Human surrogates

Study Type. Metabolic and pharmacokinetic data from a rodent species and a nonrodent species (usually the dog) used for repeat dose safety assessments (14 days, 28 days, 90 days or six months) are recommended. If a dose dependency is observed in metabolic and pharmacokinetic or toxicity studies with one species, the same range of doses should be used in metabolic and pharmacokinetic studies with other species. If human metabolism and pharmacokinetic data also are available, this information should be used to help select test species for the full range of toxicity tests, and may help to justify using data from a particular species as a human surrogate in safety assessment and risk assessment. 

The value of an ADI is entirely dependent on the quality of the experimental data and the judicious selection of the safety (uncertainty) factor, which is entirely judgmental. Among the factors influencing the quality of the experimental data, beyond the mechanics, are the selection of the appropriate animal model as the human surrogate, the... 

Subacute or subchronic assays assess the effects of daily exposures of an animal population to a toxicant over approximately 10% of the animal s lifetime. In rats, this corresponds to about 3 months. Careful study of the animals—including examination of all body tissues and fluids—reveals the dose at which toxic effects begin to occur at several endpoints, such as organ dysfunction, behavioral changes, or alterations in levels of normal body fluid components. The highest dose at which none of the animals show toxic effects is called NOAEL (i.e., no observable adverse effect). Other doses include LOEL (lowest observed effect level), the lowest dose for which effects were expressed and LOAEL (lowest observed adverse effect level), a stricter version of LOEL that addresses only adverse effects. In these tests several species are tested and the most sensitive one is selected as a human surrogate. See Figure 9.32. 

The principal aim of impact biomechanics is the prevention of injury through environmental modification, such as the provision of an airbag for automotive occupants to protect them during a frontal crash. To achieve this aim effectively, it is necessary that workers in the field have a clear understanding of the mechanisms of injury, be able to describe the mechanical response of the tissues involved, have some basic information on human tolerance to impact, and be in possession of tools that can be used as human surrogates to assess a particular injury [Viano et al., 1989]. This chapter deals with the biomechanics of blunt impact injury to the head and neck. 

The most serious bottleneck in pharmaceutical development is the abiKfy to complete ADMET (adsorption-distribution-metaboHsm-eHmination-toxicity) studies early enough in the development process to focus resources on the best drug candidates. Of particular importance will be human surrogates that can improve the probability that a drug wiU be successful in clinical trials. Such trials may cost more... 

Albert I. King 52.4 Human Surrogates of the Head and Neck The Experimental Surrogate The Injury-Assessment Tool 52-9... 

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