Upstream adverse effects in risk assessment: A model of polychlorinated biphenyls, thyroid hormone disruption and neurological outcomes in humans

Abstract

a b s t r a c tBackground: Increasing data on early biological changes from chemical exposures requires new interpretation tools to support decision-making. Objectives: To test the possibility of applying a quantitative approach using human data linking chemical exposures and upstream biological perturbations to overt downstream outcomes. Methods: Using polychlorinated biphenyl (PCB) exposures and maternal thyroid hormone (TH) perturbations as a case study, we model three relationships: (1) prenatal PCB exposures and TH changes, using free T 4 (FT 4 ); (2) prenatal TH and childhood neurodevelopmental outcomes; and (3) prenatal PCB exposures and childhood neurodevelopmental outcomes (IQ). We surveyed the epidemiological literature; extracted relevant quantitative data; and developed models for each relationship, applying meta-analysis where appropriate. Results: For relationship 1, a meta-analysis of 3 studies gives a coefficient of À 0.27 pg/mL FT 4 per ln(sum of PCBs) (95% confidence interval [CI] À 0.82 to 0.27). For relationship 2, regression coefficients from three studies of maternal FT 4 levels and cognitive scores ranged between 0.99 IQ points/(pg/mL FT 4 ) (95% CI À 0.31 to 2.2) and 7.6 points/(pg/mL FT 4 ) (95% CI 1.2 to 16.3). For relationship 3, a metaanalysis of five studies produces a coefficient of À 1.98 IQ points (95% CI À 4.46 to 0.50) per unit increase in ln(sum of PCBs). Combining relationships 1 and 2 yields an estimate of À 2.0 to À 0.27 points of IQ per unit increase in ln(sum of PCBs). Conclusions: Combining analysis of chemical exposures and early biological perturbations (PCBs and FT 4 ) with analysis of early biological perturbations and downstream overt effects (FT 4 and IQ) yields estimates within the range of studies of exposures and overt effects (PCBs and IQ). This is an example approach using upstream biological perturbations for effect prediction.

Application of the Navigation Guide systematic review methodology to the evidence for developmental and reproductive toxicity of triclosan

“…However, most of the 6 human and 13 rodent studies focused on hormone modulation as an outcome measure, and thus we focused our analysis on that outcome. Thyroid hormone disruption is an upstream indicator of developmental toxicity 57–60 .…”

“…Our results were primarily based on postnatal effects in the non-human mammalian literature, as only one of the studies evaluated effects on thyroid hormones during gestation. This is a challenge as previous literature finds that thyroid hormone levels during gestation is an indicator of future neurodevelopment 60, 65, 66 . Our findings also illustrate a strength of systematic reviews in that the method identifies research gaps which can inform how scarce research funding could be most efficiently and effectively targeted to answer a policy relevant question.…”

“…We did not require that these three criteria be met in order to consider triclosan “possibly” toxic. We base this on previous literature identifying that thyroid hormone disruption, in particular thyroxine decrements, is an indicator of adverse effects 57–60 . In short, having consistent disruption of all thyroid system endpoints, in human studies (implicit if rats are to be discounted), and a documented mode of action sets a very high bar for demonstrating a chemical’s toxicity.…”

“…Thyroid hormone disruption is concerning because even small reductions in thyroxine in pregnant women can have adverse effects on neurodevelopment of children 57, 58, 60, 69, 70 . Because there is widespread exposure to triclosan, a finding that triclosan is “possibly toxic” has important public health implications.…”

Adverse effects in risk assessment: Modeling polychlorinated biphenyls and thyroid hormone disruption outcomes in animals and humans

“…TH perturbations have already been identified as an endpoint with sufficient data to characterize the relationship between exposure, TH changes, and downstream overt effects, making efforts to identify quantitative methods for integration into risk assessment warranted (Woodruff et al, 2008). We have also previously identified PCBs as having sufficient data to describe the relationship between exposure, early biological perturbations, and subsequent overt effects in both animals and humans (Wise et al, submitted for publication). …”