Toxicokinetic and toxicodynamic studies of carbaryl alone or in binary mixtures with azinphos methyl in the freshwater gastropod Planorbarius corneus.

Carbamate insecticides such as carbaryl and organophosphates such as azinphos-methyl share the ability to inhibit the activity of B-esterases. This study aimed to (1) assess the inhibitory effects of carbaryl on B-esterase activity in soft tissues and hemolymph of Planorbarius corneus; (2) establish whether binary mixtures of carbaryl and azinphos-methyl depart or not from a model of concentration addition on the inhibition of cholinesterase activity; (3) determine the bioconcentration and elimination of the pesticides. The results showed that exposure of gastropods to increasing concentrations of carbaryl (0.1-5 mg L-1) for 48 h inhibited cholinesterase activity in a concentration-dependent manner, with an EC50 of 1.4 ±â€¯0.3 mg L-1 and 1.2 ±â€¯0.1 mg L-1 for soft tissue and hemolymph, respectively. Carboxylesterase activity, measured with the substrates p-nitrophenyl butyrate and p-nitrophenyl acetate, was between 2.3 and 25 times more sensitive to carbaryl inhibition than cholinesterase activity. Binary mixtures corresponding to 0.5 EC50 carbaryl + 0.5 EC50 azinphos-methyl and 0.75 EC50 carbaryl + 0.75 EC50 azinphos-methyl produced inhibitions of cholinesterase activity similar to those of individual pesticides, following a model of concentration addition. Bioconcentration was analyzed using a one-compartment model. The absorption kinetics (k1) for both pesticides alone (1.4 mg L-1 of carbaryl or 1.8 mg L-1 of azinphos-methyl) or mixed (1.4 mg L-1 of carbaryl + 1.8 mg L-1 of azinphos-methyl) were similar. The elimination kinetics ratio (k2) estimated for the pesticides alone or in the mixtures showed that carbaryl was eliminated 3.5 times faster than azinphos-methyl. These results suggest that exposure of Planorbarius corneus to binary mixtures of carbaryl and azinphos-methyl for 48 h follow a concentration addition model on inhibition of cholinesterase activity and that the pesticide mixtures do not change the toxicokinetic parameters of the parent compounds.

Comparison of Lindane and Carbaryl Pesticide Bioaccumulation in the Common Sole (Solea solea).

Organochlorines and carbamates are common pesticides predominantly employed in agriculture. Large amounts of pesticides make their way into rivers and marine habitats. They accumulate in aquatic organisms through different exposure routes and gradually move up the food chain. Since contaminant bioaccumulation in animals is affected by several factors, this work harnessed several different approaches to explore the persistence of lindane, a long banned organochlorine pesticide, and carbaryl, a newer generation pesticide, in common sole (Solea solea), a major commercial species in Adriatic fisheries. Lindane was not only more accumulated than carbaryl in sole liver, but it was also detected in greater amount in muscle tissue, the edible part (lindane, 7 ± 4 ng/g; carbaryl, <0.004 ng/g w/w). Additional assays documented a greater accumulation of lindane in adults compared with juveniles and in specimens caught offshore than in those collected close to the coast. The present findings demonstrate the different accumulation dynamics of the two pesticides to confirm the benefits derived from the replacement of organochlorine pesticides with carbamate compounds.

In vitro metabolism of methiocarb and carbaryl in rats, and its effect on their estrogenic and antiandrogenic activities.

In this work, we examined the metabolism of the carbamate insecticides methiocarb and carbaryl by rat liver microsomes and plasma, and its effect on their endocrine-disrupting activities. Methiocarb and carbaryl were not enzymatically hydrolyzed by rat liver microsomes, but were hydrolyzed by rat plasma, mainly to methylthio-3,5-xylenol (MX) and 1-naphthol, respectively. When methiocarb was incubated with rat liver microsomes in the presence of NADPH, methiocarb sulfoxide was formed. The hydrolysis product, MX, was also oxidized to the sulfoxide, 3,5-dimethyl-4-(methylsulfinyl)phenol (SP), by rat liver microsomes in the presence of NADPH. These oxidase activities were catalyzed by cytochrome P450 and flavin-containing monooxygenase. Methiocarb and carbaryl both exhibited estrogen receptor α (ERα) and ERß agonistic activity. MX and 1-naphthol showed similar activities, but methiocarb sulfoxide and SP showed markedly decreased activities. On the other hand, methiocarb and carbaryl exhibited potent antiandrogenic activity in the concentration range of 1×10(-6)-3×10(-5) M. Their hydrolysis products, MX, and 1-naphthol also showed high activity, equivalent to that of flutamide. However, methiocarb sulfoxide and SP showed relatively low activity. Thus, hydrolysis of methiocarb and carbaryl and oxidation of methiocarb to the sulfoxide markedly modified the estrogenic and antiandrogenic activities of methiocarb and carbaryl.

Reconstructing exposures from biomarkers using exposure-pharmacokinetic modeling--A case study with carbaryl.

Sources of uncertainty involved in exposure reconstruction for short half-life chemicals were characterized using computational models that link external exposures to biomarkers. Using carbaryl as an example, an exposure model, the Cumulative and Aggregate Risk Evaluation System (CARES), was used to generate time-concentration profiles for 500 virtual individuals exposed to carbaryl. These exposure profiles were used as inputs into a physiologically based pharmacokinetic (PBPK) model to predict urinary biomarker concentrations. These matching dietary intake levels and biomarker concentrations were used to (1) compare three reverse dosimetry approaches based on their ability to predict the central tendency of the intake dose distribution; and (2) identify parameters necessary for a more accurate exposure reconstruction. This study illustrates the trade-offs between using non-iterative reverse dosimetry methods that are fast, less precise and iterative methods that are slow, more precise. This study also intimates the necessity of including urine flow rate and elapsed time between last dose and urine sampling as part of the biomarker sampling collection for better interpretation of urinary biomarker data of short biological half-life chemicals. Resolution of these critical data gaps can allow exposure reconstruction methods to better predict population-level intake doses from large biomonitoring studies.

Use of in vitro data in developing a physiologically based pharmacokinetic model: Carbaryl as a case study.

In vitro-derived information has been increasingly used to support and improve human health risk assessment for exposure to chemicals. Physiologically based pharmacokinetic (PBPK) modeling is a key component in the movement toward in vitro-based risk assessment, providing a tool to integrate diverse experimental data and mechanistic information to relate in vitro effective concentrations to equivalent human exposures. One of the challenges, however, in the use of PBPK models for this purpose has been the need for extensive chemical-specific parameters. With the remarkable advances in in vitro methodologies in recent years, in vitro-derived parameters can now be easily incorporated into PBPK models. In this study we demonstrate an in vitro data based parameterization approach to develop a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model, using carbaryl as a case study. In vitro experiments were performed to provide the chemical-specific pharmacokinetic (PK) and pharmacodynamic (PD) parameters for carbaryl in the PBPK model for this compound. Metabolic clearance and cholinesterase (ChE) interaction parameters for carbaryl were measured in rat and human tissues. These in vitro PK and PD data were extrapolated to parameters in the whole body PBPK model using biologically appropriate scaling. The PBPK model was then used to predict the kinetics and ChE inhibition dynamics of carbaryl in vivo. This case study with carbaryl provides a reasonably successful example of utilizing the in vitro to in vivo extrapolation (IVIVE) approach for PBPK model development. This approach can be applied to other carbamates with an anticholinesterase mode of action as well as to environmental chemicals in general with further refinement of the current shortcomings in the approach. It will contribute to minimizing the need for in vivo human data for PBPK model parameterization and evaluation in human risk assessments.

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.

Golfer exposure to chlorpyrifos and carbaryl following application to turfgrass.

Exposure of golfers to pesticides following their application to turfgrass is of concern to regulators, turfgrass professionals, and consumers. Multipathway exposures were evaluated for golfers on turfgrass treated with chlorpyrifos and carbaryl. Air concentrations and transferable foliar residues (TFRs) were measured to assess potential respiratory and dermal exposures, respectively. At the same time, exposure to individuals simulating the play of golf was determined by dosimetry and urinary biomonitoring. Individual golfer exposure was determined in 76 rounds of golf following eight applications of chlorpyrifos and two applications of carbaryl. Estimated exposures to golfers following full course and full rate applications of chlorpyrifos and carbaryl were 19-68 times below current U.S. EPA acute reference dose (Rfd) values, indicating safe exposures under U.S. EPA hazard quotient criteria. Dermal exposure was determined to be the dominant exposure pathway to golfers, accounting for approximately 60% of the chlorpyrifos absorbed dose and 100% of the carbaryl absorbed dose. This study also provides a set of transfer factors (TFs) that may be used to determine dermal exposure of golfers to pesticides using transferable residue data.

Simulating toxicity of carbaryl to Gammarus pulex after sequential pulsed exposure.

Aquatic nontarget organisms are typically exposed to sequential pulses of contaminants with fluctuating concentrations. We use the semimechanistic threshold damage model (TDM) to simulate survival of the aquatic invertebrate Gammarus pulex after sequential pulsed exposure to carbaryl and compare itto a simpler model based on time-weighted averages (TWA). The TDM is a process-based model and we demonstrate how to parametrize it with data from an uptake and elimination experimenttogether with data from a survival experiment with sequential pulses. The performance of the two models is compared by the fit to the first survival experiment and the simulation of another, independent survival experiment with different exposure patterns. Measured internal concentrations in the first survival experiment are used to evaluate the toxicokinetic submodel of the TDM. The TDM outperforms the TWA model, facilitates understanding of the underlying ecotoxicological processes, permits calculation of recovery times (3, 15, and 25 days for pentachlorophenol, carbaryl and chlorpyrifos respectively) and enables us to predict the effects of long-term exposure patterns with sequential pulses or fluctuating concentrations. We compare the parameters of the TDM for carbaryl, pentachlorophenol and chlorpyrifos and discuss implications for ecotoxicology and risk assessment.

An in vitro approach for demonstrating the critical role of serum albumin in the detoxication of the carbamate carbaryl at in vivo toxicologically relevant concentrations.

The hydrolysis of carbaryl by bovine serum albumin (BSA) was studied at toxicologically relevant concentrations (range 15-300 microM) in order to determine the role of this protein in the detoxication of the carbamate in vivo. The 1-naphthol released during the hydrolysis of carbaryl was monitored using gas chromatography coupled with mass spectrometry. BSA hydrolyzed carbaryl in a time-progressive way. The hydrolysis was also dependent of enzyme (1.0, 2.5, 5.0 and 7.0 mg ml(-1)) and substrate (range between 15 and 1,000 microM) concentration. The estimated turnover number and Michaelis-Menten constant were 1.6 x 10(-4) s(-1) and 430 microM, respectively. Thus, the second order rate constant was 0.37 M(-1) s(-1). At enzyme concentrations of 7.0 mg ml(-1) and substrate concentrations ranging between 50 and 300 microM about 80% of substrate was hydrolyzed in 3 h. At lower substrate concentrations (15 and 30 microM carbaryl) also significant hydrolysis was detected at the highest enzyme concentration, even when these substrate concentrations were 30 and 15 times lower than the Michaelis-Menten constant. Although the efficacy of the enzymatic hydrolysis is low, the extrapolation of our results to the physiological albumin high concentrations (around 40 mg ml(-1)) suggests that the hydrolysis of carbaryl by serum albumins plays a critical role in the detoxication of this carbamate at in vivo toxicologically relevant concentrations.

Carbaryl, 2,4-D, and Triclopyr adsorption in thatch-soil ecosystems.

Thatch development in intensively managed turf sites may cause environmental concerns for greater sorption or leaching of applied chemicals in terrestrial ecosystems. To determine the adsorption potential of Carbaryl (1-Napthyl N-methylcarbamate), 2,4-D (2,4-dichloro-phenoxyacetic acid), and Triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) in turf ecosystems, composite thatch and underlying soil samples from three-and six-year-old stands of cool-season Southshore creeping bentgrass (Agrostis palustris Huds.) and warm-season Meyer zoysiagrass (Zoysia japonica Steud.) were collected. The samples were processed and analyzed for total organic carbon (COrg); extractable (CExt), humic (CHA) and fulvic acid (CFA); anthrone reactive nonhumic carbon (ARC) fractions; and CHA and CFA associated iron (Fe) contents. Pesticide adsorption capacity (Kf) and intensity (1/n), organic carbon partition coefficient (KOC) and Gibbs free energy change (deltaG) were calculated for thatch materials and the underlying soils using a modified batch/flow technique. Both bentgrass (BT) and zoysiagrass thatch (ZT) contained a greater concentration of CExt, CFA, CHA, and ARC than the respective soils (BS and ZS). The CExt, CFA, CHA, and ARC concentration was higher in BT compared with ZT. The BT contained a greater concentration of bound Fe in both CFA and CHA fractions than in BS, whereas ZT had more bound Fe in CHA fraction than in ZS. On average, the BT had a greater concentration of bound Fe in CExt, CFA, and CHA fractions than in the ZT. Among the pesticides, Carbaryl had higher Kf and 1/n values than 2,4-D and Triclopyr for both thatch and soil. Although the KOC and deltaG values of Carbaryl were higher in both BT and ZT than in the underlying soils, the KOC and deltaG values of 2,4-D were significantly higher in BS and ZS than in the overlying thatch materials. The 2,4-D and Triclopyr had higher leaching indices (LI) than Carbaryl for both BT and ZT materials than the respective soils. The Carbaryl, however, had a higher LI for soils than for thatch materials. Averaged across thatch materials and soils, COrg accounted for 96, 85, and 84% variations in Carbaryl, 2,4-D, and Triclopyr adsorption, respectively. Among the COrg fractions, lignin followed by CFA and CHA accounted for greater adsorption of pesticides, especially Carbaryl. The concentration of CHA and CFA bound Fe did not correlate with Kf and 1/n values of pesticides.

Hydrolysis of carbaryl by human serum albumin.

Human serum (HS) and human serum albumin (HSA) were able to hydrolyse the carbamate carbaryl. Carbarylase activity found in HSA was slightly activated by 1 mM Zn2+, Mn2+, Cd2+, Ni2+ and Na+ and by 0.01 mM Pb2+. The organophosphorus compounds paraoxon and O-hexyl O-2,5-dichlorophenyl phosphoramidate, caprylic acid, palmitic acid and the carboxyl ester p-nitrophenyl butyrate inhibited the hydrolysis of carbaryl by HSA, being in the last case a competitive inhibition. Using selective amino acid reagents, we concluded that Cys, Trp, Arg and Tyr seem to play important roles in the carbarylase activity of HSA. In addition, Tyr and Arg seem to be located in the active centre of the enzyme since carbaryl protected the activity from the inhibition. It was concluded that HSA hydrolyses carbaryl by a mechanism similar to that described for rabbit serum albumin based in transient carbamylation of a Tyr residue. The extrapolation of the hydrolysis rate to physiological albumin concentrations suggests that albumin might be playing a critical role in the detoxication of carbaryl.

Influences of a laboratory diet and natural seston on the bioavailability of carbaryl, chlorpyrifos, and malathion to black fly larvae (Diptera: Simuliidae) in an acute toxicity test.

To determine the effects organic food particles can have on insecticide bioavailability, two food types, a laboratory diet and dried, natural seston, were evaluated using black fly larvae, Simulium virtatum Zetterstedt cytospecies IS-7, in a 24-h orbital shaker toxicity test. The bioavailability of all three insecticides was significantly altered when diet concentrations in the flasks were > or = 150 mg/L. Chlorpyrifos availability decreased, whereas carbaryl and malathion availability increased. Dried, natural seston had little effect on the bioavailability of these insecticides except in carbaryl-dosed larvae where mortality was significantly increased when seston concentrations were 150 mg/L in the flasks. Differences in insecticide bioavailability between the two food types in these experiments might have been related to the particle size and organic carbon content of the two materials. Laboratory diet particles were significantly smaller (11.7 +/- 0.5 microm) and had a significantly greater organic carbon content (26.4%) than the seston particles (30.9 +/- 3.3 microm; 1.1%). These results suggest that the concentration, as well as the physical and chemical component of the food source, are important factors in determining the effects of food on insecticide bioavailability in aquatic systems.

The use of the radioisotope method in studies of pesticide penetration into the eyeball.

The studies concerning the effects of pesticides on the human body focused mainly on their local action or chronic poisoning of the organism. In this study we examine the pesticide penetration into the eyeball resulting from direct contact with the eye. We used an isotope-labelled carbamate pesticide -- carbaryl. The determinations of the amount and concentration of this substance in the cornea, aqueous humour, vitreous humour and retina were performed using the method measuring beta radiation emitted by radioactive carbon. The results revealed measurable concentrations of labelled carbamate in the cornea and aqueous humour 10 and 30 min after application. The levels of this pesticide in the vitreous humour and retina were very low and difficult to analyse statistically. The described method appears to be useful in determining the range and rate of eye penetration by environmental toxins having direct contact with the eyeball.

Rabbit serum albumin hydrolyzes the carbamate carbaryl.

One of the main detoxification processes of the carbamate insecticides is the hydrolysis of the carbamic ester bond. Carboxylesterases seem to play important roles in the metabolization of carbamates. This study performs a biochemical characterization of the capabilities of rabbit serum albumin (RSA) to hydrolyze the carbamate carbaryl. Rabbit serum albumin was able to hydrolyze carbaryl with a K(cat) of 7.1 x 10(-5) s(-1). The K(m) for this hydrolysis reaction was 240 microM. Human, chicken, and bovine serum albumins were also able to hydrolyze carbaryl. The divalent cation Cu(2+) at 1 mM concentration inhibited around 50% of the hydrolysis of carbaryl by RSA. Other mono- and divalent cations at 1 mM concentration and 5 mM EDTA exerted no significant effects on the hydrolysis of carbaryl by RSA. The inhibition of the carbaryl hydrolysis by sulfydril blocking agents suggests that a cysteine residue plays an important role in the active center of the catalytic activity. Both caprylic and palmitic acids were noncompetitive inhibitors of the carbaryl hydrolysis by RSA. The carboxyl ester p-nitrophenyl butyrate is a substrate of RSA and competitively inhibited the hydrolysis of carbaryl by this protein, suggesting that the hydrolysis of carbaryl and the hydrolysis of carboxyl esters occur in the same catalytic site and through a similar mechanism. This mechanism might be based on the carbamylation of a tyrosine residue of the RSA. Serum albumin is a protein universally present in nontarget species of insecticides; therefore, the capability of this protein to hydrolyze other carbamates must be studied because it might have important toxicological and ecotoxicological implications.

Histological and ultrastructural studies of rats exposed to carbaryl.

The aim of the study was to assess the general toxic effects of dermally applied carbaryl, based on histological and ultrastructural examinations of internal organs and to relate these effects to earlier own studies where 14C carbaryl was used for determining the pesticide penetration. The pesticide was applied in doses of 1/5 and 1/10 LD50, administered to the tail skin of male Wistar rats 4 hours daily, for 4 weeks except Saturdays and Sundays. After the experiment, the animals were anaesthetized and the following organs were taken for histological study: brain, lung, heart, liver, kidney, skin from the site of exposure and skin from a place at least 2 cm distant from the exposure site. Lung, liver, kidney, heart and skin were used for ultrastructural studies. Dermal application of carbaryl resulted only in slight histological changes in skin, liver, brain and lung. Even in brain and liver, where large amounts of 14C carbaryl, compared to other organs (lung, kidney, heart), where the intensity of histologic changes was earlier stated to below. Ultrastructural changes were observed in skin, liver, lung, heart and kidney.

Dermal absorption and distribution of (14)C carbaryl in Wistar rats.

The level of (14)C carbaryl was determined in blood (leukocytes, erythrocytes, all blood cells, plasma) and organs (brain, heart, lungs, liver, spleen, skin at the site of exposure) of male Wistar rats after dermal administration. The application liquid was (14)C carbaryl solution in 96% ethyl alcohol. This preparation, possessing an activity of 670 kBq/ml, containing 1.67 mg of carbaryl, was applied to the skin of the tail according to Massmann's method in own modification. The amount of the preparation per 1 cm(2) of the tail skin was 0.19 mg of carbaryl (74.4 kBq). The tails of experimental rats were exposed to (14)C carbaryl by soaking for 4 h daily: once, twice or three times. Beta radiation from (14)C was measured in homogenized organs (brain, heart, lungs, liver, skin) and in blood by computer controlled Wallac scintillation counter Model 1409, using Multi Calc software. The dermal absorption of carbaryl at the site of exposure and in the surrounding area of about 2 cm was observed already during 4 hour exposure. Carbaryl reached plasma within 4 h of a single dermal exposure and penetrated into leukocytes, erythrocytes, heart, liver, lung, kidney and brain. The largest amount of (14)C carbaryl, about 2% of absorbed dose, was detected in liver

Relationship between toxicokinetics of carbaryl and effect on acetylcholinesterase activity in Pomacea patula snail.

The 96-h LC(50) value of carbaryl was 14.6 microg/mL for the snail Pomacea patula. Organisms were exposed for 72 h to a low sublethal concentration (0.1 of LC(50)) using a semistatic contamination system; bioconcentration and elimination experiments were performed evaluating simultaneously acetylcholinesterase (ACHase) activity. The inhibition of the digestive gland ACHase reached 76% when the carbaryl concentration in tissue was 3.2 microg/g. The increased enzyme inhibition was observed concomitantly with the bioconcentration of carbaryl until 7 h. ACHase inhibition was linearly dependent on the uptake and bioconcentration of carbaryl (r(2)=0.87). The transfer of snails to carbaryl-free water after 72 h of exposure was followed by rapid monophasic elimination with a half-life of 1.0 h. However, ACHase activity levels never returned to control values. These results revealed that the bioconcentration might play a critical role in contributing to the toxicity of carbaryl.

Influence of inert ingredients in pesticide formulations on dermal absorption of carbaryl.

OBJECTIVES: To assess the influence of solvent plus various mixtures on percutaneous absorption and disposition of the carbamate insecticide, carbaryl (CA). ANIMALS: Skin was obtained from the dorsum of 14 female weanling specific-pathogen-free Yorkshire pigs. PROCEDURE: In this 8-hour in vitro flow-through diffusion study, porcine skin sections were dosed with 40 micrograms of CA/cm2 of surface area, different amounts of solvents (40 or 80% acetone or dimethyl sulfoxide [DMSO]), different amounts of a surfactant (0, 1, or 5% sodium lauryl sulfate [SLS]), an insect repellent (0 or 15% diethyl-m-toluamide [DEET]), an insecticide synergist (0 or 2% piperonyl butoxide [PB]), and a CA metabolite (40 micrograms/cm2 1-naphthol [1-NA]). RESULTS: In general, CA absorption was greater from acetone than from DMSO mixtures, and CA penetration into skin and stratum corneum was greater from DMSO at 8 hours. This is consistent with the flux-time profiles, which depicted initial peak flux within 2 to 3 hours for most acetone mixtures, but a slow increase in flux for DMSO mixtures. Irrespective of the solvent, increasing water content in pesticide dosing mixtures significantly increased CA absorption from SLS mixtures only. The SLS also enhanced CA absorption, especially at low solvent concentrations. The DEET significantly reduced CA absorption from acetone, but not from DMSO mixtures, and 1-NA enhanced CA absorption from acetone, but not from DMSO mixtures. Piperonyl butoxide significantly enhanced CA absorption from acetone and DMSO mixtures. However, addition of PB or PB plus SLS did not significantly increase CA flux above that observed from solvent plus surfactant mixtures. CONCLUSIONS: Inert ingredients can modulate percutaneous absorption of toxicologically important pesticides and their effect or activity on CA disposition is dependent on solvent specificity and solvent concentration. Whereas SLS, PB, and 1-NA can enhance pesticide absorption, DEET can reduce absorption.