Dermal absorption factor

In practice, the dermal absorption factor is considered to be so significant that no air concentration, however low, will provide protection if skin contact with the liquid is permitted. 

This chapter provides an overview of factors affecting dermal absorption. Factors influencing absorption are among others related to the skin (e.g. anatomical site, difference between species, metabolism, etc.) and the exposure conditions (e.g. area dose, vehicle, occlusion and exposure duration). In order to provide relevant information for the risk assessment of pesticides, dermal absorption studies should take these aspects into account. With respect to the methods being used nowadays for the assessment of dermal absorption, it is important to realize that neither in vitro nor in vivo animal studies have been formally validated. Available data from various in vitro studies, however, indicate that the use of the total absorbed dose (i.e. the amount of test substance in the receptor medium plus amount in the skin) could be used in a quantitative manner in risk assessment. Tape stripping of the skin can be adequate to give a good indication of test chemical distribution, and hence its immediate bioavailability. 

They dosed rats dermally with laboratory contaminated soil and observed that as the dose Increased, the liver concentration of TCDD Increased from 0.05 to 2.2%. The authors did not estimate a value for dermal bioavailablllty. On the basis of this study, Kimbrough and co-workers estimated a dermal bioavailablllty of 1% for humans (1). The use of a 1% dermal absorption factor (bioavailablllty) almost surely overestimates the actual uptake of TCDD on soil through human skin since Investigators In the dermal field generally agree that rodent skin Is approximately 10 times more permeable than human skin. As discussed In the next section, dermal bioavailablllty (like oral bioavailablllty) Is also likely to decrease with the "age of the soil. (41.42)... 

Dermal Absorption. To determine the toxicity of parathion following dermal application, the method of Draize, Woodard, and Calvery (3) was followed. Variables considered in the design of these experiments were concentration as a factor of area, solvent, exposure time, and number of exposures. In some cases the wettable powder was applied in the dry form, while in other cases sufficient water was added to produce a viscid paste. All doses in the table are presented as milligrams per kilogram of parathion, regardless of the concentration or solvent. 

Safety factors were acceptable for all operators, even without considering the low dermal absorption of cyromazine. 

The skin is a complex multilayered tissue with a large surface area exposed to the environment. Skin anatomy, physiology, and biochemistry vary among species, within species, and even between anatomic sites within an individual animal or human. Logically these biological factors alone can influence dermal absorption. What is consistent is that the outer layer, the stratum corneum (SC), can provide as much as 80% of the resistance to absorption to most ions as well as aqueous solutions. However, the skin is permeable to many toxicants, and dermal exposure to agricultural pesticides and industrial solvent can result in severe systemic toxicity. 

There are other factors that can influence dermal absorption, and these can include environmental factors such as air flow, temperature, and humidity. Preexisting skin disease and inflammation should also be considered. The topical dose this is usually expressed in per unit surface area can vary, and relative absorption usually decreases with increase in dose. 

Stochastic Risk Index for Hazardous Chemical Constituents. Calculation of the risk index for all hazardous chemicals in the waste that cause stochastic effects is performed in the same manner as in the previous examples for radioactive wastes. The calculated risk for each such substance, based on the assumed exposure scenario, is summed and then divided by the acceptable lifetime risk of 10 3 for classification as low-hazard waste (see Table 7.1). The risk for each chemical is calculated by multiplying the arithmetic mean of the concentration in the waste given in Table 7.5 by the intake rate from ingestion, inhalation, or dermal absorption per unit concentration discussed in Section 7.1.7.3 and 10 percent of the appropriate slope factor in Table 7.7 (see Section 7.1.7.1) adjusted for the exposure time. Since the slope factors assume chronic lifetime exposure, they must be reduced by a factor of 70 based on the assumption that the exposure scenario at the hazardous waste site occurs only once over an individual s lifetime. In addition, a simplifying assumption is made that whenever more than one slope factor is given for a hazardous substance in Table 7.7, the higher value was applied to the total intake rate by all routes of exposure of about 4 X 10 8 mg (kg d) 1 per ppm. This assumption should be conservative. 

Okrent and Xing (1993) estimated the lifetime cancer risk to a future resident at a hazardous waste disposal site after loss of institutional control. The assumed exposure pathways involve consumption of contaminated fruits and vegetables, ingestion of contaminated soil, and dermal absorption. The slope factors for each chemical that induces stochastic effects were obtained from the IRIS (1988) database and, thus, represent upper bounds (UCLs). The exposure duration was assumed to be 70 y. Based on these assumptions, the estimated lifetime cancer risk was 0.3, due almost entirely to arsenic. If the risk were reduced by a factor of 10, based on the assumption that UCLs of slope factors for chemicals that induce stochastic effects should be reduced by this amount in evaluating waste for classification as low-hazard (see Section 7.1.7.1), the estimated risk would be reduced to 0.03. Either of these results is greater than the assumed limit on acceptable risk of 10 3 (see Table 7.1). Thus, based on this analysis, the waste would be classified as high-hazard in the absence of perpetual institutional control to preclude permanent occupancy of a disposal site. 

General considerations and other factors influencing dermal absorption... 

Recently, Riviere and Brooks (2007) published a method to improve the prediction of dermal absorption of compounds dosed in complex chemical mixtures. The method predicts dermal absorption or penetration of topically applied compounds by developing quantitative structure-property relationship (QSPR) models based on linear free energy relations (LFERs). The QSPR equations are used to describe individual compound penetration based on the molecular descriptors for the compound, and these are modified by a mixture factor (MF), which accounts for the physical-chemical properties of the vehicle and mixture components. Principal components analysis is used to calculate the MF based on percentage composition of the vehicle and mixture components and physical-chemical properties. 

Studies conducted in vivo in humans and in vitro using human skin indicate that benzene can be absorbed dermally. The data show that dermal absorption is not as substantial as absorption following inhalation exposure to benzene vapor or oral exposure. The movement of a substance through the skin to the blood occurs by passive diffusion and has been described mathematically by Fick s law. However, this is an oversimplification of the process of skin absorption various factors (e.g., interaction of benzene with molecules within the skin) affect the transport of the solvent through the skin (Loden 1986). 

In the past few years, there have been increasing efforts towards international harmonization of approaches to pesticide exposure assessment. Harmonization allows exposure assessors to share expertise and resources and develop better methods. Ongoing efforts towards international harmonization are discussed in Chapter 10. The development of generic databases has provided an impetus for harmonization of methodologies for generating the data. Further harmonization would increase the number of studies that could be included in databases, thus improving the exposure estimates derived from them. The use of harmonized factors for dermal absorption and clothing penetration, plus protective factors... 

A method to set REIs would account for the rate of dermal absorption, the rate of foliar contact and the rate of change in cholinesterase. These factors were used in the Popendorf and Leffingwell (1982) Unified Field Model for determining REIs. This model also accounts for the relative rate of DFR dissipation, and differences in potency based on the dermal LD50 of the pesticide. The Unified Field Model is an elegant technique that takes into account many variables affecting exposure and cholinesterase inhibition as a response. Ultimately, the rate of cholinesterase inhibition, and not a fixed level of inhibition, is the primary... 

The UK-POEM database is based on a review of the data available on the exposure of pesticide spray operators (in the UK). The review indicated that several factors determined the dose absorbed by a spray operator. These included the following the volume of external contamination, the extent to which this external contamination penetrated clothing to reach the skin and the rate at which the chemical came into direct contact with the skin surface and was absorbed (JMP, 1986 Martin, 1990). These various independent factors were assumed, with the exception of dermal absorption, to be of a sufficient generic nature to be suitable for extrapolation purposes. Two major work activities were differentiated mix-ing/loading and application. An update of the default values in UK-POEM has been presented (POEM, 1992). 

FACTORS INFLUENCING DERMAL ABSORPTION 319 Factors Related to the Skin 319 Intraspecies Differences 319 Inter-individual Differences 319 Skin Condition 319 Anatomical Site 320 Skin Metabolism 320... 

Dermal absorption is influenced by several factors, e.g. the physico-chemical properties of the substance, vehicle, occlusion, concentration, exposure pattern and skin site of the body (ECETOC, 1993 Howes et al., 1996 Schaefer and Redelmeier, 1996). Despite the fact that guidance exists for the conduct of dermal absorption studies (USEPA, 1998, 2004 OECD, 2004a,b,c), there continues to be discussion on some experimental details. In order to harmonize the use of dermal absorption data in human risk assessment within the EU, a guidance document was prepared by the Commission (EC, 2002). 

Many factors have been shown to influence the dermal absorption of compounds (ECETOC, 1993 Howes et al., 1996 Schaefer and Redelmeier, 1996). Here, we evaluate the most important factors affecting the outcome of an in vivo or in vitro study for dermal absorption testing of pesticides. 

In addition to in vivo and in vitro experimentation, mathematical models and quantitative structure-permeability relationship (QSAR) methods have been used to predict skin absorption in humans. These models use the physico-chemical properties of the test compound (e.g. volatility, ionization, molecular weight, water/lipid partition, etc.) to predict skin absorption in humans (Moss et al 2002). The models are particularly attractive because of the low cost and rapidity. However, because of the above-mentioned factors influencing dermal absorption, mathematical models are of limited use for risk assessment purposes. Since these models are currently not accepted by regulatory agencies involved in pesticide evaluations, they will not be further discussed in this chapter. 

If appropriate dermal penetration data are available for rats in vivo and for rat and human skin in vitro, the in vivo dermal absorption in rats may be adjnsted in light of the relative absorption throngh rat and human skin in vitro. The latter adjustment may be carried out because the permeability of human skin is often lower than that of animal skin (McDougal et al., 1990 Sato et al., 1991 Barber et al., 1992 Howes et al., 1996). A generally applicable correction factor for extrapolation to man can, however, not be derived, because the extent of overestimation appears to be agent- and animal-specific (Bronaugh and Maibach, 1987 ECETOC, 1993). 

Although certain pyrethroids exhibit striking neurotoxicity in laboratory animals whenadminista edby intravenous injection, and some are toxic by the oral route, systemic toxicity by inhalation and dermal absorption is low. There have been very few systemic poisonings of humans by pyrethroids. Although limited absorption may account for the low toxicity of some pyrethroids, rapid biodegradation by mammalian Uver enzymes (ester hydrolysis and oxidation) is probably the major factor responsible. Most pyrethroid metabolites are promptly excreted, at least in part, by the kidney. 

Ingestion and inhalation are the primary routes of exposure. Boron can be found in dusts, water, and in fruits and vegetables. Dermal absorption will not be a factor unless the dermal barrier is compromised. 

Chlorofluorocarbons have low dermal absorption characteristics. Absorption by the lungs is slow (based on data collected from animal studies). The main factor affecting distribution of chlorofluorocarbons in an individual is the amount of body fat. Chlorofluorocarbons are concentrated in the body fat and are slowly released into the blood at concentrations that do not present a risk of cardiac sensitization. 

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