Derivation of the critical effect size/benchmark response for the dose-response analysis of the uptake of radioactive iodine in the human thyroid.
Potential adverse effects of chemical substances on thyroid function are usually examined by measuring serum levels of thyroid-related hormones. Instead, recent risk assessments for thyroid-active chemicals have focussed on iodine uptake inhibition, an upstream event that by itself is not necessarily adverse. Establishing the extent of uptake inhibition that can be considered de minimis, the chosen benchmark response (BMR), is therefore critical. The BMR values selected by two international advisory bodies were 5% and 50%, a difference that had correspondingly large impacts on the estimated risks and health-based guidance values that were established. Potential treatment-related inhibition of thyroidal iodine uptake is usually determined by comparing thyroidal uptake of radioactive iodine (RAIU) during treatment with a single pre-treatment RAIU value. In the present study it is demonstrated that the physiological intra-individual variation in iodine uptake is much larger than 5%. Consequently, in-treatment RAIU values, expressed as a percentage of the pre-treatment value, have an inherent variation, that needs to be considered when conducting dose-response analyses. Based on statistical and biological considerations, a BMR of 20% is proposed for benchmark dose analysis of human thyroidal iodine uptake data, to take the inherent variation in relative RAIU data into account. Implications for the tolerated daily intakes for perchlorate and chlorate, recently established by the European Food Safety Authority (EFSA), are discussed.
Weterings Consultancy BV, Iepenlaan 16, 5248AK Rosmalen, The Netherlands. Electronic address: weterings.peter@gmail.com.
Peter J J M
PJ
Weterings
Gradient, 600 Stewart Street, Suite 1900, Seattle, WA 98101, USA.
Christine
C
Loftus
Gradient, 600 Stewart Street, Suite 1900, Seattle, WA 98101, USA.
Thomas A
TA
Lewandowski
D019985:Benchmarking; D001692:Biological Transport; D002704:Chlorates / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism*; D019055:No-Observed-Adverse-Effect Level; D010472:Perchlorates / Q000009:adverse effects; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D018570:Risk Assessment; D013960:Thyroid Function Tests / Q000592:standards*; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism*
D002704:Chlorates; D007457:Iodine Radioisotopes; D010472:Perchlorates; C494474:perchlorate
Benchmark dose analysis; Benchmark response; Critical effect size; Intra-individual variation; Perchlorate; RAIU; Radioiodine; Risk assessment; TDI; Thyroid