Cancer dose–response assessment for acrylonitrile based upon rodent brain tumor incidence: Use of epidemiologic, mechanistic, and pharmacokinetic support for nonlinearity

Kirman, Christopher R.; Gargas, Michael L.; Marsh, Gary M.; Strother, Dale E.; Klaunig, James E.; Collins, James J.; Deskin, Randy

doi:10.1016/j.yrtph.2005.06.007

Cited by 19 publications

(8 citation statements)

References 73 publications

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“…These RfD values reflect the available toxicological information available for AN, and incorporate the latest tools for addressing chemical pharmacokinetics (PBPK modeling) and dose‐response characterization (BMD modeling). The RfD values for noncancer derived here are higher in magnitude than the cancer RfD value of 0.009 mg/kg/day recently derived for AN based upon brain tumors in exposed rats (Kirman et al , 2005), indicating that risk assessment decisions made for the oral exposure to AN will largely be driven by its carcinogenic effects. Overall, confidence in the subchronic and chronic oral RfD values for AN is considered to be medium to high when the individual components of the assessment are considered.…”

Section: Discussioncontrasting

confidence: 64%

“…Traditionally, default uncertainty factors of three or 10 each have been used to account for: (1) the variation in sensitivity among the members of the human population, i.e., interindividual variability (UFh); (2) the uncertainty in extrapolating animal data to humans, i.e., interspecies uncertainty (UFa); (3) the uncertainty in extrapolating from data obtained in a study with less‐than‐lifetime exposure to lifetime exposure, i.e., extrapolating from subchronic to chronic exposure (UFs); (4) the uncertainty in extrapolating from a LOAEL rather than from a NOAEL (UFl); and (5) the uncertainty associated with extrapolation when the database is incomplete (USEPA, 1994, 2002). However, there is growing support for the use of data‐driven uncertainty factors in noncancer risk assessment, which incorporate chemical‐specific toxicokinetic and toxicodynamic data.…”

Section: Methodsmentioning

confidence: 99%

“…Over the past 24 years there have been a number of advances in our understanding of AN with respect to its mechanism of toxic action, epidemiology, toxicity, and pharmacokinetics, many of which specifically address the data gaps identified by USEPA in 1983. The goal of the article is to derive subchronic and chronic RfC and RfD values within USEPA's framework for deriving reference values (USEPA, 1994, 2002) using up‐to‐date information with the best available tools and methods.…”

Section: Introductionmentioning

confidence: 99%

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Derivation of Noncancer Reference Values for Acrylonitrile

et al. 2008

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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.

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Section: Discussioncontrasting

confidence: 64%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Derivation of Noncancer Reference Values for Acrylonitrile

et al. 2008

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“…Chronic exposure to ACN have been shown to cause liability of autonomic functions, such as lowered arterial pressure, labile pulse, diffuse dermographia, increased sweating and change in orthostatic reflex have been observed in occupational exposures to ACN (Buchter and Peter, 1984). Similar effects have been observed in rats exposed to ACN, as well as the presence of primary brain tumors (Bigner et al, 1986; Kirman et al, 2005). Epidemiology data has not shown a direct correlation between ACN exposure and cancer in humans (Cole et al, 2008; IARC, 1999; Klaunig, 2008), prompting a classification as a group 2B possible carcinogen by the International Agency for Research on Cancer (IARC).…”

Section: Introductionsupporting

confidence: 78%

Differential response to acrylonitrile toxicity in rat primary astrocytes and microglia

Caito

Aschner

2013

NeuroToxicology

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Acrylonitrile (ACN) is a widely used chemical in the production of plastics, resins, nitriles, acrylic fibers, synthetic rubber and acrylamide. While acute high level exposures to ACN are known to be lethal, chronic low dose exposures causes glial cell tumors in rats. Recently, these glial tumors have been characterized as microglial in origin. While effects of ACN on astrocytes, the more numerous glial cell, have been investigated, the effects on microglia are unknown. This study was conducted to compare the responses of astrocytes and microglia to ACN treatment in vitro to address differential sensitivities and adaptive responses to this toxic chemical. Cell viability, ACN uptake, lipid peroxidation byproducts (F2-isoprostanes), glutathione (GSH) levels and expression of NF-E2-related factor 2 (Nrf2) were evaluated in primary rat microglia and astrocytes following ACN treatment. Results indicate that microglia are more sensitive to ACN than astrocytes, accumulating less ACN while demonstrating higher F2-isoprostane levels. GSH levels were up-regulated in both cell types, as a protective mechanism against ACN-induced oxidative stress, while Nrf2 levels were only induced in microglia. Our data suggest that microglia and astrocytes exhibit different sensitivities and responses to ACN, which are linked to the intracellular thiol status inherent to each of these cell types.

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“…Risk estimates are not notably different from those reported in Wood et al 21 Toxicologic studies show that AN is carcinogenic in rats; however, the exact mechanism by which tumors develop is unclear. 44,45 The findings of previous epidemiologic studies, particularly within this occupational cohort, have implicated respiratory system cancer as being of a priori concern. As of 2002, 3.6% of the exposed workers in this cohort have died from respiratory system cancer with the number of such deaths nearly doubling in the past 11 years.…”

Section: Discussionmentioning

confidence: 87%