assessing safety when toxicity data are...

Assessing Safety When Toxicity Data are Limited

Ron BrownUS Food and Drug Administration

Center for Devices and Radiological [email protected]

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Disclaimers• The presenter is an employee of the US Food and Drug

Administration and has no conflict of interest with regard to the products or approaches described in the presentation.

• The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the Department of Health and Human Services.

• The findings and conclusions in this article have not been formally disseminated by the U.S. Food and Drug Administration and should not be construed to represent any Agency determination or policy.

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OverviewProblem

Data from a well-conducted, repeat dose toxicity study are not available to derive a compound-

specific exposure level for a compound of interest.

Potential solutions

Use LD50 as an alternative to a NOAEL or LOAEL value.

Use NOAEL/LOAEL data from a structurally related surrogate

compound.

Use a Threshold of Toxicological Concern (TTC)

value as a default.

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Approaches for biocompatibility evaluation of medical devices

A major limitation to implementing the chemical characterization/risk assessment approach is the lack of toxicity data for many of the compounds released

from medical devices.

Toxicity testing of extracts

Chemical characterization

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Exposure and toxicity data are needed for risk characterization

Risk Assessment Based Appraoch

Exposure AssessmentWhat Dose is Received by a Patient?

ISO 10993-18Chemical Characterization

Toxicity AssessmentWhat is a "Safe" Level of Exposure?

ISO 10993-17Derivation of Tolerable Intake Values

Risk CharacterizationCompare Dose Received by Patient to Tolerable Intake Value

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Application of the chemical characterization/risk assessment approach to compounds released from

device materials

• With the growing acceptance of the chemicalcharacterization/risk assessment approach for the biologicalevaluation of medical devices, there is an increasing need toderive Tolerable Intake (TI) values for compounds released fromdevice materials.

• This method is best implemented when adequate toxicity dataare available for the compounds of interest following toxicitytesting by a clinically relevant route and duration of exposure.

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Application of the chemical characterization/risk assessment approach to compounds released from

device materials

• However, a practical limitation to the implementation of this approach is the availability of “high quality” dose-response toxicity data for many compounds released from device materials.

• The goal of this presentation is to provide practical guidance on deriving TI values when only limited toxicity data are available.

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What is a Tolerable Intake Value?ISO 10993-17

• Definition: The highest dose of a compound (mg/kg/day) that is not expected to produce adverse effects in patients. Conceptually equivalent to an RfD, ADI, MRL, etc.

• Noncancer TI values are based on NOAEL or LOAEL values (or other point-of-departure) from toxicity studies.

• Uncertainty Factors (UF) are used to account for differences in differences in sensitivity to a compound among individuals in the human population and between experimental animals and humans.

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TI for cancer endpoints

• Nongenotoxic carcinogens: Use NOAEL/UF approach, as for noncarcinogens

• Genotoxic carcinogens: Approach depends on country/regulatory agency– Find dose associated with given excess cancer

risk using quantitative risk assessment– Reduce exposure as low as reasonably

practicable (ALARP) and reduce risk using risk management approaches.

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Flowchart in ISO 10993‐17:2008

Biological evaluationof medical devices—

Part 17: Methods for theestablishment of allowable limits

for leachable substancesOr use

alternate approach to provide

default NOAEL

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Options for deriving TI values in the absence of needed NOAEL/LOAEL values

• Derive TI values from LD50/TD50 values– Predict LD50/TD50 values using computational

models

• Derive TI values using toxicity data from structural analogs

• Use of Threshold of Toxicological Concern (TTC) approach

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models



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Use of LD50 values to derive noncancer TI values

• Problem: Data from repeat-dose toxicity studies are not available to serve as the basis for a TI for many compounds released from device materials.

• In the absence of these preferred data, acute lethality data (LD50 values) have been used as the basis for TI derivation.

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Use of LD50 data as the basis for TI determination

Typical (preferred) approach• Identify NOAEL from well-conducted, repeat dose

toxicity study• Apply default Uncertainty Factors to account for

interspecies extrapolation (10) and interindividual variability (10)

• TI = NOAEL/100

What modifying factor should be used when only LD50 data are available for a compound? 14

What does the ISO 10993-17 standard say?

If only acute lethality data is available, a modifying factor greater than 10,000 may be necessary to

establish a TI for permanent contact. Any situation that results in a modifying factor of greater than 10,000 is

indicative of a high degree of imprecision in the analysis and consideration should be given, in such

cases, to the urgent need for additional data.

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Support in the scientific literature for an LD50-to-TI conversion factor

• Venman and Flaga (1985) compared oral LD50 values for compounds to their respective NOAEL values from long-term repeat dose studies.

• The 95th percentile of the distribution of these LD50/NOAEL ratios was 0.0001

• An additional UF is needed to derive a TI value from NOAEL = 100

• Total conversion factor to go from LD50 to TI0.0001 x 0.01 = 0.000001 16

Support in the scientific literature for an LD50-to-TI conversion factor

• Layton and colleagues (1987) recommended a factor of 1 x 105 to 5 x 106 to convert an oral LD50 to an equivalent Acceptable Daily Intake (ADI) value.

• Same ballpark as conversion factor based on Venman and Flaga (1985) analysis.

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LC50 to acute exposure limit conversion factor

Acute exposure limit = LC50/8.3 x 105

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Reanalysis of LD50-to-TI CF using compounds in Munro et al. dataset

Method• LD50 values were identified in the Chem ID or

HSDB databases for compounds with NOAEL values in the Munro et al. data set (Food Chem Toxicol 34: 829-867, 1996).

• A reduced data set (n =263) was also compiled that consists of the full Munro data set (n=498) without pesticides and drugs. The reduced data set is intended to be more representative of compounds released from device materials.

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Method• Statistical distributions of LD50/NOAEL values were

obtained and the 50th, 25th, 10th, and 5th percentile values of the distributions were identified for the full and reduced data sets.

• Percentiles of the distributions were also provided for compounds in each data set in Cramer Class I, II, and III.

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Data Set 5th percentile 10th percentileFull (n=498) 2.0 x 105 8.3 x 104

Reduced (n=263)

5.3 x 104 1.9 x 104

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Limited validation of LD50-to-TI CFReduced data set, 10th percentile

CF = 189

NOAEL of 2 compounds under predicted, but only by about 2‐fold22

Limited validation of LD50-to-TI CFReduced data set, 5th percentile

CF = 533

CF was able to adequately predict NOAEL for all compounds23

Comparison of LD50-to-EL Conversion Factors

Study LD50‐to‐EL CFVenman and Flaga (1985) 1 x 106

Layton et al. (1987) 1 x 105 to 5 x 106

Grant et al. (2007) 8 x 105

Young et al. (2014) - Full 2 x 105

Young et al. (2014) -Reduced

5 x 104

ISO 10993‐17 ≥ 1 x 10424

Take home messageLD50-to-EL Conversion Factors

• In the absence of a NOAEL or LOAEL value from a repeat-dose toxicity study, TI values can be derived from LD50 values providing that an appropriately conservative CF is used.

• The guidance provided in the ISO 10993-17 standard (CF ≥ 10,000) is supported by the results of multiple studies.

• A CF on the order of 1 x 104 – 1 x 105 can be justified when deriving a TI from an LD50 for compounds that are likely to be released from device materials. 25

Take home messageLD50-to-EL Conversion Factors

• LD50/100 or LD50/1000 not appropriate

• Proposed CF is intended to be conservative to protect against potential health effects of very potent compounds

• This is a default approach. LD50 values should not be used to derive a TI value for compounds released from device materials when appropriate data from repeat-dose studies are available.

• Any TI value derived using LD50 values should be considered to be interim or provisional until relevant data from repeat-dose toxicity studies are available to derive the TI. 26

TI for cancer endpoints• No detailed guidance offered in ISO 10993-17• Use weight-of-evidence test to determine if

compound is a genotoxic carcinogen• Nongenotoxic carcinogens: Use NOAEL/UF

approach, as for noncarcinogens• Genotoxic carcinogens: Approach (depends

on country/regulatory agency)– Find dose associated with given excess cancer

risk using quantitative risk assessment– Reduce exposure as low as reasonably

practicable (ALARP) and reduce risk using risk management approaches. 27

Alternate approach: Derivation of a “Virtually Safe Dose” for Carcinogens

• Process described by Gaylor and Gold, 1995, Regul Tox Pharmacol. 22:57-63

• Based on TD50 values from Carcinogenic Potency Database: http://toxnet.nlm.nih.gov/cpdb/

• Virtually Safe Dose = 10-6 x TD50/0.8728


• Similar approach in ICH M7 guidance

• Linear extrapolation to estimate a dose associated with 10-5 excess cancer risk:– TD50/50,000

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Example – Ethylene oxide

TD50 values for ethylene oxide according to the Carcinogenic Potency Database are 21.3 mg/kg body weight/day (rat) and 63.7 mg/kg

body weight/day (mouse). For the calculation of a cancer-based TI, the lower (i.e., more

conservative) value of the rat is used.

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Example – Ethylene oxide• To derive a dose associated with tumors in 1 in 100,000

animals, divide by 50,000: – 21.3 mg/kg ÷ 50,000 = 0.42 μg/kg

• To derive a total human daily dose: – 0.42 μg/kg/day x 70 kg body weight =

29 μg/person/day

• Allowable Limit for EO in ISO 10993-7 standard– 100 µg/person/day

As a first approximation, use of the VSD approach seems reasonable 31



models



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Use of QSAR models to predict toxicity valuesPrediction of oral LD50

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Validation of predictive ability for methacrylate compounds

Use of QSAR models to predict toxicity valuesPrediction of oral LD50

• The computational model was able tosuccessfully predict LD50 values for aseries of acrylate and methacrylatecompounds.

• When the model under predicted theacute toxicity of the compounds, the

• predictions were generally within a 2- to3-fold difference of the experimentallyderived values.

• When applied to dental acrylates andmethacrylates, the model producedacceptable results for all compoundsexcept, triethylene glycol dimethacrylate,for which the model under predicted thetoxicity by about five-fold.

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Case study – Application to dental methacrylates

Use of QSAR models to predict toxicity valuesPrediction of carcinogenic TD50

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Use of QSAR models to predict toxicity valuesPrediction of carcinogenic TD50

Accuracy of Prediction Predicted/Observed Percent (n = 265)

Under-predicted > 5 7Accurately predicted 0.2 < 5 82Over-predicted < 0.2 11 36

Evaluate ability of Danish QSAR model (http://qsar.food.dtu.dk/) to predict TD50 of compounds in CPDB

Take home messageUse of computational models to predict toxicity values

• The use of computational models to predict toxicity values (LD50, TD50) shows promise, but these models require additional validation before the results can be used with confidence for regulatory decision making.

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models



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Use of NOAEL values from a structural analog as a surrogate

Compound A

• Released from medical device material

• No relevant toxicity available to derive a TI.

Compound B• Structurally related to

Compound A• Has adequate toxicity

data for derivation of a TI value

• Use NOAEL for Compound B as a surrogate for the missing NOAEL for Compound A. 39

Use of NOAEL values from a structural analog as a surrogate

• How should appropriate structural analogs be identified?

• How structurally/toxicologically similar do the compounds need to be?

• There is currently no guidance available from FDA/CDRH or ISO TC194 in this area.

• Option to consider: use Read Across programs40

Use of Read Across Programs to identify structural analogs

Read Across definition

Endpoint information for one substance (source analogue) is used to predict the same endpoint for another substance (target), which is considered to be similar in some way (usually on the basis of structural similarity, though not exclusively so).

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Use of Read Across Programs to identify structural analogs

The similarities may be based on the following:• a common functional group (e.g. aldehyde, epoxide, ester,

specific metal ion)• common constituents or chemical classes, similar carbon

range numbers• an incremental and constant change across the category (e.g. a

chain-length category)• the likelihood of common precursors and/or breakdown

products, via physical or biological processes, which result in structurally similar chemicals (e.g. the metabolic pathway approach of examining related chemicals such as acid/ester/salt)

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Categorizing compounds using OECD Toolbox

Takes into account structure

and toxicity

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OECD ToolboxStep-by-step example for estimating repeat-dose toxicity

http://www.oecd.org/chemicalsafety/risk-assessment/Tutorial_16_TB%203.2.pdf

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Take home messageUse of data from structural analogs

• Process for identifying structural analogs for the purpose of estimating a NOAEL value for a compound of interest lacking toxicity data should not be arbitrary.

• Read Across software programs (e.g., OECD Toolbox) are available to help with the process of identifying structural analogs and identifying an appropriate surrogate for the compound of interest.

• TC194/WG11 will be working to provide more specific guidance in this area.

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models



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Use of TTC values in absence of compound-specific toxicity data

Use of a Threshold of Toxicological Concern (TTC) approach has been proposed for use as a means for setting priorities for testing and evaluation.

Can this approach be used to derive default exposure limits (EL) for compounds released from cosmetics and medical device materials?

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Threshold of Toxicological Concern

The threshold of toxicological concern (TTC) is a pragmatic risk assessment tool that is based on the principle of establishing a human exposure threshold value for all chemicals, below which there is a very low probability of an appreciable risk to human health.

Kroes et al. (2004) Food Chem Toxicol 42: 65–83

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Applicability of the TTC approach for cosmetic ingredients

Conclusion of the Colipa expert group

The COLIPA Expert Group concluded that itis scientifically justifiable to use the TTCapproach and the database underlying theTTC values established for food chemicals forthe safety evaluation of cosmetic ingredientsand impurities. Regarding the potentialsystemic toxicity arising from dermalexposure, the COLIPA Expert Group agreedthat substances such as proteins, heavymetals, and chemicals that may have or aresuspected to have pharmacologicalproperties, in addition to substances withspecific structural alerts of concern, should beexcluded for application of the TTC.

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The objectives of this work were to evaluate the applicability of theTTC database to ingredients used in consumer products based on acomparison of the diversity of chemical structures with those in theoriginal TTC database and to confirm that the range of NOELs forthese ingredients is consistent with the range of NOELs in the originaldatabase. The results show good coverage of the product ingredientstructures and confirm that the NOELs for the ingredient chemicalsare similar in range to the original dataset, supporting the use of theTTC for ingredients in consumer products.

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Development of inhalation TTC values for volatile compounds released from respiratory devices

• Patients can be exposed to volatile organic compounds (VOCs) released from plastic materials used in the breathing circuit of respiratory devices, like ventilators.

• Efforts are underway to develop inhalation TTC values for volatile compounds released from device materials.

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Derivation of inhalation TTC values

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Chemical space analysis of inhalation data sets

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Chemical space analysis of compounds used in respiratory devices vs. compounds in RepDose database (modified to exclude pesticide, drugs)

Structural comparison using StarDrop software Physicochemical property comparison

Proposed inhalation TTC values for compounds released from device materialsShort-term TTC values

(< 30 days)Long-term TTC values

(≥ 30 days)

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Take home messagesTTC approach

• Use of TTC values as default exposure limits for compounds released from device materials can serve as a practical alternative to compound-specific values when data from repeat-dose toxicity studies are not available.

• ISO TC194/WG11 is working on a Technical Specification document that will provide guidance on the application of the TTC approach for compounds released from device materials

• The approach only applicable as an alternative to assess systemic toxicity, carcinogenicity, genotoxicity, NOT all endpoints necessary in a biocompatibility evaluation of a device

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SummaryWhy is this topic important?

• There is a growing need for the risk assessment of compounds released from device materials and compounds in consumer products.

• However, a practical limitation to the implementation of this approach is the availability of “high quality” dose-response toxicity data for many compounds.

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models



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SummaryLD50-to-TI Conversion Factor

• In the absence of a NOAEL or LOAEL value from a repeat-dose toxicity study, TI values can be derived from LD50 values providing that an appropriately conservative CF is used.

• The guidance provided in the ISO 10993-17 standard (CF ≥ 10,000) is supported by the results of multiple studies.

• A CF on the order of 1 x 104 – 1 x 105 can be justified when deriving a TI from an LD50 for compounds that are likely to be released from device materials.

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SummaryUse of NOAEL values from structural analogs

• Process for identifying structural analogs for the purpose of estimating a NOAEL value for a compound of interest lacking toxicity data should not be arbitrary.

• Read Across software programs (e.g., OECD Toolbox) are available to help with the process of identifying structural analogs and identifying an appropriate surrogate for the compound of interest.

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SummaryThreshold of Toxicological Concern

• Use of TTC values as default exposure limits for compounds released from device materials can serve as a practical alternative to compound-specific values when data from repeat-dose toxicity studies are not available.

• The TTC approach has been used to assess the safety of cosmetic ingredients lacking compound-specific toxicity data.

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Questions?

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