Inter-individual variation in chlorpyrifos toxicokinetics characterized by physiologically based kinetic (PBK) and Monte Carlo simulation comparing human liver microsome and Supersome™ cytochromes P450 (CYP)-specific kinetic data as model input

Abstract

The present study compares two approaches to evaluate the effects of inter-individual differences in the biotransformation of chlorpyrifos (CPF) on the sensitivity towards in vivo red blood cell (RBC) acetylcholinesterase (AChE) inhibition and to calculate a chemical-specific adjustment factor (CSAF) to account for inter-individual differences in kinetics (HKAF). These approaches included use of a Supersome™ cytochromes P450 (CYP)-based and a human liver microsome (HLM)-based physiologically based kinetic (PBK) model, both combined with Monte Carlo simulations. The results revealed that bioactivation of CPF exhibits biphasic kinetics caused by distinct differences in the Km of CYPs involved, which was elucidated by Supersome™ CYP rather than by HLM. Use of Supersome™ CYP-derived kinetic data was influenced by the accuracy of the intersystem extrapolation factors (ISEFs) required to scale CYP isoform activity of Supersome™ to HLMs. The predicted dose–response curves for average, 99th percentile and 1st percentile sensitive individuals were found to be similar in the two approaches when biphasic kinetics was included in the HLM-based approach, resulting in similar benchmark dose lower confidence limits for 10% inhibition (BMDL10) and HKAF values. The variation in metabolism-related kinetic parameters resulted in HKAF values at the 99th percentile that were slightly higher than the default uncertainty factor of 3.16. While HKAF values up to 6.9 were obtained when including also the variability in other influential PBK model parameters. It is concluded that the Supersome™ CYP-based approach appeared most adequate for identifying inter-individual variation in biotransformation of CPF and its resulting RBC AChE inhibition.

Physiologically based Kinetic Modeling-Facilitated Quantitative In Vitro to In Vivo Extrapolation to Predict the Effects of Aloe-Emodin in Rats and Humans

“…In the present study, the kinetics for the microsomal clearance of aloe-emodin and its conversion to rhein were quantified using pooled human liver microsomes. Future studies could quantify the effect of variation in CYP-mediated clearance and bioactivation of aloe-emodin by combining our PBK modeling with Monte Carlo simulations that select the respective kinetic parameters from the distribution describing the probability of the values for V max and K m within the human population . The sensitivity analysis presented in the present study reveals that especially variability in V max and K m for conversion of aloe-emodin to rhein will be of influence (Figure S8).…”

Acetylcholinesterase Inhibition in Rats and Humans Following Acute Fenitrothion Exposure Predicted by Physiologically Based Kinetic Modeling-Facilitated Quantitative In Vitro to In Vivo Extrapolation

“…Following exposure to organophosphate pesticides, liver CYP450s-mediated bioactivation and detoxification take place . For FNT, the bioactivation instead of its detoxification is found to be more efficient in rats and humans (Figure ), as opposed to the results found for chlorpyrifos and diazinon. , Several CYP450s including 1A2, 2B6, 2C19, and 3A4 were reported to participate in both bioactivation and detoxification of organophosphate pesticides, , while specific information on the CYP450s involved in FNT metabolism is limited. Levi et al purified two chemically induced isoforms (named as P-450 PB and P-450 BNF) from livers of mice that were pretreated orally or intraperitoneally with phenobarbital (PB) or β-naphthoflavone (BNF), inducers for CYP2B9/10 and 1A1/2 in mice, respectively. , In their study, P-450 PB and P-450 BNF were reported to produce higher amounts of FNO compared to MNP production.…”

“…Hydrolysis efficiency of PON1 toward oxons varies among organophosphate pesticides, as a slight change in their leaving groups can affect the orientation of the oxon in the active site and hence their conversion . For example, the PON1-catalyzed detoxification of methyl paraoxon was found to be less efficient than that of CPO in both rats and humans. , This observation is in agreement with the lower PON1 catalytic efficiency toward FNO (Table S4) as compared to that of CPO, considering that methyl paraoxon and FNO are highly similar in structure. Similar to CYP450s, the activity of PON1 shows interindividual differences, while relevant information is limited on how it will affect the resulting toxicity among individuals following acute FNT exposure.…”

“…The mechanism of acute neurotoxicity following organophosphate pesticide exposures is the inhibition of neuronal AChE; however, relevant in vivo data for it are usually unavailable especially for humans. In the absence of this information, the inhibition of erythrocyte AChE is considered to be an acceptable surrogate endpoint in scientific studies − and by regulatory bodies because erythrocyte AChE is more sensitive than the neuronal AChE, suggesting that a conservative POD could be derived with this endpoint.…”

“…New approach methodologies are currently explored in accordance with the principles of Next Generation Risk Assessment for chemical exposures to reduce the reliance on animal approaches. , As an example, physiologically based kinetic (PBK) modeling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE) has been widely employed for the prediction of the in vivo toxicity of chemicals with various endpoints, , including AChE inhibition following acute exposure to organophosphate pesticides in both rats and humans. − PBK models mathematically describe the body tissues as interconnected compartments linked by the blood, and can simulate time profiles of chemical concentrations in tissues under certain dose levels. ,, Using the PBK modeling-based QIVIVE approach, in vitro concentration-based toxic effects can be converted to corresponding in vivo dose-dependent responses, supporting the derivation of PODs for risk assessment without generating new animal data. − …”