Causation or Canard: Use of Brain Weight to Body Weight Ratios in Developmental Neurotoxicity

Abstract

DNT guideline-based testing requires the assessment of neurologic, behavioural, and neuropathological endpoints. A review of the impact of DNT studies on regulatory actions revealed that the most common findings at the LOAEL were change in body weight, motor activity, auditory startle response, brain weight and brain morphometrics. An important issue in the interpretation of DNT study findings is that in many of these studies use exposures that impact systemic development as evidenced by decreased body weight and/or body weight gain, especially during the early postnatal period prior to weaning. Currently, there is no international consensus on what degree of growth reduction during early development causes alterations in DNT endpoints. This includes the controversial use of changes body weight adjusted brain weights in concluding that the brain weight changes represent an adverse finding. The current effort compiled brain and body weight changes from 173 publicly available DNT studies designed in line with DNT EPA or OECD test guidelines. This allowed a simple comparison of between a decrease in neonatal body weight and a decrease in brain weight. Results from this project clearly show that developmental exposure induced body weight decreases are not a reliable indicator of whether or not brain weight decreases. From the 173 retrieved studies, 70% showed decreased body weights in pups (122 studies), but only 50 of these studies (41%) reported concomitant decreased brain weights. In addition, there were three studies that reported brain weight decreases when body weight was not changed at any age. This suggests that while changes in body weight may be a confounding factor for some studies, it fails to be a reliable predictor of alteration in brain weight. Thus, use of the ratio of brain weight to body weight is not appropriate as a common approach to dismiss brain weight as a DNT effect. Clearly an international consensus on the interpretation of brain weight changes in DNT studies is needed that takes into account the data presented herein.