PMID- 12634130
OWN - NLM
STAT- MEDLINE
DCOM- 20030506
LR  - 20181113
IS  - 0091-6765 (Print)
IS  - 0091-6765 (Linking)
VI  - 110 Suppl 6
IP  - Suppl 6
DP  - 2002 Dec
TI  - Physiological modeling and extrapolation of pharmacokinetic interactions from 
      binary to more complex chemical mixtures.
PG  - 989-94
AB  - The available data on binary interactions are yet to be considered within the 
      context of mixture risk assessment because of our inability to predict the effect 
      of a third or a fourth chemical in the mixture on the interacting binary pairs. 
      Physiologically based pharmacokinetic (PBPK) models represent a potentially 
      useful framework for predicting the consequences of interactions in mixtures of 
      increasing complexity. This article highlights the conceptual basis and validity 
      of PBPK models for extrapolating the occurrence and magnitude of interactions 
      from binary to more complex chemical mixtures. The methodology involves the 
      development of PBPK models for all mixture components and interconnecting them at 
      the level of the tissue where the interaction is occurring. Once all component 
      models are interconnected at the binary level, the PBPK framework simulates the 
      kinetics of all mixture components, accounting for the interactions occurring at 
      various levels in more complex mixtures. This aspect was validated by comparing 
      the simulations of a binary interaction-based PBPK model with experimental data 
      on the inhalation kinetics of m-xylene, toluene, ethyl benzene, dichloromethane, 
      and benzene in mixtures of varying composition and complexity. The ability to 
      predict the kinetics of chemicals in complex mixtures by accounting for binary 
      interactions alone within a PBPK model is a significant step toward the 
      development of interaction-based risk assessment for chemical mixtures.
FAU - Krishnan, Kannan
AU  - Krishnan K
AD  - Universit de Montreal, Montreal, Canada. kannan.krishnan@umonreal.ca
FAU - Haddad, Sami
AU  - Haddad S
FAU - Beliveau, Martin
AU  - Beliveau M
FAU - Tardif, Robert
AU  - Tardif R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
PL  - United States
TA  - Environ Health Perspect
JT  - Environmental health perspectives
JID - 0330411
RN  - 0 (Environmental Pollutants)
RN  - 0 (Xenobiotics)
SB  - IM
MH  - Animals
MH  - Drug Interactions
MH  - Environmental Pollutants/*adverse effects/*pharmacokinetics
MH  - Forecasting
MH  - Humans
MH  - *Models, Theoretical
MH  - *Pharmacokinetics
MH  - Reproducibility of Results
MH  - Risk Assessment/methods
MH  - Xenobiotics/*adverse effects/*pharmacokinetics
PMC - PMC1241283
EDAT- 2003/03/14 04:00
MHDA- 2003/05/07 05:00
PMCR- 2002/12/01
CRDT- 2003/03/14 04:00
PHST- 2003/03/14 04:00 [pubmed]
PHST- 2003/05/07 05:00 [medline]
PHST- 2003/03/14 04:00 [entrez]
PHST- 2002/12/01 00:00 [pmc-release]
AID - sc271_5_1835 [pii]
AID - 10.1289/ehp.02110s6989 [doi]
PST - ppublish
SO  - Environ Health Perspect. 2002 Dec;110 Suppl 6(Suppl 6):989-94. doi: 
      10.1289/ehp.02110s6989.