Derivation of a no‐significant‐risk‐level for tetrabromobisphenol A based on a threshold non‐mutagenic cancer mode of action

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.

The Pebble Remains in the Master's Hand: Two Careers Spent Learning (Still) from John Evans

“…Some of these articles (e.g., Bogen, 2019; Calabrese, 2004; Clewell, Thompson, & Clewell, 2019; Slikker et al., 2004) make generic claims about the ubiquity of thresholds for many carcinogens, or about levels below which exposures to carcinogens are salutary (via hormesis) rather than benign or harmful. Other articles (e.g., Pecquet, Martinez, Vincent, Erraguntla, & Dourson, 2018; Stelljes, Young, & Weinberg, 2019) claim that one particular carcinogen has, or “must have” a threshold. This controversy is quite fundamental: if a dose–response relationship has a threshold, then it may be irrelevant that effects are seen at “high” doses, and therefore any positive epidemiology or toxicology study should be discounted, ignored, or deemed “interesting” but not an indication of human risk.…”

“…For example, Pecquet et al. (2018) recently developed an ingestion level of 0.26 mg/kg/day for tetrabromobisphenol A, which they state is a “no‐significant‐risk level,” by estimating the lower bound of exposure causing a 10% tumor increase (from the animal tumor data) and dividing by a factor of 100 to adjust for inter‐ and intraspecies sensitivity differences.…”

Current intelligence bulletin 69: NIOSH practices in occupational risk assessment.

“…In assessments supporting regulation in the United States, most have estimated the carcinogenic risk at low doses by using LNT, with the exception of the EPA's assessment of chloroform [EPA 2001]. In contrast, others have used a PoD/UF approach to derive safe levels for non-genotoxic and some genotoxic carcinogens [Bevan and Harrison 2017;Kirman et al 2016;Pecquet et al 2018;Seeley et al 2001;Thompson et al 2016…”