Toward a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny – part I: which parameters from human studies are most relevant for toxicological assessments?

Towards a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny – part II: how can key events of relevant adverse outcome pathways be addressed in toxicological assessments?

“…Appendix A presupposes that, "in the absence of substance-specific data which provide proof of the contrary, humans and rodents are considered to be equally sensitive to thyroid disruption, including cases where liver enzyme induction is responsible for increased thyroid hormone clearance" (EFSA andECHA 2018, EFSA 2020). However, Appendix A does not provide any scientific evidence to support this statement (Sauer et al 2020), even though the assumption of equal species sensitivity to thyroid disruption constitutes a paradigm change as compared to what has been commonly agreed for many years, i.e. that rats are more sensitive than humans (Jahnke et al 2004;Bartsch et al 2018).…”

“…Since internationally agreed generic ranges for normal fT4 are unavailable, human fT4 data are usually compared to population-based reference ranges, with "population" referring to any pre-defined group of people (Sauer et al 2020; Figure 4). Hence, population-based reference ranges need to be established for every single epidemiological study or clinical trial (see Table 1 in Sauer et al (2020) for an overview of the population-based reference ranges that were calculated for the respective human studies considered).…”

“…Since internationally agreed generic ranges for normal fT4 are unavailable, human fT4 data are usually compared to population-based reference ranges, with "population" referring to any pre-defined group of people (Sauer et al 2020; Figure 4). Hence, population-based reference ranges need to be established for every single epidemiological study or clinical trial (see Table 1 in Sauer et al (2020) for an overview of the population-based reference ranges that were calculated for the respective human studies considered). Therefore, comparisons of the findings from any given human study to the respective population-based fT4 reference range should consider that these reference ranges are dependent on the characteristics of the pre-defined population (including the gestational period considered since fT4 levels vary physiologically during pregnancy), and that they are further assayand laboratory-dependent (Sauer et al 2020).…”

“…The first review (Sauer et al 2020) evaluated available human studies to explore how low serum thyroid hormone levels in pregnant mothers affect child neurodevelopment. This activity aimed at identifying parameters in the human studies which are most relevant for toxicological assessments, and should hence be included in the planned testing strategy.…”

“…Clearly, none of the recorded studies included histological evaluations of the mothers' thyroid gland. Also, none of the human studies allowed establishing a link between substance-mediated liver enzyme induction and increased thyroid hormone clearance, and the impact of these on child neurodevelopment (Sauer et al 2020).…”