Pub Date : 1977-03-01DOI: 10.1080/15287397709529486
Magee Pn
Serious problems of interpretation may arise when metabolic studies are carried out with radioactively labeled drugs and other foreign chemicals. Detection of free or bound radioactivity in tissues or body fluids may indicate the presence of the unchanged chemical or of various products of its decomposition. Some radioactivity may, however, represent incorporation of certain metabolites of foreign chemicals into body constituents by normal biosynthetic pathways. The interpretation of the results of such metabolic experiments from the standpoint of safety evaluation will be profoundly different if the radioactivity represents covalent binding to a cellular macromolecule than if it results from normal endogenous incorporation. These two distinct types of binding of radioactivity to body constituents are well illustrated by experimental studies with some carcinogenic nitroso compounds, such as dimethylnitrosamine and N-methylnitrosourea. Dimethylnitrosamine requires metabolic activation by microsomal enzymes and yields formaldehyde and a chemically reactive methylating intermediate, probably a methyl carbonium ion. The latter reacts with nucleophilic sites in nucleic acids and proteins, and also with water to yield methanol. N-Methylnitrosourea does not require metabolic activation but yields the same methylating intermediate spontaneously under physiologic conditions. Both formaldehyde and methanol are metabolized largely to CO2, but they also enter the one-carbon metabolic pool and became biosynthetically incorporated into nucleic acids, proteins, and other cell components. Alkylation of cellular constituents is associated with various biological effects, including cytotoxicity, carcinogensis, and mutagenesis, and the same effects are produced by the activated forms of a variety of other chemical carcinogens. It is clearly of paramount importance to distinguish between these two types of incorporation of radioactivity.
{"title":"Covalent binding and endogenous incorporation as illustrated by nitroso carcinogens.","authors":"Magee Pn","doi":"10.1080/15287397709529486","DOIUrl":"https://doi.org/10.1080/15287397709529486","url":null,"abstract":"Serious problems of interpretation may arise when metabolic studies are carried out with radioactively labeled drugs and other foreign chemicals. Detection of free or bound radioactivity in tissues or body fluids may indicate the presence of the unchanged chemical or of various products of its decomposition. Some radioactivity may, however, represent incorporation of certain metabolites of foreign chemicals into body constituents by normal biosynthetic pathways. The interpretation of the results of such metabolic experiments from the standpoint of safety evaluation will be profoundly different if the radioactivity represents covalent binding to a cellular macromolecule than if it results from normal endogenous incorporation. These two distinct types of binding of radioactivity to body constituents are well illustrated by experimental studies with some carcinogenic nitroso compounds, such as dimethylnitrosamine and N-methylnitrosourea. Dimethylnitrosamine requires metabolic activation by microsomal enzymes and yields formaldehyde and a chemically reactive methylating intermediate, probably a methyl carbonium ion. The latter reacts with nucleophilic sites in nucleic acids and proteins, and also with water to yield methanol. N-Methylnitrosourea does not require metabolic activation but yields the same methylating intermediate spontaneously under physiologic conditions. Both formaldehyde and methanol are metabolized largely to CO2, but they also enter the one-carbon metabolic pool and became biosynthetically incorporated into nucleic acids, proteins, and other cell components. Alkylation of cellular constituents is associated with various biological effects, including cytotoxicity, carcinogensis, and mutagenesis, and the same effects are produced by the activated forms of a variety of other chemical carcinogens. It is clearly of paramount importance to distinguish between these two types of incorporation of radioactivity.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1977-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73432012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1976-05-01DOI: 10.1097/00132586-197708000-00009
H. F. Cascorbi, R. M. Gesinski, M. Komar
Male and female DBA 11 mice recovered from 1 hr of anesthesia with chloroform of fluoroxene apparently unharmed. However, many of the animals died within 24-48 hr after anesthesia. Pretreatment with phenobarbital increased, while pretreatment with a small dose of carbon tetrachloride decreased, this toxicity. Relatively more males than females died. Pretreatment with estradiol in males and testosterone in females reversed this ratio. We conclude that the murine toxicity of chloroform and fluoxene is dependent on biotransformation by hepatic microsomal enzymes and that the testosterone enhances postanesthetic toxicity of these agents.
{"title":"Biotransformation, sex hormones, and toxicity of two volatile anesthetics in mice.","authors":"H. F. Cascorbi, R. M. Gesinski, M. Komar","doi":"10.1097/00132586-197708000-00009","DOIUrl":"https://doi.org/10.1097/00132586-197708000-00009","url":null,"abstract":"Male and female DBA 11 mice recovered from 1 hr of anesthesia with chloroform of fluoroxene apparently unharmed. However, many of the animals died within 24-48 hr after anesthesia. Pretreatment with phenobarbital increased, while pretreatment with a small dose of carbon tetrachloride decreased, this toxicity. Relatively more males than females died. Pretreatment with estradiol in males and testosterone in females reversed this ratio. We conclude that the murine toxicity of chloroform and fluoxene is dependent on biotransformation by hepatic microsomal enzymes and that the testosterone enhances postanesthetic toxicity of these agents.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1976-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88588372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1900-01-01DOI: 10.1201/9781420042627.sec5
J. Godin-Ethier, J. Leiva, M. Toneva, I. Shaikh, A. Nelson
• The continuous emergence of novel immunomodulatory therapeutics has brought more attention in the past decades to the evaluation of potential adverse effects on the immune system and in particular for the developing immune system in the early life stages. • A functional evaluation, such as the T-dependent antibody response is considered as most appropriate to address immunotoxicity in non-clinical setting1. • These assays need to be optimized for use in younger animals.
{"title":"Inhalation toxicology.","authors":"J. Godin-Ethier, J. Leiva, M. Toneva, I. Shaikh, A. Nelson","doi":"10.1201/9781420042627.sec5","DOIUrl":"https://doi.org/10.1201/9781420042627.sec5","url":null,"abstract":"• The continuous emergence of novel immunomodulatory therapeutics has brought more attention in the past decades to the evaluation of potential adverse effects on the immune system and in particular for the developing immune system in the early life stages. • A functional evaluation, such as the T-dependent antibody response is considered as most appropriate to address immunotoxicity in non-clinical setting1. • These assays need to be optimized for use in younger animals.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76592136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This Health Risk Assessment for Lewisite is a draft report from September 1996 (editorial corrections made April 1997), prepared for U.S. Department of the Army, Army Environmental Center under Interagency Agreement 1769-1769-A1, prepared by the Life Sciences Division of Oak Ridge National Laboratory (managed by Lockheed Martin Energy Research Corp. for the U.S. Department of Energy under contract DE-AC05-96OR22464), Oak Ridge, TN. It was submitted to Material Chemical Risk Assessment Working Group Advisory and Coordinating Committee, Environmental Risk Assessment Program, Strategic Environmental Research Development Program. This document is an internal review draft for review purposes only and does not constitute U.S. government policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.
{"title":"Appendix F : Health Risk Assessment for Lewisite","authors":"K. Bakshi, Susan N. J. Pang, R. Snyder","doi":"10.1080/009841000156871","DOIUrl":"https://doi.org/10.1080/009841000156871","url":null,"abstract":"This Health Risk Assessment for Lewisite is a draft report from September 1996 (editorial corrections made April 1997), prepared for U.S. Department of the Army, Army Environmental Center under Interagency Agreement 1769-1769-A1, prepared by the Life Sciences Division of Oak Ridge National Laboratory (managed by Lockheed Martin Energy Research Corp. for the U.S. Department of Energy under contract DE-AC05-96OR22464), Oak Ridge, TN. It was submitted to Material Chemical Risk Assessment Working Group Advisory and Coordinating Committee, Environmental Risk Assessment Program, Strategic Environmental Research Development Program. This document is an internal review draft for review purposes only and does not constitute U.S. government policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use.","PeriodicalId":17418,"journal":{"name":"Journal of Toxicology and Environmental Health, Part A","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1900-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89474928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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