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merican· Chemistry

ouncil

C Threshold of Toxicological

Concern (TTC)

Richard A. Becker PhD DABT September 6, 2018

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Threshold of Toxicological Concern (TTC)

What is the TTC?

Potential uses of the TTC

Recommendations for exploring utility of TTC as a NAM within safety evaluation programs

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Fitted Distribution Class I

Class II V

Class Ill 0

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TTC is based on frequency distributions (5th percentile) of NOAELs of systemic toxicants

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Threshold of Toxicological Concern (TTC) TTC: a health protective human exposure reference value for daily exposure over a lifetime below which there would be no appreciable risk to human health (similar to an referencedose)

TTC – based on accumulated data & knowledge regarding the distribution of potencies of relevant classes of chemicals for which solid toxicity data exist

Threshold of Toxicological Concern (TTC)

Type of substance TTC μg/person/day (µg/kg-day 60 kg adult)

Alerts for potential genotoxic carcinogenicity Kroes: 0.15 (0.0025 μg/kg-day) ICH: 1.5 (0.025 μg/kg-day)

Acetylcholinesterase inhibitors (AChEI) Organophosphate/carbamate

18 (0.3 μg/kg-day )

Cramer Class III 90 (1.5 μg/kg-day)

Cramer Class II 540 (9.0 μg/kg-day)

Cramer Class I 1800 (30 μg/kg-day)

Exclusions: Aflatoxin-like, Azo-compounds, Nitroso-compounds, Benzidines, Metals and Organometallics, Proteins, Steroids, Substances with a potential for bioaccumulation, Nanomaterials, Radioactive substances, Mixtures of substances containing unknown chemical structures

1. Is the subsl.:ince a non-c.sential metal or mebl conL1ining compound, or is i i a polyhalogenatcd-<fiben.iodiOxin, .dibcn.zofuran, 01 -bi phenyl 1

NO

2. Arc 1herc struClural aler1!. that raise concern /or potential gcnocoxici1yl

YES

i Risk assessment requires compound-specific : IOKicily d:ita NO YES .._ ________ ,. . -- ----.. --- ------------ --------------------- -----..

S. ~ ~•im:ned inLlke c:>.c-eoo TTC of 1.5µg/d.ay1

YES NO ·----------------· --- .. -------------· . . · Substance "-ould not be · i expected _to be a_salety concem j

6. Is the compound an organophosphatc1

NO YES

3. Is the chcmic.11 an aOa1oxin-lik~, YES

azoxy., or N-nitroso- compound/ --------

NO

4. Does estimated ,ntake e.xcood TTC ~------.... of 0.15jJg/day?

YES

NO --- • --- - • ----- ---- - --- • - • --- • ---- - ---------- - ---- - •4

j Negl~iblc risk (low probability ol a lire-time j i .. ca.ncer rislc greater than 1 in 106-.Stt text).)

8. Is 1he compound in Cramer s1ruC1ural clas.s 1111

7. OOe estimated intake exc:ccd

TIC or 1 81-'!lfday? YES

NO 9. Docs estimated intake exceed

9~1f/day1

NO ....................... ............ ............. . . : Risk afS(!Simenl rcquircs :

1 compound-i,pec:ific 10,dci1y data j . .................................................. .

10. I, th<! compocmd in Cramer struoural class II?

YES

YES j Subsl,mc:e would not ~ expected

NO

12. Does estimated intake exceed 1800).isfdayl

YES NO

: to be~ safety concern

11. 000. ~ timated inl.lke excood ------ 5-l~g/d.lyl

NO YES

Substance would not be expeded to

be a safety conc:em

Risk as~s~enl rtquires compound~peci fic: 1oicld1y d.11a

Threshold of Toxicological Concern (TTC) Kroes et al (2004)

In a safety evaluation, use the TTC in the same manner as a

Reference Dose

TTC

Margin of Safety = Predicted (or measured) Exposure

Some TTC References • I.C. Munro, A.G. Renwick, B. Danielewska-Nikiel. The Threshold of Toxicological Concern (TTC) in risk assessment. Toxicol. Lett., 180

(2008), pp. 151-156, 10.1016/j.toxlet.2008.05.006

• S. Barlow. Threshold of Toxicological Concern: A Tool for Assessing Substances of Unknown Toxicity Present at Low Levels in the Diet. ILSI Concise Monograph Series. 2105 ILSI Press, Washington DC and Brussels (2005)Kroes et al (2004)

• R. Kroes, A.G. Renwick, M. Cheeseman, J. Kleiner, I. Mangelsdorf, A. Piersma, B. Schilter, J. Schlatter, F. van Schothorst, J.G. Vos, G. Würtzen. European branch of the international life sciences institute, structure-based t hresholds of toxicological concern (TTC): guidance for application to substances present at low levels in the diet Food Chem. Toxicol., 42 (2004), pp. 65-83

• Health Canada, Science Approach Document Threshold of Toxicological Concern (TTC)-based Approach for Certain Substances Health Canada. https://www.ec.gc.ca/ese-ees/326E3E17-730A-4878-BC25-D07303A4DC13/HC%20TTC%20SciAD%20EN%202017-03-23.pdf, 2016 (accessed 21 January 2018)

• S. Felter, R.W. Lane, M.E. Latulippe, G .C. Llewellyn, S.S. Olin, J.A. Scimeca, T.D. Trautman. Refining the threshold of toxicological concern (TTC) for risk prioritization of trace chemicals in food. Food Chem. Toxicol., 47 (2009), pp. 2236-2245, 10.1016/j.fct.2009.06.018

• M.C. Laufersweiler, B. G adagbui, I.M. Baskerville-Abraham, A. Maier, A. Willis, A.R. Scialli, G.J. Carr, S.P. Felter, K. Blackburn, G. Daston Correlation of chemical structure with reproductive and developmental toxicity as it relates to the use of the threshold of toxicological concern Regul. Toxicol. Pharmacol., 62 (2012), pp. 160-182, 10.1016/j.yrtph.2011.09.004

• EFSA & WHO. Review of the Threshold of Toxicological Concern (TTC) approach and development of new TTC decision tree 2016. https://efsa.onlinelibrary.wiley.com/doi/epdf/10.2903/sp.efsa.2016.EN-1006

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Determine if TTC approach is appropriate based on chemical structure.

If the substance is one of these types, then TTC is not appropriate

an inorganic substance

a metal or organometalic

E E

bioaccumulative (e.g., PCDD/Fs)

a radioactive substance

a nanomatcrial

a mixture of substances with

unl<nown chemical structures

JJ TTCis not appropriate

Perform Substance-Specific Risk Evaluation

No such alerts ~-> Proceed

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Are there alerts for high potency genotoxic

compounds {e.g., aflatoxin­like, azoxy- or N-nitroso)?

I I Yes there are

such alerts therefore

TTC is not

appropriate

No such aler) I

Proceed

Compare to the appropriate TTC based on chemical

structure

Genotoxic Alerts 0.15 µg/day

(0.0025 µg/kg-day)

Anti-CH Es (OPs & carbamates) 18 µg/day;

(0.3 µg/kg-day)

Cramer Class Ill 90 µg/day

(1.5 µg/kg-day)

Cramer Class II 540 ,uglday

(9 µg/kg-day)

Cramer Class I 1800 µg/day

(30 µg/kg-day)

Compare and rank high-throughput exposures

to TTC values

Candidates for further

evaluation of hazard and exposure

Lower priority for further evaluation at

this time

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Uses of the TTC Risk-Based Priority Setting Patlewicz et al. 2018. Utilizing Threshold of Toxicological

Concern (TTC) with high throughput exposure predictions (HTE) as a risk-based prioritization approach for thousands of chemicals Comp Toxicology 7: 58-67, 2016.

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10 100 1000 Chemical Rank by One-Sided Upper 95% Credible Limit in 'Total' Demographic

• 6-11 Year Olds • Total

TTC category # of chemicals

Total dataset 7968

Dataset with available strnctures 7699

TIC is not appropriate 904

TTC is appropriate 6795

Genotox alerts 1853

AChETs 102

Cramer class ill 3214

Cramer class TT 332

Cramer class I 1294

Uses of the TTC Risk-Based Priority Setting Patlewicz et al. 2018. Utilizing Threshold of Toxicological

Concern (TTC) with high throughput exposure predictions (HTE) as a risk-based prioritization approach for thousands of chemicals Comp Toxicology 7: 58-67, 2016.

Wambaugh and colleagues (2014) developed a rapid heuristic high throughput exposure (HTE) model that enables prediction of potential human exposure to thousands of substances for which little or no empirical exposure data are available

category Number of TTC (µg/kg-day Percentage of Substances Exceeding che1nicals for 60 kg adult) the TTC

U CI Exposure Median Exposure Value (nmnber of Value (number of chemicals) chenricals)

Cramer class III 3214 1. 5 µg/kg-day 2% (58l 0

Cramer class 11 332 9.0 ~tg/kg-day 0 0

Crainer class I 1294 30 ~tg/kg-day 0 0

AChEis 102 0.3 µg/kg-day 1% (1) 0

Genotoxic alerts 1853 Kroes 0.0025 94% (1740) 43/c, (79) µg/kg-day

ICH 0.025 18% (333) 1 % (19) µg/kg-day

Uses of the TTC Risk-Based Priority Setting Patlewicz et al. 2018. Utilizing Threshold of Toxicological

Concern (TTC) with high throughput exposure predictions (HTE) as a risk-based prioritization approach for thousands of chemicals Comp Toxicology 7: 58-67, 2016.

Tab. 1: Current regulatory use of TTC

Area Authority Reference

Food packaging migrants and flavoring agents US FDA, JECFA, WHO FDA, 1995, 2001; JECFA, 1998; WHO, 2000

Food flavorings and pesticide metabolites in groundwater; EFSA EFSA, 2012, 2016 Under discussion for: food contact materials; impurities and breakdown/reaction products in food and feed additives; plant metabolites and degradants of pesticides; metabolites of feed additives; technological feed additives; flavoring substances in feed

Genotoxic impurities in (veterinary and human) EMEA, EMA EMEA, 2004; FDA, 2008; EMA, 2006, 2013 pharmaceutical preparations and genotoxic constituents in herbal substances and preparations

Genotoxic and carcinogenic impurities US FDA McGovern and Jacobson-Kram, 2006; in drugs ICH guidance MS, 2015a

Within REACH registrations for industrial chemicals ECHA ECHA, 2016

a https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegu1atorylnformation/Guidances/UCM347725.pdf

1 https://www.kvcv.be/index.php/en/food-contact-materials

Uses of the TTC Filling a Toxicity Data Need

Hartung 2017. ALTEX 34(3), 2017

Recommendations TTC was featured in EPA OPPT’s draft strategic plan, but is inexplicably absent in the final doc “Alternative Test Methods and Strategies to Reduce Vertebrate Animal Testing”

“EPA believes that exploration and potential implementation of the toxicological threshold of concern approach, at least for some chemical structural classes, is an important possible avenue for making some TSCA decisions. EPA is considering this topic as part of collaborative efforts…” https://www.epa.gov/sites/production/files/2018-06/documents/epa_alt_strat_plan_6-20-18_clean_final.pdf

Let’s start the collaboration!! and include TTC as part of the ICCVAM / NICEATM set of activities