Bekæmpelsesmiddelforskning fra Miljøstyrelsen, 90 – Hudpenetration af pesticider

Skin Penetration of Pesticides

Summary and conclusions

Background
Effect of detergents on skin integrity and penetration
Effects of mixtures of pesticides on dermal penetration
Effect of gloves on dermal penetration of pesticides
Penetration of pesticides through slightly damaged skin
Conclusions and future perspectives

Background

Pesticides are among the few substances distributed into our environment with the intent to harm biological systems. The selectivity of pesticides varies and many of the toxicological endpoints that pesticides target also make humans a potential target. Toxicity may involve systemic as well as local effects, depending on the route of exposure. The primary occupational exposure to pesticides is dermal, and occurs during mixing and spraying, and in green houses during re-entry activities, i.e. activities related to handling recently treated plants.

The purpose of the project was to study:

Effect of detergents on skin integrity and penetration
Effects of mixtures of pesticides on dermal penetration
Effects of gloves on dermal penetration of pesticides
Penetration of pesticides through slightly damaged skin

The present study examined the in-vitro percutaneous penetration of five pesticides widely used in agriculture and green houses. The five pesticides were the fungicides methiocarb, pirimicarb, and prochloraz, the growth retardant paclobutrazol and the insecticide dimethoate. An experimental model with static diffusion cells mounted with human breast or abdominal skin was used, and pesticide concentrations were quantified by HPLC. The pesticides covered a wide range of solubilities, as well as different molecular weights, which allowed discussion of penetration characteristics of the single pesticides as well as comparisons between penetration characteristics as influenced by product formulation and selected detergents. Further, the degree of protection that different glove materials offered against dermal penetration of pesticides was studied. Finally, the degree to which a slightly damaged dermal barrier would affect penetration characteristics of the five pesticides was evaluated.

An overall aim was to generate data that could feed directly into the hazard assessment process for the selected detergents, pesticides and their mixtures. This information could be used as a basis for substituting to less hazardous detergents, when writing safety data sheets, and when giving recommendations on the use of gloves during work with pesticides. The sub-project on slightly damaged skin was to specifically question the guidelines based on penetration data from skin with full integrity.

Effect of detergents on skin integrity and penetration

Pesticides are not used commercially as pure chemicals, but are mixed with different detergents to change solubility characteristics and in some cases increase the penetration into leaves of plants. The three detergents included in this study were chosen on the basis of their use in several product formulations and an expected low dermal toxicity.

None of the three detergents (ethylene glycol, propylene glycol and lignosulfonic acid) damaged the skin integrity significantly following 48 hours exposure to 10 mM.

The three detergents (ethylene glycol, propylene glycol and lignosulfonic acid) only marginally affected the dermal penetration of methiocarb, pirimicarb and paclobutrazol. The detergents used in the sales formulations of methiocarb (Mesurol) and pirimicarb (PirimorG) did, however, change penetration characteristics significantly compared to the pure pesticides. The time between application of the pesticides on the apical side of the skin and appearance below the skin (the lag-time) was significantly reduced for both pesticides, which caused a significantly increased total penetration during the experimental period. The reduced lag-time demonstrated the range of effects that different detergents may have on penetration of pesticides, and suggests that regulatory agencies consider these data when evaluating pesticides resubmitted for approval after a change in formulation. At present, the Danish EPA does not require updated penetration data when re-evaluating known pesticides in changed formulations.

Effects of mixtures of pesticides on dermal penetration

Pesticides may be used as mixtures or distributed one at a time on plant cultures with very short time intervals. In both cases, employees handling these recently treated cultures will potentially be exposed to a mixture of pesticides. Knowledge on interactions between pesticides is scarce, and often focuses on toxicity in animals following oral exposure. The present study used three pesticides to evaluate whether one pesticide would change penetration characteristics of another pesticide when applied together. The experiments demonstrated that interactions do occur, and may cause increased as well as decreased penetration depending on the pesticides mixed. As regulatory guidelines only relate to single pesticides, the present results suggest that this area might deserve a higher focus.

Effect of gloves on dermal penetration of pesticides

When dermal exposure to pesticides cannot be avoided through prolonged re-entry intervals, gloves are used to prevent dermal absorption. We have evaluated the penetration of methiocarb and pirimicarb through a double layer consisting of human skin plus glove. Gloves made of nitrile or latex were used in this study. None of the gloves reduced significantly the break-through time, i.e. the time from application of the pesticide on top of the glove to appearance below the skin. Both glove materials significantly reduced the pesticide penetration during the initial 12 hours exposure compared to unprotected skin. The protection offered by latex gloves was not significant after 24 hours. During a 48 hours observation period the nitrile gloves offered significantly better protection against pesticide penetration than gloves made of latex. As both glove materials apparently offer equal protection during short-term exposure, it would be more important from a preventive perspective to avoid re-using gloves instead of focusing on the glove material being latex or nitrile. An important caveat to these studies is, however, that they only included pure pesticides and not the sales formulations, which potentially may affect results for penetration through the different glove materials.

Penetration of pesticides through slightly damaged skin

International guidelines for experimental studies on dermal penetration require full integrity of the dermal barrier. However, workplace experience and occupational epidemiology repeatedly describes sub-optimal skin conditions for many employees. It was therefore prudent to study whether a slightly damaged skin would change penetration characteristics of pesticides.

Sodium Lauryl Sulfate (SLS) is known to affect the barrier integrity of the skin. Slightly damaged skin is achieved through three hours' exposure to 0.1% or 0.3% SLS. Following this pre-treatment, SLS is removed, the skin is washed, and pesticides applied.

The lag-time for the pesticides included in the study was significantly reduced and the total amount of pesticide penetrating the skin during a specified period increased significantly. These findings will have clear implications as to the guidance of workers exposed to pesticides and their use of gloves.

Conclusions and future perspectives

The pesticides included in the present study covered a wide range of lipophilicities with logPow values ranging from 0.7 to 4.4. Comparison between penetration characteristics of the five pesticides demonstrated that neither a too low, nor a too high logPow is optimal for dermal penetration. The experiments with slightly damaged skin demonstrated a significantly reduced lag-time for the pesticides tested; knowledge that ought to be considered in future guidelines related to dermal exposure to pesticides. Further, these studies indicated that the apical damage introduced mainly affects the passage from donor and into the skin and will have largest consequences for the most hydrophile pesticides. The study on gloves included gloves made of nitril and gloves made of latex. As both glove materials apparently offer equal protection during short-term exposure, it would be more important from a preventive perspective to avoid re-using gloves instead of focusing on the glove material being latex or nitrile.

An important area for further research will be to study the fate of the pesticides that enter the skin compartment, which acts as a reservoir for further absorption, and whether this reservoir is emptied on the apical side or absorbed. This problem would be especially relevant for the pesticides with prolonged lag-times. A further implication of the prolonged lag-times, which may extend beyond exposure time at the workplace, is that biological monitoring of workers through blood samples will be compromised if this factor is not considered.