1. Committee on Carcinogenicity (COC) Approach to Risk Assessment of Genotoxic Carcinogens David H. Phillips* COC Chairman Descriptive vs. Quantitative Risk Assessment of Genotoxic Carcinogens IGHRC Meeting 2nd April *Institute of Cancer Research, Sutton, Surrey, UK

2. Guidance documents from Committees on Carcinogenicity (COC) and Mutagenicity (COM)

3. 4-stage evaluation strategy for the risk assessment process of carcinogenic hazard
Hazard identification
Hazard characterisation
Exposure assessment
Risk characterisation

4. 1. Hazard identification
Recognition of adverse effects from:
Epidemiological evidence
Long-term animal bioassays
Short-term studies in animals
Mutagenicity studies in vitro and in vivo (see COM guidance)
Mechanism: genotoxic v non-genotoxic?

5. 2. Hazard characterisation
Qualitative description of the nature of the hazard
Quantitative description of the dose-response relationship
Evidence from epidemiological studies
Dose-response data from animals studies
ADME (absorption, distribution, metabolism, excretion)
Data to assist extrapolation from animals to humans
Clarify differences in species, sex, age, tissue, route of exposure
Establish relevance to humans; define Mode of Action (MOA)

6. 2. Hazard characterisation (cont.)
Potency estimates
T25 – dose eliciting a 25% increase in incidence of a specific tumour above background level
For potency ranking of genotoxic carcinogens this is an acceptable pragmatic approach
There are uncertainties about whether relative ranking identified in observed dose range would be maintained at low doses

7. 2. Hazard characterisation (cont.)
Potency estimates
TD50 – chronic dose-rate which would induce tumours in a given target site in 50% of test animals (if no tumours in controls) or dose rate that halves probability of animal remaining tumour free
Evaluation of tumour incidence complicated by early mortality and failure to observe tumour onset prior to death
Use of potency estimates best confined to priority setting and ranking of carcinogens

8. 3. Exposure assessment
Critical for assessment of risk, but often the main area of uncertainty
Knowledge of external dose/concentration
Internal dose – levels of chemical or metabolites in biological samples
Biomarkers of exposure (e.g. adducts) – can represent target dose but may only reveal short-term or medium-term exposure
Biomarkers of effect (e.g. cytogenetic changes) – some recent advances in validation; usually not exposure- or agent-specific

9. 4. Risk characterisation
Establish Mode of Action (MOA)
If genotoxic, exposure should be As Low As Reasonably Practicable (Achievable) – ALARP (or ALARA)
If non-genotoxic, derive Margin of Safety (MOS) based on No Observed Adverse Effect Level (NOAEL)

10. Quantitative risk assessment (QRA)
Produces numerical estimates of cancer risk
Usually carried out using data from animal carcinogenicity studies because insufficient human data are available
However, there are significant uncertainties because the models are not based on biological mechanisms and the data are extrapolated to well below the range of doses given to animals

11. Result of using different quantitative cancer risk models when modelling the same data set
0.0001
0.1 1
0.001 10
Observed
data
Theoretical
One Hit
Multistage
Probit
Logit
Weibull
0.01
No. of cases of cancer per lifetime
Dose (mg/kg bw/day)

12. Margin of Exposure approach for genotoxic carcinogens
A technique developed to assist in the management or communication of risks from genotoxic carcinogens (not risk assessment)
Compares Point of Departure (POD) with the actual exposure to a chemical and makes a judgement on the basis of the ratio between the two, i.e.
Margin of Exposure = POD
Exposure
Point of Dep may be a BMDL, NOAEL, T25, usually BMDL

13. The benchmark dose % Response BMDL10 BMD10 Best fit to60 50
5050 40
Best fit to
experimental
data points
% Response
Lower 95% confidence
interval on dose giving
a 10% response 30
10% response = BMR 20
The benchmark dose is the dose which causes a predetermined increase in cancer incidence – usually 10%. However, it is the statistically 95% lower confidence limit of the BMD, termed the BMDL or in this case, the BMDL10. 10
BMDL10
BMD10 1 10
Daily dose

14. MOE – Current COC recommendations
MOE Band
Interpretation
<10,000
May be a concern
10,000 – 1,000,000
Unlikely to be a concern
>1,000,000
Highly unlikely to be concern

15. Summary
Range of data available means evaluation will be on a case-by-case basis
4 stages: hazard identification, hazard characterisation, exposure assessment, risk characterisation
If non-genotoxic, may apply a threshold approach – NOAEL + uncertainty factors – Margin of Safety (MOS)
If genotoxic, then non-threshold. Extrapolation of dose-response curves to low dose is imprecise. Recommend ALARP
Consider MOE for risk communication