Pecquet AM, Martinez JM, Vincent M, Erraguntla N, Dourson M. 2018. Derivation of a no-significant-risk-level for tetrabromobisphenol A based on a threshold non-mutagenic cancer mode of action. J Appl Toxicol 38(6):862–878, doi: 10.1002/jat.3594.
A no‐significant‐risk‐level of 20 mg day was derived for tetrabromobisphenol A (TBBPA). Uterine tumors (adenomas, adenocarcinomas, and malignant mixed Müllerian) observed in female Wistar Han rats from a National Toxicology Program 2‐year cancer bioassay were identified as the critical effect. Studies suggest that TBBPA is acting through a non‐mutagenic mode of action. Thus, the most appropriate approach to derivation of a cancer risk value based on US Environmental ProtectionAgency guidelines is a threshold approach, akin to a cancer safe dose (RfDcancer). Using the NationalToxicology Program data, we utilized Benchmark dose software to derive a benchmark dose lower limit (BMDL10) as the point of departure (POD) of 103 mg kg–1day–1. The POD was adjusted to a human equivalent dose of 25.6 mg kg–1day–1 using allometric scaling. We applied a composite adjustment factor of 100 to the POD to derive an RfDcancer of 0.26 mg kg–1day–1. Based on a human bodyweight of 70 kg, the RfDcancer was adjusted to a no‐significant‐risk‐level of 20 mg day–1. This was compared to other available non‐cancer and cancer risk values, and aligns well with our understanding of the underlying biology based on the toxicology data. Overall, the weight of evidence from animal studies indicates that TBBPA has low toxicity and suggests that high doses over long exposure durations are needed to induce uterine tumor formation. Future research needs include a thorough and detailed vetting of the proposed adverse outcome pathway, including further support for key events leading to uterine tumor formation and a quantitative weight of evidence analysis.