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, - PowerPoint PPT Presentation

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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,

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Title: 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,


1
Committee on Carcinogenicity (COC) Approach to
Risk Assessment of Genotoxic CarcinogensDavid
H. PhillipsCOC ChairmanDescriptive vs.
Quantitative Risk Assessment of Genotoxic
CarcinogensIGHRC Meeting 2nd April
2009Institute 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
  1. Hazard identification
  2. Hazard characterisation
  3. Exposure assessment
  4. 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
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

13
The benchmark dose
60
5050
50
40
Best fit to experimental data points
Response
Lower 95 confidence interval on dose giving a
10 response
30
10 response BMR
20
10
BMDL10
BMD10
1
10
Daily dose
14
MOE Current COC recommendations
MOE Band Interpretation
lt10,000 May be a concern
10,000 1,000,000 Unlikely to be a concern
gt1,000,000 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
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