Subchronic urinary bladder toxicity evaluation of N‐Nitrosodiphenylamine in Fischer 344 rats

Abstract

Female Fischer 344 (F344) rats were exposed to N-nitrosodiphenylamine (NDPA) by dietary feed at concentrations of 0, 250, 1000, 2000, 3000 or 4000 ppm for 5 days, 2, 4 and 13 weeks duration. Endpoints evaluated included clinical observations, body weights, urinary bladder weights, blood NDPA, gross pathology and urinary bladder histopathology. There were no NDPA exposure-related clinical signs of toxicity. The mean body weight decreased 3% to 5% compared with the control in the 4000 ppm group during study weeks 2 through to 13. Statistically significant increases in urinary bladder weight were observed as early as after 5 days exposure and were concentration dependent at ≥ 3000 ppm. NDPA-related urinary bladder microscopic alterations consisted of mixed cell infiltrates, increased mitosis, increased necrosis of epithelial cells, diffuse and/or nodular transitional epithelial hyperplasia and squamous metaplasia of transitional epithelium. These changes affected only rats exposed to NDPA concentrations ≥ 2000 ppm. Blood NDPA concentrations were negligible in animals exposed to ≤ 1000 ppm and ranged from 0.12 to 0.19 µg ml(-1) in rats of the ≥ 2000 ppm groups at the 5 days and 2 weeks time points. A no observable adverse effect level (NOAEL) of 1000 ppm NDPA (60 mg kg(-1) day(-1) ) was selected based on the absence of urinary bladder histopathology.

Recommended approaches in the application of toxicogenomics to derive points of departure for chemical risk assessment

“…The lowest BMD a s across all time points by our calculations were: 4.9 mkd for TBB (hepatocyte hypertrophy), 1567 ppm for NDPA (diffuse transitional epithelial hyperplasia), 55 ppm for HZB (bile duct duplication), 47 mkd for BB (increase in absolute liver weight), 4.5 mkd for TCP (hepatocyte hypertrophy), and 43 ppm for MDA (follicular cell hypertrophy). The lowest BMD a s across all time points for TBB, NDPA, and HZB were similar to the NOAEL values (5 mkd, 1000, and 80 ppm, respectively) reported in previous studies (Dodd et al 2012b, d, 2013a). However, the BMD a values for BB, TCP, and MDA were approximately fourfold, twofold, and fourfold lower than NOAEL values (200, 10 mkd, and 200 ppm, respectively) (Dodd et al 2012a, c, 2013b).…”

“…The lowest apical responses for each time point and across all time points are shown in italics and bold fonts, respectively NA not available: no finding, NC not calculated: no BMD a can be calculated; failed BMD a modeling; NC*: BMD a  > the highest dose a Dodd et al (2012d) b Dodd et al (2013b) c Dodd et al (2012a) d Dodd et al (2012c) e Dodd et al (2013a) f Dodd et al (2012b)…”

“…1Study method overview. White boxes show animal exposures, necropsies, histology and microarray procedures that were conducted in previous studies (Dodd et al 2012a, b, c, d, 2013a, b; Thomas et al 2013a, b). Blue boxes represent procedures that were conducted in the current study (color figure online) …”

“…BMD(L) a values were modeled for apical endpoint measurements [described in Dodd et al (2012a, b, c, d, 2013a, b)] using the US EPA’s BMD Software (BMDS, version 2.60) (Davis et al 2011) with BMDS Wizard (ICF international, version 1.1). The dose-dependent histological changes including hypertrophy, hyperplasia, necrosis, and vacuolation were fit as dichotomous data, and organ weight increases were fit as continuous data.…”

Estudos sobre o comportamento eletroquímico da >i<N>/i<-nitrosodifenilamina e sua determinação em amostras de urina sintética

“…Após serem ingeridas, parte das nitrosaminas percorre o sistema urinário e são eliminadas através da urina (LOEPPKY, 1994). Durante esse percurso, diversos órgãos como a bexiga e os rins ficam em contato com esses compostos, que são tóxicos e carcinogênicos conforme já mencionado, o que pode causar sérios problemas à saúde (DODD et al, 2013;HICKS et al, 1977;KUYOORO et al, 2014).…”