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Better Exposure-Dose models for Pesticides ^

James B. Knaak1, Rogelio Tornero-Velez2, Fred Power2, Jeny H. Blancato2, Curtis C. Dary2
'State University of Hew York at Buffalo, MY. 2U.S. EPA, Human Exposure and Atmospheric Sciences Division, Las Vegas, NV

Technologies

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Reduce uncertainties in
risk assessment through
improved exposure-dose
models.

To address this need,
physiologically-based
pharmacokinetic (PBPK)
models are increasingly
being used in the evaluation
of chemical exposures on
human health.

?MSI®

PBPK models require
metabolism parameters to
properly estimate tissue dose;
however, no single parameter
value is universal to all people
due to population variability in
enzyme levels.

Account for human variability
in metabolism in exposure-
dose model. igfeJtJish a
tractable relationship between
the tissue enzyme content and
metabolic activity in the model.

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1 . Determine the specific
metabolic activity (Vmax, Km)
for each isozyme
(e.g., CYPs, PONi).

3. Employ normalized
metabolism parameter,
based on content of
individual CYP isozymes
in the PBPK model.

NR =

pmol

pmolCYP

pmolCYV

ma MSP

PBPK Model for Parathion

Described in model: q^g^Jnrome P450
isozymes (CYPs) located in the liver catalyze
the activation of parathion to paraoxon, the
toxic cholinesterase (ChE) inhibiting agent.
A-esterases oxonases (PON1), located in brain
catalyze the hydrolysis of paraoxon to nontoxic
hydrolysis products.

2. Determine the specific content of
CYP isozymes in human liver
microsomes (pmol/ mg MSP).

CYP

1A2*

2A6

2B6*

2C9

2C19

2D6

2E1

3A4*

3A5

HLM-3

83

42

83

95

HLM-23

50

20

74

52

38

0.5

HLM-24

85

56

41

85

0.72

HLM-34

77

54

42

29

84

79

1.00

HLM-43

23

70

53

28

306

1.1

HLM-56

35

30

47

22

94

0.7

46.2

52.2

15.6

17.0

14.0

51.6

116

0.82



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