What lines of scientific data (in vitro toxicity and other relevant properties) should the state of California consider and use for decision-making in the absence of traditional animal toxicity data?
CSPA supports the use of in vitro test methodologies where they have been validated by the U.S. by the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) as acceptable substitutes for animal testing (see: http://iccvam.niehs.nih.gov). DTSC should not require studies involving the use of laboratory animals, when other professionally accepted means of evaluation are available. Review of available toxicity information in scientific literature should also be used as a primary means of evaluating human health effects and can also eliminate the vast majority of animal testing for the purposes of health hazard evaluation.
There are a number of validated in vitro methods approved for assessing a wide range of health effects such as skin and eye irritation, and skin sensitization; and, quantitative Structure Activity Relationship (QSAR) models area available in the areas of skin and eye irritation, skin sensitization and oral toxicity assessments, which can be used in a comprehensive assessment program. In vitro techniques are used to test both products and raw materials, for endpoints like eye and skin irritation. As indicated above, in vitro techniques used to replace animal tests in whole or in part are validated in the U.S. by the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM). The ICCVAM coordinates and advises on federal interagency issues on development, validation, and regulatory acceptance of new, improved and alternative test methods, and the national and international harmonization of such methods. Congress recently enacted the ICCVAM Authorization Act (Public Law 106-545, December 19, 2000) “to establish, wherever feasible, guidelines, recommendations, and regulations that promote the regulatory acceptance of new or revised scientifically valid toxicological tests that protect human and animal health and the environment while reducing, refining, or replacing animal tests and ensuring human safety and product effectiveness.” As a result, ICCVAM, which was initially assembled as an ad hoc committee and had evolved to a standing committee, became a permanent committee.
The Institute for In Vitro Sciences (see: http://www.iivs.org) provides useful information on specific in vitro tests that can be used to replace animal testing. One key in vitro technique that many CSPA members have used to evaluate products and raw materials is called the Bovine Corneal Opacity Permeability (BCOP) assay. A description of the BCOP assay from the IIVS website is provided at: http://www.iivs.org/pages/methods/BCOP_symbol.pdf
In vitro testing, and analysis of chemical structure and chemical class combined with professional judgment can also be utilized to effectively characterize health hazards and minimize the need for animal testing. It is also critical that any chemical evaluation process include an assessment of health risk (which includes analysis of the exposure to the product and its specific components) rather than relying simply on identification of the health hazards. With this approach, only after exhausting other reasonable means of evaluation, will animal testing need to be considered.
The State of California should consider and use data from all scientific evaluations that are conducted according to internationally recognized scientific principles. The State’s decision-making should be test method neutral, allowing different approaches as long as they are scientifically sound and validated according to international procedures.
There are a number of internationally recognized conventions for evaluating the quality of data in the context of chemicals management programs. For example, the OECD's Manual for Investigation of HPV Chemicals addresses the issue within the context of the high production volume (HPV) chemical program under the OECD’s chemical safety program.
Paraphrasing from the manual: consideration of all available existing information on a chemical is important because, if it is judged to be of sufficient quality, there is no need for additional testing, resulting in savings in resources, such as time, costs and laboratory animals.
The manual goes on to state: “The process of determining the quality of existing data takes into consideration three aspects - adequacy, reliability and relevance of the available information to describe a given SIDS element. These terms were defined by Klimisch et al. (Klimisch, H.J., Andreae, E., and Tillmann, U. 1997. A systematic approach for evaluating the quality of experimental and ecotoxicological data. Reg.Tox. and Pharm. 25:1-5) along the following lines:
Reliability - evaluating the inherent quality of a test report or publication relating to preferably standardised methodology and the way the experimental procedure and results are described to give evidence of the clarity and plausibility of the findings;
Relevance - covering the extent to which data and tests are appropriate for a particular hazard identification or risk characterisation; and
Adequacy - defining the usefulness of data for hazard/risk assessment purposes. When there is more than one study for each SIDS element, the greatest weight is attached to the study that is the most reliable and relevant. Robust study summaries are prepared for the highest quality or “key” studies.”
More over, the OECD Manual is compatible and synergistic with similar programs in the U.S. (EPA HPV), Europe (REACH), Canada (CMP) and Japan (Japan HPV program). The State of California should use a similar approach when considering scientific data for decision-making in order to create synergy between the California program and these other programs.
At a minimum, test methods recommended by ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods) or its European counterpart ECVAM (European Centre for the Validation of Alternative Methods) should be considered. These agencies rigorously evaluate alternative methods for their validity and accuracy, and also specify under what conditions they may reliably be used.
California is likely aware that the EU has done extensive work evaluating reasonable possible data sources for REACH. The 4 parts of the RIP 3.3 Phase 2 documents, released in final draft in June 2007, contain identification and evaluation of in-vitro, QSAR, and analogy approaches, as well as databases, databanks, journals, and data search methods. It also has information on what to do with the data – how to evaluate it – including “weight of evidence”, scoring methods, and other evidence-based approaches. Considerable effort was spent to leverage every available data source to meet the REACH mandate to AVOID animal testing. It is a valuable source of methods to assess chemicals in the absence of animal toxicology data.
GHS also includes recommendations for such evaluations.
In vitro assays must be validated to understand the relevance of their results for human health, especially in the absence of animal models. Criteria for the validation of alternative test methods (in vitro methods designed to replace animal tests in whole or in part) have generally been agreed upon in the U.S. by Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM,) in Europe by the European Centre for the Validation of Alternative Methods (ECVAM,) and internationally by the Organization for Economic Cooperation and Development (OECD.) (http://www.epa.gov/endo/pubs/edsp_validation_paper_v%205.4.pdf) OECD employs a phased approach to the inter-laboratory validation of assays in their Test Guidelines Program. EPA’s approach for validating assays for the Endocrine Disruptor Screening Program (EDSP) is outlined in “Validation of Screening and Testing Assays Proposed for the EDSP.” (http://www.epa.gov/endo/pubs/edsp_validation_paper_v%205.4.pdf) Existing validated assays ought to be used in a preliminary assessment of a chemical to minimize duplicative efforts and maximize available resources.
Currently evolving philosophies related to weight-of-evidence and integrated approches dictate that the use of any and all available data, while keeping in mind the source, method, and quality of that data, is acceptable and encouraged. The OECD, ECVAM, the European Commission (through REACH), ILSI, and the US EPA are all involed in projects intended to bring structure to WOE approaches and/or utilise data other than in vivo guideline studies to make decisions on the prioritization, classification and risk characterization of chemicals.
While it is clear that testing methods should be scientifically accepted for use by California, it is less clear how to determine scientific acceptance. The US Interagency Coordinating Committee for the Validation of Alternative Methods, while providing information and guidelines for one-to-one replacement method validation, has made progress at a glacial pace compared to its European counterpart. Funding and resources are partly to blame, but the general unwillingness of the US government to lead in alternatives development and validation should not prevent California from benefiting from methods accepted by ECVAM or the OECD.
Dr. Skerrett's comment is echoed as well. Many lines of evidence, from the OECD QSAR Toolbox data and output (freely available from OECD), to information on pH, hydrolysis potential, or other phys-chem properties can lend much to an evaluation.
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5 Comments
Reader Comments (5)
CSPA supports the use of in vitro test methodologies where they have been validated by the U.S. by the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM) as acceptable substitutes for animal testing (see: http://iccvam.niehs.nih.gov). DTSC should not require studies involving the use of laboratory animals, when other professionally accepted means of evaluation are available. Review of available toxicity information in scientific literature should also be used as a primary means of evaluating human health effects and can also eliminate the vast majority of animal testing for the purposes of health hazard evaluation.
There are a number of validated in vitro methods approved for assessing a wide range of health effects such as skin and eye irritation, and skin sensitization; and, quantitative Structure Activity Relationship (QSAR) models area available in the areas of skin and eye irritation, skin sensitization and oral toxicity assessments, which can be used in a comprehensive assessment program. In vitro techniques are used to test both products and raw materials, for endpoints like eye and skin irritation. As indicated above, in vitro techniques used to replace animal tests in whole or in part are validated in the U.S. by the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM). The ICCVAM coordinates and advises on federal interagency issues on development, validation, and regulatory acceptance of new, improved and alternative test methods, and the national and international harmonization of such methods. Congress recently enacted the ICCVAM Authorization Act (Public Law 106-545, December 19, 2000) “to establish, wherever feasible, guidelines, recommendations, and regulations that promote the regulatory acceptance of new or revised scientifically valid toxicological tests that protect human and animal health and the environment while reducing, refining, or replacing animal tests and ensuring human safety and product effectiveness.” As a result, ICCVAM, which was initially assembled as an ad hoc committee and had evolved to a standing committee, became a permanent committee.
The Institute for In Vitro Sciences (see: http://www.iivs.org) provides useful information on specific in vitro tests that can be used to replace animal testing. One key in vitro technique that many CSPA members have used to evaluate products and raw materials is called the Bovine Corneal Opacity Permeability (BCOP) assay. A description of the BCOP assay from the IIVS website is provided at: http://www.iivs.org/pages/methods/BCOP_symbol.pdf
In vitro testing, and analysis of chemical structure and chemical class combined with professional judgment can also be utilized to effectively characterize health hazards and minimize the need for animal testing. It is also critical that any chemical evaluation process include an assessment of health risk (which includes analysis of the exposure to the product and its specific components) rather than relying simply on identification of the health hazards. With this approach, only after exhausting other reasonable means of evaluation, will animal testing need to be considered.
The State of California should consider and use data from all scientific evaluations that are conducted according to internationally recognized scientific principles. The State’s decision-making should be test method neutral, allowing different approaches as long as they are scientifically sound and validated according to international procedures.
There are a number of internationally recognized conventions for evaluating the quality of data in the context of chemicals management programs. For example, the OECD's Manual for Investigation of HPV Chemicals addresses the issue within the context of the high production volume (HPV) chemical program under the OECD’s chemical safety program.
Paraphrasing from the manual: consideration of all available existing information on a chemical is important because, if it is judged to be of sufficient quality, there is no need for additional testing, resulting in savings in resources, such as time, costs and laboratory animals.
The manual goes on to state:
“The process of determining the quality of existing data takes into consideration three aspects - adequacy, reliability and relevance of the available information to describe a given SIDS element. These terms were defined by Klimisch et al. (Klimisch, H.J., Andreae, E., and Tillmann, U. 1997. A systematic approach for evaluating the quality of experimental and ecotoxicological data. Reg.Tox. and Pharm. 25:1-5) along the following lines:
Reliability - evaluating the inherent quality of a test report or publication relating to preferably standardised methodology and the way the experimental procedure and results are described to give evidence of the clarity and plausibility of the findings;
Relevance - covering the extent to which data and tests are appropriate for a particular hazard identification or risk characterisation; and
Adequacy - defining the usefulness of data for hazard/risk assessment purposes. When there is more than one study for each SIDS element, the greatest weight is attached to the study that is the most reliable and relevant. Robust study summaries are prepared for the highest quality or “key” studies.”
More over, the OECD Manual is compatible and synergistic with similar programs in the U.S. (EPA HPV), Europe (REACH), Canada (CMP) and Japan (Japan HPV program). The State of California should use a similar approach when considering scientific data for decision-making in order to create synergy between the California program and these other programs.
At a minimum, test methods recommended by ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods) or its European counterpart ECVAM (European Centre for the Validation of Alternative Methods) should be considered. These agencies rigorously evaluate alternative methods for their validity and accuracy, and also specify under what conditions they may reliably be used.
California is likely aware that the EU has done extensive work evaluating reasonable possible data sources for REACH. The 4 parts of the RIP 3.3 Phase 2 documents, released in final draft in June 2007, contain identification and evaluation of in-vitro, QSAR, and analogy approaches, as well as databases, databanks, journals, and data search methods. It also has information on what to do with the data – how to evaluate it – including “weight of evidence”, scoring methods, and other evidence-based approaches. Considerable effort was spent to leverage every available data source to meet the REACH mandate to AVOID animal testing. It is a valuable source of methods to assess chemicals in the absence of animal toxicology data.
GHS also includes recommendations for such evaluations.
In vitro assays must be validated to understand the relevance of their results for human health, especially in the absence of animal models. Criteria for the validation of alternative test methods (in vitro methods designed to replace animal tests in whole or in part) have generally been agreed upon in the U.S. by Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM,) in Europe by the European Centre for the Validation of Alternative Methods (ECVAM,) and internationally by the Organization for Economic Cooperation and Development (OECD.) (http://www.epa.gov/endo/pubs/edsp_validation_paper_v%205.4.pdf) OECD employs a phased approach to the inter-laboratory validation of assays in their Test Guidelines Program. EPA’s approach for validating assays for the Endocrine Disruptor Screening Program (EDSP) is outlined in “Validation of Screening and Testing Assays Proposed for the EDSP.” (http://www.epa.gov/endo/pubs/edsp_validation_paper_v%205.4.pdf) Existing validated assays ought to be used in a preliminary assessment of a chemical to minimize duplicative efforts and maximize available resources.
Currently evolving philosophies related to weight-of-evidence and integrated approches dictate that the use of any and all available data, while keeping in mind the source, method, and quality of that data, is acceptable and encouraged. The OECD, ECVAM, the European Commission (through REACH), ILSI, and the US EPA are all involed in projects intended to bring structure to WOE approaches and/or utilise data other than in vivo guideline studies to make decisions on the prioritization, classification and risk characterization of chemicals.
While it is clear that testing methods should be scientifically accepted for use by California, it is less clear how to determine scientific acceptance. The US Interagency Coordinating Committee for the Validation of Alternative Methods, while providing information and guidelines for one-to-one replacement method validation, has made progress at a glacial pace compared to its European counterpart. Funding and resources are partly to blame, but the general unwillingness of the US government to lead in alternatives development and validation should not prevent California from benefiting from methods accepted by ECVAM or the OECD.
Dr. Skerrett's comment is echoed as well. Many lines of evidence, from the OECD QSAR Toolbox data and output (freely available from OECD), to information on pH, hydrolysis potential, or other phys-chem properties can lend much to an evaluation.