Dose‐ and Sex‐related Carcinogenesis by N‐Bis(2‐hydroxypropyl)nitrosamine in Wistar Rats

Abstract

Currently, the most important in vivo experimental procedure to identify chemical carcinogens is the long-term assay with rodents.1, 2) The extended duration, the complex operational procedures and the high cost per test substance make the use of the long-term bioassay very limited. These and other disadvantages of the long-term bioassay, e.g., the inconvenience of not considering the multistage character of chemical carcinogenesis, imply that more convenient and faster procedures for testing potential chemical carcinogens are necessary. 3)A multi-organ medium-term system, the "initiated rat bioassay" (IRB), based on the initiation-promotion concept of chemical carcinogenesis, 4) has been proposed as an alternative/complementary approach to the conventional long-term bioassay.5-9) Five genotoxic chemicals [N-diethylnitrosamine (DEN), N-methyl-N-nitrosourea (MNU), Nbutyl-N-(4-hydroxybutyl)nitrosamine (BBN), N,N′-dimethylhydrazine (DMH) and N-bis(2-hydroxypropyl)nitrosamine (DHPN)] are used to initiate carcinogenesis in multiple organs, in what has been referred to as the DMBDD initiation protocol, based on the initials of these agents. Developed in the male F344 rat, the IRB has the advantages of shorter duration, the use of a single rodent species, and faster results at lower cost. The results of the IRB have been shown to be in line with those of the longterm conventional bioassay. [5][6][7][8] Since 1996, the IRB bioassay has been adopted, with some modifications, by the Brazilian Agency for the Environment (IBAMA) as a valid source of evidence of carcinogenicity of chemicals.10) Among the modifications established in the protocol is the use of both sexes of the Wistar strain of rats as subjects. Recently, a task-group gathered at the International Agency for Research on Cancer (IARC) recognized that, although the possibility of false-positive has not been rigorously tested, assay systems based on the initiation-promotion concept of carcinogenesis could be considered appropriate for identifying carcinogens in rodents. 11)Our laboratory has conducted studies to establish the IRB protocol in the Wistar strain of rats.

Role of NKX2-1 in N-bis(2-hydroxypropyl)-nitrosamine-induced thyroid adenoma in mice

“…Chemically induced thyroid follicular cell tumors in rodents are thought to arise from two different modes of action, mutagenic and anti-thyroid or a combination of the two (1). N-bis(2-hydroxypropyl)-nitrosamine (DHPN) is a genotoxic mutagen that initiates carcinogenesis in target organs such as lung, thyroid, kidneys and liver (2)(3)(4). Many studies were carried out to examine the effect of anti-thyroidal agents on DHPN-induced thyroid carcinogenesis, including sulfadimethoxine (SDM) (5)(6)(7), xylazine hydrochloride (8), propylthiouracil (7) and phenobarbital (9).…”

Alternative Multiorgan Initiation–Promotion Assay for Chemical Carcinogenesis in the Wistar Rat

“…The DMBDD target organs in previous studies with the local Wistar rats were the liver, kidneys, intestines, urinary bladder, and thyroid (Barbisan et al 2003; Bononi et al 1999; da Silva Franchi 2003; de Camargo 1991; de Camargo et al 1999a, b; Moreira et al 2000; Rodrigues et al 2002; Spinardi et al 1999; Rocha 1998). In these organs, the preneoplastic and neoplastic lesions observed under H&E staining were classified according to the Standardized System of Nomenclature and Diagnostic Criteria (Society of Toxicologic Pathologists 2001).…”

“…As many developing countries do not have enough technical expertise, animal breeders, and/or suitable facilities to routinely run the conventional long-term bioassay, the adoption of less complex, shorter, and less costly assays was deemed necessary (de Camargo et al 1999b). An academic laboratory at the Department of Pathology, Botucatu Medical School, UNESP, developed a series of studies in order to establish a variation in the DMBDD bioassay that could attend those needs (Barbisan et al 2003; Bononi et al 1999; da Silva Franchi 2003; de Camargo 1991; de Camargo et al 1999a, b; Moreira et al 2000; Rodrigues et al 2002; Spinardi et al 1999). Eventually, this variation in the DMBDD bioassay (indicated from now on as DMBDD b ) was officially adopted by the Brazilian Agency for the Environment as a valid source of evidence of the carcinogenic potential of agrochemicals (Instituto Brasileiro do Meio Ambiente e dos Recursos Naturais Renováveis [IBAMA] 1996).…”

Evaluation of Pendrin Expression Using Nuclear Imaging Modalities and Immunohistochemistry in Animal Thyroid Cancer Model

“…[ 13 ] It is a potent chemical mutagen and wide-spectrum carcinogen that induces different types of tumors, including TC of both sexes in various rat strains. [ 14 ]…”