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Regulatory Relevance of the Threshold of Toxicological Concern (TTC)

R B Cope BVSc BSc (Hon 1) PhD cGLPCP DABT ERT

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Content & Focus

• What is the TTC and how was it developed?

• What is the regulatory relevance of the TTC?

• Future directions of the TTC approach.

• Benefits and risks of the TTC approach?

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The glass metaphor: A toxicologist’s perspective

Economics Department: The glass is twice as big as it needs to be. Somebody needs to talk to manufacturing. We could save a fortune by only producing the bottom half of the glass.

Manufacturing Department: Response to the Economics Department - the glass is clearly full: half with water and half with air. What is your problem?

Accounts Department: Who needs economists when you have accountants?

Marketing Department: If the glass was in a forest with nobody watching, what would it be?

Toxicology Department: The glass has acceptable safety properties allowing for an uncertainty factor of 100, erring on the side of the precautionary principle, assuming: that animal to human extrapolation is valid, that there was adequate experimental power, the study Klimisch score was 1, life is good today, the mice felt fine right up until they died, marketing has not complained about the toxicology department lately, the manufacturing department ignores us anyway, the economists don’t see the point of the toxicology department, marketing does not understand toxicology, the accountants don’t like the CRO we are using, the regulators are saying nice things about our submission, the product stewards like us at the moment, my paper has just been accepted for publication, its Friday and I have a great weekend coming up, its payday, …………………

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Slide acknowledgement: Watze de Wolf, DuPont 5

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Where does the TTC come from?• US FD&C Act amendments 1958

– Required premarket approval or review of food additives prior to their inclusion in food:

• Precisely defined what is a “food additive;”

• Established the standards of review and safety for food-additive approvals;

• "food additive" to include components of food-contact articles (food packaging and food processing equipment) that migrate, or may reasonably be expected to migrate, into food, making them subject to premarket approval [Section 201(s) of the Act];

• For premarket approval for use of food additives, the Act required that the safety of the proposed use be demonstrated by data submitted to the FDA in a food-additive petition;

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Where does the TTC come from?• Amendments resulted in numerous petitions for

exemptions from the food additive requirements of the act (regulation must not be overly burdensome to industry);

• For next 37 years or so exemptions were granted on an “ad hoc” basis;

• During this time, industry also approached the FDA to propose that the Agency handle the issue of minimal migration of these substances into food through a so-called "Threshold of Regulation" (TOR) policy.

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Where does the TTC come from?

• TOR– 1967: Industry TOR proposal of 100 ppb dietary

concentration for food-packaging materials, excluding pesticides and heavy metals, based on the results of two-year chronic oral feeding studies of 220 compounds;

– 1969: FDA proposed a TOR of 50 ppb for levels of migrants into food or food-simulating solvents;

– 1977: Society of the Plastics Industry proposed a TOR of 50 ppb for migrants into food.

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Where does the TTC come from?

• TOR– 1995: FDA establishes a TOR on the basis of• Reasonable certainty of no harm;• Did not violate the Delany Clause of the FD&C Act;• Provided acceptable protection even if the exempted

substance was later shown to be carcinogenic

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Where does the TTC come from?• US FDA TOR

– Substance is not a carcinogen nor bears chemical resemblance to known carcinogens;

– Substance does not contain carcinogenic impurities OR if it does, does not contain a carcinogenic impurity with a lowest TD50 ≤ 6.25mg/kg BW/d;

– Dietary concentration ≤ 0.5 ppb (≤1.5 μg/person/d based on a diet of 1,500 g of solid food and 1,500 g of liquid food/person/d);

– OR

– The substance is currently regulated for direct addition into food, and the dietary exposure to the substance resulting from the proposed use is at or below 1 percent of the acceptable daily intake as determined by safety data in the Food and Drug Administration's files or from other appropriate sources;

– The substance has no technical effect in or on the food into which it migrates;

– The substance use has no significant adverse impact on the environment.12

Where does the TTC come from?

• US FDA TOR

– FDA has right of refusal irrespective of the data;

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Main Example: TTC For Food An Example of TTCs in Complex Mixtures

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Main Example: TTC For Food

1. How do you prioritize?2. Can you safely store this food item? 3. Do you really have to chemically identify each new peak?4. Do you really have to chemically isolate all the unknowns, purify them and develop a

toxicology package to ensure human safety?5. Could you realistically perform all the studies required?

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TTC

• Examples of other reasons for “new peaks”:– Change in food contact material or new contact

materials;– New food processes;– Changes in storage conditions;– Fermentation/bacterial action;– Cooking or other heat/freeze processes;– Changes in agrichemical use.

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Cohorts of Concern and TTC Excluded Classes• Potent human-relevant mutagenic carcinogens

– Mutagens: aflatoxins, N-nitroso group, azoxy group, PAHs, etc. Included based on linear low dose extrapolation to cancer risk of 1 x 10-6 (high cancer slope factor);

– aH-receptor agonists: PHDDs, PHDBFs, co-planar PHBP. High potency human-relevant non-mutagenic carcinogens;

– Steroids and other endocrine-active substances;

• Protein/peptide allergens and toxins (notably the Clostridial & Staphylococcal toxins);

• High molecular weight polymers ( mw > 1000 Da). Note: remnant oligomers and monomers in polymers are included in the TTC method;

• Bioaccumulative non-essential metals, notably Cd, Hg, Pb, As, Tl, – Ag (argyria);

• Allergenic metals e.g. Ni, Cr, Ag

• Radioactive materials (Fukushima) 18

Cramer Classes• Class I substances are simple chemical structures with

efficient modes of metabolism suggesting a low order of oral toxicity; – Problem: many toxicants are poisonous because they are

rapidly and efficiently metabolized to an ultimate toxicant (i.e. they are really pro-toxicants);

– Efficient metabolism (excretion) does not guarantee low toxicity;

• Class III substances are those that permit no strong initial presumption of safety, or may even suggest significant toxicity or have reactive functional groups;

• Class II are assigned to intermediate substances 19

Cramer Classes• The Cramer decision tree is set up such that it

detects few harmless compounds as Class I (low concern) substances, and virtually all other compounds as Class III (high concern, i.e. no assumptions of safety possible);

• Cramer decision tree errs on the side of the precautionary principle (conservative).

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WHO/IPCS TTC Exposure ThresholdsTTC Tier (μg/d) Dose Equivalent (mg/kg BW/d) Basis

0.15 2.5 x 10-6 Structural alerts for genetox

18 3 x 10-4 Organophosphate ACh inhibitors

90 0.0015 Cramer Class III 5th percentile NOAEL

540 0.009 Cramer Class II 5th percentile NOAEL

1800 0.03 Cramer Class I 5th percentile NOAEL

Assumptions: • Continuous life-time consumption• Default human body weight of 60 kg• UF of 100 applied to the NOAEL• Based on adults, but subsequent studies have demonstrated that TTC

thresholds are protective for repro/developmental effects

Trivial Nitpicking:• NOAELs across different studies and study designs do NOT denote the same

level of risk because of different statistical power• In general, OECD studies have a sensitivity of about 10% (5% for repro)• BMDLo is a better measure • However, TTC thresholds are very conservative! 21

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What is the regulatory relevance of the TTC?What are the proposed uses of the TTC?

• WHO JECFA 1997: Adopted a TTC approach for food flavoring additives;

• EU 2003 (DG SANCO 2003): Metabolites of active substances of plant protection products in groundwater;

• EFSA 2004: Adopted a TTC approach for food flavoring additives;

• EMEA 2004: Genetoxic and carcinogenic impurities in pharmaceuticals;

• Flavor and Extract Manufacturers Association (FEMA) 2005: Safety evaluations of natural flavor complexes (NFC)

• Merck 2005: Used for risk assessment of workplace exposure to pharmaceutical actives, impurities and excipients during pharma manufacturing;

• Merck 2005: Used for pharma plant cleaning validations;

;

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What is the regulatory relevance of the TTC?What are the proposed uses of the TTC?

• US FDA CDER 2008: Genetoxic and carcinogenic impurities in pharmaceuticals – “In general, an exposure level of 1.5 μg per person per day for each impurity can be considered an acceptable qualification threshold for supporting a marketing application. Any impurity found at a level below this threshold generally should not need further safety qualification for genetoxicity and carcinogenicity concerns. The threshold is an estimate of daily exposure expected to result in an upper bound lifetime risk of cancer of less than one in a million, a risk level that is thought to pose negligible safety concerns;”

• EMEA 2008: Genetoxic constituents of herbal medicinal products / preparations;

• EFSA 2009: Dietary risk assessment of metabolites, degradation and reaction products of pesticides;

• US NSF 2010: Proposed use of TTC for unknown contaminants of water and migrants from water contact materials; (also ILSI 1998 and several other industry groups)

• EFSA 2012: Food – “The Scientific Committee concluded that the TTC approach can be recommended as a useful screening tool either for priority setting or for deciding whether exposure to a substance is so low that the probability of adverse health effects is low and that no further data are necessary;

;

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What is the regulatory relevance of the TTC?What are the proposed uses of the TTC?

• EFSA & COSMOS 2012: Cosmetics – EFSA is currently evaluating the use of TTC method for cosmetics;

• 2012: Multiple proposals for use of the TTC concept in ecotoxicolgy;

• 2012: Multiple proposals for use of the TTC concept in personal care products;

• 2012: Proposal for the use of TTC concept for genetoxic impurities in veterinary medicinal products;

• 2012: Proposal for use of TTC concept for air pollutants;

• 2012: Proposal for use of TTC concept for medical devices.

;

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Benefits of the TTC Approach.

• Triage for toxicologists: provides a structured basis for focusing resources on things that are likely to make a bigger difference;

• Fast;

• Simple and clear;

• Considers available data;

• The structure of the Cramer decision tree generally means that there is an assumption that a lack of data ≠ absence of effect i.e. errs on the side of safety and conservatism.

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Downsides of the TTC Approach.

• We don’t know what we don’t know – assessments are only as good as today’s data!

• Open to a high level of misuse and misinterpretation: requires a careful, thinking approach. There are no short-cuts and should not be seen as “toxicology by wrote”

• Does not mean that the substances are “safe”; means that as far as we know, they have a low priority in terms of further investigation of the risk that they pose.

• Discourages further research on interesting and potentially useful molecules;

• Accurate “worst case” and comprehensive exposure assessment is critical to the reliability of the approach ;

• Potential loss of information;

• Uses uncertainty factors which are themselves arbitrary (Could potentially use a CSAF if data was available?);

• Still largely dependent on animal to human extrapolation: a key question – are the putative effects really human relevant?

• Some aspects are highly conservative e.g. assumes life-long continuous exposure, does not take into account adaption/tolerance etc.

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Downsides of the TTC Approach.

• Heavily dependent on data quantity and quality; particularly the databases used to support the necessary in silico modeling;

• Heavily dependent on the confidence of the fitted NOAEL distributions;

• Relies on NOAELs;– NOAELS across different studies and experimental designs DO NOT DENOTE THE SAME LEVEL OF RISK; only benchmark dose

procedures can do this;– NOAELs typically only have a sensitivity of 10% of the response due to experimental design constraints;– NOAELs are strongly experimental design-dependent where as BMD techniques are not;

• Still requires massive linear extrapolation beyond measured experimental data i.e. makes assumptions about the shape of the low dose response curve that may not be valid. This may be particularly important with endocrine active substances and some carcinogens;

• Ignores the possibility of hormesis-like effects;

• Cramer risk alerts are based on relatively small data bases when you consider the sheer number of chemicals out there;

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Future Developments.

• Integration of the TTC and high throughput in vitro screening (“omics”) and other bioassays;

• Use of biosensor technology;

• More representative exposure assessments (e.g. intermittent versus lifetime);

• More accurate in silico approaches;• Inclusion of more chemical classes/modes of action

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Life is a fatal process. Most of us will not die from chemical exposure.

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