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Approaches to the Threshold of Toxicological Concern

Approaches to the Threshold of Toxicological Concern. Clif McLellan Director of Toxicology Services NSF International March 16, 2010. Overview of Presentation. Who is NSF and how do we use health based risk assessments ?

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Approaches to the Threshold of Toxicological Concern

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  1. Approaches to the Threshold of Toxicological Concern Clif McLellan Director of Toxicology Services NSF International March 16, 2010

  2. Overview of Presentation Who is NSF and how do we use health based risk assessments ? Setting Health based criteria when no chemical specific toxicology data is available. Threshold of Evaluation Threshold of Toxicological Concern Class Based Evaluation Levels

  3. NSF International • Independent, private, not-for -profit organization which provides third party services through programs which focus on public health and environmental quality • Test & certify products • Inspect production facilities • Register quality systems • Develop and maintain consensus standards; many of which are related to drinking water and food

  4. NSF Was Established In 1944 To Develop Standards, And Test And Certify Food Equipment. - 3 public health experts found the National Sanitation Foundation (NSF) in the University of Michigan’s School of Public Health 66 years ago. - Initially serviced the food industry

  5. NSF International in 2010 - Developed more than 72 national consensus standards - Utilize more that 200,000 square feet of laboratory space for chemistry, engineering and microbiology - Client base over 12,000 companies - Certified more than 225,000 products made in more than 100 countries

  6. Certification Process for Products Contributing Direct or Indirect Additives • Review each material formulation to the individual chemical level, to identify potential leachates based on material formulations and manufacturing processes • Perform material leachate tests based on established protocol to match end use to potential contaminants • Normalized test results to determine potential “at the tap” contaminants for regulated and unregulated chemicals • Determine whether the “at the tap” concentrations exceeds health based criteria

  7. What are the results of Material Extraction Testing? More than 2,500 different chemicals have been identified as a result of material leachate tests. - 41 have MCL’s - 109 IRIS or Health Advisories - 300 have sufficient toxicology data - > 2000 insufficient data for assessment

  8. Process of Setting Acceptance Criteria for Unregulated Substances With Data • Perform literature search for compound • Determine the quality of data • Use appropriate data to arrive at an RfD or Cancer Risk Level, using the EPA guidelines • Internal Peer Review • External Peer Review • Publish on ITER and adoption for use in appropriate standards

  9. Total Allowable Concentration (TAC) RfD(mg/kg/day) x BW(70 kg) x Relative Source Contribution (2 L/day) Total Allowable Concentration (Equivalent to a DWEL) is the maximum concentration of a nonregulated expressed in mg/L and calculated as follows:

  10. Setting Health based criteria when no chemical specific toxicology data is available. The Threshold of Evaluation The Threshold of Toxicological Concern Class Based Evaluation Levels

  11. The Threshold of Evaluation (TOE) The Threshold of Evaluation (TOE) is based on the FDA’s Threshold of Regulation (TOR). Prior to 1958, the Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act (FFDCA) considered all substances food additives if they were found in food. As analytical limits of detection improved, FDA had to come up with a paradigm to address these low-level migrants. Thus the Threshold of Regulation (TOR) was developed. • In 1958, an exemption (Delaney Clause) was created which stated that if a chemical was present at less than 0.5 ppb in food it was not considered a food additive and would be exempt from the regulation. To qualify for the exemption • The substance could not be a known carcinogen

  12. The Threshold of Evaluation (TOE) The Threshold of Regulation of 0.5 ug/ kg food or 1.5 ug/person/day was converted to a drinking water concentration based on the following conversion. 0.5 ug/ kg food/ day * (3 kg food / day) / (2 L water / day) = 0.75 ug / L

  13. The Threshold of Evaluation (TOE) Exclusion to the use of The Threshold of Evaluation Not applied to any substance for which available toxicity data and sound scientific judgment such as structure activity relationships indicate that an adverse health effect results at these exposure concentrations.

  14. Threshold of Toxicological Concern (TTC) • The TTC approach is used as a substitute for evaluating health risks in the absence of complete substance-specific health effects data • TTC risk assessments are based on an analysis of toxicological and/or structural data of a broad range of different chemicals including carcinogenic and non-carcinogenic endpoints • The TTC approach is used in the U.S. and Europe • FDA allows the use of a TOR when evaluating health risks from food contact materials (e.g., sandwich bags, retort cups) • JECFA uses a TTC when evaluating health risks from food additives

  15. “ Threshold of Toxicological Concern” (TTC) The Threshold of Toxicological Concern (TTC) is based on a number of published papers. Estimation of Toxic Hazard-A Decision Tree Approach (Cramer and Ford, 1978). Correlation of Structural Class with No-Observed-Effects Levels: A Proposal for Establishing a Threshold of Concern (Munro et al., 1996) A Tiered Approach to the Threshold of Regulation (Cheeseman et al., 1999) Structure Based Thresholds of Toxicology Concern (TTC): Guidance for the applications of substances present at low levels in the Diet (Kroes et al., 2004)

  16. Threshold of Toxicological Concern (Noncancer) The first steps is a determination of the structural classes identified according to the Cramer et al. (1978) decision tree • Class I – Simple chemicals, efficient metabolism, low oral toxicity • Class II – May contain reactive functional groups, slightly more toxic than Class I • Class III – Substances that have structural features that permit no strong initial presumption of safety or may even suggest significant toxicity • Organophoshates (Added Munro et al. (1999)) Cramer evaluated the published literature to classify hundreds of chemicals, including 247 carcinogens, food additives, drugs, industrial chemicals and pesticides.

  17. Step One: TTC Approach (Noncancer) The Cramer et al. (1978) decision tree comprises 33 questions related to chemical structure, functional groups, and source of the chemical

  18. Threshold of Toxicological Concern (Noncancer) For each group, the 5th percentile of the distribution of NOELs from the subchronic and chronic animal studies were determined. The NOELs from the chronic study were divided by a 100-fold safety factor and the NOELs from the subchronic studies were divided by a 300-fold safety factor. Body weight of 60 kg was used.

  19. Threshold of Toxicological Concern (Cancer) FDA’s TOR was reviewed by Rulis et al. (1986, 1989) and extended by Cheeseman et al. (1999) • A threshold value of 0.5 ppb in the diet based on carcinogenic potencies of 500 substances from 3500 experiments of Gold et al.’s (1984, 1989) Carcinogenic Potency Database • The distribution of chronic dose rates [mg/kg bw/day] that would induce tumors in 50% of test animals (TD50s) was plotted • This distribution was extrapolated to a Virtually Safe Dose (10-6 risk of cancer) in humans

  20. Kroes Decision-Tree (Kroes et al., 2004)

  21. TTC Acceptable Drinking Water Levels Calculation [X] µg/person/day x 0.20 = acceptable level in mg/L 2 L/person (60 kg/ 70 kg) Where: • X = 1800 µg/day for class I compounds, 540 µg/day for class II compounds, and 90 µg/day for class III compounds • Relative Source Contribution = 0.2 • Drinking water intake = 2 L/day • Human body weight of 70 kg

  22. Analysis of TTC against Previously Established Risk Levels Procedure: NSF evaluated each EPA and NSF established risk level against the TTC approach to compare the established risk level with what would have been derived if no information was available for that compound. Limitations using the TTC approach: • TTC does not address a number of chemical classes. Not all functional groups are included in the classification scheme. • Naming convention used in scheme does not follow IUPAC nomenclature and can be ambiguous. • Halogenated compounds may result in underestimated values. The toxicity class that would allow an acceptance level which exceeds potential health effects. • It is possible to interpret questions differently and arrive at a different Cramer class classification. Inconsistencies are possible between reviewers.

  23. Class Based Evaluation Levels (CBEL) Establishment of the chemical class The chemical class shall consist of a clearly defined and closely related group of substances, and shall be defined according to chemical structure (e. g., aliphatic or aromatic), primary chemical functional group(s) (e. g., alcohol, aldehyde, or ketone), and molecular weight or weight range.

  24. Class Based Evaluation Levels (CBEL) Review of all toxicity information for each chemical in the class including all risk values including: – USEPA risk assessments, including MCL’s, Health Advisories and IRIS entries, – Health Canada risk assessments, – risk assessments previously performed to the requirements of annex A; – state or provincial drinking water standards and guidelines; and – World Health Organization (WHO) or other international drinking water standards and guidelines.

  25. Class Based Evaluation Levels (CBEL) Review of chemical class toxicity information Carcinogenic potential shall be evaluated using QSAR (e. g., OncoLogic®) and all other non cancer data shall be evaluated to verify that the toxicity potential of the chemical without data is no greater than that of the chemicals being used to define the class-based evaluation criteria.

  26. Class Based Evaluation Levels (CBEL) Determination of the class-based evaluation criteria The class-based evaluation criteria shall not exceed the lowest MCL or TAC in the defined chemical class until such time as sufficient toxicity data are available to determine chemical-specific evaluation criteria.

  27. EXAMPLE: Aliphatic glycol ethers and their acetates This CBEL class includes aliphatic glycol ethers and their acetates with constituents of methoxy, ethoxy, propoxy and butoxy groups as part of the general identification as a glycol ether also including the corresponding methyl, ethyl, propyl and butyl acetates. This class also includes compounds identified as ethyl, propyl or butyl isomers or -ethyl, -propyl or –butyl glycols polymers, oligomers and dimers.

  28. Chemicals Identified to be Included in This Class .

  29. Chemicals Identified to be Included in This Class .

  30. Surrogates with Quantitative Risk Assessment Values .

  31. Total Allowable Concentration (TAC) for Aliphatic glycol ethers and their acetates based on ethyl ether RfD(mg/kg/day) x BW(70 kg) – total contribution of other sources(mg/day) DWI (2 L/day) 0.2 (mg/kg/day) x BW(70 kg) * 0.2 (RSC) DWI (2 L/day) = 1.4 (mg/kg/day) rounded to 1 (mg/kg/day)

  32. Other CBEL’s that have been developed at NSF

  33. Questions???

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