Absorption - Pesticide Biotransformation and Disposition - page 46

These in vitro systems can be used to assess the relative influence of several formu-
lation and biological factors that determine dermal and oral absorption of pesticides
without having to use in vivo animal models or humans in the early stages of for-
mulation development or human health risk assessments. The recent improvements in
computer modeling capabilities have resulted in the development of numerous quan-
titative structure permeability relationships (QSPRs) that have proven to be predictive
of dermal and oral permeability in humans for several solutes, including many pesti-
cides currently in use ( Baynes et al., 2008; Potts and Guy, 1992; Riviere and Brooks,
2007; Zhao et al., 2002 ). A very popular method, the Rule of 5, utilizes similar QSPR
principles and has proven to be useful as a rapid screen for compounds that are likely
to be poorly absorbed orally ( Lipinski et al., 1997 ). This rule states that if a compound
satisfies any two of the following rules, it is likely to exhibit poor intestinal absorp-
tion: (1) molecular weight  500, (2) number of hydrogen bond donors  5 (a donor
being any O-H or N-H group), (3) number of hydrogen acceptors  10 (an accep-
tor being any O or N including those in donor groups), and (4) C log P  5.0 or
M log P  4.15. There are numerous other original peer-reviewed research articles
that readers are encouraged to review to get a glimpse of how these QSPR models
are being developed and applied to human risk assessment. It should be noted that, in
many instances, many of the data used in developing these models are often obtained
from multiple sources and laboratories with diverse dosing and experimental proto-
cols, and the statistical analyses (e.g., appropriate measures of goodness-of-fit, robust-
ness, and predictivity) and a defined application domain may not be reported. Many
of these criteria are important for valid evaluation of QSAR models that could predict
pesticide absorption as new regulatory frameworks such as REACH in the European
Union are implemented in various jurisdictions ( Bouwman et al., 2008 ). Caution
should therefore be exercised with the mechanistic interpretation and application of
these permeability models to any given exposure scenario. The future of risk assess-
ment of pesticides will depend heavily on the quality of these permeability models and
their flexibility in predicting dermal and oral absorption in a variety of human expo-
sure scenarios at home and at work.
REFERENCES
Abrams, K., Hogan, D. J., & Maibach, H. I. (1991). Pesticide-related dermatoses in agricultural workers.
Occup. Med. , 6 , 463-492.
Alvinerie, M., Dupuy, J., Kiki-Mvouaka, S., Sutra, J. F., & Lespine, A. (2008). Ketoconazole increases the
plasma levels of ivermectin in sheep. Vet. Parasitol. , 157 (1-2), 117-122.
Anadon, A., Martinez-Larranaga, M. R., Diaz, M. J., & Bringas, P. (1991). Toxicokinetics of permethrin in
the rat. Toxicol. Appl. Pharmacol. , 110 , 1-8.
Barry, B. W. (1991). The LPP theory of skin penetration enhancement. In R. L. Bronough & H. I. Maibach
(Eds.), In vitro percutaneous absorption: Principles, fundamentals, and applications (pp. 165-185). Boca Raton,
FL: CRC Press.