Primary brain tumours in Fischer 344 rats chronically exposed to acrylonitrile in their drinking-water

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

“…A large amount of information has been collected over the past 22 years, much of which can be used to speciWcally address data gaps identiWed by USEPA in their 1983 assessment, including the following (numbers in parentheses correspond to numbered data gaps listed in the introduction): (1) several large well-designed, epidemiology studies have been conducted including those with extensive exposure information (Blair et al, 1998;Swaen et al, 1998Swaen et al, , 2004Wood et al, 1998); (2) two follow-up studies have been conducted for the O'Berg (1980) cohort (O'Berg et al, 1985;Wood et al, 1998); (3) a three-generation reproductive toxicity study in rats has been published for AN (Friedman and Beliles et al, 2002); (4) additional cancer bioassays have been conducted for AN using mice following oral exposure (NTP, 2001) and rats following oral and inhalation exposure (Bigner et al, 1986;Ghanayem et al, 2002;Maltoni et al, 1988); (5) an in vitro cell transformation study has been conducted for AN in Syrian hamster embryo cells (Zhang et al, 2000); (6) a number of mechanistic studies have been conducted for AN that demonstrate a role for oxidative stress in the formation of rat brain tumors (Jiang et al, 1998;Kamendulis et al, 1999a;Murata et al, 2001;Whysner et al, 1998a;Zhang et al, 2002); (7) a large amount of pharmacokinetic data has been collected and compiled into physiologically based pharmacokinetic (PBPK) models for AN in rats (Gargas et al, 1995;Kedderis and Fennell, 1996) and humans (Sweeney et al, 2003); (8) a mutagenicity study has been conducted for AN in human lymphoblasts (Recio and Skopek, 1988); and (9) dominant lethal studies have been conducted for AN (Working et al, 1987;Butterworth et al, 1992).…”

Spontaneous Brain and Spinal Cord/Nerve Neoplasms in Aged Sprague-Dawley Rats

“…Brain neoplasms in laboratory rats have been important to the safety assessment of a few chemicals including acrylonitrile and ethylene oxide, which also produced neoplasms in other organs (1,5); the statistically significant increase of gliomas observed in high-dose Sprague-Dawley male rats with Food Drug & Cosmetic blue No. 2 was unaccompanied by increases in other neoplasms and was not considered biologically significant (12).…”

Examination of Low-Incidence Brain Tumor Responses in F344 Rats Following Chemical Exposures in National Toxicology Program Carcinogenicity Studies

“…A glioma was also present in a high-dose (12, (1,6,17,20). Of the 10 chemicals that show any evidence of having neoplastic effects in the brain, glycidol was the only chemical for which there was clear evidence of carcinogenicity (Table IV) (Table IV) and that most of them are mutagenic (Table IV).…”

“…In chronic bioassays in rats, 2 industrial chemicals, acrylonitrile and ethylene oxide, have been identified as being neurocarcinogenic (1,7,23). The classification of ethylene oxide and acrylonitrile as neurocarcinogenic agents was based on the fact that these chemicals met some of the following criteria (17): (a) they induced an increased incidence of brain tumors, beyond expected control levels, in males and females; (b) they yielded a shift in tumor appearance to a younger age (decreased survival time); (c) there was a demonstrated dose-effect relationship; (d) they induced higher tumor incidence following transplacental exposure; (e) they induced a trend toward anaplasia; (f) they led to the presence of preneoplastic lesions; (g) they induced a multiplicity of tumors in individual animals; (h) they also induced tumor occurrence in the peripheral nervous system; (i) they induced tumors outside of the nervous system; and (j) they led to genotoxicity, mutagenicity, and chromosomal aberrations.…”