Risk Assessment – History and Future

Risk Assessment – History
and Future
Alan R Boobis
Imperial College London
a.boobis@imperial.ac.uk
ILSI Europe 2011 Annual Symposium
24-25 March 2011, Brussels

The basis of toxicology (and
pharmacology)
"All substances are poisons; there
is none which is not a poison. The
right dose differentiates a poison
from a remedy.“
Areolus Phillipus Theophrastus
Bombastus von Hohenheim
Paracelsus (1493-1541)

Risk assessment
• A scientific process to assess likelihood of harm
on the basis of current knowledge
• Not intended to “solve” problems
• A framework to organise and evaluate all
available information and knowledge relevant to
the risk, with attendant uncertainties
• Provides an objective basis for risk management
decisions based on current (imperfect)
knowledge – i.e. a decision-support tool

National Research Council, “Red Book”
model of risk analysis (1983)

Threshold or non-threshold?
NEL = No Effect Level
10 2 Experimental
observations
10 -5 10 -4 10 -3 10 -2 10 -1 10 0 10 1 10 2
10 1
Response
10 -1
10 -3
Non-threshold
response
NEL
Threshold
response
10 -6
Dose

Threshold effects: Identify the
NOAEL
• No observed adverse effect level (NOAEL)
• By definition, must be one of doses tested
• Fewer animals, or less precise estimates, result in higher NOAELs
• Wide dose spacing can result in low NOAELs
• Not necessarily a dose without any effect
L/NOAEL = Lowest/No
observed adverse
effect level

Risk assessment: threshold
Hazard ID
Hazard characterisation
POD
Uncertainty
factor
0 0.1 1 10 100
Reference value (e.g. ADI)
[RV] = NOAEL/UF
Exposure assessment
Risk characterisation

Chemical specific adjustment
factors (CSAFs)
• IPCS scheme in which interspecies and
intraspecies UFs are divided into toxicokinetic
(TK) and toxicodynamic (TD) components
• Where data are available, used to replace
default UF
Kinetics
Dynamics
Total
Interspecies
Intraspecies
4.0 2.5
3.2 3.2
10
10

Risk assessment: non-threshold effect,
e.g. DNA-reactive carcinogens
Dose-response extrapolation
100
10
Region of
acceptable
risk
Region of
experimental
data
% Response
1
0.1
0.01
0.001
Multi-stage
One hit
Weibull
Log-normal
0.0001
0.00001
0.00001 0.0001 0.001 0.01 0.1 1 10 100
Dose (mg/kg/day)

BMD for a given incidence of a
response
% animals responding
1
0.8
0.6
0.4
0.2
BMD
BMD Lower Bound
NOAEL
0
BMDL
BMD
0 50 100 150 200
Dose

Margin of exposure (MOE)
• DNA-reactive genotoxic carcinogens – assume no threshold
• Linear, low-dose extrapolation is very uncertain
• As an alternative, derive margin of exposure (MOE)
• POD/Human exposure (measured or predicted)
• Usually, POD = BMDL10 for animal data, BMDL1 or less for
human data
• MOE of >10,000 based on animal data – of low concern
• Enables ranking and prioritisation of risks; assessment of
outcome of different risk management options;
communication of level of concern
• NB: MOE concept is applicable to threshold toxicants
• Interpretation of MOE

Postulated MOA for CHCl 3
Oxidative
CYP2E1
Metabolism
Chloroform
Cl
Cl
C
H
Phosgene
Cl
Sustained cytoxicity
Key events
Regenerative cell proliferation
Tumour development

Key event
• An empirically observable, precursor step that is a
necessary element of the mode of action, or is a marker
for such an element
• Examples of key events
• Specific metabolic transformation
• Receptor-ligand changes
• Increased cell growth and organ weight
• Hormonal or other physiological perturbations
• Modifying factors
• Processes that can influence the magnitude of the toxicological
effect, but are not essential for that effect to occur
• Example: autoinduction of detoxication

Why does risk assessment have to
change (further)
• Large number of environmental chemicals with limited toxicity
information
• HPVs, REACH, etc
• 90,000 chemicals on the EPA TSCA inventory; 140,000 chemicals
preregistered under REACH, ~70,000 will require toxicity data
• Only 1,547 chemicals have ever been tested in a rodent cancer
bioassay (CPDB, 2010)
• Metabolites and degradation products, process intermediates,
mixtures
• Novel materials and processes, e.g. nanomaterials
• Accuracy of risk assessments, based on laboratory species
• Use of laboratory animals in toxicity testing
• 3R’s – reduction, refinement and replacement

Toxicity Testing in the 21st
Century: A Vision and a Strategy
Committee on Toxicity Testing and Assessment
of Environmental Agents, National Research
Council (2007)
1. Introduction
2. Vision
3. Components of vision
4. Tools and technologies
5. Developing the science base and
assays to implement the vision
6. Prerequisites for implementing the
vision in regulatory contexts

Components of the Vision
Circular diagram with outer ring stating "Risk Contexts" and "Population and Exposure Data", inner area stating
"Toxicity Testing" containing smaller circles that slightly overlap that say "Toxicity Pathways" and "Targeted Testing".
Two other ovals are also overlapping the "Tosicity Testing" oval, they say "Chemical Characterization" and
"Dose-Response and Extrapolation Modeling".

Perturbation of toxicity pathways
Exposure
Low Dose
Tissue Dose
Biologic Interaction
Perturbation
Higher Dose
Higher yet
Biologic
Inputs
Normal
Biologic
Function
Early Cellular
Changes
How do we distinguish
adaptive versus adverse
(toxic) responses?
Adaptive Stress
Responses
Cell
Injury
Morbidity
and
Mortality

Methods validated by ICCVAM, ECVAM, and
accepted for regulatory use by OECD
Endpoint Method Validated and Recommended for Regulatory Use:
Skin Penetration In Vitro Skin absorption OECD 428
Skin Irritation
EPISKIN with MTT
Reduction and IL-1α release
ECVAM: as a replacement
ICCVAM: as a screen in a tiered-testing strategy
EpiDerm with MTT
Reduction and IL-1α release
ECVAM: as a replacement (a negative result may require further testing)
ICCVAM: as a screen in a tiered-testing strategy
Skin Corrosivity Corrositex ECVAM: as a replacement
ICCVAM: as a screen in a tiered-testing strategy
OECD 435
In Vitro Skin Corrosion: Human Skin Model Test OECD 431
Genotoxicity Ames-Bacterial Reverse Mutation Test OECD 471
In Vitro Mammalian Chromosome Aberration Test OECD 473
In Vitro Mammalian Cell Gene Mutation Test OECD 476
Skin Sensitization LLNA in mice OECD 429

Science and Decisions: Advancing
Risk Assessment (2009)
National Research Council
Committee on Improving Risk Analysis Approaches Used by EPA
Board on Environmental Studies and Toxicology
The ‘Silver Book’

Conceptual model: Linear at the
population level
• Threshold exists at individual level
• Threshold differs within the population
• As dose increases, recruit more resistant individuals into the
response group
• At population level, no threshold
• Even very low doses have some finite risk
• More likely if there is already a significant background risk
• Intersection with aging or disease process
• Interaction with similarly acting agents
• Interaction with unique host vulnerability factors
• Possibility of separate assessment for subgroups
• Examples: PM, mercury, lead, ozone, arsenic
• Extrapolation - linear slope at low dose that can be shallower
than at high dose

Advantages of focusing on MOA
• Use of in vitro and in silico models to characterise key
events
• Development and application of mechanism-based
biodynamic models to identify rate-limiting processes in
modes of action
• Understanding interindividual variability in the rate
determining events may enable a true population
threshold(s) to be identified
• Characterisation of the population dose-response curve
and identification of susceptibility factors
• Development of mechanistically-informed biomarkers

The future of risk assessment
• The basic principles of risk assessment will not change
• Make the best use of all available information to inform policy to
protect human health
• The nature of the information for risk assessment will
change to a more bottom-up approach
• Uncertainty will increase, at least initially, as new
approaches are evaluated
• There is likely to be a move from “bright line” safety to levels
of protection
• Need to bound uncertainty
• Society will increasingly have to make choices between risks
and benefits, not all health-based
• Need for adequate risk-benefit analysis methodology

Consider …..
• “Some aspects of reality might elude us
because they are beyond human brains,
just as surely as Einstein's ideas would
baffle a chimpanzee.”
- Martin Rees, Astronomer Royal (2010)
• My appreciation to all at ILSI HESI, ILSI
Europe, ILSI RF, IPCS, EFSA, JMPR,
COT, COC, etc

Some contributions of ILSI Europe
to chemical risk assessment
• Kroes et al (2000). Threshold of toxicological concern for chemical
substances present in the diet: a practical tool for assessing the
need for toxicity testing. Food Chem Toxicol 38:255-312
• Kroes et al (2004). Structure-based thresholds of toxicological
concern (TTC): guidance for application to substances present at
low levels in the diet. Food Chem Toxicol 42:65-83
• Renwick et al (2003). Risk characterisation of chemicals in food
and diet. Food Chem Toxicol 41: 1211–1271 [FOSIE]
• Barlow et al (2006). Risk assessment of substances that are both
genotoxic and carcinogenic report of an International Conference
organized by EFSA and WHO with support of ILSI Europe. Food
Chem Toxicol 44:1636-1650
• Hoekstra et al (in press). BRAFO tiered approach for benefit-risk
assessment of foods. Food Chem Toxicol

HESI Risk 21 – Key areas of focus
• Exposure science
• Dose-response
• Tiered (integrated) evaluation
• Cumulative risk