13 Conclusions and perspectives

Dermal absorption of pesticides - evaluation of variability and prevention

13.1 Regulatory aspects

Knowledge on percutaneous penetration may originate from in vitro as well as in vivo experiments and from observational studies in humans during and after exposure. Quantitative differences will exist, and is primarily due to the inherent heterogeneity between humans and therefore also between donors for the in vitro experiments, but qualitative comparisons across different approved methods appear quite solid.
- Results based on in vitro experiments carried out on human skin according to the present OECD guidelines have repeatedly demonstrated good agreement with experience from human exposure situations.
- Results from in vitro experiment on human skin following OECD guidelines are normally seen as more predictive than animal experiments in mice or rats.
- Evaluation of dermal penetration of chemicals with known skin metabolism requires special attention.
The OECD guidelines state that the amount of substance not found in the donor chamber should be considered absorbed and therefore potentially available in the systemic circulation. This also accounts for the amount of substance deposited in the skin. Experiments demonstrate that absorption of chemicals temporarily deposited in the skin continues for up to 24 h after exposure has ended. Studies have agreed on this statement but this report also indicates that a fraction of the substance temporarily deposited in the skin returns to the donor chamber.
- For lipophilic substances, the overestimated absorption is however not considered big and should probably not influence the present conservative estimates used by regulatory agencies.
- Conclusions regarding more hydrophilic chemicals still need some elaboration on the hydrophilic part of the spectrum.
- Temporary skin deposition will potentially underestimate the true absorption if assessed in blood or urine immediately following exposure.
Percutaneous penetration is strongly influenced by the solubility (e.g. logPow) as well as the molecular size of the penetrant. Several mathematical models to predict percutaneous penetration based on large databases on penetration of +100 chemicals exist.
- For chemicals with logPow values between -2 and 2, there appear to be a positive correlation between logPow and Kρ (penetration rate).
- If a chemical does not have specified and reactive chemical groups or high affinity for proteins in the skin, these models will within a reasonable broad spectrum of solubilities deliver valid predictions on expected skin penetration.
- Use of mathematic models for regulatory purposes requires significant experience and knowledge, and several studies have demonstrated that many chemicals without known reasons do not fit the present mathematical models.
Washing the skin after exposure has proved to decrease the amount of substance available for later penetration significantly. The deposition of hydrophilic substances is most affected and the absorption is reduced to one third.
- There is solid evidence that hand wash following skin exposure to pesticides will reduce systemic exposure.
- This observation has a clear preventive perspective in relation to training and personal hygiene for pesticide users.
Slightly damaged skin results in a generally increased penetration rate of all substances.
- The effect is most significantly in the hydrophilic substances.
- This observation is important given that a significant part of the work force suffers from more or less chronic skin problems and therefore has a compromised skin barrier.
- Regulatory agencies should consider how this information can be included in their rule setting, regulatory policies, as well as their guidance given to users of pesticides.
Gloves have proven to decrease the penetration and absorption rate of pesticides, but breakthrough-times differ between glove materials and some glove materials offer better protection against specific pesticides than others.
- By short-term exposure (< 2 hours) to low concentrations of pesticides (not mixing and loading) latex gloves will offer slightly less but fair protection compared to nitril gloves.
- Repeated use of disposable gloves not intended for re-use should be avoided.
- Repeated use of gloves produced for that purpose requires attention regarding training and personal hygiene.
Penetration through gloves depends on amount and concentration of the pesticide and accumulation within glove material may occur.
- During use of sales products with high concentrations of pesticides (e.g. during mixing and loading), the protective efficacy of disposable gloves made of latex or nitril will be severely reduced and other or more effective material is recommended.
- If accumulation of pesticide in the glove material is suspected, this may reduce the re-use of the gloves significantly.

13.2 Research aspects

A future perspective is the investigation of the reservoir effect in relation to solubility and molecular weight. This include:
- a thorough analysis of the amount of substance persisting in the skin after end of exposure
- the quantification of the fraction of substance that continuously penetrates to the systemic circulation after end exposure
- the assessment of the fraction that may be removed from the skin following different cleansing procedures
When studying dermal penetration it has been custom to focus on the active ingredient and not the commercial products. This report has described the influence of different detergents present in formulated products on penetration rate and lag-time.
- Therefore, there is a need to focus research on influence of detergents on penetration characteristics of sales products.
- Recognizing that the evidence for extrapolation between products containing the same active ingredient but different detergents may not be adequate, will require a continued focus on development of a best practice on reevaluation of already approved pesticides is needed.
Pesticides are often used in combination, and research has demonstrated increased as well as a decreased penetration rates depending on the substances.
- The studying of pesticides in combination is therefore an area that needs continued attention.
More recent experimental evidence demonstrates accumulation of chemicals in glove materials, which have clear implications for gloves used repeatedly.
- This area should receive specific attention as the exposure situations involving use of non-disposable gloves often involves use of sales formulations of pesticides (production, mixing, loading), where concentrations of pesticides handled are orders of magnitude higher than used during application.