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.

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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.