ICCVAM Biennial Report 2018-2019

Read-across is a computational technique that uses toxicity data from data-rich chemicals to predict toxicity for an untested or data-poor chemical. Despite the potential usefulness of read-across to provide information on chemical hazard and risk assessment, its application and acceptance varies among U.S. federal agencies. ICCVAM established a read-across workgroup sponsored by EPA and FDA that conducted a survey of the current applications, tools used, and needs of the agencies represented in the workgroup. Of the agencies surveyed, EPA had the greatest experience in using read-across. However, other agencies indicated that they would benefit from gaining a perspective of the landscape of available tools and guidance. The paper summarizing the survey (Patlewicz et al. 2019) also provided practical case studies to illustrate how the read-across approaches applied by two agencies varied based on agency decision contexts.

Understanding the current regulatory use and acceptance of non-animal data is a necessary starting point for future method development, optimization, and validation efforts. Therefore, the ICCVAM Acute Toxicity Workgroup reviewed (Strickland et al. 2018) acute systemic toxicity testing requirements for six U.S. agencies and noted whether there is flexibility in satisfying data needs with methods that replace or reduce animal use. The review informed the development of the Strategic Roadmap for implementing non-animal approaches to assess potential hazards associated with acute exposures to industrial chemicals and medical products.

Chemical regulation authorities in the United States require or consider eye and skin irritation test data to develop product hazard labeling or to assess risks for exposure to skin- and eye-irritating chemicals. The ICCVAM Ocular and Dermal Irritation Workgroup reviewed U.S. agencies’ data needs for skin and eye irritation (Choksi et al. 2019). Information reviewed included the type of skin and eye irritation data required by each agency and the associated decision context: hazard classification, potency classification, or risk assessment; the preferred tests; and whether alternative or non-animal tests are acceptable. Information on the specific information needed from non-animal test methods was also collected. The review revealed a willingness to consider non-animal or alternative test methods by participating agencies, who encouraged sponsors to consult with the relevant agency to discuss the use and acceptance of alternative methods for local skin and eye irritation testing in designing their testing program.

U.S. regulatory and research agencies often rely upon skin sensitization test data to assess the sensitization hazards associated with dermal exposure to chemicals and products and ensure that such substances will not cause unreasonable adverse effects to human health when used appropriately. The ICCVAM Skin Sensitization Workgroup conducted a review of U.S. agencies (Strickland et al. 2019) to identify the standards, test guidelines, or guidance documents that are applicable to satisfy each of these agency's needs; the current use of animal testing and flexibility for using alternative methodologies; information needed from alternative tests to fulfill the needs for skin sensitization data; and whether data from non-animal alternative approaches are accepted by these agencies.

NICEATM scientists and International Cooperation on Alternative Test Methods (ICATM) participants also reviewed skin sensitization testing requirements for ICATM participating countries or regions (Daniel et al. 2018). The survey considered the type of skin sensitization data required for each chemical sector and whether these data were used in a hazard classification, potency classification, or risk assessment context; the preferred tests; and whether alternative non-animal tests were acceptable. An understanding of national and regional regulatory requirements for skin sensitization testing will inform the development of ICATM's international strategy for the acceptance and implementation of non-animal alternatives to assess the health hazards and risks associated with potential skin sensitizers.

While the Strategic Roadmap focuses primarily on human health, ICCVAM also recognizes the need to implement non-animal approaches for ecotoxicity testing. Development and implementation of alternative approaches to reduce and replace animal use for this testing will involve four key steps: (1) defining testing needs, (2) identifying the available alternative approaches, (3) developing defined approaches to testing and assessment, and (4) addressing both scientific and non-scientific (including regulatory) challenges. Accordingly, in 2018 ICCVAM established an ecotoxicology workgroup to provide expertise in identifying and evaluating alternative approaches to identify ecological and environmental hazards using in vitro and/or in silico methods. The workgroup is sponsored by DoD, DOI, and EPA and has representatives from seven ICCVAM agencies. Members are currently compiling a summary of ecotoxicity tests that require the use of animals, emerging technologies for ecotoxicity and environmental safety, and the utility of those technologies in regulatory testing. This summary, planned for publication in 2020, will help advance the development and evaluation of defined approaches for screening, testing, and assessment of relevant endpoints.

IVIVE can facilitate the use of in vitro toxicity testing data in risk assessment and regulatory decision-making. In 2018, ICCVAM established an IVIVE workgroup to explore how IVIVE can best be applied to these purposes. The workgroup is sponsored by ATSDR and EPA, and currently has members from seven ICCVAM agencies. The workgroup is currently cataloging and evaluating currently available IVIVE approaches. Activities have focused on harmonizing the technical terms used in IVIVE application, evaluating their suitability for specific research or regulatory purposes, and assessing whether additional tools or models are needed. The workgroup’s findings will be reported in a publication planned for 2021 that will systematically present the best practices and encourage the judicious use of IVIVE.

Nanomaterials are used in a broad range of consumer products, but their unique properties make them challenging to test in both in vivo and in vitro toxicity assays. ICCVAM established its Nanomaterials Workgroup to evaluate the suitability of alternative methods to assess potential toxicity of nanomaterials. The workgroup is sponsored by CPSC and NIST, and has members from seven ICCVAM agencies. The workgroup has surveyed federal agencies to determine needs and activities relevant to nanomaterials testing, potential applicability of alternative methods to testing needs, and the challenges that would be faced in implementing them. Its findings will be reported in a paper planned for publication in 2020.

Tests to detect and measure botulinum neurotoxin are required by multiple federal agencies for regulatory and other decision contexts. Currently, the standard test for these endpoints is a mouse lethality assay that can use large numbers of animals. In a June 2018 Federal Register notice (83 FR 27622), NICEATM requested available data and information on approaches and/or technologies currently used to detect and measure botulinum neurotoxin. The scope of the request included information on any activities relevant to the development or validation of alternatives to in vivo test methods currently used by federal agencies for regulatory and other decision contexts. The announcement also requested available data from in vivo botulinum neurotoxin tests used for similar applications as the proposed alternative, such as distinguishing between botulinum neurotoxin serotypes in biological matrix samples or measuring the potency of therapeutic botulinum neurotoxin preparations. Submitted information is being used to assess the state of the science and determine technical needs for non-animal test methods that are used to detect the presence of botulinum neurotoxin and measure potency of botulinum neurotoxin preparations.

Developmental toxicity tests evaluate the extent to which exposure to a substance can interfere with normal development. This testing is required by multiple regulatory agencies and uses large numbers of animals. In a May 2018 Federal Register notice (83 FR 20082), NICEATM requested available data and information on approaches and/or technologies currently used to identify potential developmental toxicants. Submitted information has been used to assess the state of the science for these approaches and technologies and determine technical needs for approaches to assess this endpoint.