Programs & Policies - US
Animal Welfare in the US EPA’s Chemical Assessment and Management Program and the Extended High Production Volume Program
Published: July 17, 2008
Dr. Sandusky was a Manager of Toxicology and Risk Assessment at ENVIRON and has extensive experience at both the EPA and ENVIRON in pesticide toxicology as well as exposure and risk assessments.
Dr. Sandusky has extensive international experience including the coordination and submission of dossiers for the EU Reauthorization process under EU 91/414 and presentation of the results to member states. Dr. Sandusky also represented the Institute of Food Technology at the Codex Committee for Pesticide Residues (CCPR) in The Hague for several years. In addition, he also coordinated preparation and reviews of dossiers for chemicals approved as GRAS as well as directed the preparation and submission of Food Contact Notifications (FCNs) to the FDA.
For the past 4 years, Dr. Sandusky has represented the International Council of Animal Protection Organizations (ICAPO) at OECD meetings in Paris, Tokyo and Bern on the Existing Chemicals Programme. At present, PCRM, with Dr. Sandusky as lead, serves as Secretariat to ICAPO, and coordinates participation of all ICAPO member organizations (from North America, the EU, and Japan) and their consultants in numerous expert working groups, international task forces on chemical hazard testing and has liaised with the US Ambassador to OECD.
Dr. Sandusky received his Ph.D. in Pharmacology from the Emory University. He served as a Postdoctoral Fellow at the Georgetown University Schools of Medicine and Dentistry in Washington, D.C.
Chad Sandusky, Ph.D.
Physicians Committee for Responsible Medicine
5100 Wisconsin Ave, NW
Washington, DC 20016
For this reason animal welfare groups who participated in the original HPV program recently submitted to EPA (June 4, 2008) a brief summary of the original guidance under HPV as well as expanded guidance that was developed based on extensive review of test plans in HPV. The process of reviewing HPV test plans provided valuable experience in identifying the many ways in which proposed testing would have been either superfluous (e.g., insoluble materials and fish testing) or the resultant data difficult to interpret in terms of human and environmental health. These principles have been through a vetting process during the course of the original program, and are considered scientifically acceptable by many major stakeholders.
We therefore asked EPA to update the animal welfare guidance for participants in ChAMP and requested that EPA notify the manufacturers of this updated guidance, both in a letter to participants and by posting the guidance on the ChAMP website.
The impetus to reduce and replace the use of animals in regulatory testing is growing stronger every year. As shown by the original HPV Program, throughout the course of just a few years new ideas are put into practice that could reduce the number of animals killed. There are a number of initiatives underway in the US and the European Union designed to explore ways to minimize traditional in vivo testing, by developing alternative in vitro or in silico test methods and by integrating weight-of-evidence and alternative approaches into testing strategies. As ChAMP begins, it would be prudent to include provisions that allow for continuous and consistent update of testing guidelines, in order to recommend the most updated assays, test guidelines, protocols, and/or approaches. Information along this line of thought is also included in the guidance submitted to EPA.
Tools and Concepts to Consider as ChAMP is Implemented
While there is currently no international consensus for applying weight-of-evidence (WoE) approaches, work at several agencies, including the Organization for Economic Cooperation and Development (OECD), the US EPA, International Life Sciences Institute (ILSI), and the Dutch chemicals agency RIVM, is ongoing and should be given consideration for inclusion into ChAMP as appropriate. RIVM has recently completed a report investigating the potential for the use of Integrated (or Intelligent) Testing Strategies (ITS) under the new European REACH legislation.1 Considerations that may apply to ChAMP include an investigation of the regulatory impact of a 2-generation reproduction test (versus a 1-generation). The report also gives a more general discussion of alternative methods and ITS, including (Q)SARS and chemical categories, in vitro studies, toxicogenomics, and exposure-based waiving of testing. A WoE approach using Bayesian analysis of existing information from all potential sources makes this report a useful tool for anyone designing a plan for the testing of a candidate chemical.
Work is also ongoing to determine ways to avoid additional in vivo genotoxicity testing while satisfying concerns regarding high rates of false positive results for in vitro tests. Attention should be given to any work in this area before commencement of in vivo genotoxicity testing.2,3
Broad international support for WoE approaches was shown at a December 2007 OECD workshop titled Integrated Approaches to Testing and Assessment.
Principles that will be followed during the REACH process in an attempt to maximally avoid in vivo testing were presented, and include:
- Existing human and animal information
- Non-test based info ((Q)SAR, categories)
- Weight of evidence
- Non-guideline toxicity tests
- In vitro methods
- Situations where testing is not feasible
- No requirements for polymers and intermediates with no exposure
- Exposure-driven regulations
- Evaluation of testing proposals
More information can be found on the European Chemicals Bureau Website. While some of these considerations are already taken into account as part of established animal welfare principles, others are not and deserve careful consideration.
In addition, the OECD workshop summary and recommendations for future work, once published, have the potential to be valuable tools for those seeking to use (Q)SARS, WoE, and other “alternative” approaches to fulfilling chemical hazard information needs.
At the US EPA, work is also ongoing to develop specific in vitro assessment methods and strategies, such as the efforts of the National Center for Computational Toxicology’s ToxCast Program. As ChAMP is implemented, it will become more clear how participants can take advantage of these tools.
Finally, since the advent of the original US EPA HPV Program, a number of online tools for determining chemical hazards have been created. The first, eChemPortal, draws together available data from many sources to provide master search capabilities. This free service is available at http://webnet3.oecd.org/echemportal/. The second is the OECD (Q)SAR Toolbox, the first version of which was just made available in March of 2008. Download instructions can be found at www.oecd.org/env/exisingchemicals/qsar. The Toolbox is a library of hazard information and (Q)SAR models, and can extrapolate missing experimental values by read-across and trend analysis. These in silico tools are only going to become more relevant as interest increases, and ChAMP participants should be required to consider using these and other tools as part of any participation plan.
These tools and concepts should always be employed before consideration of new in vivo testing, in conjunction with the animal welfare considerations outlined below.
Animal welfare principles for EPA’s original HPV Program participants are described in the Letter to Manufacturers/Importers,4 which states that animal experiments should not be performed if another validated method is available. Additional principles allowed the maximum use of existing data in a weight-of-evidence approach that avoided check-the-box toxicology. For example, the formation of scientifically appropriate categories of related chemicals and use of structure activity relationships was encouraged. No terrestrial testing and no new dermal testing were to be conducted on HPV chemicals and no sub-chronic or reproduction studies were to be conducted with closed-system intermediates. Special consideration was given to GRAS (Generally Recognized as Safe) chemicals, and in vitro genotoxicity testing was recommended unless known chemical properties preclude this approach.
Chemical Assessment and Management Program (ChAMP)
According to EPA’s new Chemical Assessment and Management Program (ChAMP), the Agency
“is committed to fulfilling U.S. commitments made under the Security and Prosperity Partnership of North America (SPP). The SPP of North America Leaders’ Summit, held in Montebello, Canada, in August 2007, called for cooperation on chemicals and outlined commitments on behalf of the United States, Canada, and Mexico to work together to ensure the safe manufacture and use of industrial chemicals. Each country is sharing scientific information and approaches to chemical testing and risk management.
To fulfill its part of the SPP commitment, the United States will, by 2012, complete screening-level risk characterizations and take action, as appropriate, on more than 6,750 chemicals produced above 25,000 pounds per year. The U.S. commitment to complete assessments and initiate needed action on these chemicals will apply the results of EPA’s work on High-Production Volume (HPV) chemicals – those chemicals produced or imported in the United States in quant of 1 million pounds or more per year – and extend its efforts to moderate production volume chemicals – those produced or imported in quantities above 25,000 and less than 1 million pounds per year.
As part of the efforts under ChAMP, EPA is developing screening-level documents that summarize basic hazard and exposure information on HPV chemicals, identify potential risks, note scientific issues and uncertainties, and indicate the initial priority being assigned by the Agency for potential future appropriate action. EPA has begun posting hazard characterizations and has posted an initial set of risk-based prioritizations.”
More information may be found at: http://www.epa.gov/champ/
Specific Examples of Ways to Reduce Animal Testing in ChAMP
The Extended HPV (EHPV) Program and the Chemical Assessment and Management Program (ChAMP) should follow the guidelines from the original HPV program, and, in addition, the animal welfare principles described briefly below, which are based on practical experience gained during the original HPV Program.
Use of Combined Endpoint Screening Protocols
If data are lacking on several endpoints for a candidate chemical, the use of protocols which combine these assessments into one study are appropriate for ChAMP and EHPV. This would be in lieu of conducting a separate study for each endpoint and would greatly reduce animal use. For example, instead of conducting three studies according to OECD TG 408, 415/416, and 414 for the repeat dose, reproductive, and developmental endpoints, one study according to the OECD TG 422 protocol should be conducted. This would also be appropriate for individual areas of concern, e.g., an OECD screening protocol for potential reproductive/developmental effects (OECD 421) is sufficient for ChAMP and EHPV rather than a traditional 1- or 2-generation reproduction (OECD 415/416) and/or developmental study (OECD 414), again greatly reducing the number of animals used in testing.
Rapid Hydrolysis of Parent Chemical
The candidate chemical need not be tested via oral exposure in animals if it hydrolyzes to well-characterized products in an aqueous environment at low pH. If available, existing data on the hydrolysis products may then be used to meet Screening Information Data Set (SIDS) endpoints without additional testing. In some cases, this principle can be applied to known metabolites of the parent chemical, if the toxicological properties of these metabolites are well-known.
If a candidate chemical is known to be a strong acid, it may be completely ionized in aqueous environments and is expected to cause localized, corrosive effects in the gastrointestinal tract and in the respiratory system. Unless a substance is neutralized, results from animal tests may be confounded by the corrosivity of the chemical and mammalian testing would not yield meaningful results. This can also be true for severely irritating chemicals. However, the results from a neutralized test substance may not be relevant to understanding the potential systemic effects from the non-neutralized test substance i.e., the product in commerce. The effect of these confounding factors on the interpretation of results (e.g., the extrapolation to human health effects) of testing such materials in animals should be carefully evaluated prior to conducing in vivo tests.
Highly Reactive Materials
Mammalian and/or ecotoxicity testing with candidate chemicals that are highly reactive to air and/or water, as demonstrated by physical/chemical data, may not be feasible.
Candidate chemicals in gas form may present several concerns, including flammability and/or explosivity at test levels and the potential for asphyxiation of test subjects versus systemic toxicity per se. Additionally, some gases are minimally toxic and rapidly excreted. Thus, chemical and physical properties may impact the ability to perform testing and additional testing may not yield meaningful results.
Additional testing with a variable mixture may not provide additional useful information and existing data on major constituents of the candidate mixture may be sufficient to fill SIDS endpoints.
Several considerations that may apply to a candidate chemical could, if utilized, lead to a reduction or elimination of in vivo testing and should be considered before plans for testing are undertaken. For example, where histopathology data on reproductive organs from a subchronic study are available and show no effects, these data in combination with an available developmental study may eliminate additional testing for reproductive toxicity.5 In some cases, traditional reproduction/developmental studies may be avoided if existing data from other studies, i.e. 2-year cancer bioassays, have evaluated reproductive and developmental parameters. Moreover, a separate developmental study may be avoided if data are available from one- or two-generation reproduction studies. Dermal systemic testing may be avoided if studies (in vitro, in silico, or existing in vivo) show little potential for percutaneous absorption of the candidate chemical. Finally, if higher-tier toxicity tests have been conducted, lower-tier screening tests may not be needed for the purposes of ChAMP or EHPV.
Methods to Reduce Fish Toxicity Testing
Recently, a new fish acute threshold (step-down) test strategy has been described for new chemicals6 and human pharmaceuticals,7 based on the observation that fish are rarely more sensitive than algae and daphnia. It is proposed that the fish median lethal concentration (LC50) test may be replaced with an acute threshold test in which fish testing would be performed at one concentration only (the lowest EC50 concentration obtained with previous algae and daphnia testing). This approach is predicted to reduce the total number of fish used by approximately 73%.
©2008 Chad Sandusky
2 Kirkland, D.J., et al. (2007). In vitro approaches to develop weight of evidence and mode of action discussions with positive in vitro genotoxicity results. Mutagenesis. 22(3), 161-175.
3 Kirkland, D.J., et al. (2007). How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM Workshop. Mutation Research. 628, 31-55.
4 Wayland, S.H. (1999). Letter to manufacturers/importers. See http://www.epa.gov/chemrtk/ceoltr2.htm.
5 OECD Secretariat. (2004). Manual for Investigation of HPV Chemicals. (Section 4.3) See http://www.oecd.org/dataoecd/35/38/31179717.pdf
6 Jeram, S., et al. (2005). A strategy to reduce the number of fish in acute ecotoxicity testing of new chemical substances notified in the European Union. Reg. Tox. Pharm. 42, 218-224.
7 Hutchinson, T.H., et al. (2003). A strategy to reduce the numbers of fish used in acute ecotoxicity testing of pharmaceuticals. Environ. Toxicol. Chem. 22, 3031-3036.