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Neurotoxicity. The nervous system is complex, both structurally and functionally, and toxicants can affect one or more units of this system in selective fashion. It is necessary therefore to devise tests, or sequences of tests, that measure not only changes in overall function but that also indicate which basic unit is affected and how the toxicant interacts with its target. This is complicated by the fact that the nervous system has a considerable functional reserve, and speci c observable damage may not affect overall function until it becomes even more extensive. Types of damage to the nervous system are classi ed in various ways but include neuronal toxicity, axonopathy, toxic interruption of impulse transmission, myelinopathy, and synaptic alterations in transmitter release or receptor function. Signs of neuropathy are frequently revealed by the acute, subchronic, chronic, and other tests that are required by regulatory agencies.

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; McKenna, P; De Clercq, E Use of the yellow fever virus vaccine strain 17D for the study of strategies for the treatment of yellow fever virus infections Antiviral Res 1996, 30, 125 132 87 Diamond, M S; Zachariah, M; Harris, E Mycophenolic acid inhibits dengue virus infection by preventing replication of viral RNA Virology 2002, 304, 211 221 88 Sbrana, E; Xiao, S Y; Guzman, H; Ye, M G; Travassos da Rosa, A P A; Tesh, R B Ef cacy of post-exposure treatment of yellow fever with ribavirin in a hamster model of the disease Am J Trop Med Hyg, 2004, 71, 306 312 89 Buckwold, V E; Wei, J Y; Wenzel-Mathers, M; Russell, J.

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Neurotoxicity is of great signi cance in toxicology, however, and tests have been devised to supplement those routinely required. These include acute and subchronic neurotoxicity studies as well as developmental neurotoxicity studies.

^ ^ To compute the LT P sj0 , we only need the LSTs f^jk s and gj s associated with the basic holding-time cdf 's Fjk and Gj . Abate and Whitt [3 5] give special attention to heavy-tail probability densities whose Laplace transforms can be computed and, ^ ^ thus, inverted. However, to compute P sjx , we also need to compute D sjx and ^ h sjx , which require computing the LSTs of the conditional cdf's Hjk tjx and Gj tjx in Eq. (17.9). In general, even if we know the LST of a cdf, we do not necesssarily know the LST of an associated conditional cdf. However, in special cases, the LSTs of conditional cdf 's are easy to obtain because the cdf's inherit their structure upon conditioning. For example, this is true for phase-type, hyperexponential and Pareto distributions; Duf eld and Whitt [15, Section 4]. Moreover, other cdf's can be approximated by hyperexponential or phase-type cdf 's; see Asmussen et al. [6] and Feldman and Whitt [17]. If the number of levels is not too large, then it will not be dif cult to compute the required matrix inverse I q s 1 for all required s. Note that, because of the probability structure, the inverse is well de ned for all complex s with Re s > 0. To illustrate with an important simple example, we next give the explicit formula for an on=off source. Suppose that there are two states with transition probabilities

P12 P21 1 and holding time cdf 's G1 and G2 . From Eq. (17.9) or by direct calculation, ! ^ ^ P11 sj0 P12 sj0 ^ ^ ^ P sj0 I q s 1 D s ^ ^ P21 sj0 P22 sj0 ^ ^ ^ g1 s 1 g2 s 1 g1 s 1 : ^ ^ s 1 g1 s g2 s g2 s 1 g1 s ^ ^ ^ 1 g2 s

Behavioral and Pharmacological Tests Behavioral and pharmacological tests involve the observation of clinical signs and behavior These include signs of changes in awareness, mood, motor activity, central nervous system excitation, posture, motor incoordination, muscle tone, re exes, and autonomic functions If these tests so indicate, more specialized tests can be carried out that evaluate spontaneous motor activity, conditioned avoidance responses, operant conditioning, as well as tests for motor incoordination such as the inclined plane or rotarod tests Tests for speci c classes of chemicals include the measurement of transmitter stimulated adenyl cyclase and Na/K-ATPase for chemicals that affect receptor function or cholinesterase inhibition for organophosphates or carbamates Electrophysiological techniques may detect chemicals such as DDT or pyrethroids, which affect impulse transmission Acute and Subchronic Neurotoxicity Tests.

Synergistic in vitro interactions between alpha interferon and ribavirin against bovine viral diarrhea virus and yellow fever virus as surrogate models of hepatitis C virus replication Antimicrob Agents Chemother 2003, 47, 2293 2298..

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