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:

m.t.cronin@ljmu.ac.uk

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