National Institutefor Public Healthand the Environment The bioaccessibility and relative
bioavailability of lead from soils for fasted and fed conditionsDerivation of the “average physiological state”
correction factorWerner Hagens and Agnes Oomen
National Institutefor Public Healthand the Environment
Lead contamination in the Netherlands
several sources
(historic) use
National Institutefor Public Healthand the Environment
Exposure to lead via soil
- Contamination of lead in soils of old cities due to historical use and misuse
- Contact human-soil is relevant: Potential risk
- Especially children are at risk• Hand-to-mouth contact• Lead absorption is better (associated with calcium)• Toxic effects (neurobehavioral functioning, intelligence)
National Institutefor Public Healthand the Environment
Exposure to contaminant in a matrix
Ingestion of matrix + contaminant
Fb = Fraction released from matrix = bioaccessible fraction
Fa = Fraction of Fb absorbed by small intestine
Fh = Fraction of Fa passing liver without being metabolised
F = Fraction reaching systemic circulation = bioavailable fraction
F = Fb x Fa x Fh
In vitro digestion model
Oral bioavailabilityExternal exposure
small intestineportal vein
liver
mouth
oesophagus, stomach, small intestine
systemic circulation
Internal exposureF
FhFh
Fb
Fa
National Institutefor Public Healthand the Environment
• Bioavailability of lead from soil ≠
bioavailability dietary lead• Aim is to obtain a value for the relative bioavailability
• Where FMPR represents the bioavailability of lead in the matrix that was used in the studies for deduction of the Maximum Permissible Risk (MPR)
• MPR-studies based on dietary lead in which it was indicated that bioavailability of lead was about 40% (children)
Further information: ⇒ RIVM-report 711701042 (http://www.rivm.nl/en/)
b,soil a,soil h,soilsoil
MPR b,MPR a,MPR h,MPR
F F FFRelative F=F F F F
× ×=
× ×
Relative bioavailability
National Institutefor Public Healthand the Environment
Implementation of relative bioavailability in risk assessment
Risk assessment needs relative oral bioavailability as input (Rel F)
sA ID C FD IW
R e l× ×=
With:
•DI: uptake via ingestion (mg contaminant×kg-1×d-1)
•AID: daily intake soil/house dust via ingestion (kg×d-1)
•W: body weight (kg)
•Rel F: relative oral bioavailability factor (-)
•Cs : Concentration contaminant in soil/house dust (mg contaminant×kg-1)
National Institutefor Public Healthand the Environment
FED versus FASTED physiological state
• Lead is better absorbed in fasted conditions (Fa )• Bioaccessibility of lead from soil is higher for fasted
conditions (Fb )• In risk assessment, fasted state results in more
conservative relative bioavailability values (Rel F)
National Institutefor Public Healthand the Environment
Fed-Fasted physiological state in Dutch risk assessment
The choice of the physiological state (fed, fasted or average fed/fasted) influences bioaccessibility from lead
Dutch policy encourage an “average physiological state” condition
Rational:• A child will not always ingest soil when he/she is fasted or fed• Average conditions would be more realistic (not worst-case)
Derive an “average physiological state” correction factor- In vitro bioaccessibility for fasted conditions can be used to derive
Fb,average conditions- Reduction in time and costs - More realistic
National Institutefor Public Healthand the Environment
The Correction Factor for the Average Physiological State (CFAPS )
• α
= Fb soil, Fasted / Fb soil, Fed- α
= ratio bioaccessibility fasted/fed from soils- Fb soil, Fed = Bioaccessibility of lead from soil as estimated for fed conditions- Fb soil, Fasted = Bioaccessibility of lead from soil as estimated for fasted
conditions
• CFAPS = (1 + α)/2 - CFAPS = Correction Factor “Average Physiological State”- α
= ratio bioaccessibility fasted/fed from soils
• Fb soil, APS = Fb soil, Fasted x CFAPS
National Institutefor Public Healthand the Environment
From bioaccessibility to relative bioavailability factor for “average” physiological conditions
Fill in:• Fa, soil = 0.8 • Fh, soil = 1 (no lead metabolism)• Fb, soil = value from in vitro digestion model• FMPR = 0.4
• Rel FAverage physiological state = 2 x Fb soil, fasted x CFAPS
b,soil a,soil h,soilsoil
MPR b,MPR a,MPR h,MPR
F F FFRelative F=F F F F
× ×=
× ×
b,soil a,soil b,soil b,soil
b,MPR a,MPR
F F F 0.8 FRelative F=
F F 0.4 0.5× ×
= =×
National Institutefor Public Healthand the Environment
The current use of CFAPS
Up till now, fasted and fed conditions were tested for only 11 soils
A conservative percentile (P80) was chosen by Dutch policy makers to ensure safe application of the correction factor.
soil number breakfast spaghetti1 1.00 0.462 0.73 0.333 no data * no data *4 0.59 0.215 0.52 0.156 0.51 0.547 0.50 0.54 P50 0.56 0.7818 0.71 0.85 P60 0.59 0.7979 0.60 0.67 P70 0.66 0.832
10 0.70 0.65 P80 0.71 0.85511 0.58 0.34 P90 0.74 0.87112 0.36 0.74 P95 0.85 0.923
Percentile
Ratio fed/fasted conditions
α
"Average physiological state" correction factor
CFAPS
Bioaccessibility ratio for fed/fasted conditions
National Institutefor Public Healthand the Environment
Current use of bioavailability in Human risk assessment in the Netherlands (Lead)
• TDI (Tolerable daily intake) of lead in humans is 3.6 µg Pb/kg body weight/day (based on 40% bioavailability in MPR study)
• Intervention value for lead in soil should be 301 mg/kg for scenario “living with garden” in the Netherlands
But….. Dutch intervention value for lead is currently 530 mg soil
Because:1- assumption of daily ingestion of 100 mg soil (in stead of 150 mg)2- intervention value correction factor (see next sheet!)
National Institutefor Public Healthand the Environment
Current intervention value correction factor
Intervention value correction factor = 0.74• P80 for relative bioavailability of lead in tested soils (all
soils till 2007) (=Rel F soil,fasted )• P80 for difference between fasted and average state
in gastrointestinal tract (=CFAPS )
The current intervention value correction factor• P80 Rel Ffasted x P80 CFAPS = 0.87 x 0.855 = 0.74
The decision which percentile level is chosen in risk assessment is made by policy makers, depending on the level of certainty that is desired
National Institutefor Public Healthand the Environment
Objective of this study
• Derive an “average physiological state” correction factor (CFAPS )• To estimate the bioaccessibility of lead for “average physiological state”
conditions based on the bioaccessibility determined for fasted conditions. • To make risk assessment more realistic.
• Previously, the “average physiological state” correction factor (CFAPS ) was derived from fasted and fed data obtained with the in vitro digestion model for 22 samples (11 separate soils with 2 different food types).
• By order of the Ministry of Housing, Spatial Planning and Environment (VROM), this correction factor is now further substantiated by investigation of 45 additional soils
• With this study, the CFAPS can be determined more reliable, as the number of soils used for the calculation is increased.
National Institutefor Public Healthand the Environment
Materials and Methods• 45 Dutch city soils (+ reference soil MS2711)• RIVM in vitro digestion model
• Fed (solid-to fluid ratio of 1:1063, 0.04 gram soil)- Baby food
• Fasted (solid-to fluid ratio of 1:958, 0.06 gram soil)
Calculation of CFAPS based on- Previous 11 soil (spaghetti and breakfast)- Additional 45 soils (baby food)- Statistical analysis
National Institutefor Public Healthand the Environment
In vitro determination of bioaccessibility
saliva gastric juice
duodenal juicebile
5 minpH ± 1.5
pH ±
2.5
pH ± 6.0
pH ±
6.5
soil
2 h 2 hpH ± 6.5
pH ±
6.8
empty tube
Ingestion Mouth Stomach SmallIntestine
Fasted
Fed
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In vitro determination of bioaccessibility
chyme
+
pellet (destruction)
Analysisby ICP-MS
Centrifuge
Pellet (destruction)
pellet
chyme
National Institutefor Public Healthand the Environment
Results
Dataset*Avarage
StdvNumber of data
Percentile
P50 0.56 0.781 0.62 0.809P60 0.59 0.797 0.66 0.828P70 0.66 0.832 0.72 0.859P80 0.71** 0.855** 0.84 0.922P90 0.74 0.871 0.92 0.961P95 0.85 0.923 0.97 0.984
22 70
Ratio fed/fasted (α)
"Average physiological state"
correction factor (CFAPS)
Ratio fed/fasted (α)
"Average physiological state"
correction factor (CFAPS)
Current provisional dataset (2006), used in risk assessment
Newly proposed dataset (2008), used in risk assessment
0.20
II + III0.55
I + II + III0.640.23
National Institutefor Public Healthand the Environment
Discussion• The new dataset (70 sample) results in a smaller difference between
the bioaccessibility of lead from soils for fasted and fed conditions.
• As a consequence, the ratio fasted-fed (α) and its derived “average physiological state” correction factor (CFAPS ) are higher for the given percentiles compared to the current dataset (based on 11 soils).
- As the current data set is based on 11 soils only, a conservative P80 value of CFAPS (=0.855) was chosen for the scientific foundation of the intervention value of lead in soil.
- Based on the new dataset (70 samples), the P80 value of CFAPS, NEW will become 0.922.
• The new dataset (70 samples) results in a better foundation of the CFAPS : a lower percentile could be chosen by policy makers (P50- P80), resulting in a CFAPS of 0.81-0.92, depending on the level of conservatism that is desired.
National Institutefor Public Healthand the Environment
Acknowledgement
• Johannes Lijzen• Peter Kootstra• Menno Duits• Gerard Boom• Nikolaj Walraven (Geoconnect)
National Institutefor Public Healthand the Environment
QuestionsQuestions??
Agnes.OomenAgnes.Oomen@@rivm.nlrivm.nl