Thresholds of Toxicological Concern

Transcription

1 Thresholds of Toxicological Concern Introduction to the Concept Heli M Hollnagel (hmhollnagel@dow.com)

2 Next 20 Minutes TTC Databases Grouping schemes Risk assessment approach What is excluded from TTC Most important decision points 2

3 TTC: Large Database Read-across Approach All toxicity data for all substances Which are most toxic? Typical toxicants distribution Lowest NOAELs Safety factors De minimis thresholds 3

4 TTC Concept The Principle Cancer Endpoints: TD50 low dose linear extrapolation > 700 substances Database(s) with toxicity information on as many substances as possible Other Endpoints: Repeated dose NOAEL / 100 > 600 substances Threshold based on virtually safe dose (10-6 ) 3 Cramer structure classes Thresholds at 5 th percentile of each class 4

5 Limitations of the TTC Concept Oral exposure Toxicity Databases Highly potent toxicant Chemical category not in database Effect type not in database TTC Thresholds aflatoxins, nitrosamines etc. inorganics, proteins etc. local irritation, sensitisation etc. Other limitations Use of 5th/15th percentile leads to very low thresholds often don t allow a conclusion of no concern TTC should only be used by persons understanding the principle and limitations not a laymen tool (similar to QSAR and read-across!) Thresholds of oral exposure if extrapolating route of exposure, be diligent! 5

6 Refining Thresholds by Grouping Highly potent carcinogens excluded from concept DNA-reactive carcinogens Non- DNA-reactive carcinogens Organophosphates/ carbamates Cramer III: Structural features with tox concern Cramer II: intermediate Cramer I: Structural features without tox concern 6

7 Human Exposure Thresholds - Original Munro Dataset Dataset (number of chemicals) Munro-1996 (613) CC I CC II CC III 30 (137) 9.0 (28) Human exposure threshold values (ug/kg-bw/day) 1.5 (448) Organophosphate / carbamate 0.3 (31) DNA-reactive (ca 700) TTC uses the same approach in TTC is specific where it uses - NOAEL setting from repeated dose studies - SAR to identify genotoxic carcinogens - Extrapolating interspecies differences etc - Crude structural classes (Cramer, OPs, carbamates) - Read-across to 5th/15th percentile 7

8 Endpoints of Concern? Generic threshold derived from database What about effects Detected by specific studies only or At low exposures? Are those covered by TTC? 8

9 Endpoints of Concern? Generic threshold derived from database What about effects Detected by specific studies only or At low exposures? Are those covered by TTC? Genotoxic Carcinogens Developmental Toxicants Neurotoxicants Bioaccumulation Endocrine activity... 9

10 Endpoints of Concern? Genotoxic Carcinogens Developmental Toxicants Neurotoxicants Bioaccumulation Endocrine activity... Initially, all carcinogens were analysed together to result in the 1.5 µg/person cancer threshold (Rulis 1987 and Munro 1990) Cheeseman (1999) demonstrated that Ames-positive carcinogens in the TTC cancer database were more potent than Ames-negative carcinogens Kroes et al. (2004) identified highly potent DNA-reactive carcinogens in the database, excluded the most potent groups from the concept and assigned a lower threshold of 0.15 µg/person ( µg/kg bw/day) to all other DNA-reactive carcinogens Boobis et al. (2017) discuss a framework to enhance the cancer database and to differentiate between DNA-reactive and non-dna-reactive carcinogens in the analysis for thresholds (linear low dose extrapolation versus threshold approach) Database update project by Cronin et al. to conclude within 2018 (Cefic LRI B18) 10

11 % compounds with >1: risk Kroes et al Refinement of Cancer Threshold Aflatoxin Ar amines Ar nitrates Azo Azoxy Classes excluded due to high excess cancer risk even at 0.15µg/day 60 Benzidine Carbamates Daily intake (micrograms) Heavy metal High Cl Hydrazines Ashby alerts Nitro fury; Nitroso Ops Steroids Strained Dioxins Vinyls Note that this is based on linear extrapolation applied to steroids and dioxins, which is not necessarily state of the art

12 Why are genotoxic carcinogens handeled differently? Simplified view: Genotoxic Carcinogens Cause cancer via alteration of DNA structure or DNA processing during cell division Mutagens and clastogens (DNA-reactive carcinogens) Alter the DNA-structure Aneugens alter the number of chromosomes by interaction with proteins involved in DNA /chromosome processing Non-Genotoxic Carcinogens Cause cancer via enhanced cell proliferation by other mechanisms, mainly cytotoxicity non-thresholded Linear risk extrapolation approach. TTC 0.15µg/person. Threshold effects Most probably adequately covered by safe levels set based on repeated dose studies. In this case the Cramer class thresholds. Which in vitro / in vivo assays are suitable to detect which effect type, see presentation by David Kirkland 12

13 Endpoints of Concern? Genotoxic Carcinogens Developmental Toxicants Neurotoxicants Bioaccumulation Endocrine activity... Several analyses were performed to examine whether developmental/reproductive toxicity studies would suggest lower thresholds: EFSA (2012) opinion on TTC Laufersweiler et al Regulatory Toxicology and Pharmacology 62: Muller et al Regulatory Toxicology and Pharmacology 63, van Ravenzwaay et al Regulatory Toxicology and Pharmacology 88, All analyses concluded that the NOAELs of developmental and reproductive effects are overlap with the NOAELs of general toxicity studies, i.e. TTC applies 13

14 Endpoints of Concern? Genotoxic Carcinogens Developmental Toxicants Neurotoxicants Bioaccumulation Endocrine activity... Kroes et al. 2000/2004 concluded that organophosphates and carbamates build a group of high potency within Cramer Class III and recommended to apply a separate threshold of 18 µg/person (as opposed to 90 µg/person for CCIII) EFSA SC 2012 confirmed the threshold with additional analyses 14

15 Endpoints of Concern? Genotoxic Carcinogens Developmental Toxicants Neurotoxicants Bioaccumulation Endocrine activity... Kroes et al excluded polyhalogenated dioxins, furans and biphenyls, and other substances with large species differences in bioaccumulation, from the TTC concept. However, the TTC dataset contains multiple halogenated substances with high Kow Leeman et al analysed the repeated dose TTC dataset. Chemicals with potential for bioaccumulation were identified based on logpow and H bond acceptor parameters. The NOAELs of potentially accumulating chemicals did not differ significantly from the NOAELs of all other chemicals moderate bioaccumulation is covered by TTCs (e.g. with <3 halogen atoms), but not extreme accumulation with large differences between human and animals (e.g. some perflourinated and perchlorinated substances). This area needs more work to develop clearer criteria. 15

16 Endpoints of Concern? Genotoxic Carcinogens Developmental Toxicants Neurotoxicants Bioaccumulation Endocrine activity... TTC thresholds do not distinguish between different mode of action (MoA). Regardless of MoA, the lowest relevant NOAEL is assigned to each substance. Some of the TTC dataset NOAELs are based on adverse effects on endocrine glands or reproductive tissues, but most often, other effects occur at lower doses. Steroids are excluded from the TTC concept (Kroes et al. 2004). However, this is based on a virtually safe dose obtained via linear low dose extrapolation, a questionable approach EFSA SC (2012) concluded with regard to endocrine activity that untested substances, other than steroids, can be evaluated using the TTC approach 16

17 Relevant Decision Points Exempt from TTC: Not part of database: Proteins, Metals, Steroids, Radioactive materials Animal studies not suitable for threshold setting: Strongly accumulating substances, e.g. Polyhalogenated dioxins Analyte possibly member of exempt class? no DNAreactive? no Acetylcholin Esterase inhibitor? Carbamates, organophospates no no Structure sufficiently characterised to assign Cramer Class? yes CC III CC II CC I High potency carcinogens: Aflatoxins, N-Nitroso and Azoxycompounds (benzidines) yes* yes* yes* Specific data required TTC TTC 0.3 TTC 1.5 TTC 9 TTC 30 TTC thresholds given in µg/kg bw/day 17 * Can be Yes or do not know

18 Not adressed today! De minimis thresholds for 1. Ecotox (ILSI HESI Project) 2. Inhalation (Fraunhofer ITEM) 3. Flavorings (Renwick 2004) 4. Personal Care (Kroes 2007, Yang 2017) 5. Skin sensitisation (Safford 2011, 2015) 6. Acute toxicity (Buist 2016) 7. Short duration exposure (Felter 2011) 8. Pharmaceutical actives (ICH, Stanard 2015) 9. Medical device leachables (Borschard 2016) 10. Proteins 11. Coexposures 12. Uncertainty specific to TTC

19 Acknowledgements S. Barlow, A. Renwick, A.R. Boobis, C. Yang, M. Cheeseman, M. Cronin, S.P. Felter, K.L. Muldoon Jacobs, R. Safford, V. Vitcheva, A. P. Worth, M. Cronin, K. Arvidson, J. Edwards, C. L. Galli, J. Goodman, A. Jacobs, D. Kirkland, M. Luijten, C. Marsaux, M. Martin, S. Escher, S. Melching-Kolmuss, et al.

20 Useful Reading Munro 1990 REGULATORY TOXICOLOGY AND PHARMACOLOGY 12, 2-12 (1990) Kroes et al Food and Chemical Toxicology 42 (2004) EFSA Scientific Committee; EFSA Journal 2012;10(7):2750 EFSA and WHO (2016). EFSA supporting publication 2016: EN Boobis et al CRITICAL REVIEWS IN TOXICOLOGY, 2017 Yang et al Food Chem Toxicol. 2017;109(Pt 1):