A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in wistar rats

A 28-day repeated dose study in rats (OECD407) enhanced for endocrine and immune parameters was performed with hexabromocyclododecane (HBCD). Rats were exposed by daily gavage to HBCD dissolved in corn oil in 8 dose groups with doses ranging between 0 and 200 mg/kg bw per day (mkd). Evaluation consisted of dose-response analysis with calculation of a benchmark dose at the lower 95% one-sided confidence bound (BMDL) at predefined critical effect sizes (CESs) of 10-20%. The most remarkable findings were dose-related effects on the thyroid hormone axis, that is, decreased total thyroxin (TT4, BMDL 55.5 mkd at CES--10%), increased pituitary weight (29 mkd at 10%) and increased immunostaining of TSH in the pituitary, increased thyroid weight (1.6 mkd at 10%), and thyroid follicle cell activation. These effects were restricted to females. Female rats also showed increased absolute liver weights (22.9 mkd at 20%) and induction of T4-glucuronyl transferase (4.1 mkd at 10%), suggesting that aberrant metabolization of T4 triggers feedback activation of the thyroid hormone system. These effects were accompanied by possibly secondary effects, including increased cholesterol (7.4 mkd at 10%), increased tibial bone mineral density (> 49 mkd at 10%), both in females, and decreased splenocyte counts (0.3-6.3 mkd at 20%; only evaluated in males). Overall, female rats appeared to be more sensitive to HBCD than male rats, and an overall BMDL is proposed at 1.6 mkd, based on a 10% increase of the thyroid weight, which was the most sensitive parameter in the sequence of events

Probabilistic dietary exposure assessment taking into account variability in both amount and frequency of consumption.

Probabilistic dietary exposure assessments that are fully based on Monte Carlo sampling from the raw intake data may not be appropriate. This paper shows that the data should first be analysed by using a statistical model that is able to take the various dimensions of food consumption patterns into account. A (parametric) model is discussed that takes into account the interindividual variation in (daily) consumption frequencies, as well as in amounts consumed. Further, the model can be used to include covariates, such as age, sex, or other individual attributes. Some illustrative examples show how this model may be used to estimate the probability of exceeding an (acute or chronic) exposure limit. These results are compared with the results based on directly counting the fraction of observed intakes exceeding the limit value. This comparison shows that the latter method is not adequate, in particular for the acute exposure situation. A two-step approach for probabilistic (acute) exposure assessment is proposed: first analyse the consumption data by a (parametric) statistical model as discussed in this paper, and then use Monte Carlo techniques for combining the variation in concentrations with the variation in consumption (by sampling from the statistical model). This approach results in an estimate of the fraction of the population as a function of the fraction of days at which the exposure limit is exceeded by the individual

Comparing BMD-derived genotoxic potency estimations across variants of the transgenic rodent gene mutation assay.

There is growing interest in quantitative analysis of in vivo genetic toxicity dose-response data, and use of point-of-departure (PoD) metrics such as the benchmark dose (BMD) for human health risk assessment (HHRA). Currently, multiple transgenic rodent (TGR) assay variants, employing different rodent strains and reporter transgenes, are used for the assessment of chemically-induced genotoxic effects in vivo. However, regulatory issues arise when different PoD values (e.g., lower BMD confidence intervals or BMDLs) are obtained for the same compound across different TGR assay variants. This study therefore employed the BMD approach to examine the ability of different TGR variants to yield comparable genotoxic potency estimates. Review of over 2000 dose-response datasets identified suitably-matched dose-response data for three compounds (ethyl methanesulfonate or EMS, N-ethyl-N-nitrosourea or ENU, and dimethylnitrosamine or DMN) across four commonly-used murine TGR variants (Muta™Mouse lacZ, Muta™Mouse cII, gpt delta and BigBlue® lacI). Dose-response analyses provided no conclusive evidence that TGR variant choice significantly influences the derived genotoxic potency estimate. This conclusion was reliant upon taking into account the importance of comparing BMD confidence intervals as opposed to directly comparing PoD values (e.g., comparing BMDLs). Comparisons with earlier works suggested that with respect to potency determination, tissue choice is potentially more important than choice of TGR assay variant. Scoring multiple tissues selected on the basis of supporting toxicokinetic information is therefore recommended. Finally, we used typical within-group variances to estimate preliminary endpoint-specific benchmark response (BMR) values across several TGR variants/tissues. We discuss why such values are required for routine use of genetic toxicity PoDs for HHRA. Environ. Mol. Mutagen. 58:632-643, 2017. © 2017 Her Majesty the Queen in Right of Canada. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc