Neoplastic lesions

The type and location of the neoplastic lesion (as stated on the patient s chart)... 

The carcinogenicity of technical endosulfan was reevaluated in Sprague-Dawley rats using lower doses of endosulfan (Hoechst 1989a). Endosulfan was administered in the diet for 2 years, and no effect on survival was observed in either sex at any dose. Under the conditions of this assay, dietary consumption of doses as high as 3.8 mg/kg/day by females or 2.9 mg/kg/day by males did not result in an increase in the incidence of any neoplastic lesions in these animals. The results from the Hoechst (1989a) bioassay... 

The carcinogenicity of technical endosulfan was also evaluated in NMRI mice exposed through the diet to endosulfan for 2 years at doses as high as 2.51 mg/kg/day in males and 2.86 mg/kg/day in females (Hoechst 1988b). Sixty mice/sex/dose were used. No increase in the incidence of any neoplastic lesion was identified in either males or females at any dose. These results were later published in the open literature (Hack et al. 1995). 

McDowell, E. M. and B. F. Trump. Histogenesis of preneoplastic and neoplastic lesions in tracheobronchial epithelium, Surv. Synth. Path. Res. 2 235-279 (1983). 

In a 13-week study in rats exposed intermittently to <1.4 mg/m3, the author reported that comprehensive histological examination of organs and tissues revealed no treatment- related neoplastic lesions (Shiotsuka 1989). However, chronic-duration inhalation studies, which would be more appropriate to assess possible carcinogenicity, were not located for disulfoton. 

In studies of the fate of hydrocarbons in terrestrial animals, considerable attention is directed toward relations between aromatic hydrocarbon metabolism, interactions of metabolites with macromolecules (e.g., DNA), and the formation of neoplastic lesions (] ). A broad perspective exists in studies with marine organisms. In the aquatic forms, exposure to pollutants that are rich in aromatic hydrocarbons, such as petroleum, leads to a wide variety of acute and chronic effects (2J. Attempts to delineate these effects require an understanding of the accumulation of the xenobiotics in tissues and an assessment of metabolite formation and retention. The important additional problem of the interaction of metabolites with genetic materials has not been studied to an appreciable degree in marine life. 

The importance of NF-kB to inflammation, apoptosis resistance and tumour progression has resulted in the development of unique NF-kB inhibitors as part of cancer therapeutic regimens for GI and other cancers. Efforts are also being made to understand the efficacy of using natural substances obtained from plants, such as feverfew (e.g. parthenolide), bee glue (e.g. caffeic acid phenylethyl ester), tea (e.g. EGCG), spices (e.g. curcumin from turmeric) and mulberry figs (e.g. morin, a flavone) for the prevention both of persistent NF-kB activation and of the development of inflammatory pre-neoplastic lesions. 

Esophagus (cells of BE, a pre-neoplastic lesion) Increased resistance to DOC-induced apoptosis in BE cells compared to control cells. Increased expression of anti-apoptotic proteins Bc1-xl, and Mcl-l 47,126... 

The tumorigenic potential of API no. 2 fuel oil was evaluated by dermal application in male and female C3H/Bdf mice (Witschi et al. 1987). Fifty microliters of the fuel oil was applied neat, or as a 50% or 25% dilution (w/v, in acetone) three times per week. Negative controls consisted of mice treated with acetone or animals that received no treatment. Positive controls received 50, 25, or 12.5 mg of benzo[a]pyrene dissolved in 50 microliters of acetone. Over all the doses, 15 of the 150 mice developed skin tumors (the first tumor appeared at 75 to 80 weeks), while 299 of the 300 mice treated with benzo[a pyrene developed skin tumors (first tumor appeared at 19 weeks). Neither of the negative control groups developed neoplastic lesions). 

In the US-EPA test guidelines for carcinogenicity and combined chronic toxicity/carcinogeni-city (OPPTS 870.4200 and OPPTS 870.4300, respectively), the following definition is provided Carcinogenicity is the development of neoplastic lesions as a result of the repeated daily exposure of experimental animals to a chemical by the oral, dermal, or inhalation routes of exposure. ... 

The multi-hit models are most suitable for extrapolating the effect of genotoxic substances. It is implicit in these models that aU hits occur in one specific cell that only begins to divide and develop into a tumor when it has received the necessary number of hits. However, this is in poor agreement with experimental data, which show that prohferation of the cells that have had their first hit (the initiated cells) into pre-neoplastic lesions considerably increases the risk of a second hit in an initiated cell. While the one-hit model often oversimplifies the process, the multi-hit models impose an unreasonable tight restriction of the possibdity of more than one critical hit affecting the same cell. 

Ito et al. (1995) examined the combined dietary administration to rats of 19 organophosphate pesticides and 1 organochlorine pesticide, aU permitted for use in Japan, each at its ADI level. The dietary exposure at this level did not enhance the development of diethyl nitrosamine initiated pre-neoplastic lesions whereas at 100 times the ADI, the number and area of lesions were increased. The authors concluded that the study provided direct support for the present use of the safety factor approach in the quantitative hazard evaluation of pesticides. 

Flagiwara A, Takesada Y, Tanaka H, et al Dose-dependent induction of glandular stomach preneoplastic and neoplastic lesions in male F344 rats treated with catechol chronically. Toxicol Pathol 29(2) 180-186, 2001... 

Administered in the drinking water for 113 weeks, 42mg/l crotonaldehyde induced neoplastic lesions in rats 2 of 27 animals had hepatocellular carcinomas and 9 of 27 had neoplastic lesions. Altered liver cell foci occurred in 23 of the 27 animals. The increased incidence of neoplastic and preneoplastic lesions was not observed at the higher dose (421 mg/1). Crotonaldehyde produced variable results in a variety of genetic assays. ... 

In a carcinogenic study, male and female rats were given DMHP by gavage 5 days/week for 103 weeks. At 200mg/kg, there were increases in alveolar/bronchiolar carcinomas, squamous cell carcinomas of the lung, and carcinomas of the stomach in male rats. Neoplastic lesions did not occur in mice after similar treatments. Species-dependent differences in the metabolism of DMPH were limited to more rapid metabolism and elimination by mice compared with rats. Therefore, the... 

Alison RH, Capen CC, Prentice DE Neoplastic lesions of questionable significance to humans. Toxicol Pathol 22(2) 179-86, 1994... 

Rats exposed for 2 years to 400 ppm had increased incidence of papillary adenomas of the nasal cavity the incidences of alveolar/ bronchiolar adenomas or carcinomas (combined) were also increased in the male rats, but not in the females. Nonneoplastic lesions of the nasal cavity included inflammation, epithelial hyperplasia, and squamous metaplasia of the nasal epithelium, as well as atrophy of the olfactory sensory epithelium. Mice exposed at 50 or lOOppm for 2 years had no significant increases in the incidence of neoplastic lesions... 

In mice and rats exposed to 500, 2500, or 5000 ppm 6 hours/day, 5 days/week for up to 104 weeks, the only neoplastic lesion showing an increased incidence was interstitial cell (Leydig cell) adenomas in male rats. The tumor was not considered to be treatment related because of its occurrence in control rats. The lARC has determined that there is inadequate evidence for the carcinogenicity of isopropyl alcohol in experimental animals and humans. 

Chronic exposure (12 months) of rats and mice to 1000 or 5000 mg/m JP-4 did not cause respiratory tract irritation or pulmonary lesions in rats at the end of the exposure or at 12 months after exposure. An increase of interstitial cell tumors was observed in the testis 12 months after exposure. No effect on the incidence of neoplastic tumors was seen in mice in the same study. A 1-year JP-7 exposure study to rats at 750mg/m produced no toxicologi-cally significant treatment-related neoplastic lesions in mice or rats except for a small increase in incidence of C-cell adenomas and kidney adenomas in male rats. However, these tumors are of the type that are considered to be specific to the male rat and not relevant to humans or other animals. The exposure period in these two studies was 1 year, rather than the typical 2-year lifetime period. This time period... 

PBNA has been tested for carcinogenicity in a number of species without conclusive results. There was no evidence of carcinogenic activity in male or female rats or in male mice fed 2500 or 5000 ppm in the diet for 2 years. The lack of carcinogenicity in rats may be related to an inability to metabolize PBNA to the known animal and human urinary bladder carcinogen P-naphthylamine. There was equivocal evidence for carcinogenicity in female mice, as indicated by the occurrence of two rare kidney tumors. Chemical-related non-neoplastic lesions, including nephropathy, karyomegaly, and hyperplasia, occurred in the kidneys of both species. 

Lam, S., Kennedy, T., and Unger, M. (1998). Localisation of bronchial intraepithelial neoplastic lesions by fluorescence bronchoscopy. Chest 13,696-702. 

Reuber MD, Glover EL. 1967. Hyperplastic and early neoplastic lesions of the liver in buffalo strain rats of various ages given subcutaneous carbon tetrachloride. J Natl Cancer Inst 38 891-899. 

Rao, M.S., Usuda, N., Subbarao, V. Reddy, J.K. (1987) Absence of y-glutamyl transpeptidase activity in neoplastic lesions induced in the liver of male F-344 rats by di-(2-ethylhexyl)phthalate, a peroxisome proliferator. Carcinogenesis, 9, 1347-1350 Rao, M.S., Yeldandi, A.V. Subbarao, V. (1990) Quantitative analysis of hepatocellular lesions induced by di(2-ethylhexyl)phthalate in F-344 rats. J. Toxicol, environ. Health, 30, 85-89 Ray, L.E., Murray, HE. Giam, C.S. (1983) Analysis of water and sediment from the Nueces Estuary/ Corpus Christi Bay (Texas) for selected organic pollutants. Chemosphere, 12, 1039-1045... 

Table 1. Neoplastic lesions in mice treated with 2,2-bis(bromomethyl)-propane-l,3-diol in the diet...

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