Pesticide percutaneous absorption

Maibach and co-workers (18) have reported the percutaneous absorption of a number of pesticides using a technique they developed, in which 14C labelled pesticide is applied to the skin, and the total urine output is collected until all the radioactivity has been excreted. These data are corrected for incomplete excretion by using the excretion data obtained following intravenous or intramuscular injection. 

The next level of in vitro systems employed is the use of isolated perfused skin flap preparations that are surgically prepared vascularized skin flaps harvested from pigs and then transferred to an isolated organ perfusion chamber. This model allows absorption to be assessed in skin that is viable and anatomically intact and that has a functional microcirculation. Studies conducted to assess the percutaneous absorption of drugs and pesticides in this model compared to humans show a high correlation. Validation of these in vitro methods is a prerequisite for regulatory acceptance. 

It is commonly known that the skin contains a large range of enzymes capable of metabolizing topically applied compounds. Eor pesticides, esterase activity is among the most important (van de Sandt et al, 1993 Hewitt et al, 2000). Although the stratum comeum is generally accepted as the most important barrier in skin absorption, there are some indications that skin metabolism in other skin layers influences the percutaneous absorption of compounds (Potts etal, 1989). The interrelation between metabolism and absorption rate, however, has not been unequivocally established. 

Currently, for pesticide registration, there is an increasing consideration by regulatory jurisdictions of in vitro data as an alternative to in vivo dermal absorption data. At present, based on the OECD inventory and provided that levels of the pesticide remaining in the skin are included as absorbed, the results from in vitro methods seem to adequately reflect those from in vivo experiments, so supporting their use as a replacement test to measure percutaneous absorption (OECD, 2000 van de Sandt et al., 2004). This calculation, i.e. the inclusion of the amount... 

Wester, R.C. and H.I. Maibach (1985). In vivo Percutaneous Absorption and Decontamination of Pesticides in Humans, J. Toxicol. Environ. Health, 16, 25-37. 

Percutaneous absorption The process by which pesticides pass through the skin barrier and enter systemic circulation normally expressed as flux (mass per unit skin surface area per unit time), but may also be expressed as a percentage (fraction of amount deposited on skin (exposure) reaching systemic circulation times 100) per unit time (USEPA, 1998). 

Different methods of human exposure assessment vary with respect to the input data or information required and the degree of uncertainty associated with resulting estimates. Eor example, the film-thickness approach to dermal exposure assessment is a screening-level methodology that assumes a uniform layer of material (e.g., a liquid consumer product) is on the skin, and that a portion of the material in this layer is absorbed, per the dermal absorption characteristics of the chemical. In contrast, dermal exposure assessment and percutaneous absorption methods can include metrics that account for time-dependent exposure and absorption processes. Eor example, in the case of secondary dermal contact with chemicals on surfaces (e.g., transfer of pesticide residues from... 

Feldman RJ, Maibach HI. Percutaneous absorption of some pesticides and herbicides. Tox Appl Pharmacol 1974 28 126-32. 

Bronaugh, R. L. 1985. In vitro methods for the percutaneous absorption of pesticides. In Dermal exposure to pesticide use, edited by R. Honeycutt, G. Zweig, and N. N. Ragsdale. Washington, D.C. American Chemical Society, pp. 33—41. 

Dermal absorption of agricultural chemicals and animal drugs in food-producing animals must be considered as a potential route from which tissue residues of drugs and chemicals may occur. This has been supported in studies of topical pesticide exposure in cows and sheep. Despite the many advances made in in vitro and in vivo techniques for assessing percutaneous absorption in laboratory animals and man, very little systematic attention has been focussed on food-producing animals. The only exception is the pig since it is an accepted model for human studies. The purpose of this manuscript is to overview the literature on dermal xenobiotic absorption in food-producing animals to illustrate the risk that is present, and to outline how in vitro and in vivo methods could be applied to this problem. 

The majority of the research articles identified in a search of the literature of dermal absorption in food-producing animals were concerned with studies utilizing pour-on or dipped pesticides in small groups or even individual animals. In almost all instances, specific formulations were used with quantitative data on dosimetry variables not reported. Although as will be discussed, percutaneous absorption can unequivocally be documented, data is not available in the open literature to quantitatively assess the mechanisms of absorption in different species. 

Webster. R. C., and Maibach, H. 1. (1985a). fit vivo percutaneous absorption and decontamination of pesticides in humans. J. Toxicol. Environ. Health 16,25-37. 

The radiotracer method has also been used in hiunan subjects if the test compoimd is not toxic (Feldmann and Maibach, 1969, 1970, 1974). This approach was employed to assess percutaneous absorption of pesticides in swine (Qiao etal., 1994), in human testing of ultraviolet filters (Benech-Kieffer et al., 2003), and for determination of topical absorption of cosmetics (Malhotra et al., 2001) for clinical safety assessment. 

Occupational disease, caused by skin contact with toxic substances, represents a major health problem In the United States (1). Dermal exposure of agricultural workers to pesticide agents, of course. Is a particularly pertinent example of this problem. Prediction of the detrimental toxic effects of hazardous chemical exposure Is difficult, however, because of the complexity of the percutaneous absorption process in man and a lack of any consistently Identifiable relatlonshlp(s) between transport rate and chemical properties. In addition, the very diverse approaches, which have been used to measure skin penetration, further complicate the situation since the extrapolation of results to man In his workplace may Involve questionable, non-valldated assumptions. Our specific aim Is to predict accurately the toxicokinetics of occupationally-encountered molecules (e.g., pesticides) absorbed across human skin In vivo. We present... 

Percutaneous absorption measurements of a limited number of pesticides have previously been reported. Permeation of DDT, lindane, parathion, uld meilathlon was measured in human volunteers by Maibach and coworlcers ( , ] ). In vivo absorption values for the same compounds were obtained for monkey, pig, and rabbit (11). The dermeil penetration of lU pesticides in mice (12) end three pesticides in rats ( ) was measured by Shah and coworkers using in vivo techniques. 

Percutaneous absorption studies using in vitro techniques appear to be of value in the assessment of pesticide absorption as well as with other types of compounds. As with any procedure, precautions may need to be taken in certain steps to ensure the accuracy of the data. For water-insoluble compounds, the llpophilicity of the... 

Maibach et al., (19) conducted percutaneous absorption studies in man and Shah et al. (22) in the mouse. Carbaryl was absorbed more readily than parathion in these studies. The relationship between the dose and the adverse health effect (OiE inhibition) was not examined. According to the skin loss and plasma elimination data of Knaak et al. (iL) reviewed in this paper, carbaryl was not absorbed more rapidly than parathion in the adult male rat. More carbaryl residues were found in skin (penetrated) than were found in the case of parathion. The difference (2X) may be related to the ability of the rat skin to metabolize these pesticides prior to their absorption into blood. Fredriksson (22) showed that parathion was not metabolized to any extent in rat skin. Studies by Chin et al. (24) suggest that carbaryl may be partially metabolized in skin to water soluble products prior to their absorption into blood. 

The effect of a topically applied dose of parathion, carbaryl, and thiodicarb on red blood cell cholinesterase activity in the rat was reviewed along with pharmacokinectic data developed on their percutaneous absorption. Parathion and thiodicarb inhibited 50% of the red cell cholinesterase activity at dose levels of 3.2 and 33 mg/kg of bw, while no inhibition was detected with carbaryl at dose levels as high as 417 mg/kg of w. Parathion and carbaryl were absorbed at 0.33 and 0.18 ug/hr/cm, while thiodicarb was absorbed at rates varying from 0.27 to 0.042 ug/hr/cm of skin. Skin loss and plasma elimination data were used to calculate the values. The topically applied pesticides slowly penetrated skin and were available for absorption into blood and redistribution to other tissues. Recovery data suggested that evaporative losses occurred during the course of the 5-day study. The pesticides may be removed from skin by washing, thus reducing the amount available for absorption. 

Exposure by workers in the manufacture of agricultural chemical products or by the mixer, loader or applicators who use these products may be considerable. Thus, the risk to these workers may be greater than to the consumer of treated products. The two recognized major routes of exposure are inhalation and topical. However, contrary to what was first believed, topical exposure constitutes the major route and it is for this reason that interest in percutaneous absorption of pesticides has increased to a considerable degree. 

In order to assess the risk from topical exposure a number of investigators have sought animal models that could predict percutaneous absorption rates of chemicals in humans. Considerable efforts by Wester and Maibach (2-6) have shown that monkeys and pigs give dermal absorption data most comparable to humans with a range of drugs and pesticides which varied in their physicochemical properties as well as use. A similar rank order for species comparisons has been observed in in vitro (12-14) absorption data which in most cases exceeded the human values (Table I). For this reason, and because of the availability of rhesus monkeys within our facility, dermal absorption studies with rhesus monkeys were considered an appropriate model. 

Percutaneous absorption studies utilizing rhesus monkeys have one Important single advantage. That is, their skin type and absorption characteristics seem to be similar to humans. This is of utmost concern since the purpose of this study is to simulate the human case. This is not a toxicology study, and it should not be the purpose of this study to estimate a worst case scenario as in a hazard identification study. Thus, in spite of the many shortcomings of the described procedures, monkey percutaneous absorption studies could play an important role in pesticide risk assessments. 

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