.73 and 0.36 mg/kg/day (fogger), respectively. The dermal exposure estimates (99th percentile) for the crack and crevice scenario were 16.52, 12.82, 3.57, and 3.30 mg/kg/day for CARES, Calendex, SHEDS, and ConsExpo, respectively. Dermal exposure estimates for the fogger scenario from CARES and Calendex (1.50 and 1.47 mg/kg/day, respectively) were slightly higher than those from SHEDS and ConsExpo (0.74 and 0.55 mg/kg/day, respectively). The ConsExpo derived non-dietary ingestion estimates (99th percentile) under these two scenarios were higher than those from SHEDS, CARES, and Calendex. All models produced extremely low exposure estimates for the flying insect killer scenario. Using similar data inputs, the model estimates by route for these scenarios were consistent and comparable. Most of the models predicted exposures within a factor of 5 at the 50th and 99th percentiles. The differences identified are explained by activity assumptions, input distributions, and exposure algorithms.

Chapter 74 – Toxicological Profile of Carbaryl

Publisher Summary Carbaryl is a broad-spectrum insecticide widely used in agriculture, professional turf management, ornamental production, and residential settings and it is sold under many trade names, but the most common one is Sevin. It belongs to the N-methyl carbamate chemical family, which act via inhibition of acetylcholinesterase. The pure (technical) material is a white to light tan solid with a water solubility of approximately 40 ppm at 25 °C. Carbaryl has a very robust toxicity database including acute, chronic, developmental, reproductive, and neurotoxicity studies. It is moderately toxic by the oral route and exhibits a low level of toxicity following dermal or inhalation exposures. In animal studies following single and repeated dosing, the carbamylation of ChE is reversible, and at oral exposures of 50 mg/kg or less, enzyme activity is similar to baseline values within 24 h after exposure. In neurotoxicity testing, the most sensitive endpoints were observations in the FOB, reduced motor activity, and ChEI in RBC and brain. The severity and frequency of clinical signs and ChEI were dose related and decreased with time. Two-year studies with carbaryl administered via the diet have been conducted in rats and mice. In both of these studies, the highest dose tested exceeded the maximum tolerated dose (MTD), and thus, the findings described in the following sections for these high dietary exposures cannot be considered relevant for the assessment of hazard or risk.

CHAPTER 20 – Occupational Exposure Data Bases/Models for Pesticides

The requirement to quantify worker exposures to active ingredients during use of pesticide formulations is an integral part of risk assessments associated with the pesticide registration process in several countries. Because the evaluation of risk requires knowledge of both exposure and toxicity, exposures to the active ingredient associated with a given pesticide formulation must be assessed. This chapter provides a summary of the most commonly used worker exposure databases and models for mixing/loading and application of pesticides. A tiered approach is often taken to estimate exposures. The first tier (tier I) of the risk assessment process for worker exposures to pesticides can involve the use of generic exposure data from databases such as the Pesticide Handlers Exposure Database (PHED) developed and used in North America, the Predictive Operator Exposure Database (POEM) developed in the United Kingdom, and EUROPOEM used within the European Union. If an unacceptable risk is obtained with a tier I assessment, it may be necessary to proceed with a more refined exposure assessment or to collect formulation-specific exposure data (tier II). Tier II typically involves collection of external dosimetry data for workers on the formulation of interest, for specific use patterns of interest, thus circumventing the need to use surrogate monitoring data (for example, from PHED or POEM) because compound-specific exposure data are collected.

Operator and Field Worker Occupational Exposure Databases and Modeling

Publisher Summary This chapter provides a summary of the most commonly used worker exposure databases and models for mixing/loading and application of pesticides. The development of a new generic database for field worker exposures during re-entry activities following application is also presented. An overview of the databases currently being used to make regulatory decisions and the transition to new models both in North America and Europe is also presented. A discussion on the models and databases developed to predict exposure to re-entry workers is also covered. The development of PHED in North America and UK-POEM and the German model within the European Union has provided powerful predictive tools for estimating worker exposure for specific pesticide use scenarios. Detailed knowledge of the workings of the database and models, appropriate selection of pesticide use information, and familiarity with the features and limitations of pesticide worker exposure studies are critical to their effective use. The development of a worker re-entry exposure database provides an important predictive tool for selected worker activity/crop combinations and, thus, fills an important gap for exposure assessors. Use of these widely available tools will continue to provide guidance to regulatory agencies and the agrochemical industry in regulation, product development, and product stewardship. The risk assessment process enables regulatory agencies and the agrochemical industry to predict the extent of risk of adverse human health effects associated with the use of a given pesticide under specific use conditions. Because the evaluation of risk requires knowledge of both exposure and toxicity, exposures to the active ingredient associated with a given pesticide formulation must be assessed.