Low dose effect Alan R Boobis Imperial College London ILSI Europe March 2014 Annual Symposium Brussels, Belgium

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1 Low dose effect Alan R Boobis Imperial College London (a.boobis@imperial.ac.uk) ILSI Europe 2014 Annual Symposium March 2014 Brussels, Belgium

2 "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 ( )

3 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 10 6 (or 1 in 10 5 ) 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 10 5 (based on BMDL10 as POD and linear extrapolation)

4 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)

5 Mega-studies Plots indicate non-linearity at lower doses However, there are no experimental data at acceptable human risk levels ( 1 in 10 5 ) 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

6 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 10 5 increase in cancer incidence from experimental data and human epidemiology, respectively The ratio human/animal was 1 in all cases

7 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 10 5 ) Uncertainty associated with many of the estimates

8 Frequency 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 Low probability hgv will be below this value Murray-Rust et al, 1997 Log hgv (mg/kg/d)

9 Relative probability density TTC for compounds that are potentially genotoxic Specific groups of potent genotoxic carcinogens (CoC) excluded 0.15 µg/day 1 in 10 6 risk TD50s VSDs 1.5 µg/day -log 10 Dose (mg/kg bw per day) Potency From Kroes et al (2004)

10 Examples of compounds that should probably not be considered in deriving a TTC for genotoxic carcinogens Chloroform 1,4-Dioxane Nafenopin Oxazepam Penobarbital Retinol acetate

11 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

12 Derivation of reference values Toxic effect Sensitive human Average human Test species RV 10 UF 10 NOAEL/ BMDL

13 Dose-association for blood lead levels and IQ Lanphear et al. (2005) Jusko et al. (2008) The BMDL 01 for developmental neurotoxicity = 1.2 μg/dl (B-Pb) (EFSA)

14 Identification of POD Andrade et al, 2006a Andrade et al, 2006b 6 5 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

15 Mode of action and key events 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) KEY EVENT KEY EVENT [S] External dose Absorption Target tissue exposure Biological perturbation[s] Pathological change[s] Adverse health effect EXPOSURE KEY EVENT KEY EVENT[S] Other factors (e.g. lifestyle, environment, homeostasis) Other factors (e.g. lifestyle, environment, homeostasis) Host characteristics (e.g. lifestage, genetics) Host characteristics (e.g. lifestage, genetics)

16 Sturla et al, 2014 Systems-based approach

17 Conclusions Available evidence tends to support the adequacy of current risk assessment approaches The TTC value for potential genotoxins merits reevaluation 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

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