Quantitative risk assessment for multivariate continuous outcomes with application to neurotoxicology: the bivariate case.

The neurotoxic effects of chemical agents are often investigated in controlled studies on rodents, with multiple binary and continuous endpoints routinely collected. One goal is to conduct quantitative risk assessment to determine safe dose levels. Such studies face two major challenges for continuous outcomes. First, characterizing risk and defining a benchmark dose are difficult. Usually associated with an adverse binary event, risk is clearly definable in quantal settings as presence or absence of an event; finding a similar probability scale for continuous outcomes is less clear. Often, an adverse event is defined for continuous outcomes as any value below a specified cutoff level in a distribution assumed normal or log normal. Second, while continuous outcomes are traditionally analyzed separately for such studies, recent literature advocates also using multiple outcomes to assess risk. We propose a method for modeling and quantitative risk assessment for bivariate continuous outcomes that address both difficulties by extending existing percentile regression methods. The model is likelihood based; it allows separate dose-response models for each outcome while accounting for the bivariate correlation and overall characterization of risk. The approach to estimation of a benchmark dose is analogous to that for quantal data without the need to specify arbitrary cutoff values. We illustrate our methods with data from a neurotoxicity study of triethyl tin exposure in rats.

Assessment of chemically-induced alterations in brain development using assays of neuron- and glia-localized proteins.

Chemical-induced injury of the developing central nervous system (CNS) is often manifested by alterations in the cellular ontogeny of specific neuroanatomical regions. Within the affected area, critical developmental processes encompassing a variety of neuronal and glial cell types may be transiently or permanently altered. Because the cellular heterogeneity of the developing CNS is expressed by unique neuronal and glial proteins, we proposed that radioimmunoassays of these proteins can be used to define normal and chemically- altered patterns of CNS development. We are testing this hypothesis by administering prototype neurotoxicants to the developing rat and then assessing the effects of these agents on previously characterized neuronal and glial proteins. Using this approach, we have characterized several features associated with perinatal chemical exposure: (1) region-dependent patterns of altered brain development are revealed by changes in the amounts of specific neuronal and glial proteins; (2) chemical-induced changes in neuronal and glial proteins depend on the time of exposure and nature of the insult; and (3) significant changes in neuron- and glial-localized proteins can be observed in the absence of cytopathology or decreases in brain weight. Data obtained from studies of toxicant-induced injury of the CNS will be presented as models for the use of neuron- and glial-localized proteins as biochemical indicators of altered brain development.