approach to assess risk for developmental defects. In Chapter 9, the interface of risk assessment and developmental toxicology is further explored within the fourth charge to the committee to develop recommendations for research in developmental toxicology and developmental biology to assist in risk assessment.
The approach is multidisciplinary and multilevel because it invokes a wide variety of sources of information for risk assessment, including not only the assessment of toxicity and mechanism of action of chemicals in a variety of model systems (in vitro assays, nonmammalian models, and mammalian models), but also the assessment of toxicity, susceptibility, and exposure in human populations. The approach is appropriate to the risk assessment task, because assessing developmental toxicity is a broad and difficult area. The understanding of toxicity mechanisms entails both toxicokinetics and toxicodynamics, ranging from molecules to pathogenesis. Furthermore, the analysis of the differences between model systems (e.g., test organisms) and humans, as needed to improve extrapolation of test results, will require extensive comparative work at a variety of levels. These advances will depend on knowledge from chemistry, biochemistry, molecular biology, cell biology, developmental biology, genetics, ecogenetics, anatomy and organ physiology, genomics, and even systematics and evolutionary biology (e.g., finding conserved and nonconserved processes of development). A multidisciplinary, multilevel approach is needed to “bridge the gap” between the emerging scientific information and the assessment of human risk. At the same time, an interactive approach is needed for the dynamic interplay between the sources of new information and the needs of risk assessors.
The committee’s multilevel approach should not be mistaken for a multi-tiered approach, where a specific order of evaluation and types of testing are specified. In a strict tiered approach, screening data at a low tier (low-cost, high-throughput tests, low assurance of relevance to humans) are first used to estimate risks of a large number of agents, and an agent with a high potential risk estimate at this tier triggers more rigorous and relevant tests, with higher associated costs, at successively higher tiers. For example, the Endocrine Disruptor Screening Program (EDSP) will use a tiered approach (EPA 1998g). Although the committee’s multilevel approach also involves tests ranging from inexpensive, high-throughput tests to slow, rigorous, and expensive tests, the approach differs in several respects. First, there is no uni-directional triggering of higher level testing by results obtained from a lower level test. Testing can be done independently at any level or at several levels, depending on the particular compound, the risk assessment questions, the anticipated human exposures, and the commercial uses considered for that compound. Results at one level could lead to tests at lower levels rather than higher levels. Second, the different testing levels yield different kinds of information, all with the potential to contribute to the knowledge of toxicity mechanisms, from molecular interactions to pathogenesis, and the understanding of the basis for extrapolation. All levels are designed to provide information useful for human developmental toxicity risk assessments. For