Pesticide regulations: exposure-dose modeling from FIFRA to FQPA.

The federal laws and regulations governing the registration and use of pesticides in the United States under the Federal Insecticide, Fungicide, and Rodenticide Act are published in the Federal Register, while state laws such as California are published in the California Food and Agricultural Code, Divisions 6, 7, and 13. Up until the passage of the Food Quality Protection Act (FQPA of 1996), federal and state regulations pertaining to the registration and use of pesticides were in most cases identical except for the fact that food tolerances were enforced but not set at the state level. The California Department of Pesticide Regulation's Worker Health and Safety Program continues to monitor worker exposure to pesticides and report illnesses among workers associated with pesticide exposure. Under FQPA, the United States Environmental Protection Agency (EPA) has taken a leadership role in the development of probabilistic pesticide exposure models (i.e., DEEM, SHEDS, etc.) using pesticide application, human activity, and exposure databases (i.e., CPPAES, CHAD, CSFII, FCID, NHANES, and NHEXAS). A physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling framework has been established by EPA to assess cumulative risk of dose and injury to infants and children to organophosphorus, carbamate (NMC), and pyrethroid insecticides from aggregate sources and routes. Probabilistic models are being linked to PBPK/PD models to improve risk assessments.

Parameters for Carbamate Pesticide QSAR and PBPK/PD Models for Human Risk Assessment.

Our interest in providing parameters for the development of quantitative structure physiologically based pharmacokinetic/pharmacodynamic (QSPBPK/PD) models for assessing health risks to carbamates (USEPA 2005) comes from earlier work with organophosphorus (OP) insecticides (Knaak et al. 2004). Parameters specific to each carbamate are needed in the construction of PBPK/PD models along with their metabolic pathways. Parameters may be obtained by (1) development of QSAR models, (2) collecting pharmacokinetic data, and (3) determining pharmacokinetic parameters by fitting to experimental data. The biological parameters are given in Table 1 (Blancato et al. 2000). Table 1 Biological Parameters Required for Carbamate Pesticide Physiologically Based Pharmacokinetic/Pharmacodynamic (PBPK/PD) Models.(a).

Physicochemical and biological data for the development of predictive organophosphorus pesticide QSARs and PBPK/PD models for human risk assessment.

A search of the scientific literature was carried out for physiochemical and biological data [i.e., IC50, LD50, Kp (cm/h) for percutaneous absorption, skin/water and tissue/blood partition coefficients, inhibition ki values, and metabolic parameters such as Vmax and Km] 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 (Vmax, Km) 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.