Toxicity Testing for Assessment of Environmental Agents Interim Report (2006) / Chapter Skim
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4 Strategies for Toxicity Testing
4 Strategies for Toxicity Testing
Pages 92-117
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From page 92... ...
industrial chemicals in the United States and the European Union, and risks associated with endocrine-disrupting chemicals, developmental toxicants, and carcinogens. The widespread inclusion of genetic-toxicity tests in testing schemes followed scientific advancements that led to the understanding and general recognition that chemicals could cause mutations and mutations could cause cancer.
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From page 93... ...
Tailored testing strategies may start with a flexible test battery and evolve to different tiers or types of testing in an iterative manner based on scientific judgment. Characterizing an overall testing strategy as a battery, tiered, or tailored approach is often not possible, because testing strategies are typically combinations of these three basic elements.
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From page 94... ...
To provide a basis for evaluating the safety of pesticides and food additives, FDA and EPA require a series of tests from applicants and petitioners, as discussed in the following sections. Federal Insecticide, Fungicide, and Rodenticide Act Testing Program The EPA Office of Pesticide Programs regulates the use of pesticides under the authority of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA)
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From page 95... ...
EPA has the authority to impose data requirements on pesticides beyond what is required routinely if it determines that more data are needed to characterize the hazard potential of a particular pesticide, including potential hazards to infants and children.
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From page 96... ...
. FDA Testing Strategies for Food Additives FDA provides guidance to industry and the public concerning the procedures and methods for assessing the safety of direct and indirect food and color additives.
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From page 97... ...
Indirect food additives -- chemicals that become part of food in trace amounts because of packaging, storage, or other handling -- are categorized for testing only according to dietary concentration. TABLE 4-3 Concern Levels for Direct Food Additivesa Degree of Concern Higher Lower Concern Level III Concern Level II Concern Level I Structure C 0.25 ppm Structure C 0.0125 ppm Structure C <0.0125 ppm Structure B 0.5 ppm Structure B 0.025 ppm Structure B <0.025 ppm Structure A 1.0 ppm Structure A 0.05 ppm Structure A <0.05 a All concentrations listed in the table are estimated concentrations in the total diet.
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From page 98... ...
The tests increase in complexity and duration as the level of concern or dietary concentration increases. As Table 4-4 indicates, some tests are contingent on other test findings, but there is no formal guidance on proceeding TABLE 4-4 Testing Required for Direct and Indirect Food Additives Direct Food Additives Toxicity Tests Concern Levela Testing A
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From page 99... ...
TOXICITY-TESTING STRATEGIES FOR SCREENING OF INDUSTRIAL CHEMICALS In addition to the vast number of chemicals already in commerce, many chemicals are introduced each year. The following describes testing strategies used in the United States and Europe to screen and provide the basis for toxicity assessment of new and existing industrial chemicals.
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From page 100... ...
. To address the lack of data on existing industrial chemicals, EPA implemented a voluntary program in negotiation with the American Chemistry Council, the American Petroleum Institute, and Environmental Defense known as the HPV chemical testing program.
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From page 101... ...
. European Union Testing Strategies Toxicity testing of environmental agents to inform human health risk assessments occurs in the European Union (EU)
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From page 102... ...
The EPA and OECD endocrinedisruptor screening approaches and work of the NRC are provided as examples of testing approaches aimed at addressing specific systems and end points. Environmental Protection Agency Endocrine-Disruptor Testing Strategy In 1996, EPA formed the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC)
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From page 103... ...
TABLE 4-5 European Union Testing Strategy 10-100 kg/manufacturer per year 1-10 tons/manufacturer per year 10-1,000 tons/manufacturer per year Acute toxicity -- oral or inhalation Acute toxicity -- oral route and a second (50-5,000 tons cumulative) depending on likely route of exposure Level 1 Base Testing Set 100 kg-1 ton/manufacturer per year Skin irritation Acute toxicity -- oral route and a second Acute toxicity -- oral route and a second Eye irritation depending on likely route of exposure depending on likely route of exposure Skin sensitization Skin irritation Skin irritation Repeated-dose toxicity -- 28 day Eye irritation Eye irritation Mutagenicity -- bacteriologic and Skin sensitization Skin sensitization nonbacteriologic tests Repeated-dose toxicity -- 28 day Mutagenicity -- bacteriologic test Reproductive-toxicity screen Mutagenicity -- bacteriologic and nonReproductive-toxicity screen Pharmacokinetic assessment -- based on bacteriologic tests Pharmacokinetic assessment -- based on data derived from above tests Reproductive-toxicity screen data derived from above tests Pharmacokinetic assessment -- based on data derived from above tests Fertility study -- in one species for one generation May be required on basis of level 1 testing results Fertility -- second-generation study Teratogenicity -- in second species Prenatal-development toxicity Subchronic/chronic toxicity Mutagenicity -- additional testing (Continued)
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From page 104... ...
TABLE 4-5 Continued 104 >1,000+ tons/manufacturer per year (>5,000 tons cumulative) Level 2 Base Testing Set Acute toxicity -- oral route and a second depending on likely route of exposure Skin irritation Eye irritation Skin sensitization Repeated-dose toxicity -- 28 days Mutagenicity -- bacteriologic and nonbacteriologic tests Reproductive-toxicity screen Fertility study -- in one species for one generation Chronic toxicity Carcinogenicity Pharmacokinetic assessment -- based on data derived from base testing set plus additional studies May be required on basis of level 1 testing results Fertility -- multigeneration study Prenatal-development toxicity Acute toxicity -- in second species Repeated-dose toxicity -- 28 days -- in second species
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From page 105... ...
) developed its Endocrine Disruptor Screening Program (EDSP)
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From page 106... ...
Chemicals with existing data sufficient to bypass both tier 1 and tier 2 testing for direct hazard assessment. The EDSTAC also recommended that a scheme be developed for setting testing priorities among common mixtures.
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From page 107... ...
The OECD endocrine-disruptor testing framework indicates that a chemical can enter at any step on the basis of available data or data requirements and leave the testing framework when available data are sufficient for an assessment. Developmental-Toxicity Testing Given the potentially devastating effects of human developmental defects, the NRC convened the Committee on Developmental Toxicity to
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From page 108... ...
In vivo assays − Hershberger assay (androgenic related) providing data about − Non-receptor mediated hormone function single endocrine − Others (e.g., thyroid)
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From page 109... ...
evaluate the impact of environmental agents on human development. The committee proposed a multidisciplinary, multilevel, interactive approach to developmental-toxicity testing (NRC 2000, Chapter 8)
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From page 110... ...
110 Toxicity Testing for Assessment of Environmental Agents: Interim Report Chemicals Level 1 Toxicity Testing Level 3 Toxicity Testing High-throughput In vivo mammalian biochemical and developmental cellular assays toxicity testing Level 2 Toxicity Testing Level 4 Toxicity Testing Developmental assays Detailed mechanistic with genetically optimized studies to understand and sensitized mode of action for selected nonmammalian animals developmental toxicants Data Databases Human Developmental Outcomes; Human Genome and Genetic Polymorphisms; Biomarkers for Exposure, Effect, and Susceptibility; Human Gene-Environment Interactions Estimate of Human Developmental Toxicity FIGURE 4-2 Developmental-toxicity testing approach.
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From page 111... ...
Another important concept mentioned is the combining of information obtained from the model system and animal tests with that accumulated through an improved human surveillance program. It is less clear how the large mass of information generated in the proposed multilevel testing scheme is translated in practice into risk assessments.
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From page 112... ...
Thus, the basis for establishing priorities and requiring testing for industrial chemicals in the United States has not progressed much over the last 20 years. The HPV program, which was a response to the lack of data collected under TSCA, uses a simple criterion to determine whether a chemical is to be included in the HPV testing program: nonpolymeric organic chemicals produced in or imported into the United States at a volume of 1 million pounds or more during the 1990 reporting year.2 Similarly, the EU uses production volume to assign priorities and define testing requirements.
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From page 113... ...
The testing strategies discussed above generally use traditional, standardized toxicology tests. Results of an initial series of mandated tests can trigger additional testing to provide broader coverage of end points, exposure routes, or life stages or a greater depth of understanding of the effects observed.
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From page 114... ...
Different testing approaches generally stem from legislative mandates or from differences in individual agencies or program offices. Different approaches can result in inconsistent testing strategies among agencies or categories of chemicals even if the ultimate regulatory goal is the same.
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From page 115... ...
1993. Draft toxicology principals for safety assessment of direct food additives and color additives used in
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From page 116... ...
B.1. in Redbook 2000, Toxicological Principles for the Safety Assessment of Food Ingredi ents, Office of Food Additive Safety, U.S.
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From page 117... ...
Strategies for Toxicity Testing 117 A study of twelve Southern California communities with differing levels and types of air pollution.
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