Abstract
A no‐significant‐risk‐level of 20 mg day–1 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 Protection Agency guidelines is a threshold approach, akin to a cancer safe dose (RfDcancer). Using the National Toxicology 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–1 day–1. The POD was adjusted to a human equivalent dose of 25.6 mg kg–1 day–1 using allometric scaling. We applied a composite adjustment factor of 100 to the POD to derive an RfDcancer of 0.26 mg kg–1 day–1. Based on a human body weight 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.
Highlights
In line with the Wikoff et al (2015) assessment, we modeled the incidence of combined uterine adenomas, adenocarcinomas, and malignant mixed Müllerian tumors (MMMTs) observed in female rats (NTP, 2014)
While the availability of the National Toxicology Program (NTP) 2‐year comprehensive cancer bioassay is sufficient to inform the database for cancer and while there is a lack of evidence suggesting tetrabromobisphenol A (TBBPA) is highly carcinogenic, we opted to include an additional factor of 3 given the uncertainty associated with modeling the tumor precursor data due to potential toxicity masking and for the decision to model an overt tumor endpoint as opposed to the precursor
Building off of previously published work investigating the mode of action (MOA) and toxicity of TBBPA (ESFA, 2011; Health Canada, 2013; Lai et al, 2015; Wikoff et al, 2015, 2016), and using the cancer results seen from the recent NTP 2‐year cancer bioassay, we have derived an NSRL for TBBPA of 20 mg day–1
Summary
OEHHA recently announced its Prop notice of intent to list tetrabromobisphenol A (TBBPA) as known to the state to cause cancer. In the absence of data to the contrary, no threshold is assumed for the cancer effect of concern, and OEHHA (2013) develops an NSRL through the use of no‐threshold models (cancer slope factor development) based on US EPA guidance (1986, 2005) These NSRL values are compared to exposure estimates to determine the potential to evoke a biological response at relevant environmental exposure levels. Identification of mutagenicity mechanisms for cancer development is often a key diagnostic for identification of threshold vs non‐threshold mechanisms (Bevan & Harrison, 2017) This determination affects the choice of either the derivation of a cancer slope factor and a risk‐specific dose, or a threshold‐based toxicity reference value for cancer effects (RfDcancer). A risk characterization was conducted, building off of previous publications, by identification of the critical tumor effect, identification of a point of departure (POD) utilizing benchmark dose (BMD) modeling, review of the MOA for tumor formation, derivation of a cancer risk value, and adaptation to an NSRL
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