Summary

Transport af bekæmpelsesmidler over moderkagen, analogier til percutan transport og modellering

Knowledge on absorption of pesticides across the human placenta is limited. Ex-vivo perfusion of the human term placenta is a method to study placental passage. Results from this model will be an important element in assessment of risk related to reproductive toxicity. Absorption across the human skin as well as placenta depends to a large extent on passive diffusion. This study was designed to provide and use data from 9 substances including 5 pesticides in current use to develop a mathematical model enabling prediction of placental transfer of new compounds.

The placental perfusion method with maternal and fetal recirculating compartments studies transport from the maternal to the fetal compartment by measurements of the concentration of the studied compound in the maternal compartment C_M and the fetal compartment C_F. The ratio of C_F versus C_M (FM-ratio) increases linearly for the first 30-60 minutes of the study period and later reach equilibrium. The initial slope of the the FM ratio is named the indicative permeability coefficient (IPK) and this parameter is used as indicator of the initial transport across placenta. The study includes data from skin penetration studies of lag-time, skin deposition and skin penetration (Kρ). The model compounds included were benzoic acid, bisphenol A, caffeine, antipyrine and the pesticides dimethoate, glyphosate, methiocarb, miconazol, tebuconazole.

Caffeine and dimethoate cross the placenta by passive diffusion as indicated by their transfer rates. The initial transfer rate of benzoic acid was more limited in the first part of the perfusion compared to caffeine, but reached the same steady state level by the end of perfusion as measured by the FM-ratio. The placental transfer of glyphosate, bisphenol A, tebuconalzol and methiocarb was restricted throughout perfusion with a lower permeation rate and a lower FM ratio. Miconazol did not pass the placenta, but accumulated in the placental tissue.

In the placenta perfusion model a clear relationship was seen between placental transfer, estimated by the indicative permeability coefficient (IPK) and the (FM-ratio₁₅₀) and the lipophilicity (logKow). Thus, the higher the logKow, the lower the permeability coefficient (IPK) between foetal and maternal compartments. Glyphosate however does not show this relationship. A linear relationship between IPK and LogKow of r²=0.96 is seen excluding glyphosate from the calculations. In a logarithmic model the IPK values increase by increasing water solubility.

In the skin transport model no clear relationship was observed between molecular weight and Kρ values (Kρ is the permeability coefficient for diffusion across the skin). With increasing molecular weight, the lag-time was increased. The relative deposition in the skin was highest for the lipophilic model compounds. For logKow values between -3.5 and 2 a linear relationship was observed between logKow and logKρ.

For several model substances a considerable lag-time is observed for the skin absorption (dimethoate, bisphenol A, tebuconazol). During placental transfer a lag-time in the same scale is not observed as only a small lag-time is observable for bisphenol A, tebuconazol and methiocarb. The reason is probably a possibility of temporary deposit in the skin compared to the placenta

Our studies demonstrate comparability between dermal and placental transport and common relationships between transport and hydrophilicity of compounds. Antipyrin does not comply with the relations for dermal absorption as antipyrin does not pass the dermal barrier but crosses the placenta and is inscluded as the control substance. The lack of skin penetration is assumed caused by the high water solubility of antipyrine (51.9 g/L) indicating water solubility of importance in skin penetration. Our studies confirm comparability in modelling of the transport across skin and placenta barriers of different origin. The model should be extended with data from more compounds and could potentially be improved through the inclusion of transport data from in vitro transport models using cells resembling placental and dermal tissues.

Our studies demonstrate comparability between dermal and placental passage of chemicals. For both skin- and placental passage of chemicals hydrophilicity, lipophilicity and size is relevant parameters. The observed comparability may be used to extrapolate existing knowledge of the dermal penetration of single substances or groups of substances to an expected placental passage. There will be considerable differences for single substances; also seen in this study, but simple qualitative extrapolation of skin absorption to placenta passage is anticipated. Generally and quantitative extrapolation, however, are not expected.

Reproducibility and validity of the extrapolations should be extended by supplementary placenta- and skin absorption datasets. In the future, such data is expected to be part of QSAR models predicting absorption/passage of specific substances across different barriers. In the long-term and in combination with supplementary in vitro tests the model results are expected to contribute to a reduction in the use of laboratory animals to study the transport of chemicals over biological barriers.

Part of the transport data has already been published and more papers are expected from this project

Mose T, Kjaerstad MB, Mathiesen L, Nielsen JB, Edelfors S, Knudsen LE. Placental passage of benzoic acid, caffeine, and glyphosate in an ex vivo human perfusion system. J Toxicol Environ Health A. 2008;71(15):984-91.

Nielsen JB, Sørensen JA, Nielsen F. The usual suspects - influence of physico-chemical properties on lag-time, skin deposition and percutaneous penetration of nine model compounds. J Toxicol Environ Health. 2008b; In press.