oral bioaccessibility data: missing the point in exposure … · 2019. 4. 27. · october 1, 2010...
TRANSCRIPT
October 1, 2010
Oral Bioaccessibility Data: Missing the Point in Exposure Assessment of Soil-borne Chemicals
Dr Sohel Saikat
Centre for Radiation, Chemicals and Environmental Hazards London
Outline
Concepts
Why Does Bioaccessibility Matter?
Some Observation on the In-vitro Bioaccessibility Data
Conclusion and Way forward
Concepts - Relationships
Total ≥≥≥≥ acid extrac. ≥≥≥≥ bioaccess≥≥≥≥ bioavail.
Bioavailable. Bioaccessible.
The Concept
Definitions
Bioavailability, absolute : Is a measure of uptake or fraction of an administered dose absorbed by the body
Relative bioavailability : Comparative bioavailabilities of different forms of a chemical or for different exposure media cont aining the chemical
Bioaccessibility, oral : Is a measure of dissolution , or fraction of contaminant released into solution from the soil duri ng digestion
[Bioavailability requires in-vivo test with live animal; bioaccessibility can be measured in-vitro (with artificial non-animal bench-top procedure)]
In-vivo Bioavailability
Routinely used in US
Animals as surrogate of human
But not feasible
Costs and time
Expertise
Reproducibility
Ethical reservation
In-vitro Bioaccessibility
Absorption depends on solubility
Incorporates certain human gut parameters depending on the specific test
• Stomach pH and small intestine pH
• Stomach mixing
• Stomach emptying rates
• Cost and time reductions
• Conforms to the three ‘ R’principle (Reduce, Refine and Replace)
Maddaloni and Beringer 2005
In-vitro Method Development
Contaminated soils
In-vivo study In-vitro studyCompare
BioaccessibilityBioavailability
Why Does Bioaccessibility / Bioavailability Matter?
Toxicity related to absorbed dose not to applied do se
Some chemicals are readily absorbed from the gut than others
Default assumption that a chemical is equally bioavailable in all media
Tox study is based on high doses with most soluble form of chemical
May not be appropriate where contaminant is bound
Bioavailability in Risk Assessment
Contaminants Phases
In pore water
Weakly absorbed
Associated with carbonate
Associated with Fe, Mn oxides
Complexed by organics
Associated with sulphide
In the mineral lattice
Free aquoion
Inorganiccomplexes
Org. complexes & chelates
T
O
T
A
L
Total = available + sequestered
HIGH
LOW
Factor: pH, redox condition, grain size, cations and anions etc.
RBA ESTIMATES: Soil-Lead at 20 Sites
Relative Bioavailability (RBA) per Tissue(Rank Ordered)
0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
120.0%
0 2 4 6 8 10 12 14 16 18 20
Test Materials
RB
A (
test
vs
PbA
c)
Pt. Est.
Blood
Liver
Kidney
Bone
EPA defaultRBA = 60%
Impact of Food: Human Study withPb contaminated Bunker Hill Soil
Group(n=6)
Age(yrs)
Weight(kg)
Pb Dose(ug)
Soil Dose(mg)
Bioavailability(%)
Fasted 28 59.7 213 72.9 26.2(18.0-35.6)
Fed 28 67.9 242 82.9 2.52(0.2-5.2)
Maddaloni et al. 1998
Soil Treatment: Impact on PbBioavailability
Group
Age (yrs)
Weight
(kg)
Pb Dose (µg)
Soil Dose (mg)
Bioavailability (%, Absolute)
Untreated 28.9 62.6 231.5 44.5 34.7
(16.5-54.2)
Amended 31.4 69.6 251.2 59.2 19.9 (10.8-38.5)
Maddaloni et al. 2005
Comparative Results for Pb Bioavailability: animal, in vitro & human
Animal
In vitro (pH 2.3)
Human
% Reduction in Bioavailability
38 38 43
Relative Costs:Remedies for Metal-Contaminated Soils
0 0.5 1 1.5 2
$ (Millions)
Phosphate Inactivation
Soil Cap
Asphalt Cap
Phytoextraction
Soil Wash
Excavate & Landfill
Net Present Cost for 1 Hectare Site
1.62
0.79
0.25
0.16
0.14
0.06
• Use the Integrated Exposure Uptake Biokinetic Model to predict blood lead levels in young children
• Absolute bioavailability of soluble lead in food/water = 50%
• Relative bioavailability (RBA) of lead in soil = 60%
• 30% absolute bioavailability (model input)
• A sensitive parameter in predicting blood lead levels and potential risks to children
• RBA of 80% = soil cleanup goal of 265 mg/kg• RBA of 60% = soil cleanup goal of 400 mg/kg (defaul t)• RBA of 40% = soil cleanup goal of 530 mg/kg • RBA of 20% = soil cleanup goal of 1075 mg/kg
Bioavailability Assumptions inEvaluating Risks to Children from Lead
Some Observation on the In-vitro Bioaccessibility Data
Criteria for Credible In-vitro Method
Ability to predict bioavailability
Data are reproducible
Robustness and sensitivity
Model validation, QA and QC (Reference soils)
(based on ECVAM, ICCVAM and US EPA validation and r egulatory acceptance criteria)
Lead – Correlation Between In Vivo RBA and In Vitro Bioaccessibility (IVBA)
Arsenic – Correlation Between In Vivo RBA and In Vitro Bioaccessibility (IVBA)
Dutch Study with RIVM and TNO TIM Models
Number of soils 90 16 16
average 0.72 0.63 0.11Lowest value 0.11 0.40 0.04Higest value 1.77 1.03 0.21
Percentile 50 0.67 0.64 0.12Percentile 60 0.71 0.68 0.12Percentile 70 0.78 0.69 0.12Percentile 80 0.91 0.71 0.15Percentile 90 1.02 0.81 0.17
relative oral bioavailability factoraverage physiological state
IVD (I) IVD (II) Tiny-TIM
Round Robin Study - Data Comparability
Methods: PBET, SBRC, RIVM, EDTA+CH 3COOH
Lab
mg/kg
lkjhgfedcba
100
90
80
70
60
50
40
30
20
Individual Value Plot of Arsenic Bioaccessibility (mg/kg) in Soil 1
Median: 47.5
Range: 20-89
Total As: 112
Lab
mg/kg
lkjhgfedcba
40
35
30
25
20
15
10
Individual Value Plot of Arsenic Bioaccessibility (mg/kg) in Soil 2
Median: 20
Range: 13-38
Total As: 120
Methods: PBET, SBRC, RIVM, EDTA+CH 3COOH
Round Robin Study - Data Comparability
Lab
mg/kg
lkjhgfedcba
8000
7000
6000
5000
4000
3000
2000
1000
0
Individual Value Plot of Arsenic Bioaccessibility (mg/kg) in Soil 4
Median: 218.5
Range: 121-7011
Total As: 10307
Methods: PBET, SBRC, RIVM, EDTA+CH 3COOH
Round Robin Study - Data Comparability
Data Comparability (summary) (excludes overseas and one UK lab)
Test soils Arsenic (mg/kg)
Lead (mg/kg)
Nickel (mg/kg)
Soil 1 (n = 8) R: 20-77 Med: 43
R: 1-39 Med: 10
R: 4-23 Med: 8
Soil 2 (n = 8) R: 13-88 Med: 18
R: 1462-8219 Med: 1911
R: 1-5 Med: 2
Soil 3 (n = 8) R: 121-7011 Med: 194
R: 2920-84979 Med: 10480
R: 5-25 Med: 9
US Soil (n = 3)
R: 5-9 Med: 5
R: 348-542 Med: 477
R: 1.35-1.75 Med: 2
Labs using the same method and same operating procedure
produce comparable results.
Labs using different methods produced different results
Arsenic – Correlation Between In Vivo RBA and Bioaccessibility (UBM)
Arsenic – Correlation Between In Vivo RBA and Bioaccessibility (RIVM method)
Some Conclusions to Date
In-vitro bioaccessibility data can make the exposure a ssessment more realistic
Evidence on in-vitro methods in predicting bioavailab ility is inconclusive for most of the chemicals
Variability of in-vitro data between the methods using the same samples
Laboratories use same method irrespective of chemical, chemical form, matrix
Way Forward
Coordinated leadership and approach in undertaking fur ther research required
Continue effort in in-vitro method development and validation with appropriate data
What can be done to increase confidence in in-vitro data?
Using multiple lines of evidence to support in-vitro bioaccessibility method/data:
• consolidation of available knowledge
• integration of geochemistry with exposure science
Increasing confidence: integrated approach
Geochemistry
Exposure Toxicology
In-vitro approach
-Method screening
-Geochemical matching
-Geochemical classification
-Biomarker
Qualitative use of in-vitro bioaccessibilityas a line of evidence
Highly contaminated
×
Moderately contaminated
√ + ??
Background √
Fixed √ Moderately
fixed √
Mobile √ +?