Bekæmpelsesmiddelforskning fra Miljøstyrelsen, 109 – Hudoptagelse af pesticider - betydning af lag-time og reservoir-effekt

Hudoptagelse af pesticider - betydning af lag-time og reservoir-effekt

Summary

This project had four primary aims:

Through the use of a range of model compounds, to identify an interval in relation to lipophilicity, where the most effective dermal absorption would be expected.
To describe the importance of temporary deposition in the skin (reservoir effect) in relation to delayed absorption after end of exposure.
To assess whether washing skin after exposure might remove part of the pesticide deposited on or within the upper stratum corneum, and whether regulators should continue seeing this fraction as de facto absorbed.
To assess the importance of slightly damaged skin for dermal absorption as well as temporary deposition in the skin.

Among the nine model compounds selected for this study, eight where pesticides in use in Denmark at the time the study was initiated. The model compounds were chosen to cover a wide spectrum of solubilities and molecular weights. The pesticides included were glyphosate, dimethoate, pirimicarb, malathion, paclobutrazol, methiocarb, prochloraz, and benzoic acid, the ninth model compound being caffeine. Four of the model compounds where used as radioactive isotopes and quantified through beta counting, whereas the remaining model compounds were analysed with HPLC. Static diffusion cells mounted with human skin were used as the experimental model, and experiments were carried out in accordance with requirements given in the OECD guideline for experimental studies of dermal penetration.

Results from one of the model compounds (malathion) were clearly at variance with what was expected on the basis of results from the other model compounds as well as the physical-chemical data. No explanation for this deviation from the expected was identified. Generally, however, the data obtained enables discussion and valid conclusions on the primary aims for the project. The main conclusions are summarized in four sections, each comprising five paragraphs.

On identification of an interval in relation to lipophilicity, where the most effective dermal absorption would be expected, the following was concluded:

Results indicate a general inverted U-shaped relationship between Kp and logPow. Thus, the fastest dermal penetration occurs for compounds with logPow values between 1½ and 4. Malathion does not fit into this generalisation.
No obvious relationship was observed between molecular weight Kp values.
The shortest lag-time was observed for model compounds with water solubility between 3 g/L and 20 g/L.
With increasing molecular weight, lag-time increased. Thus, the lag-time for the smallest model compound with a molecular weight of 122 g was close to 1½ hours, while the lag-time exceeded 20 hours for a model compound with a molecular weight of 377 g. A difference in lag-time of this size inevitably also causes differences in the amounts of compounds able to penetrate the skin within a limited period of time.
The relative deposition in dermis was highest for the lipophilic model compounds, which was also expected given that dermis is seen as a lipophilic compartment.

On the importance of the temporary deposition in the skin (reservoir effect) in relation to delayed absorption after end of exposure the following was concluded:

Absorption of model compounds temporarily deposited in the skin compartment continues after exposure is terminated; for certain model compounds for more than 24 hours.
Thus, a certain fraction of a compound deposited temporarily within the skin compartment will penetrate the skin at a later point and appear as absorbed.
For a compound with a long lag-time and limited affinity for the lipophilic skin compartment, neither significant temporary skin deposition nor significant dermal penetration through the skin can be expected following short-term exposure (i.e. less than one third of the lag-time).
The present data does not warrant conclusions on the relationship between temporary skin deposition and later skin penetration for hydrophilic compounds.
For lipophilic compounds, data indicates that rule setting and administration on use of pesticides based on data generated along the lines of OECD guidelines for experimental studies on dermal penetration to some extent overestimates the actual degree of penetration. However, the overestimated dermal penetration for lipophilic compounds is probably relatively limited. Thus, at least for lipophilic compounds, regulators are advised to continue the pragmatic approach and use the total fraction of an administered compound not recovered in the donor compartment as a measure for the amount potentially available for absorption.

On the assessment of whether washing skin after exposure removes part of the pesticide deposited on or within the upper stratum corneum the following was concluded:

A skin wash after six hours exposure removes a significant fraction of the pesticide administered on the skin and significantly reduces the amount available for later absorption.
For the most hydrophilic model compounds (glyphosate and caffeine) a skin wash after 6 hours reduces skin deposition by 80-90 %, while the reduction for the most lipophilic model compounds (malathion and methiocarb) was around 35 %.
A reduced amount of model compound in the skin reduces the concentration gradient between skin and receptor causing reduced flux of the model compound.
For the most hydrophilic model compounds, overall skin penetration was reduced by close to 67 % following skin wash, for lipophilic model compounds the effect was slightly less. Gentle washing removes not only what is left on the skin, but also a fraction of what is deposited in the upper part of stratum corneum.
This observation has clear preventive implications, and documents the importance of washing hands following dermal exposure to chemicals.

On the implications of slight skin damage for dermal absorption as well as temporary deposition in the skin the following was concluded:

Slightly damaged skin causes general increased dermal penetration for all model compounds.
The increase is marginal for compounds with good penetration characteristics through uncompromised skin.
The increased penetration is significant for the more lipophilic compounds, but the largest increase in penetration rate is seen for the more hydrophilic compounds.
Washing the damaged skin after exposure significantly reduces skin deposition as well as skin penetration though it does not bring deposition and penetration down to a level comparable to uncompromised skin.
The significantly increased penetration of especially the more hydrophilic compounds through slightly damaged skin may have regulatory consequences. Thus, traditional extrapolation from in vitro guideline studies may significantly underestimate the actual systemic exposure following dermal exposure in people with slightly damaged skin.