Developmental Neurotoxicity Studies Research Articles

Developmental neurotoxicity after toluene inhalation exposure in rats.

Rats were exposed to 1200 ppm or 0 ppm toluene (CAS 108-88-3) for 6 h per day from day 7 of pregnancy until day 18 postnatally. Developmental and neurobehavioral effects in the offspring were investigated using a test battery including assessment of functions similar to those in the proposed OECD TG for Developmental Neurotoxicity Study, i.e., physical development, reflex ontogeny, motor function, motor activity, sensory function, and learning and memory. The exposure did not cause maternal toxicity or decreased viability of the offspring. Lower birth weight, delayed ontogeny of reflexes, and increased motor activity in the open field was registered in the exposed offspring. Impaired cognitive function was revealed in the exposed female offspring at the age of 3.5 months, i.e., they used more time to locate the hidden platform in the Morris water maze after platform relocation. The difference was not related to poorer swimming capabilities, because swim speeds were similar to control values. The results show that exposure to 1200 ppm toluene during brain development caused long-lasting developmental neurotoxicity in rats.

A retrospective analysis of the criteria used to determine the need for a developmental neurotoxicity study for the regulation of pesticides and toxic substan

A retrospective analysis of the criteria used to determine the need for a developmental neurotoxicity study for the regulation of pesticides and toxic substan

DEVELOPMENT OF AN INHALATION SYSTEM FOR THE SIMULTANEOUS EXPOSURE OF RAT DAMS AND PUPS DURING DEVELOPMENTAL NEUROTOXICITY STUDIES

Due to mass flux constraints, the exposure of pups along with dams to particles cannot be easily done in traditional whole-body inhalation systems. Typical inhalation developmental neurotoxicity studies rely on maternal separation during exposure, resulting in pup stress that may alter behavioral development, thereby confounding study results. We developed an individual-rat, whole-body inhalation exposure cylinder that allows for the simultaneous exposure of rat dams and their pups to vapors, aerosols, and particles. We evaluated pup growth and development following gestational and lactational 6-h/ day exposures to HEPA-filtered air using the novel exposure cylinder, in which dams and pups were maintained together, versus rat pups for which only the dams were exposed or control animals that remained in the domiciliary cage with the dams. Rat pups that were separated from their dams during neonatal exposure to HEPA-filtered air demonstrated significant delays in several developmental landmarks such as surface righting, negative geotaxis, and eye opening, as well as decreased terminal body and brain weights. Increased spontaneous motor activity was observed on postnatal day (PND) 13, 17, and 60 in pups that were separated from their dams. Malnutrition is the likely cause for the observed hyperactivity and delayed development. We then compared maternal blood levels of tertiary amyl methyl ether (TAME) and its metabolite tertiary amyl alcohol (TAA) in the 2 exposure systems following exposure to 500 ppm TAME for 6 h. Dams exposed in the novel exposure cylinder had higher blood levels of TAME compared with those exposed in stainless steel caging. We also compared levels of particulate manganese phosphate within the novel exposure cylinder to determine if levels achieved within the exposure cylinder were similar to levels generated within a 1-m3 chamber. The novel exposure cylinder is an ideal system for exposure of dams and pups to particles, due to the high horizontal flow rates, which result in an adequate mass flux flowing past the breathing zone of the animals with retained normal growth and development.

Tests of Learning and Memory in the EPA Developmental Neurotoxicity Study Design.

Tests of Learning and Memory in the EPA Developmental Neurotoxicity Study Design.

Tests of learning and memory in the EPA developmental neurotoxicity study design

Tests of learning and memory in the EPA developmental neurotoxicity study design

Prospective, longitudinal assessment of developmental neurotoxicity.

Methodological issues in the design of prospective, longitudinal studies of developmental neurotoxicity in humans are reviewed. A comprehensive assessment of potential confounding influences is important in these studies because inadequate assessment of confounders can threaten the validity of causal inferences drawn from the data. Potential confounders typically include demographic background variables, alcohol and smoking during pregnancy, the quality of parental stimulation, the child's age at test, and the examiner. Exposure to other substances is assessed where significant exposure is expected in the target population. In most studies, control variables even weakly related to outcome are included in all multivariate statistical analyses, and a toxic effect is inferred only if the effect of exposure is significant after controlling for the potential confounders. Once a neurotoxic effect has been identified, suspected mediating variables may be added to the analysis to examine underlying processes or mechanisms through which the exposure may impact on developmental outcome. Individual differences in vulnerability may be examined in terms of either an additive compensatory model or a synergistic "risk and resilience" approach. Failure to detect real effects (Type II error) is of particular concern in these studies because public policy considerations make it likely that negative findings will be interpreted to mean that the exposure is safe. Important sources of Type II error include inadequate representation of highly exposed individuals, overcontrol for confounders, and inappropriate correction for multiple comparisons. Given the high cost and complexity of prospective, longitudinal investigations, cross-sectional pilot studies focusing on highly exposed individuals can be valuable for the initial identification of salient domains of impairment.

Scientific and regulatory issues relevant to assessing risk for developmental neurotoxicity: An overview

The effects of chemical exposure on the developing nervous system have been documented in both humans and animals for a variety of agents. However, the comparability of these effects has not been carefully evaluated to determine the predictability of animal models to adverse effects in humans. A workshop sponsored by the U.S. Environmental Protection Agency (EPA) and the National Institute on Drug Abuse was held on April 11–13, 1989, to address the Qualitative and Quantitative Comparability of Human and Animal Developmental Neurotoxicity. Invited experts were asked to review the human and animal data on several agents that are known to cause developmental neurotoxicity in humans, including lead, methylmercury, selected abused agents, anticonvulsants, polychlorinated biphenyls (PCBs), ethanol and X-irradiation, and to make qualitative comparisons on a specific end point basis as well as on a functional category basis. In addition, they were asked to make quantitative comparisons when adequate dose-effect data were available. The data also were evaluated in the context of the proposed EPA developmental neurotoxicity testing battery to determine whether or not the battery would adequately detect the effects of each agent. Finally, four work groups were asked to reach consensus on issues relating to: 1) comparability of end points across species for developmental neurotoxicity; 2) testing methods in developmental neurotoxicity for use in human risk assessment; 3) weight-of-evidence and quantitative evaluation of data from developmental neurotoxicity studies; and 4) triggers for developmental neurotoxicity testing.