(MOE) calculation to the WHO Study Group on Tobacco Product

P009
Application of the Margin of Exposure (MOE) calculation
to the WHO Study Group on Tobacco Product Regulation
(TobReg) list of tobacco smoke toxicants.
Fiona Helen Cunningham, Stacy Fiebelkorn and
Clive Meredith
British American Tobacco, Southampton, UK
Tobacco smoke contains over 6,000 constituents, some with wellestablished toxicological properties. We have previously used a
Margin of Exposure (MOE) calculation to prioritise tobacco smoke
toxicants and here we apply this approach to 18 tobacco smoke
toxicants identified by the WHO Study Group on Tobacco Product
Regulation (TobReg). An MOE is a ratio between a benchmark
dose and a specific human exposure. Toxicants with MOEs >10,000
accompanied by dialogue are considered to be “low priority for
risk management actions”. Our approach calculates MOE values
from a range of published studies to determine consistency across
data sets and enables segregation of toxicants into high and low
priority groupings dependent upon their relationship to the critical
value of 10,000. The 18 TobReg toxicants segregated as follows:
High Priority (Acetaldehyde, Acrolein, Acrylonitrile, Benzene, 1,3Butadiene, Cadmium, Formaldehyde); Low Priority (Benzo(a)pyrene);
No clear segregation (4-aminobiphenyl, 2-aminonaphthalene,
N-Nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3pyridyl)-1-butanone (NNK)); No MOE generated (Carbon monoxide,
Catechol, Crotonaldehyde, Hydrogen Cyanide, Hydroquinone,
Nitrogen Oxides). Further work is required to prioritise those toxicants
where no MOEs were generated or where MOEs did not clearly
segregate. We suggest the use of mode of action (MOA) reviews,
combined with in vitro testing and physiologically-based pharmacokinetic (PBPK) modelling to elucidate details regarding exposure
and ADME of these toxicants. We believe that an evidence-based
risk assessment method to identify and prioritise individual tobacco
smoke toxicants, reflecting the range of yields and human characteristics related to exposure is a beneficial tool for tobacco product
regulation and the establishment of product standards.