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 2009

*Institute of Cancer Research, Sutton, Surrey, UK

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

4-stage evaluation strategy for the risk assessment process of

carcinogenic hazard

1. Hazard identification

2. Hazard characterisation

3. Exposure assessment

4. Risk characterisation

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?

2. Hazard characterisationQualitative description of the nature of the hazardQuantitative 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 exposureEstablish relevance to humans; define Mode of

Action (MOA)

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

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

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

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)

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

Result of using different quantitative cancer risk models when modelling the

same data set

Dose (mg/kg bw/day)

0.000001

0.0001

0.1

1

0.000010.0000001 0.001 0.1 10

Observed data

Theoreticaldata

One Hit

Multistage

Probit

LogitWeibull

0.01

0.001

0.00001

No.

of

case

s of

can

cer

per

lifet

ime

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

The benchmark dose

Daily dose

1 10

10

20

30

40

5050

50

60

BMDL10 BMD10

10% response = BMR

Lower 95% confidence interval on dose givinga 10% response

Best fit to experimental data points

% R

espo

nse

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

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