Disposition of styrene-acrylonitrile (SAN) trimer in female rats: Single dose intravenous and gavage studies

Gargas, Michael L.; Collins, Brad; Fennell, Timothy R.; Gaudette, Norman F.; Sweeney, Lisa

doi:10.1016/j.toxlet.2008.01.016

Cited by 5 publications

(5 citation statements)

References 6 publications

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“…Metabolic processes and bioavailability may also be important considerations for the outcomes of the acute genotoxicity and the 2-year carcinogenicity studies, which utilized oral gavage and dosed feed, respectively, as routes of chemical administration. Reported results of a toxicokinetic study suggest that SAN Trimer is extensively metabolized and rapidly eliminated in the urine and feces of dosed rats, indicating that the compound probably does not accumulate in blood and tissues, although clearance mechanisms may become saturated at high doses (≥200 mg/kg) [Gargas et al, 2008]. Compared to delivery of a bolus dose by oral gavage, ingestion of smaller fractionated doses over a prolonged period of time via dosed feed may lead to different patterns of bioavailability.…”

Section: Discussionmentioning

confidence: 99%

Genotoxicity of styrene–acrylonitrile trimer in brain, liver, and blood cells of weanling F344 rats

Hobbs

Chhabra

Recio

et al. 2012

Environ and Mol Mutagen

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Styrene–acrylonitrile Trimer (SAN Trimer), a by-product in production of acrylonitrile styrene plastics, was identified at a Superfund site in Dover Township, NJ, where childhood cancer incidence rates were elevated for a period of several years. SAN Trimer was therefore tested by the National Toxicology Program in a 2-year perinatal carcinogenicity study in F344/N rats and a bacterial mutagenicity assay; both studies gave negative results. To further characterize its genotoxicity, SAN Trimer was subsequently evaluated in a combined micronucleus (MN)/Comet assay in juvenile male and female F344 rats. SAN Trimer (37.5, 75, 150, or 300 mg/kg/day) was administered by gavage once daily for 4 days. Micronucleated reticulocyte (MN-RET) frequencies in blood were determined by flow cytometry, and DNA damage in blood, liver, and brain cells was assessed using the Comet assay. Highly significant dose-related increases (P < 0.0001) in MN-RET were measured in both male and female rats administered SAN Trimer. The RET population was reduced in high dose male rats, suggesting chemical-related bone marrow toxicity. Results of the Comet assay showed significant, dose-related increases in DNA damage in brain cells of male (P < 0.0074) and female (P < 0.0001) rats; increased levels of DNA damage were also measured in liver cells and leukocytes of treated rats. Chemical-related cytotoxicity was not indicated in any of the tissues examined for DNA damage. The results of this subacute MN/Comet assay indicate induction of significant genetic damage in multiple tissues of weanling F344 male and female rats after oral exposure to SAN Trimer.

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Section: Discussionmentioning

confidence: 99%

Genotoxicity of styrene–acrylonitrile trimer in brain, liver, and blood cells of weanling F344 rats

Hobbs

Chhabra

Recio

et al. 2012

Environ and Mol Mutagen

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“…While the cancer rates for the SAN workers are not presented separately, these large studies of acrylonitrile workers found no increased risk of leukemia, brain cancer or any other cancer or cause of death (Blair et al 1997; Swaen et al 2006). SAN Trimer is readily metabolized in animals, having a half-life in blood of 3–4 h following oral exposure (Gargas et al 2008). Based on these findings, there is no evidence to indicate that SAN Trimer is carcinogenic, and therefore it is inappropriate to characterize potential cancer risks to potentially exposed human populations.…”

Section: Resultsmentioning

confidence: 99%

“…The findings from the studies conducted by the NTP along with those conducted by Union Carbide were that SAN Trimer exerts low toxicity in animals, with the most prominent and consistent effect observed being liver weight increases. It is rapidly eliminated following oral exposure with a half-life of 3–4 h (Gargas et al 2008). The weight of evidence indicated that SAN Trimer is not genotoxic (NTP 2011a), and the NTP cancer bioassay conclusively demonstrated SAN Trimer is not a carcinogen (NTP 2010 2011b).…”

Section: Discussion/conclusionmentioning

confidence: 99%

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Screening-Level Risk Assessment for Styrene-Acrylonitrile (SAN) Trimer Detected in Soil and Groundwater

Kirman¹,

Gargas

Collins

et al. 2012

Journal of Toxicology and Environmental Health, Part A

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A screening-level risk assessment was conducted for styrene-acrylonitrile (SAN) Trimer detected at the Reich Farm Superfund site in Toms River, NJ. Consistent with a screening-level approach, on-site and off-site exposure scenarios were evaluated using assumptions that are expected to overestimate actual exposures and hazards at the site. Environmental sampling data collected for soil and groundwater were used to estimate exposure point concentrations. Several exposure scenarios were evaluated to assess potential on-site and off-site exposures, using parameter values for exposures to soil (oral, inhalation of particulates, and dermal contact) and groundwater (oral, dermal contact) to reflect central tendency exposure (CTE) and reasonable maximum exposure (RME) conditions. Three reference dose (RfD) values were derived for SAN Trimer for short-term, subchronic, and chronic exposures, based upon its effects on the liver in exposed rats. Benchmark (BMD) methods were used to assess the relationship between exposure and response, and to characterize appropriate points of departure (POD) for each RfD. An uncertainty factor of 300 was applied to each POD to yield RfD values of 0.1, 0.04, and 0.03 mg/kg-d for short-term, subchronic, and chronic exposures, respectively. Because a chronic cancer bioassay for SAN Trimer in rats (NTP 2011a) does not provide evidence of carcinogenicity, a cancer risk assessment is not appropriate for this chemical. Potential health hazards to human health were assessed using a hazard index (HI) approach, which considers the ratio of exposure dose (i.e., average daily dose, mg/kg-d) to toxicity dose (RfD, mg/kg-d) for each scenario. All CTE and RME HI values are well below 1 (where the average daily dose is equivalent to the RfD), indicating that there is no concern for potential noncancer effects in exposed populations even under the conservative assumptions of this screening-level assessment.

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“…Animals were exposed during their in utero and neonatal developmental periods, which are generally considered to be especially susceptible to CNS toxicity and carcinogenicity compared to the adult phase of life (Rice and Wilbourn, 2000). This design is further strengthened by the Union Carbide Corporation-sponsored study results that showed that SAN Trimer was transported across the placenta to the developing fetus and that neonates are also exposed through their mother’s milk (Gargas et al ., 2008). …”

Section: Discussionmentioning

confidence: 99%

Perinatal toxicity and carcinogenicity studies of styrene-acrylonitrile trimer, a ground water contaminant

et al. 2013

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Styrene Acrylonitrile (SAN) Trimer is a by-product in the production of acrylonitrile styrene plastics. Following a report of a childhood cancer cluster in the Toms River section of Dover Township, New Jersey, SAN Trimer was identified as one of the groundwater contaminants at Reich Farm Superfund site in the township. The contaminants from the Reich Farm site’s ground water plume impacted two wells at the Parkway well field. The National Toxicology Program (NTP) studied the toxicity and carcinogenicity of SAN Trimer in rats exposed during their perinatal developmental period and adulthood. The chronic toxicity and carcinogenicity studies in F344/N rats were preceded by 7- and 18-week perinatal toxicity studies to determine the exposure concentrations for the 2-year studies. Subsequently, Fisher 344 pregnant dams were exposed to SAN Trimer containing diet at 400, 800, or 1600 ppm concentrations during gestation, nursing and weaning periods of offspring followed by two year of adult exposures to both male and female pups. There was no statistically significant evidence of carcinogenic activity following SAN-Trimer exposure; however, rare neoplasms in the brain and spinal cord were observed in males and to lesser extent in female rats. These incidences were considered within the range of historical background in the animal model used in the current studies. Therefore, the presence of a few rarely occurring CNS tumors in the treated groups were not judged to be associated with the SAN Trimer exposure. The major finding was a dose-related peripheral neuropathy associated with the sciatic nerves in females and spinal nerve roots in males and females thereby suggesting that SAN trimer is potentially a nervous system toxicant.

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Disposition of styrene-acrylonitrile (SAN) trimer in female rats: Single dose intravenous and gavage studies

Cited by 5 publications

References 6 publications

Genotoxicity of styrene–acrylonitrile trimer in brain, liver, and blood cells of weanling F344 rats

Genotoxicity of styrene–acrylonitrile trimer in brain, liver, and blood cells of weanling F344 rats

Screening-Level Risk Assessment for Styrene-Acrylonitrile (SAN) Trimer Detected in Soil and Groundwater

Perinatal toxicity and carcinogenicity studies of styrene-acrylonitrile trimer, a ground water contaminant

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