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Low dose effect
Alan R Boobis
Imperial College London ([email protected])
ILSI Europe 2014
Annual Symposium
20-21 March 2014
Brussels, Belgium
"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/management of genotoxic carcinogens
Management based on assumption of no threshold in
dose-response relationship
ALARA/P (as low as reasonable
achievable/practicable)
Low dose extrapolation, usually linear
Acceptable risk level of 1 in 106 (or 1 in 105)
Margin of exposure (=point of departure/estimated
human exposure)
MOE ≥ 10,000 considered to be of low concern (JECFA,
EFSA)
NB: MOE of 10,000 is equivalent to risk level of 1 in 105
(based on BMDL10 as POD and linear extrapolation)
Cancer ‘mega-studies’ and other relevant studies
‘Mega-rat’ study of nitrosamines (n~4,000) Peto et al (1991a, b)
ED01 study of 2-AAF in mice (n>24,000) Gaylor (1980, 1985)
Study in trout of dibenzo[a,l]pyrene (n>40,000) Bailey et al (2009)
Studies of pre-neoplastic effects of 2-AAF and DEN in rat Williams et al. (1993, 1998, 1999, 2004)
In vivo and in vitro studies of MMS, MNU, EMS and ENU Doak et al. (2007) and Gocke & Muller (2009)
‘Mega-studies’
Plots indicate non-linearity at lower doses
However, there are no experimental data
at acceptable human risk levels (≤ 1 in
105)
The feasibility and resources required to
conduct such studies in vertebrate
species are such that it is not possible to
achieve the necessary power for this
purpose
Epidemiological data for human cancers
Comparison of animal and human data for
IARC class 1 carcinogens
Aflatoxin B1, benzidine, chromium VI and vinyl
chloride
Derive dose resulting in 1 in 105 increase in
cancer incidence from experimental data and
human epidemiology, respectively
The ratio human/animal was ≥ 1 in all cases
Integration of findings
Plot of data from different lines of evidence using same
scale
‘Mega-studies’
Comparison of experimental data with human epidemiology
IARC class 1 carcinogens
IARC class 2a carcinogens (no significant increase in risk in exposed
populations)
Estimates obtained by expert elicitation
Evidence for non-linearity at low exposure levels
Little or no data at acceptable human risk levels (1 in 105)
Uncertainty associated with many of the estimates
The TTC approach
A TTC value is:
A human exposure value for a chemical of unknown
toxicity below which the probability of adverse effects
on human health is considered to be very low
following (oral) exposure for a lifetime
Fre
qu
en
cy
Log hGV (mg/kg/d)
Low probability
hGV will be
below this
value
Murray-Rust et al, 1997
TTC for compounds that are potentially genotoxic
From Kroes et al (2004)
0.15 µg/day
1.5 µg/day
Potency
Specific groups of potent
genotoxic carcinogens
(CoC) excluded
Rela
tive p
robabili
ty d
ensity
-log10 Dose (mg/kg bw per day)
1 in 106 risk
TD50s VSDs
Examples of compounds that should probably not be considered in deriving a TTC for genotoxic carcinogens
Nafenopin Oxazepam
Penobarbital
Chloroform
Retinol acetate
1,4-Dioxane
Re-evaluation of TTC for potential genotoxins
Human relevance of included studies, tumour types and
data points
Study design, maximum dose, route of exposure, dose groups,
number of animals per group, duration, etc
Mode of action (DNA-reactive: yes/no/unknown)
Criteria for DNA reactivity
POD selection for potency estimate
Choice of POD, method of extrapolation
‘Safe dose’ definition and derivation based on current
approaches
Review appropriateness of cohort of concern and update
as necessary
Toxic effect
NOAEL/
BMDL
0 0.1 1 10 100 1000
10 10
RV
UF
Test species Average human Sensitive
human
Derivation of reference values
Dose-association for blood lead levels and IQ
Lanphear et
al. (2005)
Jusko et al.
(2008)
The BMDL01 for
developmental
neurotoxicity = 1.2
μg/dL (B-Pb) (EFSA)
Identification of POD
Andrade et al, 2006a Andrade et al, 2006b
Hypothalamic/preoptic area aromatase
activity in newborn (PND1) male rats,
exposed in utero from GD6-PND1
Sperm morphology in male (PND144) rats
exposed in utero from GD6-PND21
*cf concurrent controls; § cf historical controls
5 6
Mode of action and key events
•External dose
EXPOSURE
•Absorption
KEY EVENT
•Target tissue exposure
KEY EVENT
•Biological perturbation[s]
KEY EVENT [S]
•Pathological change[s]
KEY EVENT[S]
•Adverse health effect
Other factors (e.g. lifestyle, environment, homeostasis)
Host characteristics (e.g.
lifestage, genetics)
Other factors (e.g. lifestyle, environment, homeostasis)
Host characteristics (e.g.
lifestage, genetics)
Other factors (e.g. lifestyle, environment, homeostasis)
Host characteristics (e.g.
lifestage, genetics)
Other factors (e.g. lifestyle, environment, homeostasis)
Host characteristics (e.g.
lifestage, genetics)
Conclusions
Available evidence tends to support the adequacy
of current risk assessment approaches
The TTC value for potential genotoxins merits re-
evaluation
ILSI Europe Expert Group “Update of the cancer potency
database (CPDB)”
Uncertainties are such that establishing
unequivocally the nature of the dose-response
relationship at human relevant exposures will
require systems-base approaches