approaches for establishing limits for different routes of ... for... · approaches for...
TRANSCRIPT
Approaches for establishing limits for different routes
of administration
Trish Parris
When to consider route specific exposure limit -
Only data available
• Volatile compounds
• Oral carcinogenicity data unavailable
• Bis(chloromethyl)ether (BCME)
Effect Summary
Human exposure Known carcinogen
Mutagenicity In vitro mutagen
Carcinogenic Effects ip injection (only 1 dose group TD50 of 182 μg/kg/day), inhalation and
dermal studies. Rat inhalation study most sensitive and robust (multiple
doses and >50 animals/group). Increase in olfactory epithelium tumours
(esthesioneuroepitheliomas). TD50 of 3.57 μg/kg/day.
M7 Addendum, 2015; Leong et al. (1981)
BCME
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• Using the TD50 of 3.57μg/kg/day, linear extrapolation
o Acceptable intake (AI) = 4 ng/day
• Similar to published regulatory limit US EPA for drinking water
o 3.2 ng/day
• Highly conservative, applicable to all routes
Route specific toxicity/sensitivity
• Local or site of contact effects – irritation and/or cancer
• Dimethylcarbamyl Chloride (DMCC)
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Effect Summary
Human exposure Probable carcinogen
Mutagenicity In vitro mutagen
Carcinogenic Effects ip, sc injection, dermal and inhalation carcinogenicity studies.
Only TD50s available for ip and inhalation.
Mouse ip injection malignant tumours at injection site, TD50 of
4.59 mg/kg/day. Hamster inhalation Squamous cell
carcinoma of nasal cavity, TD50 of 0.625 mg/kg/day.
M7 Addendum, 2015; Sellakumar et al. 1980; Van Duuren et al. 1974
DMCC
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TD50 AI Route
Mouse ip injection site tumours:
TD50 4.59 mg/kg/day
5 μg/day Parenteral and oral
Hamster inhalation nasal cavity
tumours: TD50 0.625 mg/kg/day
0.6 μg/day Inhalation
• Mutagenic AI = linear extrapolation from TD50
Chemical specific adjustment factor
• Reduce conservatism in route to route extrapolations
Renwick et al, 1991
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AF Description
F1 Extrapolation between species, max value 10
TK TD
4 2.5
Poorly soluble - Titanium dioxide (not nano!)
• Metal catalyst, packaging leachable
• Minimal parenteral data, no chronic (EHC 24, 1982; OECD, 2013)
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Effect Summary
Human exposure Possible carcinogen
Mutagenicity Overall, not mutagenic or genotoxic (some +ve in vitro
genetox)
Non-Carcinogenic Effects
(oral,iv)
Not toxic
Carcinogenic Effects (oral) NOAEL: mice 6,500 mg/kg/day and rats 2,500 mg/kg/day.
Carcinogenic Effects
(inhalation)
Rats, bronchioloalveolar adenomas, squamous metaplasias,
pulmonary keratin cysts and squamous cell carcinomas
observed at 250 mg/m3, no compound-related lung tumors.
NOEAC 50 mg/m3
Titanium dioxide
• Non-genotoxic rodent carcinogen - PDE using ICH Q3C
• Oral – PDE not calculated
• Inhalation – NOEAC of 50 mg/m3 = 6.1 mg/kg/day
• PDE = 3.1 mg/day
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AF Description Value
F1 Extrapolation between species 1 (usually 5 but rat more sensitive
than human, ILSI, 2000)
F2 Variability between people 10
F3 Short-term to long term extrapolation 1 (carci study)
F4 Severe toxicity 10 (non-genotoxic carcinogen)
F5 NO(A)EL established 1
Titanium dioxide - Parenteral
• no chronic repeat-dose parenteral data available
• inhalation carcinogenicity considered most sensitive endpoint suitable to derive
parenteral PDE
o Using inhalation NOEAC of 50 mg/m3 = 6.1 mg/kg/day
o PDE = 1.2 mg/day
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AF Description Value
F1 Extrapolation between
species
2.5 (as per ECHA guidance)
F2 Variability between people 10
F3 Short-term to long term
extrapolation
1 (carci study)
F4 Severe toxicity 10 (non-genotoxic carcinogen)
F5 NO(A)EL established 1
OECD, 2013;
IPCS 2005
Bioavailability adjustment factor - Parenteral
• Often lack of chronic data
• Extrapolation from oral studies
ICH Q3D, 2014
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Oral bioavailability AF
< 1% Divide by 100
< 50% Divide by 10
50-90% Divide by 2
> 90% Divide by 1
Discussion
• 2 compounds ~ 3 tables/compound
• Acrolein and Methyl bromide (Bercu et al., 2018)
• High level summary of available genotoxicity and carcinogenicity data
(pre-read)
• 2 questions to discuss and answer with poll everywhere (10 mins)
• Feedback to group (10 mins)
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Acrolein - 1
• Mutagenicity/Genotoxicity
o Highly reactive and cytotoxic
o Ames +ve
o Genotoxic in some in vitro systems – intrinsic reactivity may explain –ve results
• Non-Carcinogenic Effects
o Severe dermal, nasal and ocular irritant
➢ Nasal irritation most sensitive respiratory effect
o Chronic oral exposure with dogs, mice and rats results in irritation of GI mucosa
o 13-week studies with rats and mice mortality and stomach lesions
predominant effects12
Compound Structure In vitro
Mutagen
Rodent
Carcinogen
Limit (AI or PDE)
Acrolein
(CAS# 107-02-8)Yes No ???
Acrolein - 2
• Carcinogenic Effects
o IARC Group 3 - not classifiable as to carcinogenicity in humans; US EPA -
inadequate data
o 2 of 3 oral carci studies –ve and 1 questionable
➢ Critical effect is NOAEL of 0.05 mg/kg/day for decreased survival in
male and female rats treated by oral gavage for 2 years. Deaths were
attributed to localized effects (i.e. gastric irritation) with a clear dose-
dependant increase
o 2 inhalation studies –ve (although exposure only 1 yr, with a single
exposure concentration, and limited no. of animals)
➢ Critical effect is LOAEL of 0.1 mg/kg/day for nasal lesions in male and
female rats exposed to acrolein 6 hours/day, 5 days/week for 13
weeks
o Weight of evidence indicates that acrolein is not a rodent carcinogen13
Poll Question 1
While mutagenic, the weight of evidence indicates that
acrolein is not carcinogenic and therefore, which
methodology should be used to calculate exposure limits?
A. Linear extrapolation from TD50
B. Benchmark Dose approach
C. ICH Q3C PDE methodology
Answer: PDE
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Poll Question 2
Based on the summary information, which data would you use
to calculate route specific exposure limits for acrolein?
A. Mutagenicity/genotoxicity data
B. Dermal, nasal and ocular irritation study data
C. Chronic oral study data
D. Carcinogenicity study data
Answer: D
Local irritation driving most sensitive endpoint via oral and
inhalation exposure. Use oral and inhalation carci studies to
derive route specific exposure limits 15
Acrolein Oral PDE
• Oral carci study in rats, NOAEL of 0.05 mg/kg/day
• Lifetime PDE = 50 μg/day
• US EPA oral RfD = 25 µg/day, based on the same 2-year rat study
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AF Description Value
F1 Extrapolation between
species
5 (rat to human)
F2 Variability between people 10
F3 Short-term to long term
extrapolation
1 (carci study)
F4 Severity of effect 1 (gastric irritation has a clear
threshold)
F5 NO(A)EL established 1
Acrolein Inhalation PDE
• Inhalation carci study in rats, LOAEL of 0.1 mg/kg/day
• Lifetime PDE = 7 μg/day
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AF Description Value
F1 Extrapolation between
species
5 (rat to human)
F2 Variability between people 10
F3 Short-term to long term
extrapolation
5 (3-month study duration)
F4 Severity of effect 1 (effects not severe at the
LOAEL)
F5 LO(A)EL established 3
Methyl bromide - 1
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Compound Structure In vitro
Mutagen
Rodent
Carcinogen
Limit (AI or PDE)
Methyl bromide
(CAS# 74-83-9)Yes No ???
• Mutagenicity/Genotoxicity
o Ames +ve (gas sealed dessicators)
o UDS –ve and chrom abs –ve in vivo rat bone marrow
o SCE +ve bone marrow and MN +ve blood in mouse 14-day inhalation study
• Non-Carcinogenic Effects
o Moderate acute toxicity via oral and inhalation
o 5 developmental inhalation studies. 4/5 No abnormalities observed
o 1/5 abnormalities observed in rabbit pups at 80 ppm due to significant maternal
toxicity. NOAEC 40 ppm (14 mg/kg/day)
Methyl bromide - 2
• Carcinogenic Effects
• IARC Group 3 - not classifiable as to carcinogenicity in humans; US
EPA Group D - not likely to be a human carcinogen
• Oral chronic studies in rats (2 years). Lowest NOAEL from 2 rat
dietary studies 2.2 mg/kg/day, BW changes at high doses.
• Oral chronic study in dogs (12 months duration). No effect up to top
dose 0.28 mg/kg/day
• Inhalation chronic study in rats. 3 ppm (1.4 mg/kg/day) inflammation
/ hyperplasia of nasal epithelium NOAEC not defined.
• Inhalation chronic study in mice, LOAEC of 10 ppm (10.7
mg/kg/day) with hyperplasia of the nasal epithelium at all doses.
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Poll Question 1
While mutagenic, the weight of evidence indicates that methyl
bromide is not carcinogenic and therefore, Which
methodology should be used to calculate exposure limits?
A. Linear extrapolation from TD50
B. Benchmark Dose approach
C. ICH Q3C PDE methodology
Answer: PDE
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Poll Question 2
Based on the summary information, which data should be used to calculate
the route specific exposure limits?
A. Oral rat carcinogenicity study data
B. Oral dog chronic study data
C. Inhalation rat carcinogenicity data
D. Inhalation mouse carcinogenicity data
Answer: A and C
Separate PDEs calculated for oral (A) and inhalation (C)
• Chronic inhalation studies more sensitive than oral
– effects in nasal region, site of contact 21
Methyl bromide Oral PDE
• NOAEL 2.2 mg/kg/day in rats, with BW changes observed at higher doses
• Lifetime PDE = 2.2 mg/day
• Oral PDE appropriate for parenteral
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AF Description Value
F1 Extrapolation between
species
5 (rat to human)
F2 Variability between people 10
F3 Short-term to long term
extrapolation
1 (chronic, study at least half a
lifetime)
F4 Severity of effect 1 (bodyweight changes)
F5 NO(A)EL established 1
Methyl bromide inhalation PDE
• Inhalation carcinogenicity study in rats, LOAEC 3 ppm (1.4 mg/kg/day)
• Main adverse effects of at low doses are localized at the site of contact
• Lifetime PDE for = 467 µg/day
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AF Description Value
F1 Extrapolation between
species
5 (rat to human)
F2 Variability between people 10
F3 Short-term to long term
extrapolation
1 (chronic, study at least half a
lifetime)
F4 Severity of effect 1 (inflammation and hyperplasia
of nasal region)
F5 LOAEC established 3
Take home message
• Generally, compound specific exposure limits are applicable
to all routes of administration
• Careful review of all data
• Calculate route specific exposure limit if you can!
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References - 1
• ICH M7(R2), 2015. Assessment and Control of DNA Reactive (Mutagenic)
Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk.
• Leong BKJ, Kociba RI, Jersey GC. A lifetime study of rats and mice
exposed to vapors of bis(chloromethy1) ether. Toxicol Appl Pharmacol
1981; 58:269-81.
• Sellakumar AR, Laskin S, Kuschner M, Rush G, Katz GV, Snyder CA, et
al. Inhalation carcinogenesis by dimethylcarbamoyl chloride in Syrian
golden hamsters, J Environ Pathol Toxicol 1980; 4:107-15.
• Van Duuren BL, Goldschmidt BM, Katz C, Seidman 1770 I, Paul JS.
Carcinogenic activity of 1771 alkylating agents, J Natl Cancer Inst 1974;
53:695-700.
• Renwick, A.G., 1991. Safety factors and establishment of acceptable daily
intakes. Food Addit. Contam. 8, 135-149.
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References - 2
• Organization for Economic Cooperation and Development (OECD) 2013. SIDS
Initial Assessment Profile (SIAP) on Titanium dioxide (CAS No. 13463-67-7)
• Environmental Health Criteria (EHC) 24 Titanium. World Health Organization
Geneva, 1982.
• ILSI, 2000. Technical Report 122. Relevance of lung overload for humans.
Accessed Feb 2018
• ICH Q3C(R6). Impurities: Guideline for Residual Solvents
• IPCS 2005. Chemical-specific adjustment factors for Interspecies differences and
human variability: Guidance document for use of data in dose/concentration-
response assessment
• ICH Q3D. Guideline for Elemental Impurities
• Bercu et al., 2018. Potential impurities in drug substances: Compound-specific
toxicology limits for 20 synthetic reagents and by-products, and a class-specific
toxicology limit for alkyl bromides. Regul Toxicol Pharmacol. 2018 Apr;94:172-
182.26
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