ttc basics and latest developments - ilsi...
TRANSCRIPT
© Fraunhofer
TTC – BASICS AND LATEST
DEVELOPMENTS
Non-oral Routes and Influence of Local
Effects
Continuing Education Course - Eurotox 2015 Porto
Sylvia Escher, Fraunhofer ITEM
© Fraunhofer
Dr. Sylvia Escher
Chemical Risk Assessment
Databases and Expert systems
Fraunhofer Institut für Toxikologie und experimentelle Medizin,
Hannover
Non-oral Routes and Influence of Local
Effects
© Fraunhofer
Toxicology
Testing (focus on inhalation)
Fraunhofer ITEM -Overview
Pre-clinical
Pharmacology
Early-Phase
Clinical Trials
Manufacturing of
Biopharmaceuticals
for Clinical Trials
Environmental,
Occupational and
Consumer Protection
Registration and
Risk Assessment
© Fraunhofer
Cramer et al. grouped chemicals into 3 structural classes
via a series of 33 questions:
I = low, II = medium, III = high toxicity
Thresholds based on RDT studies with oral exposure
Current TTC concept
© Fraunhofer
Human exposure
Beside oral exposure humans are exposed to chemicals via
inhalation or dermal uptake
• Is the TTC concept applicable to these other routes of
exposure?
• Under which conditions?
© Fraunhofer
TTC dermal uptake (1)
TTC use for cosmetic ingredients (COLIPA proposal)*
The COLIPA Expert Group concluded that it is scientifically justifiable to use the
TTC approach and the database underlying the TTC values established for food
chemicals for the safety evaluation of cosmetic ingredients and impurities.
• Applicability domain: Chemical structures of cosmetic ingredients and cmpds in
the TTC databases comparable (Kroes et al. 2007)
• Exclude chemicals that have or are suspected to have pharmacological
properties (Kroes et al. 2007)
• TTC approach not applicable to assess local effects. In principle possible, but
the databases on local effects (e.g. skin irritation and contact allergies) are
currently too small.
• Systemic exposure after topical application to be measured or estimated e.g. by
using Jmax (maximum flux).
* SCCP/1171/082012: Opinion on the Use of the TTC Approach for Human Safety Assessment of
Chemical Substances with focus on Cosmetics and Consumer Products
© Fraunhofer
TTC dermal uptake (2)
Differences in systemic bioavailability - route-dependent differences after topical
exposure compared to oral uptake
• More extensive first pass metabolism in the liver, compared with the skin, prior to
reaching the general circulation.
• Slower and incomplete transfer across the skin compared with the intestinal wall,
due to the physico-chemical properties of the chemical and different
physiological properties of the tissues.
• The slower absorption after topical application may result in a different shape of
the plasma concentration–time curve, even if the area under the curve is
identical.
TTC values for Cramer Class I-III cmpds likely to overestimate the potential toxicity
of the same chemical following topical exposure, even if 100% of the topical dose
entered the systemic circulation. (Kroes et al., 2007).
© Fraunhofer
TTC dermal uptake (3)
* Kroes et al. (2007) Application of the threshold of toxicological concern (TTC) to the
saftey evaluation of cosmetic ingredients. Food and Chem Toxicol 45, 2533-2562
Jmax (µg/cm2/h) Default % dose
absorbed per 24 h
Non-reactive cmpd with MW > 1000
Da
Negligible
Jmax <0.1 10
0.1 >Jmax <10 40
Jmax > 10 80
Proposed default adjustment factors for the % absorbed dose of cosmetic
ingredients across the skin *
Not covered rinse of products such as shampoos with short exposure period
© Fraunhofer
TTC inhalation exposure (1)
• Screening tool for assessment of air contaminants (Drew and
Frangos, 2007).
• General ToR of 1.5 μg/person/d from FDA used to calculate a
"Concentration of No Toxicological Concern" (CoNTC).
• 50% of the ToR, human body weight of 70 kg, inhalation of 20 m3 of
air per day a general TTC for air contaminants calculated as 0.03
μg/m3.
• CoNTC compared with occupational exposure limits (OEL): OELs
divided by a factor of 42
• factor of 4.2 to convert occupational (8h/d; 5d/w) to consumer
exposure (24 h/d; 7 d/w)
• factor of 10 to account for greater intraspecies sensitivity of the
general population as compared to workers
• 4/1857 OEL values (0.2%) below the CoNTC
© Fraunhofer
TTC inhalation exposure (2)
Is it possible to use the Cramer decision tree to determine inhalation
thresholds?
© Fraunhofer
TTC inhalation (2): Application of Cramer
decision tree to inhalation datasets
• TTC inhalation < orale TTC
• Route specific difference?
Dataset Route Type N Class 1 Class 3
Munro et al. 1996 Oral General 611 1800 90
Carthew et al.
2009
Inhalation Local 92 200 67
Systemic 92 980 170
RepDose
(Escher et al.
2010)
Inhalation General 203
(136*)
71
(180*)
4
(4*)
* Cmpds with structural alert for genotoxicity excluded
© Fraunhofer
Local versus systemic effects
Hypothesis*
Sensitivity to local effects differs for
inhalation and oral exposure
To be confirmed:
Are targets of the resp. tract more
frequently affected than other targets?
Do effects in the respiratory tract occur at
LOEL? Are these effects more sensitive?
*Escher et al. 2010
wikipedia
© Fraunhofer
Frequency of targets at LOEL in inhalation studies
Local targets frequently occur at the LOEC of inhalation studies
Escher et al. 2010
© Fraunhofer
Inhalation TTCs
• New grouping concept developed
• large database on RDT studies with inhalation exposure
• Dataset splitted into high toxic, moderate toxic and low toxic cmpds
based on NOEC distribution
• 21 structural groups identified being charateristic for high or low
toxicity
• MoA analysis, PC properties, structural homogenity to conclude on
final grouping (28 structural groups)
• TTC values derived for groups of toxic and lower toxic cmpds
© Fraunhofer
TTC database
www.repdose-fraunhofer.de
29%
66%
4% 1%
Routes inhalation oral dermal other
TTC dataset
608 inhalation studies
296 cmpds
834 inhalation studies/
362 cmpds
© Fraunhofer
Characterisation of TTC dataset
Local versus systemic effects at LOEC
„Local effect“
N= 56 cmpds
„systemic effect“
N=148 cmpds
„Local and systemic effects“
N=62 cmpds
„Local DB“
N= 118 cmpds
„systemic DB“
N= 210 cmpds
© Fraunhofer
Inhalation TTCs
• Results submitted for publication
1. Inhalation Threshold of Toxicological Concern (TTC) - Structural
Alerts Discriminate High from Low Repeated-Dose Inhalation
Toxicity. G. Schüürmann, R.U. Ebert, I. Tluczkiewicz, S.E. Escher,
R. Kühne. Environment International, submitted August 2015
2. Inhalation TTC values: A new integrative grouping approach based
on structural, toxicological and mechanistic features. I.
Tluczkiewicz, R. Kühne, R. U. Ebert, M. Batke, G. Schüürmann,
Inge Mangelsdorf, S.E. Escher. Regulatory Toxicology and
Pharmacology, submitted August 2015
© Fraunhofer
Route independent TTC values?
• Internal dose instead of external dose will enable route to route
extrapolation
© Fraunhofer
Route independent TTC values?
• Internal dose instead of external dose will enable route to route
extrapolation*
• Three independent datasets used
• Munro DB (Munro et al. 1996, N=613)
• New chemical database (ELINCS DB, N=765)
• Database on food contact materials (FCM DB, N=199)
• Oral external NOAELs were converted to internal NOAELs taking into
account bioavailability by using an in silico prediction tool (ACD
Percepta from ACD Labs)
* Partosch et al. (2014) Internal threshold of toxicological concern values: enabling route to
route extrapolation. Arch Toxicol. DOI 10.1007/s00204-014-1287-6.
© Fraunhofer
Comparison: Internal TTC vs. external TTC
* Partosch et al. (2014) Internal threshold of toxicological concern values: enabling route to
route extrapolation. Arch Toxicol. DOI 10.1007/s00204-014-1287-6.
Cramer class TTC type Munro DB ELINCS DB FCM DB
N=137 N=53 N=97
Class 1 TTC extern 53.4 60 10
TTC intern 1 22.8 5.2
N=476 N=712 N=102
Class 2+3 TTC extern 2 24.8 3
TTC intern 0.15 0.07 0.0012
TTC given as µg/kg bw/d; based on the empiric 5th NOAEL percentile;
Default uncertainty factor of 100 used for external and 25 for internal TTC
values.
© Fraunhofer
Proposed internal TTC values
* Partosch et al. (2014) Internal threshold of toxicological concern values: enabling route to
route extrapolation. Arch Toxicol. DOI 10.1007/s00204-014-1287-6.
Internal TTC
Cramer class 1
Internal TTC
Cramer class 2+3
Based on 5th NOAEL 6.9 0.1
90% Confidence
interval
3.8-11.5 0.08-0.14
© Fraunhofer
Dr. Sylvia Escher
Chemikalienbewertung
Fraunhofer-Institute für Toxikologie und Experimentelle Medizin
Nikolai-Fuchs-Straße 1
30625 Hannover
Tel: +49 (0) 5 11 / 53 50 - 330
Fax: +49 (0) 5 11 / 53 50 - 335