A Signal-to-Noise Crossover Dose as the Point of Departure for Health Risk Assessment

By Sand, Salomon; Portier, Christopher J. et al. | Environmental Health Perspectives, December 2011 | Go to article overview

A Signal-to-Noise Crossover Dose as the Point of Departure for Health Risk Assessment


Sand, Salomon, Portier, Christopher J., Krewski, Daniel, Environmental Health Perspectives


BACKGROUND: The U.S. National Toxicology Program (NTP) cancer bioassay database provides an opportunity to compare both existing and new approaches to determining points of departure ([(PoD).sub.s]) for establishing reference doses ([(RfD).sub.s]).

OBJECTIVES: The aims of this study were a) to investigate the risk associated with the traditional PoD used in human health risk assessment [the no observed adverse effect level (NOAEL)]; b) to present a new approach based on the signal-to-noise crossover dose (SNCD); and c) to compare the SNCD and SNCD-based RfD with [(PoD).sub.s] and [(RfD).sub.s] based on the NOAEL and benchmark dose (BMD) approaches.

METHODS: The complete NTP database was used as the basis for these analyses, which were performed using the Hill model. We determined [(NOAEL).sub.s] and estimated corresponding extra risks. Lower 95% confidence bounds on the BMD ([(BMDL).sub.s]) corresponding to extra risks of 1%, 5%, and 10% ([(BMDL).sub.01], [(BMDL).sub.05], and [(BMDL).sub.10], respectively) were also estimated. We introduce the SNCD as a new PoD, defined as the dose where the additional risk is equal to the "background noise" (the difference between the upper and lower bounds of the two-sided 90% confidence interval on absolute risk) or a specified fraction thereof.

RESULTS: The median risk at the NOAEL was approximately 10%, and the default uncertainty factor (UF = 100) was considered most applicable to the [(BMDL).sub.10]. Therefore, we chose a target risk of 1/1,000 (0.1/100) to derive an SNCD-based RfD by linear extrapolation. At the median, this approach provided the same RfD as the [(BMDL).sub.10] divided by the default UF.

CONCLUSIONS: Under a standard BMD approach, the [(BMDL)sub.10] is considered to be the most appropriate PoD. The SNCD approach, which is based on the lowest dose at which the signal can be reliably detected, warrants further development as a PoD for human health risk assessment.

KEY WORDS: benchmark dose, cancer bioassay, human exposure guideline, low-dose extrapolation, point of departure, reference dose, signal-to-noise crossover dose, uncertainty factor. Environ Health Perspect 119:1766-1774 (2011). http://dx.doi.org/10.1289/ehp.1003327 [Online 3 August 20111]

Since the introduction of the benchmark dose (BMD) by Crump (1984), there has been considerable discussion about the merits of this measure relative to the traditional no observed adverse effect level (NOAEL), originally introduced by Lehman and Fitzhugh (1954) as a point of departure (PoD) for establishing human exposure guidelines, expressed in the form of a reference dose (RfD) (Barnes and Dourson 1988).

In its simplest form, the RfD is determined by the formula RfD = PoD/UF, where the uncertainty factor (UF) denotes the combined effect of inter- and intraspecies differences, as well as other uncertainties associated with the available data (Dourson et al. 1996). Essentially the same approach is used to derive other exposure guidelines, such as the tolerable daily intake or acceptable daily intake, but here we use the term "RfD" to represent a human exposure guideline, regardless of the type of test agent or critical end point considered.

In practice, a lower confidence limit on the BMD (the BMDL) is used as the PoD when the BMD approach is invoked. The introduction of the BMD for noncancer end points has increased comparability between approaches to estimate exposure guidelines for noncancer and cancer agents. Currently, a single approach is generally recommended to derive the PoD, but differences exist in terms of how to proceed after the derivation of the PoD, depending on whether the agent is nongenotoxic or a genotoxic carcinogen [European Food Safety Authority (EFSA) 2005, 2009a; U.S. Environmental Protection Agency (EPA) 2005]. Several authors have specifically suggested that the BMDL may serve as a PoD for carcinogens and noncarcinogens alike, leading to an integrated approach to cancer and noncancer risk assessment (Gaylor et al. …

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