lri-b18: carcinogen dose-response database for threshold...
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Mark Cronin1, Sylvia Escher2, Cyril Marsaux3, Katarzyna Przybylak1, Jim Rathman4,
Stéphane Vidry3, Bastian Weber2, Chihae Yang5
LRi-B18: Carcinogen Dose-Response Database for Threshold of
Toxicological Concern (CDRD-TTC)
Contact:
1Liverpool John Moores University, England; 2Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Hannover,
Germany; 3ILSI Europe, Brussels, Belgium; 4Altamira LLC, Columbus, OH, USA; 5MN-AM GbmH, Erlangen, Germany
This project aims to generate a fully-curated, quality-controlled and publically-available database on genotoxic and non-genotoxic carcinogens.
The novel database will form the basis of analysis of TTC distributions for cancer thresholds.
Aim of Project
The final cancer TTC and genotoxicity databases will become new inventories.
On completion of the project, the complete database will be downloaded and provided to CEFIC LRI as a Microsoft Excel or Access database file.
The dataset will also be made available to be entered into the CEFIC Toolbox.
Transparent and robust methods are used to calculate TD50 and model BMDL:
− Logistic logit method to calculate TD50
− Nine models within BMDS260 program to model BMDL
Summary
Modelling of dose-response data from CPDB
database is performed to estimate the
Benchmark Dose Limit (BMDL).
11,340 tumour types (tt) in CPDB.
BMD modelling is not possible/or reasonable
for all types of studies index from 0 to
10 was given to studies to prioritise BMD
calculation.
BMDS260 program used for calculation
− semi-automated way for data calculation
− nine models used to fit the incidence data
e.g. gamma, logistic, log logistic
− dichotomous data.
Calculations are under investigation for 5%,
10%; 25% and 50% bench mark risk level.
Acknowledgements: The funding from the CEFIC LRi Project (LRi-B18) is gratefully acknowledged.
TD50 Calculations BMDL Modelling
MOA Strategy
Existing data:
• 652 chemicals from acceptable studies
• 572 carcinogens from acceptable
studies
• 428 carcinogens from acceptable
studies and having Ames data Median=76.6 mkd
Mean= 821.7 mkd
N= 120
Median=16.4 mkd
Mean= 282.6 mkd
N= 147
Median=44.7 mkd
Mean= 524.9 mkd
N= 267
Salmonella negative Salmonella positive
New data:
• NTP studies
• RDT studies from RepDose database
Content curation/QC:
• Chemoinformatics curation
• Toxicity study reviews
The study inclusion criteria have been defined.
In general the FDA Redbook 2000 recommendations
were followed.
The lowest TD50 values
from oral studies with
significant tumorigenic
effects (p≤ 0.01)
GLP studies or
equivalent protocols
Appropriate sample size
(>40)
Exposures shorter than
life time included if
results are statistically
positive
Single dose studies
Mixed tumors
‒TBA (all tumor bearing
animals), MXA, MXB, etc.
Negative studies with no
significant tumor findings
‒ Negative studies should
have duration of 18
months for mouse, 24
months for rats
Equivocal studies
Excluded Included
TD50 calculated from dose-response curves.
Three methods for TD50 calculations were
correlated with the Gold method.
Gold Least squares Logistic log Logistic logit
Gold 1.000 0.7605 0.7600 0.5845
Least squares 0.7605 1.0000 0.8829 0.7290
Logistic log 0.7600 0.8829 1.000 0.7892
Logistic logit 0.5845 0.7290 0.7892 1.000
Least squares and logistic log methods give
better agreement with Gold than the logistic logit
regression model.
However, the logistic logit method seems more
realistic for describing the dose-response.
− TD50 calculated for
12,145 compounds
− TD50 values
between 0 and 5000
mg/kg/day
Study Inclusion Criteria