Physicochemical and Biological Data for the Development of Predictive Organophosphorus Pesticide QSARs and PBPK/PD Models for Human Risk Assessment

ABSTRACT

A search of the scientific literature was carried out for physiochemical and biological data [i.e., IC₅₀, LD₅₀, K_p (cm/h) for percutaneous absorption, skin/water and tissue/blood partition coefficients, inhibition k_i values, and metabolic parameters such as V_max and K_m] on 31 organophosphorus pesticides (OPs) to support the development of predictive quantitative structure–activity relationship (QSAR) and physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) models for human risk assessment. Except for work on parathion, chlorpyrifos, and isofenphos, very few modeling data were found on the 31 OPs of interest. The available percutaneous absorption, partition coefficients and metabolic parameters were insufficient in number to develop predictive QSAR models. Metabolic kinetic parameters (V_max, K_m) varied according to enzyme source and the manner in which the enzymes were characterized. The metabolic activity of microsomes should be based on the kinetic activity of purified or cDNA-expressed cytochrome P450s (CYPs) and the specific content of each active CYP in tissue microsomes. Similar requirements are needed to assess the activity of tissue A- and B-esterases metabolizing OPs. A limited amount of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and carboxylesterase (CaE) inhibition and recovery data were found in the literature on the 31 OPs. A program is needed to require the development of physicochemical and biological data to support risk assessment methodologies involving QSAR and PBPK/PD models.

KEYWORDS:

• A- and B-esterases
• cytochrome P450 (CYP isozymes)
• K_m values for metabolism
• organophosphorus pesticides
• PBPK/PD models
• PON1
• QSAR
• skin permeability constants
• tissue partition coefficients
• V_max

ACKNOWLEDGMENTS

Our thanks are extended to Drs. Herb Nigg, University of Florida, James Olson, University of Buffalo, and Kurt Enslein, Rochester, NY, for reviewing the manuscript of this article and making helpful suggestions that improved its quality The work on this review was funded by the U.S. Environmental Protection Agency (EPA) through General Services Administration (GSA) contract GS–09K–99–BHD–0001, task 9T3Z061TMA with Anteon Corporation, Las Vegas, NV. It has been peer reviewed and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation by the U.S. EPA.