Enhancing biological equivalen ts by biologically effective dose using a generic pbtk model the case of bpa and dehp

SOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013

ENHANCING BIOMONITORING EQUIVALENTs BY BIOLOGICALLY EFFECTIVE DOSE USING A GENERIC

PBTK MODEL - THE CASES OF BPA AND DEHP

D.A. SarigiannisS.P. KarakitsiosA. Gotti

1Aristotle University of Thessaloniki, Department of Chemical Engineering, Environmental Engineering Laboratory, Thessaloniki, 54124, Greece; 2Centre for Research and Technology Hellas (CE.R.T.H.), Thessaloniki, 57001,Greece

GI tract – portal vein

Liver

Heart

Brain

Muscles

Skin

Kidneys

Adipose

Bones

Breast

Uterus - gonads

Lungs


Liver

Heart

Brain

Muscles

Skin

Kidneys

Adipose

Bones

Breast

Uterus - gonads

Lungs

BPA - Glu &BPA – Sulfformation


Liver

Heart

Brain

Muscles

Skin

Kidneys

Adipose

Bones

Gonads

Lungs


Liver

Heart

Brain

Muscles

Skin

Kidneys

Adipose

Bones

Gonads

Lungs


PlacentaPlacenta

Arterial blood Venous blood Arterial blood Venous blood Arterial blood Venous blood Arterial blood Venous blood


This study attempts to refine the Risk Characterization Ratio (RCR) calculation comparing Biomonitoring Equivalents (BEs) with tissue-specific Biologically Effective Dose (BED) of the chemicals in question. This is expected to improve significantly the efficacy of risk assessment.

Rationale

Social BenefitSocial cost

Incr

easi

ng c

ost →

Incr

easi

ng b

enef

it →

Optimal cost-benefit

Acceptable risk

Exposure reduction →


Rationale

The overall methodology is demonstrated for Bisphenol-A (BPA) and di(2-ethylhexyl)phthalate (DEHP), both known to be Endocrine Disruptors (EDs).


Methodological concept – current status

Animal POD

Human Equiv. POD

UF A

H

BEPOD

BE

UF H

Estimate sum of metabolites using excretion fraction data; divide by avg. daily creatinine

excretion or urinary volume

Simple PK considerations

Animal dose

UF

AH

Human dose(e.g. RfC, TDI)

UF A

BE



excretion or urinary volume - UFH


Threshold value systemic reference

BPANOAEL 5 mg µg/kg_bw/day →UF = 10 intra-species and 10 for inter-individual differences → TDI 5 µg/kg bw/day

EFSA, 2006

DEHP

NOAEL 44 mg µg/kg_bw/day →UF = 10 intra-species and 10 for inter-individual differences, 10 for potential teratogenicity) → TDI 5 µg/kg bw/day

Health Canada, 1998

NOAEL 5 mg µg/kg_bw/day →UF = 10 intra-species, 10 (for adults) 20 (kids above 3 months) - 25 (neonates up to 3 months) inter-individual differences) → TDI 50-20 µg/kg bw/day

ECB, 2008

NOAEL 5 mg µg/kg_bw/day →UF = 10 intra-species, 10 inter-individual differences) → TDI 50 µg/kg bw/day

EFSA, 2005

Methodological concept – current statusfor BPA and DEHP


Animal POD

Human Equiv. POD

UF A

H

BEPOD

BE

UF H




Animal dose

UF

AH


UF A

Human BED

UF

H

BE

Human PBTK

Reverse dosimetry

Human dose(capturing

bioavailability differences)

Human PBTK

Human PBTK

Methodological concept [a] – Uncertain about MOA and PD similarities

BE




UFAH


Animal POD

Human Equiv. POD

UF A

H

BEPOD

BE

UF H




Animal dose

UF

AH


UF A

Animal BED to Human BED (equal (?) with respect to the mode of action)

Human BED

UF

H

BE

Human PBTK

Animal BED Reverse dosimetry

Human dose(capturing

bioavailability differences)

UFA

Human PBTK

Animal PBTK

Methodological concept [b] – confident about MOA and PD similarities

BE





Mother –Fetus interaction

Breast feeding link

b dV a T c T e

Organ volumes (V) and blood flows (Q) were taken from the ICRP (2002) report and the obtained data were fitted to time (T) in order to exclude continuous time depended non lineal polynomial formulas in the form of:

0.75

__ _

_

tissue childtissue child tissue adult

tissue adult

VPS PS

V

The permeability parameters PS were scaled according to the formula:

ADME processes

( ) lim Priji i j ij ij ij ij ij

dCV Q CA CV Metab E Absorp Binding

dt

__ _ _ _ _

uterus_M uterus Muterus M art M d uter pla placenta uterus M

uterus

Q CF C K C C

t P

_ _ _ _

_ _ _

placenta placentad uter pla placenta uterus M placenta_B art B

placenta

placentad pla amniot placenta amniot m placenta placenta

amniot

Q CK C C F C

t P

PK C C K C

P

_ __ _ _ int_

_

breast breastcell breast breast excr

breast

dC CV PS fu C L

dt K

__ _ /

_

breastexcr milk milk blood

breast

CL Q P

K

_ __ /

_ _

ow tissue tissuemilk blood

ow blood blood

K Fl FwP

K Fl Fw

_ _ _ _ _

_ _ _ _ _

placentaamniotd pla amniot placenta amniot e gut B gut B

amniot

e bile B liver B a amniot B amniot

PQK C C K C

t P

K C K C


Liver

Heart

Brain

Muscles

Skin

Kidneys

Adipose

Bones

Breast

Uterus - gonads

Lungs


Liver

Heart

Brain

Muscles

Skin

Kidneys

Adipose

Bones

Breast

Uterus - gonads

Lungs


PlacentaPlacenta

Arterial blood Arterial blood Venous blood


Liver

Heart

Brain

Muscles

Skin

Kidneys

Adipose

Bones

Gonads

Lungs


Liver

Heart

Brain

Muscles

Skin

Kidneys

Adipose

Bones

Gonads

Lungs


Arterial blood Arterial blood Venous blood

/ow tissue tissue

tissue bloodow blood blood

K Fl FwP

K Fl Fw

The blood/tissue partition coefficients are contaminant specific and are estimated by the tissue lipids content and the octanol/water partition coefficient of the contaminant by the following formula

Sarigiannis DA, Karakitsios SP. A dynamic physiology based pharmacokinetic model for assessing lifelong internal dose. AIChE 2012, Pittsburgh, PA, 2012.

Generic human/rodents lifelong PBTK model


BPA human/rattoxicokinetic differences

0.0

0.5

1.0

1.5

2.0

2.5

3.0

Human

Rat

Time (h)

Free

pla

sma

BP

A (μ

g/L)

Single oral dose of 50μg/kg_bw

Actual BED is higher in mice due to enterohepatic recirculation

↓Toxicokinetic factor for animal to human extrapolation not quite necessary if PBTK model is used

↓What about human inter-individual variability?


BPA human inter-individual variability

- BPA-GLU de-conjugates to BPA in the placenta, increasing the actual dose during pregnancy

- BPA-GLU de-conjugates to BPA in the stomach, increasing the actual dose during breast feeding, thus, the sum of BPA and BPA-GLU needs to be taken into account as BPA dose during breast feeding

- Very strong plasma protein binding

- Wider inter-individual variability regarding glucuronidation capacity (significantly lower clearance for neonates/infants)

- First-pass metabolism decisive for clearance – wide bioavailability differences are expected from routes beyond oral (up to six times higher internal dose concentrations for inhalation compared to oral)

0.1441026083543190.163595684840363 0.18340316578586

Adult EFSA TDI dose (50 μg/kg-bw/d) BED

Free plasma BPA (μg/L)


BPA daily exposure and RCR

EFSA BED-BE [a] BED-BE [b]0.00

0.20

0.40

0.60

0.80

1.00

1.20 Fetus

Premature infants

Bottle fed neonates

Breastfed neonates

Children

Adults

RC

R

Daily intake under typical exposure scenarios

RCR under different methodological schemes

Fetus Premature infants

Bottle fed neonates

Breastfed neonates

Children Adults0

2

4

6

8

10

12

14

Expo

sure

(μg/

kg_b

w/d

)


DEHP human/rat toxicokinetic differences

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0

50

100

150

200

250Human DEHPRat DEHPHuman MEHP

Time (h)

DE

HP

pla

sma

(μg/

L)

ME

HP

pla

sma

(μg/

L)

Single oral dose of 50μg/kg_bw

Actual BED is higher in rat (especially MEHP) due to enterohepatic recirculation and slower renal elimination of MEHP-Glu

↓Toxicokinetic factor for animal to human extrapolation not quite necessary if PBTK model is used


Inhalation Oral Skin0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4 Adults

Kids

Upt

ake

(μg/

kg_b

w/d

)DEHP daily exposure and RCR

Daily intake under typical exposure scenarios

RCR under different methodological schemes

EFSA BED-BE [a] BED-BE [b]0.00

0.01

0.02

0.03

0.04Adults

Children

RC

R


Conclusions

• Incorporating toxicokinetic considerations in animal to human extrapolation allows multiple options for minimizing uncertainty and unnecessary conservatism, based on whether uncertainty and knowledge gaps are related mostly to MOA or toxicokinetics

• Identification of inter-individual differences in bioavailability related to - inter-individual variability of enzyme related genotypes- windows of developmental susceptibility (e.g. pregnancy and infancy) due to

immature detoxification processes- route of administration might be more important than inter-species differences

• Refinement of RCR should rely not only on the accurate identification of toxicological thresholds, but also on the relevance of exposure scenarios in terms of age groups and administration route.

• This way, unnecessary conservatism (e.g oral exposure scenarios for adults exposed to levels marginally above TDI) is avoided and exposure scenarios posing risks are identified (e.g. premature infants hosted to intensive care units exposed to BPA at levels below TDI)


Thank you for your kind attention

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Enhancing biological equivalen ts by biologically effective dose using a generic pbtk model the case of bpa and dehp