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Evaluating pharmacokinetic and pharmacodynamic interactions with computational models in supporting cumulative risk assessment.

Tan YM, Clewell H, Campbell J, Andersen M - Int J Environ Res Public Health (2011)

Bottom Line: In such cases, conducting quantitative cumulative risk assessment for chemicals present as a mixture is difficult.The uncertainties that arise from PK interactions can be addressed by developing physiologically based pharmacokinetic (PBPK) models to describe the disposition of chemical mixtures.Further, PK models can be developed to describe mechanisms of action and tissue responses.

View Article: PubMed Central - PubMed

Affiliation: National Exposure Research Laboratory, Office of Research and Development, US Environmental Protection Agency, 109 TW Alexander Drive, Research Triangle Park, NC 27711, USA.

ABSTRACT
Simultaneous or sequential exposure to multiple chemicals may cause interactions in the pharmacokinetics (PK) and/or pharmacodynamics (PD) of the individual chemicals. Such interactions can cause modification of the internal or target dose/response of one chemical in the mixture by other chemical(s), resulting in a change in the toxicity from that predicted from the summation of the effects of the single chemicals using dose additivity. In such cases, conducting quantitative cumulative risk assessment for chemicals present as a mixture is difficult. The uncertainties that arise from PK interactions can be addressed by developing physiologically based pharmacokinetic (PBPK) models to describe the disposition of chemical mixtures. Further, PK models can be developed to describe mechanisms of action and tissue responses. In this article, PBPK/PD modeling efforts conducted to investigate chemical interactions at the PK and PD levels are reviewed to demonstrate the use of this predictive modeling framework in assessing health risks associated with exposures to complex chemical mixtures.

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Related in: MedlinePlus

The impact of pharmacokinetic (PK) interactions on target tissue dose. The term “PK interaction” refers to the case in which one unit of applied dose to chemical X in the presence of other chemicals leads to less (examples in Section 3.1) or more (examples in Section 3.2) than one unit of target tissue dose compared to exposure to chemical X by itself.
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f2-ijerph-08-01613: The impact of pharmacokinetic (PK) interactions on target tissue dose. The term “PK interaction” refers to the case in which one unit of applied dose to chemical X in the presence of other chemicals leads to less (examples in Section 3.1) or more (examples in Section 3.2) than one unit of target tissue dose compared to exposure to chemical X by itself.

Mentions: When assessing the toxicity and the resulting risk of chemical mixtures, a more mechanistic approach should be taken to characterize the interactions among individual chemicals in a mixture. In this article, two types of interactions will be discussed: Pharmacokinetic (PK) and pharmacodynamic (PD) interactions [6]. Interactions related to cell signaling networks that can affect a common physiological process are also important when assessing cumulative risk, but are not the focus of this article. Simply put, PK depicts the process of chemicals being absorbed, distributed to, metabolized within, and eliminated (ADME) from various organs and tissues. The term ‘PK interaction’ refers to the case in which one unit of applied dose to chemical “X” in the presence of other chemicals leads to more or less than one unit of target tissue dose compared to exposure to chemical “X” by itself (Figure 2). Most interactions studied to date are PK interactions. On the other hand, PD describes how chemicals bring about tissue responses. The term “PD interaction” refers to the case which one unit of target tissue dose brought about by chemical “X” in the presence of other chemicals leads to more or less than one unit of tissue response compared to response caused by chemical “X” by itself (Figure 3). With the proper identification of interactions occurring at various levels, a more integrated systems approach can then be applied to provide a better perspective on how both biology and biochemistry impact mixture toxicity and cumulative risk.


Evaluating pharmacokinetic and pharmacodynamic interactions with computational models in supporting cumulative risk assessment.

Tan YM, Clewell H, Campbell J, Andersen M - Int J Environ Res Public Health (2011)

The impact of pharmacokinetic (PK) interactions on target tissue dose. The term “PK interaction” refers to the case in which one unit of applied dose to chemical X in the presence of other chemicals leads to less (examples in Section 3.1) or more (examples in Section 3.2) than one unit of target tissue dose compared to exposure to chemical X by itself.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3108131&req=5

f2-ijerph-08-01613: The impact of pharmacokinetic (PK) interactions on target tissue dose. The term “PK interaction” refers to the case in which one unit of applied dose to chemical X in the presence of other chemicals leads to less (examples in Section 3.1) or more (examples in Section 3.2) than one unit of target tissue dose compared to exposure to chemical X by itself.
Mentions: When assessing the toxicity and the resulting risk of chemical mixtures, a more mechanistic approach should be taken to characterize the interactions among individual chemicals in a mixture. In this article, two types of interactions will be discussed: Pharmacokinetic (PK) and pharmacodynamic (PD) interactions [6]. Interactions related to cell signaling networks that can affect a common physiological process are also important when assessing cumulative risk, but are not the focus of this article. Simply put, PK depicts the process of chemicals being absorbed, distributed to, metabolized within, and eliminated (ADME) from various organs and tissues. The term ‘PK interaction’ refers to the case in which one unit of applied dose to chemical “X” in the presence of other chemicals leads to more or less than one unit of target tissue dose compared to exposure to chemical “X” by itself (Figure 2). Most interactions studied to date are PK interactions. On the other hand, PD describes how chemicals bring about tissue responses. The term “PD interaction” refers to the case which one unit of target tissue dose brought about by chemical “X” in the presence of other chemicals leads to more or less than one unit of tissue response compared to response caused by chemical “X” by itself (Figure 3). With the proper identification of interactions occurring at various levels, a more integrated systems approach can then be applied to provide a better perspective on how both biology and biochemistry impact mixture toxicity and cumulative risk.

Bottom Line: In such cases, conducting quantitative cumulative risk assessment for chemicals present as a mixture is difficult.The uncertainties that arise from PK interactions can be addressed by developing physiologically based pharmacokinetic (PBPK) models to describe the disposition of chemical mixtures.Further, PK models can be developed to describe mechanisms of action and tissue responses.

View Article: PubMed Central - PubMed

Affiliation: National Exposure Research Laboratory, Office of Research and Development, US Environmental Protection Agency, 109 TW Alexander Drive, Research Triangle Park, NC 27711, USA.

ABSTRACT
Simultaneous or sequential exposure to multiple chemicals may cause interactions in the pharmacokinetics (PK) and/or pharmacodynamics (PD) of the individual chemicals. Such interactions can cause modification of the internal or target dose/response of one chemical in the mixture by other chemical(s), resulting in a change in the toxicity from that predicted from the summation of the effects of the single chemicals using dose additivity. In such cases, conducting quantitative cumulative risk assessment for chemicals present as a mixture is difficult. The uncertainties that arise from PK interactions can be addressed by developing physiologically based pharmacokinetic (PBPK) models to describe the disposition of chemical mixtures. Further, PK models can be developed to describe mechanisms of action and tissue responses. In this article, PBPK/PD modeling efforts conducted to investigate chemical interactions at the PK and PD levels are reviewed to demonstrate the use of this predictive modeling framework in assessing health risks associated with exposures to complex chemical mixtures.

Show MeSH
Related in: MedlinePlus