Hazard identification, classification and risk assessment of carcinogens Alan R Boobis Imperial College London
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org Definitions . Hazard – Inherent property of an agent or situation having the potential to cause adverse effects when an organism, system or (sub)population is exposed to that agent . Risk – The probability of an adverse effect in an organism, system or (sub)-population caused under specified circumstances by exposure to an agent
2 EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org Hazard and risk assessment
Hazard ID Hazard characterisation POD
0 0.1 1 10 100
Uncertainty factor Exposure assessment Risk characterisation
Exposure cf toxicity Risk
Reference value (e.g. ADI) [RV] = POD/UF
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org Why hazard classification . Immediate estimates of concern are needed – e.g. Storage and transport of chemicals where an accident could result in a major release . Exposure cannot be estimated, even with conservative estimates . Typical exposure during normal use can exceed the threshold for an adverse effect and cannot be mitigated . There is no threshold for an irreversible adverse effect
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org The cancer bioassay . Compounds are tested in rodents (rats and mice) for a lifetime, at high doses, to facilitate hazard identification . The basis of hazard identification is tumour incidence . The background incidence of many tumour types in the test organisms is high and may be variable . Many chemicals cause carcinogenicity secondary to their toxicity, i.e. via a non-genotoxic mechanism . The relevance of tumours produced at toxic doses of a chemical to risk assessment is highly questionable . Some mechanisms of carcinogenicity in rodents are of little or no relevance to human safety
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org Chemical carcinogenicity
Doe et al, 2019
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org Mode of Action (MOA)
Associative event
Adverse effect Exposure
ADME/TK KE1 KE2 KE3
Mode of Action Key events (based on Bradford Hill considerations)
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org IPCS Human Relevance Framework
Adverse effect Problem formulation Mode of action Hypothesized mode of action Key events (key events) based on Bradford Hill considerations
Assessment Implications for risk specific data Level of confidence assessment generation
Critical data data Critical Qualitative and gaps identified quantitative human concordance
Assessment specific data Level of confidence
generation data Critical
gaps identified Meek et al, 2014
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org TTC for compounds with evidence of genotoxicity y t
i Specific groups of potent genotoxic s
n carcinogens (CoC) excluded 0.15 µg/day e d
y t i l i b a b
o 1.5 µg/day r p
e v i t a l e R
-Log10 Dose (mg/kg bodyweight per day) Modified from Munro et al (1999) and Kroes et al (2004) Potency
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org Is the weight of Risk assessment: evidence sufficient to establish a mode MOA for renal carcinogenicity of action (MOA)? GSH- and GSH conjugation and downstream further metabolism to Chemical X metabolites found in Cys conjugates urine
Accumulation of Active uptake of Cys • Classify as a carcinogen? radiolabel in kidney; conjugate by proximal • Manage risk of renal inhibition by probenecid convoluted tubule toxicity?
Evidence from studies with analogous Metabolism to thiols by C-S lyase YES compounds
Consistent time-and dose- dependent histopathological Renal cytotoxicity and clinical chemical evidence for toxicity Increased renal adenoma and
Proliferation observed Renal cell carcinoma within 7 days; dose regenerative and time-dependent prolferation hyperplasia Assessment of carcinogenicity in 21st century?
Cohen et al, 2019
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org Conclusions
. Considerable advances have been made in developing the concept of a mode of action (MOA) for carcinogenesis . Cancer is often secondary to primary toxicity . The key events are often reversible and will occur some time before the development of a carcinogenic response, usually at lower doses . Hence a risk-based approach would be more than adequate to prevent cancer risk and would avoid unnecessary attrition and restrictions on otherwise useful chemicals
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org The next step
Workshop Organizing Committee: Susan Felter, Chair (Procter & Gamble); Alan Boobis, Co-Chair (Imperial College London); Phil Botham (Syngenta); Helmut Greim (Professor Emeritus, Technical University of Munich); Heli Hollnagel (Dow); Alice Brousse (ECETOC)
Registration: No cost to attend, but registration is required. Please register directly via the EUROTOX 2019 website
For additional information: Alice Brousse: [email protected] Francesca Uguccioni: [email protected]
EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS www.ecetoc.org