Derivation of Noncancer Reference Values for Acrylonitrile

Abstract

Dose-response assessments were conducted for the noncancer effects of acrylonitrile (AN) for the purposes of deriving subchronic and chronic oral reference dose (RfD) and inhalation reference concentration (RfC) values. Based upon an evaluation of available toxicity data, the irritation and neurological effects of AN were determined to be appropriate bases for deriving reference values. A PBPK model, which describes the toxicokinetics of AN and its metabolite 2-cyanoethylene oxide (CEO) in both rats and humans, was used to assess the dose-response data in terms of an internal dose measure for the oral RfD values, but could not be used in deriving the inhalation RfC values. Benchmark dose (BMD) methods were used to derive all reference values. Where sufficient information was available, data-derived uncertainty factors were applied to the points of departure determined by BMD methods. From this assessment, subchronic and chronic oral RfD values of 0.5 and 0.05 mg/kg/day, respectively, were derived. Similarly, subchronic and chronic inhalation RfC values of 0.1 and 0.06 mg/m(3), respectively, were derived. Confidence in the reference values derived for AN was considered to be medium to high, based upon a consideration of the confidence in the key studies, the toxicity database, dosimetry, and dose-response modeling.

Evolution of chemical-specific adjustment factors (CSAF) based on recent international experience; increasing utility and facilitating regulatory acceptance

“…With the exception of 1,3-butadiene in mice (Kirman & Grant 2012) and methylphenidate in monkeys (Yang et al 2014), CSAF estimated from PBPK-based extrapolations were all based on data in rats and ranged from 0.6 for acrylonitrile ingestion to 2.5 for acrylonitrile inhalation (Kirman et al 2008) (Supplemental Table B). For 1,3-butadiene (Kirman & Grant 2012), the calculated CSAF of 0.03, thereby increasing the HED by $30-fold relative to the POD in mice, was based on a model incorporating TK data from both rats and mice; that for methylphenidate was based on juvenile or adult rhesus monkeys (where the calculated CSAF ranged from 0.03 to 0.1 depending on AUC or Cmax and age (juvenile or adult).…”

A Workflow for Global Sensitivity Analysis of PBPK Models

“…PBPK models, more often than not, do describe non-linear processes, such as metabolism, and certainly contain interactions between parameters, e.g., tissue and organ masses and blood perfusion rates are related to body mass and cardiac output, respectively. Very often the purpose of the model is to extrapolate beyond the domain of “observation” used to construct and evaluate the model (Andersen and Krishnan, 1994; Andersen, 2003; Barton et al, 2007, 2009; Chiu et al, 2007; Kirman et al, 2008). These model applications and model behaviors along with input variables that are often affected by uncertainties of different orders of magnitude call for a global SA that is independent from assumptions about the model structure (Campolongo and Saltelli, 1997; Campolongo et al, 1999; Saltelli et al, 2004).…”

Ecological and Human Health Risk Assessment

“…Subchronic and chronic oral reference doses (RfDs) and inhalation reference concentrations (RfCs) for acrylonitrile were determined to be 0.5 and 0.05 mg/kg day and 0.1 and 0.06 mg/m 3 by Kirman et al (2008).…”