Safety assessment of aditoprim acute,subchronic toxicity and mutagenicity studies

Aditoprim (ADP), a new developed dihydrofolate reductase (DHFR) inhibitor, has great potential in clinical veterinary medicine because of its greater pharmacokinetic properties than structural analogs. Preclinical toxicology studies were performed to assess the safety of ADP including an acute oral toxicity test, a subchronic toxicity test and five mutagenicity tests. In the acute oral toxicity test, ADP was administered singly by oral gavage to Wistar rats and Kunming mice. The LD₅₀ calculated was 1400 mg kg^–1 body weight (BW) day^–1 in rats and 1130 mg kg^–1 BW day^–1 in mice. In a subchronic study, Wistar rats were administered ADP at dose levels of 0, 20, 100 and 1000 mg kg^–1 diet for 90 days. Significant decreases were observed on body weight and food efficiency in the high‐dose group. Treatment‐related changes in clinical serum biochemistry were found in the medium‐ and high‐dose groups. Significant increases in the relative weights of livers and kidneys in females and testis in males in the 1000 mg kg^–1 diet, and significant decrease in relative weights of livers in males in the 100 mg kg^–1 diet were noted. Histopathological observations revealed that the 1000 mg kg^–1 ADP diet could induce lymphocytic infiltration and hepatocytic necrosis near the hepatic portal area. The genotoxicity of ADP was negative in tests, such as the bacterial reverse mutation assay, mice bone marrow erythrocyte micronucleus assay, in vitro chromosomal aberration test, in vitro cho/hgprt mammalian cell mutagenesis assay and mice testicle cells chromosome aberration. Based on the subchronic study, the no‐observed‐adverse‐effect level for ADP was a 20 mg kg^–1 diet, which is about 1.44‐1.53 mg kg^–1 BW day^–1 in rats. Copyright © 2015 John Wiley & Sons, Ltd.     

Urinary excretion of frameshift mutagens in rats caused by passive smoking

Summary Several male Wistar rats were individually placed in a chamber resembling a room provided with minimal air flow. They were exposed separately to the main- and sidestream smoke of a commerical brand of cigarettes smoked by a smoking machine. Exposure to both sidestream and mainstream smoke of at least two cigarettes resulted in significant excretions of frameshift mutagens in urine within 24h, detected by the bacterial microtiter fluctuation test with Salmonella typhimurium TA1 538. Doubling exposure to the mainstream smoke resulted in similar quantitative mutagenic activities. Doubling exposure to the side-stream smoke resulted in reduced water intake by the animals and thus toxic effects of the urine concentrates on the test bacteria.     

Considerations for the Use of Mutation as a Regulatory Endpoint in Risk Assessment

Assessment of a chemical's potential to cause permanent changes in the genetic code has been a common practice in the industry and regulatory settings for decades. Furthermore, the genetic toxicity battery of tests has typically been employed during the earliest stages of the research and development programs of new product development. A positive outcome from such battery has a major impact on the chemical's utility, industrial hygiene, product stewardship practices, and product life cycle analysis, among many other decisions that need to be taken by the industry, even before the registration of a chemical is undertaken. Under the prevailing regulatory paradigm, the dichotomous (yes/no) evaluation of the chemical's genotoxic potential leads to a conservative, linear no-threshold (LNT) risk assessment, unless compelling and undeniable data to the contrary can be provided to satisfy regulators, typically in a number of different global jurisdictions. With the current advent of predictive methods, new testing paradigms, mode-of-action/adverse outcome pathways, and quantitative risk assessment approaches, various stakeholders are starting to employ these state-of-the-science methodologies to further the conversation on decision making and advance the regulatory paradigm beyond the dominant LNT status quo. This commentary describes these novel methodologies, relevant biological responses, and how these can affect internal and regulatory risk assessment approaches. Environ. Mol. Mutagen. 61:84–93, 2020. © 2019 Wiley Periodicals, Inc.     

Possible roles of excess tryptophan metabolites in cancer

Tryptophan is metabolized through serotonin, indole, and kynurenine (KN) pathways. Uptake of an excess amount of tryptophan accompanied with vitamin B6 deficiency may result in the accumulation of higher concentrations of metabolites mainly from the KN pathways in the bladder. These metabolites could interact with nitrite to become mutagenic nitrosamines. They could be a promoter in the initiator–promoter model of carcinogenesis. They produced bladder cancer when implanted in the bladder. They also interact with transition metals copper or iron to form reactive radicals or reactive oxygen species (ROS). Some metabolites, 3‐hydroxy‐anthranilic acid, were autooxidized to mutagenic cinnabarinic and anthranilyl radical intermediates. These radical intermediates could also be ligands that interact with aryl hydrocarbon receptor (AhR) and induce xenobiotic metabolizing enzymes (XMEs) to metabolize contaminated carcinogens. When tryptophan is exposed to either visible or UV light, a photoproduct of 6‐formylindolo[3,2b]‐carbazole is formed, which has a very high affinity for the AhR that plays a role in carcinogenesis. This review gives an insight into various mechanisms through which tryptophan metabolites cause carcinogenesis. It could be concluded that tryptophan metabolites play a complementary role in promoting carcinogenesis along with carcinogens like aflatoxin, CCl₄, 2‐acetylaminofluorene, 4‐aminobiphenyl, 2‐naphthylamine, or N‐[4‐(5‐nitro‐2‐furyl)?2‐thiazolyl] formamide. The underlying mechanisms could be their autoxidation, exposure to either visible or UV light, interaction with nitrite or transition metals to form reactive intermediates, serving as ligands to interact with an AhR that is known to play a role in carcinogenesis through induction of XMEs. Further research is warranted.Environ. Mol. Mutagen. 52:81–104, 2011. © 2010 Wiley‐Liss, Inc.     

Absence of mutagenicity of acid pyrogallol-containing hair gels.

In the present work, three commercial acid (pH 3.5-4) pyrogallol-containing hair gels, SunSet Alizador Negro (two formulations) and Embelleze Henê Gel, were tested for mutagenicity using two well-established assays. In the Salmonella mutagenicity assay using 648-5000 microg/plate of cosmetic samples, none of the samples reached a 2-fold increase in revertants relative to the controls. Both in the absence and in the presence of S9, the dose-response relation in strains TA98, TA100, TA102, TA1535, and TA1537 was not significant (p>0.01). In the mouse bone marrow micronucleus assay, 10 Swiss male mice were orally administered 2000 mg/kg of sample per body weight/day. The ratio between polychromatic and normochromatic erythrocytes as well as the presence of micronuclei in bone marrow cells were determined. Equal numbers of micronucleated polychromatic erythrocytes were detected between the cells of each treated group and the negative control, using ANOVA and chi-square analyses. Thus, none of the products induced mutagenesis in either assay. Previous studies have shown pyrogallol is mutagenic in various test systems, including Salmonella. However studies have also shown that acidic conditions may repress the reactive-oxygen species (ROS) produced by pyrogallol, and ROS is considered the primary mechanism for the mutagenicity of pyrogallol. Consistent with this are our results, which show that acidic, commercially available pyrogallol-containing hair gels are neither mutagenic in Salmonella nor induce micronuclei in mouse bone marrow in vivo.     

镉铬砷铅离子单存与共存时诱变作用的特性及其机理初探

镉、铬、砷、铅离子共存时诱变作用的活性小于镉、铬、砷离子共存时诱变作用的活性小于镉、铬、砷、铅离子共存时诱变作用的活性．其联合作用呈拮抗作用，机理可能是混合液中某些离子浓度降低所致。同时从诱变性出发，探讨了地面水中上述离子最高容许浓度的安全性问题。     

Activating mutations in human C-Ha-ras-1 protooncogene induced by stereoisomeric fjord-region benzo[c]chrysene diol-epoxides

The mutagenicity of fjord-region benzo[c]chrysene diol-epoxide (a) stereoisomers ((+) anti-BcCDE, (-)anti-BcCDE, (+)syn-BcCDE, and (-)syn-BcCDE) was studied in a forward-mutation system. pEC plasmid containing the human c-Ha-ras-1 proto-oncogene was reacted in vitro with each optically active isomer separately and transfected into NIH/3T3 cells. Morphologically transformed foci were cloned, and DNA obtained from these foci was tested for the presence of Ha-ras-1 sequence by Southern blot analysis. A total of 50 transformed foci (11-14 for each diastereomer) were generated. To determine the nature of mutations responsible for activating the proto-oncogene, regions of the gene likely to contain the activating mutations were amplified by polymerase chain reaction and then subjected to hybridization with specific oligonucleotides. Gene mutations in 42 of 50 transformed foci were characterized by these methods, and most were found at codon 61 (27), followed by codons 12 (13) and 13 (a). All mutations observed were either G → T or A → T transversions. Thirty-six were G → T transversion mutations occurring at codons 61, 12, and 13. The remaining six were A → T transversions at codon 61. BcCDE stereoisomers may specifically attack guanine and adenine and result in the mutations observed. Some differences in codon preference but not in the types of mutations were found among these optically active isomers. © 1995 Wiley- Liss, Inc.     

清,污灌区土壤,深井水和蔬菜的致突变研究

本文通过Ａｍｅｓ试验对清、污灌区土壤、蔬菜和深井水有机提取物进行了致突变研究。结果表明污灌区土壤有机提取物对ＴＡ９８（±Ｓ９）、深井水对ＴＡ９８（－Ｓ９）致突阳性。而清灌区土壤、深井水及清、污灌区芥菜、大白菜有机提取物对ＴＡ９８（±Ｓ９）、ＴＡ１００（±Ｓ９）致突阴性。说明多年来的污水灌田已经污染了土壤，并有可能使深井水和蔬菜遭受污染。