(MOE) calculation to the WHO Study Group on

Application of the Margin of Exposure (MOE) calculation to the
WHO Study Group on Tobacco Product Regulation (TobReg) list
of tobacco smoke toxicants
Fiona H Cunningham, Stacy A Fiebelkorn, Clive Meredith
British American Tobacco, Group Research and Development, Southampton, SO15 8TL, United Kingdom.
Correspondence: [email protected]
INTRODUCTION
Tobacco smoke contains over 6,000 constituents, some with well-established toxicological
properties (1). To date approximately 150 tobacco smoke constituents have been identified as
‘tobacco smoke toxicants’ (2). We have previously described the use of Margin of Exposure
(MOE) calculations to prioritise tobacco smoke toxicants for risk reduction research (3) and
here we apply this approach to 18 tobacco smoke toxicants identified by the WHO Study
Group on Tobacco Product Regulation (TobReg) (4).
RESULTS
Table 3 shows the range of MOEs generated (where possible) for the 18 TobReg tobacco
smoke toxicants:
Table 3 – MOEs generated for the TobReg 18 tobacco smoke toxicants
Tobacco Smoke Toxicant
MOE Range
Acetaldehyde
45-347
Acrolein
0.3-1
Benzene
252-3292
Benzo(a)pyrene
16,805-2,400,000
1,3-Butadiene
220-1826
Carbon Monoxide
No MOE
Formaldehyde
2-89
4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK)
278-89,544
N-nitrosonornicotine (NNN)
2759-260,000
Acrylonitrile
5-217
2-Aminonaphthalene
1,870,000
4-Aminobiphenyl
21,000,000-36,000,000
Cadmium
6-602
Catechol
No MOE
Crotonaldehyde
No MOE
Hydrogen Cyanide
No MOE
Hydroquinone
No MOE
Nitrogen Oxides
No MOE
BACKGROUND
In 2008, the WHO Study Group on Tobacco Product Regulation published a list of 18 tobacco
smoke toxicants, which were split across two lists; those they recommended for mandatory
lowering and those they recommended for mandatory monitoring (Table 1) (4).
Table 1 – TobReg 18 Tobacco Smoke Toxicants
Toxicants Recommended for Mandatory Lowering
Toxicants Recommended for Mandatory Monitoring
Acetaldehyde
Acrylonitrile
Acrolein
2-Aminonaphthalene
Benzene
4-Aminobiphenyl
Benzo(a)pyrene
Cadmium
1,3-Butadiene
Catechol
Carbon Monoxide
Crotonaldehyde
Formaldehyde
Hydrogen Cyanide
4-(N-nitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK)
Hydroquinone
N-Nitrososnornicotine (NNN)
Nitrogen Oxides
METHODS
An MOE is a ratio between a point of departure (POD) and a specific human exposure. A
consensus has been reached that a benchmark dose corresponding to a 10% increase in
incidence of the effect in animal studies above control values is an appropriate POD (5). The
proposed human exposure scenario was generated by dividing the machine smoked yield of
20 3R4F (University of Kentucky reference cigarettes) smoked under Health Canada Intense
(HCI) regime (55 ml puff volume, 2 second puff duration, 30 second puff interval) (6) into the
average daily volume of air inhaled by a human subject of 20 m3.
Toxicants with MOEs >10,000 accompanied by a dialogue are considered to be “low priority
for risk management actions” (5). 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. In addition to this we have proposed increasing the number of priority
bandings to allow for further prioritisation of the toxicants we believe require exposure
reduction research focus (Table 2) (3).
Table 2 – Proposed Additional Priority Bandings
Priority Rating
Banding
Top Priority
1 to 10
Very High Priority
10 to 100
High Priority
100 to 1000
Medium Priority
1000 to 10,000
Low Priority
10,000 to 1,000,000
Very Low Priority
1,000,000+
It should be noted that it was not possible to generate MOE values for six of the 18 toxicants.
This was due to a lack of relevant endpoint data (catechol, crotonaldehyde, hydrogen
cyanide, hydroquinone and nitrogen oxides) or we have been unable to clearly identify a
relevant endpoint for that toxicant based on available literature (carbon monoxide).
There are also four toxicants for which the priority rating is not achievable. In the case of both
NNN and NNK the range of MOEs generated split across multiple priorities. This clearly
demonstrates the importance of using multiple data sets to ensure confidence in your overall
conclusion. For both of these toxicants we suggest that further investigation is carried out to
allow for their prioritisation. In the case of 2-aminonaphthalene, a single useable data set was
available, with a relatively short exposure time (3 times a week for 8 weeks followed by a
recovery period of 16 weeks (8)) and therefore additional data would be recommended to
ensure a firm conclusion. In the case of 4-aminobiphenyl, data used was not based on the
target tissue of the lung and gave very large MOEs, the relevance of which can be
questioned.
Based on the MOE assessments the following priorities can be proposed:
Table 4 – Proposed Priority Ratings
For each of the 18 tobacco smoke toxicants identified by TobReg, a literature search was
conducted to identify (where available) lung specific epidemiological and experimental studies
which met the criteria for the generation of multiple BMDL10 values using the Benchmark Dose
Software (BMDS) available from the US EPA. From these studies a range of MOEs could then
be calculated (3).
Example
For acetaldehyde, one study identified from the literature was by Woutersen et al (7) in which
rats were exposed to acetaldehyde via inhalation for 6 hours per day, 5 days a week for up to
28 months. One of the data sets within that study analysed the number of nasal
adenocarcinomas present in the male rats. This data set was run through the BMDS
producing a BMDL10 of 154 ppm and the graph seen in figure one, which ultimately resulted in
an MOE of 45.
Figure 1 – BMDS output for nasal adenocarcinoma in rats (7)
Toxicant
Priority Rating
Acrolein
Top Priority
Acrylonitrile, Cadmium, Formaldehyde
Very High Priority
Acetaldehyde, 1,3-Butadiene
High Priority
Benzene
Medium Priority
Benzo(a)pyrene
Low Priority
4-Aminobiphenyl, 2-Aminonaphthalene, NNN, NNK
No clear prioritisation
Carbon Monoxide, Catechol, Crotonaldehyde,
Hydrogen Cyanide, Hydroquinone, Nitrogen oxides
No MOEs
DISCUSSION
The generation of MOE values for individual tobacco smoke toxicants is the first step towards
prioritising toxicants. As can be seen from the data presented, there are still a large number
of unknowns or uncertainties around suitability and availability of data sets. However, it must
be noted that the criteria used for data selection was very strict (3), in particular focussing on
inhalation (not a very common route of exposure in experimental systems) and lung related
data sets (often not the target organ of concern for other industries). Where no MOEs or
clear prioritisations can be made, utilisation of this approach allows us to focus work
programmes on these toxicants to further our assessment and ultimately their prioritisation.
However, we recognise a criticism of this approach is that it only investigates toxicants as
individual species, rather than factoring in any mixture effects. We have previously proposed
a method for investigating a cumulative MOE approach for a group of toxicants with similar
modes of action (9), but this approach should be extended to other mixtures.
CONCLUSION
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 useful tool.
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