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Overview of Approach to Noncancer Risk Assessment
Published in John C. Lipscomb, Edward V. Ohanian, Toxicokinetics and Risk Assessment, 2016
As noted in their definitions, risk values such as RfDs or ADIs are generally intended to apply to lifetime exposures. While a full lifetime exposure is generally considered to be 2 years for rats and mice and 70 years for humans, exposures of greater than approximately 10% of the lifetime (i.e., more than 90 days for rodent studies) are often considered to be chronic exposures. Other agencies (e.g., ATSDR) define chronic exposure as a year (365 days) or longer. However, often only subchronic toxicity data are available. In such cases, risk assessors often extrapolate between durations using the assumption that an effect seen at shorter durations will also be seen after a lifetime of exposure, but may occur at lower doses. They may also assume that some effects may only be seen after an experimental group is exposed chronically. This may be either due to accumulation of damage, or due to accumulation of the toxicant, resulting in ongoing damage. This UF addresses the question, “If data in subchronic studies exist on which to base the estimation of a subthreshold dose, would data in chronic studies yield lower NOAELs?” Note that consideration of the appropriate value for UFS requires consideration of the chemical’s mode of action (MOA). For example, if the chemical causes toxicity via a reactive metabolite (which therefore does not accumulate in the body) with no evidence of progression of damage, a reduced UFS may be appropriate. For organizations that use this factor, the default value is 10 when extrapolating from a subchronic study, while a value of 1 is used when using a chronic study. A reduced factor of 3 is typically used when the study is longer than subchronic duration (e.g., a 6–7 months rat study, as used for the cumene RfD), or if there is evidence based on other routes or on the MOA that toxicity does not progress with additional exposure (e.g., hexachlorocyclopentadiene RfD) (4).
Critical review of renal tubule karyomegaly in non-clinical safety evaluation studies and its significance for human risk assessment
Published in Critical Reviews in Toxicology, 2018
Although with a long history of clinical application in humans, no published report of toxicity testing of auranofin in non-human primates was found in this literature search. However, auranofin has recently been evaluated as a latency reversal agent in several studies on macaques in the monkey model of AIDS (Policicchio et al. 2016). In some of these studies, there was a 12-week exposure to auranofin and a long period of follow-up, with no debilitating renal effects reported. This suggests that the auranofin-induced nephrotoxicity observed in rats is not mirrored in the non-human primate. Another compound that induced renal tubule karyomegaly in rats, hexachlorocyclopentadiene, also produced no histological alterations in cynomolgus when administered by inhalation for 90 days (Rand et al. 1982).